Idea Transcript
VII
Volume Editors Preface
Remarkable advancements in stereoselective synthesis have occurred over the past halfcentury. For decades, the Diels–Alder reaction was perhaps the only reaction providing reliably high and predictable stereoselectivity with broadly applicable efficacy. Subsequent developments in catalytic asymmetric hydrogenations and oxidations of alkenes, asymmetric hydroborations, and diastereoselective/enantioselective aldol reactions, among others, opened the floodgates to a host of highly tuned reactions that provided access to compounds in stunningly high diastereo- and enantioselectivities. This evolution was alluded to in the preface to Houben–Weyl, Vol. E 21 (Stereoselective Synthesis, published in 1995), wherein Helmchen, Hoffmann, Mulzer, and Schaumann pointed to the enormous progress in stereoselectivity made in the 20 years prior to their extraordinary contribution. In the intervening 15 years, one can see that further advancements have been, if anything, even more breathtakingly impressive. Whereas in the 1970s a 4:1 stereoselectivity in any given reaction might have been acceptable, if not remarkable, and in the 1990s the goal of 20:1 stereoselectivity was achieved in pockets of transformations of variable scope, in 2010 anything less than 20:1 stereoselectivity across a wide range of transformations and reacting partners is now decidedly unacceptable. These many advancements called for an update that was timely, state-of-the-art, and focused on those modern methods likely to influence the course of organic synthesis for the foreseeable future. The result is Stereoselective Synthesis, a part of the Science of Synthesis Reference Library. Stereoselective Synthesis is a major reference work that critically reviews the status of the discipline and serves as a foundation to forge the future of the field. Although the original Stereoselective Synthesis focused largely on stoichiometric methods, the increasing significance of catalytic processes has transformed the field. This latest version of Stereoselective Synthesis reflects and highlights the stunning advancements in these many catalytic methods (metal-based, organocatalytic, or enzymatic), in addition to reemphasizing the importance of stoichiometric transformations. Unlike other reference works, Stereoselective Synthesis is not a comprehensive review or treatise, but rather a critical selection of those synthetic methods that are viewed by distinguished experts as most significant. Typical or general experimental procedures for the methods have been carefully selected. In evaluating protocols for inclusion, the authors were asked to consider yields, selectivities, breadth of applicability, atom economy, robustness, scalability, and environmental impact. The result is a snapshot of the best, most useful synthetic methods available for constructing a wide range of important organic substructures. The organization of Stereoselective Synthesis is based on synthetic methods, which are arranged according to the type of reaction. The contributions have been divided into three volumes. Volume 1 considers stereoselective reactions of carbon-carbon double bonds. In the second volume, stereoselective reactions of carbonyl and imine groups have been collected. The third volume discusses pericyclic reactions, cross-coupling reactions, and reactions taking place by C–H and C–X activation. Each chapter within these volumes covers a specific synthetic method.
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Volume Editors Preface
The Editors have benefited tremendously from the expertise and dedicated efforts of all of the authors who have devoted their valuable time and energy to participate in this unique contribution. We thank all of these individuals, as well as the editorial staff in Stuttgart, for the outstanding efforts they have made throughout the entire publication process, making Stereoselective Synthesis a gold standard in Thiemes Science of Synthesis reference series.
Volume Editors
J. G. de Vries (Geleen, the Netherlands) P. A. Evans (Liverpool, UK) G. A. Molander (Philadelphia, USA)
Science of Synthesis Reference Library Stereoselective Synthesis © Georg Thieme Verlag KG
October 2010
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Abstracts
p7 [m + n]-Cycloaddition Reactions (Excluding [4 + 2])
3.1
G.-J. Jiang, Y. Wang, and Z.-X. Yu
This manuscript covers asymmetric [m + n] cycloadditions for the synthesis of four- to seven-membered rings and nine-membered rings, catalyzed by transition metals or organic molecules using either chiral ligands orchiral catalysts as the chiral sources. These cycloaddition reactions can construct mono-, bi-, or even polycyclic compounds and generate up to four stereocenters in one pot, providing high efficiency in synthesis. X1
m
+
X1m
chiral catalyst
X2
n
X2n
m + n = 4−7, 9
Keywords: asymmetric cycloaddition • [m + n] cycloaddition • C-C bond formation • chiral catalysts • chiral ligands • four-membered rings • five-membered rings • six-membered rings • seven-membered rings • nine-membered rings
p 67 [4 + 2]-Cycloaddition Reactions
3.2
K. Ishihara and A. Sakakura
The Diels–Alder reaction is one of the most powerful organic transformations available and is a versatile tool for the synthesis of many bioactive natural products. Since the discovery of the effective promotion of the Diels–Alder reaction by Lewis acids, stereoselective versions have been extensively investigated. The presence of Lewis acid catalysts bearing chiral ligands allows the Diels–Alder reaction to be conducted under mild conditions, and regio-, diastereo-, and enantioselective reactions can be achieved. In addition, organocatalysis has been successfully applied to the asymmetric Diels–Alder reaction. Various chiral catalysts for the asymmetric hetero-Diels–Alder reactions are also described in this manuscript. O
O R1
+ R2
ML∗ (cat.)
X
∗
R1
R2
X
M = B, Cu, H, etc.
Keywords: asymmetric catalysis • Brønsted acid catalysts • cycloaddition • diastereoselectivity • Diels–Alder reaction • dienes • dienophiles • enantioselectivity • hetero-Diels–Alder reaction • Lewis acid catalysts
p 125 3.3
[m + n + 1]-Carbocyclization Reactions T. Shibata
In this chapter [2 + 2 + 1]-carbocyclization reactions are discussed and the enantioselective Pauson–Khand reaction, namely a carbonylative alkyne–alkene coupling, is described comprehensively. Reactions catalyzed by chiral titanium, rhodium, iridium, and cobalt complexes are included. The use of aldehydes as a carbon monoxide donor in place of toxScience of Synthesis Reference Library Stereoselective Synthesis Volume 3 © Georg Thieme Verlag KG
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Abstracts
ic carbon monoxide gas is also discussed. Other stereoselective and/or regioselective [m + n + 1] carbocyclizations, such as [3 + 2 + 1], [4 + 2 + 1], and [5 + 2 + 1] reactions, are also described. R1 R2
X
R1
chiral Co, Ir, Rh, or Ti catalyst CO(g) or R3CHO
X
O
∗
R2
Keywords: aldehydes • alkyne–alkene coupling • bicyclopentenones • carbonylation • carbocyclization • cobalt catalysis • enynes • iridium catalysis • Pauson–Khand reaction • titanium catalysis • rhodium catalysis
p 145 3.4
[m + n + 2]-Carbocyclization Reactions C. Aubert, M. Malacria, and C. Ollivier
The [m + n + 2] carbocyclization reactions of unsaturated compounds, which include the [2 + 2 + 2], [3 + 2 + 2], and [4 + 2 + 2] cyclizations, provide a very powerful synthetic tool for the construction of several carbon-carbon bonds in a single chemical transformation. The selection of the transition-metal catalyst, which orchestrates the cyclization reactions, is critical for attaining optimal chemo-, regio-, and stereoselectivity. This review outlines the various factors that govern these important processes using numerous examples to illustrate the synthetic utility. [2 + 2 + 2] MeO
OMe
, [Rh]∗
OMe
TsN
OMe
R1 = H; R2 = Me 81%; 97% ee
TsN R1
[4 + 2 + 2]
R2
, [Rh] R1 = Me; R2 = H 75%
TsN H
[3 + 2 + 2] O , [Rh]
TsN
91%
H
O
TsN
Keywords: asymmetric catalysis • asymmetric synthesis • chirality • cocyclization • cyclic compounds • [2 + 2 + 2] cycloaddition • [3 + 2 + 2] cycloaddition • [4 + 2 + 2] cycloaddition • cyclotrimerization • diastereoselectivity • enantioselectivity • green chemistry • homogeneous catalysis • transition metals
p 243 3.5
Asymmetric Cycloisomerizations I. D. G. Watson and F. D. Toste
This chapter will describe topics relating to the asymmetric cycloisomerization reaction. It will summarize some of the most important and recent developments in this area. The chapter will focus primarily on asymmetric C-C bond-forming cycloisomerizations, although some C-X bond-forming reactions (where X = heteroatom) are described. In parScience of Synthesis Reference Library Stereoselective Synthesis Volume 3 © Georg Thieme Verlag KG
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Abstracts
ticular, ene–yne and diene cycloisomerization, carbonyl-ene, Conia-ene, intramolecular hydroacylation and hydrosilation reactions will be discussed. O
O 5 mol% {Rh[(S)-BINAP]}SbF6 1,2-dichloroethane, rt, 12 h 86%; >99% ee
HO CHO
OH O HO2C OH
O
N H O
(−)-platensimycin
Keywords: Alder–ene reactions • asymmetric cycloisomerization • asymmetric catalysis • atom economy • carbocyclic compounds • carbonyl-ene reactions • C-H activation • Coniaene reactions • cyclization • hydroacylation • hydrosilylation • intramolecular reactions
p 309 Ene Reactions
3.6
M. Terada
This manuscript focuses on recent achievements in the development of asymmetric ene reactions using chiral metal catalysts and organocatalysts. The contents are divided between intra- and intermolecular reactions, and are further subdivided according to the specific type of enophile used, including aldehydes, ketones, imines, alkynes, alkenes, and heteroatom-containing double bonds. enophile: ene:
R2
R1 ... Y X
chiral metal complex or organocatalyst
H
R1 ... Y X R2
∗
H
Keywords: acid catalysts • asymmetric catalysts • C-C bonds • carbonyl additions • chiral compounds • enantioselectivity • ene reactions • homoallylic alcohols • intramolecular reactions • Lewis acid catalysts • organocatalysts • pericyclic reactions
p 347 Sigmatropic Rearrangements
3.7
J. Zeh and M. Hiersemann
This manuscript covers stereoselective sigmatropic rearrangements, i.e. the Claisen, Cope, and [2,3]-Wittig rearrangement. It focuses on examples from natural product syntheses between 2005 and 2009. X
X O
X = O Claisen rearrangement X = C Cope rearrangement
Science of Synthesis Reference Library Stereoselective Synthesis Volume 3 © Georg Thieme Verlag KG
[2,3]-Wittig rearrangement
O
XIV
Abstracts
Keywords: asymmetric synthesis • sigmatropic rearrangements • Claisen rearrangement • Ireland–Claisen rearrangement • Cope rearrangement • [2,3]-Wittig rearrangement • carbonyl compounds • C-C bonds • homoallylic alcohols
p 383 Electrocyclic Reactions
3.8
B. Gaspar and D. Trauner
Electrocyclic reactions have provided many classic examples of stereoselectivity governed by orbital symmetry. Herein, we discuss the use in synthesis of electrocyclizations and electrocyclic ring openings involving four, six, and eight -electrons. Both all-carbon systems and systems with heteratom substitution are presented. The role of electrocyclizations in stereoselective reaction cascades is highlighted. R1
R2
R1
R1
8π "con"
R2
R2
cyclooctatriene
(E,Z,Z,E)-octatetraene
R1
R2
6π "dis"
H
H
bicyclo[4.2.0]octadiene
R1
R2
6p "dis"
H
H
Keywords: asymmetric catalysis • cyclobutenes • cyclohexadienes • cyclooctatrienes • electrocyclization • electrocyclic ring opening • Nazarov cyclizations • Woodward–Hoffmann rules • reaction cascades
p 403 Allylic Substitution Reactions
3.9
M. L. Crawley
The allylic substitution reaction has evolved from a limited process of primarily academic interest to a powerful tool for the asymmetric formation of C-C, C-N, and C-O bonds. Nu− X
a ML∗n
R1 R2
Nu
ML∗n R1
R1 R2
b
Nu−
R2
Keywords: allylic substitution • asymmetric allylic alkylation • enantioselective • regioselective • transition-metal catalysis
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Abstracts
p 443 Isomerizations To Form a Stereogenic Center and Allylic Rearrangements
3.10
S. Jautze and R. Peters
Isomerizations are often attractive reactions since they provide high atom and step economy. This manuscript describes Lewis acid catalyzed or promoted enantioselective isomerizations to form one or more stereogenic centers with a special focus on allylic rearrangements. R2
X
Y
Z
Lewis acid [3,3]-rearrangement
R1
R2
X
Y Z
R1
R2
Z
Lewis acid [1,3]-rearrangement
R1
R2
Z
R1
Keywords: allylic amines • allylic rearrangement • aza-Claisen rearrangement • aza-phospha-oxa-Cope rearrangement • Carroll rearrangement • Claisen rearrangement • imidates • isomerization • Lewis acid catalysis • Meerwein–Eschenmoser–Claisen rearrangement • palladacycles • sigmatropic rearrangement • thia-Claisen rearrangement • Wagner–Meerwein rearrangement
p 469 3.11
Allylic and Benzylic Oxidation M. B. Andrus
The selective oxidation of alkenes to give allylic alcohols and their derivatives is commonly performed using selenium dioxide. Conversion of alkenes into allylic esters is also facilitated using a palladium(II) acetate catalyst with benzoquinone and with catalytic copper complexes using perester oxidants. Regio- and stereoselectivity are reliably controlled through proper choice of reagent or additive, and by variation of the metal/ligand combination, but are often dependent on the substrate. Enone formation is promoted by various metal catalysts with tert-butyl hydroperoxide, and benzylic oxidation can be achieved using various metal catalysts and oxidants to give benzoyl and benzyl alcohol moieties. Biocatalytic methods have also been developed in a limited number of cases, using catalysts related to metal porphyrin cytochrome P450. C-H activation reactions at the allylic and benzylic position can thus be employed as an efficient approach to the installation of oxygen functionality at a late stage of a multistep synthesis and used as a means to construct enantioenriched starting materials. This section illustrates these transformations and examples are presented which demonstrate high levels of diastereo- and enantioselectivity. O [O]
[O]
O
Keywords: alcohol synthesis • allylic oxidation • benzylic oxidation • C-H activation • copper–perester oxidation • enone synthesis • ketone synthesis • palladium–quinone oxidation • selenium dioxide Science of Synthesis Reference Library Stereoselective Synthesis Volume 3 © Georg Thieme Verlag KG
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Abstracts
p 483 Mizoroki–Heck Reaction
3.12
M. Shibasaki, T. Ohshima, and W. Itano
This manuscript covers both intermolecular and intramolecular Mizoroki–Heck reactions (palladium-catalyzed arylation or alkenylation of alkenes) with brief discussion of the mechanistic aspects relevant for stereoselection. R3 R1X
+ R2
R4
Pd(0) (cat.) base − base•HX
R1
R3
R2
R4
R1 = aryl, alkenyl; X = halide, pseudohalide
Keywords: alkenylation • arylation • enantioselectivity • palladium catalysts • phosphorus ligands • regioselectivity
p 513 C-C Bond Formation by C-H Bond Activation
3.13
H. M. L. Davies and D. Morton
This manuscript describes the C-C bond-forming reactions that are available via C-H activation. It provides an overview of the many developments in this field, highlighting the most efficient approaches and their application to relevant targets. R3 N2 R1 N2 R2
H
R4
R5
R1 MLn
R1
R2
R3
H R2
R4
R5
metal carbenoid C−H functionalization
MLn
R4
R4
oxidative addition C−H activation
R3
R5
MLn
H R4
X
R5
R3 H MLn
R3
X
R5
Keywords: carbenoids • carbocyclic compounds • C-C bond formation • C-H activation • chiral compounds • diazo compounds • rhodium complexes • rhodium catalysis • palladium complexes • palladium catalysis
p 567 3.14
Cross Coupling M. Shimizu and T. Hiyama
Transition-metal-catalyzed cross-coupling reactions of organometallic reagents with organic (pseudo)halides have been developed to become one of the most powerful and straightforward methods for C-C bond formation available. This section focuses on those cross-coupling reactions that provide versatile solutions for a variety of stereochemical issues in modern organic synthesis. Science of Synthesis Reference Library Stereoselective Synthesis Volume 3 © Georg Thieme Verlag KG
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Abstracts
R1 M +
R2X
Ni catalyst or Pd catalyst
R1 R 2
Keywords: alkenylation • alkylation • alkynylation • allylation • asymmetric synthesis • boron compounds • cross-coupling reactions • Grignard reagents • nickel catalysts • palladium catalysts • silicon compounds • tin compounds
p 615 Protonation, Alkylation, Arylation, and Vinylation of Enolates
3.15
B. M. Stoltz and J. T. Mohr
In this manuscript methods for enantioselective functionalization of enolates are reviewed, and strategies for controlling enolate formation, geometry, and steric environment are highlighted. The transformations discussed include protonation, alkylation, arylation, and vinylation of enolates. Enantioselective protonation methods including biocatalytic, stoichiometric, and catalytic processes are discussed. Chiral auxiliaries for alkylation, including acyclic and cyclic enolates, are compared. Other techniques for controlling enolate alkylation, such as chelation of the counterion or generation of transition metal enolates in situ, are analyzed. Enolate arylation with chiral auxiliaries or chiral transition-metal catalysts is reviewed and the processes compared. Vinylation of enolates, including very recent developments, is discussed. The methods covered provide an overview of the available transformations for functionalizing carbonyl compounds via the corresponding enolates. Synthetic applications are highlighted to show the utility of the techniques described. O
O R3
R1
protonation
R2
R3
R1 R4
alkylation
R2
O arylation
R
R3
1
vinylation
R2 O
O R3
R1 Ar1
R2
R3
R1
R2
Keywords: asymmetric catalysis • chiral auxiliaries • chiral ligands • cross coupling • enantioselective alkylation • enantioselective arylation • enantioselective protonation • enantioselective vinylation • enolates • nickel catalysis • palladium catalysis
p 675 3.16
Æ-Functionalization of Carbonyl Compounds D. W. C. Macmillan and A. J. B. Watson
Chiral amine organocatalysts enable the facile asymmetric Æ-functionalization of carbonyl compounds. Under the enamine, SOMO, and photoredox catalysis platforms, C-C and C-X bonds (where X = heteroatom) can be forged, providing access to a broad range of enantioenriched products.
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Abstracts O
O
R4
H
OH R4
R1 R2 O N H
R1
R3
R3
N
(cat.)
R1
R2
R2
O R5X
R5
R1 R2
Keywords: aldehydes • asymmetric aldol reaction • alkylation, amine catalysts • asymmetric catalysis • C-C bonds • C-X bonds • chiral compounds • enamines • ketones • asymmetric Mannich reaction • asymmetric Michael reaction • organocatalysis • photoredox catalysis • singly occupied molecular orbital catalysis
p 747 Baeyer–Villiger Reactions
3.17
S. Levinger
Baeyer–Villiger oxidation of chiral and achiral cyclic ketones occuring within the chiral coordination space of metal catalysts or the active site of enzymes leads to the enantioselective formation of lactones accompanied by the kinetic resolution of chiral ketones. Various enzymatic approaches are presented. O
30% H2O2 (1.3 equiv) chiral Co catalyst (0.05 equiv) EtOH, 0 oC, 24 h
O O
85%; 75% ee
Ph
Ph baker's yeast aq medium 30 oC, 20 h
O
racemic
O
O +
58%; 98% ee
O
59%; 98% ee
Keywords: asymmetric catalysis • Baeyer–Villiger reaction • chiral cyclic ketones • chiral lactones • chiral metal catalysis • enzyme catalysis • kinetic resolution • monooxygenases • oxidation
p 759 3.18
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides J. B. Johnson
Epoxides and aziridines are well established as versatile synthetic intermediates. The electrophilic nature of these compounds dictates their reactivity, and nucleophiles readily attack to open the strained ring and produce 1,2-difunctionalized compounds. Cyclic anhydrides share similar characteristics, as they are also subject to nucleophilic attack and ring opening. Enantioselective ring-opening reactions of these species presents a means of transforming readily available and inexpensive starting materials into a wide range of synthetically viable difunctionalized materials while generating contiguous steScience of Synthesis Reference Library Stereoselective Synthesis Volume 3 © Georg Thieme Verlag KG
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Abstracts
reocenters in a single transformation. The asymmetric addition of nucleophiles to epoxides, aziridines, and cyclic anhydrides has been achieved through enzymatic, main group and transition metal, and organocatalyic methods, presenting numerous means for the generation of a broad range of asymmetric synthons in high yields and enantioselectivities. O R
Nu
Nu−
R1
R1
NR2
Nu
Nu−
R1
R1
O
R1
NHR2
R1
R1
O
OH
R1
1
O
Nu−
R1
O
Nu
R1
OH R1
O
Keywords: asymmetric catalysis • aziridine • cyclic anhydride • epoxide • nucleophilic addition • ring opening • stereoselective synthesis
p 829 Acylation of Alcohols and Amines
3.19
T. Oriyama
Chiral acyl-transfer catalysts catalyze the asymmetric acylation of alcohols and amines. These reactions result in the stereoselective formation of new C-O and C-N bonds. OH R1
R2
O
acyl-transfer catalyst achiral acylating agent
OH R3
O R1
R2 R1
racemic
R2
Keywords: amide synthesis • asymmetric acylation • chiral acyl-transfer catalysts • ester synthesis • kinetic resolution • meso-diol desymmetrization • racemic secondary alcohols • racemic amines
p 851 3.20
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions V. Gouverneur and O. Lozano
Organofluorine chemistry has established itself as an expanding area of research which benefits agricultural, medicinal, and materials science. With respect to industrial applications, stereoselective fluorination is of great use to medicinal chemists. This chapter presents the most efficient methods developed to date for stereoselective fluorination and fluoroalkylation. The field has progressed rapidly with the development of suitable reagents for direct fluorination as well as mono-, di-, and trifluoromethylation. Asymmetric fluorination is dominated by methods that rely on electrophilic (N-F) fluorinating reagents. Both transition-metal catalysts and organocatalysts have been adopted for the preparation of enantiopure compounds featuring a fluorine substituent on a stereogenic center, and dual activation using these two classes of catalysts simultaneously provides an elegant solution for the fluorination of the least activated substrates. In contrast to direct fluorination, asymmetric fluoroalkylation is more commonly performed using nuScience of Synthesis Reference Library Stereoselective Synthesis Volume 3 © Georg Thieme Verlag KG
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Abstracts
cleophilic reagents, in particular the Ruppert–Prakash reagent (TMSCF3) as well as monoand difluoro sulfone derivatives. To date, asymmetric catalytic fluoroalkylations are largely outnumbered by asymmetric methods, a notable exception being the photoredox organocatalytic trifluoromethylation of aldehydes with trifluoro(iodo)methane. F
CH2F R1
R1 chiral reagents R chiral auxiliaries S transition metal catalysts organocatalysts
CF3
CHF2
R1
R1
Keywords: chiral auxiliaries • chiral reagents • cinchona alkaloids • difluoromethylation • fluorination • fluorine • 1-fluorobis(phenylsulfonyl)methane • monofluoromethylation • N-fluorobenzene-1,2-disulfonimide • N-fluorobenzenesulfonimide • organocatalysis • Prins cyclization • Ruppert–Prakash reagent • Selectfluor • transition-metal catalysis • trifluoromethylation • Umemoto reagent
p 931 3.21
Stereoselective Polymerization J.-F. Carpentier and E. Kirillov
This chapter exemplifies methods for stereocontrolled synthesis of several important classes of macromolecular/polymeric materials using organometallic/inorganic precatalysts and initiators. The facile and efficient methods of Ziegler–Natta-type catalytic polymerization and ring-opening metathesis polymerization (ROMP) are selected to provide access to stereoregular polyalkenes and polyalkynes. Stereoselective polymerization of methacrylate monomers, ring-opening polymerization (ROP) of cyclic esters, and syntheses of polycarbonates, polyethers, and polyketones are also featured.
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Abstracts
R1 R1
R2
R1 R2
R1
n R1
R2
R1
R2
R1
R1 n
R1
O
R1
O
stereoselective polymerization catalysis
O
R1 n
O
O
O O
n
R1
R1
R1
n R1
O
O
R1 O n
O
OH
O
O O
n
R1 CO2R2 R1 CO2R2 R1 CO2R2 n
Keywords: catalysis • enantioselectivity • polyalkenes • polycarbonates • polyethers • polyketones • polylactides • polymerization • polymers • polymethacrylates • polyesters • ring-opening polymerization • ring-opening metathesis polymerization • stereoselectivity • tacticity • Ziegler–Natta polymerization
p 973 3.22
Oxidation of Sulfides A. Lattanzi
This review focuses on the most efficient stoichiometric and catalytic methodologies reported for the highly stereoselective oxidation of sulfides to sulfoxides. The diastereoselective oxidation of sulfides bearing preexisting stereogenic centers by common metal and metal-free achiral oxidants is outlined. The chiral metal based procedures are described according to the metal in the complex used, namely titanium, vanadium, iron, aluminum, niobium, and molybdenum, in conjunction with structurally diverse chiral ligands. A section on metal-free oxidation of sulfides, illustrating the use of chiral oxaziridines and oxaziridinium salts as a mild and recoverable chiral source, is also included. Finally, the oxidation of sulfides with isolated enzymes such as peroxidases, monooxygenases, or more recently discovered whole-cell systems is included. Selected examples of industrial applications of oxidative methodologies for the synthesis of biologically active sulfoxides are also highlighted in the various sections.
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Abstracts chiral metal complex catalyzed oxidation
R1
S
O
organocatalyzed oxidation
R2
R1
S∗
R2
enzymatic oxidation
R1 = alkyl; R2 = aryl, alkyl, SR3, NR3R4, OR3
Keywords: sulfides • sulfoxides • sulfones • diastereoselectivity • enantioselectivity • metal-based oxidative systems • metal-free oxidation • titanium(IV) isopropoxide • tartrate esters • hydroperoxides • thiosulfinates • sulfinamides • sulfinates • 1,3-dithianes • 1,3-dithiolanes • kinetic resolution • chiral ligands • oxaziridinium salts • chiral dioxiranes • enzymes
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Stereoselective Synthesis 3: Stereoselective Pericyclic Reactions, Cross Coupling, and C—H and C—X Activation Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
V
Volume Editors Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
VII
Abstracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
XI
Table of Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XXV
3.1
3.2
Introduction P. A. Evans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2]) G.-J. Jiang, Y. Wang, and Z.-X. Yu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
[4 + 2]-Cycloaddition Reactions K. Ishihara and A. Sakakura . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
3.3
[m + n + 1]-Carbocyclization Reactions T. Shibata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
3.4
[m + n + 2]-Carbocyclization Reactions C. Aubert, M. Malacria, and C. Ollivier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
3.5
Asymmetric Cycloisomerizations I. D. G. Watson and F. D. Toste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
3.6
Ene Reactions M. Terada . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
3.7
Sigmatropic Rearrangements J. Zeh and M. Hiersemann . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
3.8
Electrocyclic Reactions B. Gaspar and D. Trauner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
3.9
Allylic Substitution Reactions M. L. Crawley . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
3.10
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements S. Jautze and R. Peters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
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3.11
Allylic and Benzylic Oxidation M. B. Andrus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
469
Mizoroki–Heck Reaction M. Shibasaki, T. Ohshima, and W. Itano . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
483
C-C Bond Formation by C-H Bond Activation H. M. L. Davies and D. Morton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
513
Cross Coupling M. Shimizu and T. Hiyama . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
567
Protonation, Alkylation, Arylation, and Vinylation of Enolates B. M. Stoltz and J. T. Mohr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
615
3.12
3.13
3.14
3.15
3.16
3.17
3.18
3.19
3.20
3.21
3.22
Æ-Functionalization of Carbonyl Compounds D. W. C. MacMillan and A. J. B. Watson . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
675
Baeyer–Villiger Reactions S. Levinger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
747
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides J. B. Johnson . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
759
Acylation of Alcohols and Amines T. Oriyama . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
829
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions V. Gouverneur and O. Lozano . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
851
Stereoselective Polymerization J.-F. Carpentier and E. Kirillov . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
931
Oxidation of Sulfides A. Lattanzi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
973
Keyword Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017 Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1081 Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Table of Contents Introduction P. A. Evans Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1
1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2]) G.-J. Jiang, Y. Wang, and Z.-X. Yu
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2]) . . . . . . . . . . . . . . . . . . . . . . . .
7
3.1.1
[2 + 2]-Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
3.1.1.1
[2 + 2] Cycloadditions Catalyzed by Transition Metals . . . . . . . . . . . . . . . . . . . . . . . .
8
3.1.1.1.1
Chiral Titanium Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
3.1.1.1.2
Chiral Copper Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
3.1.1.1.3
Chiral Rhodium Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
3.1.1.1.4
Chiral Iridium Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
3.1.1.2
[2 + 2] Cycloadditions Catalyzed by Organic Molecules . . . . . . . . . . . . . . . . . . . . . . .
14
3.1.1.2.1
Lectkas Quinine-Derived Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
3.1.1.2.2
Fus 4-Pyrrolidinopyridine Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
3.1.1.2.2.1
Asymmetric Staudinger Synthesis of -Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
3.1.1.2.2.2
[2 + 2] Cycloadditions of Disubstituted Ketenes with Aldehydes . . . . . . . . . . . . . .
17
3.1.1.2.2.3
[2 + 2] Cycloadditions of Ketenes with Azo Compounds . . . . . . . . . . . . . . . . . . . . . .
18
3.1.1.2.2.4
[2 + 2] Cycloadditions of Ketenes with Nitroso Compounds . . . . . . . . . . . . . . . . . . .
19
3.1.1.2.3
Coreys Oxazaborolidine Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.1.1.2.4
Yes N-Heterocyclic Carbene Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
3.1.1.2.4.1
N-Heterocyclic Carbene Catalyzed Staudinger Reaction of Ketenes . . . . . . . . . . . 22
3.1.1.2.4.2
N-Heterocyclic Carbene Catalyzed [2 + 2] Cycloadditions of Disubstituted Ketenes with 2-Oxoaldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3.1.1.2.4.3
N-Heterocyclic Carbene Catalyzed [2 + 2] Cycloadditions of Ketenes with Ketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.1.2.4.4
3.1.2
24
N-Heterocyclic Carbene Catalyzed [2 + 2] Cycloadditions of Ketenes with Azodicarboxylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 [3 + 2]-Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Phosphine-Catalyzed [3 + 2]-Cycloaddition Reactions of Allenoates with Dienophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
3.1.2.1.1
Cycloaddition Reactions Catalyzed by P-Chiral 7-Phosphabicyclo[2.2.1]heptane
28
3.1.2.1.2
Cycloaddition Reactions Catalyzed by Binaphthyl-Derived Phosphines . . . . . . . . 29
3.1.2.1.3
Cycloaddition Reactions Catalyzed by Amino Acid Based Phosphines . . . . . . . . .
3.1.2.1
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3.1.2.1.4
Cycloaddition Reactions Catalyzed by Planar-Chiral 2-Phospha[3]ferrocenophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.1.2.1.5
Cycloaddition Reactions Catalyzed by Chiral Thiourea-Containing Phosphines
3.1.2.2
Palladium-Catalyzed Asymmetric [3 + 2] Trimethylenemethane Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
3.1.3
33
[4 + 1]-Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.1.3.1
Rhodium- and Platinum-Catalyzed Asymmetric [4 + 1]-Cycloaddition Reactions of Vinylallenes and Carbon Monoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.1.3.2
Copper-Catalyzed Asymmetric [4 + 1] Cycloadditions of Enones with Diazo Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.1.4
[3 + 3]-Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
3.1.4.1
Chiral Lewis Acid Catalyzed [3 + 3] Cycloadditions of Nitrones to Doubly Activated Cyclopropanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
3.1.4.2
Palladium-Catalyzed Asymmetric [3 + 3] Cycloadditions of Trimethylenemethane Derivatives with Nitrones . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.5
47
[4 + 3]-Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
3.1.5.1
Asymmetric Organocatalysis of [4 + 3]-Cycloaddition Reactions of Allylic Cations and Dienes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
3.1.5.2
Chiral Lewis Acid Catalyzed [4 + 3] Cycloadditions of Nitrogen-Stabilized Oxyallyl Cations Derived from N-Allenylamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
3.1.5.3
Rhodium-Catalyzed Asymmetric [4 + 3] Cycloadditions between Æ-Diazo ,ª-Unsaturated Esters and Dienes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
3.1.5.4
Palladium-Catalyzed [4 + 3] Cycloadditions of ª-Methylene--valerolactones
54
3.1.5.5
Palladium-Catalyzed [4 + 3] Intramolecular Cycloadditions of Alkylidenecyclopropanes and Dienes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
3.1.6 3.1.6.1
3.1.7
[5 + 2]-Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
57
Rhodium-Catalyzed Asymmetric [5 + 2] Cycloadditions of Vinylcyclopropanes and -Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
57
[6 + 3]-Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
3.1.7.1
Palladium-Catalyzed Asymmetric [6 + 3] Cycloaddition of Trimethylenemethane with Tropones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
3.2
[4 + 2]-Cycloaddition Reactions K. Ishihara and A. Sakakura
3.2
[4 + 2]-Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
3.2.1
Enantioselective Diels–Alder Reactions Catalyzed by Chiral Lewis Acids . . . . . . .
67
3.2.1.1
Enantioselective Catalysis Using Chiral Boron Compounds . . . . . . . . . . . . . . . . . . .
67
3.2.1.1.1
Using a Cationic Oxazaborolidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
3.2.1.1.2
Using Boronic Acid Esters of Chiral 3-(2-Hydroxyphenyl)binaphthols . . . . . . . . . . 73
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3.2.1.2
Enantioselective Catalysis Using Chiral Copper(II) Complexes . . . . . . . . . . . . . . .
76
3.2.1.2.1
Using a Chiral Copper(II)–Bis(4,5-dihydrooxazole) Complex . . . . . . . . . . . . . . . . .
76
3.2.1.2.2
Using a Chiral Copper(II)–3-Arylalanine Amide Complex . . . . . . . . . . . . . . . . . . . .
83
3.2.1.2.3
Using a Copper(II)–DNA Complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
3.2.1.3
Enantioselective Catalysis Using Other Chiral Lewis Acids . . . . . . . . . . . . . . . . . . .
86
3.2.2
Enantioselective Diels–Alder Reactions Catalyzed by Organoammonium Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
3.2.2.1
Enantioselective Catalysis Using Chiral Secondary Ammonium Salts . . . . . . . . .
90
3.2.2.2
Enantioselective Catalysis Using Chiral Primary Ammonium Salts . . . . . . . . . . . .
94
3.2.2.3
Enantioselective Catalysis Using Hydrogen-Bonded Complexes . . . . . . . . . . . . . .
99
3.2.3
Hetero-Diels–Alder Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
3.2.3.1
Enantioselective Hetero-Diels–Alder Reactions of Carbonyl Compounds . . . . . 103
3.2.3.1.1
Enantioselective Catalysis Using a Chiral Chromium(III) Complex . . . . . . . . . . . . 104
3.2.3.1.2
Enantioselective Catalysis Using Other Chiral Lewis Acids . . . . . . . . . . . . . . . . . . . 108
3.2.3.1.3
Enantioselective Catalysis Using Chiral Organocatalysts . . . . . . . . . . . . . . . . . . . . .
110
Enantioselective Hetero-Diels–Alder Reactions of Imines and Related Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
113
Enantioselective Aza-Diels–Alder Reaction of Electron-Rich Dienes with Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
113
Enantioselective Aza-Diels–Alder Reaction of 1-Azabuta-1,3-dienes . . . . . . . . .
117
3.2.3.2
3.2.3.2.1
3.2.3.2.2
3.3
[m + n + 1]-Carbocyclization Reactions T. Shibata
3.3
[m + n + 1]-Carbocyclization Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
3.3.1
[2 + 2 + 1] Carbocyclization of Enynes with Carbon Monoxide . . . . . . . . . . . . . . . . 125
3.3.1.1
Enantioselective Titanium-Catalyzed Pauson–Khand Reactions . . . . . . . . . . . . . . 125
3.3.1.2
Rhodium-Catalyzed Pauson–Khand Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
3.3.1.2.1
Enantioselective Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
3.3.1.2.2
Diastereoselective Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
3.3.1.3
Enantioselective Iridium-Catalyzed Pauson–Khand Reactions . . . . . . . . . . . . . . . . 132
3.3.1.4
Enantioselective Cobalt-Catalyzed Pauson–Khand Reactions . . . . . . . . . . . . . . . . 133
3.3.2
3.3.2.1 3.3.3
Rhodium-Catalyzed [2 + 2 + 1] Carbocyclization Using Aldehydes as a Carbon Monoxide Source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 Enantioselective Rhodium-Catalyzed Reactions Using Aldehydes . . . . . . . . . . . . 136 Ruthenium-Catalyzed [3 + 2 + 1] Carbocyclization of Silylalkynes and Enones with Carbon Monoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
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3.3.4
Nickel-Catalyzed [4 + 2 + 1] Carbocyclization of Dienynes with Diazomethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
3.3.5
Rhodium-Catalyzed [5 + 2 + 1] Carbocyclization of Vinylcyclopropanes and Alkynes with Carbon Monoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
3.3.6
Palladium-Catalyzed [4 + 4 + 1] Carbocyclization of Two Vinylallenes with Carbon Monoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
3.4
[m + n + 2]-Carbocyclization Reactions C. Aubert, M. Malacria, and C. Ollivier
3.4
[m + n + 2]-Carbocyclization Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
3.4.1
[2 + 2 + 2]-Carbocyclization Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
3.4.1.1
Ruthenium(II)-Mediated [2 + 2 + 2] Carbocyclizations . . . . . . . . . . . . . . . . . . . . . . . . 145
3.4.1.1.1
Control of Diastereoselectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
3.4.1.1.1.1
Intramolecular Carbocyclization of Dienynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
3.4.1.2
Cobalt(I)-Mediated [2 + 2 + 2] Carbocyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
3.4.1.2.1
Control of Diastereoselectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
3.4.1.2.1.1
Cocyclization of Alkynylboronates and Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
3.4.1.2.1.2
Cocyclization of Diynes and Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
3.4.1.2.1.3
Cocyclization of Yne-Heterocycles with Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
3.4.1.2.1.4
Intramolecular Carbocyclization of Enediynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
3.4.1.2.1.5
Intramolecular Carbocyclization of Diynals and Diynones . . . . . . . . . . . . . . . . . . . 161
3.4.1.2.1.6
Intramolecular Carbocyclization of Allenediynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
3.4.1.2.1.7
Intramolecular Cyclotrimerization of Chiral Triynes . . . . . . . . . . . . . . . . . . . . . . . . . 163
3.4.1.2.2
Control of Central Chirality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
3.4.1.2.2.1
Intramolecular Cyclotrimerization of Allenediynes . . . . . . . . . . . . . . . . . . . . . . . . . . 165
3.4.1.2.3
Control of Axial Chirality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
3.4.1.2.3.1
Carbocyclization of Acetylene and Aryl-Substituted Monoynes Bearing Phosphoryl Moieties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
3.4.1.2.3.2
Carbocyclization of 1,7-Diynes with Nitriles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
3.4.1.3
Rhodium(I)-Mediated [2 + 2 + 2] Carbocyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . 168
3.4.1.3.1
Control of Central Chirality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
3.4.1.3.1.1
Carbocyclization of Tertiary Propargylic Alcohols, Bispropargylic Alcohols, and Dialkynylphosphine Oxides with 1,6-Diyne Esters . . . . . . . . . . . . . 169
3.4.1.3.1.2
Carbocyclization of 1,6-Diynes with Substituted Alkenes . . . . . . . . . . . . . . . . . . . . 172
3.4.1.3.1.3
Carbocyclization of 1,6-Diynes with Electron-Deficient Ketones . . . . . . . . . . . . . 175
3.4.1.3.1.4
Carbocyclization of 1,6-Enynes and Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
3.4.1.3.1.5
Carbocyclization of 1,6-Enynes with Electron-Deficient Ketones . . . . . . . . . . . . . 177
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3.4.1.3.1.6
Cocyclization of Alkenyl Isocyanates and Terminal Alkynes . . . . . . . . . . . . . . . . . . 179
3.4.1.3.1.7
Cocyclization of Alkenyl Carbodiimides and Terminal Alkynes . . . . . . . . . . . . . . . 181
3.4.1.3.1.8
Intramolecular Carbocyclization of Enediynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
3.4.1.3.1.9
Intramolecular Carbocyclization of Dienynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
3.4.1.3.1.10
Intramolecular Carbocyclization of 1,n-Dienynes (n = 4–6) . . . . . . . . . . . . . . . . . . 185
3.4.1.3.2
Control of Helical Chirality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
3.4.1.3.2.1
Cocyclization of Tetraynes with Diynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
3.4.1.3.2.2
Intramolecular Carbocyclization of Triynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
3.4.1.3.3
Control of Axial Chirality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
3.4.1.3.3.1
Cyclotrimerization of Internal Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
3.4.1.3.3.2
Cocyclization of 1,6-Diynes and Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
3.4.1.3.3.3
Double Cocyclization of 1,6-Diynes with 1,3-Diynes . . . . . . . . . . . . . . . . . . . . . . . . . 194
3.4.1.3.3.4
Cocarbocyclization of 1,6-Diynes with Ynamides . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
3.4.1.3.3.5
Cocarbocyclization of 1,6-Diynes with trans-Alkenes . . . . . . . . . . . . . . . . . . . . . . . . 198
3.4.1.3.3.6
Cocarbocyclization of 1,6-Diynes with Isocyanates . . . . . . . . . . . . . . . . . . . . . . . . . . 199
3.4.1.3.3.7
Cocyclization of 1,7-Diynes and Internal Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
3.4.1.3.3.8
Intramolecular Cyclotrimerization of Enediynes and Dienynes . . . . . . . . . . . . . . . 201
3.4.1.2.3.9
Intramolecular Cyclotrimerization of Bis(diynyl)malononitriles . . . . . . . . . . . . . . 203
3.4.1.3.4
Control of Planar Chirality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
3.4.1.3.4.1
Cocyclization of Internal Diynes and Di-tert-butyl Acetylenedicarboxylate . . . . 203
3.4.1.3.4.2
Intramolecular Cyclotrimerization of Triynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
3.4.1.4
Iridium(I)-Mediated [2 + 2 + 2] Carbocyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
3.4.1.4.1
Control of Axial Chirality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
3.4.1.4.1.1
Cocyclization of 1,n-Diynes and Internal Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
3.4.1.4.1.2
Intramolecular Cyclotrimerization of Triynes and Hexaynes . . . . . . . . . . . . . . . . . 209
3.4.1.5
Nickel(0)-Mediated [2 + 2 + 2] Carbocyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . .
211
3.4.1.5.1
Control of Diastereoselectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
211
3.4.1.5.1.1
Cocyclization between 1,6-Diynes and Activated Alkenes . . . . . . . . . . . . . . . . . . .
211
3.4.1.5.1.2
Cocyclization between Norbornadiene and Activated Alkenes . . . . . . . . . . . . . . .
212
3.4.1.5.2
Control of Central Chirality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
3.4.1.5.2.1
Intermolecular Cyclotrimerization between Two Alkynes and an Alkene . . . . . .
3.4.1.5.2.2
Bimolecular Cocyclization of Diynes and Acetylene . . . . . . . . . . . . . . . . . . . . . . . . . 214
3.4.1.5.3
Control of Helical Chirality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
3.4.1.5.3.1
Cycloisomerization of Triynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
3.4.1.6
Palladium(0)-Mediated [2 + 2 + 2] Carbocyclizations . . . . . . . . . . . . . . . . . . . . . . . . . 216
3.4.1.6.1
Control of Helical Chirality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
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3.4.1.6.1.1
Carbocyclization of Arynes with Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
3.4.2
[3 + 2 + 2]-Carbocyclization Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
3.4.2.1
Ruthenium(II)-Mediated [3 + 2 + 2]-Carbocyclization Reactions . . . . . . . . . . . . . . . 219
3.4.2.1.1
Cocyclizations between an Å3-Allylruthenium(II) Complex and Alkynes . . . . . . . 219
3.4.2.2
Cobalt(III)-Mediated [3 + 2 + 2]-Carbocyclization Reactions . . . . . . . . . . . . . . . . . . 221
3.4.2.2.1
Cocyclizations between Å3-Allyl-Type Cobalt Complexes and Alkynes . . . . . . . . 221
3.4.2.3
Rhodium(I)-Mediated [3 + 2 + 2]-Carbocyclization Reactions . . . . . . . . . . . . . . . . . 224
3.4.2.3.1
Cocyclizations between Alk-6-enylidenecyclopropanes and Activated Alkynes
3.4.2.4
Iridium(III)-Mediated [3 + 2 + 2]-Carbocyclization Reactions . . . . . . . . . . . . . . . . . . 225
3.4.2.4.1
Cocyclizations between Å3-Allyliridium Complexes and Alkynes . . . . . . . . . . . . . 225
3.4.2.5
Nickel(0)-Mediated [3 + 2 + 2]-Carbocyclization Reactions . . . . . . . . . . . . . . . . . . . 226
3.4.2.5.1
Cocyclization of Ethyl Cyclopropylideneacetate and Alkynes or Diynes . . . . . . . 226
3.4.2.5.2
Cocyclization of Chromium Fischer Carbene Complexes with Terminal Alkynes 227
3.4.3
[4 + 2 + 2]-Carbocyclization Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
3.4.3.1
Cobalt-Mediated [4 + 2 + 2]-Carbocyclization Reactions . . . . . . . . . . . . . . . . . . . . . . 230
3.4.3.1.1
Cocyclization of Norbornadiene with 2-Substituted Buta-1,3-dienes . . . . . . . . . 230
3.4.3.2
Rhodium(I)-Mediated [4 + 2 + 2]-Carbocyclization Reactions . . . . . . . . . . . . . . . . . 232
3.4.3.2.1
Cocyclization of Enynes with Buta-1,3-dienes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
3.4.3.2.2
Cocyclization of Dienynes with Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
3.4.3.2.3
Cocyclization of Enedienes with Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
3.4.3.2.4
Cocyclization of Dienyl Isocyanates with Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
3.5
224
Asymmetric Cycloisomerizations I. D. G. Watson and F. D. Toste
3.5
Asymmetric Cycloisomerizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
3.5.1
Enyne Cycloisomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
3.5.1.1
Palladium-Catalyzed Cycloisomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
3.5.1.2
Rhodium-Catalyzed Cycloisomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
3.5.1.3
Gold- and Platinum-Catalyzed Cycloisomerization . . . . . . . . . . . . . . . . . . . . . . . . . . 267
3.5.2
Diene Cycloisomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
3.5.2.1
Cycloisomerization of 1,6- and 1,7-Dienes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
3.5.2.2
Cycloisomerization of 1,6- and 1,7-Allenenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
3.5.3
Carbonyl-Ene Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
3.5.4
Conia-Ene Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
3.5.5
Intramolecular Cyclization Initiated by C-H Activation . . . . . . . . . . . . . . . . . . . . . . 292
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XXXI
Ene Reactions M. Terada
3.6
Ene Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
3.6.1
Intramolecular Ene Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
3.6.1.1
Aldehydes and Ketones as Enophiles (Carbonyl-Ene Reactions) . . . . . . . . . . . . . . 310
3.6.1.1.1
Type-I Cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
3.6.1.1.1.1
Diastereoselective Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
3.6.1.1.1.2
Enantioselective Reaction of Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
311
3.6.1.1.1.3
Enantioselective Reaction of Ketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
312
3.6.1.1.2
Type-II Cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
3.6.1.1.2.1
Diastereoselective Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
3.6.1.1.2.2
Enantioselective Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.6.1.2
Alkynes as Enophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
3.6.1.2.1
Type-I Cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
3.6.1.2.1.1
Enantioselective Reaction of 1,6-Enynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
3.6.1.2.1.2
Enantioselective Reaction of 1,7-Enynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
3.6.1.2.2
Conia-Ene Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
3.6.1.2.2.1
Enantioselective Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
3.6.2
Intermolecular Ene Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
3.6.2.1
Aldehydes and Ketones as Enophiles (Carbonyl-Ene Reactions) . . . . . . . . . . . . . . 321
3.6.2.1.1
Enantioselective Reaction of Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
3.6.2.1.1.1
Unactivated Alkenes as Ene Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
3.6.2.1.1.2
Enol Ethers as Ene Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
3.6.2.1.1.3
Enamides or Enecarbamates as Ene Components . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
3.6.2.1.2
Enantioselective Reaction of Ketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
3.6.2.1.2.1
Unactivated Alkenes as Ene Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
3.6.2.1.2.2
Activated Alkenes as Ene Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
3.6.2.2
Imines as Enophiles (Imino-Ene Reactions) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
3.6.2.2.1
Enantioselective Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
3.6.2.2.1.1
Unactivated Alkenes as Ene Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
3.6.2.2.1.2
Enecarbamates as Ene Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
3.6.2.3
Electron-Deficient Alkenes as Enophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
3.6.2.3.1
Enantioselective Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
3.6.2.3.1.1
Unactivated Alkenes as Ene Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
3.6.2.3.1.2
Enecarbamates as Ene Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
3.6.2.4
Heteroatom-Heteroatom Double Bonds as Enophiles . . . . . . . . . . . . . . . . . . . . . . 341
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3.6.2.4.1
Enantioselective Reaction of Azodicarboxylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
3.6.2.4.1.1
Unactivated Alkenes as Ene Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
3.6.2.4.1.2
Enecarbamates as Ene Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
3.7
Sigmatropic Rearrangements J. Zeh and M. Hiersemann
3.7
Sigmatropic Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
3.7.1
The Claisen Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
3.7.1.1
The Classic Claisen Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
3.7.1.2
The 3-Aza-Claisen Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
3.7.1.3
The Thio-Claisen Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
3.7.1.4
The Claisen Rearrangement of Chelated Enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
3.7.1.5
The Carroll–Claisen Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
3.7.1.6
The Eschenmoser–Claisen Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
3.7.1.7
The Ireland–Claisen Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
3.7.1.8
The Johnson–Claisen Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
3.7.1.9
The Aromatic Claisen Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
3.7.2
The Cope Rearrangement and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
3.7.2.1
The Classic Cope Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
3.7.2.2
The Anionic Oxy-Cope Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
3.7.2.3
The 2-Oxonia-Cope Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
3.7.2.4
The 2-Azonia-Cope Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
3.7.3
The [2,3]-Wittig Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
3.7.3.1
The Classic [2,3]-Wittig Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
3.7.3.2
The Enolate [2,3]-Wittig Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
3.8
Electrocyclic Reactions B. Gaspar and D. Trauner
3.8
Electrocyclic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
3.8.1
Synthesis of Dienes through Electrocyclic Ring Opening of Cyclobutenes . . . . 383
3.8.2
Synthesis of Cyclobutenes through Electrocyclization of Dienes . . . . . . . . . . . . . 385
3.8.3
Synthesis of Five-Membered Rings through Electrocyclization of Pentadienyl Cations: The Nazarov Cyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
3.8.3.1
Stoichiometric Nazarov Cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
3.8.3.2
Catalytic Nazarov Cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
3.8.3.3
Interrupted Nazarov Cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
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3.8.4
Electrocyclizations of Hexatrienes and Octatetraenes . . . . . . . . . . . . . . . . . . . . . . . 392
3.8.4.1
Electrocyclizations of 6 Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392
3.8.4.2
Electrocyclizations of 8 Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
3.9
Allylic Substitution Reactions M. L. Crawley
3.9
Allylic Substitution Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
3.9.1
C-C Bond-Forming Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
3.9.1.1
Enantioselective Reactions with Achiral Electrophiles and Symmetric Intermediate -Allyl Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
3.9.1.1.1
Palladium-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
3.9.1.1.2
Copper-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
3.9.1.1.3
Molybdenum-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.9.1.1.4
Iridium-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
3.9.1.2
Dynamic Kinetic Asymmetric Resolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
3.9.1.2.1
Palladium-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
3.9.1.2.2
Molybdenum-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
417
3.9.1.3
Stereospecific Allylic Substitution with Chiral Electrophiles . . . . . . . . . . . . . . . . . .
419
3.9.1.3.1
Rhodium-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
419
3.9.2
C-N Bond-Forming Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
3.9.2.1
411
Enantioselective Reactions with Achiral Electrophiles and Symmetric Intermediate -Allyl Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
3.9.2.1.1
Palladium-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
3.9.2.1.2
Iridium-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
3.9.2.2
Dynamic Kinetic Asymmetric Resolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
3.9.2.2.1
Palladium-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
3.9.2.3
Stereospecific Allylic Substitution with Chiral Electrophiles . . . . . . . . . . . . . . . . . . 429
3.9.2.3.1
Rhodium-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
3.9.3
C-O Bond-Forming Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
3.9.3.1
Enantioselective Reactions with Achiral Electrophiles and Symmetric Intermediate -Allyl Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
3.9.3.1.1
Palladium-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
3.9.3.1.2
Iridium-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
3.9.3.2
Dynamic Kinetic Asymmetric Resolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
3.9.3.2.1
Palladium-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
3.9.3.3
Stereospecific Allylic Substitution with Chiral Electrophiles . . . . . . . . . . . . . . . . . . 437
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Rhodium-Catalyzed Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
3.10
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements S. Jautze and R. Peters
3.10
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements
3.10.1
Synthesis by Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
3.10.1.1
[3,3]-Sigmatropic Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
3.10.1.1.1
Claisen Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
3.10.1.1.2
Meerwein–Eschenmoser–Claisen Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . 446
3.10.1.1.3
Carroll Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
3.10.1.1.4
Aza-Claisen Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
3.10.1.1.4.1
Using Benzimidate Substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
3.10.1.1.4.2
Using Trichloroacetimidate Substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
3.10.1.1.4.3
Using Trifluoroacetimidate Substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452
3.10.1.1.4.4
Using Miscellaneous Substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457
3.10.1.1.5
Miscellaneous Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457
3.10.1.1.5.1
Thia-Claisen Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457
3.10.1.1.5.2
Aza-Phospha-Oxa-Cope Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458
3.10.1.2
[2,3]-Sigmatropic Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
3.10.2
Synthesis by Isomerization and Migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460
3.10.2.1
Double-Bond Isomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460
3.10.2.1.1
Isomerization of Allylic Amines to Enamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460
3.10.2.1.2
Isomerization of Allylic Alcohols to Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
3.10.2.2
Wagner–Meerwein Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
3.10.3
Tandem Reactions Involving an Isomerization or Rearrangement . . . . . . . . . . . . 464
3.10.3.1
Domino Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
3.10.3.1.1
Claisen Rearrangement/Intramolecular Carbonyl-Ene Reaction . . . . . . . . . . . . . . 464
3.10.3.1.2
Ketene Addition/Acyl Claisen Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
3.11
443
Allylic and Benzylic Oxidation M. B. Andrus
3.11
Allylic and Benzylic Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
3.11.1
Allylic Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
3.11.1.1
Oxidation To Afford Allylic Alcohols and Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . 470
3.11.1.1.1
Reaction with Selenium Dioxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
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3.11.1.1.2
Reaction with Palladium/Quinone/Oxygen Reagents . . . . . . . . . . . . . . . . . . . . . . . . 471
3.11.1.1.3
Reaction with Copper/Perester Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
3.11.1.2
Oxidation To Afford Enones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
3.11.2
Benzylic Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
3.11.2.1
Oxidation To Afford Benzylic Alcohols and Derivatives . . . . . . . . . . . . . . . . . . . . . . 479
3.11.2.2
Oxidation To Afford Lactones and Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
3.12
Mizoroki–Heck Reaction M. Shibasaki, T. Ohshima, and W. Itano
3.12
Mizoroki–Heck Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
3.12.1
Intermolecular Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
3.12.1.1
Regioselective Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
3.12.1.1.1
Reaction of Electron-Poor Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
3.12.1.1.2
Reaction of Electron-Rich Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489
3.12.1.1.3
Chelation-Controlled Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
3.12.1.2
Asymmetric Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
3.12.2
Intramolecular Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
3.12.2.1
Formation of Tertiary Carbon Centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
3.12.2.1.1
6,6-Ring System Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
3.12.2.1.2
6,5-Ring System Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
3.12.2.1.3
5,5-Ring System Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
3.12.2.2
Formation of Quaternary Carbon Centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
3.12.2.2.1
6,6-Ring System Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
3.12.2.2.2
6,5-Ring System Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
3.12.2.2.3
6,6,6-Ring System Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
3.12.2.2.4
Spirocyclic System Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
3.13
C-C Bond Formation by C-H Bond Activation H. M. L. Davies and D. Morton
3.13
C-C Bond Formation by C-H Bond Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
3.13.1
Intramolecular C-C Bond Formation by C-H Activation . . . . . . . . . . . . . . . . . . . .
515
3.13.1.1
Intramolecular Activation of sp C-H Bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
515
3.13.1.1.1
Synthesis of Carbocycles by Activation of sp3 C-H Bonds . . . . . . . . . . . . . . . . . . .
515
3.13.1.1.1.1
Dirhodium(II)-Catalyzed Carbene C-H Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
3.13.1.1.2
Intramolecular Synthesis of Lactones by Activation of sp3 C-H Bonds . . . . . . . 519
3.13.1.1.2.1
Dirhodium(II)-Catalyzed Carbene C-H Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519
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3.13.1.1.3
Intramolecular Synthesis of Lactams by Activation of sp3 C-H Bonds . . . . . . . . 522
3.13.1.1.3.1
Dirhodium(II)-Catalyzed Carbene C-H Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522
3.13.1.2
Intramolecular Activation of sp2 C-H Bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
3.13.1.2.1
Synthesis of Carbocyclic Derivatives by Activation of sp2 C-H Bonds . . . . . . . . 524
3.13.1.2.1.1
Directed sp2 C-H Bond Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
3.13.1.2.2
Synthesis of Oxygen Heterocycles by Activation of sp2 C-H Bonds . . . . . . . . . . 530
3.13.1.2.2.1
Directed sp2 C-H Bond Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
3.13.1.2.2.2
Oxidative Palladium(II)-Catalyzed sp2 C-H Bond Activation . . . . . . . . . . . . . . . . . 533
3.13.1.2.3
Synthesis of Nitrogen Heterocycles by Activation of sp2 C-H Bonds . . . . . . . . . 535
3.13.1.2.3.1
Directed sp2 C-H Bond Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
3.13.1.2.3.2
Oxidative Palladium(II)-Catalyzed sp2 C-H Bond Activation . . . . . . . . . . . . . . . . . 537
3.13.1.3
Intramolecular Activation of Benzylic C-H Bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . 538
3.13.1.3.1
Synthesis of Carbocyclic Derivatives by Benzylic C-H Bond Insertion . . . . . . . . 538
3.13.1.3.1.1
Dirhodium(II)-Catalyzed Carbene C-H Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538
3.13.1.3.2
Synthesis of Oxygen Heterocycles by Benzylic C-H Bond Insertion . . . . . . . . . . 539
3.13.1.3.2.1
Dirhodium(II)-Catalyzed Carbene C-H Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540
3.13.1.3.3
Synthesis of Nitrogen Heterocycles by Benzylic C-H Bond Insertion . . . . . . . . . 540
3.13.1.3.3.1
Dirhodium(II)-Catalyzed Carbene C-H Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540
3.13.1.4
Intramolecular Activation of C-H Bonds Æ to Oxygen . . . . . . . . . . . . . . . . . . . . . . 541
3.13.1.4.1
Dirhodium(II)-Catalyzed Carbene C-H Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
3.13.1.5
Intramolecular Activation of C-H Bonds Æ to Nitrogen . . . . . . . . . . . . . . . . . . . . . 542
3.13.1.5.1
Dirhodium(II)-Catalyzed Carbene C-H Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
3.13.2
Intermolecular C-C Bond Formation by C-H Activation . . . . . . . . . . . . . . . . . . . . 544
3.13.2.1
Intermolecular Activation of sp3 C-H bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545
3.13.2.1.1
Dirhodium(II)-Catalyzed Carbene C-H Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545
3.13.2.2
Intermolecular Activation of sp2 C-H Bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547
3.13.2.2.1
Heteroatom-Directed C-H Functionalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547
3.13.2.3
Intermolecular Activation of Benzylic C-H Bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . 551
3.13.2.3.1
Dirhodium(II)-Catalyzed Carbene C-H Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551
3.13.2.4
Intermolecular Activation of Allylic C-H Bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553
3.13.2.4.1
Dirhodium(II)-Catalyzed Carbene C-H Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553
3.13.2.5
Intermolecular Activation of C-H Bonds Æ to Oxygen . . . . . . . . . . . . . . . . . . . . . . 560
3.13.2.5.1
Dirhodium(II)-Catalyzed Carbene C-H Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 560
3.13.2.6
Intermolecular Activation of C-H Bonds Æ to Nitrogen . . . . . . . . . . . . . . . . . . . . . 562
3.13.2.6.1
Dirhodium(II)-Catalyzed Carbene C-H Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562
3.13.3
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563
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3.14
XXXVII
Cross Coupling M. Shimizu and T. Hiyama
3.14
Cross Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567
3.14.1
Asymmetric Synthesis of Tertiary Carbon Centers . . . . . . . . . . . . . . . . . . . . . . . . . . 569
3.14.1.1
Reaction of Secondary Organometallic Reagents with Organic Halides . . . . . . 569
3.14.1.2
Reaction of Organometallic Reagents with Secondary Organic Halides . . . . . . 575
3.14.2
Stereoselective Synthesis of Multisubstituted Alkenes . . . . . . . . . . . . . . . . . . . . . . 584
3.14.2.1
Reaction of gem-Dimetalated Alkenes with Organic Halides . . . . . . . . . . . . . . . . . 584
3.14.2.2
Reaction of gem-Dihalogenated Alkenes with Organometallic Reagents . . . . . 587
3.14.2.3
Reaction of vic-Dimetalated Alkenes with Organic Halides . . . . . . . . . . . . . . . . . . 595
3.14.2.4
Reaction of 1,2-Dihaloalk-1-enes with Organometallic Reagents . . . . . . . . . . . . . 598
3.14.3
Stereoselective Synthesis of Alkenes Bearing a Chiral Center at the Allylic Position . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600
3.14.3.1
Reaction of Achiral Allylic Metals with Organic Halides . . . . . . . . . . . . . . . . . . . . . . 600
3.14.3.2
Reaction of Chiral Allylic Metals with Organic Halides . . . . . . . . . . . . . . . . . . . . . . . 601
3.14.4
Asymmetric Synthesis of Optically Active Allenes . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
3.14.4.1
Reaction of Propargylic Carbonates or Sulfonates with Organometallic Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
3.14.4.2
Reaction of 2-Bromo-Substituted 1,3-Dienes with Organometallic Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
604
3.14.5
Asymmetric Synthesis of Biaryls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
3.14.5.1
Reaction of Arylmetals with Aryl Halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
3.14.5.2
Reaction of Dihalobiaryls with Organometallic Reagents . . . . . . . . . . . . . . . . . . . . 609
3.15
Protonation, Alkylation, Arylation, and Vinylation of Enolates B. M. Stoltz and J. T. Mohr
3.15
Protonation, Alkylation, Arylation, and Vinylation of Enolates . . . . . . . . . . . 615
3.15.1
Enantioselective Protonation of Enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
3.15.1.1
Biocatalytic Enantioselective Protonation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
3.15.1.1.1
Hydrolysis of Enol Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616
3.15.1.1.2
Decarboxylative Protonation of Malonic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
3.15.1.2
Protonation of Enolates with Chiral Proton Donors . . . . . . . . . . . . . . . . . . . . . . . . . 618
3.15.1.2.1
Using -Hydroxy Sulfoxide Brønsted Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
3.15.1.2.2
Using Lewis Acid Activated Brønsted Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
3.15.1.3
Protonation of Enolates with Chiral Proton Acceptors . . . . . . . . . . . . . . . . . . . . . . . 622
3.15.2
Alkylation of Enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
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3.15.2.1
Alkylation of Amide Enolates via Chiral Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . 626
3.15.2.1.1
Using Oxazolidinone Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
3.15.2.1.2
Using Camphorsultam Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628
3.15.2.1.3
Using Pseudoephedrine Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629
3.15.2.2
Alkylation of Enolates via Chiral Metalloenamines . . . . . . . . . . . . . . . . . . . . . . . . . . 634
3.15.2.2.1
Using Imine-Type Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634
3.15.2.2.2
Using Hydrazone-Type Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
3.15.2.3
Alkylation of Enolates with Chiral Counterions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
3.15.2.4
Alkylation of Enolates via Chiral Transition-Metal Catalysts . . . . . . . . . . . . . . . . . . 642
3.15.2.4.1
Decarboxylative Allylic Alkylation of Enol Carbonates and Silanes with Palladium Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
3.15.2.4.2
Decarboxylative Allylic Alkylation of -Keto Esters with Palladium Catalysts
3.15.2.4.3
Decarboxylative Conjugate Addition/Allylic Alkylation Cascades with Palladium Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647
645
3.15.2.4.4
Alkylation of Tin Enolates Using Chromium Catalysts . . . . . . . . . . . . . . . . . . . . . . . 649
3.15.2.4.5
Alkylation of Æ-Bromoamides Using Nickel Catalysts . . . . . . . . . . . . . . . . . . . . . . . . 650
3.15.3
Arylation of Enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
3.15.3.1
Arylation of Enolates via Chiral Auxiliary Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
3.15.3.2
3.15.3.2.1 3.15.3.2.2
Arylation of Enolates with Aryl Halides and Trifluoromethanesulfonates Using Chiral Transition-Metal Catalysts . . . . . . . . . 655 Palladium- and Nickel-Catalyzed Arylation with Aryl Halides . . . . . . . . . . . . . . . . . 656 Palladium- and Nickel-Catalyzed Arylation with Aryl Trifluoromethanesulfonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658
3.15.3.3
Nickel-Catalyzed Arylations with Arylmetals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
3.15.3.3.1
Hiyama-Type Arylation of Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 660
3.15.3.3.2
Negishi-Type Arylation of Ketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661
3.15.3.3.3
Kumada-Type Arylation of Ketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
3.15.3.3.4
Suzuki-Type Arylation of Amides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
3.15.4
Vinylation of Enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
3.15.4.1
Vinylation of Enolates via Chiral Auxiliary Control . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
3.15.4.2
Vinylation of Enolates via Chiral Transition-Metal Catalysts . . . . . . . . . . . . . . . . . . 667
3.15.4.2.1
Palladium-Catalyzed Vinylation with Vinyl Halides . . . . . . . . . . . . . . . . . . . . . . . . . . 667
3.15.4.2.2
Nickel-Catalyzed Vinylation with Vinylsilanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
3.15.4.2.3
Nickel-Catalyzed Vinylation with Vinylzirconocenes . . . . . . . . . . . . . . . . . . . . . . . . . 669
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XXXIX
Æ-Functionalization of Carbonyl Compounds D. W. C. MacMillan and A. J. B. Watson
3.16
Æ-Functionalization of Carbonyl Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
3.16.1
Enamine-Mediated Enantioselective Aldol and Mannich Processes . . . . . . . . . . . 678
3.16.1.1
Aldol Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
3.16.1.1.1
Aldol Processes with Aldehyde Donors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
3.16.1.1.1.1
Intramolecular Aldol Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
3.16.1.1.1.2
Intermolecular Aldol Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
3.16.1.1.2
Aldol Processes with Ketone Donors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684
3.16.1.1.2.1
Intramolecular Aldol Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684
3.16.1.1.2.2
Intermolecular Aldol Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687
3.16.1.2
Mannich Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
3.16.1.2.1
Mannich Processes with Preformed Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
3.16.1.2.2
Direct (Three-Component) Mannich Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization . . . . . . . . . . . . . . . . . . . . 698
3.16.2.1
Æ-Halogenation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
3.16.2.1.1
Æ-Fluorination Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
3.16.2.1.2
Æ-Chlorination Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
3.16.2.1.3
Æ-Bromination Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
3.16.2.2
Æ-Oxidation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
3.16.2.2.1
Æ-Oxidation Reactions Using Nitrosobenzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
3.16.2.2.2
Æ-Oxidation Reactions Using Dibenzoyl Peroxide . . . . . . . . . . . . . . . . . . . . . . . . . . . 707
3.16.2.2.3
Æ-Oxidation Reactions Using Molecular Oxygen . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
3.16.2.3
Æ-Amination Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710
3.16.2.3.1
Æ-Amination Reactions Using Azodicarboxylates . . . . . . . . . . . . . . . . . . . . . . . . . . . 710
3.16.2.3.2
Æ-Amination Reactions Using Nitrosobenzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
3.16.2.4
Æ-Sulfanylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715
3.16.2.5
Æ-Selanylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
3.16.2.6
Æ-Alkylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717
3.16.2.6.1
Æ-Alkylation Reactions Using Alkyl Halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717
3.16.2.6.2
Æ-Alkylation Reactions Using Michael Acceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718
3.16.2.7
Æ-Arylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722
3.16.3
OrganoSOMO Mediated Enantioselective Æ-Functionalization . . . . . . . . . . . . . . . 724
3.16.3.1
Æ-Allylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725
3.16.3.2
Æ-Enolation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
3.16.3.3
Æ-Vinylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
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Æ-Homobenzylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728
3.16.3.5
Æ-Nitroalkylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729
3.16.3.6
Æ-Arylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
3.16.3.7
Æ-Oxidation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734
3.16.3.8
Æ-Chlorination Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735
3.16.4
Photoredox Organocatalysis Mediated Enantioselective Æ-Functionalization
3.16.4.1
Æ-Alkylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737
3.16.4.2
Æ-Perfluoroalkylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739
3.17
736
Baeyer–Villiger Reactions S. Levinger
3.17
Baeyer–Villiger Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 747
3.17.1
Chemical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748
3.17.1.1
Reactions Promoted by Chiral Metal Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748
3.17.1.2
Reactions Promoted by Organic Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750
3.17.1.3
Reactions Using Stoichiometric Chiral Oxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
3.17.2
Biochemical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752
3.17.2.1
Reactions Using Whole-Cell Cultures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752
3.17.2.2
Reactions Using Purified Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753
3.17.2.3
Reactions Using Engineered Organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 754
3.18
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides J. B. Johnson
3.18
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides . . . . . . . . . . . . . 759
3.18.1
Ring Opening of Epoxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759
3.18.1.1
Enantioselective Ring Opening of meso-Epoxides . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
3.18.1.1.1
Reaction with Oxygen Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
3.18.1.1.1.1
Using Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
3.18.1.1.1.2
Using Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761
3.18.1.1.1.3
Using Carboxylic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 763
3.18.1.1.2
Reaction with Nitrogen Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764
3.18.1.1.2.1
Using Amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764
3.18.1.1.2.2
Using Azides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
3.18.1.1.3
Reaction with Sulfur Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
3.18.1.1.4
Reaction with Halide Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
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3.18.1.1.5
Reaction with Carbon Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773
3.18.1.1.5.1
Using Indole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773
3.18.1.1.5.2
Using Cyanide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774
3.18.1.1.6
Reaction with Selenium Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775
3.18.1.1.7
Isomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776
3.18.1.2
Kinetic Resolution in Epoxide Ring-Opening Reactions . . . . . . . . . . . . . . . . . . . . . . 777
3.18.1.2.1
Reaction with Oxygen Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778
3.18.1.2.2
Reaction with Nitrogen Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779
3.18.1.2.3
Reaction with Chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781
3.18.1.2.4
Reaction with Carbon Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782
3.18.1.2.4.1
Using Indoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782
3.18.1.2.4.2
Using Stabilized Enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783
3.18.1.2.5
Isomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785
3.18.1.3
Stereospecific and Regioselective Ring Opening of Epoxides . . . . . . . . . . . . . . . . 786
3.18.1.3.1
Reaction with Oxygen Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786
3.18.1.3.2
Reaction with Nitrogen Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787
3.18.1.3.3
Reaction with Sulfur Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
3.18.1.3.4
Reaction with Halide Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
3.18.1.3.5
Reaction with Carbon Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
3.18.1.3.6
Reaction with Miscellaneous Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795
3.18.2
Ring Opening of Aziridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798
3.18.2.1
Enantioselective Ring Opening of meso-Aziridines . . . . . . . . . . . . . . . . . . . . . . . . . . 798
3.18.2.1.1
Reaction with Nitrogen Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798
3.18.2.1.1.1
Using Amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798
3.18.2.1.1.2
Using Azides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801
3.18.2.1.2
Reaction with Sulfur Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
3.18.2.1.3
Reaction with Chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 806
3.18.2.1.4
Reaction with Carbon Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 807
3.18.2.1.4.1
Using Cyanide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 807
3.18.2.1.4.2
Using Stabilized Enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809
3.18.2.2
Regioselective and Stereospecific Ring Opening of Aziridines . . . . . . . . . . . . . . . 810
3.18.2.2.1
Reaction with Oxygen Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
3.18.2.2.2
Reaction with Nitrogen Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
811
3.18.2.2.3
Reaction with Halide Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
812
3.18.2.2.4
Reaction with Sulfur Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
813
3.18.2.2.5
Reaction with Carbon Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 814
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3.18.2.2.6
Reaction with Miscellaneous Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 816
3.18.3
Ring Opening of Cyclic Anhydrides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 816
3.18.3.1
Reaction with Oxygen Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 817
3.18.3.2
Reaction with Sulfur Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819
3.18.3.3
Reaction with Carbon Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 820
3.19
Acylation of Alcohols and Amines T. Oriyama
3.19
Acylation of Alcohols and Amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829
3.19.1
Asymmetric Acylation of Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829
3.19.1.1
Kinetic Resolution of Racemic Secondary Alcohols by Catalytic Asymmetric Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829
3.19.1.1.1
Asymmetric Acylation with Anhydrides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 830
3.19.1.1.1.1
Asymmetric Acylation of Aryl Alkyl Carbinols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 831
3.19.1.1.1.2
Asymmetric Acylation of Allylic Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 832
3.19.1.1.1.3
Asymmetric Acylation of Propargylic Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 834
3.19.1.1.2
Asymmetric Acylation with Acid Chlorides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
3.19.1.1.3
Asymmetric Acylation with Carboxylic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838
3.19.1.2
Desymmetrization of meso-Diols by Catalytic Asymmetric Acylation . . . . . . . . . 840
3.19.1.2.1
Asymmetric Acylation of meso-1,2-Diols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840
3.19.1.2.2
Asymmetric Acylation of Symmetrical 1,3-Diols . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841
3.19.1.2.3
Asymmetric Acylation of cis-Cyclopent-4-ene-1,3-diols . . . . . . . . . . . . . . . . . . . . . 842
3.19.1.2.4
Asymmetric Acylation of meso-1,5-Diols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844
3.19.2
Asymmetric Acylation of Amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844
3.19.2.1
Asymmetric Acylation of Primary Amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844
3.19.2.2
Asymmetric Acylation of Secondary Amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846
3.20
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions V. Gouverneur and O. Lozano
3.20
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851
3.20.1
Stereoselective Fluorination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 852
3.20.1.1
Stereoselective Electrophilic Fluorination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 852
3.20.1.1.1
Diastereoselective Electrophilic Fluorination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 853
3.20.1.1.1.1
Preparation of Æ-Fluoro Ketones from Æ-Silyl Ketones . . . . . . . . . . . . . . . . . . . . . . 853
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3.20.1.1.1.2
Preparation of Æ-Fluoro Carboxylic Acids, -Fluoro Alcohols, Æ-Fluoro Aldehydes, Æ-Fluoro Ketones, and ª-Lactones from Carboxylic Acids
XLIII
855
3.20.1.1.1.3
Preparation of Æ-Fluoro Phosphonic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857
3.20.1.1.1.4
Preparation of Monofluoro Ketomethylene Dipeptide Isosteres . . . . . . . . . . . . . 859
3.20.1.1.1.5
Preparation of Allylic Fluorides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 860
3.20.1.1.1.6
Preparation of Fluorinated Tetrahydrofurans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
3.20.1.1.2
Enantioselective Electrophilic Fluorination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
3.20.1.1.2.1
Reagent-Controlled Enantioselective Fluorination . . . . . . . . . . . . . . . . . . . . . . . . . . 863
3.20.1.1.2.1.1
Preparation of Æ-Fluorinated Æ-Cyano Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864
3.20.1.1.2.1.2
Preparation of Fluorinated Keto Esters, Indolones, and Allylsilanes . . . . . . . . . . . 865
3.20.1.1.2.2
Catalytic Enantioselective Fluorination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867
3.20.1.1.2.2.1
Catalytic Asymmetric Fluorination Mediated by Chiral Metal Complexes . . . . . 868
3.20.1.1.2.2.1.1
Fluorination of -Keto Esters and Lactones with Palladium Catalysts . . . . . . . . . 869
3.20.1.1.2.2.1.2
Fluorination of -Oxo Phosphonates with Palladium Catalysts . . . . . . . . . . . . . . . 870
3.20.1.1.2.2.1.3
Fluorination of Æ-Cyano tert-Butyl Esters with Palladium Catalysts . . . . . . . . . . . 871
3.20.1.1.2.2.1.4
Fluorination of Indolones with Palladium Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . 872
3.20.1.1.2.2.1.5
Fluorination of Æ-Aryl Acetic Acid Derivatives with Nickel Catalysts . . . . . . . . . . 873
3.20.1.1.2.2.1.6
Enantioselective Fluorination of 1,3-Dicarbonyl Derivatives Capable of Two-Point Binding with Nickel Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . 874
3.20.1.1.2.2.1.7
Sequential Nazarov–Fluorination with Copper Catalysts . . . . . . . . . . . . . . . . . . . . . 876
3.20.1.1.2.2.2
Catalytic Enantioselective Fluorination Mediated by Organocatalysts . . . . . . . . 878
3.20.1.1.2.2.2.1
Organocatalytic Fluorination of Aldehydes: Preparation of Æ-Fluoro Aldehydes, -Fluoro Alcohols, and Propargylic Fluorides . . . . . . . . . . . 878
3.20.1.1.2.2.2.2
Catalytic Asymmetric Fluorodesilylation of Allylsilanes, Silyl Enol Ethers, and Indolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881
3.20.1.1.2.2.2.3
Preparation of Fluorinated Flavanones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884
3.20.1.1.2.2.2.4
Asymmetric Fluorination with Chiral Bifunctional Phase-Transfer Catalysts . . . 885
3.20.1.1.2.2.3
3.20.1.2 3.20.1.2.1
Catalytic Enantioselective Fluorination Mediated by Metals and Organocatalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 887 Stereoselective Nucleophilic Fluorination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 888 Prins Cyclization To Access Fluorinated Tetrahydrothiopyrans, Thiacyclohexanes, and Piperidines . . . . . . . . . . . . . . . . . . . 888
3.20.1.2.2
Catalytic Asymmetric Ring Opening of Achiral Epoxides . . . . . . . . . . . . . . . . . . . . . 889
3.20.2
Stereoselective Fluoroalkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891
3.20.2.1
Monofluoromethylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891
3.20.2.1.1
Diastereoselective Nucleophilic Monofluoromethylation . . . . . . . . . . . . . . . . . . . . 892
3.20.2.1.1.1
Preparation of Chiral Æ-Monofluoromethyl Amines Using Fluoromethyl Phenyl Sulfone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 892
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3.20.2.1.2
Catalytic Enantioselective Nucleophilic Monofluoromethylation . . . . . . . . . . . . . 895
3.20.2.1.2.1
Preparation of Æ-Monofluoromethylated Amines . . . . . . . . . . . . . . . . . . . . . . . . . . . 895
3.20.2.1.2.2
Preparation of -Monofluoromethylated Ketones and ª-Monofluoromethylated Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897
3.20.2.1.2.3
Asymmetric Allylic Monofluoromethylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 900
3.20.2.2
Difluoromethylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 902
3.20.2.2.1
Diastereoselective Nucleophilic Difluoromethylation . . . . . . . . . . . . . . . . . . . . . . . 903
3.20.2.2.1.1
Preparation of Homochiral Æ- and -Difluoromethyl Amines . . . . . . . . . . . . . . . . 903
3.20.2.2.1.2
Preparation of Chiral Difluoromethylated 1,3-Diols . . . . . . . . . . . . . . . . . . . . . . . . . 908
3.20.2.2.2
Electrophilic and Radical Difluoromethylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909
3.20.2.3
Trifluoromethylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910
3.20.2.3.1
Diastereoselective Nucleophilic Trifluoromethylation . . . . . . . . . . . . . . . . . . . . . . . 910
3.20.2.3.1.1
Trifluoromethylation of Carbohydrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910
3.20.2.3.1.2
Trifluoromethylation of Steroidal Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.20.2.3.1.3
912
Asymmetric Synthesis of Trifluoromethylated Aldehydes, Diols, Amino Alcohols, and Triols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914
3.20.2.3.1.3.1
Trifluoromethylated Aldehydes, 1,2-Diols, and 1,2-Amino Alcohols . . . . . . . . . . 914
3.20.2.3.1.3.2
Asymmetric Synthesis of 2-(Trifluoromethyl)-1,2,3-triols . . . . . . . . . . . . . . . . . . . . 916
3.20.2.3.1.4
Asymmetric Synthesis of Trifluoromethylated Amines and Diamines . . . . . . . . . 918
3.20.2.3.2
Enantioselective Trifluoromethylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 920
3.20.2.3.2.1
Nucleophilic Trifluoromethylation of Aryl Ketones, Aryl Aldehydes, and Azomethine Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 920
3.20.2.3.2.2
Electrophilic Trifluoromethylation of -Keto Esters . . . . . . . . . . . . . . . . . . . . . . . . . 923
3.20.2.3.2.3
Asymmetric Radical Æ-Trifluoromethylation of Aldehydes . . . . . . . . . . . . . . . . . . . 924
3.21
3.21 3.21.1
Stereoselective Polymerization J.-F. Carpentier and E. Kirillov Stereoselective Polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931 Stereoselective Polymerization of Propene: Isotactic Polypropene; Syndiotactic Polypropene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931
3.21.1.1
Isotactic Polypropene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 932
3.21.1.2
Syndiotactic Polypropene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 933
3.21.2
Stereoselective Polymerization of Higher Alk-1-enes: Isotactic Poly(hex-1-ene) and Poly(oct-1-ene); Syndiotactic Poly(hex-1-ene) and Poly(oct-1-ene) . . . . . . 934
3.21.2.1
Isotactic Poly(alk-1-ene)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
3.21.2.2
Syndiotactic Poly(alk-1-ene)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
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3.21.3
XLV
Stereoselective (Co)Polymerization of Styrene: Isotactic and Syndiotactic Polystyrenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
3.21.3.1
Isotactic Polystyrene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937
3.21.3.2
Syndiotactic Polystyrene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 938
3.21.4
Stereoselective Polymerization of Cycloalkenes: alt-cis/trans-1,3-Poly(cyclopentene) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 939
3.21.4.1
Polycycloalkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 939
3.21.4.1.1
Poly(cyclopentene)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 940
3.21.5
Stereoselective Polymerization of Linear Conjugated Dienes: cis- and trans-1,4-Polybutadiene and -Polyisoprene; Syndiotactic 1,2-Polybutadiene; Isotactic 3,4-Polyisoprene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
3.21.5.1
cis-1,4-Polybutadiene and -Polyisoprene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942
3.21.5.2
trans-1,4-Polybutadiene and -Polyisoprene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942
3.21.5.3
Syndiotactic 1,2-Polybutadiene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943
3.21.5.4
Isotactic 3,4-Polyisoprene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943
3.21.6
Stereoselective Polymerization of Cyclic Conjugated Dienes: cis-1,4-Poly(cyclohexa-1,3-diene) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 944
3.21.7
Stereoselective Cyclopolymerization of Nonconjugated Dienes: Isotactic and Syndiotactic cis/trans-Poly(hexa-1,5-diene) . . . . . . . . . . . . . . . . . . . . 945
3.21.7.1 3.21.8
Poly(methylene-1,3-cyclopentane) from Hexa-1,5-diene . . . . . . . . . . . . . . . . . . . . 946 Stereoselective Ring-Opening Metathesis Polymerization of Cyclic Alkenes: cis-Isotactic and cis-Syndiotactic Poly(norbornene) and Poly(endo-dicyclopentadiene); Tactic trans-Poly(3-substituted cyclopropene) . . . . . . . . . . . . . . . . . 947
3.21.8.1
Polymers of Cyclic Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 947
3.21.8.1.1
Poly(norbornene)s and Poly(norbornadiene)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 947
3.21.8.1.2
Poly(endo-dicyclopentadiene)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 949
3.21.8.1.3
Poly(3-substituted cyclopropene)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951
3.21.9
Stereoselective Polymerization of Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951
3.21.9.1
Poly(acetylene) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 952
3.21.9.2
Substituted Poly(acetylene)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 953
3.21.10
Stereoselective Copolymerization of Alk-1-enes and Carbon Monoxide: Isotactic and Syndiotactic Polyketones Derived from Propene and Styrene . . . 954
3.21.10.1
Polyketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 954
3.21.10.1.1
Isotactic Poly(propene-alt-carbon monoxide) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955
3.21.10.1.2
Isotactic and Syndiotactic Poly(styrene-alt-carbon monoxide)s . . . . . . . . . . . . . . 956
3.21.11
3.21.11.1
Stereoselective Polymerization of Acrylates: Syndiotactic, Isotactic, and Heterotactic Poly(alkyl methacrylate)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 957 Isotactic Poly(alkyl methacrylate)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 958
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3.21.11.2
Syndiotactic Poly(alkyl methacrylate)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
958
3.21.11.3
Heterotactic Poly(alkyl methacrylate)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
959
Stereoselective Polymerization of Racemic and Meso Epoxides and Their Copolymerization with Carbon Dioxide: Optically Active Isotactic Polyethers and Polycarbonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
960
3.21.12.1
Isotactic Polyethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
961
3.21.12.2
Stereoregular Polycarbonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
963
3.21.12.2.1
Isotactic Poly(cycloalkene carbonate)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
963
3.21.12.2.2
Syndiotactic Poly(cycloalkene carbonate)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
963
Stereoselective Ring-Opening Polymerization of Lactones: Isotactic, Stereoblock, Syndiotactic, and Heterotactic Poly(lactide)s; Syndiotactic Poly(3-Hydroxybutanoate) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
964
3.21.13.1
Poly(lactide)s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
964
3.21.13.1.1
Isotactic Poly(lactide) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
965
3.21.13.1.2
Stereoblock Isotactic Poly(lactide) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
965
3.21.13.1.3
Syndiotactic Poly(lactide) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
966
3.21.13.1.4
Heterotactic Poly(lactide) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
967
3.21.13.2
Poly(3-hydroxybutanoate) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
967
3.21.12
3.21.13
3.22
Oxidation of Sulfides A. Lattanzi
3.22
Oxidation of Sulfides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
973
3.22.1
Oxidation of Sulfides Using Achiral Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
974
3.22.2
Chiral Metal Complex Catalyzed Oxidation of Sulfides . . . . . . . . . . . . . . . . . . . . .
976
3.22.2.1
Catalysis Using Titanium/Chiral Diols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
976
3.22.2.1.1
Using Titanium(IV) Isopropoxide/(R,R)-Diethyl Tartrate . . . . . . . . . . . . . . . . . . . .
976
3.22.2.1.2
Using Titanium(IV) Isopropoxide/1,1¢-Bi-2-naphthol or Diols . . . . . . . . . . . . . . . .
984
3.22.2.1.3
Using Titanium(IV) Isopropoxide/Chiral Alkyl Hydroperoxides . . . . . . . . . . . . . .
988
3.22.2.2
Catalysis Using Titanium/Chiral Schiff Base Ligands . . . . . . . . . . . . . . . . . . . . . . . .
989
3.22.2.3
Catalysis Using Vanadium/Chiral Schiff Base Ligands . . . . . . . . . . . . . . . . . . . . . . .
991
3.22.2.4
Catalysis Using Iron/Chiral Schiff Base Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
995
3.22.2.5
Catalysis Using Aluminum/Salalen-Based Ligands . . . . . . . . . . . . . . . . . . . . . . . . . .
999
3.22.2.6
Catalysis Using Chiral Molybdenum- and Niobium-Based Catalysts . . . . . . . . . 1000
3.22.3
Organocatalytic Oxidation of Sulfides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1002
3.22.3.1
Using Chiral Oxaziridines and Oxaziridinium Salts . . . . . . . . . . . . . . . . . . . . . . . . . . 1002
3.22.3.2
Using a Chiral Ketone/Oxone System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1004
3.22.4
Biological Oxidation of Sulfides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005
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3.22.4.1
Oxidation Using Isolated Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1006
3.22.4.1.1
Using Peroxidases and Monooxygenases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1006
3.22.4.2
Oxidation Using Whole-Cell Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010 Keyword Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017 Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1081 Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction P. A. Evans
Chirality plays an important role in almost every aspect of modern day life, which in turn provides the impetus to develop new methods for the construction of chiral molecules. The stereoselective construction of specific molecular entities has traditionally been most relevant to the biological arena, since in general only one stereoisomer can interact with a receptor. More recently, the stereoselective construction of new materials has also provided an opportunity to showcase these methods, given that modifications in stereochemistry can significantly impact the properties of a macromolecule. Thus, methods that provide access to chiral entities in an expeditious manner are critical to the continued development of these and related areas of research. Nevertheless, the ability to prepare an enantiomerically enriched starting material was particularly challenging less than 30 years ago, and almost completely reliant on chiral-pool starting materials and tedious chiral resolutions. The introduction of chiral auxiliaries was an important development in the diversification of enantiomerically enriched starting precursors; however, the necessity to covalently attach and remove the auxiliary to facilitate a specific reaction is suboptimal in terms of efficiency and atom economy. Furthermore, the installation of additional stereocenters generally relies on simple diastereocontrol, which has the potential for additional problems with respect to controlling the formation of a specific diastereomer. The advent of asymmetric catalysis provides two fundamentally important advantages. Firstly, it enables efficient access to a variety of chiral nonracemic intermediates without the necessity for a chiral auxiliary, chiral-pool intermediate, or chiral resolution, and secondly it can often reverse the inherent preference of simple diastereoselection, thereby providing access to both diastereomers. Volume 3 of Stereoselective Synthesis is devoted to stereoselective pericyclic reactions, cross coupling, and C—H and C—X activation, where the major emphasis is on enantioselective reactions using asymmetric catalysts. As in the companion volumes, the chapters provide a summary of the optimal methods in terms of reaction efficiency, generality, selectivity, and the impact on the environment, rather than a comprehensive review of the area. The inclusion of specific examples from the synthesis of various natural and unnatural targets validates the utility of the various synthetic methods, and provides the reader with context and confidence in the relevance of a particular method. Thus, this three-volume series should provide an invaluable resource to the practicing synthetic organic chemist. The first four chapters in the volume focus on stereoselective cycloaddition reactions. For instance, the first chapter by G.-J. Jiang, Y. Wang, and Z.-X. Yu (Section 3.1) outlines the critical developments in [m + n]-cycloaddition reactions, excluding [4 + 2] reactions. This chapter summarizes several excellent procedures for the stereoselective construction of four-, five-, six-, seven-, and nine-membered rings, with the omission of eightmembered and larger rings due to the lack of enantioselective variants. Each section details the optimal methods in terms of chemo-, regio-, diastereo-, and enantioselectivity using a range of chiral catalysts. In a continuation of this theme, K. Ishihara and A. Sakakura describe the important advances in asymmetric [4 + 2] cycloadditions, or Diels–Alder reactions (Section 3.2). This chapter outlines the optimal chiral Lewis acids, Brønsted acids, and related organocatalysts for the enantioselective Diels–Alder and hetero-Diels– Stereoselective Pericyclic Reactions, Cross Coupling, and C—H and C—X Activation, Evans, P. A. Science of Synthesis 4.0 version., Section 3 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Alder reaction. A particularly attractive feature of this section is the detail given to the mechanistic implications of using a specific catalyst. The subsequent chapter by T. Shibata (Section 3.3) outlines the stereoselective, metal-catalyzed [2 + 2 + 1] carbocyclizations, or Pauson–Khand (PK) reactions, using an array of transition-metal complexes. This section also includes examples of sequential processes involving either one or two catalysts, which facilitate an allylic substitution followed by a diastereoselective Pauson–Khand reaction. Finally, the higher homologues of the Pauson–Khand reaction, namely the [m + n + 1] reactions (where m = 3–5 and n = 2 and 4), which facilitate the construction of larger rings, complete this account. In the final chapter on cycloaddition reactions, C. Aubert, M. Malacria, and C. Ollivier provide a comprehensive overview of stereoselective, metalcatalyzed, higher-order [m + n + 2]-carbocyclization reactions (Section 3.4). The chapter is organized in terms of the type of carbocyclization (where m = 2–4 and n = 2), the metal complex employed, and the degree of unsaturation, which translates into regio-, diastereo-, and enantioselectivity. The section on metal-catalyzed [2 + 2 + 2] reactions dominates the review with seminal advances in both stoichiometric and catalytic reactions, which include applications to several challenging and important total syntheses. Finally, a detailed discussion of both [3 + 2 + 2] and [4 + 2 + 2] metal-catalyzed carbocyclizations completes this chapter and provides a perspective on the future direction of this particular area. Rearrangement reactions are important processes for the construction of one or more stereogenic centers from achiral intermediates. I. D. G. Watson and F. D. Toste provide a detailed account of the development of asymmetric cycloisomerization reactions, which facilitate the atom-economical construction of complex structural motifs with a high degree of chemo-, regio-, diastereo-, and enantioselectivity (Section 3.5). This chapter outlines the reactions of enynes, diynes, dienes, and allenenes with various chiral and achiral metal complexes, and includes relevant applications to target-directed synthesis. The focus is primarily on simple diastereocontrol; however, there are examples that employ chiral auxiliaries and catalysts. The final part of the chapter is a summary of related processes, namely ene, hydroacylation, and hydrosilylation reactions. In a continuation of this theme, M. Terada summarizes the important developments in intra- and intermolecular ene reactions using various enophiles (aldehydes, ketones, alkynes, etc.) in the context of diastereo- and enantioselectivity (Section 3.6). Related reactions with enamides and enecarbamates as the ene components, in conjunction with imines and diazo derivatives as the enophiles, are described in activated and unactivated systems to afford acyclic and cyclic amines. In the next chapter, J. Zeh and M. Hiersemann describe more classical sigmatropic rearrangements, namely the Claisen, Cope, and Wittig rearrangements, with specific applications to target-directed synthesis (Section 3.7). For example, various heteroatom and named adaptations of the Claisen rearrangement are described (e.g., the Carroll, Eschenmoser, Ireland, and Johnson reactions) and, although there are similar versions of the Cope reaction, there are surprisingly few adaptations of the Wittig rearrangement. Each of the reactions in this chapter is restricted to diastereocontrol using chiral auxiliaries and existing stereogenic centers. In the last chapter covering rearrangements, B. Gaspar and D. Trauner provide an overview of electrocyclic reactions, which have several important applications in total synthesis (Section 3.8). The first part of this chapter describes the construction of cyclobutenes and their electrocyclic ring-opening reactions, whereas the next section describes diastereo- and enantioselective Nazarov-cyclization reactions, including examples of the interrupted version. The final part of this chapter outlines a series of 6- and 8-electrocyclization reactions with either a chiral auxiliary or organocatalyst, and the implementation of these transformations in a series of cascade cyclization sequences to form polycyclic systems. Allylic rearrangement and functionalization reactions provide the theme for the next section of the volume. The first chapter in this section, by M. L. Crawley, details the venerable metal-catalyzed allylic substitution reaction, primarily in the context of intermoStereoselective Pericyclic Reactions, Cross Coupling, and C—H and C—X Activation, Evans, P. A. Science of Synthesis 4.0 version., Section 3 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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3
lecular C—C, C—N, and C—O bond construction using an array of transition-metal catalysts for the synthesis of important targets (Section 3.9). A compelling feature of the chapter is the classification of the reactions into one of the three mechanistic pathways, namely enantioselective, dynamic kinetic resolution, and stereospecific processes. Each reaction represents a specific example from a synthetic application which proceeds with high yield, turnover, and selectivity. Notably, the section on C—C bond formation highlights the recent developments with unstabilized carbon nucleophiles, which provide a convenient method for the asymmetric construction of acyclic tertiary and quaternary carbon stereogenic centers. S. Jautze and R. Peters continue this theme with a series of Lewis acid catalyzed and promoted enantioselective isomerization reactions that provide one or more stereogenic centers (Section 3.10). The chapter is divided into [3,3]- and [2,3]sigmatropic rearrangements, which can be combined in several very interesting domino processes. The first part of the chapter details the most significant enantioselective [3,3]rearrangement reactions for the asymmetric construction of allylic amines using electrophilic chiral metal complexes. The [2,3]-rearrangement reactions complement this reaction with the asymmetric construction of homoallylic amines containing two stereogenic centers. Other rearrangement reactions include the isomerization of allylic amines and alcohols to the corresponding enantiomerically enriched enamines and aldehydes. This chapter also outlines the asymmetric Wagner–Meerwein rearrangement for the preparation of enantiomerically enriched cyclopentanones. Finally, the combination of rearrangement reactions with other transformations provides domino reaction sequences that facilitate the construction of several stereogenic centers in a single operation. The last chapter in this part, by M. B. Andrus, provides an overview of allylic and benzylic oxidation reactions with a stoichiometric or catalytic mediator in the presence of a terminal oxidant (Section 3.11). The first part summarizes some of the critical developments using selenium dioxide and palladium complexes to afford allylic alcohols, and includes several diastereoselective examples. This naturally leads into discussion of the enantioselective Kharasch oxidation using chiral copper complexes, which provides enantiomerically enriched allylic esters. Another notable aspect of this section is the oxidation of alkenes to Æ,-unsaturated ketones using palladium and rhodium complexes. The chapter concludes with benzylic oxidations to provide benzylic alcohols and esters, including reactions that provide the higher oxidation state, namely aldehydes and lactones, in an analogous manner to the previous section. The next part of the volume focuses on the asymmetric construction of C—C bonds through cross-coupling and C—H bond functionalization reactions. The first contribution in this section by M. Shibasaki, T. Ohshima, and W. Itano provides an overview of interand intramolecular Mizoroki–Heck reactions, which represent a convenient method for the construction of substituted alkenes and stereogenic centers (Section 3.12). A particularly attractive feature of this chapter is the discussion of the mechanistic implication of neutral and cationic metal complexes on selectivity, which provides the rationale for selecting the optimal reaction conditions for a specific transformation. For example, the first part of the chapter describes a series of intermolecular addition reactions with electron-deficient and electron-rich alkenes, which includes chelation-controlled and asymmetric reactions. The last part of the chapter deals with intramolecular variants, which provide a convenient method for the asymmetric construction of tertiary and quaternary stereogenic centers, including spirocycles. In a continuation of this theme, H. M. L. Davies and D. Morton describe asymmetric C—C bond formation by C—H bond activation reactions (Section 3.13). The chapter is subdivided into intra- and intermolecular reactions, which detail both diastereo- and enantioselective variants. For instance, the first section describes the challenges associated with stereoselective intramolecular insertion reactions with diazocarbonyl compounds. It also documents more recent studies that involve direct C—H functionalization using directing groups. The last section of this chapter provides a summary of important intermolecular C—H functionalization reactions, which Stereoselective Pericyclic Reactions, Cross Coupling, and C—H and C—X Activation, Evans, P. A. Science of Synthesis 4.0 version., Section 3 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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provide a conceptually different method for asymmetric C—C bond formation. Notably, allylic systems provide an opportunity to combine C—H functionalization with rearrangement reactions to provide vicinal stereogenic centers in a series of novel domino processes. The final chapter in this section, by M. Shimizu and T. Hiyama, provides an overview of more classical stereoselective cross-coupling reactions (Section 3.14). The chapter initially outlines the recent advances in diastereo- and enantioselective sp3-cross-coupling reactions and the stereocontrolled construction of polyfunctionalized alkenes, namely triand tetrasubstituted alkenes. The subsequent discussion on asymmetric allylic cross-coupling reactions details an alternative approach to reactions that proceed via a more classical -allyl intermediate. Finally, the chapter concludes with reactions that result in axial chirality, namely the construction of enantiomerically enriched allenes and biaryl derivatives. The stereocontrolled Æ-functionalization of carbonyl compounds provides an important and versatile process in target-directed synthesis. The first contribution in this section, by B. M. Stoltz and J. T. Mohr, provides a detailed account of the development of asymmetric reactions of enolates in the context of chemo-, regio-, diastereo-, and enantioselectivity (Section 3.15). The first section in the chapter outlines the important advances in the asymmetric protonation of enolates using enzymes, which nicely complements the related processes using chiral proton donors and acceptors. The remaining portion of the chapter outlines various asymmetric alkylation reactions according to the type of alkylation (e.g., alkylation, arylation, or vinylation) and the mode of asymmetric induction. In this context, chiral auxiliaries derived from carboxylates and ketones provide a reliable method for the stereoselective enolate alkylation reaction. However, the asymmetric transition-metal-catalyzed enolate alkylation reactions represent the highlight of this chapter. For instance, the asymmetric Tsuji–Trost allylation of allyl enol carbonates and trialkylsilyl enol ethers provides a direct method for the construction of a variety of tertiary and quaternary carbon stereogenic centers. Additionally, the asymmetric arylation and vinylation of enolates, using chiral auxiliaries and transition-metal catalysts, expands the limited repertoire of electrophiles available for alkylations. D. W. C. MacMillan and A. J. B. Watson describe an alternative approach to the asymmetric Æ-functionalization of carbonyl compounds, which does not involve the formation of an enolate (Section 3.16). The first section of this chapter describes the enamine-mediated enantioselective intraand intermolecular Aldol and Mannich reactions with both aldehyde and ketone donors. The next section on enantioselective enamine-mediated halogenation, oxygenation, amination, sulfanylation, selanylation, alkylation, and arylation reactions provides an important aspect of this chapter. For instance, the discussion of the conceptually novel OrganoSOMO and photoredox reactions provides a direct comparison with the enamine process. A particularly noteworthy outcome from the photoredox reaction is the ability to affect alkylations, which have proven particularly challenging for enamine catalysis. The next section of the volume combines three methods that facilitate the preparation of enantiomerically enriched alcohols, amines, and esters, albeit through entirely different methods. The first chapter in this section, by S. Levinger, details the venerable Baeyer–Villiger oxidation in the context of asymmetric reactions that employ both chemical and biochemical methods (Section 3.17). For example, the first part of the section covers asymmetric oxidation reactions with chiral transition-metal catalysts and organocatalysts using racemic and prochiral ketones, which includes reactions that utilize stoichiometric chiral oxidants. The next part of this chapter provides an outline of asymmetric oxidation reactions using whole cells and purified enzymes, with additional discussion on engineering organisms to facilitate specific reactions. The latter part is particularly relevant given the growing emphasis and reliance on enzyme-catalyzed reactions in industry. In the subsequent chapter, J. B. Johnson provides a detailed account of the development of asymmetric ring-opening reactions of epoxides, aziridines, and cyclic anhydrides using a range of carbon and heteroatom nucleophiles (Section 3.18). The first Stereoselective Pericyclic Reactions, Cross Coupling, and C—H and C—X Activation, Evans, P. A. Science of Synthesis 4.0 version., Section 3 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
Introduction
5
section of this chapter details the enantioselective ring opening of meso-epoxides with oxygen, nitrogen, sulfur, selenium, halide, and carbon nucleophiles, including ring-opening isomerization reactions. This leads into the discussion of related processes, namely kinetic resolution and stereospecific ring-opening reactions using many of the same nucleophiles. The next section in the chapter describes the analogous ring-opening reactions with aziridines, albeit without the dynamic kinetic resolution, and the enantioselective ring opening of cyclic anhydrides with oxygen, sulfur, and carbon nucleophiles. The final chapter in this section, by T. Oriyama, provides a summary of the asymmetric acylation of alcohols and amines (Section 3.19). The main focus of this contribution is on the kinetic resolution of secondary alcohols, which includes the reactions of aryl, allylic, and propargylic alcohols with a range of anhydrides, carboxylic acids, and acid chlorides. The chapter concludes with the desymmetrization of meso-diols and prochiral diols and the asymmetric acylation of primary amines and secondary amides. The fluorination of organic molecules, particularly in a stereoselective manner, represents a particularly important and vibrant area of research. V. Gouverneur and O. Lozano provide a comprehensive discussion of various stereoselective fluorination reactions, which provides an invaluable resource for selecting the optimal method to install this important functionality (Section 3.20). The chapter initially describes the diastereoselective electrophilic fluorination of enolates and allylsilanes, using chiral auxiliaries, reagents, metal catalysts, and organocatalysts. Alternatively, the diastereo- and enantioselective nucleophilic addition of fluorine, in the context of ring-forming and ring-opening reactions, nicely complements the previous section on electrophilic processes. The chapter continues with stereoselective fluoroalkylation using a series of carbon nucleophiles for the introduction of one, two, or three fluorine atoms. This transformation involves diastereoselective addition to imines, Æ,-unsaturated ketones, allylic acetates, aldehydes, and ketones. The chapter concludes with enantioselective trifluoromethylation using nucleophilic and electrophilic reagents. The stereoselective construction of polymers is a particularly important area of investigation, given the growing importance of tailoring specific properties in macromolecules. J.-F. Carpentier and E. Kirillov describe the optimal methods and catalysts that facilitate stereoselective polymerization reactions (Section 3.21). The first part of this chapter details the stereoselective construction of isotactic and syndiotactic polypropene, as well as the polymerization of higher alkenes, styrene, and cyclic and strained alkenes, including conjugated and nonconjugated dienes. The next section of the chapter outlines the polymerization of alkynes to provide poly(acetylene)s and the copolymerization of alkenes with carbon monoxide to provide isotactic and syndiotactic polyketones. In contrast, the polymerization of acrylates provides isotactic, syndiotactic, and heterotactic poly(alkyl methacrylate)s, which contain a quaternary stereogenic center. Alternatively, the polymerization of racemic and meso-epoxides, which includes the copolymerization with carbon dioxide, provides isotactic polyethers and polycarbonates. Finally, the stereoselective ring opening of lactones provides a convenient approach to a range of poly(lactide)s. The final chapter in the volume, by A. Lattanzi, describes the stereoselective oxidation of sulfides, including disulfides (Section 3.22). The chapter initially outlines the diastereoselective oxidation of sulfides with a variety of achiral oxidants. This provides context for the subsequent discussion on asymmetric oxidation reactions using chiral metal catalysts and organocatalysts. For instance, the asymmetric oxidation of sulfides can be accomplished using a chiral metal catalyst in conjunction with an achiral oxidant and vice versa. In contrast, oxidation reactions with an organocatalyst are generally accomplished with a stoichiometric reagent, with the exception of the chiral ketone/Oxone system, which is substoichiometric. The final section in the chapter outlines the oxidation of sulfides using purified enzymes and whole cell systems, which is becoming increasingly relevant for industrial applications as previously noted. Stereoselective Pericyclic Reactions, Cross Coupling, and C—H and C—X Activation, Evans, P. A. Science of Synthesis 4.0 version., Section 3 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
6
Stereoselective Synthesis
Introduction
In conclusion, I would like to acknowledge Phillip A. Inglesby, Sean Ng, Ryan OConnor, and Samuel Oliver for their assistance in the proofreading of the chapters. I also thank my lovely wife Katie for her unconditional love and support during this important and time-consuming project. Finally, I am deeply indebted to the authors for their respective contributions, which enabled the successful completion of this volume as previously noted.
Stereoselective Pericyclic Reactions, Cross Coupling, and C—H and C—X Activation, Evans, P. A. Science of Synthesis 4.0 version., Section 3 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
7 3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2]) G.-J. Jiang, Y. Wang, and Z.-X. Yu
General Introduction
The [m + n]-cycloaddition reaction provides an important method to construct an array of cyclic compounds. These reactions can generate up to four new stereogenic centers in one pot, providing an important complexity-building process for target-directed synthesis. In this review, asymmetric [m + n] cycloadditions for the construction of four- to nine-membered rings are described. Due to page limitation, the asymmetric [m + n]-cycloaddition reactions discussed are those that either use transition-metal catalysts or organocatalysts as the chiral sources. The [m + n] reactions using chiral substrates or chiral auxiliaries, which are also powerful in preparing stereochemically pure cyclic compounds, will not be described. The preparation of three-membered compounds[1–11] such as cyclopropanes, epoxides, and aziridines that may formally constitute [2 + 1]-cycloaddition reactions, are discussed elsewhere in Stereoselective Synthesis, in particular Sections 1.2, 1.3, and 2.6 (epoxidation), Section 1.4 (aziridination), and Section 1.14 (cyclopropanation). The sections in this review are organized according to the size of ring formed, beginning with the asymmetric construction of four-membered rings and ending with ninemembered rings. Each of the sections is subdivided based on the type of process. For example, the [2 + 2] cycloadditions are divided into transition-metal-catalyzed (Section 3.1.1.1) and organocatalytic (Section 3.1.1.2) methods. Five-membered rings may be formed by asymmetric [3 + 2] (Sections 3.1.2) and [4 + 1] (Section 3.1.3) cycloadditions. In Section 3.1.2, the chiral phosphine catalyzed [3 + 2] cycloadditions of allenic esters with various dienophiles are described (Section 3.1.2.1), followed by palladium-catalyzed asymmetric [3 + 2] cycloadditions using trimethylenemethane (TMM) (Section 3.1.2.2). The synthesis of five-membered heterocycles via asymmetric 1,3-dipolar cycloaddition reactions will not be described herein.[12–14] Asymmetric [4 + 2] cycloadditions are discussed in detail in Section 3.2. The only method relevant to the construction of six-membered rings described in the present review is the asymmetric [3 + 3]-cycloaddition reaction (Section 3.1.4). For the asymmetric synthesis of seven-membered compounds, several examples of asymmetric [4 + 3] cycloaddition (Section 3.1.5) and two examples of [5 + 2] reactions (Section 3.1.6) are described. Even though chiral eight-membered rings are ubiquitous in many natural products, highly and generally enantioselective [m + n] syntheses of these privileged skeletons have not been described.[15] An example of the asymmetric synthesis of nine-membered rings, using the asymmetric [6 + 3] cycloaddition of trimethylenemethane is, however, discussed in Section 3.1.7. Finally, although there are several [8 + 2] reactions, which provide ten-membered rings, an asymmetric version has not been described.[16,17] Despite the prevalence of large-ring compounds in natural products and pharmaceuticals, asymmetric [m + n]-cycloaddition reactions for the preparation of larger rings are not well developed.
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for references see p 63
8
Stereoselective Synthesis
3.1.1
[2 + 2]-Cycloaddition Reactions
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
There are formally two types of [2 + 2] cycloaddition, namely, transition-metal-catalyzed and organocatalyzed reactions. For example, the transition-metal-catalyzed [2 + 2] cycloadditions of alkenes and alkynes that provide cyclobutanes and cyclobutenes are effective since the metal activates the alkene, alkyne, or diene and thereby significantly enhances its reactivity.[18–20] More importantly, not only are rate enhancements observed in the presence of the metal catalysts, but also the potential for asymmetric transformations by merely changing the achiral ligands. This is in contrast to the [2 + 2]-cycloaddition reactions of unactivated alkenes, alkynes, and dienes, since they usually require high temperatures and pressures, which limits the reaction to ketenes and electron-deficient alkenes. 3.1.1.1
[2 + 2] Cycloadditions Catalyzed by Transition Metals
Transition-metal-catalyzed cycloadditions can be broadly categorized into two types of reactions. The first is where the transition metals act as Lewis acids to activate the substrates, and the second involves the formation of metallacycle intermediates using the redox manifold of the metal complex. 3.1.1.1.1
Chiral Titanium Catalysts
A particularly impressive Lewis acid catalyzed method for the construction of chiral cyclobutane skeletons has been described by Narasaka, using the chiral complex 1 (Scheme 1) generated in situ from dichlorodiisopropoxytitanium(IV) and a chiral 1,4-diol derived from tartrate.[21] This complex facilitates the combination of alkenes that contain an alkylsulfanyl group (e.g., ketene dithioacetals, alkenyl sulfides, alkynyl sulfides, and allenyl sulfides) with electron-deficient alkenes to afford the corresponding cyclobutane, cyclobutene, and methylenecyclobutane derivatives in high yield and with excellent enantioselectivity. Methyl (E)-4-oxo-4-(2-oxooxazolidin-3-yl)but-2-enoate (2) is a common dienophile for the titanium-catalyzed asymmetric Diels–Alder reaction.[22–24] Treatment of ester 2 and ketene dithioacetal 3 (R1 = Me) with only 10 mol% of the chiral titanium catalyst 1 at 0 8C in a mixture of toluene and petroleum ether in the presence of molecular sieves (4 ) affords exclusive formation of the cyclobutane derivative 4 (R1 = Me) in nearly enantiomerically pure form (98% ee). The [2 + 2]-cycloaddition reactions of allenes with ethylene derivatives are generally limited in scope.[25,26] Nevertheless, the introduction of an alkylsulfanyl group allows an allene to be utilized effectively in the [2 + 2]-cycloaddition reaction. Allenyl methyl sulfides 5 (R1 = SnMe3, TMS) react with unsaturated ester 2 to afford the corresponding methylenecyclobutanes 6 in good yield (93–100%) and with excellent asymmetric induction (96–98% ee). More importantly, bicyclo[n.2.0] (n = 4–6) compounds 8 can also be prepared by this method, using the cycloalkenyl sulfides 7, with excellent enantioselectivity (>98% ee). Finally, alkynyl sulfides 9 also undergo the cycloaddition, yielding tetrasubstituted cyclobutenes 10 with excellent enantiomeric excess (>98% ee). Scheme 1 Ph Ph
[2 + 2] Cycloadditions of a But-2-enoate with Alkenes, Allenes, or Alkynes[21] Ph
O
OH
O
OH
•TiCl2(OiPr)2
Ph
Ph 1
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
O
O
SR1
O +
N MeO2C
O
O MeO2C
O
N SR1 SR1
3
4
eea (%) Yield (%) Ref
Me 98
96
Et
82
a
1 (0.1 equiv) 4-Å molecular sieves toluene, petroleum ether 0 oC, 30 min
SR1 2
R1
9
[2 + 2]-Cycloaddition Reactions
3.1.1
88
[21] [21] 1
Determined by H NMR of the (+)-MTPA esters of the products.
O
O
R1
O
O MeO2C
N
O
•
O +
N
1 (0.1 equiv) 4-Å molecular sieves toluene, petroleum ether 0 oC, 12−18 h
R1
SMe
MeO2C
SMe 2
R1 TMS
96
93
[21]
>98
100
[21]
Determined by 1H NMR of the (+)-MTPA esters of the products.
O
O
SBu
n
2
n dr
1 (1.1 equiv) 4-Å molecular sieves toluene, petroleum ether 0 oC, 12−18 h
H
CO2Me O
O +
N MeO2C
7
n
SBu
N
O
O 8
eea (%) Yield (%) Ref
1 >99:1 >98
96
[21]
2
92:8 >98
97
[21]
3
91:9 >98
89
[21]
a
6
eea (%) Yield (%) Ref
SnMe3 a
5
Determined by 1H NMR of the (+)-MTPA esters of the products.
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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10
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
1 (1.1 equiv) 4-Å molecular sieves toluene petroleum ether 0 oC, 12−18 h
O
O N
O +
R1
SMe
O
O MeO2C
N
O
MeO2C R1 2
R1
9
eea (%) Yield (%) Ref
Bu >98
92
[21]
Me >98
90
[21]
Cy
84
a
SMe 10
>98
[21] 1
Determined by H NMR of the (+)-MTPA esters of the products.
Methyl (1R,2R)-3,3-Bis(methylsulfanyl)-2-[(2-oxooxazolidin-3-yl)carbonyl]cyclobutanecarboxylate (4, R1 = Me); Typical Procedure:[21]
The chiral titanium reagent 1 was prepared by mixing TiCl2(OiPr)2 (125 mg, 0.53 mmol) and the chiral 1,4-diol (305 mg, 0.58 mmol) in toluene (5 mL) at rt for 30 min with stirring. To a reaction vessel containing powdered 4- molecular sieves (100 mg) were added successively a part of the soln of the above chiral titanium reagent 1 (0.5 mL, 0.053 mmol), toluene (1.5 mL), and petroleum ether (2.0 mL). The mixture was cooled to 0 8C, at which point methyl (E)-4-oxo-4-(2-oxooxazolidin-3-yl)but-2-enoate (2; 107 mg, 0.54 mmol) and a soln of 1,1-bis(methylsulfanyl)ethene (3, R1 = Me; 115 mg, 0.96 mmol) in petroleum ether (1.5 mL) were added. After the mixture was stirred for 30 min at 0 8C (vigorous stirring was essential), the reaction was quenched with pH 7 phosphate buffer, and the inorganic materials were removed by filtration. The organic materials were extracted with EtOAc, and the extracts were washed with brine and dried (Na2SO4). After evaporation of the solvent, the crude product was purified by chromatography (hexane/EtOAc 1:1); yield: 164.5 mg (96%). 3.1.1.1.2
Chiral Copper Catalysts
Akiyama has developed a novel enantioselective [2 + 2]-cycloaddition reaction of allenylsilanes with imines, which provides important four-membered heterocycles for the synthesis of biologically active compounds.[27] The catalytic, enantioselective [2 + 2]-cycloaddition reactions of (1-methoxypropa-1,2-dienyl)silanes 11 and Æ-imino ester 12 using a catalyst derived from tetrakis(acetonitrile)copper(I) tetrafluoroborate and (R)-2,2¢-bis(di-4-tolylphosphino)-1,1¢-binaphthyl [(R)-Tol-BINAP] afford 3-methyleneazetidine-2-carboxylates 13 in moderate to good yield and with excellent enantiomeric excess (Scheme 2). Interestingly, the acid-catalyzed ring opening of the azetidines affords chiral Æ-amino esters 14 bearing an acylsilane moiety in quantitative yield and with equivalent enantioselectivity (92–97% ee).
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3.1.1
11
[2 + 2]-Cycloaddition Reactions
Scheme 2
Enantioselective [2 + 2] Cycloadditions of Allenylsilanes with an Imine[27]
P(4-Tol)2 P(4-Tol)2
(R)-Tol-BINAP
OMe R1
• 11
N
Ts
10 mol% [Cu(NCMe)4]BF4 10 mol% (R)-Tol-BINAP 4-Å molecular sieves, THF −78 oC, 9−24 h
OMe
Ts N
R1
+ EtO2C
EtO2C
12
13
NHTs O aq HCl, 0 oC
R1
EtO2C 14
R1
ee (%) of 13 Yield (%) of 13 ee (%) of 14 Yield (%) of 14 Ref
TMS
97
90
97
100
[27]
TBDMS 95
60
92
100
[27]
Ethyl (2S)-4-Methoxy-3-methylene-1-tosyl-4-(trimethylsilyl)azetidine-2-carboxylate (13, R1 = TMS); Typical Procedure:[27]
A suspension of powdered 4- molecular sieves (100 mg), [Cu(NCMe)4]BF4 (6.3 mg, 0.02 mmol), and (R)-Tol-BINAP (14.9 mg, 0.022 mmol) in THF (0.75 mL) was stirred at rt for 30 min. Then the mixture was cooled to –78 8C, and a soln of iminoacetate 12 (51.1 mg, 0.20 mmol) in THF (0.75 mL) and allenylsilane 11 (R1 = TMS; 56.9 mg, 0.40 mmol) were added successively. After being stirred at this temperature for 24 h, the reaction was quenched by addition of 1 M aq NaHCO3, and extracted with EtOAc. The combined organic layers were washed with sat. NaHCO3 soln and brine, dried (Na2SO4), and concentrated to dryness. The crude mixture was purified by chromatography (silica gel, hexane/EtOAc/ Et3N 81:9:10); yield: 71.5 mg (90%); 97% ee (Daicel Chiralpak AD-H column). 3.1.1.1.3
Chiral Rhodium Catalysts
Shibata and co-workers developed the enantioselective rhodium-catalyzed [2 + 2] cycloadditions of ester-containing alkynes with norbornene derivatives.[28] Chiral tri- and tetracyclic cyclobutenes are obtained in moderate to high enantioselectivity (Scheme 3). The electron-rich aryl group on the alkyne terminus provides higher enantioselectivity to afford the corresponding cyclobutene 15 (R1 = 4-MeOC6H4) in excellent yield with 90% ee using 5 mol% catalyst. Furthermore, the [2 + 2] cycloadditions of benzonorbornadiene 16 with aryl- or alkyl-substituted propynoates proceed under refluxing conditions to generate the cycloadducts 17 in moderate to good yield and with high enantioselectivity.
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12
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
[2 + 2] Cycloadditions of Alkynyl Esters and Norbornene Derivatives[28]
Scheme 3
PPh2 PPh2
(S)-H8-BINAP
CO2Me
5 mol% {Rh(cod)[(S)-H8-BINAP]}BF4 1,2-dichloroethane, 60 oC
+
CO2Me
R1
R1 15
R1
ee (%) Yield (%) Ref
4-MeOC6H4
90
98a
[28]
4-Tol
86
97
[28]
a
10 mol% of catalyst was used.
CO2Me +
5 mol% {Rh(cod)[(S)-H8-BINAP]}BF4 1,2-dichloroethane, reflux
CO2Me
R1
R1 16
17
R1
ee (%) Yield (%) Ref
4-MeOC6H4
87
95
[28]
Me
94
68
[28]
Methyl 4-(4-Methoxyphenyl)tricyclo[4.2.1.02,5]non-3-ene-3-carboxylate (15, R1 = 4-MeOC6H4); Typical Procedure:[28]
Under an atmosphere of argon, {Rh(cod)[(S)-H8-BINAP]}BF4 (9.3 mg, 0.010 mmol) was stirred in degassed 1,2-dichloroethane (0.4 mL) at rt to give a yellow soln. Then, methyl 3-(4-methoxyphenyl)propynoate (38.0 mg, 0.20 mmol) and norbornene (94.2 mg, 1.00 mmol) in 1,2-dichloroethane (1.6 mL) were added to the soln, and the mixture was stirred at 60 8C for 6 h. The solvent was removed under reduced pressure, and the crude products were purified by TLC (EtOAc/hexane 1:20) to give a pale yellow oil; yield: 55.7 mg (98%). 3.1.1.1.4
Chiral Iridium Catalysts
The first catalytic asymmetric [2 + 2] cycloaddition of oxabicyclic alkenes with terminal alkynes was developed by Shao et al.[29] The reaction is performed with the chiral complex derived from dichlorobis(cyclooctadiene)diiridium(I) with a bisphosphino cyclophane ligand [(R)-Xyl-PHANEPHOS] (Scheme 4) in tetrahydrofuran at 90 8C. Terminal aromatic alkynes 19 react with the oxabicyclic alkenes 18 (R1 = R2 = H) smoothly to provide the corresponding adducts 20 with excellent enantioselectivity (95–99% ee). Moreover, the [2 + 2] cycloadditions of oxabenzonorbornenes 18 bearing substituents on the aromatic ring with phenylacetylene (19, Ar1 = Ph) also provide the corresponding cycloadducts with [m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.1
13
[2 + 2]-Cycloaddition Reactions
good enantioselectivity (94–98% ee). Interestingly, only the exo-isomer is observed for this iridium-catalyzed [2 + 2] cycloaddition. Scheme 4 Iridium-Catalyzed Asymmetric [2 + 2] Cycloaddition of 7-Oxabicyclic Alkenes with Terminal Alkynes[29]
P
P
(R)-Xyl-PHANEPHOS
R1
R2
2.5 mol% [IrCl(cod)]2 6.5 mol% (R)-Xyl-PHANEPHOS THF, 90 oC, 20 h
O +
R2
R2
20
19
R1
R2
Ar1
ee (%)a Yield (%) Ref
H
H
Ph
99
79
[29]
H
H
4-FC6H4
97
70
[29]
H
H
4-BrC6H4
97
67
[29]
H
H
4-F3CC6H4
98
61
[29]
H
H
3-MeOC6H4
95
69
[29]
H
H
4-Tol
96
57
[29]
H
H
4-F3COC6H4
97
81
[29]
H
H
3,5-(MeO)2C6H3
98
60
[29]
Ph
98
60
[29]
Me Ph
94
63
[29]
a
Ar1 R1
18
H
O
Ar1
R1
OMe H
R1
R2
Determined by chiral HPLC using a Chiralcel OD-H or OJ-H column.
1-Aryl-3,8-epoxy-2a,3,8,8a-tetrahydrocyclobuta[b]naphthalenes 20; General Procedure:[29]
[IrCl(cod)]2 (5.1 mg, 0.0075 mmol) and (R)-Xyl-PHANEPHOS (13.4 mg, 0.0195 mmol) were added to a dried Schlenk tube under N2. Dry THF (1 mL) was added, and the mixture was stirred at rt for 30 min. To the soln was added oxabenzonorbornene 18 (0.3 mmol) in THF (1 mL), and the resulting mixture was stirred at ambient temperature for 20 min. Arylacetylene 19 (0.6 mmol) was added under vigorous stirring. The resulting soln was stirred at 90 8C under N2 with TLC monitoring until completion of the reaction. The soln was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel).
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14
Stereoselective Synthesis
3.1.1.2
[2 + 2] Cycloadditions Catalyzed by Organic Molecules
3.1.1.2.1
Lectka’s Quinine-Derived Catalysts
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
The Staudinger ketene cycloaddition reaction provides an efficient route to -lactams through a formal [2 + 2] cycloaddition of a ketene with an imine. Lectka has demonstrated the highly stereoselective coupling of imines with a range of monosubstituted ketenes, as well as one symmetrical disubstituted ketene, using a quinine-derived catalyst.[30] Interestingly, the combination of a cinchona alkaloid derivative such as benzoylquinine 21 with the non-nucleophilic amine base Proton-sponge (22) as a proton sink, provides the optimal combination for amine-based catalysts (>95% ee). This methodology is compatible with aryl-, alkyl-, alkenyl-, halo-, azo-, and oxy-substituted ketenes.[31,32] The benzoylquinine plays two distinct catalytic roles as a dehydrohalogenation agent and a nucleophilic catalyst (Scheme 5). Scheme 5
[2 + 2] Cycloadditions toward Optically Active -Lactams[30] OMe N
OMe O
Cl
H
BzO
N
O
21
R1
•
R2
N
+
R1
•
R2
H
BzO
Me2N
HCl
N
NMe2
OMe O 22
• R1
+
N
R2 BzO
H
N
21 OMe N
Ts
N
Ts
BzO
H
O N
EtO2C − 21
N R1
O R2
R2 EtO2C
R1
36−65%; dr up to 99:1; >95% ee
Although this method provides -lactams in high enantioselectivity, the yields are only modest (36–65%). The addition of catalytic (10 mol%) quantities of metal trifluoromethanesulfonate salts [e.g., Sc(III), Al(III), Zn(II), and In(III)] with benzoylquinine 21 (10 mol%) provides significantly increased yields (91–98%) (Scheme 6).[30,33]
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.1
15
[2 + 2]-Cycloaddition Reactions
Scheme 6 Improved Yields of -Lactams through the Use of Bifunctional Lewis Acid–Nucleophile-Based Catalysts[33] O
Cl
R1 21 (cat.), 22
OMe O
N
• R1
H
BzO
H
N
O R1 Ts
O N
EtO2C
91−98%; dr >9:1; 96−98% ee
Ts
N
R1
Ln M
In(OTf)3 (cat.)
EtO2C
N
Ts
EtO2C
Interestingly, indium(III) trifluoromethanesulfonate provides the optimal catalyst, followed by the zinc(II), aluminum(III), and scandium(III) salts, wherein the latter complexes are slightly less effective. The reason for this difference has been attributed to the fact that indium(III) complexes bond to the benzoylquinine ligand with comparatively low affinity, which results in fast on/off rates. This system has been applied to various substrates to determine the scope (Scheme 7); the reactions proceed to give -lactams 23 in excellent yield (>91%) and selectivity (dr ‡9:1; ‡96% ee). Scheme 7 Reactions of Acid Chlorides and Imines Catalyzed by Benzoylquinine and Indium(III) Trifluoromethanesulfonate[33]
O
Cl
N
10 mol% 21 10 mol% In(OTf)3 22, toluene −78 oC to rt
Ts
+ R1
Ts
O N
EtO2C
R1
EtO2C 23
R1
Ratio (cis/trans) ee (%) Yield (%) Ref
Ph
60:1
98
95
[33]
Bn
9:1
98
94
[33]
CH2OPh
12:1
96
93
[33]
OPh
22:1
97
93
[33]
OAc
34:1
98
92
[33]
OBn
11:1
96
98
[33]
Br
10:1
96
91
[33]
CH=CH2
10:1
96
92
[33]
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
16
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
Ethyl (2R,3R)-4-Oxo-3-phenyl-1-tosylazetidine-2-carboxylate (23, R1 = Ph); Typical Procedure:[33]
To a suspension of In(OTf )3 (7.3 mg, 0.013 mmol), benzoylquinine 21 (5.6 mg, 0.013 mmol), and Proton-sponge (22; 28 mg, 0.13 mmol) in toluene (7.5 mL) at –78 8C was added, dropwise, phenylacetyl chloride (20 mg, 0.13 mmol) in toluene (0.5 mL). A soln of ethyl (tosylimino)acetate (32 mg, 0.13 mmol) in toluene (1 mL) was then added via syringe pump over 1 h. The mixture was allowed to warm to rt over 16 h before the reaction was quenched with 1 M HCl (3 mL). The aqueous layer was then extracted with CH2Cl2 (2 ) and the combined organic layers were dried (MgSO4) and filtered through Celite. Absorption onto silica gel followed by column chromatography (EtOAc/hexanes 1:10) afforded the product; yield: 46 mg (95%); dr 60:1; 98% ee. 3.1.1.2.2
Fu’s 4-Pyrrolidinopyridine Catalysts
Fu has pursued the application of planar-chiral 4-(dimethylamino)pyridine and 4-(pyrrolidino)pyridine derivatives 24 and 25 (Scheme 8) in asymmetric catalytic reactions.[34–37] These types of catalysts are suitable for a range of enantioselective nucleophile-catalyzed transformations. This section outlines four types of asymmetric [2 + 2]-cycloaddition reactions using this type of strategy. Scheme 8 Planar-Chiral 4-(Dimethylamino)pyridine and 4-(Pyrrolidino)pyridine Derivatives[34–37]
Me2N
N N R1
N Fe
R1
R1
3.1.1.2.2.1
R1
R1
Fe
R1 R1
R1
R1
R1
(−)-24
(−)-25
Asymmetric Staudinger Synthesis of -Lactams
The Staudinger ketene cycloaddition reaction, which involves the [2 + 2] cycloaddition of a ketene with an imine, provides an efficient and convergent route to -lactams. Although a number of chiral auxiliary based Staudinger processes have been described, few investigations with asymmetric catalysis have been reported. Lectka has demonstrated that chiral quinine derivatives catalyze this type of process using monosubstituted ketenes as substrates, with one example of the use of a symmetrical disubstituted ketene (see Section 3.1.1.2.1).[30–33] In related work, Fu has demonstrated that the planar-chiral 4-(pyrrolidino)pyridine derivative 28 is an effective catalyst for the asymmetric Staudinger reaction of symmetrical and unsymmetrical disubstituted ketenes 26 with a range of imines 27, furnishing the corresponding -lactams 29 with very good asymmetric induction (Scheme 9).[34] The improved reaction scope with respect to the imine coupled with the fact that both cyclic and acyclic disubstituted ketenes can be employed, represents a significant improvement over prior studies on this reaction.
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.1
17
[2 + 2]-Cycloaddition Reactions
Scheme 9 Catalytic Asymmetric Staudinger Reactions of Disubstituted Ketenes with Imines[34]
N
10 mol%
N Fe
O N
• R
1
R
28
R1
R3
R2 27
R3
R3
29
Yield (%) Ref
(CH2)6 Ph
81
–
84
[34]
(CH2)6 2-furyl
92
–
90
[34]
(CH2)6 CH=CHPh
91
–
82
[34]
(CH2)6 cyclopropyl 94
–
89
[34]
a
[34]
(CH2)6 Cy
94
–
76
Et Et
2-furyl
92
–
93b
[34]
Et Et
CH=CHPh
92
–
83b
[34]
Ph iBu Ph
98
8:1 88
[34]
Ph iBu 2-furyl
98
11:1 97
[34]
Ph iBu CH=CHPh
98
10:1 95
[34]
Ph iBu cyclopropyl 89
15:1 88
[34]
Ph Et
2-furyl
95
9:1 97
[34]
Ph Et
cyclopropyl 98
10:1 98
[34]
b
Ts N
ee (%) dr
a
O
toluene, rt
+ 2
26
R1 R2
Ts
Reaction was started at –40 8C. Reaction was run at 35 8C in toluene/THF (1:1) with 1.5 equiv of ketene.
(S)-3-Phenyl-2-tosyl-2-azaspiro[3.6]decan-1-one [29, R1,R2 = (CH2)6; R3 = Ph]; Typical Procedure:[34]
In a N2-filled glovebox, a soln of ketene 26 [R1,R2 = (CH2)6; 22.2 L, 0.154 mmol] and N-benzylidene-4-toluenesulfonamide (27; R3 = Ph; 45.9 mg, 0.177 mmol) in toluene (2.0 mL) was added to catalyst 28 (5.8 mg, 0.0155 mmol). The mixture was stirred at rt for 1 h, and then purified directly by flash chromatography to obtain a white solid; yield: 49.2 mg (84%). The ee of the product was assayed by HPLC (Diacel Chiralcel OD column; 1.0 mL • min–1; iPrOH/hexanes 1:9; tR: 7.3 min and 9.9 min). 3.1.1.2.2.2
[2 + 2] Cycloadditions of Disubstituted Ketenes with Aldehydes
Fu and co-workers have demonstrated that the Staudinger-type conditions which are used to combine ketenes with imines are suitable for the synthesis of -lactones, provided the reaction is conducted at low temperature. For example, diethylketene reacts with an array of aldehydes 30 in the presence of chiral catalyst 28 to provide the corresponding -lactones 31 in high yield (77–92%) and with excellent enantiomeric excess (89–91% ee) using tetrahydrofuran as the solvent (Scheme 10).[35] [m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
18
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
Scheme 10 Catalytic Asymmetric Synthesis of -Lactones by Cycloadditions of a Disubstituted Ketene with Aldehydes[35] O
O
• + Et
Et
O
5 mol% 28 THF, −78 oC
O
R1
H
Et Et
30
R1
31
R1
ee (%) Yield (%) Ref
Ph
91
92
[35]
2-naphthyl
89
77
[35]
(R)-3,3-Diethyl-4-phenyloxetan-2-one (31, R1 = Ph); Typical Procedure:[35]
A soln of catalyst 28 (6.0 mg, 0.016 mmol) in THF (0.40 mL) was added dropwise over 5 min to a –78 8C soln of diethylketene (38 mg, 0.38 mmol) and PhCHO (30, R1 = Ph; 32 L, 0.32 mmol) in THF (1.5 mL). The mixture was stirred at –78 8C for 5.5 h, and then filtered through a short pad of silica gel with copious washings with Et2O. The solvent was removed, and the product was purified by chromatography (silica gel Et2O/pentane 1:9), which furnished a clear oil; yield: 61.0 mg (92%). HPLC analysis [Daicel Chiralcel AD column; 1.0 mL • min–1; iPrOH/hexanes 3.5:96.5; tR: 6.4 min (minor), 7.4 min (major)]: 91% ee. 3.1.1.2.2.3
[2 + 2] Cycloadditions of Ketenes with Azo Compounds
The first catalytic asymmetric [2 + 2] cycloaddition of ketenes with azo compounds to prepare aza--lactams was accomplished using the planar-chiral 4-(pyrrolidino)pyridine derivative 28.[36] The aza--lactams 33 are produced with good enantioselectivity (83–95% ee) (Scheme 11), and the lower enantioselectivities can easily be improved by recrystallization. For example, the product generated from ethyl(phenyl)ketene (32, R1 = Ph; R2 = Et) can be obtained in >99% ee after a single recrystallization. In the case of ketenes that contain a secondary alkyl group (e.g., Cy or iPr), the planar-chiral catalyst 28 also affords the aza--lactams with excellent yield (>90%) and enantioselectivity (>90% ee). Scheme 11 Catalytic Asymmetric [2 + 2] Cycloadditions of Ketenes with Azo Compounds[36] O •
N
+ R1
R2
MeO2C
CO2Me
O
5 mol% 28 CH2Cl2, −20 oC
CO2Me N
R1
N
N CO2Me
R2
32
33
R1
R2
ee (%)
Ph
Et
86 (>99)a 89
[36]
3-Tol
Et
85
79
[36]
2-MeOC6H4
Et
93
89
[36]
Ph
iBu
83
87
[36]
Ph
cyclopentyl
86
84
[36]
Ph
Cy
94
90
[36]
Ph
iPr
95
91
[36]
Yield (%) Ref
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
19
[2 + 2]-Cycloaddition Reactions
3.1.1
R1
R2
ee (%)
Yield (%) Ref
4-MeOC6H4
iPr
96
91
[36]
4-ClC6H4
iPr
92
90
[36]
3-thienyl
iPr
96
90
[36]
a
The ee value was determined after a single recrystallization from iPrOH; overall yield: 71%.
Dimethyl 3-Oxo-1,2-diazetidine-1,2-dicarboxylates 33; General Procedure:[36]
In a glovebox, a soln of the ketene 32 (0.68 mmol) and DMAD (100 mg, 0.68 mmol) in CH2Cl2 (49 mL) was prepared. A soln of catalyst 28 (13 mg, 0.035 mmol) in CH2Cl2 (0.8 mL) was also prepared. Both vessels were removed from the glovebox and placed in a –20 8C bath. After 10 min, the soln of the catalyst was added by syringe to the soln of the ketene and DMAD. The mixture was stirred for 2 h at –20 8C (the reaction was temperature sensitive), and then the solvent was removed and the residue was purified by column chromatography. 3.1.1.2.2.4
[2 + 2] Cycloadditions of Ketenes with Nitroso Compounds
The planar-chiral 4-(pyrrolidino)pyridine derivative 28 can also catalyze the cycloadditions of ketenes 34 with the nitroso compound 35 to form 1,2-oxazetidin-3-ones 36 (Table 1).[37] Hence, through the appropriate choice of chiral catalyst and nitroso compound, the synthesis of these intriguing heterocycles is achieved with very good regioand enantioselectivity. For example, the aryl(methyl)ketenes, in which the aryl group is ortho-substituted, provide highly enantioenriched products (entries 1–3). In the case of aryl(ethyl)ketenes, the enantioselectivity is very good with large aromatic groups (entries 4 and 5). Additionally, a range of alkyl(aryl)ketenes that contain a secondary alkyl substituent also undergo cycloaddition with very good enantioselectivity (entries 6–11). Catalytic Asymmetric Cycloadditions of Ketenes with a Nitrosoarene[37]
Table 1
F3C O
F3C +
Ar
1
O
5 mol% 28 CH2Cl2, 0 oC
•
N Ar1
N
1
R
R1
O 34
Entry
O
35
Ar1
36
R1
ee (%)
Yield (%)
Ref
1
2-Tol
Me
90
90
[37]
2
2-MeOC6H4
Me
97
92
[37]
3
2-BrC6H4
Me
94
93
[37]
4
2-Tol
Et
96
90
[37]
5
2-MeOC6H4
Et
98
93
[37]
6
Ph
iBu
91
90
[37]
7
Ph
iPr
92
85
[37]
8
4-ClC6H4
iPr
92
84
[37]
9
4-MeOC6H4
iPr
90
81
[37]
10
Ph
cyclopentyl
91
81
[37]
11
Ph
Cy
93
84
[37]
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
20
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
2-[2-(Trifluoromethyl)phenyl]-1,2-oxazetidin-3-ones 36; General Procedure:[37]
An oven-dried 50-mL round-bottomed flask under N2 was charged with a soln of 1-nitroso2-(trifluoromethyl)benzene (35; 96 mg, 0.55 mmol) in CH2Cl2 (15 mL). A soln of catalyst 28 (9.0 mg, 24 mol) in CH2Cl2 (1.0 mL) was added in one portion. The resulting pink soln was cooled to 0 8C and stirred for 15 min. Then, a soln of the ketene 34 (0.50 mmol) in CH2Cl2 (1.0 mL) was added portionwise over 30 min. The mixture was stirred at 0 8C for 16 h. The soln was then allowed to warm to rt, and the mixture was concentrated. The residue was taken up in toluene (1 mL) and purified by flash chromatography. 3.1.1.2.3
Corey’s Oxazaborolidine Catalysts
Oxazaborolidine catalysts, such as 38 (Table 2), have proven successful for the enantioselective Corey–Bakshi–Shibata (CBS) reduction over the past 20 years.[38,39] The catalyst is conveniently generated in situ by the addition of a solution of aluminum tribromide in dibromomethane to a cold (99:1 and 99% ee). For example, 2,3-dihydrofuran reacts with Æ,-unsaturated ester 37 to afford the corresponding bicyclobutane in 87% yield (endo/exo 1:>99) and 99% ee in only 3 hours (entry 1).
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.1
21
[2 + 2]-Cycloaddition Reactions [2 + 2] Cycloadditions of 2,2,2-Trifluoroethyl Acrylate to Enol Ethers[40]
Table 2
H Ph Ph 10 mol%
N
O B
Br3Al
OR
O 2
R
+
O
2-Tol
1
OR1
38 CH2Cl2, −78 oC
O
R2
O
CF3
CF3
R3
R3 37
Entry Substrate
Time (h)
Product
dr (endo/ exo)
ee (%)
Yield (%)
Ref
1:>99
99
87
[40]
82:18
92
97
[40]
97:3
92a
99
[40]
99:1
99a
99
[40]
1:99
98
99
[40]
10:90
98
99
[40]
96:4
98
91
[40]
O
1
O
H
3
O
O
CF3 H O
OTBDMS
2
TBDMSO O
6
CF3 H O
OTIPS
3
TIPSO O
12
CF3 H O
OTIPS
4
TIPSO O
6
CF3 H O OTBDMS
5
TBDMSO O
0.5
CF3
O
OTBDMS
6
TBDMSO O
16
CF3
O
OTBDMS
7
TBDMSO
4
O CF3
a
Determined by reduction of CO2CH2CF3 to CH2OH, conversion into the Mosher ester, and 1 H NMR analysis.
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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22
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
2,2,2-Trifluoroethyl (1R,5S,7R)-2-Oxabicyclo[3.2.0]heptane-7-carboxylate (Table 2, Entry 1); Typical Procedure:[40]
A ca. 0.2 M soln of oxazaborolidine 38 (0.05 mmol) in CH2Cl2/CH2Br2 was cooled to –78 8C and 2,2,2-trifluoroethyl acrylate (37; 0.154 g, 1.0 mmol) was added, followed by 2,3-dihydrofuran (0.035 g, 0.5 mmol). The mixture was stirred for 3 h, quenched with Et3N (100 L), and immediately warmed to rt. The cloudy soln was directly purified by column chromatography (silica gel, EtOAc/hexane 1:100) to give a colorless oil; yield: 0.097 g (87%); 99% ee [determined by GC analysis using a J&W Scientific Cyclosil-B column (30 m 0.25 mm, 100 8C); tR: 25.3 min (major), 26.0 min (minor)]. 3.1.1.2.4
Ye’s N-Heterocyclic Carbene Catalysts
N-Heterocyclic carbenes (NHCs) provide catalysts for a variety of important reactions.[42–45] Ye and co-workers have discovered that the chiral N-heterocyclic carbenes generated from precursors 39–41 (Scheme 12) catalyze the enantioselective [2 + 2]-cycloaddition reactions of ketenes with various 2 components to afford four-membered rings.[46–49] Scheme 12
N-Heterocyclic Carbene Precursors[46–49] N
N Ph
N
N
Ph
OTBDMS
Ph
BF4−
N N
Ph
OTMS
N
N
Ph
OTBDMS
BF4−
40
39
Ph
Ph
Pri
N
Ph
BF4−
41
3.1.1.2.4.1
N-Heterocyclic Carbene Catalyzed Staudinger Reaction of Ketenes
Similarly to the mechanism proposed for the catalytic Staudinger [2 + 2] reactions described in Section 3.1.1.2.2.1, an N-heterocyclic carbene can also react with a ketene to afford a reactive zwitterion that undergoes the Staudinger reaction with an imine to furnish a -lactam. The N-heterocyclic carbene precursor 39 provides an efficient catalyst for the Staudinger reaction of ketenes with N-tosyl- and N-(tert-butoxycarbonyl)imines.[46] The process is applicable to a wide variety of ketenes and imines, which provide the corresponding -lactams 42 in good yields and with excellent enantioselectivities (91–99% ee), albeit with a variable diastereocontrol (dr 71:29 to ‡99:1) (Scheme 13). Moreover, several other advantages of this methodology, including the availability of precatalyst 39, facile removal of the tert-butoxycarbonyl group, and easy scale-up, make it a useful transformation for the construction of cis--lactams with Æ-quaternary and -tertiary stereogenic centers.
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3.1.1
23
[2 + 2]-Cycloaddition Reactions
Asymmetric Staudinger Reaction Catalyzed by an N-Heterocyclic Carbene[46]
Scheme 13
N 10 mol% Ph
N
N
Ph
BF4−
Ph
O • Ar1
N
+ R1
Boc
OTBDMS 39 10 mol% Cs2CO3, THF, rt
O
Boc N
R1
Ar2
Ar2
Ar1 42
Ar1
R1
Ar2
dr (cis/trans) ee (%) of cis-42 Yield (%) Ref
Ph
Et
4-ClC6H4
75:25
96
72
[46]
Ph
Et
2-ClC6H4
91:9
99
71
[46]
Ph
Et
2-BrC6H4
94:6
97
58
[46]
Ph
Et
3-ClC6H4
80:20
99
66
[46]
Ph
Et
4-BrC6H4
78:22
99
71
[46]
Ph
Et
4-O2NC6H4
71:29
99
75
[46]
Ph
Et
Ph
75:25
99
64
[46]
Ph
Et
2-furyl
83:17
98
57
[46]
Ph
Me 2,4-Cl2C6H3 86:14
93
53
[46]
4-MeOC6H4
Et
2-ClC6H4
91
78
[46]
4-MeOC6H4
Et
2,4-Cl2C6H3 89:11
96
62
[46]
4-ClC6H4
Et
2-ClC6H4
99:1
97
61
[46]
4-ClC6H4
Et
4-ClC6H4
83:17
99
53
[46]
93:7
N-(tert-Butoxycarbonyl)--lactams 42; General Procedure:[46]
To a mixture of the N-(tert-butoxycarbonyl)imine (0.5 mmol) and precatalyst 39 (0.05 mmol) in THF (2.5 mL), the ketene (0.6 mmol) and Cs2CO3 (16.3 mg, 0.05 mmol) were added. The mixture was stirred under N2 at rt until TLC indicated complete consumption of the imine. The solvent was removed under reduced pressure and a small portion of the residue was collected to determine the cis/trans ratio of the -lactam product by 1 H NMR. The residue was purified by flash chromatography (silica gel). 3.1.1.2.4.2
N-Heterocyclic Carbene Catalyzed [2 + 2] Cycloadditions of Disubstituted Ketenes with 2-Oxoaldehydes
Chiral N-heterocyclic carbenes are also efficient catalysts for the formal [2 + 2]-cycloaddition reactions of alkyl(aryl)ketenes 43 with 2-oxoaldehydes 44 to afford -lactones 45 with Æ-quaternary and -tertiary stereocenters (Scheme 14).[47] The bulky N-heterocyclic carbene precatalyst 39 with a tert-butyldimethylsilyl substituent provides high yields and excellent enantioselectivities (up to 99% ee), albeit with variable diastereoselectivities. For example, both 2-aryl-2-oxoacetaldehydes 44 with an electron-donating substituent (Ar2 = 4-MeOC6H4) and with an electron-withdrawing substituent (Ar2 = 4-BrC6H4) afford the corresponding -lactones in excellent yield and selectivity. Aldehydes 44 with bulky aryl groups (Ar2 = 1-naphthyl, 2-naphthyl) proceed in an analogous manner. Aryl(isopropyl)ketenes 43 (R1 = iPr) provide only modest diastereocontrol (dr 4:1) in good yield and again with excellent enantioselectivity (94–99% ee).
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
24
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
[2 + 2] Cycloadditions of Disubstituted Ketenes with 2-Oxoaldehydes[47]
Scheme 14
N 12 mol% Ph
N
N
Ph
BF4−
Ph
O • Ar1
OTBDMS 39 10 mol% Cs2CO3, THF, rt
O +
Ar2
H
R1
O O R1
O
Ar1
O
Ar 43
45
44
Ar1
R1 Ar2
dr
ee (%) Yielda (%) Ref
2-ClC6H4
Et Ph
>20:1
97
85
[47]
2-ClC6H4
Et 4-MeOC6H4
>20:1
99
98
[47]
2-ClC6H4
Et 4-BrC6H4
1:0
99
99
[47]
2-ClC6H4
Et 1-naphthyl
10:1
95
65
[47]
2-ClC6H4
Et 2-naphthyl
1:0
97
88
[47]
4-ClC6H4
iPr Ph
4:1
99
76
[47]
4-ClC6H4
iPr 4-Tol
4:1
94
77
[47]
Ph
iPr Ph
4:1
99
76
[47]
a
2
Isolated yields of pure trans-isomers.
-Lactones 45; General Procedure:[47] To an oven-dried 50-mL reaction tube containing a stirrer bar was added triazolium salt 39 (70 mg, 0.12 mmol), anhyd Cs2CO3 (32 mg, 0.1 mmol), and THF (4 mL). The mixture was stirred for 1 h at rt. Ketene 43 (1.5 mmol) was then added via syringe followed by the addition of 2-oxoaldehyde 44 (1.0 mmol), and the mixture was stirred overnight. The mixture was then filtered through a pad of silica gel and washed with petroleum ether/EtOAc (10:1). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (silica gel, petroleum ether/EtOAc 20:1). 3.1.1.2.4.3
N-Heterocyclic Carbene Catalyzed [2 + 2] Cycloadditions of Ketenes with Ketones
The highly diastereo- and enantioselective synthesis of -(trifluoromethyl)--lactones 47 is accomplished by chiral N-heterocyclic carbene catalyzed [2 + 2]-cycloaddition reaction of alkyl(aryl)ketenes and trifluoromethyl ketones 46 (Scheme 15).[48] Contrary to the [2 + 2] cycloadditions discussed in Sections 3.1.1.2.4.1 and 3.1.1.2.4.2, the most suitable N-heterocyclic carbene catalyst for this transformation is 40. Interestingly, both electron-donating and electron-withdrawing groups within the aryl-substituted ketenes and the trifluoromethyl ketones provide suitable substrates for this cycloaddition. Moreover, methyl- and ethyl-substituted ketenes are also excellent substrates. However, ketenes with a sterically bulky substituent, such as 2-chlorophenyl or isopropyl, which work well in the cycloaddition reaction with 2-oxoaldehydes (see Section 3.1.1.2.4.2), fail to afford the -lactones.
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3.1.1
25
[2 + 2]-Cycloaddition Reactions
Scheme 15 N-Heterocyclic Carbene Catalyzed Ketene–Ketone [2 + 2]-Cycloaddition Reactions[48] N 12 mol% Ph Ph
O
Ar1
+
Ar2
N
BF4−
OTBDMS
O
40
O
•
N
Pri
O
10 mol% Cs2CO3, toluene, −40 oC
Ar1
CF3
R1
CF3 R1 Ar2 47
46
Ar1
R1
Ar2
Ph
Et
Ph
6:1
97
81
[48]
4-Tol
Et
Ph
7:1
95
86
[48]
4-MeOC6H4
Et
Ph
7:1
93
90
[48]
Ph
Me Ph
23:1
99
76
[48]
4-Tol
Me Ph
17:1
99
84
[48]
Ph
Et
4-ClC6H4
9:1
98
89
[48]
4-Tol
Et
4-ClC6H4
11:1
99
93
[48]
4-MeOC6H4
Et
4-ClC6H4
11:1
97
95
[48]
4-ClC6H4
Et
4-ClC6H4
16:1
93
90
[48]
4-BrC6H4
Et
4-ClC6H4
16:1
93
83
[48]
4-Tol
Me 4-ClC6H4
12:1
99
96
[48]
Ph
Et
7:1
96
56a
[48]
a
4-Tol
dr (trans/cis) ee (%) of trans-47 Yield (%) Ref
The ketene was added in three portions at 3-h intervals.
-Lactones 47; General Procedure:[48] To an oven-dried 50-mL reaction tube containing a stirrer bar was added precatalyst 40 (73.4 mg, 0.12 mmol), Cs2CO3 (32.6 mg, 0.10 mmol), and toluene (5 mL). The mixture was stirred under N2 for 1 h at rt, and then cooled to –40 8C. Ketone 46 (1.0 mmol) was added via syringe followed by addition of the ketene (1.5 mmol), and the mixture was stirred at –40 8C until the reaction was complete (12–82 h). The reaction was then quenched by the addition of silica gel, and the mixture was stirred for a further 5 min. The mixture was diluted with EtOAc and filtered through a pad of silica gel, which was washed with EtOAc. The solvent was removed under reduced pressure and the residue was purified by chromatography (silica gel, typically petroleum ether). 3.1.1.2.4.4
N-Heterocyclic Carbene Catalyzed [2 + 2] Cycloadditions of Ketenes with Azodicarboxylates
N-Heterocyclic carbenes also catalyze the formal [2 + 2] cycloaddition of alkyl(aryl)ketenes with azodicarboxylates 48 to afford the corresponding aza--lactams 49 in high yields (74–95%) and with very good enantioselectivities (up to 91% ee) (Scheme 16).[49] The reaction employs the N-heterocyclic carbene precatalyst 41 (10 mol%) with cesium carbonate (10 mol%) using dichloromethane/toluene (9:1) as solvent. Interestingly, electron-donating groups (4-Me or 4-OMe) on the phenyl ring of the ketene lead to the desired aza--lactams with slightly decreased yield and with moderate to good enantiomeric excess, whereas electron-withdrawing substituents (Cl or Br) in the para or meta position lead to excellent yields with very high enantioselectivity. Ketenes with propyl and butyl groups [m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
26
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
also afford the products in good yields and with high enantioselectivities. In addition to diethyl azodicarboxylate (48, R2 = Et), other dialkyl azodicarboxylates 48 (R2 = Me, t-Bu) also work well in the formal [2 + 2]-cycloaddition reaction. Scheme 16 Enantioselective Formal [2 + 2] Cycloadditions of Ketenes with Azodicarboxylates[49] N N
Ph
OTMS
CO2R2
O • Ar1
10 mol% Ph
+ R1
N
N
Ph
BF4−
41
CO2R2
O N
10 mol% Cs2CO3, CH2Cl2/toluene (9:1), rt
N
Ar1
R2O2C
N R1
CO2R2 49
48
Ar1
R1 R2
ee (%) Yield (%) Ref
Ph
Et Et
91
93
[49]
4-Tol
Et Et
81
74
[49]
4-MeOC6H4
Et Et
65
95
[49]
4-ClC6H4
Et Et
90
90
[49]
4-BrC6H4
Et Et
91
93
[49]
3-ClC6H4
Et Et
90
90
[49]
Ph
Pr Et
91
84
[49]
Ph
Bu Et
89
83
[49]
4-ClC6H4
Bu Et
90
92
[49]
Ph
Et Me
85
88
[49]
Ph
Et t-Bu 91
91
[49]
Diethyl (3R)-3-Ethyl-4-oxo-3-phenyl-1,2-diazetidine-1,2-dicarboxylate (49, Ar1 = Ph; R1 = R2 = Et); Typical Procedure:[49]
To a soln of N-heterocyclic carbene, which was generated freshly from the precursor 41 (26.4 mg, 0.05 mmol) and Cs2CO3 (16.3 mg, 0.05 mmol) in CH2Cl2/toluene (9:1; 3 mL) at rt for 10 min, was added DEAD (48, R2 = Et; 87.1 mg, 0.5 mmol). A soln of ethyl(phenyl)ketene (109.6 mg, 0.75 mmol) in CH2Cl2/toluene (9:1; 2 mL) was added by syringe pump over 1 h. After stirring for another 1 h at rt, the mixture was diluted with Et2O and passed through a short silica gel pad. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (silica gel) to give a colorless oil; yield: 148 mg (93%). 3.1.2
[3 + 2]-Cycloaddition Reactions
There are already several excellent reviews on asymmetric 1,3-dipolar cycloaddition reactions for the construction of five-membered heterocycles.[12–14] This section will focus on [3 + 2] cycloadditions that furnish carbocycles using three- and two-carbon synthons and the asymmetric variants to illustrate the scope and limitations of these reactions.
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.2
3.1.2.1
27
[3 + 2]-Cycloaddition Reactions
Phosphine-Catalyzed [3 + 2]-Cycloaddition Reactions of Allenoates with Dienophiles
In 1995, Lu and co-workers discovered that alka-2,3-dienoate esters (allenoates), in the presence of a phosphine catalyst, act as three-carbon synthons in [3 + 2] cycloadditions with various dienophiles.[50,51] Treatment of ethyl buta-2,3-dienoate (50) with electron-deficient alkenes such as ethyl acrylate, in the presence of substoichiometric (10 mol%) triphenylphosphine, results in a formal [3 + 2]-cycloaddition reaction to afford the regioisomeric cyclopentenes, such as 51 and 52 (76% yield) (Scheme 17). Scheme 17 CO2Et
[3 + 2] Cycloaddition between an Allenoate and Ethyl Acrylate[50]
+
•
CO2Et
10 mol% Ph3P benzene, rt
CO2Et
CO2Et +
76%
EtO2C
EtO2C 50
51
52
75:25
In addition to acrylates, methyl vinyl ketone, acrylonitrile, diethyl fumarate [(E)-53], and diethyl maleate [(Z)-53] provide suitable substrates for the cycloaddition. The reactions with the fumarate (E)-53 and maleate (Z)-53 are stereospecific, furnishing cyclopentenes trans-54 and cis-54, respectively (Scheme 18). Scheme 18 Stereospecific [3 + 2] Cycloadditions with Diethyl Fumarate and Diethyl Maleate[50]
+ •
CO2Et
10 mol% Ph3P benzene, rt
CO2Et
CO2Et
EtO2C
67%
EtO2C EtO2C (E)-53
50
CO2Et
CO2Et + •
trans-54
10 mol% Ph3P benzene, rt
CO2Et EtO2C
46%
CO2Et EtO2C 50
(Z)-53
cis-54
The mechanism of this [3 + 2] cycloaddition has been studied computationally and experimentally.[52–54] The reaction starts with 1,3-dipole formation between the allenoate and phosphine, which then undergoes cycloaddition with the dienophile to afford the [3 + 2] cycloadduct (only one regioisomer is illustrated in Scheme 19). Trace quantities of water in the reaction system catalyze the [1,2]-hydrogen shift to furnish the [3 + 2] product. The role of the water is supported by deuterium-labeling experiments and density functional theory calculations. Other proton sources such as methanol can also catalyze the [1,2]-hydrogen shift.
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
28
Stereoselective Synthesis
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
3.1
Mechanism of the [3 + 2]-Cycloaddition Reaction[52]
Scheme 19 E
E Hb
CO2Et
O
R13P
Ha
Ha
CO2Et
Hb
Hb
CO2Et PR13
•
E
Ha CO2Et
R13P
PR13
CO2Et Hb Ha O Hb
E
E
[3+2]
O R1
3P
3.1.2.1.1
CO2Et H
Hb
a
Hb (trace)
Cycloaddition Reactions Catalyzed by P-Chiral 7-Phosphabicyclo[2.2.1]heptane
The asymmetric version of the cycloaddition reaction of allenoates with acrylates (10 equiv) to give regiomeric products 56 and 57 using structurally rigid P-chiral 7-phosphabicyclo[2.2.1]heptanes 55 as the catalysts has been described by Zhang and co-workers.[55] The optimal reaction conditions utilize 10 mol% of chiral phosphine catalyst 55 (R3 = Me, iPr) in benzene or toluene (Table 3). Changing the size of the ester group (R2) in the electron-deficient acrylate alters the enantioselectivity. For example, the enantioselectivity increases as the size of the ester increases using phosphine 55 (R3 = Me) (entries 1–3). A similar trend is observed with phosphine 55 (R3 = iPr) (entries 5–7, and 9). Additionally, cooling the reaction in toluene to 0 8C increases the enantioselectivity of the product 56 (93% ee) with excellent regioselectivity for both catalysts (entries 4 and 8). Increasing the size of the ester moiety (R1) in the allenoates, also increases the enantioselectivity achieved with phosphine 55 (R3 = Me; entry 1, vs entry 10), but has a negative effect on the enantioselectivity using phosphine 55 (R3 = iPr; entry 5 vs entry 11). Catalyst 55 (R3 = iPr) generally gives higher conversion of the starting materials into products than catalyst 55 (R3 = Me).
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.2
Table 3
Phosphine-Catalyzed Asymmetric [3 + 2] Cycloaddition[55] Ph P
O
CO2R1
O
R3
OR2 O
10 mol% R3
OR
+
•
29
[3 + 2]-Cycloaddition Reactions
55
2
OR2
+ CO2R1 56
Entry R1
R2
R3
Solvent
Temp (8C)
Ratioa (56/57)
CO2R1 57
eea (%) of 56
Yield (%) of 56 and 57
Ref
1
Et
Et
Me benzene
rt
95:5
81
66
[55]
2
Et
iBu
Me benzene
rt
100:0
86
46
[55]
3
Et
t-Bu Me benzene
rt
95:5
89
69
[55]
4
Et
t-Bu Me toluene
0
97:3
93
42
[55]
5
Et
Me
iPr
benzene
rt
96:4
79
87
[55]
6
Et
Et
iPr
benzene
rt
97:3
81
76
[55]
7
Et
iBu
iPr
benzene
rt
100:0
88
92
[55]
8
Et
iBu
iPr
toluene
0
100:0
93
88
[55]
9
Et
t-Bu iPr
benzene
rt
95:5
88
75
[55]
10
t-Bu Et
Me benzene
rt
97:3
89
13
[55]
11
t-Bu Et
iPr
rt
94:6
69
84
[55]
a
benzene
Determined by GC with - and ª-DEX columns.
3-Ethyl 1-Methyl (R)-Cyclopent-3-ene-1,3-dicarboxylate (56, R1 = Et; R2 = Me); Typical Procedure:[55]
Under N2, to a soln of ethyl buta-2,3-dienoate (112 mg, 1.0 mmol) and methyl acrylate (0.9 mL, 10 mmol) in benzene (5 mL) (CAUTION: carcinogen) was added a 0.1 M soln of chiral ligand 55 (R3 = iPr) in toluene (1.0 mL, 0.1 mmol) dropwise via syringe at rt. After the mixture was stirred for 3 h, TLC showed the reaction was complete. The ratio of the two regioisomers [(56/57) 96:4] and enantiomeric excesses (56: 79% ee; 57: 0% ee) of the crude mixture were measured by Capillary GC (Supelco ª-225 column, 130 8C). After the mixture was concentrated under reduced pressure, the residue was purified by column chromatography (silica gel, hexanes/EtOAc 15:1); yield: 175 mg (87%). 3.1.2.1.2
Cycloaddition Reactions Catalyzed by Binaphthyl-Derived Phosphines
Fu and co-workers have described the cycloaddition of -substituted enones and allenoates with the binaphthyl-derived phosphine 58.[56] Treatment of allenoate 50 with enones in the presence of the phosphine catalyst 58 provides the cyclopentene products 59 and 60 with two contiguous stereogenic centers in moderate to good yield (39–74%) and with high regioselectivity [(59/60) up to >20:1] and enantioselectivity (up to 90% ee) (Scheme 20). Surprisingly, the regioselection in Fus system differs from that of the triphenylphosphine-catalyzed acrylate cycloadditions. The major product 59 in this case results from addition of the ª-centered anion of the zwitterion to the Æ,-unsaturated ketone.
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
30
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
Scheme 20 Synthesis of Functionalized Cyclopentenes through Catalytic Asymmetric [3 + 2] Cycloadditions[56]
PBut
10 mol%
CO2Et
O CO2Et •
58
R2
+
CO2Et
O
R1
toluene, rt
R2
R1
+ O
R1 R2
50
59
60
R1
R2
Equiv of 50 Ratio (59/60)
ee (%) of 59 Yield (%) of 59 and 60
Ref
Ph
4-Tol
1.2
20:1
87
61
[56]
4-ClC6H4
Ph
1.2
9:1
87
74
[56]
Ph
1.2
20:1
88
52a
[56]
1.2
>20:1
89
54a
[56]
N
4-ClC6H4 O
Ph
2-thienyl
1.2
6:1
90
74
[56]
C”CTES
Ph
1.2
>20:1
87
70
[56]
(CH2)4Me
Ph
2.0
>20:1
75
39b
[56]
a b
Because of the low solubility of the enone in toluene, CH2Cl2 was used as a cosolvent. The enone was recovered in 56% yield.
Additional studies have demonstrated that this process can be applied to the enantioselective synthesis of the spirocyclic ketone 62 using the trisubstituted enone 61, thereby generating adjacent quaternary and tertiary stereocenters. Dienones such as 63 undergo a single enantioselective cycloaddition to furnish the spirocyclic enone, e.g. 64, which is produced in 81% yield and with 89% ee, using the same phosphine catalyst (Scheme 21).[56] Scheme 21
Enantioselective [3 + 2] Cycloadditions with Trisubstituted Enones[56] EtO2C O
O
CO2Et
10 mol% 58 toluene, rt
+
•
97%; 89% ee
Ph
Br
Br Ph
50
61
CO2Et
O +
•
62
10 mol% 58 toluene, rt
Ph
Ph
EtO2C O Ph
81%; 89% ee
Ph 50
63
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
64
3.1.2
31
[3 + 2]-Cycloaddition Reactions
Ethyl Acylcyclopentenecarboxylates 59 and 60; General Procedure Using Ethyl Buta-2,3dienoate (1.2 equiv):[56]
In a glovebox, a soln of phosphine 58 (14.7 mg, 0.040 mmol) in toluene (0.5 mL) was added to a stirred soln of the enone (0.400 mmol) and ethyl buta-2,3-dienoate (50; 56 L, 0.48 mmol) in toluene (1.5 mL). The mixture was stirred at ambient temperature for 16 h, and then the product was directly purified by flash chromatography. Ethyl Acylcyclopent-1-enecarboxylates 59 and 60; General Procedure Using Ethyl Buta2,3-dienoate (2.0 equiv):[56]
In a glovebox, a soln of phosphine 58 (14.7 mg, 0.040 mmol) in toluene (0.5 mL) was added to a stirred soln of the enone (0.400 mmol) and ethyl buta-2,3-dienoate (50, 46 L, 0.40 mmol) in toluene (1.5 mL). After 3 h, further ethyl buta-2,3-dienoate (50; 46 L, 0.40 mmol) was added, the mixture was stirred at ambient temperature for an additional 16 h, and then the product was directly purified by flash chromatography. 3.1.2.1.3
Cycloaddition Reactions Catalyzed by Amino Acid Based Phosphines
Miller and co-workers have demonstrated that an amino acid based phosphine facilitates the enantioselective allenoate–enone cycloaddition reaction for ª-substituted allenic esters.[57] They propose that the addition of the phosphine 66 to the racemic allenoate (€)-65 generates zwitterion 67, thereby removing the axis of chirality in the allene and providing an opportunity to effect an enantioselective cycloaddition through a dynamic kinetic resolution (Scheme 22). This strategy is effective using 1,3-diarylprop-2-en-1-ones (chalcones) 68 as the enone-coupling partners, affording the cycloadducts 69 in high yield (89–96%) with three contiguous stereogenic centers as single regio- and diastereomers with excellent asymmetric induction (87–91% ee). The more sterically encumbered allenes require 1 equivalent of catalyst 66 to provide useful reaction rates. Scheme 22
Deracemization Reactions of a ª-Substituted Allenoate[57] BocHN
CO2Me (1 equiv) PPh2
CO2Bn
BnO2C
66 toluene, 23 oC
•
NHBoc
P Ph
H (±)-65
Ph CO Me 2 67 O Ar1 Ph
CO2Bn
68
Ph
O
Ar1
69
Ar1
ee (%) Yield (%) Ref
Ph
91
94
[57]
4-ClC6H4
87
96
[57]
4-MeOC6H4
90
89
[57]
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
32
Stereoselective Synthesis
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
3.1
Benzyl (3S,4R,5R)-4-Benzoyl-3-methyl-5-phenylcyclopent-1-enecarboxylate (69, Ar1 = Ph); Typical Procedure:[57]
To a flame-dried round-bottomed flask equipped with a magnetic stirrer bar was added (E)-1,3-diphenylprop-2-en-1-one (68, Ar1 = Ph; 10.4 mg, 0.050 mmol) and toluene (400 L). Allenic ester (€)-65 (14.1 mg, 0.075 mmol) was then added and the flask was sealed with a rubber septum and purged with dry N2 for 15 min. A soln of chiral phosphine 66 (19.4 mg, 0.050 mmol) in toluene (100 L) was then added to the tube dropwise. The soln was allowed to stir for 7 h at 23 8C at which point it was passed through a 20-cm plug of silica gel using EtOAc/hexanes (3:2) as eluent. Concentration of this soln under reduced pressure and purification of the resulting residue by flash column chromatography (silica gel, hexanes to hexanes/EtOAc 19:1) afforded a clear oil; yield: 18.6 mg (94%). Cycloaddition Reactions Catalyzed by Planar-Chiral 2-Phospha[3]ferrocenophanes
3.1.2.1.4
Marinetti and co-workers have designed an air-stable planar-chiral 2-phospha[3]ferrocenophane catalyst 71 to facilitate a highly enantioselective [3 + 2] cyclization of ethyl buta-2,3-dienoate (50) with Æ,-unsaturated esters and ketones 70 (Scheme 23).[58] The substrate scope consists mainly of 1,3-diarylprop-2-en-1-ones (chalcone) derivatives, which furnish 72 and 73 in high yields (63–87%), and with excellent regioselectivity [(72/73) up to >20:1] and enantioselectivities (90–96% ee). Diethyl fumarate (70, R1 = CO2Et; R2 = OEt) also participates in a highly enantioselective cycloaddition (90% ee) with 50 using the same phosphine catalyst. Scheme 23 2-Phospha[3]ferrocenophane-Catalyzed Enantioselective [3 + 2] Cycloadditions with Fumarate and Chalcones[58]
10 mol%
TMS Fe
TMS PCy
O CO2Et
R2
+
•
71 toluene, rt
R1 50
70
CO2Et
CO2Et + R1
R2
O R2 72
R1 O 73
R1
R2
Equiv of 50
Ratio (72/73)
ee (%) of 72
Yield (%) of 72 and 73
Ref
CO2Et
OEt
0.5
–
90
68
[58]
Ph
Ph
2.0
20:1
92
65
[58]
1-naphthyl
Ph
2.0
>20:1
96
87
[58]
4-MeOC6H4
Ph
2.0
>20:1
93
71
[58]
4-O2NC6H4
Ph
1.2
10:1
92
63
[58]
2-furyl
Ph
2.0
8:1
93
71a
[58]
Ph
4-MeOC6H4
2.0
>20:1
95
85
[58]
C”C(CH2)4Me
Ph
1.2
15:1
90
70
[58]
a
Acetone used as solvent.
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.2
33
[3 + 2]-Cycloaddition Reactions
Triethyl (1S,2R)-Cyclopent-3-ene-1,2,3-tricarboxylate (72, R1 = CO2Et; R2 = OEt); Typical Procedure:[58]
To a mixture of diethyl fumarate (70, R1 = CO2Et; R2 = OEt; 53 mg, 0.30 mmol) and phosphine 71 (7.1 mg, 0.015 mmol) in degassed toluene (0.5 mL), was added, under argon, ethyl buta-2,3-dienoate (50; 18 L, 0.15 mmol). The soln was stirred at rt for 24 h. The crude mixture was concentrated under reduced pressure and purified by flash chromatography (silica gel, EtOAc/heptanes 15:85); yield: 68%; 90% ee. 3.1.2.1.5
Cycloaddition Reactions Catalyzed by Chiral Thiourea-Containing Phosphines
The phosphine-promoted reactions of allenoates are not limited to annulations with electron-deficient alkenes. Activated aldimines also provide competent coupling partners for these types of transformations, which expands the scope to the formation of heterocycles.[59–61] The asymmetric version of this reaction developed by Jacobsen and co-workers involves the cycloaddition of N-(diphenylphosphoryl)imines 74 with ethyl buta-2,3-dienoate (50) using the chiral thiourea-containing phosphine catalyst 75 (Scheme 24).[62] Although N-(diphenylphosphoryl)imines outperform N-tosylimines in terms of enantioselectivity, the reaction rates with the former are significantly slower. Nevertheless, the inclusion of substoichiometric triethylamine (5 mol%) and water (20 mol%) provides improved reaction rates, which is attributed to the additives abilities to facilitate proton transfer and thereby regenerate the catalyst. This further supports the role of water for promoting the [1,2]-hydrogen shift as outlined by Yu and co-workers (Section 3.1.2.1).[52–54] Under the optimal conditions, a variety of N-(diphenylphosphoryl)imines 74 participate in the cyclizations with 50 to furnish the dihydropyrroles 76 in high yields (70–90%) and with excellent enantioselectivity (94–98% ee). Scheme 24
Imine–Allene [3 + 2] Cycloadditions Catalyzed by Thiourea[62] S Bn2N O
O CO2Et N
+
•
P
Ph Ph
N H
N H
PPh2
Ar1
N
Ar1
50
CO2Et
75 20 mol% H2O, 5 mol% Et3N o toluene, −30 C, 48 h
O P Ph Ph 74
76
Ar1
mol% of 75 ee (%) Yield (%) Ref
Ph
10
98
84
[62]
4-FC6H4
10
95
72
[62]
4-MeOC6H4
20
97
80
[62]
4-PhC6H4
10
96
81
[62]
3-O2NC6H4
10
95
70
[62]
3,4,5-(MeO)3C6H2
20
95
70
[62]
2-BrC6H4
10
95
90
[62]
3-pyridyl
10
95
85
[62]
4-pyridyl
10
94
70
[62]
2-furyl
20
94
79
[62]
2-thienyl
20
97
77
[62]
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
34
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
Ethyl (S)-1-(Diphenylphosphoryl)-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate (76, Ar1 = Ph); Typical Procedure:[62]
To a 1-dram vial was charged imine 74 (Ar1 = Ph; 76.3 mg, 0.25 mmol) and thiourea 75 (15 mg, 0.025 mmol), and the vial was capped with a screw cap bearing a Teflon septum. After the vial was evacuated and charged with N2 three times, dry toluene (2.5 mL) was added followed by H2O (0.9 L, 0.2 equiv). The mixture was stirred vigorously for 10 min at rt, then Et3N (1.8 L, 0.05 equiv) was added, and the resulting mixture was immediately cooled in a –30 8C iPrOH bath, and stirred for another 15 min. Allene 50 (35 L, 0.3 mmol) was added via microsyringe, and the mixture was stirred at this temperature for 48 h. The resulting soln was rapidly loaded on a short silica gel column (2.5 cm 3 cm) and eluted with EtOAc/hexanes (1:1 then 7:3 then 1:0). The mixed fractions were further purified by preparative TLC (EtOAc/hexanes 3:1). The combined product was obtained as a white foamy solid; yield: 87.7 mg (84%); 98% ee [chiral supercritical fluid chromatography (Chiralpak AS-H, 5% MeOH/CO2, 3 mL • min–1, 30 8C, 210 nm. tR: 7.27 min (minor), 8.19 min (major)]. 3.1.2.2
Palladium-Catalyzed Asymmetric [3 + 2] Trimethylenemethane Cycloaddition Reactions
Transition-metal-catalyzed [3 + 2] cycloaddition using trimethylenemethane (TMM) as the dipolar three-carbon synthon is a powerful and versatile method for the construction of cyclopentanes.[18] Palladium–trimethylenemethane complexes generated from 3-acetoxy2-[(trimethylsilyl)methyl]prop-1-ene (77) with catalytic palladium, react with electron-deficient alkenes to produce exo-methylenecyclopentanes in a highly chemo-, regio-, and diastereoselective manner (Scheme 25).[63–65] This methodology has also been employed in a number of total syntheses.[66–68] Meanwhile, there have been a few accounts detailing trimethylenemethane cycloaddition reactions of imines to form pyrrolidines,[69–71] which are ubiquitous in pharmaceutical agents and natural product targets.[72] Nevertheless, the asymmetric processes were limited to chiral auxiliaries[73] until the development of several highly enantioselective palladium-catalyzed [3 + 2] trimethylenemethane cycloaddition reactions.[74–76] Scheme 25 Palladium-Catalyzed [3 + 2] Trimethylenemethane Cycloaddition[63–65]
R1 OAc
TMS
PdLn
+ EWG
77
R1
EWG
The difficulty in designing a catalyst for the asymmetric palladium–trimethylenemethane cycloaddition reaction is illustrated in the proposed mechanism outlined in Scheme 26.[77] The formation of the zwitterionic intermediate is generated by oxidative addition of the low-valent palladium complex into allylic acetate 77 followed by attack of the displaced acetate anion onto the trimethylsilyl group. The enantiodetermining step is most likely the initial nucleophilic attack of the zwitterionic intermediate, which occurs distal to the metal complex. Hence, bulky chiral phosphoramidite ligands 78–80 are required to induce asymmetry (Scheme 27).[74–76]
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.2
35
[3 + 2]-Cycloaddition Reactions
Scheme 26 Proposed Mechanism for Palladium-Catalyzed [3 + 2] Trimethylenemethane Cycloaddition[77] L L TMS
R1
Pd
OAc O 77
LnPd0
L L
Pd
R1
O
R1 H O
Scheme 27
Bulky Chiral Phosphoramidite Ligands[74–76]
Ph O O
O
P N
O
P N
O O
P N
Ph
78
79
80
Using ligand 78, high levels of asymmetric induction are observed for palladium-catalyzed [3 + 2] trimethylenemethane cycloadditions with electron-deficient alkenes.[74] For example, in the presence of 5 mol% of bis(dibenzylideneacetone)palladium(0) and 10 mol% of the chiral phosphoramidite ligand 78, 3-acetoxy-2-[(trimethylsilyl)methyl]prop-1-ene (77) reacts with the electron-deficient alkene 81 to provide the corresponding exo-methylenecyclopentane 82 in 79% yield and 84% ee (Scheme 28). The analogous reaction with the benzylidenedihydronaphthalenone 83 affords the corresponding spirocyclic cycloadduct 84 in 94% yield and with excellent asymmetric induction (92% ee).
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
36
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
Scheme 28 Asymmetric Palladium-Catalyzed [3 + 2] Cycloadditions of Trimethylenemethane with Alkenes[74] O 4
81 10 mol% 78, 5 mol% Pd(dba)2 toluene, −25 oC 79%; 84% ee 4
O 82 O
TMS
OAc Ph
77 83
O
10 mol% 78, 5 mol% Pd(dba)2 toluene, −25 oC 94%; 92% ee
Ph 84
Palladium-catalyzed [3 + 2] trimethylenemethane cycloadditions also provide an excellent strategy for the enantioselective construction of spirocyclic oxindole cyclopentanes.[75] Treatment of the 3-alkylidene-1,3-dihydro-2H-indol-2-one 85 (X = NCO2Me) and the cyano-substituted trimethylenemethane precursor 86 with 2.5 mol% of tris(dibenzylideneacetone)dipalladium and 10 mol% of chiral ligand 79 or 80, affords the corresponding spirocyclic oxindole cyclopentanes trans-87 and cis-87, in excellent yield and selectivity (Table 4). The trans/cis ratio of the [3 + 2] cycloadducts ranges from 1:6.2 to 19:1, and is dependent on the ligand and the 3-alkylidenedihydroindol-2-one. Interestingly, ligand 80 usually provides trans-87 as the major cycloadduct, while ligand 79 (which differs from ligand 80 only by the position of the naphthyl substituents) often provides cis-87 as the major product. Ligand 79 affords optimal diastereoselection with no substitution in the substrate aryl ring (entry 1), whereas ligand 80 provides optimal selectivity with more highly substituted systems (entries 4, 8, and 10). Enantiomeric excesses greater than 90% are generally observed in these cycloadditions with chiral ligand 79 or 80. Replacing the oxindole residue by the related benzofuranone 85 (X = O) (entries 11 and 12) provides comparable results to the parent substrate (entries 1 and 2).
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.2
37
[3 + 2]-Cycloaddition Reactions
Table 4 Enantioselective Construction of Spirocyclic Oxindolic Cyclopentanes by Asymmetric PalladiumCatalyzed [3 + 2] Cycloadditions of Trimethylenemethane[75] TMS
OAc
CN
CN 86 2.5 mol% Pd2(dba)3•CHCl3 10 mol% ligand, toluene
O X
O
+ O X
R2 R1
X
R2
R2
R1
R1
trans-87
85
Entry X
CN
R1
R2
Ligand Temp (8C)
cis-87
dr (trans87/cis-87)
ee (%) of trans-87
ee (%) of Total Yield cis-87 (%) of 87
Ref
1
NCO2Me
H
H
79
–20
1:6.2
96
>99
97
[75]
2
NCO2Me
H
H
80
0
4.3:1
92
95
97
[75]
3
NCO2Me
H
Cl
79
–20
1:2.7
99
92
90
[75]
4
NCO2Me
H
Cl
80
0
19:1
93
77
99
[75]
5
NCO2Me
H
OMe
79
0
1:2.7
95
99
94
[75]
6
NCO2Me
H
OMe
80
23
4:1
85
84
94
[75]
7
NCO2Me
OMe
OMe
79
–20
1.3:10
>99
99
96
[75]
8
NCO2Me
OMe
OMe
80
0
14:1
96
80
97
[75]
9 10
NCO2Me NCO2Me
79 80
–20 0
1:2.3 15:1
99 86
99 99
[75]
76
11
O
H
H
79
–20
1:5.7
>99
>99
99
[75]
12
O
H
H
80
0
4.6:1
94
92
91
[75]
O
>99
[75]
Under the same reaction conditions, a smooth cycloaddition reaction is observed even with sterically demanding trisubstituted alkenes bearing a tert-butyl group (Scheme 29).[75] The unsymmetrical substitution pattern on the alkene creates a third stereogenic center in the cycloadduct with excellent enantioselectivity (92–99% ee). Although the cycloaddition is stereospecific with respect to the alkene geometry, diastereomers are derived from the nucleophilic addition of the palladium–trimethylenemethane complex. Scheme 29 Palladium-Catalyzed [3 + 2] Cycloadditions of Trimethylenemethane with Trisubstituted Alkenes[75] TMS
OAc CN
CN
86 2.5 mol% Pd2(dba)3•CHCl3 10 mol% 79 toluene, −20 oC
But O N MeO2C
89%
CN But
But +
O
O N
N
MeO2C 98% ee
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MeO2C 1:2.6
99% ee
for references see p 63
38
Stereoselective Synthesis
3.1
TMS
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
OAc CN
But
CN
86 2.5 mol% Pd2(dba)3•CHCl3 10 mol% 79 toluene, 23 oC
O
But
But +
86%; 92% ee
N
CN
O
O N
MeO2C
N
MeO2C
MeO2C 3.4:1
The asymmetric [3 + 2] reaction also permits the enantioselective construction of pyrrolidines.[76] Treatment of the N-(tert-butoxycarbonyl)imines 88 and 3-acetoxy-2-[(trimethylsilyl)methyl]prop-1-ene (77) with the complex derived from bis(dibenzylideneacetone)palladium(0) and the chiral ligand 79, provides the pyrrolidines 89 in good yield (60–96%) and with excellent enantioselectivities (90–93% ee) (Scheme 30). The reaction temperature can be reduced to –15 8C in some cases, which affords slightly lower efficiency but excellent enantioselectivity. Similar results are obtained regardless of the substitution pattern or electronic nature of the aryl substituent. Scheme 30 Asymmetric Palladium-Catalyzed [3 + 2] Cycloadditions of Trimethylenemethane and N-(tert-Butoxycarbonyl)imines[76]
Boc OAc
TMS
N
+
5 mol% Pd(dba)2 10 mol% 79 toluene
NBoc
Ar1 77
Ar1
Ar1 88
89
Temp (8C) ee (%) Yield (%) Ref
Ph
4
91
84
[76]
2-MeOC6H4
4
92
80
[76]
3-MeOC6H4
–15
90
73
[76]
4-MeOC6H4
4
93
94
[76]
4-FC6H4
4
90
91
[76]
4-ClC6H4
4
91
96
[76]
3,5-Me2C6H3 –15
90
65
[76]
3-furyl
4
91
71
[76]
–15
90
60
[76]
3-thienyl
1-[(1S,2S)-4-Methylene-2-pentylcyclopentyl]ethanone (82); Typical Procedure:[74]
A vial containing Pd(dba)2 (8 mg, 0.01 mmol) and ligand 78 (16 mg, 0.030 mmol) was evacuated and purged with N2 (3 ) and toluene (1.0 mL) was added. The mixture was stirred for 2 min while a separate vial containing alkene 77 (100 L, 0.483 mmol) and (E)-non-3-en-2one (81; 50 L, 0.30 mmol) was evacuated and purged with N2 (3 ) and toluene (1.0 mL) was added. The latter soln was added to the catalyst soln and the mixture was stirred at –25 8C until the ketone was completely consumed, as determined by GC. Toluene was removed on a rotary evaporator and the crude residue was dissolved in CH2Cl2 and adsorbed onto a silica gel column, which was eluted with EtOAc/petroleum ether (1:9 to 1:4) to give a colorless oil; yield: 46 mg (79%). [m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.3
39
[4 + 1]-Cycloaddition Reactions
Methyl 3-Cyano-2,2-dimethyl-4-methylene-2¢-oxo-1¢,2¢-dihydrospiro[cyclopentane-1,3¢-indole]-1¢-carboxylate (87, X = NCO2Me; R1 = R2 = H); Typical Procedure:[75]
A test tube containing Pd2(dba)3•CHCl3 (2.55 mg, 2.50 mol), ligand 79 (6.4 mg, 0.01 mmol), and oxindole 85 (X = NCO2Me; R1 = R2 = H; 23.1 mg, 0.10 mmol), was purged three times with N2. Dry toluene (0.5 mL) was added, and the mixture was stirred for 5 min and subsequently equilibrated at –20 8C. The trimethylenemethane-precursor 86 (31.6 mg, 0.15 mmol) was added at once via syringe and the mixture was stirred for 15 h, after which it was directly loaded on a silica gel column (CH2Cl2). The cycloadduct 87 [(trans/cis) 10:62] was obtained as a colorless solid; yield: 30.1 mg (97%). (2R)-1-(tert-Butoxycarbonyl)-4-methylene-2-phenylpyrrolidines 89; General Procedure:[76]
A flask containing Pd(dba)2 (2.2 mg, 3.75 mol) and ligand 79 (4.8 mg, 7.5 mol) was evacuated and purged with argon. Toluene (0.3 mL) was added and the mixture was stirred at rt for 2 min. A soln of imine 88 (0.075 mmol) in toluene (0.2 mL) was added via cannula. 3-Acetoxy-2-[(trimethylsilyl)methyl]prop-1-ene (77; 25 L, 0.12 mmol) was added and the soln was stirred at the stated temperature for 4–24 h, monitored by GC for complete consumption of the imine. The mixture was loaded directly onto a column and purified by flash chromatography (silica gel, EtOAc/pentane). 3.1.3
[4 + 1]-Cycloaddition Reactions
3.1.3.1
Rhodium- and Platinum-Catalyzed Asymmetric [4 + 1]-Cycloaddition Reactions of Vinylallenes and Carbon Monoxide
Carbon monoxide is an important one-carbon synthon for transition-metal-catalyzed carbonylation reactions, which provide methods for the synthesis of various carbonyl-containing compounds that range from small-scale laboratory reactions to industrial-scale processes.[78] Murakami and Ito have demonstrated that vinylallenes 90 provide four-carbon synthons in carbonylative rhodium-catalyzed [4 + 1]-cycloaddition reactions for the construction of 5-substituted 2-alkylidenecyclopent-3-enones 91 (Scheme 31).[79,80] Scheme 31 Rhodium-Catalyzed [4 + 1] Cycloadditions of Vinylallenes and Carbon Monoxide[79,80] R2
R2 R3
• R1
+
CO
Rh(I) (cat.)
R1 R3 R1
R1 90
O 91
The development of the asymmetric version of the metal-catalyzed [4 + 1] cycloaddition has proven challenging. This can primarily be attributed to the displacement of the chiral ligand(s) by carbon monoxide, which is a strong -donor/-acceptor ligand. Despite this challenge, Murakami and Ito have successfully developed the enantioselective variant of this reaction using bisphosphine 92 [(R,R)-Me-DuPHOS] or 93 [(R,R)-Et-DuPHOS] as the chiral ligands with carbon monoxide (5 atm) in 1,2-dimethoxyethane at 55–60 8C for 6–20 hours.[81,82] In most cases, the reactions provide high yields and modest enantioselectivities for the 2-alkylidenecyclopent-3-enones 94 (Scheme 32). Nevertheless, these results are very encouraging, considering the challenges associated with controlling stereocontrol in substrates that lack directive heteroatom functionality.
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
40
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
Scheme 32 Rhodium- and Platinum-Catalyzed Asymmetric [4 + 1] Cycloadditions of Vinylallenes[81,82] Et P
P Et Et
P
P Et
92
93
R2
R2 R3
• 1
R
+
catalyst, ligand, DME 55−60 oC, 6−20 h
R1
CO
R3
R1
R1
O 94
R1
R2
R3 Catalyst
Ligand ee (%) Config Yield (%) Ref
Me Pr
Pr [Rh(cod)2]PF6
92
64.5
5S
87
[81]
Me Pr
Pr Pt(cod)2
92
74.8
5R
76
[82]
Me
(CH2)4
[Rh(cod)2]PF6
92
78.0
5S
99
[81]
Me
(CH2)4
Pt(cod)2
93
74.1
5R
87
[82]
[Rh(cod)2]PF6
92
74.6
5S
97
[81]
Me Et
Et [Rh(cod)2]PF6
92
41.9
5S
72
[81]
Me Et
Et Pt(cod)2
93
76.6
5R
99
[82]
Me Bu
Bu [Rh(cod)2]PF6
92
14.8
5S
98
[81]
Me Bu
Bu Pt(cod)2
92
70.7
5R
97
[82]
Et
Et
Et [Rh(cod)2]PF6
92
17.3
5S
45
[81]
Et
Et
Et Pt(cod)2
92
75.8
5R
98
[82]
Me
Me
(CH2)5
[Rh(cod)2]PF6
92
10.6
5S
98
[81]
Me
(CH2)5
Pt(cod)2
92
76.9
5R
96
[82]
The introduction of ester groups on the vinylallenes permits the cycloaddition to proceed at lower temperatures with remarkable selectivity (up to 95% ee) (Scheme 33).[81] The cyclopentenones 95 can be reduced to furnish the cis-cyclopentenols 96 in high yield (93– 96% over 2 steps) and with outstanding diastereo- and enantiocontrol. The selectivity in the reduction of 95 is presumably due to the directing effect of the phenyl substituent.
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.3
41
[4 + 1]-Cycloaddition Reactions
Scheme 33
Rhodium-Catalyzed Asymmetric [4 + 1] Cycloadditions of Vinylallenes[81]
CO2R1 •
CO2R1
CO (5 atm) [Rh(cod)2]PF6, 92 DME, 10 oC, 24−90 h
Ph
NaBH4, CeCl3 MeOH
Ph O 95 CO2R1 Ph OH 96
R1
ee (%) of 96 Overall Yield (%) of 96 Ref
Et
92.0
93
[81]
iBu 91.5
96
[81]
Bn 95.0
94
[81]
Contrary to the variable enantioselectivities obtained for the rhodium-catalyzed [4 + 1] reactions, which are significantly affected by the substrate structure, the analogous process with a platinum catalyst modified with the same chiral ligand generally affords superior enantioselectivities (Scheme 32).[82,83] Interestingly, the observed absolute configuration of the products in the platinum-catalyzed [4 + 1] reactions is opposite to that obtained in the rhodium-catalyzed reactions. To understand the origin of different chirality transfer of rhodium compared to platinum in the [4 + 1] reactions, Murakami and Ito postulated the mechanism:[81,82] first, vinylallene in an s-cis conformation coordinates to a metal center beset with a chiral environment in a Å4-binding mode; next, carbon monoxide is introduced into the coordination sphere to give a (vinylallene)(carbonyl)metal complex, which acquires a significant contribution from a metallacyclopent-3-ene form, or actually assumes a 2-binding structure; finally, migratory insertion of the carbonyl group in the metal—carbon bond and subsequent reductive elimination of the metal catalyst produces a [4 + 1] cycloadduct. Although it might be difficult to assign concrete binding structures to the species involved in a catalytic process, it is possible to attribute the origin of the enantioselectivity to a Å4-bound form, a 2-bound form, or a later stage. In the case of rhodium, the chirality is installed on a vinylallene which binds to rhodium in a Å4-fashion (97 and 98, Scheme 34) rather than in a 2-format. In this case, intermediate 97 suffers from greater steric repulsions than that of the alternative binding pattern in 98. This results in the preferential formation of the 5S configuration in the product cyclopentenone. However, in the platinum-catalyzed reaction, the binding step to give a Å4-complex leading to a planar 2-bonded metallacyclopentene form is reversible and the first irreversible step which dictates the enantioselection lies after the establishment of a planar 2-bonded metallacyclopentene form (99 and 100) on the reaction coordinate. Although complex 99 suffers from steric repulsion more seriously than intermediate 100 and thus is thermodynamically less stable than 100, it is more reactive for the subsequent irreversible incorporation of carbon monoxide to release the steric congestion, which favors the kinetic formation of the 5R-isomer.
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
42
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
Scheme 34 Origin of Different Chirality Transfer of Rhodium and Platinum[82]
P •
P
R1
R1
P
Rh
Rh R2
R2
97
98
R2
R2 R1
R1
O
O
5R
5S
P Pt
99
P •
P H
H
R1 R2
R1 R2
P
P Pt
100
(6S)-8-Isopropylidenebicyclo[4.3.0]non-1(9)-en-7-one [94, R1 = Me; R2,R3 = (CH2)4]; Typical Procedure:[81]
CAUTION: Carbon monoxide is extremely flammable and exposure to higher concentrations can quickly lead to a coma. A mixture of [Rh(cod){(R,R)-Me-DuPHOS}]PF6 (4.5 mg, 6.8 mol) and 1-(3-methylbuta-1,2dienyl)cyclohex-1-ene (20.0 mg, 135 mol) in DME (3 mL) under CO (5 atm) in an autoclave was stirred in an oil bath at 58 8C for 9 h. After the mixture was cooled, the solvent was removed under vacuum. The residue was subjected to preparative TLC (silica gel, Et2O/ hexane 1:10); yield: 23.5 mg (99%). 3.1.3.2
Copper-Catalyzed Asymmetric [4 + 1] Cycloadditions of Enones with Diazo Compounds
The only asymmetric [4 + 1] cycloaddition to form dihydrofurans has been reported by Fu and co-workers, who have developed a copper-catalyzed asymmetric [4 + 1] cycloaddition of enones with diazoacetates employing chiral ligand 101 (Scheme 35).[84] This work was inspired by the development of the symmetrical version by Spencer.[85–87] In this [4 + 1] reaction, the four-atom synthon comes from the enone, and the one-atom synthon comes from the diazo compound. The reaction is presumed to proceed via intermediate 102.
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.3
43
[4 + 1]-Cycloaddition Reactions
Scheme 35 Copper-Catalyzed Asymmetric [4 + 1] Cycloadditions of Enones with Diazo Compounds[84]
Fe N
N
Fe
101
1 mol% CuOTf 1.3 mol% 101 CH2Cl2, rt
O
O R1
R2
OAr1
+
CO2Ar1 O ∗ CuL∗
N2
R1
R2 102
CO2Ar1 O R1
R2
The scope of the copper-catalyzed asymmetric synthesis of 2,3-dihydrofurans 104 has been examined, and the planar-chiral bipyridine ligand 101 in conjunction with the hindered 2,6-diisopropylphenyl ester 103 are optimal for asymmetric induction (Table 5). The highest enantiomeric excesses are obtained with aryl-substituted enones. Hence, regardless of whether R1 or R2 are electron-poor or electron-rich aromatic groups, good enantioselectivity is typically observed (entries 2–6). Furthermore, the reaction proceeds with useful enantioselectivity with heteroaromatic substituents (entries 7 and 8). Finally, a vinyl-substituted enone also undergoes cycloaddition with high efficiency (entry 9). This method for the synthesis of 2,3-dihydrofurans may also be applied to alkyl-substituted enones, albeit with modest enantioselectivity (entries 10–12). Table 5 Copper-Catalyzed Asymmetric [4 + 1] Cycloadditions of 2,6-Diisopropylphenyl Diazoacetate[84]
O
O R1
R2
Pri
1 mol% CuOTf 1.3 mol% 101 CH2Cl2, rt
O
+
O O R1
Pri
N2
Pri O
103
Pri
R2 104
Entry
R1
R2
dr
ee (%)
Yield (%)
Ref
1
Ph
Ph
13:1
85
79
[84]
2
4-F3CC6H4
Ph
19:1
76
59
[84]
3
4-ClC6H4
Ph
19:1
88
77
[84]
4
4-MeOC6H4
Ph
>20:1
92
84a
[84]
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
44
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
Table 5
(cont.)
Entry
R1
R2
5
Ph
4-ClC6H4
6
Ph
4-MeOC6H4
7
dr
Ph
N
ee (%)
Yield (%)
Ref
>20:1
88
81
[84]
9:1
93
84
[84]
>20:1
93
68
[84]
Boc
8
Ph
3-furyl
6:1
87
63
[84]
9
Ph
CH=CHPh
7:1
93
76
[84]
10
Ph
Bu
>20:1
78
92
[84]
11
(CH2)5Me
Ph
13:1
75
69
[84]
12
(CH2)5Me
Me
>20:1
71
80
[84]
a
The product was hydrolyzed and then acetylated prior to isolation.
The asymmetric copper-catalyzed [4 + 1] cycloaddition can be applied to the concise synthesis of deoxy-C-nucleosides, which are important compounds of interest in medicinal chemistry as mimics of naturally occurring nucleosides (Scheme 36).[84] For example, the Æ-diazoacetate 103 can be combined with vinylogous ester 105 to furnish the 2,3-dihydrofuran 106, which is not isolated due to its lability. Hydrogenation of the alkene followed by reduction of the ester affords the desired tetrahydrofuran 107 in good yield and with excellent diastereoselectivity (77% yield for 3 steps; dr >20:1). Deprotection of the (trimethylsilyl)ethyl group provides the enantiomerically enriched deoxy-C-nucleoside 108 (94% ee). Catalytic Asymmetric Synthesis of a Deoxy-C-nucleoside[84]
Scheme 36
O
O Ph
TMS
O
+
Pri O Pri
N2 103
105
O Ph
1 mol% CuOTf 1.3 mol% 101 CH2Cl2, rt
Pri 1. H2, Pd/C 2. LiAlH4
O
Ph
O OH
O O 106
O
Pri TMS 107
TMS
77%; dr >20:1
BF3•OEt2
Ph
O OH
86%
OH 108
94% ee; dr >20:1
2,6-Diisopropylphenyl (2R,3S)-3,5-Diphenyl-2,3-dihydrofuran-2-carboxylate (104, R1 = R2 = Ph); Typical Procedure:[84]
The catalyst was prepared by adding a soln of ligand 101 (8.4 mg, 0.013 mmol) in CH2Cl2 (4 mL) to CuOTf•0.5(toluene) (2.6 mg, 0.010 mmol) and stirring the resulting mixture for [m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.4
45
[3 + 3]-Cycloaddition Reactions
20 min. This soln was then added to (E)-1,3-diphenylprop-2-en-1-one (208 mg, 1.0 mmol), and the mixture was stirred for 5 min. Then, a soln of 2,6-diisopropylphenyl diazoacetate (103; 271 mg, 1.1 mmol) in CH2Cl2 (1.0 mL) was added. After being stirred for 1 h at rt, the mixture was filtered through a plug of silica gel (hexanes/Et2O 100:1), and the product was isolated as a colorless oil; yield: 340 mg (79%). 3.1.4
[3 + 3]-Cycloaddition Reactions
3.1.4.1
Chiral Lewis Acid Catalyzed [3 + 3] Cycloadditions of Nitrones to Doubly Activated Cyclopropanes
Doubly activated cyclopropanes generally undergo direct nucleophile addition to afford ring-opened products, albeit under forcing condition;[88–92] however, several groups have demonstrated that Lewis acids catalyze the addition of electron-rich alkenes, indoles, and -keto esters under relatively mild conditions.[93–95] For example, Young and Kerr reported the ytterbium(III) trifluoromethanesulfonate mediated addition of nitrones to provide racemic tetrahydro-1,2-oxazines,[96–98] which prompted Sibi and co-workers to develop the enantioselective version using a chiral Lewis acid to promote the formation of tetrahydro-1,2-oxazines with very high enantioselectivity.[99] The cycloaddition of nitrones 110 to the doubly activated cyclopropanes 109 in the presence of nickel(II) perchlorate and the chiral ligand 111 furnishes the tetrahydro-1,2oxazines 112 in high yield and with excellent enantioselectivity (Table 6). The diester groups in cyclopropanes 109 directly affect the yield and selectivity. For example, the diethyl derivative 109 (R1 = Et) provides excellent results with the N-methyl- and N-phenylnitrone (entries 2 and 4), whereas the reaction with the bulky tert-butyl ester 109 (R1 = t-Bu) is significantly slower (entry 5). Additionally, the more reactive N-phenylnitrone provides higher enantioselectivities than the N-methylnitrone (cf. entries 1 and 3, and entries 2 and 4). Diethyl cyclopropane-1,1-dicarboxylate (109, R1 = Et) reacts with a variety of nitrones in high yields (entries 6–10) and usually with excellent enantioselectivity (entries 6–8); however, the nitrones derived from cinnamyl aldehyde (entry 9) and furfural (entry 10) provide lower enantioselectivity. Table 6
[3 + 3] Cycloadditions of Nitrones to Doubly Activated Cyclopropanes[99]
O
N
N
O
Ph
O
O
O OR1 +
R 1O
N
R3
Ph 111 Ni(ClO4)2, CH2Cl2 4-Å molecular sieves rt, 1.5−4 d
O O R1O
OR1 R2
R2 O 109
NR3
112
110
Entry
R1
R2
R3
mol% of Ni(ClO4)2/111
ee (%)
Yield (%)
Ref
1
Me
Ph
Me
30
89
96
[99]
2
Et
Ph
Me
10
92
99
[99]
3
Me
Ph
Ph
30
91
97
[99]
4
Et
Ph
Ph
10
94
99
[99]
5
t-Bu
Ph
Ph
30
95
39
[99]
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
46
Stereoselective Synthesis Table 6
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
(cont.) R1
Entry
3.1
R2
R3
mol% of Ni(ClO4)2/111
ee (%)
Yield (%)
Ref
6
Et
4-BrC6H4
Me
10
95
99
[99]
7
Et
Ph
Bn
10
93
99
[99]
8
Et
4-MeOC6H4
Bn
10
90
99
[99]
9
Et
CH=CHPh
Me
10
71
99
[99]
10
Et
2-furyl
Me
10
79
95
[99]
2-Mono- and 2,2-disubstituted cyclopropane-1-dicarboxylates also provide suitable substrates for this transformation (Table 7). Racemic methyl- and phenyl-substituted cyclopropanes 113 provide the cycloadducts 114 in high yields (entries 1–3) and in a completely regioselective manner, with the oxygen of the dipole adding to the substituted rather than the unsubstituted carbon of the cyclopropane. For monosubstituted cyclopropanes, although cis/trans mixtures are obtained, the chiral catalyst provides good enantioselectivity for both diastereomers, particularly for the trans-isomers (‡95% ee, entries 1–3). The cycloaddition with the 2,2-dialkyl-substituted derivatives 113 [R1 = R2 = Me, R1,R2 = (CH2)5] is also completely regioselective and proceeds with superb enantioselectivity (entries 4 and 5), albeit in somewhat lower yields. In terms of reactivity, the substituted cyclopropanes in Table 7 are much more reactive than the unsubstituted substrates shown in Table 6, which is reflected in the shorter reaction times (2–8 h vs 1.5–4 d). [3 + 3] Cycloadditions of Nitrones with Substituted Cyclopropanes[99]
Table 7
MeO2C
O
CO2Me
N
Me
+
R1
30 mol% Ni(ClO4)2, 30 mol% 111 CH2Cl2, 4-Å molecular sieves rt, 2−8 h
R1
Ar1
R2
O
NMe
R2
113
Entry
CO2Me Ar1
MeO2C
R1
114
R2
Ar
Ratio (trans/cis)
ee (%) of trans-114
ee (%) of cis-114
Yield (%)
Ref
1
Me H
4-BrC6H4
0.8:1
96
90
99
[99]
2
Ph
H
4-BrC6H4
1.4:1
95
90
99
[99]
3
Ph
H
Ph
1.4:1
96
4 5 a
Me Me Ph (CH2)5
4-BrC6H4
90
99
[99]
–
a
96
–
73
[99]
–
99a
–
54
[99]
ee (%) of 114; cis/trans descriptor not applicable in this case.
Dimethyl 3-Aryl-2-methyltetrahydro-2H-1,2-oxazine-4,4-dicarboxylates 114; General Procedure:[99]
A flame-dried vial was charged with Ni(ClO4)2•6H2O (0.090 mmol), the ligand 111 (0.099 mmol), and freshly dried 4- molecular sieves (150–250 mg). Dry CH2Cl2 (3 mL) was added under N2, and the mixture was then stirred at rt overnight (or 2 h), until all the Ni(ClO4)2•6H2O was dissolved. To the pale green soln, cyclopropyl substrate 113 (0.30 mmol) in dry CH2Cl2 (0.3 mL) was added via syringe and the mixture changed slightly to a darker blue/green color. After the mixture was stirred at rt for 15 min, the nitrone (0.40 mmol) was added. An immediate color change to a more yellow/green was normally observed. The soln was then stirred at rt for the appropriate time. The mixture was then filtered through a 35-mm layer of silica gel (7 g). The silica gel layer was washed with Et2O (40–60 mL) (TLC). The solvent was removed under reduced pressure to give the crude prod[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.4
47
[3 + 3]-Cycloaddition Reactions
uct, which was analyzed using 1H NMR to determine the diastereomeric ratio by comparison with data from standard trans- and cis-product samples. The diastereomers were separated by flash chromatography (silica gel, hexane/EtOAc 95:5 to 80:20). The ee was estimated on the basis of HPLC analysis using a chiral column (Daicel Chiralcel OD or AD; hexane/iPrOH). The absolute stereochemistry for the tetrahydro-1,2-oxazine products has not been established. Palladium-Catalyzed Asymmetric [3 + 3] Cycloadditions of Trimethylenemethane Derivatives with Nitrones
3.1.4.2
Since the introduction of palladium–trimethylenemethane complexes by Trost and Chan in 1979 they have served as an important three-carbon unit for the construction of various cyclic frameworks, particularly in the context of [3 + 2]-cycloaddition reactions (Section 3.1.2.2).[63–65] Shintani and Hayashi have utilized this synthon in the development of the asymmetric version of the [3 + 3] cycloaddition. They have demonstrated the highly stereoselective cycloaddition of trimethylenemethane derivatives 115 (Scheme 37) with nitrones in the presence of a catalyst derived from Å3-allyl(cyclopentadienyl)palladium(II) and the bulky chiral phosphoramidite ligand 116 (Ar2 = Ph, 2-naphthyl) to generate the corresponding tetrahydro-1,2-oxazines 117.[100] The reaction tolerates a variety of aryl groups on the electrophilic carbon atom of the nitrone, and affords the [3 + 3] cycloadducts in excellent yield (92–99% yield) and with relatively high diastereoselectivity [(trans/cis) 76:24–89:11] and excellent enantioselectivity (91–92% ee). Several trimethylenemethane precursors with different aryl groups can also be used in the [3 + 3]-cycloaddition reaction with similar efficiency. Nevertheless, alkyl-substituted nitrones and unsubstituted trimethylenemethane precursors 115 (Ar1 = H) are unsuitable substrates under these reaction conditions, due to low efficiency and enantioselectivities. Scheme 37 Palladium-Catalyzed Asymmetric [3 + 3] Cycloadditions[100] Ar2 O
10−16 mol%
O
N
P
Ar2 116
TMS O OAc
+
N
R1
Ar1
R2
O
5−8 mol% Pd(η3-C3H5)(Cp) CH2Cl2, 40 oC, 48 h
N
R2 R1
H Ar1
115
117
Ar1
R1
R2
Ar2
Ratio (trans/cis)
ee (%) of trans-117
Yield (%)
Ref
Ph
4-F3CC6H4
4-EtO2CC6H4
2-naphthyl
89:11
92
95
[100]
2-naphthyl
84:16
91
99
[100]
O Ph
Ph
4-F3CC6H4
Ph
3-ClC6H4
4-EtO2CC6H4
2-naphthyl
85:15
91
98
[100]
Ph
2-FC6H4
4-EtO2CC6H4
2-naphthyl
76:24
91
99
[100]
Ph
Ph
4-EtO2CC6H4
2-naphthyl
85:15
92
92
[100]
4-Tol
4-F3CC6H4
4-EtO2CC6H4
2-naphthyl
83:17
88
78
[100]
N Me
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
48
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
Ar1
R1
R2
Ar2
Ratio (trans/cis)
ee (%) of trans-117
Yield (%)
Ref
4-ClC6H4
4-F3CC6H4
4-EtO2CC6H4
2-naphthyl
86:14
90
91
[100]
4-ClC6H4
3-ClC6H4
4-EtO2CC6H4
2-naphthyl
85:15
93
98
[100]
2-naphthyl
4-F3CC6H4
4-EtO2CC6H4
Ph
88:12
89
85
[100]
2-naphthyl
3-ClC6H4
4-EtO2CC6H4
Ph
85:15
93
99
[100]
4-Aryl-5-methylenetetrahydro-2H-1,2-oxazines 117; General Procedure:[100]
A soln of Pd(Å3-C3H5)(Cp) (2.1 mg, 9.9 mol, or 3.4 mg, 16 mol) and ligand 116 (Ar2 = 2-naphthyl; 12.9 mg, 19.9 mol, or 20.7 mg, 32.0 mol) in CH2Cl2 (0.30 mL) was stirred for 10 min at rt. The nitrone (0.200 mmol) and trimethylenemethane precursor 115 (0.400 mmol) were added to the soln with the aid of CH2Cl2 (0.20 mL), and the resulting mixture was stirred for 48 h at 40 8C. The mixture was directly passed through a pad of silica gel with EtOAc, and the solvent was removed under vacuum. The residue was purified by preparative TLC (silica gel). 3.1.5
[4 + 3]-Cycloaddition Reactions
The [4 + 3]-cycloaddition reaction provides an efficient and convenient method to construct seven-membered rings.[101–103] Although the asymmetric [4 + 3] cycloaddition has attracted considerable attention since the mid-1990s, only a few investigations have focused on the development of the catalytic asymmetric version. Since the asymmetric [4 + 3] cycloaddition using chiral auxiliaries have been reviewed,[104–106] this section will focus on catalytic asymmetric [4 + 3] cycloadditions using chiral organocatalysts, Lewis acids, and transition-metal complexes. 3.1.5.1
Asymmetric Organocatalysis of [4 + 3]-Cycloaddition Reactions of Allylic Cations and Dienes
In 2003, Harmata and co-workers reported the first example of an asymmetric [4 + 3]-cycloaddition reaction of allylic iminium ions with dienes using the MacMillan catalyst.[107] The process is initiated through the in situ generation of the iminium ion 120 from pentadienal 118 with the chiral secondary amine 119. Intermediate 120 reacts with electronrich 2,5-disubstituted furans to afford, upon acid-catalyzed hydrolysis, the [4 + 3] cycloadducts 121 and regenerating the catalyst (Scheme 38). A substoichiometric amount of the chiral amine 119 (20 mol%) is sufficient to effect the formation of oxo aldehydes 121 as a single diastereomer in moderate to high yield (18–74%) with excellent enantioselectivity (80–90% ee). However, a limitation of this transition-metal-free methodology is that only 2,5-disubstituted furans provide the [4 + 3] cycloadducts in reasonable yield and enantioselectivity. The reactions employing monosubstituted or unsubstituted furans lead to complex mixtures (including some alkylation products). Nevertheless, the ability to employ a triorganosilane as a substituent provides a number of opportunities for post-cyclization functionalization reactions.
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.5
49
[4 + 3]-Cycloaddition Reactions
Scheme 38
Asymmetric [4 + 3]-Cycloaddition Reactions of 2,5-Disubstituted Furans[107] O Bn
NMe
20 mol%
O
HN But
OR1
Bn
119 TFA, CH2Cl2
NMe N
CHO
R1O
But
118
120 O R2
O
R2
CHO O R2
R2 121
R1
R2
TMS
Me –78
96
89
64
[107]
TES
Me –60
96
81
51
[107]
TBDMS Me –60
96
80
44
[107]
TIPS
Me –60
96
90
21
[107]
TMS
Et
–60
22
81
55
[107]
TBDMS Et
–65
91
87
18
[107]
TES
Et
–65
91
84
46
[107]
TES
Pr
–65
95
85
74
[107]
TMS
Pr
–65
95
89
33
[107]
a
Temp (8C) Time (h) eea (%) Yield (%) Ref
Determined by analysis of the N-butylpyrrole derivative of the cycloadducts using chiral HPLC (see procedure).
{(2R)-3-Oxo-8-oxabicyclo[3.2.1]oct-6-en-2-yl}acetaldehydes 121; General Procedure:[107]
To a soln of (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one (119) in CH2Cl2 (1 mL) was added TFA and the mixture was placed in a cooling bath at the desired temperature. The soln was stirred for 10 min before the addition of silyl enol ether 118 in CH2Cl2 (1 mL). The mixture was stirred for an additional 10 min and then the furan (2–5 equiv) was added. The resulting soln was stirred at a constant temperature for a period of time, as indicated in Scheme 38. The reaction was then quenched with cold H2O and the mixture was extracted with Et2O. The separated organic layer was dried (MgSO4) and concentrated. The residue was purified by flash chromatography to afford the [4 + 3] cycloadducts 121. For the measurement of enantiomeric excess, the product was treated with BuNH2 (2–3 equiv) in CHCl3 to give the corresponding fused N-butylpyrrole derivative. The ee was then determined by chiral HPLC (Chiralcel OD-H or Chiralpak AD column). 3.1.5.2
Chiral Lewis Acid Catalyzed [4 + 3] Cycloadditions of Nitrogen-Stabilized Oxyallyl Cations Derived from N-Allenylamides
Hsung and Huang have demonstrated that nitrogen-stabilized chiral oxyallyl cations, generated in situ through the epoxidation of N-allenylamides such as 123 (Scheme 39), readily undergo highly diastereoselective inter-[108] and intramolecular[109,110] [4 + 3] cycloadditions with dienes. Additional studies have focused on the examination of chiral Lewis [m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
50
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
acids for the catalytic asymmetric [4 + 3]-cycloaddition reaction.[111] Treatment of 124 with the complex derived from copper(II) trifluoromethanesulfonate, the chiral bis(dihydrooxazole) (bisoxazoline) ligand 122, and silver(I) hexafluoroantimonate, furnishes the nitrogen-stabilized oxyallyl cation 125, which undergoes asymmetric cycloaddition with furan to afford the cycloadduct 126 (R1 = H) in 91% yield and with 99% ee. The reaction also proceeds with 3-methylfuran, providing analogous results. Nevertheless, 2-substituted and 2,5-disubstituted furans afford poor asymmetric induction, in contrast to Harmatas [4 + 3] reaction (Section 3.1.5.1). Chiral Lewis Acid Catalyzed [4 + 3] Cycloadditions[111]
Scheme 39 O Ph
O N
Ph
N
Ph
Ph 122
O O
O O
N
O
O O
•
O
N
O
N O
124
123
125
O (9 equiv)
O
R1 25 mol% Cu(OTf)2, 32 mol% 122 AgSbF6, 4-Å molecular sieves acetone, CH2Cl2, −78 oC
O
O N O R1 126
R1
ee (%) Yield (%) Ref
H
99
91
[111]
Me 99
91
[111]
3-{(1S,2R,5S)-3-Oxo-8-oxabicyclo[3.2.1]oct-6-en-2-yl}oxazolidin-2-ones 126; General Procedure:[111]
To a dry flask in an inert-atmosphere drybox was added Cu(OTf )2 (10.9 mg, 0.030 mmol), AgSbF6 (20.9 mg, 0.060 mmol), and ligand 122 (17.5 mg, 0.036 mmol). The flask was fitted with a septum, and was removed from the drybox and charged with CH2Cl2 (1.5 mL). The resulting heterogeneous mixture was stirred for 12 h in the absence of light before being filtered through Celite into a dry flask. The catalytic system was diluted with acetone (1.0 mL) and cooled to –78 8C. Then, N-allenylamide 123 (15.0 mg, 0.12 mmol), the furan (9.0 equiv, 1.08 mmol), and 4- molecular sieves (300.0 mg) were added. The mixture was stirred at –78 8C for 15 min, and then a chilled soln of dimethyldioxirane (3.0–5.0 equiv) in acetone was added over 3–4 h at –78 8C using a syringe pump. The syringe pump was cooled using dry ice at all times during the addition. After the addition, the mixture was stirred for another 4 h before being concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexane to EtOAc/hexane 3:2). [m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.5
3.1.5.3
51
[4 + 3]-Cycloaddition Reactions
Rhodium-Catalyzed Asymmetric [4 + 3] Cycloadditions between Æ-Diazo ,ªUnsaturated Esters and Dienes
The tandem rhodium-catalyzed cyclopropanation/Cope rearrangement of Æ-diazo ,ª-unsaturated esters with dienes provides a formal [4 + 3] cycloaddition for the asymmetric synthesis of highly functionalized seven-membered rings.[112] The reaction has broad substrate scope for a range of dienes, including furans,[113] pyrroles,[114] pyridinones,[115] and benzene derivatives.[116] The chiral dirhodium complexes 127 [Rh2(S-DOSP)4] and 128 [Rh2(S-PTAD)4] provide excellent enantioselectivities, thereby making this an attractive and useful strategy for the construction of seven-membered rings (Scheme 40).[117–120] Scheme 40
Tandem Cyclopropanation/Cope Rearrangement[117–120]
H O
Rh O
N S O
O
Rh
N
O 11
O
Rh
O
Rh
O
4 4
127
128
CO2Me
R6
N2
R7 R3
R5 R4
R1
+ R2
R7 R6
[Rh]
R5 R4
CO2Me R1
R3
R2
R7 R6
CO2Me
R5 R
R1 4
R3 R 2
For example, treatment of the substituted unsaturated Æ-diazo esters 129 with 1 mol% of catalyst 127 facilitates a formal [4 + 3] reaction to provide the cycloheptadienes 130 in a highly diastereo- and enantioselective manner (93–98% ee; Table 8, entries 1–3).[117] Furthermore, the asymmetric synthesis of a bicyclo[3.2.1]octa-2,6-diene is readily achieved from the reaction of the diazo ester 129 with cyclopentadiene in exclusive endo fashion (entry 4). Terminus disubstituted dienes can also be tolerated in this reaction, providing products with excellent regio- and enantioselectivity (entry 5). The [4 + 3]-cycloaddition reactions of unsaturated -siloxy Æ-diazo esters catalyzed by complex 128 also provide the cycloadducts in a highly efficient and selective manner (entries 6–10).[118] In all cases, the cycloadducts are formed in very good yield (70–88%) and with excellent enantioselectivity (87–99% ee). Interestingly, the reaction is stereospecific with respect to the alkene geometry, with (E)- and (Z)-penta-1,3-diene provide opposite enantiomers with the same catalyst (entries 6 and 7).
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
52
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
Asymmetric [4 + 3] Cycloadditions between Æ-Diazo ,ª-Unsaturated Esters and Dienes[117,118]
Table 8
R4
CO2Me
R3
N2
R4 R5
R1
+
R3
1 mol% catalyst hexanes
R1 R6
R2
R6
CO2Me
129
Entry R1
R 5 R2 130
R2
R3
R4 R5
R6
Catalyst
Temp (8C)
ee (%)
Yield (%)
Ref
1
H
Me
H
H
H
Ph
127
–78
98
87
[117]
2
H
Ph
H
H
H
Ph
127
–78
98
83
[117]
3
H
CH=CHPh
H
H
H
Ph
127
–78
93
84
[117]
4
H
CH=CHPh
H
H
127
–78
90
80
[117]
5
H
CH=CHPh
Me
H
Me Me 127
–78
97
87
[117]
6
OTBDMS
H
H
H
H
–26
95
88
[118]
7
OTBDMS
H
H
H
Me H
128
–26
87
80
[118]
8
OTBDMS
H
H
H
H
Ph
128
–26
95
82
[118]
9
OTBDMS
H
OTBDMS
H
H
Me 128
–26
99
70
[118]
10
OTBDMS
H
H
H
–26
92
86
[118]
CH2
CH2
Me 128
128
The rhodium-catalyzed asymmetric [4 + 3] cycloadditions of pyrroles 131 with the ,ª-unsaturated -siloxy Æ-diazo esters 132 has been applied to the preparation of the tropane skeleton 133, which is ubiquitous in pharmaceutical agents and natural product targets (Scheme 41).[119] Treatment of the esters 132 with N-(tert-butoxycarbonyl)- or N-phenylsubstituted pyrroles in the presence of a catalytic amount of dirhodium complex 128 in 2,2-dimethylbutane at 50 8C furnishes the 8-azabicyclo[3.2.1]octane skeleton in high yield and with excellent enantioselectivity. The process is also tolerant of various substituted pyrroles, as outlined in Scheme 41. Scheme 41 Asymmetric Synthesis of Tropanes by Rhodium-Catalyzed [4 + 3] Cycloadditions[119] R2 CO2Me N R1 +
N2
R
R4
R3
131
R2
R3
R4
ee (%) Yield (%) Ref
Boc
H
H
H
92
86
[119]
Boc
H
H
Me
96
69
[119]
Boc
Me H
Me
98
72
[119]
Boc
H
H
CO2Me 89
71
[119]
Ph
H
H
H
97
64
[119]
4-Tol H
H
H
94
68
[119]
91
76
[119]
(CH2)4
CO2Me OTBDMS
R4 133
132
R1
H
N R2
OTBDMS
3
Boc
R1
1 mol% 128 2,2-dimethylbutane, 50 oC
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.5
53
[4 + 3]-Cycloaddition Reactions
The scope of this methodology can be broadened to cycloadditions between the benzofuranyl(diazo)acetates 134 and a variety of cyclic and acyclic conjugated dienes (Scheme 42).[120] For instance, the diazo derivative 134 is added slowly at –78 8C to 1 mol% of dirhodium complex 127 and the requisite diene, and the mixture is warmed to room temperature to afford the formal [4 + 3] cycloadducts 135 in moderate to high yield (43–92%) and with high diastereoselectivity (>94% de) and enantioselectivity (91–98% ee). Nevertheless, in some cases where the diene has a Z-substituent, more-forcing reaction conditions are required to drive the Cope rearrangement of the cis-divinylcyclopropane intermediate. Scheme 42 Dienes[120]
Asymmetric [4 + 3] Cycloadditions between Benzofuranyl(diazo)acetates and
R3
MeO2C
N2
1 mol% 127, toluene −78 oC to rt
R3 +
R2
O
MeO2C
R1
O H R1 R
2
134 R3 MeO2C
O
R1
R2
135
R1
R2
R3 de (%) ee (%) Yield (%) Ref
H
CH2
>94
98
83a
[120]
H
O
>94
96
92
[120]
Me
O
>94
96
83
[120]
Ph H
H >94
98
68
[120]
Me H
H >94
98
66
H
Me H >94
Me Me H – a
b
[120]
93
43
b
[120]
91
82a
[120]
Cope rearrangement required heating to 110 8C. Cope rearrangement required heating to 140 8C; the initial cyclopropane was produced with dr 2.7:1.
Methyl Cyclohepta-1,5-dienecarboxylates 130 (Table 8, Entries 6–10); General Procedure:[118]
To a flame-dried 25-mL flask containing dirhodium complex 128 (4.7 mg, 3.0 mol, 0.01 equiv) and the 1,3-diene (1.50 mmol, 5.0 equiv) in hexane (6 mL) and (trifluoromethyl)benzene (0.2 mL) under argon was added a soln of Æ-diazo ester 129 (R1 = OTBDMS, R2 = H; 77 mg, 0.30 mmol, 1.0 equiv) in hexane (6 mL) by syringe pump over 2 h at –26 8C. The soln was stirred at –26 8C overnight and then heated under reflux for an additional 1 h. The mixture was concentrated under reduced pressure and purified by flash chromatography (silica gel).
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
54
Stereoselective Synthesis
3.1.5.4
Palladium-Catalyzed [4 + 3] Cycloadditions of ª-Methylene--valerolactones
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
Shintani and Hayashi have developed a new type of palladium-catalyzed stereoselective [4 + 3] cycloaddition, in which ª-methylene--valerolactones 138 provide a four-carbon synthon in the form of a 1,4-zwitterionic species (Table 9).[121] The formation of this zwitterion is initiated by the oxidative addition of palladium(0) into the allylic ester of 138, followed by decarboxylation. The synthetic utility of ª-methylene--valerolactones for stereoselective cycloadditions was first demonstrated with nitrones. Treatment of the ª-methylene--valerolactones 138 and nitrones 139 with the complex derived from Å3-allyl(cyclopentadienyl)palladium and the phosphoramidite ligand 136, furnishes the corresponding 1,2-oxazepines 140 in high yields with good to excellent diastereoselectivities (Table 9, entries 1–6). Furthermore, the chiral phosphoramidite ligand 137 facilitates the enantioselective version of this process, which creates two contiguous tertiary and quaternary stereogenic centers with good to excellent enantioselectivity (83–96% ee; entries 7–10). Table 9 Palladium-Catalyzed [4 + 3] Cycloadditions of ª-Methylene--valerolactones with Nitrones[121] Ph O P O
Pri
O
Pri
O
P
N
N Ph
136
137
CO2Et O O Ar1
+
O
5 mol% Pd(η3-C3H5)(Cp) 10 mol% ligand CH2Cl2, 40 oC, 24 h
N
CO2Me Ar2
H
138
139 CO2Et O
N Ar2
Ar1
CO2Me 140
Entry
Ar1
Ar2
Ligand
dr
eea (%)
Yieldb (%)
Ref
1
Ph
Ph
136
90:10
–
99
[121]
2
4-MeOC6H4
Ph
136
93:7
–
95
[121]
3
3-thienyl
Ph
136
91:9
–
92
[121]
4
1-naphthyl
Ph
136
94:6
–
96
[121]
5
1-naphthyl
4-ClC6H4
136
93:7
–
98
[121]
6
1-naphthyl
4-F3CC6H4
136
94:6
–
98
[121]
7
Ph
4-F3CC6H4
137
81:19
83
98
[121]
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
Table 9
(cont.) Ar1
Ar2
Ligand
dr
eea (%)
Yieldb (%)
Ref
8
4-MeOC6H4
4-F3CC6H4
137
86:14
84
99
[121]
9
1-naphthyl
4-F3CC6H4
137
80:20
96
98
[121]
99
[121]
Entry
c
10 a b c d
55
[4 + 3]-Cycloaddition Reactions
3.1.5
1-naphthyl
4-Tol
137
70:30
d
89
ee of the major diastereomer. Combined yield of two diastereomers. The reaction was conducted with 10 mol% of catalyst for 48 h. The minor diastereomer was 91% ee.
This methodology has been adapted to facilitate the construction of seven-membered carbocycles.[122] The cycloaddition reaction of the ª-methylene--valerolactone 141 (Ar1 = Ph) with 1,1-dicyanocyclopropane proceeds smoothly at 20 8C using a palladium complex with chiral phosphoramidite ligand 78 {also employed in palladium-catalyzed asymmetric [3 + 2] trimethylenemethane cycloadditions (see Section 3.1.2.2)}, to provide the cycloheptane 142 (Ar1 = Ph) in 87% yield and with 86% ee (Scheme 43). Similarly, lactone 141 (Ar1 = Fc) affords 142 (Ar1 = Fc) at 40 8C in 87% yield with improved enantioselectivity (93% ee). The chiral phosphoramidite ligand 78 is also effective for the reaction of ª-methylene-valerolactone 141 (Ar1 = Ph) with aziridine 143 to furnish the azepane 144 with good asymmetric induction (85% ee). Scheme 43 [4 + 3] Cycloadditions of ª-Methylene--valerolactones with 1,1-Dicyanocyclopropane and N-Tosylaziridine[122]
NC
O O Ar1
NC
5 mol% Pd(η3-C3H5)(Cp) 10 mol% 78 toluene, 24 h
CN
+
CO2Me Ar1
141
CN
CO2Me
142
Ar1 Temp (8C) ee (%) Yield (%) Ref Ph 20
86
87
[122]
Fc
93
87
[122]
40
Ts
O O
+
N
Ts
5 mol% Pd(η3-C3H5)(Cp) 10 mol% 78 toluene, 40 oC, 24 h
N
70%; 85% ee
CO2Me Ph
Ph 143
CO2Me
144
Methyl 3,4-Diaryl-6-methylene-1,2-oxazepane-4-carboxylates 140; General Procedure:[121]
A soln of Pd(Å3-C3H5)(Cp) (1.1 mg, 5.2 mol), ligand 136 or 137 (10 mol), nitrone (0.10 mmol), and lactone 138 (0.18 mmol) in CH2Cl2 (0.5 mL) was stirred for 24 h at 40 8C. The mixture was directly passed through a pad of silica gel with EtOAc and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (silica gel).
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 63
56
Stereoselective Synthesis
3.1.5.5
Palladium-Catalyzed [4 + 3] Intramolecular Cycloadditions of Alkylidenecyclopropanes and Dienes
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
MascareÇas and co-workers have developed a novel palladium-catalyzed [4 + 3] cycloaddition, which is based on their previous work on the [3 + 2] intramolecular cycloaddition,[123–125] that affords 5,7-fused bicyclic systems from readily accessible dienylidenecyclopropanes.[126] Treatment of 145 with the catalyst derived from tris(dibenzylideneacetone)dipalladium and the chiral ligand 146 furnishes the [4 + 3] cycloadduct 147 as the major product in moderate yield (56–74%), along with the [3 + 2] products 148 (Table 10). Remarkably, the cycloadducts 147 are all obtained as single diastereomers with the configuration of the diene preserved in the products (entries 2 and 3). However, the enantioselectivity is generally unsatisfactory (45–64% ee; entries 1, 2, and 6), as is the distribution of constitutional isomers.[126] Table 10 Palladium-Catalyzed [4 + 3] Intramolecular Cycloadditions of Alkylidenecyclopropanes and Dienes[126] Ph O
24 mol%
O
P
N Ph
146
X
R
1
R2
H
H
6 mol% Pd2(dba)3 dioxane, 101 oC, 2−3 h
R2 + X
X
R1
R1
R2 145
148
147
Entry Starting Material
Ratio eea (147/ (%) 148) of 147
Major Product
Yield Ref (%) of 147
H
1
EtO2C
EtO2C CO2Et EtO2C
CO2Et 10:1
47
73
[126]
CO2Et
10:1
45
74
[126]
CO2Et
2.1:1 n.r.
56
[126]
EtO2C H H
2
O
CO2Et
O H
H
3
O
O CO2Et
H
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.6
57
[5 + 2]-Cycloaddition Reactions
Table 10
(cont.)
Entry Starting Material
Major Product
Ratio eea (147/ (%) 148) of 147
Yield Ref (%) of 147
15:1
n.r.
58
[126]
4:1
n.r.
60
[126]
3.5:1 64
59
[126]
H
4
EtO2C
EtO2C
EtO2C
EtO2C H H
5
BnN
BnN
H
H
6
EtO2C a
EtO2C
EtO2C
CO2Et CO2Et
EtO2C
n.r. = not reported.
Triethyl (3aS,6S,8aS)-8-Methylene-3,3a,6,7,8,8a-hexahydroazulene-2,2,6(1H)-tricarboxylate (Table 10, Entry 1); Typical Procedure:[126]
Triene 145 [X = C(CO2Et)2; R1 = H; R2 = CO2Et; 91 mg, 0.25 mmol] was added to a suspension of Pd2(dba)3 (13.7 mg, 6 mol %) and phosphoramidite 146 (24 mol%) in dry, freshly distilled, and carefully deoxygenated dioxane (5 mL, 50 mM). The resulting mixture was placed in a preheated bath and refluxed for 3 h. After cooling to rt, the mixture was diluted with hexanes (8 mL) and filtered through a short pad of silica gel, eluting with EtOAc/ hexanes (1:9). The filtrate was concentrated and purified by flash chromatography (Et2O/ hexanes 3:97) to give 147 and 148 as colorless oils. 3.1.6
[5 + 2]-Cycloaddition Reactions
3.1.6.1
Rhodium-Catalyzed Asymmetric [5 + 2] Cycloadditions of Vinylcyclopropanes and -Systems
The metal-catalyzed [5 + 2]-cycloaddition reaction between vinylcyclopropanes (VCPs) and dienophiles also provides seven-membered carbocycles. Under thermal reaction conditions, the [5 + 2] reactions are limited to heteroatom-embedded vinylcyclopropanes such as homofurans and homopyrroles (2-oxa- and 2-azabicyclo[3.1.0]hex-3-enes, respectively).[127,128] If no such activating element or substituent is present in the vinylcyclopropanes, the [5 + 2] reaction requires a transition-metal catalyst.[129–140] Wender and co-workers have pioneered the transition-metal-catalyzed [5 + 2] reaction using rhodium catalysts. In 1995, the first intramolecular [5 + 2] reaction of yne-vinylcyclopropanes (yne-VCPs) using chlorotris(triphenylphosphine)rhodium(I) as the catalyst was described.[129] Wender has also demonstrated that ene-vinylcyclopropanes (ene-VCPs)[130–132] and allene-vinylcyclopropanes (allene-VCPs)[133,134] undergo the rhodium-catalyzed [5 + 2] reaction. Additional studies demonstrated the intermolecular [5 + 2] process of vinylcyclopropanes with alkynes,[135,136] and hetero-[5 + 2] reactions of iminocyclopropanes with dimethyl azodicar[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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58
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
boxylate.[137] Inspired by rhodium-catalyzed [5 + 2] chemistry, Trost[138,139] and Frstner[140] have demonstrated that ruthenium and iron complexes also catalyze the intramolecular [5 + 2] cycloadditions of yne-vinylcyclopropanes. Asymmetric variants of the [5 + 2] reactions have only been realized using rhodium complexes at present. The first highly enantioselective example was reported by Wender and co-workers, using 10 mol% of rhodium catalyst 150 to catalyze the intramolecular [5 + 2] reaction of ene-vinylcyclopropanes 149 in high yields (72–92%) and with excellent enantioselectivity (>95% ee); the products 151 contain synthetically versatile sulfonamide or malonic diester groups (Table 11).[141] Methyl and benzyloxymethyl substituents are also tolerated by the reaction (entries 1 and 2); however, the catalyst 150 is not suitable for the cycloadditions of yne-vinylcyclopropanes, which provide low enantioselectivities. Table 11 Rhodium-Catalyzed Asymmetric [5 + 2] Cycloadditions of Ene-Vinylcyclopropanes[141] + Ph P
Ph Rh•2MeOH
10 mol%
SbF6−
P Ph Ph
R1
R1
150
X
1,2-dichloroethane
X H
R2 151
149
Entry X
R2
R1
R2
Substrate Concentration (M) Temp (8C) Time (d) ee (%) Yield (%) Ref
1
C(CO2Me)2
Me
H
0.05
70
2
>95
72
[141]
2
C(CO2Me)2
CH2OBn
H
0.01
70
2
>99
80
[141]
3
NTs
H
H
0.01
40–60
8
96
90
[141]
4
C(CO2Me)2
H
Me 0.01
70
6
95
92
[141]
In 2009, Hayashi and co-workers discovered that the asymmetric [5 + 2] cycloadditions of yne-vinylcyclopropanes with a rhodium complex employing the chiral phosphoramidite ligand 137 [also used in palladium-catalyzed [4 + 3] cycloadditions of ª-methylene-valerolactones (Section 3.1.5.4)] proceed with very high enantiomeric excesses (up to >99.5% ee) (Table 12).[142] Aryl- and alkyl-substituted alkynes 152 are well tolerated, furnishing the corresponding cycloadducts 153 in excellent yield and enantioselectivity (87–90% yield; ‡94% ee; entries 1–5). Significantly, the amount of ligand 137 can be reduced to 6 mol% (entry 1), and terminal alkynes also provide excellent enantioselectivity, albeit with lower yield due to decomposition of the substrate during the reaction (entry 6). Yne-vinylcyclopropanes with a methyl group on the cyclopropane, or with an oxygen or carbon tether are also effective substrates under these reaction conditions (82–90% yield; 83–99% ee; entries 7–9).
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.6
59
[5 + 2]-Cycloaddition Reactions
Table 12 Rhodium-Catalyzed Asymmetric [5 + 2] Cycloadditions of Yne-Vinylcyclopropanes[142] 2.5 mol% [RhCl(C2H4)2]2 7.5 mol% 137 6 mol% Na[BARF] CH2Cl2, 30 oC, 5 h
R1 X
R1
X
R2
H
R2
153
152 [BARF]− = [3,5-(F3C)2C6H3]4B−
Entry X
R1
R2
ee (%) Yield (%) Ref
1a
NTs
Ph
H
99
89
[142]
2
NTs
4-MeOC6H4
H
98
89
[142]
3
NTs
4-ClC6H4
H
94
90
[142]
4
NTs
Me
H
>99.5
87
[142]
NTs
iPr
H
99
87
[142]
NTs
H
H
92
53
[142]
7
NTs
Ph
Me
99
87
[142]
8c
O
(CH2)2Ph
H
95
90
[142]
9
C(CO2Me)2
Ph
H
83
82
[142]
5 6
a b
c
b
6 mol% of 137 was used. The reaction was conducted at 40 8C for 48 h at a 0.01 M concentration. The reaction was conducted for 24 h at a 0.01 M concentration.
Dimethyl (3aR,8aR)-3a-Methyl-3,3a,4,5,6,8a-hexahydroazulene-2,2(1H)-dicarboxylate [151, X = C(CO2Me)2; R1 = Me; R2 = H]; Typical Procedure:[141]
The ene-vinylcyclopropane 149 [X = C(CO2Me)2; R1 = Me; R2 = H, 17.6 mg; 66.1 mol] was weighed out in an oven-dried 10-mL vial. Chiral catalyst 150 (6.8 mg, 6.6 mol) and 1,2-dichloroethane (1.32 mL) were then added, and the mixture was heated at 70 8C for 25 h. The mixture was concentrated by rotary evaporation, and the crude product was purified by flash column chromatography (Et2O/pentane 1:9). Product-containing fractions were identified and concentrated by rotary evaporation to give the product as a colorless oil; yield: 12.7 mg (72%); >95% ee. Annulated Cyclopentadienes 153; General Procedure:[142]
A soln of [RhCl(C2H4)2]2 (1.9 mg, 9.8 mol Rh) and the chiral phosphoramidite ligand 137 (7.9 mg, 15 mol) in CH2Cl2 (1.0 mL) was stirred for 20 min at rt. Substrate 152 (0.20 mmol) was added to the soln with additional CH2Cl2 (0.5 mL), and then sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (11 mg, 12 mol) was added with additional CH2Cl2 (0.5 mL). The resulting soln was stirred for 5 h at 30 8C, and the reaction was quenched with H2O. After extraction with CH2Cl2, the organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel).
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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60
Stereoselective Synthesis
3.1.7
[6 + 3]-Cycloaddition Reactions
3.1.7.1
Palladium-Catalyzed Asymmetric [6 + 3] Cycloaddition of Trimethylenemethane with Tropones
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
The palladium-catalyzed [3 + 2] cycloaddition of trimethylenemethane to electron-deficient -systems introduced by Trost and co-workers provides a highly efficient method for the construction of substituted cyclopentanes, tetrahydrofurans, and pyrrolidines (see Section 3.1.2.2).[63–65] Following the initial reports, direct access to bicyclo[4.3.1]decadienes via [6 + 3] trimethylenemethane cycloaddition to cycloheptatrienones (tropones) was also demonstrated,[143] which prompted the development of the asymmetric version using bulky chiral phosphoramidite ligands. The palladium-catalyzed cycloaddition of 86 with tropones affords the [6 + 3] products such as 155, without any of the [3 + 2] or [4 + 3] adduct, in high yields with excellent regio-, diastereo-, and enantioselectivities using the chiral phosphoramidite ligand 154 (Table 13).[144] As the position of the ester functionality in the tropone varies, only one [6 + 3] regioisomer, which is predicted from electronic considerations, is obtained (entries 1–3). The cycloaddition reaction of the less-electron-deficient unsubstituted parent tropone proceeds smoothly at higher temperature to afford the cycloadduct in good yield, and with modest diastereo- and excellent enantioselectivity (entry 4). A series of 2-substituted tropones, such as 2-chloro-, 2-acetoxy-, and 2-phenyltropone can also be subjected to this reaction, affording the products in good yield and stereoselectivity (entries 5–7). However, 2-bromo-, 2-methoxy-, and 2-(dimethylamino)tropone are not suitable substrates for the cycloaddition, suggesting the need for an electron-deficient heteroatom to enhance the tropones reactivity.
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.1.7
61
[6 + 3]-Cycloaddition Reactions
Table 13 Palladium-Catalyzed Asymmetric [6 + 3] Cycloaddition of Trimethylenemethane with Tropones[144] Ph
O
10 mol%
O
O
P N
Ph
NC
154
OAc
TMS
5 mol% Pd(dba)2, toluene
+
CN
H
H O
R1
86
Entry
R1
155
Substrate
Temp (8C)
O
Product
dra
ee (%)
Yield (%)
Ref
>10:1
99
75b
[144]
>10:1
99
80b
[144]
>10:1
99
77b
[144]
6:1
99
89c
[144]
NC
1
0–4
H
H O
CO2Et
CO2Et
O
NC
2
rt CO2Et
CO2Et
H
EtO2C
O
3
H O
NC
0–4
H
CO2Et O
O
4
NC
45
H
H O
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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62
Stereoselective Synthesis
3.1
[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
Table 13 (cont.) Entry
Substrate
Temp (8C)
O Cl
5
Product
dra
ee (%)
Yield (%)
Ref
>10:1
94
94b
[144]
>10:1
96
90b
[144]
6:1
93
64c
[144]
NC
0–4
H
Cl O
O OAc
6
NC
0–4
H
OAc O
O
7
Ph
NC
rt
H
Ph O
a b c
Determined by NMR analysis of the crude mixture. Isolated yield of major diastereomer. Isolated yield of both diastereomers.
(7S)-8-Methylene-10-oxobicyclo[4.3.1]deca-2,4-diene-7-carbonitriles 155; General Procedure:[144]
A mixture of the tropone (0.200 mmol), Pd(dba)2 (5.8 mg, 0.010 mmol), and phosphoramidite ligand 154 (0.020 mmol) were placed in a flask and purged with argon for 10 min. The solids were dissolved in toluene (0.8 mL) and the mixture was stirred for 5–10 min. After the flask was cooled to 0 8C for a further 5 min using an ice bath, the trimethylenemethane donor 86 (0.074 mL, 0.320 mmol) was added and the mixture was left overnight at 0–4 8C under argon. The mixture was then passed through a small pad of silica gel and the solvents were evaporated under reduced pressure. Diastereomeric ratios were determined by crude 1H NMR analysis. Purification was achieved using flash chromatography.
[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
References
63
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[10] [11] [12] [13] [14] [15] [16] [17]
[18] [19] [20]
[21] [22]
[23] [24] [25] [26] [27] [28] [29] [30] [31]
[32]
[33]
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[m + n]-Cycloaddition Reactions (Excluding [4 + 2])
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[m n]-Cycloaddition Reactions (Excluding [4 2]), Jiang, G.-J., Wang, Y., Yu, Z.-X. Science of Synthesis 4.0 version., Section 3.1 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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67 3.2
[4 + 2]-Cycloaddition Reactions K. Ishihara and A. Sakakura
3.2.1
Enantioselective Diels–Alder Reactions Catalyzed by Chiral Lewis Acids
3.2.1.1
Enantioselective Catalysis Using Chiral Boron Compounds
The Diels–Alder reaction is one of the most powerful and versatile organic transformations and has been extensively applied in syntheses of countless bioactive natural products.[1–3] Since the discovery of the Diels–Alder reaction, stereoselective versions of the reaction have been widely investigated. In 1960, the Diels–Alder reactions of anthracene with maleic anhydride, benzo-1,4-quinone, and dimethyl fumarate were shown to be markedly accelerated by the presence of aluminum trichloride.[4] This catalytic effect is the result of coordination of the Lewis acid with the dienophile, which lowers the energy of the lowest unoccupied molecular orbital, thereby allowing the Diels–Alder reaction to be conducted under mild conditions with enhanced regio- and diastereoselectivity. Furthermore, enantioselectivity in the reaction can be achieved by using Lewis acid catalysts bearing chiral ligands, such as the chiral acyloxyborane catalyst 1, which is derived from O-(2,6-diisopropoxybenzoyl)-l-tartaric acid and borane–tetrahydrofuran adduct. This catalyst facilitates the enantioselective Diels–Alder reactions of acrylic acid, Æ,-alkenals, or Æ,-alkynals (Scheme 1).[5–8] The effective shielding of the Si face of the coordinated Æ,alkenal by catalyst 1 arises from – stacking between the 2,6-diisopropoxybenzene ring and the coordinated aldehyde.[8] Similarly, the chiral oxazaborolidine 2, derived from N-tosyl-l-tryptophan and butylboronic acid, catalyzes the enantioselective Diels– Alder reaction of 2-bromopropenal (Scheme 1).[9,10] The high level of asymmetric induction in this reaction is ascribed to the attractive interaction between the -donor indole ring and the coordinated aldehyde.[11] Scheme 1 Early Examples of Chiral Lewis Acid Catalysts Based on – Attractive Interactions[7,9] OPri 10 mol%
O
O BH
O OPri O
O CO2H
1
Br
CHO
+
CH2Cl2, −78 oC
CHO
quant; (exo/endo) 94:6; 95% ee
S
Br H N
O
O B
5 mol%
Bu
N Ts 2
Br +
CHO
CH2Cl2, −78 oC 95%; (exo/endo) 96:4; 99% ee
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
R
CHO
Br
for references see p 120
68
Stereoselective Synthesis
3.2.1.1.1
Using a Cationic Oxazaborolidine
3.2
[4 + 2]-Cycloaddition Reactions
The cationic chiral oxazaborolidines 3–6 (Scheme 2), derived from Æ,Æ-diaryl-l-prolinols and tri-2-tolylboroxin are powerful catalysts for the enantioselective Diels–Alder reaction.[12,13] Oxazaborolidines 3 (X = OTf, NTf2) and 4 are activated by superacids, e.g. trifluoromethanesulfonic acid[14,15] and trifluoromethanesulfonimide (Tf2NH),[16,17] or by strong Lewis acids, e.g. aluminum tribromide,[18] through coordination of nitrogen to increase the Lewis acidity of the resulting complex. Oxazaborolidines 3 (X = OTf, NTf2) and 4 show excellent catalytic activities for Diels–Alder reactions of various Æ,-enals, Æ,-enones, and Æ,-unsaturated esters. Cationic Chiral Oxazaborolidine Catalysts[12–21]
Scheme 2 H Ph
H Ph Ph
X−
N
O B
H
H Ph Ph
N
O
N
B
Br3Al
Ph
Ph
Ph O
N
B
Me
Tf
H
Tf
O B
F
F
Ph
Tf2N−
F
F F
3
4
6
5
As shown in Table 1, the face selectivities of the enantioselective Diels–Alder reaction of Æ,-enones and Æ,-unsaturated esters are opposite those observed for Æ-substituted propenals. Table 1 Enantioselective Diels–Alder Reaction of Æ,-Unsaturated Carbonyl Compounds Catalyzed by Oxazaborolidines[14–18] Reactantsa
Entry
Dienophile CHO
1
CHO
2
Catalyst (mol%)
Product
Yield (%) dr (endo/exo) ee (%) Ref
Diene 3 (X = OTf ) (6)
S
CHO
99
9:91
91
[14]
4 (4)
S
CHO
99
8:92
93
[18]
97
[14]
>99
[16]
OHC R
3
Br
CHO
Br
3 (X = OTf ) (6)
98
–
97
98:2
7
O
4
R
CF3 O
3 (X = NTf2) (20)
O
O CF3
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
Table 1
69
Enantioselective Diels–Alder Reactions Catalyzed by Chiral Lewis Acids
3.2.1
(cont.) Reactantsa
Entry
Dienophile
O
5
Catalyst (mol%)
Product
Yield (%) dr (endo/exo) ee (%) Ref
Diene
R
CF3
4 (4)
O
O
O
99
[18]
–
>99
[16]
95
–
98
[18]
97
91:9
93
[15]
99
94:6
95
[18]
98
97:3
99
CF3 CO2Et
6
S
3 (X = NTf2) (20)
CO2Et
CO2Et
CO2Et
CO2Et
7
S
4 (4)
CO2Et
CO2Et
CO2Et
O
H
8
3 (X = OTf ) (20)
O
R
H O
H
9
4 (4)
O
R
H a
Conditions: diene (1.1 equiv), oxaborolidine catalyst (4–20 mol%), CH2Cl2.
This reversal in face selectivity can be explained in terms of the pre-transition-state complexes 8 and 9 (Scheme 3).[15] In the pre-transition-state complex 8 for Æ,-enals, the oxygen of the oxaborolidine catalyst interacts with the formyl CH proton (formyl CH…O interaction), whereas for other Æ,-unsaturated carbonyl compounds, the oxygen interacts with the Æ-CH proton (Æ-CH…O interaction) in the pre-transition-state complex 9. In the case of the Diels–Alder reaction of Æ,-unsaturated esters, an alternative mode of coordination that does not involve an Æ-CH…O interaction has also been proposed on the basis of computational investigations.[22] Scheme 3 Proposed Pre-Transition-State Complexes of Catalysts and Substrates[15]
N B O
X− H
N B O
H
O
X− H
H
O
R2 R
R1
1
R2 8
9
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
70
Stereoselective Synthesis
[4 + 2]-Cycloaddition Reactions
3.2
In general, quinones are highly reactive dienophiles and the scope of their reactions is broad. The Diels–Alder reaction of quinones is very useful for the synthesis of natural products and other complex molecules. For example, oxazaborolidines 3 (X = NTf2) and 4 successfully catalyze the Diels–Alder reaction of quinones 10 to afford the corresponding adducts 11 with high regio- and enantioselectivities (Scheme 4).[17,18] In particular, aluminum tribromide activated oxazaborolidine 4 shows excellent catalytic activity and can promote the reaction of quinones with a low catalyst loading (4 mol%). The sense of the enantioselectivity of the Diels–Alder reactions of quinones 10 is consistent with the pretransition-state complex 9, in which the catalyst coordinates at the oxygen lone pair on the CÆ—H side rather than on the CÆ—R side. Scheme 4 Enantioselective Diels–Alder Reactions of Quinones Catalyzed by Oxazaborolidines[17,18] O
H
20 mol% 3 or 4 mol% 4 CH2Cl2, −95 to −78 oC
O
+ TIPSO
R2
R1
TIPSO
O 10
R1
R2
Catalyst
R2
R1 O
11
Yield (%) ee (%) Ref >99
[17]
99
99
[18]
Me Me 3 (X = NTf2) 98
99
[17]
>99
[17]
99
[18]
Me H
3 (X = NTf2) 98
Me H
4
I
Me 3 (X = NTf2) 99
I
Me 4
99
Another type of chiral Lewis acid with an oxazaborolidine core is the N-methyloxazaborolidinium cation 5,[19] which generally affords better results than catalyst 4. For instance, the ent-5-catalyzed Diels–Alder reaction of diene 12 with 2-methylcyclopent-2enone gives the corresponding endo-adduct 13 in 98% yield and 82% ee (Scheme 5), whereas the corresponding reaction with catalyst 4 provides ent-13 in 50% yield and with lower enantioselectivity (75%). Scheme 5 Enantioselective Diels–Alder Reaction Catalyzed by a Chiral N-Methyloxazaborolidinium Cation[19] O O +
20 mol% ent-5 CH2Cl2, 23 oC
H
98%; 82% ee
MeO
H MeO
12
13
Intramolecular versions of the Diels–Alder reaction are widely utilized as key steps in the syntheses of polycyclic cores of various bioactive natural compounds.[23–27] Type I intramolecular Diels–Alder reactions, in which the diene and dienophile are joined at the C1 position of the diene, lead to fused bicyclic adducts. In contract, Type II intramolecular Diels–Alder reactions, in which diene and dienophile are joined at the C2 position of the diene, furnish bridged bicyclic ring systems. Cationic oxazaborolidines 3–6 are effective catalysts for enantioselective Type I intramolecular Diels–Alder reaction of triene 14 [4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.1
Enantioselective Diels–Alder Reactions Catalyzed by Chiral Lewis Acids
71
(Scheme 6).[20] Slow addition of catalyst 3 (X = NTf2; 20 mol%) to a toluene solution of triene 14 results in formation of the endo-adduct 15 in very good yield and 90% ee. The structure and absolute configuration of 15 are as predicted on the basis of a transition state involving a formyl CH…O interaction. The adduct 15 is a key intermediate in the syntheses of several natural products, including palominol, dolabellatrienone, -araneosene, and isoedunol. Scheme 6 Enantioselective Type I Intramolecular Diels–Alder Reaction of a Triene Catalyzed by an Oxazaborolidine[20]
20 mol% 3 (X = NTf2) toluene, −93 to −78 oC
CHO
CHO
71−74%; 90% ee
OTIPS 14
H 15
OTIPS
Despite advances in asymmetric catalysis, only a few methods have been reported for enantioselective Diels–Alder reactions of alkynes. The l-valine-derived cationic oxazaborolidine 6 demonstrates good catalytic activity for the regio- and enantioselective Diels– Alder reactions of the Æ,-ynones 16 (Scheme 7 and Table 2).[21] Both cyclic and acyclic dienes provide the corresponding adducts in high yield and with excellent enantioselectivities. Importantly, a high level of asymmetric induction is observed with dienophiles that lack the hydrogen-bonding motif required for cationic oxazaborolidine-catalyzed Diels– Alder reactions. Scheme 7 Æ,-Ynones Acting as Dienophiles for Oxazaborolidine-Catalyzed Enantioselective Diels–Alder Reactions[21] O R1 R2 16 R1 = Et, Ph; R2 = TMS, TBDMS
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Stereoselective Synthesis
Table 2
3.2
[4 + 2]-Cycloaddition Reactions
Oxazaborolidine-Catalyzed Diels–Alder Reactions of Æ,-Ynones[21] Reactantsa
Dienophile
Product
Yield (%)
ee (%)
Ref
96
99
[21]
85
99
[21]
96
99
[21]
96
99
[21]
94
99
[21]
Ph
88
99
[21]
Et
90
95
[21]
98
90
[21]
Diene Et
TMS
O S
16 (R1 = Et; R2 = TMS)
H
Ph
TMS
O 1
S
2
16 (R = Ph; R = TMS)
H
TMS
16 (R1 = Et; R2 = TMS)
Et S
O TMS
16 (R1 = Ph; R2 = TMS)
Ph S
O TMS
16 (R1 = Et; R2 = TMS)
Et S
H
O TMS
16 (R1 = Ph; R2 = TMS) S
H
O O
1R
16 (R1 = Et; R2 = TBDMS) 4S
TBDMS O 1R
16 (R1 = Ph; R2 = TBDMS)
Ph 4S
TBDMS a
Conditions: diene (1.3 equiv), 6 (cat.), CH2Cl2, –78 to –20 8C, 12 h.
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3.2.1
Enantioselective Diels–Alder Reactions Catalyzed by Chiral Lewis Acids
73
(1R)-1-Bromo-4-methylcyclohex-3-enecarbaldehyde (7); Typical Procedure:[14]
A 100-mL, two-necked, round-bottomed flask was equipped with a stirrer bar, a glass stopper, and a 50-mL pressure-equalizing addition funnel (containing a cotton wool plug and ~10 g of 4- molecular sieves to function as a Soxhlet extractor), and fitted on top with a reflux condenser and a N2-inlet adaptor. The flask was then charged with bis(3,5-dimethylphenyl)[(2S)-pyrrolidin-2-yl]methanol (93.9 mg, 0.303 mmol), tri-2-tolylboroxin (35.8 mg, 0.101 mmol), and toluene (35 mL). The resulting soln was heated to reflux (bath temperature ~145 8C) for 4 h and then cooled to ~60 8C. The addition funnel and condenser were quickly replaced with a short-path distillation head, and the mixture was concentrated by distillation (air-cooling) to a volume of ~5 mL. This distillation protocol was repeated three times by recharging with 3 5 mL of toluene. The soln was then allowed to cool to rt and the distillation head was quickly replaced with a N2-inlet adaptor. Finally, concentration under reduced pressure (0.1 Torr, 1 h) gave the corresponding oxazaborolidine as a clear oil, which was dissolved in CH2Cl2 and used in the Diels–Alder experiments. An aliquot of the oxazaborolidine precursor (0.072 mmol, theoretical) in CH2Cl2 (5 mL) at –78 8C was treated by dropwise addition of a freshly prepared 0.200 M soln of TfOH in CH2Cl2 (300 L, 0.060 mmol) During the addition, the catalyst solution initially turned orange in color, but immediately became colorless again. Near the end of the reaction, a small amount of orange precipitate was observed. After 10 to 15 min at –78 8C, the orange precipitate disappeared and a colorless homogeneous soln was obtained. The soln of catalyst 3 (X = OTf ) was cooled to –95 8C (MeOH/dry ice/liq N2 bath) and 2-bromopropenal (80.8 L, 135 mg, 1.00 mmol) and a 2:1 (v/v) solution of buta-1,3-diene (1.25 mL, 10.0 mmol) in CH2Cl2 at –78 8C were successively added dropwise along the side of the flask from a cannula. The mixture was stirred for 2 h at –95 8C and then the reaction was quenched by the addition of Et3N (100 L). The mixture was warmed to rt, the solvent was removed by rotary evaporation at 0 8C, and the residue was purified by chromatography (silica gel, Et2O/pentane 1:99) to give the Diels–Alder adduct; yield: 183 mg (97%). 3.2.1.1.2
Using Boronic Acid Esters of Chiral 3-(2-Hydroxyphenyl)binaphthols
Chiral boronic acid esters of binaphthols, e.g. (R)-17 and (R)-18 (Scheme 8), can serve as Brønsted acid assisted chiral Lewis acid (BLA) catalysts for the enantioselective Diels– Alder reactions of Æ,-enals.[28–30] Scheme 8
Brønsted Acid Assisted Chiral Lewis Acid Catalysts[28–31]
CF3
O O
O B OH
O O
B
CF3
OH Ph
(R)-17
(R)-18
For example, in the presence of (R)-17 (10 mol%), the Diels–Alder reaction of 2-bromopropenal with benzyl cyclopenta-2,4-dienyl ether (19) gives the corresponding (S)-exo-adduct 20 in 94% ee (Scheme 9).
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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74
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
Scheme 9 Diels–Alder Reaction of 2-Bromopropenal in the Presence of a Brønsted Acid Assisted Chiral Lewis Acid Catalyst[28–30] BnO
BnO Br
CHO
+
10 mol% (R)-17, CH2Cl2, −78 oC
CHO
>99%; (exo/endo) >99:1; 94% ee
S
Br 19
20
The asymmetric induction in the Diels–Alder reaction catalyzed by the boronic acid ester (R)-17 can be understood in terms of the most favorable transition-state complex 21 (Scheme 10). It is conceivable that the coordination of a proton of the 2-hydroxyphenyl group with an oxygen of the adjacent B—O bond in complex 21 plays an important role in the facial selection. Hydrogen bonding through the Brønsted acid presumably causes the Lewis acidity of boron and the -basicity of the phenoxy moiety to increase to stabilize the transition state. In transition state 21, the hydroxyphenyl group blocks the CÆ-Re face of the C=C bond in the dienophile (R1 = Br), which leaves the Si face open to approach by diene. Proposed Transition-State Complexes[28–30]
Scheme 10
F3 C
CF3
O O O H
diene
B
O
O B O O O H
O
H Ph R1
R1
R2
diene
21
22
The BLA catalyst (R)-18 shows excellent catalytic activity for the Diels–Alder reactions of Æ,-enals 24 with both Æ-unsubstitution (R2 = H) and Æ-substitution (R2 „ H) with the cyclopentadienyl derivatives 23 (Scheme 11). In the presence of 5–10 mol% of (R)-18, the Diels– Alder reaction proceeds smoothly to afford the corresponding adducts 25 with excellent diastereo- and enantioselectivities. The asymmetric induction in the (R)-18-catalyzed Diels–Alder reaction is opposite that in the reaction catalyzed by (R)-17, which can be understood in terms of the transition state 22, which is analogous to transition state 21 (Scheme 10). Scheme 11 Enantioselective Diels–Alder Reaction of Cyclic Dienes with Æ,-Enals Catalyzed by a Brønsted Acid Assisted Chiral Lewis Acid Catalyst[29,30] R1 R1
R2
CHO
+
CHO R3 R2
R3 23
R1
5−10 mol% (R)-18 CH2Cl2, −78 oC
24
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
exo-25
+
R2 R3 CHO endo-25
3.2.1
Enantioselective Diels–Alder Reactions Catalyzed by Chiral Lewis Acids
R1
R2
R3
Yield (%) dr (exo/endo) ee (%) Config Ref
CH2OBn
Br
H
>99
H
Me H
96
H
H
H
84
H
H
Me
94
>99
R
[30]
99
S
[30]
3:97
95
S
[29]
10:90
95
S
[29]
89:11 –
75
The boron catalysts 17 and 18 are also efficient catalysts for the enantioselective Diels– Alder reactions of acetylenic dienophiles.[31] The reaction of cyclic dienes with acetylenic dienophiles in the presence of (R)-17 or (R)-18 (10–20 mol%), proceeds smoothly to afford the corresponding cycloadducts with a range of enantioselectivities (Scheme 12). Interestingly, (R)-17 generally gives higher enantioselectivity than does (R)-18. As in the case of the reaction with Æ,-enals, the absolute configurations of the adducts with (R)-17 are opposite those with (R)-18. The absolute configuration of the products of these reactions can be explained in terms of an anti-exo transition-state model, a view that is strongly supported by theoretical studies. Scheme 12 Enantioselective Diels–Alder Reaction of Cyclic Dienes with Acetylenic Aldehydes Catalyzed by Brønsted Acid Assisted Chiral Lewis Acid Catalysts[31] CHO n
10−20 mol% (R)-17 or (R)-18 CH2Cl2, −78 oC
+
n
CHO
4 1
R1
n R1
R1
Catalyst Yield (%) ee (%) Config
Ref
1 CO2Et (R)-17
97
95
(+)-(1R,4S)
[31]
1 CO2Et (R)-18
98
63
(–)-(1S,4R)
[31]
2 CO2Et (R)-17
81
84
(–)
[31]
2 CO2Et (R)-18
54
34
(+)
[31]
1 I
(R)-17
72
85
(–)-(1S,4R)
[31]
1 I
(R)-18
85
81
(+)-(1R,4S)
[31]
(R)-3-{4-[3,5-Bis(trifluoromethyl)phenyl]dinaphtho[1,2-f:2¢,1¢-d][1,3,2]dioxaborepin-2yl}biphenyl-2-ol [(R)-18]
A mixture of (R)-3-(2-hydroxybiphenyl-3-yl)-1,1¢-binaphthalene-2,2¢-diol (27.3 mg, 0.060 mmol) and a 0.043 M soln of monomeric 3,5-bis(trifluoromethyl)phenylboronic acid in CH2Cl2/THF/H2O (20:3:0.054; 1.16 mL, 0.050 mmol) was stirred at rt for 2 h. The resulting colorless soln was transferred to a Schlenk tube containing anhyd CH2Cl2 and powdered 4- molecular sieves [250 mg, activated by heating at 200 8C under vacuum (~3 Torr) for 12 h], and the mixture was stirred at rt for another 12 h. The solvents were then evaporated and the resulting solid was heated at 100 8C (oil bath) for 2 h under vacuum (~3 Torr) to dry the catalyst, which was then cooled to rt. Bicyclo[2.2.1]hept-5-ene-2-carbaldehydes 25; General Procedure:[30]
The flask containing catalyst (R)-18 (prepared as described above) was purged with argon, CH2Cl2 (2 mL, distilled from CaH2) was added, and the mixture was cooled to –78 8C. Dienophile 24 (1 mmol) was added dropwise followed 1 min later by freshly distilled diene 23 (4 mmol), which was slowly added along the wall of the flask. The mixture was stirred for several hours, and then the reaction was quenched with pyridine (20 mL, 0.25 mmol). The [4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
mixture was warmed to rt and filtered to remove the molecular sieves. The filtrate was washed with Et2O, dried (MgSO4), and concentrated to give a crude product, which was purified by chromatography (silica gel, pentane/Et2O). 3.2.1.2
Enantioselective Catalysis Using Chiral Copper(II) Complexes
As part of their studies on the synthesis of prostaglandins, Corey and co-workers discovered that copper(II) tetrafluoroborate catalyzes the Diels–Alder reactions of 2-chloroacrylonitrile.[32–34] This catalyst accelerates the Diels–Alder reaction at 0 8C without isomerization of 5-(methoxymethyl)cyclopenta-1,3-diene. Since this was reported in 1969, various copper(II) salts have been used as Lewis acid catalysts for Diels–Alder reactions.[35] 3.2.1.2.1
Using a Chiral Copper(II)–Bis(4,5-dihydrooxazole) Complex
Bis(4,5-dihydrooxazole) [bis(oxazoline)] ligands are a major class of chiral ligands for asymmetric catalysis, among which 26 (R1 = t-Bu, iPr), 27, and 28 (R1 = t-Bu, Ph) are representative examples (Scheme 13).[36–39] The copper(II) complexes of these ligands are efficient catalysts for enantioselective Diels–Alder reactions. Representative Bis(4,5-dihydrooxazole) Ligands[36–39]
Scheme 13
O
O
O N
O O N
N
N
R1
R1 26
NHMs
MsHN 27
R
O
N
N
N
1
R1 28
The C2-symmetric copper(II) complexes of bis(4,5-dihydrooxazole) 26 (R1 = t-Bu) demonstrate high catalytic activity for the enantioselective Diels–Alder reaction of dienes with N-alkenoyloxazolidinones 29 (Scheme 14 and Table 3).[37,40,41] The salts of copper(II) are the most effective among those of the first-row transition metals, because they offer both strong Lewis acid activation and rapid ligand exchange. Representative results for enantioselective Diels–Alder reactions catalyzed by the copper(II) salt of 26 (R1 = t-Bu) are summarized in Table 3. Most acyclic and cyclic dienes afford the corresponding endo-adducts in high yields and high enantioselectivities, whereas 2-substituted buta-1,3-dienes, such as isoprene and 2,3-dimethylbuta-1,3-diene, provide moderate enantioselectivities. The absolute configuration of the adducts is consistent with activation of the dienophile through bidentate coordination to a distorted square-planar copper(II) center. Scheme 14 N-Alkenoyloxazolidinones for Enantioselective Diels–Alder Reactions Catalyzed by Copper Bis(4,5-dihydrooxazole) Complexes[40,41] O
O R1
N
O
29
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3.2.1
77
Enantioselective Diels–Alder Reactions Catalyzed by Chiral Lewis Acids
Table 3 Enantioselective Diels–Alder Reaction of N-Alkenoyloxazolidinones Catalyzed by a Copper–Bis(4,5-dihydrooxazole) Complex[40,41] Entry
Reactantsa Dienophile
1
Product
S
29 (R1 = H) Ph
O
N
S
Ref
95
85:15
97
[41]
57
73:27
98
[41]
81
96:4
59
[41]
90
95:5
93
[41]
97
80:20
97
[41]
99
85:15
99
[40]
O
OAc O
S
29 (R1 = H)
O
N
O
N O
O
4
ee (%)
O
O
29 (R1 = H) OAc
3
dr (endo/ exo)
Diene
Ph
2
Yield (%)
S
29 (R1 = H) O
N O
O O
5
29 (R1 = H)
O
S
O
N O
O
6
R
29 (R1 = Me) O
N O
O
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78
Stereoselective Synthesis Table 3
3.2
[4 + 2]-Cycloaddition Reactions
(cont.) Reactantsa
Entry
Dienophile
Product
Yield (%)
dr (endo/ exo)
ee (%)
Ref
77
88:12
98
[40]
88
82:18
87
[40]
96
87:13
96
[40]
Diene Ph R
29 (R1 = Ph)
7
O
N O
O
CO2Et 1
R
29 (R = CO2Et)
8
O
N O
O
Cl R
29 (R1 = Cl)
9
O
N O
O a
Conditions: Cu(SbF6)2•26 (R1 = t-Bu) (cat.), CH2Cl2, –55 to –10 8C, 20–48 h.
The high level of enantioselection is explained in terms of the transition-state structure 30, in which the dienophile 29 coordinates in a bidentate manner to a distorted squareplanar copper center (Scheme 15). The 2,3-unsubstituted diene can then approach the CÆRe face of the activated s-cis dienophile via an endo transition state 30 to afford the corresponding cycloadduct with excellent enantioselectivity. In contrast, 3-methylbuta-1,3-dienyl acetate shows a significant exo preference (endo/exo 73:27). The steric effect of a 3-methyl substituent could explain the low enantioselectivity obtained in the reaction with isoprene (59% ee). Isoprene is presumed to approach the activated dienophile largely via an exo transition-state 31. The disfavored exo approach of isoprene to the CÆ-Si face of the activated dienophile does not involve substantial steric interaction with the ligand to decrease the enantioselectivity. In contrast, the acetoxy group of 3-methylbuta-1,3-dienyl acetate contacts the ligand substituent in the disfavored exo approach to generate high enantioselectivity. Scheme 15
Proposed Transition-State Complexes[40,41] O
O N
2+
N
O O
X
N But
Cu
But
O
O 2+
O
O
R1 N
N
Cu
But
O
But O
N R1
30
endo approach (favored for X = H)
31
X
exo approach (favored for X = Me)
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.1
79
Enantioselective Diels–Alder Reactions Catalyzed by Chiral Lewis Acids
The chiral adduct of copper(II) trifluoromethanesulfonimide complex of the bis(4,5-dihydrooxazole) 27 produces a high degree of enantioselectivity in the Diels–Alder reaction of dienophile 29 with cyclic and acyclic dienes, including 2-substituted buta-1,3-dienes (Table 4).[42] The reaction of acyclic dienes with -substituted dienophiles, which is one of the most challenging reactions, successfully affords the corresponding adducts with high enantioselectivities. For example, the catalytic Diels–Alder reaction of isoprene with dienophile 29 (R1 = CH2OTBDMS) gives the corresponding endo-adduct with 95% ee; this product is a key intermediate for the synthesis of decahydrofluorene core of hirsutellones.[43] Table 4 Enantioselective Diels–Alder Reactions of N-Alkenoyloxazolidinones Catalyzed by a Bis(4,5-dihydrooxazole)–Copper Complex[42] Reactantsa Dienophile
Product
Isomer Ratio
ee (%)
Ref
92
85:9:6
92
[42]
O
96
52:48
99
[42]
O
93
–
99
[42]
O
87
94:6
90
[42]
Diene
R
29 (R1 = H)
O
R
29 (R1 = H) OAc
O
N O
29 (R1 = H)
Yield (%)
N O
O
OAc
R
N O
O CO2Et 1
29 (R = CO2Et)
S
N O
O
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80
Stereoselective Synthesis Table 4
3.2
[4 + 2]-Cycloaddition Reactions
(cont.) Reactantsa
Dienophile
Product
Yield (%)
Isomer Ratio
ee (%)
Ref
Diene OTBDMS
29 (R1 = CH2OTBDMS)
S
O
N
76
>99:1
95
[42]
95
99:1
92
[42]
92
76:24
98
[42]
O
O
R
29 (R1 = H)
O
N O
O O R
O
29 (R1 = H)
O
N O
a
O
Conditions: diene (3 equiv), Cu(NTf2)2•27 (1–20 mol%), MeNO2 or EtNO2.
A theoretical study suggests that the n electrons of the 4,4¢-sulfonamide groups interact with the copper(II) cation, and the counteranions interact with the sulfonamidyl protons (transition-state complex 32; Scheme 16).[42] This coordination is thought to be essential for high catalytic activity, since it results in the formation of a cationic but stable catalyst. It is conceivable that dienes predominantly approach the CÆ-Si face side of s-cis-29, because a sulfonamide group and a trifluoromethanesulfonimide cation preferentially shield the Re face of the acrylimide moiety. The flexible but highly efficient asymmetric environment, created by the secondary interactions, provides broad substrate scope and a high level of asymmetric induction. n-Cation Interaction in the Proposed Transition-State Complex[42]
Scheme 16
n-cation interaction
Me
O O H O
Tf N Tf
H N
S O O N N N H 2+ Cu O N
O
hydrogen bonding
N Tf Tf
S O
Me O
endo, Cα-Si face approach
32
In related reactions, the lactams 34 and 37 also provide good dienophiles for the Diels– Alder reaction catalyzed by the copper(II) hexafluoroantimonate adduct of the bis(4,5-dihydrooxazole) 26 (R1 = t-Bu) (Scheme 17). In this context, the diene 33 reacts with lactam 34 to afford the spirolactam 35, a key intermediate in the synthesis of the spirocyclic imine core of (–)-gymnodimine.[44] In a related example, the cycloaddition of the diene 36 with lactam 37 gives the spirolactam 38, useful as an intermediate in the synthesis [4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.1
81
Enantioselective Diels–Alder Reactions Catalyzed by Chiral Lewis Acids
of the azaspiro[5.6]dodec-9-ene system in the marine toxins pinnatoxin A and pteriatoxin A.[45] For the enantioselective Diels–Alder reaction of Æ-substituted Æ,-enals 39, such as 2-methylpropenal and 2-bromopropenal, the copper(II) complex of a tridentate bis(4,5-dihydrooxazolyl)pyridine 28 (R1 = t-Bu), is among the most efficient catalysts affording the corresponding exo-adducts 40 with high diastereo- and enantioselectivity (Scheme 18).[46] Scheme 17 Chiral Copper(II)–Bis(4,5-dihydrooxazole) Complex Catalyzed Diels–Alder Reactions in the Syntheses of Bioactive Natural Compounds[44,45] O +
TBDMSO
20 mol% Cu(SbF6)2•26 (R1 = t-Bu) CH2Cl2, 3-Å molecular sieves
NCbz
33
85%; dr >19:1; 95% ee
34
O NCbz TBDMSO
35
O NCbz
+ OTBDMS
OTBDMS
20 mol% Cu(SbF6)2•26 (R1 = t-Bu) CH2Cl2, 3-Å molecular sieves
O
Cbz N
79%; dr 99:1; 96% ee
OBn
OBn 36
38
37
Scheme 18 Enantioselective Diels–Alder Reaction of Æ-Substituted Æ,-Enals Catalyzed by a Tridentate Bis(4,5-dihydrooxazolyl)pyridine–Copper(II) Complex[46] R2
CHO
+
5 mol% Cu(SbF6)2•28 (R1 = t-Bu) CH2Cl2
CHO R2
39
40
R2
dr
Br
98:2 96
[46]
Me 97:3 92
[46]
ee (%) Ref
The chiral adduct of copper(II) hexafluoroantimonate and bis(4,5-dihydrooxazole) 26 (R1 = t-Bu) is also an efficient catalyst for Type I intramolecular Diels–Alder reactions (Scheme 19). Thus, treatment of the trienimide 41 with this chiral complex (5 mol%) in dichloromethane at room temperature gives the corresponding bicyclic adduct 42 with 96% ee.[47] The cycloadduct 42 can then be converted into (–)-isopuloupone in additional five steps.
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
82
Stereoselective Synthesis Scheme 19
3.2
[4 + 2]-Cycloaddition Reactions
Enantioselective Type I Intramolecular Diels–Alder Reaction of a Trienimide[47] H
OTBDMS 5 mol% Cu(SbF6)2•26 (R1 = t-Bu) CH2Cl2, rt
3
O
O
81%; dr >99:1; 96% ee
N
3 OTBDMS
H O
O
N O
O 41
42
N-Alkenoylpyrazolidinones 43 can also act as dienophiles in copper-catalyzed enantioselective Diels–Alder reactions to give the corresponding cycloadducts 44.[48,49] Although the copper(II) complex of bis(4,5-dihydrooxazole) 26 (R1 = iPr) generally shows a poor enantioselectivity for the reaction of cyclopentadiene with N-alkenoyloxazolidinones 29,[40] the reaction of 43 (R2 = 1-naphthyl) provides a high enantioselectivity (Scheme 20).[48] Interestingly, this dienophile provides higher enantioselectivities when Lewis acids with relatively small chiral ligands are used; this has been attributed to the size of the fluxional group (R2 = Me < Ph < 1-naphthyl) and the ability of the pyrazolidinone template to relay stereochemical information from the ligand to the reaction center. Scheme 20 Enantioselective Diels–Alder Reactions of Cyclopentadiene with N-Alkenoylpyrazolidinones[49]
O
O
15 mol% Cu(OTf)2•26 (R1 = t-Bu, iPr) CH2Cl2, rt
N
+ R2
N
R2
N 44
43
R2
O
85−90%
N
R1
O
dr (endo/exo) ee (%) Ref
t-Bu Me
93:7
77
[49]
t-Bu Ph
92:8
97
[49]
t-Bu 1-naphthyl
90:10
99
[49]
iPr
Me
96:4
56
[49]
iPr
Ph
92:8
84
[49]
iPr
1-naphthyl
93:7
95
[49]
3-(Bicyclo[2.2.1]hept-5-en-2-ylcarbonyl)oxazolidin-2-ones (Table 3, Entries 6–9); General Procedure:[40]
CuCl2 (13.4 mg, 0.10 mmol), ligand 26 (R1 = t-Bu; 32.4 mg, 0.11 mmol), and AgSbF6 (68.7 mg, 0.20 mmol) were combined in a drybox under an inert atmosphere. The sealed flask was then removed from the box and connected to a N2 line. Anhyd CH2Cl2 (1 mL) was added, and the flask was wrapped in Al foil to protect the mixture from light. The heterogeneous mixture was vigorously stirred for 6–8 h at rt. The mixture was then filtered through a short column of Celite (rinsed with 0.2 mL of CH2Cl2) to give a clear dark blue soln of Cu(SbF6)2•26 (R1 = t-Bu), which was cooled to –78 8C. A soln of dienophile 29 (1.0 mmol) in CH2Cl2 (1 mL) was then added from a cannula, immediately followed by addition of cyclopentadiene (0.83 mL, 10 mmol) from a syringe. The resulting soln was stirred at –55 to –10 8C for 20–48 h. The mixture was then diluted with EtOAc/hexane [4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.1
Enantioselective Diels–Alder Reactions Catalyzed by Chiral Lewis Acids
83
(1:1; 10 mL), and the soln was applied directly to a short column of silica gel and eluted with EtOAc/hexane (1:1; ~100 mL) to remove the Cu salts. The soln was then concentrated to give a crude product, which was purified by chromatography (silica gel, EtOAc/hexane). 3.2.1.2.2
Using a Chiral Copper(II)–3-Arylalanine Amide Complex
The enantioselective Diels–Alder reaction of cyclopentadiene with 3-phenyl-1-(2-pyridyl)prop-2-en-1-one is catalyzed by copper(II) nitrate and the sodium salt of l-abrine (N-methyl-l-tryptophan) or N-methyl-l-tyrosine in water.[50,51] In this reaction, water enhances the enantioselectivity to give a product of up to 74% ee. The origin of the asymmetric induction may be the intramolecular -cation interaction between the indole ring of l-abrine and the copper(II) cation. On the basis of such an intramolecular -cation interaction, the chiral copper(II)–3-l-arylalanine amide complexes CuX2•45 [Ar1 = 3,4-(MeO)2C6H3, 2-naphthyl] were designed as efficient catalysts for the enantioselective Diels–Alder reactions of 1-alkenoyl-3,5-dimethylpyrazoles 46 (Scheme 21).[52,53] In particular, the copper(II) complex of 45 [Ar1 = 3,4-(MeO)2C6H3] shows excellent catalytic activity. In the presence of 2–10 mol% of the adduct of this ligand with copper(II) trifluoromethanesulfonate or the more active adduct of copper(II) trifluoromethanesulfonimide, cyclic and acyclic dienes undergo Diels–Alder reactions with various -substituted dienophiles 46 to afford the corresponding endo-adducts 47 with high enantioselectivities (Scheme 21). Scheme 21
Diels–Alder Reactions of Acrylamides Catalyzed by Copper(II) Complexes[52–54] Ar1 N
N H
O 45
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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84
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
O
R3
R1 R2
R4
+
R
5
N
10 mol% Cu(NTf2)2•45 [Ar1 = 3,4-(MeO)2C6H3] 3-Å molecular sieves, MeCN
N
46 R1 R3
R5
R4
R
R2
N N
O 47
R1
R2
R3
R4
R5
Yield (%) dr (endo/exo) ee (%) Ref
CH2
H
H
Me
95
97:3
97
[52]
CH2
H
H
Ph
93
93:7
95
[52]
CH2
H
H
OBz
89
93:7
90
[52]
CH2
H
H
Cl
95
>99:1
97
[52]
87
[52]
H
H
Me
H
H
H
Me
Me CO2Et 76
H H a
H
Ph
H
CO2Et 83
H
93:7
93
[52]
a
91
[52]
a
97
[52]
–
CO2Et 93
OMe H
a
>99:1
CO2Et 96
>99:1
The molar ratio of the 4- and 3-substituted diastereomers is shown.
The stereochemical outcome for the Diels–Alder reaction with CuX2•45 [Ar1 = 3,4(MeO)2C6H3] can be understood in terms of the transition-state complex trans-s-cis-48 (Scheme 22).[52,53] Furthermore, the N-cyclopentyl and pyrrolidinyl groups in the ligand 45 sterically assist the –cation interaction whereas the 3- and 4-methyl groups on the pyrazole moiety sterically control the coordination environment around the copper(II) complex [cis (disfavored) vs trans (favored)] and the conformation of 46 [s-cis (favored) vs s-trans (disfavored)], respectively. Interestingly, the catalytic activity of CuX2•45 [Ar1 = (MeO)2C6H3, 2-naphthyl] is slightly higher than that of the corresponding CuX2. The –cation interaction promotes the release of counteranions from copper(II) center, thereby increasing the catalytic activity. Scheme 22
Proposed Transition-State Complex[52,53] OMe OMe
N
O
2+
Cu N H
N N s-cis
O R1 endo, Cα-Re face approach
48
In general, alkynes are less reactive as electron-deficient dienophiles than are the corresponding alkenes. Furthermore, alkynes are more challenging substrates for asymmetric [4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.1
85
Enantioselective Diels–Alder Reactions Catalyzed by Chiral Lewis Acids
induction with a chiral Lewis acid due to the presence of the linear sp—sp bond, which orientates the alkynyl moiety away from the metal center and the cylindrical orbital symmetry of the alkyne. However, propynamide derivatives 50 undergo catalytic and highly enantioselective Diels–Alder reactions with cyclopentadienes 49 in the presence of the chiral copper complex CuX2•45 (Ar1 = 2-naphthyl) (10 mol%) to afford the corresponding 3-cycloadducts 51 with excellent enantioselectivities (Scheme 23).[54] Since the 3-iodo adducts 51 (R1 = I) can be readily transformed into 3-nonsubstituted and 3-alkyl derivatives by known methods, the alkyne 50 (R1 = I) represents the synthetic equivalent of alkyl or aryl substituted alkynes. Diels–Alder Reaction with Propynamides Catalyzed by a Copper Complex[54]
Scheme 23
O R3
n
+ R2
N
10 mol% Cu(NTf2)2•45 (Ar1 = 2-naphthyl) CH2Cl2, 4-Å molecular sieves
N
R1
49
50
n
R3
O N
R2
N
R1 51
R1
n R2 R3
Yield (%) ee (%) Ref
H
1 H
H
91
88
[54]
Me 1 H
H
22
89
[54]
I
1 H
H
82
89
[54]
I
2 Ph H
83
95
[54]
I
2 Bn H
83
96
[54]
I
2 H
OMe 84
96
[54]
1-(Bicyclo[2.2.1]hepta-2,5-dien-2-ylcarbonyl)-3,5-dimethyl-1H-pyrazole (51, R1 = R2 = R3 = H); Typical Procedure:[54]
In a glovebox with an argon atmosphere, a mixture of (S)-CuX2•45 (Ar1 = 2-naphthyl; 11.1 mg, 0.033 mmol) and Cu(NTf2)2 (18.7 mg, 0.030 mmol) was dissolved in MeCN (1 mL), and the soln was concentrated under reduced pressure at rt for 30 min. The residue was mixed with activated 4- molecular sieves (100 mg) and CH2Cl2 (1.2 mL), and then alkyne 50 (R1 = H; 44.4 mg, 0.30 mmol) and cyclopentadiene 49 (99.6 L, 1.2 mmol) were added to the mixture at –40 8C. The mixture was stirred for 7 h at –40 8C before the reaction was quenched with a few drops of Et3N. The crude product was directly purified by chromatography (silica gel, hexane/EtOAc); yield: 91%; 88% ee. 3.2.1.2.3
Using a Copper(II)–DNA Complex
The chirality of the DNA double helix can be transferred directly to the copper(II)-catalyzed Diels–Alder reaction.[55–58] DNA from salmon testes (st-DNA) in combination with the achiral copper(II) complex of 4,4¢-dimethyl-2,2¢-bipyridine successfully catalyzes the Diels–Alder reaction of cyclopentadiene with azachalcones 52 and Æ,-unsaturated
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
86
Stereoselective Synthesis
[4 + 2]-Cycloaddition Reactions
3.2
2-acyl-1-methylimidazoles in water to afford the corresponding endo-adducts 53, with excellent enantioselectivity (Scheme 24). Interestingly, the enantioselectivity and reaction rates are dependent on the DNA sequence.[58] DNA-Based Asymmetric Catalysis of a Diels–Alder Reaction[55–58]
Scheme 24
st-DNA 30 mol% Cu(NO3)2 30 mol% 4,4'-dimethyl-2,2'-bipyridine aq MOPS buffer (pH 6.5), 5 oC
O N
+ R1
R1
>80% conversion; dr >99:1
O N 52
53
O + Cu2+
R1
N
R1
52
O N 53
MOPS = 3-morpholinopropane-1-sulfonic acid
R1
ee (%) Ref
Ph
99
[58]
4-MeOC6H4
99
[58]
t-Bu
97
[58]
2-(Bicyclo[2.2.1]hept-5-en-2-ylcarbonyl)pyridines 53; General Procedure:[56]
A soln of salmon testes DNA [10 mL of a 2 mg • mL–1 soln in 30 mM 3-morpholinopropane1-sulfonic acid buffer (20 mmol, pH 6.5)], prepared 24 h in advance, was mixed with 0.9 mM aq [Cu(4,4¢-dimethyl-2,2¢-bipyridine)2(NO3)2] (5 mL), prepared by adding a soln of [Cu(4,4¢-dimethyl-2,2¢-bipyridine)2(NO3)2] in a minimal amount of DMSO to H2O (5 mL). An aliquot of 0.5 M stock soln of dienophile 52 in MeCN (30 L) was added, and the mixture was cooled to 5 8C. The reaction was started by the addition of cyclopentadiene (21 L) and the mixture was agitated by continuous inversion for 3 d. The product was then extracted with Et2O and purified by column chromatography. 3.2.1.3
Enantioselective Catalysis Using Other Chiral Lewis Acids
Several other chiral catalysts, including compounds of magnesium(II), aluminum(III), scandium(III), titanium(IV), zinc(II), and lanthanides, have also been used in enantioselective Diels–Alder reactions. Although several methods are available for the enantioselective hetero-Diels–Alder reactions of Danishefsky-type dienes, only a limited number are known for the carboDiels–Alder reaction. Ytterbium(III) complexes of chiral N,N¢-1,1¢-binaphthalene-2,2¢-diylbis(3,5-difluorobenzamide) (54; BINAMIDE) (Scheme 25) catalyze the highly enantioselective Diels–Alder reactions of Danishefsky-type dienes with electron-deficient alkenes.[59] [4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.1
87
Enantioselective Diels–Alder Reactions Catalyzed by Chiral Lewis Acids
Scheme 25 N,N¢-1,1¢-Binaphthalene2,2¢-diylbis(3,5-difluorobenzamide) F
F
N H H N
O O
F
F
54
In the presence of the ytterbium(III)–BINAMIDE complex prepared from ytterbium(III) trifluoromethanesulfonate, BINAMIDE (54), and 1,8-diazabicyclo[5.4.0]undec-7-ene, the Danishefsky-type dienes 55 undergoes cycloaddition with a series of dienophiles 56 to afford the corresponding exo-adducts 57 (Scheme 26). Acid treatment of adducts 57 gives the corresponding cyclohexenones 58 quantitatively with high enantioselectivity. In the reaction of dienophile 56 (R2 = H), the diene 55 (R1 = TIPS) provides the optimal enantioselectivity (71% ee). In contrast, when the substituent on 56 is large (R2 = iBu), the diene 55 (R1 = TMS), which bears a smaller trimethylsilyl group, provides the optimum selectivity (87% ee). Scheme 26 Enantioselective Diels–Alder Reaction of Danishefsky-Type Dienes Catalyzed by Ytterbium(III)–BINAMIDE Complexes[59]
R 1O +
R2
10 mol% Yb(OTf)3 12 mol% 54 24 mol% DBU CH2Cl2
O
O N
O
R 1O
R2 O
N
OMe
O
OMe O
55
56
57
TFA 1,2-dichloroethane 60 oC
O
R2 O
N O
O
58
R1
R2
Yield (%) ee (%) Ref
TIPS
H
93
71
[59]
TBDMS Me
94
94
[59]
TMS
88
87
[59]
TBDMS CH2OBn
97
89
[59]
TMS
93
92
[59]
iBu CO2Me
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88
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
Chiral Lewis acid complexes derived from the pybox ligand 28 (R1 = Ph) (see Scheme 13) with lanthanide trifluoromethanesulfonates are effective catalysts in the enantioselective Diels–Alder reactions of quinones.[60] In the presence of the samarium(III) and gadolinium(III) trifluoromethanesulfonate adducts of ligand 28 (R1 = Ph) (10 mol%), the cycloaddition of various dienes 59 with quinone 60 in tetrahydrofuran/toluene (1:1) gives the corresponding endo-adducts 61 with high regio- and enantioselectivity (Scheme 27). Scheme 27 Enantioselective Diels–Alder Reactions of Quinones Catalyzed by Chiral Lanthanide(III) Complexes[60] O +
MeO2C
O
MeO
R3
R3 R2
R2
60
R3
O
61
87
97
[60]
Me 97
91
[60]
99
98
[60]
Me 99
97
[60]
Gd Me H Gd H
H
Yield (%) ee (%) Ref
Sm Me H Sm H
R2
O
59
M
O
10 mol% M(OTf)3•28 (R1 = Ph) THF/toluene (1:1), −78 oC
Zinc(II) complexes of the chiral ligands 62 (Scheme 28) also catalyze enantioselective Diels–Alder reactions.[61] For example, the chiral complex derived from zinc(II) trifluoromethanesulfonate and a chiral ligand 62 (13 mol%), catalyzes the cycloaddition of various dienes with 3-alkenoyloxazolidin-2-one 63 to afford the corresponding endo-(S)-adducts 64 with high enantioselectivity (for examples, see Scheme 29). The level of selectivity depends on the size of the fluxional group (R1 = Me < Ph < 1-naphthyl), in which the larger group provides higher selectivity for both the endo- and the exo-isomers. Scheme 28 Chiral Ligand for Zinc Complexes[61]
Ph
N N
N
Me
OH
R1 62
Scheme 29 Examples of Enantioselective Diels–Alder Reactions Catalyzed by a Zinc(II) Trifluoromethanesulfonate Complex[61]
+ R2
13 mol% Zn(OTf)2 13 mol% 62 (R1 = 1-naphthyl) CH2Cl2, 0 oC to rt
O
O N
O
R2
O 63
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
64
O
N
S
O
Enantioselective Diels–Alder Reactions Catalyzed by Organoammonium Salts
3.2.2
R2
Yield (%) ee (%) Ref
H
69
95
[61]
Me 67
90
[61]
89
3-{[(1S,6R)-6-Methyl-4-oxocyclohex-2-enyl]carbonyl}oxazolidin-2-one (58, R2 = Me); Typical Procedure:[59]
A mixture of Yb(OTf )3 (18.6 mg, 0.030 mmol) and BINAMIDE (54; 20.3 mg, 0.036 mmol) was dried at 90 8C under reduced pressure (100:1
R1
R2
Yield (%) ee (%) Ref
OMe
H
88
96
[66]
NHCbz H
91
98
[66]
H
Ph 92
90
[66]
Me
Me 90
90
[66]
H
Me 79
85
[66]
O Et
R2
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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92
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
Several types of chiral secondary ammonium salt catalysts are available for enantioselective Diels–Alder reactions of -substituted propenals. For example, the chiral secondary amines 71 (R1 = H, Me), 72, and 73 (R1 = TMS, TES) catalyze the enantioselective Diels– Alder reactions of -substituted propenals (Scheme 36). Representative Chiral Secondary Amines[68–74]
Scheme 36
But CF3 R1O NHMe
NH O
N H
NHMe
N
CF3
Ph
CF3
R1
F3C But
71
72
73
Organoammonium salts of chiral secondary amines 71 with trifluoromethanesulfonic acid are efficient catalyst for the Diels–Alder reaction of cyclopentadiene with -substituted propenals (Scheme 37).[68–70] The reaction catalyzed by aqueous solutions of these salts (20 mol%) gives the corresponding adducts with high enantioselectivities, albeit the diastereoselectivities are modest. The substituted benzylic amine 71 (R1 = Me) provides better results than does the unsubstituted variant (R1 = H).[70] In general, the Diels–Alder reactions of -substituted propenals give the corresponding endo-adducts as the major products. In contrast, exo selectivity, particularly in catalystcontrolled Diels–Alder reactions, is generally not readily attainable. However, an exo-selective, enantioselective Diels–Alder reaction of -substituted propenals occurs in the presence of the binaphthyl-substituted secondary diammonium salt 72•0.8TsOH (10 mol%) when the reaction is conducted in (trifluoromethyl)benzene. This reaction gives the corresponding exo-adducts with up to >20:1 diastereoselectivity.[71,72] Another exo-selective enantioselective Diels–Alder reaction uses the diarylprolinol silyl ethers 73 (Scheme 37).[73,74] For instance, the hydroperchlorate salt 73•HClO4 (R1 = TMS) (5 mol%) catalyzes the Diels–Alder reaction of -substituted propenals in water to furnish the corresponding exo-adducts (exo/endo 2:1 to 6:1) with excellent enantioselectivity. Salts of diarylprolinol silyl ethers 73 also catalyze the enantioselective Diels–Alder reaction of cyclic dienes and acyclic dienes, such as cyclopentadiene and isoprene. Scheme 37 Chiral Secondary Ammonium Salts for the Enantioselective Diels–Alder Reactions of Cyclopentadiene with -Substituted Propenals[70–74] CHO
2
5−20 mol% catalyst
R2
CHO
+
+ 2
R2
R2
CHO
exo
Catalyst
R1
R2
Yield (%) dr (exo/endo)
ee (%) exo
endo
Ref
endo
71•TfOH
H
Me 74
1.1:1
68 (2S) 72 (2S)
[70]
71•TfOH
Me
Me 78
1.8:1
82 (2S) 80 (2S)
[70]
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.2
Enantioselective Diels–Alder Reactions Catalyzed by Organoammonium Salts R1
Catalyst
R2
Yield (%) dr (exo/endo)
ee (%) exo
Ref
endo
Ph 94
2.8:1
95 (2R) 93 (2R)
[70]
72•0.8TsOH –
Me 72
>20:1
88 (2S) –
[72]
72•0.8TsOH –
Ph 80
12.8:1
92 (2R) 91 (2R)
[72]
73•HClO4
TMS Me 73
2.6:1
99
[73]
73•HClO4
TMS Ph 93
4:1
97 (2S) 92 (2S)
[73]
73•2TFA
TES
5.7:1
97 (2S) 88 (2S)
[74]
71•TfOH
Me
Ph quant
93
99
Diels–Alder reactions catalyzed by secondary ammonium salts can be used to produce key intermediates for total syntheses of bioactive natural compounds. Thus, the imidazolidin4-one hydrochloride 65•HCl (see Scheme 31) catalyzes the Diels–Alder reaction of 1,3-dimethylcyclohexa-1,3-diene with Æ,-enal 74 in dimethylformamide/methanol (1:1) containing 5% water, to afford the endo-adduct 75 in 35% yield and with 93% ee (Scheme 38);[75] the product is a key intermediate for the synthesis of (+)-hapalindole Q. Similarly, the organoammonium salt of 1-naphthylmethyl-substituted ent-67 (Ar1 = 1-naphthyl) with tribromoacetic acid is used to construct the central tetracyclic pyrroloindole framework of (+)-minfiensine through an elegant organocascade sequence starting with the Diels– Alder reaction of thioether 76 with propynal (Scheme 38).[76] The endo-selective Diels– Alder reaction gives an adduct that undergoes reduction to afford the allylic alcohol 77 in 87% yield and 96% ee. Scheme 38 Chiral Secondary Ammonium Salt Catalyzed Diels–Alder Reaction for the Synthesis of Bioactive Natural Compounds[75,76] CHO 40 mol% 65•HCl DMF/MeOH/H2O (10:10:1), rt
+
NTs
35%; (endo/exo) 85:15; 93% ee
TsN
CHO 74
75
NHBoc SMe
+
CHO
1. 15 mol% ent-67•Br3CCO2H (Ar1 = 1-naphthyl) Et2O, −40 oC 2. NaBH4, CeCl3, MeOH 87%; 96% ee
N PMB 76
OH NBoc N PMB
SMe
77
Ammonium salts of secondary amines 65–67 (see Scheme 31) can also promote the Type I intramolecular Diels–Alder reaction of trienes 78.[77] In the presence of salts of 67 (Ar1 = Ph) (20 mol%), the intramolecular Diels–Alder reaction of trienes 78 proceeds in aqueous acetonitrile to afford the bicyclic endo-adduct 79 with high diastereo- and enantioselectivity (Scheme 39). The adduct 79 [Y = (CH2)2, R1 = Me] can be converted into the phytotoxic polyketide solanapyrone D in five steps. [4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
94
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
Scheme 39 Type I Intramolecular Diels–Alder Reaction of Trienes Catalyzed by Secondary Ammonium Salts[77] Y
CHO
H
20 mol% 67•HX (Ar1 = Ph) MeCN, H2O
CHO R1
Y
(endo/exo) >20:1
R1
H
78
79
Y
R1
HX
Yield (%) ee (%) Ref
CH2
Ph
TFA
85
93
[77]
CH2
(E)-CH=CHMe
TFA
75
94
[77]
O
Ph
HClO4 84
93
[77]
TfOH
90
[77]
(CH2)2 Me
71
The ammonium salt of 67 (Ar1 = Ph) also catalyzes the Type II intramolecular Diels–Alder reaction of triene 80 to provide the [5.3.1]cycloadduct 81 with excellent diastereo- and enantioselectivity (Scheme 40).[77] Scheme 40
Type II Intramolecular Diels–Alder Reaction of a Triene[77]
CHO
CHO
20 mol% 67•TsOH (Ar1 = Ph) CHCl3, 25 oC
Ph Ph
65%; (endo/exo) 99:1; 98% ee
80
81
Cyclohex-3-enecarbaldehydes 69; General Procedure:[65]
The Æ,-unsaturated aldehyde was added to a 1.0 M soln of catalyst 65•HCl (640 mg, 2.5 mmol) in MeOH/H2O (95:5 v/v). The soln was stirred for 1–2 min before addition of the diene (3–4 equiv). When the Æ,-unsaturated aldehyde had been consumed, the mixture was diluted with Et2O and washed successively with H2O and brine. The organic layer was then dried (Na2SO4), filtered, and concentrated. The resulting dimethyl acetal was hydrolyzed by stirring the crude product mixture in TFA/H2O/CHCl3 (1:1:2) for 2 h at rt, followed by neutralization with sat. aq NaHCO3 and extraction with Et2O to give a crude product, which was purified by chromatography (silica gel). 3.2.2.2
Enantioselective Catalysis Using Chiral Primary Ammonium Salts
Although secondary ammonium salts can promote the Diels–Alder reactions of Æ-unsubstituted propenals, it is difficult to activate Æ-substituted propenals with these sterically hindered salts, presumably because of the problems associated with the generation of the corresponding iminium intermediates. As a result, chiral primary ammonium salt catalysts[78,79] have been developed for the Diels–Alder reaction of Æ-substituted propenals. Representative chiral primary amines 82–86 for the enantioselective Diels–Alder reaction are shown in Scheme 41.
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.2
Enantioselective Diels–Alder Reactions Catalyzed by Organoammonium Salts
Scheme 41
95
Representative Chiral Primary Amine Catalysts[80–87] But
But
Bui NH Ph
N
NH2
NH2
NH2
NH2
NH2
But
But 82
83
84
OMe Ph
NH
Ph
NH2
NH2 N
85
N
H 86
The primary ammonium salt of a dipeptide-derived triamine 82 and that of 1,1¢-binaphthyl-2,2¢-diamine (83) are efficient catalysts for the enantioselective Diels–Alder reactions of Æ-(acyloxy)propenals 87.[80–83] Æ-(Acyloxy)propenals 87[88] are among the most promising alternatives to Æ-halopropenals,[9,10,89–91] since they are outstanding dienophiles for catalytic Diels–Alder reactions due to their high reactivity and the exceptional synthetic versatility of the resultant cycloadducts. In contrast to Æ-halopropenals, Æ-(acyloxy)propenals 87 are relatively stable and their reactivity can be controlled by changing the acyloxy group. The salt of triamine 82 (10–20 mol%) and pentafluorobenzenesulfonic acid catalyze the reaction of various acyclic dienes (Scheme 42) and cyclopentadienes (Scheme 43) with Æ-(acyloxy)propenal 87 (R1 = 4-MeOC6H4) with good to excellent enantioselectivity to give the corresponding (S)-adducts 88 and 89.[80] In the Diels–Alder reaction of cyclopentadienes, the ammonium salt of binaphthyldiamine 83 with trifluoromethanesulfonimide (Tf2NH) provides a higher catalytic activity than does the ammonium salt of triamine 82 (Scheme 43).[81,82] Since 83 is an aromatic diamine, the catalytic activity of its ammonium salt is greater than that of the ammonium salt of 82, and the reaction can be conducted at a lower reaction temperature (–75 8C) with a lower catalyst loading (5–10 mol%). The silylated Æ-(acyloxy)propenal 87 (R1 = 4-TIPSOC6H4) is suitable as a dienophile for the 83•1.9Tf2NH-catalyzed Diels–Alder reaction, because of the electron-donating nature of the acyloxy group and the good solubility of 87 (R1 = 4-TIPSOC6H4) under the reaction conditions.
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
96
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
Scheme 42 Enantioselective Diels–Alder Reaction of Acyclic Dienes with Æ-(Acyloxy)propenals Catalyzed by Primary Organoammonium Salts[80–82] R1
R2 +
O
10−20 mol% catalyst EtNO2
R2
CHO
88
R1
R2
Yield (%) ee (%) Ref
82•2.75C6F5SO3H 4-MeOC6H4
Me 92
92
[80]
83•1.9Tf2NH
Cy
Me 88
70
[81]
83•1.9Tf2NH
4-TIPSOC6H4 Me 85
85
[82]
H
90
88
[80]
4-TIPSOC6H4 H
85
82
[82]
82•2.75C6F5SO3H 4-MeOC6H4 83•1.9Tf2NH
O
S
CHO
87
Catalyst
R1
O
O
Scheme 43 Enantioselective Diels–Alder Reaction of Cyclopentadienes with Æ-(Acyloxy)propenals Catalyzed by Primary Organoammonium Salts[80–82] R2 1
R R
2
+
O O
5−20 mol% catalyst THF or EtCN
CHO
CHO
R1
O O 87
(2S)-exo-89
Catalyst
R1
R2
Yield (%)
dr (exo/endo)
ee (%)
Ref
82•2.75C6F5SO3H
4-MeOC6H4
H
99
87:13
83
[80]
82•2.75C6F5SO3H
4-MeOC6H4
CH2OBn
81
88:12
83
[80]
83•1.9Tf2NH
Cy
H
88
92:8
91
[81]
83•1.9Tf2NH
4-TIPSOC6H4
H
76
93:7
94
[82]
A possible mechanism that accounts for the observed absolute stereochemistry of the adducts is shown in Scheme 44. The Diels–Alder reaction of cyclopentadiene catalyzed by 82•2.75C6F5SO3H may proceed via a (Z)-iminium intermediate 90, in which the phenyl group of 82 shields the CÆ-Re face of the Æ,-unsaturated iminium moiety.[80,84] Although, the mechanism for asymmetric induction for the reaction catalyzed by 83•2.75C6F5SO3H is still unclear,[84] it most likely proceeds via an (E)-iminium intermediate 91, in which the acyloxy group interacts with the other ammonium group through hydrogen bonding.[81,82] The electron-donating nature of the 4-(triisopropylsiloxy)benzoyloxy group presumably enhances hydrogen bonding between the acyl group and the ammonium proton to stabilize the conformation of the (E)-iminium intermediate 91. In both cases, dienes should approach the CÆ-Si face of electron-deficient alkene enantioselectively.
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.2
Enantioselective Diels–Alder Reactions Catalyzed by Organoammonium Salts
97
Proposed Transition-State Complexes[80–82,84]
Scheme 44
Cα-Si face approach
R2
H
Cα-Si face approach
OCOR1
N
H
C6F5SO3− H
O R1
N H H H
N H
O 90
91
Ammonium salts of the chiral triamine 82 can also be used as catalysts for the Diels–Alder reaction with 2-phthalimidopropenal to provide cyclic Æ-quaternary Æ-amino acid precursors.[84] The cycloaddition reaction of cyclic and acyclic dienes with 2-phthalimidopropenal in the presence of 82•2.75C6F5SO3H (2.5–10 mol%) in nitroethane affords the corresponding endo-adducts 92 with high enantioselectivity (Scheme 45). Scheme 45
Enantioselective Diels–Alder Reactions of 2-Phthalimidopropenal[84] O
+
NPhth
10 mol% 82•2.75C6F5SO3H EtNO2, 0 oC
CHO N
R1
CHO R1
O 92
R1
Yield (%) ee (%) Ref
Me
82
94
[84]
Ph
80
88
[84]
(CH2)CH=CMe2
73
94
[84]
The Diels–Alder reaction with Æ-alkyl-substituted propenals 93 can provide cycloadducts with one all-carbon quaternary stereocenter. For example, the binaphthyl-based primary ammonium salt 84•0.5TfOH is an efficient catalyst for the enantioselective Diels–Alder reaction of with cyclopenta-1,3-diene with propenals 93.[85] Interestingly, the reaction of 2-methylpropenal gives the corresponding adduct 94 (R1 = Me) with moderate enantioselectivity (55% ee), whereas the introduction of longer alkyl substituents at the Æ-carbon of the propenal significantly improves the level of asymmetric induction (Scheme 46).
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
98
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
Scheme 46 Enantioselective Diels–Alder Reactions of Æ-Alkyl-Substituted Propenals[85]
R1
+
20 mol% 84•0.5TfOH mesitylene, −20 oC
CHO
CHO 1
R 93
94
R1
Yield (%) ee (%) Ref
CH2CH=CH2
86
94
[85]
Bn
79
91
[85]
(CH2)2OBn
90
89
[85]
An ammonium salt of the primary diamine 85 is also an effective organocatalyst for the enantioselective Diels–Alder reaction.[86] Although the reactions of Æ-unsubstituted propenals catalyzed by the dihydrochloride salt of diamine 85 give the corresponding adducts with high enantioselectivities, Æ-substituted propenals provide poor reactivity and give low enantioselectivities. Cinchona alkaloids are widely used as asymmetric organocatalysts.[92,93] They are abundant natural products that exist as pseudoenantiomeric pairs, as exemplified by quinine and quinidine. The ammonium salt of the cinchona alkaloid derived primary amine 86 provides an efficient catalyst for the enantioselective Diels–Alder reaction of 3-hydroxypyran-2-ones 95 with simple Æ,-unsaturated ketones 96.[87] In the presence of 86•4TfOH (5 mol%), the reactions of 3-hydroxypyran-2-ones 95 with enones 96 afford the corresponding exo-adducts 97 with excellent enantioselectivities (Scheme 47). Scheme 47 Enantioselective Diels–Alder Reaction of 3-Hydroxypyran-2-ones with Æ,-Unsaturated Ketones[87] O R3
5 mol% 86•4TfOH CH2Cl2, −30 to 0 oC
O O
+ R
2
R
R1
R2
O R1
R3 HO
96
R2 97
R3 Yield (%) dr (exo/endo) ee (%) Ref
Me Ph
H
87
80:20
98
[87]
Me 2-thienyl
H
85
80:20
99
[87]
Me Me
H
92
84:16
99
[87]
Me (CH2)3OBn H
92
76:24
99
[87]
Et
99
97:3
99
[87]
H
O
1
OH 95
O
H
Me Ph
Ph 83
83:17
96
[87]
Me 4-BrC6H4
Cl 63
67:33
90
[87]
The ammonium salt of 86 presumably promotes the reaction by simultaneously activating the 3-hydroxypyran-2-one and the Æ,-unsaturated ketone 96 with its primary amine and quinuclidine moieties, respectively (Scheme 48).[87]
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.2
Enantioselective Diels–Alder Reactions Catalyzed by Organoammonium Salts
99
Scheme 48 Proposed TransitionState Complex[87]
N
H
O
OMe
H
O O R
H
R1
3
N
R2
N
1-(Acyloxy)cyclohex-3-enecarbaldehydes 88 or 2-(Acyloxy)bicyclo[2.2.1]hept-5-ene-2-carbaldehydes 89; General Procedure:[80]
The diene (1.6 mmol) was added to a soln of triamine 82 (24.3 mg, 0.08 mmol) and C6F5SO3H (56.8 mg, 0.22 mmol) in EtNO2 (0.125 mL) or THF (0.25 mL), and the mixture was stirred at 0 8C or rt. The Æ-(acyloxy)propenal 87 (0.8 mmol) was then added in one portion. When the Æ-(acyloxy)propenal 87 had been consumed, the reaction was quenched with sat. aq NaHCO3. The mixture was then diluted with pentane and washed with H2O and brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure to give a crude product, which was purified by chromatography (silica gel). 3.2.2.3
Enantioselective Catalysis Using Hydrogen-Bonded Complexes
Some small organic molecules that are capable of forming hydrogen-bonded complexes are also useful catalysts for asymmetric Diels–Alder reactions.[94–97] For instance, several representative chiral Brønsted acid catalysts 98–101 for enantioselective Diels–Alder reactions are illustrated in Scheme 49. Representative Chiral Brønsted Acid Catalysts[98,101]
Scheme 49
Pri
Pri
O Pri O O
OH
P
OH
O Pri
Pri
O NHTf
Pri
99
98
R1 CF3 Et
N
H O
N OH 100
S H F3C
N H
N H
N
N
MeO 101
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
100
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
The commercially available chiral diol 98 (TADDOL)[102] markedly accelerates the reaction of the electron-rich siloxydienamine 102 with Æ-substituted propenals. Reduction of the intermediate endo-adducts 103 with lithium aluminum hydride followed by acidic hydrolysis provides the corresponding alcohols 104 with high enantioselectivities (up to 92% ee) (Scheme 50).[98] Interestingly, the enantioselective Diels–Alder reaction with propenal is less enantioselective than the analogous reaction of Æ-substituted propenals, probably because of the greater conformational flexibility of propenal. Scheme 50 TADDOL-Catalyzed Enantioselective Diels–Alder Reactions of a Siloxydienamine[98] OTBDMS
OTBDMS 20 mol% 98 toluene, −80 oC
R1 + CHO
Me2N
Me2N
102
R1
CHO
endo-103
O 1. LiAlH4, Et2O 2. HF, MeCN
OH
R1 104
R1
Yield (%) ee (%) Ref
H
77
73
[98]
Me
83
91
[98]
iPr
81
92
[98]
(CH2)2OTBDMS
80
86
[98]
TADDOL (98) is believed to exist in a well-defined, internally hydrogen-bonded arrangement 105 (Scheme 51). Æ-Substituted propenals interact with 98 through hydrogen bonding with the free hydroxy group and through – interactions with the proximal equatorial 1-naphthyl group, which selectively shield the CÆ-Re face of the dienophile.[98] Scheme 51
Proposed Transition-State Complex[98] R1 H O
s-cis
H O O O H O H H
Cα-Si face approach
diene
105
Binaphthyl-based chiral phosphoric acids are an important class of chiral Brønsted acid catalysts,[103,104] especially for the activation of relatively Brønsted-basic imines. However, chiral phosphoric acids are difficult to use in Diels–Alder reactions of simple carbonyl dienophiles. The binaphthyl-based N-(trifluoromethylsulfonyl)phosphoramide 99, which is [4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.2
Enantioselective Diels–Alder Reactions Catalyzed by Organoammonium Salts 101
more acidic than phosphoric acids, can catalyze the Diels–Alder reactions of 1-substituted 2-siloxybuta-1,3-dienes 106 with Æ,-unsaturated ketones, e.g. pent-1-en-3-one, to give the corresponding endo-adducts 107 with high enantioselectivities (Scheme 52).[99] Scheme 52 N-(Trifluoromethylsulfonyl)phosphoramide-Catalyzed Enantioselective Diels–Alder Reactions of Pent-1-en-3-one[99] O
O 5 mol% 99 toluene, −78 oC
Et
+
Et
TIPSO
TIPSO R1
R1 endo-107
106
R1
Yield (%) dr
Me
95
76:24 92
[99]
quant
–
87
[99]
quant
–
91
[99]
OMOM
(CH2)2OBz
ee (%) Ref
Cinchona alkaloids bearing an active proton can act as acid–base bifunctional catalysts for enantioselective Diels–Alder reactions. For example, the Diels–Alder reaction of 3-hydroxypyran-2-ones 108 with the enediones 109 is catalyzed by the cinchona alkaloid derived catalyst 100 to give corresponding exo-adducts 110 with high enantioselectivities (Scheme 53).[100] Scheme 53 Enantioselective Diels–Alder Reaction of 3-Hydroxypyran-2-ones Promoted by a Cinchona Alkaloid Derived Bifunctional Catalyst[100] O O R1
R2 O
OH
+
O
O
O
Ph R1 HO
O
108
R1 R2
5 mol% 100 Et2O or EtOAc, rt
109
O
Ph R2
exo-110
Yield (%) dr (exo/endo) ee (%) Ref
H
OEt 87
93:7
94
[100]
H
Ph
93:7
90
[100]
Ph OEt 84
95:5
85
[100]
Cl OEt 77
86:14
84
[100]
quant
In the case of the bifunctional catalysts 100 and 101 (R1 = CH=CH2) (see Scheme 49), the 6¢-phenol group and the thiourea moiety act as Brønsted acids to activate the dienophile, whereas the tertiary amino groups act as Brønsted bases to activate the lactone. Furthermore, by using such cinchona alkaloid derived bifunctional catalysts it is possible to control the endo/exo selectivity (Scheme 54).[100] For example, the Diels–Alder reaction of 3-hydroxy-2H-pyran-2-one (111) with 2-chloroacrylonitrile (112) in the presence of catalyst 100 selectively provides the endo-adduct 113A, whereas the urea-derived catalyst 101 (R1 = CH=CH2) affords the exo-adduct 113B. [4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
102
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
Catalyst-Controlled exo/endo Selectivity[100]
Scheme 54
O
O
5 mol% 100, Et2O
Cl
93%; dr 87:13; 85% ee
OH
CN 113A
O + Cl
O
CN
111
O
5 mol% 101 (R1 = CH=CH2) THF
OH 112
O
NC
90%; dr 91:9; 85% ee
OH
Cl 113B
The cinchona alkaloid derived organocatalyst 101 (R1 = Et) promotes the enantioselective Diels–Alder reaction of 3-vinylindoles 114 (Scheme 55).[101] In the presence of organocatalyst 101 (R1 = Et) (20 mol%), the reaction of vinylindoles 114 with N-substituted maleimides 115 in dichloromethane provides the corresponding endo-adducts endo-116 in good yield and with excellent enantioselectivity.[101] Scheme 55 Diels–Alder Reactions of 3-Vinylindoles Promoted by a Cinchona Alkaloid Derived Bifunctional Catalyst[101] R3 R3 R2
NR4
+ N H 114
1. 20 mol% 101 (R1 = Et) CH2Cl2, −55 oC 2. TFAA
O
(endo/exo) >95:5
O
H NR4 N
O F3C 115
H O
O
endo-116
R2
R3
R4 Yield (%) ee (%) Ref
H
H
Ph 91
98
[101]
Br
H
Ph 86
90
[101]
OMe H
Ph 77
96
[101]
H
Me Ph 79
96
[101]
H
H
96
[101]
Bn 89
H R2
The bifunctional catalyst 101 (R1 = Et) can simultaneously activate the vinylindole 114 and the N-substituted maleimide 115 through hydrogen bonding to the tertiary amine moiety and the thiourea moiety of the catalyst, respectively (Scheme 56).[101] The tetracyclic product endo-116 (R1 = R2 = H; R3 = Ph) can be converted into a known intermediate for the synthesis of the Strychnos alkaloid, tubifolidine. Benzoquinones and naphthoquinones can also be used as dienophiles to afford the corresponding adducts with high enantioselectivities.
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.3
103
Hetero-Diels–Alder Reactions
Scheme 56 Proposed Double Activation through Dual Hydrogen Bonding[101] MeO
N
CF3 S
N Et H N
N
N
H
H
CF3
O R2N
R1
O
(4S)-4-(Hydroxymethyl)-4-methylcyclohex-2-enone (104, R1 = Me); Typical Procedure:[98]
CAUTION: Solid lithium aluminum hydride reacts vigorously with a variety of substances, and can ignite on rubbing or vigorous grinding. CAUTION: Hydrogen fluoride fumes are severely irritating and extremely destructive to the respiratory system. Siloxydienamine 102 (260 mL, 1.0 mmol) was added to a soln of TADDOL (98; 66.7 mg, 0.1 mmol) and H2C=C(Me)CHO (41.5 L, 0.5 mmol) in toluene (0.75 mL) at –80 8C. The mixture was stirred for 48 h and then treated with a 1.0 M soln of LiAlH4 in Et2O (2.0 mL, 2.0 mmol) at –80 8C. The resulting mixture was stirred for 0.5 h at –80 8C and then for an additional 1.5 h at rt. The mixture was then cooled to 0 8C and excess LiAlH4 was quenched with H2O (0.5 mL). The solids were removed by filtration and washed extensively with Et2O (5 3 mL). The organic filtrate was concentrated in vacuo to give an oil, which was taken up in MeCN (2.0 mL). The soln was cooled in an ice bath, treated with a 5% soln of HF in MeCN (3.0 mL), and stirred for 0.5 h at rt. Volatile components were removed under reduced pressure, and the residue was purified by chromatography (silica gel, hexanes/ EtOAc 3:7) to give a colorless oil; yield: 116 mg (83%); 91% ee. 7,8-Dibenzoyl-4-hydroxy-3-oxo-2-oxabicyclo[2.2.2]oct-5-enes 110; General Procedure:[101]
Dienophile 109 (0.6–1.2 mmol, 2–4 equiv) was added to a soln of 3-hydroxypyran-2-one 108 (0.3 mmol) and catalyst 100 (0.015 mmol, 5 mol%) in Et2O (3.0 mL) at rt. The mixture was kept at a selected temperature for 11–72 h and then passed through a short plug of silica gel to remove the catalyst. The silica gel plug was washed with Et2O or EtOAc (3–4 mL), and the eluent was concentrated under reduced pressure to give a residue which was purified by chromatography (silica gel). 3.2.3
Hetero-Diels–Alder Reactions
3.2.3.1
Enantioselective Hetero-Diels–Alder Reactions of Carbonyl Compounds
The asymmetric hetero-Diels–Alder reaction of carbonyl compounds is among the most powerful methods for the construction of optically active heterocycles, which has been used extensively in syntheses of bioactive natural and synthetic compounds.[105–111] The two concepts underlying the hetero-Diels–Alder reactions of carbonyl compounds are illustrated in Scheme 57. In the normal-electron-demand reaction, a carbonyl compound reacts with an electron-rich diene. To promote this reaction, an acid catalyst activates the carbonyl compound by lowering its LUMO energy. Conversely, in the inverse-elec[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
104
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
tron-demand reaction, the Æ,-unsaturated carbonyl compound reacts with an electronrich dienophile. This type of reaction can also be promoted by using acid catalysts to lower the LUMO energy of the Æ,-unsaturated carbonyl compound. Hence, the introduction of additional electron-withdrawing groups (R2) provides additional activation for both types of hetero-Diels–Alder reaction. Scheme 57 Conceptual Hetero-Diels–Alder Reactions of Carbonyl Compounds[105–111] O R
R
R2
O
R2 R2 inverse electron demand
+
R
R3
R1
2
1
3.2.3.1.1
O
normal electron demand
R3
+ 1
R3
O
R1
R3
Enantioselective Catalysis Using a Chiral Chromium(III) Complex
Chiral chromium(III) complexes, such as 117 (X = Cl, SbF6) and 118 (X = BF4, Cl) (Scheme 58) catalyze the hetero-Diels–Alder reactions of nonactivated aldehydes.[112–115] Scheme 58 Chiral Chromium(III) Complex Catalysts for Hetero-Diels–Alder Reactions[112–115]
H
H N
N
O
O
Cr O X O
But
Cr X
N
But
117
But
But 118
The chiral tridentate Schiff base chromium(III) complexes 117 are the most efficient catalysts for the reactions of less nucleophilic dienes bearing fewer than two oxygen substituents.[112,113] For example, complex 117 (X = Cl, SbF6) (3 mol%) promotes the reaction of a 2-siloxy-1,3-diene 119 with a nonactivated aldehyde 120 to afford the corresponding tetrahydropyranone 121 with excellent diastereo- and enantioselectivity (Scheme 59).[112] The reaction is performed at room temperature and requires the presence of molecular sieves for optimal results. Although acetone is generally beneficial and is critical for aromatic aldehydes, solvent-free conditions are satisfactory for some substrates. Scheme 59 Hetero-Diels–Alder Reactions of 2-Siloxydienes with Nonactivated Aldehydes Catalyzed by Chiral Chromium(III) Complexes[112] 1. 3 mol% 117 4-Å molecular sieves, rt 2. TBAF, AcOH, THF, 0 oC or TFA, CH2Cl2, 0 oC
R1 O + R3
H
TESO R2 119
R1 O R3
O R2
120
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
121
R1
105
Hetero-Diels–Alder Reactions
3.2.3
R3
X
Solvent
Yield (%) ee (%) Ref
Me Me CH2OTBDMS
Cl
acetone
90
99
[112]
Me H
CH2OTBDMS
Cl
acetone
78
98
[112]
Me CH2OTBDMS
Cl
none
50
91
[112]
H
R2
Me Me Ph
SbF6 acetone
72
90
[112]
Me Me (CH2)4CH=CH2
SbF6 none
78
98
[112]
Me Me (CH2)2NHBoc
SbF6 acetone
28
96
[112]
The hetero-Diels–Alder reaction of 1-alkoxydienes 122 and 124 with aldehydes provides the corresponding cyclic acetals 123 and 125 with excellent enantioselectivities, which can be subjected to hydrolysis and oxidation to afford the corresponding lactones (Scheme 60).[112] This method provides highly efficient access to several interesting natural product structures; for example, adduct 123 is a key intermediate in a total synthesis of fostriecin (CI-920).[114] Scheme 60 Hetero-Diels–Alder Reaction of 1-Alkoxydienes with Nonactivated Aldehydes Catalyzed by a Chiral Chromium(III) Complex[112,114] OBn OBn
3 mol% 117 (X = Cl) 4-Å molecular sieves, rt, 36 h
O +
H
O
90%; dr 95:5; >99% ee R
TIPS
TIPS 122
123
OMe
3 mol% 117 (X = Cl) 4-Å molecular sieves, rt, 36 h
O + H
OTBDMS
OMe O
91%; 97% de; >99% ee R
124
OTBDMS 125
The tridentate Schiff base chromium(III) complexes 117 (X = Cl, SbF6) and the (salen)chromium(III) complexes 118 (X = BF4, Cl) (see Scheme 58) are efficient catalysts for the heteroDiels–Alder reaction of highly nucleophilic Danishefsky-type dienes 126 with nonactivated aldehydes 127 (Scheme 61).[115] In the presence of 117 and 118 (2–5 mol%), the reactions of 126 with 127, followed by treatment with a Brønsted acid provide the corresponding dihydropyranones 128 with high enantioselectivity.[116–119] In the case of the 118-catalyzed reaction, noncoordinating ethereal solvents such as tert-butyl methyl ether provide the highest reactivity and enantioselectivity.
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
106
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
Scheme 61 Hetero-Diels–Alder Reaction of Danishefsky-Type Dienes with Nonactivated Aldehydes[116–119] OMe + H
R1
1. catalyst, 4-Å molecular sieves 2. TFA, CH2Cl2
O
R1
R
3
R1
127
R2
Me TMS
H
128
R3
Catalyst
Solvent
Temp (8C)
Yield (%)
ee (%)
Ref
(CH2)3OBn
117 (X = Cl) (5 mol%)
none
rt
90
94 (S)
[116]
117 (X = SbF6)
acetone
rt
60
ent-118 (X = BF4) (4 mol%)
t-BuOMe –78 to –20
71
118 (X = Cl) (5 mol%)
t-BuOMe rt
89
TBDMS
O O
H
TMS
H
TMS
∗ R3
O
R2O 126
O
84 (S)
[117]
O
(CH2)3CO2Me OTBDPS OBn
84 (R) 94 (S)
[118]
[119]
Chiral chromium(III) catalysts 117 can also promote the inverse-electron-demand heteroDiels–Alder reaction of Æ,-enals, which do not bear electron-withdrawing groups.[120] In the presence of 117 (X = Cl) (5–10 mol%), the Æ,-enals 129 react with ethyl vinyl ether under solvent-free conditions to give the corresponding dihydropyran derivatives 130 in high yield and excellent enantioselectivity (Scheme 62). The reaction of 3-oxoprop-1-enyl benzoate (129, R1 = H; R2 = OBz) provides the corresponding 4-benzoyloxy-substituted dihydropyran derivative, which is a versatile intermediate for an assortment of useful substitution reactions.[121] Scheme 62 Inverse-Electron-Demand Hetero-Diels–Alder Reaction of Æ,-Enals Catalyzed by a Chromium(III) Complex[120] R2
R2 5−10 mol% 117 (X = Cl) 4-Å molecular sieves, rt
R1
R1
+ H
O
O
OEt
129
130
R1
R2
Yield (%) ee (%) Ref
H
Me
75
94
[120]
H
Ph
75
98
[120]
H
CH2OBn
90
95
[120]
H
OBz
80
89
[120]
Br
Ph
75
98
[120]
Me Me
75
92
[120]
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
OEt
3.2.3
107
Hetero-Diels–Alder Reactions
In the presence of ent-117 (X = Cl) (1–5 mol%), the hetero-Diels–Alder reaction of enal 131 with ethyl vinyl ether affords the corresponding adduct 132 with 93–96% enantiomeric excess: This product undergoes a highly stereoselective allylboration reaction with various aldehydes to give the corresponding dihydropyrans 133 in high yields (61–92%) and with excellent diastereoselectivities (Scheme 63).[122,123] Scheme 63 Hetero-Diels–Alder/Allylboration Sequence Catalyzed by a Chromium(III) Complex[122]
O
O
O
B
96% ee
OEt
O
R1CHO (2 equiv) 25−45 oC
1 mol% ent-117 (X = Cl) 4-Å molecular sieves, rt
+ H
O B
O
OEt 132
131
H
HO B O O
R1
R1 O
OH
H
O
OEt
133 OEt
R1
Yield (%) Ref
4-O2NC6H4
92
[122]
4-MeOC6H4
75
[122]
CH2OTBDMS
90
[122]
(E)-CMe=CHMe
80
[122]
This methodology has been successfully applied to the synthesis of various natural compounds. For example, the hetero-Diels–Alder/allylboration sequence between enal 131, enol ether 134, and aldehyde 135 gives the dihydropyran 136 in 76% yield and 96% ee (Scheme 64). Although the 2-substituted enol ether 134 is an isomeric mixture, the Z-form is more reactive than the E-form, and this provides dihydropyran 136 as a single diastereomer. The cycloadduct 136 is a key intermediate for the total synthesis of a potent thiomarinol antibiotic.[124,125] Scheme 64 Hetero-Diels–Alder/Allylboration Sequence as Part of the Synthesis of a Potent Thiomarinol Antibiotic[124] 1. 3 mol% ent-117 (X = Cl) BaO, rt
O
O B
2. EtO C 2
+ H
O 131
CHO 135
EtO2C
76%; 96% ee
OEt 134
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
OH
H
O
OEt
136
for references see p 120
108
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
(2R,3R,6R)-3,6-Dimethyl-2-phenyltetrahydro-4H-pyran-4-one (121, R1 = R2 = Me; R3 = Ph); Typical Procedure:[112]
PhCHO (0.10 mL, 1.0 mmol) was added to a mixture of Cr(III) complex 117 (X = SbF6; 21 mg, 0.03 mmol), acetone (0.20 mL), and 4- molecular sieves (200 mg), and the mixture was stirred for 3 h under N2 at rt. Diene 119 (R1 = R2 = Me; 72% pure, 0.34 mL, 1.4 mmol) was added, and the mixture was stirred for another 40 h and then diluted with THF (4 mL). The mixture was then cooled to 0 8C and AcOH (0.11 mL, 2.0 mmol) and a 1.0 M soln of TBAF in THF (1.5 mL, 1.5 mmol) were added. The mixture was stirred for 0.5 h. The mixture was diluted with hexane/Et2O (2:1; 60 mL) and washed successively with H2O (2 30 mL), sat. aq NaHCO3 (30 mL), and sat. aq NaCl (30 mL). The pale yellow organic solution was dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue which was purified by chromatography (silica gel); yield: 147 mg (72%); 90% ee. Ethyl (2E,4R)-4-[(2R,5R,6S)-6-Ethoxy-5-(3-methylbut-2-enyl)-5,6-dihydro-2H-pyran-2-yl]-4hydroxy-3-methylbut-2-enoate (136):[124]
A mixture of enal 131 (2.73 g, 15.0 mmol) and diene 134 (3.15 g, 22.5 mmol) was placed in an oven-dried 50-mL flask. Catalyst ent-117 (X = Cl; 220 mg, 0.45 mmol) and powdered BaO (4.0 g) were added to the mixture, which was stirred for 5 h at 20 8C. The mixture was diluted with Et2O (50 mL), filtered through Celite, and concentrated under reduced pressure. The catalyst was removed through a short column (deactivated silica gel, hexane/ Et2O 9:1), and excess diene 134 was partly recovered by Kugelrohr distillation. A mixture of the product and enoate 135 (4.0 g, 28 mmol) was stirred at 110 8C for 48 h under argon. The mixture was cooled to rt, sat. aq NaHCO3 (20 mL) was added, and the mixture was stirred for 30 min. The mixture was then extracted with Et2O (2 60 mL). The organic layers were combined, washed with brine (50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to evaporate the Et2O. Some enoate 135 was recovered by Kugelrohr distillation. The residue was purified by chromatography (deactivated silica gel, hexane/Et2O 6:1) to give a yellow oil; yield: 3.85 g (76%); 96% ee. 3.2.3.1.2
Enantioselective Catalysis Using Other Chiral Lewis Acids
Chiral bis(4,5-dihydrooxazole)–copper(II) complexes are the catalysts most frequently used for inverse-electron-demand hetero-Diels–Alder reactions with ,ª-unsaturated Æ-keto esters 137.[126–128] In the presence of the copper(II) trifluoromethanesulfonate adduct of bis(4,5-dihydrooxazole) 26 (R1 = t-Bu) (2–20 mol%; see Scheme 13), enoates 137 react with various vinyl ethers and vinyl thioethers to give the corresponding endo-adducts 138 with high diastereo- and enantioselectivity (Scheme 65). Scheme 65 Inverse-Electron-Demand Hetero-Diels–Alder Reaction of ,ª-Unsaturated Æ-Keto Esters[126–128] R2
R2 R
3
+ EtO2C
O
2−20 mol% Cu(OTf)2•26 (R1 = t-Bu) THF or Et2O
R3 EtO2C
X
137
O 138
R2
R3
X
Me
H
OEt THF
0 8C
87a
24:1
97
[126]
Ph
H
OEt THF
0 8C
93a
>20:1
97
[126]
0 8C
a
59:1
98
[126]
a
>20:1
99
[126]
OMe SBn
H H
Solvent Temp Yield (%) dr (endo/exo) ee (%) Ref
OEt THF OEt THF
0 8C
90 97
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
X
3.2.3
109
Hetero-Diels–Alder Reactions
R2
R3
OEt
OAc OBn –
rt
61
–
66
[127]
OEt
OAc OEt –
rt
60
–
96.5
[127]
NPhth OAc OEt –
rt
82
92.5:7.5
99
[128]
Ph
(CH2)2O
Et2O
rt
96
16:1
97
[126]
iPr
(CH2)2O
Et2O
rt
94
16:1
95
[126]
NPhth
(CH2)2O
Et2O
rt
95
78:22
96
[128]
SPh Et2O
rt
91
99
[126]
Ph a
X
H
Solvent Temp Yield (%) dr (endo/exo) ee (%) Ref
>20:1
4-Å molecular sieves also added.
The reaction is presumed to proceed through the bidentate intermediate 139 (Scheme 66).[126] The synthetic potential of the present reaction is demonstrated by the construction of various enantiopure carbohydrate derivatives, such as spirosugars, C-branched sugars, and amino sugars. Scheme 66 Proposed Chelated Activated Intermediate[126] O
O N
But
2+
O
X
N
Cu O
But
R2 endo, Cβ-Re face approach
EtO R1 139
Chiral zirconium complexes prepared from zirconium(IV) tert-butoxide and the (R)-3,3¢-disubstituted binaphthol derivatives 140 (X = CF2CF3, I) (Scheme 67) in aqueous propan-1-ol, catalyze the hetero-Diels–Alder reaction of Danishefsky-type dienes with nonactivated aldehydes.[129] Scheme 67 (R)-3,3¢-Diiodobinaphthol Derivatives[129] I
X
OH OH I
X 140
In contrast to the chromium(III)-complex-catalyzed reaction, the zirconium-complex-catalyzed reactions of Danishefsky-type dienes 141 give the corresponding 2,3-trans-adducts trans-142 with high diastereo- and enantioselectivity (Scheme 68). The cycloadducts from this hetero-Diels–Alder reaction can be used in syntheses of biologically important pyranone-containing natural products.
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
110
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
Scheme 68 Zirconium-Complex-Catalyzed Reactions of Substituted DanishefskyType Dienes[129]
OBu
1. 10 mol% 140 12−15 mol% Zr(Ot-Bu)4 80 mol% PrOH, 20 mol% H2O toluene, −20 or −40 oC 2. TFA or Sc(OTf)3
t
O + H
TMSO
R
1
O
141
3.2.3.1.3
R1
O trans-142
R1
X
Ph
CF2CF3 99
24:1
97
[129]
4-Tol
CF2CF3 99
16:1
93
[129]
4-ClC6H4
CF2CF3 99
24:1
98
[129]
(E)-CH=CHPh
CF2CF3 96
9:1
90
[129]
(CH2)2Ph
I
97
9:1
90
[129]
(CH2)4Me
I
94
10:1
95
[129]
Yield (%) dr (trans/cis) ee (%) Ref
Enantioselective Catalysis Using Chiral Organocatalysts
Hydrogen-bonding catalysts such as TADDOL (98) (see Scheme 49, Section 3.2.2.3) or the axially chiral 1,1¢-biaryl-2,2¢-dimethanols (BAMOLs) 143 (Ar1 = 4-F-3,5-Me2C6H2, 4-F-3,5Et2C6H2) (Scheme 69) provide highly effective catalysts for the hetero-Diels–Alder reactions of reactive substrates.[130,131] Scheme 69 Axially Chiral 1,1¢-Biaryl2,2¢-dimethanols[130,131] Ar1 Ar1 OH OH Ar
1
Ar1
143
For example, TADDOL (98) (20 mol%) catalyzes the enantioselective hetero-Diels–Alder reaction of the highly reactive diene 102 with various nonactivated aldehydes to give, after treatment with acetyl chloride, the corresponding (2S)-dihydropyrones 144 with high enantioselectivity (Scheme 70).[130] The BAMOLs 143 generally give superior results to TADDOL (98) under similar reaction conditions.[131]
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.3
111
Hetero-Diels–Alder Reactions
Scheme 70 Diols[130,131]
Hetero-Diels–Alder Reaction of an Aminobuta-1,3-diene Catalyzed by Chiral
NMe2
1. 20 mol% 98 or 143 toluene, −40 or −80 oC 2. AcCl, CH2Cl2, toluene, −78 oC
O + H
TBDMSO
O
R1
∗ R1
O
102
144
R1
Catalyst
Yield (%) ee (%) Ref
(E)-CH=CHPh
98
52
94 (S)
[130]
1
Me
143 (Ar = 4-F-3,5-Et2C6H2)
75
97
[131]
Cy
98
64
86 (S)
[130]
Cy
143 (Ar = 4-F-3,5-Me2C6H2) 99
84 (R)
[131]
Ph
98
70
>98 (S)
[130]
1
1
Ph
143 (Ar = 4-F-3,5-Et2C6H2)
84
98 (R)
[131]
2-furyl
98
67
92 (S)
[130]
96
>99 (R)
[131]
1
2-furyl
143 (Ar = 4-F-3,5-Et2C6H2)
The binaphthalenediyl hydrogen phosphate (R)-145 (Scheme 71) catalyzes the heteroDiels–Alder reaction of the activated aldehyde ethyl glyoxylate with less nucleophilic dienes that have fewer than two oxygen substituents.[132] In the presence of (R)-145 (5 mol%), the reaction of 2-siloxydienes or 1-methoxydienes with ethyl glyoxylate gives the corresponding (2S)-exo-adducts with high diastereo- and enantioselectivity. Scheme 71 Hetero-Diels–Alder Reactions of Ethyl Glyoxylate Catalyzed by a Chiral Phosphoric Acid[132] Ph O
O P
O
R1
OH
R1
Ph
R2
O +
R3
Et
(R)-145 4-Å molecular sieves, toluene, rt
CHO
R2
CO2Et 2S
O
R3
R4
R4
R1
R2
R3
R4
Yield (%) dr (exo/endo) ee (%) Ref
Me
OTBDMS
H
Me
95
Me
OTBDMS
H
H (CH2)4
>99:1
99
[132]
56
79:21
99
[132]
H
OMe
84
93:7
98
[132]
H
OMe
75
95:5
97
[132]
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
112
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
Chiral secondary amines are also effective catalysts for the enantioselective reactions of aldehydes, which proceed via chiral enamine intermediates. Thus, generation of a chiral trans-enamine in situ from the secondary amine catalyst 147 with a nonactivated aldehyde, followed by an inverse-electron-demand hetero-Diels–Alder reaction with Æ,-enones 146 affords the corresponding endo-adducts 148 with high enantioselectivity (Scheme 72).[133] The presence of silica facilitates the hydrolysis of an aminal intermediate to form the acetal 148 and regenerate the amine catalyst. Scheme 72 Inverse-Electron-Demand Hetero-Diels–Alder Reaction of Æ,-Enones Catalyzed by a Chiral Secondary Amine[133]
10 mol% N H
MeO2C
O
147 silica gel, CH2Cl2, −15 oC to rt
CHO +
MeO2C
O
R2
OH R2
R1
R1
146
148
R1
R2 Yield (%) ee (%) Ref
Ph
Et 69
84
[133]
Ph
iPr 93
89
[133]
Ph
Bn 65
86
[133]
4-ClC6H4
iPr 70
90
[133]
Several o-quinones undergo hetero-Diels–Alder reactions with ketene enolates generated in situ from the corresponding acyl chlorides.[134] In the presence of the benzoylquinidine 150 (10 mol%) and N,N-diisopropylethylamine (1 equivalent), 3,4,5,6-tetrachlorobenzo1,2-quinone (149, X = Cl) reacts with various acyl chlorides to afford the corresponding adducts 151 (X = Cl) with high enantioselectivity (Scheme 73). For less reactive acyl chlorides, the reactivity is improved by the addition of a Lewis acid cocatalyst.[135,136] For example, in the presence of trans-dichlorobis(triphenylphosphine)palladium(II) (10 mol%), the reaction of quinone 149 (X = Cl) with 3-methylbutanoyl chloride gives the corresponding adduct in 98% yield and with 93% ee. 3,4,5,6-Tetrabromobenzo-1,2-quinone (149, X = Br) also gives the corresponding cycloadducts 151 (X = Br) with high enantioselectivity. The same catalytic system can be used in the hetero-Diels–Alder reactions of ketene enolates with o-benzoquinone imides[137,138] and o-benzoquinone diimides.[139] The cycloadducts can be readily converted into Æ-hydroxy and Æ-amino carboxylic acid derivatives by methanolysis followed by oxidation with cerium(IV) ammonium nitrate.
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.3
113
Hetero-Diels–Alder Reactions
Scheme 73 Hetero-Diels–Alder Reaction of Tetrahalo-o-quinones with Ketene Acetals Catalyzed by a Benzoylquinidine Derivative[134] OMe N 10 mol%
N BzO
X
X +
X
O
150 iPr2NEt (1 equiv), THF, −78 oC
O
O
X
X
O
O
X
O
R1
Cl R1
X
X
149
151
X R1
Yield (%) ee (%) Ref
Cl Et
91
99
[134]
Br Et
90
95
[134]
Cl iPr
75
93
[134]
Cl Ph
90
90
[134]
Cl 4-MeOC6H4
58
99
[134]
Ethyl 3,4-Dihydro-2H-pyran-6-carboxylates 138; General Procedure:[126]
A mixture of Cu(OTf )2•26 (R1 = t-Bu; 2 mol%) and 3- molecular sieves in THF (0.004 M) was stirred for 1 h to produce a heterogeneous light-green soln. This was cooled to 0 8C and treated sequentially with keto ester 137 (1.0 equiv) and an enol ether (3.0 equiv). After the appropriate reaction time, the mixture was purified directly by column chromatography (silica gel). 5,6,7,8-Tetrachloro-1,4-benzodioxin-2(3H)-ones 151 (X = Cl); General Procedure:[134]
Benzoylquinidine 150 (0.055 mmol) was placed in a 25-mL flask and dissolved in THF (8 mL). The soln was cooled to –78 8C and iPr2NEt (0.55 mmol) was added followed by a soln of quinone 149 (X = Cl; 0.55 mmol) in THF (4 mL). A soln of an acyl chloride (0.55 mmol) in THF (3 mL) was then added and the reaction was monitored by TLC. When all of the quinone had been consumed (ca. 5 h), the mixture was filtered through a plug of silica, and the plug was rinsed thoroughly with hexane. The filtrate was concentrated under reduced pressure to give the pure product. 3.2.3.2
Enantioselective Hetero-Diels–Alder Reactions of Imines and Related Compounds
The hetero-Diels–Alder reaction of imines or related compounds (the aza-Diels–Alder reaction) is also a useful method for constructing nitrogen-containing heterocycles.[107,109,140,141] In light of the fundamental importance of nitrogen-containing natural compounds, significant attention has been given to the development of asymmetric azaDiels–Alder reactions. 3.2.3.2.1
Enantioselective Aza-Diels–Alder Reaction of Electron-Rich Dienes with Imines
The pyridinium salt of the chiral phosphoric acid derivative 152 is an efficient catalyst for the aza-Diels–Alder reaction of electron-rich 1,3-dimethoxy-1-(trimethylsiloxy)buta-1,3diene (153, Brassards diene) with aldimines 154 in mesitylene at –40 8C.[142] Subsequent [4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
114
Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
addition of benzoic acid (1 equiv) provides the dihydropyridinone derivatives 155 with high enantioselectivity (Scheme 74). The methyl enol ether provides a useful functional handle for transforming the product into other functionalities, e.g. by acid hydrolysis followed by addition–elimination reactions. Scheme 74 Aza-Diels–Alder Reaction of Brassard’s Diene with Imines Catalyzed by a Pyridinium Salt of a Chiral Phosphoric Acid[142]
O P
O
O O− HN
152
HO
OMe
N
+
N R
MeO
R1
MeO
HO O
1. 3 mol% 152 mesitylene, −40 oC 2. BzOH (1−5 equiv)
OTMS
154
153
R1 155
R1
Yield (%) ee (%) Ref
Ph
87
94
[142]
4-MeOC6H4
84
99
[142]
2-furyl
63
97
[142]
CH=CHPh
76
98
[142]
Cy
69
99
[142]
The aza-Diels–Alder reaction of Danishefsky-type dienes 156 with N-sulfonylimines 157 is catalyzed by the dimeric copper(I) complex 158 (Ar1 = 1-naphthyl) to afford the dihydropyridinones 159 with high enantioselectivity (Scheme 75).[143] An active cationic form of the copper(I) catalyst may be generated in situ as a result of the presence of silver(I) perchlorate (10 mol%), which acts as a halogen scavenger.
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Hetero-Diels–Alder Reactions
3.2.3
Scheme 75 Aza-Diels–Alder Reactions of N-Sulfonylimines Catalyzed by a Copper(I) Complex[143] But S Cu
P 5.1 mol%
Fe
Ar1
Br
Ar1
2
158
OMe R1
N
+
10 mol% AgClO4, CH2Cl2, rt then TFA (5 equiv)
Ts
R1
R2
TMSO 156
N
Ts R2
O 159
157
R1
R2
Yield (%) ee (%) Ref
H
Ph
90
93
[143]
H
4-MeOC6H4
76
91
[143]
H
CH=CHPh
66
83
[143]
Me CH=CHPh
57
88
[143]
A one-pot three-component aza-Diels–Alder reaction between enone 160, aqueous formaldehyde, and an aromatic amine 161 in the presence of (S)-proline as a catalyst in dimethyl sulfoxide gives the corresponding azabicyclic ketones 162 with excellent regio- and enantioselectivity (Scheme 76).[144] The reaction may proceed through a stepwise Mannich– Michael reaction between a chiral dienamine, generated in situ from the enone and (S)-proline, and an imine, generated in situ from formaldehyde and the aromatic amine. Scheme 76 Direct Three-Component Aza-Diels–Alder Reaction Catalyzed by (S)-Proline[144] 30 mol%
O
CO2H N H
+
HCHO
160
DMSO, rt
+ Ar1NH2
161
Ar1N
O
162
Ar1
Yield (%) ee (%) Ref
4-MeOC6H4
70
>99
[144]
Ph
54
>96
[144]
4-BrC6H4
20
>99
[144]
The completely regioselective nitroso-Diels–Alder reaction of dienamine 163 with aryl nitroso compounds 164 in the presence of the chiral binaphthol 165 provides single regioisomers of the corresponding 2-oxa-3-azabicyclo[2.2.2]octan-5-ones 166 with high enantioselectivity (Scheme 77).[145]
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
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Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
Scheme 77 Diastereo- and Enantioselective Synthesis of Nitroso-Diels–AlderType Bicyclic Ketones from a Dienamine[145] SiAr23 OH
1. 30 mol%
OH
O
SiAr23 165
N
pentane/CH2Cl2 (9:1), −78 oC 2. 1 M HCl, THF, −78 oC
O +
N
163
1 N Ar
O
Ar1
O 166
164
Ar2 = 3,5-Me2C6H3
Ar1
Yield (%) ee (%) Ref
Ph
90
90
[145]
4-BrC6H4
65
87
[145]
4-PhOC6H4
63
92
[145]
3,5-Me2C6H3
52
80
[145]
In contrast, the pyrrolidine-derived tetrazole 168 catalyzes the reaction of 4,4-dimethylcyclohex-2-enone (167) with aryl nitroso compounds to give 2-oxa-3-azabicyclo[2.2.2]octan-6-ones 169 with excellent enantioselectivity (Scheme 78). These bicyclic ketones are useful precursors of various optically active cyclic amino alcohols. Scheme 78 Diastereo- and Enantioselective Synthesis of Nitroso Diels–Alder-Type Bicyclic Ketones from 4,4-Dimethylcyclohex-2enone[145] N 20 mol% N H
O
N H 168
O +
N
MeCN, 40 oC
N N
O
O N
Ar1
Ar1
167
169
Ar1
Yield (%) ee (%) Ref
Ph
64
99
[145]
4-Tol
47
99
[145]
3,5-Me2C6H3
52
98
[145]
4-BrC6H4
50
99
[145]
The 2-azopyridine 171 undergoes a silver(I)-catalyzed hetero-Diels–Alder reaction with the 1,4-disubstituted siloxydienes 170 in the presence of a 2:1 complex of silver(I) trifluoromethanesulfonate and (R)-BINAP (5 mol%) in propanenitrile to give the corresponding cycloadducts 172 in good yield and with excellent enantioselectivity (Scheme 79).[146] The cycloadducts 172 can be readily converted into the corresponding acyclic 1,4-diamines by reductive cleavage of the N—N bond with samarium(II) iodide. [4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.3
117
Hetero-Diels–Alder Reactions
Scheme 79 Hetero-Diels–Alder Reaction of a 2-Azopyridine Catalyzed by a Chiral Silver(I) Complex[146] R1
10 mol% AgOTf 5 mol% (R)-BINAP EtCN, −78 to −40 oC
N +
TIPSO
N N
R2
O
CCl3
O 171
170
R1
TIPSO R2
N
N
N
O
CCl3
O 172
R1
R2
Yield (%) ee (%) Ref
(CH2)4Me
Me
84
95
[146]
iPr
Me
65
84
[146]
(CH2)3CO2Me
Me
74
98
[146]
2-furyl
Me
78
92
[146]
CH2OBn
(CH2)3OTBDMS
84
98
[146]
(6R)-1-(2-Hydroxy-5-methylphenyl)-4-methoxy-6-(4-methoxyphenyl)-5,6-dihydropyridin2(1H)-one (155, R1 = 4-MeOC6H4); Typical Procedure:[142]
A soln of Brassards diene (153; 25 L, 0.12 mmol) was added dropwise over 1 min to a soln of imine 154 (R1 = 4-MeOC6H4; 36.6 mg, 0.15 mmol) and catalyst 152 (3.9 mg, 0.0050 mmol) in mesitylene (5 mL) at –40 8C. After 2 h, a second equal portion of 153 was added similarly. This addition was repeated three times at two-hourly intervals until a total of 100 L (0.46 mmol) of 153 had been introduced. The mixture was stirred at –40 8C for 11 h, and then the reaction was quenched by the addition of sat. aq NaHCO3 at –40 8C. The mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The resultant oil was treated with a 4:1 mixture of THF (4 mL) and 1 M HCl (1 mL) at 0 8C for 10 min. The mixture was then extracted with EtOAc and the combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude product was purified by chromatography (silica gel, hexane/EtOAc 10:1 to 1:1) to give an oil. The oil was mixed with BzOH (19.2 mg, 0.16 mmol), dissolved in mesitylene (2 mL), and stirred at 110 8C for 12 h. The resulting mixture was purified by chromatography (silica gel, hexane/EtOAc 3:1 to 1:1); yield: 43.3 mg (84%); 99% ee. 3.2.3.2.2
Enantioselective Aza-Diels–Alder Reaction of 1-Azabuta-1,3-dienes
1-Azabuta-1,3-dienes are versatile building blocks for the construction of various heterocyclic compounds.[147,148] Because of their electron-deficient character, 1-azabuta-1,3-dienes tend to undergo inverse-electron-demand Diels–Alder reactions with electron-rich dienophiles. Thus, treatment of the N-(8-quinolylsulfonyl)-1-aza-1,3-dienes 173 with propyl vinyl ether in the presence of a catalytic amount of nickel(II) perchlorate hexahydrate and the chiral ligand 174 (DBFOX-Ph) gives the corresponding endo-adducts 175 with high
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
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Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
diastereo- and enantioselectivity (Scheme 80).[149] Interestingly, the 8-quinolylsulfonyl group and Ni(II)–DBFOX-Ph catalyst are both critical for obtaining a high enantioselectivity. Scheme 80 Aza-Diels–Alder Reaction of N-Sulfonyl-1-aza-1,3-dienes Catalyzed by a Chiral Nickel(II) Complex[149]
O
11 mol%
N
O
O R1
O S N
N
N
Ph
Ph
N
O
O
174 10 mol% Ni(ClO4)2•6H2O, CH2Cl2, rt
OPr +
R1
R2
R2
173
175
R1
R2
Yielda (%) dr (endo/exo) eea (%) Ref
Ph
Ph
66
98:2
91
[149]
Ph
2-furyl
52
97:3
77
[149]
Ph
t-Bu
61
98:2
84
[149]
4-NCC6H4
CH=CHPh
70
98:2
92
[149]
a
O S N
OPr
Of the endo-adduct.
Chiral enamines are also important intermediates in the aza-Diels–Alder reactions of 1-azabuta-1,3-dienes. N-Sulfonyl-1-azabuta-1,3-dienes undergo organocatalytic aza-Diels– Alder reactions with aldehydes. A combination of the chiral secondary amine 178 and acetic acid catalyzes the reaction of N-tosyl-1-azabuta-1,3-dienes 176 with butanal (177) to give the corresponding endo-adducts 179 with excellent diastereo- and enantioselectivities (Scheme 81).[150] This method can also be successfully applied to Æ,-unsaturated aldehydes, which afford the corresponding endo-adducts bearing a substituted vinyl group at the 5-position.[151] Scheme 81 Aza-Diels–Alder Reaction of N-Sulfonyl-1-azabuta-1,3-dienes Catalyzed by a Chiral Secondary Amine[150] Ph Ph
10 mol% N H
R1
NTs
178
CHO
Ts
OTMS
R1
N
+
Et
Et R2
R2
176
OH
10 mol% AcOH, MeCN/H2O (10:1), rt
177
179
R1
R2
Yield (%) ee (%) Ref
Ph
Ph
88
97
[150]
Ph
2-furyl 83
98
[150]
Ph
CO2Et
95
99
[150]
PhCH=CH
Ph
91
99
[150]
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.2.3
119
Hetero-Diels–Alder Reactions
Chiral N-heterocyclic carbenes catalyze the enantioselective aza-Diels–Alder reaction of N-sulfonyl-1-azabuta-1,3-dienes with Æ,-enals.[152] In the presence of the chiral N-heterocyclic carbene 182 (10 mol%) and N,N-diisopropylethylamine (10 mol%), the reaction of N-sulfonyl-1-azabuta-1,3-dienes 180 with enals 181 gives the corresponding endo-adducts 183 with high diastereo- and enantioselectivities (Scheme 82). Scheme 82 Aza-Diels–Alder Reaction of N-Sulfonyl-1-azabuta-1,3-dienes Catalyzed by a Chiral N-Heterocyclic Carbene[152] Mes N
OMe
10 mol%
N
OMe O
O O S N
CHO
182
R2
O
O S N
R1
R1 181
180
R2
O O
10 mol% iPr2NEt, toluene/THF (10:1), rt
+
R1
Cl− N
O
R2 183
Yield (%) ee (%) Ref 90
99
[152]
OEt 2-furyl 71
99
[152]
OEt Pr
58
99
[152]
Me Pr
71
98
[152]
OEt Ph
The N-heterocyclic carbene catalyst reacts with the enal to form a Z-enolate that undergoes cycloaddition with azabutadienes 180 via an endo transition state 184 (Scheme 83). Scheme 83 Proposed Transition-State Complex[152] O N
N OMe
N Mes
O N
S
O
O EtO2C R1 184
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 120
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[4 + 2]-Cycloaddition Reactions
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Stereoselective Synthesis
3.2
[4 + 2]-Cycloaddition Reactions
Nakashima, D.; Yamamoto, H., J. Am. Chem. Soc., (2006) 128, 9626. Wang, Y.; Li, H.; Wang, Y.-Q.; Liu, Y.; Foxman, B. M.; Deng, L., J. Am. Chem. Soc., (2007) 129, 6364. Gioia, C.; Hauville, A.; Bernardi, L.; Fini, F.; Ricci, A., Angew. Chem., (2008) 120, 9376; Angew. Chem. Int. Ed., (2008) 47, 9236. Pellissier, H., Tetrahedron, (2008) 64, 10 279. Terada, M., Chem. Commun. (Cambridge), (2008), 4097. Adair, G.; Mukherjee, S.; List, B., Aldrichimica Acta, (2008) 41, 31. Pellissier, H., Tetrahedron, (2009) 65, 2839. Jørgensen, K. A., Eur. J. Org. Chem., (2004), 2093. Jørgensen, K. A., Angew. Chem., (2000) 112, 3702; Angew. Chem. Int. Ed., (2000) 39, 3558. Jørgensen, K. A.; Johannsen, M.; Yao, S.; Audrain, H.; Thorhauge, J., Acc. Chem. Res., (1999) 32, 605. Waldmann, H., Synthesis, (1994), 535. Weinreb, S. M., In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, (1991); Vol. 5, p 401. Boger, D. L., In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, (1991); Vol. 5, p 451. Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N., Angew. Chem., (1999) 111, 2549; Angew. Chem. Int. Ed., (1999) 38, 2398. Chavez, D. E.; Jacobsen, E. N., Org. Synth., Coll. Vol. XI, (2010), 498. Chavez, D. E.; Jacobsen, E. N., Angew. Chem., (2001) 113, 3779; Angew. Chem. Int. Ed., (2001) 40, 3667. Schaus, S. E.; Brnalt, J.; Jacobsen, E. N., J. Org. Chem., (1998) 63, 403. Majumder, U.; Cox, J. M.; Johnson, H. W. B.; Rainier, J. D., Chem.–Eur. J., (2006) 12, 1736. Bhattacharjee, A.; De Brabander, J. K., Tetrahedron Lett., (2000) 41, 8069. Wender, P. A.; Hilinski, M. K.; Soldermann, N.; Mooberry, S. L., Org. Lett., (2006) 8, 1507. Fu, F.; Loh, T.-P., Tetrahedron Lett., (2009) 50, 3530. Gademann, K.; Chavez, D. E.; Jacobsen, E. N., Angew. Chem., (2002) 114, 3185; Angew. Chem. Int. Ed., (2002) 41, 3059. Steinhuebel, D. P.; Fleming, J. J.; Du Bois, J., Org. Lett., (2002) 4, 293. Gao, X.; Hall, D. G., J. Am. Chem. Soc., (2003) 125, 9308. Deligny, M.; Carreaux, F.; Toupet, L.; Carboni, B., Adv. Synth. Catal., (2003) 345, 1215. Gao, X.; Hall, D. G., J. Am. Chem. Soc., (2005) 127, 1628. Gao, X.; Hall, D. G.; Deligny, M.; Favre, A.; Carreaux, F.; Carboni, B., Chem.–Eur. J., (2006) 12, 3132. Evans, D. A.; Johnson, J. S.; Olhava, E. J., J. Am. Chem. Soc., (2000) 122, 1635. Audrain, H.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A., J. Org. Chem., (2000) 65, 4487. Zhuang, W.; Thorhauge, J.; Jørgensen, K. A., Chem. Commun. (Cambridge), (2000), 459. Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S., J. Am. Chem. Soc., (2003) 125, 3793. Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H., Nature (London), (2003) 424, 146. Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H., J. Am. Chem. Soc., (2005) 127, 1336. Momiyama, N.; Tabuse, H.; Terada, M., J. Am. Chem. Soc., (2009) 131, 12 882. Juhl, K.; Jørgensen, K. A., Angew. Chem., (2003) 115, 1536; Angew. Chem. Int. Ed., (2003) 42, 1498. Bekele, T.; Shah, M. H.; Wolfer, J.; Abraham, C. J.; Weatherwax, A.; Lectka, T., J. Am. Chem. Soc., (2006) 128, 1810. Abraham, C. J.; Paull, D. H.; Bekele, T.; Scerba, M. T.; Dudding, T.; Lectka, T., J. Am. Chem. Soc., (2008) 130, 17 085. Paull, D. H.; Abraham, C. J.; Scerba, M. T.; Alden-Danforth, E.; Lectka, T., Acc. Chem. Res., (2008) 41, 655. Wolfer, J.; Bekele, T.; Abraham, C. J.; Dogo-Isonagie, C.; Lectka, T., Angew. Chem., (2006) 118, 7558; Angew. Chem. Int. Ed., (2006) 45, 7398. Paull, D. H.; Alden-Danforth, E.; Wolfer, J.; Dogo-Isonagie, C.; Abraham, C. J.; Lectka, T., J. Org. Chem., (2007) 72, 5380. Abraham, C. J.; Paull, D. H.; Scerba, M. T.; Grebinski, J. W.; Lectka, T., J. Am. Chem. Soc., (2006) 128, 13 370. Rowland, G. B.; Rowland, E. B.; Zhang, Q.; Antilla, J. C., Curr. Org. Chem., (2006) 10, 981. Buonora, P.; Olsen, J.-C.; Oh, T., Tetrahedron, (2001) 57, 6099. Ito, J.; Fuchibe, K.; Akiyama, T., Angew. Chem., (2006) 118, 4914; Angew. Chem. Int. Ed., (2006) 45, 4796. MancheÇo, O. G.; Array s, R. G.; Carretero, J. C., J. Am. Chem. Soc., (2004) 126, 456.
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Momiyama, N.; Yamamoto, Y.; Yamamoto, H., J. Am. Chem. Soc., (2007) 129, 1190. Kawasaki, M.; Yamamoto, H., J. Am. Chem. Soc., (2006) 128, 16 482. Behforouz, M.; Ahmadian, M., Tetrahedron, (2000) 56, 5259. Groenendaal, B.; Ruijter, E.; Orru, R. V. A., Chem. Commun. (Cambridge), (2008), 5474. Esquivias, J.; Array s, R. G.; Carretero, J. C., J. Am. Chem. Soc., (2007) 129, 1480. Han, B.; Li, J.-L.; Ma, C.; Zhang, S.-J.; Chen, Y.-C., Angew. Chem., (2008) 120, 10 119; Angew. Chem. Int. Ed., (2008) 47, 9971. Han, B.; He, Z.-Q.; Li, J.-L.; Li, R.; Jiang, K.; Liu, T.-Y.; Chen, Y.-C., Angew. Chem., (2009) 121, 5582; Angew. Chem. Int. Ed., (2009) 48, 5474. He, M.; Struble, J. R.; Bode, J. W., J. Am. Chem. Soc., (2006) 128, 8418.
[4 2]-Cycloaddition Reactions, Ishihara, K., Sakakura, A. Science of Synthesis 4.0 version., Section 3.2 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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125 3.3
[m + n + 1]-Carbocyclization Reactions T. Shibata
General Introduction
Various types of stereoselective [m + n + 1] carbocyclizations have been reported. This chapter focuses on the carbonylative [2 + 2 + 1] reactions of enynes, namely the Pauson–Khand reaction, which yields synthetically important bicyclopentenones and has been comprehensively studied.[1] Other types of [m+n+1] carbocyclizations, including [3 + 2 + 1], [4 + 2 + 1], [5 + 2 + 1], and [4 + 4 + 1] reactions, are also mentioned, where the C1 source is carbon monoxide or (trimethylsilyl)diazomethane. SAFETY: Carbon monoxide is colorless, odorless, and tasteless, but highly toxic; therefore, it must be treated with extreme care in a high-performance hood. (Trimethylsilyl)diazomethane is much less explosive than diazomethane itself but must be treated with care. 3.3.1
[2 + 2 + 1] Carbocyclization of Enynes with Carbon Monoxide
In 1973, Khand and Pauson reported the intermolecular coupling of alkyne–hexacarbonyldicobalt(0) complexes with alkenes for the construction of cyclopentenones.[2] In early work on the Pauson–Khand reaction only symmetrical alkenes, such as ethene and norbornene, were used because of the problems associated with the formation of regioisomers with unsymmetrical alkynes and alkenes. The intramolecular reaction of enynes overcomes this problem, and it has been employed extensively in natural product syntheses.[3] A catalytic Pauson–Khand reaction of enynes has been achieved using the hexacarbonyldicobalt(0)–triphenyl phosphite [Co2(CO)6–P(OPh)3] complex under a slightly pressurized atmosphere of carbon monoxide.[4] Other significant improvements in the Pauson–Khand reaction have been achieved using transition metals other than cobalt as the catalyst. For example, a low-valent titanium complex is the first complex able to catalyze the carbonylative coupling under an almost atmospheric pressure of carbon monoxide.[5] 3.3.1.1
Enantioselective Titanium-Catalyzed Pauson–Khand Reactions
The low-valent titanium complex dicarbonylbis(Å5-cyclopentadienyl)titanium(II) [Ti(Cp)2(CO)2] catalyzes the intramolecular Pauson–Khand reaction of various enynes under an almost atmospheric pressure of carbon monoxide, to provide bicyclopentenones in good to excellent yield.[5] This was the first Pauson–Khand reaction catalyzed by a non-cobalt transition-metal complex. The first catalytic and enantioselective Pauson– Khand reaction was also realized using the low-valent titanium complex 2 [(S,S)-Ti(EBTHI)(Me)2; EBTHI = 1,1¢-ethylenebis(Å5-4,5,6,7-tetrahydroindenyl)].[6] In the presence of the chiral titanium catalyst, where the metal center and cyclopentadienyl moiety are connected by a -bond, various carbon- and heteroatom-tethered 1,6-enynes 1 are transformed into the bicyclopentenones 3, which have a stereogenic center at the ring fusion.[7,8] The reaction tolerates an array of substituents at the alkyne terminus, including aryl groups with electron-donating or electron-withdrawing groups in addition to alkyl groups (Scheme 1). In the case of an enyne with an unsubstituted alkyne terminus, the yield is good but the enantioselectivity is poor. The reaction of an enyne with a 1,1-disubstituted alkene moiety [m n 1]-Carbocyclization Reactions, Shibata, T. Science of Synthesis 4.0 version., Section 3.3 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
3.3
[m + n + 1]-Carbocyclization Reactions
affords a bicyclopentenone with an asymmetric quaternary carbon stereogenic center with modest enantiomeric excess. A practical limitation of the process is that the low-valent titanium species and chiral cyclopentadienyl ligands are unstable, and must be utilized under strictly oxygen- and moisture-free conditions. Scheme 1 Enantioselective Titanium-Catalyzed Pauson–Khand Reaction of Various Enynes[6–8]
Ti
Me
Me 2
R1 R1
o
CO (0.95 atm), toluene, 90 C
R2
X
X
O R2
1
3
X
R1
R2
2 (mol%) ee (%) Yield (%) Ref
O
Ph
H
20
C(CO2Et)2
Ph
H
C(CO2Et)2
4-MeOC6H4
H
C(CO2Et)2
4-F3CC6H4
H
C(CO2Et)2
Pr
C(CO2t-Bu)2
96
85
[6]
7.5
94
92
[6]
7.5
92
89
[7]
10
93
88
[7]
H
5
89
94
[6]
H
H
20
50
87
[7]
C(CO2t-Bu)2
Me
Me 20
72
90
[6]
N(CH2CH=CH2)
Me
H
94
91
[8]
10
In a related study, the same chiral titanium complex 2 catalyzes the enantioselective [2 + 2 + 1] carbocyclization of ,-unsaturated aldehydes and ketones with carbon monoxide in the presence of trimethylphosphine as a cocatalyst.[9] The corresponding ª-butyrolactones 4 are obtained with high enantiomeric excess for an array of substitution patterns (Scheme 2). Scheme 2 Enantioselective Titanium-Catalyzed [2 + 2 + 1] Carbocyclization of Enals and Enones[9]
Me 10 mol%
Ti
Me 2
O R1
R1 O
Me3P, CO (3.4 atm), toluene, 100 oC
R2 R2
O R
2
R2 4
[m n 1]-Carbocyclization Reactions, Shibata, T. Science of Synthesis 4.0 version., Section 3.3 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.3.1
127
[2 + 2 + 1] Carbocyclization of Enynes with Carbon Monoxide
R1
R2
H
Me 30
Me3P (mol%) ee (%) Yield (%) Ref 89
86
[9]
50
90
80
[9]
Me Me 50
90
88
[9]
Me H
(S,S)-[1,1¢-Ethylenebis(Å5-4,5,6,7-tetrahydroindenyl)]dimethyltitanium(IV) [(S,S)-2]:[7]
Under an atmospheric pressure of argon, (S,S)-Ti(EBTHI)Cl2 (700 mg, 1.83 mmol) and Et2O (50 mL) were added to a Schlenk flask, and the flask was immersed in a water bath. A 1.4 M soln of MeLi in pentane (7 mL, 9.8 mmol) was slowly added, and the mixture was stirred at rt for 4 h. The solvent was removed under reduced pressure, and the crude products were taken into a glovebox and dissolved in hexane (50 mL). Insoluble impurities were removed by filtration through a plug of Celite, which was rinsed with additional hexane. The solvent was removed under reduced pressure to give (S,S)-2 as yellow-orange crystals; yield: 520 mg (83%). Bicyclopentenones 3; General Procedure:[7]
CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. In an argon-filled glovebox, (S,S)-Ti(EBTHI)(Me)2 (2; 8 mg, 0.025 mmol), toluene (3 mL), and an enyne (0.50 mmol) were added to a dry, sealable Schlenk flask. The flask was removed from the glovebox, evacuated, and backfilled with CO(g) (14 psi, ca. 1 atm). The mixture was heated to 90 8C for 12–16 h, and then cooled to rt. After excess gas was carefully released in the hood, the crude products were filtered through a plug of silica gel using Et2O as eluent and purified by flash chromatography to afford the pure cycloadduct.
ª-Butyrolactones 4; General Procedure:[9] CAUTION: Trimethylphosphine is pyrophoric and has a very unpleasant odor. CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. An enal or enone, (S,S)-Ti(EBTHI)(Me)2 (2), Me3P, and toluene (25 mL) were added to a dry Fisher–Porter bottle inside a N2- or argon-filled glovebox. The bottle was removed from the glovebox, and then evacuated and backfilled with CO(g) (50 psi, ca. 3 atm). The mixture was heated at 100 8C for 36–40 h, and then cooled to rt and the CO pressure was carefully released inside a fume hood. The crude products were filtered through a plug of silica gel using Et2O as eluent and purified by flash chromatography to afford the pure cycloadduct. 3.3.1.2
Rhodium-Catalyzed Pauson–Khand Reactions
3.3.1.2.1
Enantioselective Reactions
The rhodium-catalyzed carbonylative coupling of enynes with carbon monoxide using dicarbonylchlororhodium(I) dimer {[RhCl(CO)2]2} proceeds smoothly at atmospheric pressure. Although the addition of a phosphine ligand deactivates the rhodium catalyst,[10] the cationic rhodium–diphosphine ligand complex, prepared by anion exchange using a silver salt, demonstrates high catalytic activity. This represents the first enantioselective Pauson–Khand reaction with a late-transition-metal complex using the axially chiral diphosphine ligand 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl (BINAP).[11] Unlike the chiral cyclopentadienyl ligand in the titanium complex described in Section 3.3.1.1, BINAP is [m n 1]-Carbocyclization Reactions, Shibata, T. Science of Synthesis 4.0 version., Section 3.3 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
3.3
[m + n + 1]-Carbocyclization Reactions
commercially available and air stable, making this a practical alternative. The reaction was originally performed by heating the components at reflux in tetrahydrofuran under atmospheric pressure or a pressurized atmosphere of carbon monoxide. By this method, the yield and enantioselectivity are moderate to good depending on the substrate.[11] On the other hand, under a low partial pressure of carbon monoxide,[12] the reaction proceeds at ambient temperature with carbon- and heteroatom-tethered 1,6-enynes using 2,2¢-bis[bis(3,5-dimethylphenyl)phosphino]-1,1¢-binaphthyl (XylBINAP; 5) as a chiral ligand to provide the enantiomerically enriched bicyclopentenones 6 with excellent yield and enantioselectivity (Scheme 3).[13] Near-perfect enantioselectivity is achieved even with an enyne having an unsubstituted alkyne moiety. Scheme 3 Enantioselective Rhodium-Catalyzed Pauson–Khand Reaction of Enynes with a Chiral Cationic Complex[13]
P
2
P
2
5
(R)-XylBINAP
R1 X
R1
5 mol% [RhCl(CO)2]2, 10 mol% (R)-XylBINAP 5 12 mol% AgOTf, CO/argon (1:10; 1 atm) THF, 18−20 oC
X
O 6
X
R1
Time (h) ee (%) Yield (%) Ref
O
Ph
3
92
99
[13]
O
4-MeOC6H4
3
92
82
[13]
O
4-ClC6H4
2
90
95
[13]
NTs
Me
1
98
96
[13]
C(CO2Et)2
H
0.5
99
60
[13]
C(CO2Et)2
Me
1
96
50
[13]
In the above reactions, the addition of the silver salt is essential to generate the cationic rhodium complex. In contrast, the rhodium-catalyzed Pauson–Khand reaction in a mixed solvent of water and 1,4-dioxane affords the bicyclopentenones 7 even in the absence of the silver salt (Scheme 4).[14] However, a catalytic amount of a surfactant agent, such as sodium dodecyl sulfate (SDS), is required, and the yield is lower than that obtained in the cationic rhodium-catalyzed reaction.
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3.3.1
129
[2 + 2 + 1] Carbocyclization of Enynes with Carbon Monoxide
Scheme 4 Enantioselective Rhodium-Catalyzed Pauson–Khand Reaction in Aqueous Media[14] 3 mol% [RhCl(cod)]2 6 mol% (S)-BINAP 6 mol% sodium dodecyl sulfate CO (1 atm), H2O, 1,4-dioxane 90 oC, 1.5 h
R1 X
R1 X
O H 7
X
R1
ee (%) Yield (%) Ref
O
4-MeOC6H4
91
65
[14]
93
86
[14]
NTs Me
Cationic rhodium-catalyzed Pauson–Khand reactions can also be used to achieve asymmetric desymmetrization and kinetic resolution reactions. Here, BINAP derivatives are more efficient than the parent BINAP ligand. For example, an oxygen-tethered bicyclopentenone 8 has been obtained with two adjacent stereogenic centers with excellent diastereo- and enantioselectivity by desymmetrization of a prochiral diene (Scheme 5).[13] In a related process employing (R)-BINAP derivative 9, kinetic resolution provides the recovered 1,6-enyne and the cycloadduct with good enantiomeric excess with an S value (the ratio of reaction rates of both enantiomers) of 83 (Scheme 6).[15] The experimental procedures for the reactions shown in Schemes 5 and 6 are essentially the same as in Scheme 3, except for the chiral ligands and substrates used. Scheme 5
Desymmetrization of a Dienyne via a Pauson–Khand Reaction[13] 10 mol% (S)-DIFLUORPHOS 5 mol% [RhCl(CO)2]2, argon/CO (10:1; 1 atm) 12 mol% AgOTf, THF, 18−20 oC, 2 h
Ph O
91%; 95% ee
Ph O
O H 8
F
O
F
O
PPh2
F
O
PPh2
F
O
(S)-DIFLUORPHOS =
Scheme 6
Kinetic Resolution via a Pauson–Khand Reaction[15] CF3 P
2
P CF3 2
9
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Stereoselective Synthesis
Ph
3.3
[m + n + 1]-Carbocyclization Reactions
6 mol% 9 3 mol% [RhCl(CO)2]2 9 mol% AgOTf argon/CO (10:1; 1 atm) THF, 18−20 oC, 1.7 h
Ph Ph
O
O
Ph
Ph
+
O Ph
48%; 84% ee
O H 41%; 90% ee
Bicyclopentenones 6; General Procedure:[13]
CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. [RhCl(CO)2]2 (3.4 mg, 0.009 mmol, 5 mol%), (R)-XylBINAP (12.8 mg, 0.017 mmol, 10 mol%), and THF (2 mL) were added to a flask, and the mixture was stirred for 30 min at 20 8C under an atmospheric pressure of argon. A soln of AgOTf (5.4 mg, 0.021 mmol, 12 mol%) in THF (1 mL) was added, and the resultant mixture was stirred for a further 30 min at 20 8C. The argon atmosphere was replaced with CO in argon (CO/argon 1:10, total 1 atm), and then a soln of an enyne (0.174 mmol) in THF (1 mL) was added. The mixture was stirred at 20 8C and, after completion of the reaction, excess gas was released in the hood, and the crude mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane/EtOAc) to afford the pure cycloadduct. Bicyclopentenones 7; General Procedure:[14]
CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. [RhCl(cod)]2 (25 mg, 0.05 mmol), (S)-BINAP (63 mg, 0.1 mmol), and H2O/1,4-dioxane (1:1; 1 mL) were added to a flask, and the mixture was stirred for 20 min at rt. A balloon filled with CO(g) was then attached to the flask. After further stirring for 20 min, an enyne (1.5 mmol), sodium dodecyl sulfate (29 mg, 0.1 mmol), and H2O (2 mL) were added, and the resulting mixture was stirred at 90 8C for 1.5 h. After the soln had been cooled to rt, CH2Cl2 (10 mL) was added. H2O was removed by using anhyd MgSO4, and then the crude products were purified by column chromatography (silica gel, hexane/Et2O) to afford the pure cycloadduct. 3.3.1.2.2
Diastereoselective Reactions
The same types of compounds have been prepared by a sequential rhodium-catalyzed allylic substitution/Pauson–Khand sequence. Thus, treatment of an allylic carbonate with the alkali metal salt of a propargylic malonate, amine, or alcohol regioselectively affords substituted enynes 10, which undergo in situ diastereoselective Pauson–Khand reactions to furnish the substituted bicyclopentenones 11 (Scheme 7).[16] These one-pot reactions employ a single rhodium catalyst, using temperature to modulate the reactivity of the individual steps. Finally, the use of chiral nonracemic allylic carbonates, e.g. (S)-12, provides enantiomerically enriched substituted bicyclopentenones, e.g. the bicyclopentenones 13A and 13B (dr 43:1; 98% enantiomeric excess) (Scheme 8).
[m n 1]-Carbocyclization Reactions, Shibata, T. Science of Synthesis 4.0 version., Section 3.3 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Scheme 7
131
[2 + 2 + 1] Carbocyclization of Enynes with Carbon Monoxide
3.3.1
Regio- and Diastereoselective Sequential Allylic Substitution/Pauson–Khand Reaction[16]
OCO2Me
R1
5 mol% [RhCl(CO)dppp]2 CO (1 atm), MeCN 30 oC, 5 h
+
MX
R1
R1 + X
X
10A
10B
R1
R1
reflux, 24 h
O + X
X
X
R1
M
C(CO2Me)2
H
Na 27:1
C(CO2Me)2
Me
NTs
Ratio(10A/10B)
Ratio(11A/11B)
O
H
H
11A
11B
Combined Yield (%)of 11A and 11B
Ref
5:1
82
[16]
Na 19:1
6:1
80
[16]
Me
Li
32:1
6:1
84
[16]
NTs
Ph
Li
57:1
7:1
81
[16]
O
Ph
Li
8:1
>19:1
81
[16]
Scheme 8 Sequential Allylic Substitution/Pauson–Khand Reaction of a Chiral Nonracemic Allylic Carbonate[16] OCO2Me LiN
+
[RhCl(CO)dppp]2 CO (1 atm), MeCN 30−80 oC 82%
Ts (S)-12
TsN
TsN
O H
13A
H
+
43:1
O
13B
(1S,2S)-2-(2-Naphthyl)-3-tosyl-2,3,3a,4-tetrahydrocyclopenta[c]pyrrol-5(1H)-one (13A); Typical Procedure:[16]
CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. A 1.0 M soln of LiHMDS in THF (575 L, 0.575 mmol) was added dropwise to a soln of N-(4-toluenesulfonyl)prop-2-yn-1-amine (126 mg, 0.6 mmol) in anhyd MeCN (3.0 mL) at 30 8C under an atmospheric pressure of CO. The mixture was stirred for ca. 20 min and then transferred into a soln of [RhCl(CO)dppp]2 (31.4 mg, 0.03 mmol) in anhyd MeCN (1.0 mL) at 30 8C via a Teflon cannula, rinsing with anhyd MeCN (2 0.5 mL). An allylic car[m n 1]-Carbocyclization Reactions, Shibata, T. Science of Synthesis 4.0 version., Section 3.3 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
3.3
[m + n + 1]-Carbocyclization Reactions
bonate (0.5 mmol) was then added from a tared vial, and the mixture was stirred at 30 8C for 5 h and then heated at reflux under an atmospheric pressure of CO for an additional 24 h. The mixture was then concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/EtOAc) to afford the cycloadduct as a white, crystalline solid; yield: 0.162 g (82%); (13A/13B) 43:1 (determined by crude HPLC); 98% ee. 3.3.1.3
Enantioselective Iridium-Catalyzed Pauson–Khand Reactions
An iridium–chiral diphosphine complex also provides an effective catalyst for highly enantioselective Pauson–Khand reactions. The complex is prepared in situ from chloro(cycloocta-1,5-diene)iridium(I) dimer {[IrCl(cod)]2} and 2,2¢-bis(di-4-tolylphosphino)-1,1¢-binaphthyl (TolBINAP), both of which are commercially available and air stable. Oxygenand nitrogen-tethered enynes can be transformed into the corresponding cycloadducts 14 with excellent enantioselectivity (>95% ee).[17] In the case of inactive substrates, such as a carbon-tethered enyne or enynes with a 1,1-disubstituted alkene group, a low partial pressure of carbon monoxide is required to increase the yield and enantioselectivity (Scheme 9).[18] Scheme 9 Enantioselective Iridium-Catalyzed Pauson–Khand Reaction of Various Enynes[17,18] 10 mol% [IrCl(cod)]2 20 mol% (S)-TolBINAP CO (0.2 or 1 atm), toluene, reflux
R1 X
R2
R1 X
O R2 14
X
R1
R2
CO Pressure (atm)
Time (h)
ee (%)
Yield (%)
Ref
O
Ph
H
1
18
93
83
[17]
O
4-MeOC6H4
H
1
20
96
80
[17]
O
4-ClC6H4
H
1
20
95
78
[18]
O
Me
H
1
48
97
75
[17]
NTs
Ph
H
1
12
95
85
[17]
C(CO2Et)2
Ph
H
0.2
72
86
89
[18]
O
Ph
Me
0.2
72
93
86
[18]
O
Ph
CH2CH=CH2
0.2
96
94
62
[18]
Alternatively, the cationic iridium–PHOX complex {PHOX = 2-[2-(diphenylphosphino)phenyl]-4-isopropyl-4,5-dihydrooxazole} also provides an excellent catalyst for the enantioselective Pauson–Khand reaction. The use of slightly pressurized carbon monoxide is required, but high enantioselectivity is achieved for the phenyl-substituted 1,6-enynes to afford the bicyclopentenones 15 through the judicious choice of counterion and solvent (Scheme 10).[19]
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3.3.1
133
[2 + 2 + 1] Carbocyclization of Enynes with Carbon Monoxide
Scheme 10 Enantioselective Iridium-Catalyzed Pauson–Khand Reaction with a Cationic Complex[19] + O 9 mol% Ph2P
X−
N Ir (cod)
Ph
Ph
CO (2.2 atm), solvent, 120 oC
Z
Z
O H 15
X–
Z
Solvent ee (%) Yield (%) Ref
SbF6– BF –
O
DME
91
96
[19]
C(CO2Me)2
THF
91
76
[19]
4
Bicyclopentenones 14; General Procedure:[18]
CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. A balloon filled with mixed CO/argon gas (1:4) was prepared as follows: CO (2 atm) and argon (8 atm) were introduced into an autoclave (30 mL), and then the pressurized mixed gas (total 10 atm) was released into a balloon at an atmospheric pressure. (S)-TolBINAP (34.0 mg, 0.050 mmol) and [IrCl(cod)]2 (16.8 mg, 0.025 mmol) were stirred in toluene (2.0 mL) at rt for 30 min under an atmospheric pressure of CO (1.0 atm or 0.2 atm). Following the addition of a soln of an enyne (0.25 mmol) in toluene (2.0 mL), the mixture was stirred under reflux for 12–96 h. The solvent was removed under reduced pressure, and the crude products were purified by TLC to give the pure cycloadduct. Bicyclopentenones 15; General Procedure:[19]
CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. An enyne (0.22 mmol), [Ir(cod)(PHOX)]X (2.2–20.0 mol), and a solvent (5 mL) were added to a flame-dried Youngs tube with a Teflon screw cap in a glovebox. The mixture was degassed with three freeze–pump–thaw cycles and the tube was filled with CO(g) (2.2 atm), and then sealed. After the mixture had been stirred at 120 8C for 24 or 48 h, the solvent was removed under reduced pressure and the crude products were purified by TLC to give the pure cycloadduct. 3.3.1.4
Enantioselective Cobalt-Catalyzed Pauson–Khand Reactions
A combination of octacarbonyldicobalt(0) and BINAP derivatives has also been utilized in an enantioselective Pauson–Khand reaction.[20,21] Enynes 16 and 18 with an unsubstituted alkyne moiety can be transformed into bicyclopentenones 17 and 19, respectively, with high enantiomeric excess (Scheme 11).[20,21] The reaction generally proceeds under an atmospheric pressure of carbon monoxide; however, in the case of relatively inactive carbon-tethered enyne 18, pressurized conditions provide better results.[21]
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134
Stereoselective Synthesis Scheme 11
3.3
[m + n + 1]-Carbocyclization Reactions
Enantioselective Cobalt-Catalyzed Pauson–Khand Reaction[20,21] 20 mol% Co2(CO)8, 20 mol% (S)-BINAP CO (1 atm), 1,2-dichloroethane, reflux, 17−19 h
X
X
O H
16
17
X
ee (%) Yield (%) Ref
C(CO2Me)2
91
62
[20]
NTs
90
64
[20]
7.5 mol% (R)-MeO-BIPHEP 5 mol% Co2(CO)8 CO (1.8 atm), DME, 110 oC, 4.5 h
EtO2C
86%; 92% ee
EtO2C
EtO2C O EtO2C H
18
(R)-MeO-BIPHEP =
19
MeO
PPh2
MeO
PPh2
A similar type of sequential allylic substitution/Pauson–Khand reaction to that described in Scheme 7 (Section 3.3.1.2.2), can be achieved using a chiral palladium catalyst and an achiral cobalt complex. Thus, enantioselective allylic alkylation of 1,3-disubstituted allyl acetates with a propargylmalonate affords the enantiomerically enriched 1,6-enynes, which undergo a subsequent cobalt-catalyzed Pauson–Khand reaction under high-pressure conditions to afford the enantiomerically enriched, multisubstituted bicyclo- and tricyclopentenones 20 and 21 (Scheme 12).[22] Enynes with a cyclic alkene moiety have not been utilized in the titanium-, rhodium-, or iridium-catalyzed enantioselective reactions. Hence, this reaction provides an alternative method for asymmetric Pauson–Khand reactions of enynes containing a cyclic alkene.
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3.3.1
135
[2 + 2 + 1] Carbocyclization of Enynes with Carbon Monoxide
Scheme 12 Sequential Allylic Alkylation and Pauson–Khand Reactions Involving Two Catalysts[22] PPh2 N
6 mol% O
2.5 mol% [Pd(η3-C3H5)Cl]2 BSA, KOAc, THF, rt, 4 h
OAc +
MeO2C CO2Me
Ph
Ph
MeO2C
Co/C, CO (30 atm) 130 oC, 12 h
MeO2C O
MeO2C Ph
MeO2C
Ph
Ph 20
1.
O
H
Ph
81%; 95% ee
O NH
HN
6 mol% PPh2 Ph2P Trost ligand
OAc MeO2C
2.5 mol% [Pd(η3-C3H5)Cl]2 BSA, Cs2CO3, CH2Cl2, rt, 12 h 2. Co/C, CO (30 atm), 130 oC, 18 h
+ 92%; 94% ee
CO2Me
MeO2C O MeO2C H
H
H
21
Bicyclopentenones 17; General Procedure:[20]
CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. Co2(CO)8 (22.8 mg, 0.067 mmol) and (S)-BINAP (41.5 mg, 0.067 mmol) were added to a 25-mL, two-necked flask. The flask was flushed with CO and then maintained under a positive pressure of CO. 1,2-Dichloroethane (4 mL) was added at rt, and the mixture was stirred at reflux for 2 h. A soln of enyne 16 (0.333 mmol) in 1,2-dichloroethane (4 mL) was added, and the resulting mixture was then stirred at reflux for 17–19 h. After cooling at rt, the mixture was filtered through a plug of silica gel with the aid of EtOAc. The solvent was removed under reduced pressure, and the crude products were purified by TLC (EtOAc/hexane) to give the pure cycloadduct.
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Stereoselective Synthesis
3.3
[m + n + 1]-Carbocyclization Reactions
Dimethyl (3R,3aS,4R)-6-Methyl-5-oxo-3,4-diphenyl-3,3a,4,5-tetrahydropentalene2,2(1H)-dicarboxylate (20); Typical Procedure:[22]
CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. 2-[2-(Diphenylphosphino)phenyl]-4-isopropyl-4,5-dihydrooxazole (PHOX; 0.048 mmol), [Pd(Å3-C3H5)Cl]2 (7.3 mg, 0.020 mmol), and THF (10 mL) were placed in a 100-mL high-pressure reactor. The resulting soln was stirred at rt for 10 min, and then Co/C (0.20 g, 14 wt% of Co), (E)-1,3-diphenylprop-2-enyl acetate (0.20 g, 0.79 mmol), dimethyl 2-(but-2-ynyl)malonate (0.16 g, 0.87 mmol), BSA (0.25 mL, 1.0 mmol), and a catalytic amount of KOAc (or Cs2CO3) were added. The soln was stirred at rt for 4 h, and then the reactor was pressurized with CO (30 atm) and heated at 130 8C for 12 h. After cooling the reactor to rt, the pressure was released. The solvent was removed under reduced pressure, and the crude product was purified by flash column chromatography (silica gel, hexane/Et2O 3:1) to give the pure bicyclic product; yield: 0.286 g (81%); 95% ee. 3.3.2
Rhodium-Catalyzed [2 + 2 + 1] Carbocyclization Using Aldehydes as a Carbon Monoxide Source
The enantioselective, transition-metal-catalyzed Pauson–Khand reaction is a facile method for preparing chiral cyclopentenones. However, a serious problem with this method is the necessity to utilize highly toxic carbon monoxide gas. The use of aldehydes as an alternative to carbon monoxide gas has therefore been investigated.[23,24] The rhodium-catalyzed decarbonylation of aldehydes was reported in the 1960s[25,26] and has been used in synthesis.[27] However, the use of the carbon monoxide generated in this manner has been largely neglected. Two groups have independently disclosed non-asymmetric Pauson– Khand reactions using aldehydes in place of carbon monoxide gas, in which a rhodium complex catalyzes both the decarbonylation and carbonylation. The choice of aldehyde is very important in achieving easy carbon monoxide transfer, and pentafluorobenzaldehyde[23] and cinnamaldehyde[24] are the preferred sources. 3.3.2.1
Enantioselective Rhodium-Catalyzed Reactions Using Aldehydes
Studies have identified the chiral diphosphine ligand 2,2¢-bis(di-4-tolylphosphino)-1,1¢-binaphthyl (TolBINAP) as the optimal ligand for enantioselective reaction.[28] Unlike in the case of rhodium-catalyzed reactions using carbon monoxide gas (see Scheme 3, Section 3.3.1.2.1), the addition of silver salts is unnecessary and a neutral rhodium complex catalyzes the Pauson–Khand reaction of enynes to afford the bicyclopentenones 22 under solvent-free conditions using a large excess of cinnamaldehyde as the carbon monoxide source (Scheme 13). Scheme 13 Enantioselective Pauson–Khand Reaction Using Cinnamaldehyde as the Carbon Monoxide Source[28] 5 mol% [RhCl(cod)]2 10 mol% (S)-TolBINAP
R1
Ph 120 oC
R1
CHO (20 equiv)
O
O
O 22
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3.3.2
Rhodium-Catalyzed [2 + 2 + 1] Carbocyclization Using Aldehydes
R1
Time (h) ee (%) Yield (%) Ref
Ph
4
82
89
[28]
4-MeOC6H4
6
81
86
[28]
4-ClC6H4
9
79
82
[28]
(CH2)3Ph
2
90
72
[28]
137
The chiral diphosphine ligand P-Phos is also efficient in this type of Pauson–Khand reaction (Scheme 14). The carbonylation proceeds using a slight excess of the aldehyde in water, and the yields and enantioselectivities of the cyclopentenone products 23 are comparable to those obtained using TolBINAP.[29] Scheme 14 Enantioselective Pauson–Khand Reaction Using Cinnamaldehyde as a Carbon Monoxide Source in Aqueous Media[29] 6 mol% (S)-P-Phos 3 mol% [RhCl(cod)]2 CHO (1.5 equiv) Ph H2O, 100 oC, 36 h
R1 O
R2
R1 O
O R
2
23 OMe N
(S)-P-Phos =
MeO
PPh2
MeO
PPh2 N OMe
R1
R2
ee (%) Yield (%) Ref
Ph
H
84
82
[29]
Ph
Me 90
71
[29]
Me
H
95
82
[29]
4-MeOC6H4
H
93
93
[29]
In another study, the reaction is subjected to microwave irradiation, which facilitates the formation of bicyclopentenones 24 using SYNPHOS within 1 hour (Scheme 15).[30] Moreover, improved enantioselectivity is observed for some 1,6-enynes.
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Stereoselective Synthesis
3.3
[m + n + 1]-Carbocyclization Reactions
Scheme 15 Asymmetric Pauson–Khand Reaction Using Cinnamaldehyde as a Carbon Monoxide Source under Microwave Irradiation[30] 6.6 mol% (S)-SYNPHOS 3 mol% [RhCl(cod)]2 CHO (1.5 equiv)
Ph
R
1
R1
2-methylbutan-2-ol microwave, 100 oC, 45 min
O
O
O 24
O
(S)-SYNPHOS =
O
PPh2
O
PPh2
O
R1
ee (%) Yield (%) Ref
Ph
89
78
[30]
2-thienyl
90
58
[30]
This method can also be used for the asymmetric desymmetrization of diallyl acetals of alkynals, to afford the cycloadducts 25, which upon hydrolysis deliver the multifunctionalized cyclopentenones 26 with excellent enantiomeric excess (Scheme 16).[31] Asymmetric Desymmetrization by Enantioselective Pauson–Khand Reaction[31]
Scheme 16
5 mol% [RhCl(CO)2]2 13 mol% (R)-TolBINAP
R1
R1
O
CHO Ph 120 oC, 1.5 h
O
3 mol% TsOH THF, H2O, 80 oC, 6 h
H O
O
O H 25 R1 OHC O HO 26
R1 H Me CH2CH=CH2 a
b
ee (%) Yield (%) of 26 Ref 97
60a
[31]
94
b
[31]
b
[31]
>95
66 70
Summation of the yields of two reaction steps. One-pot operation of two reaction steps.
A disadvantage of using aldehydes as a carbon monoxide source is the formation of byproducts. For example, styrene is formed when cinnamaldehyde is used as the carbon monoxide source. Hence, from an atom-economical point of view, formaldehyde is the most suitable carbon monoxide source because the byproduct is hydrogen gas.[32] In prac[m n 1]-Carbocyclization Reactions, Shibata, T. Science of Synthesis 4.0 version., Section 3.3 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.3.2
139
Rhodium-Catalyzed [2 + 2 + 1] Carbocyclization Using Aldehydes
tical terms, the best source is formalin, which requires the reaction to be undertaken in aqueous media. The enantioselective Pauson–Khand reaction with formalin requires a combination of a chiral diphosphine and a hydrophilic phosphine ligand using a surfactant agent (Scheme 17).[33] Oxygen- and nitrogen-tethered enynes are transformed into the corresponding bicyclopentenones 27 with high enantiomeric excess. Although hydrogen is formed as a byproduct, hydrogenation of the cycloadduct is not a problem. Scheme 17 Enantioselective Pauson–Khand Reaction Using Formaldehyde as a Carbon Monoxide Source[33] 5 mol% [RhCl(cod)]2 10 mol% (S)-TolBINAP 15 mol% TPPTS 37% formalin sodium octyl sulfate H2O, 100 oC
R1 X
R2
R1 X
O R2 27
TPPTS = (3-NaO3SC6H4)3P
X
R1
R2
C(CO2Et)2
Ph H
0.5
6
81
83
[33]
O
Bu H
2.0
3
95
75
[33]
O
Ph Me 1.0
5
94
73
[33]
NTs
Bu H
3
92
60
[33]
Sodium Octyl Sulfate (equiv) Time (h) ee (%) Yield (%) Ref
2.0
3a,4-Dihydro-1H-cyclopenta[c]furan-5(3H)-ones 22; General Procedure:[28]
[RhCl(cod)]2 (8.1 mg, 0.016 mmol), (S)-TolBINAP (22.4 mg, 0.033 mmol), an enyne (0.33 mmol), and cinnamaldehyde (872 mg, 6.60 mmol) were placed in a flask under an atmosphere of argon. The mixture was stirred at 120 8C for 2–9 h, excess cinnamaldehyde was removed under reduced pressure, and the thus-obtained crude product was purified by TLC to give the pure bicyclic enone. 3a,4-Dihydro-1H-cyclopenta[c]furan-5(3H)-ones 23; General Procedure:[29]
[RhCl(cod)]2 (4.4 mg, 0.009 mmol), (S)-P-Phos (11.6 mg, 0.018 mmol), and cinnamaldehyde (59 mg, 0.45 mmol) were placed into a screw-cap vial at rt. An enyne (0.3 mmol) was then added under air, the vial was evacuated and backfilled with N2 (three cycles), and H2O (0.2 mL) was added. The mixture was heated to 100€2 8C for 36 h, the vial was cooled to rt, and EtOAc (2 mL) was added. The crude products were then passed through a short plug of Na2SO4, the solvent was removed by rotary evaporation, and the crude mixture was purified by flash column chromatography (silica gel, hexane/ EtOAc) to afford the pure cycloadduct. 3a,4-Dihydro-1H-cyclopenta[c]furan-5(3H)-ones 24; General Procedure:[30]
[RhCl(cod)]2 (4.4 mg, 0.009 mmol) and (S)-SYNPHOS (12.6 mg, 0.0198 mmol) were placed in a reaction vial at rt. The vial was transferred to a glovebox, and then it was evacuated and backfilled with N2 (three cycles). 2-Methylbutan-2-ol (0.2 mL), cinnamaldehyde (59 mg, 0.45 mmol), and an enyne (0.3 mmol) were added, and the vial was sealed using an airtight lid. It was then transferred to a microwave oven and the mixture was heated to 100 8C by microwave irradiation (500 W) for 45 min. The vial was then cooled to rt, Et2O or EtOAc (ca. 2 mL) was added, and the crude mixture was directly purified by column chromatography (silica gel, hexane/EtOAc) to give the pure cycloadduct. [m n 1]-Carbocyclization Reactions, Shibata, T. Science of Synthesis 4.0 version., Section 3.3 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
3.3
[m + n + 1]-Carbocyclization Reactions
Cyclopentenones 26; General Procedure:[31]
A mixture of [RhCl(cod)]2 (4.8 mg, 0.010 mmol), (R)-TolBINAP (15.8 mg, 0.023 mmol), and a diallyl acetal (0.19 mmol) in cinnamaldehyde (0.5 mL, 3.9 mmol) was placed in a flask under an atmospheric pressure of argon. The mixture was stirred at 120 8C for 1.5 h and, after completion of the reaction, the mixture was diluted with THF/H2O (6:1; 3.5 mL) and TsOH (1.3 mg, 0.007 mmol) was added. The resulting mixture was stirred at 80 8C for 6 h, and then quenched with sat. aq NaHCO3 (10 mL) and extracted with EtOAc (3 5 mL). The combined organic materials were washed with brine and dried (MgSO4). After removal of the insoluble materials by filtration, the filtrate was concentrated under reduced pressure. The crude products were purified by flash chromatography (silica gel, hexane/ EtOAc 3:1) to give the pure product. Bicyclopentenones 27; General Procedure:[33]
[RhCl(cod)]2 (6.2 mg, 0.013 mmol), (S)-TolBINAP (17.0 mg, 0.025 mmol), tris(3-sulfonatophenyl)phosphine trisodium salt (TPPTS; 21.3 mg, 0.038 mmol), and H2O (0.5 mL) were placed in a 5-mL, two-necked flask equipped with a reflux condenser. The mixture was stirred at rt for 15 min with formation of a light yellow suspension. Sodium octadecyl sulfate (46.6 mg, 0.13 mmol), 37% formalin (0.1 mL, 1.25 mmol), an enyne (0.25 mmol), and H2O (1.4 mL) were then added and the mixture was degassed, charged with N2, and stirred at 100 8C under a stream of N2 until the enyne was consumed. Et2O (10 mL) was added and the biphasic mixture was stirred for an additional 15 min. The separated aqueous layer was extracted with Et2O (3 10 mL), and the combined organic materials were dried (MgSO4) and then concentrated under reduced pressure. The crude products were purified by column chromatography (silica gel, hexane/EtOAc 3:1) to give the pure cycloadduct. 3.3.3
Ruthenium-Catalyzed [3 + 2 + 1] Carbocyclization of Silylalkynes and Enones with Carbon Monoxide
A ruthenium-catalyzed [3 + 2 + 1] carbocyclization of silylalkynes and Æ,-unsaturated ketones proceeds under a highly pressurized atmosphere of carbon monoxide.[34] The yield is generally low to moderate, but this reaction provides a new protocol for the construction of tetrasubstituted pyran-2-ones 28 (Scheme 18). Scheme 18 Regioselective Ruthenium-Catalyzed [3 + 2 + 1] Carbocyclization[34] 6 mol% Ru3(CO)12 20 mol% Et2MeNH•HI CO (20 atm), toluene 160 oC, 8 h
O
TMS +
O TMS
O
Ar1
Ar1
28
Ar1
Yield (%) Ref
Ph
52
[34]
4-MeOC6H4
66
[34]
4-FC6H4
57
[34]
2-Tol
59
[34]
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3.3.4
Nickel-Catalyzed [4 + 2 + 1] Carbocyclization of Dienynes with Diazomethane
141
2H-Pyran-2-ones 28; General Procedure:[34]
CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. The 1-aryl-2-(trimethylsilyl)acetylene (0.48 mmol), methyl vinyl ketone (67.2 mg, 0.96 mmol), diethyl(methyl)ammonium iodide (21.3 mg, 0.10 mmol), Ru3(CO)12 (20.5 mg, 0.03 mmol), and toluene (2 mL) were placed in a 30-mL stainless-steel autoclave. The vessel was purged three times with CO, pressurized with 20 atm of CO(g), and then heated at 160 8C for 8 h. After cooling to rt, the CO pressure was carefully released inside a hood. The solvent was then removed under reduced pressure and the crude products were purified by flash chromatography (silica gel, hexane/EtOAc 10:1 to 3:1) to afford the pure cycloadduct. 3.3.4
Nickel-Catalyzed [4 + 2 + 1] Carbocyclization of Dienynes with Diazomethane
The diastereoselective nickel-catalyzed carbocyclization of dienynes with (trimethylsilyl)diazomethane affords [4 + 2 + 1] cycloadducts 30 having 5,7-bicyclic ring systems.[35,36] The process is consistent with an intramolecular cyclopropanation of a vinyl carbenoid to provide an intermediary divinylcyclopropane 29, which undergoes a stereospecific [3,3]-sigmatropic rearrangement to generate the seven-membered ring system. The Cope rearrangement potentially explains the high stereoselectivity for this process (Scheme 19). Scheme 19
Stereoselective Nickel-Catalyzed [4 + 2 + 1] Carbocyclization[35]
R1 X
TMS
R1
TMSCHN2 10 mol% Ni(cod)2 THF, 60 oC
X H 29 R1
TMS
X H 30
X
R1
dr
NTs
H
>95:5 68
[35]
O
H
10:1 65
[35]
C(CO2Me)2
H
13:1 76
[35]
C(CO2Me)2
Me >95:5 78
[35]
Yield (%) Ref
Cyclohepta-1,4-dienes 30; General Procedure:[35]
To a mixture of the dienyne (0.50 mmol) in THF and 2.0 M TMSCHN2 in Et2O (0.5 mL, 1.0 mmol) was added a soln of Ni(cod)2 (15 mg, 0.05 mmol) in THF at 60 8C. The resulting brown soln was stirred at 60 8C for 10–30 min and then cooled to rt. The solvent was removed under reduced pressure and the crude products were purified by flash chromatography (silica gel) to afford the pure cycloadduct.
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142
Stereoselective Synthesis
3.3.5
Rhodium-Catalyzed [5 + 2 + 1] Carbocyclization of Vinylcyclopropanes and Alkynes with Carbon Monoxide
3.3
[m + n + 1]-Carbocyclization Reactions
A rhodium-catalyzed three-component carbocyclization of a vinylcyclopropane, an alkyne, and carbon monoxide has been reported (Scheme 20).[37] The primary cycloadducts have eight-membered ring systems that undergo transannular ring closure to give bicyclo[3.3.0]octadienes. Acid-catalyzed hydrolysis of the enol ether affords bicyclo[3.3.0]octenones 31. The coupling of the unsymmetrical activated alkynes is highly regioselective, making this an attractive strategy. Scheme 20
Regio- and Stereoselective Rhodium-Catalyzed [5 + 2 + 1] Carbocyclization[37] R1
O
2.5 mol% [RhCl(CO)2]2 CO, 1,4-dioxane, 60 oC
OMe + R2
R1
O
MeO
O
H
MeO
R1
R2 OH R2
O
O
H
H3O+
R1 OH R2 31
R1
R2
CO Pressure (atm) Time (h) Yield (%) Ref
Ac
Et
2
20
97
[37]
Ac
Ph 1
26
88
[37]
CONH2 Ph 1
40
96
[37]
CO2Et
24
79
[37]
Ph 1
3a-Hydroxy-3,3a,6,6a-tetrahydropentalen-1(2H)-ones 31; General Procedure:[37]
CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. [RhCl(CO)2]2 (0.025 mmol) and 1,4-dioxane (2.0 mL) were added to an oven-dried, septumcapped test-tube. A vinylcyclopropane (1.0 mmol) was added via a syringe and the mixture was purged with a stream of CO(g) from a balloon for 15 min. An alkyne (1.2 mmol) was then added via a syringe. The septum was pierced with a needle and the test tube was placed in an autoclave, which was pressurized to 2 atm and heated to 60 8C in a thermostat-controlled oil bath. (In the case of reactions under 1 atm, the test tube was heated directly in an oil bath using a balloon of CO). After the reaction was complete, the test tube was cooled to rt. H2O (200 L) and 1% HCl in EtOH (25 L) were added, and the mixture was stirred for 24 h. After hydrolysis, the mixture was concentrated under reduced pressure. The crude products were purified by flash chromatography (silica gel, EtOAc/pentane 1:1) to afford the pure cycloadduct. [m n 1]-Carbocyclization Reactions, Shibata, T. Science of Synthesis 4.0 version., Section 3.3 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.3.6
3.3.6
143
Palladium-Catalyzed [4 + 4 + 1] Carbocyclization of Two Vinylallenes
Palladium-Catalyzed [4 + 4 + 1] Carbocyclization of Two Vinylallenes with Carbon Monoxide
The palladium-catalyzed [4 + 4 + 1] carbocyclization of two vinylallenes with carbonyl insertion is a unique method for the construction of nine-membered ring systems.[38] Oxidative coupling of the palladium complex with the diene moiety of a vinylallene affords an Æ-methylenepalladacyclopentene, which undergoes regioselective intermolecular coupling with another vinylallene to provide a diallylpalladium complex that presumably undergoes migratory insertion and reductive elimination leading to cyclonona-3,7-dienones 32 (Scheme 21). Scheme 21 Regioselective Palladium-Catalyzed [4 + 4 + 1] Carbocyclization of Vinylallenes[38] R1 2
5 mol% Pd(PPh3)4 CO (1 atm), THF 30 oC, 40−43 h
•
R1
Pd
R1
R1
Pd
• R1
R1
O
R1 32
R1
Yield (%) Ref
Ph
87
[38]
CH=CH2
61
[38]
Cyclonona-3,7-dienones 32; General Procedure:[38]
CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. Pd(PPh3)4 (54 mg, 47 mol) and a vinylallene (940 mol) were stirred in THF (3 mL) under an atmospheric pressure of CO at 30 8C for 40–43 h. The mixture was passed through a pad of Florisil to remove the insoluble materials, and the eluent was concentrated under reduced pressure. The crude products were purified by flash chromatography (silica gel, Et2O/hexane 1:10) to afford the pure cycloadduct.
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Stereoselective Synthesis
3.3
[m + n + 1]-Carbocyclization Reactions
References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
[14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]
[28] [29]
[30] [31]
[32]
[33] [34] [35] [36] [37] [38]
Shibata, T., Adv. Synth. Catal., (2006) 348, 2328. Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E., J. Chem. Soc., Perkin Trans. 1, (1973), 975. Exon, C.; Magnus, P., J. Am. Chem. Soc., (1983) 105, 2477. Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, Y. K., J. Am. Chem. Soc., (1994) 116, 3159. Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L., J. Am. Chem. Soc., (1996) 118, 9450. Hicks, F. A.; Buchwald, S. L., J. Am. Chem. Soc., (1996) 118, 11 688. Hicks, F. A.; Buchwald, S. L., J. Am. Chem. Soc., (1999) 121, 7026. Sturla, S. J.; Buchwald, S. L., J. Org. Chem., (1999) 64, 5547. Mandal, S. K.; Amin, S. R.; Crowe, W. E., J. Am. Chem. Soc., (2001) 123, 6457. Koga, Y.; Kobayashi, T.; Narasaka, K., Chem. Lett., (1998), 249. Jeong, N.; Sung, B. K.; Choi, Y. K., J. Am. Chem. Soc., (2000) 122, 6771. Kobayashi, T.; Koga, Y.; Narasaka, K., J. Organomet. Chem., (2001) 624, 73. Kim, D. E.; Kim, I. S.; Ratovelomanana-Vidal, V.; GenÞt, J.-P.; Jeong, N., J. Org. Chem., (2008) 73, 7985. Suh, W. H.; Choi, M.; Lee, S. I.; Chung, Y. K., Synthesis, (2003), 2169. Kim, D. E.; Kwak, J.; Kim, I. S.; Jeong, N., Adv. Synth. Catal., (2009) 351, 97. Evans, P. A.; Robinson, J. E., J. Am. Chem. Soc., (2001) 123, 4609. Shibata, T.; Takagi, K., J. Am. Chem. Soc., (2000) 122, 9852. Shibata, T.; Toshida, N.; Yamasaki, M.; Maekawa, S.; Takagi, K., Tetrahedron, (2005) 61, 9974. Lu, Z.-L.; Neumann, E.; Pfaltz, A., Eur. J. Org. Chem., (2007), 4189. Hiroi, K.; Watanabe, T.; Kawagishi, R.; Abe, I., Tetrahedron Lett., (2000) 41, 891. Schmid, T. M.; Consiglio, G., Tetrahedron: Asymmetry, (2004) 15, 2205. Son, S. U.; Park, K. H.; Seo, H.; Chung, Y. K.; Lee, S.-G., Chem. Commun. (Cambridge), (2001), 2440. Morimoto, T.; Fuji, K.; Tsutsumi, K.; Kakiuchi, K., J. Am. Chem. Soc., (2002) 124, 3806. Shibata, T.; Toshida, N.; Takagi, K., Org. Lett., (2002) 4, 1619. Blum, J.; Oppenheimer, E.; Bergmann, E. D., J. Am. Chem. Soc., (1967) 89, 2338. Ohno, K.; Tsuji, J., J. Am. Chem. Soc., (1968) 90, 99. Fessard, T. C.; Andrews, S. P.; Motoyoshi, H.; Carreira, E. M., Angew. Chem., (2007) 119, 9492; Angew. Chem. Int. Ed., (2007) 46, 9331. Shibata, T.; Toshida, N.; Takagi, K., J. Org. Chem., (2002) 67, 7446. Kwong, F. Y.; Li, Y. M.; Lam, W. H.; Qiu, L.; Lee, H. W.; Yeung, C. H.; Chan, K. S.; Chan, A. S. C., Chem.–Eur. J., (2005) 11, 3872. Lee, H. W.; Lee, L. N.; Chan, A. S. C.; Kwong, F. Y., Eur. J. Org. Chem., (2008), 3403. Kim, D. E.; Lee, B. H.; Rajagopalasarma, M.; GenÞt, J.-P.; Ratovelomanana-Vidal, V.; Jeong, N., Adv. Synth. Catal., (2008) 350, 2695. Fuji, K.; Morimoto, T.; Tsutsumi, K.; Kakiuchi, K., Angew. Chem., (2003) 115, 2511; Angew. Chem. Int. Ed., (2003) 42, 2409. Fuji, K.; Morimoto, T.; Tsutsumi, K.; Kakiuchi, K., Tetrahedron Lett., (2004) 45, 9163. Fukuyama, T.; Higashibeppu, Y.; Yamaura, R.; Ryu, I., Org. Lett., (2007) 9, 587. Ni, Y.; Montgomery, J., J. Am. Chem. Soc., (2004) 126, 11 162. Ni, Y.; Montgomery, J., J. Am. Chem. Soc., (2006) 128, 2609. Wender, P. A.; Gamber, G. G.; Hubbard, R. D.; Zhang, L., J. Am. Chem. Soc., (2002) 124, 2876. Murakami, M.; Itami, K.; Ito, Y., Angew. Chem., (1998) 110, 3616; Angew. Chem. Int. Ed., (1998) 37, 3418.
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145 3.4
[m + n + 2]-Carbocyclization Reactions C. Aubert, M. Malacria, and C. Ollivier
General Introduction
The transition-metal-catalyzed [m + n + 2]-carbocyclization reactions of unsaturated compounds, namely [2 + 2 + 2], [3 + 2 + 2], and [4 + 2 + 2] cyclizations, provide one of the most powerful one-step methods for the construction of multiple C—C bonds in a highly chemo-, regio-, and stereoselective manner. Moreover, it provides new opportunities to enhance the efficiency of complex organic molecule synthesis by significantly reducing the number of steps in an atom-economical manner, thereby providing an environmentally friendly process. The search for new and efficient stereoselective methods for the synthesis of substituted medium and large rings embedded in polycyclic systems has been an active area of research in organic synthesis in the 21st century. Tremendous progress has been achieved in asymmetric catalysis of [m + n + 2]-carbocyclization reactions. This review is dedicated to the stereochemical aspects of these processes, using numerous examples to illustrate the salient features. The review is primarily organized based on the type of [m + n + 2]-carbocyclization process, where m = 2–4 and n = 2. Since much of the chemistry has focused on [2 + 2 + 2]carbocyclization reactions, this aspect naturally dominates the review; however, the [3 + 2 + 2] and [4 + 2 + 2] reactions are also described. The different approaches are classified strictly according to the metal complex that catalyzes the transformation, i.e. ruthenium, cobalt, rhodium, iridium, nickel, and palladium. Each section is divided into the specific mode of cyclization, i.e. inter- and intramolecular reactions, and by the types of substrate, which is based on the degree of unsaturation and heteroatoms. This classification system is utilized throughout the review. 3.4.1
[2 + 2 + 2]-Carbocyclization Reactions
The cyclotrimerization of unsaturated compounds is a useful method for the construction of three new bonds in a single-step process. Since the initial reports of the formation of benzene by thermal cyclization of three molecules of acetylene by Berthelot[1] and the pioneering work of Reppe in transition-metal-mediated cyclizations,[2] there are no less than 17 early to late transition metals that have been developed for the cyclotrimerization of acetylenic compounds. In addition to alkynes, a large variety of other unsaturated partners, such as alkenes, allenes, nitriles, aldehydes, ketones, imines, isocyanates, isothiocyanates, etc., take part in related [2 + 2 + 2] cyclizations to afford products with four-, five-, six-, and eight-membered rings. Many of these cyclizations proceed with good chemo-, regio-, and stereoselectivities and have applications in the synthesis of complex polycyclic molecules. More recently, these processes have regained interest, which can be attributed to new cyclization partners and catalytic systems and the advent of asymmetric catalysis. Since the 1980s, this family of reactions has been extensively investigated and the topic has been thoroughly reviewed.[3–16]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.4.1.1
Ruthenium(II)-Mediated [2 + 2 + 2] Carbocyclizations
3.4
[m + n + 2]-Carbocyclization Reactions
Ruthenium complexes provide efficient catalysts for [2 + 2 + 2] cyclotrimerization of alkynes, which lead to the preparation of substituted benzene rings. Recent investigations have examined the problem of regioselectivity and also confirmed the superiority of chloro(cycloocta-1,5-diene)(Å5-pentamethylcyclopentadienyl)ruthenium(II) [Ru(Cp*)Cl(cod)] over the previously used ruthenium catalysts. The scope of the reaction has been extended to cocyclization of 1,6-diynes with alkenes and also new partners, such as isocyanates, isothiocyanates, nitriles, and carbonyl derivatives. The resulting cyclohexa-1,3-dienes and heterocycles are formed efficiently, as exemplified by the preparation of various pyridinones, pyridines, pyrans, etc. However, there are relatively few examples that examine the stereoselective aspects of these processes. 3.4.1.1.1
Control of Diastereoselectivity
3.4.1.1.1.1
Intramolecular Carbocyclization of Dienynes
Relatively few examples of ruthenium(II)-catalyzed intramolecular [2 + 2 + 2] carbocyclization have been reported. Nevertheless, the complex chloro(cycloocta-1,5-diene)(Å5-pentamethylcyclopentadienyl)ruthenium(II) facilitates the cyclization of a variety of 1,11-dien6-ynes 1 into the corresponding tricyclic compounds 2 with a cis-fused cyclohexene core as single diastereomers (Scheme 1). Interestingly, the carbonyl group has a remarkable beneficial effect on the reactivity of alkyne in the carbocyclization process.[17] Scheme 1 Ruthenium(II)-Mediated Intramolecular [2 + 2 + 2] Carbocyclization of Dienynes[17]
X1
R1 2
5 mol% Ru(Cp∗)Cl(cod) toluene
R1
R2
X R2
X1
X3
X2
1
X1
X3
2
X2
X3
R1
R2
Conditions
Yield (%) Ref
>98
[17]
O
O
C=O
CH2 H
H
rt, 2 h
O
O
CH(OAc)
CH2 H
H
rt, 24 h
O
O
CH2
CH2 H
H
reflux, 24 h >98
[17]
NTs
C=O
CH2 H
H
rt, 2 h
95
[17]
NTs
CH2
CH2 H
H
rt, 48 h
>98
[17]
NTs
CH2
NTs H
H
rt, 30 h
84
[17]
97a
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
[17]
3.4.1
147
[2 + 2 + 2]-Carbocyclization Reactions
X1
X2
X3
R1
R2
Conditions
Yield (%) Ref
O
CH2
O
H
H
rt, 15 h
>98
[17]
NTs
CH2
NTs Me H
rt, 2 h
>98
[17]
NTs
CH2
NTs Me Me 60 8C, 24 h
40
[17]
a
Isolated as a single product.
3a¢,4¢,5¢,5a¢,6¢,7¢-Hexahydro-1¢H-spiro[1,3-dioxane-2,2¢-as-indacen]-8¢(3¢H)-one (2, X1 = 1,3Dioxane-2,2-diyl; X2 = C=O; X3 = CH2; R1 = H; R2 = H); Typical Procedure:[17]
A soln of dienyne 1 (X1 = 1,3-dioxane-2,2-diyl; X2 = C=O; X3 = CH2; R1 = H; R2 = H; 80.1 mg, 0.29 mmol) and Ru(Cp*)Cl(cod) (5.5 mg, 0.014 mmol) in toluene (9.5 mL) was stirred at rt for 2 h under argon. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/EtOAc 5:1) to give a colorless oil; yield: 80.4 mg (>98%). 3.4.1.2
Cobalt(I)-Mediated [2 + 2 + 2] Carbocyclizations
Cobalt complexes have proved to be versatile reagents for several carbocyclization reactions, which facilitate the selective formation of multiple C—C in a single chemical step. For instance, the cobalt(I)-catalyzed [2 + 2 + 2]-carbocyclization reaction is an expedient method for the preparation of six-membered ring systems, such as benzenes, pyridines, and cyclohexadienes from alkynes, nitriles, and alkenes, respectively.[3–16] The mechanism for such reactions has been studied with density functional theory (DFT).[18,19] Numerous applications have been reported, mainly by Vollhardt, who has utilized this chemistry in a number of very elegant and efficient total syntheses of natural products and compounds of theoretical interest.[20] Among the cyclopentadienyl catalysts, the complexes with carbonyl, cyclooctadiene, and ethene ligands [CoCp(CO)2, CoCp(cod), and CoCp(H2C=CH2)2] are probably the most widely used for mediating cocyclizations of unsaturated substrates, often with high levels of chemo-, regio-, and stereoselectivity; see Science of Synthesis, Vol. 1 [Compounds with Transition Metal—Carbonyl -Bonds and Compounds of Groups 10–8 (Ni, Pd, Pt, Co, Rh, Ir, Fe, Ru, Os) (Section 1.4)]. Recently, new easyto-handle air-stable complexes of the type alkene(carbonyl)(Å5-cyclopentadienyl)cobalt(I) have been developed, which efficiently catalyze various [2 + 2 + 2]-carbocyclization reactions.[21] Cobalt-mediated [2 + 2 + 2] cocyclization is a vast field of investigation despite the fact that there is a paucity of studies focused on enantioselective reactions. 3.4.1.2.1
Control of Diastereoselectivity
3.4.1.2.1.1
Cocyclization of Alkynylboronates and Alkenes
Pinacol alkynylboronates such as 3 provide valuable partners for cobalt-mediated [2 + 2 + 2] carbocyclizations with alkenes, which afford 1,3- and 1,4-diborylcyclohexa-1,3-dienes. For example, the reactions are generally carried out with 2 equivalents of pinacol alkynylboronic esters and 1 equivalent of alkene using (Å5-cyclopentadienyl)bis(ethene)cobalt(I). With symmetrical monocyclic alkenes (e.g., 2,5-dihydrofuran, cyclopentene, and cyclohexene), the reactions proceed regioselectively with very good overall yields and with moderate to excellent stereoselectivity in favor of the endo-diastereomer endo-4.[22] Unsymmetrical cyclic alkenes (e.g., indene, cyclopent-2-enone, cyclohex-2-enone, and 2,3-dihydrofuran) furnish endo-diastereomers as the major product. The air- and heat-sensitive dienes, e.g. 5, are then liberated through rapid oxidative demetalation using iron(III) chloride hexahydrate in acetonitrile (Scheme 2). The resulting metal-free cyclohexadienes may then be used in Suzuki–Miyaura cross-coupling reactions, as in the preparation of 6.[23] [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
[m + n + 2]-Carbocyclization Reactions
3.4
Scheme 2 Cobalt(I)-Mediated [2 + 2 + 2] Carbocyclization of a Pinacol Alkynylboronate and Cyclic Alkenes[22,23]
O CoCp(H2C=CH2)2 (1 equiv) THF, −40 oC to rt
O
O B
(Cp)Co Ph
O B
X
+
X O
B O
Ph
Ph 3
exo-4
O (Cp)Co Ph
O
O
B FeCl3•6H2O MeCN, rt, 1 min
+
O B
Ph
X O
X O
B O
B O
Ph
Ph 5
endo-4
X
Ratio (exo-4/endo-4) Yield (%) of 4 Yield (%) of 5 Ref
O
1:3.6
88
69
[22]
CH2
1:1.9
86
–
[22]
(CH2)2 1:20
70
–
[22]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.1
149
[2 + 2 + 2]-Carbocyclization Reactions
O
O B
CoCp(H2C=CH2)2 (1 equiv) THF, −40 oC to rt, 4 h
+
78%
Ph 3
O (Cp)Co Ph O
O
O
B +
(Cp)Co Ph
B
B O
Ph
Ph
1:2.1
exo
FeCl3•6H2O MeCN, rt, 1 min 86%
O
O
O B
endo
OMe I
MeO
O
O B
Ph
10 mol% Pd[P(t-Bu)3]2 NaOH (5 equiv) THF/H2O, 60 oC, 24 h
Ph
77%
O
O
B O
Ph
B O
Ph 6
A range of alkenes can take part in these cyclizations, although some acyclic electron-deficient alkenes decompose under the reaction conditions. Other terminal and internal alkenes provide interesting regio- and stereoselectivities. For example, styrene generates 8 (R1 = Ph) in 50% isolated yield and with complete chemo-, regio-, and endo-diastereoselectivity. Trimethyl(vinyl)silane and tributyl(vinyl)stannane also lead to the formation of 8 in which the substituted ethene carbon is adjacent to the boron-bearing terminus, but favoring the exo-isomer (Scheme 3).[22,23]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Scheme 3 Cobalt(I)-Mediated [2 + 2 + 2] Carbocyclization of a Pinacol Alkynylboronate and Acyclic Alkenes[22,23]
O
O B
CoCp(H2C=CH2)2 (1 equiv) THF, −40 oC to rt
R1 +
Ph 3
O
O B
O
(Cp)Co
+ B O
Ph
8
R1
Product Ratio
Yield (%) Ref
Ph
endo-8 only
50
[22]
Ot-Bu
exo-8 only
65
[23]
OTHP
(exo-7/exo-8) 1:2.5 69
[23]
O
(exo-8/exo-9) 1:1.2 62
[23]
TMS
(exo-8/exo-9) 2.8:1 68
[23]
SnBu3
(exo-8/exo-9) 3.1:1 45
[23]
O B
+
Ph (Cp)Co O B
O
7
B
O R1
Ph (Cp)Co O B
Ph O
O B
R1
Ph
R1
O
Ph
9
O
(Å5-Cyclopentadienyl)[2,2¢-(2,4,6-triphenylcyclohexa-1,3-diene-1,3-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)]cobalt(I) (8, R1 = Ph); Typical Procedure:[22]
CoCp(H2C=CH2)2 (360 mg, 2 mmol) was dissolved in THF (8 mL), and neat styrene (1.04 g, 10 mmol, 5 equiv) was added. The mixture was allowed to stir for 4 h at rt, and then cooled to –40 8C as the alkyne 3 (912 mg, 4 mmol) in THF (2 mL) was transferred into it by means of a cannula. The cold bath was removed and the mixture was stirred at rt for 4 h before the solvent was removed using a rotary evaporator. The residue was purified by flash column chromatography [silica gel, pentane/Et2O (deep red bands)] to afford a red solid; yield: 684 mg (50%). 3.4.1.2.1.2
Cocyclization of Diynes and Alkenes
Cobalt-mediated [2 + 2 + 2] carbocyclizations of 1,6- and 1,7-diynes with pyrimidine derivatives afford (Å5-cyclopentadienyl)cobalt-complexed tricyclic quinazolines, as exemplified by the formation of 10 (n = 1; X = O).[24] Alternatively, the 2,3-double bond of indoles undergoes the analogous reaction to provide (Å5-cyclopentadienyl)cobalt-complexed dihydrocarbazoles 11 (Scheme 4).[25] [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.1
151
[2 + 2 + 2]-Carbocyclization Reactions
Cobalt(I)-Mediated [2 + 2 + 2] Carbocyclization of Diynes and Cyclic Alkenes[24,25]
Scheme 4
X NMe
+ N Me
n
X
(Cp)Co
CoCp(CO)2, hν
NMe
toluene or xylenes, reflux
O
N Me
n
O
10
n X
Yield (%) Ref
1 O
53
[24]
2 O
76
[24]
2 NMe 79
[24]
R
CoCp(H2C=CH2)2 (1 equiv) THF, 65−70 oC, 45−60 min
1
(Cp)Co
R1
+ N
n
N
n
R2
R2 11
n R1
R2
Ratio (exo/endo) Yield (%) Ref
2 H
Ac
4:1
65
[25]
1 TMS SO2Ph 1:0
36
[25]
Diborylated diynes also participate in bimolecular carbocyclizations to provide fused systems using various cyclic alkenes, such as cyclopentenone, 2,5-dihydrofuran, or other heterocycles containing a suitable double bond. These substrates enforce the 1,4-orientation of the boryl substituents in the resulting diene and thereby allowed the construction of the first polycyclic 1,4-diborylcyclohexa-1,3-diene derivatives. For example, these reactions provide the polycyclic adducts 12 and 13, in moderate to good yield with high stereoselectivity (Scheme 5).[22,23] Scheme 5 Cobalt(I)-Mediated [2 + 2 + 2] Carbocyclization of Diboryldiynes and Cyclic Alkenes[22,23]
O
O B
CoCp(H2C=CH2)2 (1 equiv) THF, −40 oC to rt
O + O
O
(Cp)Co
O B O
80%; (endo/exo) 9:1
B O
B O
O
12
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Stereoselective Synthesis
3.4
O
O
O
B
CoCp(H2C=CH2)2 (1 equiv) THF, −40 oC to rt
O +
TsN O
[m + n + 2]-Carbocyclization Reactions
52%
(Cp)Co
O
TsN
B O
O B
B O
O
13
(Å5-Cyclopentadienyl)[(5,5a,8a,9-Å)-1,3-dimethyl-endo-6,7,8,9a-tetrahydro-1H-cyclopenta[g]quinazoline-2,4(3H,4aH)-dione]cobalt(I) (10, n = 1; X = O); Typical Procedure:[24]
1,3-Dimethyldihydropyrimidine-2,4(1H,3H)-dione (0.145 g, 1.035 mmol) was dissolved in toluene (10 mL) contained in a 50-mL round-bottomed flask equipped with a coil condenser. This mixture was degassed under N2 by three freeze–pump–thaw cycles on a vacuum line, and then allowed to warm to rt. Hepta-1,6-diyne (0.191 g, 2.07 mmol) was dissolved in toluene (7 mL) and degassed as before, and then CoCp(CO)2 (0.373 g, 2.07 mmol) was added by means of a syringe. The resulting soln was loaded into a 10-mL gastight syringe and added to the pyrimidinedione soln by means of a syringe pump over 19 h. During the addition, the flask was irradiated with a slide-projector lamp (Sylvania ELH 300 W) at a distance of 5 cm from the center of the flask with an applied potential of 65 V, while its contents were refluxed. The mixture was then cooled to rt and the black soln was filtered through a short pad of Celite and rinsed with toluene until the filtrate was clear. The solvent was then removed from the combined filtrate and washings under reduced pressure, and the residue was purified by flash chromatography (silica gel, hexanes/Et2O 1:4) to afford orange crystals; yield: 0.194 g (53%). 3.4.1.2.1.3
Cocyclization of Yne-Heterocycles with Alkynes
Formal bimolecular carbocyclizations between enynes and alkynes produce polycyclic compounds with high selectivity. The C=C bonds in heteroaromatic compounds provide excellent cocyclization partners, as exemplified by furans,[26] benzofurans,[27] thiophenes,[26] indoles,[25,28] pyrroles,[29] imidazoles,[30] pyrimidines,[24,31] pyridinones, and pyrazinones.[32] For instance, the cocyclization of the N-but-3-ynylpyridinone 14 (n = 1) with bis(trimethylsilyl)acetylene in the presence of (Å5-cyclopentadienyl)bis(ethene)cobalt(I) furnishes the (Å5-cyclopentadienyl)cobalt-complexed tricycle 15 in moderate yield via a chemo-, regio-, and diastereoselective [2 + 2 + 2] carbocyclization. The length of the tether attached to N1 of the heterocycle is important, since in the case of the homologue 14 (n = 2) the formation of the (Å5-cyclopentadienyl)cobalt-complexed 1,3-diene 16 rather than the tricyclic derivative is observed.[32] which was rationalized using DFT calculations.[33] In a related process, the carbocyclization of N-alkynylated uracil derivatives 17 with simple alkynes affords modified nucleosides 18, when the reaction mixtures are irradiated with light,[24,31] whereas 4a,9a-dihydro-9H-carbazoles 20 can be formed from 1-(pent-4ynoyl)indoles 19 under thermal conditions.[28] The complex (Å5-cyclopentadienyl)bis(ethene)cobalt(I) also facilitates the [2 + 2 + 2] carbocyclization of alkynylboronates to 1-(pent-4-ynoyl)-1H-indole (21) to furnish the heterocycle-fused borylcyclohexadienes 22 in a regioselective manner, with the isomer 23 being formed as a minor product in some cases (Scheme 6).[34]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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[2 + 2 + 2]-Carbocyclization Reactions
Scheme 6 Cobalt(I)-Mediated [2 + 2 + 2] Carbocyclization of Enynes and Cyclic Alkenes[24,28,31–34] H
TMS TMS Co(Cp)
O TMS O
N
CoCp(H2C=CH2)2 (1 equiv) THF, rt
H 15
+
N
TMS
TMS
n
TMS
14 O
N
Co(Cp) 16
n Product Yield (%) Ref 1 15
35
[32]
2 16
85
[32]
O R1
R2
N
O
CoCp(CO)2, THF, hν
+ N
R2
17 O R1
H
R2
N
O
N
H
O
H
R2
N
R2 Co(Cp)
N
H exo-18
Ratio (endo/exo) Yield (%) Ref
Bz CO2Me 0:1
61
[24,31]
H
73
[24,31]
CO2Me 0:1
Bz TMS
1:5
23
[24,31]
H
1:10
35
[24,31]
TMS
R1
Co(Cp) +
endo-18
R1 R2
O R2
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
154
Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
R1 TMS CoCp(H2C=CH2)2, THF, rt
+
N
R2
O 19
R2
TMS R1
R2
TMS R1
Co(Cp)
Co(Cp)
+ N
N
H
O
O
endo-20
exo-20
R1
R2
H
TMS 1:0
64
[28]
(CH2)2OTBDMS
OMe 1:0
50
[28]
Ratio (endo/exo) Yield (%) Ref
O
1. CoCp(H2C=CH2)2,THF, rt, 3 h 2. Fe(NO3)3•9H2O, THF/H2O (3:1) 0 oC, 5 min
O B
+
N
H
O R1
21
O
O R1
O B H
B O
R1 H +
N O 22
R1
H
N
H
O 23
Ratio (22/23) Yield (%) Ref
iPr
1:0
58
[34]
(CH2)5Me
1:0
42
[34]
CH2OTHP
1:0
52
[34]
TMS
77:23
29
[34]
Ph
54:46
53
[34]
This methodology has inspired a novel approach to the galanthan alkaloid core, as exemplified by anhydrolycorinone (26). The cobalt-mediated [2 + 2 + 2] carbocyclization of N-alkynylated isoquinolinone 24 with bis(trimethylsilyl)acetylene furnishes the (Å5-cyclopentadienyl)cobalt-complexed pentacycles exo-25 and endo-25 as a 2:1 ratio (in 57% yield). Removal of the two silyl groups with fluoride followed by oxidative demetalation affords an[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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155
[2 + 2 + 2]-Carbocyclization Reactions
hydrolycorinone.[32] The carbocyclization of the benzofuran nucleus with alkynes provides a novel strategy toward the morphinoids. Chemo- and diastereoselective cocyclization of the enynes 27 with bis(trimethylsilyl)acetylene affords the tetracycles 28 as the cobalt complexes.[27] A convergent total synthesis of racemic strychnine (30), involving cobalt-mediated [2 + 2 + 2] carbocyclization of an alkynylindole nucleus 29 to acetylene, has also been achieved (Scheme 7).[35] Scheme 7 Cobalt(I)-Mediated [2 + 2 + 2] Carbocyclization as a Key Step for the Syntheses of Anhydrolycorinone, Morphinoids, and Strychnine[27,32,35] TMS TMS TMS O
O
rt
+
N
O
57%; (exo/endo) 2:1
N
O
TMS
O
Co(Cp)
H
CoCp(H2C=CH2)2
H
O exo-25
24 TMS TMS H
Co(Cp)
O
1. TBAF, THF, rt 2. Fe(NO3)3•9H2O
O
THF/H2O, rt
+
N
O
H
41%
N
O O
O endo-25
26
X
anhydrolycorinone
H X TMS + O
CoCp(H2C=CH2) Et2O, 0 oC, 0.5 h
Co(Cp) TMS
H
TMS MeO
O
H
TMS
OMe 28
27
X
Yield (%) Ref
OH
63
[27]
OTMS 53
[27]
NH2
[27]
66
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
156
Stereoselective Synthesis
NHAc
[m + n + 2]-Carbocyclization Reactions
3.4
NHAc CoCp(H2C=CH2)2 HC≡CH, THF, 0oC
N
Co(Cp)
47%
N
O
H
O
29 NH2 30% KOH H2O/MeOH, reflux
Co(Cp)
93%
N
Fe(NO3)3•9H2O MeCN/THF/H2O, 0 oC 77%
H
O
NH
N H
N
N
H
O
O 30
H
O H
(+ −)-strychnine
2-Isopropyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,11b,11c-tetrahydro6H-pyrido[3,2,1-jk]carbazol-6-one (22, R1 = iPr); Typical Procedure:[34]
To a degassed soln of 1-(pent-4-ynoyl)-1H-indole (21; 197 mg, 1 mmol) and 4,4,5,5-tetramethyl-2-(3-methylbut-1-ynyl)-1,3,2-dioxaborolane (242 mg, 1.25 mmol) in THF (15 mL) at 0 8C under argon was added CoCp(H2C=CH2)2 (150 mg, 0.833 mmol) in degassed THF (6 mL) over 3 h via syringe pump. The ensuing dark red soln was treated with bright yellow Fe(NO3)3•9H2O (337 mg, 0.834 mmol) in THF/H2O (3:1; 5 mL). After being stirred for 5 min at 0 8C, the brown mixture was poured into iced H2O (50 mL) and the soln was extracted with CH2Cl2 (3 100 mL), followed by sat. aq NaHCO3 (3 150 mL). The extracts were dried (MgSO4), filtered through a short silica gel column to give a red-orange foam, and then subjected to flash column chromatography (silica gel, hexanes/acetone 9:1) to yield a white solid; yield: 189 mg (58%); mp 91–92 8C. 3.4.1.2.1.4
Intramolecular Carbocyclization of Enediynes
Cobalt complexes can also be used to trigger intramolecular [2 + 2 + 2] carbocyclization of linear achiral enediynes with a terminal double bond to afford (Å5-cyclopentadienyl)cobalt(I)-complexed polycyclic fused cyclohexa-1,3-dienes with a pronounced chemo-, regio-, and stereoselectivity, depending on the substitution of the unsaturated groups.[36–39] The level of the exo/endo diastereoselectivity is improved by substituting the terminal position of the triple or the double bond partner with an ester, phosphine oxide, or sulfoxide group.[40,41] The chiral phosphine oxide substituted linear enediynes provide good diastereoselectivities (up to 74% de), depending on the substituents on the phosphorus atom.[41] For instance, cyclization of enediynes 31 catalyzed either by dicarbonyl(Å5-cyclopentadienyl)cobalt(I),[36–39] or (Å5-cyclopentadienyl)bis(ethene)cobalt(I),[39] furnish the desired (Å5-cyclopentadienyl)cobalt-complexed tricyclic dienes 32 containing hydrocyclobutaindane, hydrocyclobutanaphthalene, hydrocyclopentanaphthalene, hydrodicyclopentabenzene, and hydrophenanthrene frameworks (Scheme 8).
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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[2 + 2 + 2]-Carbocyclization Reactions Cobalt(I)-Mediated Intramolecular Cyclizations of Enediynes[36–43]
Scheme 8
(Cp)Co
R2 X
X
n
R1
(Cp)Co
n
R2
R3
+
n
R2
X
R3
R3
R1 31
R1
endo-32
X
R1
R2
R3
n Conditions
CH2
H
H
H
1 CoCp(H2C=CH2)2, THF, rt, 1 h
(CH2)2 H
H
H
(CH2)2 TMS
H
(CH2)2 H O
exo-32
Yield (%)
Ref
–
90
[39]
1 CoCp(H2C=CH2)2, THF, rt, 1 h
–
92
[39]
H
2 CoCp(CO)2, isooctane, reflux, 4–5 d
1:0
85
[36,37]
H
H
2 CoCp(CO)2, isooctane, reflux, 4–5 d
1:1
65
[36,37]
TMS
H
H
2 CoCp(CO)2, isooctane, reflux, 4–5 d
1:0
35
[36,37]
(CH2)2 TMS
H
H
3 CoCp(CO)2, isooctane, reflux, 4–5 d
1:1
93
[36,37]
(CH2)2 CO2Me
H
H
2 CoCp(CO)2, toluene, h, reflux
1.17:1
78
[42]
(CH2)2 CO2Me
H
H
3 CoCp(CO)2, toluene, h, reflux
3:2
94
[40,42]
(CH2)2 P(O)Ph2
H
H
3 CoCp(CO)2, toluene, h, reflux
3:1
96
[40,42]
(CH2)2 S(O)4-Tol
H
H
3 CoCp(CO)2, toluene, h, reflux
3:1
31
[40,42]
(CH2)2 H
H
CO2Et
2 CoCp(CO)2, decane, reflux, overnight
1:3.6
62
[42]
(CH2)2 H
H
CO2Et
3 CoCp(CO)2, toluene, h, reflux
1:6.1
71
[40,42]
(CH2)2 H
Me P(O)Ph2 3 CoCp(CO)2, toluene, h, reflux
0:1
32
[40]
(CH2)2 P(O)(Me)t-Bu
H
2.4:1a
>99
[41]
a
H
3 CoCp(CO)2, THF, h, reflux, 1 h
Ratio (exo/ endo) (de)
exo-32: 74% de; endo-32: 72% de.
These efficient and stereoselective transformations have been successfully used for the construction of steroid derivatives.[44] Intramolecular cyclization of enediyne 33 provides cobalt complex 34 in good yield.[37,45] Alternatively, enediyne 36 containing a stereogenic center gives the desired steroid 38 with a remarkable diastereoselectivity. Although there are four possible products, cycloadduct 37 is formed in 72% yield, in addition to the 17Æisomer (20%).[46] These transformations correspond to a one-step construction of the BCD framework of steroids from an A-ring precursor (Scheme 9). Oxidative demetalation using iron(III) chloride, and deprotection of the dioxolane and the methoxymethyl ether from 34 and 37, respectively, results in the isomerization of the endocyclic 1,3-dienes to the heteroannular 1,3-dienes 35 and 38, which are known intermediates in the Torgov synthesis of estrone and estradiol methyl ether, respectively. [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
158
Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Scheme 9 Cobalt(I)-Mediated Intramolecular Cyclizations of Enediynes of as a Key Step in the Syntheses of Estrone and Estradiol Methyl Ether[37,45,46]
O
O
O
O
CoCp(CO)2 isooctane, reflux 65%
Co(Cp) MeO
MeO 33
34
O
O
FeCl3•6H2O MeCN, 0 oC, 1 h
TsOH THF/H2O, 23 h
78%
95%
MeO
O
MeO 35 TMS
OMOM
CoCp(CO)2
TMS
m-xylene hν, reflux 72%
MeO
Co(Cp) MeO
OMOM 36
37 OH FeCl3, Et3N, HCl MeCN, 0 oC, 0.5 h 82%
MeO 38
Although methylenecyclopropanes and bicyclopropylidenes are very useful intermediates in organic synthesis, studies have demonstrated that they behave as simple alkenes without participation of the cyclopropyl units in [2 + 2 + 2] reactions.[47] For instance, irradiation of the enediyne 39, which has an electron-withdrawing group at the terminal alkyne, in the presence of a stoichiometric amount of dicarbonyl(Å5-cyclopentadienyl)cobalt(I), affords an inseparable mixture of the diastereomeric spirocyclopropanated compounds 40 in excellent yield (Scheme 10).
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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[2 + 2 + 2]-Carbocyclization Reactions
Scheme 10 Cobalt(I)-Mediated Intramolecular Cyclizations of (Methylenecyclopropyl)diynes[47] R2 R3
R5 R
CoCp(CO)2 (1 equiv)
(Cp)Co
R5
THF, hν, 66 oC
4
R1
R4 R3 R2
R1 40
39
R1
R2
R3
R4
R5 dr
Yield (%) Ref
CO2Me
(CH2)2
CH2
1:0 42
[47]
P(O)Ph2
(CH2)2
CH2
1.5:1 94
[47]
H
H
CH2
1:0 31
[47]
P(O)Ph2 H
H
CH2
2.1:0 85
[47]
CO2Me CO2Me
(CH2)2
H
H
1:0 47
[47]
P(O)Ph2
(CH2)2
H
H
1.8:0 91
[47]
A variety of substituted enediynes with internal double bonds have also been subjected to intramolecular [2 + 2 + 2] carbocyclization in the presence of stoichiometric amounts of cobalt to afford Å4-complexed polycyclic fused cyclohexa-1,3-dienes. The reaction proceeds efficiently with complete stereospecificity with respect to the original double bond geometry and remarkable exo/endo diastereoselectivity relative to the cobalt center. For example, the cycloadducts 42 and 44 are prepared by the intramolecular reaction of the Z- and E-enediynes 41 and 43, respectively, using dicarbonyl(Å5-cyclopentadienyl)cobalt(I) in conjunction with heat and light in toluene or m-xylene (Schemes 11 and 12). The endo/ exo selectivity depends on the position of the substituents in the enediyne and the presence of ester or phosphine oxide groups.[42,43,48] Moreover, the reaction allows the one-step construction of a tricyclic diene containing two adjacent quaternary carbons. Indeed, unlike many carbocyclization reactions, the steric hindrance of the double bond has little influence on the successful outcome of the reaction.[49] This strategy has provided the basis of an approach to the provitamin D nucleus.[44,50]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Scheme 11 Cobalt(I)-Mediated Intramolecular Cyclizations of Enediynes with Internal Z-Double Bonds[42,43,48,49] CoCp(CO)2
R1
n
(Cp)Co
toluene or m-xylene hν, reflux
R2
m
(Cp)Co n
n
R1 R2
R1 R2
+
R3
R3 m
R3 41
m
endo-42
R1
R2
R3
n m Ratio (endo/exo) Yield (%) Ref
H
H
H
3 3
0:1
63
[48]
H
H
H
3 2
0:1
65
[48]
Me H
H
3 3
1:0
74
[48]
Me Me H
3 3
1:0
60
[49]
H
H
CO2Me
3 3
1:0
65
[42]
H
H
P(O)Ph2 3 3
1:0
77
[43]
exo-42
Scheme 12 Cobalt(I)-Mediated Intramolecular Cyclizations of Enediynes with Internal E-Double Bonds[48]
n
R1
CoCp(CO)2
(Cp)Co
toluene or m-xylene hν, reflux
(Cp)Co n
n 1
R H
m
R1 H
+
m
m
43
endo-44
R1
n m Ratio (endo/exo) Yield (%) Ref
H
3 3
Me 3 3
–
63
[48]
3:1
76
[48]
exo-44
(Tricyclo[6.3.0.02,5]undeca-1,7-diene)(Å5-cyclopentadienyl)cobalt(I) (32, X = CH2; R1 = R2 = R3 = H; n = 1); Typical Procedure:[39]
To a soln of undec-10-ene-1,6-diyne (31, X = CH2; R1 = R2 = R3 = H; n = 1; 82.5 mg, 0.564 mmol) in freshly distilled THF (5 mL) at rt was added, via cannula, a soln of CoCp(H2C=CH2)2 (99.4 mg, 0.564 mmol) in freshly distilled THF (5 mL). The resulting mixture was stirred for 1 h, the volatiles were removed under reduced pressure, and the residue was chromatographed [alumina (activity 3), degassed hexanes] under N2. A fast-moving red band gave 32, which was crystallized (hexane) to give the title compound as red plates; yield: 137 mg (90%). (Å5-Cyclopentadienyl)[Å4-(13S)-exo-3-methoxy-13-methyl-6,7,12,13,15,16-hexahydrospiro[cyclopenta[a]phenanthrene-17,2¢-[1,3]dioxolane]cobalt(I) (34), Typical Procedure:[37]
To a degassed soln of enediyne 33 (37 mg, 0.114 mmol) in degassed isooctane (5 mL) in a dry 10-mL pear-shaped flask equipped with a stirrer bar was added CoCp(CO)2 (0.045 mL, 0.36 mmol). This excess is recommended in small-scale preparations. On a larger scale (0.5 g) typically only 10% excess Co has to be used. After 46 h of heating at reflux, all starting material had been consumed, as determined by TLC (silica gel). The solvent and excess CoCp(CO)2 were removed, first in a N2 stream and then by exposure to high vacuum for [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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[2 + 2 + 2]-Carbocyclization Reactions
0.5 h. The reddish-brown residue was dissolved in Et2O/petroleum ether (5:95) and chromatographed [alumina (activity 3), Et2O/petroleum ether 5:95], yielded a fraction containing some residual CoCp(CO)2. Elution with Et2O/petroleum ether (1:4) gave the title compound as orange crystals; yield: 35 mg (65%); mp 108–110 8C. Cyclopropane-Fused and Spirocyclopropanated (1,2,3,3a,4,6,7,8-Octahydro-as-indacene)–(Å5-Cyclopentadienyl)cobalt(I) Complexes 40; General Procedure:[47]
A soln of the enediyne 39 (0.25 mmol) in dry THF (5 mL) in a round-bottomed flask equipped with a reflux condenser, which had been passivated with (TMS)2NH, was carefully deoxygenated by three freeze–pump–thaw cycles and heated under reflux. Then, CoCp(CO)2 (30 L, 250 mol) was added, and the mixture was irradiated by means of a projector lamp (General Electric GE ELH 120 V/300 W, 80% of its power) until the starting material had been consumed [monitored by TLC (silica gel)]. Subsequently, the mixture was cooled to rt and the solvent was removed by vacuum transfer. The residue was purified by column chromatography. 3.4.1.2.1.5
Intramolecular Carbocyclization of Diynals and Diynones
Aldehydes and ketones also undergo cocyclization with alkynes in an inter- and intramolecular manner using stoichiometric dicarbonyl(Å5-cyclopentadienyl)cobalt(I) and (Å5-cyclopentadienyl)bis(ethene)cobalt(I) to provide the complexed bi- and tricyclic-2H-pyrans (Scheme 13). Although the ketones provide the expected [2 + 2 + 2] cycloadducts, e.g. 45, the aldehydes provide lower yields in addition to unsaturated carbonyl isomers, e.g. 46, which are derived from electrocyclic ring opening and isomerization, in many cases.[51,52] Scheme 13 Cobalt(I)-Mediated Intramolecular Cyclizations of Diynals and Diynones[51,52] CoCp(CO)2 toluene, hν 110 oC, 5−14 h
n
R
(Cp)Co n
1
O
R1
O
R1
n
H
1
5
[52]
H
2
25
[52]
Me 1
69
[52]
Me 2
57
[52]
Yield (%) Ref
O
TMS +
Co(Cp) CoCp(H2C=CH2)2 23 oC, 4−6 h
TMS
86%
O
TMS
TMS
45
O
TMS
CoCp(H2C=CH2)2
TMS
(Cp)Co
23 oC, 4−6 h
H
+
TMS
18%
O
TMS 46
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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162
Stereoselective Synthesis
3.4.1.2.1.6
Intramolecular Carbocyclization of Allenediynes
3.4
[m + n + 2]-Carbocyclization Reactions
Allenes provide important substrates for transition-metal-catalyzed carbocyclization reactions, given their inherent reactivity and the ability to relay stereochemical information. Although allenes are reactive -components, only a few examples of [2 + 2 + 2] carbocyclizations using this type of group have been reported.[53–59] Nevertheless, allenes have been utilized in intramolecular [2 + 2 + 2]-carbocyclization reactions.[55,56] Although the reaction is chemo- and regioselective, the cyclization of allene–diyne compounds provide moderate to low diastereoselectivities. Å4-Complexed tricyclic compounds are obtained in moderate to good yield as endo/exo mixtures of diastereomers that are independent of the substitution on the allene. For example, allenediyne 47 (R1 = Me; R2 = H), with a tetrasubstituted internal allene, furnishes the corresponding Å4-complexed tricyclic compound 48 (R1 = Me; R2 = H) in 42% yield, in a chemo and regioselective manner, albeit as a 7:3 diastereomeric mixture.[56,57,59] Additionally, the cyclization is also compatible with oxygen-functionality on the allene 47 (R1 = Ph; R2 = OMe) (Scheme 14). Scheme 14 Cobalt(I)-Mediated [2 + 2 + 2] Intramolecular Carbocyclization of Allenediynes[56,59] R1
•
R1
CoCp(CO)2 xylenes, hν heat
R1
+
R2 R2 47
Co(Cp) endo-48
R1
R2
Ratio (endo/exo) Yield (%) Ref
Me
H
70:30
42
[56]
Ph
H
55:45
60
[59]
4-F3CC6H4
H
53:47
65
[59]
4-MeOC6H4 H
61:39
62
[59]
OMe 65:35
62
[59]
Ph
R2
Co(Cp) exo-48
This strategy has been extended to the synthesis of 11-aryl steroid frameworks. The tetracyclic complex 51 is prepared via the intramolecular [2 + 2 + 2] carbocyclization of allenediyne 49, which has a preexisting D-ring. This process constructs the ABC ring system, which is substituted at C10 and C11 in a single step. For example, treatment of the allenediyne 49 in the presence of a stoichiometric amount of the cobalt(I) mediator furnishes the expected fused tetracyclic complex 50 in 60% yield as a single diastereomer. The free skeleton 51 can be readily obtained in 90% yield upon the treatment of the (Å5-cyclopentadienyl)cobalt complex with silica gel. Based on this observation, the cyclization and decomplexation sequence have been carried out without purifying the complex, to furnish the 11-aryl steroid skeleton in 48% overall yield (Scheme 15).[58,59]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Scheme 15 Cobalt(I)-Mediated [2 + 2 + 2] Intramolecular Carbocyclization of an Allenediyne that Incorporates a Five-Membered Ring[58,59] Ph
O
O
Ph CoCp(CO)2 (1.2 equiv) xylenes, hν, heat
•
60%
Co(Cp) 49
50
O Ph silica gel, CH2Cl2 90%
51
(Å5-Cyclopentadienyl)(1,2,3,4,4a,6,7,8-octahydrophenanthrene)cobalt(I) Complexes 48; General Procedure:[56,59]
CoCp(CO)2 (1.2 equiv) was added to a boiling soln of allenediyne 47 (1 equiv) in xylenes degassed by three freeze–pump–thaw cycles, and the mixture was irradiated with light from a projector lamp (ELW, 300 W, 50% of its power). The reaction was monitored by TLC and after completion, the mixture was concentrated under reduced pressure. The crude oil was purified by flash column chromatography (the chromatography solvents were not degassed) either on deactivated alumina (petroleum ether/H2O 97:3) or on silica gel neutralized with Et3N and dried (petroleum ether/Et2O 95:5) to furnish cycloadduct 47 as an inseparable endo/exo mixture. 10,13-Dimethyl-11-phenyl-3,4,10,12,13,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17(2H)-one (51); Typical Procedure:[58,59]
CoCp(CO)2 (25 L, 0.19 mmol, 1.2 equiv) was added to a boiling soln of allenediyne 49 (54 mg, 0.16 mmol) in xylenes (10 mL) degassed by three freeze–pump–thaw cycles, and the mixture was irradiated with light from projector lamp (ELW, 300 W, 50% of its power). The reaction was monitored by TLC, and after completion, the mixture was concentrated under reduced pressure. The crude oil was purified by flash column chromatography [silica gel (neutralized with Et3N and dried), petroleum ether/Et2O 9:1; the chromatography solvents were not degassed] to give the cycloadduct 50 as a red solid; yield: 45 mg (60%); mp 68–70 8C. A soln of complex 50 (80 mg, 0.17 mmol) in CH2Cl2 (5 mL) was stirred in the presence of silica gel at rt. The reaction was monitored by TLC and after completion, the mixture was filtered, and furnished 11-aryl steroid skeleton 51; yield: 52 mg (90%). 3.4.1.2.1.7
Intramolecular Cyclotrimerization of Chiral Triynes
Enantiomerically enriched helicenes have attracted significant interest as challenging targets, due to their unique nonplanar aromatic structure and intrinsic helical chirality. The intramolecular [2 + 2 + 2] carbocyclization of triyne systems provides a very convenient method for the construction of [5]-, [6]-, and [7]-helicene-like molecules.[60–62] The P versus M helicity of the compounds can be controlled by an enantiopure carbon stereocenter present in the triyne precursor, which translates central-to-helical chirality. For example, a stoichiometric amount of dicarbonyl(Å5-cyclopentadienyl)cobalt(I)/triphenylphosphine (1:2) mediates the cyclotrimerization of the triynes 52, 54, and 56, with [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
4-tolyl groups at the alkyne termini, into the corresponding helicenes 53, 55, and 57 with good to excellent diastereoselectivities for a limited number of examples (Scheme 16).[62–64] Cobalt(I)-Mediated [2 + 2 + 2] Intramolecular Cyclotrimerization of Triynes[62–64]
Scheme 16
4-Tol O
MeO
O CoCp(CO)2 (1 equiv) Ph3P (2 equiv) decane, hν, 140 oC, 4 h
4-Tol MeO
R1
R1
(−)-(1S)-52
(+)-(P,1S)-53
R1
Ratio [(M,1S)/(P,1S)] Yield (%) Ref
H
10:90
56
[64]
9:91
89
[64]
OMe
OMe 4-Tol O
O CoCp(CO)2 (1 equiv) Ph3P (2 equiv) dioxane, hν, 120 oC, 36 h
4-Tol MeO
50%; [(M,1S)/(P,1S)] 1:9
(−)-(1S)-54
(+)-(P,1S)-55
4-Tol O
O CoCp(CO)2 (1 equiv) Ph3P (2 equiv)
4-Tol
dioxane, 95−120 oC, 63−70 h
R1
R1
(−)-(1S)-56
(+)-(P,1S)-57
R1
Ratio [(M,1S)/(P,1S)] Yield (%) Ref
H
92:8
4-Tol
0:100
60
[62]
63
[62]
(+)-(P,1S)-1-Methyl-19-(4-tolyl)-1,3,16,17-tetrahydrobenzo[5,6]phenanthro[3,4-c]naphth[1,2-e]oxepin (57, R1 = H); Typical Procedure:[62]
A Carius tube equipped with a rubber septum was charged with triyne (–)-(1S)-56 (16 mg, 0.032 mmol) and Ph3P (17 mg, 0.064 mmol). The tube was flushed with argon, and dioxane (1.5 mL) and CoCp(CO)2 (4 L, 0.032 mmol) in dioxane (1.0 mL) were added. The septum was replaced with a PTFE Young stopcock in a stream of argon and the tightly closed [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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[2 + 2 + 2]-Carbocyclization Reactions
tube was heated to 120 8C for 70 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, petroleum ether/Et2O 100:0 to 85:15) to afford an amorphous solid; yield: 11 mg (60%); [Æ]D22 +199 (c 0.08, CH2Cl2). 3.4.1.2.2
Control of Central Chirality
3.4.1.2.2.1
Intramolecular Cyclotrimerization of Allenediynes
Treatment of allenediynes such as 58, bearing a phosphine oxide group at one alkyne terminus, with dicarbonyl(Å5-cyclopentadienyl)cobalt(I) affords the corresponding [2 + 2 + 2] cycloadducts, e.g. 59, in high yields with complete chemo-, regio-, and diastereoselectivities (Scheme 17).[56] Enantiomerically enriched allenes facilitate the transfer of chiral information from axial to central chirality, which makes this a powerful tool for the preparation of enantiomerically enriched tricyclic exomethylene derivatives.[57] Scheme 17 Cobalt(I)-Mediated [2 + 2 + 2] Enantioselective Intramolecular Carbocyclization of an Allenediyne[57] CoCp(CO)2
• O P Ph Ph
(Cp)Co
THF, hν, heat
Ph
H
>98%; 95% ee
58
Ph
Ph P O Ph 59
(Å5-Cyclopentadienyl)[Å4-(S,E)-5-(diphenylphosphoryl)-4-(1-phenylethylidene)2,3,3a,4,6,7,8,9-octahydro-1H-cyclopenta[a]naphthalene]cobalt(I) (59); Typical Procedure:[57]
CoCp(CO)2 (120 L, 1 mmol) was added to a refluxing soln of enantioenriched allenediyne 58 (95% ee; 0.476 g, 1 mmol) in THF (20 mL; degassed by three freeze–pump–thaw cycles), and the mixture was irradiated with light from a projector lamp (ELW, 240 W, 80% of its power). The reaction was monitored by TLC and after completion, the solvent was removed under reduced pressure. The residue was purified by flash chromatography to give the tricyclic compound 59; yield: 598 mg (>98%); 95% ee {determined using 31P NMR by titration of the complex in the presence of (+)-zinc TADDOLate [obtained by the reaction of Me2Zn with the (+)-TADDOL]. 3.4.1.2.3
Control of Axial Chirality
3.4.1.2.3.1
Carbocyclization of Acetylene and Aryl-Substituted Monoynes Bearing Phosphoryl Moieties
Asymmetric cyclotrimerization is a particularly attractive route for the enantioselective construction of axially chiral biaryls bearing a phosphoryl moiety. Treatment of various 2-methoxy-1-(phosphorylethynyl)naphthalenes 60 and acetylene (2 equiv) in the presence of 5 mol% of the chiral (+)-menthyl-derived cobalt(I) complex (+)-(pR)-61 under photochemical conditions furnishes the biaryl derivatives 62 in good to moderate yields and with reasonable enantioselectivity (up to 82% ee). Further recrystallization of these intermediates affords enantiomerically enriched material (>99% ee). Reduction of the phosphoryl moieties with aluminum trihydride to the corresponding phosphines provides potential monodentate P- and bidentate P,O-ligands such as 63 (NAPHEP) (Scheme 18).[63] [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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[m + n + 2]-Carbocyclization Reactions
3.4
Scheme 18 Cobalt(I)-Mediated Enantioselective [2 + 2 + 2] Carbocyclization between Acetylene and 1-Ethynyl-2-methoxynaphthalenes Bearing a Phosphoryl Moiety[63] Pri 5 mol%
O
Co
R1 P R1 (+)-(pR)-61
H 2
+ H
R1
O
P R1 MeO
THF, hν
OMe
62
60
R1
Conditions
ee (%) Yield (%) Ref
Ph
45 8C, 48 h
79a
49
[63]
4-MeOC6H4
45 8C, 24 h
72a
51
[63]
3,5-(F3C)2C6H3 45 8C, 24 h
56
24
[63]
t-Bu
82a
61
[63]
a
25 8C, 48 h
>99% ee after recrystallization.
Ph
O P
Ph MeO
AlH3 THF, 40 oC
Ph2P
96%; >99% ee
MeO
63
(+)-(pR)-(Å4-Cycloocta-1,5-diene)(Å5-1-neomenthylindenyl)cobalt(I) [(+)-(pR)-61]; Typical Procedure:[65]
A 2.5 M soln of BuLi in hexanes (2 mL, 5 mmol) was added in one portion to a soln of (–)-3neomenthylindene (1.27 g, 5 mmol) in THF (15 mL) at –78 8C. The mixture was stirred for 5 min, the temperature was allowed to rise to 20 8C for 30 min, and stirring was continued for 2 h at rt. The soln of 1-neomenthylindenyllithium was again cooled to –78 8C, and CoCl(PPh3)3 (4.41 g, 5 mmol) was added. The stirred soln was allowed to warm to rt over 1 h and was then stirred for an additional 1 h. Cyclooctadiene (0.92 mL, 7.5 mmol) was added to the dark red mixture, which was then heated to reflux for 0.5 h. The color soon changed to red-orange, and the soln was cooled and filtered through a thin pad of degassed silica gel (2 3 cm), eluting with THF. The solvent was removed under reduced pressure, and the oily residue was dried for 1 h under high vacuum and purified by column chromatography [degassed silica gel (1.5 30 cm)]. Elution with pentane allowed the separation of the main diastereomer as the first red-orange fraction, and the more slowly moving second minor fraction was set aside. The eluate was concentrated under reduced pressure to a volume of 5 mL. Cooling to –78 8C caused the precipitation of the complex (+)-(pR)-61 as a dark red crystalline compound, which was collected by filtration and dried under high vacuum; yield: 1.11 g (52%); mp 89 8C; [Æ]D20 +1568 (c 0.06, toluene).
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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[2 + 2 + 2]-Carbocyclization Reactions
(–)-(S)-1-[2-(Diphenylphosphoryl)phenyl]-2-methoxynaphthalene (62, R1 = Ph); Typical Procedure:[63]
A thermostated (45 8C) reaction vessel was loaded with 1-[(diphenylphosphoryl)ethynyl]-2methoxynaphthalene (60, R1 = Ph; 1.15 g, 3 mmol), catalyst (+)-(pR)-61 (63 mg, 0.15 mmol), and THF (30 mL) under acetylene. The mixture was stirred and irradiated with two 460-W lamps (º = 420 nm) for 48 h. The reaction was quenched by switching off the lamps and simultaneously opening the vessel to the air, the degree of conversion of the starting acetylene was determined by GC, the solvent was evaporated, and the oily residue was purified by column chromatography (silica gel, EtOAc) to give a colorless solid; yield: 639 mg (49%); 79% ee [determined by HPLC at rt using a chiral column (Daicel Chiralpack AD-H, hexane/EtOH 98:2, flow rate 2 mL • min–1; tR 28.81 min and 38.68 min)]. Recrystallization (EtOAc/hexane) gave the product in enantiomerically pure form; yield: 391 mg (30%); >99% ee; [Æ]D25 –80.7 (c 0.56, CHCl3). (–)-(S)-[2-(2-Methoxynaphthalen-1-yl)phenyl]diphenylphosphine (63, NAPHEP); Typical Procedure:[63]
(–)-(S)-1-[2-(Diphenylphosphoryl)phenyl]-2-methoxynaphthalene (266 mg, 0.612 mmol; >99% ee) was dissolved in THF (5 mL), and 0.5 M AlH3 in THF (1.32 mL, 0.652 mmol) was added dropwise. The mixture was stirred at 50 8C for 30 min and cooled, and dry MeOH (0.1 mL) was added. The mixture was filtered through a pad of silica gel, which was washed with THF (3 5 mL), and the organic extract was concentrated and purified by flash chromatography (silica gel, hexane/EtOAc 9:1) to give a colorless solid; yield: 246 mg (96%); >99% ee. 3.4.1.2.3.2
Carbocyclization of 1,7-Diynes with Nitriles
The (–)-menthyl-derived cobalt(I) complex (–)-(pS)-61 catalyzes the [2 + 2 + 2] carbocyclization of diynes with nitriles. Treatment of 2-methoxy-1-(octa-1,7-diynyl)naphthalene with various nitriles affords the 1-aryl-5,6,7,8-tetrahydroisoquinolines 64 in 74–88% yield with high levels of enantioselectivity (88–93% ee) (Scheme 19). Furthermore, higher enantiomeric excess can be obtained with benzonitrile when the reaction temperature is lowered from 3 to –20 8C; it can be further improved by recrystallization for all cases.[66]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Scheme 19 Cobalt(I)-Mediated Enantioselective [2 + 2 + 2] Carbocyclization between 2-Methoxy-1-(1,7-octadiynyl)naphthalene and Nitriles[66] Pri 1 mol%
Co
R1 R1
(−)-(pS)-61
N
THF, hν
+ OMe
OMe
N
64
R1
Temp (8C) eea (%)
Yielda (%) Ref
Ph
3
89 (>98) 86 (57)
[66]
Ph
–20
93 (>98) 86 (56)
[66]
Me
3
88 (>98) 88 (54)
[66]
t-Bu
3
88 (>98) 74 (46)
[66]
a
Values after recrystallization in parentheses.
(–)-(pS)-(Å4-Cycloocta-1,5-diene)(Å5-1-neomenthylindenyl)cobalt [(–)-(pS)-61]; Typical Procedure:[65]
The reaction was carried out similarly to the preparation of (+)-(pR)-61 (see Section 3.4.1.2.3.1 for details). (+)-3-Neomenthylindene (1.27 g, 5 mmol) in THF (15 mL), 2.5 M BuLi in hexanes (2 mL, 5 mmol), CoCl(PPh3)3 (4.41 g, 5 mmol), and cod (0.92 mL, 7.5 mmol) gave the cobalt complex as dark red crystals; yield: 1.14 g (54%); mp 89 8C; [Æ]D20 –1600 (c 0.15, toluene). 1-(2-Methoxynaphthalen-1-yl)-3-phenyl-5,6,7,8-tetrahydroisoquinoline (64, R1 = Ph); Typical Procedure:[66]
A thermostated (3 8C) reaction vessel was loaded with 2-methoxy-1-(octa-1,7-diynyl)naphthalene (524 mg, 2 mmol), catalyst (–)-(pS)-61 (8.4 mg, 0.02 mmol), THF (20 mL), and PhCN (412 L, 4 mmol) under argon. The mixture was stirred and irradiated by two 460-W lamps (º = 420 nm) for 24 h. The reaction was quenched by switching off the lamps and simultaneously letting in air. The conversion of the starting 2-methoxy-1-(octa-1,7-diynyl)naphthalene, was determined by GC. The mixture was filtered through a thin pad of silica gel, eluting with THF. The solvent was removed under reduced pressure to give an oily residue, which was further dissolved in Et2O (10 mL). Colorless crystals were collected by filtration and washed with Et2O; yield: 413 mg, (57%); mp 200–201 8C; [Æ]D25 +202.5 8 (c 0.1, toluene); >98% ee [determined by HPLC at rt using a chiral column (Daicel Chiralpack ADH, hexane/EtOH 99:1; flow rate 1 mL • min–1; tR 6.67 min and 8.31 min)]. 3.4.1.3
Rhodium(I)-Mediated [2 + 2 + 2] Carbocyclizations
Muller was the first to recognize the merit of rhodium complexes, such as Wilkinsons catalyst, to catalyze inter- and intramolecular [2 + 2 + 2]-carbocyclization reactions.[67] Although the neutral rhodium complex chlorotris(triphenylphosphine)rhodium(I) promotes the cyclotrimerization of diynes or triynes, it is quite often inefficient for the cyclotrimerization of terminal alkynes and leads to the formation of linear dimers. The introduction of cationic rhodium complexes opened new horizons for the [2 + 2 + 2] carbocycli[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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3.4.1
zation of alkynes. For example, bis(cyclooctadiene)rhodium(I) tetrafluoroborate in combination with the chiral bisphosphine ligand DTBM-SEGPHOS catalyzes the cyclotrimerization of terminal alkynes in high yields with very good regioselectivities in favor of the 1,2,4-trisubstituted arenes. Applications of this process to enantioselective [2 + 2 + 2] carbocyclization have also been reported and contribute to its development as an impressive transformation. 3.4.1.3.1
Control of Central Chirality
3.4.1.3.1.1
Carbocyclization of Tertiary Propargylic Alcohols, Bispropargylic Alcohols, and Dialkynylphosphine Oxides with 1,6-Diyne Esters
The cationic rhodium(I) complex bis(cyclooctadiene)rhodium(I) tetrafluoroborate in combination with the chiral bisphosphine (R)-Solphos promotes the one-pot transesterification of the 1,6-diyne esters 65 with racemic tertiary propargylic alcohols 66 followed by the [2 + 2 + 2] carbocyclization of the resulting triyne to form enantioenriched tricyclic 3,3disubstituted phthalides 67 in moderate yield and with high enantiomeric excess (Scheme 20). The selective formation of the quaternary stereogenic center can be explained by kinetic resolution of the racemic tertiary propargylic alcohols in the esterification. Under similar conditions, the bispropargylic tertiary alcohols 69 are more reactive in the desymmetrization reaction; however, the products are obtained with a similar range of yields and enantioselectivities (Scheme 21). Interestingly, switching from internal to terminal alkynes leads to a significant reduction in the enantioselectivity (from 92 to 48% ee). In most cases, the tosylamide-linked diynes 68 (X = NTs) give improved yields of tricyclic products 70, compared to the ether and methylene counterparts.[68] Scheme 20 Rhodium(I)-Catalyzed Kinetic Resolution of Racemic Tertiary Propargylic Alcohols and [2 + 2 + 2] Carbocyclization with 1,6-Diyne Esters[68] Me N O
PPh2
O
PPh2
N Me (R)-Solphos
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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[m + n + 2]-Carbocyclization Reactions
3.4
X CO2Me
Ph
HO
O
5 mol% [Rh(cod)2]BF4/(R)-Solphos CH2Cl2, rt
+
X
O R1
65
R1
X
Ref
55
[68]
56
[68]
Ph
90
O
Me
94 a
Ph
67
ee (%) Yield (%)
O
NTs Ph
86
79
[68]
NTs Me
93
89
[68]
a
R1
66
The absolute configuration was R, as determined by the anomalous dispersion method.
Scheme 21 Rhodium(I)-Catalyzed Desymmetrization of Symmetrical Tertiary Bispropargylic Alcohols through [2 + 2 + 2] Carbocyclization with 1,6-Diyne Esters[68] X
R2 5 mol% [Rh(cod)2]BF4/(R)-Solphos CH2Cl2, rt
CO2Me X
+
HO
R2 R2
68
R2 70
69
X
R1
R2
O
Me
Ph 92
82
[68]
O
Me
Me 90
67
[68]
O
Me
H
48
66
[68]
Ph 93
85
[68]
Me 90
87
[68]
CH2 CO2Me Ph 80
61
[68]
NTs Me a
O R1
R1
NTs Me
O
ee (%) Yield (%) Ref
a
The absolute configuration was R, as determined by the anomalous dispersion method.
Symmetrical dialkynylphosphine oxides have also been studied in this type of kinetic resolution. The cationic rhodium(I)/(R)-DTBM-SEGPHOS complex promotes the desymmetrization of dialkynylphosphine oxides 71 and through a highly selective [2 + 2 + 2] carbocyclization with various 1,6-diynes, which constitutes a convenient approach to P-enantioenriched alkynyl aryl oxides 72 (Scheme 22). In contrast to the dihex-1-ynylphosphine oxides 71 (R1 = Bu), the phenyl substituted derivative 71 (R1 = Ph) provides improved asymmetric induction.[69]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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[2 + 2 + 2]-Carbocyclization Reactions
Scheme 22 Rhodium(I)-Catalyzed Desymmetrization of Symmetrical Dialkynylphosphine Oxides through [2 + 2 + 2] Carbocyclization with 1,6-Diyne Esters[69] OMe But
But But
O
OMe
O
P
O
P
But But OMe
O But
But
But
OMe (R)-DTBM-SEGPHOS
R1
Me +
X
O 5 mol% [Rh(cod)2]BF4/(R)-DTBM-SEGPHOS CH2Cl2, rt
O P
P Me X R1
R
1
71
R1
72
X
R1
ee (%) Yield (%) Ref
O
Ph
93
>99
[69]
O
4-MeOC6H4
95
96
[69]
O
4-F3CC6H4
91
83
[69]
O
Bu
35
71
[69]
NTs Ph
85
>99
[69]
CH2 Ph
93
98
[69]
(+)-3,5-Dimethyl-4-phenyl-3-(phenylethynyl)-6,8-dihydrobenzo[1,2-c:3,4-c¢]difuran1(3H)-one (70, X = O; R1 = Me; R2 = Ph); Typical Procedure:[68]
Under argon, (R)-Solphos (6.6 mg, 0.010 mmol) and [Rh(cod)2]BF4 (4.1 mg, 0.010 mmol) were dissolved in CH2Cl2 (1.0 mL), and the mixture was stirred at rt for 5 min. H2 was introduced to the resulting soln in a Schlenk tube. After stirring at rt for 0.5 h, the soln was concentrated to dryness and dissolved in CH2Cl2 (0.4 mL). To this soln was added a soln of bispropargylic tertiary alcohol 69 (R2 = Ph; 147.7 mg, 0.60 mmol) in CH2Cl2 (0.2 mL), rinsing with additional CH2Cl2 (0.2 mL) to ensure transfer of all the substrate. To this soln was added dropwise over 10 min a soln of 1,6-diyne 68 (X = O; R1 = Me; 33.2 mg, 0.20 mmol) in CH2Cl2 (1.0 mL) at rt, again rinsing with additional CH2Cl2 (0.2 mL) to ensure transfer of all the material. The mixture was stirred at rt for 1 h. The resulting soln was concentrated and purified by preparative TLC (silica gel, hexane/EtOAc 2:1), which furnished the title compound as a colorless solid; yield: 62.1 mg (82%); mp 156.2–156.5 8C; 92% ee {determined by HPLC at rt using a chiral column [Chiralpak AD-H, hexane/iPrOH 98:2, flow rate 0.8 mL • min–1; tR 16.3 min (major isomer) and 18.4 min (minor isomer)]}; [Æ]D25 +276.5 (c 1.62, CHCl3).
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
(+)-(4,7-Dimethyl-6-phenyl-1,3-dihydroisobenzofuran-5-yl)(methyl)(phenylethynyl)phosphine Oxide (72, X = O; R1 = Ph); Typical Procedure:[69]
(R)-DTBM-SEGPHOS (11.8 mg, 0.01 mmol) and [Rh(cod)2]BF4 (4.1 mg, 0.01 mmol) were dissolved in CH2Cl2 (1.0 mL) and the mixture was stirred at rt for 30 min. H2 (1 atm) was introduced to the resulting soln in a Schlenk tube. After stirring at rt for 1 h, the resulting soln was concentrated and redissolved in CH2Cl2 (0.4 mL). To this soln was added a soln of dialkynylphosphine oxide 71 (R1 = Ph; 63.4 mg, 0.24 mmol) in CH2Cl2 (0.4 mL) in a portion and then a soln of dibut-2-ynyl ether (24.4 mg, 0.20 mmol) in CH2Cl2 (1.2 mL) dropwise over 15 min at rt. After being stirred at rt for 1 h, the resulting soln was concentrated and purified by preparative TLC (silica gel, hexane/EtOAc 1:4), which furnished a pale yellow oil; yield: 77.3 mg (>99%); 93% ee {determined by HPLC at rt using a chiral column [Daicel Chiralpack AD-H, hexane/iPrOH 90:10, flow rate 1 mL • min–1; tR 25.7 min (major isomer) and 33.9 min (minor isomer)]}; [Æ]D25 +152.4 (c 3.96, CHCl3). 3.4.1.3.1.2
Carbocyclization of 1,6-Diynes with Substituted Alkenes
The enantioselective rhodium-catalyzed [2 + 2 + 2] carbocyclization also provides a convenient strategy to chiral tri- and tetracyclic compounds that contain a cyclohexa-1,3-diene ring. Treatment of 1,6-diyne esters and norbornene derivatives with the complex derived from bis(cyclooctadiene)rhodium(I) tetrafluoroborate and (S)-DIFLUORPHOS, furnishes the cycloadducts 73 with good to excellent enantiomeric excesses (Scheme 23).[70] Scheme 23 Rhodium(I)-Catalyzed [2 + 2 + 2] Carbocyclization of 1,6-Diynes and Norbornene Derivatives[70] F
O
F
O
PPh2
F
O
PPh2
F
O (S)-DIFLUORPHOS
R1 10 mol% [Rh(cod)2]BF4/(S)-DIFLUORPHOS CH2Cl2, rt
R1 X
+
Z
Z
X
CO2Me CO2Me
73
X
R1
C(CO2Me)2
Ph (CH2)2
1
91
71
[70]
C(CO2Me)2
Me (CH2)2
1
99
82
[70]
NTs
Ph (CH2)2
6
95
83
[70]
O
Ph (CH2)2
3
95
51
[70]
NTs
Ph
24
92
67
[70]
a
Z
Time (h) ee (%) Yielda (%) Ref
Ratio (diyne substrate/alkene substrate) 1:2.
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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[2 + 2 + 2]-Carbocyclization Reactions
Similarly, the rhodium-catalyzed [2 + 2 + 2] carbocyclization of exomethylene lactones with malonate-, ether-, and sulfonamide-tethered 1,6-diynes affords the spirocyclic adducts 74 with up to 99% enantiomeric excess, using a preformed chiral rhodium complex ({Rh(cod)[(S)-XylBINAP]}BF4) (Scheme 24). Interestingly, methylenecyclopentanone affords lower enantiomeric excess (82% ee), whereas methyl acrylate derivatives 75 required 2,2bis(but-2-ynyl)malonate and (S)-H8-BINAP to achieve high enantioselectivities (Scheme 25).[71] Scheme 24 Rhodium(I)-Catalyzed [2 + 2 + 2] Carbocyclization of 1,6-Diynes and Exomethylene Lactones[71]
P P
(S)-XylBINAP
R1 O
R1 X
+
O n
X
O
n
R1
O
5 mol% {Rh(cod)[(S)-XylBINAP]}BF4 1,2-dichloroethane, 80 oC
R1
74
X
R1
na
ee (%) Yield (%) Ref
C(CO2Bn)2
Me
1
99
94
[71]
C(CO2Bn)2
Me
2
98
93
[71]
C(CO2Bn)2
Me
3
97
88 b
C(CO2Bn)2
Me
1
81
62
NTs
Me
1c
97
92
O a
b c d
Et
1
d
92
b
50
[71] [71] [71] [71]
3 equiv of exomethylene lactone was used unless otherwise noted. At 60 8C, 2.5 h. 10 equiv of exomethylene lactone was used. 20 equiv of exomethylene lactone was used.
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
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[m + n + 2]-Carbocyclization Reactions
Scheme 25 Rhodium(I)-Catalyzed [2 + 2 + 2] Carbocyclization of a 1,6-Diyne and Acrylates[71]
PPh2 PPh2
(S)-H8-BINAP
5 mol% {Rh(cod)[(S)-H8-BINAP]}BF4 1,2-dichloroethane, 60 oC
O
BnO2C
1 + R
OMe
BnO2C 75
O BnO2C
OMe R1
BnO2C
R1
Equiv of 75 ee (%) Yield (%) Ref
Me 3
>99
Ph 10
93
54
H
91
87
a
3
[71]
92 a
[71] [71]
The diyne was added dropwise at 80 8C.
(+)-Methyl 9-Phenyl-6-tosyl-6-azatetracyclo[9.2.1.02,10.04,8]tetradeca-3,8-diene-3-carboxylate [73, X = NTs; R1 = Ph; Z = (CH2)2]; Typical Procedure:[70]
Under argon, (S)-DIFLUORPHOS (6.8 mg, 0.010 mmol) and [Rh(cod)2]BF4 (4.1 mg, 0.010 mmol) were stirred in CH2Cl2 (1.0 mL) at rt for 5 min. After the reaction vessel was purged with H2, the soln was stirred for a further 30 min. Both the solvent and H2 were removed under reduced pressure and the reaction vessel was then filled with argon gas. After the addition of CH2Cl2 (0.40 mL), methyl 4-[tosyl(3-phenylprop-2-ynyl)amino]but-2ynoate (38.1 mg, 0.10 mmol) in CH2Cl2 (0.80 mL) and norbornene (18.8 mg, 0.20 mmol) in CH2Cl2 (0.80 mL) were subsequently added, and the mixture was stirred at rt for 3 h. After completion of the reaction, the volatiles were removed under reduced pressure, and the obtained crude products were purified by TLC; yield: 39.4 mg (83%); 95% ee {determined by HPLC using a chiral column [Daicel Chiralpak IA 2: 4 250 mm, hexane/CH2Cl2 7:3; flow rate 1.0 mL • min–1; tR 22 min (major isomer) and 24 min (minor isomer)]}; [Æ]D24 +130.0 (c 1.29, CHCl3). Dibenzyl 4¢,7¢-Dimethyl-2-oxo-1¢,4,5,6¢-tetrahydrospiro[furan-3,5¢-indene]-2¢,2¢(3¢H)-dicarboxylate [74, X = C(CO2Bn)2; R1 = Me; n = 1]; Typical Procedure:[71]
{Rh(cod)[(S)-XylBINAP]}BF4 (5.4 mg, 0.005 mmol) and 3-methylenedihydrofuran-2(3H)-one (29.8 mg, 0.30 mmol) were stirred in 1,2-dichloroethane (0.3 mL) at 80 8C. To the yellow-orange soln, dibenzyl 2,2-dibut-2-ynylmalonate (38.4 mg, 0.10 mmol) in 1,2-dichloroethane (0.7 mL) was added dropwise over 30 min at 80 8C and the mixture was stirred for 5 min. After completion of the reaction, the solvent was removed under reduced pressure, and the crude product was purified by TLC [silica gel, EtOAc/benzene (CAUTION: carcinogen) 10:1]; yield: 45.1 mg (94%); 97% ee {determined by HPLC using a chiral column [Daicel Chir[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.1
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[2 + 2 + 2]-Carbocyclization Reactions
alpak AD-H, hexane/iPrOH 7:3; flow rate 1.0 mL • min–1; tR 10 min (major isomer) and 9 min (minor isomer)]}; [Æ]D34 –22.43 (c 0.21, CHCl3). 3.4.1.3.1.3
Carbocyclization of 1,6-Diynes with Electron-Deficient Ketones
Cationic rhodium complexes also serve as excellent catalysts for [2 + 2 + 2] cocyclization of diynes with carbonyl compounds. The resulting bicyclic 2H-pyrans are formed in almost quantitative yield, albeit they undergo partial electrocyclic ring opening at room temperature. For example, the carbocyclization of a 1,6-diyne with methyl pyruvate using a chiral rhodium complex prepared from bis(cyclooctadiene)rhodium(I) tetrafluoroborate and (S)-BINAP furnishes the bicyclic 2H-pyran 76 with a quaternary stereogenic center in 48% yield and 97% enantiomeric excess, in addition to the ring-opened product 77, which exists as a mixture of E- and Z-isomers (Scheme 26).[72,73] Scheme 26 Cationic Rhodium(I) Catalyzed [2 + 2 + 2] Carbocyclization of a 1,6-Diyne and Methyl Pyruvate[72,73]
BnO2C
Ph
5 mol% [Rh(cod)2]BF4 5 mol% (S)-BINAP 1,2-dichloroethane, rt
O +
BnO2C
CO2Me
Ph
BnO2C
O ∗
BnO2C
CO2Me
BnO2C
O
BnO2C
Ph
+
MeO2C 76
3.4.1.3.1.4
48%; 97% ee
77
26%
Carbocyclization of 1,6-Enynes and Alkynes
The asymmetric rhodium-catalyzed [2 + 2 + 2] carbocyclization of carbon- and heteroatomtethered 1,6-enynes with alkynes results in the formation of a series of annulated cyclohexa-1,3-dienes with a stereogenic center at the ring junction. The cyclization of enynes 78 with acetylene and symmetrical 1,2-disubstituted alkynes, using the complex derived from bis(cyclooctadiene)rhodium(I) tetrafluoroborate and (S)-TolBINAP, provides a direct approach for the enantioselective construction of quaternary stereocenters (Scheme 27). Although the enantioselectivities are excellent, the regioselectivities for the formation of 79/80 with terminal alkynes, propargylic methyl ethers, and propargylic alcohols are only moderate.[74] In contrast, the analogous process with activated unsymmetrical 1,2-disubstituted alkynes, such as methyl arylpropynoates, proceed in a highly regio- and enantioselective manner to give bicyclohexa-1,3-dienes 81/82 using chlorobis(cyclooctadiene)rhodium(I) with (S)-Xyl-P-Phos modified with silver(I) tetrafluoroborate (Scheme 28). This process provides a method for the enantioselective preparation of tertiary and quaternary carbon stereogenic centers at a ring junction.[75]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Scheme 27 Rhodium(I)-Catalyzed [2 + 2 + 2] Carbocyclization of 1,6-Enynes and Terminal and Internal Alkynes[74]
P(4-Tol)2 P(4-Tol)2
(S)-TolBINAP
X
10 mol% (S)-TolBINAP 1,2-dichloroethane
+
X R
R4
R3
+ R2
R1
R1
10 mol% [Rh(cod)2]BF4
R3
R1
4
R4
R2
78
X
79
R2
80
X
R1
R3
R4
Temp (8C)
Time (h)
Ratio (79/ 80)
ee (%) of Major Product
Yield (%)
NTs
Me Me H
H
40
–
–
91
65a
[74]
b
NTs
Me Me CH2OMe
H
40
–
4:1
92
83
NTs
Me Me CH2OH
H
60
–
7:1
98c
63
[74]
NTs
Me Me CH2OH
CH2OH
60
–
98
50
[74]
3
c
NTs
Me Me CH2OMe
CH2OMe
60
12
–
97
81
[74]
NTs
Me Ph CH2OMe
CH2OMe
82
24
–
89
61d,e
[74]
d,e
NTs
Ph Me CH2OMe
CH2OMe
82
4
–
88
96
[74]
NTs
H
CH2OMe
40
15
–
98
72f
[74]
97
f
[74]
f
[74]
C(CO2Me)2 a b c d e f
H H
Me CH2OMe Me CH2OMe Me CH2OMe
CH2OMe CH2OMe
80 40
1 12
– –
92
65 60
Pressure of acetylene to 0.2 atm. Minor product 80: 95% ee. Minor product 80: 97% ee. Ratio (enyne/alkyne) 1:2. The volume of solvent was half as much as that in the other entries. Ratio (enyne/alkyne) 1:10.
Scheme 28 Rhodium(I)-Catalyzed [2 + 2 + 2] Carbocyclization of 1,6-Enynes and Activated Internal Alkynes[75] MeO N P
MeO
P
Ref
[74]
O
MeO
R3
R2
N MeO (S)-Xyl-P-Phos
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.1
5 mol% [RhCl(cod)2]2 12 mol% (S)-XylP-Phos 20 mol% AgBF4 THF, 60oC
R2 X
+ R1
177
[2 + 2 + 2]-Carbocyclization Reactions
R2 X
+
∗
R1
R3
R3 X
R3
81
X
R1
R2
R3
NTs
H
CO2Me
Ph
10:1
NTs
H
Ac
Ph
NTs
Me Ac
O
H
O
Ratio (81/82)
∗
R1
R2
82
ee (%) of Major Product
Yield (%)
Ref
97
98
[75]
>19:1
95
86
[75]
Ph
10:1
>99
84
[75]
CO2Me
Ph
>19:1
>99
86
[75]
H
CO2Me
4-MeOC6H4
>19:1
98
95
[75]
O
H
CO2Me
4-F3CC6H4
17:1
97
72
[75]
C(CO2Me)2
H
CO2Me
Ph
9:1
>99
88
[75]
5,6-Bis(methoxymethyl)-3a-methyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindole (79, R1 = H; R2 = Me; R3 = R4 = CH2OMe; X = NTs); Typical Procedure:[74]
Under an atmosphere of argon, (S)-TolBINAP (6.8 mg, 0.010 mmol) and [Rh(cod)2]BF4 (4.1 mg, 0.010 mmol) were stirred in 1,2-dichloroethane (0.25 mL) at rt to give a yellow soln. 1,4-Dimethoxybut-2-yne (114.1 mg, 1.00 mmol) and the sulfonamide 78 (R1 = H; R2 = Me; X = NTs; 26.3 mg, 0.10 mmol) in 1,2-dichloroethane (0.75 mL) were added to the soln and the mixture was stirred at 40 8C for 15 h. The solvent was removed under reduced pressure, and the crude products were purified by TLC to give a colorless oil; yield: 27 mg (72%); 98% ee {determined by HPLC at rt using a chiral column [Daicel Chiralpak AD-H, 4 250mm, hexane/iPrOH 9:1; flow rate 1.0 mL • min–1; tR 18 min (minor isomer) and 23 min (major isomer)]}; [Æ]D26 +11.6 (c 0.82, CHCl3). Methyl (7aS)-6-Phenyl-2-tosyl-2,3,7,7a-tetrahydro-1H-isoindole-5-carboxylate (81, R1 = H; R2 = CO2Me; R3 = Ph; X = NTs); Typical Procedure:[75]
[RhCl(cod)]2 (6.2 mg, 0.0125 mmol) and AgBF4 (9.7 mg, 0.05 mmol) were suspended in anhyd THF (1.0 mL) and stirred at rt under argon for ca. 10 min. (S)-Xyl-P-Phos (22.7 mg, 0.03 mmol) in anhyd THF (3.0 mL) was then added to the yellow suspension, and the mixture was stirred at rt for an additional ca. 30 min. Methyl phenylpropynoate (120.1 mg, 0.75 mmol) was added in one portion, followed by addition of N-prop-2-enyl-N-prop-2ynyl-4-toluenesulfonamide (62.3 mg, 0.25 mmol) in anhyd THF (2.0 mL) via syringe pump over ca. 2 h at 60 8C. The mixture was then stirred for an additional ca. 30 min (TLC monitoring). The mixture was allowed to cool to rt, and was then filtered through a short pad of silica gel (EtOAc/hexanes 1:1) and concentrated under reduced pressure to afford the crude product. Purification by flash chromatography (silica gel, EtOAc/hexanes 1:9 to 3:7) afforded a mixture of regioisomeric products 81/82 (10:1) as a white solid; yield: 94.1 mg (98%); 97% ee {determined by HPLC at rt using a chiral column [Daicel AD-H, 4.6 250 mm, hexane/iPrOH 9:1; flow rate 1.0 mL • min–1; tR 51.49 min (minor isomer) and 78.21 min (major isomer)]}; [Æ]D25 –87.6 (c 1.80, CHCl3) (major regioisomer). 3.4.1.3.1.5
Carbocyclization of 1,6-Enynes with Electron-Deficient Ketones
The regio- and diastereoselective [2 + 2 + 2] carbocyclization of 1,6-enynes with the carbonyl moiety of oxo esters affords fused dihydropyrans with two quaternary carbon stereogenic centers in a highly enantioselective manner, using the chiral catalyst derived from bis(cyclooctadiene)rhodium(I) tetrafluoroborate and (R)-H8-BINAP (Scheme 29). For exam[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
ple, 1-methylisatin (83) provides the enantioenriched spirocyclic compound 84 with excellent enantiomeric excess (92% ee).[76] In contrast to 1,6-diynes, the resulting cycloadducts are relatively stable and not susceptible to the electrocyclic ring-opening reactions observed in Section 3.4.1.3.1.3.[72,73] Scheme 29 Rhodium(I)-Catalyzed [2 + 2 + 2] Carbocyclization of 1,6-Enynes and ElectronDeficient Ketones[76]
PPh2 PPh2
(R)-H8-BINAP
R1
10 mol% [Rh(cod)2]BF4
R1
10 mol% (R)-H8-BINAP 1,2-dichloroethane, 80 oC, 16 h
O R3
R2
X
R1
R2
R3
R4
NTs
Me
Me
Me
CO2Et
ee (%) Yield (%) Ref 95a
>99a
[76]
b
[76]
c
NTs
Me
Me
Me
Ac
98
73
NTs
Me
Me
CO2Et
CO2Et
97
89
c
[76]
C(CO2Me)2
4-BrC6H4
Me
Me
CO2Et
98
49
[76]
O
Ph
Me
Me
CO2Et
>99
67
[76]
O
Ph
Me
CO2Et
CO2Et
96
64
[76]
O
CO2Me
Me
CO2Et
CO2Et
93
61
[76]
b c
O
R4
R2
a
R3
X
+
X
R4
Performing the reaction with 20 mol% of catalyst in CH2Cl2 at 25 8C gave >99% ee (91% yield). 2 equiv of diketone was used. Performing the reaction with 20 mol% of catalyst in CH2Cl2 at 25 8C gave >99% ee (82% yield).
O
+ N Me
NMe
10 mol% (R)-H8-BINAP 1,2-dichloroethane, 80 oC, 16 h
Ph O
Ph O
10 mol% [Rh(cod)2]BF4
O
85%; 92% ee
83
O
O
84
(+)-1¢,3a-Dimethyl-7-phenyl-3a,4-dihydro-1H,3H-spiro[furo[3,4-c]pyran-6,3¢-indol]2¢(1¢H)-one (84); Typical Procedure:[76]
(R)-H8-BINAP (18.9 mg, 0.030 mmol) and [Rh(cod)2]BF4 (12.2 mg, 0.030 mmol) were dissolved in CH2Cl2 (2.0 mL) in a Schlenk tube under argon, and the mixture was stirred at rt for 5 min. H2 was introduced into the resulting soln, which was then stirred at rt for 0.5 h, concentrated to dryness, and dissolved in 1,2-dichloroethane (0.5 mL). A soln of {3-[(2-methylprop-2-enyl)oxy]prop-1-ynyl}benzene (55.9 mg, 0.300 mmol) and 1-methylisatin (83; 96.7 mg, 0.600 mmol) in (CH2Cl)2 (1.5 mL) was added at rt, and the resulting mix[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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[2 + 2 + 2]-Carbocyclization Reactions
ture was stirred at 80 8C for 16 h. The mixture was then concentrated, and the product was purified by preparative TLC (EtOAc/hexane 2:1) to furnish the title compound as a pale yellow oil and a single diastereomer; yield: 88.8 mg (85%); 92% ee {HPLC analysis at rt using a chiral column [Chiralcel OD-H, hexane/iPrOH 9:1; flow rate 1.0 mL • min–1; tR 8.5 min (major isomer) and 12.9 min (minor isomer)]}. Cocyclization of Alkenyl Isocyanates and Terminal Alkynes
3.4.1.3.1.6
The regio- and enantioselective rhodium-catalyzed [2 + 2 + 2]-carbocyclization reaction of alkenyl isocyanates 90 and alkynes using chiral phosphoramidite ligands provides an excellent method for the construction of bicyclic lactams and vinylogous amides with indolizinone and quinolizinone skeletons.[77] The nature of the alkyne and ligand is critical for controlling the product distribution. For instance, reactions with aliphatic terminal alkynes in the presence of piperidinyl-substituted TADDOL-derived phosphoramidite 86 provide the lactam products 91 with good enantioselectivity,[78] whereas the vinylogous amide adducts 92 that result from a carbonyl migration, are favored with aromatic and aliphatic terminal alkynes using the pyrrolidinyl-substituted ligand 85 and biphenolbased phosphoramidite ligand 89, respectively (Scheme 30).[78,79] Furthermore, 2-substituted alkenyl isocyanates 90 (R1 „ H) furnish bicyclic compounds with a quaternary stereocenter at the ring junction.[80] The synthetic utility of this methodology has been nicely demonstrated in concise asymmetric total syntheses of (+)-lasubine II and the indolizidine (–)-209D. Scheme 30 Rhodium(I)-Catalyzed [2 + 2 + 2] Carbocyclization of Alkenyl Isocyanates and Terminal Alkynes[78–80] Ph
Ph
Ph
O
O
P O
O Ph
Ph
N
P O
Ph O
O
85
O
O
O
N
P
O Ph
Ph
Ph
O
Ph
Ph 86
NMe2
Ph 87
But O
O
O P
O
O
N
O
P
NMe2
But
88
89
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
180
Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
O 10 mol% ligand
N R1
n
R2
O
5 mol% [RhCl(H2C=CH2)2]2
•
toluene, 110 oC
N
+
+
n
R
2
R1
90
R
N n
2
O
R1
(S)-91
(R)-92
R1
R2
n Ligand Ratioa (91/92)
eeb (%) of 91
eeb (%) of 92
Combined Yield (%)
Ref
H
Ph
1 85
1:7.3
89
94
87
[78]
H
2-MeOC6H4
1 85
99 (111)
61
[85]
Me Ph
40
0.5
(110/112) 1.5:1
99 (112)
95
[85]
NTs
Me 2-PhC6H4
40
2
(110/112) 1:13
99 (112)
78
[85]
O
Me 2-PhC6H4
40
2
(110/112) 1:13
99 (112)
75
[85]
a
The ee was determined for the compound in parentheses.
Scheme 38 Rhodium(I)-Catalyzed Enantioselective Intramolecular [2 + 2 + 2] Carbocyclization of 1,6Dienynes[85] R1 X
10 mol% {Rh(cod)[(S)-TolBINAP]}BF4 1,2-dichloroethane
Z R2 113 R1
R1
R2 X ∗
Z
R2
∗
+
X Z 115
114
X
Z
R1
NTs
CH2
NTs
R2
Temp (8C)
Time (h)
Ratio (114/115)
Me H
rt
24
13:1
CH2
Ph
H
rt
24
O
CH2
Ph
H
rt
NTs
O
Me H
rt
NTs
O
Me Me 60
ee (%) of 114
Total Yield (%)
Ref
>99
93
[85]
14:1
95
91
[85]
3
>20:1
89
63
[85]
3
2.5:1
98
75
[85]
6
>20:1
98
75
[85]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
188
Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Chiral Multicyclic Compounds, e.g. 107, 108, 110–112, 114, and 115; General Procedure:[85]
Under argon, (S)-TolBINAP (6.8 mg, 0.010 mmol) and [Rh(cod)2]BF4 (4.1 mg, 0.010 mmol) were stirred in CH2Cl2 (0.25 mL). Then, the reaction vessel was filled with H2 gas. The mixture was stirred at rt for 30 min under a H2 gas atmosphere. After removal of the solvent and H2 under reduced pressure, the reaction vessel was filled with argon. 1,2-Dichloroethane (0.25 mL) was added to the flask and the soln was stirred at rt to give a Mars yellow soln. Then, the dienyne (0.10 mmol) in 1,2-dichloroethane (0.75 mL) was added to the soln and the mixture was stirred at the appropriate temperature. After completion of the reaction, the volatiles were removed under reduced pressure and the crude products were purified by TLC to give a chiral cycloadduct. The ee was determined by HPLC using a chiral column. 3.4.1.3.2
Control of Helical Chirality
3.4.1.3.2.1
Cocyclization of Tetraynes with Diynes
In a particularly attractive approach to controlling helical chirality, the enantioenriched fluorenones 118 have been prepared via a one-step intermolecular rhodium-catalyzed double [2 + 2 + 2] carbocyclization of the 2-naphthol-linked tetraynes 116 and substituted dialkynyl ketones 117 (Scheme 39). This process facilitates the construction of the [9]helicene-like derivative through the installation of five successive rings with moderate asymmetric induction (up to 60% ee) using (R)-SEGPHOS as the chiral ligand.[88] Scheme 39 Rhodium(I)-Catalyzed Enantioselective Intermolecular Double [2 + 2 + 2] Carbocyclization of Tetraynes with Dialkynyl Ketones[88]
O
X
R1
+
O
X
116
10−40 mol% [Rh(cod)2]BF4/(R)-SEGPHOS CH2Cl2, rt
O
R1
117 O
X R1
O R1 O
X 118
X
R1
mol% of Catalyst ee (%) Yield (%) Ref
CH2
Me
10
47
56
[88]
CH2
Bu
10
39
40
[88]
C=O Ph
20
31
61
C=O CH2OMe a
40
60
a
32
[88] [88]
Conditions: 1,2-dichloroethane, 40 8C.
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.1
189
[2 + 2 + 2]-Carbocyclization Reactions
In a similar manner, the enantioenriched benzopyrano-fused helical phosphafluorenes 121 are prepared from the phenol-linked tetraynes 119 and dialkynyl phosphorus derivatives 120 using the chiral complex derived from bis(cyclooctadiene)rhodium(I) tetrafluoroborate with (R)-TolBINAP (Scheme 40).[89] Scheme 40 Rhodium(I)-Catalyzed Enantioselective Intermolecular Double [2 + 2 + 2] Carbocyclization of Tetraynes with Dialkynyl Phosphorus Compounds[89]
R1 R2
O
O
R1 O +
P
R2
20 mol% [Rh(cod)]BF4/(R)-TolBINAP 1,2-dichloroethane, rt, 1 h
O P
R3
R3
R1 R2
O
R2
O R1 120
119
R3
121
R1
R2
H
Ph OMe 73
40
[89]
H
Ph Me
34
50
[89]
H
Ph Ph
32
53
[89]
H
Me OMe 57
16
ee (%) Yield (%) Ref
Me Ph OMe 50 a
a
23
[89] [89]
(R)-H8-BINAP was used as the chiral ligand.
(+)-6,8-Dibutyl-5,9-dimethyl-3,4,10,11-tetrahydro-3,11-dioxa-7H-fluoreno[3,4-c:6,5-c¢]diphenanthren-7-one (118, X = CH2; R1 = Bu); Typical Procedure:[88]
A soln of (R)-SEGPHOS (4.6 mg, 0.0075 mmol) in CH2Cl2 (0.8 mL) was added to a soln of [Rh(cod)2]BF4 (3.1 mg, 0.0075 mmol) in CH2Cl2 (0.8 mL) at rt, and the mixture was stirred for 5 min. The resulting soln was stirred under H2 (1 atm) at rt for 1 h, concentrated to dryness, and dissolved in CH2Cl2 (1.0 mL). To this soln was added a soln of trideca-5,8-diyn-7one (117, R1 = Bu; 17.1 mg, 0.090 mmol) in CH2Cl2 (0.8 mL), and then a soln of bis[2-(but-2ynyloxy)naphthalen-1-yl]buta-1,3-diyne (116, X = CH2; 32.9 mg, 0.075 mmol) in CH2Cl2 (2.0 mL) was added dropwise at rt. The soln was stirred at rt for 1 h. The resulting soln was concentrated and purified by preparative TLC (silica gel, hexanes/EtOAc 5:1), which furnished the title compound as a yellow solid; yield: 19.0 mg (40%); 39% ee {determined by HPLC at rt using a chiral column [Chiralcel OD-H, 254-nm UV detector, iPrOH/hexanes 1:19; flow rate 0.5 mL • min–1; tR 19.9 min (major isomer) and 25.1 min (minor isomer)]}; [Æ]D25 +585 (c 0.402, CHCl3). 3.4.1.3.2.2
Intramolecular Carbocyclization of Triynes
Enantioselective intramolecular metal-catalyzed [2 + 2 + 2]-carbocyclization reactions also provide a convenient approach to [7]helicene-like skeletons. For instance, treatment of the aromatic triynes 122 with the chiral cationic rhodium complex derived from bis(cyclooctadiene)rhodium(I) tetrafluoroborate with (R,R)-Me-DuPhos facilitates the one-step construction of three rings to provide 123 with good enantioselectivity (Scheme 41). This represents an important method for the construction of helically chiral molecules.[90] [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
190
Stereoselective Synthesis
[m + n + 2]-Carbocyclization Reactions
3.4
Rhodium(I)-Catalyzed Enantioselective [2 + 2 + 2] Carbocyclization of Triynes[90]
Scheme 41
P
P
(R,R)-Me-DuPhos
O O R1
20 mol% [Rh(cod)2]BF4/(R,R)-Me-DuPhos CH2Cl2
R1
R1
R1
O O 123
122
R
Conditions
ee (%) Yield (%) Ref
CO2Me rt, 15 h
71
80
[90]
CO2Bu rt, 15 h
77
71
[90]
40 8C, 140 h 85
71
[90]
Bu
(–)-Dimethyl (M)-7,8,11,12-Tetrahydro-7,12-dioxabenzo[1,2-c:4,3-c¢]diphenanthrene-9,10dicarboxylate (123, R1 = CO2Me); Typical Procedure:[90]
Under argon, (R,R)-Me-DuPhos (6.1 mg, 0.02 mmol) and [Rh(cod)2]BF4 (8.1 mg, 0.02 mmol) were dissolved in CH2Cl2 (1.0 mL) and the mixture was stirred for 5 min. H2 was introduced to the resulting soln in a Schlenk tube. After being stirred at rt for 1 h, the mixture was concentrated to dryness. To a soln of the residue in CH2Cl2 (1.0 mL) was added a soln of triyne 122 (R1 = CO2Me; 50.3 mg, 0.10 mmol) in CH2Cl2 (3.0 mL), rinsing with additional CH2Cl2 (1.0 mL) to ensure complete transfer of the substrate. The mixture was stirred at rt for 15 h, concentrated, and purified by preparative TLC (silica gel, hexanes/EtOAc/ CH2Cl2 10:1:1) to furnish the title compound as a yellow solid; yield: 40.3 mg (80%); 71% ee {determined by HPLC at rt using a chiral column [Chiralpak AD, 254-nm UV detector, iPrOH/hexanes 1:4; flow rate 1.0 mL • min–1; tR 9.7 min (minor isomer) and 15.2 min (major isomer)]}; [Æ]D25 –908.6 (c 1.49, CHCl3). 3.4.1.3.3
Control of Axial Chirality
3.4.1.3.3.1
Cyclotrimerization of Internal Alkynes
The intermolecular metal-catalyzed [2 + 2 + 2] cyclotrimerization of internal alkynes has emerged as a conceptually important method to generate axial chirality during the formation of aryl rings. Various unsymmetrical acetylenic derivatives 124 bearing both acyloxymethyl (or hydroxyethyl) and ortho-substituted phenyl (or 1-naphthyl) groups react with dialkyl acetylenedicarboxylates in the presence of the chiral rhodium complex derived from bis(cyclooctadiene)rhodium(I) tetrafluoroborate and (S)-H8-BINAP, to furnish the axially chiral biaryls 125 in good yield with high enantioselectivity (up to 96% ee) (Scheme 42).[91] [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.1
191
[2 + 2 + 2]-Carbocyclization Reactions
Scheme 42 Rhodium(I)-Catalyzed Enantioselective [2 + 2 + 2] Cyclotrimerization of Aryl-Substituted Internal Alkynes with Dialkyl Acetylenedicarboxylates[91] CO2R1
R2
CO2R1
5 mol% {Rh(cod)[(S)-H8-BINAP]}BF4 CH2Cl2, rt, 16 h
1
CO2R1
R O2C
+ CO2R1
Ar1 125
124
R1
Ar1
Me 2-Tol
R2
ee (%) Yield (%) Ref
OAc
89
81 a
[91]
OAc
93
80
[91]
Me 2-Tol
OC(O)Et
91
73
[91]
Me 2-BrC6H4
OAc
91
61
[91]
Me 1-naphthyl
OAc
95
89
[91]
Et
CH2OH
96
75b
[91]
Et
a b
2-Tol
1-naphthyl
R2
R1O2C
Ar1
(R)-H8-BINAP was used. Isolated as the corresponding acetate by treatment with Ac2O/Et3N.
(+)-Tetramethyl 6-(Acetoxymethyl)-2¢-methylbiphenyl-2,3,4,5-tetracarboxylate (125, R1 = Me; Ar1 = 2-Tol; R2 = OAc); Typical Procedure:[91]
Under argon, a soln of (S)-H8-BINAP (9.5 mg, 0.015 mmol) in CH2Cl2 (1.0 mL) was added to a soln of [Rh(cod)2]BF4 (6.1 mg, 0.015 mmol) in CH2Cl2 (1.0 mL) at rt. The mixture was stirred at rt for 5 min. H2 was introduced to the resulting soln in a Schlenk tube. After stirring at rt for 0.5 h, the soln was concentrated to dryness and dissolved in CH2Cl2 (0.5 mL). This soln was added to a soln of 3-(2-tolyl)prop-2-ynyl acetate (56.4 mg, 0.300 mmol) in CH2Cl2 (0.5 mL), rinsing with further CH2Cl2 (0.5 mL) to ensure complete transfer of the catalyst. To this soln was added a soln of DMAD (85.3 mg, 0.600 mmol) in CH2Cl2 (0.5 mL), rinsing with further CH2Cl2 (0.5 mL) to ensure complete transfer of the substrate. The soln was stirred at rt for 16 h, concentrated, and purified by preparative TLC (silica gel, hexanes/ EtOAc 2:1) to give a colorless solid; yield: 114.8 mg (81%); 89% ee {determined by HPLC at rt using a chiral column [Chiralpak AD, 254-nm UV detector, iPrOH/hexanes 1:4; flow rate 0.8 mL • min–1; tR 9.7 min (minor isomer) and 11.1 min (major isomer)]}; [Æ]D25 +27.5 (c 0.754, CHCl3). 3.4.1.3.3.2
Cocyclization of 1,6-Diynes and Alkynes
In a related approach, the rhodium-catalyzed [2 + 2 + 2] carbocyclization of the ester-tethered 1,6-diynes 126 with propargylic alcohols and acetates 127 in the presence of a cationic rhodium(I)–H8-BINAP complex provides the axially chiral phthalides 128 and 129 with good regio- and enantioselectivity (up to 90:10 and 87% ee, respectively) (Scheme 43). Interestingly, the symmetrical but-2-yne-1,4-diols and acetates 127 (R1 = H; R2 = CH2OH and R1 = Ac; R2 = CH2OAc), which avoid the inherent problem with regioselectivity, significantly improve the level of asymmetric induction.[92]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
192
Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Scheme 43 Rhodium(I)-Catalyzed Enantioselective [2 + 2 + 2] Carbocyclization of Unsymmetrical Electron-Deficient 1,6-Diynes and Both Terminal and Internal Monoynes[92] OR1 O Ar1
5 mol% {Rh(cod)[(S)-H8-BINAP]}BF4 CH2Cl2, rt, 3 h
+
O
R2 126
127 R2 O O
OR1
OR1
+ O R2 O
Ar1
Ar1
128
129
Ar1
R1 R2
Ratio (128/129) ee (%) of 128 Yield (%) Ref
2-Tol
Ac H
90:10
87
79
[92]
1-naphthyl
Ac H
88:12
82
91
[92]
2-F3CC6H4
Ac H
66:34
81
86
[92]
2-Tol
H
70:30
78
90
[92]
2-Tol
Ac CH2OAc –
>99
67
[92]
1-naphthyl
Ac CH2OAc –
94
57
[92]
2-F3CC6H4
Ac CH2OAc –
>99
73
2-Tol a
H
H
CH2OH
–
>99
a
63
[92] [92]
The reaction was carried out in THF.
The analogous intermolecular rhodium-catalyzed [2 + 2 + 2] carbocyclization of (2-methoxynaphthalen-1-yl)alkynylphosphonates and -phosphine oxides 130 with symmetrical and unsymmetrical 1,6-diynes provides a direct route to the ortho-substituted axially chiral biaryl phosphorus derivatives 131 with excellent regio- and enantioselectivity (Scheme 44).[93] Scheme 44 Rhodium(I)-Catalyzed Enantioselective [2 + 2 + 2] Carbocyclization between Electron-Rich 1,6-Diynes and Internal Aryl-Substituted Alkynylphosphonates and -phosphine Oxides[93]
O
X
R3 P R3
R1 5 mol% {Rh(cod)[(R)-H8-BINAP]}BF4
R1
CH2Cl2, rt, 1 h
+
X R2
P R3 R3 OMe
OMe
130
131
X
R1
R2
R3
ee (%) Yield (%) Ref
O
Me
Me
OEt
97
>99
[93]
CH2 Me
Me
OEt
97
>99
[93]
NTs Me
Me
OEt
95
96
[93]
O
Me
Ph
91
92
[93]
Me
O R2
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.1
[2 + 2 + 2]-Carbocyclization Reactions
X
R1
R2
R3
ee (%) Yield (%) Ref
O
Me
Me
Cy
95
>99
[93]
O
Ph
Me
OEt
86
80
[93]
O
Ph
H
OEt
96
73
[93]
193
More recently, the chiral complexes derived from bis(cyclooctadiene)rhodium(I) tetrafluoroborate and (S)-SEGPHOS and (S)-BINAP have been shown to facilitate the enantioselective [2 + 2 + 2] carbocyclization of 1,6-diynes with internal alkynyl amides 132 to give the atropisomeric N,N-dialkylbenzamides 133 (Scheme 45). Notably, the N,N-diisopropylpropynamides 134 with an ortho-substituted phenyl group at the alkyne terminus furnish the corresponding C(aryl)—C(aryl) and C(aryl)—C(carbonyl) axially chiral biaryl benzamides 135 in a highly diastereo- and enantioselective manner (Scheme 46). Interestingly, terminal diynes generate achiral products under analogous reaction conditions.[94] Scheme 45 Rhodium(I)-Catalyzed Enantioselective [2 + 2 + 2] Carbocyclization between Electron-Rich 1,6-Diynes and N,N-Dialkylalkynamides[94] NR12
O X
R2
CH2Cl2, rt, 1 h
+ R2
X
132
133
X
R1 R2
ee (%) Yield (%) Ref
C(CO2Bn)2
iPr CMe2OMe
>99
92
[94]
NTs
iPr CMe2OMe
>99
85
[94]
O
iPr CMe2OMe
>99
81
[94]
C(CO2Bn)2
Et CMe2OMe
>99
94
[94]
C(CO2Bn)2
iPr t-Bu
>99
90
C(CO2Bn)2
iPr iPr
>99
C(CO2Bn)2
iPr Bu
>99
a
NR12
O 5 mol% {Rh(cod)[(S)-SEGPHOS]}BF4
[94]
a
[94]
96a
[94]
>99
(S)-BINAP was used as the chiral ligand.
Scheme 46 Rhodium(I)-Catalyzed Enantioselective [2 + 2 + 2] Carbocyclization between an Ether-Linked 1,6-Diyne and N,N-Diisopropyl-3-(2-tolyl)propynamide[94] O
NPri2
O
NPri2
5 mol% {Rh(cod)[(S)-BINAP]}BF4 CH2Cl2, rt, 1 h
O
+
91%; >99% ee; dr >30:1
O 134
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
135
for references see p 239
194
Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
(+)-5,6-Bis(acetoxymethyl)-7-(2-tolyl)benzo[c]furan-1(3H)-one (128, Ar1 = 2-Tol; R1 = Ac; R2 = CH2OAc); Typical Procedure:[92]
Under argon, (S)-H8-BINAP (7.9 mg, 0.0125 mmol) and [Rh(cod)2]BF4 (5.1 mg, 0.0125 mmol) were dissolved in CH2Cl2 (1.0 mL), and the mixture was stirred for 5 min. H2 was introduced to the resulting soln in a Schlenk tube. The mixture was stirred for 30 min at rt and then concentrated to dryness. The residue was taken up in CH2Cl2 (1.0 mL), and to this soln was added a soln of prop-2-ynyl ester 126 (Ar1 = 2-Tol; 49.8 mg, 0.250 mmol) and 1,4-diacetoxybut-2-yne (127, R1 = Ac; R2 = CH2OAc; 212.7 mg, 1.25 mmol) in CH2Cl2 (1.0 mL) at rt; the vial was rinsed with CH2Cl2 (0.5 mL). The mixture was stirred at rt for 3 h, concentrated, and purified by preparative TLC to furnish a yellow solid; yield: 61.7 mg, (67%); >99% ee {determined by HPLC at rt using a chiral column [Chiralpak AS, 254-nm UV detector, iPrOH/hexanes 1:4; flow rate 0.8 mL • min–1; tR 28.6 min (minor isomer) and 30.3 min (major isomer)]}; [Æ]D25 17.3 (c 0.274, CHCl3). (–)-Diethyl [6-(2-Methoxynaphthalen-1-yl)-4,7-dimethyl-1,3-dihydrobenzo[c]furan-5yl]phosphonate (131, X = O; R1 = R2 = Me; R3 = OEt); Typical Procedure:[93]
(R)-H8-BINAP (6.3 mg, 0.010 mmol) and [Rh(cod)2]BF4 (4.1 mg, 0.010 mmol) were dissolved in CH2Cl2 (1.0 mL) and the mixture was stirred at rt for 5 min. H2 (1 atm) was introduced to the resulting soln in a Schlenk tube. After being stirred at rt for 1 h, the soln was concentrated and redissolved in CH2Cl2 (0.4 mL). To this soln was added a soln of diethyl alkynylphosphonate 130 (R3 = OEt; 63.7 mg, 0.200 mmol) in CH2Cl2 (0.4 mL) and then a soln of dibut-2-ynyl ether (33.6 mg, 0.3 mmol) in CH2Cl2 (1.2 mL) was added dropwise over 20 min at rt. After being stirred at rt for 1 h, the resulting soln was concentrated and purified by preparative TLC (silica gel, hexanes/EtOAc/Et3N 2:1:1), which furnished a colorless solid; yield: 88.1 mg (>99%); 97% ee {determined by HPLC at rt using a chiral column [Chiralpak AD-H, 254-nm UV detector, iPrOH/hexanes 1:9; flow rate 1.0 mL • min–1; tR 8.56 min (major isomer) and 12.9 min (minor isomer)]}; [Æ]D25 –22.8 (c 20.8, CHCl3). (–)-Dibenzyl 5-(Diisopropylcarbamoyl)-6-(2-methoxypropan-2-yl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylate [133, X = C(CO2Bn)2; R1 = iPr; R2 = CMe2OMe]; Typical Procedure:[94]
A soln of (S)-SEGPHOS (4.6 mg, 0.0075 mmol) in CH2Cl2 (0.5 mL) was added to a soln of [Rh(cod)2]BF4 (3.0 mg, 0.0075 mmol) in CH2Cl2 (0.5 mL) at rt, and the mixture was stirred for 5 min. The resulting soln was stirred under H2 (1 atm) at rt for 1 h, concentrated to dryness, and dissolved in CH2Cl2 (0.5 mL). To this soln was added a soln of N,N-diisopropylalkynamide 132 (R1 = iPr; R2 = CMe2OMe; 37.2 mg, 0.165 mmol) in CH2Cl2 (0.5 mL). Then, a soln of dibenzyl 2,2-dibut-2-ynylmalonate (58.3 mg, 0.15 mmol) in CH2Cl2 (1.0 mL) was added dropwise over 5 min at rt. The soln was stirred at rt for 1 h, concentrated, and purified by chromatography (silica gel, hexane/EtOAc 5:1–2:1) to give a pale yellow oil; yield: 85.1 mg (92%); >99% ee {determined by HPLC at rt using a chiral column [Chiralpak AD, 254-nm UV detector, iPrOH/hexanes 1:9; flow rate 1.0 mL • min–1; tR 8.58 min (major isomer) and 13.0 min (minor isomer)]}; [Æ]D25 –9.81 (c 4.00, CHCl3). 3.4.1.3.3.3
Double Cocyclization of 1,6-Diynes with 1,3-Diynes
The sequential asymmetric rhodium-catalyzed [2 + 2 + 2] carbocyclization of two 1,6-diynes with a 1,3-diyne provides a powerful method for the construction of enantiopure C2-symmetrical tetra-ortho-substituted axially chiral biaryls 136 (Scheme 47). Interestingly, the optimal combination requires an electron-deficient 1,6-diyne with an electron-rich buta-1,3-diyne and vice versa.[95,96]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.1
195
[2 + 2 + 2]-Carbocyclization Reactions
Scheme 47 Rhodium(I)-Catalyzed Enantioselective Double [2 + 2 + 2] Carbocyclization between Symmetrical 1,6-Diynes and Symmetrical 1,3-Diynes[95,96] X R2
R1 5 mol% {Rh(cod)[(S)-SEGPHOS]}BF4
R1
CH2Cl2, rt
+
X R1
R1
R2
R1
R2
R2
R1 X 136
X
R1
R2
Time (h) ee (%) Yield (%) Ref
C(CO2Me)2
CO2Et
CH2OAc
16
>99
59
[95]
C(CO2Me)2
CO2Et
CH2OMe
16
98
48
[95]
CH2
CO2Me CH2OAc
16
>99
30
[95]
O
Me
1
>99a
65
[96]
a
74
[96]
98a
54
[96]
P(O)(OEt)2
NTs
Me
P(O)(OEt)2
1
NTs
Me
CO2Et
3
a
>99
(R)-SEGPHOS was used.
(–)-Tetraethyl {(4,4¢,7,7¢-Tetramethyl-1,1¢,3,3¢-tetrahydro-[5,5¢-bi(benzo[c]furan)]-6,6¢-diyl)bis(methylene)}bis(phosphonate) [136, X = O; R1 = Me; R2 = P(O)(OEt)2]; Typical Procedure:[96]
(R)-SEGPHOS (6.2 mg, 0.010 mmol) and [Rh(cod)2]BF4 (4.1 mg, 0.010 mmol) were dissolved in CH2Cl2 (1.0 mL), and the mixture was stirred at rt for 5 min. H2 (1 atm) was introduced into the soln in a Schlenk tube. After stirring at rt for 1 h, the resulting soln was concentrated and dissolved in CH2Cl2 (0.4 mL). To this soln was added a soln of tetraethyl buta-1,3diyn-1,4-diylbis(phosphonate) (64.4 mg, 0.200 mmol) in CH2Cl2 (0.4 mL), and then a soln of dibut-2-ynyl ether (73.3 mg, 0.600 mmol) in CH2Cl2 (1.2 mL) was added dropwise over 20 min at rt. After being stirred at rt for 1 h, the resulting soln was concentrated and purified by preparative TLC (silica gel, EtOAc/Et3N 20:1) to furnish a colorless solid; yield: 73.5 mg (65%); 99% ee {determined by HPLC at rt using a chiral column [Sumichiral OA3100, 254-nm UV detector, EtOH/hexanes 1:4; flow rate 1.0 mL • min–1; tR 11.3 min (major isomer) and 12.7 min (minor isomer)]}; [Æ]D25 –15.4 (c 3.29, CHCl3). 3.4.1.3.3.4
Cocarbocyclization of 1,6-Diynes with Ynamides
Another class of synthetically useful -components for intermolecular metal-catalyzed [2 + 2 + 2] carbocyclizations are ynamides, which were first reported in the preparation of indoles and carbazoles.[97–99] More recently, particular attention has been devoted to controlling axial chirality in anilide and N,O-biaryl formation, either using a chiral metal complex or a chiral auxiliary. For instance, the carbocyclization of 1,6-diynes with various Nsubstituted (trimethylsilyl)ynamides 137 in the presence of a catalytic rhodium(I)–(S)-XylBINAP complex affords C(aryl)—N(amide) axially chiral anilides 138 with excellent enantioselectivity (up to 98% ee) (Scheme 48).[100,101]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Scheme 48 Rhodium(I)-Catalyzed Enantioselective [2 + 2 + 2] Carbocyclization between Symmetrical 1,6-Diynes and N-Substituted (Trimethylsilyl)ynamides[100,101] O
O R3
R1
R2
N
10 mol% [Rh(cod)2]BF4/(S)-XylBINAP
R2
CH2Cl2, rt
R1
+
X
R3 N TMS
1
R
R1
TMS
X
137
R2
138
X
R1
R3 ee (%) Yield (%) Ref
C(CO2Me)2
Me Ph
Ph 97
79
[100]
C(CO2Me)2
Me Ph
Bn 97
29
[100]
Me Ph
Ph 84
50
[100]
Me OMe Bn 98
69a
[100]
Et
62
[100]
O N S O
Br O N S O
Br
O a
Ph
Ph 96
(R)-TolBINAP was used as the chiral ligand.
Interestingly, the achiral cationic rhodium complex catalyzed [2 + 2 + 2] carbocyclization of diynes with N-aryl ynamides such as 139, bearing an Evans-type chiral auxiliary, promotes central-to-axial chirality transfer. The corresponding biaryl amides (P)-140 and (M)-140 are formed with modest diastereoselectivity favoring the M-atropisomer (Scheme 49).[102]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Scheme 49 Rhodium(I)-Catalyzed Enantioselective [2 + 2 + 2] Carbocyclization between Diynes and Chiral Aryl Ynamides Containing Evans’ Auxiliary[102] O O
N
15 mol% RhCl(PPh3)3 16.5 mol% AgSbF6
Ph
1,2-dichloroethane 4-Å molecular sieves, 85 oC
+
94%; [(P)-140/(M)-140] 1:4
MeO
139
Ph
O
N
+
Ph
N
OMe
O
MeO H
O O
H
(P)-140
(M)-140
Additional studies have examined the effect of achiral ynamides with a chiral rhodium complex to control both C(aryl)—C(aryl) and C(aryl)—N(amide) axial chirality. Treatment of dimethyl 2,2-dibut-2-ynylmalonate and ynamide 141 with the cationic complex derived from bis(cyclooctadiene)rhodium(I) tetrafluoroborate and (S)-XylBINAP affords the highly enantiomerically enriched biaryl products (P,p)-142 and (M,p)-142 in high yield, albeit with modest diastereoselectivity (Scheme 50).[103,104] Scheme 50 Chiral Rhodium(I) Complex Catalyzed Enantioselective [2 + 2 + 2] Carbocyclization between a Diyne and an Achiral Aryl Ynamide[103,104] O 10 mol% [Rh(cod)2]BF4
O
10.5 mol% (S)-XylBINAP 1,2-dichloroethane
N
MeO2C
4-Å molecular sieves, 85 oC
+
93%; [(P,p)-142/(M,p)-142] 1:6
MeO2C MeO
141 CO2Me
CO2Me MeO2C
MeO2C
p P
N
p
+
99% ee
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
N
M
OMe
O
MeO
(P,p)-142
O
(M,p)-142
O O
99% ee
for references see p 239
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Stereoselective Synthesis
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[m + n + 2]-Carbocyclization Reactions
(+)-Dimethyl 5-(N-Benzylbenzamido)-4,7-dimethyl-6-(trimethylsilyl)-1,3-dihydro-2H-indene-2,2-dicarboxylate [138, X = C(CO2Me)2; R1 = Me; R2 = Ph; R3 = Bn]; Typical Procedure:[100]
Under argon, (S)-XylBINAP (18.4 mg, 0.0250 mmol) and [Rh(cod)2]BF4 (10.2 mg, 0.0250 mmol) were dissolved in CH2Cl2 (1.0 mL) and the mixture was stirred at rt for 5 min. H2 was introduced to the resulting soln in a Schlenk tube. After being stirred at rt for 1 h, the soln was concentrated to dryness and dissolved in CH2Cl2 (1.0 mL). To this soln was added dropwise over 1 min a soln of dimethyl 2,2-dibut-2-ynylmalonate (59.1 mg, 0.250 mmol) and (trimethylsilyl)ynamide 137 (R2 = Ph; R3 = Bn; 76.9 mg, 0.250 mmol) in CH2Cl2 (1.0 mL) at rt, rinsing with additional CH2Cl2 (3.0 mL) to ensure complete transfer of the substrates. The mixture was stirred at rt for 38 h. The resulting soln was concentrated and purified by preparative TLC (hexane/EtOAc/Et3N 10:1:2) to give a colorless oil, yield: 38.9 mg (29%); 97% ee {determined by HPLC at rt using a chiral column [Chiralpak AD, hexane/iPrOH 95:5; flow rate 1.0 mL • min–1; tR 21.0 min (major isomer) and 26.3 min (minor isomer)]}; [Æ]D25 +101.0 (c 0.845, CHCl3). Chiral Biaryl Compounds, e.g. 142; General Procedure:[104]
To a soln of [Rh(cod)2]BF4 (10 mol%) and (S)-XylBINAP (10 mol%) in anhyd 1,2-dichloroethane (to give a 5.0 mM soln) was added 4- molecular sieves in a sealed tube. The mixture was stirred at rt for 10 min before the ynamide 141 (1.00 mmol) and the diyne (2.00 mmol) were added. The soln was heated to 85 8C and monitored by LC/MS. After the reaction was complete, the soln was cooled to rt and filtered through a short pad of silica gel. Elution with EtOAc/hexanes (1:1) followed by concentration under reduced pressure afforded a crude mixture of diastereomers. Separation and purification of the resulting crude residue via flash column chromatography (silica gel, EtOAc/hexanes) afforded the desired biaryl diastereomers. Diastereomeric ratios were determined by 1H NMR of the crude product, and the ee of each diastereomer was determined by HPLC using a chiral column (Chiralcel OD-H, iPrOH/hexanes). 3.4.1.3.3.5
Cocarbocyclization of 1,6-Diynes with trans-Alkenes
The asymmetric carbocyclization of 1,6-diynes with substituted alkenes facilitates the construction of enantiomerically enriched cyclohexadienes. For example, treatment of dimethyl fumarate (5 equiv) and 1,6-diynes 143 with a cationic rhodium(I)–(R)-H8-BINAP complex, affords the C2-symmetric bicyclic dimethyl cyclohexadienedicarboxylate 144 in 35–96% yield and with excellent asymmetric induction (up to 98% ee) (Scheme 51).[105] Scheme 51 Rhodium(I)-Catalyzed Enantioselective [2 + 2 + 2] Carbocyclization between 1,6-Diynes and Dimethyl Fumarate[105] 5 mol% [Rh(cod)2]BF4/(R)-H8-BINAP CH2Cl2, rt, 16 h
MeO2C +
X
CO2Me X
CO2Me 143
CO2Me 144
X
ee (%) Yield (%) Ref
O
90
74
[105]
NTs
82
96
[105]
C(CO2Me)2
98
35
[105]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Annulated Dimethyl Cyclohexa-3,5-diene-1,2-dicarboxylates 144; General Procedure:[105]
Under argon, the BINAP-type ligand (0.010 mmol) and [Rh(cod)2]BF4 (0.010 mmol) were dissolved in CH2Cl2 (2.0 mL), and the mixture was stirred at rt for 5 min. H2 (1 atm) was introduced into the resulting soln in a Schlenk tube. After stirring at rt for 0.5 h, the soln was concentrated and redissolved in CH2Cl2 (0.5 mL). To this soln was added a soln of dimethyl fumarate (1.00 mmol) in CH2Cl2 (0.5 mL), and then a soln of diyne 143 (0.20 mmol) in CH2Cl2 (1.0 mL) was added dropwise over 20 min at rt. After stirring at rt for 1 h, the resulting soln was concentrated, and the product 144 was isolated by preparative TLC. 3.4.1.3.3.6
Cocarbocyclization of 1,6-Diynes with Isocyanates
Isocyanates also participate in an analogous [2 + 2 + 2] carbocyclization with terminal alkynes and diynes to afford pyridin-2-ones. An asymmetric version of this reaction has been developed using 2-chlorophenyl- and 2-bromophenyl-substituted 1,6-diynes 145 using a cationic rhodium catalyst with (R)-DTBM-SEGPHOS as the chiral ligand to provide the enantioenriched fused pyridin-2-ones 146 in a highly efficient manner with axially chiral C(aryl)—C(pyridyl) bonds (up to 92% ee) (Scheme 52).[106] Scheme 52 Rhodium(I)-Catalyzed Enantioselective [2 + 2 + 2] Carbocyclization between 2-Halophenyl-Substituted 1,6-Diynes and Alkyl Isocyanates[106] R1 N + X
R2
5 mol% [Rh(cod)2]BF4/(R)-DTBM-SEGPHOS CH2Cl2, −20 oC
R1
• O
N
X
R2 O
145
146
X
R1 R2
ee (%) Yield (%) Ref
CH2
Cl Bn
87
81
[106]
CH2
Br Bn
85
83
[106]
CH2
Cl (CH2)7Me
90
75
[106]
O
Cl Bn
91
58
[106]
C(CO2Me)2
Cl Bn
92
89
[106]
In an analogous process, 2-substituted phenyl isocyanates undergo enantioselective bimolecular carbocyclizations with 1,6-diynes to provide the C—N axially chiral N-arylpyridin2-ones 147, using a cationic rhodium complex with (R)-BINAP (Scheme 53).[107] Interestingly, terminal alkynes undergo the fully intermolecular process with lower yield and modest enantioselectivity, using (R)-TolBINAP as the chiral ligand (79% ee).
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Scheme 53 Rhodium(I)-Catalyzed Enantioselective [2 + 2 + 2] Carbocyclization between Disubstituted 1,6-Diynes and Aryl Isocyanates[107] R1 R1 N
1
R
+ R1
•
O 5 mol% [Rh(cod)2]BF4/(R)-BINAP CH2Cl2, rt
R2
N
O R2
147
R1
R2
Time (h) ee (%) Yield (%) Ref
CO2Me
Br
18
87
27a
[107]
CO2Me
iPr
1
67
31
[107]
CO2Me
OMe
1
58
92
[107]
CH2OMe
OMe 18
68
72
[107]
a
20 mol% of catalyst was used.
(+)-2-Benzyl-1-(2-chlorophenyl)-2,5,6,7-tetrahydro-3H-cyclopenta[c]pyridin-3-one; (146, X = CH2, R1 = Cl, R2 = Bn); Typical Procedure:[106]
Under argon, (R)-DTBM-SEGPHOS (29.5 mg, 0.0250 mmol) and [Rh(cod)2]BF4 (10.2 mg, 0.0250 mmol) were dissolved in CH2Cl2 (3.0 mL) and the mixture was stirred at rt for 5 min. H2 was introduced into the resulting soln in a Schlenk tube. After being stirred at rt for 0.5 h, the mixture was concentrated to dryness and the residue was redissolved in CH2Cl2 (3.5 mL). To this soln was added a soln of 1-chloro-2-hepta-1,6-diynylbenzene (145, X = CH2, R1 = Cl; 101.3 mg, 0.5 mmol) and benzyl isocyanate (133.2 mg, 1.0 mmol) in CH2Cl2 (0.5 mL) below –20 8C, rinsing with additional CH2Cl2 (1.0 mL) to ensure complete transfer of the substrates. The mixture was kept at –20 8C for 12 h, concentrated, and purified by preparative TLC (silica gel, hexane/EtOAc 2:1) to give a colorless oil; yield: 135.5 mg (81%); 87% ee {determined by HPLC at rt using a chiral column [Chiralpak AD, 254-nm UV detector, hexanes/iPrOH 96:4; flow rate 0.9 mL • min–1; tR 58.1 min (minor isomer) and 62.4 min (major isomer)]}; [Æ]D25 +26.2 (c 2.22, acetone). Enantioenriched Fused 1-Arylpyridin-2-ones 147; General Procedure:[107]
Under argon, a soln (0.5 mL) of (R)-BINAP (0.010–0.040 mmol, 5–20 mol%) in CH2Cl2 was added to a soln of [Rh(cod)2]BF4 (0.010–0.040 mmol, 5–20 mol%) in CH2Cl2 (0.5 mL) at rt, and the mixture was stirred for 5 min. The resulting soln was stirred under H2 (1 atm) at rt for 1 h, concentrated to dryness, and dissolved in CH2Cl2 (0.4 mL). To this soln was added a soln of the 1.6-diyne (0.220 mmol) in CH2Cl2 (0.7 mL) and then a soln of the aryl isocyanate (0.200 mmol) in CH2Cl2 (0.9 mL) at rt. After being stirred at rt for 1–18 h, the resulting soln was concentrated and the axially chiral 1-arylpyridin-2-one was isolated by chromatography (silica gel). 3.4.1.3.3.7
Cocyclization of 1,7-Diynes and Internal Alkynes
The asymmetric rhodium-catalyzed [2 + 2 + 2] carbocyclization of symmetrical and unsymmetrical internal alkynes with naphthyl- and 2-tolyl-substituted 1,2-bis(propynoyl)benzenes 148 afford the bis-axially chiral aryl-substituted anthraquinones 149 in good yield using the complex derived from bis(cyclooctadiene)rhodium(I) tetrafluoroborate and (S)-SEGPHOS (Scheme 54). This process facilitates the construction of axial chirality at [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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[2 + 2 + 2]-Carbocyclization Reactions
two positions with excellent enantioselectivity (up to 98% ee), albeit with modest diastereoselectivity favoring the dl-isomer.[108] Scheme 54 Rhodium(I)-Catalyzed Enantioselective [2 + 2 + 2] Carbocyclization between 1,2-Bis(propynoyl)benzenes and Internal Alkynes[108] O
R1
Ar1
O
Ar1
10 mol% [Rh(cod)2]BF4/(S)-SEGPHOS CH2Cl2, rt, 16 h
R1
+ Ar1
R2
R2
O
O 148
Ar
1
149
Ar1
R1
R2
Ratio (dl/meso) ee (%) Yield (%) Ref
Ph
CH2OMe
CH2OMe
–
–
76
[108]
2-Tol
CH2OMe
CH2OMe
2:1
97
70
[108]
2-Tol
Et
Et
4:1
97
78
[108]
2-Tol
Pr
Pr
6:1
98
75
[108]
2-Tol
Me
(CH2)4Me 8:1
97
80
[108]
2-Tol
Me
CH2OH
3:1
87
68
[108]
2-Tol
Me
CO2Et
3:1
89
93
[108]
1-naphthyl
Pr
Pr
3:1
85
71
[108]
2,3-Bis(methoxymethyl)-1,4-diphenylanthra-9,10-quinone; (149, Ar1 = Ph; R1 = R2 = CH2OMe); Typical Procedure:[108]
Under argon, a soln of (S)-SEGPHOS (9.2 mg, 0.015 mmol) in CH2Cl2 (0.5 mL) was added to a soln of [Rh(cod)2]BF4 (6.1 mg, 0.015 mmol) in CH2Cl2 (0.5 mL) at rt, and the mixture was stirred for 5 min. The resulting soln was stirred under H2 (1 atm) at rt for 0.5 h, concentrated to dryness, and dissolved in CH2Cl2 (0.5 mL). To this soln was added a soln of 1,2-bis(phenylpropynoyl)benzene (148, Ar1 = Ph; 50.1 mg, 0.15 mmol) and 1,4-dimethoxybut-2yne (18.8 mg, 0.165 mmol) in CH2Cl2 (0.5 mL), rinsing with additional CH2Cl2 (0.5 mL) to ensure complete transfer of the substrates. The mixture was stirred at rt for 16 h, concentrated, and purified by column chromatography (silica gel, hexanes/Et3N 15:1) to give a yellow solid; yield: 51.3 mg (76%); mp 160.0–160.8 8C. 3.4.1.3.3.8
Intramolecular Cyclotrimerization of Enediynes and Dienynes
The enantioselective intramolecular rhodium-catalyzed [2 + 2 + 2] carbocyclization of symmetrical E-enediynes 150, using bis(cyclooctadiene)rhodium(I) tetrafluoroborate with H8BINAP, affords the C2-symmetric tricyclic cyclohexadienes 151 (Scheme 55). Although both carbon- and nitrogen-tethered enediynes participate in the cyclization process, the carbon-tethered substrates provide high enantioselectivities irrespective of the nature of the substituents at the alkyne terminus, whereas the selectivity for the nitrogen counterparts is dependent on the electronic nature of the substituents.[84] In contrast, the terminal and methoxycarbonyl-substituted ether-linked E-enediynes 150 (X = O; R1 = H, CO2Me) provide moderate enantioselectivity under analogous conditions.[105] Interestingly, the enantioselective intramolecular carbocyclization of symmetrical dienyne 152 furnishes the C2-symmetric tricyclic cyclohexa-1,3-diene dl-153 as the minor product, albeit enantiomerically enriched (>99% ee) (Scheme 56).[105]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Scheme 55 Rhodium(I)-Catalyzed Enantioselective Intramolecular [2 + 2 + 2] Carbocyclization of Symmetrical Enediynes with an E-1,2-Disubstituted Alkene Moiety[84,105] R1
H H
X
10 mol% {Rh(cod)[(S)-H8-BINAP]}BF4
X
X
CH2Cl2, rt
X
R1
R1 150
151
X
R1
C(CO2Me)2
H
0.25
78
81
[84]
C(CO2Me)2
CO2Me
1
98
72
[84]
C(CO2Me)2
CH2OBn
6
98
63
C(CO2Me)2 C(CO2Me)2
Time (h) ee (%) Yield (%) Ref
Me Br
24
97
24
91
[84]
a
[84]
a
[84]
a,b
81 48
95
41
[84]
0.25
98
68c
[84]
CO2Me
0.5
21
69
[84]
Bu
4
89
C(CO2Me)2
Ph
C(SO2Ph)2
H
NTs NTs
24
90
[84]
d
O
H
16
48
78
[105]
O
CO2Me
16
59d
95
[105]
a b c d
R1
1,2-Dichloroethane was used as solvent at 60 8C. 20 mol% of the catalyst. 1,2-Dichloroethane was used at 40 8C. (S)-TolBINAP was used as chiral ligand.
Scheme 56 Rhodium(I)-Catalyzed Enantioselective Intramolecular [2 + 2 + 2] Carbocyclization of a Symmetrical Dienyne[105] NTs
NTs
5 mol% [Rh(cod)2]BF4/(R)-H8-BINAP
TsN
CH2Cl2, rt
NTs
+
>99%; (meso-153/dl-153) 4:1
NTs 152
meso-153
NTs dl-153
>99% ee
Tetramethyl trans-1,3,6,8,8a,8b-Hexahydro-as-indacene-2,2,7,7-tetracarboxylate [151, X = C(CO2Me)2; R1 = H]; Typical Procedure:[84]
Under argon, {Rh(cod)[(S)-H8-BINAP]}BF4 (10.0 mg, 0.01 mmol) was stirred in CH2Cl2 (1.0 mL) at rt. The flask was purged with H2 gas, and the soln was stirred for a further 30 min. After the solvent and H2 were removed under reduced pressure, argon gas was introduced. To the flask was added CH2Cl2 (0.2 mL), and the soln was stirred; then, enediyne 150 [X = C(CO2Me)2; R1 = H; 39.2 mg, 0.10 mmol] in CH2Cl2 (0.8 mL) was added, and the mixture was stirred at rt for 15 min. The solvent was removed under reduced pressure, and the resulting crude product was purified by TLC (silica gel) to give a white solid; yield: 31.8 mg (81%); 78% ee {determined by HPLC at rt using a chiral column [Daicel Chiralcel Doubly Arrayed OD-H, 4 250 mm, 254-nm UV detector, iPrOH/hexanes 5:95; flow rate [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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[2 + 2 + 2]-Carbocyclization Reactions
1.0 mL • min–1; tR: 21 min (minor isomer) and 23 min (major isomer)]}; [Æ]D25 +42.0 (c 1.36, CHCl3). 3.4.1.2.3.9
Intramolecular Cyclotrimerization of Bis(diynyl)malononitriles
The enantioselective tandem intramolecular rhodium-catalyzed [2 + 2 + 2] cyclization of bis(diynyl)malononitriles 154 provides an expeditious route to C2-symmetric spirobipyridines 155 in excellent yield, albeit with modest enantioselectivity (up to 71% ee) (Scheme 57). The optimal results are obtained using aryl-substituted alkynes 154 (R1 = aryl) and the cationic rhodium complex derived from bis(cyclooctadiene)rhodium(I) tetrafluoroborate with (R)-SEGPHOS.[109] Scheme 57 Rhodium(I)-Catalyzed Enantioselective Intramolecular Double [2 + 2 + 2] Carbocyclization of Bis(diynyl)malononitriles[109] R1 R1 O NC
X
NC
X
O
N
[Rh(cod)2]BF4/(R)-SEGPHOS (cat.) CH2Cl2, rt, 16−24 h
X X
O
O
R1
N R1
154
155
X
R1
mol% of Catalyst ee (%) Yield (%) Ref
CH2
Ph
10
64
99
[109]
CH2
4-ClC6H4
5
71
89
[109]
CH2
4-MeOC6H4
5
62
85
[109]
10
45
90
[109]
(CH2)2 Ph
4,4¢-Diphenyl-1,1¢,3,3¢,7,7¢,8,8¢-octahydro-6,6¢-spirobi[cyclopenta[b]furo[3,4-d]pyridine] (155, X = CH2; R1 = Ph); Typical Procedure:[109]
(R)-SEGPHOS (6.1 mg, 0.01 mmol) and [Rh(cod)2]BF4 (4.1 mg, 0.01 mmol) were dissolved in CH2Cl2 (1.0 mL) and the mixture was stirred at rt for 5 min. H2 was introduced into the resulting soln in a Schlenk tube. After stirring at rt for 0.5 h, the soln was concentrated and dissolved in CH2Cl2 (0.5 mL). To this soln was added a soln of bis(diynyl)malononitrile 154 (X = CH2; R1 = Ph; 45.8 mg, 0.10 mmol) in CH2Cl2 (0.25 mL) at rt, rinsing with CH2Cl2 (0.25 mL) to ensure complete transfer of the substrate. The mixture was stirred at rt for 16 h, concentrated, and purified by column chromatography (silica gel, CH2Cl2/EtOAc 100:3) to give a colorless solid; yield: 45.4 mg (99%); 64% ee {determined by HPLC using a chiral column [Chiralpak OD-H, hexanes/iPrOH 7:3; flow rate 0.9 mL • min–1; tR 9.5 min (major isomer) and 12.9 min (minor isomer)]}; [Æ]D25 –200.7 (c 1.06, CHCl3); mp 212.5– 213.5 8C. 3.4.1.3.4
Control of Planar Chirality
3.4.1.3.4.1
Cocyclization of Internal Diynes and Di-tert-butyl Acetylenedicarboxylate
The stereoselective construction of planar chirality via an asymmetric rhodium(I)-catalyzed [2 + 2 + 2] carbocyclization is nicely illustrated by the synthesis of chiral metacyclophanes. For instance, treatment of the methoxymethyl-substituted ether-linked internal [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
[m + n + 2]-Carbocyclization Reactions
3.4
diynes 156 with di-tert-butyl acetylenedicarboxylate in the presence of bis(cyclooctadiene)rhodium(I) tetrafluoroborate/(S)-Xyl-H8-BINAP affords the corresponding [6]-, [7]-, and [9]metacyclophanes 157 as the major products and with excellent enantioselectivity, along with minor amounts of the ortho- and/or paracyclophane regioisomers (Scheme 58). Nevertheless, this strategy does not enable the construction of [8]- and [15]metacyclophanes, and the [10]–[12]metacyclophanes are isolated with significantly lower enantioselectivities. It is also interesting to note that the cycloadduct generated from deca-1,9-diyne and diethyl acetylenedicarboxylate does not exhibit planar chirality, whereas the related ether-linked terminal 1,9-diyne, 1,2-bis(prop-2-ynyloxy)ethane, furnishes the [6]metacyclophanes with poor asymmetric induction (23% ee). Scheme 58 Rhodium(I)-Catalyzed Enantioselective [2 + 2 + 2] Carbocyclization of Internal Diynes and Di-tert-butyl Acetylenedicarboxylate[110,111]
P P
(S)-Xyl-H8-BINAP
OMe
CO2But
O +
n
O
10 mol% [Rh(cod)2]BF4/(S)-Xyl-H8-BINAP CH2Cl2, rt
CO2But OMe 156 O CO2But
n
CO2But MeO
O
OMe 157
n
Ratio (ortho/meta/para) ee (%) of 157 Yield (%) of 157 Ref
0
98
10
[110,111]
C=O 2 15:13
>98
13
[110,111]
C=O 3 40:10
98
10
[110,111]
C=O 4 23:13
91
13
[110,111]
CH2
1 37:25
90
25
[110,111]
CH2
2 35:33
93
33
[110,111]
CH2
3 15:21
94
21
[110,111]
CH2
4 23:30
93
30
[110,111]
(–)-[7]Metacyclophane 159 (X = CH2; n = 1); Typical Procedure:[110,111]
Under argon, a soln of (R)-H8-BINAP (7.9 mg, 0.0125 mmol) in CH2Cl2 (1.0 mL) was added to a soln of [Rh(cod)2]BF4 (5.1 mg, 0.0125 mmol) in CH2Cl2 (1.0 mL) at rt. The mixture was stirred at rt for 5 min. H2 was introduced into the resulting soln in a Schlenk tube. After being stirred at rt for 0.5 h, the resulting soln was concentrated to dryness and the residue was dissolved in CH2Cl2 (20 mL). To this soln was added dropwise over 10 min a soln of [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
206
Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
triyne 158 (X = CH2; n = 1; 69.6 mg, 0.250 mmol) in CH2Cl2 (2.0 mL), rinsing with additional CH2Cl2 (3.0 mL) to ensure complete transfer of the substrate. The soln was stirred at rt for 16 h, concentrated, and purified by preparative TLC (silica gel, hexane/EtOAc 1:2) to give a colorless solid; yield: 17.5 mg, (25%); 90% ee {determined by HPLC using a chiral column [Chiralcel AD-H, hexane/iPrOH 95:5; flow rate 1.0 mL • min–1; tR 16.1 min (major isomer) and 22.6 min (minor isomer)]}; [Æ]D25 –16.4 (c 0.250, acetone). The regioisomeric [7]orthocyclophane was also obtained as a colorless solid; yield: 25.8 mg (37%). Iridium(I)-Mediated [2 + 2 + 2] Carbocyclizations
3.4.1.4
Iridium complexes also catalyze [2 + 2 + 2]-carbocyclization reactions to provide benzene and cyclohexa-1,3-dienes from the combination of 1,6-diynes with monoalkynes and alkenes, respectively. Complexes derived from bis[chloro(cyclooctadiene)iridium] and a diphosphine ligand provide the optimal catalytic system for a number of synthetic applications. Nevertheless, only a few asymmetric iridium-catalyzed [2 + 2 + 2] transformations have been reported, and most of these studies are dedicated to controlling axial chirality in the synthesis of enantioenriched biaryls. 3.4.1.4.1
Control of Axial Chirality
3.4.1.4.1.1
Cocyclization of 1,n-Diynes and Internal Alkynes
The first intermolecular [2 + 2 + 2] carbocyclization that employed a chiral iridium catalyst was reported for symmetrical 1,6-diynes with internal monoalkynes for the construction of axially chiral 1¢,4¢-teraryls. For example, treatment of the 1-naphthyl-substituted 1,6-diynes 160 with a symmetrical alkyne in the presence of bis[chloro(cyclooctadiene)iridium] with (S,S)-Me-DuPhos, furnishes 161 as a unique dl-isomer with excellent enantioselectivity (>99% ee) (Scheme 60). Additionally, the carbocyclization of unsymmetrical 1,6-diynes 162 with internal monoalkynes also provide excellent levels of stereoselectivity in this process (Scheme 61).[112,113] Scheme 60 Iridium(I)-Catalyzed Enantioselective and Diastereoselective Intermolecular [2 + 2 + 2] Carbocyclization of 1,7-dinaphthyl-1,6-diynes and Internal Monoalkynes[112,113]
P
P
(S,S)-Me-DuPhos
R1
10 mol% [IrCl(cod)]2
R1
20 mol% (S,S)-Me-DuPhos
X
+
X
R2
R2
160
161
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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[2 + 2 + 2]-Carbocyclization Reactions
3.4.1
X
R1
R2
Solvent Temp (8C) Time (h) dr
O
CH2OMe
CH2OMe
xylene
100
ee (%) Yield (%) Ref
1
>20:1a >99
83
[112]
a
O
CH2OTBDMS
CH2OTBDMS
xylene
100
1
>20:1
>99
74
[112]
NTs
CH2OMe
CH2OMe
xylene
100
1
>20:1a >99
92
[112]
1
a
>99
77
[112]
a
>99
C(CO2Et)2 CH2
CH2OMe
CH2OMe
CH2OMe
O
xylene
CH2OMe
CH2N(Ac)Bn
100
xylene
CH2N(Ac)Bn
100
xylene
>20:1
1
100
>20:1
2
CH2
CH2N(Ac)Bn
CH2N(Ac)Bn
xylene
100
1
CH2
CH2N(Ac)Bn
Me
xylene
100
0.3
1:2
a
4:1
a
5:1
96
[112]
>99
b,c
64
[113]
>99
b,c
75
[113]
>99d
95
[113]
e
>20:1
>95
94
[113]
60
–e
>20:1
>99
24
[113]
O
CH2N(Me)Ts
CH2OH
xylene
O
P(O)Ph2
Me
xylene
O
CH2OH
CH2OH
DME
reflux
2
>20:1
>99
62
[113]
CH2
CH2OH
CH2OH
DME
reflux
2
>20:1
>99
87
[113]
O
CH2OH
Me
DME
reflux
3
>20:1
89
89
[113]
CH2
CH2OH
Me
DME
reflux
2
>20:1
99
87
[113]
81
[113]
O
CO2Me
CO2Me
rt
xylene
–
100
2
a
>99
a
5:1
b
NTs
CO2Me
CO2Me
xylene
100
1
>20:1
99
86
[113]
O
CO2Me
Me
xylene
100
1
>20:1
>99
>95
[113]
a b c d e
Ratio (dl/meso). ee of the dl isomer. Yield and ee of the cycloadduct after reduction by LiAlH4. Both the major and minor isomers are produced in >99% ee. Not reported.
Scheme 61 Iridium(I)-Catalyzed Enantioselective and Diastereoselective Intermolecular [2 + 2 + 2] Carbocyclization of 2-Substituted-Phenyl 1,6-Diynes and Internal Monoalkynes[112,113]
R1 R1
R3
10 mol% [IrCl(cod)]2
X R2
R3
20 mol% (S,S)-Me-DuPhos
+
X R4
R4
R2
162
X
R1
R2
O
Me 2-Tol
R3
R4
Solvent Temp (8C)
CH2OMe
CH2OMe
xylene
100
Time (h) ee (%) Yield (%) Ref 1
>99
85 a
O
Me 2-Tol
CH2OH
CH2OH
DME
reflux
2
>99
O
Cl
CH2OMe
CH2OMe
xylene
100
1
98
2-ClC6H4
C(CO2Et)2
Me Me
CH2OMe
CH2OMe
xylene
100
C(CO2Et)2
Me H
CH2OH
CH2OH
DME
reflux
C(CO2Et)2 a b c d
Cl
H
CH2OH
CH2OH
DME
reflux
b
80 85
c
[112] [113] [112]
1
81
85
[112]
12
83
38d
[112]
92
d
[113]
6
52
ee of the dl isomer. Ratio (dl/meso) >20:1. Using (S,S)-Et-DuPhos as ligand. Using 5 mol% [IrCl(cod)]2/10 mol% (S)-BINAP.
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
The consecutive intermolecular carbocyclization of tetraynes, and an octayne, including a naphthalene spacer with monoalkynes provides a strategy to biaryl systems with four, and eight, axial chiral motifs, thus affording helically chiral quinquearyl and noviaryl derivatives with excellent enantiomeric excess. For example, treatment of tetrayne 163 with 1,4-dimethoxybut-2-yne in the presence of the chiral iridium complex derived from bis[chloro(cyclooctadiene)iridium] and (S,S)-Me-DuPhos affords 164 in excellent yield and with outstanding enantioselectivity (99% ee) (Scheme 62). Alternatively, tetraynes with a 1,3-diyne linker furnish the corresponding axially chiral biaryl systems under similar conditions. Treatment of the tetrayne 165 with 1,4-bis(tert-butyldimethylsiloxy)but-2-yne and a chiral iridium complex furnishes the chiral biaryl system 166 in modest yield and with very good enantioselectivity (Scheme 63). The enantiomeric excess (89% ee) was determined using the corresponding deprotected tetraol compound.[114,115] Scheme 62 Iridium(I)-Catalyzed Enantioselective Intermolecular [2 + 2 + 2] Carbocyclization of a Naphthalene-Bridged Tetrayne and 1,4-Dimethoxybut-2-yne[114,115]
OMe
O
OMe OMe
O O
+
20 mol% [IrCl(cod)]2 40 mol% (S,S)-Me-DuPhos xylene, 100 oC, 10 min 89%; >99% ee
OMe MeO MeO
163
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
O
164
3.4.1
209
[2 + 2 + 2]-Carbocyclization Reactions
Scheme 63 Iridium(I)-Catalyzed Enantioselective Intermolecular [2 + 2 + 2] Carbocyclization of a Tetrayne Possessing a 1,3-Diyne Moiety and 1,4-Bis(tert-butyldimethylsiloxy)but-2yne[115] PPh2
EtO2C
CO2Et
40 mol%
TBDMSO
PPh2 Chiraphos 20 mol% [IrCl(cod)]2 xylene, 100 oC, 3 h
Ph Ph
+
49%; 89% ee
TBDMSO EtO2C
CO2Et 165 Ph EtO2C
OTBDMS
EtO2C
OTBDMS
EtO2C
OTBDMS
EtO2C
OTBDMS Ph 166
(+)-[5,6-Bis(methoxymethyl)-4,7-bis(1-naphthyl)-1,3-dihydrobenzo[c]furan (161, R1 = R2 = CH2OMe; X = O); Typical Procedure:[112]
(S,S)-Me-DuPhos (6.4 mg, 0.021 mmol) and [IrCl(cod)]2 (7.1 mg, 0.0105 mmol) were stirred in degassed xylene (1.0 mL) at rt to give a reddish yellow soln. After the addition of a soln of 1,4-dimethoxybut-2-yne (36.0 mg, 0.315 mmol) in xylene (1.5 mL) and a soln of diyne 160 (X = O; 36.5 mg, 0.105 mmol) in xylene (1.5 mL), the resulting mixture was stirred under reflux for 1 h. The solvent was removed under reduced pressure, and purification of the crude products by TLC (silica gel, toluene/EtOAc 15:1) gave a white solid; yield: 40.3 mg (83%); (dl/meso) >20:1 (determined by 1H NMR); >99% ee (dl) {determined by HPLC using a chiral column [Daicel Chiralcel AD-H, iPrOH/hexane 2:98; tR 9 min (major isomer) and 12 min (minor isomer)]}; [Æ]D26 +43.37 (c 1.95, CHCl3); mp 161–162 8C. The CD spectrum of 161 prepared by (S,S)-Me-DuPhos showed a negative first Cotton effect at 299 nm and a positive second Cotton effect at 278 nm; therefore, the product has negative chirality and its absolute configuration was determined to be the S,S-form. 3.4.1.4.1.2
Intramolecular Cyclotrimerization of Triynes and Hexaynes
The intramolecular iridium-catalyzed [2 + 2 + 2] carbocyclization of symmetrical ortho-substituted-aryl 1,6,11-triynes provides a direct approach to atropisomeric 1,2-diarylbenzene derivatives. For example, treatment of the oxygen-tethered triyne 167 with the chiral iridium(I) catalyst used in the previous study affords the corresponding 1,2-bis(1-naphthyl)benzene 168 in 82% yield and with excellent enantioselectivity (90% ee), albeit with modest diastereocontrol (Scheme 64).[116] The extension of this process to hexaynes that contain a 1,3-diyne motif provides a convenient route to axially chiral polycyclic biaryls. This is nicely illustrated in the conversion of 169 to the biaryl system 170 in a highly enantioselective manner (97% ee) using (S)-XylBINAP as the chiral ligand (Scheme 65).[115]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
210
Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Scheme 64 Iridium(I)-Catalyzed Enantioselective Intramolecular [2 + 2 + 2] Carbocyclization of a 1,6,11-Triyne[116]
10 mol% [IrCl(cod)]2 20 mol% (S,S)-Me-DuPhos xylene, 60 oC, 30 min
O
82%; (dl/meso) 5:1; 90% ee (dl isomer)
O O
167
O
168
Scheme 65 Iridium(I)-Catalyzed Enantioselective Intramolecular [2 + 2 + 2] Carbocyclization of a 1,6,11,13,18,23-Hexayne[115] O
Ph O 10 mol% [IrCl(cod)]2
O
20 mol% (S)-XylBINAP xylene, rt, 15 min
O Ph
81%; 97% ee
O
Ph O
O Ph
O 169
170
(–)-4,5-Bis(1-naphthyl)-1,3,6,8-tetrahydrobenzo[1,2-c:3,4-c¢]difuran (168); Typical Procedure:[116]
(S,S)-Me-DuPhos (6.1 mg, 0.02 mmol) and [IrCl(cod)]2 (6.7 mg, 0.01 mmol) were stirred in degassed xylene (1.0 mL) at rt to give a reddish yellow soln. After the addition of a soln of triyne 167 (41.5 mg, 0.10 mmol) in xylene (3.0 mL), the mixture was stirred at 60 8C for 30 min. The solvent was removed under reduced pressure, and purification of the crude products by TLC (silica gel, benzene/EtOAc 20:1) gave a white solid; yield: 33.9 mg (82%); (dl/meso) 5:1 (determined by 1H NMR); 90% ee (dl) {determined by HPLC using a chiral column [Daicel Chiralpak AD-H 2, hexane/iPrOH 95:5; flow rate 1.0 mL • min–1; tR: 14 min (major isomer) and 15 min (minor isomer)]}; [Æ]D29 –347.9 (c 1.7, CHCl3); mp >230 8C. (–)-5,5¢-Diphenyl-1,1¢,3,3¢,6,6¢,8,8¢-octahydro-4,4¢-bibenzo[1,2-c:3,4-c¢]difuran (170); Typical Procedure:[115]
[IrCl(cod)]2 (10.8 mg, 0.016 mmol) and (S)-XylBINAP (23.6 mg, 0.032 mmol) were stirred in xylene (1.7 mL) at rt to give a reddish soln. Hexayne 169 (76.0 mg, 0.16 mmol) in xylene (4.8 mL) was added to the soln and the mixture was stirred at rt. The solvent was removed under reduced pressure, and the crude products were purified by column chromatography (Florisil) to give a yellow oil; yield: 62 mg (81%); 97% ee {determined by HPLC using a chiral column] Daicel Chiralpak AD, hexane/iPrOH 4:1; flow rate 1.0 mL • min–1); tR 15 min (major isomer) and 22 min (minor isomer)]}; [Æ]D26.7 –23.8 (c 1.58, CHCl3).
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.1.5
211
[2 + 2 + 2]-Carbocyclization Reactions
3.4.1
Nickel(0)-Mediated [2 + 2 + 2] Carbocyclizations
Since the pioneering work of Reppe on cyclotrimerization of alkynes, the nickel-catalyzed [2 + 2 + 2] carbocyclization has been the subject of significant interest. A variety of catalytic systems (including NiBr2/Zn/dppe and Ni(cod)2/N-heterocyclic carbene) are effective in catalyzing this reaction. For example, alkynes, arynes, isocyanates, carbon dioxide, aldehydes, and ketones undergo the [2 + 2 + 2]-carbocyclization reaction with monoalkynes and diynes to afford substituted benzene derivatives and heterocycles, e.g. pyrimidinediones, isocyanurates, pyridinones, pyranones, and pyrans. Although the first asymmetric version was performed with a chiral nickel complex, other applications involving nickel complexes have received relatively little attention, since only three examples have been reported, two of which appeared before 2003. 3.4.1.5.1
Control of Diastereoselectivity
3.4.1.5.1.1
Cocyclization between 1,6-Diynes and Activated Alkenes
The intermolecular nickel-catalyzed [2 + 2 + 2] carbocyclization of 1,6- and 1,7-diynes with Æ,-unsaturated ketones affords the corresponding bicyclohexa-1,3-dienes in moderate to high yield. For example, treatment of the mono- and disubstituted diynes with the binary metal system derived from nickel(II) chloride and zinc in conjunction with zinc(II) chloride and triethylamine additives provides the cycloadducts 171 and 172 with excellent regioselectivity, favoring the product with the acetyl group adjacent the trimethylsilyl group (Scheme 66). However, the reaction proceeds with poor diastereocontrol (up to 4:1), which can be attributed the nature and the substitution of the diyne. Alternatively, the unsubstituted terminal diynes provide the corresponding aromatized compounds directly.[117] Scheme 66 Nickel(0)-Catalyzed Intermolecular [2 + 2 + 2] Carbocyclization of 1,6/1,7-Diynes and Methyl Vinyl Ketone[117] 10 mol% NiCl2 Zn (1 equiv) ZnCl2 (1.4 equiv) Et3N (1.5 equiv) MeCN, reflux, 2 h
R2 O
TMS
O
TMS
R2
R1
R3
+ R1 R3
171
R1
R2
R3
dr
H
H
OTBDMS
ca. 4:1 80
[117]
H
OTBDMS
H
ca. 3:1 68
[117]
Me OTBDMS
H
ca. 2:1 63
[117]
Yield (%) Ref
O
TMS
10 mol% NiCl2 Zn (1 equiv) ZnCl2 (1.4 equiv) Et3N (1.5 equiv)
O
TMS
MeCN, reflux, 2 h
+
64%; dr ca. 4.1
OTBDMS
OTBDMS 172
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
5-Acetyl-1-(tert-butyldimethylsiloxy)-2,2-dimethyl-4-(trimethylsilyl)-2,3,5,6-tetrahydro1H-indene (171, R1 = R2 = H; R3 = OTBDMS); Typical Procedure:[117]
NiCl2 (13 mg, 0.1 mmol), ZnCl2 (190 mg, 1.4 mmol), Zn dust (66 mg, 1.0 mmol), MeCN (4 mL), and Et3N (152 mg, 1.5 mmol) were placed in a 20-mL three-necked flask, and the soln was stirred at rt for 5 min. To this suspension were added 1-(tert-butyldimethylsiloxy)-4,4-dimethyl-5-(trimethylsilyl)hepta-1,6-diyne (322 mg, 1.0 mmol) and methyl vinyl ketone (148 mg, 2.1 mmol) at rt, and the mixture was then stirred at reflux for 2 h. After cooling and the addition of aq HCl, the aqueous layer was extracted with Et2O. The combined organic layers were washed successively with aq NaHCO3 and brine, dried (MgSO4), and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, hexane/EtOAc 10:1) gave colorless crystals; yield: 313 mg (80%); bp 150 8C/1.2 Torr; Rf 0.4 (silica gel, hexane/EtOAc 10:1). 3.4.1.5.1.2
Cocyclization between Norbornadiene and Activated Alkenes
Nickel complexes promote the intermolecular [2 + 2 + 2] homo-Diels–Alder reaction between strained cyclic 1,5-dienes and activated alkenes to afford deltacyclanes. For example, methyl vinyl ketone reacts with norbornadiene using the catalytic system derived from bis(cyclooctadiene)nickel(0) and triphenylphosphine to afford the exo-cycloadduct exo-173 as the major product at high temperature (Scheme 67). Interestingly, the phenyl vinyl sulfoxide requires triisopropyl phosphite as the ligand, which results in the formation of exo-174 as the major stereoisomer at room temperature.[118] Scheme 67 Nickel(0)-Catalyzed Intermolecular [2 + 2 + 2] Homo-Diels–Alder Carbocyclization of Norbornadiene and Activated Alkenes[118] Ac (2 equiv) 5 mol% Ni(cod)2 10 mol% Ph3P 1,2-dichloroethane
+ Ac exo-173
Ac endo-173
Temp (8C) Ratio (exo-173/endo-173) Yield (%) Ref rt
14:1
85
[118]
80
>20:1
99
[118]
O (0.42 equiv) S Ph 5−10 mol% Ni(cod)2 10−20 mol% P(OPh)3 1,2-dichloroethane, rt
+
73%; (exo-174/endo-174) >19:1
S O exo-174
Ph
S
Ph
O endo-174
Methyl Tetracyclo[4.3.0.02,4.03,7]nonan-8-yl Ketone (173); Typical Procedure:[118]
In a glovebox, Ni(cod)2 (36 mg, 0.13 mmol) was added to a flame-dried flask equipped with a magnetic stirrer bar and a rubber septum. Ph3P (69 mg, 0.26 mmol) was introduced under a positive flow of N2, and a soln of norbornadiene (0.22 mL, 2.0 mmol) in 1,2-dichloroethane was added, followed by methyl vinyl ketone (0.32 mL, 4.0 mmol) as a neat liquid. [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.1
213
[2 + 2 + 2]-Carbocyclization Reactions
The mixture was stirred at rt under N2 for 16–48 h. The catalyst was oxidized by stirring with the flask open to the air for 1–2 h. The mixture was filtered through a plug of silica gel using CH2Cl2 (100 mL) as the eluant. Evaporation of the solvent gave a crude product, which was purified by Kugelrohr (bulb-to-bulb) distillation to give the cycloadduct; yield: 280 mg (85%); (exo/endo) 14:l. The same reaction was carried out at 80 8C; yield: 99%; (exo/ endo) >20:l. 3.4.1.5.2
Control of Central Chirality
3.4.1.5.2.1
Intermolecular Cyclotrimerization between Two Alkynes and an Alkene
The enantioselective nickel-catalyzed [2 + 2 + 2] carbocyclization of cyclic unsaturated ketones with two terminal or internal alkynes requires a dual catalyst system, which consists of a nickel complex modified by a monodentate dihydrooxazole and an aluminum phenoxide. The binary metal system {[Ni(acac)2/dihydrooxazole 175]/MenAl(OPh)3-n (n = 0–2)} facilitates the formation of the substituted bicyclohexa-1,3-dienes 177 with complete chemo- and regioselectivity, albeit with poor enantioselectivity (up to 34% ee) (Scheme 68). Interestingly, the introduction of the gem-diphenyl substituents on the dihydrooxazole ligand 176 improves the enantioselectivity (up to 77% ee), albeit to the detriment of the yield in some cases.[119] Scheme 68 Nickel(0)-Catalyzed Intermolecular [2 + 2 + 2] Carbocyclization of Alkynes and Cyclic Unsaturated Ketones[119] Ph O
O Ph
Ph
Ph N
N
Ph
(R)-175
Ph
(R)-176
5 mol% Ni(acac)2 10 mol% ligand Me3Al (0.4 equiv) PhOH (1 equiv)
O +
R2
R3
O
H
R2
THF, rt, 2 h
R1 R1
R1
R1 H R3
R3 R2
177
R1
R2
R3 Ligand
H
Et
Et (R)-175 34
77
[119]
H
Et
Et (R)-176 45
22
[119]
H
Bu
H (R)-176 66
48a
[119]
H
(CH2)2OTBDMS
H (R)-176 77
62
[119]
H
t-Bu
H (R)-176 72
58
[119]
H
Ph
H (R)-176 65
55
[119]
Me Et
Et (R)-176 21
44
[119]
a
ee (%) Yield (%) Ref
95% regioselectivity.
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
(–)-(3aR,7aS)-4,5,6,7-Tetraethyl-2,3,3a,7a-tetrahydro-1H-inden-1-one (177, R1 = H; R2 = R3 = Et); Typical Procedure:[119]
CAUTION: Neat trimethylaluminum is highly pyrophoric. A 1.0 M soln of Me3Al in hexane (0.4 mL, 0.4 mmol) was added to a soln of Ni(acac)2 (14 mg, 0.05 mmol) and the dihydrooxazole ligand (R)-175 (23 mg, 0.1 mmol) in THF (5 mL) at 0 8C under N2. After the soln was stirred for 5 min, PhOH (109 mg, 1.1 mmol) in THF (1 mL) was added, and the mixture was stirred for 5 min. To the resulting dark red soln were introduced hex-3-yne (180 mg, 2.2 mmol) and cyclopent-2-enone (82 mg, 1.0 mmol) at 0 8C, and the mixture was then stirred at rt for 2 h. A 0.2 M aqueous soln of HCl (30 mL) was added and stirring was continued for 10 min. The aqueous layer was extracted with Et2O. The combined organic layer was washed with brine, dried (MgSO4) for 30 min, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EtOAc 14:1) to give a colorless oil; yield: 189 mg (77%); 34% ee {determined by HPLC using a chiral column [Daicel Chiralpak AS, hexane/iPrOH 19:1; flow rate 0.2 mL min–1; tR 19.9 min (minor isomer) and 22.0 min (title compound)]}; [Æ]D22 –124 (c 0.51, CHCl3); bp 130 8C/2.5 Torr; Rf 0.31 (hexane/EtOAc 14:1). 3.4.1.5.2.2
Bimolecular Cocyclization of Diynes and Acetylene
The nickel-catalyzed desymmetrization of prochiral triynes with acetylene represents the first example of an asymmetric [2 + 2 + 2]-carbocyclization reaction. Treatment of the triyne 178 with excess acetylene furnishes the isoindoline 179 in 52% yield with 73% enantiomeric excess using the nickel complex derived from bis(cyclooctadiene)nickel(0) with (R,S)-BPPFA (1-[1¢,2-bis(diphenylphosphino)ferrocenyl]-N,N-dimethylethanamine) (Scheme 69). The enantiomeric excess of 179 is determined after conversion into the benzoyl derivative 180. The application of this strategy to the enantioselective construction of isoquinoline derivatives occurs with slightly lower enantioselectivity (up to 58% ee) using (S)-MeO-MOP [2-(diphenylphosphino)-2¢-methoxy-1,1¢-binaphthyl] as the chiral ligand.[120,121] Scheme 69 Nickel(0)-Catalyzed Desymmetrization of Symmetrical Branched Triynes through Intermolecular Enantioselective [2 + 2 + 2] Carbocyclization with Acetylene[120,121]
NMe2 PPh2 Fe PPh2 (R,S)-BPPFA
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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[2 + 2 + 2]-Carbocyclization Reactions
8 mol% Ni(cod)2 20 mol% (R,S)-BPPFA HC≡CH (4 equiv) THF, rt, 150 h
NTr TMS
NTr ∗
TMS
52%
TMS
TMS 178
179 1. silica gel 2. BzCl, NaHCO3 CH2Cl2 71%; 73% ee
NBz ∗
TMS TMS 180
2-Benzoyl-7-(trimethylsilyl)-1-(trimethylsilylethynyl)-2,3-dihydro-1H-isoindole (180); Typical Procedure:[121]
To a soln of Ni(cod)2 (8 mol%) and (R,S)-BPPFA (20 mol%) in degassed THF was added a soln of triyne 178 in degassed THF. Then, a 0.50 M soln of acetylene (4 equiv) in degassed THF was introduced at 0 8C. After being stirred for 150 h at rt, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel) to afford the trityl derivative 179 as a colorless solid (yield: 52%) and recovered starting material 178 (yield: 33%). After deprotection of the trityl group and conversion of the liberated amine into the N-benzoyl-protected analogue, the enantiomeric purity of 180 was determined by HPLC analysis using a chiral column (Daicel Chiralpak AS, hexane/PrOH 9:1); 73% ee. The absolute configuration of the dihydroisoindole derivative has not been determined. 3.4.1.5.3
Control of Helical Chirality
3.4.1.5.3.1
Cycloisomerization of Triynes
The asymmetric intramolecular [2 + 2 + 2] carbocyclization of triyne 181 using the catalytic system derived from bis(cyclooctadiene)nickel(0) and (S)-MeO-MOP in tetrahydrofuran at –20 8C provides the tetrahydro[6]-helicene 182 (R1 = H) in modest yield and poor enantioselectivity (up to 48% ee) (Scheme 70).[122] Similarly, the modified chiral ligand (S)-BnOMOP [(S)-2-(benzyloxy)-2¢-(diphenylphosphino)-1,1¢-binaphthyl] facilitates the preparation of the 3-methoxy derivative 182 (R1 = OMe) with similar enantiomeric excess (42% ee).[123] This methodology has also been extended to the synthesis of tetrahydro[7]helicene (+)-183, which is also obtained with low enantiomeric excess (40% ee) using (S)-MeO-MOP as the chiral ligand.[62,124] Scheme 70 Nickel(0)-Catalyzed Enantioselective [2 + 2 + 2] Cyclotrimerization of Triynes[62,122–124]
OMe
OBn
PPh2
PPh2
(S)-MeO-MOP
(S)-BnO-MOP
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
R1 R1 20 mol% Ni(cod)2 40 mol% ligand THF, −20 oC, 1−3 h
181
(+)-182
R1
Ligand
H
(S)-MeO-MOP 48
OMe (S)-BnO-MOP
ee (%) Yield (%) Ref 42
53
[122]
74
[123]
20 mol% Ni(cod)2 40 mol% (S)-MeO-MOP THF, rt, 1.5 h 40%; 41% ee
(+)-183
(+)-5,6,9,10-Tetrahydrohexahelicene (182, R1 = H); Typical Procedure:[122]
A Schlenk flask was charged with (S)-MeO-MOP (11.2 mg, 0.024 mmol) and flushed with argon, and the ligand was dissolved in THF (2 mL) at rt and then cooled to –20 8C. Then, 0.063 M Ni(cod)2 in THF (190 L, 0.012 mmol) was added and the mixture was stirred for 5 min. Triyne 181 (R1 = H; 20 mg, 0.060 mmol) in THF (1 mL) was added and the mixture was stirred at –20 8C for 2 h. Volatiles were removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, petroleum ether/Et2O 100:0 to 96:4) to give an amorphous solid; yield: 10.6 mg (53%); 48% ee [HPLC on an (R,R)-Whelk-01]. 3.4.1.6
Palladium(0)-Mediated [2 + 2 + 2] Carbocyclizations
Palladium complexes also catalyze inter- and intramolecular [2 + 2 + 2] cyclotrimerization of monoalkynes and triynes through a cascade process, which is based on the metals natural affinity for alkynes. Interestingly, arene motifs in polycyclic compounds are also accessible through the cocyclization of unusual -components, such as benzynes with diynes, and cyclohexa-1,3-dienes with enyne esters. 3.4.1.6.1
Control of Helical Chirality
3.4.1.6.1.1
Carbocyclization of Arynes with Alkynes
Arynes are highly reactive intermediates that can be generated from O-(trimethylsilyl)aryl trifluoromethanesulfonates with a fluoride source, such as cesium fluoride, and undergo facile cyclotrimerization with alkynes in the presence of a suitable palladium complex. A typical example is the synthesis of dimethoxypentahelicene 184 via an enantioselective palladium-catalyzed [2 + 2 + 2] carbocyclization of dimethyl acetylenedicarboxylate with [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.2
217
[3 + 2 + 2]-Carbocyclization Reactions
two molecules of 7-methoxy-1,2-didehydronaphthalene, using tris(dibenzylideneacetone)dipalladium with (R)-BINAP as the chiral ligand (Scheme 71). The pentahelicene 184 is isolated in poor yield, along with two other regioisomers, and with moderate enantioselectivity (up to 67% ee) under the optimized conditions.[125] Scheme 71 Palladium(0)-Catalyzed Enantioselective [2 + 2 + 2] Trimerization of 7-Methoxy1,2-didehydronaphthalene and Dimethyl Acetylenedicarboxylate[125]
TMS MeO
CO2Me
OTf +
5 mol% Pd2(dba)3 10 mol% (R)-BINAP CsF (2 equiv) THF, rt
MeO
11%; 67% ee
MeO
CO2Me CO2Me
CO2Me 184
(–)-Dimethyl (M)-9,12-Dimethoxydibenzo[c,g]phenanthrene-3,4-dicarboxylate (184); General Procedure:[125]
A soln of Pd2(dba)3•CHCl3 (5 mol%) and (R)-BINAP (10 mol%) in THF (2.5 mL) was stirred at rt for 20 min. Then, a soln of 7-methoxy-1-(trimethylsilyl)naphthalen-2-yl trifluoromethanesulfonate (ca. 0.32 mmol) in THF (4.0 mL), DMAD (140 mol%), and finely powdered anhyd CsF (200 mol%) were successively added. After being stirred at rt for 15 h, the mixture was concentrated under reduced pressure and quickly chromatographed (silica gel, hexanes/ Et2O 3:1) to afford a mixture of three regioisomers including the title compound. The ratio of regioisomers was determined by integration of diagnostic signals in the 1H NMR spectrum. A second chromatography allowed the isolation of pure pentahelicene as a solid, which was analyzed by HPLC analysis with a chiral column [Chiralpak AS, iPrOH/hexane 3:97 or OL-86, CH2Cl2/hexane 35:65] to determine the enantiomeric excess. 3.4.2
[3 + 2 + 2]-Carbocyclization Reactions
Although a large number of transition-metal-mediated reactions have been developed for the construction of six-membered rings, including [2 + 2 + 2] cocyclizations, only a few methods are available for the preparation of substituted seven-membered carbocycles. Among these, the transition-metal-mediated [3 + 2 + 2]-carbocyclization reaction provides a competitive one-step transformation. Nevertheless, since the pioneering work in the mid 1990s this topic has received limited attention, and even less in terms of synthetic applications. The significant developments in this area have focused mainly on six different inter- and intramolecular approaches, in which aspects of regio- and stereoselective have generally been addressed, with the notable exception of enantioselectivity. Intermolecular coupling between Å3-allyl complexes of ruthenium(II),[126] cobalt(III),[127] and iridium(III)[128] with two alkynes provides the corresponding Å5-cycloheptadienyl- and/or Å1,Å4-cycloheptadienylmetal complexes, depending upon the substitution pattern of the alkynes (see Sections 3.4.2.1, 3.4.2.2, and 3.4.2.4). The resulting Å5-cycloheptadienylcobalt trifluoromethanesulfonate complexes are highly reactive toward nucleophiles, such as malonate sodium salts (Scheme 72), as illustrated by the important contributions of Stryker.
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Scheme 72 Intermolecular [3 + 2 + 2] Carbocyclization To Give Å5-Cycloheptadienylmetal Complexes and Subsequent Nucleophilic Substitution[126–128] R1 MLn
R4 R3
R2
+
R4
M = Ru, Co, Ir
Nu− M = Co
R2 LnM
R3
R1 R4
R4 R3
Nu
R3
Nu [O]
R2
R2
LnCo R1
R1
Intermolecular nickel-catalyzed coupling of chromium Fischer alkenyl carbene complexes with two terminal alkynes has been used for the construction of cyclohepatriene–chromium complexes (Scheme 73) (see Section 3.4.2.5.2).[129] Scheme 73 Intermolecular Nickel(0)-Catalyzed Cyclization of Alkenyl Carbenes and Terminal Alkynes[129] R2
OMe
R1
Ni(cod)2 (cat.) MeCN, −10 oC to rt
R2
(OC)5Cr
+ R1
(OC)5Cr
R2
Ethyl cyclopropylideneacetate[130–133] or bicyclopropylidene[134] can be used as three-carbon synthons in nickel-catalyzed intermolecular coupling with alkynes and diynes (Scheme 74) (see Section 3.4.2.5.1).[135] Scheme 74 Intermolecular Nickel-Catalyzed Coupling Using Ethyl Cyclopropylideneacetate or Bicyclopropylidene[130–134] R1
CO2Et +
R3
CO2Et
Ni(cod)2 (cat.) Ph3P (cat.) toluene, rt
+ R4 R2
R1
R4
R1 R3
R2
Ni(cod)2 (cat.) Ph3P (cat.) toluene, rt
+ R1
Intermolecular coupling of 2-substituted allylic alcohols with alkynes to give cycloheptatrienes is catalyzed by palladium (Scheme 75).[136]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.2
219
[3 + 2 + 2]-Carbocyclization Reactions
Scheme 75
Palladium-Catalyzed [3 + 2 + 2] Carbocyclization Using Allyl Alcohols[136] Pd2(dba)3•CHCl3
R R
2
R1
(2-Tol)3P, TsOH
R1
1,2-dichloroethane
1
80 oC, 17 h
OH
+
+ R2 R2
R2 R2
R2
R2
R2 R2
R2
R1 = Me, Ph, 4-ClC6H4, 4-MeOC6H4, CO2Me; R2 = Me, Et
Alternatively, intermolecular rhodium-catalyzed coupling of alk-6-enylidenecyclopropanes with activated alkynes provides a route to fused methylenecycloheptenes (Scheme 76) (see Section 3.4.2.3.1).[137] Scheme 76 Rhodium-Catalyzed Intermolecular Carbocyclization of Alk-6-enylidenecyclopropanes and Activated Alkynes[137] [RhCl(cod)]2 (cat.) P(OPh)3 (cat.)
R3
H
H
toluene, reflux
X
X
+
R2 R1
E R1 R2
E
+
R3
X R1 R2
R3
E
X = NTs, O, C(CO2Me)2; E = CO2Me, Ac
Intramolecular palladium(0)-catalyzed cycloisomerization of enynylidenecyclopropanes provides tricyclic cycloheptene compounds (Scheme 77).[138] Scheme 77
Intramolecular Cycloisomerization of Enynylidenecyclopropanes[138] Pd2(dba)3 (cat.) (2,4-t-Bu2C6H3O)3P (cat.)
R1
X
H
dioxane, 90 oC
R1 H
X
Z Z X = O, C(CO2Et)2; Z = NTs, NMe, CH2, O, C(CO2Me)2;
R1
= H, CO2Et
3.4.2.1
Ruthenium(II)-Mediated [3 + 2 + 2]-Carbocyclization Reactions
3.4.2.1.1
Cocyclizations between an Å3-Allylruthenium(II) Complex and Alkynes
The (Å3-allyl)(Å6-hexamethylbenzene)ruthenium(II) trifluoromethanesulfonate (185) undergoes a [3 + 2 + 2] carbocyclization with alkynes to produce either Å5- or Å1,Å4-cycloheptadienyl complexes, depending on the nature of the substituents on the alkyne partner. The trifluoromethanesulfonate complex 185 is readily prepared in two steps by an allylation of Bennetts dimer {[Ru(C6Me6)Cl2]2} with tetraallylstannane and treatment with silver(I) trifluoromethanesulfonate.[139] The cocyclization reaction of 185 with two molecules of tert-butylacetylene provides the (1,4-di-tert-butyl-Å5-cycloheptadienyl)ruthenium(II) complex 186, while its reaction with dimethyl acetylenedicarboxylate affords the Å1,Å4-cycloheptadienyl complex 187 as a single diastereomer (Scheme 78). Oxidative decomplexation of 187 with iodine promotes the formation of the tricyclic lactone 188 in moderate yield.[126] [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Scheme 78 [3 + 2 + 2] Carbocyclization of (Å3-Allyl)(Å6-hexamethylbenzene)ruthenium(II) Trifluoromethanesulfonate with Alkynes[126,139]
1. (H2C=CHCH2)4Sn, MeCN, rt 2. AgOTf, acetone, rt
Cl
Ru
Cl Cl
Ru
Cl
Ru
80%
TfO 185 But But CH2Cl2, −78 oC to rt
+ Ru
64%
OTf−
But 186
MeO2C
CO2Me
Ru TfO
OTf−
Ru+
CH2Cl2, 0 oC to rt
CO2Me
75%
CO2Me MeO2C CO2Me
185
187 O I2 CHCl3, rt
O CO2Me
57%
CO2Me MeO2C 188
(Å3-Allyl)(Å6-hexamethylbenzene)ruthenium(II) Trifluoromethanesulfonate (185); Typical Procedure:[139]
A dry Schlenk flask was charged with [Ru(C6Me6)Cl2]2 (1.6 g, 2.39 mmol) and MeCN (200 mL), and the resulting red slurry was placed under N2. Tetraallylstannane (1.36 mL, 4.80 mmol) was added via syringe and the mixture was stirred at rt for 12 h, forming a clear orange soln. MeCN was removed under reduced pressure, leaving an oily orange residue. This crude mixture was placed under vacuum, and then transferred to a drybox, where it was rinsed with several portions of Et2O to remove triallylchlorostannane and unreacted tetraallylstannane. The crude product was recrystallized (toluene/hexane) to give orange crystals of RuCl(Å3-C3H5)(C6Me6); yield: 1.48 g (91%). A soln of RuCl(Å3C3H5)(C6Me6) in acetone (100 mL) was degassed and placed under N2. A soln of AgOTf (0.776 g, 3.02 mmol) in acetone (5 mL) was then added via syringe and a white precipitate was immediately observed. The mixture was allowed to stir at rt for a further 2 h and then quickly filtered through Celite to remove insoluble silver salts, and the bright orange soln was concentrated under reduced pressure. The resulting air-sensitive solid was transferred to the drybox, where it was dissolved in toluene and filtered through Celite again to remove any remaining traces of silver salts. The toluene was removed by evaporation under reduced pressure to give an orange solid, which was stored under N2; yield: 1.185 g (88%). [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.2
221
[3 + 2 + 2]-Carbocyclization Reactions
(1:3,4,5,6-Å)-1,2,3,7-Tetrakis(methoxycarbonyl)cyclohepta-3,5-dienyl)(Å6-hexamethylbenzene)ruthenium(II) Trifluoromethanesulfonate (187); Typical Procedure:[126]
A soln of Ru(Å3-C3H5)OTf(C6Me6) (185; 110 mg, 0.243 mmol) in CH2Cl2 was cooled to 0 8C using an ice bath, and DMAD (0.061 mL, 0.50 mmol) was added by syringe. After being stirred for 2 h at 0 8C, the soln was removed from the ice bath and stirring was continued for another 12 h at rt. After evaporation of the solvent, the residue was taken up in a minimum of CH2Cl2 and purified by flash chromatography (silica gel, CH2Cl2/MeOH 95:5) to give a yellow solid; yield: 137 mg (75%). Trimethyl 3-Oxo-4-oxatricyclo[3.3.1.02,8]non-6-ene-1,7,8-tricarboxylate (188); Typical Procedure:[126]
A soln of complex 187 (100 mg, 0.136 mmol), and I2 (110 mg, 0.433 mmol) in CHCl3 (7 mL) was placed in a small glass reaction vessel. The tube was sealed and heated to 50 8C using an oil bath, without stirring, for 48 h. After the reaction was cooled to rt, black crystals were removed by filtration and the brown filtrate was rinsed with 20% Na2S2O3. After removal of the solvent under reduced pressure, the residue was purified by flash chromatography (silica gel, CH2Cl2) to give a yellow oil; yield: 24 mg (57%). 3.4.2.2
Cobalt(III)-Mediated [3 + 2 + 2]-Carbocyclization Reactions
3.4.2.2.1
Cocyclizations between Å3-Allyl-Type Cobalt Complexes and Alkynes
The (Å3-allyl)cobalt(III) trifluoromethanesulfonate complexes 189 (R1 = H, Me) are readily prepared from the corresponding 1,3-dienes with bis(ethene)(Å5-pentamethylcyclopentadienyl)cobalt(I) and trifluoromethanesulfonic acid. These complexes undergo [3 + 2 + 2]carbocyclization reactions with two molecules of acetylene to furnish the red (Å5-cycloheptadienyl)cobalt(II) trifluoromethanesulfonate complexes 190 (Scheme 79). These types of allyl complexes are of particular interest owing to their high reactivity toward nucleophiles. For instance, treatment of 190 with the dimethyl malonate anion provides 191 in good yield and in a highly regio- and diastereoselective manner. The functionalized diene complexes 191 are demetalated with ferricenium salts in a two-phase solvent system, to produce the metal-free trans-1,3-disubstituted cycloheptadienes 192.[127]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Scheme 79 [3 + 2 + 2] Carbocyclization of (Å3-Crotyl)(Å5-pentamethylcyclopentadienyl)cobalt(III) Trifluoromethanesulfonates with Acetylene[127] Co(Cp∗)(H2C=CH2)2 hexane, 65 oC
Co(Cp∗) R1
R1
R1 Cp∗
TfOH Et2O, −78 oC to rt
H H CH2Cl2, −78 oC to rt
(Cp∗)Co+
Co
OTf−
NaCH(CO2Me)2 THF, rt
TfO R1 189
190
MeO2C
MeO2C CO2Me
CO2Me
[(Cp)2Fe]+PF6− MeCN/pentane, −35 oC to rt
(Cp∗)Co
R1
R1
191
192
R1
Yield (%) of 189 Yield (%) of 190 Yield (%) of 191 Yield (%) of 192 Ref
H
92
79
63
62
[127]
Me 89
80
89
49
[127]
Alternatively, the cyclic (Å3-allyl)cobalt(III) complex 193 can be generated in situ by oxidative addition of bis(ethene)(Å5-pentamethylcyclopentadienyl)cobalt(I) into an allylic bromide, which undergoes counterion exchange with a silver salt to afford the corresponding tetrafluoroborate. In the case of 2-bromo-1-methylenecyclohexane, the crude tetrafluoroborate complex undergoes a [3 + 2 + 2]-carbocyclization reaction with acetylene at room temperature to form the (Å5-cycloheptadienyl)cobalt(II) complex 194 in modest yield (Scheme 80). Sequential nucleophilic alkylation and oxidative decomplexation then results in the formation of trans-5,7-disubstituted cyclohepta-1,3-diene 195 as a single diastereomer.[127]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.2
223
[3 + 2 + 2]-Carbocyclization Reactions
Scheme 80 [3 + 2 + 2] Carbocyclization of (Å3-Methylenecyclohexyl)(Å5-pentamethylcyclopentadienyl)cobalt(III) Trifluoromethanesulfonate with Acetylene[127] Co(Cp∗)(η2-H2C=CH2)2 THF, 0 oC to rt
Cp∗ Co
59%
Br
Br
HC CH AgBF4 acetone, rt
193 Co+(Cp∗) BF4−
Co(Cp∗) NaCH(CO2Me)2 THF, rt 96%
H
H 194
CO2Me
MeO2C [(Cp)2Fe]+PF6− MeCN/pentane, −35 oC to rt 62%
H
CO2Me
MeO2C 195
(Å3-But-2-enyl)(Å5-pentamethylcyclopentadienyl)cobalt(III) Trifluoromethanesulfonate (189, R1 = H); Typical Procedure:[127]
In a drybox, a soln of Co(Cp*)(H2C=CH2)2 (103.5 mg, 0.414 mmol) in hexane (5 mL) was placed in a medium-walled glass vessel fitted with a vacuum stopcock. The reaction vessel was removed to a Schlenk line, the Teflon stopcock was replaced by a rubber septum under a N2 flow and buta-1,3-diene was bubbled through the soln for 20 min. The bomb was sealed and then heated to 65 8C for 5 h. The solvent was evaporated and the residue was dissolved in pentane and filtered through a plug of Celite in the drybox. Concentration gave Co(Cp*)(Å4-C4H6) as a dark red solid [94.9 mg (92%)], which was used without further purification. A soln of Co(Cp*)(Å4-C4H6) (82.2 mg, 0.331 mmol) in Et2O (6 mL) was placed on the Schlenk line and cooled to –78 8C. A 1 M soln of TfOH in Et2O (0.33 mL, 0.33 mmol) was added. The resulting mixture was allowed to warm to rt, and was stirred overnight. The solvent was evaporated and benzene (5 mL) (CAUTION: carcinogen) was added. After being stirred overnight at rt, the soln was filtered through a plug of Celite in the drybox. Lyophilization gave a brown powder [121.5 mg (92%)] which was recrystallized (toluene/pentane) at –35 8C to give dark brown needles; yield: 118.6 mg (90%). (Å5-Methylcycloheptadienyl)(Å5-pentamethylcyclopentadienyl)cobalt(III) Trifluoromethanesulfonate (190, R1 = H); Typical Procedure:[127]
Co complex 189 (98.5 mg, 0.247 mmol) was dissolved in CH2Cl2 (15 mL) under argon and cooled to –78 8C. Acetylene was bubbled through the soln for 15 min, after which the soln was slowly warmed to rt. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (silica gel, CH2Cl2/MeOH 96:4) to give an orange solid; yield: 88.5 mg (79%). {Å4-1-[Bis(methoxycarbonyl)methyl]-6-methylcyclohepta-2,4-diene}(Å5-pentamethylcyclopentadienyl)cobalt(I) (191, R1 = H); Typical Procedure:[127]
In a drybox, a soln of Co complex 190 (32.0 mg, 0.071 mmol) in dry THF (10 mL) was prepared. To this red soln, solid sodium dimethyl malonate (86.5 mg, 0.561 mmol) was added and the soln was stirred for 4 h. The color gradually darkened. The solvent was removed [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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[m + n + 2]-Carbocyclization Reactions
under reduced pressure and the residue was extracted with pentane until the extracts were colorless. The combined extracts were filtered through a Celite pad and the solvent was removed under reduced pressure, leaving a deep red oil; yield: 19.3 mg (63%). Dimethyl 2-(6-Methylcyclohepta-2,4-dienyl)malonate (192, R1 = H); Typical Procedure:[127]
To a cold (–35 8C) slurry of ferricenium hexafluorophosphate (143.5 mg, 0.439 mmol) in dry MeCN (10 mL) was added a soln of diene complex 191 (72.9 mg, 0.169 mmol) in pentane (10 mL). The cooling bath was removed and the soln was allowed to warm to rt. After the soln was stirred for 5 min, the pentane layer was separated. H2O (5 mL) was added to the MeCN layer, and the mixture was then was extracted with pentane (3 20 mL). The combined pentane layers were dried (MgSO4) and concentrated. The residue was purified by flash chromatography (silica gel, hexane/EtOAc 95:5) to give a colorless oil; yield: 25 mg (62%). 3.4.2.3
Rhodium(I)-Mediated [3 + 2 + 2]-Carbocyclization Reactions
3.4.2.3.1
Cocyclizations between Alk-6-enylidenecyclopropanes and Activated Alkynes
The rhodium-catalyzed [3 + 2 + 2] carbocyclization of alkenylidenecyclopropanes with unsymmetrical activated alkynes provides a powerful approach to cis-fused cycloheptadienes. For example, treatment of the alkenylidenecyclopropane 196 with an activated alkyne in the presence of the rhodium complex derived from bis[chloro(cyclooctadiene)rhodium] with triphenyl phosphite furnishes the cis-fused bicycloheptadiene 197 in high yield with almost complete chemo-, regio-, and diastereoselectivity (Scheme 81). The E-alkenyl substrate 196 (R2 = Me) leads to the stereospecific incorporation of an additional stereogenic center, whereas the Z-isomer leads to a complex mixture.[137] Scheme 81 Rhodium(I)-Catalyzed [3 + 2 + 2] Carbocyclization of Alk-6-enylidenecyclopropanes with Activated Alkynes[137] 4 mol% [RhCl(cod)]2
R3
H
24 mol% P(OPh)3
H O
toluene, 105 oC
X
R2 R1
X
+
R1 R2
R4
O
R3
197
196
X
R1
R2
R3
R4
NTs
H
H
Me OMe
NTs
Me H
H
NTS
H
NTs
Me H
NTs
H
O
Me H
O
Ratio (197/198) Yield (%)a Ref 80
[137]
5:1
85
[137]
Me Me
>19:1
82
[137]
H
>19:1
91
[137]
OMe >19:1
85b
[137]
H
OMe >19:1
68
[137]
Me H
H
Me
>19:1
83
[137]
C(CO2Me)
Me H
H
OMe
4:1
82
[137]
C(CO2Me)
Me H
H
Me
>19:1
95
[137]
a b
H
Me H
Me
Diastereoselectivity at the ring junction: dr >19:1. Diastereoselectivity between CR1 and CR2: dr >19:1.
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
R1 R2 198
10:1
OMe
R3
+ X R4
O R4
3.4.2
225
[3 + 2 + 2]-Carbocyclization Reactions
cis-Fused Cycloheptadienes 197 and 198; General Procedure:[137]
[RhCl(cod)]2 (0.01 mmol) and P(OPh)3 (0.06 mmol) were suspended in anhyd toluene (4 mL) under argon, and heated to 105 8C for ca. 10 min. The alkenylidenecyclopropane 196 (0.250 mmol) and alkyne (0.750 mmol) were dissolved in anhyd toluene (1 mL) and then added to the catalyst soln. The resultant soln was stirred at 105 8C for ca. 24 h (TLC monitoring) and was allowed to cool to rt. The soln was applied directly to a silica gel column without evaporation and purified by flash chromatography (silica gel, EtOAc/hexanes) to afford the bicycloheptadienes 197 and 198. 3.4.2.4
Iridium(III)-Mediated [3 + 2 + 2]-Carbocyclization Reactions
3.4.2.4.1
Cocyclizations between Å3-Allyliridium Complexes and Alkynes
The reactivity of allyliridium complexes in the metal-mediated [3 + 2 + 2]-carbocyclization reaction has been briefly examined. Diphenylacetylene reacts with (Å3-allyl)(but-2yne)iridium complex 200 to afford the tetrasubstituted (Å5-cycloheptadienyl)iridium(III) complex 201 in 55–60% yield, the structure of which has been confirmed by X-ray crystallography (Scheme 82).[128] The key (Å3-allyl)iridium–alkyne complex 200 is obtained in good yield by photolysis of the (Å3-allyl)(propene)iridium trifluoromethanesulfonate complex 199, which is prepared from bis[dichloro(Å5-pentamethylcyclopentadienyl)iridium] by sequential treatment with silver(I) trifluoromethanesulfonate and propene,[140] followed by complexation with but-2-yne.[141] Scheme 82 Iridium(III)-Catalyzed [3 + 2 + 2] Carbocyclization of Å3-Allyl(but-2-yne)iridium(III) with Diphenylacetylene[128,141]
Cp∗ Cl
1. AgOTf acetone, rt
Ir
Cl Cl
Ir
Cl Cp∗
hν acetone
Cp∗
2. MeCH=CH2
OTf−
Ir+
81%
0 oC
Cp∗ Ir
95%
TfO 199 Ph Et2O, benzene, rt
Cp∗ Ir+
79% (2 steps)
Ph
CH2Cl2
OTf−
0 oC, 12 h to rt, 24 h
Cp∗Ir+
Ph OTf−
55−60%
Ph 200
201
(Å3-Allyl)(Å2-but-2-yne)(Å5-pentamethylcyclopentadienyl)iridium(III) Trifluoromethanesulfonate (200); Typical Procedure:[141]
A soln of [Ir(Cp*)(Å3-C3H5)]OTf in benzene (CAUTION: carcinogen) was prepared by photolysis (Hanovia 450-W lamp) of [Ir(Cp*)(Å3-C3H5)(MeCH=CH2)]OTf (199; 194.5 mg, 0.348 mmol) in four portions of ca. 50 mg in acetone (5 mL) for 20 min under a strong N2 purge. Photolysis was followed by evaporation of the solvent under reduced pressure and extraction of the combined fractions into dry, degassed benzene. The benzene soln was transferred via cannula through a plug of Celite under a steam of N2 to remove insoluble salts and then concentrated under vacuum to a volume of approximately 2 mL. The soln was degassed via several freeze–pump–thaw cycles and then but-2-yne (350 Torr, 58.5 mL, 1.1 mmol) was added by vacuum transfer. The resulting mixture was stirred at rt for 35 min. Et2O (ca. 10 mL) was then added and the product precipitated out of the soln as a [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
colorless powder. This material was rinsed with several portions of Et2O and then dried for several hours under reduced pressure. The off-white solid was weighed under air; yield: 157.2 mg (79%). (Å5-6,7-Dimethyl-4,5-diphenylcycloheptadienyl)(Å5-pentamethylcyclopentadienyl)iridium(III) Trifluoromethanesulfonate (201); Typical Procedure:[128]
Allyl(but-2-yne)iridium(III) complex 200 (58.7 mg, 0.103 mmol) and diphenylacetylene (98 mg, 0.55 mmol) were placed in a small Schlenk flask capped with a rubber septum. An N2 atmosphere was established and the bottom of the flask was cooled to –60 8C. Precooled, deoxygenated CH2Cl2 (0.5 mL) was introduced via cannula. The mixture was warmed to 0 8C and stirred at that temperature for 12 h, and then warmed to rt and stirred for a further 24 h. The mixture was then concentrated to a volume of about 1 mL and a yellow oil separated upon addition of Et2O (5–10 mL). This oil became a beige foam upon exposure to vacuum. The crude material [74.6 mg (97%)] gave rise to a clean 1H NMR spectrum; integration of the 1H NMR spectrum against an internal standard at long pulse delay, however, indicated yields of complex 201 of 55–60%. Analytically pure material suitable for X-ray crystallography was obtained by crystallization (THF/Et2O) at –20 8C; yield: 20–30%. 3.4.2.5
Nickel(0)-Mediated [3 + 2 + 2]-Carbocyclization Reactions
3.4.2.5.1
Cocyclization of Ethyl Cyclopropylideneacetate and Alkynes or Diynes
The intermolecular nickel-catalyzed [3 + 2 + 2] carbocyclization has also proven to be an effective method for the construction of seven-membered carbocycles. Slow addition to the nickel complex derived from bis(cyclooctadiene)nickel(0) and triphenylphosphine to ethyl cyclopropylideneacetate and the requisite alkynes affords various substituted cycloheptadienes 202 in moderate to good yields with high regioselectivities, regardless of the substitution pattern on the alkyne, as single geometrical isomers (Scheme 83). In the case where identical terminal alkynes are employed, the presence of bulky groups at the termini controls the regioselectivity, whereas the steric hindrance of the substituents influence the overall efficiency.[130] Moreover, the combination of two different terminal alkynes in a 4:1 ratio also proceeds with excellent chemo-, regio-, and stereoselectivity, which further highlights the inherent versatility of this process.[131] In specific cases, internal alkynes can be successfully employed; however, they are significantly less reactive, as exemplified by diphenylacetylene. Nevertheless, the poor reactivity can be overcome using activated alkynes at elevated temperatures, such as dimethyl acetylenedicarboxylate at 50 8C.[132] Scheme 83 Nickel(0)-Catalyzed [3 + 2 + 2] Carbocyclization of Ethyl Cyclopropylideneacetate and Alkynes[130–132] CO2Et
10 mol% Ni(cod)2
CO2Et +
R1
R2
+
R3
R4
20 mol% Ph3P toluene, rt
R4
R1 R3
R2 202
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.2
227
[3 + 2 + 2]-Carbocyclization Reactions
R1
R2
R3
R4
Yield (%) Ref
TMS
H
TMS
H
70
[130]
t-Bu
H
t-Bu
H
89
[130]
Ph
H
Ph
H
74
[130]
CMe2OH
H
CMe2OH
H
56
TMS
H
Ph
Ph
CO2Et a
b
CMe2OH Ph
CO2Et CO2Et
H Ph
[131]
b
[132]
b
[132]
69 39
[130]
a
CO2Et 71
5 equiv of R1C”CR2 and 1 equiv of R3C”CR4 were used. Reaction was performed at 50 8C.
1,6-Diynes also participate in the cocyclization with ethyl cyclopropylideneacetate, to afford fused bicyclic cycloheptatriene systems. This process demonstrates that the geometrical isomers can be modulated using the requisite phosphine ligand, albeit with modest selectivity, as outlined in Scheme 84[135] Scheme 84 [3 + 2 + 2] Cocyclization of Ethyl Cyclopropylideneacetate and a Diyne: Influence of the Phosphine Ligands[135] CO2Et 10 mol% Ni(cod)2
EtO2C
20 mol% ligand toluene, rt
CO2Et +
+ N Bn N Bn
N Bn
Ligand Ratio (E/Z) Yield (%) Ref Ph3P
32:68
57
[135]
Et3P
87:13
73
[135]
Ethyl (E)-Cyclohepta-2,4-dienylideneacetates 202; General Procedure:[130,132]
To a dark red mixture of Ni(cod)2 (27.5 mg, 0.1 mmol) and Ph3P (52.5 mg, 0.2 mmol) in dry toluene (0.5 mL) was added dropwise a soln of ethyl cyclopropylideneacetate (126 mg, 1 mmol) and the alkyne (5 mmol) in dry toluene (0.5 mL) at rt over 5 h under argon. The mixture was stirred until the starting material disappeared (overnight), and then passed through a short column of silica gel (or alumina), eluting with Et2O. Evaporation of the solvent gave a residue, which was further purified by flash chromatography (silica gel, hexane/EtOAc 20:1). 3.4.2.5.2
Cocyclization of Chromium Fischer Carbene Complexes with Terminal Alkynes
The chromium Fischer alkenyl alkoxycarbene complexes 203 also undergo intermolecular nickel-catalyzed [3 + 2 + 2]-carbocyclization reactions with alkynes in the presence of bis(cyclooctadiene)nickel(0) to provide the cycloheptatriene–tricarbonylchromium(0) complexes 204 in good yields as the syn-diastereomer (Scheme 85). This reaction proceeds through chromium–nickel exchange followed by double regioselective alkyne insertion of the transient nickel carbene complex to provide 204.[129] [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Scheme 85 Nickel(0)-Catalyzed [3 + 2 + 2] Carbocyclization of Chromium Fischer Alkenylcarbene Complexes with Terminal Alkynes[129] R1
10 mol% Ni(cod)2
OMe R2
+ (OC)5Cr
R
MeO
MeCN, −10 oC to rt
R2
(OC)5Cr
1
R2 204
203
R1
R2
Yield (%) Ref
Ph
Pr
86
[129]
Ph
TMS
80
[129]
Ph
(CH2)3CN
78
[129]
a
75
[129]
2-furyl Pr
76
[129]
Pr
62
[129]
Ph
a
CO2Et Pr
Decomplexed product.
syn-(Å6-5-Methoxy-7-phenylcyclohepta-1,3,5-triene)tricarbonylchromium(0) Complexes 204 (R1 = Ph); General Procedure:[129]
To a soln of alkenylcarbene complex 203 (R1 = Ph; 169 mg, 0.5 mmol) and the terminal alkyne (1.5 mmol) in MeCN (7 mL) was added Ni(cod)2 (151 mg, 0.55 mmol) at –10 8C. The mixture was allowed to reach rt over 2 h. The solvent was then removed and the resulting residue was subjected to flash chromatography (silica gel, hexane/EtOAc 10:1) to give the corresponding tricarbonyl(cycloheptatriene)chromium(0) complex as a red solid. 3.4.3
[4 + 2 + 2]-Carbocyclization Reactions
Since 1990, a number of new strategies have been developed for the construction of eightmembered carbocycles. The transition-metal-catalyzed [4 + 2 + 2] carbocyclization provides an attractive and efficient method for the construction of this type of ring system.[142] Many of these investigations involve the assembly of unsaturated partners using ruthenium, cobalt, rhodium, and nickel catalysts. In most cases, the cycloadducts can be obtained directly with high regio-, chemo-, and stereoselectivities, as outlined below: The intermolecular coupling of a 1,3-diene with two alkynes,[143,144] or norbornadi[145] and related compounds[146] (Scheme 86) (see Section 3.4.3.1.1). ene Scheme 86 Intermolecular Coupling of 1,3-Dienes with Two Alkynes or Norbornadiene and Derivatives[143–146] A: [CoL]Br2 (cat.) Fe, Zn, ZnI2 CH2Cl2
R2
R1 +
B: [RhCl(cod)]2 (cat.) AgOTf (cat.) toluene, 15−20 oC
R3
R2
R2
R3 +
2 R2 R3
R1 R3
R1 = H, Me; L = N
NPri
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
R2
R1 R3
3.4.3
229
[4 + 2 + 2]-Carbocyclization Reactions X
Co(acac)2 (cat.) dppe or (R)-Prophos (cat.)
X
Et2AlCl, benzene, rt
+ R1
R1 (R)-Prophos = Ph2P
PPh2
Intermolecular coupling of a diyne with a 1,3-diene[147] or a cyclobutanone[148] (Scheme 87). Intermolecular Coupling of 1,3-Dienes with a Diyne[147,148]
Scheme 87
R1 X
R1
[RuCp(MeCN)3]PF6 (cat.) Et4NCl (cat.) DMF
+
X R2
R2
X = C(CO2Me)2, NTs, O
O R1 X
+ R1
R2
R3
Ni(cod)2 (cat.) Pri Bu3P, Cy3P, or
N Pri
Pri (cat.)
N
R1
O
Pri
toluene, rt or reflux
X
R2 R3 R1
X = C(CO2Me)2, C(CH2OMe)2, NTs, O, (CH2)2
Intermolecular coupling of a 1,6-enyne with a buta-1,3-diene (Scheme 88) (see Section 3.4.3.2.1).[149–154] Scheme 88 Intermolecular Coupling of 1,6-Enynes with Buta-1,3diene[149–153]
R1 X
R1
RhCl(PPh3) (cat.) AgOTf (cat.) toluene, reflux
+
R2
X R2
H
X = NTs, SO2, O
Intermolecular coupling of a dienyne[155,156] or an enediene[157] with a terminal alkyne (Scheme 89) (see Sections 3.4.3.2.2 and 3.4.3.2.3). [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
230
Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
Intermolecular Coupling of Dienynes and Trienes with Terminal Alkynes[155–157]
Scheme 89
R2
R2 [RhCl(nbd)]2/Me-DuPhos/AgSbF6 (1:2:1) (cat.) CH2Cl2/EtOAc (6:1), 60 oC
X
X R1
R1 H
X = O, NTs
R4 [RhCl(CO)2]2 (cat.) AgSbF6 (cat.)
R1
X
R3
R1
1,2-dichloroethane 40 oC
R4
R1
X
+
R4
X
R3 H
2
R
R3 H
R2
R2
X = O, NTs, C(CO2Me)2
Intermolecular coupling of a dienyl isocyanate with a terminal alkyne (Scheme 90) (see Section 3.4.3.2.4).[158] Scheme 90
Intermolecular Coupling of Dienyl Isocyanates with Terminal Alkynes[158]
O
O
O
O
P
N
(cat.)
O O
R1 +
R2
•
N
[RhCl(H2C=CH2)2]2 (cat.) toluene, 110 oC
R1
N
R2
H
3.4.3.1
Cobalt-Mediated [4 + 2 + 2]-Carbocyclization Reactions
3.4.3.1.1
Cocyclization of Norbornadiene with 2-Substituted Buta-1,3-dienes
The intermolecular cobalt-catalyzed [4 + 2 + 2] carbocyclization of strained cyclic 1,5-dienes with acyclic 1,4-dienes provides an expedient route to polycyclic carbocycles with an embedded cyclooctanoid ring. For example, treatment of norbornadiene with isoprene in the presence of the cobalt catalyst derived from the reduction of bis(acetylacetonato)cobalt(II) with diethylaluminum chloride, in combination with 1,2-bis(diphenylphosphino)ethane, furnishes the deltacyclene 205 (R1 = Me) in moderate yield. The enantioselective variant with various 2-substituted buta-1,3-dienes affords the cycloadducts with modest enantioselectivities (up to 79% ee) using (R)-Prophos [1,2-bis(diphenylphosphino)propane] as the chiral diphosphine ligand (Scheme 91). Alternatively, the intramolecular cobalt-catalyzed [4 + 2 + 2] carbocyclization of the tethered norbornadienyl-1,3-diene 206 provides the unusual and strained polycyclic structure 207 as a single diastereomer (Scheme 92).[145] [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.3
231
[4 + 2 + 2]-Carbocyclization Reactions
Scheme 91 Cobalt-Catalyzed [4 + 2 + 2] Carbocyclization of Norbornadiene and Various 2-Substituted Buta-1,3-dienes[145]
Ph2P
PPh2
(R)-Prophos
2 mol% Co(acac)2 2 mol% ligand 8 mol% Et2AlCl benzene, rt
+ R1 R1 205
R1
Ligand
ee (%) Yield (%) Ref
Me
dppe
–
40a
[145]
Me
(R)-Prophos
72
66
[145]
(CH2)8Me
(R)-Prophos
74
40
[145]
(CH2)2CH=CMe2
(R)-Prophos
79
49
[145]
(CH2)3OTBDMS
(R)-Prophos
73
40
[145]
(CH2)3OAc
(R)-Prophos
73
52
[145]
CH2TMS
(R)-Prophos
71
49
[145]
a
Using Co(acac)3 as the precatalyst; the yield was improved by 5–10% with Co(acac)2.
Scheme 92 Cobalt-Catalyzed Intramolecular [4 + 2 + 2] Carbocyclization of a 1,3-Dienyl-Linked Norbornadiene[145] 8 mol% Co(acac)2 8 mol% dppe 32 mol% Et2AlCl benzene, rt 40%
H
206
207
6-Substituted 1,2,3,3a,4,5,8,8a-Octahydro-1,2,4-(epimethanetriyl)azulenes 205; General Procedure:[145]
To a flame-dried flask equipped with a magnetic stirrer bar, a rubber septum, and a temperature probe were added Co(acac)2 (2 mol%) and the chiral phosphine ligand (2 mol%). The flask was flushed with argon, then benzene (CAUTION: carcinogen), norbornadiene (1 mmol), and the 2-substituted buta-1,3-diene (1.5–3 mmol) were added. A soln of Et2AlCl (4 mol%) in toluene was added dropwise and the temperature was monitored using an internal temperature probe. The temperature was controlled by placing a cool water bath under the flask when necessary. It is important that the reaction temperature remains above 24–25 8C to promote the reaction, but below 30–35 8C to optimize asymmetric induction. The reaction turned brownish green upon addition of Et2AlCl. The reaction was stirred at rt for 1–4 d. The workup consisted of passing the mixture through a short plug of
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
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[m + n + 2]-Carbocyclization Reactions
silica gel to remove the catalyst, and removal of solvent under reduced pressure to give dark green oils, which were purified by bulb-to-bulb distillation or flash chromatography to obtain clear, colorless oils. 3.4.3.2
Rhodium(I)-Mediated [4 + 2 + 2]-Carbocyclization Reactions
3.4.3.2.1
Cocyclization of Enynes with Buta-1,3-dienes
The intermolecular rhodium-catalyzed [4 + 2 + 2] carbocyclization of 1,6-enynes with 1,3dienes has emerged as an efficient method for the stereoselective construction of 5,8-bicyclic octadiene systems. Interestingly, the chemoselectivity is heavily influenced by the nature of the silver salt additive. For instance, when trifluoromethanesulfonate is the counterion, the desired cycloadduct is formed almost exclusively, whereas the hexafluoroantimonate counterion leads to homodimerization of the enyne.[149,153,154] Treatment of substituted nitrogen-tethered enyne derivatives 208 and buta-1,3-diene using the silver(I) trifluoromethanesulfonate modified rhodium(I) N-heterocyclic carbene complex chloro(cyclooctadiene)(1,3-dimesityl-1,3-dihydro-2H-imidazol-2-ylidene)rhodium(I) [RhCl(IMes)(cod)] affords a variety of bicyclic cyclooctadienes 209 in excellent yields (Scheme 93). The procedure allows two or three stereocenters to be constructed in a single operation with complete cis/cis and cis/trans diastereoselectivity, respectively.[150–152] Scheme 93 Rhodium(I)-Catalyzed [4 + 2 + 2] Carbocyclization of 1,6-Enynes and Buta-1,3diene[150–152] R3 TsN
toluene, reflux
+ R
R3
10 mol% RhCl(IMes)(cod) 20 mol% AgOTf
R3
TsN
+
TsN
1
R1
R2 208
H R2
R1
209A
H R2 209B
R1
R2
R3
Me
H
Me >19:1
84
[150]
iPr
H
Me >19:1
84
[150]
Bn
H
Me >19:1
79
[150]
CH2OH
H
Me >19:1
55
[150]
CH2OTBDMS
H
Me >19:1
83
[150]
CO2Me
H
Me >19:1
71
[150]
CH=CH2
H
Me >19:1
81
[150]
Ph
H
Me >19:1
89
[150]
Me
CH2OTBDMS
Ph >19:1
70
[150]
dr (209A/209B) Yield (%) Ref
Nevertheless, a critical problem with this process is the inability to utilize substituted 1,3dienes. The temporary silicon-tethered variant provides complete chemo-, regio-, and diastereoselectivity with substituted 1,3-dienes and also reduces the necessity for a large excess of the diene. For example, treatment of the silicon-tethered 1,3-dienes 210 with Wenders catalyst, cyclooctadiene(Å6-naphthalene)rhodium(I) hexafluoroantimonate {[Rh(cod)(Np)]SbF6}, in acetonitrile furnishes the tricyclic octanoids 211 in high yields as single regioisomers and diastereomers (Scheme 94). This reaction is stereospecific with respect to the alkene, which provides a convenient method for constructing either (trans,[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.3
233
[4 + 2 + 2]-Carbocyclization Reactions
cis)-211A and (cis,trans)-211A from (E)- and (Z)-210, respectively. In contrast, the intermolecular reactions of 1,6- enynes with substituted 1,3-dienes afford a mixture of regioisomers. Scheme 94 Rhodium (I)-Catalyzed [4 + 2 + 2] Intramolecular Carbocyclization of SiliconTethered 1,6-Enynyl 1,3-Dienes[153] R1 20 mol% [Rh(cod)(Np)]SbF6 MeCN, 110 oC
X O
Si Pri Pri
(E)-210
R1
R1 X
X +
H
H
Si Pri O Pri
O
(trans,cis)-211A
(trans,trans)-211B
X
R1
dr [(trans,cis)-211A/(trans,trans)-211B] Yield (%) Ref
NTs
H
>19:1
75
[153]
NTs
Me >19:1
85
[153]
O
H
>19:1
73
[153]
C(CO2Et)2
H
>19:1
86
[153]
R1
R1
20 mol% [Rh(cod)(Np)]SbF6
X
MeCN, 110 oC
X
R1 +
H
Si Pri O Pri (Z)-210
Si Pri Pri
Si Pri O Pri
(cis,trans)-211A
X H O
Si Pri Pri
(cis,cis)-211B
Np = naphthalene
X
R1
dr [(cis,trans)-211A/(cis,cis)-211B] Yield (%) Ref
NTs
H
>19:1
60
[153]
NTs
Me >19:1
71
[153]
O
H
>19:1
39
[153]
C(CO2Et)2
H
>19:1
71
[153]
Chloro(cyclooctadiene)(1,3-dimesityl-1,3-dihydro-2H-imidazol-2-ylidene)rhodium(I):[150]
Ag2O (231 mg, 1.0 mmol) was added to a stirred soln of 1,3-dimesitylimidazolium chloride (685 mg, 2.0 mmol) in CH2Cl2 (15 mL) at rt and allowed to stir for an additional 2 h. The resulting suspension was filtered through a small plug of Celite into a soln of [RhCl(cod)]2 (490 mg, 1.0 mmol) and CH2Cl2 (5 mL). The yellow soln was stirred at rt for ca. 18 h and the solvent was concentrated under reduced pressure to afford a crude solid. Purification by flash column chromatography (silica gel, Et2O/pentane 1:9 to 1:1) afforded orange-yellow crystals; yield: 938 mg (86%); mp 212–214 8C. [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
234
Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
3,9-Dimethyl-2-tosyl-2,3,3a,4,5,8-hexahydro-1H-cycloocta[c]pyrrole (209A, R1 = R3 = Me; R2 = H); Typical Procedure:[150]
AgOTf (13.0 mg, 0.05 mmol) was added to RhCl(IMes)(cod) (14.0 mg, 0.025 mmol) in anhyd toluene (5.0 mL) under N2 in a sealed tube. The catalyst was stirred in the dark for ca. 15 min. Enyne 208 (R1 = R3 = Me; R2 = H; 69.0 mg, 0.25 mmol) was then added to the catalyst under a stream of N2. The sealed tube was evacuated and refilled with buta-1,3-diene three times. The sealed tube was then heated in a 110 8C oil bath overnight. The resulting mixture was purified by flash column chromatography (silica gel, EtOAc/hexanes 5:95 to 1:9) to give a thick, clear oil; yield: 62 mg (75%). Tricyclic Cyclooctadienes 211; General Procedure:[150]
A 10-mL sealed tube was charged with (E)- or (Z)-210 (0.25 mmol), [Rh(cod)(Np)]SbF6 (0.05 mmol), and MeCN (3.0 mL) via syringe under a stream of N2. The sealed tube was then heated in a 110 8C oil bath for ca. 16 h. Concentration under reduced pressure and subsequent purification by flash column chromatography (silica gel, Et2O/pentane 5:95 to 1:4) provided the products. 3.4.3.2.2
Cocyclization of Dienynes with Alkynes
In a related process, dienynes undergo the rhodium-catalyzed [4 + 2 + 2] dimerization via intermolecular alkyne insertion rather than the more conventional intramolecular [4 + 2] carbocyclization. For example, treatment of dienyne 212 with the catalyst derived from bis[chloro(norbornadiene)rhodium] with (S,S)-Me-DuPhos modified with silver(I) hexafluoroantimonate affords the bicyclo[6.3.0]octanoid 213 in good yield and with excellent chemo-, regio-, and diastereoselectivity, in which the product 214 formed by intramolecular [4 + 2] cycloaddition, is not observed (Scheme 95). In contrast, the introduction of an excess of a terminal alkyne promotes the crossed carbocyclization reaction rather than the dimerization of the dienyne to afford substituted bicyclic cyclooctatrienes 216. The enantioselective carbocyclization has also been examined, in which the highest enantiomeric excess (41% ee) is obtained by the combination of the ether tethered dienyne 215 (X = O) with O-trimethylsilyl propargylic alcohol (Scheme 96).[155,156] Scheme 95
Rhodium(I)-Catalyzed [4 + 2 + 2] Dimerization of Dienynes[155,156] X [4 + 2]
X H [RhCl(nbd)]2/(S,S)-Me-DuPhos/AgSbF6 (1:2:1) CH2Cl2/EtOAc (6:1)
X
212
213
[4 + 2 + 2]
X H 214
X
Temp (8C) Yield (%) Ref
O
rt
NTs 60
80
[155]
72
[155]
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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[4 + 2 + 2]-Carbocyclization Reactions
Scheme 96 Rhodium(I)-Catalyzed [4 + 2 + 2] Carbocyclization of Dienynes and Terminal Alkynes[155,156] R1 [RhCl(nbd)]2/(S,S)-Me-DuPhos/AgSbF6 (1:2:1)
R1
X
CH2Cl2/EtOAc (6:1), 60 oC
+
X H
215
216
X
R1
Yield (%) Ref
O
H
62
[155,156]
O
Pr
41
[155,156]
O
CH2OCH2CH=CH2
36 a
[155,156]
O
CH2OTMS
63
[155,156]
O
CH2OBn
73
[155,156]
NTs CH2OBn
70
[155,156]
a
41% ee.
8-{[(2E,4E)-Hexa-2,4-dienyloxy]methyl}-6-methyl-1,3,3a,6-tetrahydrocycloocta[c]furan (213, X = O); Typical Procedure:[155,156]
Preparation of the catalyst: To a vial containing [RhCl(nbd)]2 (75 mg, 0.16 mmol), THF (2 mL) was added, and the mixture was stirred for 15 min. The resulting orange soln was quickly transferred via cannula to a vial containing a soln of (S,S)-Me-DuPhos (98 mg, 0.32 mmol) in THF (2 mL). After stirring for 15 min, the red soln was transferred via cannula to a vial containing a soln of AgSbF6 (56 mg, 0.16 mmol) in THF (2 mL). After 15 min, the dark suspension was transferred to a vial using a syringe fitted with a filter. The cherry-red filtrate was concentrated under reduced pressure and kept under vacuum (19:1
37a
[157]
Me 1.5:1
a
[157]
H
iPr H a
68
OMe
R3
MeO2C +
R2
MeO2C H
R1
219
Reaction carried out at 60 8C.
5-(Methoxymethyl)- and 6-(Methoxymethyl)-Substituted Dimethyl (3aS,9aR)-8-Isopropyl1,3,3a,4,7,9a-hexahydro-2H-cyclopentacyclooctene-2,2-dicarboxylates 218 and 219 (R1 = iPr; R2 = R3 = H); Typical Procedure:[157]
Freshly distilled 1,2-dichloroethane (0.90 mL) was added to an oven-dried, N2 flushed, round-bottomed flask equipped with a septum and containing [RhCl(CO)2]2 (3.5 mg, 0.009 mmol) and a stirrer bar. A 0.02 M soln of AgSbF6 in 1,2-dichloroethane (0.90 mL, 0.018 mmol) was added via syringe under N2, followed by triene 217 (R1 = iPr; R2 = R3 = H; [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.4.3
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[4 + 2 + 2]-Carbocyclization Reactions
50 mg, 0.18 mmol) and methyl propargyl ether (19 L, 0.22 mmol). The N2 pressure was removed and the reaction vessel placed into a temperature-controlled oil bath set to 40 8C. After 3 h, no starting material could be detected by TLC. The solvent was removed under reduced pressure and the residue was purified via flash column chromatography (silica gel, Et2O/pentane 1:4), to give cycloadducts 218 and 219 as clear oils; yields: 40 mg (67%) and 9 mg (18%), respectively. 3.4.3.2.4
Cocyclization of Dienyl Isocyanates with Alkynes
In a very interesting adaptation to the rhodium-catalyzed [4 + 2 + 2] carbocyclization, isocyanates provide interesting partners for the reaction. For example, treatment of the dienyl isocyanate 220 and terminal alkynes with the rhodium complex derived bis[chlorobis(ethene)rhodium] with the chiral phosphoramidite ligand 221 facilitates the regio- and stereoselective formation of bicyclo[6.3.0]-azocine derivatives 222 in moderate to good yield and with outstanding enantioselectivity (>99% ee) (Scheme 98). Moreover, a range of substituents are tolerated within the alkyne, making this a relatively versatile method.[158] Scheme 98 Rhodium(I)-Catalyzed [4 + 2 + 2] Carbocyclizations of Dienyl Isocyanates and Terminal Alkynes[158]
O
O
O
O
P
10 mol%
O +
R2
N
O
221
•
5 mol% [RhCl(H2C=CH2)2]2 toluene, 110 oC
N
R1
N
R1 H
R2 220
222
R1
R2
ee (%) Yield (%) Ref
(CH2)5Me
H
99
74
[158]
CH2OTIPS
H
99
82
[158]
(CH2)3CO2Et
H
99
70
[158]
(CH2)4Cl
H
99
69
[158]
Bn
H
99
68
[158]
4-BrC6H4
H
99
35
[158]
(CH2)5Me
Me 99
62
[158]
CH2OTIPS
Me 99
51
[158]
(S)-1,2,3,10a-Tetrahydropyrrolo[1,2-a]azocin-5(8H)-ones 222; General Procedure:[158]
A flame-dried round-bottomed flask was charged with [RhCl(H2C=CH2)2]2 (3.5 mg, 0.0089 mmol) and the phosphoramidite ligand 221 (12.4 mg, 0.0179 mmol), and was fitted with a flame-dried reflux condenser in an inert-atmosphere (N2) glovebox. Upon removal of the reaction vessel from the glovebox, toluene (2.0 mL) was added via syringe [m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 239
238
Stereoselective Synthesis
3.4
[m + n + 2]-Carbocyclization Reactions
and the resulting yellow soln was stirred at rt under argon flow for 15 min. To this soln was added a soln of the alkyne (0.268 mmol) and isocyanate 220 (0.179 mmol) in toluene (3 mL) via syringe or cannula. After the addition of more toluene (2 mL) to wash down the remaining residue, the resulting soln was heated to 110 8C in an oil bath, and maintained at reflux for 12 h. The mixture was cooled to rt, concentrated under reduced pressure, and purified by flash column chromatography (silica gel, typically hexane/EtOAc 1:1 followed by neat EtOAc). Evaporation of the solvent afforded the analytically pure product.
[m n 2]-Carbocyclization Reactions, Aubert, C., Malacria, M., Ollivier, C. Science of Synthesis 4.0 version., Section 3.4 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
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[m + n + 2]-Carbocyclization Reactions
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Asymmetric Cycloisomerizations I. D. G. Watson and F. D. Toste
General Introduction
Cycloisomerization reactions are powerful, atom-economical ring-forming reactions that produce useful structural motifs often with high levels of chemo-, regio-, diastereo-, and increasingly enantioselective control. Cycloisomerization reactions are defined as bondforming processes that occur intramolecularly, proceeding with quantitative atom economy. Atom economy refers to the conversion efficiency of a chemical process in terms of the atoms involved.[1–3] In cycloisomerization reactions, all the atoms in the starting materials are present in the products. These are reactions in which no atom is wasted. This review will focus primarily on asymmetric C—C bond-forming cycloisomerizations, although some carbon—heteroatom bond-forming reactions are described. Many aspects of cycloisomerization reactions have already been reviewed,[4–9] including mechanistic[10] and asymmetric aspects of the reaction.[11] Surprisingly, compared to other transition-metal-catalyzed transformations, relatively few asymmetric cycloisomerization processes have been developed. This section will endeavor to summarize some of the most important and more recent developments in this area. Related reactions such as metal-catalyzed Diels–Alder reactions and Pauson–Khand-type carbonylations will not be discussed. Although certain transformations such as the intramolecular aldol, Michael, and hydroamination reactions are technically cycloisomerization reactions, they will also not be discussed herein. 3.5.1
Enyne Cycloisomerization
The quintessential cycloisomerization reaction is the intramolecular Alder-ene reaction of 1,n-enynes. As the alkyne variant of the ene reaction (Scheme 1), this reaction has been known since the 1940s in its uncatalyzed, thermal form.[12] This classic process involves the reaction of an alkene containing an allylic hydrogen (the ene) with an alkyne (the enophile). The result is a six-electron pericyclic rearrangement causing the formation of two bonds (Scheme 1). The thermal reaction, in the absence of a transition metal, has had few applications in organic synthesis. This is presumably due to limitations in its scope, since high temperatures are required. Scheme 1
H ene
The Ene Reaction
X
X
X
Y
Y
Y
H
H
enophile
X=Y = C=C, C≡ C, C=O, C=S, C=N, N=N, N=O
A palladium-catalyzed variant of the reaction was first discovered in 1985[13] and since then a multitude of metals have been reported to catalyze the cycloisomerization of 1,nenynes (n = 5, 6, 7, 8, etc.), including titanium, cobalt, iron, rhodium, ruthenium, nickel, chromium, palladium, platinum, and gold. Whereas the thermal variant of this transforAsymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Asymmetric Cycloisomerizations
mation only provides 1,4-dienes, the transition-metal-catalyzed version can provide either 1,3- or 1,4-dienes, often with high selectivity (Scheme 2). In fact, the catalyzed version of the reaction often affords different regiochemical and stereochemical outcomes to the thermal process, which sometimes fails to proceed. The reaction has developed into a powerful method for the rapid assembly of complex carbo- and heterocyclic frameworks in a highly chemo-, regio-, and diastereoselective manner. Scheme 2
Metal-Catalyzed Cycloisomerization of 1,n-Enynes metal catalyst
X
+
X
n
X
n
n
1,3-diene
1,4-diene
n = 1−4
Different mechanistic pathways are possible for the transition-metal-catalyzed cycloisomerization reaction depending on the reaction conditions and the choice of catalyst. The metal may complex to the alkene or alkyne, which can either activate one or both of the -components. Three key active intermediates that are thought to operate in the different mechanistic pathways for the cycloisomerization of enynes are highlighted in Scheme 3. In the first case, simultaneous activation of both the alkene and alkyne leads to a metallacycle intermediate 1. Hydrometalation of the alkyne may instead lead to a vinylmetal species 2, which may then carbometalate the alkene. Alternatively, complexation of the alkyne by the metal catalyst (intermediate 3) may activate it toward nucleophilic attack by the alkene generating carbocation intermediates. These multiple mechanistic manifolds allow a variety of useful carbocyclic skeletons to be assembled from this powerful transformation. Scheme 3
Key Intermediates in Cycloisomerization Mechanistic Manifolds M
H X
M
M
X
X
H 1
3.5.1.1
2
3
Palladium-Catalyzed Cycloisomerization
In 1985 Trost and Lautens disclosed the discovery of the palladium-catalyzed cycloisomerization reaction.[13] Using palladium(II) salts, they observed the cyclization of 1,6-enynes into 1,3- and/or 1,4-dienes (Scheme 4). Their best yields were obtained using bis(triphenylphosphine)palladium(II) acetate as the catalyst in nonpolar solvents such as benzene. The 1,4-diene products are formed with high stereoselectivity for the E-alkenes. Trost has made an array of important contributions to the development and understanding of this reaction, in the context of its application to synthesis and the reaction mechanism.
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Enyne Cycloisomerization
Scheme 4
Palladium-Catalyzed Cycloisomerization of 1,6-Enynes[13] 2 mol% Pd(OAc)2(PPh3)2
EtO2C
EtO2C
EtO2C
benzene, 60 oC
+ EtO2C
EtO2C
R1
EtO2C
R1 R1
The reaction is thought to proceed through either a palladium(0)–palladium(II) or palladium(II)–palladium(IV) cycle, depending on the reaction conditions and the choice of precatalyst. The use of a palladium(II) salt such as palladium(II) acetate in the absence of a reducing agent is thought to favor a palladium(II)–palladium(IV) cycle, which proceeds through a palladacyclopentene intermediate (Scheme 5).[14] Scheme 5 Proposed Mechanism of Palladium-Catalyzed Cycloisomerization via a Palladium(II)–Palladium(IV) Cycle[14] H X
Pd(II)
X
reductive elimination
Pd
H
X
X
β-hydride elimination
Pd(II)
oxidative coupling
X
Pd(IV) H
The mechanistic cycle initiates with coordination of the enyne to the coordinatively unsaturated palladium complex. Oxidative coupling produces the key palladium(IV) metallacyclopentene intermediate. This then undergoes fast -hydride elimination followed by reductive elimination to afford either one or a mixture of 1,4- and 1,3-diene products 4 and 5, respectively (Scheme 6). The regioselectivity of the -hydride elimination, HA versus HB, determines whether the product is a 1,3- or 1,4-diene. Although elimination of HB is thermodynamically favorable (the hydrogen is allylic), HA may align more favorably, resulting in faster -hydride elimination.
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-Hydride Elimination of the Metallacyclopentene Intermediate[14]
Scheme 6
HA
Pd
X
X
X
4
Pd HB
HA
1,4-diene
HB
Pd
X
X
5
1,4-diene
If instead of a palladium(II) catalyst, a palladium(0) catalyst is used in the presence of a Brønsted acid, a different mechanistic manifold is entered which similarly provides diene products (Scheme 7).[15] A typical example of such a combination would be the use of tris(dibenzylideneacetone)dipalladium(0)–chloroform complex and acetic acid. The mechanistic cycle is entered upon oxidative addition of the palladium(0) species into the acid H—A bond to generate a palladium(II) hydride species. After complexation to the enyne, hydrometalation of the alkyne produces a vinylpalladium species that then carbometalates the alkene. Finally, -hydride elimination provides 1,3- or 1,4-diene products, regenerating the palladium(II) hydride. Unlike the metallacyclopentene mechanism, this mechanism does not require an oxidation level change during the catalytic cycle. Scheme 7 Proposed Mechanism of Palladium-Catalyzed Cycloisomerization via a Palladium(0)–Palladium(II) Cycle[15] Pd(0) +
HOAc
H Pd(II)
OAc
X X
β-hydride elimination
X Pd(II)(OAc)
H
X
Pd OAc
H
H
carbometalation
X
Pd
hydrometalation
OAc
The scope of the palladium-catalyzed cycloisomerization reaction has been extensively examined since its initial discovery. Substitution on the tether is not required, but accelerates the rate of cyclization.[16] Differently substituted enynes can have significant effects on the ratio between 1,3- and 1,4-diene products. For example, an oxygen substituent at the allylic position of enyne 6 produces 1,4-diene 7 (Table 1, entry 4).[17] Similarly, an oxygen substituent at the homoallylic position of enyne 8 exclusively provides 1,4-diene Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Enyne Cycloisomerization
product 9 (entry 5).[16] Since this is thought to be an electronic effect, either diene can be obtained by simply interchanging the alkene and alkyne (entry 6).[14] The diastereoselectivity for products shown in entries 3 and 4 in the transformation arises from unfavorable eclipsing interactions within the palladacyclopentene intermediate forcing the neighboring substituents anti.[16] Table 1
Palladium-Catalyzed Cycloisomerization of 1,6-Enynes[13,14,16–20]
En- Substrate try
Catalysta
Conditions
Pd(OAc)2(PPh3)2
benzene-d6, MeO2C 60 8C
Product
Yield Ref (%)
MeO2C MeO2C
MeO2C
1 8
MeO
71
[13]
85
[13]
8
MeO
OMe
OMe
MeO2C
MeO2C H
2
MeO2C
Pd(OAc)2(PPh3)2
benzene-d6, MeO2C H 60 8C
MeO2C
MeO2C
MeO2C
3
4
MeO2C
MeO2C
PMBO
Pd(OAc)2(PPh3)2
benzene-d6, 60 8C MeO2C
68
[13]
Pd(OAc)2[P(2-Tol)3]2
benzene, 80 8C
80
[17]
77b
[16]
93
[14]
PMBO
OTBDMS
OTBDMS
6
5
7
Pd(OAc)2(PPh3)2
PMBO
benzene, 80 8C
PMBO
MeO
MeO 9
8
6
Pd(OAc)2, BBEDA PMBO
benzene-d6, 60 8C PMBO
MeO
OMe
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Stereoselective Synthesis
Table 1
3.5
Asymmetric Cycloisomerizations
(cont.) Catalysta
En- Substrate try
Conditions
Product
Yield Ref (%)
TMS
TMS
Pd2(dba)3•CHCl3, BBEDA
7 N
AcOH, benzene, 60– 65 8C
N
90
[18]
63
[19]
Br 70
[20]
O
O O TMS
Pd2(dba)3•CHCl3, (2-Tol)3P
8
AcOH, benzene, 80 8C O
9
Br Pd(OAc)2, dbpp, TBDMSO
O
dpba
1,2-dichloroethane, 60 8C
TBDMSO
TBDMSO a
b
TMS
O TBDMSO
BBEDA = N,N¢-bis(benzylidene)ethylenediamine; dbpp = 1,3-bis(dibenzophosphol-5-yl)propane; dpba = 2-(diphenylphosphino)benzoic acid. dr >99:1.
The reaction is highly chemoselective, tolerating free alcohols, silyl ethers, amines, and acetals. It is possible to substitute the alkyne with alkyl and silyl groups, as well as polarized groups such as enamines[18] (Table 1, entry 7) and alkynones[19] (entry 8). The -palladium intermediate produced from the initial carbometalation can be trapped with tethered alkenes, leading to tandem cycloisomerizations. Through this iterative trapping approach the process can lead to the synthesis of triquinanes, propellanes, and polyspiranes (Scheme 8).[21,22] The palladium-catalyzed cycloisomerization reaction has been successfully employed as the key step in the synthesis of a number of natural products, such as merulidial,[23] the picrotoxanes,[20,24–26] cassiol,[27] the carbapenem core,[28] (–)-sterepolide,[29] petiodial,[30] dendrobine,[31] -necredol,[32] and phyllanthocin.[33,34]
Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.5.1
249
Enyne Cycloisomerization
Scheme 8
Iterative Trapping Cycloisomerization Approach to a Polyspirane[21,22] OMe
PhO2S
2.5 mol% Pd2(dba)3•CHCl3 10 mol% Ph3Sb benzene, AcOH, 50−65 oC
PhO2S
77%
MeO
PhO2S PhO2S
One of the earliest approaches toward an enantioselective cycloisomerization reaction involved the use of a chiral auxiliary. For example, the introduction of a C2-symmetric chiral diol into an alkynone provides substrate 10, in an approach to the total synthesis of chokol C (Scheme 9). Palladium(II)-catalyzed cycloisomerization of the chiral ketal 10 affords the 1,4-diene product 11 as a single regioisomer with a diastereomeric ratio of 8.5:1.[19] Scheme 9
Chiral Auxiliary Approach Toward Chokol C[19] CO2Et
EtO2C
Pd(OAc)2 (cat.) benzene, 60 oC
O O
TMS
O
55%; dr 8.5:1
O TMS
EtO2C CO2Et
10
11
OH
4 steps
OH chokol C
In another example, a double stereodifferentiation approach is utilized, in which different phosphine ligands are used in combination with an appendant chiral tartrate ester auxiliary to effect a diastereoselective cycloisomerization (Scheme 10).[35] In the presence of tri-2-tolylphosphine, the palladium(0)-catalyzed cycloisomerization of modified 1,7enyne 12 (R1 = OBz) furnishes the 1,4-diene product 13 (R1 = OBz) with 71% diastereomeric excess (Scheme 10). Interestingly, when aminobisphosphine ligand 14 is used, the reaction produces the product with slightly lower diastereocontrol (60% de), favoring the C4 epimer. When the chiral auxiliary is modified into an achiral auxiliary, the product 13 (R1 = H) is prepared in 50% enantiomeric excess.
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250
Stereoselective Synthesis
3.5
Asymmetric Cycloisomerizations
Scheme 10 Double Stereodifferentiation Strategy in Palladium(0)-Catalyzed Cycloisomerization[35] PhO2S
3 mol% Pd2(dba)3•CHCl3
R1
O
PhO2S
6 mol% ligand, benzene, rt
OH
O R1
O
12 PhO2S R1
O
PhO2S
OH
O R1
O
13
R1
Ligand
de or ee
Ref
OBz (2-Tol)3P 71% de
[35]
OBz 14
60% de
[35]
H
50% ee
[35]
14
Ph2P PPh2 O O NH HN
14
In the first example of an asymmetric cycloisomerization reaction, Trost and co-workers used a combination of palladium(0) and chiral acids to catalyze the cycloisomerization of 1,6-enynes through a proposed palladium(II) hydride species. Most of these acids produce low enantioselectivities, although (–)-(S)-binaphthoic acid gives 1,4-diene 15 in 33% ee (Scheme 11).[36] Scheme 11
Asymmetric Palladium(0)-Catalyzed Cycloisomerization with Chiral Acid[36] 2.5 mol% Pd2(dba)3•CHCl3 5 mol% Ph3P, benzene, rt
5 mol%
MeO2C
CO2H CO2H
MeO2C
MeO2C +
MeO2C
MeO2C
MeO2C 15
61%; 33% ee
3:1
Pyrrolidine products 18 and 19 have been prepared by an enantioselective palladium-catalyzed cycloisomerization of 1,6-enynes 16.[37] The reaction is carried out with catalytic Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.5.1
251
Enyne Cycloisomerization
tris(dibenzylideneacetone)dipalladium(0)–chloroform and superstoichiometric acetic acid (2.7 equiv) using trans-coordinating bidentate (R,R)-2,2¢-bis[(S)-1-(diarylphosphino)ethyl]-1,1¢-biferrocenyl ligands 17 [(R,R)-(S,S)-TRAP], in benzene or toluene at 40 8C (Scheme 12). Other chiral phosphines such as 2,3-bis(diphenylphosphino)butane (Chiraphos) and 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane (Diop) give poor results, while 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl (BINAP) provides no conversion even at 80 8C. The ligand 17 proves most successful when it is substituted with electron-withdrawing aryl groups. For example, the 4-(trifluoromethyl)phenyl group increases the enantioselectivity of product 18 from 36 to 76% as compared to the simple phenyl substituent (Scheme 12). The enyne substrates that have been examined are limited, since only substituents at the allylic position have been varied. Interestingly, changing the alkene configuration in the starting material 16 from Z to E reverses the absolute configuration of the stereocenter in the product. Scheme 12
Asymmetric Palladium(0)-Catalyzed Cycloisomerization[37]
(Ar1)2P P(Ar1)2
Fe
Fe
17 2.25 mol% Pd2(dba)3•CHCl3 AcOH (2.7 equiv), benzene
PhO2S N R1 16
PhO2S N
PhO2S N R1 R1 18
19
R1
Ar1
Temp (8C) Ratio (18/19) ee (%) Yield (%) Ref
TMS
Ph
40
TMS
4-F3CC6H4
CH2TMS 4-F3CC6H4 Et Et a
b
4-F3CC6H4 4-F3CC6H4
–
36
77
[37]
0
>98:2
76
24
[37]
25
3.5:1
95
35 35
8.9:1 >15:1
68
[37]
a
74
[37]
b
66
[37]
69
59
1
Alkene 16 (R = Et) has E configuration; product 18 has R configuration. Alkene 16 (R1 = Et) has Z configuration; product 18 has S configuration.
Mikami and co-workers demonstrated that (R)-2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl [(R)-20, (R)-BINAP] and structurally related ligands give high enantioselectivity for the asymmetric palladium-catalyzed cycloisomerization of 1,6-enyne 23 to furan 24, containing a quaternary carbon stereogenic center (Scheme 13). Typical palladium catalysts [e.g. Pd(OAc)2, Pd2(dba)3•CHCl3/AcOH, and Pd2(dba)3•CHCl3/TFA] give poor yields (99
[38]
Pd(OCOCF3)2
(R)-21
benzene-d6 48
100
95
R
>99
[38]
Pd(OCOCF3)2
(R)-22 (Ar1 = Ph)
benzene-d6 37
100
>99
S
>99
[38]
80
96
R
>99
[38]
Precatalyst
Ligand
Solvent
Pd(OAc)2
(R)-20
Pd(OCOCF3)2
1
[Pd(NCMe)4](BF4)2 (R)-22 (Ar = 2,6Me2C6H3)
DMSO
Time (h)
14
In an extension of their methodology, Mikami and Hatano have applied their catalyst system to 1,7-enyne substrates, which represents the first asymmetric cycloisomerization of enynes of this type.[40] Using a cationic palladium complex {[Pd(NCMe)4](BF4)2/(S)-BINAP} catalyst system, in the presence of formic acid in dimethyl sulfoxide at 100 8C, the 1,7-enynes are cycloisomerized to form six-membered quinoline derivatives having quaternary carbon stereogenic centers (Scheme 14). Substituted and unsubstituted alkynes can be employed, although aryl- and silylalkynes do not provide any product. Enyne 25 (R1 = CO2Me; R2,R3 = CH2) affords the desired spiro product 26 (R1 = CO2Me; R2,R3 = CH2) along with an achiral 1,5-diene resulting from alkene migration. Scheme 14 Enynes[40]
Asymmetric Palladium(0)-Catalyzed Cycloisomerization of 1,7-
5 mol% [Pd(NCMe)4](BF4)2
R1
R1
R2
10 mol% (S)-BINAP [(S)-20] HCO2H (1 equiv) DMSO, 100 oC
N Ts R2
R3
25
Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
N Ts 26
R3
3.5.1
253
Enyne Cycloisomerization
R1
R2
R3 ee (%) Yield (%) Ref
CO2Me H
H >99
99
[40]
H
H >99
99
[40]
71
62
[40]
44
96
[40]
H
CO2Me
CH2
CO2Me (CH2)2 CO2Me
CH2O
>99
>99
[40]
H
CH2O
98
>99
[40]
H
(CH2)11
86
53
[40]
In both of the previously proposed palladium-catalyzed cycloisomerization mechanisms (Schemes 1 and 3), a hydride is added to the alkyne, by either reductive elimination, or hydropalladation. Enynes can also undergo a different reaction, in which a nucleophile is added across the alkyne followed by cyclization. In an example of such a transformation, Lu and co-workers have developed an asymmetric synthesis of ª-butyrolactones by the acetoxypalladation-initiated cycloisomerization of enyne esters (Scheme 15).[41,42] Various (Z)-4-acetoxybut-2-enyl alk-2-ynoates 27 undergo reaction in acetic acid at 60 8C in the presence of catalytic palladium(II) acetate and a bidentate dinitrogen ligand. Optimal enantioselectivities are achieved using either bis(4,5-dihydrooxazole) ligand 28, or the pyridyl-4,5-dihydrooxazole ligand 29. Additionally, the reaction tolerates a number of different substituents at the terminal position of the alkyne with good enantioselectivities (Scheme 15). Scheme 15 Asymmetric Acetate-Assisted Palladium-Catalyzed Cycloisomerization[41,42] 5 mol% Pd(OAc)2 6 mol% ligand AcOH, 60 oC
O R1
AcO
O
R1
O
O
OAc 27
R1
Ligand ee (%) Yield (%) Ref
Me
29
92
78
[41]
Pr
29
80
80
[41]
Ph
28
81
70
[41]
(CH2)4iPr 28
84
86
[41]
CO2Me
87
67
[41]
29
O
O N
O
N
N
N Ph
Ph 28
Ph 29
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Stereoselective Synthesis
3.5
Asymmetric Cycloisomerizations
The mechanism of the reaction is thought to proceed by initial coordination of palladium(II) to the 1,6-enyne followed by trans-acetoxypalladation of the triple bond. Cyclization onto the allyl acetate sets up the system for -acetoxy elimination to yield the vinyl group and regenerate the catalytic species (Scheme 16). Scheme 16 Proposed Mechanism for Acetate-Assisted Palladium-Catalyzed Cycloisomerization[41,42] Pd(OAc)2 + O
L
OAc
O R1
R1 O
O
PdL(OAc)2
β-acetoxy elimination
O
OAc
OAc
−OAc
O
R1
R1
O
O PdL
PdL
OAc OAc
AcO O
R1
O
PdL
carbometalation
trans-acetoxypalladation
OAc
Tanaka and co-workers have employed a palladium(II)/(S)-XylSEGPHOS [(S)-22] catalyst system in the cycloisomerization of N-alkenyl-3-arylpropynamides 30 for the enantioselective construction of axially chiral 4-arylpyridin-2-ones 31 (Table 2).[43] The reaction occurs in 1,2-dichloroethane at room temperature allowing the cycloisomerization of a number of 1,5-enynes. There are 10 examples presented with most of the products prepared with good enantioselectivity (64–96% yield, 51–97% ee). Unlike the previously discussed catalyst systems, the reaction is thought to proceed by -complexation of the chiral palladium complex with the alkyne, facilitating cyclization by attack of the enamine functionality.
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3.5.1
Cycloisomerization of Enamine 1,5-Enynes to Axially Chiral 4-Arylpyridin-2-ones[43]
Table 2 R3
255
Enyne Cycloisomerization
R4 O
5 mol% [Pd(NCMe)4](BF4)2 6 mol% (S)-XylSEGPHOS [(S)-22] 1,2-dichloroethane, rt
R3
R4
PdΙΙ
NBn R1
NBn
R2
R1 R5
O
R2
R6
R5
R6
30
R1
R3
R2
R4
R5 R6
N Bn
O
31
Substrate
Time (h)
Product
ee (%)
Yield (%)
Ref
91
93
[43]
90
75
[43]
51
77
[43]
OMe O OMe NBn
24 N Bn
O
OMe O NBn
OMe
62 Ph
Ph
N Bn
O
O NBn
72 N Bn
Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
O
for references see p 305
256
Stereoselective Synthesis Table 2
3.5
Asymmetric Cycloisomerizations
(cont.)
Substrate
Time (h)
Product
ee (%)
Yield (%)
Ref
94
89
[43]
97
91
[43]
87
64
[43]
OMe O OMe NBn
72 N Bn
O
OMe O OMe NBn
28 N Bn
O
O
O
O O
O
Cl NBn
48
Cl N Bn
O
1-(Phenylsulfonyl)-3-methylenepyrrolidines 18 and 19; General Procedure:[37]
A soln of Pd2(dba)3•CHCl3 (2.25 mol%) and ligand 17 (Ar1 = 4-F3CC6H4; 8.1 mol%) in toluene (0.5 mL) was stirred under N2 at 25 8C for 30 min. AcOH (0.250 mmol) was added, and, after 5 min, the enyne 16 (0.093 mmol) was added and the mixture was stirred for 20 h. The solvent was evaporated and the residue was purified by preparative TLC (silica gel, hexanes/ EtOAc 5:1) affording the 1,3- and 1,4-diene products 18 and 19 as a mixture. Methyl (Z)-2-[4-Methyl-4-vinyldihydrofuran-3(2H)-ylidene]acetate (24); General Procedure:[38]
Thoroughly degassed benzene-d6 (2 mL) (CAUTION: carcinogen) was injected under argon into a Pyrex Schlenk tube containing Pd(OCOCF3)2 (5 mol%) and the bisphosphine ligand (10 mol%), and the suspension was stirred at rt for 5–10 min, at which time the soln became clear. Then, enyne 23 (91 mg, 0.5 mmol) was added, the tube was sealed with a screw cap, and the mixture was heated to 100 8C for 24 h. After cooling, the crude mixture was purified by column chromatography. 4-Methylene-1-tosyl-1,2,3,4-tetrahydroquinolines 26; General Procedure:[40]
Thoroughly degassed DMSO (2 mL) was injected under argon into a Pyrex Schlenk tube containing [Pd(NCMe)4](BF4)2 (2.2 mg, 0.005 mmol) and (S)-BINAP (6.2 mg, 0.010 mmol), and this suspension was stirred at rt for 5 min. Then, the enyne substrate 25 (0.10 mmol) and HCO2H (3.7 L, 0.10 mmol) were added. The tube was sealed with a screw cap and the mixture was stirred at 100 8C for 1–3 h (monitored by TLC). The resultant mixture was washed with brine and extracted with Et2O. The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography to afford the quinoline product.
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3.5.1
3.5.1.2
Enyne Cycloisomerization
257
Rhodium-Catalyzed Cycloisomerization
The rhodium-catalyzed reactions result in some of the most reliable and wide-ranging substrate scopes of all currently developed asymmetric cycloisomerization reactions. These reactions are highly efficient and provide excellent enantioselectivities, often using 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl (BINAP) as the chiral ligand. The first racemic rhodium-catalyzed cycloisomerization reaction was developed by Zhang and coworkers.[44] 1,6-Enyne substrates 32 containing Z-alkenes react with cationic rhodium(I) complexes in 1,2-dichloroethane (0.1 M) at room temperature, to afford 1,4-diene products 33 in excellent yield (Table 3, entries 1–3). Interestingly, although the Z-alkenes cycloisomerize efficiently, the E-alkenes are often unreactive. Additionally, it is essential to prepare the clean catalyst precursors before generating the cationic complexes in situ by reacting with silver(I) hexafluoroantimonate. Dimeric rhodium catalysts containing ligand 34 or 1,4-bis(diphenylphosphino)butane {[RhCl(BICPO)]2 and [RhCl(dppb)]2} are both excellent precatalysts for the reaction. Additionally, a cyclic alkene affords the cisfused ring system (entry 3), while the but-2-enyl but-2-ynoate furnishes an Æ-methylene lactone (entry 4).
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258
Stereoselective Synthesis Table 3
3.5
Asymmetric Cycloisomerizations
Rhodium(I)-Catalyzed Cycloisomerization of 1,6-Enynes[44] R1 R1
[RhCl(ligand)]2, AgSbF6 1,2-dichloroethane, rt
X
X
R2
R2 32
33
Entry Substrate
Ligand
Catalyst (mol%)
Product
Ph2P O H
Ph
Yield (%)
Ref
81
[44]
89
[44]
85
[44]
50
[44]
Ph
O
1
10
H
O
O PPh 2 34
(R,R)-BICPO
Ph2P EtO2C
2
O
H
EtO2C H
3
EtO2C EtO2C
O PPh 2 34
O
3
dppb
10
O
H
H
O
O
4
O
dppb
10
O
The proposed mechanism for rhodium(I)-catalyzed cycloisomerization consists of initial bidentate coordination of the rhodium(I) species to the enyne. Oxidative cyclization then forms the rhodium(III) metallacyclopentene, followed by regiospecific -hydride elimination to give the E-alkene geometry. Finally, reductive elimination provides the 1,4-diene product (Scheme 17).
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3.5.1
259
Enyne Cycloisomerization
Scheme 17
Proposed Mechanism of Rhodium(I)-Catalyzed Cycloisomerization
R1 H
R1
X X
Rh(I) R2
R2
reductive elimination
R1
R1 Rh
X
H
Rh(I)
X R2
R2
H
R1 β-hydride elimination
oxidative coupling
X
Rh(III)
R2
H
Zhang and co-workers also reported the first asymmetric rhodium-catalyzed cycloisomerization of 1,6-enynes 37 (Table 4).[45] A number of chiral bidentate phosphines and phosphinites were examined, with 34 (BICPO), 35 (Me-DuPhos), and 36 (BICP) providing the highest enantioselectivities. Interestingly, the bidentate phosphine 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl (20, BINAP) is completely unreactive in this reaction. Many enyne substrates were examined and high enantioselectivities and yields were observed (Table 4, entries 1–3). Ligand choice was not general, with subtle changes in the substrate dramatically affecting both the yield and enantioselectivity of the product 38. The 1,4diene product readily isomerizes to the 1,3-diene in the presence of the rhodium(I) catalyst; this unwanted transformation was minimized by carefully monitoring the reaction, and quenching it as soon as the substrates were consumed. Interestingly, the in situ preparation of the rhodium catalyst leads to a significant improvement in both the yield and enantioselectivity.[46,47] In particular, (S)-BINAP [(S)-20] affords uniformly high enantioselectivities and yields over a wide variety of enyne substrates (entries 4–6). Asymmetric Rhodium(I)-Catalyzed Cycloisomerization of 1,6-Enynes[45–47]
Table 4 Ph2P
O P
H H
P
H PPh2
O PPh 2 34
Ph2P H
35
36
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260
Stereoselective Synthesis
3.5
Asymmetric Cycloisomerizations R1
[RhCl(ligand)]2, AgSbF6 1,2-dichloroethane, rt
R1 X
X R2
R2 37
Entry
38
R1
X
R2
Ligand
Catalyst (mol%)
ee (%)
Yield (%)
Ref
1
O
Ph
Me
35
5
96
62
[45]
2
O
Bu
Me
36
5
98
67
[45]
3
NSO2Ph
Me
Me
34
3
82
98
[45]
a
4
O
Ph
Et
(S)-BINAP [(S)-20]
10
>99.5
96
[46]
5
O
CO2Et
Et
(S)-BINAP [(S)-20]
10a
>99.9
82
[46]
(S)-BINAP [(S)-20]
a
>99
92
[47]
6 a
C(CO2Et)2
Ph
OMe
5
The catalyst was prepared in situ from [RhCl(cod)]2 and (S)-BINAP.
Zhang and co-workers also applied their methodology to the asymmetric synthesis of Æ-methylene lactones 40 (X = O).[48] These reactions were carried out in the presence of a dimeric rhodium complex {[RhCl(cod)]2}, ligand (R)-20 [(R)-BINAP], and silver(I) hexafluoroantimonate in 1,2-dichloroethane at room temperature to afford the lactone product in minutes with uniformly high yield and enantioselectivity (Scheme 18). The same protocol has also been applied to enyne amides to provide functionalized lactams in high yields and enantioselectivities.[49] The reaction is again broadly applicable to a wide range of substrates, providing the lactam products 40 (X = NBn) in high yield and enantioselectivity (Scheme 18). Unprotected amides 39 (X = NH) do not undergo the cyclization, presumably because these amides exist predominantly as the trans-isomer. Scheme 18 Asymmetric Rhodium(I)-Catalyzed Cycloisomerization of 1,6Enynes[48,49] O R1 X
5 mol% [RhCl(cod)]2 12 mol% (R)-BINAP [(R)-20] 20 mol% AgSbF6, 1,2-dichloroethane, rt
O
R1
X R2
R2 40
39
X
R1
R2
ee (%) Yield (%) Ref
O
Ph
Me
>99
92
[48]
O
Me
H
>99
92
[48]
O
Ph
OAc
>99
96
[48]
O
Me
OAc
>99
93
[48]
NBn
Ph
Et
>99
96
[49]
NBn
Me
H
>99
91
[49]
NBn
Ph
OMe
>99
88
[49]
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3.5.1
261
Enyne Cycloisomerization
The potential power of the asymmetric rhodium-catalyzed cycloisomerization was demonstrated with a formal synthesis of (+)-pilocarpine (Scheme 19).[48] In addition, it was established that some 1,6-enyne substrates, with substituents in the allylic position, participate in a stereoselective kinetic resolution to afford the substituted furan products with high enantioselectivity.[50] Scheme 19 Synthesis of (+)-Pilocarpine via Asymmetric Rhodium(I)-Catalyzed Cycloisomerization[48] O
5 mol% [RhCl(cod)]2 11 mol% (R)-BINAP [(R)-20] 20 mol% AgSbF6 1,2-dichloroethane, rt, 10 min
O
99%; >99% ee
OH
O O
O 2 steps
H
N
O
N
O
Me (+)-pilocarpine
Nicolaou and co-workers have extended the rhodium(I)-catalyzed asymmetric enyne cyclization reaction to substrates with terminal alkynes.[51–54] A critical feature for the success of this process is to employ the preformed catalytic complex ([Rh{(S)-BINAP}]SbF6) rather than use the more conventional in situ protocol. The reaction is optimal for a variety of Z-allylic alcohols 41 to afford the aldehydes 42 in excellent yields and enantioselectivities (Table 5).
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Stereoselective Synthesis
3.5
Asymmetric Cycloisomerizations
Rhodium(I)-Catalyzed Cycloisomerization of Terminal Alkyne 1,6-Enynes[51–54]
Table 5
10 mol% [Rh{(S)-BINAP}]SbF6 1,2-dichloroethane, rt
X
H
X
O OH 41
42
Substrate
Product
ee (%) Yield (%) Ref
TsN TsN
H
>99
86
[53]
93
89
[53]
97
78
[53]
>98
93
[53]
O OH O O BnN BnN
H O
OH MeO2C MeO2C
MeO2C
MeO2C
H O
OH
TsN TsN
The genesis for the extension of the reaction scope arose from its use as a key step in the formal asymmetric synthesis of (–)-platensimycin. The key intermediate 43 is converted into the spiro dienone aldehyde 44 in 86% yield and with greater than 99% enantiomeric excess (Scheme 20). The preformed catalyst complex ([Rh{(S)-BINAP}]SbF6) is again optimal for this process as noted earlier. The aldehyde 44 intersects an intermediate from the authors previous synthesis and therefore constitutes a formal asymmetric total synthesis of (–)-platensimycin.
Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.5.1
263
Enyne Cycloisomerization
Scheme 20 Synthesis of (–)-Platensimycin via Asymmetric Rhodium(I)-Catalyzed Cycloisomerization[51–54] O
O 5 mol% [Rh{(S)-BINAP}]SbF6 1,2-dichloroethane, rt, 12 h 86%; >99% ee
HO CHO 43
44 OH O HO2C OH
O
N H O
(−)-platensimycin
Hayashi and co-workers have developed an asymmetric cycloisomerization reaction of 1,6-enynes 45 to afford 3-aza- and 3-oxabicyclo[4.1.0]hept-4-ene derivatives 46 (X = NTs, O), with high enantioselectivity (Scheme 21).[55] The optimized catalyst complex is a rhodium–chiral diene complex with an achiral monophosphine as the second ligand. Chiral diene 47 is optimal and provides a less hindered, less electron-donating environment than a standard bisphosphine ligand. In fact, the use of bidentate phosphines (such as dppe or BINAP) under these conditions does not afford any of the bicyclo[4.1.0]heptene products. Diene 47 provides the cyclopropane products with good to excellent enantioselectivities (Scheme 21).
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264
Stereoselective Synthesis Scheme 21 Enynes[55]
Asymmetric Cycloisomerizations
Asymmetric Rhodium(I)-Catalyzed Hydroarylation/Cyclization of 1,6-
5 mol% [RhCl(PPh3)L] 10 mol% Na[BARF] 1,2-dichloroethane, 24 h
R2
X
3.5
R1
X R1
R3
R1
R1 R2
R3
46
45 F F L=
F ; [BARF]− = [3,5-(F3C)2C6H3]4B−
F OMOM
MOMO (R,R)-47
X
R1 R2
R3
Temp (8C) ee (%) Yield (%) Ref
NTs H
H
Ph
50
80
94
[55]
NTs H
H
4-MeOC6H4 40
81
91
[55]
NTs H
H
2-MeOC6H4 40
90
87
[55]
NTs H
H
2,6-Me2C6H3 60
95
71
[55]
NTs H
H
4-ClC6H4
60
76
92
[55]
NTs H
H
Ph
60
73
73
[55]
NTs H
Me
H
40
68
81
[55]
Ph
20
90
86
[55]
20
99
99
[55]
O
Ph H
O
Ph
O(CH2)2
Widenhoefer and co-workers have developed an asymmetric rhodium(I)-catalyzed cycloisomerization–hydrosilation reaction (Scheme 22).[56] Although the rhodium–2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl complex is not an effective catalyst for this transformation, the closely related complex using the methylated ligand 48 (BIPHEMP) is highly effective. Treatment of a number of functionalized 1,6-enynes 49 with excess trialkylsilane and the catalyst in dichloroethane at 70 8C, furnishes the functionalized silylated alkylidenecyclopentanes 50 with high enantioselectivities (Scheme 22). Scheme 22 Asymmetric Rhodium(I)-Catalyzed Cycloisomerization–Hydrosilylation of 1,6-Enynes[56]
PPh2 PPh2
(R)-48
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3.5.1
265
Enyne Cycloisomerization HSiR12R2 (5 equiv) 2.5 mol% [RhCl(cod)]2, 5 mol% (R)-48 5 mol% AgSbF6, 1,2-dichloroethane, 70 oC
X
R2 Si R1
X
49
R1
50
R1 R2 ee (%) Yield (%) Ref
X
C(CO2Me)2 Et Et 92
81
[56]
C(CH2OAc)2 Et Et 83
58
[56]
NTs
73
[56]
Ph Me 80
Krische and co-workers have developed a rhodium-catalyzed reductive cyclization reaction of 1,6-enynes that is mediated by hydrogen.[57] The reaction is thought to proceed by formation of a rhodium hydride followed by reaction with the 1,6-enyne to form a rhodium(III) metallacycle. Reductive elimination from this species generates the cyclic products. The reaction is rendered asymmetric by the addition of chiral bidentate phosphine ligands.[58] In the presence of ligands (R)-20 [(R)-BINAP] or (R)-51 [(R)-Cl-MeO-BIPHEP], 1,6enynes 53 afford cyclic products 54 with very high enantiomeric excess (Table 6). The reaction works on a wide substrate scope including enynes with nitrogen, oxygen, and carbon tethers. Although (R)-52 [(R)-PHANEPHOS] usually affords complex mixtures of conventional hydrogenated products, with the propargylic esters and amides (Table 6, entries 4 and 5) it affords the expected cyclic derivatives in high yields and enantioselectivities. Table 6
Asymmetric Reductive Cyclization of 1,6-Enynes[58–60] Cl
PPh2
MeO
PPh2
PPh2
MeO
PPh2 PPh2 Ph2P
Cl (R)-20
(R)-51
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(R)-52
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266
Stereoselective Synthesis
3.5
Asymmetric Cycloisomerizations
3−5 mol% [Rh(cod)2]OTf
R1
3−5 mol% ligand
R
H2 (1 atm), 1,2-dichloroethane or CH2Cl2
1
23 oC, 2−3 h
X
X
R2
R2 53
54
Entry Substrate
Ligand Product Ph
Ph
1
ee (%) Yield (%) Ref
O
(R)-20
97
80
[58]
93
79
[58]
95
77
[58]
94
73
[58]
91
73
[58]
98
68
[58]
94
63
[58]
O
2
3
TsN
(R)-20
O
O
O
O
(R)-52
O
O
5
O
O
(R)-52
BnN
CO2Me
6
OH
(R)-51 OH
4
TsN
BnN
CO2Me
O
(R)-20
O
CO2Me
CO2Me O
7
(R)-51
O Cl
Cl
Cl Cl
1,4-Dienes 33; General Procedure:[44]
In a glovebox, a Schlenk tube was charged with enyne 32 (0.4 mmol), [RhCl(dppb)]2 (10 mol%), and 1,2-dichloroethane (4 mL). The mixture was stirred for 1 min, followed by addition of AgSbF6 (10 mol%). A precipitate was observed and the mixture was allowed to stir at rt until TLC indicated that the reaction was complete, normally 2–6 h. The crude Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.5.1
267
Enyne Cycloisomerization
mixture was diluted with Et2O, filtered to remove AgCl, concentrated, and purified by flash chromatography. 1,4-Dienes 38; General Procedure:[45]
The enyne 37 (0.4 mmol), [RhCl(BICP)]2 (5 mol%), and 1,2-dichloroethane (2 mL) were introduced into a Schlenk tube in a glovebox. The mixture was stirred for 1 min. AgSbF6 (5 mol%) was added and a precipitate was observed. The mixture was stirred at rt and the reaction was monitored by TLC, with the cyclization normally complete in 2–6 h. The crude mixture was diluted with Et2O and filtered to remove AgCl before purification by flash chromatography.
Æ-Alkylidene -Vinyl Lactones or Lactams 40; General Procedure:[48,49] The enyne 39 (0.1 mmol), [RhCl(cod)]2 (5 mol%), (R)-BINAP [(R)-20; 12 mol%], and 1,2-dichloroethane (1 mL) were introduced into a Schlenk tube in a glovebox. The mixture was stirred for 1 min, then AgSbF6 (20 mol%) was added, and a precipitate was observed. The mixture was stirred at rt and the reaction was monitored by TLC, with the cyclization normally complete in 1–10 min. The crude mixture was diluted with Et2O and filtered to remove AgCl before purification by flash chromatography. Alk-4-enyl Aldehydes 42; General Procedure:[51]
To a vial containing the 1,6-enyne substrate 41 (0.08 mmol) under argon was added 0.04 M [Rh{(S)-BINAP}]SbF6 in 1,2-dichloroethane or acetone (0.20 mL, 8 mol). The resulting mixture was stirred at 23 8C for 12–16 h. After removal of the solvent by a stream of argon, the residue was purified by flash column chromatography (EtOAc/hexanes 1:3 to 1:1). 3-Aza- and 3-Oxabicyclo[4.1.0]hept-4-enes 46 (X = NTs, O); General Procedure:[55]
[RhCl(PPh3)L] [L = (R,R)-47; 0.010 mmol] and Na[BARF] {[BARF]– = [3,5-(F3C)2C6H3]4B–; 0.020 mmol} were added to 0.5 M 1,6-enyne 45 (0.20 mmol) in 1,2-dichloroethane, and the mixture was stirred at 50 8C for 24 h. The mixture was then passed through a short column of silica gel with hexane/EtOAc/Et3N (20:5:1) as eluent. After evaporation of the solvent, the residue was subjected to flash column chromatography (silica gel, hexanes/ EtOAc/CHCl3/Et3N 20:1:1:1) to give the product. Alk-1-enyltriethylsilanes 50 (R1 = R2 = Et); General Procedure:[56]
A soln of 1,6-enyne 49 (0.51 mmol), TESH (2.5 mmol), [Rh(cod)2][SbF6] (0.025 mmol), and (R)-BIPHEMP [(R)-48; 0.027 mmol] in 1,2-dichloroethane (5 mL) was heated at 70 8C for 3 h. The resulting soln was cooled to rt, diluted with hexanes, filtered through a plug of silica gel, and concentrated, and the product was purified by chromatography (silica gel). Exocyclic Alkenes 54; General Procedure:[58]
To a 0.1 M soln of enyne 53 in 1,2-dichloroethane at ambient temperature was added the Rh catalyst (5 mol%) and the bisphosphine ligand (5 mol%). The system was purged with H2 and the mixture was allowed to stir under an atmosphere of H2 until complete consumption of enyne was observed. At this point, the mixture was adsorbed onto silica gel and the product was purified by chromatography (silica gel). 3.5.1.3
Gold- and Platinum-Catalyzed Cycloisomerization
The air and moisture stability of phosphine–gold(I) complexes makes them particularly appealing transition-metal catalysts for synthesis. However, it is the propensity of gold(I) to activate alkynes, coupled with its ability to stabilize carbocation intermediates, that makes it an especially useful catalyst in cycloisomerization reactions.[61] Distinctive carbocyclic products are produced by the reaction of unsaturated substrates with these cataAsymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.5
Asymmetric Cycloisomerizations
lysts.[59,60,62] Unlike the Alder-ene type rearrangements observed with palladium and rhodium, gold catalysts promote skeletal rearrangement of 1,6-enynes to give 1,3-diene products in good yield (Scheme 23). Gold(I)-Catalyzed Cycloisomerization of 1,6-Enynes[63]
Scheme 23
AuX(PPh3) (cat.) AgSbF6 (cat.) solvent, rt
E R
3
E
Au E E
R1
E
R2
E
R1 R3
R3
R1
R2
47−100%
R2 E = SO2Ph, CO2Me
The cationic gold(I)-catalyzed cycloisomerization of 1,5-enynes to [3.1.0]bicyclic products was first reported in 2004 (Table 7, entries 1 and 2),[64,65] followed by the reported cycloisomerization (entry 3) and methoxycyclization (entry 4) of 1,6-enynes to five-membered products.[63] By changing the reaction conditions, either the skeletally rearranged or methanol-trapped products can be isolated for these substrates. Allyl(propargyl)amine substrates cyclize to six-membered products (entry 5).[63] Table 7
Gold(I)-Catalyzed Cycloisomerization of 1,5- and 1,6-Enynes[63–65]
Entry Substrate
Catalyst
1
AuCl(PPh3), AgSbF6
Solvent Product
Yield (%)
Ref
75
[64]
98a
[65]
91
[63]
97
[63]
78b
[63]
H HO
CH2Cl2
Ph
Ph O H
Pr
2 Bn
AuCl(PPh3), AgSbF6
CH2Cl2
Pr H
Bn MeO2C
3
MeO2C
AuCl(PPh3), AgSbF6
CH2Cl2
AuMe(PPh3), HBF4
MeOH
AuCl(PPh3), AgSbF6
CH2Cl2
MeO2C
MeO2C
4
MeO2C
TsN
5
a b
MeO2C
MeO2C
dr >99:1. The 1,3-diene product (6%) was also isolated.
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MeO2C
TsN H
OMe
3.5.1
269
Enyne Cycloisomerization
The mechanism for the cycloisomerization of 1,6-enynes is thought to proceed by Å2-coordination the metal to the alkyne (Scheme 24). Attack by the alkene may occur in either a 5-exo-dig or a 6-endo-dig manner to generate metal cyclopropyl carbene complexes 55 and 56, respectively. From intermediate 56, skeletal rearrangement may form various conjugated dienes (Table 7, entry 3). Alternatively, the attack of nucleophiles such as alcohols onto intermediate 55 gives the products of alkoxy- or hydroxycyclization. Products derived from intermediate 56 have been isolated for substrates where X = O or NTs. In these cases, -hydrogen elimination followed by protonation gives bicyclo[4.1.0]heptene derivatives. These pathways are distinct from the previously discussed mechanistic processes, where the simultaneous coordination of the metal to the alkyne and the alkene triggers cycloisomerization through metallacyclopentene intermediates (see Sections 3.5.1.1 and 3.5.1.2). Scheme 24
Proposed Mechanism of Gold(I)-Catalyzed Cycloisomerization Au 5-exo-dig
R1
X
R2OH
X
R1
H OR
55
LAu+
or
X R1
2
OR
2
X R1 6-endo-dig
Au
X
X
H H
Au
X
H H
R1
H H
R1
R1
56
Chiral bisphosphine–gold(I) complexes, where the phosphine/gold stoichiometry is 1:1, have been employed in a number of asymmetric variants. These complexes have a twocoordinate, linear geometry, making it remarkable that such high enantioselectivities are achieved in these processes.[66] An asymmetric variant of the methoxycyclization of 1,6-enynes to give carbocycles such as 57 has been developed by Echavarren and co-workers (Scheme 25).[67] A variety of gold complexes have been screened, with a gold(I) complex with ligand (S)-60 [(S)-TolBINAP] providing the best selectivity. Under the optimized conditions, enyne 58 is converted into the cyclopentane product 59 with 94% enantiomeric excess. Interestingly, the other five substrates only provided modest enantioselectivity (£55% ee). Scheme 25
Asymmetric Gold(I)-Catalyzed Cycloisomerization of 1,6-Enynes[67] 1.6 mol% (AuCl)2L 2 mol% AgSbF6
PhO2S PhO2S
MeOH/CH2Cl2 (1:1), 60 oC
PhO2S
100%; 49% ee
PhO2S
Ph H
Ph
OMe
57
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Stereoselective Synthesis
3.5
1.6 mol% (AuCl)2L 2 mol% AgSbF6 MeOH, 24 oC
Ph
PhO2S
Asymmetric Cycloisomerizations
52%; 94% ee
PhO2S
PhO2S
Ph
PhO2S
OMe
59
58
1.6 mol% (AuCl)2L 2 mol% AgSbF6
MeO2C
MeO2C
MeOH, 24 oC
MeO2C
41%; 30% ee
MeO2C
OMe
P(4-Tol)2
L=
P(4-Tol)2
(S)-60
In a related version of this reaction, GenÞt and co-workers have developed an asymmetric platinum(II)-catalyzed variant of the alkoxycyclization reaction.[68,69] Contrary to the gold(I)-catalyzed rearrangements, these reactions proceed over a number of days. The cycloisomerizations are performed in screw-capped tubes at 80 8C using catalytic platinum(II) chloride with ligand (R)-61 [(R)-Ph-BINAPINE] in a mixture of dioxane with either water or methanol. The malonate and N-tosyl tethered enynes 62 react smoothly under these conditions to afford functionalized carbo- and aza-heterocycles 63 with good yields and moderate to good enantioselectivities (Scheme 26). In contrast, allyl propargyl ethers lead to a complex mixture of products. Scheme 26 Asymmetric Platinum(II)-Catalyzed Hydroarylation/Cyclization of 1,6-Enynes[68,69]
PPh
(R)-61
5 mol% PtCl2, 15 mol% (R)-61 25 mol% AgSbF6, R3OH, dioxane 60−80 oC
X
X R
1
R2 62
X
R1 H 2 R3 O R 63
R1 R2 R3 Time (d) ee (%) Yield (%) Ref
C(CO2Me)2 Ph H
H
4
85
94
[68]
NTs
H
7
84
86
[68]
3.5
66
87
[68]
Ph H
C(CO2Me)2 Me Me H
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271
Enyne Cycloisomerization
X
R1 R2 R3 Time (d) ee (%) Yield (%) Ref
NTs
Me Me H
NTs
Ph H
6.5
56
57
[68]
Me 2.5
78
49
[68]
C(CO2Me)2 Me Me Me 5.5
50
100
[68]
Michelet and co-workers have developed a related asymmetric hydroarylation/cyclization reaction to afford functionalized cyclopentene products 66.[70] The optimal catalyst is a gold complex containing bulky ligand 64 [(R)-DTBM-MeO-BIPHEP] with silver(I) trifluoromethanesulfonate in diethyl ether at room temperature. A number of malonate-tethered enynes and different electron-rich aromatic nucleophiles have been examined under these conditions (Scheme 27). Interestingly, increasing the steric crowding in the tether group improves the enantioselectivity (compare entries with E = CO2Me with those with E = CO2iPr), with the sulfone-substituted enyne 65 (E = SO2Ph; R1 = Ph; R2 = H) reacting with a number of methoxybenzenes with uniformly high enantioselectivities. A particularly impressive example is with the phenyl substituted enyne 67, which affords the tricyclic product 68 with excellent enantioselectivity (Scheme 27). Scheme 27
Asymmetric Gold(I)-Catalyzed Hydroarylation/Cyclization of 1,6-Enynes[70] OMe
But
But But OMe P
MeO
But But
MeO
P OMe But
But
But
OMe (R)-64 (R)-DTBM-MeO-BIPHEP
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Stereoselective Synthesis
3.5
Asymmetric Cycloisomerizations
3 mol% (R)-DTBM-MeO-BIPHEP(AuCl)2 6 mol% AgOTf, NuH, Et2O, rt
E
E R1
E
E
H Nu
R1
R2
R2 65
E
66
R1 R2 NuH
Nu
ee (%)
Yield (%)
Ref
72
92
[70]
80
86
[70]
95
94
[70]
95
99
[70]
81
99
[70]
82
99
[70]
98
86
[70]
OMe
CO2Me Ph H
1,3,5-trimethoxybenzene MeO
CO2Me Ph H
pyrrole
CO2iPr Ph H
1-methylindole
OMe
N H
N Me
CO2iPr Ph H
1-methyl-2-phenylindole N Me
CO2Bn Ph H
Ph
1-methylindole N Me
CO2Bn Ph H
1-methyl-2-phenylindole N Me
SO2Ph Ph H
Ph
1,3-dimethoxybenzene MeO
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OMe
3.5.1
273
Enyne Cycloisomerization R1 R2 NuH
E
Nu
ee (%)
Yield (%)
Ref
98
99
[70]
94
85
[70]
88
37
[70]
OMe
SO2Ph Ph H
1,3,5-trimethoxybenzene MeO
OMe OMe
SO2Ph Ph H
Br
2-bromo-1,3,5-trimethoxybenzene
MeO
OMe
SO2Ph Me Me 1-methylindole N Me
3 mol% (R)-DTBM-MeO-BIPHEP(AuCl)2 6 mol% AgOTf, Et2O, rt
MeO2C
MeO2C
99%; 93% ee
MeO2C
MeO2C
67
68
Michelet and co-workers have also developed an asymmetric gold(I)-catalyzed intramolecular cyclopropanation reaction.[71] The same complex as in the preceding reactions [(R)-DTBM-MeO-BIPHEP(AuCl)2] modified with silver(I) trifluoromethanesulfonate in toluene at 0 8C promotes the rearrangement of 1,6-enynes 69 to provide the bicyclo[4.1.0]heptene derivatives 70 with high enantioselectivities (Scheme 28). Nevertheless, despite the excellent enantioselectivities, the chemical yields are low, with only one example above 70% yield, which was conducted at higher temperature (Scheme 28). Scheme 28 Enynes[71]
Asymmetric Gold(I)-Catalyzed Hydroarylation/Cyclization of 1,6-
R1
3 mol% (R)-DTBM-MeO-BIPHEP(AuCl)2 6 mol% AgOTf, toluene
X
R1
X R2
H
69
70
X
R1
R2 Temp (8C) ee (%) Yield (%) Ref
O
Ph
Ph rt
98
34
[71]
O
4-MeO2CC6H4 Ph rt
94
25
[71]
O
4-MeOC6H4
Ph rt
96
47
[71]
NTs Ph
H 60
98
74
[71]
O
Ph rt
91
24
[71]
Et
R2
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Stereoselective Synthesis
Asymmetric Cycloisomerizations
3.5
Marinetti and co-workers have developed an asymmetric intramolecular cyclopropanation reaction of enynes 71 using well-defined chiral platinum(II) complexes.[72] The platinum(II) complexes 72 contain a six-membered metallacycle, which is comprised of an Nheterocyclic carbene—platinum and a -aryl—platinum bond (Scheme 29). Addition of the chiral monodentate phosphine (S)-61 [(S)-Ph-BINEPINE] affords the cycloisomerization products 73 in good yield and with high enantioselectivity (Scheme 29). An iridium system has also been developed to access similar products, albeit with lower enantioselectivities.[73] Asymmetric Platinum(II)-Catalyzed Cycloisomerization of 1,6-Enynes[72]
Scheme 29
4 mol%
N N
Pt L I
R4 72 12.5 mol% AgBF4, toluene
R1 TsN
R
2
R1
TsN
R3
R2
71
R3
73
PPh
L=
(S)-61
R1
R2
R3 R4 Temp (8C) ee (%) Yield (%) Ref
Ph
H
H Me 60
93
88
[72]
4-MeOC6H4 H
H Et 60
91
77
[72]
4-O2NC6H4
H Bn 60
97
51
[72]
Bn 90
92
40
[72]
Ph
H
Toste and co-workers have developed an efficient method for the asymmetric gold(I)-catalyzed preparation of small and medium-sized rings 78 (n = 0–3) from enynes 77 (Scheme 30).[74] The method provides seven- to nine-membered rings in excellent yield with high enantioselectivities employing gold(I) complexes containing the chiral ligands (R)-74 [(R)-XylBINAP], (R)-75 [(R)-DTBM-SEGPHOS], or (R)-76 [(R)-DIFLUORPHOS]. Notably, the yields for the formation of the notoriously difficult eight-membered carbocycles 78 (n = 2) are extremely good.
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3.5.1
275
Enyne Cycloisomerization Asymmetric Gold(I)-Catalyzed Intramolecular Cyclopropanation[74]
Scheme 30
OMe But
But But
O P
OMe P
O
But But
O
P
P
OMe
O But
But
But
OMe (R)-74
(R)-75
(R)-XylBINAP
F
O
F
O
PPh2
F
O
PPh2
F
O
(R)-76
(R)-DTBM-SEGPHOS
(R)-DIFLUORPHOS
R2
R2
R1
R1 O
O
2.5 mol% (AuCl)2L 5 mol% AgSbF6, MeNO2
O
n
O
n
R3
R3 77
78
R1
R2
R3 n Ligand
Me
Me H
2 (R)-XylBINAP [(R)-74]
–25
92
94
[74]
CH2CH=CH2
Me H
2 (R)-XylBINAP [(R)-74]
–25
90
98
[74]
(CH2)2Ph
Me H
2 (R)-XylBINAP [(R)-74]
–25
90
80
[74]
H
t-Bu H
1 (R)-DTBM-SEGPHOS [(R)-75]
rt
85
44
[74]
Me
Me Me 2 (R)-DIFLUORPHOS [(R)-76]
–25
75
88
[74]
Temp (8C) ee (%) Yield (%) Ref
Scheme 31 outlines the proposed mechanism for the intramolecular cyclopropanation reaction, which is believed to involve the coordination of cationic gold(I) to the alkyne followed by a 1,2-shift of the acetate to generate a gold-stabilized vinyl carbenoid. Cyclopropanation of the pendant alkene then generates the tricyclic system. It is notable that the gold-catalyzed reaction of propargyl ester 77 (R1 = CH2CH=CH2; R2 = Me; R3 = H; n = 2) containing two alkenes selectively affords the larger eight-membered ring 78 over the fivemembered ring, emphasizing the remarkable selectivity of the reaction for mediumsized rings.
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Stereoselective Synthesis
3.5
Asymmetric Cycloisomerizations
Scheme 31 Proposed Mechanism of the Intramolecular Gold(I)-Catalyzed Cyclopropanation[74]
OAc 5 mol% AuCl(PPh3) 5 mol% AgSbF6, CH2Cl2
O
O O AuL
O
AuL
OAc AuL
OAc
Bicyclo[3.1.0]hex-2-enes, e.g. Table 7, Entry 2; General Procedure:[65]
To a 1-dram vial with a threaded cap containing a magnetic stirrer bar and 0.5 M 1,5-enyne (100 mg) in CH2Cl2 were added AgSbF6 (1–5 mol%) and AuCl(PPh3) (1–5 mol%) sequentially. A cloudy white mixture formed during the course of the reaction. The mixture was stirred at rt and monitored by TLC analysis. Upon completion, the mixture was filtered through a short plug of silica gel and eluted with CH2Cl2. Evaporation of the solvent followed by column chromatography afforded the desired bicyclo[3.1.0]hexene. Methoxy exo-Methylenecarbocycles, e.g. 57; General Procedure:[67]
A mixture of (S)-TolBINAP(AuCl)2 (1.6 mol%) and AgSbF6 (2 mol%) in MeOH (1 mL) was stirred at rt for 5 min. The enyne (0.12 mmol) in MeOH (2 mL) was added and the mixture was stirred at rt. The mixture was filtered through silica gel, and the solvent was evaporated. The crude mixture was purified by flash chromatography (hexane/EtOAc) to give the carbocycles. exo-Methylenecyclopentanes or -pyrrolidines 63; General Procedure:[68]
A mixture of enyne 62 (1 equiv), PtCl2 (5 or 10 mol%), (R)-Ph-BINEPINE [(R)-61; 3 equiv/Pt], and AgSbF6 (25 mol%) was degassed and stirred at 60–80 8C in MeOH (screw-capped tube at 80 8C) or 14% aq dioxane (1.75 mL solvent/mmol starting material). After completion of the reaction, the mixture was cooled to rt and filtered through a short pad of Florisil (cyclohexane/EtOAc 7:3), and the solvents were evaporated under reduced pressure. The crude product was purified if necessary by flash chromatography (Florisil, cyclohexane/EtOAc 9:1). Methylenecyclopentanes 66; General Procedure:[70]
A mixture of (R)-DTBM-MeO-BIPHEP(AuCl)2 (3 mol%) and AgOTf (6 mol%) in distilled Et2O (to give a 10–2 M soln of the resulting Au complex) was stirred under argon at rt for 30 min. The aromatic nucleophile (3 equiv) was then added and the mixture was stirred for 5 min. Enyne 65 (1 equiv) was finally added and the mixture was stirred until compleAsymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.5.2
Diene Cycloisomerization
277
tion of the reaction. The mixture was then filtered through a short pad of silica gel using EtOAc as the eluent and the solvents were evaporated under reduced pressure. The crude product was purified by flash chromatography (silica gel, petroleum ether/EtOAc 9:1 to 7:3). 3-Aza- or 3-Oxabicyclo[4.1.0]hept-4-enes 70; General Procedure:[71]
A mixture of (R)-DTBM-MeO-BIPHEP(AuCl)2 (3 mol%) and AgOTf (6 mol%) in distilled toluene (to give a 0.5 M soln of the resulting Au complex) was stirred under argon at rt for 30 min. Enyne 69 (1 equiv) was then added and the mixture was stirred until completion of the reaction. The mixture was then filtered through a short pad of silica gel using EtOAc as the eluent and the solvents were evaporated under reduced pressure. The crude product was purified by flash chromatography (silica gel, petroleum ether/EtOAc 98:2 to 80:20). 3-Tosyl-3-azabicyclo[4.1.0]hept-4-enes 73; General Procedure:[72]
To a soln of the platinum(II) complex 72 (0.0064 mmol, 4 mol%) in toluene (0.5 mL) under argon was sequentially added AgBF4 (4 mg, 0.02 mmol) and a soln of the enyne 71 (0.16 mmol) in toluene (4.5 mL). The mixture was stirred at 60 8C for 18–24 h and the reaction was monitored by NMR. The solvent was removed under reduced pressure and the final product was purified by column chromatography. Fused Cyclopropanes 78; General Procedure:[74]
CAUTION: Nitromethane is flammable, a shock- and heat-sensitive explosive, and an eye, skin, and respiratory tract irritant. To a screw-cap scintillation vial was added AgSbF6 (5 mol%), the chiral gold(I) complex (5 mol%), and MeNO2. The resultant cloudy soln was allowed to sit for 10 min at rt and filtered, resulting in a clear, colorless soln. This soln was then cooled to –25 8C and allowed to equilibrate for 30 min. To this soln was quickly added the propargyl ester substrate 77 in MeNO2, also cooled at –25 8C, and the resultant soln (0.1 M overall) was allowed to sit at –25 8C. Upon completion, as judged by TLC analysis of the mixture, the soln was quenched with a few drops of Et3N, warmed to rt, and loaded directly onto a silica gel column. Purification by flash chromatography afforded the desired cyclized product. 3.5.2
Diene Cycloisomerization
3.5.2.1
Cycloisomerization of 1,6- and 1,7-Dienes
The transition-metal-catalyzed cycloisomerization of 1,6-dienes may be catalyzed by a number of different metals, including palladium, nickel, rhodium, ruthenium, and titanium. However, there have been relatively few successful enantioselective variants of this transformation. Heumann and co-workers developed an asymmetric palladium(II) system using (–)-sparteine and a bis-oxazole ligand, albeit with modest enantioselectivity (up to 60% ee).[75] In related studies, a menthylphosphine-modified cationic nickel complex catalyzes the asymmetric cyclization of hepta-1,6-diene and diallyl ether, but with even lower enantioselectivity (up to 37% ee).[76] Leitner and co-workers have developed a nickel(II) system for the enantioselective preparation of cyclopentene products.[77,78] Diethyl diallylmalonate is cycloisomerized to diethyl 3-methylene-4-methylcyclopentane-1,1-dicarboxylate (80) with a nickel catalyst {[Ni(Å3-CH2CH=CH2)(cod)][BAr14] [Ar1 = 3,5-(F3C)2C6H3] and the azaphospholene ligand all(R)-79 in 97% yield and with 80% enantiomeric excess (Scheme 32), with the limitation that this study was only carried out on this substrate. Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis Scheme 32
3.5
Asymmetric Cycloisomerizations
Nickel(II)-Catalyzed Cycloisomerization of a Diene[77,78]
Ph H Me
P N
N P
Me
H
Ph
all-(R)-79
EtO2C
5 mol% [Ni(η3-CH2CH=CH2)(cod)][BARF] 5 mol% all-(R)-79, 1,2-dichloroethane, rt
EtO2C
EtO2C EtO2C 80
[BARF]− = [3,5-(F3C)2C6H3]4B−
Gagn and co-workers have developed platinum(II) catalysts for diene cycloisomerization. Using 1,1,1-tris[(diphenylphosphino)methyl]ethane (triphos)–platinum(II) catalysts, 1,6and 1,7-dienes react to form bicyclopropane products.[79–81] The key principle that guided the groups choice of ligands for this reaction was to block the sites cis to the intermediate alkylmetal species, thereby inhibiting competing -hydride elimination. In order to transfer the tridentate architecture of the triphos ligands into an asymmetric variant, it was reasoned it could be deconstructed into a combination of a bi- and monodentate phosphine ligand. The catalyst is therefore generated by adding monodentate trimethylphosphine to the precursor complex containing a chiral bidentate phosphine [PtI2L] to generate the precatalyst [(Me3P)PtI]+, followed by activation with 2.5 equivalents of silver(I) tetrafluoroborate in the presence of the diene substrate 81. The reaction yield is very sensitive to solvent, with nitromethane providing the best results. Optimal enantioselectivities are achieved with chiral ligands (R)-74 [(R)-XylBINAP] and in one case (R)-22 [(R)-SEGPHOS], which furnish the cyclopropane-containing products 82 in 43–70% yield and with 69– 96% enantiomeric excess (Table 8).
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3.5.2
279
Diene Cycloisomerization Asymmetric Platinum(II)-Catalyzed Diene Cycloisomerization[79–81]
Table 8
5 mol% PtI2L, 5 mol% Me3P 12.5 mol% AgBF4, MeNO2, rt
X
X R1
R1 81
82
Substrate
Catalyst
Product
ee Yield Ref (%) (%)
[Pt{(R)-XylBINAP}(PMe3)](BF4)2 OMe
[81]
69 43
[81]
87 47
[81]
96 44
[81]
OMe
[Pt{(R)-XylBINAP}(PMe3)](BF4)2
MeO2C
MeO2C
MeO2C
[Pt{(R)-XylBINAP}(PMe3)](BF4)2
TsN
[Pt{(R)-SEGPHOS}(PMe3)](BF4)2 TsN
a
95 70a
MeO2C
dr 3.9:1.
The mechanism of the reaction is proposed to be ionic, involving carbocation intermediates (Scheme 33). For example, electrophilic activation of the terminal alkene results in cyclization that forms a carbocation intermediate. The cyclization is reversible and studies indicate that several cations are in equilibrium prior to proton transfer.[79–81] Indeed, the initial cyclization may proceed by either a 6-endo or 5-exo route; the actual pathway is not known. Either way, a 1,2-hydride shift then occurs generating a 1,3-relationship between the alkylmetal species and cation. Ring closing of this species results in the final cyclopropane product.
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Stereoselective Synthesis Scheme 33
3.5
Asymmetric Cycloisomerizations
Proposed Mechanism of Platinum(II)-Catalyzed Cycloisomerization[79–81]
(PPP)Pt
H
Pt(PPP)
H
H (PPP)Pt
H
H
(PPP)Pt
(PPP)Pt
Widenhoefer and co-workers have developed a platinum(II)-catalyzed intramolecular asymmetric hydroarylation of nonactivated alkenes with indoles for the preparation of tetrahydrocarbazoles 84 (n = 1).[82,83] The bulky ligand (S)-64 [(S)-DTBM-MeO-BIPHEP] is optimal for the transformation, which is performed in methanol at 60 8C without any special precautions to exclude air or moisture. Although this procedure provides the functionalized tricyclic indole derivatives in high yield, the enantioselectivity is somewhat variable (Scheme 34). Interestingly, 1,7-diene 83 (n = 2; R1 = CO2Me; R2 = Me; R3 = H) successfully undergoes cyclization at room temperature to afford the corresponding product with 74% enantiomeric excess (Scheme 34). Scheme 34
Asymmetric Platinum(II)-Catalyzed Intramolecular Hydroarylation[82,83] OMe
But
But But OMe P
MeO
But But
MeO
P OMe But
But
But
OMe (S)-64
R1 R
(S)-DTBM-MeO-BIPHEP
R2
n
N
1
10 mol% (S)-DTBM-MeO-BIPHEP (S)-64, PtCl2 10 mol% AgOTf, MeOH
R1
R2
n
N
R1
R3 83
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R3 84
3.5.2
281
Diene Cycloisomerization
n R1
R2
R3
Temp (8C) ee (%) Yield (%) Ref 60
88
93
[83]
1 CO2Me Me OMe 60
87
96
[83]
1 CO2Me Me F
60
88
93
[83]
1 Me
60
68
90
[83]
rt
74
69
[83]
1 CO2Me Bn H
Me H
2 CO2Me Me H
Widenhoefer and co-workers have developed a highly diastereoselective palladium(II)-catalyzed cycloisomerization–hydrosilation protocol.[84] This advance prompted the development of the enantioselective variant for the conversion of functionalized dienes into cyclopentane products with excellent diastereo- and enantioselectivities.[84–88] The ability to either isolate the products as alkylsilanes or oxidize them to alkyl alcohols 87 adds versatility to this approach (Scheme 35). A number of palladium complexes containing chiral bidentate nitrogen ligands were screened in the reaction, in which the pyridyldihydrooxazole ligand 86 proved optimal. For instance, the diene 85 is treated with the catalyst activated by sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate in dichloromethane at –20 8C with 3 equivalents of dimethyl(diphenylmethyl)silane to facilitate this reaction. Interestingly, the process tolerates both allylic and terminal alkenic substitution. Scheme 35 Asymmetric Platinum(II)-Catalyzed Cycloisomerization–Hydrosilation of 1,6-Dienes[84–88] 1. 5 mol% Pd(Me)ClL 5 mol% Na[BARF], HSiMe2CHPh2 2. H2O2, TBAF
R1 R1 R2
R1
R4 R2 R3
R4
R3 85
L=
OH
R1
87
O
N
; [BARF]− = [3,5-(F3C)2C6H3]4B−
N Pri 86
R1
R2
R3
R4
ee (%) Yield (%) Ref
CO2Me
H
H
H
93
78
[88]
CO2Me
H
H
Me 90
66
[88]
CH2OC(O)t-Bu
(CH2)5 H
93
58
[88]
CO2Me
(CH2)4 H
88
96
[88]
Fused Cyclopropanes 82; General Procedure:[81]
CAUTION: Nitromethane is flammable, a shock- and heat-sensitive explosive, and an eye, skin, and respiratory tract irritant. CAUTION: Trimethylphosphine is pyrophoric and has a very unpleasant odor. To a screw-cap scintillation vial was added PtI2[(R)-XylBINAP] (0.013 mmol) and MeNO2 (to give a 0.06 M soln). To this suspension was added Me3P (0.013 mmol) and the suspension was stirred until the Pt complex was completely dissolved. Then, diene 81 (20 equiv) was added followed by AgBF4 (0.029 mmol). The soln was stirred in the dark until shown to be Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.5
Asymmetric Cycloisomerizations
complete by GC. The mixture was extracted with Et2O, and the extracts were washed with H2O, dried (MgSO4), filtered, and concentrated before being purified on a Ag+ silica column to afford the bicyclopropane. Cyclopentylmethanols 87; General Procedure:[85]
Diene 85 (0.47 mmol) and dimethyl(diphenylmethyl)silane (1.5 mmol) were added sequentially to a soln of [Pd(Me)Cl(N-N)] [N-N = (+)-(R)-4-isopropyl-2-(2-pyridyl)-4,5-dihydrooxazole; 8 mg, 0.023 mmol] and Na[BARF] {[BARF]– = [3,5-(F3C)2C6H3]4B–; 21 mg, 0.023 mmol} in CH2Cl2 (10 mL) at 20 8C, and the resulting pale yellow soln was stirred overnight to form a dark brown soln. Solvent and excess silane were evaporated under vacuum, and the residue was chromatographed (hexanes/EtOAc 24:1) to give the alkylsilane intermediate as a pale yellow oil. A suspension of the alkylsilane (325 mg, 0.65 mmol), 1.0 M TBAF in THF (7.0 mL, 7.0 mmol), KHCO3 (100 mg, 1.0 mmol), and 50 wt% aq H2O2 (0.75 mL, 13.0 mmol) in MeOH (3 mL) was refluxed for 24 h. Workup (H2O/EtOAc) followed by chromatography gave the product alcohol. 3.5.2.2
Cycloisomerization of 1,6- and 1,7-Allenenes
The cycloisomerization of tethered ene–allene substrates is known to occur with rhodium, palladium, ruthenium, and nickel/chromium catalysts, typically forming five-membered-ring products, although seven-membered rings have also been prepared. In a logical progression from their work on diene cyclizations,[79–81] Gagn and co-workers developed a gold(I) system for the cycloisomerization of 1,6-allenenes 88.[89] Interestingly, unlike the other catalyst systems, gold(I) catalysts afford six-membered vinylcyclohexenes 89 and 90 as products (Scheme 36). Scheme 36
Asymmetric Gold(I)-Catalyzed Cycloisomerization of 1,6-Allenenes[89] 5 mol% (R)-XylBINAP(AuCl)2 15 mol% AgOTf
• R1O
2C
R3
MeNO2, rt, 16 h
R1O2C R2 88
R1O2C
R3
R 1 O 2C
R3
+ R 1 O 2C
R1O2C
R2
R2 89
R1
R2
R3 Ratio (89/90) ee (%) of 89 Yield (%) Ref
Me Me H 7:2
72a
83
[89]
Me Ph
H 3:2
45
70
[89]
(CH2)4 1:0
65
70
[89]
Me a
90
The enantioselectivity was improved (77% ee) at –12 8C.
Using chiral gold(I)–phosphine complexes, the complex containing ligand (R)-74 [(R)-XylBINAP] with silver(I) trifluoromethanesulfonate is the optimal catalyst for the enantioselective variant. Unfortunately, the enantioselectivities are relatively modest (up to 77% ee) Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.5.2
283
Diene Cycloisomerization
and the product is obtained as a mixture of isomers 89 and 90 (Scheme 36). Substrates 88 (R2 = H) that are only monosubstituted at the internal position of the alkene are unreactive, and substitution at the internal position of the allene also furnishes products with lower yields and enantioselectivities. The reactions were generally run in nitromethane at room temperature over 16 hours, although a slight improvement in enantioselectivity can be achieved by conducting the reaction at –12 8C [77 vs 72% ee for product 89 (R1 = R2 = Me; R3 = H)]. The reaction is thought to occur by electrophilic activation of the internal allene by cationic gold(I). Nucleophilic attack by the alkene then generates a stabilized tertiary carbocation. Elimination and protodeauration complete the generation of the vinylcyclohexene products (Scheme 37). Scheme 37 Proposed Mechanism of Gold(I)-Catalyzed Ene–Allene Cycloisomerization[89]
E E
LAu
LAu
•
E
E
E
E
+ E E
Interestingly, Toste and co-workers have independently developed a similar gold(I)-catalyzed cycloisomerization of 1,6-allenenes. However, these 1,6-allenenes are not internally substituted alkenes, but instead terminal styrene systems 91 that cyclize to remarkably provide alkylidenecyclobutane products 92 (Scheme 38).[90] Using a gold(I) complex containing the chiral biarylphosphine ligand (R)-75 [(R)-DTBM-SEGPHOS] as the catalyst allows access to highly enantioenriched bicyclo[3.2.0] structures (Scheme 38). Scheme 38 Asymmetric Gold(I)-Catalyzed Cycloisomerization of 1,6-Allenenes to Alkylidenecyclobutanes[90] R1 •
R1
3 mol% (R)-DTBM-SEGPHOS(AuCl)2 6 mol% AgBF4 CH2Cl2, 4 oC
R2
X
H
R2
X
Ar1
Ar1
H 91
X
92
R1
R2
Ar1
ee (%) Yield (%) Ref 95
92
[90]
Ph
95
86
[90]
C(CO2Me)2 Me
Me Ph
54
70
[90]
C(CO2Me)2 Me
Me 2-naphthyl 97
81
[90]
C(CO2Me)2 Me NTs
Me Ph
(CH2)5
The reaction, a formal [2 + 2] cycloaddition, is thought to proceed through a series of cationic intermediates in a stepwise manner (Scheme 39). Activation of the allene 93 by Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.5
Asymmetric Cycloisomerizations
gold(I) initiates cyclization to generate the five-membered cyclopentane ring and a benzylic cation. This cyclization can occur to generate either the trans-substituted cyclopentene system 94 or the cis-substituted cyclopentene system 96. Evidence for the reversibility of the cyclization steps comes from experiments in the presence of methanol, in which the presumed kinetic cation is trapped to give the trans-cyclopentene product 95. After cyclization, cyclobutane formation occurs from the reaction of the vinylgold species with the benzylic carbocation of the cis-species to generate 97. Proposed Mechanism of the Gold(I)-Catalyzed [2 + 2] Cycloaddition[90]
Scheme 39
R1 LAu X
•
H
R1
H
MeOH
H Ar1
X
R1
H
H Ar1
− LAu+
H
MeO
AuL+ X
R1
94
R1 Ar1 R2
95
93 H X
H
H
AuL Ar1 R
1
R
X
R1
H
− LAu+
Ar1
R1
1
96
H 97
Widenhoefer and co-workers have developed an intramolecular gold(I)-catalyzed hydroarylation of allenes with indoles for the preparation of tetrahydrocarbazoles.[91] Chiral biarylphosphine–gold(I) complexes are again utilized for the asymmetric version of the reaction, with the bulky ligand (S)-64 [(S)-DTBM-MeO-BIPHEP] providing optimal results. The reactions are performed in toluene at –10 8C and are complete in 18–24 hours, to provide the tricyclic indole derivatives 98 (n = 1) with good enantioselectivities (Scheme 40). Interestingly, a 1,7-allenene successfully undergoes a 7-exo-trig cyclization at room temperature to afford the product 98 (n = 2; R1 = R2 = H) in 91% enantiomeric excess. The protocol is similar to another Widenhoefer procedure involving hydroarylation of an alkene,[82,83] although the enantioselectivities are significantly improved. Asymmetric Gold(I)-Catalyzed Intramolecular Hydroarylation[91]
Scheme 40
R1 R1
R1 • MeO2C MeO2C
2.5 mol% (S)-DTBM-MeO-BIPHEP(AuCl)2 5 mol% AgBF4, toluene, −10 oC, 17 h
n
NMe
MeO2C
R1 n
NMe
MeO2C
R2
R2 98
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3.5.3
285
Carbonyl-Ene Reaction
n R1
R2
ee (%) Yield (%) Ref
1 H
H
92
88
[91]
1 H
OMe 78
85
[91]
1 H
F
75
90
[91]
1 Me H
91
82
[91]
2 H
91
80
[91]
H
Fused Alkylidenecyclobutanes 92; General Procedure:[90]
To a screw-cap scintillation vial was added (R)-DTBM-SEGPHOS(AuCl)2 (3–5 mol%) and AgBF4 (3–6 mol%) in CH2Cl2 (0.3 mL), which was stirred for 5 min. This suspension was added into another vial containing a 0.1 M soln of the allenene 91 (100 mg, 1 equiv) in CH2Cl2 at 0 8C or rt. A cloudy mixture was formed over the course of the reaction. The mixture was stirred at rt and monitored by TLC analysis. Upon completion, the mixture was filtered through a short silica plug and eluted with CH2Cl2. Evaporation of the solvent followed by column chromatography afforded the desired cycloadduct. 3.5.3
Carbonyl-Ene Reaction
The ene reaction tolerates a wide number of variants in terms of the enophile (see Scheme 1). When a carbonyl group is used as the enophile, the reaction is often called the carbonyl-ene reaction.[92] A large number of intermolecular diastereo- and enantioselective variants of the carbonyl-ene reaction have been developed; however, there have been relatively few asymmetric intramolecular versions of this reaction disclosed (Scheme 41).[93] Scheme 41 Intramolecular Carbonyl-Ene Cyclization Reaction O
H
O
H
Early approaches to the reaction involved using stoichiometric chiral Lewis acids. For example, a zinc–(R)-1,1¢-bi-2-naphthol [(R)-BINOL] catalyst (3 equiv) cyclizes 3-methylcitronellal (99, R1 = Me) with 90% enantiomeric excess, whereas 99 (R1 = H) affords a racemic product (Scheme 42).[94] A titanium catalyst with a tartrate-derived diol as the ligand (1.1 equiv) cycloisomerizes deca-2,8-dienoic acid derivative 100 in greater than 98% enantiomeric excess (Scheme 42).[95] In a related study, the chiral europium Lewis acid catalysts give low enantioselectivities (19–38% ee) for the carbonyl-ene cyclization of the key intermediate in the synthesis of anguidine, a trichothecene natural product.[96]
Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
Asymmetric Cycloisomerizations
Stoicheometric Enantioselective Carbonyl-Ene Cyclization Reactions[94,95]
Scheme 42 R1
3.5
Me2Zn (3 equiv) (R)-BINOL (3 equiv) CH2Cl2, −78 to 0 oC
R1
R1
R1
CHO
OH
99
R1
ee (%) Yield (%) Ref
Me 90
90
[94]
H
31
[94]
0
Ph Ph
O
O
O
O O
O Ph
N
O
Ph Ti
Cl Cl
(1.1 equiv)
Ph
CCl2FCCl2F, 4-Å molecular sieves
O
O
63%; >98% ee
N
O
100
Mikami and co-workers have developed a chiral titanium perchlorate–(R)-1,1¢-bi-2-naphthol system for the cyclization of Æ-alkoxy aldehydes.[97,98] The reaction preferentially produces the trans-substituted six-membered ring 101A with moderate enantioselectivity for the two substrates that have been tested (Scheme 43). Scheme 43 Asymmetric Titanium–(R)-1,1¢-Bi-2-naphthol Catalyzed Carbonyl-Ene Cyclization To Give Six-Membered Rings[97,98] O H X
OH
OH
10 mol% TiCl2(OiPr)2 10 mol% (R)-BINOL, 22 mol% AgClO4 CH2Cl2, 4-Å molecular sieves
+
X 101A
X
Ratio (101A/101B) ee (%) of 101A ee (%) of 101B Yield (%) Ref
O
80:20
84
50
50
[98]
CH2 69:31
55
66
66
[98]
X 101B
When the alkene is substituted at the internal position the sense of cyclization switches and a seven-membered-ring alcohol is formed with good enantioselectivity (Scheme 44).[97,98]
Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Carbonyl-Ene Reaction
3.5.3
Scheme 44 Asymmetric Titanium–(R)-1,1¢-Bi-2-naphthol Catalyzed Carbonyl-Ene Cyclization To Give Seven-Membered Rings[98] O
10 mol% TiCl2(OiPr)2 10 mol% (R)-BINOL, 22 mol% AgClO4 4-Å molecular sieves
H
O
O R1
HO
R1
R1
R1
ee (%) Yield (%) Ref
H
91
43
[98]
Me 82
40
[98]
R1
Yang and co-workers have developed a Lewis acid catalyzed cyclization of Æ-oxo esters to cyclic alcohols. In the absence of a catalyst, these reactions proceed at high temperature over several days. After examining different combinations of Lewis acid and chiral bis(4,5dihydrooxazole) ligands, it was determined that the complex of copper(II) with ligand (S,S)-102 [(S,S)-Ph-box] is an effective catalyst for the cyclization of a number of Æ-oxo esters 103 (Scheme 45).[99] The reaction is selective for 104A, where the alcohol and vinyl group have a syn orientation. The Æ-oxo ester 103 (n = 1; R1 = R2 = Me), prepared from (+)-(R)-citronellic acid, furnishes the corresponding tertiary alcohol 104 with modest diastereo- and enantiocontrol (dr 7.3:1, 93% ee) in the absence of a chiral ligand; however, when the ligand (S,S)-103 is included, an amplification of both the diastereo- and enantioselectivity is observed (Scheme 45). The same matched case is observed for substrate 103 (n = 1; R1 = Bn; R2 = Me). Scheme 45 Asymmetric Copper(II)-Catalyzed Cyclization of Æ-Oxo Esters[99] O
O N
Ph (S,S)-102
N Ph (S,S)-Ph-box
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Stereoselective Synthesis
R2
Asymmetric Cycloisomerizations
R2
O
R2 CO2R1
20 mol% Cu(OTf)2 22 mol% ligand, CH2Cl2, rt
OR1 n
3.5
OH
O
OH +
n
103
CO2R1 n
104A
104B
n R1
R2
Ligand
Ratio (104A/104B)
ee (%) of 104A
Yield (%)
Ref
2 Et
H
(S,S)-Ph-box [(S,S)-102]
>50:1
91
81
[99]
1 Et
H
(S,S)-Ph-box [(S,S)-102]
>50:1
75
87
[99]
1 Me Me –
7.3:1
93
76
[99]
1 Me Me (S,S)-Ph-box [(S,S)-102]
24:1
97
91
[99]
1 Me Me (R,R)-Ph-box [(R,R)-102]
1.3:1
87
54
[99]
8:1
98
86
[99]
1 Bn
Me –
1 Bn
Me (S,S)-Ph-box [(S,S)-102]
34:1
99
94
[99]
1 Bn
Me (R,R)-Ph-box [(R,R)-102]
1.3:1
98
56
[99]
1-Hydroxy-2-isopropenylcycloalkanecarboxylates 104; General Procedure:[99]
Chiral ligand (S,S)-102 (66.2 mg, 0.20 mmol) and Cu(OTf )2 (68.2 mg, 0.19 mmol) were mixed in dry CH2Cl2 (4 mL) for 30 min at rt. Then, Æ-oxo ester 103 (0.95 mmol) was added and the mixture was stirred at rt. When the reaction was complete as shown by TLC, the mixture was filtered through a thin pad of silica gel and then concentrated to give an analytically pure compound. 3.5.4
Conia-Ene Reaction
The thermal cyclization of ketones onto a tethered alkene or alkyne is known as the Conia-ene reaction.[100] The reaction is a variant of the ene reacton, and is thought to occur as a six-electron process, involving an enol hydrogen shift, followed by a concerted cyclization (Scheme 46). Scheme 46 R1
O
The Conia-Ene Reaction R1
O
H
R1
O
H
The development of transition-metal-catalyzed versions offers significant advantages over the thermal process, including operating at much lower temperatures. Recent developments include the palladium(II)-catalyzed cyclization of 1,3-diones onto alkenes[101,102] and the gold(I)-catalyzed cyclization of -oxo esters with alkynes.[103–105] Toste and co-workers have developed an enantioselective variant of the cyclization of -oxo esters with alkynes to form Æ-vinylated ketone products.[106] Although initial attempts with chiral gold(I) complexes were unfruitful, the bis(trifluoromethanesulfonate)–palladium(II) complex of (R)-75 [(R)-DTBM-SEGPHOS] affords the Conia-ene product in high enantioselectivity, albeit with low yield. The addition of 10 equivalents of acetic acid and ytterbium(III) trifluoromethanesulfonate (20 mol%) in diethyl ether results in both high yields and enantioselectivities (Scheme 47). The reaction works for a range of Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.5.4
289
Conia-Ene Reaction
-dicarbonyl compounds (16 examples, 44–94% ee). For example, esters are tolerated, although tert-butyl esters provide slightly lower enantioselectivity. The 2-iodophenyl ketone 105 (R1 = 2-IC6H4; R2 = OEt) furnishes 106 (R1 = 2-IC6H4; R2 = OEt) with 85% enantiomeric excess. Subsequent exposure of 106 (R1 = 2-IC6H4; R2 = OEt) to Heck conditions causes a second diastereoselective cyclization onto the alkene, resulting in a tricyclic ketone. In contrast, the aliphatic ketone 105 (R1 = Cy; R2 = OEt) and -diketone substrate 105 (R1 = Ph; R2 = Me) undergo cyclization with diminished enantioselectivity (Scheme 47). The reaction is thought to occur by the generation of a palladium enolate that then undergoes Lewis acid promoted addition to the alkyne. Scheme 47 O
Palladium(II)-Catalyzed Enantioselective Conia-Ene Reaction[106]
O
R1
10 mol% Pd{(R)-DTBM-SEGPHOS}(OTf)2 20 mol% Yb(OTf)3
R2
AcOH (10 equiv), Et2O
O
O R2
R1
105
106
R1
R2
Time (h) ee (%) Yield (%) Ref
Ph
OEt
12
89
86
[106]
2-IC6H4
OEt
12
85
95
[106]
1-naphthyl OEt
8
89
70
[106]
Cy
OEt
6
44
97
[106]
Ph
Me
3
70
90
[106]
Toste and co-workers have also developed an intramolecular enantioselective cyclization of siloxy-1,6-enynes 108. Using palladium(II) trifluoromethanesulfonate complexes containing a chiral ligand, functionalized methylenecyclopentane adducts 109 are formed in high yields and enantioselectivities.[107] Although not formally a cycloisomerization, the relationship of these products to the Conia-ene products makes this reaction a useful complement to the enantioselective Conia-ene reaction discussed previously. Depending on the substrate, one of two ligands can be used for optimal results. Aryl-substituted tertbutyldimethylsilyl enol ethers undergo efficient cyclization with (R)-75 [(R)-DTBM-SEGPHOS] as the ligand, whereas when (R)-107 [(R)-Binaphane] is utilized as the ligand a greater range of substrates are transformed with high enantioselectivity and improved reaction rates (Table 9). The reaction permits the use of O-silyl ketene aminals as substrates (Table 9, entry 7), while also allowing the formation of spiro centers (entries 6–8). The geometry of the starting material about the enol impacts the enantioselectivity, as does the type of silyl group, with the tert-butyldimethylsilyl group proving optimal. Table 9
Palladium(II)-Catalyzed Enantioselective Cyclization of Siloxy-1,6-enynes[107]
P
(R)-107
P
(R)-Binaphane
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Stereoselective Synthesis
3.5
Asymmetric Cycloisomerizations O
OTBDMS
10 mol% Pd(OTf)2L AcOH/Et2O (1:100)
R
R2
1
R1 R2 108
109
Entry Substrate
L
Time Product (h)
ee Yield Ref (%) (%)
OTBDMS
O
(R)-DTBM-SEGPHOS 12 [(R)-75]
1 MeO
I
91 93
[107]
85 88
[107]
88 92
[107]
73 70
[107]
89 83
[107]
87 91
[107]
98 80
[107]
91 83
[107]
MeO I
OTBDMS
(R)-DTBM-SEGPHOS [(R)-75]
2
O
H
6
OTBDMS O
3
(R)-DTBM-SEGPHOS 12 [(R)-75]
Ph
Ph
O
OTBDMS
(R)-DTBM-SEGPHOS 12 [(R)-75]
4
MeO
MeO OBn
OTBDMS
(R)-Binaphane [(R)-107]
5 N Me
O
0.5
OBn MeN
OTBDMS
O
(R)-Binaphane [(R)-107]
6
0.5
O
OTIPS
7
BnN
(R)-Binaphane [(R)-107]
8
TBDMSO
(R)-Binaphane [(R)-107]
0.3
0.3
BnN
O
N Bz
Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
N Bz
3.5.4
291
Conia-Ene Reaction
This palladium-catalyzed cyclization featured as a key step in the asymmetric total synthesis of (–)-laurebiphenyl, a dimeric cyclolaurane-type sesquiterpene. Conversion of the aryl ketone into (Z)-enol ether 110, followed by palladium(II)-catalyzed cyclization affords the cyclopentane 111 in 96% yield and with 95% enantiomeric excess, which was then further transformed into the natural product 112 (Scheme 48). Total Synthesis of (–)-Laurebiphenyl by Palladium(II)-Catalyzed Cyclization[107]
Scheme 48 I
I
OTBDMS
O
10 mol% Pd{(R)-DTBM-SEGPHOS}(OTf)2 AcOH/Et2O (1:100) 96%; 95% ee
110
111
OH
HO 112
(−)-laurebiphenyl
A different approach was undertaken by Dixon and co-workers, who have developed a cooperative catalyst system for the asymmetric Conia-ene reaction.[108] The groups cinchona-derived bifunctional catalysts are effective at generating enolates from -oxo esters 115, to form methylenecyclopentanes 116. A number of Brønsted base–Lewis acid combinations have been attempted, and the combination of copper(I) trifluoromethanesulfonate with one of the bifunctional 9-amino-9-deoxyepicinchona-derived urea compounds 113 or 114, in a 20:5 molar ratio, proved optimal for the asymmetric reaction. Both components are required for catalytic activity, since there is no reaction when they are examined individually. The reaction generally provides good to excellent enantioselectivity for a range of -oxo esters (Scheme 49). Scheme 49
N
O
F3C 113
Asymmetric Conia-Ene Reaction[108]
N
N
NH
HN NH
HN
CF3
F3C
O
N
CF3 114
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Stereoselective Synthesis
O
3.5
Asymmetric Cycloisomerizations O O
O 5 mol% (CuOTf)2•benzene
R1
R2
R
1
R2
20 mol% ligand, CH2Cl2, rt
115
116
R1
R2
Ph
OMe 113
Ligand Time (h) ee (%) Yield (%) Ref
4-MeOC6H4 OMe 113
92
98
[108]
10
91
91
[108]
1.5
4-FC6H4
OMe 113
4
92
74
[108]
4-PhC6H4
OMe 113
1
89
89
[108]
2-naphthyl
OMe 113
2
91
84
[108]
Et
OMe 113
3.5
79
77
[108]
Ph
NHPh 113
5
83
85
[108]
OMe
Ph
2
89
92
[108]
114
1,1-Diacyl-2-methylenecyclopentanes 106; General Procedure:[106]
To a scintillation vial with a magnetic stirrer bar was added substrate 105 (20–60 mg, 1 equiv), Et2O (to make a 0.02 M soln), glacial AcOH (10 equiv), and Yb(OTf )3 (20 mol%) followed by Pd{(R)-DTBM-SEGPHOS)}(OTf )2 (10 mol%). The reaction was monitored by TLC until the starting material was consumed. The solvent was evaporated and the yellow residue was chromatographed (hexanes/EtOAc) to give the cyclized product. 1-Acyl-2-methylenecyclopentanes 109; General Procedure:[107]
A soln of substrate 108 (0.02 mmol), AcOH (2 drops, 10 L), and Pd{(R)-DTBM-SEGPHOS)}(OTf )2 (10 mol%) or Pd{(R)-Binaphane}(OTf )2•2H2O (5 mol%) in Et2O (1 mL) was stirred until the reaction was complete as determined by TLC. The solvent was removed and the residue was purified (silica gel) to give the products. 1,1-Diacyl-2-methylenecyclopentanes 116; General Procedure:[108]
To a soln of [CuOTf ]2•benzene (2.5 mg, 0.005 mmol, 0.01 mmol CuOTf ) and cocatalyst 113 (22 mg, 0.04 mmol) in dry CH2Cl2 (2 mL) was added -oxo ester 115 (0.2 mmol). The mixture was stirred at rt until complete consumption of the -oxo ester was indicated by TLC. The solvent was then removed under reduced pressure and the obtained crude product was purified by flash column chromatography. 3.5.5
Intramolecular Cyclization Initiated by C—H Activation
Hydroacylation involves the addition of an acyl group and a hydrogen atom across an alkene or alkyne. The first examples were stoichiometric,[109] but advances have rendered a powerful reaction that proceeds with low catalyst loadings under mild conditions in both inter- and intramolecular cases (Scheme 50), with high yields and stereoselectivities.[110,111] When the reaction is performed in an intramolecular sense, it is a cycloisomerization reaction.
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Intramolecular Cyclization Initiated by C—H Activation
3.5.5
Scheme 50
Intra- and Intermolecular Hydroacylations
O
O H
intramolecular hydroacylation
O R1
O
intermolecular hydroacylation
H
+
2
R
R1
R2
The mechanism of intramolecular hydroacylation is thought to initiate with oxidative addition of rhodium(I) into the C—H bond of the aldehyde. The resultant rhodium(III) acylmetal hydride then coordinates with, and hydrometalates, the alkene. Reductive elimination completes the cyclization, generating the cyclopentanone product and regenerating the rhodium(I) catalyst (Scheme 51). Scheme 51 Proposed Mechanism of Rhodium(I)-Catalyzed Intramolecular Hydroacylation O Rh(I)L
CHO
reductive elimination
oxidative addition
O
O Rh(III)
Rh(III)
H
O hydrometalation
Rh
H
CO Rh
H − [Rh(CO)]
Early approaches toward the development of an asymmetric intramolecular hydroacylation reaction gave moderate yields and enantioselectivities for the conversion of ª,-unsaturated aldehydes into cyclopentanone products.[112–115] The development of cationic rhodium(I) complexes incorporating chiral phosphine ligands enables high yields and enantioselectivities to be achieved in the cyclization of pent-4-enals 117 to cyclopentanones 118 (Table 10).[116–120] The chiral ligand (S)-20 [(S)-BINAP] affords particularly high enantioselectivities for substrates with a carbonyl, silyl, or tertiary alkyl group at C4 (Table 10, entries 3 and 4),[117] whereas (S,S)-35 [(S,S)-Me-DuPhos] gives high enantioselectivities for 4-alkyl-substituted substrates (entry 1).[118] Aryl-substituted products provide lower selectivities, in which (2S,3S)-2,3-bis(diphenylphosphino)butane [(S,S)-Chiraphos] is the optimal ligand (entry 2).[117,121] The reaction has also been applied to symmetrical dienes, allowing for enantioselective desymmetrization reactions and leading to the formation of cyclopentanone products with two stereocenters.[122,123] The cationic rhodium catalyst ([Rh{(R)-BINAP}]ClO4) furnishes the trans-products in good yield and with high enantioselectivity (Table 10, entries Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.5
Asymmetric Cycloisomerizations
6 and 7). Interestingly, when the neutral complex is used the diastereoselectivity of the process switches to provide the cis-products selectively. When increased catalyst loading is required (50 mol%, Table 10, entry 5) yields are low. Table 10 Asymmetric Rhodium(I)-Catalyzed Intramolecular Hydroacylation[116–123] O
O H
2 mol% (RhL)ClO4
R1
R1
R2
R2 118
117
Entry Substrate
Conditions
O
O
[Rh{(S,S)-Chiraphos}]ClO4, CH2Cl2, 25 8C
O
[Rh{(S)-BINAP}]ClO4, acetone, 25 8C
–
94
–a
[118]
–
78
–a
[119]
–
>99
–a
[117]
–
>99
–a
[117]
97:3
>95c
25
[122]
CO2Et
CO2Et O
O H
[Rh{(S)-BINAP}]ClO4, CH2Cl2, 25 8C TMS
TMS
O
O
5
Ref
O H
4
Yield (%)
Ph
Ph
3
ee (%)
O H
2
dr (cis/ trans)
O
[Rh{(S,S)-Me-DuPhos}]PF6, acetone, 25 8C
H
1
Product
H
[Rh{(R)-BINAP}]Cl,b CH2Cl2, 25 8C, 72 h
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Intramolecular Cyclization Initiated by C—H Activation
Table 10 (cont.) Entry Substrate
Conditions
Product
dr (cis/ trans)
ee (%)
Yield (%)
Ref
O
O H
6
[Rh{(R)-BINAP}]ClO4,d CH2Cl2, 25 8C, 1 h
3:97
>95c 81
[122]
17:83
>95c 76
[123]
O
O H
7
[Rh{(R)-BINAP}]ClO4,d CH2Cl2, 25 8C, 1 h Ph
Ph a b c d
Ph
Ph
Yield not reported; >95% conversion by NMR. 50 mol% of catalyst was used. ee of major diastereomer. 5 mol% of catalyst was used.
The asymmetric hydroacylation reaction has been used for the asymmetric synthesis of carbocyclic nucleosides, structural analogues of nucleosides where the internal oxygen atom is replaced with a methylene group. These analogues lack the labile glycosidic bond and are stable to phosphoroylases and hydrolases. The ª,-unsaturated aldehyde 119 is treated with 5 mol% of a chiral rhodium complex ([Rh(nbd){(S,S)-Me-DuPhos}]BF4) in refluxing acetone, to afford the cyclopentanone product 120 in 85% yield and greater than 95% enantiomeric excess (Scheme 52).[124] Scheme 52 Synthesis of a Carbocyclic Nucleoside by Rhodium(I)-Catalyzed Asymmetric Hydroacylation[124] O H TBDPSO
O
5 mol% [Rh(nbd){(S,S)-Me-DuPhos}]BF4 acetone, reflux 85%; >95% ee
TBDPSO
119
120 NH2 N N
N N
HO carbocyclic-ddA
The process has been extended toward the asymmetric synthesis of 3-substituted indanones.[125] The rhodium(I)-catalyzed hydroacylation of 2-vinylbenzaldehydes 121 produces chiral indanones 122 in high yield and with excellent enantioselectivities (Scheme 53). Substitution has only been examined at the internal position of the alkene, with alkyl, aryl, and electron-withdrawing groups being well tolerated at that position.
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Stereoselective Synthesis
3.5
Asymmetric Cycloisomerizations
Scheme 53 Asymmetric Rhodium(I)-Catalyzed Hydroacylation of 2-Vinylbenzaldehydes[125] O
O
2 mol% [Rh{(R)-BINAP}]ClO4
H
CH2Cl2, rt
R1
R1 121
122
R1
ee (%) Yield (%) Ref
Me
99
97
[125]
Ph
98
98
[125]
(CH2)2OH 96
97
[125]
TMS
70
93
[125]
CF3
99
90
[125]
CO2Et
96
89
[125]
Dong and co-workers have developed an asymmetric hydroacylation approach for the preparation of seven- and eight-membered heterocycles, e.g. 124, from O-alkenylated salicaldehyde derivatives 123.[126] A rhodium complex containing chiral phosphine (R,R)-35 [(R,R)-Me-DuPhos)] catalyzes the hydroacylation of 2-(but-3-enyloxy)benzaldehyde to the seven-membered ring product with 15:1 selectivity over the eight-membered ring derivative. In addition, the product was produced in 88% yield and with 98% enantiomeric excess (Table 11, entry 1). Electron-withdrawing and -donating groups are tolerated on the aryl ring without a significant drop in yield or enantioselectivity (entries 2–4). Experiments have demonstrated that the efficiency of the reaction relies on the coordination of rhodium to the aryl ether linkage, helping to promote hydroacylation over competing nonproductive pathways such as alkene isomerization, aldehyde decarbonylation, and catalyst decomposition.
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Intramolecular Cyclization Initiated by C—H Activation
Table 11 Asymmetric Intramolecular Rhodium(I)-Catalyzed Hydroacylation[126] O
O R1
5 mol% [RhL]BF4 CH2Cl2, rt
H
R1
X
X
123
124
Entry Substrate
L
Product O
O
1
ee (%) Yield (%) Ref
(R,R)-Me-DuPhos [(R,R)-35]
H O
F
(R,R)-Me-DuPhos [(R,R)-35]
H
95
[126]
96
86
[126]
98
86
[126]
97
89
[126]
93
86
[126]
O
O H
(R,R)-Me-DuPhos [(R,R)-35]
MeO
O
O O
O
4
H
(R,R)-Me-DuPhos [(R,R)-35]
O
O O
O H
(R)-DTBM-SEGPHOS [(R)-75]
S
S O
O
6
96 O
MeO
5
[126]
O F
O
3
88
O O
2
98
H
(R,R)-Me-DuPhos [(R,R)-35]
S
S
Dong and co-workers have also developed an asymmetric ketone hydroacylation reaction for the synthesis of seven-membered lactones.[127,128] The oxo aldehyde substrates 125 must contain either the ether or thioether group, which is thought to coordinate to rhodium during the catalytic cycle, suppressing decarbonylation and facilitating hydroacylation.[128] Using a rhodium(I)–phosphine (R)-75 [(R)-DTBM-SEGPHOS)] complex as the catalyst, in dichloromethane at room temperature, a number of 4,5-dihydrobenz[c]oxepin1(3H)-ones 126 were prepared in high yield and with excellent enantioselectivity (Scheme 54). Interestingly, both aryl and alkyl ketones are excellent substrates for this reaction.
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Stereoselective Synthesis
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Asymmetric Cycloisomerizations
Scheme 54 Lactones by Rhodium(I)-Catalyzed Enantioselective Ketone Hydroacylation[127,128] O
O 5 mol% [Rh{(R)-DTBM-SEGPHOS}]BF4 CH2Cl2, rt
H
O R1
O
X
X R1
125
X R1
126
ee (%) Yield (%) Ref
O Ph
99
92
[127]
O Me
99
91
[127]
O t-Bu >99
94
[127]
S Ph
93
[128]
>99
The extension of this methodology to the synthesis of five-membered lactones initially posed problems, as the ether required for coordination is no longer present. However, a careful study of counterion effects led to the discovery that more coordinating counterions afford better selectivity for hydroacylation over decarbonylation, while also increasing the reaction time and having an effect on enantioselectivity.[129] Finally silver(I) nitrate was chosen as the additive, in combination with ligand (S,S,R,R)-128 [(S,S,R,R)-DuanPhos], giving optimal yield and enantioselectivity while providing the product in a suitable reaction time. The method allows the synthesis of functionalized phthalides 129 in excellent yield and enantioselectivity (Scheme 55).[129] Electron-withdrawing and -donating substituents on the aryl ring of the substrate 127 are tolerated, with the exception of the position ortho to the ketone (R2), which inhibits the reaction. Both aryl and alkyl ketones react, although some fine tuning of counterion and reaction conditions are required for certain substrates. Finally, the alkyl ketone 127 (R1 = R2 = H; R3 = Bu) undergoes this reaction to give the celery extract (–)-(S)-3-butylphthalide (129; R1 = R2 = H; R3 = Bu), which provides a short asymmetric synthesis of this natural product (Scheme 55). Scheme 55 Asymmetric Intramolecular Rhodium(I)-Catalyzed Ketone Hydroacylation[129]
10 mol%
P P H But But (S,S,R,R)-128
O R1
H
H
5 mol% [RhCl(cod)]2 10 mol% AgNO3, toluene, 100 oC
O R1 O
O R2
R3
127
Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
R2 129
R3
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Intramolecular Cyclization Initiated by C—H Activation
R1
R2
R3
H
H
Me 97
97
[129]
CO2Me H
Me 95
94
[129]
H
Ph
81a
[129]
H
ee (%) Yield (%) Ref
93
H
Me Me –
99:1. (R,R)-TBDM-SILOP = (R,R)-2,3-bis(tert-butyldimethylsiloxy)-1,4-bis(diphenylphosphino)butane.
Bergman, Ellman, and co-workers have developed a rhodium-catalyzed enantioselective cyclization reaction of aromatic ketimines (Scheme 56).[136–138] This imine directed C—H bond activation forms a C—C bond between the aromatic ring and a pendant alkenyl group, tethered at the meta position. Using chlorobis(cyclooctene)rhodium(I) dimer and Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Intramolecular Cyclization Initiated by C—H Activation
one of the phosphoramidite ligands 131 or 132, substrates 133 react to afford the functionalized bicyclic products 134 in excellent yield and with high enantioselectivity (Scheme 56). Ketimine 133 (R2 = H; R3 = SiMe2Ph) affords the chiral silane 134 (R2 = H; R3 = SiMe2Ph), which can be stereoselectively oxidized to the corresponding alcohol. 1,2Disubstituted alkenes are particularly challenging substrates for this type of cyclization as Z/E isomerization often occurs at rates that are competitive to cyclization. However, experiments with ligand 131 [R1 = (S)-CHMePh] indicate that both the Z- and E-isomers react to afford the product with the same stereochemistry, and isomerization of the alkene was observed during the reaction. Therefore, ketimines 133 (R2 = R3 = Me) and 133 (R2 = Ph; R3 = H), present as Z/E-mixtures, react to give the corresponding bicyclic products 134 in good yield and enantioselectivity (Scheme 56). The stereochemical induction in the products is predominantly determined by the 1,1¢-bi-2-naphthol backbone rather than the stereochemistry of the substituents on the amino group of the ligand. In contrast, chelating bidentate phosphines are inefficient catalysts for the reaction. A related asymmetric reaction had been reported earlier by Murai and co-workers,[139,140] albeit with modest enantioselectivities, whereas in this work the yields and enantioselectivities are generally high over a range of substrates (Scheme 56). Scheme 56 Asymmetric Rhodium(I)-Catalyzed Cyclization of Aromatic Imines by Directed C—H Bond Activation[136–138]
O
P
O
O
NR12
O
131
P
NR12
132
BnN
BnN R2 5 mol% [RhCl(coe)2]2 15 mol% ligand, toluene
R2 X
R3 X
R3
133
134
coe = cyclooctene
R2
X
R3
CH2 H
Me
CH2 H
SiMe2Ph
CH2 H O O
H
Ph Me
Me H
O
Ph
O
Me Me
O a b
Ph
H H
Temp (8C) Time (h) Ligand 50 125 75 125 50
ee (%) Yield (%) Ref 1
9
131 [R = (R)-CHMePh]
95
94
[136]
0.3
131 (R1 = iPr)
3 1 46
70
91
[136]
1
90
96
[136]
1
96
95
[136]
1
90
82
[138]
1
93
[138]
131 (R = iPr) 131 [R = (R)-CHMePh] 132 (R = iPr)
75
21
132 (R = iPr)
87
50
72
132 [R1 = (R)-CHMePh]
91–93 80a
[138]
b
[138]
75
92
1
132 [R = (R)-CHMePh]
89–90 50
Ratio (Z/E) in substrate 133 4:1. Ratio (Z/E) in substrate 133 9:1.
Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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NBn
NBn 5 mol% [RhCl(coe)2]2 15 mol% 131 [R1 = (R)-CHMePh] toluene, rt, 23 h
N
N
90%; 70% ee
The reaction has been used in the enantioselective synthesis of a PKC inhibitor by rhodium(I)-catalyzed C—H bond activation.[137] The synthesis required the aldimine instead of a ketimine as directing group. Aldimine directing groups are known to be much less active than the corresponding ketimines in this system. By fine-tuning of the N-benzyl group, it was found that the electron-withdrawing N-[3,5-bis(trifluoromethyl)benzyl]imine allows the reaction of aldimine 135 to proceed successfully to give dihydropyrroloindole 136 in 61% yield and with 90% enantiomeric excess (Scheme 57). The enantioselective synthesis of tricyclic indole 137 was completed in four more steps. Scheme 57 Enantioselective Synthesis of a PKC Inhibitor by Rhodium-Catalyzed C—H Bond Activation[137] F3C
F3C
1. 10 mol% [RhCl(coe)2]2 20 mol% 131 [R1 = (R)-CHMePh] toluene, 90 oC
N
2. AcOH/THF (1:9)
N
OMe
61%; 90% ee
135 O HN CHO
NHPh
O
N
OMe
136
N
OMe
137
Cyclopentanones 118; General Procedure:[117]
Dry solvents were degassed immediately prior to use by bubbling argon through them for at least 5 min. H2 was bubbled through a soln of the precatalyst [Rh(nbd){(S)-BINAP}]ClO4 for 5 min, and then the soln was stirred for 15 min before argon was bubbled through it for 5 min to purge any H2(g). The pent-4-enal substrate 117 (0.4692 mmol) was then added by syringe. When the reaction was complete, the solvent was removed at rt under reduced pressure (15 Torr). The residue was freed of catalyst by being dissolved in pentane/CH2Cl2 (2:1; 3 mL) and passed through a Florisil plug (1 g), washing the plug with the solvent mixture (5–10 mL). The solvents were again removed under reduced pressure to yield the cyclopentanone products. Indan-1-ones 122; General Procedure:[125]
Inside a glovebox, to a dry, 10-mL round-bottomed flask containing a magnetic stirrer bar and fitted with a septum was added [Rh(nbd){(R)-BINAP}]ClO4 (57 mg, 0.062 mmol, 2 mol%) followed by degassed anhyd CH2Cl2 (2 mL). H2(g) was then passed through the soln for Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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5 min. During this time the soln changed color from bright orange to dark brownish red. The 2-vinylbenzaldehyde 121 (3.12 mmol) was dissolved in degassed anhyd CH2Cl2 (2 mL), and was added at once to the above catalyst soln via syringe. The mixture was stirred for 2 h at ambient temperature and then passed through a silica gel plug to remove the catalyst, washing with CH2Cl2. After removal of the solvent under reduced pressure, the product was isolated by flash chromatography. Fused Cyclic Ketones, e.g. 124; General Procedure:[126]
Inside a glovebox, the phosphine ligand (0.005 or 0.01 mmol, 2.5 or 5 mol%) was dissolved in degassed CH2Cl2 (1 mL) and added to [Rh(nbd)2]BF4 (0.005 or 0.01 mmol, 2.5 or 5 mol%). This soln was transferred to a Schlenk tube containing a magnetic stirrer bar and the tube was sealed. The tube was removed from the glovebox and the soln was stirred for 5 min. The tube was then placed on a Schlenk line and the head-space evacuated by one freeze– pump–thaw cycle. H2(g) was passed into the tube for 30 min at rt with stirring. The soln was then degassed by three freeze–pump–thaw cycles and the sealed Schlenk tube was returned to the glovebox. A soln of the substrate 123 (0.2 mmol) in degassed CH2Cl2 (1 mL) was added to the Schlenk tube, and the mixture was stirred at rt for 24 h. The mixture was then concentrated under reduced pressure and purified by preparative TLC. 4,5-Dihydrobenz[c]oxepin-1(3H)-ones 126; General Procedure:[127,128]
To a dry 25-mL Schlenk-sealed tube containing a magnetic stirrer bar was added a soln of [Rh(nbd)2]BF4 (3.7 mg, 0.0099 mmol, 5 mol%) and (R)-DTBM-SEGPHOS [(R)-75; 13 mg, 0.011 mmol, 5.5 mol%] in dry, degassed CH2Cl2 (1 mL) in a glovebox. The resulting soln was stirred for 2–5 min and then H2(g) was passed through the soln for 30 min. During this time the soln changed color from orange-red to deep red. The resulting soln was then degassed by freeze–pump–thaw three times and refilled with argon. A soln of the substrate 125 (0.2 mmol) in dry, degassed CH2Cl2 (1 mL) was added to the above catalyst soln in the glovebox. The reaction vessel was sealed and stirred at rt for 2 d. The mixture was then concentrated under reduced pressure and purified by flash column chromatography (EtOAc/hexanes 1:9) to afford the product. Phthalides 129; General Procedure:[129]
In a vial was placed (S,S,R,R)-Duanphos [(S,S,R,R)-128; 0.01 mmol, 5 mol%] and [RhCl(cod)]2 (0.005 mmol, 2.5 mol%) in toluene (0.6 mL). The mixture was stirred at rt for 15 min and then transferred to another vial containing AgNO3 (0.01 mmol, 5 mol%). Toluene (2 0.15 mL) was used to rinse the vial and combined with the mixture in the reaction vial. The vial was capped and stirred at rt for 15 min during which AgCl crashed out. The substrate 127 (0.2 mmol) was added to the mixture using toluene (0.6 mL). The mixture was stirred at 100 8C for 1 d, when TLC indicated that the reaction was complete. 6,6¢-Dimethyl-5,5¢,6,6¢-tetrahydro-4,4¢-spirobi(silolo[3,2-b]thiophene) (Table 12, Entry 7); Typical Procedure:[135]
A mixture of [Rh(hexa-1,5-diene)Cl]2 (4.4 mg, 0.010 mmol), (R,R)-TBDM-SILOP (15.0 mg, 0.022 mmol), and CH2Cl2 (0.5 mL) was stirred for 30 min at rt. To the mixture was added bis(2-isopropenyl-3-thienyl)silane (146 mg, 0.528 mmol) via syringe at –20 8C and the mixture was stirred for a further 3 h. After completion of the reaction as judged by 1H NMR, the mixture was concentrated and the resulting residue was purified by column chromatography (silica gel); yield: 121 mg (83%); 99% ee. (2,3-Dihydrobenzofuran-4-yl)methanimines 134; General Procedure:[138]
In a glass flask in a glovebox was placed [RhCl(coe)2]2 (5 mol%), the chiral ligand (15 mol%), and dry toluene (to give a 0.1 M soln of the Rh complex). The catalyst was then premixed before addition of the substrate. The ketimine substrate 133 was then added and the mixAsymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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ture was stirred at the relevant temperature, for the noted reaction time (see Scheme 56). The mixture was then concentrated and the product was hydrolyzed by the addition of 1 M aq HCl and stirring for 3 h. The aqueous layer was extracted with EtOAc (3 ) and the combined organic extracts were dried, filtered, and concentrated. The crude product was purified by chromatography (silica gel).
Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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307
Ziegler, F. E.; Sobolov, S. B., J. Am. Chem. Soc., (1990) 112, 2749. Mikami, K.; Sawa, E.; Terada, M., Tetrahedron: Asymmetry, (1991) 2, 1403. Mikami, K.; Terada, M.; Sawa, E.; Nakai, T., Tetrahedron Lett., (1991) 32, 6571. Yang, D.; Yang, M.; Zhu, N.-Y., Org. Lett., (2003) 5, 3749. Conia, J. M.; Le Perchec, P., Synthesis, (1975), 1. Pei, T.; Widenhoefer, R. A., J. Am. Chem. Soc., (2001) 123, 11 290. Qian, H.; Widenhoefer, R. A., J. Am. Chem. Soc., (2003) 125, 2056. Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D., J. Am. Chem. Soc., (2004) 126, 4526. Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D., Angew. Chem., (2004) 116, 5464; Angew. Chem. Int. Ed., (2004) 43, 5350. Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.; LaLonde, R. L.; Toste, F. D., Angew. Chem., (2006) 118, 6137; Angew. Chem. Int. Ed., (2006) 45, 5991. Corkey, B. K.; Toste, F. D., J. Am. Chem. Soc., (2005) 127, 17 168. Corkey, B. K.; Toste, F. D., J. Am. Chem. Soc., (2007) 129, 2764. Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D. J., J. Am. Chem. Soc., (2009) 131, 9140. Sakai, K.; Ide, J.; Oda, O.; Nakamura, N., Tetrahedron Lett., (1972), 1287. Willis, M. C., Chem. Rev., (2010) 110, 725. Fu, G. C., In Modern Rhodium-Catalyzed Reactions, Evans, P. A., Ed.; Wiley-VCH: New York, (2005); pp 79–91. James, B. R.; Young, C. G., J. Chem. Soc., Chem. Commun., (1983), 1215. James, B. R.; Young, C. G., J. Organomet. Chem., (1985) 285, 321. Taura, Y.; Tanaka, M.; Funakoshi, K.; Sakai, K., Tetrahedron Lett., (1989) 30, 6349. Taura, Y.; Tanaka, M.; Wu, X.-M.; Funakoshi, K.; Sakai, K., Tetrahedron, (1991) 47, 4879. Bosnich, B., Acc. Chem. Res., (1998) 31, 667. Barnhart, R. W.; Wang, X.; Noheda, P.; Bergens, S. H.; Whelan, J.; Bosnich, B., J. Am. Chem. Soc., (1994) 116, 1821. Barnhart, R. W.; McMorran, D. A.; Bosnich, B., Chem. Commun. (Cambridge), (1997), 589. Barnhart, R. W.; McMorran, D. A.; Bosnich, B., Inorg. Chim. Acta, (1997) 263, 1. Wu, X.-M.; Funakoshi, K.; Sakai, K., Tetrahedron Lett., (1992) 33, 6331. Fujio, M.; Tanaka, M.; Wu, X.-M.; Funakoshi, K.; Sakai, K.; Suemune, H., Chem. Lett., (1998), 881. Wu, X.-M.; Funakoshi, K.; Sakai, K., Tetrahedron Lett., (1993) 34, 5927. Tanaka, M.; Imai, M.; Fujio, M.; Sakamoto, E.; Takahashi, M.; Eto-Kato, Y.; Wu, X. M.; Funakoshi, K.; Sakai, K.; Suemune, H., J. Org. Chem., (2000) 65, 5806. Marc, P.; Daz, Y.; Matheu, M. I.; Castilln, S., Org. Lett., (2008) 10, 4735. Kundu, K.; McCullagh, J. V.; Morehead, A. T., Jr., J. Am. Chem. Soc., (2005) 127, 16 042. Coulter, M. M.; Dornan, P. K.; Dong, V. M., J. Am. Chem. Soc., (2009) 131, 6932. Shen, Z.; Khan, H. A.; Dong, V. M., J. Am. Chem. Soc., (2008) 130, 2916. Shen, Z.; Dornan, P. K.; Khan, H. A.; Woo, T. K.; Dong, V. M., J. Am. Chem. Soc., (2009) 131, 1077. Phan, D. H. T.; Kim, B.; Dong, V. M., J. Am. Chem. Soc., (2009) 131, 15 608. Tamao, K.; Tohma, T.; Inui, N.; Nakayama, O.; Ito, Y., Tetrahedron Lett., (1990) 31, 7333. Bergens, S. H.; Noheda, P.; Whelan, J.; Bosnich, B., J. Am. Chem. Soc., (1992) 114, 2121. Bergens, S. H.; Noheda, P.; Whelan, J.; Bosnich, B., J. Am. Chem. Soc., (1992) 114, 2128. Wang, X.; Bosnich, B., Organometallics, (1994) 13, 4131. Barnhart, R. W.; Wang, X.; Noheda, P.; Bergens, S. H.; Whelan, J.; Bosnich, B., Tetrahedron, (1994) 50, 4335. Tamao, K.; Nakamura, K.; Ishii, H.; Yamaguchi, S.; Shiro, M., J. Am. Chem. Soc., (1996) 118, 12 469. Thalji, R. K.; Ellman, J. A.; Bergman, R. G., J. Am. Chem. Soc., (2004) 126, 7192. Wilson, R. W.; Thalji, R. K.; Bergman, R. G.; Ellman, J. A., Org. Lett., (2006) 8, 1745. Harada, H.; Thalji, R. K.; Bergman, R. G.; Ellman, J. A., J. Org. Chem., (2008) 73, 6772. Fujii, N.; Kakiuchi, F.; Yamada, A.; Chatani, N.; Murai, S., Chem. Lett., (1997), 425. Mikami, K.; Hatano, M.; Terada, M., Chem. Lett., (1999), 55.
Asymmetric Cycloisomerizations, Watson, I. D. G., Toste, F. D. Science of Synthesis 4.0 version., Section 3.5 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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309 3.6
Ene Reactions M. Terada
General Introduction
The ene reaction can be broadly classified as a six-electron pericyclic process that involves the addition of an alkene (ene) with an allylic hydrogen atom to an electron-deficient multiple bond (enophile) (Scheme 1).[1–15] The reaction is accompanied by the migration of the double bond through a 1,5-hydrogen shift, in which the activation energy is significantly larger than for the mechanistically related Diels–Alder cycloaddition. Although high reaction temperatures are generally required to promote the thermal reaction, Lewis acid catalysis enables the reactions to be carried out under milder conditions with significant rate enhancements. Since the inception of Lewis acid catalysis, significant progress has been made in the area of both intra- and intermolecular ene reactions using carbonyl compounds and electron-deficient alkynes, as well as alkenes as enophiles. To date, ene reactions have received considerable attention, since they permit the formation of C—C and C—X bonds (X = heteroatom) using simple and unmodified alkenes, which constitutes an atom-economical process. Scheme 1 enophile:
Y
A Generalized Ene Reaction
...
Y
six-electron pericyclic reaction
...
X H
H
ene:
3.6.1
X
Intramolecular Ene Reactions
Intramolecular ene reactions are often classified into three main variants. These categories differ only in the position of attachment of the tether that connects the ene and enophile components (Scheme 2). The intramolecular ene reaction is entropically more favored than the intermolecular version, and hence Lewis acid promoted intramolecular reactions have been widely investigated. In this section, the contents are arranged according to the type of enophiles, followed by specific modes of cyclization (e.g., Type-I or TypeII). Type-III ene cyclization is not included here because it has not been developed to the same extent. Scheme 2 Reactions
Y
Classification of Intramolecular Ene
Type-I
X
Y
X H
H
Y
X H
Type-II
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X H
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Stereoselective Synthesis X H
3.6.1.1
Y
3.6
Ene Reactions X
Type-III
Y
H
Aldehydes and Ketones as Enophiles (Carbonyl-Ene Reactions)
The intramolecular ene reaction of carbonyl compounds, namely carbonyl-ene cyclization, is a very useful method for the preparation of cyclic alcohols, especially cyclohexanols. This type of reaction has been extensively developed in the context of the total synthesis of natural products and biologically relevant compounds. 3.6.1.1.1
Type-I Cyclizations
3.6.1.1.1.1
Diastereoselective Reactions
The diastereoselective Type-I ene cyclization of carbonyl compounds has been the most systematically investigated area of intermolecular ene reactions using Lewis acid promoters.[6,15] The method is applicable to the asymmetric synthesis of five-, six-, and sevenmembered cyclic alcohols. The most extensive studies in this area have been for the industrially important process of converting (R)-3,7-dimethyloct-6-enal [1; (+)-citronellal] into (1R,2S,5R)-2-isopropenyl-5-methylcyclohexanol [3; (–)-isopulegol], which is the key intermediate en route to (–)-menthol. The first industrial process developed utilized stoichiometric zinc(II) bromide as the promoter for the Type-I ene-cyclization. This catalyst affords higher diastereoselectivity for the desired anti-isomer than other common Lewis acids (e.g., ZnCl2, FeCl3, TiCl4, and SnCl4).[16] Although these conditions provide the product with excellent diastereomeric excess (up to 94%), an improved procedure has recently been reported (Scheme 3)[17] using a bulky Lewis acid catalyst, namely tris(2,6-diphenylphenoxy)aluminum (2).[18] This reaction affords the desired cyclohexanol 3 in high chemical yield with extremely high diastereomeric purity (up to 99.3% together with 0.7% of other stereoisomers). Scheme 3 Synthesis of (1R,2S,5R)-2-Isopropenyl-5-methylcyclohexanol Catalyzed by Tris(2,6-diphenylphenoxy)aluminum[17] Ph 1 mol% Al
O Ph
3
2 toluene, 0
CHO
oC,
4h
95%; dr (3/other isomers) 99:3:0.7
1
OH
3
(1R,2S,5R)-2-Isopropenyl-5-methylcyclohexanol (3); Typical Procedure:[17]
2,6-Diphenylphenol (240 mg, 1 mmol) and toluene (5 mL) were added to a 50-mL Schlenk tube at rt under an argon atmosphere to give a soln. A 0.93 M soln of Et3Al in toluene (0.35 mL, 0.33 mmol) was added to this soln, and the resulting mixture was stirred at rt for 30 min to prepare the catalyst. The catalyst soln obtained was cooled to 0 8C and aldehyde 1 (5.07 g, 32.9 mmol), cooled to –15 8C, was added dropwise followed by stirring at 0 8C for 4 h. After completion of the reaction, 8% aq NaOH (2 mL) was added to the mixture and dodecane (5.05 g) was added as an internal standard. The organic layer was analyzed by GC to determine product distribution; yield: 95%; ratio (3/other isomers) 99.3:0.7. Ene Reactions, Terada, M. Science of Synthesis 4.0 version., Section 3.6 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.6.1
3.6.1.1.1.2
311
Intramolecular Ene Reactions
Enantioselective Reaction of Aldehydes
In recent years, tremendous progress has been made in enantioselective intermolecular carbonyl-ene reactions catalyzed by chiral Lewis acids (see Section 3.6.2.1). The first enantioselective ene reaction described was the Type-I ene cyclization of unsaturated aldehydes using a 1,1¢-bi-2-naphthol (BINOL) derived zinc complex.[19,20] Further developments have been somewhat limited,[21–25] which is somewhat surprising given the wide application of the intramolecular carbonyl-ene reaction in the total synthesis of complex natural products. A highly enantioselective Type-I ene cyclization of unsaturated aldehydes using a catalytic amount of a 1,1¢-bi-2-naphthol-derived titanium complex has been described.[21,22] More recently, a highly enantioselective Type-I ene cyclization of ,-unsaturated aldehydes using the chiral chromium complex 4, which has a tridentate Schiff base ligand, has been developed (Scheme 4).[24] This latter process proceeds smoothly using 0.8– 10 mol% of catalyst 4 to afford the cyclic homoallylic alcohols 5 and 6 in good yield and with excellent enantioselectivity. Of particular note are those unsaturated aldehydes that have enantiotopic ene moieties, which have proven to be outstanding substrates. This method also enables cyclopentanol derivatives bearing three contiguous stereogenic centers to be prepared in a highly efficient and stereoselective manner. Scheme 4 Enantioselective Type-I Ene Cyclization of Aldehydes Catalyzed by a Chromium Catalyst[24]
But
N Br
O
H2O Cl O Cr Cr O Cl OH2
O
Br
N
But
4
R1 R2
CHO
0.8−10 mol% 4 4-Å molecular sieves toluene, 4
X
oC,
R1
OH
R2
30 h
X n
n
5
R1
R2
X
n Catalyst 4 (mol%) dr
H
H
O
2 10
4.5:1 85a
58–78b
[24]
Me
Me
O
1
0.8
>30:1 93
77
[24]
CH2CH=CH2
CH2CH=CH2
O
1
1
>30:1 96
96
[24]
Me
Me
NTs 1
2
>30:1 95
98
[24]
(CH2)2CH=CMe2
OCH2CH=CH2
CH2 1
2
7:1 99
87
[24]
(CH2)2CH=CMe2
CO2Et
CH2 1
2
>30:1 98
95
[24]
a b
ee (%) Yield (%) Ref
ee for the major diastereomer; ee for the minor diastereomer is 92%. Yield from reaction in an anisole/toluene mixture for 24 h.
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Stereoselective Synthesis
CHO
R1
R2
3.6
Ene Reactions
1−5 mol% 4 4-Å molecular sieves toluene, 4 oC, 30 h
OH R1 R2 O
O
6
R1
R2
Catalyst 4 (mol%) dr
H
(CH2)2CH=CMe2
1
20:1 96
94
[24]
5
>30:1 75
78
[24]
Me Me
ee (%) Yield (%) Ref
(3R,4R)-4-Isopropenyl-2,2-dimethyltetrahydrofuran-3-ol (5, R1 = R2 = Me; X = O; n = 1); Typical Procedure:[24]
Toluene (25 L) and 2-methyl-2-[(3-methylbut-2-enyl)oxy]propanal (31 mg, 0.2 mmol) were added under a N2 atmosphere to a cooled (0 8C), stirred mixture of 4- molecular sieves (40 mg) and catalyst 4 (1.6 mg, 1.6 mol, 0.8 mol%) in a flame-dried, 0.5-dram reaction vial. The mixture was warmed to 4 8C and allowed to stir until conversion of the unsaturated aldehyde was deemed complete by TLC (ca. 30 h). The mixture was diluted with Et2O/ hexanes (1:1; 0.5 mL) and purified by flash column chromatography (silica gel, Et2O/hexanes 1:9) to afford the product; yield: 77%; 93% ee. 3.6.1.1.1.3
Enantioselective Reaction of Ketones
The first enantioselective copper-catalyzed Type-I ene cyclization of Æ-oxo esters was reported in 2003.[23] Subsequent work has outlined a tandem enantioselective Type-I ene cyclization/polyene cyclization sequence with Æ-oxo esters (Scheme 5).[25] In this sequence, treatment of Æ-oxo esters 7 with the chiral complex derived from scandium(III) trifluoromethanesulfonate and the pybox ligand 8 gives the tertiary alcohols 9 in high yield as single diastereomers with good enantioselectivity. The alcohols 9 are readily transformed with excess titanium(IV) chloride into the trans-fused polycyclic alcohols 10 in good yield with excellent diastereocontrol and without significant loss of enantiopurity.
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313
Intramolecular Ene Reactions
Scheme 5 Enantioselective Type-I Ene Cyclization of Æ-Oxo Esters Catalyzed by a Chiral Scandium Complex, Followed by Polyene Cyclization[25] 20 mol% Sc(OTf)3
O 20 mol%
O
N N
N
8 4-Å molecular sieves, 1,2-dichloroethane, rt, 36 h
O
CO2Me
R1
R2
7 R2 TiCl4 (4 equiv) CH2Cl2, rt, 12 h
HO
H CO2Me
R1
R2
R1 HO
10
9
R1
R2
ee (%) of 9 Yield (%) of 9 ee (%) of 10 Yield (%) of 10 Ref
H
H
93
60
88
90
[25]
OMe H
95
87
93
85
[25]
H
OMe 92
81
86
75
[25]
H
Cl
83
87
53a
[25]
a
91
H CO2Me
Trifluoromethanesulfonic acid was employed instead of titanium(IV) chloride.
Cyclic Homoallylic Alcohols 9; General Procedure:[25]
Ligand 8 (7.6 mg, 0.019 mmol, 0.2 equiv), Sc(OTf )3 (9.8 mg, 0.02 mmol, 0.2 equiv), 4- molecular sieves (0.15 g), and 1,2-dichloroethane (2 mL) were added to a round-bottomed flask equipped with a magnetic stirrer bar, and the resulting suspension was stirred at rt for 2 h. To this soln was added the appropriate Æ-oxo ester 7 (0.1 mmol, 1.0 equiv), and the soln was stirred at ambient temperature for 36 h, at which point the reaction was deemed complete by TLC. The mixture was then purified by loading directly onto a flash column (silica gel, hexane/Et2O) to give the product. Polycyclic Alcohols 10; General Procedure:[25]
Homoallylic alcohol 9 (0.05 mmol, 1.0 equiv) and CH2Cl2 (3 mL) were added to a round-bottomed flask equipped with a magnetic stirrer bar. 1.0 M TiCl4 in CH2Cl2 (0.2 mmol, 4.0 equiv) was added via syringe at rt. The resulting mixture was stirred at this temperature for 12 h, before quenching with sat. aq NaHCO3 (10 mL). The aqueous layer was extracted with CH2Cl2 (3 20 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give the product.
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Stereoselective Synthesis
3.6.1.1.2
Type-II Cyclizations
3.6
Ene Reactions
Type-II ene cyclization reactions of unsaturated carbonyl compounds also provide a useful method for the construction of carbocyclic and heterocyclic alcohols. In contrast to Type-I cyclizations, the Type-II variants have not been studied extensively; however, the construction of seven- rather than six- and five-membered rings is facilitated preferentially.[26] Despite this preference, recent applications of Type-II cyclization have focused on diastereoselective syntheses of cyclohexanol derivatives, which provide additional insight into the mechanism and the synthetic applicability of this process. Diastereoselective Reactions
3.6.1.1.2.1
The development of highly diastereoselective Type-II ene cyclizations using chiral unsaturated carbonyl compounds in the presence of Lewis acid promoters has been extensively studied.[15] The Type-II cyclization of Æ-substituted aldehydes 12 was originally investigated using stoichiometric dimethylaluminum chloride as a Lewis acid promoter,[27] and this reaction provides cis-13 as the major adduct (90%). A highly trans-selective cyclization, using sterically demanding aluminum complex 11, has also been developed to give trans-13 (Scheme 6).[28,29] The exclusive formation of trans-isomers is observed for certain Æ-substituted aldehydes 12 with dimethylaluminum chloride, in stark contrast to the usual formation of cis-isomers. The mechanistic nuances of these intriguing results have been independently investigated by different authors,[30,31] using deuterium-labeling experiments. Scheme 6 Diastereoselective Type-II Ene Cyclization of Unsaturated Aldehydes Using an Aluminum Catalyst[27–29] But
But Br
O
O
Br
Al But
Me But 11
R1
R1
Lewis acid, CH2Cl2
R1 +
CHO
OH
12
cis-13
OH trans-13
R1
Lewis Acid (equiv)
Conditions
Yield (%)
Ref
Me
Me2AlCl (1.0)
–78 8C, 0.3 h
9:1
65
[27]
Et
Me2AlCl (1.2)
–78 8C, 0.3 h
19:1
60
[28,29]
iPr
Me2AlCl (1.2)
–78 8C, 0.3 h
33:1
70
[28,29]
CH2CH=CH2
Me2AlCl (1.2)
–78 8C, 0.7 h
17:1
59
[28,29]
Ph
Me2AlCl (1.2)
–78 8C, 0.5 h
26:1
95
[28,29]
SPh
Me2AlCl (1.2)
–78 8C, 0.3 h
1:3
95
[28,29]
Me
11 (1.2)
–78 8C, 2 h, then –40 8C, 1 h
1:32
85
[28,29]
Et
11 (2.0)
–78 8C, 2.5 h, then –40 8C, 0.5 h
1:30
89
[28,29]
iPr
11 (2.0)
–78 8C, 0.5 h, then –40 8C, 2 h
1:17
85
[28,29]
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Ratio (cis/trans)
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315
Intramolecular Ene Reactions
R1
Lewis Acid (equiv)
Conditions
Yield (%)
Ref
CH2CH=CH2
11 (2.0)
–78 8C, 0.5 h, then –40 8C, 1 h
1:62
82
[28,29]
Ph
11 (2.0)
–78 8C, 0.5 h, then –40 8C, 2 h
1:62
98
[28,29]
SPh
11 (2.0)
–78 8C, 1.5 h
1:200
75
[28,29]
Ratio (cis/trans)
2-Substituted 5-Methylenecyclohexanols trans-13; General Procedure:[28,29]
,-Unsaturated aldehyde 12 (0.5 mmol) was added at –78 8C to a soln of complex 11 (1.0 mmol) in CH2Cl2 (5 mL). The resulting mixture was stirred at –78 to –40 8C for several hours, then poured into dil HCl, and extracted with CH2Cl2. The combined CH2Cl2 extracts were dried (Na2SO4), the solvent was removed, and the residue was purified by column chromatography (Et2O/hexane) to give the product. 3.6.1.1.2.2
Enantioselective Reactions
In contrast to the studies on the enantioselective Type-I cyclization, the corresponding Type-II ene reaction has not been extensively investigated. The first enantioselective variants employed chiral Lewis acid catalysts [e.g., Eu(hfc)3[32] and 1,1¢-bi-2-naphthol-derived chiral titanium complexes[33]], which provided the products with modest enantioselectivity (up to 38% ee in the case of the titanium catalyst). Interestingly, the chiral titanium complex was almost the only catalyst employed for enantioselective Type-II cyclization reactions[21,22,34] until the introduction of the chiral chromium complex 4 (Scheme 7),[24] which is also an excellent catalyst for enantioselective Type-I ene cyclization reactions (see Section 3.6.1.1.1.2). For example, 1–5 mol% of complex 4 is effective for facilitating the Type-II ene cyclization of ,-unsaturated aldehydes to provide homoallylic alcohols 14 in good yield and with excellent enantioselectivity. It is noteworthy that this process is also applicable to the enantiotopic group-selective cyclization with alkenyl aldehydes that have either a prochiral alkene or aldehyde. As such, this method facilitates the construction of structurally complex carbocycles with a quaternary carbon stereogenic center in a highly stereoselective manner. Scheme 7 Enantioselective Type-II Ene Cyclization of ,-Unsaturated Aldehydes Using a Chromium Catalyst[24]
But
N Br
O
H2O Cl O Cr Cr O Cl
O
Br
N
OH2
But
X
R2
4
X
4-Å molecular sieves, toluene, 4 oC, 30 h
R2 R1
R1 CHO
OH 14
R1
R2
X
Catalyst 4 (mol%)
dr
ee (%) Yield (%) Ref
CH2CH=CH2
CH2CH=CH2
O
5
–
93
72
[24]
OMe
OMe
CH2 2.5
–
94
88
[24]
OCH2CH=CH2
(CH2)2CMe=CH2
CH2 2
>30:1
97
89
[24]
CO2Et
(CH2)2CMe=CH2
CH2 1
>30:1
99
99
[24]
CHO
iPr
CH2 1
2.2:1 91
57
[24]
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Stereoselective Synthesis
3.6.1.2
Alkynes as Enophiles
3.6.1.2.1
Type-I Cyclizations
3.6
Ene Reactions
The transition-metal-catalyzed Type-I ene cyclization of enynes is formally a type of cycloisomerization[35] that provides a powerful method for the construction of carbocyclic and heterocyclic compounds, albeit by a different mechanism to the pericyclic pathway of a classical ene cyclization. The first enantioselective version of the Type-I ene cyclization was reported in 1989,[36,37] and prompted the development of several highly enantioselective variants (further information on enyne cycloisomerization can also be found in Section 3.5.1). The preparation of five-membered cyclic compounds from 1,6-enynes has dominated this area. In contrast, there are relatively few examples of the transitionmetal-catalyzed cyclization of 1,7-enynes to provide six-membered cyclic products, which is presumably due to the difficulty associated with the formation of the larger ring. This section is divided into the cyclization reactions of 1,6-enynes and 1,7-enynes, respectively. 3.6.1.2.1.1
Enantioselective Reaction of 1,6-Enynes
The first highly enantioselective ene cyclization of 1,6-enynes was accomplished using a chiral palladium complex derived from a trans-coordinating chiral bisphosphine ligand.[38] A highly enantioselective ene cyclization, using a chiral palladium complex bearing a 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl derivative as the chiral ligand, has since been developed.[39] Various chiral ligands and palladium sources have been screened to improve the catalytic activity and selectivity of this system,[40] and the chiral palladium complex derived from a palladium tetrafluoroborate species {[Pd(NCMe)4](BF4)2} and the axially chiral P,N-ligand 15 bearing an achiral gem-dimethyldihydrooxazole subunit, is currently optimal (Scheme 8). Treatment of nitrogen-tethered 1,6-enynes with this catalytic system, in the presence of formic acid, gives the pyrrolidines 16 in good yield and with excellent enantioselectivity, albeit with the formation of alkene-migrated products. Scheme 8 Enantioselective Type-I Ene Cyclization of Nitrogen-Tethered 1,6-Enynes Catalyzed by a Chiral Palladium Complex[40] 5 mol% [Pd(NCMe)4](BF4)2 O N
10 mol%
PPh2
R2
MeO2C
R2 15
R1
HCO2H (0.5−1.0 equiv), DMSO, 100 oC, 1−3 h
R1
MeO2C
N Ts
N Ts 16
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R1
R2
ee (%) Yield (%) Ref 93
>99a
[40]
(CH2)2
96
b
90
[40]
(CH2)3
84
71c
[40]
(CH2)2O 93
a
[40]
Me H
a b
c
317
Intramolecular Ene Reactions
3.6.1
>99
1 equiv of HCO2H is used. The alkene-migrated byproduct is obtained in 9% yield. The alkene-migrated byproduct is obtained in 29% yield.
In related studies, a highly enantioselective ene cyclization using a chiral rhodium complex with 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl as the chiral ligand has been developed.[41] Additional studies have modified the catalytic system to generate the catalytically active species in situ by simply mixing commercially available chloro(cyclooctadiene)rhodium(I) dimer, (R)- or (S)-2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl, and silver(I) hexafluoroantimonate.[42] This provides a more general protocol, which has been applied to a broad range of propargyl ethers to afford the corresponding furans 17 in good yield and with outstanding asymmetric induction (Scheme 9). The construction of pyrrolidine[43] and lactone[44] derivatives in a highly enantioselective fashion has also been accomplished using this catalyst. Scheme 9 Enantioselective Type-I Ene Cyclization of Oxygen-Tethered 1,6Enynes Catalyzed by a Chiral Rhodium Complex[42] 5 mol% [RhCl(cod)]2 12 mol% BINAP 20 mol% AgSbF6
R1 R2
R2 R1
1,2-dichloroethane, rt, 5 min
O
O
17
R1
R2
BINAP Config ee (%)
Yield (%) Ref
Ph
Et
R
>99.5
96
[42]
Ph
H
R
>99.5
96
[42]
2-ClC6H4
H
R
99.0
95
[42]
3-ClC6H4
H
R
99.5
92
[42]
4-ClC6H4
H
R
>99.9
95
[42]
4-Tol
H
R
99.9
94
[42]
4-F3CC6H4
H
R
99.1
93
[42]
Me
Me
R
>99.9
82
[42]
Bu
H
R
>99.9
89
[42]
Ac
Et
S
99.5
86
[42]
Bz
Et
S
>99.9
99
[42]
OEt
Et
S
>99.9
82
[42]
CH2OH
Me
S
>99
81
[42]
CH2OMOM
H
S
>99
91
[42]
Ph
OAc S
99.7
96
[42]
Me
OAc S
>99.9
92
[42]
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Stereoselective Synthesis
3.6
Ene Reactions
R1
R2
Ph
OMe S
>99
92
[42]
Bz
OEt
S
>99
93
[42]
Ph
OH
R
99
98a
[42]
a
[42]
Me a
OH
BINAP Config ee (%)
S
99.1
Yield (%) Ref
94
The corresponding aldehyde is obtained via tautomerization.
Methyl (2Z)-(1-Tosyl-4-vinylpyrrolidin-3-ylidene)acetates 16; General Procedure:[40]
Thoroughly degassed DMSO (3.0 mL) was injected under argon into a Pyrex Schlenk tube containing [Pd(NCMe)4](BF4)2 (11.1 mg, 0.025 mmol) and P,N-ligand 15 (26.7 mg, 0.050 mmol). This soln was stirred at rt for 5 min, and then the 1,6-enyne (0.50 mmol) and HCO2H (18.8 L, 0.50 mmol) were added, and the tube was sealed with a screw cap. The mixture was stirred at 100 8C for 1 h, washed with brine, and extracted with Et2O. The combined organic layers were concentrated under reduced pressure, and the residue was purified by short column chromatography (neutral silica gel, pentane/Et2O 10:1) to afford the product. 3-Alkylidene-4-vinyltetrahydrofurans 17; General Procedure:[42]
[RhCl(cod)]2 (4.9 mg, 0.01 mmol) and (S)-BINAP (13.8 mg, 0.022 mmol) were dissolved in freshly distilled 1,2-dichloroethane (2 mL) in a dried Schlenk tube. The freshly prepared 1,6-enyne (0.2 mmol) was then added at rt under a N2 atmosphere. After the resulting mixture had stirred for 1 min, AgSbF6 (0.04 mmol) was added, and the reaction was complete within 5 min. The reaction mixture was directly subjected to column chromatography to give the corresponding cyclized product. 3.6.1.2.1.2
Enantioselective Reaction of 1,7-Enynes
The first enantioselective ene cyclization of 1,7-enynes was reported in 2003.[45] The chiral palladium complex derived from a tetrakis(acetonitrile)palladium tetrafluoroborate species {[Pd(NCMe)4](BF4)2} and (S)-2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl facilitates the unprecedented cyclization of 1,7-enynes to afford the quinolines 18 in good yield and with excellent enantiomeric excess in most cases, albeit with alkene migration when an allylic hydrogen is present (Scheme 10). The catalytic system is also applicable to terminal acetylenes without any detrimental effect upon the yield and enantioselectivity. Although the presence of the aromatic ring is essential to facilitate the formation of sixmembered products, the method provides an efficient route to quinoline derivatives with either a quaternary stereogenic center or a spirocyclic system in a highly enantioselective manner. Scheme 10 Enantioselective Type-I Ene Cyclization of 1,7-Enynes Catalyzed by a Chiral Palladium Complex[45] 5 mol% [Pd(NCMe)4](BF4)2 10 mol% (S)-BINAP HCO2H (1 equiv) DMSO, 100 oC, 1−12 h
R3
N Ts
R1
R2 R1 N Ts
R2
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3.6.1
Intramolecular Ene Reactions
R1
R2
R3
Me
H
CO2Me >99
99
[45]
Me
H
H
>99
99
[45]
71
62a
[45]
(CH2)2
a
CO2Me
ee (%) Yield (%) Ref
(CH2)2O
CO2Me >99
>99
[45]
(CH2)2O
H
>99
[45]
98
The alkene-migrated byproduct is obtained in 38% yield.
4-Alkylidene-1-tosyl-3-vinyl-1,2,3,4-tetrahydroquinolines 18; General Procedure:[45]
Thoroughly degassed DMSO (2.0 mL) was injected under argon into a Pyrex Schlenk tube containing [Pd(NCMe)4](BF4)2 (2.2 mg, 0.005 mmol) and (S)-BINAP (6.2 mg, 0.010 mmol), and this suspension was stirred at rt for 5 min. The 1,7-enyne (0.100 mmol) and HCO2H (3.7 L, 0.10 mmol) were then introduced, the tube was sealed with a screw cap, and the mixture was stirred at 100 8C for 1–12 h (monitored by TLC). The mixture was then washed with brine and extracted with Et2O, and the combined organic layers were concentrated under reduced pressure. The resulting residue was purified by short column chromatography (neutral silica gel, pentane/Et2O 2:1) to afford the product. 3.6.1.2.2
Conia-Ene Reactions
3.6.1.2.2.1
Enantioselective Reactions
The Conia-ene reaction is defined as a C—C bond-forming reaction of the enol tautomer of a carbonyl compound with an alkene or alkyne as an enophile in an ene-type reaction. In general, the thermal reaction requires extremely high reaction temperatures; however, transition-metal catalysts accelerate the reaction significantly and thereby facilitate the reaction under much milder conditions. Since this discovery, the development of the metal-catalyzed Conia-ene reaction has been investigated intensively with a variety of metal catalysts. Enantioselective variants of the intramolecular Conia-ene reaction have been developed,[46,47] and the reaction of -oxo esters with a terminal alkynyl substituent[46] has been reported using a palladium complex bearing an axially chiral bisphosphine ligand in conjunction with excess acetic acid and ytterbium(III) trifluoromethanesulfonate as the co-catalyst.[48] Additional studies demonstrated that the combination of the cinchona alkaloid derivative 19 with a copper(I) complex provides an excellent catalyst for this process (Scheme 11).[47] For example, this catalytic system facilitates the cyclization of a wide variety of -oxo esters (and -oxo amides) to give the Conia-ene products, functionalized cyclopentanes 20, in good yield and with excellent enantioselectivity.
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Stereoselective Synthesis Scheme 11 Catalyst[47]
3.6
Ene Reactions
Enantioselective Conia-Ene Cyclization of -Oxo Esters Using a Copper
5 mol% CuOTf•0.5C6H6
N
20 mol%
H
N
O
O
O
R1
CF3
NH N H 19
CF3
O
R1
CH2Cl2, rt
R2
O
R2
20
R1
R2
Ph
OMe
1.5
92
98
[47]
Ph
OEt
1.5
91
82
[47]
Ph
OBn
1.5
89
95
[47]
4-Tol
OMe
3
92
97
[47]
3-Tol
OMe
2
92
99
[47]
2-Tol
OMe
1
87
67
[47]
4-MeOC6H4
OMe
10
91
91
[47]
3-MeOC6H4
OMe
1.5
93
96
[47]
4-FC6H4
OMe
4
92
74
[47]
2-FC6H4
OMe
1
89
77
[47]
4-BrC6H4
OMe
1
93
87
[47]
3,4-Cl2C6H3
OMe
1
92
83
[47]
4-PhC6H4
OMe
1
89
89
[47]
2-naphthyl
OMe
2
91
84
[47]
Me
OEt
1.5
83
85
[47]
Me
OBn
1.5
80
67
[47]
Et
OMe
3.5
79
77
[47]
Ph
NHPh
5
83
85
[47]
Time (d) ee (%) Yield (%) Ref
1-Acylcyclopentanecarboxylates or -cyclopentanecarboxamides 20; General Procedure:[47]
The -oxo ester or -oxo amide (0.2 mmol) was added to a soln of CuOTf•0.5C6H6 (2.5 mg, 0.01 mmol) and ligand 19 (22 mg, 0.04 mmol) in dry CH2Cl2 (2 mL). The mixture was stirred at rt until complete consumption of the starting material was indicated by TLC. The solvent was then removed under reduced pressure and the crude product obtained was purified by flash column chromatography. 3.6.2
Intermolecular Ene Reactions
The first reported enantioselective intermolecular ene reaction employed a chiral aluminum catalyst.[49] This was followed by the development of a chiral titanium complex derived from 1,1¢-bi-2-naphthol for the enantioselective ene reaction of glyoxylate as the active enophile.[33] These landmark reports have provided the impetus for new variants on the enantioselective reaction. In this context, tremendous progress has been made in the development of chiral Lewis acid catalyzed intermolecular ene reactions, particularly Ene Reactions, Terada, M. Science of Synthesis 4.0 version., Section 3.6 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.6.2
321
Intermolecular Ene Reactions
with activated enophiles. This section is arranged according to the type of enophile and the ene component, which are ordered on the basis of their reactivity.
3.6.2.1
Aldehydes and Ketones as Enophiles (Carbonyl-Ene Reactions)
3.6.2.1.1
Enantioselective Reaction of Aldehydes
3.6.2.1.1.1
Unactivated Alkenes as Ene Components
The enantioselective intermolecular ene reaction with aldehydes is one of the most extensively investigated ene reactions. Early reports in this area demonstrated that a highly activated 2-oxoacetate (glyoxylate) is an efficient substrate for the enantioselective ene reaction using a 1,1¢-bi-2-naphthol-derived titanium complex as the chiral catalyst.[33,50,51] The most significant developments in catalyst design since this time have been in the carbonyl-ene reaction of oxoacetates (glyoxylates) and activated aldehydes, such as glyoxal and trihaloacetaldehydes. A number of chiral Lewis acid catalysts have been reported, including variations on the original 1,1¢-bi-2-naphthol-derived titanium system using a variety of biaryl ligands 21–25 (Scheme 12) and a number of systems using alternative metals 26–31 and ligands 8 and 32 as shown in Scheme 13. Scheme 12
Chiral Biaryl Ligands Used in Titanium Lewis Acid Catalysts
Cl OH
OH
OH
OH
OH
OH Cl
(S)-21
(R)-21
22
F F F3C F
I
OH F F
F
OH
OH
OH
OH
OH
F3C
F
I
F 23
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24
25
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322
Stereoselective Synthesis Scheme 13 Catalysts
3.6
Ene Reactions
Chiral Metal Complexes and Ligands Used as Enantioselective Lewis Acid
2+
2+
O
4-Tol NCMe Pd NCMe P 4-Tol 4-Tol
O N
But
4-Tol P
2SbF6−
N Cu
H2O
But
OH2 26
2SbF6−
27
But
But
+
Ph P
MeO
Pt
MeO
P
Ph
Cl N
Cl
SbF6−
N Co
O
O
O
O
But
But 29
28
+
Ph
Ph
N
O
N SbF6−
Co But
O SiBui3
N
But
O
TfO
N
OTf
OTf
31
O
N N
N
Sc
Bui3Si 30
O
O
N
O Pri
N
N
O
O HN
NH
O Pri
Pri
Pri 32
8
The efficiency of these catalyst systems in the reaction of various Æ-oxo aldehydes 33, including oxoacetates (R1 = alkoxy), with isopropenylbenzene (Æ-methylstyrene) as the ene component to give Æ-hydroxy ketone derivatives 34 is shown in Scheme 14.
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3.6.2
323
Intermolecular Ene Reactions
Scheme 14 Enantioselective Ene Reaction of Æ-Oxo Aldehydes Catalyzed by Chiral Metal Complexes[50,52–63] O R1
OH H
R1
+
Ph
Ph
O
O
33
34
R1
Catalyst
OMe
ligand (R)-21, TiCl2(OiPr)2
1
OBu
ligand (R)-21, ligand 22, Ti(OiPr)4
OEt
Catalyst System (mol%)
Conditions
ee (%)
Yield (%) Ref
CH2Cl2, 4-Å molecular sieves, –30 8C, 8 h
97 (R)
100
[50]
10
toluene, 0 8C, 1 h
97.2 (R)
66
[52]
ligand (S)-21, ligand 23, Ti(OiPr)4
5
toluene, –20 8C, 16 h
99 (S)
95
[53]
OEt
ligand 24, ligand 25, Ti(OiPr)4
0.1
quasi solvent free, 0 8C, 48 h
97.6 (R)
85
[54]
OEt
ligand 24, ligand 25, Ti(OiPr)4
0.01
quasi solvent free, 0 8C, 72 h
97.9 (R)
49
[54]
OEt
26
1
CH2Cl2, 0 8C
93 (S)
97
[55,56]
a
1,2-dichloroethane/ toluene (1:2), 60 8C, 4 h
88 (R)
97
[57]
2
pentafluorophenol (2 equiv), CH2Cl2, –50 8C, 5 h
85 (R)
79a,b
[58]
29
5
CHCl3, –20 8C, 48 h
88 (S)
90
[59]
OEt
30
1
toluene, rt, 3 h
98 (R)
91
[60]
OEt
30
0.1
toluene, rt, 24 h
92 (R)
99
[60]
NHPh 31
5
CH2Cl2, 4-Å molecular sieves, rt
92 (S)
73
[61]
OEt
ligand 8, In(OTf )3
5
1,2-dichloroethane, 4-Å molecular sieves, 0 8C, 6 d
95 (R)
96
[62]
Ph
ligand 32, Ni(BF4)2
1
1,2-dichloroethane, 60 8C, 32 h
99
83
[63]
OEt
ligand 32, Ni(BF4)2
5
1,2-dichloroethane, 40 8C
99 (S)
99
[63]
OEt
27
OEt
28, AgOTf (2 equiv)
Ph
a b
10
Methylenecyclohexane is used as the ene component instead of isopropenylbenzene. Conversion.
A wide range of ene components have been investigated in the enantioselective coppercatalyzed reaction of ethyl 2-oxoacetate (ethyl glyoxylate) with various alkenes.[55,56] Despite being hydrated, the cationic copper(II) complex 26 is markedly Lewis acidic, and facilitates the ene reaction to provide the Æ-hydroxy esters 37 and 38 from 1,1-disubstituted alkenes in good yield and with high enantioselectivity (Scheme 15). Interestingly, the phenyl-substituted bis(dihydrooxazole)copper complex 35 provides products with the opposite absolute configuration to those obtained with complex 26. Thus, one enantiomer Ene Reactions, Terada, M. Science of Synthesis 4.0 version., Section 3.6 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
3.6
Ene Reactions
of the ligand can afford either enantiomer of the product by simply changing the nature of the substituents.[64] Monosubstituted alkenes also undergo reaction to give Æ-hydroxy esters such as 39, using anhydro catalyst 36, while 1,2-disubstituted and cyclic alkenes give Æ-hydroxy esters 40 in the presence of catalysts 35 and 36. Scheme 15 Enantioselective Carbonyl-Ene Reaction of Ethyl 2-Oxoacetate Catalyzed by Chiral Copper(II) Complexes[55,56] 2+
O N But
2+
O
Cu OH2
O
2SbF6−
N
H2O
O N
But
2OTf−
N Cu
Ph
26
Ph 35
2+
O
O N
But
2SbF6−
N Cu
But 36
O EtO
1−10 mol% catalyst CH2Cl2, 0−25 oC, 1−48 h
R1 H
+
R2
O
R1
OH EtO
OH R2
∗
+
O
EtO
R2
Catalyst (mol%)
Temp (8C)
R2
∗
O 37
R1
R1
38
ee (%) Ratio (37/38)
Yield (%) Ref
(CH2)3
26 (1)
0
97 (S) –
90
[55,56]
(CH2)3
35 (10)
0
87 (R) –
99
[55,56]
(CH2)2
26 (1)
0
96 (S) –
95
[55,56]
(CH2)2
35 (10)
0
76 (R) –
97
[55,56]
H
H
26 (1)
0
96 (S) –
83
[55,56]
H
H
35 (10)
0
92 (R) –
92
[55,56]
H
Me
26 (1)
25
84 (S)
55:45
78
[55,56]
H
Me
35 (10)
25
90 (R)
67:33
91
[55,56]
H
Bu
26 (1)
25
96 (S)
60:40
89
[55,56]
H
Bu
35 (10)
25
91 (R)
98:2
81
[55,56]
H
OTBDPS
26 (1)
25
96 (S) >99:1
72
[55,56]
H
OTBDPS
35 (10)
25
91 (R) >99:1
85
[55,56]
H
CH2OTBDPS
26 (1)
25
55 (S) >99:1
71
[55,56]
H
CH2OTBDPS
35 (10)
25
48 (R) >99:1
75
[55,56]
H
OBn
26 (2)
25
98 (S) >99:1
62
[55,56]
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3.6.2
Intermolecular Ene Reactions
R1
R2
Catalyst (mol%)
Temp (8C)
ee (%) Ratio (37/38)
Yield (%) Ref
H
OBn
35 (10)
25
92 (R) >99:1
88
[55,56]
H
CH2OBn
26 (1)
25
82 (S)
74:26
98
[55,56]
H
CH2OBn
35 (10)
25
89 (R)
80:20
98
[55,56]
O EtO
10 mol% 36 CH2Cl2, 25 oC
Pr H
+
96%; 92% ee; (E/Z) 96:4
Pr
OH EtO
O
O 39
1−10 mol% 36 or 26 CH2Cl2, 25 oC
OH EtO
S
R3
O R1
O EtO
H O
R1
R2
40A
+ R3
R2 10 mol% 35 CH2Cl2, 25 oC
OH EtO
R1
R
O
R3
R2
40B
R1
R2 R3
H
H Me 36 (10)
98 (S)
40:60
54
[56]
H
H Me 35 (10)
90 (R)
88:12
60
[56]
Me (CH2)3 26 (1)
98 (S)
78:22
86
[56]
Me (CH2)3 35 (10)
92 (R)
89:11
86
[56]
H
(CH2)3 36 (10)
98 (S)
86:14
95
[55,56]
H
(CH2)3 35 (10)
94 (R)
95:5
70
[55,56]
H
(CH2)2 36 (10)
96 (S)
67:33
83
[56]
H
(CH2)2 35 (10)
78 (R)
73:27
72
[56]
a
Catalyst (mol%) eea (%)
Ratio (anti/syn) Yield (%) Ref
The configuration is assigned for the Æ-position.
The enantioselective ene reaction with the chiral titanium complex derived from ligand (R)-21, dichlorodiisopropoxytitanium(IV), and 4- molecular sieves has been extended to other types of activated enophiles, such as fluoral and related Æ-haloacetaldehydes,[65] formaldehyde,[66] and vinylogous oxoacetates [such as methyl (E)-3-formylacrylate and methyl 3-formylpropynoate].[67] In most cases, the reactions of these activated aldehydes with 1,1-disubstituted alkenes afford the corresponding ene products in good yield and with high enantioselectivity. However, there are relatively few examples of other chiral Lewis acid catalysts promoting the ene reactions with these types of activated aldehydes. Further attempts have been directed toward catalyst immobilization using polymerbound[68–71] and self-assembled systems,[72,73] in addition to zeolite Y[74] and nano-size gold particles[75] as supporting agents. Nevertheless, catalyst immobilization is beyond the scope of this review.
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Stereoselective Synthesis
3.6
Ene Reactions
Æ-Hydroxy Esters 37 and 38; General Procedure Using Complex 26:[55,56] The alkene (0.50 mmol), ethyl 2-oxoacetate (3–10 equiv), and CH2Cl2 (1.5 mL) were added to an oven-dried, 10-mL, round-bottomed flask containing a magnetic stirrer bar. To this soln was added solid hydrated complex 26 (0.005–0.05 mmol) in one portion. After the reaction was complete (1–48 h) the mixture was purified by loading directly onto a flash column [silica gel (2 6 cm), Et2O/hexanes] to give the product. Æ-Hydroxy Esters 39 or 40; General Procedure Using Complex 35 or 36:[55,56] The alkene (0.50 mmol) and ethyl 2-oxoacetate (3–10 equiv) were added to an oven-dried, 10-mL, round-bottomed flask containing a magnetic stirrer bar. To this mixture was added the soln of catalyst 35 or 36 (0.005–0.05 mmol in CH2Cl2 (1.5 mL) in one portion. After the reaction was complete (1–48 h), the mixture was purified by loading directly onto a flash column [silica gel (2 6 cm), Et2O/hexanes] to give the product. Enol Ethers as Ene Components
3.6.2.1.1.2
The first example of silyl enol ethers being employed as the active ene component in additions to Æ-oxo esters (glyoxylates) using the chiral titanium complex derived from ligand (R)-21 and dichlorodiisopropoxytitanium(IV) was reported in 1993.[76] Vinyl sulfides have also been employed as the nucleophilic ene component; however, activated aldehydes such as pentafluorobenzaldehyde[49] and Æ-oxo esters are required.[77] In this context, the ability to utilize simple aldehydes (i.e., less electrophilic enophiles) is challenging. Nevertheless, it has been demonstrated successfully for the reaction of alkynyl aldehydes with 2-methoxypropene as the nucleophilic ene component[78] and the solvent, together with a chiral titanium complex having a chiral tridentate Schiff base ligand as the enantioselective catalyst. Vinyl ethers have also been used as the reactive ene component.[79] Interestingly, the reaction of aromatic aldehydes 41 with 2-methoxypropene is significantly accelerated by the chiral chromium catalyst 42 (bearing a tridentate Schiff base ligand) to afford vinyl ethers 43 with excellent enantioselectivity and yields that reflect the electronic properties of the aromatic rings (Scheme 16). This method has also been applied to the silyl enol ether derived from acetone using a similar chiral chromium catalyst,[80] which allows aliphatic aldehydes to be employed. Scheme 16 Enantioselective Carbonyl-Ene Reaction of Aromatic Aldehydes with 2-Methoxypropene Using a Chromium Complex[79] But
But
5−7.5 mol% N
O Cr
O 42
O
OMe
Cl
BaO acetone or EtOAc, 4 oC, 20−40 h
OH
+ Ar1
H
Ar1
41
Ene Reactions, Terada, M. Science of Synthesis 4.0 version., Section 3.6 sos.thieme.com © 2014 Georg Thieme Verlag KG
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OMe
3.6.2
327
Intermolecular Ene Reactions
Ar1
Conditions
Time (h)
ee (%)
Yield (%)
Ref
Ph
42 (7.5 mol%), BaO (6.4 equiv), 2-methoxypropene (2.1 equiv), EtOAc, 4 8C
40
88
82
[79]
2-BrC6H4
42 (5 mol%), BaO (4.2 equiv), 2-methoxypropene (2.1 equiv), acetone, 4 8C
20
96
97
[79]
3-BrC6H4
42 (5 mol%), BaO (4.2 equiv), 2-methoxypropene (2.1 equiv), acetone, 4 8C
36
86
94
[79]
4-BrC6H4
42 (7.5 mol%), BaO (6.4 equiv), 2-methoxypropene (2.1 equiv), EtOAc, 4 8C
40
87
78
[79]
2-Tol
42 (7.5 mol%), BaO (6.4 equiv), 2-methoxypropene (2.1 equiv), EtOAc, 4 8C
40
94
41
[79]
3-Tol
42 (7.5 mol%), BaO (6.4 equiv), 2-methoxypropene (2.1 equiv), EtOAc, 4 8C
40
90
50
[79]
4-Tol
42 (7.5 mol%), BaO (6.4 equiv), 2-methoxypropene (2.1 equiv), EtOAc, 4 8C
40
89
26
[79]
2-ClC6H4
42 (5 mol%), BaO (4.2 equiv), 2-methoxypropene (2.1 equiv), acetone, 4 8C
20
96
98
[79]
3-ClC6H4
42 (5 mol%), BaO (4.2 equiv), 2-methoxypropene (2.1 equiv), acetone, 4 8C
36
84
97
[79]
4-ClC6H4
42 (7.5 mol%), BaO (6.4 equiv), 2-methoxypropene (2.1 equiv), EtOAc, 4 8C
40
85
78
[79]
2-MeOC6H4
42 (7.5 mol%), BaO (6.4 equiv), 2-methoxypropene (2.1 equiv), EtOAc, 4 8C
40
95
75
[79]
3-NCC6H4
42 (5 mol%), BaO (4.2 equiv), 2-methoxypropene (2.1 equiv), acetone, 4 8C
36
86
80
[79]
4-NCC6H4
42 (5 mol%), BaO (4.2 equiv), 2-methoxypropene (2.1 equiv), acetone, 4 8C
40
84
92
[79]
2-O2NC6H4
42 (5 mol%), BaO (4.2 equiv), 2-methoxypropene (2.1 equiv), acetone, 4 8C
20
96
89
[79]
3-O2NC6H4
42 (5 mol%), BaO (4.2 equiv), 2-methoxypropene (2.1 equiv), acetone, 4 8C
36
90
85
[79]
4-O2NC6H4
42 (5 mol%), BaO (4.2 equiv), 2-methoxypropene (2.1 equiv), acetone, 4 8C
36
70
88
[79]
2,4-Cl2C6H3
42 (5 mol%), BaO (4.2 equiv), 2-methoxypropene (2.1 equiv), acetone, 4 8C
20
92
96
[79]
2,6-Cl2C6H3
42 (5 mol%), BaO (4.2 equiv), 2-methoxypropene (2.1 equiv), acetone, 4 8C
20
86
82
[79]
1-Aryl-3-methoxybut-3-en-1-ols 43; General Procedure Using Acetone as Solvent:[79]
Complex 42 (22.2 mg, 0.05 mmol) and BaO (650 mg, 4.24 mmol) were combined in a 2-dram vial equipped with a stirrer bar. Acetone (400 L) was added and the mixture was allowed to stir for 5 h at rt. 2-Methoxypropene (200 L, 2.09 mmol) was then added and the vial was cooled to 4 8C without stirring. After cooling, stirring was started, and the aldehyde 41 (1 mmol) was added in one portion. The resulting mixture was stirred for the specified length of time, at which point it was diluted with CH2Cl2 and filtered through a small pad of Celite to remove BaO. The solvent was then removed under reduced pressure and NMR analysis of the crude brown sludge revealed the desired product to be the sole organic component present. The residue was subjected to chromatography (silica gel) to remove the catalyst. It should be noted that the enol ether products were not stable for extended periods of time under air, but could be handled in solution or under vacuum quite easily. Ene Reactions, Terada, M. Science of Synthesis 4.0 version., Section 3.6 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
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Ene Reactions
1-Aryl-3-methoxybut-3-en-1-ols 43; General Procedure Using Ethyl Acetate as Solvent:[79]
Complex 42 (33.3 mg, 0.075 mmol) and BaO (975 mg, 6.36 mmol) were combined in a 2-dram vial equipped with a stirrer bar. EtOAc (400 L) was added and the mixture was allowed to stir for 5 h at rt. 2-Methoxypropene (200 L, 2.09 mmol) was then added and the vial was cooled to 4 8C without stirring. After cooling, stirring was started, and the aldehyde (1 mmol) was added in one portion. The resulting mixture was stirred for the specified length of time, at which point it was diluted with Et2O and filtered through a small pad of Celite to remove BaO. The solvent was then removed under reduced pressure and NMR analysis of the crude brown sludge revealed the desired product to be the sole organic component present. The residue was subjected to chromatography (silica gel) to remove the catalyst. It should be noted that the enol ether products were not stable for extended periods of time under air, but could be handled in solution or under vacuum quite easily. 3.6.2.1.1.3
Enamides or Enecarbamates as Ene Components
Secondary enamides and enecarbamates had only rarely been employed as nucleophiles in the ene reaction prior to the work of Kobayashi.[81,82] The enantioselective copper-catalyzed addition of enecarbamates to ethyl 2-oxoacetate using the chiral copper(I) complex obtained with diimine ligand 44 provides N-acylimines 45 as the initial product (Scheme 17).[83,84] It seems likely that the reaction proceeds through an ene type mechanism, where the so-called aza-ene reaction of the oxoacetate with the enecarbamate is accompanied by a 1,5-hydrogen shift from the nitrogen atom to the carbonyl oxygen, and migration of the double bond from the enamine to give the imine during C—C bond formation. Interestingly, substituted enecarbamates react with excellent diastereoselectivity, and this selectivity is strictly dependent upon the geometry of the initial substrate. The N-acylimines 45 also serve as reactive electrophiles that undergo additional nucleophilic additions, thereby adding to the synthetic utility of the process. Hydrolysis under acidic conditions can be used to cleave the imine to give the corresponding ª-oxo esters 46. The enantioselective aza-ene reaction has also been performed with aldehyde-derived enecarbamates[85] and enesulfonamides.[86] Additionally, the reaction of ethyl 2-oxoacetate with enecarbamates has been reported using a 1,1¢-bi-2-naphthol-derived chiral phosphoric acid as a chiral Brønsted acid catalyst.[87]
Ene Reactions, Terada, M. Science of Synthesis 4.0 version., Section 3.6 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Intermolecular Ene Reactions
Scheme 17 Enantioselective Aza-Ene Reaction of Ethyl 2-Oxoacetate with Enecarbamates Catalyzed by a Chiral Copper(I) Complex[83,84] 10 mol% CuClO4•4MeCN
N
11 mol%
O
Br
Br
O EtO
N
44
H
+
HN
CH2Cl2, −20 to 0 oC, 0.5−2 h
OBn
R1
R3
O 2
R
O N
OH EtO
OBn
OH
48% HBr EtOH, rt, 1.5 min
R2
R1
R2
R3
Ratio (syn/anti) eea (%) Yield (%) of 46 Ref
H
H
Ph
–
97
93
[83,84]
H
H
4-MeOC6H4
–
93
94
[83,84]
H
H
4-ClC6H4
–
97
97
[83,84]
H
H
4-Tol
–
96
quant
[83,84]
H
H
2-naphthyl
–
96
91
[83,84]
H
Me
Ph
98
83
H
Me
Ph
Me
H
Ph
Me
H
Ph
H
Me
4-MeOC6H4
Me
H
4-MeOC6H4
H
Me
4-ClC6H4
Me
H
4-ClC6H4
H
Et
Ph
Et
H
Ph
H
Me
Et
Me
H
Et
H a b c
(CH2)4
1:99 98:2 98:2 2:98 98:2 2:98 99:1 1:99 99:1
b,c
98
95
98
82 b
[83,84] [83,84] [83,84]
98
96
[83,84]
98
96
[83,84]
98
97
[83,84]
98
85
[83,84]
98
79
[83,84]
98
58
[83,84]
98
92 c
[83,84]
97
83
[83,84]
92:8
98
89c
[83,84]
16:84
94
85
[83,84]
3:97
R2
46
45
1:99
R3 1 O R
R3 1 O R
O
EtO
Determined for the major diastereomer after hydrolysis of 45 to 46. Yield from reaction using 0.1 mol% of catalyst. Yield from reaction at –20 8C.
ª-Oxo Esters 46; General Procedure:[83,84] The diimine ligand 44 (9.9 mg, 0.022 mmol) in CH2Cl2 (1.5 mL) was added under argon to a flask containing CuClO4•4MeCN (6.5 mg, 0.020 mmol). The yellow soln was stirred for 12 h and cooled to 0 8C. Freshly distilled ethyl 2-oxoacetate (100 L, 0.40 mmol) in CH2Cl2 (0.8 mL) was added to the mixture, followed by the enecarbamate (0.20 mmol) in CH2Cl2 Ene Reactions, Terada, M. Science of Synthesis 4.0 version., Section 3.6 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
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Ene Reactions
(0.8 mL) in one portion. The mixture was stirred at 0 8C and then the reaction was quenched by addition of sat. aq NaHCO3. The resulting mixture was allowed to warm to rt and then extracted with CH2Cl2. The organic layer was washed with brine, dried (MgSO4), and the solvent was removed. The residue was dissolved in EtOH (3.0 mL) and 48% aq HBr (0.3 mL) was added. The mixture was stirred at rt for 1.5 min, and then the reaction was quenched by addition of sat. aq NaHCO3 at 0 8C. The mixture was allowed to warm to rt and extracted with CH2Cl2. The organic layer was washed with brine, dried (MgSO4), and the solvent was removed. The crude residue was purified by chromatography (silica gel) to give the desired product. 3.6.2.1.2
Enantioselective Reaction of Ketones
3.6.2.1.2.1
Unactivated Alkenes as Ene Components
The enantioselective intermolecular carbonyl-ene reaction with ketones is challenging due to the low reactivity of ketones as enophiles; however, the reaction affords important chiral tertiary homoallylic alcohols. The first reported enantioselective intermolecular carbonyl-ene reaction used the activated ketone methyl 2-oxopropanoate (methyl pyruvate) (Scheme 18).[56] Treatment of this ketone with 1,1-disubstituted alkenes, in the presence of the chiral copper(II) complex 36, gives the tertiary homoallylic alcohols 47 in good yield and with excellent enantioselectivity, albeit with the requirement for an excess of the alkene to achieve high catalyst turnover. Although 1,1-disubstituted alkenes provide excellent ene components, the corresponding reaction with mono-, tri-, and 1,2disubstituted alkenes has not proven trivial. Scheme 18 Enantioselective Carbonyl-Ene Reaction of Methyl 2-Oxopropanoate with 1,1-Disubstituted Alkenes Catalyzed by a Chiral Copper(II) Complex[56] R1 (10 equiv) R2 2+
O
O
5−20 mol%
N
O
2SbF6−
N Cu
But
But
R1
36
OH
CH2Cl2, 40 oC, 48 h
MeO
MeO O
R2 O 47
R1
R2
Catalyst 36 (mol%) ee (%) Yield (%) Ref
(CH2)4
20
98 (S) 84
[56]
(CH2)3
5
98 (S) 95
[56]
H
Me
10
98 (S) 76
[56]
H
Ph
5
98 (S) 94
[56]
Ethyl 3,3,3-trifluoro-2-oxopropanoate has been utilized as an activated ketone in enantioselective carbonyl-ene reactions using a chiral palladium complex.[88] This has prompted additional studies using this ketone as an activated enophile with unactivated alkenes employing an array of chiral metal complexes, such as palladium(II),[89,90] platinum(II),[90,91] nickel(II),[90] and indium(III)[92] species. The enantioselective reaction of ethyl 3,3,3-trifluoEne Reactions, Terada, M. Science of Synthesis 4.0 version., Section 3.6 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Intermolecular Ene Reactions
ro-2-oxopropanoate with isopropenylbenzene has also been reported using the thioureaderived axially chiral catalyst 48 (Scheme 19).[93] Although enantioselectivity (33% ee) and catalyst turnover is poor, this represents the first organocatalytic carbonyl-ene reaction. Inspired by this work, a highly enantioselective carbonyl-ene reaction of ethyl 3,3,3-trifluoro-2-oxopropanoate with isopropenylbenzene and its derivatives using the chiral phosphoramide 49[94] as a chiral Brønsted acid catalyst has been developed (Scheme 19).[95] Scheme 19
Organocatalysts for Carbonyl-Ene Reactions[93,95] CF3
OMe
S N H
N H
H N
CF3
O
O P
H N
CF3
O
NHTf
S CF3
OMe
48
49
Various catalysts have been screened that vary in the substituents at the 3- and 3¢-positions of the binaphthyl backbone. Catalyst 49, having 4-methoxyphenyl substituents and an octahydrobinaphthyl backbone, is optimal with respect to reactivity, yield, and selectivity. The reaction with a variety of isopropenylbenzene derivatives affords the homoallylic tertiary alcohols 50 in good yield and with excellent enantioselectivity (Scheme 20).[95] Scheme 20 Enantioselective Carbonyl-Ene Reaction of Ethyl 3,3,3-Trifluoro-2-oxopropanoate with Isopropenylbenzene Derivatives Catalyzed by a Chiral Brønsted Acid[95] O EtO
1 mol% 49 o-xylene, 10 oC, 22−60 h
CF3
+
HO CF3 EtO
Ar1
Ar1
O
O 50
Ar1
ee (%) Yield (%) Ref
Ph
96
76
[95]
4-MeOC6H4
92
69
[95]
4-Tol
96
92
[95]
3-Tol
96
91
[95]
4-EtC6H4
95
96
[95]
4-FC6H4
92
88
[95]
2-naphthyl
95
95
[95]
4-PhC6H4
97
87
[95]
4-t-BuC6H4
94
83
[95]
3,4-Me2C6H3
92
92
[95]
4-(4-BrC6H4)C6H4
96
87
[95]
Ene Reactions, Terada, M. Science of Synthesis 4.0 version., Section 3.6 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
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Ene Reactions
Ar1
ee (%) Yield (%) Ref
4-ClC6H4
93
55
[95]
95
96
[95]
95
93
[95]
Methyl (S)-3-(Cyclohex-1-enyl)-2-hydroxy-2-methylpropanoate [47, R1,R2 = (CH2)4]; Typical Procedure:[56]
Methylenecyclohexane (600 L, 5.0 mmol) and methyl 2-oxopropanoate (45 L, 0.5 mmol) were added to an oven-dried, 10-mL, round-bottomed flask containing a magnetic stirrer bar. To this mixture was added a soln of catalyst 36 (0.10 mmol) in CH2Cl2 (1.5 mL) in one portion. After the reaction was complete (48 h), the mixture was purified by loading directly onto a flash column (silica gel, EtOAc/hexanes 15:85) to give the product; yield: 84%; 98% ee. Ethyl (R)-2-Hydroxy-2-(trifluoromethyl)pent-4-enoates 50; General Procedure:[95]
The isopropenylbenzene derivative (0.20 mmol), phosphoramide 49 (1 mol%), and ethyl 3,3,3-trifluoro-2-oxopropanoate (2 equiv) were suspended in a screw-capped vial in o-xylene such that the concentration was 0.25 M. The resulting soln was cooled to 10 8C and allowed to stir for 22–60 h. The mixture was directly purified by column chromatography (silica gel, EtOAc/hexane) to afford the product. 3.6.2.1.2.2
Activated Alkenes as Ene Components
Silyl enol ethers have been utilized as active ene components[76,80] in the metal-catalyzed addition to methyl 2-oxopropanoate derivatives.[96] The dicationic palladium complex generated from complex 51 and silver hexafluoroantimonate accelerates the addition of 2-(triisopropylsiloxy)propene to the 2-oxopropanoate derivatives, to furnish the corresponding homoallylic tertiary alcohols 52 in good yield and with high enantioselectivity (Scheme 21). Interestingly, the sterically demanding triisopropylsilyl group is critical for optimal results, since other silyl groups (such as TMS, TBDMS, and TBDPS) provide lower yield and/or enantioselectivity. The catalyst loading can also be reduced to 0.01 mol%, at 0 8C for 48 hours, without significant loss of yield or enantioselectivity. Additionally, 1,2diketones are superb enophiles and afford the corresponding Æ-quaternary Æ-hydroxy ketones with high enantioselectivity. The enantioselective aza-ene reaction of butane-2,3dione as the ketone enophile with enecarbamates, using a chiral nickel complex, has also been documented and provides moderate to high enantioselectivities.[97]
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Intermolecular Ene Reactions
Scheme 21 Enantioselective Carbonyl-Ene Reaction of 2-Oxopropanoate or 1,2-Diketone Derivatives with 2-(Triisopropylsiloxy)propene Catalyzed by a Chiral Palladium Complex[96] O
Ph P
O 5 mol% O
P Ph
O
Cl Cl Ph
51
O R2
Ph Pd
R1
11 mol% AgSbF6, CH2Cl2, −78 oC, 2 h
+
HO
R1
R2
OTIPS
OTIPS O
O
52
R1
R2
eea (%) Yield (%) Ref
Me
OEt
93
96
[96]
Me
OMe 85
>99
[96]
Me
OBn 81
91
[96]
CF3
OEt
88
70
[96]
(CH2)2Ph
OEt
87
40
[96]
Ph
OEt
98
72
[96]
Me
Me
94
81
[96]
Me
Et
>99
84
[96]
a
Determined after desilylation to give the -hydroxy ketone.
Ethyl (R)-2-Hydroxy-2-methyl-4-(triisopropylsiloxy)pent-4-enoate (52, R1 = Me; R2 = OEt); Typical Procedure:[96]
AgSbF6 (15.2 mg, 0.044 mmol) was added at rt to a soln of complex 51 (15.8 mg, 0.02 mmol) in CH2Cl2 (4 mL). After stirring for 30 min, ethyl 2-oxopropanoate (98 L, 0.88 mmol) and 2-(triisopropylsiloxy)propene (85.8 mg, 0.4 mmol) were added at –78 8C, and the resulting mixture was stirred at that temperature for 2 h. Et3N (50 L) was then added at –78 8C, followed by Et2O (10 mL). The soln obtained was washed with sat. aq NaHCO3 and extracted with Et2O (3 ). The combined organic layers were washed with brine, dried (MgSO4), and concentrated under reduced pressure. Separation by chromatography (silica gel, pentane/ Et2O 40:1) gave the product; yield: >99%.
3.6.2.2
Imines as Enophiles (Imino-Ene Reactions)
3.6.2.2.1
Enantioselective Reactions
3.6.2.2.1.1
Unactivated Alkenes as Ene Components
Although the enantioselective intermolecular carbonyl-ene reaction of unactivated alkenes is extremely well studied, the corresponding reaction with an imine, namely the imino-ene reaction, has received relatively limited attention. This is somewhat surprising given that the products of diastereoselective imino-ene reactions are prevalent in the total synthesis of natural products.[10] The first enantioselective imino-ene reaction was developed independently by two groups using similar chiral copper(I) catalysts.[98–100] For example, the chiral copper(I) complex generated in situ from tetrakis(acetonitrile)copper(I) perchlorate and ligand 53 provides the optimal catalyst for the reaction of ethyl (tosylimino)acetate as an enophile with various 1,1-disubstituted alkenes, to afford the corresponding Ene Reactions, Terada, M. Science of Synthesis 4.0 version., Section 3.6 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Ene Reactions
Æ-amino acid derivatives 54 in good yield and with excellent enantioselectivity (Scheme 22). Interestingly, the use of (trifluoromethyl)benzene as the solvent in conjunction with 2 equivalents of the alkene is critical for achieving high yield and enantioselectivity. Activated ene components, such as vinyl sulfides and enol ethers, also provide the corresponding products in good yield. Scheme 22 Enantioselective Imino-Ene Reaction of an Æ-Imino Ester with Alkenes Catalyzed by a Chiral Copper(I) Complex[98,99] R1 R3
(2 equiv) R2
5 mol% CuClO4•4MeCN
P(4-Tol)2 P(4-Tol)2
6 mol%
N
Ts
53
HN
Ts
R1
(trifluoromethylbenzene), rt, 18 h
EtO
EtO O
R2 R3
O 54
R1
R2
R3
ee (%) Yield (%) Ref
H
Ph
H
99
95
[98,99]
H
SPh
H
98
85
[98,99]
H
4-MeOC6H4
Me
94
77a
[99]
(CH2)4
H
95
85
[98,99]
OCH=CH
H
90
92
[99]
H
99
94
[98,99]
H
85
90
[98,99]
NTs
a
dr (syn/anti) 6:1.
Ethyl (S)-2-(Tosylamino)-4-phenylpent-4-enoate (54, R1 = R3 = H; R2 = Ph); Typical Procedure:[98,99]
Ligand 53 (20.4 mg, 0.030 mmol) and CuClO4•4MeCN (8.2 mg, 0.025 mmol) were dissolved in (trifluoromethyl)benzene (1 mL) and stirred at rt for 30 min to give a pale yellow soln. Ethyl (tosylimino)acetate (128 mg, 0.50 mmol) was added to this soln, and the mixture was placed under N2 at rt. A soln of isopropenylbenzene (118 mg, 1.00 mmol) in (trifluoromethyl)benzene (0.5 mL) was then added, and the mixture was allowed to stir for 18 h at rt to ensure completion. The reaction was quenched with H2O (5 mL) and extracted with CH2Cl2 (2 5 mL). The combined organic layers were dried (MgSO4) and the solvent was removed under reduced pressure. The crude residue was subjected to column chromatography [silica gel plug (2.5 3 cm), EtOAc/hexanes 1:19 to 1:4] to give the product; yield: 176.5 mg (95%); 99% ee. Ene Reactions, Terada, M. Science of Synthesis 4.0 version., Section 3.6 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.6.2
3.6.2.2.1.2
335
Intermolecular Ene Reactions
Enecarbamates as Ene Components
Enamides and enecarbamates have been used as nucleophiles in the enantioselective intermolecular ene reaction.[82] For example, the copper-catalyzed aza-ene reaction of Æ-imino esters 55 with enecarbamates 56, using 10 mol% of the copper(II) complex generated in situ from copper(II) trifluoromethanesulfonate and 1,2-diamines 57, gives the enantioenriched -amino imines 58 (Scheme 23).[81] This process is applicable to a wide range of enecarbamates, including trisubstituted enecarbamates, which afford diastereomeric mixtures favoring the syn-isomer irrespective of the E/Z geometry of the enecarbamate. However, the yield and the degree of stereoselectivity are dependent on the geometry of the enecarbamate employed, with the E-isomer providing superior results compared to the corresponding Z-isomer. The -amino imines 58 obtained can be readily transformed into Æ,ª-diamino acid derivatives via nucleophilic addition to the resulting imine. Alternatively, hydrolysis under acidic conditions affords the corresponding ª-oxo esters 59. Furthermore, the enantioselective imino-ene reaction using an N-acyl-Æ-imino phosphonate as an enophile[101] has been reported, which provides an efficient method for the construction of Æ-amino phosphonates in a highly enantioselective manner. Scheme 23 Enantioselective Aza-Ene Reaction of Æ-Imino Esters with Enecarbamates Catalyzed by Chiral Copper(II) Complexes[81] 10 mol% Cu(OTf)2 Ph 10 mol%
O N
R2
+
HN Ar1 57
CH2Cl2, 0 oC, 15 min
OR5
HN R3
NH Ar1
O
R 1O
Ph
R4
O 55
56 O R2
O NH
OR5
N
R1O
O 48% HBr EtOH, rt, 1.5 min
R4 O
R
R2
3
O R4 3
O
58
R1 R2
NH
R 1O R 59
R3
R4
R5 Ar1
eea (%) Yield (%) of 59
Ref
Et
(CH2)10Me
H
Ph
Bn 1-naphthyl
93
94
[81]
Et
(CH2)10Me
H
Ph
Bn 3,5-t-Bu2C6H3
93
92
[81]
Et
Me
H
Ph
Bn 1-naphthyl
94
72
[81]
Bn (CH2)10Me
H
Ph
Bn 1-naphthyl
91
89
[81]
Et
Ot-Bu
H
Ph
Bn 2-MeOC6H4
87
78
[81]
Et
(CH2)10Me
H
4-MeOC6H4
Bn 1-naphthyl
90
97
[81]
Et
Me
H
4-MeOC6H4
Bn 1-naphthyl
92
76
[81]
Et
(CH2)10Me
H
4-ClC6H4
Bn 1-naphthyl
90
89
[81]
Et
(CH2)10Me
H
4-Tol
Bn 1-naphthyl
91
93
[81]
Et
(CH2)10Me
H
2-naphthyl
Bn 1-naphthyl
88
83
[81]
Et
Me
H
2-naphthyl
Bn 1-naphthyl
91
76
[81]
H
Me
Et
83
84
[81]
Bn (CH2)10Me
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1-naphthyl
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Stereoselective Synthesis
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Ene Reactions
R1 R2
R3
R4
R5 Ar1
eea (%) Yield (%) of 59
Ref
Bn (CH2)10Me
H
Me
Et
84
[81]
3,5-t-Bu2C6H3
81
b
c
Et
(CH2)10Me
(E)-Me 4-MeOC6H4
Et
1-naphthyl
94
77
[81]
Et
(CH2)10Me
(Z)-Me 4-MeOC6H4
Et
1-naphthyl
32b
63d
[81]
a b c d
Determined after hydrolysis of 58 to give 59. Determined for the major diastereomer. dr (syn/anti) 86:14. dr (syn/anti) 68:32.
As mentioned above, the highly enantioselective imino-ene reaction of unactivated alkenes and activated enecarbamates has been accomplished using Æ-imino esters and related analogues which form a chelate-complex with the metal catalyst. Prior to the first enantioselective imino-ene reaction of imines lacking a coordination site at the Æ-position,[102] the formation of this chelate was essential for obtaining high enantioselectivity. Thus, treatment of N-benzoylimines 60 derived from aromatic aldehydes with methyl (1-phenylvinyl)carbamate, in the presence of chiral phosphoric acid 61, provides the enantioenriched -amino imines 62 in good yield (Scheme 24). It is noteworthy that the catalyst loading can be significantly reduced (0.1 mol%), illustrating the efficiency of the phosphoric acid catalyst.[103] Hydrolysis of -amino imines 62 under acidic conditions gives -amino ketones 63. In addition, the imino-ene reaction has been expanded to a cascade reaction in which N-acylimines react with 2 equivalents of an aldehyde-derived enecarbamate to provide piperidine derivatives in a highly stereoselective manner.[104] Scheme 24 Enantioselective Aza-Ene Reaction of N-Benzoylimines with an Enecarbamate Catalyzed by a Chiral Phosphoric Acid[102]
O
O P
O
OH
61
O N R1
O Ph
+
HN
OMe
0.1 mol% 61 toluene, rt, 5 h
O Bz
NH
N
R1
Ph 60
OMe Ph
62 48% HBr MeOH, rt, 5 min
Bz
NH
R1
Ph 63
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O
3.6.2
337
Intermolecular Ene Reactions
R1
eea (%) Yield (%) of 63 Ref
Ph
95
82
[102]
4-Tol
95
90
[102]
3-Tol
93
83
[102]
b
2-Tol
93
84
[102]
4-MeOC6H4
92
82
[102]
4-BrC6H4
96
89
[102]
3-BrC6H4
95
85
[102]
2-BrC6H4
96
82b
[102]
4-FC6H4
95
89
[102]
4-ClC6H4
95
84
[102]
4-NCC6H4
98
97
[102]
1-naphthyl
95
88
[102]
2-naphthyl
95
91
[102]
(E)-CH=CHPh
93
81
[102]
a
b
Determined after hydrolysis of 62 to give 63. Reaction performed with 0.5 mol% of 61.
Æ-Amino ª-Oxo Esters 59; General Procedure:[81] Cu(OTf )2 (7.2 mg, 0.020 mmol) was dried for 2 h under vacuum at 100 8C. Ligand 57 (Ar1 = 1-naphthyl; 10.8 mg, 0.022 mmol) was added under an argon atmosphere followed by CH2Cl2 (1.5 mL). The light blue soln was stirred for over 2 h until the color changed to dark green. CH2Cl2 (1.7 mL) was then added, and the soln was cooled to 0 8C. Enecarbamate 56 (0.300 mmol) in CH2Cl2 (0.8 mL) was added to this mixture, followed by Æ-imino ester 55 (0.200 mmol) in CH2Cl2 (2.0 mL) (which was added slowly over 30 min), and the resulting mixture was stirred at 0 8C for 15 min. The reaction was quenched by addition of sat. aq NaHCO3, and the resulting mixture was allowed to warm to rt with further stirring until the color of the aqueous layer changed to blue. The mixture was then extracted with CH2Cl2, and the organic layer was washed with brine and dried (MgSO4). Removal of the solvents gave a residue, which was dissolved in EtOH (3.0 mL) and 48% aq HBr (0.3 mL) was added to the soln. The resulting mixture was stirred at rt for 1.5 min and the reaction was quenched by addition of sat. aq NaHCO3 at 0 8C. The resulting mixture was allowed to warm to rt and extracted with CH2Cl2. The organic layer was washed with brine and dried (MgSO4). Removal of the solvents gave a crude residue, which was purified by chromatography (silica gel) to give the product. (S)-N-(3-Oxo-1,3-diphenylpropyl)benzamide (63, R1 = Ph); Typical Procedure:[102]
A dried test tube was charged with N-benzoylimine 60 (R1 = Ph; 20.9 mg, 0.10 mmol) and the atmosphere was replaced with N2. The imine was dissolved in toluene (0.9 mL) and a 0.001 M soln of the chiral phosphoric acid (R)-61 in toluene (0.1 mL, 0.0001 mmol) followed by methyl (1-phenylvinyl)carbamate (21.3 mg, 0.12 mmol) were added at rt. The mixture was stirred for over 5 h at ambient temperature, and then the reaction was quenched by addition of sat. aq NaHCO3. The resulting soln was extracted with CH2Cl2 and dried (Na2SO4). The solvent was removed, the residue was dissolved in MeOH (2.0 mL), and 48% aq HBr (0.6 mL) was added. The resulting mixture was stirred at rt for 5 min, and then the reaction was quenched by addition of sat. aq NaHCO3 at 0 8C. The resulting mixture was allowed to warm to rt and was then extracted with CH2Cl2. The com-
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Stereoselective Synthesis
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Ene Reactions
bined organic layers were dried (Na2SO4), the solvent was removed, and the crude residue was purified by chromatography (hexane/EtOAc 8:1 to 1:1) to give the product as a white solid; yield: 82%; 95% ee.
3.6.2.3
Electron-Deficient Alkenes as Enophiles
3.6.2.3.1
Enantioselective Reactions
3.6.2.3.1.1
Unactivated Alkenes as Ene Components
Although the enantioselective intermolecular carbonyl-ene reaction has been extensively investigated, the enantioselective ene reaction with electron-deficient alkenes as the enophile has received limited attention even taking into account the intramolecular variant.[105,106] The first catalytic enantioselective intermolecular reaction[107] emerged during the development of the enantioselective Diels–Alder reaction, using Æ,-unsaturated aldehydes 64 with cyclopentadiene as the ene component. In this intriguing process diphenylprolinol silyl ether 65[108,109] proved to be an outstanding organocatalyst in the presence of 4-nitrophenol, affording the ene adducts in an efficient and highly enantioselective manner, albeit as a mixture of diene regioisomers 66 and 67 (Scheme 25). Interestingly, the 4-nitrophenol is critical for the success of the reaction, since other strong acids, such as trifluoroacetic acid and hydrogen chloride are unsuccessful. Scheme 25 Enantioselective Ene Reaction of Æ,-Unsaturated Aldehydes with Cyclopentadiene Catalyzed by a Diphenylprolinol Silyl Ether[107] Ph 10−20 mol%
CHO
N H
Ph OTBDMS 65
CHO
CHO
4-nitrophenol, MeOH, rt
+
+
R1
R1 64
66
R1
67
R1
Catalyst 65 (mol%) Time (h) Ratio (66/67) eea (%) Yield (%) Ref
Ph
10
20
70:30
92
84
2-naphthyl
20
3
57:43
93
70
[107] [107] b
[107]
4-O2NC6H4
20
3
43:57
90
60
4-BrC6H4
20
6
67:33
95
79
[107]
4-MeOC6H4
10
8
57:43
93
82
[107]
10
5
60:40
93
78
[107]
2-furyl
20
2
63:37
91
80
[107]
2-thienyl
10
3
40:60
77
82
[107]
2-MeOC6H4
20
3
82:18
95
80
[107]
O O
a b
Determined after reduction and hydrogenation. Diels–Alder products are obtained in 11% yield.
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Intermolecular Ene Reactions
339
(R)-3-(Cyclopenta-1,3-dien-1-yl)-3-phenylpropanal (66, R1 = Ph) and (R)-3-(Cyclopenta-1,3dien-2-yl)-3-phenylpropanal (67, R1 = Ph); Typical Procedure:[107]
(E)-3-Phenylprop-2-enal (64, R1 = Ph; 500 L, 4.0 mmol) was added to a soln of catalyst 65 (146.3 mg, 0.40 mmol) and 4-nitrophenol (110.7 mg, 0.80 mmol) in MeOH (8.0 mL) at rt. The soln was stirred for 1 min and then cyclopentadiene (0.98 mL, 12 mmol) was added. The resulting mixture was stirred for 20 h at rt and then excess cyclopentadiene was removed azeotropically with benzene (CAUTION: carcinogen). The residue was purified by column chromatography (silica gel, EtOAc/hexane 1:20) to afford the products; yield: 667.2 mg (84%). The ratio of adducts 66 and 67 was determined by 1H NMR spectroscopy (400 MHz). 3.6.2.3.1.2
Enecarbamates as Ene Components
The enantioselective ene reaction of Æ,-unsaturated aldehydes has been expanded to work with enecarbamates[110] as the ene component. Diphenylprolinol silyl ether 65 is an efficient enantioselective catalyst for the reaction, such that Æ,-unsaturated aldehydes 68 undergo reaction with enecarbamates 69 to provide the enantioenriched piperidines 70A and 70B in a formal aza-[3 + 3]-cycloaddition reaction (Scheme 26). The initial step in this transformation is the intermolecular ene reaction of iminium ion 71, generated from catalyst 65 with Æ,-unsaturated aldehyde 68, to provide intermediate 72. This is followed by isomerization of the imine to the enecarbamate and loss of catalyst 65 via hydrolysis to afford the aldehyde 73. Intramolecular nucleophilic addition of the nitrogen atom of the enecarbamate to the aldehyde then provides the cyclized hemiaminal products 70. This process provides a variety of aryl-substituted piperidine derivatives in good yield and with high enantioselectivity. In a related study the enantioselective ene reaction of vinylidene malonates (as enophiles) with enamides has been catalyzed by a chiral copper(II) complex.[111]
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Stereoselective Synthesis
Ene Reactions
3.6
Scheme 26 Enantioselective Reaction of Æ,-Unsaturated Aldehydes with Enecarbamates Catalyzed by a Diphenylprolinol Silyl Ether[110] Ph 10 mol%
CHO
NHBoc
N H
Ph
OH
OTBDMS 65 o
N
1,2-dichloroethane, 70 C
+ Ar1
R1 68
OH
R1
69
Boc
N
+ Ar1
R1
Boc Ar1
70A
70B
Ph Ph
N H
OTBDMS 65
NHBoc
Ph Ph
N
OTBDMS
Ar1 69 ene reaction
Ph Ph
N
OTBDMS NBoc
O H Boc HN
− 65
R1 R1
R1
Ar1
Ar1
71
73
72
R1
Ar1
Time (h)
Ratio (70A/70B)
ee (%) of 70A
ee (%) of 70B
Yield (%)
Ref
Ph
Ph
34
34:66
94
93
90
[110]
2-naphthyl
Ph
38
29:71
91
90
83
[110]
4-O2NC6H4
Ph
22
29:71
95
97
83
[110]
4-BrC6H4
Ph
22
31:69
91
92
88
[110]
4-MeOC6H4
Ph
48
19:81
97
97
73
[110]
2-furyl
Ph
96
27:73
99
99
80
[110]
Ph
4-BrC6H4
48
14:86
90
90
89
[110]
Ph
4-Tol
29
26:74
90
88
89
[110]
19:81
90
90
85
[110]
Ph a
2-furyl
a
23
Reaction performed at room temperature.
tert-Butyl (2S,4R)-2-Hydroxy-4,6-diphenyl-3,4-dihydropyridine-1(2H)-carboxylate (70A, R1 = Ar1 = Ph) and tert-Butyl (2R,4R)-2-Hydroxy-4,6-diphenyl-3,4-dihydropyridine1(2H)-carboxylate (70B, R1 = Ar1 = Ph); Typical Procedure:[110]
A soln of enecarbamate 69 (Ar1 = Ph; 164.5 mg, 0.75 mmol) in CH2Cl2 (0.66 mL) was added to a soln of catalyst 65 (18.3 mg, 0.05 mmol) and (E)-3-phenylprop-2-enal (68, R1 = Ph; 62.5 L, 0.5 mmol) in CH2Cl2 (0.33 mL) at rt. The resulting mixture was stirred at 70 8C for 34 h and then quenched with 1 M HCl at 0 8C. The organic materials were extracted with EtOAc (3 ) and the combined organic extracts were washed with sat. aq NaHCO3, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/hexane 1:30) to afford the products as a yellow solid; yield: 158.1 mg (90%); ratio (70A/70B) 34:66 (as determined by 1H NMR spectroscopy).
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Intermolecular Ene Reactions
3.6.2
3.6.2.4
Heteroatom—Heteroatom Double Bonds as Enophiles
3.6.2.4.1
Enantioselective Reaction of Azodicarboxylates
3.6.2.4.1.1
Unactivated Alkenes as Ene Components
The ene reaction of an azodicarboxylate with unactivated alkenes provides a novel route to allylic amines; however, the enantioselective variant has received little attention. The first reported enantioselective ene reaction used the oxazolidine-derived azodicarboxylate enophile analogue 74 with 1,2-di- and 1,1,2-trisubstituted alkenes to provide a regioisomeric mixture of hydrazines 75 and 76 using the chiral copper(II) complex ent-35 (Scheme 27).[112] The product ratio is strongly dependent upon the alkene substitution pattern, and a trisubstituted alkene gives exclusive formation of hydrazine 76 with the highest enantioselectivity (60% ee). The enantioselective ene reaction using nitroso compounds as enophiles with unactivated alkenes has also been reported using a copper(I) catalyst with a chiral diphosphine ligand; however, the enantioselectivity is moderate (up to 40% ee).[113] Scheme 27 Enantioselective Ene Reaction of an Azodicarboxylate Analogue with Unactivated Alkenes Catalyzed by a Chiral Copper(II) Complex[112] 2+
O 20 mol%
O
N
N
N
N Ph
O
O
+
CCl3 O
2OTf−
N Cu
Ph
ent-35
R2 O
O
CH2Cl2, rt
R1
R3
74 Cl3C O
N
O
R2
O
O
H N
N
O
R3 R
O
R1
CCl3 O
2
75
R1
R2
(CH2)2
a
N
N H
O
O N
O
76
R3 Time (h) Ratio (75/76) ee (%) of 75 ee (%) of 76 Yield (%) Ref H 17
Me (CH2)4 19 Et
R1
R3
+
Me H 20
>99:1 1:>99
40
–
60
–
60
94
23:77
7
33
65
[112] [112] a
[112]
Starting alkene has an E-configuration.
2,2,2-Trichloroethyl 2-Allyl-2-(2-oxooxazolidine-3-carbonyl)hydrazinecarboxylates 75 and 2,2,2-Trichloroethyl 1-Allyl-2-(2-oxooxazolidine-3-carbonyl)hydrazinecarboxylates 76; General Procedure:[112]
Cu(OTf )2 (36.2 mg, 0.1 mmol) and (4R,4¢R)-2,2¢-(propane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole) (36.8 mg, 0.11 mmol) were added to an oven-dried Schlenk tube equipped with a magnetic stirrer bar. The mixture was stirred under vacuum for 2 h and the tube was then filled with N2. Dry CH2Cl2 (1 mL) was added and the soln was stirred for 1 h to give Ene Reactions, Terada, M. Science of Synthesis 4.0 version., Section 3.6 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
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Ene Reactions
catalyst ent-35. Azodicarboxylate analogue 74 (160 mg, 0.5 mmol) was then added, followed by the alkene (1 mmol) and the mixture was stirred at rt for the appropriate time. The product was then isolated by flash column chromatography (CH2Cl2/EtOAc 4:1). Enecarbamates as Ene Components
3.6.2.4.1.2
Enecarbamates have been applied to the enantioselective ene reaction with azodicarboxylates as the ene component, and this reaction provides a novel route to various Æ-amination products.[114] For example, treatment of azodicarboxylates 77 with enecarbamates 78, using the chiral copper catalyst derived from copper(II) trifluoromethanesulfonate and the chiral 1,2-diamine ligand 79, gives the Æ-amino imines 80 with high levels of asymmetric induction (Scheme 28). The initially formed Æ-amino imines 80 can either be transformed into the ketones 81 upon acid hydrolysis or into the 1,2-diamines 82 by stereoselective reduction with sodium borohydride. Scheme 28 Enantioselective Reaction of Azodicarboxylates with Enecarbamates Catalyzed by a Chiral Copper(II) Complex[114]
O
BnHN
O R1O
NHBn 79
N
OR1
N
OR4
HN
+
Cu(OTf)2, toluene, −20 oC
R3
O R2 77
78 O 48% HBr EtOH, rt, 1.5 min
O
R1O
NH
R1O
N
R3
O R2
O R1O
NH
R1O
N O
O
OR4
N
81
R3
O
NaBH4
R2
MeOH −78 to −45 oC, 3 h
80
O
R1O
NH HN
R1O
N O
OR4 R3
R2 82
R1
R2
R3
R4
iPr Me Ph
Bn
iPr Me Ph
Catalyst (mol%)
Time (h)
Derivatization Con- Product ee ditions (%)
Yield (%)
Ref
0.2
22a
NaBH4, MeOH
82
98
84
[114]
Me
1
25
HBr, EtOH
81
92
90
[114]
iPr Me Ph
Et
1
24
HBr, EtOH
81
84
87
[114]
iPr Me Ph
CH2CH=CH2
1
24
HBr, EtOH
81
83
62
[114]
Me Me Ph
Bn
3
24
HBr, EtOH
81
82
83
[114]
Et
Me Ph
Bn
3
24
HBr, EtOH
81
84
91
[114]
Bn Me Ph
Bn
10b
6
HBr, EtOH
81
85
99
[114]
iPr Me 2-Tol
Bn
5
20
–
80
96
84
[114]
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3.6.2
R1
R2
R3
343
Intermolecular Ene Reactions R4
Catalyst (mol%)
Time (h)
Derivatization Con- Product ee ditions (%)
Yield (%)
Ref
iPr Me 3-Tol
Bn
1
24
HBr, EtOH
81
97
93
[114]
iPr Me 4-Tol
Bn
5
10
iPr Me 4-MeOC6H4 iPr Me 4-ClC6H4 iPr Me Et iPr Et
Me
iPr Me H a b c d e
Bn
3
Bn
0.2
Bn
c
Bn Bn
2
6
HBr, EtOH
81
94
90
[114]
a
NaBH4, MeOH
82
90
81
[114]
a
NaBH4, MeOH
82
96
79
[114]
24 6
NaBH4, MeOH
82
b
4
NaBH4, MeOH
82
c
26
NaBH4, MeOH
82
5 5
d
82
[114]
86
70
[114]
67
82e
[114]
82
The reaction is carried out at –10 8C. 3-Å molecular sieves are added. Ligand 57 (Ar1 = 1-naphthyl) is employed. dr (syn/anti) 28:72. The cyclic product is obtained.
Diisopropyl (R,E)-1-(1-{[(Benzyloxy)carbonyl]imino}-1-(2-tolyl)propan-2-yl)hydrazine-1,2dicarboxylate (80, R1 = iPr; R2 = Me; R3 = 2-Tol; R4 = Bn); Typical Procedure:[114]
Diamine ligand 79 (9.9 mg, 0.022 mmol) in toluene (1.5 mL) was added to a dried flask containing Cu(OTf )2 (7.2 mg, 0.02 mmol), and the mixture was stirred for 12 h at rt. To another dried flask was added a soln of the catalyst (0.75 mL, 0.01 mmol) prepared according to the above procedure. Toluene (0.75 mL) was added and the soln was cooled to –20 8C. Diisopropyl azodicarboxylate (77, R1 = iPr; 0.22 mmol) in toluene (0.7 mL) and enecarbamate 78 (R2 = Me; R3 = 2-Tol; R4 = Bn; 56.3 mg, 0.2 mmol) in toluene (0.8 mL) were added successively, and the mixture was stirred for 20 h. The reaction was then quenched with sat. aq NaHCO3, and the mixture was extracted with CH2Cl2. The organic extracts were dried (Na2SO4) and filtered, and the solvents were removed. Purification of the obtained residue by flash column chromatography (neutral silica gel) afforded the product; yield: 81.5 mg (84%); 96% ee.
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Ene Reactions
References [1] [2]
[3] [4]
[5] [6]
[7]
[8] [9] [10] [11]
[12]
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Sigmatropic Rearrangements J. Zeh and M. Hiersemann
General Introduction
A sigmatropic rearrangement is characterized by a bond reorganization event in which a -bond migrates along a -system in a concerted fashion. The -bond shift is generally classified by a numbering system that refers to the number of atoms involved; for instance, [3,3] indicates that the -bond moves along a -system to a position that is three atoms away in each direction from the original point of connectivity. To demonstrate the utility of stereodifferentiating and C—C-connecting sigmatropic rearrangements in target-oriented syntheses, this section provides selective coverage of significant examples of the Claisen, Cope, and [2,3]-Wittig rearrangements. 3.7.1
The Claisen Rearrangement
The [3,3]-sigmatropic rearrangement of allyl vinyl ethers to form ª,-unsaturated carbonyl compounds is known as the Claisen rearrangement. This reaction was named after its discoverer Ludwig Claisen (1851–1930), who reported in 1912 that ethyl 2-acetylpent-4-enoate was formed during the attempted distillation of ethyl (2E)-3-(allyloxy)but-2-enoate (Scheme 1); interestingly, this is a catalyzed rearrangement since the reaction proceeds in the presence of catalytic amounts of ammonium chloride.[1] Scheme 1 Claisen’s Original [3,3]-Sigmatropic Rearrangement[1] O EtO
O
NH4Cl (cat.) heat
O
EtO
O
The aliphatic Claisen rearrangement of acyclic allyl vinyl ethers is generally considered to be irreversible, as two C=C bonds are converted into another C=C bond and a more stable C=O bond. However, if a ª,-unsaturated carbonyl compound is sufficiently destabilized by strain, e.g. ring strain, a retro-Claisen rearrangement is possible. The Claisen rearrangement is now widely used in target-oriented syntheses, and the existence of numerous review articles and a monograph is testimony to the importance of this venerable reaction;[2–4] more details can also be found in Houben–Weyl, E 21, p 3301. In the course of the aliphatic Claisen rearrangement a C—C -bond is formed at the expense of a -bond between a carbon atom and a heteroatom with the concomitant formation of up to two adjacent stereogenic centers and a geometrically defined double bond. The biggest hurdle in terms of application of the Claisen reaction is the construction of the allyl vinyl ether, particularly with respect to stereodefined vinyl ether double bonds. Since the aliphatic Claisen rearrangement of acyclic allyl vinyl ethers proceeds predominantly through a chair-like transition-state structure,[5] the relative configuration of newly generated stereogenic carbon atoms is predetermined by the configuration of the double bonds in the allyl vinyl ether precursor (Scheme 2). Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 382
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Stereoselective Synthesis Scheme 2
3.7
Sigmatropic Rearrangements
Chair-Like Transition-State Structures
R
X Y
R1
R2
Y R2
R1
X
1 2R
Y
(±)-syn
X
R2
R1
X
X
(E,E)
R1
Y
R2
Y
(±)-anti
G ΔΔG#
boat
chair
(E,E)
(±)-syn
(±)-anti reaction coordinate
Allyl vinyl ethers with a Z,Z or E,E configuration rearrange to afford the corresponding syn-diastereomer, whereas those with an E,Z or Z,E configuration provide the anti-diastereomer (Scheme 3). This substrate-induced diastereofacial differentiation is known as “simple” or “syn/anti” diastereoselectivity. It should be emphasized that the seemingly reliable preference for a chair-like transition-state structure may be limited or even reversed, a prominent example being the well-investigated Claisen rearrangement of allyl vinyl ethers in which the allylic ether double bond is part of a ring.[6]
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The Claisen Rearrangement
3.7.1
Scheme 3
Simple Diastereoselectivity
R2
X
R1 Y
R1 Y R2
X X
R2
(E,E)
R1
Y
R1 X R2
R1
Y
Y
R2
R1
Y
(±)-syn
X
X R2
R1
X
(Z,Z)
R2
Y
R1 X
R2 Y Y R1 R2
X
R1
X
R2
(Z,E)
R1
Y
X X
R1 R1 Y
R2
R2
Y
(±)-anti
Y
X X
R2 (E,Z)
R1 R2
Y
As depicted in Scheme 3, the Claisen rearrangement of achiral allyl vinyl ethers proceeds via enantiomeric transition-state structures and, therefore, delivers racemic rearrangement products. Access to enantiomerically pure products requires a chiral catalyst, reagent, or substrate. If the enantio- and diastereoselectivity is substrate-induced, the socalled self-immolative 1,3-chirality transfer predominates. The presence of a non-hydrogen substituent at the C4 position affords two energetically distinct diastereomeric tran-
Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.7
Sigmatropic Rearrangements
sition-state structures (Scheme 4); the substituent R1 preferentially adopts the pseudoequatorial position and consequently the central chirality within the substrate is transferred self-immolatively to the product.[7] Scheme 4
Self-Immolative 1,3-Chirality Transfer[7]
faster
X
R2
Y
R1
R1
X R2
Y
Y
(E,S)
R2
4
X
R1
slower
X
R2
(E,S)
X
R1 Y
R1
R2
Y
(Z,R)
Historically, the Claisen rearrangement is classified hierarchically according to the structure of the substrate. The aromatic and the aliphatic Claisen rearrangement are considered to form different genera that belong to the family of sigmatropic rearrangements within the order of pericyclic reactions (Scheme 5); aliphatic Claisen rearrangements can be further sub-classified according to the nature of the substituent at the 2-position of the allyl vinyl ether, in which many of the known variations (species) are named reactions (Scheme 6). Scheme 5
Aromatic and Aliphatic Claisen Rearrangements
aromatic Claisen rearrangement
O
O
OH
Scheme 6
Classification of Aliphatic Claisen Rearrangements[8–18]
Y Z
O
aliphatic Claisen rearrangement
Y Z
X
X
Xa
Ya
Za
O
H
H, alkyl, aryl Claisen
[9]
alkyl, aryl
H, alkyl, aryl Claisen
[8]
O NR S
1
Variant
Ref
H, alkyl aryl H, alkyl, aryl aza-Claisen
[10]
H, alkyl, aryl H, alkyl, aryl thio-Claisen
[11]
1
chelate-enolate Claisen
[12]
Carroll–Claisen
[13]
O
OM
NHR
O
OH
C(O)R1
O
NR12
H, alkyl, aryl Eschenmoser–Claisen
[14]
O
OSiR13
H, alkyl, aryl Ireland–Claisen
[15]
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3.7.1
The Claisen Rearrangement
Xa
Ya
Za
O
OR1
H, alkyl, aryl Johnson–Claisen
[16]
O
OM
H, alkyl, aryl Arnold–Claisen
[17]
CO2R1
H, alkyl, aryl Gosteli–Claisen
[18]
O a
Variant
Ref
1
R = alkyl, aryl; M = metal.
The importance of aliphatic Claisen rearrangements in organic synthesis is a consequence of their inherent versatility. Claisen rearrangements provide the opportunity to create structural and stereochemical diversity in a highly predictable fashion. The different variants provide access to a wide range of ª,-unsaturated carbonyl compounds that can be structurally manipulated in innumerable ways. Hence, with respect to retrosynthesis, the straightforward and immediate recognition of a Claisen rearrangement retron (a substructure within the target that is accessible by a Claisen rearrangement transform) may require some experience. To assist in improving cognitive competence in this regard, some recent examples of Claisen rearrangement guided total syntheses of natural products 1–16 (Scheme 7) are discussed below. Inspection of the corresponding Claisen rearrangement retrons makes the diversity of accessible structures immediately apparent. Interestingly, the Claisen rearrangement retrons are frequently part of ring systems, even though the transformation is commonly discussed as a reaction of acyclic allyl vinyl ethers. Scheme 7
Natural Products Synthesized by the Claisen Rearrangement O
N
O
HO
O
NMe H
MeO
N
OH MeO
N
Pri OH 1
Cl 2
(+)-halichlorine (Claisen)
O
N H (−)-gleenol
3
(Claisen)
4
(±)-lysergic acid (Claisen PVE)
isoschizogamine (aza-Claisen)
O O Ph
N
OH
O
HN
NH HN
O
O
OH HO
O 5
chlamydocin (chelate−enolate Claisen)
Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
OH H
O
6
OH
OH
H zincophorin (Carroll−Claisen)
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Stereoselective Synthesis
Sigmatropic Rearrangements
3.7
OH H
N
O
HO
OH O
O
OH
O
H
H
O O 7
8
(+)-sundiversifolide (Eschenmoser−Claisen)
(+)-amabiline (Eschenmoser−Claisen)
9
(−)-4-hydroxydictyolactone (Ireland−Claisen)
N O
O
O
N HO
O OH
O
10
O
OAc OH
O
11
spirolide C
(−)-lepadiformine (Ireland−Claisen)
(Ireland−Claisen)
12
(+)-5-epi-acetomycin (Ireland−Claisen)
OH Et Br O
N Me Cl N 13
(+)-lycoposerramine-W (Johnson−Claisen)
14
(+)-obtusenyne (Johnson−Claisen)
O
OH HO
O
HO O
OH
O O
HO
HO
OH OH
15
O
(+)-frondosin A (aromatic Claisen)
16
candicanoside A (Johnson−Claisen)
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O
3.7.1
3.7.1.1
353
The Claisen Rearrangement
The Classic Claisen Rearrangement
The Claisen rearrangement usually requires high temperature or catalysis by a - or -Lewis acid, and therefore may not be applicable to substrates with sensitive functional groups. The allyl vinyl ether can be generated with a defined configuration of either double bond in situ or in a separate step that precedes the rearrangement. The allyl vinyl ether that is used in the Claisen rearrangement in the total synthesis of (+)-halichlorine (1) is generated in situ (Scheme 8).[19] The allyl alcohol 17 is etherified by treatment with butyl vinyl ether, which also serves as the solvent, in the presence of catalytic amounts of mercury(II) acetate and triethylamine. Because of the high temperature required to form the enol ether, it is not isolated, but rearranges to give the aldehyde 19. As a result of the suprafacial nature of the concerted rearrangement, which occurs via the proposed chair-like transition-state structure 18, the central chirality of the allylic alcohol is transferred to the newly generated quaternary stereocenter, and the rearrangement product is obtained as a single diastereomer. This application represents an instructive example of a Claisen rearrangement of an allyl vinyl ether that contains a nitrogensubstituted double bond. The rearrangement provides synthetic access to piperidines from dihydropyridinones, which can, in turn, be prepared from serine and terminal alkynes. The aldehyde 19 can be further transformed by a Wittig reaction to provide a methyl vinyl ether, followed by a mercury(II)-mediated cleavage to afford the homologated aldehyde 20. Claisen Rearrangement in the Total Synthesis of (+)-Halichlorine[19]
Scheme 8
Hg(OAc)2 (0.1 equiv) Et3N (0.1 equiv)
TBDMSO HO
O OTBDMS
OBu 110 oC, 36 h
N
N Cbz
Cbz
OPMB OPMB 17
18
OTBDMS N
Cbz OPMB
OMe Cl− (2.2 equiv) 1. Ph3P NaHMDS (2 equiv) THF, 0 oC, 2 h 2. Hg(OAc)2 (3 equiv)
OTBDMS N
THF, H2O, 0 oC, 4 h 77%
Cbz OPMB
H O
O H 19
20
79%
N
O O
OH 1
Cl
(+)-halichlorine
An example of a Claisen rearrangement that proceeds via a boat-like transition-state structure is outlined in Scheme 9.[20] Because of the strained nature of the tricyclic transitionSigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.7
Sigmatropic Rearrangements
state structure 24, exceptionally high temperatures are required for the rearrangement. Hence, it is possible to prepare and functionalize the allyl vinyl ether 23 from the dione 21, via the enone 22, without triggering this rearrangement. Finally, the Claisen rearrangement proceeds with a complete transfer of chirality from the allyl vinyl ether 23 to the sterically congested spiro[4.5]decane 25. Subsequent transformations afford the sesquiterpene natural product (–)-gleenol (2). Claisen Rearrangement in the Total Synthesis of (–)-Gleenol[20]
Scheme 9
1. LiAlH4 (1.25 equiv) Et2O, 0 oC, 20 min 2. imidazole (4 equiv) DMAP (0.1 equiv)
O HCl (0.01 M) EtOH, rt, 26.5 h
Pri
O
TESCl (2 equiv) DMF, 0 oC to rt, 12 h
O
90%
O
TESO
Pr 21
42%
i
22
OTES Pri
triglyme 250 oC, 2 h
O OTES Pri 23
O
O OTES Pri
Me 24
25
75%
OH Pri 2
(−)-gleenol
The propargyl vinyl ether 26, which is stable at room temperature, was employed in a total synthesis of (€)-lysergic acid (3) (Scheme 10).[21] Gold(I)-catalyzed rearrangement of ether 26 followed by reduction gives the allenic alcohol 28, which presumably proceeds via the transition state 27, with moderate selectivity (dr 80:20). Mitsunobu reaction of allenic alcohol 28 provided the sulfonamide 29, which undergoes a palladium(0)-catalyzed cascade cyclization to afford the tetracyclic framework 30 of (€)-lysergic acid (3).
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The Claisen Rearrangement
Scheme 10 Claisen Rearrangement of a Propargyl Vinyl Ether in the Total Synthesis of (±)-Lysergic Acid[21] NTs
1. 5 mol% [(Ph3PAu)3O]BF4 CH2Cl2, 40 oC, 7.5 h 2. NaBH4 (1.2 equiv) MeOH, rt, 1 h
Br
O TIPSO Ar1
O TIPSO 26
27
NTs
Br OH
H
1. TsNHFmoc (3.3 equiv) DEAD (5 equiv) Ph3P (5 equiv) THF, 0 oC to rt, 3 h 2. piperidine (4 equiv)
NTs
Br
DMF, 0 oC to rt, 1 h 73%
•
65%; dr 87:13
NHTs •
H
H
TIPSO 28
5 mol% Pd(PPh3)4 K2CO3 (2.9 equiv) DMF, 120 oC, 3 h
H
TIPSO 29
78%; dr 80:20
O OTIPS HO NTs H
N Ts
N Ts 30
NMe H
3
(±)-lysergic acid
2-[(2S,6R)-1-(Benzyloxycarbonyl)-6-[(tert-butyldimethylsiloxy)methyl]-2-{[(4-methoxybenzyl)oxy]methyl}-1,2,5,6-tetrahydropyridin-2-yl]ethanal (19); Typical Procedure:[19]
CAUTION: Mercury(II) acetate is highly toxic and may be fatal if ingested, inhaled, or swallowed. A mixture of enol 17 (0.153 g, 0.29 mmol), Hg(OAc)2 (9 mg, 0.03 mmol), and Et3N (4 L, 0.03 mmol) in butyl vinyl ether (3 mL) was heated at 110 8C (oil-bath temperature) in a sealed glass tube for 36 h. Evaporation of the volatile material followed by flash chromatography of the residue (hexane/EtOAc 5:1) gave a colorless oil; yield: 0.127 g (79%). 3.7.1.2
The 3-Aza-Claisen Rearrangement
The nitrogen variant of the Claisen rearrangement is known as the 3-aza-Claisen rearrangement.[10] For instance, N-acetylated allylic amines provide ª,-unsaturated amides. If the nitrogen atom is trisubstituted, the rearrangement occurs at only elevated temperature, whereas N-allyl enaminium ions undergo a charge-accelerated rearrangement at room temperature. The presence of the nitrogen atom also provides an opportunity to utilize a chiral auxiliary. An example of the 3-aza-Claisen rearrangement is found in a synthesis of isoschizogamine (4) (Scheme 11).[22] The N-allyl enamine structural element is generated in situ by Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
Sigmatropic Rearrangements
3.7
deprotonation of the N-acetyl aziridine 31 at low temperature. Despite the release of the aziridine ring strain during the rearrangement, the activation barrier is still significant, and the rearrangement has to be performed at elevated temperature. For stereoelectronic reasons, the rearrangement proceeds via the boat-like transition-state structure 32 to give the seven-membered lactam 33, which is subsequently converted into the six-membered lactam 35 via the amide 34. The rearrangement proceeds with complete 1,3-chirality transfer to establish the quaternary stereogenic carbon atom of isoschizogamine (4). A 3-Aza-Claisen Rearrangement[22]
Scheme 11
TBDPSO
O MeO
LiHMDS (1.4 equiv) toluene −78 oC, 25 min then reflux, 10 min
R1
H
N
CO2Me
N
OLi
O 31
32 1. NaHMDS (1.2 equiv) O S O (1.3 equiv) Cl
O2N
TBDPSO
THF, −78
oC,
3h 2. NaOMe (2 equiv)
TBDPSO
THF, MeOH rt, 30 min
O MeO
OMe 71%
OMe
O
NO2
O H N
O NH
S
O 33
34
55%; 98% ee
1. DBU (1.5 equiv) MeCN reflux, 1 h 2. K2CO3 (3 equiv) PhSH (1.2 equiv)
O
OTBDPS OMe
DMF, rt, 1 h
MeO
N
O
75%
MeO
N
O O HN 35
3.7.1.3
4
isoschizogamine
The Thio-Claisen Rearrangement
Formal replacement of the oxygen atom in the allyl vinyl ether skeleton by a sulfur atom provides allyl vinyl sulfides (allyl vinyl thioethers), which undergo the thio-Claisen rearrangement.[11] In comparison with the oxygen variant, the thio-Claisen rearrangement has a lower activation barrier, and the reaction can proceed at room temperature. On the other hand, since the thermodynamic driving force is reduced, a mixture of starting material and rearrangement product can be obtained. The required allyl vinyl sulfides can be prepared in situ in a straightforward manner by S-allylation of thioenolates. The asymmetric thio-Claisen rearrangement can be used to prepare the -substituted ª,-unsaturated amino acids 39 (Scheme 12).[23] For example, the N,S-ketene acetals 38, Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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The Claisen Rearrangement
generated in situ by deprotonation of the chiral-auxiliary-containing thioamide 36, gives the corresponding Z-thioenolate, which is treated with various allylic bromides at –78 8C. On warming, a rearrangement via the chair-like transition-state structure 37 occurs. Simple and auxiliary-induced diastereoselectivity form a coalition of stereocontrolling elements that enforce a highly diastereoselective rearrangement in many cases. Application of a one-pot S-methylation–reduction–oxidation sequence provided the unnatural amino acids 39 and the chiral auxiliary 40 was readily recycled. Scheme 12
Examples of Diastereoselective Thio-Claisen Rearrangements[23] LDA (3 equiv), HMPA (3 equiv) R2 R3
Br
S
Ph
OBn
(2 equiv)
LiO S
1
R THF, −78 oC to rt, 4 h
N
Ph
NHCbz
R1
N
R3 R2
N
Ph
Ph 36
37 But 1. MeOTf (3 equiv),
OH (0.7 equiv) But
S
Ph
R2 R3
N
CH2Cl2, rt, 15 h 2. LiBHEt3 (3 equiv), THF, −78 oC, 1 h 3. NaClO2 (2 equiv), 2-methylbut-2-ene (7 equiv) AcOH, t-BuOH, H2O, 0 oC to rt
HN R1 Cbz Ph 38
65−82%
O
R2 R 3 +
HO HN 39
R1
3.7.1.4
R2
NH
R1 Cbz
32−44%
R3
Temp (8C)
Ratio (anti/syn) dr
Yield (%) of 38 Ref
H
–78 to rt
H
H
–
>99:1
82
[23]
H
Me Me –78 to reflux –
>99:1
66
[23]
–
>99:1
74
[23]
>99:1
78
[23]
–78 to rt
Ph
Me H
H
H
H
Me –78 to 40
>99:1
H
H
Et
–78 to 40
>99:1
89:11 76
[23]
H
H
Ph –78 to rt
>73:1
87:13 65
[23]
Ph 40
The Claisen Rearrangement of Chelated Enolates
If allylic esters are substituted in the Æ- or -position with a Lewis basic heteroatom, such as oxygen, nitrogen, or sulfur, the corresponding Z-enolate is formed exclusively by deprotonation, and is assumed to exist as a five- or six-membered chelate (Scheme 13). The [3,3]-sigmatropic rearrangement of an allyl vinyl ether that contains a chelated enolate moiety is classified as a Claisen rearrangement of a chelated enolate.[12] The conversion of the intermediate chelated metal enolate into a ketene silyl acetal represents the IreSigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.7
Sigmatropic Rearrangements
land–Claisen rearrangement (see Section 3.7.1.7). Nevertheless, the chelate enolate Claisen rearrangement provides access to Æ-heteroatom-substituted ª,-unsaturated carboxylic acids, e.g. nonracemic Æ-amino acid derivatives. Scheme 13 Chelated Enolates as Substrates for the Claisen Rearrangement R1
R1
O
O X M O
X
M
O
M = metal; X = NHR2, OR2, SR2; R1 = alkyl, aryl
The cyclic peptide chlamydocin (5) contains an unusual Æ-amino acid that is prepared by the chelate enolate Claisen rearrangement (Scheme 14).[24] The allylic ester 41, as a mixture of diastereomers, is deprotonated in the presence of zinc(II) chloride to give a chelated enolate, which undergoes a Claisen rearrangement on warming to room temperature. The observed stereochemistry can be explained in terms of the chair-like transition-state structure 42, and complete 1,3-chirality transfer is observed with no interference from the remote stereogenic carbon atom. The crude Æ-amino acid is esterified in situ with iodomethane to afford the Æ-amino ester 43. The tert-butyldimethylsilyl protecting group is removed under Brønsted acidic conditions, and a diastereomer-selective enzymatic esterification gives the diastereo- and enantiomerically enriched products 44 and 45.
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The Claisen Rearrangement
Scheme 14 A Chelate Enolate Claisen Rearrangement in the Total Synthesis of Chlamydocin[24] OTBDMS
Boc
Li
−78 oC to rt, 14 h
NBoc
R1
O
Zn
O
O
HN 41
ZnCl2 (1.2 equiv) LDA (3 equiv) THF
Li+
Cl Cl
O 42
92% ee; dr 64:36
K2CO3 (1.2 equiv) MeI (3 equiv)
1. TsOH (0.1 equiv) MeOH, rt, 1 h 2. OAc (5 equiv)
OTBDMS
DMF 0 oC to rt, 5 h
Novozyme 437 (cat.) rt, 2 d
92% (2 steps)
OMe
HN Boc 43
NHBoc
O 90% ee; dr 64:36
OH
NHBoc
OAc
+ MeO
MeO O (S,R)-44
O (S,S)-45
34%; 90% ee; dr 88:12
58%; 90% ee; dr 75:25
O O Ph
N
O
HN
NH HN
O
O 5
3.7.1.5
chlamydocin
The Carroll–Claisen Rearrangement
In the case of the Carroll–Claisen rearrangement, the allyl vinyl ether is generated in situ by enolization of a -keto allyl ester. The Æ-allylated -keto acids, which are the initial products of rearrangement, undergo decarboxylation to afford the corresponding ª,-unsaturated ketones.[13] An instructive example is found in the total synthesis of zincophorin (6) illustrated in Scheme 15.[25] The -keto allylic ester 46, prepared by esterification of the corresponding tertiary allylic alcohol with diketene, is cleanly converted into the desired rearrangement product 48 by absorption on neutral alumina and heating to 60 8C. Interestingly, the thermal rearrangement gives an intractable mixture of products, and rearrangement under basic conditions (lithium diisopropylamide, refluxing tetrahydrofuran) gives a conjugated diene by elimination. The stereochemical course of the concerted bond reorganization process can be explained by the formation of a chair-like transition-state structure 47 in which an intramolecular hydrogen bond supports the formation of the E-enol. As the keto functionality is not present in zincophorin (6), it is removed in three steps by reduction to the corresponding secondary alcohol, mesylation, and reductive demesylation to give the key intermediate 49. Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.7
Sigmatropic Rearrangements
Carroll–Claisen Rearrangement in the Total Synthesis of Zincophorin[25]
Scheme 15 OBn
OMOM alumina 60 oC, 12 h
O
R1
O O
O
O
H
O 46
47 1. DIBAL-H (1.3 equiv) Et2O, −78 oC, 2 h
OBn OMOM
O
2. iPr2NEt (3 equiv) MsCl (2.3 equiv) CH2Cl2, 0 oC, 2 h 3. LiAlH4 (4 equiv)
OBn OMOM
THF, reflux, 3 h 86%
48
49
61%
OH
O HO
OH H
O
OH
H 6
3.7.1.6
OH
zincophorin
The Eschenmoser–Claisen Rearrangement
Dialkylamino-substituted allyl vinyl ethers generated in situ undergo the Eschenmoser– Claisen rearrangement at elevated temperatures to afford ª,-unsaturated amides.[14] Forcing conditions are required to form the intermediate O-allyl ketene N,O-acetal from the allylic alcohol by a transacetalization–elimination reaction. Nevertheless, many functional groups are tolerated, as this variant does not require the presence of additional basic or acidic additives. Moreover, the Eschenmoser–Claisen rearrangement is particularly successful for cases where there is a build-up of steric strain, e.g. in the synthesis of quaternary chiral carbon atoms. In comparison with the Ireland–Claisen and Johnson–Claisen rearrangement (see Sections 3.7.1.7 and 3.7.1.8, respectively), this type of Claisen rearrangement provides improved yields and selectivities. The total synthesis of (+)-sundiversifolide (7) exemplifies this process, where the cyclic allylic alcohol 50 reacts with N,N-dimethylacetamide dimethyl acetal in refluxing toluene to afford the amide 52 in good yield and as a single diastereomer (Scheme 16).[26] Since the ketene N,O-acetal double bond of the intermediate allyl vinyl ether is nonstereogenic, the suprafacial mode of the [3,3]-sigmatropic shift facilitates the 1,3-chirality transfer, in which the possible competition between a chair-like (51) and a boat-like (not depicted) transition-state structure is inconsequential on the stereochemical outcome. The amide 52 is subsequently converted into the bicyclic core 53 of (+)-sundiversifolide (7) by sequential iodolactonization and radical deiodination. The analogous Johnson–Claisen and Ireland–Claisen rearrangements proceed less efficiently both in terms of yield and diastereoselectivity. Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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The Claisen Rearrangement
Scheme 16 The Eschenmoser–Claisen Rearrangement in a Total Synthesis of (+)-Sundiversifolide[26] OH
MeO
OMe
(6 equiv)
Me2N
NMe2
O
toluene, reflux, 30 h
TBDMSO
TBDMSO 50
51
dr 98.5:1.5
NMe2 TBDMSO
1. I2 (2 equiv) THF, H2O, rt, 12 h 2. Bu3SnH (3 equiv), AIBN (0.1 equiv) benzene, reflux, 1 h 89%
O 52
96%
H
H O
O
HO
O
O
TBDMSO
H
H 53
7
(+)-sundiversifolide
The Eschenmoser–Claisen rearrangement is a powerful tool for the construction of quaternary stereogenic carbon atoms, as illustrated in Scheme 17. Treatment of the cyclic allylic alcohol 54 with N,N-dimethylacetamide dimethyl acetal in refluxing toluene gives the amide 56 in 95% yield as a single diastereomer.[27] The stereochemical course of the rearrangement involves the chair-like transition-state structure 55; however, a rearrangement via the alternative boat-like transition-state structure cannot be ruled out in this case. The total synthesis of (+)-amabiline (8) is completed using a series of functionalgroup interconversions to deliver the azide 57, which provides the key functionality for a Pictet–Spengler reaction.
Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.7
Sigmatropic Rearrangements
Scheme 17 The Eschenmoser–Claisen Rearrangement in a Total Synthesis of (+)-Amabiline[27] OPMB HO
O
MeO
OMe
NMe2
(5 equiv) NMe2 toluene, 120 oC, 16 h
O
O
Ar1
OPMB O O
O O 55
54
1. LiBHEt3 (5 equiv) THF, 0 oC to rt, 2 h 2. I2 (1.3 equiv), Ph3P (1.3 equiv) Et3N (1.3 equiv), imidazole (cat.) toluene, 0 oC to rt, 16 h 3. NaN3 (1.5 equiv) DMF, 60 oC, 20 min
OPMB O O
O
OPMB O O
80%
Me2N
O
N3
O
O 56
95%
O 57 OH N
OH
O O 8
(+)-amabiline
2-[(1R,4S,5S)-5-(tert-Butyldimethylsiloxy)-4-methylcyclohept-2-enyl]-N,N-dimethylacetamide (52); Typical Procedure:[26]
A soln of enol 50 (0.473 g, 1.84 mmol) and N,N-dimethylacetamide dimethyl acetal (1.62 mL, 11.1 mmol) in toluene (9.4 mL) was refluxed with Dean–Stark water separation for 30 h. The mixture was concentrated and the residue was purified by chromatography (hexane/EtOAc 4:1) to give a colorless oil; yield: 0.575 g (96%). 3.7.1.7
The Ireland–Claisen Rearrangement
The Ireland–Claisen rearrangement is probably the most frequently used variant of the Claisen rearrangement. The required allyl vinyl ethers are generated by deprotonation of easily accessible allylic esters at low temperatures to generate the intermediate ester enolates, which are trapped as ketene silyl acetals. The 2-siloxy-substituted allyl vinyl ethers generally undergo the [3,3]-sigmatropic rearrangement upon warming to room temperature to afford ª,-unsaturated carboxylic acids after workup.[15] The configuration of the ketene silyl acetal double bond and, ultimately, the relative configuration of the rearrangement product can be controlled by appropriate selection of the reaction conditions. Usually, the E-enolate is obtained by performing the deprotonation/O-silylation in ethereal solvents at low temperatures, whereas strongly Lewis basic cosolvents such as hexamethylphosphoric triamide preferentially provide the Z-enolate. Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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The Claisen Rearrangement
The Ireland–Claisen rearrangement facilitates the construction of the stereotriad, which contains a non-heteroatom-substituted stereogenic carbon atom, during the synthesis of (–)-4-hydroxydictyolactone (9) (Scheme 18).[28] The ester 58 is selectively converted into the E-enolate, which is trapped with chlorotrimethylsilane in tetrahydrofuran at –78 8C. Since no rearrangement occurs upon warming to room temperature, the reaction mixture is heated to reflux, to afford the carboxylic acid 60 in 85% yield and with very good diastereoselectivity. The stereochemical course of the rearrangement is rationalized by the chair-like transition-state structure 59. The carboxylic acid 60 is subsequently converted into the aldehyde 61 by a sequence of protecting-group and redox transformations. The allylic alcohol moiety in 61 is converted into an allyl bromide, which undergoes intramolecular cyclization using the Nozaki–Hiyama protocol. The ª-lactol 62 is subsequently oxidized to the ª-lactone moiety of (–)-4-hydroxydictyolactone (9). Scheme 18 The Ireland–Claisen Rearrangement in the Total Synthesis of (–)-4Hydroxydictyolactone[28] 1. TMSCl (5 equiv) Et3N (4.5 equiv) THF, −78 oC, 5 min 2. LDA (1.5 equiv)
OPMB
−78 oC, 1.5 h then rt 2 h, then reflux, 2 h
TBDMSO TMSO O
PMBO
O
O
R1
OTBDMS 58
O
59
O
HO
OTBDMS 60
H
H But
H
92%
O
OH
OPMB
1. CBr4 (2.7 equiv) Ph3P (3.5 equiv) CH2Cl2, 0 oC, 20 min 2. CrCl2 (2.1 equiv) THF, rt, 10 h
H O
H
61
85%; dr 94:6
O Bu
t
H O H
O H
OH
O H
O HO 62
9
(−)-4-hydroxydictyolactone
The E/Z-selective formation of the enolate represents a significant synthetic challenge. For instance, use of the chiral lithium amide base (S)-64 ensures selective formation of the intermediate ketene silyl acetal from the Æ-branched ester 63 (Scheme 19). The desired Z-enolate is trapped with chlorotrimethylsilane, and the resulting 2-siloxy-substituted allyl vinyl ether undergoes Claisen rearrangement upon warming to room temperature to afford the corresponding acid, which is esterified to provide the ester 66.[29] The Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
Sigmatropic Rearrangements
3.7
stereochemical result of the rearrangement can be explained in terms of the chair-like transition-state structure 65, and it is immediately evident that the exclusive formation of the Z-ketene silyl acetal is critical in obtaining a synthetically useful degree of diastereoselectivity. Once the quaternary stereogenic carbon atom is established, the ester 66 can be elaborated to the alcohol 67, which contains the E-ring of spirolide C (10). Scheme 19 C[29]
The Ireland–Claisen Rearrangement in the Synthesis of a Fragment of Spirolide
NHBn Ph
(5 equiv)
N
(S)-64 BuLi (5 equiv) THF, −78 oC, 2 h TMSCl (5.7 equiv)
BnO OTBDPS
BnO
−78 oC to rt, 6 h
O
TBDPSO
OTMS
O O 2 OPMB
PMBO 65
63 TMSCHN2 (6 equiv)
OBn
AcOH (1 equiv) CH2Cl2, MeOH 0 oC to rt, 2 h 96% (2 steps)
O OPMB
MeO
OTBDPS 66
OBn
N
O O HO OH
OMOM
67
O OH
O
O
10
O
spirolide C
Substrate-induced diastereoselectivity in the Claisen rearrangement is most effectively accomplished by a self-immolative 1,3-chirality transfer process; however, alternative modes of stereocontrol are possible. For instance, the deprotonation of the allylic ester 68 with lithium hexamethyldisilazanide in tetrahydrofuran gives the corresponding Z-enolate, possibly through chelation (Scheme 20). Subsequent O-silylation provides a ketene silyl acetal that undergoes Ireland–Claisen rearrangement to afford the acid 70, which can be esterified and further elaborated to deliver the pyrrolidine intermediate 71 for the synthesis of (–)-lepadiformine (11).[30] The proposed chair-like transition-state structure 69 explains the stereochemical course of the rearrangement, which leads to the major diastereomer 70.
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The Claisen Rearrangement
Scheme 20 The Ireland–Claisen Rearrangement in the Total Synthesis of (–)-Lepadiformine[30] O LiHMDS (2.9 equiv) TBDMSCl (1.5 equiv) THF, −78 oC to rt, 2 d
O NBoc
OBn N Boc TBDPSO
OBn
O 3
OTBDMS
TBDPSO 68
69
1. MeI (1.1 equiv), K2CO3 (1.1 equiv) acetone, reflux, 12 h
O
HO
NBoc OBn 70
2. 9-BBN dimer (0.76 equiv) THF, 50 oC, 2 h 3. TlOEt (3 equiv), Br (5 equiv)
O
MeO
PdCl2(dppf) (0.2 equiv), Ph3As (0.2 equiv) THF, DMF, 40 oC, 2 h
NBoc
68%
TBDPSO
OBn
TBDPSO
71
79%; dr 89:11
N OH 11
(−)-lepadiformine
An alternative method for the formation of silyl enol ethers is outlined in Scheme 21. A copper-catalyzed silylene transfer from the cyclic silane 73 to the Æ,-unsaturated allylic ester 72 gives the intermediate Z-configured cyclic ketene silyl acetal by a stepwise [1 + 4] cycloaddition, and Claisen rearrangement then affords silalactone 75.[31] The stereochemical course of the rearrangement can be explained by the chair-like transition-state structure 74, which involves a self-immolative 1,3-chirality transfer to determine the absolute configuration of the rearranged product. This example again demonstrates the predictability, reliability, and robustness of the Claisen rearrangement in constructing a quaternary carbon stereogenic center. Substitution of silalactone 75 at the silicon atom with allylmagnesium chloride provides a ª,-unsaturated carboxylic acid, which is reduced to the corresponding alcohol 76 and further elaborated to form (+)-5-epi-acetomycin (12).
Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
Sigmatropic Rearrangements
3.7
Scheme 21 The Ireland–Claisen Rearrangement in the Total Synthesis of (+)-5-epiAcetomycin[31] But (1.8 equiv)
Si But
73 Cu(OTf)2 (0.05 equiv)
Pri
O O
But
toluene 0 oC to rt, 7 h
Pri
O
But
Si
O Pri 72
74
>99% ee
But But O Si O
1.
MgCl
(2 equiv)
THF, rt, 2 h 2. LiAlH4 (3 equiv) THF, rt, 16 h, reflux, 4 h
HO
Si But
But
92%
Pri
Pri 75
76
97%; dr 97:3
O
O O OAc
12
(+)-5-epi-acetomycin
(2S,3R)-2-[(1R,2E)-4-(tert-Butyldimethylsiloxy)-1-{[(4-methoxybenzyl)oxy]methyl}but-2enyl]-3,7-dimethyloct-6-enoic Acid (60); Typical Procedure:[28]
A mixture of Et3N (1.30 mL, 9.09 mmol) and TMSCl (1.30 mL, 10.1 mmol) was added to a soln of ester 58 (1.02 g, 2.02 mmol) in THF (40 mL) at –78 8C. The soln was stirred for 5 min and then a 1.0 M soln of LDA in THF (3.03 mL, 3.03 mmol) cooled to –78 8C was added dropwise from a cannula. The mixture was stirred at –78 8C for 90 min and then at rt for 2 h. More THF (20 mL) was added, and the mixture was refluxed for 2 h then cooled to rt. The soln was diluted with EtOAc (50 mL) and brine (50 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (3 25 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the crude product by flash chromatography (hexanes/EtOAc 9:1 to 4:1) gave a clear oil; yield: 0.871 g (85%). 3.7.1.8
The Johnson–Claisen Rearrangement
In an analogous manner to the Eschenmoser–Claisen rearrangement, the allyl vinyl ethers required for the Johnson–Claisen rearrangement are prepared by the in situ condensation of an allylic alcohol with an ortho ester.[16] This condensation proceeds in stepwise manner through an initial transacetalization to give the mixed ortho ester, followed by elimination of an alcohol to generate the 2-alkoxy-substituted allyl vinyl ether. The transacetalization process requires high temperature and the presence of a Brønsted acid catalyst, e.g. propanoic acid. As this process is reversible, the eliminated alcohol, which in most cases is methanol or ethanol, is removed to shift the equilibrium towards the allyl vinyl ether. Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.7.1
367
The Claisen Rearrangement
In the course of a total synthesis of (+)-lycoposerramine-W (13),[32] the allylic alcohol 77 is heated with trimethoxyethane in the presence of catalytic amounts of 2-nitrophenol to generate an intermediate allyl vinyl ether, which undergoes Claisen rearrangement to provide the ª,-unsaturated ethyl ester 79. Since the double bond of the vinyl ether is nonstereogenic, the stereochemical result of the rearrangement is dictated solely by the suprafacial mode of the sigmatropic shift. The reaction presumably proceeds via the bicyclic chair-like transition-state structure 78, in which the absolute configuration of the newly generated stereogenic carbon atom is a consequence of the self-immolative 1,3-chiral transfer. The double bond generated by the rearrangement serves as a key functional group for the construction of the tetrahydroquinoline 81, by a Knoevenagel pyridine synthesis from the cyclohexanol derivative 80 (Scheme 22). Scheme 22 The Johnson–Claisen Rearrangement in the Total Synthesis of (+)-Lycoposerramine-W[32] OTBDPS
EtO
OEt
OEt
(8.2 equiv)
OEt
O
5 mol% 2-nitrophenol xylene, reflux, 24 h 3
HO
OTBDPS 77
78 1. TBAF (1.2 equiv) THF, rt, 4.5 h
OTBDPS
O OEt
BH3•THF (1.1 equiv) THF, 0 oC to rt, 3 h then aq H2O2
OTBDPS
2. (COCl)2 (10 equiv)
O OEt
aq NaHCO3 0 oC to rt, 6 h
DMSO, Et3N, CH2Cl2 −78 oC to rt, 3.5 h 3. NH2OMe (1.2 equiv) toluene, AcOH reflux, 3.5 h
75%; dr 91:9
54%
HO 79
80
92%
OH
O EtO
N Me N N 81
13
(+)-lycoposerramine-W
As an alternative to the high-temperature elimination reaction of an ortho ester, the ketene acetal may be generated in situ by the oxidation and elimination reaction of a selenoacetal.[33] This strategy was applied as a key reaction in the total synthesis of (+)-obtusenyne (14) (Scheme 23).[34] The seven-membered selenoacetal 82 is oxidized to a selenoxide, which undergoes elimination under basic conditions. The initially formed allyl vinyl ether rearranges via the bicyclic chair-like transition-state structure 83 to furnish the nine-membered lactone 84, which can be further elaborated to form the exocyclic enol ether 85. Intramolecular rhodium(I)-catalyzed hydrosilylation gives the required diol 86, which can then be converted into (+)-obtusenyne (14).
Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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368
Stereoselective Synthesis
3.7
Sigmatropic Rearrangements
Scheme 23 The Johnson–Claisen Rearrangement in the Total Synthesis of (+)-Obtusenyne[34]
SePh O
1. NaHCO3 (1.1 equiv) NaIO4 (3.3 equiv) CH2Cl2, MeOH, H2O rt, 3 h 2. DBU (6.6 equiv)
Et
toluene, reflux, 24 h
O
O
Et
O
OTBDPS
TBDPSO 82
83
Et
Et OTBDPS
OTBDPS
O
O
O
1. (Me2HSi)2NH (12 equiv) NH4Cl (0.2 equiv) 60 oC, 18 h 2. 1 mol% RhCl(PPh3)3 1.5 mol% Ph3P THF, reflux, 16 h 77%
HO 84
85
85%
Et
Et HO
O
O
Cl
HO 86
3.7.1.9
Br
OTBDPS
14
(+)-obtusenyne
The Aromatic Claisen Rearrangement
The aromatic Claisen rearrangement of aryl allyl ethers to ortho-substituted phenols is rarely used to construct stereogenic benzylic carbon atoms. However, an example that demonstrates the potential of this transformation is illustrated in Scheme 24.[35] High temperatures are required to effect rearrangement of the allyl aryl ether 87. The transitionstate structure 88 implies a suprafacial sigmatropic shift on the convex face of the bicyclic ring system, which represents another example of a synthetically useful substrate-induced diastereoselective reaction that is not self-immolative in nature. Since the resulting hydroquinone monomethyl ether is sensitive to acids, bases, and oxygen, it is directly converted into the dimethyl ether 89, which can be isolated as a single diastereomer. The hydroxy group is subsequently oxidized to afford the corresponding ketone, which undergoes a Lewis acid catalyzed ring expansion with diazo(trimethylsilyl)methane followed by desilylation to yield the Æ,-unsaturated ketone 90 that is converted into (+)-frondosin A (15).
Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.7.2
369
The Cope Rearrangement and Related Reactions
Scheme 24 A[35]
The Aromatic Claisen Rearrangement in the Total Synthesis of (+)-Frondosin
PhNEt2 220 oC, 16 h
HO
HO
H
H MeO
O
O
MeO 87
88
1. Dess−Martin periodinane (2 equiv) NaHCO3 (10 equiv), CH2Cl2, 0 oC, 1 h 2. BF3•OEt2 (1.3 equiv), TMSCHN2 (1.3 equiv) CH2Cl2, −25 oC, 8 h
MeI (4.4 equiv) K2CO3 (2.2 equiv) acetone
3. TBAF (2 equiv)
reflux, 3 h
HO
56%
MeCN, rt, 4 h
H
53%
OMe MeO 89
O
OMe
OH
MeO
HO 15
90
3.7.2
(+)-frondosin A
The Cope Rearrangement and Related Reactions
The [3,3]-sigmatropic rearrangement of 1,5-dienes can be considered as an all-carbon variant of the Claisen rearrangement. This type of rearrangement was discovered in 1940 by Arthur C. Cope (1909–1966), who observed the formation of ethyl 2-cyano-3,4-dimethylhepta-2,6-dienoate upon distillation of ethyl 2-allyl-2-cyano-3-methylpent-3-enoate (Scheme 25).[36] The Original Cope Rearrangement[36]
Scheme 25
CN CO2Et
150−160 oC, 4 h
CN CO2Et
In general, the remarks that were made in Section 3.7.1 with regard to the Claisen rearrangement are also valid for the Cope rearrangement, in that these reactions show a predictable and simple diastereoselectivity that is based on a preference for a chair-like transition-state structure. Furthermore, they also demonstrate effective substrate-induced diastereoselectivity by way of self-immolative 1,3-chirality transfer (Scheme 26). However, in contrast to the Claisen rearrangement, there is no intrinsic thermodynamic driving force for the Cope rearrangement of the parent hexa-1,5-diene. Therefore, synthetically Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
Sigmatropic Rearrangements
3.7
useful Cope rearrangements are driven by strain release, cancellation of formal charges, and the formation of thermodynamically favorable functional groups. They also proceed if the initial rearrangement product triggers a consecutive reaction, which renders the process irreversible. Scheme 26 Classification of Cope Rearrangements[36–40] Y
X
Y
X
Xa
Yb
C
H, alkyl, aryl Cope
[36]
C
OH
oxy-Cope
[37]
C
OM
anionic oxy-Cope
[38]
O NR a b
1
Variant
Ref
H, alkyl, aryl 2-oxonia-Cope
[39]
H, alkyl, aryl 2-azonia-Cope
[40]
1
R = alkyl, aryl. M = metal.
Scheme 27 shows a selection of natural products 91–94 that can be prepared by applying different variants of the Cope rearrangement. Scheme 27
Natural Products Synthesized by Cope Rearrangements OMe
OH
OH Cl
O O O
NMe
H H
O
OMe OMe
91
92
(−)-elisapterosin B (Cope)
(−)-acutumine (anionic oxy-Cope)
HO O
O O O
O P OH OH
OH
O
OH
N
O O
Pri
PMB
MeHN
OH 93
(−)-lasonolide A (oxonia-Cope)
Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
94
(−)-FR901483 (azonia-Cope)
3.7.2
3.7.2.1
371
The Cope Rearrangement and Related Reactions
The Classic Cope Rearrangement
The Cope rearrangement requires relatively high temperatures to overcome the significant activation barrier; however, substituents affect the rate and transition-metal catalysts can be used to reduce the reaction temperature significantly. A sequence involving an enantiomer-differentiating C–H activation and a Cope rearrangement was utilized in the total synthesis of (–)-elisapterosin B (91) (Scheme 28).[41] Whereas the R-enantiomer of the dihydronaphthalene 95 undergoes cyclopropanation in the presence of a chiral dirhodium(II) catalyst 96 to provide the cyclopropane 97 in 43% yield, the opposite enantiomer (S)-95 is transformed into the 1,5-diene 99 by C–H insertion of an intermediate rhodium carbenoid. This 1,5-diene immediately rearranges via the tricyclic chair-like transition-state structure 100 to afford the 1,5-diene 98 in 41% yield and with 92% ee. The thermodynamic driving force is provided by the formation of an Æ,unsaturated ester. More significantly, the rearrangement occurs rapidly at room temperature, indicating a substantial rate-accelerating effect. The relative configuration of the allylic stereogenic carbon atom generated by the C–H insertion process dictates the configuration of the product. The ester 98 can then be hydrogenated and subsequently reduced to afford the alcohol 101, which can then be converted into (–)-elisapterosin B (91). Scheme 28
Cope Rearrangement in the Total Synthesis of (–)-Elisapterosin B[41] N2
TBDMSO
(3 equiv) MeO2C 2 mol% Rh2[(R)-DOSP]4 96 Me3CEt, rt, 1.5 h
MeO
OTBDMS 95 TBDMSO TBDMSO
MeO
MeO H TBDMSO
H MeO
O
+
TBDMSO
H
MeO O
97
43%
Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
98
41%; 92% ee
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372
Stereoselective Synthesis
3.7
Sigmatropic Rearrangements
N2 (3 equiv)
TBDMSO
TBDMSO
MeO2C 2 mol% Rh2[(R)-DOSP]4 96 Me3CEt, rt, 1.5 h
MeO
H
MeO
CO2Me
OTBDMS
OTBDMS (S)-95
99 TBDMSO MeO
OMe OTBDMS TBDMSO
H
TBDMSO OMe MeO O O 98
100
1. 10 mol% Pd/C H2 (2.8 bar) EtOH, rt, 12 h 2. LiAlH4 (2 equiv) THF
TBDMSO MeO
TBDMSO
TBDMSO MeO
0 oC to rt, 1 h
H
TBDMSO
H
MeO HO O 101
98
34%; >95% ee
OH O
O 91
N Rh2[(R)-DOSP] =
O S
O
Rh
O
Rh
H H
(−)-elisapterosin B
O 11 4
96
3.7.2.2
The Anionic Oxy-Cope Rearrangement
C3-Hydroxy-substituted 1,5-dienes provide a mechanistically intriguing rate-accelerating effect that renders the 3-oxy-Cope rearrangement irreversible and thereby synthetically useful, provided that the initially formed enol undergoes enol-to-keto tautomerization.[37] Frequently, the 3-hydroxy group is deprotonated to provide an oxyanion, which leads to an even more pronounced rate acceleration in the anionic oxy-Cope rearrangement.[38] An example of the application of an anionic oxy-Cope rearrangement in the construction of a quaternary carbon stereogenic center in an exceptionally congested steric environment is outlined in Scheme 29.[42] The 3-hydroxy-1,5-diene 104 is generated by a doubly Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.7.2
373
The Cope Rearrangement and Related Reactions
diastereoselective ketone allylation of enedione 102 using Nakamuras chiral allylzinc reagent (S,S)-103. Deprotonation of 104 with potassium tert-butoxide in the presence of 18-crown-6 gives the corresponding oxyanion, which undergoes oxy-Cope rearrangement at a low temperature, presumably via the chair-like transition-state structure 105. The suprafacial nature of the [3,3]-sigmatropic rearrangement ensures the efficiency of the selfimmolative 1,3-chirality transfer. The terminal double bond in the rearranged product 106 is further elaborated by ozonolysis and reductive amination to provide the secondary amine 107, which can be converted into the pyrrolidine moiety of (–)-acutumine (92). Scheme 29
Anionic Oxy-Cope Rearrangement in the Total Synthesis of (–)-Acutumine[42] O
O N
TBDMSO
Zn
N
Ph
OBn Cl
(1.6 equiv) Ph
OBn Cl
(S,S)-103 THF, −78 oC, 1 h
TBDMSO
TBDMSO
79%; dr 93:7
O MeO
TBDMSO
OMe OMe
OMe HO MeO OMe 104
102
TBDMSO t-BuOK (3 equiv) 18-crown-6 (3 equiv) THF, 0 oC, 1 h
OBn Cl
R1 OMe OMe R2
MeO
TBDMSO
O O MeO 105
106
OMe OMe 92%
1. O3 (1.5 equiv) Et3N (3.1 equiv), py EtOAc, −78 oC, 5 min 2. MeNH2 (4.1 equiv) MeOH, 4-Å molecular sieves
OH Cl
OBn Cl
rt, 30 min 3. NaBH3CN (2 equiv), rt, 16 h 54%
OMe
TBDMSO
TBDMSO
O
NMe
MeHN O OMe MeO OMe 107
O
OMe OMe
92
(−)-acutumine
(1R,2S,2¢S,3R,5S,7a¢R)-7a¢-Allyl-2-(benzyloxy)-3,5-bis(tert-butyldimethylsiloxy)-2¢-chloro4¢,5¢,5¢-trimethoxy-3¢,5¢,7¢,7a¢-tetrahydrospiro[cyclopentane-1,1¢-inden]-6¢(2¢H)-one (106); Typical Procedure:[42]
A mixture of 18-crown-6 (34 mg, 0.13 mmol) and t-BuOK (14 mg, 0.13 mmol) in THF (0.7 mL) was stirred at 0 8C for 15 min, and then a soln of dienol 104 (30 mg, 0.042 mmol) in THF (0.15 mL) was added dropwise over 3 min. The resulting mixture was stirred at 0 8C for 1 h. The reaction was quenched by the addition of H2O (1 mL), and the mixture was diluted with Et2O (2 mL). The layers were separated, and the organic layer was dried (MgSO4) and concentrated in vacuo to give a residue, which was purified by flash chromatography (1% Et3N in hexanes/EtOAc 9:1) to give a colorless oil; yield: 27.5 mg (92%). Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.7.2.3
The 2-Oxonia-Cope Rearrangement
3.7
Sigmatropic Rearrangements
The 2-oxonia variant of the Cope rearrangement takes advantage of the equilibrium between two oxocarbenium ions, each representing a reactive intermediate, for a subsequent bond-forming event.[39] The oxonia-Cope rearrangement with a sequential Prins reaction was used in a synthesis of the C18–C25 segment of (–)-lasonolide A (93) (Scheme 30).[43] Treatment of the Æ-acetoxy ether 108 with trimethylsilyl trifluoromethanesulfonate results in the formation of an oxocarbenium ion, which rearranges via the chairlike transition-state structure 109 to provide the oxocarbenium ion 110 (equivalent to structure 111). The subsequent Prins reaction proceeds preferentially through 6-endotrig cyclization to provide the oxocarbenium ion 112, which is reduced to provide the highly substituted tetrahydropyran 113 in 80% yield. This sequence of bond-forming events utilizes the absolute configuration of the single stereogenic center in the acetal 108 to establish four new stereogenic centers with modest diastereoselectivity. Sequential 2-Oxonia-Cope Rearrangement and Prins Reaction[43]
Scheme 30
O O
O
OAc
TMSOTf (3 equiv) Bu3SnH (5 equiv)
O
CH2Cl2, −78 oC, 1 h 80%; dr 83:17
O
O
TBDPSO
3
TBDPSO
108
109
O
O
≡
O O
O
O OTBDPS
TBDPSO 110
111
O
O H
O
O
O
TBDPSO
TBDPSO
112
O
113
HO H
O
O O O O
OH
O TBDPSO
O
O O OH
113
93
Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
(−)-lasonolide A
Pri
3.7.3
3.7.2.4
375
The [2,3]-Wittig Rearrangement
The 2-Azonia-Cope Rearrangement
In an analogous manner to the 2-oxonia-Cope rearrangement, homoallylic iminium ions undergo a 2-azonia-Cope rearrangement that can be utilized to promote subsequent bondforming events. For example, a 2-azonia-Cope rearrangement followed by a Mannich cyclization sequence was employed in the total synthesis of (–)-FR901 483 (94) (Scheme 31).[44] Treatment of the amino ketone 114 with 4-toluenesulfonic acid results in the formation of a bridgehead iminium ion, which rearranges to the exocyclic iminium ion 116 via the bicyclic chair-like transition-state structure 115. The configuration of the newly generated stereogenic center is the result of substrate control. The iminium ion 116 undergoes a moderately diastereoselective Mannich cyclization with the enol ether, also generated by the Cope rearrangement, to provide the aldehyde 117, which is reduced to give the amino alcohol 118. Overall, the 2-azonia-Cope rearrangement–Mannich cyclization cascade produces the tricyclic azaspirane framework of (–)-FR901 483 (94) in a single operation. 2-Azonia-Cope Rearrangement in the Total Synthesis of (–)-FR901 483[44]
Scheme 31 OMe NH
TsOH (1.1 equiv) benzene, reflux, 3 h
O
BnO MeO
(S)-phenylalanine (1.1 equiv) reflux, 2 h
BnO
H
N
PMB PMB
OBn OBn 115
114 BnO
BnO
NaBH4 (6.5 equiv) THF, MeOH
OMe O BnO
−78 oC to rt
BnO
N
71%; dr 67:33
N
H PMB
PMB
116
117 OBn
O O P OH OH
BnO N
≡
BnO
PMB
N
HO
OBn
PMB
OH
118
3.7.3
OH
N
PMB
MeHN 94
(−)-FR901483
The [2,3]-Wittig Rearrangement
Allyloxy-substituted carbanions undergo a concerted [2,3]-sigmatropic shift known as the [2,3]-Wittig rearrangement. In this reaction, the conversion of a carbanion into an oxyanion is the thermodynamic driving force for the bond-reorganization process. This groundbreaking experimental observation was made 1949 by Georg Wittig (1897–1987) who, during a study on the isomerization of metalated fluorenyl ethers, discovered that lithiated 9-(allyloxy)-9H-fluorene rearranged to 9-allyl-9H-fluoren-9-ol (119) (Scheme 32).[45] Interestingly, a stepwise [1,2]-Wittig rearrangement, which occurs via a radical intermediSigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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376
Stereoselective Synthesis
3.7
Sigmatropic Rearrangements
ate, competes with the concerted [2,3]-sigmatropic rearrangement.[46] Fortunately, the reactivity pattern of the initially generated carbanion can be controlled by a judicious choice of the reaction conditions and substrate. Scheme 32
The Original [2,3]-Wittig Rearrangement[45]
O
PhLi (1.1 equiv) Et2O, −10 oC, 5 min
OH
80%
119
Depending on the substrate, up to two stereogenic centers and a geometrically defined double bond can be formed by the rearrangement. The concerted [2,3]-Wittig rearrangement of acyclic substrates proceeds through a five-membered transition-state structure, and the stereochemical outcome of the rearrangement can be predicted and explained by assuming that the transition state adopts an envelope-type geometry. As a result, the general rule of thumb is that the double bond configuration of the substrate correlates with the relative configuration of the rearrangement product (E to anti and Z to syn). The absolute configuration of the rearrangement can be predetermined by substrate induction, which can be effectively achieved by means of self-immolative 1,3-chirality transfer. As with the Claisen and Cope rearrangements, variants of the [2,3]-Wittig rearrangement may be classified according to the structure of the substrate, and a selection of these reactions are summarized in Scheme 33. Synthetically, the [2,3]-Wittig rearrangement provides access to homoallylic alcohols and amines; however, retrosynthetically, the resulting retron may be partially or completely hidden within the target structure. Scheme 33 Classification of [2,3]-Wittig Rearrangements[45–49] X X R1
R1
Xa
R1
Variant
Ref
O
H, alkyl, aryl [2,3]-Wittig
[45]
O
CO2R
enolate [2,3]-Wittig
[46]
O
CO2–
enediolate [2,3]-Wittig
[47]
O
CO2–
dienolate [2,3]-Wittig
[48]
NR2 H, alkyl, aryl [2,3]-aza-Wittig a
[49]
2
R = alkyl, aryl.
The opportunities provided by the various [2,3]-Wittig rearrangements are illustrated by their application in the syntheses of the natural products 120–122 (Scheme 34).
Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.7.3
377
The [2,3]-Wittig Rearrangement
Scheme 34
Natural Products Synthesized by [2,3]-Wittig Rearrangements NaO3S
OH
OH
O O
O O
HO P O HO
O
OH
O
O
HO
OMe OH
Et
OH
HN
H2N
H O
O
H 12
11 7
120
(+)-phoslactomycin B ([2,3]-Wittig)
3.7.3.1
121
(−)-candelalide A ([2,3]-Wittig, Still modification)
122
(−)-C-sulfatide (dianionic [2,3]-Wittig)
The Classic [2,3]-Wittig Rearrangement
As discussed above, the generation of the reactive intermediate for a typical [2,3]-Wittig rearrangement requires the formation of a (formal) carbanion stabilized by an appropriate - and/or -acceptor to provide a useful pKa window for the required Brønsted base and thereby to ensure chemoselectivity. On the other hand, it appears that an increase in the stabilization of the formal negative charge is detrimental to the ability of the carbanion to undergo the desired rearrangement, thereby making this a finely balanced process. A [2,3]-Wittig rearrangement of the allyl propargyl ether 124 using the alkynyl group as a carbanion-stabilizing substituent was used in the total synthesis of (+)-phoslactomycin B (120) (Scheme 35).[50] The propargyl ether 124 is prepared by etherification of the allylic alcohol 123 with a protected propargyl bromide. Following regioselective metalation of 124 with butyllithium at –78 8C, a [2,3]-Wittig rearrangement affords the homoallylic alcohol 126 as a single diastereomer in remarkable yield. If it is assumed, for the sake of simplicity, that a true carbanion is the reactive intermediate, the existence of an envelope-like transition-state structure 125 would imply that the relative configuration of the newly generated stereogenic centers is a consequence of the Z configuration of the reacting allylic ether double bond and that the absolute configuration is induced by a trustworthy self-immolative 1,3-chirality transfer. The homoallylic alcohol 126 can be further converted into the tertiary alcohol 128 by addition of the alkyne to the protected oxotriol 127. The alcohol 128 serves as a synthetic intermediate for the synthesis of (+)-phoslactomycin B (120).
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378
Stereoselective Synthesis Scheme 35
3.7
Sigmatropic Rearrangements
[2,3]-Wittig Rearrangement in the Total Synthesis of (+)-Phoslactomycin B[50] TIPS (1.1 equiv)
O OH
Br t-BuOK (1.5 equiv) THF, 0 oC, 30 min
O
BuLi (1.5 equiv) THF, −78 oC, 1 h
O
87%
Et
Et
TIPS 123
124
91% ee
O
TIPS
OH
Et O
R1O
H
Et
125
126
TIPS quant; dr >98:2
1. TBAF (1.02 equiv) THF, rt, 30 min 2. iPrMgCl (2 equiv) Et2O, −20 oC, 1 h MOMO TrO
2
2
O
(0.3 equiv)
O
OTBDPS
127 −20 oC, 1.5 h
OH MOMO
84% (based on 127); dr 92:8
Et TrO OH TBDPSO 128 O
O O
HO P O HO
OH
OH
Et H 2N
120
H
(+)-phoslactomycin B
Another commonly employed method for generating the required lithiated derivative for a [2,3]-Wittig rearrangement is transmetalation. For instance, the tin-to-lithium exchange is known as the Still modification.[51] The application of the [2,3]-Still–Wittig rearrangement to the total synthesis of (–)-candelalide A (121) provides an excellent example.[52] Treatment of the stannane 129 with butyllithium triggers the rearrangement to give the homoallylic alcohol 131 in 87% yield and with good diastereocontrol (Scheme 36) via transition state 130. The configuration of the newly formed stereocenter is presumably dictated by 1,2-asymmetric induction as a result of the presence of the angular methyl group, which effectively blocks one diastereoface of the double bond. The homoallylic alcohol 131 can be further elaborated by oxidation to the corresponding aldehyde, coupling Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.7.3
379
The [2,3]-Wittig Rearrangement
with the ª-pyrone 132, and subsequent removal of the superfluous hydroxy group to give the key intermediate 133. Still Modification of the [2,3]-Wittig Rearrangement[52]
Scheme 36
Bu3Sn
O BuLi (10 equiv) hexane −50 to 0 oC
TESO
TBDMSO OTES H O H
H
H OTBDMS 129
130 1. DMP (3 equiv), NaHCO3 (10 equiv) CH2Cl2, rt, 1 h
2. O
(4 equiv)
O Br
OMe
132 BuLi (3.7 equiv), THF, −78 to −30 oC, 2 h 3. NaHMDS (1.2 equiv), CS2 (20 equiv) THF, −78 oC, 1 h 4. MeI (10 equiv), −78 oC, 1 h 5. Bu3SnH (2 equiv), AIBN (0.2 equiv) toluene, reflux, 1 h
HO
67%
TESO
H
OTBDMS 131
87%; dr 90:10
O
O
O
OMe
TESO
OMe
O
H
O
H
OTBDMS 133
121
(−)-candelalide A
(3R,4S,5E)-7-(Allyloxy)-4-ethyl-1-(triisopropylsilyl)hept-5-en-1-yn-3-ol (126); Typical Procedure:[50]
A 2.5 M soln of BuLi in hexanes (5.26 mL, 10.6 mmol) was added dropwise to a soln of dienyne 124 (3.06 g, 8.8 mmol) in THF (88 mL) at –78 8C. After 1 h at –78 8C, the mixture was poured into sat. aq NH4Cl. The layers were separated and the aqueous phase was extracted with Et2O. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/Et2O 9:1 to 7:3) to give a colorless oil; yield: 3.09 g (quant).
Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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380
Stereoselective Synthesis
3.7
Sigmatropic Rearrangements
{(1R,4aR,5S,6R,8aS)-5-[3-(tert-Butyldimethylsiloxy)propyl]-5,8a-dimethyl-2-methylene-6(triethylsiloxy)decahydronaphthalen-1-yl}methanol (131); Typical Procedure:[52]
A 1.58 M soln of BuLi in hexanes (0.91 mL, 1.4 mmol) was added to a soln of stannane 129 (0.116 g, 0.14 mmol) in hexane (3 mL) at –50 8C. The mixture was gradually warmed up to 0 8C over 4 h, and then stirred at 0 8C for 1 h. The reaction was quenched with sat. aq NH4Cl (3 mL) at 0 8C, and the resulting mixture was extracted with EtOAc (3 30 mL). The combined organic extracts were washed with brine (2 20 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 20:1) and crystallization from hexane to give white prisms; yield: 0.058 g (78%). 3.7.3.2
The Enolate [2,3]-Wittig Rearrangement
Various -acceptor functionalities can be used to stabilize a (formal) carbanion.[47] Carboxy groups are particularly useful because they generate Brønsted acidity at the Æ-proton, and the resulting enediolates have a high charge density as a result of the presence of the dianion of the carboxylic acids. The use of the enolate [2,3]-Wittig rearrangement is nicely illustrated in the total synthesis of (–)-C-sulfatide (122), the C-analogue of the natural product sulfatide (Scheme 37).[8] Etherification of the Æ-anomer of the galactoside 134 provides the glycolate ether 135, which is treated with an excess of lithium diisopropylamide to generate an enediolate. This undergoes [2,3]-Wittig rearrangement via the transition state 136 to give an Æ-hydroxy acid that can be directly esterified to give the enoate 137. Subsequent hydrogenation provides the building block 138, which was used in the synthesis of (–)-C-sulfatide (122).
Sigmatropic Rearrangements, Zeh, J., Hiersemann, M. Science of Synthesis 4.0 version., Section 3.7 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.7.3
381
The [2,3]-Wittig Rearrangement A Dianionic [2,3]-Wittig Rearrangement[8]
Scheme 37
BnO
1. HOCH2CO2Me (5 equiv) BF3•OEt2 (2 equiv) 4-Å molecular sieves CH2Cl2, 0 oC, 4 h
OBn
2. 1 M NaOH MeOH, rt, 2 h
BnO
Bn
HO
OBn
O LDA (5 equiv) THF, −78 oC, 1 h
O
O
80%
O
BnO
Bn BnO
O
O OH
134
Bn
135
O O Bn
BnO
Li
OBn
O
O O
CH2N2 Et2O 0 oC
O H
OBn
BnO
Li
H2, Pt/C MeOH
O
BnO
rt, 5 h
80%
91%
OBn
OMe
HO O 136
137
NaO3S
OH
OH
O BnO
OBn
O
HO
BnO O
BnO
OH
HN O
OMe
HO O
12
11 7
138
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122
(−)-C-sulfatide
for references see p 382
382
Stereoselective Synthesis
3.7
Sigmatropic Rearrangements
References [1] [2] [3] [4] [5] [6] [7] [8]
[9] [10] [11] [12] [13] [14] [15] [16]
[17] [18] [19]
[20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34]
[35] [36] [37] [38] [39]
[40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52]
Claisen, L., Ber. Dtsch. Chem. Ges., (1912) 45, 3157. Ganem, B., Angew. Chem., (1996) 108, 1014; Angew. Chem. Int. Ed., (1996) 35, 936. Ziegler, F. E., Chem. Rev., (1988) 88, 1423. Lutz, R. P., Chem. Rev., (1984) 84, 205. Burgstahler, A. W., J. Am. Chem. Soc., (1960) 82, 4681. Chen, C.-L.; Namba, K.; Kishi, Y., Org. Lett., (2009) 11, 409. Burgstahler, A. W.; Nordin, I. C., J. Am. Chem. Soc., (1961) 83, 198. Modica, E.; Compostella, F.; Colombo, D.; Franchini, L.; Cavallari, M.; Mori, L.; De Libero, G.; Panza, L.; Ronchetti, F., Org. Lett., (2006) 8, 3255. Hurd, C. D.; Pollack, M. A., J. Am. Chem. Soc., (1938) 60, 1905. Hill, R. K.; Gilman, N. W., Tetrahedron Lett., (1967), 1421. Dalgaard, L.; Lawesson, S.-O., Tetrahedron, (1972) 28, 2051. Kazmaier, U., Angew. Chem., (1994) 106, 1046; Angew. Chem. Int. Ed., (1994) 33, 998. Carroll, M. F., J. Chem. Soc., (1940), 704. Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A., Helv. Chim. Acta, (1964) 47, 2425. Ireland, R. E.; Mueller, R. H., J. Am. Chem. Soc., (1972) 94, 5897. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.-t.; Faulkner, D. J.; Peterson, M. R., J. Am. Chem. Soc., (1970) 92, 741. Arnold, R. T.; Searles, S., Jr., J. Am. Chem. Soc., (1949) 71, 1150. Gosteli, J., Helv. Chim. Acta, (1972) 55, 451. Liu, D.; Acharya, H. P.; Yu, M.; Wang, J.; Yeh, V. S. C.; Kang, S.; Chiruta, C.; Jachak, S. M.; Clive, D. L. J., J. Org. Chem., (2009) 74, 7417. Nakazaki, A.; Era, T.; Kobayashi, S., Chem. Lett., (2008) 37, 770. Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H., Org. Lett., (2008) 10, 5239. Zhou, J.; Magomedov, N. A., J. Org. Chem., (2007) 72, 3808. Liu, Z.; Qu, H.; Gu, X.; Min, B. J.; Nyberg, J.; Hruby, V. J., Org. Lett., (2008) 10, 4105. Quirin, C.; Kazmaier, U., Eur. J. Org. Chem., (2009), 371. Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J., J. Org. Chem., (2004) 69, 4626. Yokoe, H.; Sasaki, H.; Yoshimura, T.; Shindo, M.; Yoshida, M.; Shishido, K., Org. Lett., (2007) 9, 969. Findlay, A. D.; Banwell, M. G., Org. Lett., (2009) 11, 3160. Williams, D. R.; Walsh, M. J.; Miller, N. A., J. Am. Chem. Soc., (2009) 131, 9038. Stivala, C. E.; Zakarian, A., Org. Lett., (2009) 11, 839. Lee, M.; Lee, T.; Kim, E.-Y.; Ko, H.; Kim, D.; Kim, S., Org. Lett., (2006) 8, 745. Calad, S. A.; Woerpel, K. A., Org. Lett., (2007) 9, 1037. Shigeyama, T.; Katakawa, K.; Kogure, N.; Kitajima, M.; Takayama, H., Org. Lett., (2007) 9, 4069. Carling, R. W.; Holmes, A. B., J. Chem. Soc., Chem. Commun., (1986), 325. Mak, S. Y. F.; Curtis, N. R.; Payne, A. N.; Congreve, M. S.; Wildsmith, A. J.; Francis, C. L.; Davies, J. E.; Pascu, S. I.; Burton, J. W.; Holmes, A. B., Chem.–Eur. J., (2008) 14, 2867. Trost, B. M.; Hu, Y.; Horne, D. B., J. Am. Chem. Soc., (2007) 129, 11 781. Cope, A. C.; Hardy, E. M., J. Am. Chem. Soc., (1940) 62, 441. Berson, J. A.; Jones, M., Jr., J. Am. Chem. Soc., (1964) 86, 5019. Evans, D. A.; Golob, A. M., J. Am. Chem. Soc., (1975) 97, 4765. Lolkema, L. D. M.; Semeyn, C.; Ashek, L.; Hiemstra, H.; Speckamp, W. N., Tetrahedron, (1994) 50, 7129. Horowitz, R. M.; Geissman, T. A., J. Am. Chem. Soc., (1950) 72, 1518. Davies, H. M. L.; Dai, X.; Long, M. S., J. Am. Chem. Soc., (2006) 128, 2485. Li, F.; Tartakoff, S. S.; Castle, S. L., J. Am. Chem. Soc., (2009) 131, 6674. Dalgard, J. E.; Rychnovsky, S. D., Org. Lett., (2005) 7, 1589. Brummond, K. M.; Hong, S.-p., J. Org. Chem., (2005) 70, 907. Wittig, G.; Dçser, H.; Lorenz, I., Justus Liebigs Ann. Chem., (1949) 562, 192. Takahashi, O.; Saka, T.; Mikami, K.; Nakai, T., Chem. Lett., (1986) 9, 1599. Nakai, T.; Mikami, K.; Taya, S.; Kimura, Y.; Mimura, T., Tetrahedron Lett., (1981) 22, 69. Hiersemann, M., Tetrahedron, (1999) 55, 2625. Durst, T.; Van den Elzen, R.; LeBelle, M. J., J. Am. Chem. Soc., (1972) 94, 9261. Druais, V.; Hall, M. J.; Corsi, C.; Wendeborn, S. V.; Meyer, C.; Cossy, J., Org. Lett., (2009) 11, 935. Still, W. C.; Mitra, A., J. Am. Chem. Soc., (1978) 100, 1927. Oguchi, T.; Watanabe, K.; Ohkubo, K.; Abe, H.; Katoh, T., Chem.–Eur. J., (2009) 15, 2826.
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383 3.8
Electrocyclic Reactions B. Gaspar and D. Trauner
General Introduction
Electrocyclic processes, namely electrocyclization and electrocyclic ring opening reactions, are an important class of pericyclic reactions that are marked by very high levels of stereocontrol and synthetic versatility.[1,2] These transformations are governed by the Woodward–Hoffmann rules,[3] and usually provide perfect simple diastereoselectivities, which makes them a powerful tool for stereoselective synthesis. Indeed, many elegant applications of electrocyclization reactions, often as part of a reaction cascade, have been reported in the total synthesis of complex natural products and other target molecules. Due to recent advances in asymmetric catalysis, enantioselective versions of these types of reactions have been developed, e.g. the asymmetric Nazarov cyclization. This will undoubtedly increase the importance of electrocyclizations in the stereoselective formation of carbocyclic and heterocyclic ring systems. This account outlines several stereoselective electrocyclic reactions according to the number of -electrons involved, i.e. from 4 systems up to 8 systems. This includes systems with heterosubstitution, namely oxa- and aza-6 electrocyclizations. Electrocyclic reactions of larger systems, while known, have relatively few synthetic applications and have been omitted. Reaction cascades are presented according to the highest number of -electrons involved, e.g. 8/6 electrocyclization cascades. The stereochemical course of electrocyclizations in the ground state (thermal) and excited state (photochemical) is summarized in Table 1. Table 1
3.8.1
Stereochemical Course of Electrocyclization Reactions
Number of -Electrons
Thermal
Photochemical
4
conrotatory
disrotatory
6
disrotatory
conrotatory
8
conrotatory
disrotatory
Synthesis of Dienes through Electrocyclic Ring Opening of Cyclobutenes
The thermal electrocyclic ring opening of substituted derivatives of cyclobutene (strain energy 28.5 kcal • mol–1) was initially observed to lead to formation of mixtures of two isomeric dienes, which significantly reduced the synthetic potential of this strategy. However, the stereochemical outcome of the process is determined by the electronic properties of the allylic substituents.[4] In general, -donor substituents tend to undergo outward conrotation, whereas -acceptor substituents favor inward conrotation. For example, the aldehyde 2, generated by the Swern oxidation of alcohol 1, is crucial for the selective formation of Z,E-dienal 3 (Scheme 1).[5,6] Importantly, the isomeric E,E-dienal 4 is accessible from 3 in excellent yield by acid-catalyzed isomerization to the thermodynamically more stable product.
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Stereoselective Synthesis
3.8
Electrocyclic Reactions
Scheme 1 Selective Formation of a Z,E-Dienal by Cyclobutene Ring Opening and an E,E-Dienal by Isomerization[5,6] O Cl , DMSO
Cl
O
O Et3N, CH2Cl2, −78 oC
OH
H
warm to rt 30 min
OPMB
OPMB 1
2 warm to rt 2 M HCl, 1 h
CHO
87%
OPMB 3
OHC
OPMB 4
86%
Stereochemically defined dienes can also be obtained from amino-substituted cyclobutenes (Scheme 2).[7] Consistent with theoretical studies, which predict that amines favor outward rotation,[8] the Z,E-diene 7 is isolated in 88% yield from the electrocyclic ring opening of the cyclobutene 6, which is prepared by the hydrolysis of lactam 5. Scheme 2 O
Synthesis of a Z,E-Dienoic Acid by Cyclobutene Ring Opening[7] LiOH, H2O, THF rt, 16 h
CO2H
CO2H
NBoc NHBoc 5
6
NHBoc 7
88%
Among cyclobutenes, cyclobutarenes are particularly attractive intermediates due to their unique reactivity.[9] Upon thermolysis, cyclobutarenes undergo conrotatory electrocyclic ring opening to form highly reactive o-quinodimethanes, which are generally too reactive to be isolated, but serve as valuable reactive intermediates for further reactions.[10] As exemplified by the total synthesis of estrone by Kametani, o-quinodimethane 9, generated by thermolysis of cyclobutarene 8, undergoes an intramolecular Diels–Alder reaction to afford O-methyl-D-homoestrone (10) in a regio- and stereoselective manner (Scheme 3).[11]
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3.8.2
385
Synthesis of Cyclobutenes through Electrocyclization of Dienes
Scheme 3
Generation of a Reactive o-Quinodimethane from a Cyclobutarene[11] O
O 1,2-dichlorobenzene reflux, 4 h
H
H
MeO
MeO 8
9 O py•HCl 200 oC, 40 min
H H
O
H
H
80%
MeO
H
H
HO 10
95%
D-homoestrone
O H H
H
HO estrone
(2Z,4E)-5-(tert-Butoxycarbonylamino)penta-2,4-dienoic Acid (7):[7]
Solid LiOH (0.37 g, 15.40 mmol) was added to a soln of compound 5 (1.0 g, 5.12 mmol) in THF (20 mL) and H2O (15 mL). The mixture was stirred at rt for 16 h, and the solvent was removed under reduced pressure. The aqueous layer was acidified with AcOH to pH 4 and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by recrystallization (MeOH) to give compound 7 as colorless crystals; yield: 0.96 g (88%); mp 175–179 8C. O-Methyl-D-homoestrone (10):[11]
A soln of 8 (30 mg) in 1,2-dichlorobenzene (4 mL) was stirred under an atmosphere of N2 for 4 h at 180 8C. After evaporation of the solvent, the residue was recrystallized (EtOAc) to give O-methyl-D-homoestrone (10) as colorless prisms; yield: 28.6 mg (95.3%); mp 160– 162 8C. 3.8.2
Synthesis of Cyclobutenes through Electrocyclization of Dienes
Electrocyclic ring opening reactions are reversible, which means that the synthesis of cyclobutenes is feasible via electrocyclic ring closure of dienes. However, the thermodynamic equilibrium for most cyclobutenes favors the open-chain diene derivative. Nevertheless, this equilibrium can be shifted toward the cyclic product by appropriate substitution. For example, some vinylallenes have been reported to undergo unidirectional electrocyclization to alkylidenecyclobutenes.[12] In this context, the combination of vinylallenes with a silyl or boryl substituent has proved particularly fruitful (Scheme 4). For example, the ring closure of vinylsilane 11 proceeds smoothly at about 145 8C to afford the trimethylsilyl-substituted cyclobutene 12 in 95% yield.[13] Similarly, the boryl-substituted vinylallene 13 undergoes cyclization to furnish 14, which provides an unusual intermediate thanks to the doubly allylic boron group.[14]
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386
Stereoselective Synthesis
3.8
Electrocyclic Reactions
Scheme 4 Synthesis of Cyclobutenes by Electrocyclic Ring Closure[13,14] Ph
Ph toluene, 145 oC, 3 h
•
95%
TMS
TMS 11
12
Ph
Ph
•
xylene, 140 oC, 3 h
O B O
B O
96%
O
13
3.8.3
14
Synthesis of Five-Membered Rings through Electrocyclization of Pentadienyl Cations: The Nazarov Cyclization
The formation of cyclopentenones via the 4 electrocyclic ring closure of pentadienyl cations, which are generated by either Lewis or Brønsted acid activation of divinyl ketones, is known as the Nazarov cyclization.[15,16] The reaction is generally accepted to proceed via pentadienyl cation 15, which cyclizes in a conrotatory fashion to oxyallyl cation 16 (Scheme 5). Elimination followed by protonation of the enolate and keto–enol tautomerization affords the cyclopentenone 17. Thanks to the well-defined mechanism, the challenges of regio- and stereoselection have in many cases been successfully addressed, rendering the reaction synthetically very useful. Scheme 5
Mechanism of the Nazarov Cyclization A
O R1
R3
R2
R4
Lewis or Brønsted acid
A
O
R1
R3
R2
R4
4π-conrotatory electrocyclization
R3 R2
O
OH
R1
R3
H+
O
R1
R3
R1
R3
− A+
− H+
R2
R4
R2
R4
R2
R4 17
A+ = Lewis acid, H+
3.8.3.1
R4 16
15 A
O
R1
Stoichiometric Nazarov Cyclizations
The introduction of a silicon directing group can control the regioselective formation of the less substituted double bond in the cyclopentenone products.[17] For example, the vinylogous acylsilanes 18 undergo an iron(III) chloride mediated cyclization to afford the cyclopentenones 19 in moderate to excellent yield, favoring the cis-fusion in the bicyclic Electrocyclic Reactions, Gaspar, B., Trauner, D. Science of Synthesis 4.0 version., Section 3.8 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.8.3
Synthesis of Five-Membered Rings through Electrocyclization
387
system (Scheme 6).[18] Various saturated and unsaturated chains, in addition to heteroatoms, are well tolerated in the reaction. Scheme 6
Silicon-Directed Nazarov Cyclization[18] O
O R1
R3
R2
TMS
R1
FeCl3 (1.05 equiv), CH2Cl2
R3
R2
18
19
R1,R2
R3
Temp (8C) Time (h) Yield (%) Ref
(CH2)4
CH2CH=CH2
–25
1
76
(CH2)4
H
0
4
84 a
[18] [18]
(CH2)3
H
20
2.5
55
[18]
(CH2)2CMe2CH2
H
0
4
78
[18]
CH=CHCMe2CH2
H
–15
1
70
[18]
(CH2)3CH(OBn)
H
0
2
76
[18]
(CH2)3O
H
20
8
60
[18]
(CH2)3N(CO2Me) (CH2)5 a b c
H H
60 0
36 1
b
[18]
c
[18]
76 74
1,2-Dichloroethane was used as the solvent. Lewis acid was ZrCl4, in 1,2-dichloroethane. Product obtained as a diastereomeric mixture; (cis/trans) 85:15.
Additional advances in this reaction have focused on the introduction of chiral auxiliaries to provide enantiomerically enriched cyclopentenones.[19,20] For example, treatment the enamides 21 with the allenyllithium 20 provides the intermediary bis-allylic carbinol, which undergoes an acid-catalyzed Nazarov cyclization with concomitant loss of the camphor-based chiral auxiliary to afford the cyclopentenones 22 with good enantiomeric excess (Scheme 7). Interestingly, the product 22 from the methyl-substituted allene 20 (R1 = Me) readily isomerizes to the thermodynamically more stable E-isomer, whereas the tertbutyl-substituted derivative 21 (R1 = t-Bu) provides the kinetic product with Z-geometry.
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388
Stereoselective Synthesis Scheme 7
3.8
Electrocyclic Reactions
Camphor-Based Traceless Chiral Auxiliary in a Nazarov Cyclization[19,20]
1. −78 to −30 oC, 1 h 2. HCl, HFIP/TFE (1:1) −78 oC
O O
H R
1
O
•
+
R2
N O
R3 Li 20
21 O
O HO
R1
HO R1 R2
R3 22A
+ R2
R3 22B
HFIP = (F3C)2CHOH; TFE = F3CCH2OH
R1
R2
R3
ee (%) Config Yield (%) Ref
H
(CH2)2CH=CH2
iPr
86
–
78
[19]
H
Me
t-Bu 87
–
84
[19]
H
Br
Me
85
–
74
[19]
H
Me
Ph
77
–
71
[19]
Me
Me
Me
85
E
62
[19]
Me
Br
Me
81
E
56
[19]
t-Bu Ph
Ph
96
Z
74
[19]
t-Bu Me
Ph
96
Z
80
[19]
t-Bu Me
Me
92
Z
61
[19]
(R)-3-But-3-enyl-2-hydroxy-4-isopropyl-5-methylenecyclopent-2-enone [22, R1 = H; R2 = (CH2)2CH=CH2; R3 = iPr]; Typical Procedure:[20]
To a soln of allene 20 (R1 = H; 1.240 g, 5.953 mmol) in THF (30 mL) at –78 8C was added 2.46 M BuLi in hexanes (2.50 mL, 6.15 mmol). After 20 min, a soln of amide 21 [R2 = (CH2)2CH=CH2; R3 = iPr; 871 mg, 3.67 mmol] in THF (30 mL) at –78 8C was added via a cannula. The mixture was warmed from –78 to –30 8C over 1 h, cooled to –78 8C, and quenched by rapid addition, through a large-bore cannula, to HCl in HFIP/TFE (generated by addition of 7.5 mL of AcCl to a soln of 30 mL of HFIP and 30 mL of TFE) at –78 8C. The flask was removed from the cooling bath, and the mixture was warmed to rt, and diluted with sat. NaHCO3, pH 7 buffer, brine, and EtOAc. The aqueous phase was extracted with EtOAc (3 ), and the combined organic extracts were washed with brine (1 ) and dried (MgSO4). Purification by flash column chromatography (silica gel, EtOAc/hexanes 1:19 to 1:9) gave cyclopentenone 22 [R1 = H; R2 = (CH2)2CH=CH2; R3 = iPr] as a colorless oil; yield: 589 mg (78%); 86% ee. 3.8.3.2
Catalytic Nazarov Cyclizations
A critical feature of the catalytic Nazarov cyclization is the necessity to employ highly polarized substrates such as 23, which has both an electron-donating and an electron-withdrawing group at the Æ-positions of the ketone. In this case, cyclization occurs with catalytic copper(II) trifluoromethanesulfonate under ambient conditions to afford the cyclopentenones 24 as single regio- and diastereoisomers, favoring the trans-diastereomer (Scheme 8).[21] Reducing the polarization in the substrate, by either replacing the oxygen Electrocyclic Reactions, Gaspar, B., Trauner, D. Science of Synthesis 4.0 version., Section 3.8 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.8.3
Synthesis of Five-Membered Rings through Electrocyclization
389
atom or the ester group with less polar substituents, leads to decreased reaction rates and lower yields. Scheme 8
Catalytic Nazarov Cyclization[21]
O
O
2 mol% Cu(OTf)2
R1
X
1,2-dichloroethane, 25 oC
R1
X
R2
R2
23
24
X
R1
R2
Time
Yield (%) Ref
O
CO2Me 2,4,6-(MeO)3C6H2
5 min
>99
[21]
O
CO2Me 4-MeOC6H4
3.5 h
99
[21]
O
CO2Me 3-MeOC6H4
48 h
96
[21]
O
CO2Me Ph
108 h
99
[21]
O
CO2Me 2-furyl
12 h
99
[21]
O
CO2Me Cy
2h
99a
[21]
O
H
2,4,6-(MeO)3C6H2
20 min
86
[21]
O
H
Cy
30 min
60
[21] b
CH2 H
2,4,6-(MeO)3C6H2
5h
30–40
[21]
CH2 H
Cy
4h
37–42c
[21]
a b c
At 55 8C. At 40 8C. At 65 8C.
Enantioselective Nazarov cyclizations have been examined with chiral Lewis acid catalysts. The chiral scandium complex 26 provides optimal results with alkoxydienone substrates.[22] For example, treatment of alkoxydienones 25 with 10 mol% of 26 in acetonitrile provides the alkoxycyclopentenones 27 in high yield and with excellent enantiomeric excess (Scheme 9). Protonation of the scandium enolate is the enantiodiscriminating step, which is significantly enhanced by the presence of the chelating ring-oxygen in the dihydropyran.
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Stereoselective Synthesis
3.8
Electrocyclic Reactions
Catalytic Enantioselective Nazarov Cyclization[22]
Scheme 9
O
O
Sc (OTf)3
N
O
26 MeCN, 3-Å molecular sieves, rt
R1
O
O
N N
10 mol%
X
X 25
R1
X
27
ee (%) Yield (%) Ref
CH2 Me
85
65
[22]
CH2 Et
92
75
[22]
CH2 Pr
93
70
[22]
CH2 Bu
94
70
[22]
a
95
88
[22]
CH2 t-Bu 97
94
[22]
CH2 Cy
76
CH2 iPr
76
[22]
a
O
iPr
72
65
[22]
O
t-Bu 91
80
[22]
a
R1
O
Reaction conducted at 0 8C.
Alternatively, in an organocatalytic version, the phosphoramide 29 catalyzes the cyclization of alkoxydienones 28 to provide cyclopentenone products with excellent enantioselectivities, albeit with modest diastereocontrol for acyclic substrates (Scheme 10).[23] The reaction is applicable to a variety of alkyl-, aryl-, and dialkyl-substituted dienones, in which the cis-product can be isomerized to the corresponding trans-isomer without loss of enantiomeric purity. Scheme 10
Phosphoramide-Catalyzed Enantioselective Nazarov Cyclization[23]
O 2 mol% O
O
NHTf
O
29
R1
O
O P
CHCl3, 0 oC
O
R2
+
R1
O
R2
28
Electrocyclic Reactions, Gaspar, B., Trauner, D. Science of Synthesis 4.0 version., Section 3.8 sos.thieme.com © 2014 Georg Thieme Verlag KG
O R1
cis
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R2 trans
3.8.3
391
Synthesis of Five-Membered Rings through Electrocyclization
R1
R2
Time (h) Ratio (cis/trans)
ee (%)
Yield (%) Ref
cis trans Me
Ph
2
6:1
87 95
88
[23]
(CH2)4Me
Ph
1
3.2:1
91 91
78
[23]
Me
2-naphthyl
2
9.3:1
88 98
92
[23]
Et
Ph
2
4.3:1
92 96
61
[23]
Pr
Ph
1
3.2:1
93 91
85
[23]
Pr
4-Tol
1
2.6:1
91 90
77
[23]
Pr
4-BrC6H4
1.5
4.6:1
92 92
87
[23]
Pr
3-BrC6H4
2
3.7:1
90 91
72
[23]
4.5
100:0
86 –
68
[23]
(CH2)4
3.8.3.3
Interrupted Nazarov Cyclizations
The interrupted Nazarov cyclization provides an opportunity for the cationic intermediate 16 to be intercepted with various nucleophiles rather than undergo elimination (see Scheme 5, Section 3.8.3).[24] For example, the cation formed from trienone 30 is trapped intramolecularly by an arylalkene side chain, resulting in a polycyclization cascade that affords the tetracycle 31 in quantitative yield as a single diastereomer (Scheme 11).[25] Scheme 11
Nazarov Reaction Induced Polycyclization Cascade[25] O
O
TiCl4, CH2Cl2, −78 oC
H
99%
H 30
31
Intermolecular trapping of the cationic intermediate is also possible with electron-rich aromatic and heteroaromatic compounds, provided bis(cycloalkenyl) ketones are utilized as the substrates (Scheme 12).[26] Treatment of dicyclopent-1-enyl ketones 32 (n = 1) with boron trifluoride–diethyl ether complex and various arenes affords the arylated triquinanes 33A in good yield and with excellent diastereoselectivity. Alternatively, the cyclohexenyl derivative 32 (n = 2) affords two isomeric products 33A and 33B with poor stereocontrol at the methine stereogenic center Æ to the ketone, albeit slightly favoring 33A (up to 4:1). Interestingly, simple acyclic dienones do not participate in this reaction.
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Stereoselective Synthesis Scheme 12
3.8
Electrocyclic Reactions
Nazarov Cyclization Interrupted with Electron-Rich Arenes[26]
O
O
BF3•OEt2 (1.1 equiv) Ar1H (10 equiv) CH2Cl2, rt
nH
32
H
33A
n
Ar1
Ratio (33A/33B) Yield (%) Ref
1
2-furyl
100:0
79
[26]
1
2-thienyl
100:0
79
[26]
100:0
78
[26]
100:0
79
[26]
N Ts
Ar1
H +
n
1
O
Ar1
H
1
2,4-(MeO)2C6H3
2
2-furyl
2:1
76
[26]
2
2-thienyl
4:1
80
[26]
2
2,4-(MeO)2C6H3
2:1
80
[26]
nH
H
33B
(8S,9R,13R,14S,16S)-9,14,16-Trimethyl-7,8,9,11,12,13,16,17-octahydro-6H-cyclopenta[a]phenanthren-15(14H)-one (31):[25]
A soln of (4E,8E)-11-phenyl-2,4,8-trimethyl-1,4,8-undecatrien-3-one (30; 97 mg, 0.34 mmol) in CH2Cl2 (47 mL) was cooled to –78 8C and treated with 1.0 M TiCl4 in CH2Cl2 (0.37 mL, 0.37 mmol). After 5 min, the reaction was quenched with brine (30 mL), the mixture was extracted with CH2Cl2 (2 30 mL), and the combined organic layers were dried (MgSO4) and filtered through a plug of silica gel (EtOAc). The solvent was removed to give 31 as a white solid; yield: 97 mg (99%); mp 95–97 8C. 3.8.4
Electrocyclizations of Hexatrienes and Octatetraenes
3.8.4.1
Electrocyclizations of 6ð Systems
The formation of cyclohexa-1,3-dienes through disrotatory electrocyclization of hexa1,3,5-trienes is a fundamentally important process, which has been proposed in the biosynthesis of several natural products and subsequently supported by biomimetic syntheses.[27] In general, relatively high reaction temperatures (150–200 8C) are necessary for this reaction to occur thermally; however, modifying the substitution in the substrate can reduce the activation barrier.[28] Alternatively, the photochemical conrotatory 6 electrocyclization used in the biosynthesis of vitamin D has been used for its total synthesis.[29] Scheme 13 highlights an example of a method that takes advantage of substituents to control the activation barrier. In this case, the 6 electrocyclization step is part of a sequence developed for the synthesis of indoles and is most likely facilitated by a push/ pull-type mechanism.[30] For example, the amidotriene 34 cyclizes smoothly under mild conditions to afford the cyclohexadiene 35, which aromatizes under oxidative conditions to provide the tetralone 36 in high overall yield. Tetralone 36 is readily converted into a variety of indoles with complex substitution patterns.
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393
Electrocyclizations of Hexatrienes and Octatetraenes Synthesis of Indoles via 6 Electrocyclization[30]
Scheme 13
toluene reflux, 1 h
O
DDQ 50 oC, 6 h
O
NHBoc
O
NHBoc
34
NHBoc
35
36
91%
N Ac
The addition of the alkenyllithiums 37 to cyclobutenones 38 at –78 8C provides anionic intermediates 39, which upon warming to room temperature undergo a sequential 4 conrotatory ring opening followed by a 6 disrotatory electrocyclization to produce the cyclohexenones 40 in good yield (Scheme 14).[31] The presence of an electron-withdrawing group, such as a sulfonyl group or an amide, is essential for the success of the electrocyclization reaction. Additionally, the reaction tolerates a variety of aromatic, heteroaromatic, and tert-alkyl substituents within the alkenyllithium. Scheme 14 Synthesis of Functionalized Cyclohexenones through Electrocyclization of Hexatrienes[31] R1
R2
Li
SO2Ar1
R3
R4
THF −78 oC to rt
R3
R1
+ R4
O
37
38
O−
R2 SO2Ar1
39 R1
R4
R2
R2
R4
4π
6π
R3 O−
SO2
Ar1
R1 R3
SO2Ar1 O 40
R1
R2
R3
R4
Ar1
Ph
H
H
Ph 4-Tol 81
[31]
2-thienyl
H
H
Ph Ph
86
[31]
t-Bu
H
H
Ph Ph
57
[31]
Ph
H
Et
Et
Yield (%) Ref
4-Tol 73 a
[31]
Ph
Ph Et
Et
Ph
63
[31]
cyclopropyl
H
H
Ph Ph
80
[31]
H
Bu H
Ph Ph
72
[31]
a
Heated at 65 8C.
Lewis acid catalysis reduces the reaction temperature and increases the rate of reaction for the 6 electrocyclization of specific hexatrienes, which either have an ester or a keElectrocyclic Reactions, Gaspar, B., Trauner, D. Science of Synthesis 4.0 version., Section 3.8 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
3.8
Electrocyclic Reactions
tone group.[32,33] For instance, the 1,3,5-triene 41 undergoes a 6 electrocyclization in the presence of dimethylaluminum chloride to provide the dienone 42 with significantly increased rate compared to the thermal reaction (Scheme 15). Moreover, the formation of the same diastereomer 42 implies that the catalytic reaction proceeds through the same disrotatory pathway as the thermal reaction. Scheme 15
Catalytic 6 Electrocyclization[32]
Ph
Ph H
O
O 41
42
Conditions
Yield (%) Ref
benzene-d6, 52 8C, rt
70
[32]
Me2AlCl, benzene-d6, rt, 1.75 h 97
[32]
The ability to catalyze electrocyclization reactions provides an opportunity to develop enantioselective variations. This challenging undertaking is best accomplished utilizing organocatalysis in conjunction with the principle of tight ion pairing.[34] As indicated in Scheme 16, the aldimines 43 are converted under phase-transfer conditions into the 2,3dihydroindoles 45 in high yield and with excellent enantioselectivity.[35] The reaction employs a cinchona alkaloid derived ammonium salt catalyst 44, and tolerates several functional groups both on the aniline and the aldehyde component of the resulting imine 43. Additionally, the condensation step followed by the cyclization can be performed in a one-pot procedure, which circumvents the isolation of the imine. Scheme 16
Organocatalytic Enantioselective Electrocyclization of Benzaldimines[35] H Cl− H
N+
10 mol%
OH
CO2 R3
Pri
CO2
R2
N
Ph
N 44 aq K2CO3, toluene, −15 oC
Pri
R4
R3 R4
R4
45
ee (%) Yield (%) Ref
H CF3 H Ph
94
87
[35]
H CF3 H 4-O2NC6H4
98
75
[35]
H CF3 H 4-BrC6H4
93
80
[35]
H CF3 H 2-naphthyl
92
92
[35]
H CF3 H 2-ClC6H4
91
78
[35]
H 4-O2NC6H4
89
Electrocyclic Reactions, Gaspar, B., Trauner, D. Science of Synthesis 4.0 version., Section 3.8 sos.thieme.com © 2014 Georg Thieme Verlag KG
a
89
[35]
(Customer-ID: 5907)
CO2Pri N H
R1 43
H H
PriO2C
R2
R1
R1 R2
R3
3.8.4
R1 R2
R3 R4
ee (%) Yield (%) Ref
H H
H Cy
90
94b
[35]
F
H
H 4-BrC6H4
91
65
[35]
H F
H 4-BrC6H4
91
67
[35]
H F
H Ph
91
60
[35]
H H
F
89
72
[35]
a b
395
Electrocyclizations of Hexatrienes and Octatetraenes
4-BrC6H4
Solvent: toluene/CHCl3 (5:1). CsOH•H2O, toluene, –55 8C.
Another example of an organocatalytic asymmetric electrocyclization utilizes Æ,-unsaturated arylhydrazones, which are isoelectronic with the pentadienyl anion.[36] Treatment of the arylhydrazones 46 with the chiral phosphoric acid 47 at 30 8C affords the 4,5-dihydropyrazoles 48 in high yield and with excellent enantiomeric excess (Scheme 17). The isolation of the hydrazone can be avoided by simply condensing the phenylhydrazine with the requisite enone in the presence of molecular sieves followed by addition of catalyst 47 to provide a convenient one-pot process. Although this reaction tolerates a variety of substitution patterns, hydrazones generated from aliphatic enones provide products with considerably lower yields and enantioselectivities. Organocatalytic Enantioselective Electrocyclization of Arylhydrazones[36]
Scheme 17
O
10 mol%
O
O P
OH
R3 R3
N R
47
NH
chlorobenzene, 30 oC, 75−96 h
R1 N N
1
R2 R2 46
48
R1
R2
R3
ee (%) Yield (%) Ref
H
H
H
76
92
[36]
F
H
H
88
94
[36]
Cl
H
H
90
96
[36]
Br
H
H
90
95 a
[36]
NO2
H
H
92
93
[36]
CF3
H
H
92
88b
[36]
H
Cl
H
92
96
H
Br
H
92
c
95
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[36] [36]
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Stereoselective Synthesis R1
R2
H
NO2 H
H
Br
OMe Br a b c d e
R3
3.8
Electrocyclic Reactions
ee (%) Yield (%) Ref 99a,d
96
[36]
e
OMe 84
91
[36]
H
93
[36]
90
Conducted at 40 8C. 9 d. 109 h. 60 h. 36 h.
In related studies, the asymmetric azaelectrocyclization provides a stereoselective method for the construction of chiral tetrahydropyridines.[37] This method was employed as the key step in the synthesis of indole alkaloid (–)-corynantheidol, as illustrated in Scheme 18.[38] The amino alcohol 49 serves as chiral auxiliary in this one-pot protocol. Condensation of 49 with iodoaldehyde 50 to form the aminal, followed by Stille coupling with stannane 51 provides the azatriene 52, which undergoes asymmetric azaelectrocyclization to afford the N,O-acetal 53 in 77% yield as a single diastereomer. Scheme 18
Asymmetric Azaelectrocyclization in the Synthesis of (–)-Corynantheidol[37,38]
OHC Pri
dioxane 5-Å molecular sieves 80 oC
Et
Pri
+
HN
H2N
O
CO2But
I
I
OH
Et 49
50
ButO2C
SnBu3 N SO2Ph 51 Pd2(dba)3, LiCl tri-2-furylphosphine
OH
reflux, 11 h
Pri
N Et N SO2Ph
CO2But
52
N
O
Pri
Et
N Et N SO2Ph 53
N H
H H
OH
CO2But
77%
(−)-corynantheidol
In the course of synthetic studies toward saudin, Stoltz and coworkers developed a diastereoselective Stille coupling/oxaelectrocyclization cascade that provides rapid access Electrocyclic Reactions, Gaspar, B., Trauner, D. Science of Synthesis 4.0 version., Section 3.8 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.8.4
397
Electrocyclizations of Hexatrienes and Octatetraenes
to a variety of polycyclic pyrans.[39] For example, more than 2 grams of fused pyran 54 was prepared in excellent yield as a single diastereomer, as illustrated in Scheme 19. Scheme 19
Diastereoselective Stille Coupling/Oxaelectrocyclization Cascade[39] O
TBDPSO I
5 mol% Pd(PPh3)4, CuI DMF, −78 oC to rt
+
92%
O
O O
O
TBDPSO
Bu3Sn
O O
O
O
O
54
3,5-Diphenyl-6-(4-tolylsulfonyl)cyclohex-2-enone (40, R1 = R4 = Ph; R2 = R3 = H; Ar1 = 4-Tol); Typical Procedure:[31]
To a soln of 2-(phenylvinyl) 4-tolyl sulfone (200 mg, 0.77 mmol) in anhyd THF (5.7 mL), cooled to –50 8C, was added a 1.87 M soln of BuLi in cyclohexane (0.5 mL, 0.93 mmol) dropwise over 3 min. After 15 min at –50 8C, cyclobutenone 38 (R3 = H, R4 = Ph; 134 mg, 0.93 mmol) in anhyd THF (2 mL) was added dropwise. The mixture was stirred at this temperature for 15 min and then warmed to rt over 1 h, after which time TLC (silica gel, hexanes/EtOAc 3:1) indicated complete consumption of starting sulfone. The mixture was quenched with sat. aq NH4Cl (5 mL). The aqueous phase was extracted with CH2Cl2 (3 5 mL) and the combined organic solns were dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (hexanes/EtOAc 4:1) provided the title product as a colorless solid; yield: 252 mg (81%). tert-Butyl (4bS,6S,9S,9aR,10aR)-9-Ethyl-4-isopropyl-6-[1-(phenylsulfonyl)-1H-indol-2-yl]1,2,3,4,4a,4b,6,9,9a,10a,11,11a-dodecahydroindeno[1¢,2¢:4,5]oxazolo[3,2-a]pyridine-8carboxylate (53):[37]
To a suspension of the vinyl iodide 50 (50 mg, 0.162 mmol) and 5- molecular sieves (162 mg) in dioxane (1 mL) was added cis-1-amino-7-isopropylindan-2-ol (49; 31 mg, 0.162 mmol) at rt, and the mixture was stirred at 80 8C for 30 min. To this soln was then added LiCl (14 mg, 0.324 mmol), tri-2-furylphosphine (3 mg, 13 mol), and Pd2(dba)3 (3 mg, 3 mol) at 80 8C, and the mixture was stirred for 10 min at this temperature. Then, vinylstannane 51 (185 mg, 0.324 mmol) in dioxane (1 mL) was added to this suspension. After the mixture had been stirred under reflux for 10 h, it was cooled to rt, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/hexane 3:97 to 9:91) to give the aminoacetal product 53 as a yellow, amorphous solid; yield: 79 mg (77%). (7aR,10aR)-4-[2-(tert-Butyldiphenylsiloxy)ethyl]-2-(3-furyl)-7a-methyl-7,7a-dihydrofuro[3,4-i][1]benzopyran-5,8(6H,10H)-dione (54):[39]
To a mixture of Pd(PPh3)4 (0.195 mmol), the vinylstannane (1.78 g, 3.90 mmol), and the vinyl iodide (2.07 g, 3.90 mmol) was added DMF (100 mL). Freshly recrystallized CuI (3.90 mmol) was added, and the flask was cooled to –78 8C under vacuum. The mixture was protected from ambient light. After 30 min of degassing, the mixture was allowed to warm to 23 8C under N2. After being stirred for 12 h, the mixture was diluted with H2O (200 mL) and extracted with Et2O (2 200 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (hexanes/EtOAc 3:1) provided polycycle 54 as an orange solid; yield: 2.05 g (92%); Rf 0.26 (hexanes/EtOAc 3:1); mp 85–86 8C.
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Stereoselective Synthesis
3.8.4.2
Electrocyclizations of 8ð Systems
3.8
Electrocyclic Reactions
Octatetraenes usually undergo 8 electrocyclizations at room temperature, since they have a lower activation barrier than the corresponding 6 electrocyclizations. The resulting octatrienes are, however, in most cases not isolated as they undergo a subsequent 6 electrocyclization to provide bicyclo[4.2.0]octadiene systems. The two internal double bonds of any tetraene system must have a Z,Z geometry to facilitate the 8 electrocyclization. Nicolaou and coworkers demonstrated that the Lindlar hydrogenation of a diene– diyne system directly provides this motif in a selective manner.[40] For example, the partial reduction of the diyne component in 55 followed by heating at 100 8C in toluene, provides endiandric acid A methyl ester (57) in 30% overall yield (Scheme 20). The strength of the method is readily apparent from the complexity of the tetracycle 57, which is prepared from a simple polyene in a single operation. Interestingly, when the reaction mixture was analyzed prior to heating, endiandric acid D methyl ester (56A) and endiandric acid E methyl ester (56B) were detected, and subsequently proven to be reaction intermediates. Scheme 20
Synthesis of Endiandric Acid A Methyl Ester[40]
1. H2, Pd/BaSO4
CO2Me
quinoline 2. toluene, 100 oC 30 %
CO2Me Ph
Ph
55
H
H
8π/6π
H
H
+ MeO2C Ph
MeO2C Ph
56A
endiandric acid D methyl ester
56B
Ph
[4+2]
endiandric acid E methyl ester
H H
H
H H
CO2Me H
57
endiandric acid A methyl ester
This strategy has been further extended to tetraenes with embedded stereodefined trisubstituted double bonds, which are conveniently prepared via a palladium-catalyzed cross coupling of two diene units with the requisite geometry. For example, Stille coupling of stannane 58 with vinyl iodide 59 produces a transient E,Z,Z,E-tetraene, which undergoes the desired 8/6 electrocyclization cascade to furnish 60 and its diastereomer ocellapyrone A (61) (ratio 9:1) in good yield (Scheme 21).[41] Treatment of the homodiene 60 with singlet oxygen then affords ocellapyrone B (62) in 89% yield.
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399
Electrocyclizations of Hexatrienes and Octatetraenes
Scheme 21
Synthesis of Ocellapyrone A and B[41] O
Et
I O
OMe
O
59 Pd(PPh3)4, CsF CuI, DMF
Et
Et O
≡
SnMe3
58
OMe
O
O
OMe
O
O
Et
8π/6π
Et O
OMe
O
+
H
60
61
78%
O
ocellapyrone A 8%
O O
Et O
OMe
H
OMe
H
1O
2
89%
MeO
O
Et
O 60
62
ocellapyrone B
The immunosuppressant polyketides SNF 4435 C (65) and SNF 4435 D (66) are prepared in a similar fashion (Scheme 22).[42] Stille coupling of stannane 63 with the vinyl iodide 64 affords the Z,Z,Z,E-tetraene, which then undergoes the 8/6 electrocyclization cascade to provide a 3:1 mixture of diastereomeric compounds 65 and 66 in 89% yield. The product distribution presumably reflects the diastereoselectivity of the 8 electrocyclization step, since the 6 electrocyclization appears to be completely diastereoselective based on the observation that the nitrophenyl substituent is syn to the cyclohexadiene ring in both stereoisomers.
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Stereoselective Synthesis Scheme 22
Electrocyclic Reactions
3.8
Synthesis of Polyketides SNF 4435 C and D[42] I
SnMe3
O2N
O
Pd(PPh3)4 CsF, CuI
+ O
O OMe
63
64
O 8π/6π
O2N O
O OMe
O
O2N
O O
H
65
O
O2N
O +
O
H
OMe
66
SNF4435 C 67%
OMe
SNF4435 D 22%
A demonstration of the power of the Woodward–Hoffmann rules in electrocyclizations is also represented by the stereoselective synthesis of (E,E)-buta-1,3-diene-1,4-diyl diacetate (68) (Scheme 23).[43,44] In the first step, bisacetoxylation of cyclooctatetraene followed by 8 electrocyclization affords bicyclooctadiene 67. Heating 67 in the presence of dimethyl acetylenedicarboxylate leads to the selective formation of E,E-buta-1,3-diene-1,4-diyl diacetate (68), presumably via a sequence of Diels–Alder/retro-Diels–Alder reactions and a conrotatory electrocyclic ring opening. Scheme 23
Synthesis of (E,E)-Buta-1,3-diene-1,4-diyl Diacetate[43,44] OAc
Hg(OAc)2, HOAc 70 oC 75−78%
OAc 67
AcO CO2Me
OAc + OAc
benzene reflux
AcO
CO2Me
CO2Me
CO2Me
AcO
OAc 68
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41−49%
3.8.4
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Electrocyclizations of Hexatrienes and Octatetraenes
SNF 4435 C (65) and SNF 4435 D (66):[42]
To a soln of iodide (–)-64 (21 mg, 0.052 mmol) and stannane 63 (29 mg, 0.078 mmol) in DMF (1 mL) at rt were added CsF (16 mg, 0.10 mmol), CuI (2 mg, 0.01 mmol), and Pd(PPh3)4 (6 mg, 0.005 mmol). The mixture was heated to 45 8C for 3 h. The mixture was cooled to rt and diluted with EtOAc (15 mL), and the organic layer was washed with sat. aq NH4Cl (3 10 mL). The combined aqueous layers were extracted with EtOAc (3 15 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated. Purification by chromatography (silica gel, hexanes/EtOAc 1:1) gave a mixture of 65 and 66 (3:1); yield: 22 mg (67% for 65; 22% for 66). trans-7,8-Diacetoxybicyclo[4.2.0]octa-2,4-diene (67):[43,44]
CAUTION: Mercury(II) acetate is highly toxic and may be fatal if ingested or inhaled. A suspension of Hg(OAc)2 (160 g, 0.502 mol) in glacial AcOH (400 mL) was added to a 1-L, three-necked flask fitted with a reflux condenser, an efficient stirrer, and a thermometer dipping well into the soln. The suspension was stirred, and cyclooctatetraene (52.0 g, 0.50 mol) was then added rapidly. A white addition compound separated after 10– 15 min. This was decomposed by careful heating of the mixture at 70–75 8C for 2 h. The warm mixture was poured through funnels containing glass-wool plugs into two 4-L beakers, each containing H2O (2 L). The mixture was allowed to stand for several hours, and the solid that separated was collected on a Bchner funnel, where it was pressed as dry as possible. The moist, yellow solid was spread out on a large piece of filter paper and allowed to dry overnight; yield: 83–86 g (75–77.5%); mp 52–55 8C; it may be used in the next step without further purification. (E,E)-Buta-1,3-diene-1,4-diyl Diacetate (68):[43,44]
In a 500-mL flask was placed a soln of the diacetate 67 (83.0 g, 0.373 mol) and DMAD (54.0 g, 0.380 mol) in benzene (250 mL) (CAUTION: carcinogen), which was then refluxed for 6 h. The soln was filtered to remove the remaining Hg and Hg salts, and the benzene was removed by distillation under reduced pressure. The residual viscous, yellow oil was distilled under reduced pressure. A mixture of buta-1,3-diene-1,4-diyl diacetate and dimethyl phthalate was collected at 140–155 8C/18–20 Torr (bath temperature 170–200 8C), from which the diene crystallized as colorless needles in the cooled receiver. The solid was broken up, washed onto a Bchner funnel with petroleum ether (bp 60–70 8C), pressed between sheets of filter paper to remove excess dimethyl phthalate, and recrystallized [acetone/petroleum ether (bp 60–70 8C) ca. 1:2] to give colorless needles; yield: 26–31 g (41–49%); mp 102–104 8C.
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Stereoselective Synthesis
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Electrocyclic Reactions
References [1] [2]
[3]
[4] [5]
[6]
[7] [8] [9] [10] [11]
[12] [13]
[14] [15] [16] [17] [18] [19] [20] [21] [22] [23]
[24] [25] [26] [27] [28] [29] [30] [31] [32]
[33] [34] [35]
[36] [37]
[38] [39] [40] [41] [42] [43] [44]
Marvell, E. N., Thermal Electrocyclic Reactions, Academic: New York, (1980). Ansari, F. L.; Qureshi, R.; Qureshi, M. L., Electrocyclic Reactions, Wiley-VCH: Weinheim, Germany, (1999). Woodward, R. B.; Hoffmann, R., The Conservation of Orbital Symmetry, VCH: Weinheim, Germany, (1970). Dolbier, W. R., Jr.; Koroniak, H.; Houk, K. N.; Sheu, C., Acc. Chem. Res., (1996) 29, 471. Binns, F.; Hayes, R.; Ingham, S.; Saengchantara, S. T.; Turner, R. W.; Wallace, T. W., Tetrahedron, (1992) 48, 515. Binns, F.; Hayes, R.; Hodgetts, K. J.; Saengchantara, S. T.; Wallace, T. W.; Wallis, C. J., Tetrahedron, (1996) 52, 3631. Gauvry, N.; Huet, F., J. Org. Chem., (2001) 66, 583. Niwayama, S.; Kallel, E. A.; Spellmeyer, D. C.; Sheu, C.; Houk, K. N., J. Org. Chem., (1996) 61, 2813. Sadana, A. K.; Saini, R. K.; Billups, W. E., Chem. Rev., (2003) 103, 1539. Segura, J. L.; Martn, N., Chem. Rev., (1999) 99, 3199. Kametani, T.; Nemoto, H.; Ishikawa, H.; Shiroyama, K.; Matsumoto, H.; Fukumoto, K., J. Am. Chem. Soc., (1977) 99, 3461. Lpez, S.; Rodrguez, J.; Rey, J. G.; de Lera, A. R., J. Am. Chem. Soc., (1996) 118, 1881. Murakami, M.; Amii, H.; Itami, K.; Ito, Y., Angew. Chem., (1995) 107, 1649; Angew. Chem. Int. Ed. Engl., (1995) 34, 1476. Murakami, M.; Ashida, S.; Matsuda, T., J. Am. Chem. Soc., (2004) 126, 10 838. Frontier, A. J.; Collison, C., Tetrahedron, (2005) 61, 7577. Tius, M. A., Eur. J. Org. Chem., (2005), 2193. Denmark, S. E.; Jones, T. K., J. Am. Chem. Soc., (1982) 104, 2642. Denmark, S. E.; Habermas, K. L.; Hite, G. A., Helv. Chim. Acta, (1988) 71, 168. Harrington, P. E.; Murai, T.; Chu, C.; Tius, M. A., J. Am. Chem. Soc., (2002) 124, 10 091. Harrington, P. E.; Tius, M. A., J. Am. Chem. Soc., (2001) 123, 8509. He, W.; Sun, X.; Frontier, A. J., J. Am. Chem. Soc., (2003) 125, 14 278. Liang, G.; Trauner, D., J. Am. Chem. Soc., (2004) 126, 9544. Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B. J., Angew. Chem., (2007) 119, 2143; Angew. Chem. Int. Ed., (2007) 46, 2097. Grant, T. N.; Rieder, C. J.; West, F. G., Chem. Commun. (Cambridge), (2009), 5676. Bender, J. A.; Arif, A. M.; West, F. G., J. Am. Chem. Soc., (1999) 121, 7443. Rieder, C. J.; Fradette, R. J.; West, F. G., Chem. Commun. (Cambridge), (2008), 1572. Beaudry, C. M.; Malerich, J. P.; Trauner, D., Chem. Rev., (2005) 105, 4757. Yu, T.-Q.; Fu, Y.; Liu, L.; Guo, Q.-X., J. Org. Chem., (2006) 71, 6157. Zhu, G.-D.; Okamura, W. H., Chem. Rev., (1995) 95, 1877. Greshock, T. J.; Funk, R. L., J. Am. Chem. Soc., (2006) 128, 4946. Magomedov, N. A.; Ruggiero, P. L.; Tang, Y., J. Am. Chem. Soc., (2004) 126, 1624. Bishop, L. M.; Barbarow, J. E.; Bergman, R. G.; Trauner, D., Angew. Chem., (2008) 120, 8220; Angew. Chem. Int. Ed., (2008) 47, 8100. Bishop, L. M.; Roberson, R. E.; Bergman, R. G.; Trauner, D., Synthesis, (2010), 2233. Vicario, J. L.; Badia, D., ChemCatChem, (2010) 2, 375. Maciver, E. E.; Thompson, S.; Smith, M. D., Angew. Chem., (2009) 121, 10 164; Angew. Chem. Int. Ed., (2009) 48, 9979. Mller, S.; List, B., Angew. Chem., (2009) 121, 10 160; Angew. Chem. Int. Ed., (2009) 48, 9975. Kobayashi, T.; Takeuchi, K.; Miwa, J.; Tsuchikawa, H.; Katsumura, S., Chem. Commun. (Cambridge), (2009), 3363. Li, Y.; Kobayashi, T.; Katsumura, S., Tetrahedron Lett., (2009) 50, 4482. Tambar, U. K.; Kano, T.; Zepernick, J. F.; Stoltz, B. M., J. Org. Chem., (2006) 71, 8357. Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E., J. Am. Chem. Soc., (1982) 104, 5560. Miller, A. K.; Trauner, D., Angew. Chem., (2005) 117, 4678; Angew. Chem. Int. Ed., (2005) 44, 4602. Beaudry, C. M.; Trauner, D., Org. Lett., (2005) 7, 4475. Carlson, R. M.; Hill, R. K., Org. Synth., (1970) 50, 24. Reppe, W.; Schlichting, O.; Klager, K.; Toepel, T., Justus Liebigs Ann. Chem., (1948) 560, 1.
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403 3.9
Allylic Substitution Reactions M. L. Crawley
General Introduction
The allylic substitution reaction has evolved over time from a limited process of primarily academic interest to a powerful tool for the asymmetric construction of C—C, C—N, and C—O bonds.[1,2] The scope of the reaction, once confined to a narrow set of palladium-catalyzed transformations, now includes copper-,[3] iridium-,[4] molybdenum-,[5] nickel-,[6] and rhodium-catalyzed variants.[7] Additionally, the depth and versatility of reactions catalyzed by palladium has increased significantly.[8,9] In fact, in the decade 2000–2009 there have often been in excess of 100 articles per year in peer-reviewed journals devoted to this vibrant research area. A factor that differentiates the allylic substitution reaction from most other metal-catalyzed processes is that nucleophilic attack occurs away from the metal center, to provide up to two contiguous stereogenic centers, one or both of which may be quaternary. This in turn makes the process valuable in the total synthesis of biologically important molecules. Given the sheer volume of articles on the topic, this review is intended to highlight only the best methods for each bond-forming reaction. Proof of the merits of each method is demonstrated in many ways, including through synthesis of biologically important molecules, exceptional stereo- or enantioselectivity in complicated transformations, and the ability to conduct the reaction on a large scale with high turnover number. All transformations discussed herein have high yields and achieve difficult bond-forming events. There will be no specific focus on the array of chiral ligands that have been developed for each metal, but all examples selected utilize ligands that have proven to be robust across a variety of substrates. The mechanism of the allylic substitution reaction has been well documented and studied for a variety of metals and substitution patterns,[10–14] and while there are some key differences between metals and substitution patterns, the general reaction pathway can be described as shown in Scheme 1. The reaction begins with metal complexation to the alkene followed by ionization of the leaving group and, based upon the type of metal and the reactivity of the intermediates, –– equilibration may or may not be rapid. Nucleophilic capture of the generated -complex then leads to a branched or linear product depending upon the regioselectivity of nucleophilic attack.
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Stereoselective Synthesis Scheme 1
3.9
Allylic Substitution Reactions
General Mechanism for Transition-Metal-Catalyzed Allylic Substitution R1 ML∗n
R1 ∗
R1 ∗
X
ML∗n
ML∗n
R
Nu Nu−
R1
R1 X
Nu
R1 ML∗n
Since this review is focused on stereoselective synthesis, only outcomes leading primarily to the chiral branched products are of interest and, dependent upon the type of starting material and the relative reaction and equilibration rates of the intermediates, there are several opportunities for stereospecific or enantioselective reactions. Thus, formation of each bond type (C—C, C—N, and C—O) will be further categorized into three types of conceptually different processes. Firstly, reactions that employ an achiral starting material, or generate symmetrical intermediates, in the context of enantioselective reactions will be evaluated. Secondly, dynamic kinetic asymmetric transformations (or resolutions) (DYKAT), whereby a racemic mixture of starting enantiomers is selectively converted into a single enantiomer of the product. Finally, allylic substitutions, where chiral nonracemic starting materials stereospecifically generate enantiomerically enriched adducts, will be discussed. When an achiral starting material is employed there are multiple steps in the process where chiral recognition can occur. In limited cases enantioselective alkene complexation, where the metal–ligand complex can distinguish between the two prochiral faces of the alkene, is the enantiodetermining step can occur. Alternatively, when there are two leaving groups in a meso starting material (Scheme 2), enantiotopic ionization can determine the outcome of the transformation.[8] Scheme 2 Enantioselective Allylic Substitution Using an Achiral Substrate (Enantiotopic Ionization of Leaving Groups) X
ML∗n
ML∗n
X
Nu Nu−
X
X
Finally, the ionization of a chiral starting material may create a symmetrical (meso) -allyl intermediate which has no memory of the starting configuration (Scheme 3). In this case, the chirality of the product can be determined by enantiotopic attack of the nucleophile at one of the two termini of the intermediate complex (pathway a or b).[8] While this scenario can occur both for cyclic and acyclic substrates, most synthetic applications to date involve cyclic examples. Allylic Substitution Reactions, Crawley, M. L. Science of Synthesis 4.0 version., Section 3.9 sos.thieme.com © 2014 Georg Thieme Verlag KG
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General Introduction Scheme 3 Enantioselective Allylic Substitution via a Symmetrical Intermediate (Enantiotopic Nucleophilic Attack) Nu− X
a ML∗n
R1 R2
Nu
ML∗n R1
R1 R2
b
R2
Nu−
It is also important to note that asymmetry may also be induced at the nucleophile as opposed to the electrophile. In this case the enantioselection is derived by the -allyl complex differentiating between prochiral faces of the nucleophile, as is the case with allylic substitution with prochiral ketone enolates (see also Section 3.15).[8] A common enantiodetermining step in transition-metal-catalyzed allylic substitutions involves differential reactivity of the rapidly interconverting diastereomeric complexes via –– equilibration.[8] When a racemic starting material is employed the process has the ability to convert a mixture of enantiomers into a single enantiomer (Scheme 4). In order for this process to function efficiently, interconversion of the two intermediate -complexes through a terminal -complex must be rapid compared to the rate of nucleophilic capture. Additionally, the two diastereomeric complexes must have substantially different rates of reaction with the nucleophile in order to generate high enantioselectivity. Scheme 4 Allylic Substitution via a Dynamic Kinetic Asymmetric Transformation R1
ML∗n
R1 ML∗n
X
R1
Nu−
ML∗n
R1
ML∗n
R1 Nu
R1
X
ML∗n
When a branched, chiral starting material is employed, and the rate of –– equilibration is slow relative to nucleophilic substitution, a stereospecific reaction is possible where the chirality of the product is determined by the chirality of the starting material. This scenario has been utilized extensively for rhodium-catalyzed allylic substitution reactions.[7] SAFETY: All of the reactions described herein should be carried out using the normal precautions applied to potentially dangerous and hazardous reactions in modern synthesis. In particular, some of the transition-metal complexes, such as the molybdenum reagents, have rather significant effects in humans if absorbed through the skin or ingested. While the specific toxicity of each transition-metal complex should be evaluated prior to its use, special care should be afforded to these catalysts in any of the reactions described.
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Stereoselective Synthesis
3.9.1
C—C Bond-Forming Reactions
3.9
Allylic Substitution Reactions
The significant majority of enantioselective and stereoselective allylic substitution reactions involve C—C bond formation. In fact, there are so many methods and metals that it is literally impossible to select a “best” method. Instead, the approach that is taken in each class is, according to each metal, to select several examples that are either highly representative of the best transformation or which highlight the significance of the transformation. Then, one experimental procedure that is both practical and/or scalable is selected from the examples. This necessarily omits hundreds of very valid and useful examples. Where applicable, one or two examples are highlighted to illustrate the promise of an emergent method. 3.9.1.1
Enantioselective Reactions with Achiral Electrophiles and Symmetric Intermediate ð-Allyl Complexes
3.9.1.1.1
Palladium-Catalyzed Reactions
The palladium-catalyzed asymmetric allylic alkylation continues to be one of the most reliable, selective, and efficient methods for the construction of chiral tertiary and quaternary carbon stereogenic centers with stabilized carbon stereogenic nucleophiles. The examples discussed herein, all involve a total synthesis of a biologically important natural product, and have been selected in part to highlight different factors in the mechanism. These include enantiotopic ionization and enantiotopic nucleophilic attack, in the context of cyclic and acyclic substrates, which also includes the formation of a chiral quaternary center at the nucleophile instead of the electrophile. The total synthesis of enantiomerically pure (–)-wine lactone (5) employs a classic palladium-catalyzed allylic alkylation of cyclohex-2-enyl acetate with dimethyl malonate (Scheme 5).[15] This type of reaction, employing a stabilized malonate nucleophile with an alkenyl acetate, is highly prevalent across the literature for testing new ligands and conditions for asymmetric palladium-catalyzed allylic substitution reactions. It is classic in that it proceeds through a meso -allyl intermediate to afford diester 4 in 91% yield (with 95% ee) using ligand 1 (Scheme 5).[15] Comparable yields and enantioselectivities can be achieved with other ligands and conditions, a few representative examples of which are illustrated in Scheme 5.[16,17] The three ligands 1–3 outlined in Scheme 5 are representative of the types of ligands used in palladium-catalyzed allylic substitution processes. With diester 4 in hand, (–)-wine lactone (5) can be obtained in under 10 synthetic steps via an intermediate lactone. Scheme 5
Allylic Substitution with a Malonate Nucleophile[15–17]
PPh2•BH3
NH
HN
P
Ph2P
PPh2
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N But
CO2H
1
Mn(CO)3
O
O
O
2
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3
Ph Ph
3.9.1
407
C—C Bond-Forming Reactions
ligand Pd2(η3-C3H5)2Cl2 MCH(CO2Me)2
OAc
MeO2C
CO2Me 4
M
Ligand Conditions
ee (%) Yield (%) Ref
Li
1
95
91
[15]
Na 2
[Me(CH2)5]4NBr, CH2Cl2, 0 8C 96
86
[16]
Na 3
THF, rt
86
[17]
THF, rt
90
H
4 steps
O
H MeO2C
H
5 steps
CO2Me
O
H
O
O 5
4
An approach which utilizes enantiotopic ionization of a meso starting material is described in the total synthesis of (+)-valienamine (8) (Scheme 6).[18] In this approach, the symmetric starting material (1R,4S)-cyclohex-2-ene-1,4-diyl dibenzoate is desymmetrized using phenylsulfonyl-substituted nitromethane as the nucleophile, a process thought to proceed through an initial addition product 6 followed by a second allylic alkylation to afford hexahydrobenz[d]isoxazole 2-oxide 7 in 87% yield with complete enantiocontrol (>99% ee). This building block is then transformed into (+)-valienamine (8) in 13 additional steps. Scheme 6
Total Synthesis of (+)-Valienamine[18] 1 mol% 2 0.5 mol% Pd2(η3-C3H5)2Cl2
OBz
O2N SO2Ph excess NaHCO3, THF/H2O
H
NO2 SO2Ph
BzO
BzO 6
OH
O O N
HO
OH
13 steps
SO2Ph
87%; >99% ee
HO NH2 7
8
Sphingofungin E (12) is an interesting natural product that has been proposed to have roles in a diverse array of biological processes. In constructing the highly functionalized tail of sphingofungin E, a palladium-catalyzed allylic substitution of a prochiral allylic gem-diacetate 9 with an azlactone nucleophile 10 using chiral ligand ent-2 is employed (Scheme 7).[19] The reaction proceeds in 68% yield with very high enantioselectivity (96% Allylic Substitution Reactions, Crawley, M. L. Science of Synthesis 4.0 version., Section 3.9 sos.thieme.com © 2014 Georg Thieme Verlag KG
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408
Stereoselective Synthesis
3.9
Allylic Substitution Reactions
ee) to afford a 2.4:1 mixture of the diastereomeric products 11A and 11B. The highly functionalized intermediate 11A is then transformed into sphingofungin E (12) in an additional 11 steps. It is worthwhile to mention that additional transformations using allylic gem-dicarboxylates were described concurrently with this synthesis, including those utilizing sulfur nucleophiles to make C—S bonds. However, despite high regio- and enantioselectivity, these procedures fall outside the scope of this review.[20] Scheme 7
Total Synthesis of Sphingofungin E[19] 3 mol% ent-2 1 mol% Pd2(η3-C3H5)2Cl2 NaH, THF, 0 oC
O OAc +
TBDPSO
PhMe2Si
O N
OAc
Ph 9
10 OAc
OAc
O
TBDPSO
+
O
O
N PhMe2Si 11A
O
TBDPSO N PhMe2Si
Ph
68%; 96% ee
11B
2.4:1.0
Ph
23%; 96% ee
OH
OH
11 steps
CO2H 5
6
O
NH2
OH OH 12
The final example presented in this section for palladium-catalyzed processes is the asymmetric synthesis of (–)-nitramine (15). While the enantioselectivity is not completely optimized for this reaction (86% ee), the transformation with chiral ligand ent-2 provides an efficient route from -oxo ester 13 to the -oxo ester 14 having a quaternary carbon stereogenic center. This intermediate then provides access to the spiro-alkaloid (–)-nitramine (15) in only four additional steps (Scheme 8).[21] Scheme 8
Asymmetric Synthesis of (–)-Nitramine[21] OAc
O CO2Et
1.2 mol% ent-2 0.5 mol% Pd2(η3-C3H5)2Cl2 (Me2N)2C=NH, toluene, 0 oC
O CO2Et
81%; 86% ee
14
13
H N
4 steps
OH 15
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3.9.1
409
C—C Bond-Forming Reactions
Dimethyl (R)-2-(Cyclohex-2-enyl)malonate (4); Typical Procedure:[15]
A soln of ligand 1 (162 mg, 0.45 mmol) and Pd2(Å3-C3H5)2Cl2 (27 mg, 74 mol) in anhyd THF (3 mL) was stirred at rt for 20 min under an argon atmosphere and (€)-cyclohex-2-enyl acetate (0.70 g, 4.99 mmol) was added. Separately, a 1.6 M soln of BuLi (5.0 mL, 8.0 mmol) in hexanes was added dropwise to a soln of dimethyl malonate (1.32 g, 10.0 mmol) in anhyd THF (15 mL) at –40 8C. This mixture was allowed to warm to rt and stirred for 10 min. The resultant suspension was added to the initial soln of ligand, Pd catalyst, and acetate and, after stirring for 1 h at rt, the reaction was quenched with sat. NH4Cl soln (30 mL). The resulting mixture was extracted with Et2O (30 mL) and the organic layer was washed with H2O, dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography (silica gel, petroleum ether/EtOAc 97:3) gave the product as a colorless oil; yield: 0.96 g (91%); 95% ee. 3.9.1.1.2
Copper-Catalyzed Reactions
Copper-catalyzed allylic substitutions with unstabilized nucleophiles, particularly organomagnesium and organozinc reagents, are complementary to the palladium-catalyzed reactions with stabilized nucleophiles. The examples cited herein highlight both magnesium and zinc nucleophiles utilized to form both tertiary and quaternary stereogenic centers, and are demonstrated in three concise syntheses where the copper-catalyzed substitution is the pivotal synthetic transformation. Copper-catalyzed enantioselective allylic substitution with alkyl Grignard reagents, particularly simple ones such as methyl and ethyl derivatives, continues to be an active area due to several target products that are easily prepared via this strategy. In a representative example, reaction of (E)-2-(3-chloroprop-1-enyl)-6-methoxynaphthalene with a copper(I) bromide catalyst in conjunction with methylmagnesium bromide and the (R,R,R)-phosphoramidite ligand 16 affords (S)-2-(but-3-en-2-yl)-6-methoxynaphthalene (17) with 93% enantiomeric excess and a branched/linear ratio of 90:10 (Scheme 9).[22] The (S,S,S)-ligand (ent-16) affords the enantiomeric (R)-product, which is a direct precursor to the anti-inflammatory drug (S)-(+)-naproxen (18). It should be noted that more recent work, albeit employing different ligands, produces similarly high enantioselectivities and yields with both methyl and ethyl Grignard reagents.[23] Scheme 9
Copper-Catalyzed Allylic Substitution with a Methyl Grignard Reagent[22] OMe O P
N
O OMe
Cl
16 5 mol% CuBr, MeMgBr CH2Cl2, −78 oC 93% ee; (branched/linear) 90:10
MeO
MeO 17
CO2H MeO 18
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Dialkylzinc reagents have also proven to be particularly effective and selective reagents for allylic substitution reactions catalyzed by copper. For example, aryl-substituted allylic phosphonates 19 undergo efficient reaction with diethylzinc, using pyridinyl peptide ligands 20, to afford allylbenzenes 21, containing a chiral quaternary center in excellent yield (80–83%) with outstanding regio- and moderate to good enantioselectivity (78–90% ee) (Scheme 10).[24] Scheme 10 Asymmetric Synthesis of Quaternary Carbon Stereogenic Centers by CopperCatalyzed Allylic Substitution[24] R2 10 mol%
O O
P OEt OEt
O
N
NHBu
N
O
Bn
OPri 20 10 mol% CuCN, excess Et2Zn o THF, −78 C, 24 h
Et
R1
R1 19
21
R1
R2
ee (%) Yield (%) Ref
H
iPr
78
80
[24]
NO2 t-Bu 86
80
[24]
OTs t-Bu 90
83
[24]
Interestingly, the reaction of the more substituted dialkylzinc reagents, such as bis(4-methylpent-3-enyl)zinc, with the tosyloxy-substituted allylic phosphonate 22 using ligand 23 gives the opposite stereochemical outcome compared to the reaction of the same phosphonate 19 (R1 = OTs) with diethylzinc. Simple saponification of the resulting product directly affords the naturally occurring fish deterrent (R)-(–)-sporochnol (24) in 82% yield and with 82% enantiomeric excess (Scheme 11).[24] Scheme 11
Concise Synthesis of (R)-(–)-Sporochnol[24] Cy 1. 10 mol%
N N
O P OEt O OEt
O
H N O
NHBu Bn
OPri 23 10 mol% CuCN, [Me2C=CH(CH2)2]2Zn THF, −78 oC, 24 h 2. KOH, aq EtOH, 80 oC 82%; 82% ee
TsO 22
HO 24
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Furthermore, it has been demonstrated that dimethylzinc can perform a highly enantioselective copper-catalyzed allylic substitution with an ester-substituted allylic phosphonate 25, using the modified peptidic scaffold 26, to give the Æ-methylated allylic ester 27 in 80% yield, in a highly regio- (branched/linear >20:1) and enantioselective manner (Scheme 12).[25] The resulting ester 27 can be subsequently transformed in two steps (via cross metathesis and ester cleavage) into the naturally occurring topoisomerase II inhibitor (R)-(–)-elenic acid (28). Scheme 12
Enantioselective Synthesis of (R)-(–)-Elenic Acid[25] Cy
O
H N
N O
OH
NHBu Bu
26
ButO2C
5 mol% (CuOTf)2•C6H6
O
OEt P OEt
ButO2C
Me2Zn, THF, −50 oC, 48 h 80%; 90% ee; (branched/linear) >20:1
O 25
27
2 steps
HO2C 18
OH 28
(S)-(+)-3-Methyl-3-phenylpent-1-ene (21, R1 = H); Typical Procedure:[24]
CAUTION: Cyanide salts can be absorbed through the skin and are extremely toxic. CAUTION: Diethyl zinc is pyrophoric. Use extreme caution. A flame-dried test tube was charged with CuCN (1.4 mg, 16 mol) and ligand 20 (R2 = iPr; 7.6 mg, 1.6 mol) and the mixture was cooled to –78 8C. A soln of allylic phosphonate 19 (R1 = H; 50 mg, 0.16 mmol) in THF (1.0 mL) was added and, after equilibration at –78 8C for 15 min, Et2Zn (50 L, 0.49 mmol) was added dropwise, at which point the soln turned bright red. The mixture was allowed to stir at –78 8C for 12 h, at which time the reaction was quenched through addition of a 10% soln of HCl (1.0 mL). The mixture was extracted with Et2O (3 2.0 mL), concentrated under reduced pressure, and purified by flash chromatography (pentanes/Et2O 20:1) to afford the product; yield: 20.5 mg (80%); 78% ee. 3.9.1.1.3
Molybdenum-Catalyzed Reactions
The molybdenum-catalyzed allylic substitution reaction complements the palladium-catalyzed process with soft nucleophiles in that the inherent preference for alkylation favors the branched rather than the linear product. Hence, the dilemma of overcoming the regioselectivity issue is minimized by molydenum-catalyzed reactions. There are numerous robust examples of this process, both with achiral and racemic starting materials, the latter of which will be discussed in Section 3.9.1.2.2. To highlight the selectivity and versatility of this reaction, examples in the context of methodology and the synthesis of biologically active molecules have been selected. The molybdenum-catalyzed alkylation of standard cinnamyl alcohol derived substrates 32 with the sodium salt of dimethyl malonate has been investigated with some of the more common ligands 29–31 (Scheme 13).[26] Although there are some differences in the yield and the branched 33 to linear 34 selectivity between the ligands, they provide Allylic Substitution Reactions, Crawley, M. L. Science of Synthesis 4.0 version., Section 3.9 sos.thieme.com © 2014 Georg Thieme Verlag KG
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good to excellent regioselectivity with near complete enantioselectivity. Replacing the phenyl group with other substituents gives both higher and lower branched to linear selectivity, albeit with outstanding enantioselectivity. Scheme 13 Enantioselective Molybdenum-Catalyzed Allylic Alkylation of Cinnamyl Alcohol Derivatives[26]
O
O NH
O
HN
O NH
N
N
N
N
O
Pri
Pri
31
CO2Me
NaH, THF, 70 oC
MeO2C
CO2Me +
OR1
CO2Me
Ph
CO2Me
Ph 32
R1
O
Pr
Pr
30
15 mol% ligand 10 mol% Mo(CO)3(NCEt)3
Ph
HN
O N
29
MeO2C
O NH
O N
O
HN
33
34
Ligand Ratio (33/34) ee (%) of 33 Yield (%) Ref
CO2Me 29
49:1
99
70
[26]
Ac
30
10:1
97
84
[26]
CO2Me 30
14:1
99
86
[26]
CO2Me 31
6:1
98
83
[26]
Another intriguing example of the allylic substitution is the allylic alkylation of 3-aryl-1,3dihydro-2H-indol-2-ones 35 to provide 3-allyl-3-aryl-1,3-dihydro-2H-indol-2-ones 36 in a highly regio-, diastereo-, and enantioselective manner (Scheme 14).[27] Remarkably, the reaction with a cinnamyl carbonate with a diverse range of substrates using ligand ent-29 occurs not only with high enantioselectivity (89–95%) but also with significant diastereoselectivity. In all cases good to excellent yields (84–92%) are obtained and in all but one case the branched to linear ratio (36/37) is greater than 10:1. It is also worth noting that the more sterically encumbered examples give better diastereocontrol.
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Scheme 14 Regio-, Diastereo-, and Enantioselective Allylic Alkylation of 3-Aryl-1,3-dihydro-2H-indol-2-ones[27] Ar1 O
OCO2Me +
Ph
15 mol% ent-29 10 mol% Mo(CO)3(cycloheptatriene) t-BuONa, THF, 60 oC
N Me 35 Ph
Ph
Ar1
Ar1 O
O
+ N Me
N Me 36
37
Ar1
Ratio (36/37) dr
Ph
18:1
8:1 92
88
[27]
4-FC6H4
16:1
6:1 91
90
[27]
4-ClC6H4
13:1
5.5:1 95
88
[27]
4-NCC6H4
7:1
4.5:1 89
84
[27]
18:1
8:1 92
92
[27]
4-Me2NC6H4 17:1
6:1 92
87
[27]
4-MeOC6H4
ee (%) of 36 Yield (%) Ref
2-Tol
17:1
19:1 94
90
[27]
1-naphthyl
15:1
19:1 95
88
[27]
The third example comes from a synthesis of (–)-˜9-trans-tetrahydrocannabinol 40, the primary psychomimetic component of marijuana.[28] In this approach, the key stereogenic center is generated by the molybdenum-catalyzed allylic alkylation reaction. For example, with the functionalized allylic carbonate 38 undergoes alkylation with sodium dimethyl malonate under rather standard conditions using ligand ent-29 to give the branched product 39 in 84% yield and with 97% enantiomeric excess (Scheme 15). It is noteworthy that the bulky flanking ortho-methoxy groups do not alter the regioselectivity of the reaction to produce any of the linear product; however, the steric congestion is likely what causes the reaction to be slower than normal. Scheme 15
Synthesis of (–)-˜9-trans-Tetrahydrocannabinol[28] 15 mol% ent-29 10 mol% Mo(CO)3(cycloheptatriene) NaH, THF, 65 oC
OMe OCO2Me
MeO2C
CO2Me 84%; 97% ee
4
OMe 38
MeO2C OMe
H
CO2Me
O H
OMe
4
4
40
39
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Allylic Substitution Reactions
Dimethyl (R)-2-[1-(2,6-Dimethoxy-4-pentylphenyl)allyl]malonate (39); Typical Procedure:[28]
Mo(CO)3(cycloheptatriene) (13.6 mg, 0.05 mmol) and ligand ent-29 (24.3 mg, 0.075 mmol) in THF (1.0 mL) were added to carbonate 38 (161.2 mg, 0.5 mmol), dimethyl malonate (79.3 mg, 0.6 mmol), and 60% NaH suspension in oil (24 mg, 0.6 mmol) in THF (4.0 mL) and the mixture was stirred under reflux for 54 h. The soln was diluted with EtOAc (25 mL), washed with H2O (25 mL), dried (MgSO4), and concentrated under reduced pressure. Flash chromatography (petroleum ether/EtOAc 9:1) afforded the product as a colorless oil; yield: 158 mg (84%); 97% ee. 3.9.1.1.4
Iridium-Catalyzed Reactions
Iridium-catalyzed allylic substitution reactions also provide an efficient method for the enantioselective construction of C—C bonds. Indeed, since 2000 there have been dozens of examples with a range of carbon nucleophiles, including aryl nucleophiles, that afford high branched to linear selectivity with excellent enantioselectivity. Nevertheless there are only a few scattered reports,[29] both in academia and industry, are examples of both the use of this reaction in the synthesis of biologically important targets and on a large scale. Although these reactions have not yet shown the broad scope and versatility demonstrated by palladium-, copper-, and molybdenum-catalyzed processes, two compelling examples of the iridium-catalyzed substitution methodology, one with stabilized carbon nucleophiles and one with arylzinc reagents, are highlighted herein. The use of highly stabilized carbon nucleophiles, such as malonates, has become well established in iridium-catalyzed substitutions. However, a procedure which highlights this concept with a more versatile nucleophile is the reaction of carbonate 41 with the functionalized ester ethyl nitroacetate, in the presence of ligand 42 and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), to give the branched product 43 (Scheme 16).[30] By varying the steric and electronic properties of the carbonate it is possible to obtain substrate-dependent moderate to high branched selectivity. In all cases high yields (85–97%) and excellent enantioselectivities (95–99% ee) are observed, and one of the intermediates generated is used in a short synthesis of (1S,2R)-2-phenylcyclopentanamine, a compound which exhibits mild antidepressant activity. Scheme 16 Iridium-Catalyzed Enantioselective Allylic Substitution Reactions with Aliphatic Nitro Compounds[30] R2 O P
N
O R2 42 Ir2Cl2(cod)2 TBD, Cs2CO3, THF EtO2C
R1
NO2
NO2
EtO2C
+
OCO2Me
NO2
R1
CO2Et
R1 41
43
N
TBD = N
N H
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R1
R2
Ratio (43/44) ee (%) of 43 Yield (%) Ref
Ph
H
99:1
96
85
[30]
Ph
OMe 99:1
98
90
[30]
(CH2)2Ph
OMe 78:22
98
86
[30]
Pr
OMe 90:10
99
92
[30]
Another example of iridium catalysis is the enantioselective substitution reaction using a phenylzinc reagent. For example, carbonate 45 reacts using ligand 16 to give branched 46 and linear 47 allylbenzenes in good to excellent yield (Scheme 17).[31] In the examples highlighted the yields and enantioselectivities are moderate to excellent (up to 99% ee), however, the main issue is the poor branched to linear selectivity. Nevertheless, despite this shortcoming, the method still gives rapid access to otherwise difficult to access chiral intermediates, and one of the products has been converted into a key intermediate in the synthesis of the antidepressant sertraline (Zoloft). Scheme 17
Iridium-Catalyzed Asymmetric Allylic Substitution with a Phenylzinc Reagent[31] OMe O P
4 mol%
N
O OMe 16 2 mol% Ir2Cl2(cod)2 PhMgBr (1.5 equiv), ZnBr2 (0.75 equiv) LiBr (1.5 equiv), THF, 25 oC
R1
OCO2Me
Ph + R1
R1
45
46
R1
Ratio (46/47) ee (%) of 46 Yield (%) Ref
Cy
69:31
74
72
[31]
3-MeOC6H4
49:51
90
67
[31]
4-MeOC6H4
33:67
91
78
[31]
4-ClC6H4
55:45
99
83
[31]
4-F3CC6H4
56:44
97
98
[31]
2-naphthyl
53:47
92
93
[31]
Ph 47
3-Substituted Ethyl 2-Nitropent-4-enoates 43 and 5-Substituted Ethyl 2-Nitropent-4-enoates 44; General Procedure for Iridium-Catalyzed Allylic Alkylation:[30]
A soln of Ir2Cl2(cod)2 (0.02 mmol) and ligand 42 (0.04 mmol) in anhyd THF (1.0 mL) was treated with 1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.08 mmol) under argon at rt. After stirring for 2 h at rt, the allylic carbonate 41 (1.0 mmol) was added and the resulting mixture was stirred for 5 min at rt. Ethyl nitroacetate (1.5 mmol) and then Cs2CO3 (1.0 mmol) were added and the mixture was stirred until complete conversion (as indicated by GC/MS). The mixture was partitioned between H2O and EtOAc and the organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography to give the products.
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Dynamic Kinetic Asymmetric Resolution
Allylic Substitution Reactions
3.9
The power of the dynamic kinetic asymmetric transformation, namely to take a mixture of enantiomers and produce a single enantiomer, is a real advantage of the allylic substitution process. Although there have been limited examples of this reaction reported to date for C—C bond formation, there are three syntheses in particular, catalyzed by palladium and molybdenum, that exemplify this type of transformation. 3.9.1.2.1
Palladium-Catalyzed Reactions
A representative example of the palladium-catalyzed transformation, which creates a quaternary carbon stereogenic center, is utilized in the synthesis of the core of viridenomycin (52), a biologically important antitumor antibiotic natural product.[32] Functionalized -oxo ester 48 is employed as the pronucleophile with isoprene monoepoxide 49 as the electrophile together with ligand 2 (Scheme 18). The transformation proceeds in 71% yield to give the hemiacetal 50 with 94% enantiomeric excess, which allows for rapid synthesis of the cyclopentene core 51 of viridenomycin. Synthesis of the Core of Viridenomycin[32]
Scheme 18
O
O 3 mol%
NH
PPh2
O
Ph2P
2 1 mol% Pd2(dba)3•CHCl3 CH2Cl2, rt
O
PhS
HN
OEt
+
O
48
71%; 94% ee
49 OMe HO
SPh
EtO2C
MeO
CO2Et
O TBDMSO OTBDMS 50
51
OH MeO
O O
NH
HO O
Ph
52
Ethyl (4S)-2-Hydroxy-4-methyl-2-[2-(phenylsulfanyl)ethyl]-4-vinyltetrahydrofuran-3-carboxylate (50); Typical Procedure:[32]
To an oven-dried, round-bottomed flask were added Pd2(dba)3•CHCl3 (156 mg, 0.15 mmol), ligand 2 (312 mg, 0.45 mmol), and a stirrer bar. The flask was placed under reduced pressure and purged with argon (this process was repeated five times), and then freshly distilled CH2Cl2 (150 mL) was added. The dark purple soln was stirred at rt until it turned deep orange (10 min). Ethyl 3-oxo-5-(phenylsulfanyl)pentanoate (48; 3.78 g, 15.0 mmol) Allylic Substitution Reactions, Crawley, M. L. Science of Synthesis 4.0 version., Section 3.9 sos.thieme.com © 2014 Georg Thieme Verlag KG
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was then added, followed by 2-methyl-2-vinyloxirane (49; 1.91 mL, 19.5 mmol). The mixture was stirred 24 h at rt, the solvent was removed under reduced pressure, and the crude residue was purified by flash chromatography (petroleum ether/EtOAc 19:1) to afford the product as a colorless oil; yield: 3.56 g (71%); 94% ee. 3.9.1.2.2
Molybdenum-Catalyzed Reactions
A molybdenum-catalyzed dynamic kinetic asymmetric resolution reaction has been performed in the synthesis of a key drug intermediate, cyclopentanone 56, where the key reaction has been run industrially on a multikilogram scale (Scheme 19).[33] Utilizing the well-known Trost ligand, (S,S)-bispyridine 29, the sodium enolate of dimethyl malonate reacts with allylic carbonate 53 to afford a mixture of branched and linear diesters 54 and 55, respectively, in up to 91% yield and 97% enantiomeric excess, with a branched to linear ratio of 19:1. The branched product is then rapidly transformed into the target drug derivative. Scheme 19 A Molybdenum-Catalyzed Dynamic Kinetic Asymmetric Transformation in the Synthesis of a Key Drug Intermediate[33]
O
O NH
15 mol%
HN
N
O
N 29
MeO
O
10 mol% Mo(CO)6
ONa O
toluene, 85 oC
+ MeO
84−91%; 96−97% ee; (branched/linear) 19:1
OMe
F 53 O
O MeO
O
OMe OMe
O + O
HO
OMe F
F
F 54
55
56
Both molybdenum- and palladium-catalyzed dynamic kinetic asymmetric resolution have been used to build core pieces of the anti-HIV drug tipranavir (57). The strategy involves the construction of the stereogenic centers with these transformations, and in which the quaternary stereocenter is prepared with a palladium-catalyzed reaction, and the tertiary stereocenter utilizes a molybdenum-catalyzed process (Scheme 20).[34] However, since the palladium-catalyzed process involves the formation of a C—O bond, rather than a C—C bond, it is discussed in Section 3.9.3.2.1.
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Stereoselective Synthesis Scheme 20
3.9
Allylic Substitution Reactions
A Retrosynthetic Approach to Tipranavir[34] CHO
OH
Pr
Et
OR2
Pd-catalyzed DYKAT
R1 Ph
Pr
O
O
N HN
CF3 Et Mo-catalyzed DYKAT
S
O
O CO2R3
57
NO2 DYKAT = dynamic kinetic asymmetric transformation
The molybdenum-catalyzed process utilized to create the second key chiral building block uses the sodium enolate of dimethyl malonate as the nucleophile, which undergoes reaction with the racemic allylic carbonate 58 in the presence of ligand ent-30 to afford the desired branched regioisomer 59 in 94% yield with excellent enantioselectivity (96% ee) (Scheme 21).[34] It should be noted that the effect of a strongly electron-withdrawing group on the -allyl system was previously undocumented, and this example serves to illustrate the diverse scope and versatility of the molybdenum-catalyzed process. Scheme 21 A Molybdenum-Catalyzed Dynamic Kinetic Asymmetric Transformation in the Synthesis of Tipranavir[34] O
15 mol% ent-29 10 mol% Mo(CO)6
ONa O ButO
O
THF, reflux
+
MeO
OMe
94%; 96% ee
NO2 58
MeO2C MeO2C NO2 59
Dimethyl (R)-2-[1-(3-Fluorophenyl)allyl]malonate (54); Typical Procedure:[33]
CAUTION: Hexacarbonylmolybdenum is highly toxic. A 12-L, three-necked, round-bottomed flask was charged with Mo(CO)6 (219 g, 0.828 mol) and ligand 29 (402 g, 1.24 mol) and evacuated/backfilled with argon (three cycles). Anhyd toluene (4.36 L) was added, the flask was evacuated/backfilled with argon (three cycles), and the resulting mixture was heated to 85 8C for 4 h. Separately, a 100-L flask was charged with dimethyl malonate sodium salt (2.36 kg, 12.42 mol), a soln of carbonate 53 (2.0 kg, 8.28 mol) in anhyd toluene (3 L), and toluene (30.6 L). This flask was heated to 70 8C followed by the addition of the catalyst soln via cannula. The resulting mixture was heated to 85 8C for 15 h and subsequently allowed to cool to rt. H2O (36 L) was added and the organic layer was separated and filtered through a pad of silica gel; yield: 91% (product Allylic Substitution Reactions, Crawley, M. L. Science of Synthesis 4.0 version., Section 3.9 sos.thieme.com © 2014 Georg Thieme Verlag KG
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C—C Bond-Forming Reactions
assay); 97% ee; ratio (54/55) 19:1. The soln was concentrated under reduced pressure, and crystallization of the sample resulted in large crystalline prisms (mp 34–35 8C). 3.9.1.3
Stereospecific Allylic Substitution with Chiral Electrophiles
Although it may appear that stereospecific allylic substitution reactions, using chiral nonracemic starting materials, should be conceptually easier to achieve than enantioselective allylic substitutions, this is not necessarily the case, as discussed in the introductory section. One of the main mechanistic features of allylic substitution, the ––-equilibration process, rapidly erodes the optical purity of the starting material in most metal-catalyzed reactions. Although some success has been achieved in this type of transformation with palladium, and more recently with copper,[35] by far the most established and practical method for this transformation is the rhodium-catalyzed variant as outlined in Section 3.9.1.3.1. 3.9.1.3.1
Rhodium-Catalyzed Reactions
Controlling both regio- and stereoselectivity in an allylic alkylation reaction is challenging. In many cases racemic starting materials are used and results on the regiochemical outcome with these substrates are reported. Since the process is stereospecific only one or two examples are required to highlight that chiral fidelity has been maintained, to illustrate the chirality transfer from the starting material to the product. Such is the case when allylic carbonate 60 reacts with the sodium salt of dimethyl malonate to give a 93% yield of substituted diester 61 in 98% enantiomeric excess (Scheme 22).[10,36] Scheme 22 Direct Stereoselective Rhodium-Catalyzed Allylic Substitution Reactions of an Unsymmetrical Substrate[10,36] Rh2Cl2(CO)4
ONa O
OCO2Me + MeO
Ph 60
MeO2C
CO2Me
DMF, 24 h
OMe
93%
Ph 61
99% ee
98% ee
More versatile stabilized nucleophiles also function quite well in the rhodium-catalyzed process. Using the sodium salt of methyl (phenylsulfonyl)acetate, a variety of chiral allylic carbonates 62 have been probed for both regioselectivity and stereospecificity (Scheme 23).[37] The reactions all proceed in high yield with outstanding regioselectivity (with one exception) and near complete conservation of enantiomeric excess. The products, substituted (phenylsulfonyl)acetates 63 and 64, are versatile intermediates, one of which has been transformed into a unique chiral lactone building block.
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3.9
Scheme 23 Regioselective and Stereospecific Rhodium-Catalyzed Allylic Alkylation Reactions[37]
OCO2Me
RhCl(PPh3)3 (cat.), P(OMe)3 NaCH(CO2Me)SO2Ph THF
MeO2C
SO2Ph
MeO2C
SO2Ph
+ R1
R1 62
R1 64
63
R1
ee (%) of 62 ee (%) of 63 Ratio (63/64) Yield (%) Ref 97
95
36:1
86
[37]
‡99
98
26:1
91
[37]
Bn
94
92
9:1
86
[37]
(CH2)2Ph
98
95
22:1
87
[37]
CH2OBn
94
92
‡99:1
86
[37]
‡99
‡99
18:1
86
[37]
98
96
61:1
97
[37]
Me (CH2)3CH=CH2
CH2OTBDMS Ph
A true demonstration of the efficiency and usefulness of a method is its application to total synthesis. Utilizing an interesting class of copper(I) enolate nucleophiles, the in situ activation of benzylic alcohol 65, followed by the rhodium-catalyzed substitution, affords ketone 66 in 80% yield with complete regioselectivity and conservation of chirality (Scheme 24).[38] It should be noted that this in situ activation protocol is adopted to avoid the relatively facile ionization and racemization of the allylic carbonate. The ketone product obtained proves a suitable building block, and is efficiently transformed in four steps into (–)-sugiresinol dimethyl ether (67), a natural product that exhibits potent antifungal activity. Scheme 24 Regioselective and Stereospecific Rhodium-Catalyzed Allylic Alkylation with a Copper(I) Enolate[38] 1. BuLi, MeOCOCl THF, 0 oC 2. MeO
OMe
Ac
LiHMDS, CuI 3. RhCl(PPh3)3 (cat.)
MeO
OMe
P(OMe)3 80%
HO
O 65
66 MeO
OMe
4 steps
O
OH 67
Another important aspect of this process is the ability to employ prochiral ketones and thereby introduce an additional stereogenic center. For example, the allylic substitution of allylic carbonate 68 with the acyclic Æ-alkoxy-substituted copper(I) enolates derived Allylic Substitution Reactions, Crawley, M. L. Science of Synthesis 4.0 version., Section 3.9 sos.thieme.com © 2014 Georg Thieme Verlag KG
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C—C Bond-Forming Reactions
3.9.1
from the aryl ketones 69 affords high yields of Æ-alkoxy ketones 70 and 71 (Scheme 25).[39] Furthermore, in addition to the high branched to linear selectivity very high diastereocontrol is obtained favoring the anti-diastereomer 70, thereby, demonstrating the power of rhodium-catalyzed transformations for acyclic diastereocontrol. Scheme 25 Regio- and Diastereoselective Rhodium-Catalyzed Allylic Substitution with Acyclic Æ-Alkoxy-Substituted Copper(I) Enolates[39] RhCl(PPh3)3 (cat.) P(OMe)3, LiHMDS CuI, THF
O OCO2Me + Ph
Ph
OR
R1
1
69
Ph
O
2
+
Ph
2
68
Ph
O
2
Ph
OR1
OR1
70
71
Ratio (70/71) Yield (%) Ref
Me 17:1
85
[39]
Bn 37:1
90
[39]
The rhodium-catalyzed allylic substitution reaction is also compatible with unstabilized nucleophiles. In a representative example, an organozinc is reacted with the chiral nonracemic allylic carbonate (S)-72 to give a regioisomeric mixture of allylbenzenes 73 and 74 [ratio (73/74) 10:1] with complete conservation of the degree of asymmetry (Scheme 26).[40] It is of interest to note than in this case the chirality of the major product has been inverted, which is the opposite to that typically obtained with a stabilized nucleophile. Oxidative cleavage of the alkene in allylbenzene 73 affords (S)-ibuprofen in just one step. Scheme 26 Rhodium-Catalyzed Allylic Substitution with an Organozinc Nucleophile in a Short Synthesis of (S)-Ibuprofen[40]
OCO2Me
Rh(C2H4)2(Tp) (cat.) 4-iBuC6H4ZnBr LiBr, dba, Et2O, 0 oC
Bui
+
90%
(S)-72
95% ee
Bui
73
95% ee
10:1
74
Tp = tris(pyrazolyl)borate
(R)-1,3-Bis(4-methoxyphenyl)pent-4-en-1-one (66); Typical Procedure:[38]
CAUTION: Trimethyl phosphite is flammable and has a powerful, obnoxious odor. Induces headache. Severe skin and eye irritant. Corrosive and irritating to the respiratory tract. The allylic alcohol 65 (81.6 mg, 0.50 mmol) was dissolved in anhyd THF (2.0 mL) and cooled to 0 8C with stirring under an atmosphere of argon. 2.5 M BuLi in hexanes (200 L, 0.50 mmol) was added dropwise, and the mixture was stirred for ca. 5 min at 0 8C before methyl chloroformate (39 L, 0.50 mmol) was added. The resulting mixture was then allowed to stir for ca. 15 min. P(OMe)3 (24 L, 0.20 mmol) was added directly to a red suspension of RhCl(PPh3)3 (Wilkinsons catalyst; 46.1 mg, 0.05 mmol) in anhyd THF (1.0 mL) and the mixture was stirred under an atmosphere of argon. The catalyst was allowed to form over ca. 15 min, resulting in a light yellow homogeneous soln. Allylic Substitution Reactions, Crawley, M. L. Science of Synthesis 4.0 version., Section 3.9 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
3.9
Allylic Substitution Reactions
A 1.0 M soln of LiHMDS in THF (950 L, 0.95 mmol) was added dropwise to a suspension of CuI (190.6 mg, 1.00 mmol, previously dried under vacuum at 160 8C) and 4-methoxyacetophenone (150.6 mg, 1.00 mmol) in anhyd THF (2.0 mL) under an atmosphere of argon, and the resulting anion was allowed to form over ca. 2 min until a light yellow homogeneous soln was obtained. The allylic carbonate, catalyst, and enolate solns were then cooled with stirring to 0 8C, and to the allylic carbonate was added the copper enolate followed by the catalyst soln via Teflon cannula. The mixture was then allowed to slowly warm to rt over ca. 4 h (TLC control) resulting in a tan heterogeneous soln. The mixture was then quenched with NH4Cl soln (1 mL) and partitioned between Et2O and sat. aq NH4Cl. The organic layers were combined, dried (MgSO4), filtered, and concentrated under reduced pressure to afford a crude oil. Flash chromatography (EtOAc/hexanes 1:9) followed by removal of excess 4-methoxyacetophenone under vacuum at 160 8C gave the product as a colorless oil; yield: 118.0 mg (80%). 3.9.2
C—N Bond-Forming Reactions
The stereoselective formation of C—N bonds is a significant challenge in organic synthesis, and one which continues to be a vibrant area of research. Whereas there is a significant body of work in allylic substitution reactions, the scope of that work is almost exclusively limited to processes catalyzed by three metals; namely palladium, iridium, and rhodium. Of these, the palladium- and iridium-catalyzed substitution reactions are directed at enantioselective transformations, and the rhodium-catalyzed reactions at stereospecific reactions. 3.9.2.1
Enantioselective Reactions with Achiral Electrophiles and Symmetric Intermediate ð-Allyl Complexes
3.9.2.1.1
Palladium-Catalyzed Reactions
From the 1990s onwards, enantioselective reactions catalyzed by palladium have proven highly useful for adding a range of nitrogen nucleophiles to allylic carbonates and acetates. The examples selected herein highlight a diverse set of reactions, including both intra- and intermolecular allylic substitutions, and illustrate various nucleophiles, which include alkylamines, stabilized amides, imides, and heterocycles. All of the examples have been selected because of their application to the construction of synthetic building blocks and biologically active natural products. One of the first examples of the intramolecular enantioselective additions with nitrogen nucleophiles is the formation of chiral pyrrolidines and piperidines. In a representative example, the achiral, acyclic alkylamine 75 affords the piperidine 76 in 97% yield and with excellent enantioselectivity using ligand ent-2 (Scheme 27).[41] In this case, given the lack of chirality in the starting material and the intramolecular nature of the reaction, the mechanism for enantiodiscrimination is consistent with enantiotopic facial discrimination of the alkene by the chiral palladium complex.
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3.9.2
423
C—N Bond-Forming Reactions Enantioselective Synthesis of a Chiral Piperidine[41]
Scheme 27
O
O 2.5 mol%
NH
HN
Ph2P PPh2 ent-2 1.0 mol% Pd2(η3-C3H5)2Cl2 Et3N, THF, −45 oC
NH
N
97%; 91% ee
OAc MeO
MeO 75
76
Sulfonamides are by far the most utilized category of nitrogen nucleophiles which provide excellent pronucleophiles in asymmetric allylic amination reactions. For example, the cyclic allylic phosphonate 77 reacts with the N-tosylaniline 78, via a meso-intermediate, to afford allylic sulfonamide 80 in good yield and with moderate enantioselectivity (Scheme 28).[42,43] This key intermediate is then transformed into the natural product (–)-tubifoline (81), a strychnos alkaloid. A striking feature of this work is the use of the BINAPO ligand 79, which has not yet featured in this review. Scheme 28 Enantioselective Addition of a Sulfonamide Nucleophile in the Total Synthesis of (–)-Tubifoline[42,43]
O O
5.6 mol%
PPh2 PPh2
79
OTBDMS O
OEt P OEt
NHTs +
80%; 84% ee
Br
O 77
2.8 mol% Pd2(dba)3•CHCl3 DMF, 0 oC
78 OTBDMS
N Et
Ts N H Br 80
N 81
Phthalimide (83) provides an outstanding nucleophile in palladium-catalyzed allylic substitution reactions. The palladium-catalyzed amination of vinyl epoxide 82 with the anion of 83 using ligand ent-2 affords the functionally diverse amino diol 84 in excellent yield and with decent enantiomeric excess (Scheme 29).[44] This amino diol is subsequently transformed into (+)-polyoxamic acid (85), a novel amino acid with antifungal activity.
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424
Stereoselective Synthesis Scheme 29 Acid[44]
3.9
Allylic Substitution Reactions
Phthalimide as a Nucleophile in the Asymmetric Synthesis of (+)-Polyoxamic
O 7.5 mol% ent-2 2.5 mol% Pd2(dba)3•CHCl3 10 mol% Cs2CO3, THF, rt
HN
O
OH
+
87%; 82% ee
O 82
83
NH2
OH
HO O
OH
O
N
O
HO
OH
OH 84
85
Another interesting recent development in palladium-catalyzed C—N bond forming reactions is the ability to employ heterocyclic pronucleophiles. For example, the bromopyrrole 87 undergoes palladium-catalyzed amination with a meso-dicarbonate 86 using ligand ent-2 to furnish carbonate 88 in 88% yield and with 87% enantiomeric excess (Scheme 30).[45] The enantiomeric excess can be increased to 92% albeit in slightly lower yield (83%). The functionalized product is then converted in an efficient seven-step sequence into (+)-agelastatin A (89), a bioactive natural product. Scheme 30 A[45]
Employing a Heterocyclic Pronucleophile in the Total Synthesis of Agelastatin
BocO Br
6.0 mol% ent-2 2.0 mol% Pd2(η3-C3H5)2Cl2
H N
+
Cs2CO3, CH2Cl2, rt
CO2Me
88%; 87% ee
BocO 86
87 Me
BocO
HO 7 steps
Br
Br
N
H N
O N NH H H NH
CO2Me O 88
89
Methyl 5-Bromo-1-{(1S,4R)-4-[(tert-butoxycarbonyl)oxy]cyclopent-2-enyl}-1H-pyrrole-2carboxylate (88); Typical Procedure:[45]
A soln of Pd2(Å3-C3H5)2Cl2 (18.3 mg, 50 mol) and ligand ent-2 (103.5 mg, 0.15 mmol) in CH2Cl2 (15 mL) was added to a mixture of carbonate 86 (750 mg, 2.5 mmol), pyrrole 87 (512.5 mg, 2.5 mmol), and Cs2CO3 (815 mg, 2.5 mmol) under argon. The mixture was stirred at rt for 3 h and then filtered through Celite. After concentration under reduced pressure, flash chromatography (petroleum ether/Et2O 25:1) afforded the product as a light yellow oil; yield: 846 mg (88%); 87% ee.
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3.9.2
3.9.2.1.2
425
C—N Bond-Forming Reactions
Iridium-Catalyzed Reactions
Allylic substitution reactions catalyzed by iridium nicely complement the palladium-catalyzed variants, by allowing transformations that are otherwise difficult to achieve with palladium. There are three examples that nicely illustrate the scope of the reaction, which utilize arylamines, sulfonamides, and ammonia as pronucleophiles. One of the classic substrates for probing the linear versus branched selectivity in allylic substitution reactions for a given ligand–catalyst system is methyl cinnamyl carbonate (90). Using this substrate with an arylamine nucleophile, and an iridium catalyst in the presence of the phosphoramidite ligand 91, furnished the branches allylic amine 92 with very high branched to linear selectivity (up to 99:1) and excellent enantioselectivity (up to 96% ee). Several representative examples using both electron-rich and electron-poor anilines are illustrated in Scheme 31.[46] Scheme 31
Enantioselective Allylic Substitution with Arylamines[46] Ph O P
N
O Ph 91
Ph
OCO2Me
+
Ar1
NH2
Ir2Cl2(cod)2 (cat.), THF 10 mol% DABCO
90 NHAr1 +
NHAr1
Ph
Ph 92
Ar1
Ratio (92/93) ee (%) of 92 Yield (%) Ref
4-Tol
99:1
94
76
[46]
4-MeOC6H4
98:2
95
91
[46]
4-FC6H4
98:2
94
90
[46]
4-F3CC6H4
94:6
96
72
[46]
2-BrC6H4
93:7
94
66
[46]
3-MeSC6H4
97:3
96
85
[46]
93
While sulfonamide nucleophiles provide excellent regio- and enantioselectivity with palladium-catalyzed processes, the examples are limited and substrate specific. Iridium-catalyzed allylic substitution with tosyl or nosyl (nitrophenylsulfonyl) amines provides an alternative method to access acyclic unsymmetrical allylic amines. Treatment of these nucleophiles with simple carbonates 94 using the phosphoramidite ligand 16 affords outstanding enantioselectivity (up to 97% ee) with variable regioselectivity ranging from low [(95/96) 3:1] to outstanding [(95/96) 49:1] (Scheme 32).[47] This reaction creates highly versatile chiral synthetic intermediates for application in target synthesis.
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Stereoselective Synthesis
3.9
Allylic Substitution Reactions
Enantioselective Aminations with Anionic N-Nucleophiles[47]
Scheme 32
OMe O 4 mol%
P
N
O OMe 16
R1
OCO2Me
+
2 mol% Ir2Cl2(cod)2 8 mol% TBD, Et3N, THF
R2NHBn
94 R2
N
Bn 1 + R
N
Bn
R2
R1 95
96
N TBD = N H
N
R1
R2
Ratio (95/96) ee (%) of 95 Yield (%) Ref
Ph
Ts
49:1
98
92
[47]
Ph
4-O2NC6H4SO2
13:1
96
91
[47]
(CH2)2Ph
Ts
4:1
95
60
[47]
(CH2)2Ph
2-O2NC6H4SO2
3:1
97
79
[47]
The ability to employ ammonia as a pronucleophile in the transition-metal-catalyzed allylic substitution has proven challenging, since the initial product is able to undergo further amination leading to mixtures of products. The following examples illustrate the power of iridium catalysis for the enantioselective monoallylation with ammonia, and provide an impressive approach to this problem. In the first example, a wide variety of allylic carbonate electrophiles 97 react to give allylic amine salts 98 with outstanding enantioselectivities using the chiral ligand 16 (Scheme 33).[48] At the time of writing, no total synthesis has been completed with this new process, as it was disclosed less than a year before, but future targets will undoubtedly be prepared by this method. Scheme 33
Iridium-Catalyzed Allylic Amination with Ammonia[48] 4 mol% 16, NH3 (100 equiv) 2 mol% Ir2Cl2(cod)2, THF 30 oC, pressure vessel
NH3 Cl
then HCl
R1
OCO2Et
R1
97
98
R1
ee (%) of 98 Yield (%) Ref
Ph
97
73
[48]
4-Tol
99
63
[48]
4-MeOC6H4 98
58
[48]
4-BrC6H4
99
57
[48]
4-F3CC6H4
99
51
[48]
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3.9.2
427
C—N Bond-Forming Reactions
R1
ee (%) of 98 Yield (%) Ref
3-MeOC6H4 98
66
[48]
(CH2)6Me
96
49
[48]
CH2OTr
97
53
[48]
99
57
[48]
The second example utilizes sulfamic acid as an ammonia equivalent.[49] In this case the allylic alcohols 99 are activated in situ to deliver primary amine salts 101 in up to 85% yield with complete control of regioselectivity using an achiral ligand (Scheme 34). The chiral ligand 100 affords the enantiomerically enriched allylic amine (up to 93% ee) after trituration of the product. The chirality of the starting material (when enantiomerically enriched starting material is employed) is transferred to the product. The in situ activation of allylic alcohols is not limited to just this example, and a similar approach with iridium has been employed for the preparation of substituted alkylamines.[50] Scheme 34
Iridium-Catalyzed Synthesis of Primary Allylic Amines from Allylic Alcohols[49]
O P
3 mol%
N
O
OH + R1
H3N
SO3
100 1.5 mol% Ir2Cl2(cod)2, DMF
NH3 HSO4 R1 101
99 R1 = alkyl, aryl
Allylic Amines 95 and 96; General Procedure:[47]
A soln of Ir2Cl2(cod)2 (0.02 mmol) and ligand 16 (0.04 mmol) in anhyd THF (0.5 mL) was treated with 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD; 0.08 mmol) under argon [note: success with this procedure requires the use of anhyd THF (19:1) and near-complete conservation of enantiomeric excess. This synthetic intermediate is readily cleaved under reductive conditions to give the free amine 121. Scheme 39
Stereospecific Allylic Amination Using an Aza-Ylide[55] LiHMDS, THF, 25 oC RhCl(PPh3)3 (cat.), P(OMe)3
OCO2Me BnO 114
I
I N NH2, LiI, AcOH 88%
98% ee
HN
N
BnO 120
96% ee
NH2
0.5 M SmI2, THF, rt 88%
BnO 121
96% ee
N-[(S)-1-(Benzyloxy)but-3-en-2-yl]-4-methyl-N-[(R)-1-phenylallyl]benzenesulfonamide (118); Typical Procedure:[54]
CAUTION: Trimethyl phosphite is flammable and has a powerful, obnoxious odor. Induces headache. Severe skin and eye irritant. Corrosive and irritating to the respiratory tract. P(OMe)3 (25 L, 0.42 mmol) was added directly to a red soln of RhCl(PPh3)3 (Wilkinsons catalyst; 0.046 g, 0.1 mmol, 10 mol%) in anhyd THF (2.0 mL) at 30 8C under an atmosphere of argon. The catalyst was allowed to form over 30 min, resulting in a light yellow homogeneous soln. The allylic amine 116 (0.332 g, 1.0 mmol) was weighed into a flame dried, 10-mL, round-bottomed flask and dissolved in anhyd THF (2 mL). The soln was then placed Allylic Substitution Reactions, Crawley, M. L. Science of Synthesis 4.0 version., Section 3.9 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.9.3
431
C—O Bond-Forming Reactions
under argon and warmed to 30 8C. A 1.0 M soln of LiHMDS in THF (1.0 mL, 1.00 mmol) was added dropwise to the soln, and the anion was allowed to form for 30 min. The anion soln was then transferred via cannula to the rhodium catalyst and the starting flask was rinsed with anhyd THF (2 0.5 mL). The optically active allylic carbonate 117 (>99% ee; 0.097 g, 0.51 mmol) was then added dropwise to the preformed catalyst system using a tared 250-L syringe. The mixture was stirred at 30 8C for 6 h and then partitioned sequentially between Et2O and sat. aq NaHCO3 and aq NaCl. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash chromatography (EtOAc/hexanes 1:20 to 1:8) afforded the product as a clear oil; yield: 0.195 g (87%); diastereoselectivity 99:1.
3.9.3
C—O Bond-Forming Reactions
3.9.3.1
Enantioselective Reactions with Achiral Electrophiles and Symmetric Intermediate ð-Allyl Complexes
3.9.3.1.1
Palladium-Catalyzed Reactions
Palladium-catalyzed allylic alkylations with oxygen nucleophiles, when compared to other metal-catalyzed allylic alkylations of this type, provide one of the most versatile methods by which to form a C—O bond. Although there are examples with alcohol nucleophiles, the most common reactions to form both tertiary and quaternary centers utilize acetate and phenol pronucleophiles. Three examples have been selected for review, one to highlight the basic reaction with acetates to make synthetically useful building blocks, and two to demonstrate the power of this transformation in total synthesis. The deracemization of cyclic allylic carbonates is an important approach to building versatile synthetic intermediates. For example, chiral indanes are often present in drug candidates, such as in an AIDS protease inhibitor. Utilizing what has become a standard protocol, (R)-1H-inden-1-yl pivalate (123) may be obtained from racemic carbonate 122 in a yield of 91% and with 98% enantiomeric excess using ligand ent-2 (Scheme 40).[56] This is just one of dozens of reports of this type of transformation. Scheme 40
Deracemization of a Cyclic Allylic Carbonate[56]
O
O 7.5 mol%
But
HN
Ph2P PPh2 ent-2 2.5 mol% Pd2(η3-C3H5)2Cl2 [Me(CH2)5]4N+ Br−, CH2Cl2, −78 oC
O +
NH
ONa
O
91%; 98% ee
OCO2Me
O
122
But
123
The enantioselective total synthesis of (–)-galanthamine (128), a potent acetylcholine esterase inhibitor, nicely demonstrates the utility of the palladium-catalyzed allylic substitution with phenolic pronucleophiles.[57,58] The allylic substitution reaction of the highly functionalized phenol 124 and a cyclic carbonate 125 utilizing the modified ligand 126 affords the desired adduct 127 in 72% yield with 88% enantiomeric excess (Scheme 41). This core is subsequently transformed into (–)-galanthamine (128) in a series of two sets of reactions to complete two divergent total syntheses. Allylic Substitution Reactions, Crawley, M. L. Science of Synthesis 4.0 version., Section 3.9 sos.thieme.com © 2014 Georg Thieme Verlag KG
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432
Stereoselective Synthesis Scheme 41
Allylic Substitution Reactions
3.9
Enantioselective Total Synthesis of (–)-Galanthamine[57,58] Ph
Ph O
O NH
3.0 mol%
Ph2P
PPh2
OH MeO
HN
126 1.0 mol% Pd2(η3-C3H5)2Cl2
O
Br +
Et3N, CH2Cl2, rt
O
O
72%; 88% ee
CHO
CO2Me
CCl3 125
124
OH H O
O CO2Me
MeO
MeO
Br N
CHO 127
Me 128
Another powerful example of a phenol pronucleophile features in the total syntheses of (–)-calanolide A (133, R1 = H; R2 = OH) and (–)-calanolide B (133, R1 = OH; R2 = H), which are natural products with potent activity against HIV.[59] Utilizing a highly functionalized phenol 130 together with allylic carbonate 129, the allylic substitution product, ether 132, is obtained in 85% yield with 92:8 regioselectivity and 98% enantiomeric excess (Scheme 42). It should be noted that an atypical modification of the standard Trost ligand 131 is used to reverse the intrinsic regioselectivity of attack of the phenol in the -allyl intermediate. The key intermediate 132 is then transformed over several steps into the (–)-enantiomer of both calanolide natural products. The correct absolute configuration of the natural product would be readily obtained by presumably using the enantiomeric ligand.
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3.9.3
433
C—O Bond-Forming Reactions
Scheme 42
Total Syntheses of (–)-Calanolide A and (–)-Calanolide B[59]
O
H N
NH
7.5 mol%
O PPh2 Ph2P
OH
131 2.5 mol% Pd2(dba)3•CHCl3 THF, rt
OCO2Me
+ O
85%; 98% ee; (branched/linear) 92:8
O Pr
129
O
130
O
O
R2 R1
O
O Pr
O O
132
O Pr
O 133
2,2-Dimethyl-5-[(S)-(3-methylbut-3-en-2-yl)oxy]-10-propyl-3,4-dihydropyrano[2,3-f ][1]benzopyran-8(2H)-one (132); Typical Procedure:[59]
A soln of phenol 130 (467 mg, 3.2mmol), Pd2(dba)3•CHCl3 (70 mg, 0.068 mmol), and ligand 131 (162 mg, 0.20 mmol) in THF (2.0 mL) was stirred at 0 8C for 15 min. To this soln was added carbonate 129 (780 mg, 2.7 mmol) in THF (4.0 mL) and the mixture was stirred at rt for 12 h. The resulting yellow soln was concentrated under reduced pressure and purified by flash chromatography (CH2Cl2) to afford the product as a colorless liquid; yield: 785 mg (85%); 98% ee; ratio (branched/linear) 92:8. 3.9.3.1.2
Iridium-Catalyzed Reactions
There are relatively few examples of the iridium-catalyzed intermolecular allylic etherification. However, a compelling example has been reported using copper aliphatic alkoxides which provide excellent numcleophiles for this type of reaction.[60,61] The protocol is somewhat limited in practicality by the necessity of employing a drybox; however, the reaction does generate remarkable branched to linear selectivity (up to ‡99:1) and excellent yields in the synthesis of allylic ethers 137 and 138 from carbonate electrophiles 134 using a variety of alkoxide nucleophiles 135 with the phosphoramidite ligand 136 (Scheme 43). Some of the branched ethers 137 obtained can be readily cyclized by alkene metathesis to afford dihydrofurans and dihydropyrans as synthetic building blocks (see Section 3.9.2.3.1).
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434
Stereoselective Synthesis Scheme 43
3.9
Allylic Substitution Reactions
Allylic Etherification with Aliphatic Alkoxides[60]
O P
N
O
R1
OCO2
But
+
136 Ir2Cl2(cod)2, CuI, THF
R2OLi 135
134
OR2 + R1
R1 137
138
R1
R2
Ratio (137/138) ee (%) 137 Yield (%) Ref
Me
Bn
95:5
97
80
[60]
Ph
CHiPr2
99:1
96
86
[60]
Ph
Cy
97:3
94
79
[60]
Ph
NBoc
98:2
95
70
[60]
Me
NBoc
97:3
94
56
[60]
Pr
NBoc
92:8
93
66
[60]
Cy
94:6
86
59
[60]
4-MeOC6H4 Cy
99:1
95
86
[60]
Ph
96:4
63
80
[60]
4-O2NC6H4
t-Bu
OR2
Allylic Ethers 137; General Procedure:[60]
Lithium alkoxide 135 (1.00 mmol) and CuI (200 mg, 1.05 mmol) were mixed in a screwcapped vial in a drybox. THF (1.0 mL) was added and the suspension was stirred for 30 min. To this suspension were added a soln of Ir2Cl2(cod)2 (3.4 mg, 0.051 mmol for primary alkoxides; 6.7 mg, 0.010 mmol for secondary and tertiary alkoxides) and ligand 136 (6.4 mg, 0.010 mmol for primary alkoxides; 12.8 mg, 0.020 mmol for secondary and tertiary alkoxides) in THF (0.5 mL for primary alkoxides; 1.0 mL for secondary and tertiary alkoxides). A stirrer bar was added and the vial was sealed with a cap containing a PTFE septum and removed from the drybox. The vial was placed in an ice–water bath, and methyl carbonate 134 (0.50 mmol) was added to the reaction by syringe. The mixture was allowed to warm to rt and stirred for 4 h. After the reaction was complete (as determined by GC and TLC) the crude mixture was passed through a pad of silica gel (EtOAc/ hexanes 1:9) and the resulting soln was concentrated. The ratio of regioisomers was determined by 1H NMR spectroscopy of the crude sample. The mixture was then purified by flash chromatography to give the desired product.
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3.9.3
435
C—O Bond-Forming Reactions
3.9.3.2
Dynamic Kinetic Asymmetric Resolution
3.9.3.2.1
Palladium-Catalyzed Reactions
As in the case of C—C bond formation (see Section 3.9.1.2), the reaction to form C—O bonds by a dynamic kinetic asymmetric resolution is a powerful tool to convert a mixture of enantiomers into a single enantiomer of product. While the promise of this type of transformation is high there have been relatively few examples reported. One compelling example features in the total synthesis of tipranavir (57) (see Scheme 20, Section 3.9.1.2.2). Here, the reaction of 4-methoxybenzyl alcohol with the racemic vinyl epoxide 139 is catalyzed by both palladium and boron, in the presence of ligand 2, to afford regioselectively the allylic ether 140 in 69% yield and with 98% enantiomeric excess (Scheme 44). The boron additive is critical to make the “ate” complex of the primary alcohol from the opened epoxide which controls the regioselectivity through proximity. Scheme 44 Palladium-Catalyzed Allylic Substitution with 4-Methoxybenzyl Alcohol in the Synthesis of Tipranavir[34]
O
O 3 mol%
NH
HN
Ph2P
PPh2 2
O Pr
1 mol% Pd2(dba)3•CHCl3
OH
PMBOH, 1 mol% BEt3 69%; 98% ee
Pr
139
OPMB 140
Alternative pronucleophiles have also been used to facilitate the total syntheses of two complex biologically important natural products. For example, highly functionalized phenol 141 undergoes reaction with racemic 5-oxo-2,5-dihydrofuran-2-yl carbonate rac142, using ligand ent-2, to afford the chiral ether 143 in 89% yield with 95% enantiomeric excess (Scheme 45).[62] This key intermediate is then transformed in just three steps into (–)-aflatoxin B lactone (144), which constitutes a formal synthesis of aflatoxin B as the final product has been obtained previously in three steps from the lactone.[63]
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436
Stereoselective Synthesis
3.9
Allylic Substitution Reactions
Scheme 45 Palladium-Catalyzed Allylic Substitution with tert-Butyl 5-Oxo-2,5-dihydrofuran-2-yl Carbonate in an Enantioselective Synthesis of (–)-Aflatoxin B Lactone[62] O O
OEt
7.5 mol% ent-2 2.5 mol% Pd2(dba)3•CHCl3
O
TBACl, CH2Cl2, rt
+
I
BocO
O
O
89%; 95% ee
OH
MeO 141
rac-142
O O
O
O
OEt
O
O
3 steps
I
O
H O
O
MeO
O
O
O
MeO
143
H
144
In a similar manner, 2-naphthol (145) may be employed with the same racemic 5-oxo-2,5dihydrofuran-2-yl carbonate rac-142, again using ligand ent-2, to give ether 146 in up to 87% yield and with 92–97% enantiomeric excess (Scheme 46). This key intermediate can then be transformed in 13 steps into the biologically active macrolactone (+)-brefeldin A (147).[64,65] Scheme 46 Palladium-Catalyzed Allylic Substitution with tert-Butyl 5-Oxo-2,5-dihydrofuran-2-yl Carbonate in an Efficient Synthesis of (+)-Brefeldin A[64,65] 7.5 mol% ent-2 2.5 mol% Pd2(dba)3•CHCl3
+ OH
TBACl, CH2Cl2, rt
BocO
145
O
O
87%; 97% ee
rac-142
H
OH
O
13 steps
HO O
O
O H 147
146
In the dynamic kinetic asymmetric resolution of 5-oxo-2,5-dihydrofuran-2-yl carbonate rac-142 the mechanism of equilibration of the diastereotopic complexes 148A and 148B, obtained from enantiomers 142A and 142B, may not be obvious. However, one regioisomer of the complex is essentially a palladium enolate, which allows interconversion to occur through an achiral -complex 149. Indeed, the aromatic nature of the furan is likely to be the driving force for equilibration between the -complex 149 and the -complexes 148A and 148B. Based on the differential rates of reactivity of the -complexes, a single enantiomer 150A and 150B is obtained dependent on the configuration of the ligand employed (Scheme 47).
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3.9.3
437
C—O Bond-Forming Reactions
Scheme 47 Mechanism for the Dynamic Kinetic Asymmetric Transformation Using tertButyl 5-Oxo-2,5-dihydrofuran-2-yl Carbonate
PdL2
path a Nu−
PdL2
BocO
O
O
O
Nu
O
148A
142A
O
O
O
150A
OPdL2
149
PdL2
path b Nu−
PdL2
BocO
O
O
O
Nu
O
O
150B
148B
142B
O
(S)-5-(2-Naphthyloxy)furan-2(5H)-one (146); Typical Procedure:[64,65]
A round-bottomed flask was charged with 2-naphthol (145; 50 mg, 0.35 mmol), carbonate rac-142 (83 mg, 0.42 mmol), Pd2(dba)3 (9.0 mg, 0.0087 mmol), ligand ent-2 (18 mg, 0.028 mmol), and TBACl (30 mg, 0.10 mmol). The flask was subjected to three cycles of a vacuum purge followed by refilling with argon and freshly distilled CH2Cl2 (3.5 mL) was then added. The resulting purple soln was stirred at 0 8C for 12 h. Flash chromatography of the solution (petroleum ether/Et2O 3:2) directly afforded the product as a white solid; yield: 68 mg (87%); 98% ee. 3.9.3.3
Stereospecific Allylic Substitution with Chiral Electrophiles
3.9.3.3.1
Rhodium-Catalyzed Reactions
In comparison to C—C and C—N bond-forming reactions, there have been far fewer efforts to enable stereospecific allylic substitution to prepare C—O bonds, in which the rhodiumcatalyzed process is by far the best method. One example that highlights the potential of this method is the reaction of a simple chiral allylic carbonate (R)-72 with the sodium salt 151 of 1,1¢-biphenyl-2-ol to afford the aryl ether 152 in 96% yield with near complete conservation of chirality [93% ee from 95% ee in (R)-72] and virtually no trace of the linear ether 153 (Scheme 48).[66] Scheme 48 Regio- and Stereospecific Rhodium-Catalyzed Intermolecular Allylic Etherification with an ortho-Substituted Phenol[66] Ph ONa 151
OCO2Me
Ph
RhCl(PPh3)3 (cat.) P(OMe)3, THF
O
(R)-72
95% ee
Allylic Substitution Reactions, Crawley, M. L. Science of Synthesis 4.0 version., Section 3.9 sos.thieme.com © 2014 Georg Thieme Verlag KG
152
96%; 93% ee
Ph +
O
153
for references see p 440 (Customer-ID: 5907)
438
Stereoselective Synthesis
3.9
Allylic Substitution Reactions
The efficacy of this method is further demonstrated by the reaction of a functionalized chiral carbonate 154 with a 2,5-disubstituted phenol 155. This process gives aryl ethers 156 and 157, favoring the branched isomer [ratio (156/157) 28:1], in good yield (87%) and with high conservation of enantiomeric excess (92% ee for branched ether 156 from 99% ee in 154) (Scheme 49).[66] The branched ether 156 can then be converted in one step into dihydrobenzo[b]furan derivatives 158 and 159 favoring the trans-form 158 (diastereoselectivity 29:1). Scheme 49 Synthesis of Functionalized Dihydrobenzo[b]furans by Allylic Etherification Using a Phenol[66]
ONa
OBn
I 155
I
RhCl(PPh3)3 (cat.) P(OMe)3, THF
BnO
O
+ OCO2Me
154
I
OBn
O
156
99% ee
157
87%; 92% ee
76%
(TMS)3SiH BEt3, O2, rt
+
BnO O 158
BnO O 159
Another compelling example utilizes copper(I) alkoxides, generated in situ from the corresponding lithium alkoxides, as the nucleophile.[61] These copper species react with allylic carbonates to afford products with very high regioselectivity and conservation of enantiomeric excess. The best example (Scheme 50) gives a single regioisomer of ether 161 from allylic carbonate 160 in 81% yield and with 96% conservation of enantiomeric excess. Scheme 50 Regio- and Enantiospecific RhodiumCatalyzed Allylic Etherification Using Copper(I) Alkoxides[61] BnOLi RhCl(PPh3)3 (cat.)
OCO2But
P(OMe)3, THF CuCl, −10 oC
OBn
81%
160
161
The best (and perhaps the lone) example of this methodology being efficiently employed in total synthesis occurs in the stereodivergent construction of cyclic ethers, as exemplified in the total synthesis of gaur acid (165), a natural mosquito deterrent (Scheme 51).[67] An in situ generated copper alkoxide, obtained from the lithium alkoxide of alcohol 163, reacts with allylic carbonate 162 to afford intermediate ether 164 in 69% yield and greater Allylic Substitution Reactions, Crawley, M. L. Science of Synthesis 4.0 version., Section 3.9 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.9.3
439
C—O Bond-Forming Reactions
than 19:1 regioselectivity and enantiospecificity. This ether is subsequently cyclized by metathesis and transformed by traditional organic reactions into the target natural product. Scheme 51
Allylic Substitution with Copper Alkoxides in the Total Synthesis of Gaur Acid[67] OCO2But
OBn +
TBDMSO
69%
7
4
LiHMDS, CuI RhCl(PPh3)3 (cat.) P(OMe)3, THF
OH 162
163
O TBDMSO
4
O
7
HO
4
O
7
OH
OBn 165
164
(R)-2-(But-3-en-2-yloxy)-1,1¢-biphenyl (152); Typical Procedure:[66]
CAUTION: Trimethyl phosphite is flammable and has a powerful, obnoxious odor. Induces headache. Severe skin and eye irritant. Corrosive and irritating to the respiratory tract. P(OMe)3 (24 L, 0.20 mmol) was added directly to a red soln of RhCl(PPh3)3 (Wilkinsons catalyst; 43.7 mg, 0.047 mmol) in anhyd THF (2.0 mL) at 30 8C under an atmosphere of argon. The catalyst was allowed to form over 15 min resulting in a light yellow, homogeneous soln. A 2.0 M soln of NaHMDS in THF (0.475 mL, 0.95 mmol) was added to phenol 151 (0.184 g, 1.1 mmol) in anhyd THF (3.0 mL) and the anion was allowed to form over 10 min. The catalyst and sodium phenoxide solutions were then cooled to 0 8C. The optically active allylic carbonate (R)-72 (65.7 mg, 0.51 mmol; 95% ee) was then added dropwise to the preformed catalyst system using a tared 100-L syringe. The sodium phenoxide soln was then transferred via cannula to the rhodium catalyst/carbonate system, and the whole was allowed to warm to rt over 4 h. The mixture was then quenched with 30% H2O2 soln (1 mL) and partitioned sequentially between Et2O and sat. aq NH4Cl and aq NaCl. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash chromatography (EtOAc/hexanes 3:97) afforded ether 152 as a colorless oil; yield: 0.108 g (96%); 93% ee.
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Stereoselective Synthesis
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Allylic Substitution Reactions
References [1] [2]
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Trost, B. M.; Van Vranken, D. L., Chem. Rev., (1996) 96, 395. Trost, B. M.; Lee, C. B., In Catalytic Asymmetric Synthesis, 2nd ed., Ojima, I., Ed.; Wiley-VCH: New York, (2000); pp 593–650. Falciola, C. A.; Alexakis, A., Eur. J. Org. Chem., (2008), 3765. Helmchen, G.; Dahnz, A.; Dbon, P.; Schelwies, M.; Weihofen, R., Chem. Commun. (Cambridge), (2007), 675. Belda, O.; Moberg, C., Acc. Chem. Res., (2004) 37, 159. Farthing, C. N.; Kocˇovsky´, P., J. Am. Chem. Soc., (1998) 120, 6661. Leahy, D. K.; Evans, P. A., In Modern Rhodium-Catalyzed Organic Reactions, Evans, P. A., Ed.; WileyVCH: Weinheim, Germany, (2005); pp 191–214. Trost, B. M.; Crawley, M. L., Chem. Rev., (2003) 103, 2921. Graening, T.; Schmalz, H.-G., Angew. Chem., (2003) 115, 2684; Angew. Chem. Int. Ed., (2003) 42, 2580. Evans, P. A.; Nelson, J. D., J. Am. Chem. Soc., (1998) 120, 5581. Krska, S. W.; Hughes, D. L.; Reamer, R. A.; Mathre, D. J.; Sun, Y.; Trost, B. M., J. Am. Chem. Soc., (2002) 124, 12 656. Lloyd-Jones, G. C.; Krska, S. W.; Hughes, D. L.; Gouriou, L.; Bonnet, V. D.; Jack, K.; Sun, Y.; Reamer, R. A., J. Am. Chem. Soc., (2004) 126, 702. Madrahimov, S. T.; Markovic, D.; Hartwig, J. F., J. Am. Chem. Soc., (2009) 131, 7228. Malkov, A. V.; Gouriou, L.; Lloyd-Jones, G. C.; Stary´, I.; Langer, V.; Spoor, P.; Vinader, V.; Kocˇovsky´, P., Chem.–Eur. J., (2006) 12, 6910. Bergner, E. J.; Helmchen, G., Eur. J. Org. Chem., (2000), 419. Trost, B. M.; Bunt, R. C., J. Am. Chem. Soc., (1994) 116, 4089. Kudis, S.; Helmchen, G., Angew. Chem., (1998) 110, 3210; Angew. Chem. Int. Ed., (1998) 37, 3047. Trost, B. M.; Chupak, L. S.; Lbbers, T., J. Am. Chem. Soc., (1998) 120, 1732. Trost, B. M.; Lee, C. B., J. Am. Chem. Soc., (2001) 123, 12 191. Trost, B. M.; Crawley, M. L.; Lee, C. B., J. Am. Chem. Soc., (2000) 122, 6120. Trost, B. M.; Radinov, R.; Grenzer, E. M., J. Am. Chem. Soc., (1997) 119, 7879. Tissot-Croset, K.; Alexakis, A., Tetrahedron Lett., (2004) 45, 7375. Lpez, F.; van Zijl, A. W.; Minnaard, A. J.; Feringa, B. L., Chem. Commun. (Cambridge), (2006), 409. Luchaco-Cullis, C. A.; Mizutani, H.; Murphy, K. E.; Hoveyda, A. H., Angew. Chem., (2001) 113, 1504; Angew. Chem. Int. Ed., (2001) 40, 1456. Murphy, K. E.; Hoveyda, A. H., J. Am. Chem. Soc., (2003) 125, 4690. Glorius, F.; Neuburger, M.; Pfaltz, A., Helv. Chim. Acta, (2001) 84, 3178. Trost, B. M.; Zhang, Y., J. Am. Chem. Soc., (2007) 129, 14 548. Trost, B. M.; Dogra, K., Org. Lett., (2007) 9, 861. Dbon, P.; Schelwies, M.; Helmchen, G., Chem.–Eur. J., (2008) 14, 6722. Dahnz, A.; Helmchen, G., Synlett, (2006), 697. Alexakis, A.; Hajjaji, S. E.; Polet, D.; Rathgeb, X., Org. Lett., (2007) 9, 3393. Trost, B. M.; Jiang, C., Org. Lett., (2003) 5, 1563. Palucki, M.; Um, J. M.; Yasuda, N.; Conlon, D. A.; Tsay, F.-R.; Hartner, F. W.; Hsiao, Y.; Marcune, B.; Karady, S.; Hughes, D. L.; Dormer, P. G.; Reider, P. J., J. Org. Chem., (2002) 67, 5508. Trost, B. M.; Andersen, N. G., J. Am. Chem. Soc., (2002) 124, 14 320. Breit, B.; Demel, P.; Studte, C., Angew. Chem., (2004) 116, 3874; Angew. Chem. Int. Ed., (2004) 43, 3786. Ashfeld, B. L.; Miller, K. A.; Martin, S. F., Org. Lett., (2004) 6, 1321. Evans, P. A.; Kennedy, L. J., Org. Lett., (2000) 2, 2213. Evans, P. A.; Leahy, D. K., J. Am. Chem. Soc., (2003) 125, 8974. Evans, P. A.; Lawler, M. J., J. Am. Chem. Soc., (2004) 126, 8642. Evans, P. A.; Uraguchi, D., J. Am. Chem. Soc., (2003) 125, 7158. Trost, B. M.; Krische, M. J.; Radinov, R.; Zanoni, G., J. Am. Chem. Soc., (1996) 118, 6297. Mori, M.; Nakanishi, M.; Kajishima, D.; Sato, Y., Org. Lett., (2001) 3, 1913. Mori, M.; Nakanishi, M.; Kajishima, D.; Sato, Y., J. Am. Chem. Soc., (2003) 125, 9801. Trost, B. M.; Krueger, A. C.; Bunt, R. C.; Zambrano, J., J. Am. Chem. Soc., (1996) 118, 6520. Trost, B. M.; Dong, G., J. Am. Chem. Soc., (2006) 128, 6054.
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Shu, C.; Leitner, A.; Hartwig, J. F., Angew. Chem., (2004) 116, 4901; Angew. Chem. Int. Ed., (2004) 43, 4797. Weihofen, R.; Dahnz, A.; Tverskoy, O.; Helmchen, G., Chem. Commun. (Cambridge), (2005), 3541. Pouy, M. J.; Stanley, L. M.; Hartwig, J. F., J. Am. Chem. Soc., (2009) 131, 11 312. Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M., Angew. Chem., (2007) 119, 3200; Angew. Chem. Int. Ed., (2007) 46, 3139. Yamashita, Y.; Gopalarathnam, A.; Hartwig, J. F., J. Am. Chem. Soc., (2007) 129, 7508. Trost, B. M.; Lemoine, R. C., Tetrahedron Lett., (1996) 37, 9161. You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou, X.-L.; Dai, L.-X., J. Am. Chem. Soc., (2001) 123, 7471. Evans, P. A.; Robinson, J. E.; Nelson, J. D., J. Am. Chem. Soc., (1999) 121, 6761. Evans, P. A.; Robinson, J. E., Org. Lett., (1999) 1, 1929. Evans, P. A.; Clizbe, E. A., J. Am. Chem. Soc., (2009) 131, 8722. Trost, B. M.; Organ, M. G., J. Am. Chem. Soc., (1994) 116, 10 320. Trost, B. M.; Toste, F. D., J. Am. Chem. Soc., (2000) 122, 11 262. Trost, B. M.; Tang, W., Angew. Chem., (2002) 114, 2919; Angew. Chem. Int. Ed., (2002) 41, 2795. Trost, B. M.; Toste, F. D., J. Am. Chem. Soc., (1998) 120, 9074. Shu, C.; Hartwig, J. F., Angew. Chem., (2004) 116, 4898; Angew. Chem. Int. Ed., (2004) 43, 4794. Evans, P. A.; Leahy, D. K., J. Am. Chem. Soc., (2002) 124, 7882. Trost, B. M.; Toste, F. D., J. Am. Chem. Soc., (1999) 121, 3543. Bchi, G.; Weinreb, S. M., J. Am. Chem. Soc., (1971) 93, 746. Trost, B. M.; Crawley, M. L., J. Am. Chem. Soc., (2002) 124, 9328. Trost, B. M.; Crawley, M. L., Chem.–Eur. J., (2004) 10, 2237. Evans, P. A.; Leahy, D. K., J. Am. Chem. Soc., (2000) 122, 5012. Evans, P. A.; Leahy, D. K.; Andrews, W. J.; Uraguchi, D., Angew. Chem., (2004) 116, 4892; Angew. Chem. Int. Ed., (2004) 43, 4788.
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443 3.10
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements S. Jautze and R. Peters
General Introduction
Isomerizations are often attractive reactions since they provide perfect atom economy. In many cases they demonstrate high step-economy due to the considerably enhanced complexity of the rearrangement products formed from readily available starting materials. This section describes Lewis acid catalyzed or promoted enantioselective isomerizations to form one or more stereogenic centers, with a special focus on methodologies with enhanced practical value. Stereoselective isomerizations that are not based on Lewis acid activation are discussed in Section 3.7. The majority of the methods highlighted in the present section involve allylic rearrangements. For asymmetric cycloisomerizations the reader is referred to Section 3.5. It should be noted that several of the reactions described in Section 3.10 might only formally provide pericyclic reaction products, because they might involve the formation of reactive intermediates, whereas a pericyclic reaction is by definition a one-step process involving only a single transition state.
3.10.1
Synthesis by Rearrangement
3.10.1.1
[3,3]-Sigmatropic Rearrangements
3.10.1.1.1
Claisen Rearrangement
The Claisen rearrangement has found widespread application as one of the most fundamental reactions in synthetic organic chemistry.[1–3] However, the number of practically useful, metal-catalyzed methods for enantioselective rearrangement is still relatively small.[4] In the majority of cases a chiral Lewis acid is used in stoichiometric amounts or even in excess as a result of product inhibition. Moreover, the few catalytic methods described are limited to special substrate classes. The first reported catalytic, enantioselective Claisen rearrangement employed allyl 1-(alkoxycarbonyl)vinyl ethers 1, which were rearranged using catalytic amounts of copper bis(4,5-dihydrooxazole) complexes (such as 2 and 3) to afford Æ-oxo esters 4 (Scheme 1).[5–7] This method constitutes enormous progress and is synthetically attractive since two vicinal stereocenters can be formed with high stereoselectivity. It is possible to control the relative configuration by changing the configuration of the vinylic double bond, while maintaining high enantioselectivity in both cases. The cationic complex 3 is found to be significantly more active than the neutral system 2. Whereas excellent diastereoselectivities are generally attained with substrates containing a Z-configured allyl group, the E-configured counterparts are problematic and sometimes provide lower diastereoselectivity. It should also be noted that substituents on the central allylic atom (e.g., R5 = Me) are not well tolerated. The catalytic activity is presumably a direct consequence of the stabilization of a highly polarized transition state by Lewis acid coordination to the ether oxygen. The transition state seems to have significant allylic cation–enolate ion pair character in a highly asynchronous concerted reaction pathway. The necessity of a 1-(alkoxycarbonyl)vinyl substituent is rationalized by bidentate substrate coordination to the copper(II) ion resultIsomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. for references see p 466 Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.10
Isomerizations and Allylic Rearrangements
ing in a rigid complex geometry that is a prerequisite for high enantioselectivity. Assuming a distorted square planar coordination geometry and a chair-like conformation of the transition state 5, the allyl group should approach the vinyl ether double bond from the face opposite to the bulky tert-butyl group on the ligand, thus explaining the reaction outcome. Recent DFT studies have revealed that chair- and boat-like transition states have a relatively small energy difference under certain circumstances, and also address the reason why catalyst 2 usually provides the opposite absolute configuration.[8] Copper-Catalyzed Claisen Rearrangement of Allyl 1-(Alkoxycarbonyl)vinyl Ethers[5–7]
Scheme 1
OR4
O R1
O
R2
OR4
O 2 or 3 CH2Cl2, rt
R1
O
R2
R3
R3
R5 1
R5 4
R1
R2
R3
R4
R5
Me
Me
Me
iPr H
Z
3 (5)
Me
Me
Me
iPr H
E
Me
Me
Me
Me H
Z
Vinyl Ether Catalyst Config (mol%)
Time (h)
Ratio (anti/syn)
ee (%)
Yield (%)
Ref
2
–
99
94a
[6]
3 (5)
2
–
99 >99
[6]
2 (5)
3
–
80
Me
Pr
H
iPr H
E
3 (10)
3
Me
Pr
H
iPr H
Z
3 (10)
3
99
[5]
b
98
99
[7]
1:99
99b
99
[7]
b
97:3
CH2OTBDPS
H
CH2OBn
iPr H
E
3 (5)
4
11:89
94
99
[7]
CH2OTBDPS
CH2OBn
H
iPr H
Z
3 (5)
4
37:63
99b
98
[7]
Me
H
H
iPr H
Z
3 (10)
24
–
95
98
[6]
Me
H
H
iPr H
E
3 (10)
24
–
97
96
[6]
Me
H
H
iPr Me Z
2 (20)
120
–
50
79
[5]
a b
Together with 5% of the [1,3]-rearrangement product. Enantiomeric excess of the major diastereomer.
2+
O
O N
N Cu
Ph
O
TfO 2
N Ph
OTf
O
But
But
Cu H 2O
2SbF6−
N OH2 3
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Synthesis by Rearrangement 2+
O
O N
But
N But
Cu O
2SbF6−
O
δ−
R1Z δ+ R5
i R1E OPr
R2
R3 5
The enantioselective palladium(II)-catalyzed Claisen reaction nicely complements this work, in that a 1-(alkoxycarbonyl)vinyl substituent is not required. However, investigations have been limited to the cyclic allyl vinyl ether 6, which gives anti- and syn-products 8A and 8B (Scheme 2).[9] In contrast to copper(II) catalysis, palladium(II) activation has been proposed to occur by bidentate diene coordination. Early work with achiral palladium(II) salts suggests that the geometry of the transition state largely depends upon the configuration of the allyl moiety.[10–12] Both (Evinyl,Eallyl)- and (Evinyl,Zallyl)-configured cyclic substrates provide anti-products suggesting that the former prefer a boat-like transition state 9 whereas the latter react via a chair-like transition state. Using a neutral bis(trifluoromethanesulfonamide)–palladium complex, prepared in situ from palladium(II) acetate and axially chiral ligand 7, only the E,E-configured substrate rearranges, since the E,Z-isomer is unreactive. Unfortunately, a reaction temperature of 80 8C is required for a preparatively useful yield, which decreases the stereoselectivity of the process. Scheme 2 Ether[9]
Palladium(II)-Catalyzed Asymmetric Claisen Rearrangement of an Allyl Vinyl
5 mol%
NHTf
7
NHTf
O
O
O 5 mol% Pd(OAc)2, MeCN, 80 oC, 24 h
+
69%; (8A/8B) 78:22
6
8A (major)
(E/Z) 83:17
77% ee
8B (minor)
O [Pd(II)]∗
9
Æ-Oxo Esters 4; General Procedure Using a Cationic Copper Catalyst:[7] The reaction was performed under inert conditions using a flame-dried, septum-sealed, round-bottomed flask under an argon atmosphere. The appropriate amount of catalyst 3 was dissolved in anhyd CH2Cl2 (5 mL/mmol of ether). After stirring for 5 min, pulverized and freshly activated 4- molecular sieves (250 mg/mmol of ether) were added, and the mixture was stirred for an additional 5 min. The ether 1 was dissolved in anhyd CH2Cl2 (5 mL • mmol–1) and added to the mixture, the flask was sealed with a rubber septum, Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. for references see p 466 Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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and the mixture was stirred for the appropriate time at rt. The mixture was then diluted with CH2Cl2 and the molecular sieves were removed by filtration. The filtrate was passed through a plug of silica gel (4 0.5 cm, CH2Cl2) to remove the catalyst [for large-scale reactions flash chromatography (heptane/EtOAc 20:1) was used]. The solvents were removed and the residual colorless oil was dried under reduced pressure to provide the analytically pure product. 3.10.1.1.2
Meerwein–Eschenmoser–Claisen Rearrangement
It took nearly half a century from the initial reports[13,14] until the development of the first catalytic enantioselective version of the Meerwein–Eschenmoser–Claisen rearrangement.[15] In classical Meerwein–Eschenmoser–Claisen rearrangements the enol ether portion of a Claisen rearrangement substrate is replaced with a ketene N,O-acetal, to provide a ª,-unsaturated amide as the product. Thus, 1H-indole-3-carboxylates 10, which are difficult to isolate in pure form due to rapid thermal rearrangement, afford indol-2(3H)-ones 13 (Scheme 3). Various metal and organocatalyst systems (e.g., copper, zinc, nickel, silver, and H-bonding derivatives) have been screened, indicating that cationic palladium(II) complexes prepared from axially chiral bisphosphines [such as 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl (11)] or the P,N-ligand (S)-4-tert-butyl-2-[2-(diphenylphosphino)phenyl]-4,5-dihydrooxazole (12) are efficient catalysts and afford good enantioselectivity. For the 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl-derived catalyst, selectivities increase with increasing size of the ester residue (R1) whereas the opposite effect is observed for the ether substituent (R2). The (S)-4-tert-butyl-2-[2-(diphenylphosphino)phenyl]-4,5-dihydrooxazole-derived catalyst acts in a complementary manner, affording high enantioselectivities with sterically demanding ether substituents (R2) in combination with small ester substituents (R1). Interestingly, slightly improved selectivity is observed on a larger scale, and high enantioselection is retained with both electron-donating and electronwithdrawing groups (R3 and R4) on the aromatic ring. In most cases 0.2 equivalents of catalyst is used; however, the reaction can also be performed with 5 mol% catalyst without loss of enantioselectivity. Ester and ether oxygen coordination has been proposed as the primary method of activation in this system. Scheme 3
Meerwein–Eschenmoser–Claisen Rearrangement[15] R2
R2
R1O2C
R1O
20 mol% PdL(SbF6)2 CH2Cl2, 0 oC
R3
R3
2C
O
O
N H
N H
R4
R4 10
R1
R2
Me
Me H H
11 20
89
89
[15]
Me
H
H H
12 10
83
>99
[15]
Me
Et
H H
12 20
92
82
[15]
Bn
H
H H
11 35
72
74
[15]
iPr
H
H H
11 40
74
91
t-Bu H
R3 R4
13
H H
L
Time (min) ee (%) Yield (%) Ref
11 15
89
a
85
[15] [15]
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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R1
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Synthesis by Rearrangement
R2
R3 R4
L
Time (min) ee (%) Yield (%) Ref
t-Bu Me H H
11 10
82
82a
[15]
Me
Me Br H
12 20
87
82
[15]
Me
Me H OMe 12 30
85
95
[15]
a
Reaction at room temperature.
O
PPh2 PPh2
PPh2 N But
11
12
(S)-Methyl 3-(2-Methylallyl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylate (13, R1 = R2 = Me; R3 = R4 = H); Typical Procedure:[15]
PdCl2(NCMe)2 (0.124 g, 0.48 mmol) and (R)-BINAP (11, 0.300 g, 0.48 mmol) were added to a round-bottomed flask followed by CH2Cl2 (15 mL). The resulting soln was stirred at rt for 24 h and concentrated under vacuum to give PdCl2[(R)-BINAP] as a yellow solid; yield: 0.384 g (quant). To a soln of PdCl2[(R)-BINAP] (4 mg, 0.008 mmol, 20 mol%) in CH2Cl2 (0.5 mL) was added a soln of AgSbF6 (5 mg, 0.014 mmol, 40 mol%) in CH2Cl2 (0.5 mL) via cannula. The resulting suspension was stirred for 3 h in the absence of light and filtered through a PTFE filter to remove precipitated AgCl. The clear yellow soln obtained was cooled to 0 8C and 1H-indole-3-carboxylate 10 (R1 = R2 = Me; R3 = R4 = H; 9 mg, 0.038 mmol) in CH2Cl2 (1.0 mL) was added via cannula. The mixture was stirred at 0 8C until complete consumption of starting material (TLC). Filtration through silica gel (2 0.5 cm, EtOAc/hexanes 1:3) and removal of the solvent under reduced pressure gave the product as a white resin; yield: 8 mg (89%). 3.10.1.1.3
Carroll Rearrangement
Owing to the ease of preparation of allylic esters, the Carroll rearrangement is a particularly attractive version of the Claisen rearrangement. Nevertheless, there are only a few reports of metal-catalyzed enantioselective methods.[16] Ruthenium catalysts are the most efficient developed to date, and the rearrangement is presumed to proceed via an allyl complex as demonstrated by crossover experiments. The scope is currently limited to allylic esters 14 with E-configured double bonds bearing an aromatic substituent at the 3-position of the allyl group. These substrates undergo reaction with the catalyst formed from an Å5-cyclopentadienyl(Å6-naphthalene)ruthenium(II) salt and ligand 15 to give ª,unsaturated ketones 16 (Scheme 4). Inclusion of alkyl substituents at the Æ-position of the oxo ester region results in moderate diastereoselectivities and lower branched to linear ratios. Although decreasing the temperature affords increased selectivity it results in lower reactivity. Furthermore, trace amounts of water have a marginal impact on the outcome. Finally, employing a cocatalyst such as magnesium trifluoromethanesulfonate to facilitate C—O bond cleavage provides improved reactivity but lower regioselectivity.[17]
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. for references see p 466 Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis Scheme 4
3.10
Isomerizations and Allylic Rearrangements
Catalytic Asymmetric Carroll Rearrangement of Allylic Esters[16,17]
PF6−
Ru
O
O
N
O
H
R3
N 15
R2
O R4
R1
R1
16
14
R1
O
R4
THF, 60 oC
R3
R2
R2
R3
R4
OMe Me H
H
H
Me H
H
Ru Complex (mol%)
eeb (%)
Conversion (%)
Ref
–
79
>97
[16]
95:5
–
77
>97
[16]
24
93:7
–
82
>97c
[17]
3.0
10
93:7
–
81
>97
[16]
3.0
400
79:21 –
79
>97
[16]
15 (mol%)
Time (h)
Ratio dr (b/l)a
2.5
3.0
6
>97:3
H
2.5
3.0
25
Me H
H
2
4.4
Cl
Me H
H
2.5
NO2
Me H
H
2.5
H
Me Me H
10
12
9
81:19 68:32 72
>97
[16]
10
12
9
87:13 64:36 81
>97
[16]
H
Me Me Me 10
12
9
83:17 –
57
>97
[16]
H
iPr H
12
9
85:15 –
67
>97
[16]
95:5
86
>97
H
H H a b c d
(CH2)3
Ph H Ph H
H H H H
10 10 2
12 4.4
64
c
24
93:7
– –
80
>97
[16] d
[17]
Ratio of branched to linear products. Enantiomeric excess determined for the major isomer. Reaction was performed at 25 8C. Magnesium trifluoromethanesulfonate (1 mol%) was used as a cocatalyst.
4-(4-Methoxyphenyl)hex-5-en-2-one (16, R1 = OMe; R2 = Me; R3 = R4 =H); Typical Procedure:[16]
Å5-Cyclopentadienyl(Å6-naphthalene)ruthenium(II) hexafluorophosphate (6.6 mg, 0.015 mmol, 2.5 mol%) and ligand 15 (4.3 mg, 0.018 mmol, 3 mol%) were dissolved in anhyd THF (0.3 mL) in a 2-mL screw-cap vial equipped with a magnetic stirrer bar. The vial was flushed with argon and capped. After heating for 1 h at 60 8C, allylic ester 14 (R1 = OMe; R2 = Me; R3 = R4 = H; 150 mg, 0.6 mmol) was added in one portion and heating was continued for 6 h. After being allowed to cool to rt, the mixture was diluted with pentane/Et2O (2:3). After precipitation, the metal salts were removed by filtration through silica gel (4 0.5 cm, pentane/Et2O 2:3) and the solvents were removed under reduced pressure to afford the crude product as a pale yellow oil; conversion: >97%. 3.10.1.1.4
Aza-Claisen Rearrangement
The aza-Claisen rearrangement, which is exemplified by the [3,3]-sigmatropic rearrangement of allylic imidates 17 to allylic amides 20, was discovered in the 1930s, when the thermal rearrangement of allylic benzimidates to form benzamides was reported.[18] In Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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1974 the first application of trichloroacetimidate substrates was reported and it was demonstrated that the rearrangement could be catalyzed by mercury(II) salts.[19] Palladium(II) salts have also been found to be suitable catalysts for this type of transformation.[20] There is ample evidence that these soft Lewis acid catalyzed reactions proceed via a cyclizationinduced rearrangement mechanism, in which the alkene moiety of imidate 17 coordinates to the palladium(II) complex, and is thereby activated, as intermediate 18, toward nucleophilic attack by the imidate nitrogen atom to give cyclic intermediate 19 (Scheme 5).[20] Scheme 5
Aza-Claisen Rearrangement of Allylic Imidates[20]
R3 R2
N
R1
O
[Pd(II)]
R N
R3
2
O
N
O
R1
R1 [Pd(II)] 17
R3
R3 R2
18
R2
N
O
R1 [Pd(II)] 19
20
Efficient catalytic enantioselective methods have only recently been developed based on the discovery that planar-chiral palladacycles prove to be selective catalysts for this rearrangement.[21] Different catalysts and conditions have been reported for different classes of imidates and as such this section is divided according to the most common imidate classes. 3.10.1.1.4.1
Using Benzimidate Substrates
The first enantioselective aza-Claisen rearrangements were described for the reaction of benzimidates to give allylic benzamides.[21] The best results are achieved with catalysts 22 (FOP-X)[22,23] and 23 (COP-X)[24] (Scheme 6) using N-aryl-substituted imidates 21 (R2 = substituted phenyl) containing various aliphatic and aromatic alkene substituents (R1). Increasing the size of the alkene substituent (R1) decreases the reactivity and leads to longer reaction times, whereas increasing the reaction temperature leads to lower enantioselectivity in amides 24. A catalytic method with shorter reaction times (£12 h) providing good yields and selectivities has been reported, but unfortunately without experimental details.[25]
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. for references see p 466 Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
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Isomerizations and Allylic Rearrangements
Rearrangement of Allylic Benzimidates to Allylic Amides[22–24]
Scheme 6
Ph O
Ph N
R2
R2 22 or 23
N
O
∗ 1
R
R
1
21
R1
24
R2
Alkene Config
Catalyst Conditions
ee (%) Yield (%) Ref
Me 4-MeOC6H4
Z
22
CH2Cl2, rt, 15 h
75
96
[22]
Pr
4-MeOC6H4
E
22
CH2Cl2, rt, 18 h
83
93
[22]
Bn
4-MeOC6H4
Z
22
CH2Cl2, rt, 23 h
88
85
[22]
Ph
4-MeOC6H4
Z
22
CH2Cl2, rt, 20 h
77
11
[22]
Pr
4-F3CC6H4
E
22
CH2Cl2, rt, 24 h
83
83
[23]
Ph
4-MeOC6H4
E
23
CH2Cl2, rt, 13 h
68
70
[24]
Pr
4-MeOC6H4
Z
23
CH2Cl2, rt, 3 h
94
92
[24]
iPr
4-MeOC6H4
Z
23
toluene, 75 8C, 72 h
86
59
[22]
But
2
Pri
2
N
X Pd
O
Pd
N
TMS
O
X Fe
Co
Ph
Ph 22
X = O2CCF3
Ph
Ph 23
X = O2CCF3
N-(1-Benzylprop-2-enyl)-N-(4-methoxyphenyl)benzamide (24, R1 = Bn; R2 = 4-MeOC6H4); Typical Procedure:[22]
A soln of precatalyst 22 (X = I; 7.0 mg, 0.0047 mmol) in anhyd CH2Cl2 (0.2 mL) was added to AgOCOCF3 (2.8 mg, 0.013 mmol). After 1.5 h at rt, the mixture was filtered through Celite under N2 directly into the test tube containing imidate 21 (R1 = Bn; R2 = 4-MeOC6H4; 39 mg, 0.12 mmol). The Celite was washed with CH2Cl2 to give a total reaction volume of 1.2 mL and, after 23 h at rt, the soln was directly purified by flash chromatography (hexanes/ EtOAc 9:1 to 4:1) to give the product as a slightly orange oil; yield: 33 mg (85%); 88% ee. 3.10.1.1.4.2
Using Trichloroacetimidate Substrates
One synthetic disadvantage of the rearrangement of benzimidates 21 to give benzamides 24 (see Section 3.10.1.1.4.1) is the problematic cleavage of the amide to form the corresponding primary or secondary amines. In contrast, allylic trichloroacetimidates 25 offer the principal advantage that trichloroacetamides 29 are more readily hydrolyzed to afford the allylic amines, which represent valuable precursors for amino acids.[26] As such, the enantioselective aza-Claisen rearrangement of trichloroacetimidates 25 has been intensively studied, and the use of catalyst 26 (COP-Cl) for the rearrangement of a broad spectrum of substrates has been reported (Scheme 7).[26] The related catalyst 27 (COP-hfacac) gives similar results but can be used in a wide range of solvents including dichloromethane, tetrahydrofuran, cyclohexane, toluene, acetone, and acetonitrile.[27] This allows for higher reaction temperatures than in dichloromethane and lower catalyst Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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loadings [1 mol% of palladium(II) rather than 10 mol%]. The catalyst loading has been further improved using acetonitrile at elevated temperatures. In these cases, the reported substrates are all E-configured,[28] and increasing the size of the alkene substituent results in lower rates of reaction (for example, substrates with R1 = t-Bu or Ph provide poor yields). Precatalyst 28, developed for trifluoroacetimidates and activated by silver(I) nitrate (see Section 3.10.1.1.4.3), has also been demonstrated to be highly active for trichloroacetimidates, providing trichloroacetamides 29 in excellent yields and enantiomeric excesses.[29] Scheme 7
Rearrangement of Allylic Trichloroacetimidates[26–29] CCl3
O
CCl3
NH
HN
26 or 27 or 28
O
∗
R1
R1 25
29
R1
Alkene Config
Catalyst (mol%)
Conditions
ee (%) Yield (%) Ref
Me
E
26 (5)
CH2Cl2, rt
92
85
[26]
Pr
E
26 (5)
CH2Cl2, 38 8C
95
99
[26]
Pr
Z
26 (5)
CH2Cl2, 38 8C
71
17
[26]
Cy
E
26 (5)
CH2Cl2, 38 8C
96
82
[26]
CH2OH
E
26 (5)
CH2Cl2, rt
80
84
[26]
(CH2)3N(Bn)Boc
E
26 (5)
CH2Cl2, 38 8C
95
96
[26]
Pr
E
26 (0.25)
MeCN, 70 8C
92
79
[28]
E
27 (1)
MeCN, 50 8C
93
86
[27]
(CH2)2Ph
E
27 (5)
THF, 38 8C
97
95
[27]
(CH2)2Ph
E
28 (0.25)
CH2Cl2, 60 8C
95
99
[29]
O O 2
CF3 2 2
Pri Cl Pd
N
F3C
O O
Pri
Pd
N O
O Ph
Co
Ph
Pri
Ph
Co
Pd Cl
N O Ph
Fe
Ph Ph
Ph 26
Ph
Ph
Ph
Ph 27
Ph Ph 28
(S)-N-(1-Cyclohexylprop-2-enyl)-2,2,2-trichloroacetamide (29, R1 = Cy); Typical Procedure:[26]
A soln of catalyst 26 (129 mg, 0.088 mmol) in CH2Cl2 (1.76 mL) was added to the imidate 25 (R1 = Cy; 500 mg, 1.76 mmol). The reaction flask was sealed, protected from light, and maintained at 38 8C for 18 h. After partial removal of the solvent, purification by chromatography (Davisil grade silica gel, hexanes/EtOAc 199:1) afforded the product as a colorless solid; yield: 412 mg (82%); 96% ee. Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. for references see p 466 Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Isomerizations and Allylic Rearrangements
(R)-N-[1-(2-Phenylethyl)prop-2-enyl]-2,2,2-trichloroacetamide [29, R1 = (CH2)2Ph]; Typical Procedure:[29]
A soln of the precatalyst 28 (6.7 mg per 500 mg substrate) activated by AgNO3 in CH2Cl2 (see Section 3.10.1.1.4.3) was transferred to a flask containing the imidate 25 [R1 = (CH2)2Ph; 1 equiv]. A stream of N2 was passed through the flask until the solvent volume reached 3 L • mol–1 or less. The flask was sealed with a plastic cap and the contents were stirred for 24 h at 60 8C. Once the reaction was complete, the residue was purified by filtration through silica gel (cyclohexane/EtOAc 9:1 or pentane/EtOAc 9:1) to furnish the product as a slightly yellow oil; yield: 99%; 95% ee. 3.10.1.1.4.3
Using Trifluoroacetimidate Substrates
Complementary to trichloroacetimidates (see Section 3.10.1.1.4.2), allylic trifluoroacetimidates 30 usually provide trifluoroacetamides 34 with an additional N-protecting group. In early investigations relatively high catalyst loadings of 10–15 mol% palladium(II) were necessary as a result of the reduced nucleophilicity of the imidate nitrogen atom.[23,30] Complex 26 is superior to its ferrocene analogue 22 (FOP-X) in a number of aspects including preparation (for example, complex 22 is not accessible by direct cyclopalladation), catalyst stability, catalytic activity, and substrate scope. More recent studies have achieved higher activities by systematic catalyst development.[29,31–36] These studies utilized a modular catalyst design based on complex 31, which allows for an adjustment of electronic and steric properties. Although ferrocene-based palladacycles were previously not as efficient as complex 26, ferrocenes were chosen as the backbone for planar chiral catalyst systems due to a greater structural variability. 4,5-Dihydroimidazole (imidazoline)[37] rather than 4,5-dihydrooxazole (oxazoline) coordination sites also provide a better motif for this modular concept. A ferrocenium core, formed during catalyst activation by oxidation with a silver salt, is a major reason for high catalytic activity. The silver salt also serves to break down the chloro bridge of the catalytically inert dimer. In combination with the electron-withdrawing effect of five phenyl groups at the cyclopentadienyl spectator ligand (Cp¢) in complex 32 (Scheme 8) the electron density on the palladium(II) center is significantly decreased, resulting in enhanced Lewis acidity. The increased bulk provides excellent enantioselectivities while in general maintaining high yields (Scheme 8) with catalyst loadings two orders of magnitude lower as compared to previous results. 4,5-Dihydrooxazole 28 activated by silver(I) nitrate is even more reactive than complex 32 (Scheme 8),[29] and allows for the investigation of substrates which are problematic due to background reactions. These substrates tend to involve the cleavage of a reactive O-allyl bond to provide a stabilized allylic carbocation (e.g., R1 = 4-Tol and CH=CHPr). Geometrically pure substrates are required to obtain high enantioselectivities due to the stereospecific conversion of sp2 stereochemistry. The activity of complexes 28 and 32 is far less pronounced for Z-configured allylic imidates. Hence, the electron density of the second cyclopentadienyl (Cp) ligand was further decreased in bis(4,5-dihydroimidazole) bispalladacycle 33, which is readily prepared in four steps from ferrocene.[38] Complex 33 is to date the only highly active enantioselective catalyst for Z-configured trifluoroacetimidates 30 (Scheme 8). The rearrangements, which generally proceed under almost solvent-free conditions, are found to be equally effective on milligram and gram scales, and are tolerant of many important functional groups.
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.10.1
Scheme 8
Rearrangement of Allylic Trifluoroacetimidates[29,32,35] CF3
R2
453
Synthesis by Rearrangement
O
MeO
OMe
CF3 N
28 or 32 or 33
N
O
R2
R1
R1 30
34
R1
R2
Catalyst (mol%)
Conditionsa
ee (%)
Yield (%)
Ref
Pr
H
32 (0.05)
AgOCOCF3 (3.7 equiv), Proton-sponge (4 equiv), CH2Cl2, 40 8C, 72 h
95
95
[32]
Me
H
32 (0.05)
AgOCOCF3 (3.7 equiv), Proton-sponge (4 equiv), CH2Cl2, 40 8C, 72 h
92
98
[32]
(CH2)2Ph
H
32 (0.05)
AgOCOCF3 (3.7 equiv), Proton-sponge (4 equiv), CH2Cl2, 40 8C, 72 h
98
99
[32]
iBu
H
32 (0.1)
AgOCOCF3 (3.7 equiv), Proton-sponge (4 equiv), CH2Cl2, 40 8C, 24 h
98
95
[32]
iPr
H
32 (0.1)
AgOCOCF3 (3.7 equiv), Proton-sponge (4 equiv), CH2Cl2, 40 8C, 72 h
93
81
[32]
Cy
H
28 (0.5)
AgNO3 (3.7 equiv), Proton-sponge (4 equiv), 99 CH2Cl2, 40 8C, 24 h
99
[29]
Pr
H
28 (0.05)
AgNO3 (3.7 equiv), Proton-sponge (4 equiv), 97 CH2Cl2, 40 8C, 24 h
99
[29]
Ph
H
28 (0.5)
AgNO3 (3.7 equiv), Proton-sponge (4 equiv), 98 CH2Cl2, 20 8C, 24 h
98
[29]
4-ClC6H4
H
28 (1.0)
AgNO3 (3.7 equiv), Proton-sponge (4 equiv), 98 CH2Cl2, 20 8C, 24 h
95
[29]
4-Tol
H
28 (1.0)
AgNO3 (3.7 equiv), Proton-sponge (4 equiv), 98 CH2Cl2, 20 8C, 48 h
99
[29]
CH=CHPr H
28 (1.0)
AgNO3 (3.7 equiv), Proton-sponge (4 equiv), 86 CH2Cl2, 20 8C, 72 h
99
[29]
H
Pr
33 (0.1)
AgOTs (6 equiv), CHCl3, 55 8C, 72 h
97
97
[35]
H
Me
33 (0.1)
AgOTs (6 equiv), CHCl3, 55 8C, 24 h
94
97
[35]
H
(CH2)2Ph
33 (0.2)
AgOTs (6 equiv), CHCl3, 55 8C, 72 h
97
92
[35]
H
iPr
33 (1.0)
AgOTs (6 equiv), CHCl3, 55 8C, 72 h
93
64
[35]
H
(CH2)2CO2Me
33 (0.5)
AgOTs (6 equiv), CHCl3, 55 8C, 72 h
98
98
[35]
H
CH2OTBDMS
33 (0.05)
AgOTs (6 equiv), CHCl3, 55 8C, 72 h
97
96
[35]
H
(CH2)2Ac
33 (0.5)
AgOTs (6 equiv), CHCl3, 55 8C, 72 h
97
97
[35]
H
(CH2)3OBn
33 (0.2)
AgOTs (6 equiv), CHCl3, 55 8C, 72 h
97
>99
[35]
H
CH2OTHP
33 (0.2)
AgOTs (6 equiv), CHCl3, 55 8C, 72 h
98
94
[35]
H
(CH2)3N(Bn)Boc
33 (0.2)
AgOTs (6 equiv), CHCl3, 55 8C, 72 h
98
99
[35]
a
Number of equivalents is relative to amount of catalyst. Proton-sponge = 1,8-bis(dimethylamino)naphthalene.
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. for references see p 466 Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.10
Isomerizations and Allylic Rearrangements
n+
2
R2
2
Ph Pd X
N R2
Ph
N R3
Fe
R1
Pd Cl
N N Ts
R1
R1
R1
Fe
Ph
Ph
Ph
R1 31
Ph
Ph 32
n = 0,1
Ph
Ph
2
Pri
N
Ts
Pd Cl
N
N Pd Cl
O Fe
Ph
2
Fe
Ph
Cl Ph
Ph
Pd
Ph
Ts
N
Ph
2
N Ph 33
28
The high catalytic activity of complexes 28 and 32 also enables the aza-Claisen rearrangement of acetimidates 35 to form the amides 36, which contain N-substituted quaternary stereocenters (Scheme 9).[29,34] The catalyst does not need to distinguish between differently sized substituents on the double bond (e.g., R1 = CD3; R2 = Me; 96% ee) indicating that coordination of the alkene is the predetermining step for stereoselectivity. Thus, in intermediate 37, the imidate nitrogen atom attacks from the face remote to the palladium center resulting in high stereospecificity. The allylic amides can be readily transferred to enantiopure quaternary Æ- and -amino acids.[29,34] Scheme 9
Rearrangement of Allylic Trifluoroacetimidates Forming Quaternary Stereocenters[29] OMe
CF3 R2
O
N
MeO
CF3 N
28 or 32
R2
R1
O
∗
R1 35
36
R1
R2
Catalyst (mol%)
Conditionsa
ee (%)
Yield (%)
Ref
(CH2)2CH=CMe2
Me
32 (2.0)
AgOCOCF3 (3.8 equiv), Proton-sponge (3 equiv), CH2Cl2, 50 8C, 60 h
98
74
[29]
(CH2)3OTIPS
Me
32 (2.0)
AgOCOCF3 (3.8 equiv), Proton-sponge (3 equiv), CH2Cl2, 50 8C, 60 h
96
73
[29]
(CH2)3OCbz
Me
32 (2.0)
AgOCOCF3 (3.8 equiv), Proton-sponge (3 equiv), CH2Cl2, 50 8C, 60 h
98
84
[29]
(CH2)3N(Bn)Boc
Me
32 (2.0)
AgOCOCF3 (3.8 equiv), Proton-sponge (3 equiv), CH2Cl2, 50 8C, 60 h
93
64
[29]
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Synthesis by Rearrangement
R1
R2
Catalyst (mol%)
Conditionsa
ee (%)
Yield (%)
Ref
Me
CH2OBn
32 (2.0)
AgOCOCF3 (3.8 equiv), Proton-sponge (3 equiv), CH2Cl2, 50 8C, 60 h
99
84
[29]
Me
(CH2)3OTIPS
32 (2.0)
AgOCOCF3 (3.8 equiv), Proton-sponge (3 equiv), CH2Cl2, 50 8C, 60 h
98
74
[29]
Bu
CH2OBn
32 (4.0)
AgOCOCF3 (3.8 equiv), Proton-sponge (3 equiv), CH2Cl2, 50 8C, 84 h
98
61
[29]
CD3
Me
32 (1.0)
AgOCOCF3 (3.8 equiv), Proton-sponge (3 equiv), CH2Cl2, 50 8C, 60 h
96
99
[29]
(CH2)2Ph
Me
28 (1.0)
AgNO3 (3.7 equiv), Proton-sponge (4 equiv), CH2Cl2, 50 8C, 72 h
99
90
[29]
Me
CH2OBn
28 (1.0)
AgNO3 (3.7 equiv), Proton-sponge (4 equiv), CH2Cl2, 50 8C, 24 h
97
98
[29]
(CH2)3OTIPS
CH2OBn
28 (2.0)
AgNO3 (3.7 equiv), Proton-sponge (4 equiv), CH2Cl2, 50 8C, 72 h
97
95
[29]
a
Number of equivalents is relative to amount of catalyst. Proton-sponge = 1,8-bis(dimethylamino)naphthalene.
OMe
R1
R2
Pd
X
N
CF3 O
Fe III
37
The same catalysts have also been examined for the highly enantioselective rearrangement of imidates 38 with aromatic and aliphatic N-substituents, and afford secondary allylic amines after reductive cleavage of the initially formed amides 39 (Scheme 10).[29,36]
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. for references see p 466 Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
Isomerizations and Allylic Rearrangements
3.10
Scheme 10 Rearrangement of Allylic Trifluoroacetimidates To Form Protected Secondary Allylic Amines[29,36] CF3
CF3 R2
O
N
R
R3
3
28 or 32 or 33
R2
R1
N
O
∗
R1 39
38
R1
R2
R3
Catalyst (mol%)
Conditionsa
ee (%)
Yield (%)
Ref
Pr
H
1-naphthyl
32 (0.05)
AgOCOCF3 (3.8 equiv), Protonsponge (3 equiv), CH2Cl2, 70 8C, 72 h
97
90
[36]
Pr
H
4-IC6H4
32 (0.2)
AgOCOCF3 (3.8 equiv), Protonsponge (3 equiv), CH2Cl2, 70 8C, 72 h
96
85
[36]
Pr
H
4-FC6H4
32 (0.1)
AgOCOCF3 (3.8 equiv), Protonsponge (3 equiv), CH2Cl2, 50 8C, 72 h
96
91
[36]
Pr
H
2,4-(MeO)2C6H3
32 (0.05)
AgOCOCF3 (3.8 equiv), Protonsponge (3 equiv), CH2Cl2, 50 8C, 48 h
98
96
[29]
Me
H
(CH2)2Ph
32 (2.0)
AgOCOCF3 (3.8 equiv), Protonsponge (3 equiv), CH2Cl2, 50 8C, 72 h
94
98
[36]
iPr
H
(CH2)2Ph
32 (2.0)
AgOCOCF3 (3.8 equiv), Protonsponge (3 equiv), CH2Cl2, 70 8C, 72 h
97
51
[36]
(CH2)2Ph
H
(CH2)5Me
32 (0.2)
AgOCOCF3 (3.8 equiv), Protonsponge (3 equiv), CH2Cl2, 50 8C, 72 h
99
91
[36]
(CH2)2Ph
H
(CH2)2iPr
32 (1.0)
AgOCOCF3 (3.8 equiv), Protonsponge (3 equiv), CH2Cl2, 50 8C, 72 h
98
99
[36]
(CH2)2Ph
H
(CH2)2OTIPS
32 (1.0)
AgOCOCF3 (3.8 equiv), Protonsponge (3 equiv), CH2Cl2, 70 8C, 72 h
98
92
[36]
(CH2)2Ph
Me
(CH2)5Me
32 (2.0)
AgOCOCF3 (3.8 equiv), Protonsponge (3 equiv), CH2Cl2, 70 8C, 72 h
98
42
[36]
(CH2)2Ph
H
(CH2)2CO2Et
32 (1.0)
AgOCOCF3 (3.8 equiv), Protonsponge (3 equiv), CH2Cl2, 70 8C, 72 h
99
84
[36]
(CH2)2Ph
H
Cy
28 (1.0)
AgNO3 (3.7 equiv), Protonsponge (4 equiv), CH2Cl2, 70 8C, 72 h
98
91
[29]
H
CH2OTBDMS
(CH2)2Ph
33 (1.0)
AgOTs (6 equiv), CH2Cl2, 50 8C, 72 h
98
98
[36]
a
Number of equivalents is relative to amount of catalyst. Proton-sponge = 1,8-bis(dimethylamino)naphthalene.
Trifluoroacetamides 34 and 36; General Procedure Using Precatalyst 28:[29]
A soln of the dimeric precatalyst 28 in anhyd CH2Cl2 (1 mL/3 mol) was added to AgNO3 (3.75 equiv) in a dry pear-shaped flask under N2. The mixture was then sealed, shielded from light, and stirred overnight at rt. The resulting suspension was filtered under a N2 Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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457
Synthesis by Rearrangement
atmosphere through Celite/CaH2 (~1:1) and the filter cake was washed with anhyd CH2Cl2 (1 mL/3 mol). A 0.1 M soln of Proton-sponge in CH2Cl2 (2–4 equiv) was then added. The calculated amount of activated catalyst was transferred as a soln in CH2Cl2 to a flask containing the imidate (1 equiv). A stream of N2 was passed through the flask until the solvent volume reached 3 L • mol–1 or less. The flask was sealed with a plastic cap and stirred for the indicated time at the indicated temperature. After the reaction was complete, the residue was purified by filtration over silica gel (cyclohexane/EtOAc 9:1 or pentane/EtOAc 9:1). 3.10.1.1.4.4
Using Miscellaneous Substrates
The rearrangement of an enolizable acetimidate 40 using the same general procedure as given in Section 3.10.1.1.4.3 has been reported. Although acetimidate 40 is in equilibrium with the ketene N,O-acetal 41, the rearrangement proceeds smoothly to give acetamide 42 with 0.2 mol% of the precatalyst 28. Reduction of acetamide 42 provides rapid access to highly enantioenriched tertiary allylic amines 43 (Scheme 11).[29] Scheme 11
Rearrangement of an Enolizable Acetimidate[29] 2
Pri Pd Cl
N 0.2 mol%
O Ph
Fe
Ph
Ph Ph
Ph 28
Ph
N
O
0.75 mol% AgNO3, 1.5 mol% Proton-sponge CH2Cl2
Ph
N
O
96%
Pr
Ph
N H
Ph
N
Et
78%
Pr 42
40
LiAlH4 (1 equiv) 10 mol% Et3N Et2O, rt
Pr 94% ee
43
O
Pr 41
3.10.1.1.5
Miscellaneous Rearrangements
3.10.1.1.5.1
Thia-Claisen Rearrangement
Various heteroatoms can, in principle, replace the carbon atoms used in a Cope-like rearrangement. A thia-Claisen (thia-oxa-Cope) rearrangement catalyzed by complex 26 forms the enantioenriched allylic carbamothioates 45 from the linear derivatives 44 (Scheme 12).[39] The influence of different alkene (R1) and nitrogen (R2/R3) substituents in the starting material has been examined. For instance, small substituents at nitrogen (R2/R3) provide good selectivities, while the overall yield and enantioselectivity are good for a range of alkene substituents (R1) using 5 mol% of the dimeric catalyst 26 (up to 87% ee when R1 = CH2OTBDMS).
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. for references see p 466 Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis Scheme 12
3.10
Isomerizations and Allylic Rearrangements
Thia-Oxa-Cope Rearrangement[39] 2
Pri Cl
Pd
N O
5 mol% Ph
NR2R3 O
Ph
Co
26
Ph
NR2R3
Ph
CH2Cl2, 40 oC
S
S
R1
O
R1 44
45
R1
R2
R3
Pr
Me Me 18
Time (h) ee (%) Yield (%) Ref 82
72
[39]
13
83
98
[39]
Me Me 18
87
97
[39]
CH2N(Ph)Boc Me Me 43
81
77
[39]
(CH2)2Ac
76
85
[39]
Pr CH2OTBDMS
(CH2)3
(CH2)3
11
(S)-S-Hex-1-en-3-yl Azetidine-1-carbothioate [45, R1 = Pr; R2,R3 = (CH2)3]; Typical Procedure:[39]
A soln of carbamothioate 44 [R1 = Pr; R2,R3 = (CH2)3; 53 mg, 0.27 mmol] and catalyst 26 (18 mg, 0.013 mmol, 0.05 equiv) in CH2Cl2 (0.51 mL) was sealed, protected from light, and maintained at 40 8C. After 13 h, the mixture was allowed to cool to rt and ethylenediamine (0.010 mL, 0.13 mmol, 0.5 equiv) was added. After 15 min, the orange soln was transferred to a round-bottomed flask with CH2Cl2 (10 mL) and dry silica gel (ca. 60 mg) was added. The slurry was concentrated and the yellow powder was loaded onto a short column (silica gel). Elution (hexanes/EtOAc 10:1) gave the product as a light yellow oil; yield: 52 mg (98%); 83% ee. 3.10.1.1.5.2
Aza-Phospha-Oxa-Cope Rearrangement
The catalytic asymmetric aza-phospha-oxa-Cope rearrangement involving three heteroatoms in the heterodiene core has been reported for the conversion of precursors 46 into N-phosphorylamines 47 (Scheme 13).[40] The thermodynamic driving force for this type of reaction, conversion of an O—P=N moiety into an O=P—N moiety, has been estimated to be about –24 kcal/mol. For the related aza-Claisen rearrangement, calculations indicate the difference to be approximately –17 kcal/mol.[40] Enantioselectivities are good for both E- and Z-configured substrates using catalyst precursor 26 activated by silver(I) trifluoroacetate. In contrast, yields are significantly higher for Z-configured substrates, and thus these results show a different trend to the aza-Claisen rearrangement catalyzed by catalyst 26. The rearrangement products can be readily converted into allylic 4-toluenesulfonamides in high yields by hydrolytic cleavage of the N—P bond.
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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459
Synthesis by Rearrangement Aza-Phospha-Oxa-Cope Rearrangement[40]
Scheme 13
2
Pri Cl Pd
N O
2.5 mol%
MeN O
NTs
Co
Ph
NMe P
Ph
Ph
Ph 26
10 mol% AgOCOCF3, toluene
MeN TsN
NMe P
O
∗
R1
R1 46
47
R1
Config of 46 Temp (8C) Concentration (M) Time (h) ee (%) Yield (%) Ref
Et
E
45
2.0
60
84
60
[40]
Et
Z
50
0.8
40
92
97
[40]
Pr
E
45
2.0
60
86
55
[40]
Pr
Z
45
0.8
40
96
90
[40]
CH2OTBDMS
E
45
2.0
60
86
44
[40]
CH2OTBDMS
Z
45
2.0
60
92
82
[40]
N-Phosphorylamines 47; General Procedure:[40]
Toluene (0.3 mL) was added to a solid mixture of precursor 46 (0.3 mmol), catalyst 26 (11 mg, 0.0075 mmol, 2.5 mol%), and AgOCOCF3 (11 mg, 0.03 mmol, 10 mol%) in a flamedried conical vial under N2. The sealed flask was heated to the appropriate temperature and the mixture was stirred for the appropriate time (conversion was checked by 31 P NMR). The brown mixture was allowed to cool to rt, concentrated under reduced pressure, dissolved in a minimum amount of CH2Cl2, and purified by column chromatography. 3.10.1.2
[2,3]-Sigmatropic Rearrangements
Two new vicinal stereocenters can be formed by a [2,3]-sigmatropic rearrangement. In addition the required anion-stabilizing group and the new alkene moiety in the product often provide numerous possibilities for further functionalization. The first reported Lewis acid promoted asymmetric [2,3]-sigmatropic rearrangement used achiral allylic amines 48 (Scheme 14).[41] Ylide formation is realized by coordination of the tertiary amino moiety of allylic amines 48 to the enantiomerically pure diazaborolidine 49 and subsequent treatment with triethylamine. Highly enantioenriched ª,-unsaturated Æ-amino amides 50 are obtained in good yields and with useful diastereoselectivities and excellent enantioselectivities.[42] The reaction is believed to proceed via a five-membered cyclic exo-transition state 51 as the kinetically preferred pathway.
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. for references see p 466 Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.10
Isomerizations and Allylic Rearrangements
[2,3]-Sigmatropic Rearrangement of Allylic Amines[42]
Scheme 14
Ph
Ph
TsN
NTs B
R2
Bn
1
R
Br
O
N
R1
49 Et3N, CH2Cl2
N
O N
R2 48
NHBn 50
R1
R2
Ratio (anti/syn) ee (%) of anti-form Yield (%) Ref
Me
H
79:21
96
82
[42]
Ph
H
67:33
97
92
[42]
CH2OBn
H
88:12
93
70
[42]
95:5
99
52
[42]
99
80
[42]
SiMe2Ph H H
R2
Me –
Ts Ph N R N BO Bn Ts N N 1
Ph
51
(2R,3R)-2-(Benzylamino)-3-[(benzyloxy)methyl]-1-(pyrrolidin-1-yl)pent-4-en-1-one (50, R1 = CH2OBn; R2 = H); Typical Procedure:[42]
Allylic amine 48 [R1 = CH2OBn; R2 = H; 42 mg, 0.11 mmol] in CH2Cl2 (2 mL) was added to the solid catalyst 49 (0.22 mmol, 2.0 equiv) and the resultant soln was stirred for 1 h. Et3N (80 L, 0.56 mmol) was then added and, after 20 h, the mixture was treated overnight at rt with concd HCl/MeOH (1:5; 2 mL). This soln was cooled and 2 M NaOH (1 mL) and sat. NaHCO3 (5 mL) were added. The aqueous phase was extracted with CH2Cl2 (2 5 mL), the combined organic phases were dried (K2CO3) and concentrated, and the residue was triturated with Et2O (3 1 mL) to provide N,N-bis(tosyl)-1,2-diphenylethane-1,2-diamine as a solid; yield: 100 mg (87%). The ethereal triturate was purified by chromatography (acetone/pentane 0:1 to 1:2, with 0.3% iPrNH2) to give the product; yield: 29.2 mg (70%) as a diastereomeric mixture [(anti/syn) 88:12] together with the remaining ligand; yield: 14.5 mg (13%).
3.10.2
Synthesis by Isomerization and Migration
3.10.2.1
Double-Bond Isomerization
3.10.2.1.1
Isomerization of Allylic Amines to Enamines
The development of the catalytic enantioselective isomerization of achiral allylic amines 52 to form chiral enamines 53 is one of the most significant milestones in the field of asymmetric catalysis. This process is used for the industrial-scale isomerization of diethyl(geranyl)amine to produce (–)-menthol and other terpenes using a rhodium(I)/2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl catalyst.[43] The product is formed in high yield and in Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.10.2
461
Synthesis by Isomerization and Migration
almost enantiopure form (Table 1, entry 2).[44] Interestingly, the reaction is relatively general, for example, secondary amines (entry 3) and substrates carrying aromatic (entry 5) or additional substituents (entries 1–4) can be utilized.[45] Spectroscopic and kinetic measurements, in combination with deuterium labeling experiments, reveal that the reaction proceeds via iminium formation through -hydride elimination, and that this hydride is then transferred in an intramolecular fashion. Enantioselection is accomplished by an efficient differentiation of the enantiotopic C1 hydrogens.[46] Consequently, the reaction is stereospecific and requires geometrically pure starting materials for high enantiomeric excesses to be obtained. Enamines 53 with an E-configuration are formed regardless of the geometry of the starting allylic amine 52. Isomerization of Allylic Amines to Enamines[45]
Table 1
1 mol% [Rh(cod){(R)-BINAP}]ClO4 THF, 40 oC, 23 h
R1 R2
R1 R2
NR3R4
NR3R4
52
53
Entry
R1
R2
R3
R4
ee (%)
1
(CH2)2CH=CMe2
Me
Et
Et
95
97
[45]
2
Me
(CH2)2CH=CMe2
Et
Et
96
>99
[45]
3
Me
(CH2)2CH=CMe2
H
Cy
96
>99
[45]
4
Me
(CH2)2CH=CMe2
Me
Cy
91
>99
[45]
5
Me
Ph
Me
Me
90
88
[45]
Conversion (%)
Ref
N,N-Diethyl-3,7-dimethylocta-1,6-dien-1-amine [53, R1 = (CH2)2CH=CMe2; R2 = Me; R3 = R4 = Et]; Typical Procedure:[45]
A soln of [Rh(cod){(R)-BINAP}]ClO4 (0.025 mmol) in THF (5 mL) was treated with H2 (1 atm) for 15 min before any excess H2 was replaced by argon. The allylamine 52 [R1 = (CH2)2CH=CMe2; R2 = Me; R3 = R4 = Et; 0.52 g, 2.5 mmol] was added to this catalyst soln and the resulting mixture was heated at 40 8C for 23 h. The reaction was quenched by addition of an excess of dppe (ca. 0.1 g, 0.5 mmol). The solvent was then removed and Kugelrohr (vacuum) distillation of the residue gave the product; conversion: 97%; 95% ee. 3.10.2.1.2
Isomerization of Allylic Alcohols to Aldehydes
The rhodium(I)/2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl catalyst is not as efficient for catalytic asymmetric isomerization of allylic alcohols 54, to provide aldehydes 56, as it is for the corresponding conversion of allylic amines to enamines (see Section 3.10.2.1.1) affording only moderate yields and enantioselectivity.[47] The merit of the planar chiral bidentate phosphaferrocene ligand 55 (Ar1 = Ph) for this type of isomerization has been investigated.[48] Promising results with this ligand were further improved upon with the closely related variant 55 (Ar1 = 2-Tol).[49] Both E- and Z-configured allylic alcohols have been employed in this procedure, in which the latter provide slightly inferior results (Scheme 15). While most substrates contain an aromatic substituent (R1 or R2) this is not essential for good enantioselectivity [e.g., reaction of alcohol 54 (R1 = Cy; R2 = Me)], and substituents with different electronic effects do not significantly impact the outcome. It is noteworthy that the air-stable catalyst can be partly recycled by precipitation with pentane. Furthermore, the reaction has been conducted without problems on a 1-gram scale using 1 mol% of the catalyst. Deuterium-labeling experiments verified the intramolecular 1,3-hydrogen migration pathway and revealed that the catalyst preferentially activates one of the enantiotopic C1-hydrogens in an analogous manner to the allylic amines. Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. for references see p 466 Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.10
Isomerizations and Allylic Rearrangements
Isomerization of Allylic Alcohols to Aldehydes[49]
Scheme 15 R1
R1
5 mol% [Rh(cod)L]BF4 THF, 100 oC
R2
CHO
R2
OH
56
54
P
PAr12
Fe
L=
55
R1
R2
Me Ph
Ar1
Timea (h) eeb (%)
2-Tol 22 (22)
Yieldb (%) Ref
75
[49]
91 c
c
[49]
iPr Ph
2-Tol 26 (22)
92 (90) 98 (94)
iPr 2-Tol
2-Tol 24 (48)
92
86d
[49]
Ph Me
2-Tol 22 (45)
59
80
[49]
iPr 4-Tol
2-Tol 22 (21)
91
90
[49]
iPr 4-ClC6H4
2-Tol 22 (21)
92
86
[49]
Cy
Me
2-Tol 21 (19)
80
87
[49]
Ph iPr
2-Tol 46 (46)
82
82
[49]
Ph t-Bu
2-Tol 22 (51)
90
90
[49]
a
b
c
d
The values in parentheses are the times for the second run using recovered catalyst. Values are the average of two runs, the first using new catalyst and the second using recovered catalyst from the first attempt. The values in parentheses are obtained with 1 mol% of catalyst 55 (Ar1 = 2-Tol). Reaction carried out at 150 8C.
(3S)-3-Phenylbutanal (56, R1 = Me; R2 = Ph); Typical Procedure:[49]
[Rh(cod)L]BF4 [L = 55 (Ar1 = 2-Tol); 9.8 mg, 0.012 mmol, 0.05 equiv], (2E)-3-phenylbut-2-en-1ol (35.0 mg, 0.237 mmol), and THF (3 mL) were added to a dry Schlenk tube in a glovebox under a N2 atmosphere, and the resulting dark red soln was stirred for 22 h at 100 8C. The mixture was then allowed to cool to rt and pentane (10 mL) was added. The resulting slurry was filtered to give orange crystals, which were washed with pentane and dissolved in THF. The solvent was removed affording the recovered catalyst as a red solid; yield: 8.4 mg (86%). The filtrate was concentrated and the residue was purified by column chromatography (silica gel, pentane/Et2O 4:1) to give the product as a colorless oil; yield: 31.8 mg (91%); 74% ee. A second run was performed according to the same procedure with recovered catalyst over 22 h; yield: 91%; 76% ee. 3.10.2.2
Wagner–Meerwein Rearrangement
The catalytic enantioselective Wagner–Meerwein rearrangement of allenyl-substituted cyclobutanols 57, using a rhodium-based catalyst with chiral ligand 58, provides a general method for the preparation of highly substituted, enantioenriched cyclopentanones 60 with an O-substituted quaternary stereocenter at the Æ-position relative to the generated carbonyl group (Scheme 16).[50,51] The ether substituent (R1) has only a marginal effect on Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.10.2
463
Synthesis by Isomerization and Migration
the enantioselectivity; however, substrates containing substituents at the 3-position of the cyclobutane core (R2/R3) usually require higher reaction temperatures in combination with a modified ligand 59 in order to provide high yields and good enantiomeric excesses. Importantly, diastereomerically enriched cyclobutanes (with R2 „ R3) give products with good diastereo- and enantioselectivities. In this case, the two bonds that can undergo migration are diastereotopic and, as a result, two stereocenters are generated. Wagner–Meerwein Rearrangement[51]
Scheme 16
OH
2.5 mol% Pd2(dba)3•CHCl3 7.5 mol% ligand 58 or 59 10 mol% BzOH, 10 mol% Et3N, 1,2-dichloroethane 4-Å molecular sieves, 12 h or overnight
•
O
OR1
R2
OR1
R2
R3
R3 60
57
R1
R2
R3
dr of 57
Ligand Temp (8C)
dr of 60
ee (%) of 60
Yield (%)
Ref
Bn
H
H
–
58
30
–
92
96
[51]
4-MeOC6H4CH2
H
H
–
58
23
–
89
97
[51]
(CH2)2CH=CH2
H
H
–
58
23
–
87
78
[51]
Bn
Ph
Ph
–
59
60
–
95
95
[51]
Bn
Et
Et
–
59
60
–
94
92
[51]
Bn
Ph
H
15:1
58
60
8.5:1
83
80
[51]
Bn
t-Bu
H
18:1
59
60
10:1
88
86
[51]
Bn
CH2OBn
H >20:1
59
60
10:1
88
88
[51]
Bn
(CH2)2CO2Me
H
59
60
4.2:1
83
73
[51]
O
O NH
HN
7:1
Ph2P
HN
O Ph2P H N
PPh2 PPh2 O 58
59
2-(Benzyloxy)-2-vinylcyclopentanone (60, R1 = Bn; R2 = R3 = H); Typical Procedure:[51]
Dried and degassed 1,2-dichloroethane (25 mL) was added under an argon atmosphere to a mixture of Pd2(dba)3•CHCl3 (65.8 mg, 63.6 mol, 2.5 mol%) and ligand 58 (150.3 mg, 0.191 mmol, 7.5 mol%). The mixture was stirred for 15 min at rt and subsequently added via cannula under argon to a mixture of cyclobutanol 57 (R1 = Bn; R2 = R3 = H; 550 mg, 2.54 mmol) and 4- molecular sieves. A 1 M soln of BzOH in CH2Cl2 (0.25 mL, 0.25 mmol, 0.1 equiv) and a 1 M soln of Et3N in CH2Cl2 (0.25 mL, 0.25 mmol, 0.1 equiv) were added via syringe, and the mixture was stirred under argon at 30 8C for 12 h, filtered through Celite, and concentrated. The crude residue was then purified directly by flash chromatography (Et2O/petroleum ether 1:19) to give the product; yield: 530 mg (96%); 92% ee.
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. for references see p 466 Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.10.3
Tandem Reactions Involving an Isomerization or Rearrangement
3.10.3.1
Domino Reactions
3.10.3.1.1
Claisen Rearrangement/Intramolecular Carbonyl-Ene Reaction
3.10
Isomerizations and Allylic Rearrangements
A catalytic, asymmetric, domino Claisen rearrangement/intramolecular carbonyl-ene reaction based on previous studies on the catalytic, asymmetric Claisen rearrangement (see Section 3.10.1.1.1) and on copper-catalyzed ene reactions[52] has been reported (Scheme 17).[53] The bis(4,5-dihydrooxazole) catalyst 2 promotes the formation of two new C—C bonds in almost quantitative yield and three stereocenters (two of which are quaternary) with excellent enantioselectivity and high catalyst-induced diastereocontrol. The reaction sequence proceeds via formation of an intermediate Æ-oxo ester 62 from enone precursor (E)-61. This intermediate is suitable for bidentate coordination to the chiral copper catalyst 2, thereby inducing an intramolecular carbonyl-ene reaction. The formation of two diastereomers 63A and 63B is a consequence of incomplete enantioselection in the Claisen rearrangement. Utilizing the isomeric substrate (Z)-61 with a Z-configured O-allyl moiety reverses the diastereomeric ratio. Scheme 17
Domino Claisen Rearrangement/Intramolecular Carbonyl-Ene Reaction[53] PriO
PriO O
O
10 mol% 2 CH2Cl2, rt
O
O
62
61 PriO2C
PriO2C
OH H
OH
+
H
63A
63B
Config of 61 Ratio (63A/63B) ee (%) of Major Diastereomer Yield (%) Ref
3.10.3.1.2
E
89:11
98
98
[53]
Z
19:81
99
93
[53]
Ketene Addition/Acyl Claisen Rearrangement
A Lewis acid promoted, enantioselective reaction of ketenes, formed in situ from (benzyloxy)acetyl chloride and allylic amines 64, to form Æ,-disubstituted ª,-unsaturated morpholine amides 66 has been reported (Scheme 18).[54] Morpholine amides are cost-efficient substitutes for the commonly used Weinreb amides.[55,56] The bis(4,5-dihydrooxazole) complex 65 provides a highly effective asymmetric environment for acid chlorides that can chelate with the metal complex, such as (benzyloxy)acetyl chloride. In contrast, poorly chelating substrates are not useful. Considerably lower enantioselectivity is obtained with substoichiometric Lewis acid loadings, indicating a competing thermal background reaction. Significant structural variation at the C3 (R1/R2) and C2 (R3) positions is possible without loss of enantioselectivity (Scheme 18). The high diastereoselectivity can be rationalized by the high preference for a chair-like transition state 67 in the acyl-Claisen-rearIsomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
465
Tandem Reactions Involving an Isomerization or Rearrangement
3.10.3
rangement step. Even all-carbon-substituted quaternary stereocenters are accessible in good yields and with excellent stereocontrol [e.g., amide 66 (R1 = CO2Et; R2 = Me)]. Domino Ketene Addition/Acyl Claisen Rearrangement[54]
Scheme 18
Cl
Cl
N
N
O
O Mg I
I
OMe
MeO 65
+
O
R2
O R2
iPr2NEt CH2Cl2, −20 oC
O
R3
N
N
Cl
R1
O
OBn
64
OBn R3 66
R1
R2
R3
Ratio (syn/anti) ee (%) Yield (%) Ref
H
H
H
–
91
80a
[54]
a
[54]
H
H
Me –
91
78
H
H
Ph –
90
79 a
[54]
CH2OBz
H
H
92:8
86
86
[54]
4-O2NC6H4
H
H
99:1
97
82
[54]
CO2Et
H
H
97:3
96
84a
[54]
Cl
H
H
98:2
91
95
[54]
H
Cl
H
91
74
[54]
CO2Et
Me H
97
75
[54]
a
R1
3:97 94:6
Reaction performed with 2.0 equiv of catalyst 65.
O N [Mg] O
R1 BnO 67
Amides 66; General Procedure:[54]
A 0.025 M soln of allylic amine 64 in CH2Cl2 (0.10 mmol) and iPr2NEt (0.15 mmol) were added sequentially to a soln of catalyst 65 (0.2 mmol) in CH2Cl2 at 23 8C. The resulting mixture was cooled to –20 8C and 1.0 M (benzyloxy)acetyl chloride (0.12 mmol) in CH2Cl2 was added over 12 h. After an additional 12 h, the resulting mixture was treated with 1 M NaOH and extracted with EtOAc. The collected organic phases were dried (MgSO4) and concentrated, and the ligand was precipitated with EtOH. The supernatant was filtered, concentrated, and purified by flash chromatography.
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. for references see p 466 Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.10
Isomerizations and Allylic Rearrangements
References [1]
[2] [3] [4]
[5]
[6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32]
[33]
[34]
[35] [36] [37] [38] [39] [40] [41] [42] [43] [44]
[45]
[46] [47] [48]
The Claisen Rearrangement, Hiersemann, M.; Nubbemeyer, U., Eds.; Wiley-VCH: Weinheim, Germany, (2007). Martn Castro, A. M., Chem. Rev., (2004) 104, 2939. Nubbemeyer, U., Synthesis, (2003), 961. Mikami, K.; Akiyama, K., In The Claisen Rearrangement, Hiersemann, M.; Nubbemeyer, U., Eds.; Wiley-VCH: Weinheim, Germany, (2007); pp 25–43. Abraham, L.; Czerwonka, R.; Hiersemann, M., Angew. Chem., (2001) 113, 4835; Angew. Chem. Int. Ed., (2001) 40, 4700. Abraham, L.; Kçrner, M.; Hiersemann, M., Tetrahedron Lett., (2004) 45, 3647. Abraham, L.; Kçrner, M.; Schwab, P.; Hiersemann, M., Adv. Synth. Catal., (2004) 346, 1281. Balta, B.; ztrk, C.; Aviyente, V.; Vincent, M. A.; Hillier, I. H., J. Org. Chem., (2008) 73, 4800. Akiyama, K.; Mikami, K., Tetrahedron Lett., (2004) 45, 7217. van der Baan, J. L.; Bickelhaupt, F., Tetrahedron Lett., (1986) 27, 6267. Mikami, K.; Takahashi, K.; Nakai, T., Tetrahedron Lett., (1987) 28, 5879. Mikami, K.; Takahashi, K.; Nakai, T., J. Am. Chem. Soc., (1990) 112, 4035. Meerwein, H.; Florian, W.; Schon, N.; Stopp, G., Justus Liebigs Ann. Chem., (1961) 641, 1. Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A., Helv. Chim. Acta, (1964) 47, 2425. Linton, E. C.; Kozlowski, M. C., J. Am. Chem. Soc., (2008) 130, 16 162. Linder, D.; Buron, F.; Constant, S.; Lacour, J., Eur. J. Org. Chem., (2008), 5778. Linder, D.; Austeri, M.; Lacour, J., Org. Biomol. Chem., (2009) 7, 4057. Mumm, O.; Mçller, F., Ber. Dtsch. Chem. Ges. B, (1937) 70, 2214. Overman, L. E., J. Am. Chem. Soc., (1974) 96, 597. Overman, L. E., Angew. Chem., (1984) 96, 565; Angew. Chem. Int. Ed. Engl., (1984) 23, 579. Hollis, T. K.; Overman, L. E., J. Organomet. Chem., (1999) 576, 290. Donde, Y.; Overman, L. E., J. Am. Chem. Soc., (1999) 121, 2933. Anderson, C. E.; Donde, Y.; Douglas, C. J.; Overman, L. E., J. Org. Chem., (2005) 70, 648. Kang, J.; Kim, T. H.; Yew, K. H.; Lee, W. K., Tetrahedron: Asymmetry, (2003) 14, 415. Kang, J.; Yew, K. H.; Kim, T. H.; Choi, D. H., Tetrahedron Lett., (2002) 43, 9509. Anderson, C. E.; Overman, L. E., J. Am. Chem. Soc., (2003) 125, 12 412. Kirsch, S. F.; Overman, L. E.; Watson, M. P., J. Org. Chem., (2004) 69, 8101. Nomura, H.; Richards, C. J., Chem.–Eur. J., (2007) 13, 10 216. Fischer, D. F.; Barakat, A.; Xin, Z.-q.; Weiss, M. E.; Peters, R., Chem.–Eur. J., (2009) 15, 8722. Overman, L. E.; Owen, C. E.; Pavan, M. M.; Richards, C. J., Org. Lett., (2003) 5, 1809. Peters, R.; Xin, Z.-q.; Fischer, D. F.; Schweizer, W. B., Organometallics, (2006) 25, 2917. Weiss, M. E.; Fischer, D. F.; Xin, Z.-q.; Jautze, S.; Schweizer, W. B.; Peters, R., Angew. Chem., (2006) 118, 5823; Angew. Chem. Int. Ed., (2006) 45, 5694. Jautze, S.; Seiler, P.; Peters, R., Angew. Chem., (2007) 119, 1282; Angew. Chem. Int. Ed., (2007) 46, 1260. Fischer, D. F.; Xin, Z.-q.; Peters, R., Angew. Chem., (2007) 119, 7848; Angew. Chem. Int. Ed., (2007) 46, 7704. Jautze, S.; Seiler, P.; Peters, R., Chem.–Eur. J., (2008) 14, 1430. Xin, Z.-q.; Fischer, D. F.; Peters, R., Synlett, (2008), 1495. Peters, R.; Fischer, D. F., Org. Lett., (2005) 7, 4137. Jautze, S.; Diethelm, S.; Frey, W.; Peters, R., Organometallics, (2009) 28, 2001. Overman, L. E.; Roberts, S. W.; Sneddon, H. F., Org. Lett., (2008) 10, 1485. Lee, E. E.; Batey, R. A., J. Am. Chem. Soc., (2005) 127, 14 887. Blid, J.; Panknin, O.; Somfai, P., J. Am. Chem. Soc., (2005) 127, 9352. Blid, J.; Panknin, O.; Tuzina, P.; Somfai, P., J. Org. Chem., (2007) 72, 1294. Noyori, R., Asymmetric Catalysis in Organic Synthesis, Wiley: New York, (1994); Chapter 3. Tani, K.; Yamagata, T.; Otsuka, S.; Akutagawa, S.; Kumobayashi, H.; Taketomi, T.; Takaya, H.; Miyashita, A.; Noyori, R., J. Chem. Soc., Chem. Commun., (1982), 600. Tani, K.; Yamagata, T.; Akutagawa, S.; Kumobayashi, H.; Taketomi, T.; Takaya, H.; Miyashita, A.; Noyori, R.; Otsuka, S., J. Am. Chem. Soc., (1984) 106, 5208. Inoue, S.-i.; Takaya, H.; Tani, K.; Otsuka, S.; Sato, T.; Noyori, R., J. Am. Chem. Soc., (1990) 112, 4897. Otsuka, S.; Tani, K., Synthesis, (1991), 665. Tanaka, K.; Qiao, S.; Tobisu, M.; Lo, M. M.-C.; Fu, G. C., J. Am. Chem. Soc., (2000) 122, 9870.
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Tanaka, K.; Fu, G. C., J. Org. Chem., (2001) 66, 8177. Trost, B. M.; Xie, J., J. Am. Chem. Soc., (2006) 128, 6044. Trost, B. M.; Xie, J., J. Am. Chem. Soc., (2008) 130, 6231. Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T., J. Am. Chem. Soc., (2000) 122, 7936. Kaden, S.; Hiersemann, M., Synlett, (2002), 1999. Yoon, T. P.; MacMillan, D. W. C., J. Am. Chem. Soc., (2001) 123, 2911. Peters, R.; Waldmeier, P.; Joncour, A., Org. Process Res. Dev., (2005) 9, 508. Peters, R.; Diolez, C.; Rolland, A.; Manginot, E.; Veyrat, M., Heterocycles, (2007) 72, 255.
Isomerizations To Form a Stereogenic Center and Allylic Rearrangements, Jautze, S., Peters, R. Science of Synthesis 4.0 version., Section 3.10 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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469 3.11
Allylic and Benzylic Oxidation M. B. Andrus
General Introduction
The selective oxidation of alkenes to give allylic alcohols and their derivatives (as illustrated in Scheme 1) may be performed using stoichiometric or catalytic quantities of selenium dioxide.[1] Conversion of alkenes into allylic esters is also achieved using a palladium(II) acetate catalyst with benzoquinone[2] and with catalytic copper complexes using perester oxidants.[3] Regio- and stereoselectivity are often dependent upon the substrate but may be controlled by the proper choice of reagent or additive and by variation of the metal/ligand combination. Oxidation to give enones is very a useful synthetic procedure, and may be promoted by various metal catalysts and tert-butyl hydroperoxide.[1] Benzylic oxidation can be achieved using various metal catalysts and oxidants to give useful benzoyl and benzyl alcohol moieties.[1] Biocatalytic methods have also been developed for this transformation using catalysts related to metal porphyrin cytochrome P450.[4] C—H activation at the allylic and benzylic position can thus be employed as an efficient approach to the installation of oxygen functionality at a late stage of a multistep synthesis and used to construct useful enantioenriched starting materials.[1] This section illustrates these transformations and examples are presented which demonstrate high levels of diastereo- and enantioselectivity. Scheme 1 Allylic Oxidation of E- and Z-Alkenes in Acyclic/Cyclic Precursors O [O]
[O]
O
SAFETY: Inorganic selenium compounds present special hazards. They are highly toxic and exposure, inhalation, ingestion, and skin or eye contact should be avoided. Common symptoms include drowsiness, headaches, nausea, abdominal pains, and a garlic odor of the breath. These substances may also cause effects on the central nervous system. Longterm exposure to selenium and related compounds can cause birth defects, so pregnant women should avoid exposure to these substances. It is recommended that organoselenium compounds should be treated with similar care. Peroxide compounds present a significant detonation hazard. Concentrated, dry samples should be avoided. Some of the preparations included in this section use tertbutyl hydroperoxide and peresters. Care should be taken to avoid skin and eye contact or the exposure of these materials to strong oxidants, strong acids, intense light, or mechanical shock.
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470
Stereoselective Synthesis
3.11.1
Allylic Oxidation
3.11.1.1
Oxidation To Afford Allylic Alcohols and Derivatives
3.11.1.1.1
Reaction with Selenium Dioxide
3.11
Allylic and Benzylic Oxidation
The most useful approach for allylic oxidation continues to be the reaction with catalytic selenium dioxide and stoichiometric tert-butyl hydroperoxide (TBHP).[5] Under this system exocyclic methylenes provide cyclic allylic alcohols with high regioselectivity via a [2,3]hetero-ene rearrangement followed by selenenic acid hydrolysis.[6] This approach has been reported in numerous total syntheses that involve the creation of allylic alcohols from alkenes with high regio- and diastereoselectivity as a key step.[7–9] For example, oxidation of an exocyclic cyclohexene with selenium dioxide (40 mol%) and stoichiometric tert-butyl hydroperoxide gives the allylic alcohol in high yield and selectivity (Table 1, entry 1).[10] In general, the less sterically hindered alcohol is formed in a regioselective and stereofacially selective manner,[11] and in this case the alcohol is formed away from the dimethylmethylene bridging group. For linear alkenes, oxidation with excess selenium dioxide usually forms the overoxidized enone or enal products, which then requires sodium borohydride reduction to access the desired alcohols.[12] However, with less reactive endocyclic alkenes, the catalytic conditions do not provide sufficient reactivity, making excess selenium dioxide often necessary. For example, the oxidation of an endocyclic cyclopentene to the cyclopentenol has been reported using excess selenium dioxide (2 equiv) in the presence of potassium dihydrogen phosphate at elevated temperature (Table 1, entry 2).[13] The oxidation of an endocyclic cyclohexene with excess selenium dioxide (3 equiv) under microwave conditions, provides the corresponding cyclohexenol with complete selectivity, has also featured in the total synthesis of the antibiotic platensimycin (Table 1, entry 3).[14] Oxidation with excess selenium dioxide (2 equiv) and tert-butyl hydroperoxide with added salicylic acid has been used to convert a linear polyene into an allylic diol together with the corresponding mono-alcohol and hydroxyaldehyde (Table 1, entry 4),[15] which undergoes a Swern oxidation to provide the bis(enal). The added salicylic acid, which has now become a common additive, aids in the breakdown of the selenenic acid intermediate.
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3.11.1
Table 1
471
Allylic Oxidation
Allylic Oxidation Using Selenium Dioxide[13–15]
Entry Starting Material
Conditions
Product
SeO2 (40 mol%), t-BuOOH, CH2Cl2, H2O
O
Yield (%)
Ref
85
[10]
69
[13]
83
[14]
48a
[15]
O O O
1
OH H N
O
2
SeO2 (2 equiv), KH2PO4, diglyme, 170 8C
NCbz
O
O
SeO2 (3 equiv), dioxane, microwave, 110 8C, 10 min
3
4
2
2
SO2Ph
a
SeO2 (2 equiv), t-BuOOH (6 equiv), salicylic acid (1 equiv), CH2Cl2, 0 8C, 3h
H N
O
NCbz
O
OH
O
HO OH
2
2
SO2Ph OH
The mono-alcohol and hydroxyaldehyde forms are also obtained in 28 and 12% yields, respectively.
(1R,3R,5S)-3-Hydroxy-8,8-dimethyl-2-methylene-6-oxabicyclo[3.2.1]octan-7-one (Table 1, Entry 1); Typical Procedure:[10]
SeO2 (321 mg, 2.89 mmol), t-BuOOH (70 wt% in H2O; 2.60 g, 28.88 mmol), and salicylic acid (cat.) were added to a stirred soln of the methylenecyclohexane [1.20 g, 7.22 mmol, (+)-form] in anhyd CH2Cl2 (80 mL) under an argon atmosphere. The mixture was then refluxed for 3 d before being allowed to cool to rt. Na2SO3 (7.50 g, 60 mmol) and H2O (1 mL) were then added, and the mixture was stirred for a further 30 min, filtered through a pad of MgSO4, and concentrated to give a solid residue. Purification by crystallization (Et2O/ hexane) gave the product as white crystals; yield: 1.13 g (85%); (+)-form; mp 157 8C. 3.11.1.1.2
Reaction with Palladium/Quinone/Oxygen Reagents
Allylic oxidation of terminal alkenes using palladium catalysts with quinone oxidants has received renewed attention due to recent innovations that provide regioselective control and offer new promise for enantioselectivity.[2] Linear products involving selective formation of primary acetates are typically formed under the standard conditions [palladium(II) acetate (10 mol%) with benzo-1,4-quinone as the oxidant]. For example, reaction of allylbenzene (1, R1 = Ph) using a 2,2¢-bipyrimidine ligand in acetic acid gives 3-phenylprop-2enyl acetate (2, R1 = Ph) (Scheme 2).[16] The mechanism involves alkene coordination, C—H activation via proton transfer with loss of acetic acid, and formation of a ð-allylpalladium species followed by acetate addition. Coordination by benzo-1,4-quinone leads to oxidation to palladium(II). Linear versus branched allylic acetate selectivity is controlled Allylic and Benzylic Oxidation, Andrus, M. B. Science of Synthesis 4.0 version., Section 3.11 sos.thieme.com © 2014 Georg Thieme Verlag KG
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472
Stereoselective Synthesis
3.11
Allylic and Benzylic Oxidation
by a subtle combination of ligand and oxidant coordination effects that remain unclear at this time. A bis(sulfoxide) ligand has been utilized for the oxidation of a terminal alkene 1 [R1 = (CH2)7Me] in dichloromethane/acetic acid to access the branched allylic acetate 3 [R1 = (CH2)7Me] with 8:1 selectivity over the linear form (Scheme 2).[17] However, without the bis(sulfoxide) ligand the linear product is obtained with 20:1 selectivity in dimethyl sulfoxide. Furthermore, it has been demonstrated that a vinyl sulfoxide ligand can further boost the selectivity for the branched acetate 3 [R1 = (CH2)7Me] to 31:1 using 1,4-dioxane/acetic acid as the solvent (Scheme 2).[18] Enantioselective oxidation is also possible using the chromium(III)–salen cocatalyst 4 and a terminal alkene 1 [R1 = (CH2)8OTBDPS] which undergoes oxidation to give the branched allylic acetate 3 [R1 = (CH2)8OTBDPS] in 84% yield with modest regioselectivity (branched/linear 4.4:1) but encouraging enantiomeric excess (63%) (Scheme 2).[19] Scheme 2
Palladium-Catalyzed Allylic Oxidation[16–19] OAc Pd(OAc)2
R1
R
1
OAc
1
+
2
R1 3
R1
Conditions
Ratio (2/3)
Yield (%)
Ref
Ph
Pd(OAc)2 (10 mol%), 2,2¢-bipyrimidine (10 mol%), benzo-1,4-quinone, AcOH, air, 80 8C, 16 h
2 only
76
[16]
(CH2)7Me
Pd(OAc)2•BnS(O)(CH2)2S(O)Bn (10 mol%), benzo-1,4-quinone, CH2Cl2, AcOH, 40 8C
1:8
74
[17]
(CH2)7Me
Pd(OAc)2 (10 mol%), benzo-1,4-quinone, DMSO, AcOH, 40 8C
20:1
42
[17]
(CH2)7Me
Pd(OAc)2•PhS(O)CH=CH2
1:31
64
[18]
1:4.4
84a
[19]
(10 mol%), benzo-1,4-quinone, AcOH, 1,4-
dioxane, air, 43 8C, 72 h (CH2)8OTBDPS a
Pd(OAc)2•PhS(O)(CH2)2S(O)Ph (10 mol%), cocatalyst 4 (10 mol%), benzo-1,4-quinone, AcOH, EtOAc, 4-Å molecular sieves, rt, 48 h
The branched acetate is obtained in 63% ee (R-form).
N
N Cr
But
O F
O
But
But
But 4
This type of oxidation can also be employed in an intramolecular macrocyclic allylic oxidation to form macrolides.[20] For example, oxidation of the terminal alkene 5 furnishes the branched large-ring phthalate ester 6 in 62% yield on a gram scale (Scheme 3). A related intramolecular oxidation (formally an addition reaction) of alkene 7, using a full equivalent of (–)-sparteine as a chiral additive, affords the vinyl-substituted benzofuran 8 in modest yield but with high enantioselectivity (Scheme 3).[21] These results illustrate the potential the process holds for future method development and complex target applications.
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473
Allylic Oxidation Intramolecular Palladium-Catalyzed Oxidation[20,21]
Scheme 3
O
10 mol% Pd(OAc)2•PhS(O)(CH2)2S(O)Ph benzo-1,4-quinone, air, CH2Cl2 45 oC, 72 h
CO2H
O
62%
O
O
O
O 5
6
10 mol% Pd(O2CCF3)2 (−)-sparteine (1 equiv) Ca(OH)2, O2, 3-Å molecular sieves toluene, 55 oC, 60 h
MeO
MeO
57%; 90% ee
O
OH 7
8
Macrocyclic Diester 6; Typical Procedure:[20]
A vial was charged with Pd(OAc)2•PhS(O)(CH2)2S(O)Ph (165.2 mg, 0.328 mmol), a 25-mL round-bottomed flask was charged with acid 5 (1.0 g, 3.3 mmol), and a scintillation vial was charged with benzo-1,4-quinone (710.3 mg, 6.57 mmol). The bis(sulfoxide)–palladium complex in CH2Cl2 (10 mL), benzo-1,4-quinone in CH2Cl2 (10 mL), and the acid 5 in CH2Cl2 (20 mL) were transferred sequentially to a 1-L round-bottomed flask. This flask was charged with an additional portion of CH2Cl2 (290 mL) and a stirrer bar was added. The apparatus was then fitted with a condenser and heated at 45 8C with two empty balloons on the top of the flask. After 72 h, the mixture was transferred to a separatory funnel and washed with sat. aq NH4Cl (1 100 mL) and H2O (1 100 mL). The combined aqueous washes were extracted (CH2Cl2) and the combined organic layers were dried (MgSO4), filtered, and concentrated to give a brown solid. Purification by flash chromatography (EtOAc/hexanes 1:9) gave the product as a clear oil; yield: 613 mg (62%). 3.11.1.1.3
Reaction with Copper/Perester Reagents
Allylic oxidation of cyclic alkenes using copper catalysts and perester oxidants allows for the efficient production of allylic esters with high enantioselectivity.[3] The original Kharasch conditions have been modified to include stable copper(I) catalysts having C2-symmetric ligands and phenylhydrazine as an additive.[22] With terminal alkenes, the internal, branched ester is the major product in accordance with the mechanism which involves an allyl radical formed by hydrogen abstraction by a tert-butoxyl radical, addition of the copper benzoate complex, rearrangement to the allylic ester product, and regeneration of the copper(I) catalyst.[3] Various ligands have been used in this process, including bis(4,5-dihydrooxazoles) 9–11,[22–25] bipyridines 12,[26] 13,[27] and 14,[28] phenanthroline 15,[29] and ferrocene 16[30] (Scheme 4). Scheme 4 R1
Ligands for Copper-Catalyzed Allylic Oxidation[22–30] R1
Et O
O
Et B
O
O
Ph N
N
Ph R
Ph 9
N
1
H
Allylic and Benzylic Oxidation, Andrus, M. B. Science of Synthesis 4.0 version., Section 3.11 sos.thieme.com © 2014 Georg Thieme Verlag KG
Ph Ph
Bn
Bn
R1 = Me, Et
N
10
O N
Ph
O
N
Ph
Ph N
Pri
Ph Pri
11
for references see p 481 (Customer-ID: 5907)
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Stereoselective Synthesis
N
3.11
Allylic and Benzylic Oxidation
N N
O
O
O
But
O
O But
O O
Et
O
Et
Et Et
12
N
N
13
N N
14
N
15
Fe
N PPh2
PPh3
16
The C2-symmetric (S,S)-bis(4,5-dihydrooxazoles) 9 have proven excellent ligands for the selective construction of (S)-allylic benzoates, when used in conjunction with a convenient copper(I) source such as tetrakis(acetonitrile)copper(I) hexafluorophosphate (15 mol%) and tert-butyl 4-nitroperoxybenzoate in acetonitrile at –20 8C over 17–24 hours.[23] Thus, ligands 9 (R1 = Me, Et) have been used in the oxidation of cyclohexene and cyclopentene to give cyclohexenyl benzoate 17 (n = 2; Ar1 = 4-O2NC6H4) and cyclopentenyl benzoate 17 (n = 1; Ar1 = 4-O2NC6H4) in 96 and 99% enantiomeric excess, respectively (Scheme 5). The yields, which are relatively modest, are based on the peroxybenzoate (1 equiv) with the alkenes typically used in excess (5 equiv). The use of borate-containing bis(4,5-dihydrooxazole) 10 with added potassium carbonate and tert-butyl peroxybenzoate over 72 hours affords the cyclohexenyl benzoate 17 (n = 2; Ar1 = Ph) in 87% yield with very good enantioselectivity (86% ee) (Scheme 5).[24] A useful modification, which has now become standard, is the use of a catalytic amount of phenylhydrazine to reduce copper(II) to copper(I) for efficient reduction of the perester. This leads to faster reaction rates and thus shorter reaction times in the region of 4–9 hours.[22] Alternatively, the pyridine-containing bis(4,5dihydrooxazole) 11 can be used with copper(II) bis(trifluoromethanesulfonate) and tertbutyl 4-methoxyperoxybenzoate to furnish various allylic benzoates 17 (n = 1–4; Ar1 = 4-MeOC6H4) in modest yields (31–60%) with good to excellent enantioselectivities (77– 96% ee) (Scheme 5).[22,25] This catalyst also oxidizes cycloocta-1,3-diene, which undergoes allylic oxidation to give the corresponding dienyl benzoate in 49% yield and 95% enantiomeric excess. Acyclic oct-1-ene produces 3-benzyloxyoct-1-ene in 39% yield and with poor enantioselectivity (31% ee), which is typical for acyclic alkenes. The bipyridine ligand 12 gives allylic benzoates 17 (n = 2, 3; Ar1 = Ph) in excellent yield and enantioselectivities (90– 97% ee) using copper(II) bis(trifluoromethanesulfonate) and phenylhydrazine in acetone at room temperature.[26] A similar bipyridine ligand 13 has been reported which is optimal for the synthesis of cyclohexenyl benzoate 17 (n = 2; Ar1 = Ph; 91% ee), whereas the cyclopentenyl and cycloheptenyl derivatives are obtained with poor enantioselectivity (34–40% ee).[27] Bipyridine ligand (–)-14, derived from (+)-3-carene, employs a lower catalyst loading (1 mol%) with added phenylhydrazine (96 h, –20 8C) to give (R)-allylic benzoate 17 (n = 2; Ar1 = Ph) with modest yield but encouraging enantioselectivity (82% ee).[28] A (+)-pinene-derived phenanthroline ligand 15 affords benzoate 17 (n = 3; Ar1 = Ph) with comparable results with a low catalyst loading (1 mol%) and reduced reaction time (0.5 h).[29] Finally, an innovative imidophosphine-substituted ferrocene ligand 16, which gives allylic benzoates 17 (n = 1–4; Ar1 = Ph) with moderate to very good yields (48–85%) and with excellent selectivities (91–98% ee), has been reported[30] Cycloocta-1,5-diene also undergoes oxidation in excellent yield (99%) and with excellent selectivity (99% ee) with this ligand. Allylic and Benzylic Oxidation, Andrus, M. B. Science of Synthesis 4.0 version., Section 3.11 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Allylic Oxidation
Scheme 5
Copper-Catalyzed Allylic Oxidation with Peresters[22–30] O O
n
Ar1
O
Cu(I)•ligand
+ O
O
But
Ar1
S n
17
n Ar1
Copper Catalyst
Ligand
2 4-O2NC6H4
Cu(NCMe)4PF6 (15 mol%)
1 4-O2NC6H4 2 Ph
Additive
Solvent
ee (%)
Yield (%)
Ref
9 – (R1 = Me)
MeCN
96
44
[23]
Cu(NCMe)4PF6 (15 mol%)
9 (R1 = Et)
–
MeCN
99
41
[23]
Cu(NCMe)4PF6 (7.5 mol%)
10
K2CO3
MeCN
86
87
[24]
1 4-MeOC6H4 Cu(OTf )2 (5 mol%)
11
PhNHNH2 acetone
77
55
[22]
2 4-MeOC6H4 Cu(OTf )2 (5 mol%)
11
PhNHNH2 acetone
93
60
[25]
3 4-MeOC6H4 Cu(OTf )2 (5 mol%)
11
PhNHNH2 acetone
91
45
[22]
4 4-MeOC6H4 Cu(OTf )2 (5 mol%)
11
PhNHNH2 acetone
96
31
[22]
2 Ph
Cu(OTf )2 (5 mol%)
12
PhNHNH2 acetone
90
91
[26]
3 Ph
Cu(OTf )2 (5 mol%)
12
PhNHNH2 acetone
97
89
[26]
2 Ph
Cu(OTf )2 (1 mol%)
13
PhNHNH2 MeCN
91
45
[27]
35
[28]
a
2 Ph
Cu(OTf )2 (1 mol%)
14
–
acetone
82
3 Ph
Cu(OTf )2 (1 mol%)
15
–
acetone
71
91
[29]
1 Ph
Cu(OTf )2 (5 mol%)
16
PhNHNH2 MeCN
98
54
[30]
2 Ph
Cu(OTf )2 (5 mol%)
16
PhNHNH2 MeCN
96
79
[30]
3 Ph
Cu(OTf )2 (5 mol%)
16
PhNHNH2 MeCN
97
85
[30]
4 Ph
Cu(OTf )2 (5 mol%)
16
PhNHNH2 MeCN
91
48
[30]
a
The product is obtained as the R configuration.
A useful copper-catalyzed peroxybenzoate oxidation has also been described using a novel quinoline imine ligand 18 (Scheme 6).[31] Treatment of 4,5-epoxycyclohexene (7-oxabicyclo[4.1.0]hept-3-ene) with a copper(I) hexafluorophosphate catalyst (5 mol%), ligand 18, and tert-butyl peroxybenzoate in acetone for 40 hours affords predominantly the desymmetrized, enantioenriched allylic benzoate 19A with trace amounts of the opposite isomer 19B in 32% overall yield. Selectivity for the major product is very good (85% ee), and this product can be employed as an intermediate in the synthesis of 2-deoxystreptamine, an RNA targeting antibiotic.
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476
Stereoselective Synthesis Scheme 6
3.11
Allylic and Benzylic Oxidation
Copper-Catalyzed Oxidation of 4,5-Epoxycyclohexene[31] 5 mol% Cu(NCMe)4PF6
N 6 mol%
But
N
OBz
OBz
18 TBPB, acetone, 25 oC, 40 h
O
32%
+
O 19A
>99:1
O 19B
(S)-Cyclohex-2-enyl Benzoate (17, n = 2; Ar1 = Ph); Typical Procedure Using a BipyridineBased Bis(O,O-acetal) Ligand:[27]
CAUTION: Phenylhydrazine is a potent skin sensitizer, and may damage the liver and kidneys. Cu(OTf )2 (6.3 mg, 17 ìmol), bipyridine ligand 13 (8.5 mg, 18 ìmol), and MeCN (2.5 mL) were added to a screw-cap vial, and the resultant soln was stirred at rt for 1 h. PhNHNH2 (2.0 ìL, 20 ìmol) was added and the mixture was stirred for an additional 5 min at rt and then cooled to 0 8C. Cyclohexene (1.8 mmol) and tert-butyl peroxybenzoate (67 ìL, 0.35 mmol) were added, and the reaction was monitored by TLC (Et2O/hexanes 1:1) until the tert-butyl peroxybenzoate had been consumed. The resulting mixture was concentrated under reduced pressure to afford a crude residue. Flash chromatography (hexanes/Et2O 5:1) gave the product in pure form as a colorless oil; yield: 45%; 91% ee. 3.11.1.2
Oxidation To Afford Enones
The use of stoichiometric metal oxides, in particular chromic oxides,[32] for allylic oxidation and the formation of enones has been replaced in recent times by the use of catalytic metal complexes with tert-butyl hydroperoxide as the terminal oxidant.[33] The formation of enones is a particularly useful transformation that allows for the late stage functionalization of simple alkenes in a regioselective manner. In general, the less sterically hindered carbonyl moiety is generated through an allyl radical process, with trapping at the least substituted position to give an allyl peroxide, followed by elimination with base to give the product. The metal catalyst accepts an electron from tert-butyl hydroperoxide, to give a peroxyl radical, which then abstracts an allylic hydrogen atom. Several examples of enone formation using various conditions are illustrated in Table 2. For example, an efficient conversion of a functionalized cyclohexene into the corresponding cyclohexenone,[34] based on the catalytic palladium conditions established by Corey,[35] has been reported (Table 2, entry 1). A similar method using substoichiometric copper(I) iodide and tert-butyl hydroperoxide, in the presence of tetrabutylammonium bromide as a phase-transfer catalyst in dichloromethane, has been reported for oxidation in a steroid system (Table 2, entry 2).[36] Related transformations with similar steroid substrates have also been reported using cobalt,[37] manganese,[38] rhodium,[39] and copper catalysts including with added sodium chlorite as the oxidant.[40] An efficient process employing a dirhodium catalyst [Rh2(cap)4, cap = caprolactamate] at a very low catalyst loading (0.1 mol%) with tert-butyl hydroperoxide as the oxidant has been used to oxidize 1-acetylcyclohexene to 3-acetylcyclohex-2-enone in good yield (Table 2, entry 3).[41] A wide range of substrates have undergone oxidation to give enones under these mild conditions and further examples are shown in Table 3. Excess sodium periodate with catalytic iodine in a biphasic chloroform/water system can be used to selectively oxidize a cyclohexenecontaining polyene trisulfone at the cyclohexene positions to afford the bis(enone) in 82% yield (Table 2, entry 4).[42] It should be noted that traditional metal catalysts and oxiAllylic and Benzylic Oxidation, Andrus, M. B. Science of Synthesis 4.0 version., Section 3.11 sos.thieme.com © 2014 Georg Thieme Verlag KG
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477
Allylic Oxidation
dants are ineffective for this transformation due to a lack of chemoselectivity regarding the polyene fragment. Treatment of the bicyclic alkene (1S,4aS,5R)-methyl 5-(tert-butyldimethylsiloxy)-1-hydroxy-1-methyl-4-oxo-1,2,3,4,4a,5,6,7-octahydronaphthalene-4a-carboxylate with more conventional methods failed, prompting the examination of alternatives, and the application of an unusual set of enone-forming conditions using dimethyldioxirane (DMDO) (Table 2, entry 5).[43] As such, application of a large excess of dimethyldioxirane at 15 8C furnishes the bicyclic enone in 76% isolated yield along with a small amount of the undesired epoxide (20%). Interestingly, this reaction is very sensitive to the substrate used and the temperature. Allylic Oxidation To Form Enones[34,36,41–43]
Table 2
En- Starting Material try
1
Conditions
Product
10% Pd/C, O t-BuOOH, K2CO3, CH2Cl2, 0 8C, 24 h
OTBDMS NHBoc
Yield Ref (%)
OTBDMS
89
[36]
78
[41]
82
[42]
76
[43]
O
CuI, t-BuOOH, TBAB, CH2Cl2
H H
[34]
NHBoc
O
2
75
H
H H AcO
AcO
Rh2(cap)4a (0.1 mol%), t-BuOOH, K2CO3, CH2Cl2, 1 h
3 Ac
H O
O
Ac
SO2Ph
SO2Ph
I2 (cat.),
SO2
SO2 NaIO 4
4
(3 equiv), CHCl3, H2O 2
O
2
HO
HO O
DMDO, acetone, 20 8C
5 TBDMSO a
O CO2Me
TBDMSO
O CO2Me
cap = caprolactamate.
Direct comparison of the palladium-[35] and rhodium-catalyzed[41] procedures illustrated in Table 2 is possible for a series of representative alkenes (Table 3). The palladium-on-carbon catalyst, used at 5 mol%, in general requires extended reaction times (48–72 h). In contrast, the dirhodium catalyst, used at only 0.1 mol%, produces enone products in good yields when performed at room temperature after a period of only hours. Both catalysts generate enediones from enones with high efficiency (Table 3, entries 1 and 2). Palladium Allylic and Benzylic Oxidation, Andrus, M. B. Science of Synthesis 4.0 version., Section 3.11 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
3.11
Allylic and Benzylic Oxidation
catalysis appears to produce higher yields for cyclic alkene acetal oxidations (Table 3, entries 3 and 4), and palladium-catalyzed allylic oxidation has also been show to produce enones from triisopropylsilyl enol ethers (Table 3, entry 5).[44] Table 3 Palladium- or Rhodium-Catalyzed Allylic Oxidation with tert-Butyl Hydroperoxide[35,41,44] Entry Starting Material 1
Ac
2
3
Conditions
Ac
O
O
Product
Pd/C (5 mol%), t-BuOOH (5 equiv), K2CO3 (0.5 equiv), CH2Cl2, 24 8C, 48 h Rh2(cap)4a (0.1 mol%), t-BuOOH (5 equiv), K2CO3 (0.5 equiv), CH2Cl2, rt, 1h
Yield (%)
Ref
Ac
81
[35]
Ac
79
[41]
80
[35]
61
[41]
75
[44]
94
[41]
O
O
O
O
Pd/C (5 mol%), t-BuOOH (5 equiv), K2CO3 (0.5 equiv), CH2Cl2, 24 8C, 72 h O
4
O
O
Rh2(cap)4a (1 mol%), t-BuOOH (10 equiv), K2CO3 (0.5 equiv), CH2Cl2, 40 8C, 3 h
O
O
O OTIPS
OTIPS
Pd/C (5 mol%), t-BuOOH (10 equiv), CsCO3 (1 equiv), CH2Cl2, 4 8C, 38 h
5
O
6 But a
O
Rh2(cap)4a (1 mol%), t-BuOOH (10 equiv), K2CO3 (0.5 equiv), CH2Cl2, rt, 1h But
cap = caprolactamate.
5-[(tert-Butoxycarbonyl)amino]-4-(tert-butyldimethylsiloxy)cyclohex-2-en-1-one (Table 2, Entry 1); Typical Procedure:[34]
10% Pd/C (0.005 g), CH2Cl2 (4 mL), 5.0–6.0 M t-BuOOH in decane (0.304 mL, 1.52 mmol), K2CO3 (0.010 g, 0.076 mmol), and the cyclohexene (0.100 g, 0.305 mmol) were added under N2 to an oven-dried, 25-mL, two-necked flask equipped with a stirrer bar. The mixture was stirred at 0 8C, monitored by TLC for consumption of the starting material (24 h), and stirred for a further 3 h at 25 8C. It was then filtered through a pad of silica gel (washing with CH2Cl2) and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography (petroleum ether/EtOAc 1:9) to provide the product as a clear liquid; yield: 0.078 g (75%).
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3.11.2
3.11.2
479
Benzylic Oxidation
Benzylic Oxidation
Benzylic oxidation reactions to provide either an aryl ketone or a chiral benzyl alcohol can be performed in a highly selective manner.[45] A variety of preparative approaches have been developed using metal catalysts and stoichiometric oxidants.[1] For example, catalysis using chiral, D4-symmetric, oxoruthenium–porphyrin complexes has been reported for asymmetric benzylic oxidation.[46] The mechanism involves formation of a stable benzyl radical that adds an oxygen atom and undergoes reduction to the alcohol or elimination with base to form the aryl ketone. 3.11.2.1
Oxidation To Afford Benzylic Alcohols and Derivatives
The hypervalent iodine compound (diacetoxyiodo)benzene has been reported to perform benzylic oxidations with catalytic amounts of copper(I) chloride and stoichiometric N-hydroxyphthalimide.[47] For example, ethylbenzene undergoes reaction to give an imide ether, which may be readily transformed into the corresponding secondary alcohol (Table 4, entry 1). Biocatalytic approaches to benzylic oxidation have included various cytochrome P450 type enzymes, as exemplified by P450 BM-3, which is isolated from the organism Bacillus megaterium.[48] The engineered enzyme mutant 9-10A-F87A has also been used preparatively for the hydroxylation of isopropyl phenylacetate to give isopropyl hydroxy(phenyl)acetate in 93% ee (Table 4, entry 2). The turnover number is very high with this enzyme/substrate combination (TTN 1640) when used in combination with reduced nicotinamide adenine dinucleotide phosphate (NADPH) in buffer for 3 hours at room temperature, albeit the yield is relatively low. An aerobic oxidation using bis(acetylacetonato)palladium(0) with 4-hydroxypyridine-2,6-dicarboxylic acid (H2hpda) as ligand in acetic acid has also been developed.[49] Under these conditions a methylquinoline derivative has been oxidized to the corresponding the benzylic acetate in 79% yield (Table 4, entry 3). An interesting halogen-directed C—H activation reaction has been developed using palladium(II) acetate and bis(diphenylphosphino)methane (dppm) in the presence of cesium 2,2-dimethylpropanoate (cesium pivaloate). Using this methodology 1-iodo-8methylnaphthalene affords a dehalogenated naphthylmethyl ester in 81% yield in dimethylformamide at 120 8C (Table 4, entry 4).[50]
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480
Stereoselective Synthesis Table 4
3.11
Allylic and Benzylic Oxidation
Benzylic Alcohols by Benzylic Oxidation[47–50]
Entry Starting Material
Conditions
Product
Yield (%)
Ref
78
[47]
16
[48]
79
[49]
81
[50]
O
CuCl (10 mol%), N-hydroxyphthalimide, PhI(OAc)2, MeCN, 70 8C, 12 h
1
OPri
2 O
O
O
OH
enzyme 9-10A-F87A, NADPH, buffer, rt, 3 h
OPri O Br
Br
Pd(acac)2 (5 mol%), H2hpdaa (5 mol%), O2, AcOH, 80 8C
3 N
N
N OAc
Pd(OAc)2•dppm (5 mol%), t-BuCO2Cs, DMF, 120 8C, 4h
4
a
3.11.2.2
But
O
I
O
H2hpda = 4-hydroxypyridine-2,6-dicarboxylic acid.
Oxidation To Afford Lactones and Aldehydes
Various metal catalysts based on bismuth,[51] chromium,[52] rhodium,[53] iron,[54] and ruthenium,[55] in conjunction with tert-butyl hydroperoxide, have been employed to convert alkylbenzene derivatives into the corresponding carbonyl-containing aryl species. For example, catalytic bismuth(0), picolinic acid (pyridine-2-carboxylic acid), and tert-butyl hydroperoxide have been used in a convenient, regioselective oxidation of a benzopyran at the benzyl ether position to give the benzopyranone 20 in high yield (Scheme 7).[51] A series of versatile oxidation methods that utilize 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (2-iodylbenzoic acid, IBX) have also been reported. In particular, the oxidation of sensitive 1-(allyloxy)-2-methylbenzene with excess 2-iodylbenzoic acid in hot dimethyl sulfoxide selectively generates 2-(allyloxy)benzaldehyde (21) in very good yield (Scheme 7).[56] Scheme 7
Aryl Aldehydes and Lactones by Benzylic Oxidation[51,56]
O
O
20 mol% Bi(0) (20 mol%) 20 mol% pyridine-2-carboxylic acid t-BuOOH, py, H2O, AcOH, 100 oC
O
91%
20
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References O O
(3 equiv)
I OH
O
O DMSO, 80 oC, 12 h
O H
85%
O 21
2-(Allyloxy)benzaldehyde (21); Typical Procedure:[56]
2-Iodylbenzoic acid (840 mg, 3.0 mmol) was added to a soln of 1-(allyloxy)-2-methylbenzene (148 mg, 1.0 mmol) in fluorobenzene/DMSO (2:1; 7.5 mL) and the mixture was heated at 80 8C for 12 h. The mixture was then cooled to rt, diluted with Et2O, washed with 5% NaHCO3 (2 20 mL), H2O (2 20 mL), and brine (20 mL), and then dried (MgSO4). Purification (silica gel, hexane/Et2O 10:1 to 5:1) furnished the product; yield: 138 mg (85%) in addition to recovered starting material; yield: 15 mg (10%).
References [1]
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Allylic and Benzylic Oxidation, Andrus, M. B. Science of Synthesis 4.0 version., Section 3.11 sos.thieme.com © 2014 Georg Thieme Verlag KG
(Customer-ID: 5907)
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Stereoselective Synthesis
3.11
Allylic and Benzylic Oxidation
Salmond, W. G.; Barta, M. A.; Havens, J. L., J. Org. Chem., (1978) 43, 2057. Muzart, J., Tetrahedron Lett., (1987) 28, 4665. Pandey, G.; Tiwari, K. N.; Puranik, V. G., Org. Lett., (2008) 10, 3611. Yu, J.-Q.; Corey, E. J., J. Am. Chem. Soc., (2003) 125, 3232. Arsenou, E. S.; Koutsourea, A. I.; Fousteris, M. A.; Nikolaropoulos, S. S., Steroids, (2003) 68, 407. Salvador, J. A. R.; Clark, J. H., Chem. Commun. (Cambridge), (2001), 33. Shing, T. K. M.; Yeung, Y.-Y.; Su, P. L., Org. Lett., (2006) 8, 3149. Choi, H.; Doyle, M. P., Org. Lett., (2007) 9, 5349. Silvestre, S. M.; Salvador, J. A. R., Tetrahedron, (2007) 63, 2439. Catino, A. J.; Forslund, R. E.; Doyle, M. P., J. Am. Chem. Soc., (2004) 126, 13 622. Choi, S.; Koo, S., J. Org. Chem., (2005) 70, 3328. Boyer, F.-D.; Descoins, C. L.; Thanh, G. V.; Descoins, C.; Prang, T.; Ducrot, P.-H., Eur. J. Org. Chem., (2003), 1172. Yu, J.-Q.; Wu, H.-C.; Corey, E. J., Org. Lett., (2005) 7, 1415. Hudlicky, M., Oxidations in Organic Chemistry, ACS Monograph 186, American Chemical Society: Washington, DC, (1990). Zhang, R.; Yu, W.-Y.; Lai, T.-S.; Che, C.-M., Chem. Commun. (Cambridge), (1999), 1791. Lee, J. M.; Park, E. J.; Cho, S. H.; Chang, S., J. Am. Chem. Soc., (2008) 130, 7824. Landwehr, M.; Hochrein, L.; Otey, C. R.; Kasrayan, A.; Bckvall, J.-E.; Arnold, F. H., J. Am. Chem. Soc., (2006) 128, 6058. Zhang, J.; Khaskin, E.; Anderson, N. P.; Zavalij, P. Y.; Vedernikov, A. N., Chem. Commun. (Cambridge), (2008), 3625. Kesharwani, T.; Larock, R. C., Tetrahedron, (2008) 64, 6090. Bonvin, Y.; Callens, E.; Larrosa, I.; Henderson, D. A.; Oldham, J.; Burton, A. J.; Barrett, A. G. M., Org. Lett., (2005) 7, 4549. Yamazaki, S., Org. Lett., (1999) 1, 2129. Catino, A. J.; Nichols, J. M.; Choi, H.; Gottipamula, S.; Doyle, M. P., Org. Lett., (2005) 7, 5167. Nakanishi, M.; Bolm, C., Adv. Synth. Catal., (2007) 349, 861. Yi, C. S.; Kwon, K.-H.; Lee, D. W., Org. Lett., (2009) 11, 1567. Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L., J. Am. Chem. Soc., (2001) 123, 3183.
Allylic and Benzylic Oxidation, Andrus, M. B. Science of Synthesis 4.0 version., Section 3.11 sos.thieme.com © 2014 Georg Thieme Verlag KG
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483 3.12
Mizoroki–Heck Reaction M. Shibasaki, T. Ohshima, and W. Itano
General Introduction
The palladium-mediated coupling of aryl or alkenyl iodides, bromides, or trifluoromethanesulfonates with alkenes in the presence of base, i.e. the metal-catalyzed arylation or alkenylation of alkenes, is generally referred to as the Mizoroki–Heck reaction.[1–12] Since the pioneering work of Mizoroki and co-workers[13] and Heck and co-workers[14] in the late 1960s, the reaction has been extensively developed and deployed in the synthesis of various complex natural products, pharmaceuticals, agrochemicals, dyes, functional materials, and other important molecules. The Heck reaction is not limited to activated alkenes: simple alkenes and those with various functional groups, such as ester, ether, carboxy, phenolic, and cyano functionalities are also suitable substrates. Despite many of the benefits usually associated with palladium-mediated reactions,[15] in particular scalability, tolerance of water and functional groups, interest in the reaction has been sporadic, which is primarily due to problems associated with regiochemical control in unsymmetrical alkene substrates. In fact, both regioselectivity (Æ and ) and geometrical selectivity (E and Z) have been found to be notoriously difficult to control in intermolecular reactions. In contrast, the tether length and the ligands on the metal center determine the regioselectivity of intramolecular reactions. Additionally, the importance of the asymmetric construction of chiral tertiary and quaternary stereocenters by C—C bond formation has prompted the development of the asymmetric variant of the Mizoroki–Heck reaction. Nevertheless, the reaction was not initially applied to the construction of stereogenic centers,[1] and chelating diphosphines were generally considered to provide unsuitable catalysts.[16] Despite the many developments with chiral phosphine ligands dating from the early 1970s,[17] the asymmetric Heck reaction was not explored until the late 1980s.[18,19] In more recent years, interest in this reaction has increased dramatically, with the development of a variety of stereoselective reactions, including asymmetric variants. The present survey covers both inter- and intramolecular Mizoroki–Heck reactions with brief discussions of the mechanistic aspects relevant for stereoselection. The classification of the sections proceeds according to the types of stereoselectivity. Because regioselective intramolecular reactions can be relatively easily controlled, compared with the intermolecular variants, only asymmetric variants of the former are included. 3.12.1
Intermolecular Reactions
3.12.1.1
Regioselective Reactions
The mechanism of the Mizoroki–Heck reaction is generally thought to follow the five-step catalytic cycle illustrated in Scheme 1, with the individual steps being (a) oxidative addition of the aryl or alkenyl (pseudo)halide 2 (R1X) to the palladium(0) complex 1 to afford the organopalladium(II) species 3, followed by (b) -complex formation (3 + 4 fi 5 or 9), then (c) syn-insertion of the alkene substrate into the Pd—R1 bond to furnish a -alkylpalladium(II) complex (5 fi 6, or 9 fi 10), which undergoes (d) syn--hydride elimination to give either the Æ-product 8 or the -product 11 [E-isomer (E)-11 through E-hydride elimination and Z-isomer (Z)-11 through Z-hydride elimination], and finally (e) regeneration of Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 510
484
Stereoselective Synthesis
3.12
Mizoroki–Heck Reaction
the palladium(0) species 1 by reductive elimination of HX from HPd(II)XL2 (7). The regioselectivity of the insertion into the Pd—R1 bond (step c) is heavily dependent upon the stereoelectronic environment provided by the substituents of the alkenes and the metal center. Control of selectivity, which has tended to limit the scope of the reaction, can be accomplished with the judicious choice of ligands and optimizing the reaction parameters. Scheme 1 Mechanism of the Intermolecular Mizoroki–Heck Reaction with Monosubstituted Alkenes step e base
Pd(0)L2
HPdXL2
− base•HX
7
1 step a R 1X 2
L R1 Pd(II) X L 3 − L or X
step b β α R2
4
L
L
X(L) Pd R1
R1 Pd X(L)
R2
R2
5
9 step c L or X
X L Pd L H H
step c L or X
R1 Hα R2
R1 HβZ HβE
6 − HαPdXL2
− HβZPdXL2 7
step d
R2 8
− HβEPdXL2 7
step d
R1
R1
R1
X Pd L H R2
10
step d
7
L
R1
R2 (Z)-11
R2 (E)-11
= aryl, alkenyl; X = halide, pseudohalide; L = monodentate ligand, solvent
The rate of the oxidative addition depends heavily on leaving group X in 2. In general, the relative order of reactivity for the oxidative addition is as follows: R1N2+ > R1I > R1OTf » R1Br >> R1Cl > R1OTs » R1OPO(OR2)2. In the case of aryl (pseudo)halides, reactivity in the oxidative addition is increased by electron-withdrawing substituents on the aromatic ring and decreased by electron-donating substituents. In the tables in the following subsections the reactions are generally listed in order of the reactivity of R1X 2. Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.12.1
3.12.1.1.1
485
Intermolecular Reactions
Reaction of Electron-Poor Alkenes
Electron-poor alkenes, typically acrylates and styrene derivatives, generally lead to the exclusive formation of the E--substituted product 17, 22, and 25 (Tables 1–3). Substrates that are reactive in the oxidative addition, e.g. aryl iodides and activated aryl bromides, react smoothly under the classical Mizoroki–Heck conditions provided that the palladium complex has at least three labile or hemilabile ligands, which typically implies a phosphine-free palladium complex. In fact, classical systems are the most robust and often provide very high turnover numbers. Strongly coordinating ligands, such as phosphines, often retard the reaction. Unactivated aryl bromides and activated aryl chlorides generally require high reaction temperatures (>140 8C), higher catalyst loadings (0.05–0.5 mol%), and polar solvents to provide high yields. Palladacycles,[20,21] heterocyclic carbene complexes,[22] and solid-supported palladium complexes[23] are also effective for these substrates. Electron-rich and bulky ligands, such as tri-tert-butylphosphine, form highly active and coordinatively unsaturated palladium complexes, making unreactive aryl chlorides suitable substrates for this reaction.[24,25] The Mizoroki–Heck reaction of aryl trifluoromethanesulfonates proceeds under mild conditions through a “cationic pathway” (see Section 3.12.1.1.2), where bidentate diphosphines are usually employed as the ligand. Mizoroki–Heck Reaction of Aryl Iodides with Electron-Poor Alkenes[14,26–33]
Table 1
Pri
N
S
O
Pd
Mes
O
N
N
Mes
+ N
BuN
CF3 13
12
14
SPh AcHN
+ N
N
N Pd Br
Me
15
R1 I
+
R2
PF6−
[bmim]PF6
Br−
Pd Cl SPh
Me
N
+ N Me
16
R1 EWG
EWG R2 17
R1
R2
EWG
Conditions
4-F3CC6H4
H
CO2Et
Ph
H
Ph
Yield (%)
Ref
PdCl2(PPh3)2 (3 mol%), Et3N (2 equiv), MeCN, 80 8C, 48 h
98
[26]
CO2Me
Pd(OAc)2 (1 mol%), Bu3N (1 equiv), 100 8C, 1 h
81
[14]
H
CO2Me
12 (0.7 ppm), Et3N (1.4 equiv), NMP, 140 8C, 18 h
100
[27]
Ph
H
CO2Me
Pd(dba)2 (0.001 mol%), 13 (0.004 mol%), Et3N (1.2 equiv), DMF, 100 8C, 10 h
>99
[28]
Ph
H
CO2Et
Pd/C (0.031 mmol), Et3N (1.5 equiv), ionic liquid 14, 100 8C, 12 h
95
[29]
Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 510
486
Stereoselective Synthesis Table 1
3.12
Mizoroki–Heck Reaction
(cont.)
R1
R2
EWG
Conditions
Ph
H
CO2t-Bu
Ph
H
Ph
Yield (%)
Ref
15 (0.1 mol%), Na2CO3 (1.5 equiv), DMF, under air, 110 8C, 5–6 h
93
[30]
CN
Pd(OAc)2 (5 mol%), TBAB (10 mol%), NaHCO3 (2 equiv), H2O, 80–90 8C, 10 h
81
[31]
H
Ph
16 (1 mol%), NaOAc (1.1 equiv), DMA, under air, reflux, 1 h
89
[32]
Ph
H
4-O2NC6H4
Pd(OAc)2 (1 mol%), Bu3N (1 equiv), 100 8C, 2 h
85
[14]
4-Tol
H
CO2H
Pd(OAc)2 (1 mol%), Amberlite IRA-400 basic (100 g • mol–1), DMF, 80 8C, 5 h
86
[33]
4-Tol
Me CO2H
Pd(OAc)2 (1 mol%), Amberlite IRA-400 basic (100 g • mol–1), DMF, 80 8C, 5 h
80
[33]
4-Tol
Me CO2Me
Pd(OAc)2 (1 mol%), Amberlite IRA-400 basic (100 g • mol–1), DMF, 80 8C, 5 h
84
[33]
4-Tol
Me CO2iBu
Pd(OAc)2 (1 mol%), Amberlite IRA-400 basic (100 g • mol–1), DMF, 80 8C, 8 h
90
[33]
4-Tol
H
Ph
Pd(OAc)2 (1 mol%), Amberlite IRA-400 basic (100 g • mol–1), DMF, 80 8C, 2 h
93
[33]
4MeOC6H4
H
Ph
Pd(OAc)2 (1 mol%), Amberlite IRA-400 basic (100 g • mol–1), DMF, 80 8C, 5 h
90
[33]
Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.12.1
487
Intermolecular Reactions
Mizoroki–Heck Reaction of Aryl Bromides with Electron-Poor Alkenes[20,27,32,34–39]
Table 2
Ph3P Ph3P
2-Tol 2-Tol P O Pd O
PPh3 PPh3
O Pd O P 2-Tol
18
2-Tol
19
OBn PBut2 Ph P 2
Pd
P
O
CF3
Fe
Ph Ph
Ph 2
Ph
O 20
R1 Br
+
R2
21
R1 EWG
EWG R2 22
R1
R2 EWG
Conditions
4-O2NC6H4
H CO2Et
Pd(OAc)2 (0.001 mol%), (2-Tol)3P (0.004 mol%), NaOAc (1.1 equiv), DMF, 130 8C, 5 h
4-O2NC6H4
Yield (%)
Ref
81
[34]
H CO2Bu [Pd(Å3-C3H5)Cl]2/18 (1:2; 10 ppm), K2CO3 (2 equiv), DMF, 130 8C, 16 h
100
[35]
3,5-(F3C)2C6H3
H CO2Bu [Pd(Å3-C3H5)Cl]2/18 (1:2; 0.01 ppm), K2CO3 (2 equiv), DMF, 130 8C, 20 h
100
[35]
4-BzC6H4
H CO2Bu [Pd(Å3-C3H5)Cl]2/18 (1:2; 1 ppm), K2CO3 (2 equiv), DMF, 130 8C, 20 h
97
[35]
4-OHCC6H4
H CO2Bu 19 (5 ppm), NaOAc (1.1 equiv), DMA, 135 8C, 10 h >99
[20]
3
1-naphthyl
H CO2Bu [Pd(Å -C3H5)Cl]2/18 (1:2; 100 ppm), K2CO3 (2 equiv), DMF, 130 8C, 72 h
91
[35]
3-pyridyl
H CO2Bu [Pd(Å3-C3H5)Cl]2/18 (1:2; 10 ppm), K2CO3 (2 equiv), DMF, 130 8C, 48 h
96
[35]
Ph
H CO2Me 12 (7 ppm), Na2CO3 (0.7 equiv), NMP, 140 8C, 43 h
96
[27]
Ph
H CO2Me 20 (0.5 mol%), Na2CO3, NMP, 135 8C, 19 h
100
[36]
Ph
H CO2Me Pd(dba)2 (2.5 mol%), 21 (5.0 mol%), Et3N (1.2 equiv), DMF, rt, 20 h
94
[37]
Ph
H CO2Bu [Pd(Å3-C3H5)Cl]2/18 (1:2; 100 ppm), K2CO3 (2 equiv), DMF, 130 8C, 72 h
95
[35]
4-MeOC6H4
H CO2Bu [Pd(Å3-C3H5)Cl]2/18 (1:2; 100 ppm), K2CO3 (2 equiv), DMF, 130 8C, 40 h
97
[35]
Ph
H Ph
16 (5 mol%), NaOAc (1.1 equiv), DMA, under air, reflux, 1 h
>99
[32]
Ph
H Ph
Pd(OAc)2 (5 mol%), Et3N (1 equiv), PEG (MW 2000), 80 8C, 10 h
93
[38]
Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 510
488
Stereoselective Synthesis Table 2
3.12
Mizoroki–Heck Reaction
(cont.)
R1
R2 EWG
Conditions
Ph
H Ph
4-MeOC6H4 4-MeOC6H4
Yield (%)
Ref
[Pd(Å3-C3H5)Cl]2/18 (1:2; 10 ppm), K2CO3 (2 equiv), DMF, 140 8C, 24 h
87
[39]
H Ph
Pd(OAc)2 (5 mol%), Et3N (1 equiv), PEG (MW 2000), 80 8C, 12 h
85
[38]
H Ph
[Pd(Å3-C3H5)Cl]2/18 (1:2; 10 ppm), K2CO3 (2 equiv), DMF, 140 8C, 24 h
82
[39]
Mizoroki–Heck Reaction of Aryl Chlorides with Electron-Poor Alkenes[20,24,40–46]
Table 3
Bu N
Bu N
Bu
N
Bu N Cl Pd Cl N
N + N
N 2PF6− N
Bu
N
PF6–
Bu Bu
N Bu N Bu 23
24
R3
R3 R1 Cl
+
R2
R1 EWG
EWG R2 25
R1
R2 R3
EWG
Conditions
Product Ratio
4-OHCC6H4
H H
CO2Bu
19 (0.05 mol%), TBAB (20 mol%), NaOAc (1.1 equiv), DMA, 130 8C, 24 h
–
4-OHCC6H4
H H
Ph
16 (0.2 mol%), NaOAc (1.1 equiv), TBAB (20 mol%), DMA, 165 8C, 0.5 h
4-BzC6H4
H H
4-MeOC6H4
Pd(OAc)2 (1.0 mol%), dippbb (2 mol%), NaOAc (1.0 equiv), DMF, 150 8C, 24 h
4-AcC6H4
H H
Ph
16 (0.2 mol%), NaOAc (1.1 equiv), TBAB (20 mol%), DMA, 165 8C, 0.25 h
4-AcC6H4
H H
Ph
Pd/zeolites (NaY) (50 ppm), Ca(OH)2 (1.2 equiv), NMP, 160 8C, 2 h
Ph
H H
CO2Me
Ph
H H
CO2Me
Yield (%)
Ref
81
[20]
90
[40]
97
[41]
98
[40]
–
95
[42]
Pd2(dba)3 (1.5 mol%), t-Bu3P (6 mol%), Cs2CO3 (1.1 equiv), dioxane, 100 8C, 42 h
–
76
[24]
23 (2 mol%), Na2CO3 (1.5 equiv), ionic liquid 24, 100 8C, 4 h
–
78
[43]
Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
8:82a
97:3c
7:91a
3.12.1
489
Intermolecular Reactions
Table 3
(cont.)
R1
R2 R3
Ph
Conditions
Product Ratio
H Me CO2Bu
Pd[P(t-Bu)3]2 (3.0 mol%), Cy2NMe (1.1 equiv), toluene, 110 8C, 22 h
Ph
H H
Ph
Pd2(dba)3 (1.5 mol%), t-Bu3P (6 mol%), Cs2CO3 (1.1 equiv), dioxane, 120 8C, 21 h
Ph
H H
Ph
PdCl2(PCy3)2 (3.0 mol%), Cs2CO3 (1 equiv), dioxane, 120 8C, 12 h
2,6Me2C6H3
H Me CO2Me
a b c
EWG
Yield (%)
Ref
–
95
[44]
–
83
[24]
93:7b
>99
[45]
Pd2(dba)3 (1.5 mol%), >20:1b [t-Bu3PH]BF4 (6 mol%), Cy2NMe (1.1 equiv), dioxane, 120 8C, 42 h
90
[46]
Ratio (Æ-product/-product). dippb = 1,4-bis(diisopropylphosphino)butane. Ratio (E/Z).
Methyl (E)-3-(4-Methylphenyl)but-2-enoate (17, R1 = 4-Tol; R2 = Me; EWG = CO2Me):[33]
A mixture of Pd(OAc)2 (45 mg, 0.2 mmol), 4-iodotoluene (20 mmol), methyl (E)-but-2-enoate (25 mmol), and Amberlite IRA-400 (basic; 2 g) in anhyd DMF (6 mL) was stirred at 80 8C for 5 h. It was cooled and filtered to remove the resin, which was washed with Et2O. The organic layer was diluted with H2O and extracted with Et2O. The Et2O layer was washed with H2O and dried (Na2SO4). Removal of Et2O furnished the solid product, which was purified by recrystallization; the resulting mother liquor was purified by passing through a chromatography column (silica gel, petroleum ether); yield: 84%. Butyl (E)-3-(4-Methoxyphenyl)acrylate (22, R1 = 4-MeOC6H4; R2 = H; EWG = CO2Bu):[35]
The reaction of bromoanisole (1.87 g, 10 mmol), K2CO3 (2.76 g, 20 mmol), and butyl acrylate (2.56 g, 20 mmol) at 130 8C during 40 h in anhyd DMF (10 mL) in the presence of [Pd(Å3C3H5)Cl]2 (0.001 mmol) and 18 (0.002 mmol) under argon afforded the corresponding coupling product after extraction with CH2Cl2, separation, drying (MgSO4), evaporation, and filtration on silica gel (Et2O/pentane 1:2); yield: 2.25 g (96%). Methyl (E)-Cinnamate (25, R1 = Ph; R2 = R3 = H; EWG = CO2Me):[24]
Under an atmosphere of argon, a soln of chlorobenzene (104 mg, 0.924 mmol) in dioxane (0.5 mL) and a soln of t-Bu3P (11.2 mg, 0.055 mmol) in dioxane (0.42 mL) were added in turn to a Schlenk tube charged with Pd2(dba)3 (12.5 mg, 0.014 mmol), Cs2CO3 (330 mg, 1.01 mmol), and a magnetic stirrer bar. Methyl acrylate (158 mg, 1.83 mmol) was then added by syringe, and the Schlenk tube was sealed and placed in a 100 8C oil bath and stirred for 42 h. The mixture was then cooled to rt, diluted with Et2O, filtered through a pad of Celite, concentrated, and purified by flash chromatography (EtOAc/hexane 5:95); yield: 118 mg (76%). 3.12.1.1.2
Reaction of Electron-Rich Alkenes
In contrast to electron-poor alkenes, the Mizoroki–Heck reaction using monodentate ligands and ligand-free conditions with electron-rich alkenes generally affords a mixture of the Æ- and -products, in which the latter are formed as a mixture of E- and Z-isomers. In the cases of electron-rich enol ethers and enamides, the reaction proceeds through a “cationic pathway” with bidentate ligands (L—L), to afford, in general, the Æ-product 32 in a highly regioselective manner (Scheme 2). The “cationic pathway” is more sensitive Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 510
490
Stereoselective Synthesis
3.12
Mizoroki–Heck Reaction
to electronic rather than steric factors, whereas the “neutral pathway” is more sensitive to steric factors, thereby affording mixtures of Æ-product 32 and -product 36. The cationic pathway is initiated with the dissociation of X from complex 26 to generate the tricoordinate 14-electron cationic complex 27 with the accompanying counterion X–. Complexation of electron-rich alkene 28 into the vacant coordination site provides the 16-electron species 29, which initiates insertion of the alkene into the Pd—R1 bond followed by re-formation of the Pd—X bond to give -alkylpalladium(II) complex 30. The corresponding neutral pathway occurs with the dissociation of one of the phosphines in the bidentate ligand to provide 14-electron neutral species 33. Association and complexation of the vacant coordination site in 33 with the alkene affords the 16-electron neutral species 34, which undergoes alkene insertion into the Pd—R1 bond and recomplexation of the previously displaced phosphine moiety to furnish a regioisomeric mixture of -alkenylpalladium(II) complexes 30 and 35. The nature of leaving group X (and thus the strength of the Pd—X bond) is clearly a critical issue. Aryl and alkenyl trifluoromethanesulfonates are generally assumed to follow the cationic pathway, whereas the corresponding halides follow the neutral pathway. Scheme 2 Cationic and Neutral Pathways of the Intermolecular Mizoroki– Heck Reaction with Electron-Rich Alkenes L cationic pathway
R1 Pd L X 26
neutral pathway
+
L R1 Pd L
L
L
R1 Pd X
X−
27 (14e−)
33 (14e−)
EDG 28
EDG 28
+
L
L
L Pd R1
L
R1 Pd X
EDG X−
EDG
29 (16e−)
L X Pd L H H
34 (16e−)
R1
R1 H H
EDG
X
L
EDG 35
30
− HPdX(L−L)
− HPdX(L−L) 31
31
R1
R1
EDG 32 L
L Pd
L = bidentate ligand
Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
EDG 36
3.12.1
491
Intermolecular Reactions
The addition of silver[47,48] and thallium[49] salts to reaction mixtures containing aryl and alkenyl halides facilitates the cationic pathway, by scavenging of the halide ion from the halo(hydrido)palladium complex 31 and replacing it with a larger anionic component (hard counteranion). Alternatively, high Æ-selectivity with aryl and alkenyl halides can be obtained by increasing the solvent polarity.[50,51] Alternatively, the tri-tert-butylphosphine ligand under neutral conditions provides high -selectivity, due to the stereoelectronic influence of the ligand.[52] Examples of regioselective Mizoroki–Heck reactions with electron-rich alkenes are given in Table 4. Regioselective Mizoroki–Heck Reaction with Electron-Rich Alkenes[50–55]
Table 4
R1 R1 X
+
+
EDG
R1
EDG
EDG 37
38
R1
X
1-naphthyl
OTf OBu
3-MeO2CC6H4
OTf NHAc Pd(OAc)2 (1 mol%), dppp (1.1 mol%), Et3N (1.2 equiv), DMF, 100 8C, 18 h
cyclohex-1-enyl
OTf OBu
Ph
Br
Ph
4-AcC6H4
a
EDG
Conditions
Ratio (37/ 38)
Yield (%)
Ref
>99:1
95
[53]
>19:1
69
[54]
Pd(OAc)2 (3 mol%), Et3N (1.5 equiv), DMSO, 60 8C, 3 h
20:1
87
[55]
OBu
Pd(OAc)2 (3 mol%), dppp (6.6 mol%), K2CO3 (1.2 equiv), H2O/DMF, 80 8C, 48 h
99:1
89
[51]
Br
OBu
Pd(OAc)2 (2.5 mol%), dppp (5 mol%), >99:1 Et3N (1.2 equiv), [bmim]BF4,a [HNEt3]BF4 (25 mol%), 115 8C, 36 h
100
[50]
Cl
OBu
19 (5 mol%), [t-Bu3PH]BF4 (10 mol%), Cy2NMe (3 equiv), H2O/DMF, microwave, 160 8C, 1 h
75
[52]
Pd(OAc)2 (2.5 mol%), Et3N (1.2 equiv), 2,9-dimethyl-1,10-phenanthroline (2.75 mol%), DMF, 40 8C, 2.5 h
3:97
[bmim]BF4 = 1-butyl-3-methylimidazolium tetrafluoroborate (ionic liquid).
(1-Butoxyvinyl)benzene (37, R1 = Ph; EDG = OBu):[50]
An oven-dried, two-necked, round-bottomed flask containing a stirrer bar was charged with PhBr (1.0 mmol), Pd(OAc)2 (0.025 mmol), dppp (0.05 mmol), and ionic liquid [bmim]BF4 (2 mL) under N2 at rt. After the mixture had been degassed three times, butyl vinyl ether (5.0 mmol) and Et3N (1.2 mmol) were injected sequentially. The flask was heated at 115 8C. After 36 h, the flask was cooled to rt. To the mixture was added 5% aq HCl (5 mL), and after the mixture had been stirred for 0.5 h, CH2Cl2 (20 mL) was added. After separation of the CH2Cl2 phase, the aqueous layer was extracted with CH2Cl2 (2 20 mL), and the combined organic layer was washed with H2O (until neutral), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, EtOAc/hexane); yield: quant. 3.12.1.1.3
Chelation-Controlled Reactions
The introduction of a directing group, such as an alcohol, an amine, or a heteroaromatic ring, into the alkene substrate can provide a powerful tool for increasing regioselectivity and reactivity.[56] The coordinating groups (L) participate in the Mizoroki–Heck reaction Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 510
492
Stereoselective Synthesis
3.12
Mizoroki–Heck Reaction
through intramolecular coordination with the metal center (Pd—L), which influences the -complexation and ultimately the -hydride elimination. Allylic alcohols and amines are typical substrates for the chelation-controlled Mizoroki–Heck reaction, and either internal or terminal selectivity can be achieved by the judicious choice of reaction conditions. Similar to electron-rich alkenes described above, the organo group from the organo (pseudo)halide is generally introduced into the terminal position (ª-position) under neutral conditions (Scheme 3),[57] which produces carbonyl compounds as a result of abstraction of HÆ in the -elimination step. Selective formation of the ª-substituted allylic alcohol through Hª elimination is possible using cationic reaction conditions (Scheme 4).[58] The cationic conditions, however, tend to also result in the -substituted allylic alcohol. The selective formation of the -substituted allylic alcohol can be achieved in an ionic liquid (Scheme 5).[59] Scheme 3 ª-Selective Mizoroki–Heck Reaction with Allylic Alcohols under Neutral Conditions[57]
γ Ph
I
β
0.3 mol% Pd(OAc)2 Et3N (1.25 equiv) MeCN, 100 oC
α OH
+ R1
L
Pd
I
Hγ Hγ
Hα R1 Ph
OH
Ph O
Ph γ
+
R1
R1 40
39
R1
Time (h) Ratio (39/40) Yield (%) Ref
H
0.5
84:16
71
[57]
Me 5.0
90:10
95
[57]
O
β
Scheme 4 ª-Selective Mizoroki–Heck Reaction with an Allylic Alcohol under Cationic Conditions[58]
γ
MeO2C 3
β
α OH
I +
6 mol% Pd(OAc)2 Ag2CO3 (1 equiv) DMF, 40−45 oC
L
+ Pd
Hγ Hγ
overnight
4
OH Hα
MeO2C
3
4
MeO2C
OH γ
3
4
75%
Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.12.1
493
Intermolecular Reactions
Scheme 5 -Selective Mizoroki–Heck Reaction with Allylic Alcohols under Cationic Conditions[59]
Br +
γ
4 mol% Pd(OAc)2 8 mol% dppp [bmim]BF4/DMSO (1:1)
β
β
115 oC, 36 h
α OH
OH
R1
R1 [bmim]BF4 = 1-butyl-3-methylimidazolium tetrafluoroborate
R1
Yield (%) Ref
Me
89
[59]
H
86
[59]
CO2Me 92
[59]
Ac
[59]
86
Substrates with directing groups attached through tethered atoms, such as vinyl ether derivatives, have been employed frequently in the chelation-controlled Mizoroki–Heck reaction (Table 5). Interestingly, bidentate ligands that prevent the coordination of a directing group to the metal center reverse the regioselectivity. Chelation-Controlled Mizoroki–Heck Reaction[60–62]
Table 5
X
Z R1 X
+
β
R1 Pd
α O
Z
X
Pd
R1
O
Z O
Z R1
O
β 41
R1
X
Z
Ph
I
NMe2 Pd(OAc)2 (3 mol%), K2CO3 (2 equiv), TBACl (1 equiv), DMF, 80 8C, 16 h
1-naphthyl 2-naphthyl
Regioisomer Ratio (Æ/)
Ratio (E/Z) for Yield -Isomer (%)
Ref
1:50
34:66
80
[60]
OTf NMe2 Pd(OAc)2 (1.5 mol%), Et3N (1 equiv), DMF, 80 8C, 16 h
only
34:66
85
[61]
OTf NMe2 Pd(OAc)2 (1.5 mol%), Et3N (1 equiv), DMF, 80 8C, 16 h
only
40:60
93
[61]
only
89:11
74
[62]
But
OTf NMe2
Conditions
Pd(OAc)2 (1 mol%), Ph3P (3 mol%), DMSO, 24 h
Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 510
494 Table 5
Stereoselective Synthesis
3.12
Mizoroki–Heck Reaction
(cont.)
R1
X
Z
Conditions
But
Pd(OAc)2 (1 mol%), Ph3P (3 mol%), DMSO, 24 h
OTf NEt2
Regioisomer Ratio (Æ/)
Ratio (E/Z) for Yield -Isomer (%)
Ref
only
89:11
70
[62]
CH=CEt2
OTf NMe2 Pd(OAc)2 (1 mol%), Ph3P (3 mol%), DMSO, 24 h
only
52:48
92
[62]
2-naphthyl
OTf NMe2 Pd(OAc)2 (3 mol%), Et3N (2 equiv), dppp (6.6 mol%), DMF, 60 8C, 14 h
Æ only
–
92
[61]
The (2-pyridyl)silyl group is also a good catalyst-directing group. For example, the Mizoroki–Heck reaction of alkenyl(2-pyridyl)silanes provide the -arylated product in high yield and with excellent E selectivity (>99%; Scheme 6).[63] Scheme 6
Mizoroki–Heck Reaction of Alkenyl(2-pyridyl)silanes[63] 0.5 mol% Pd2(dba)3•CHCl3
R1 I
+
α
R2 β
Me
2 mol% tri-2-furylphosphine Et3N (1.2 equiv)
N
THF, 50 oC, 24 h
Si Me
N R1 β R2 Me
R1
R2
Yield (%) Ref
Ph
H
93
[63]
4-Tol
H
95
[63]
(E)-CH=CHBu
H
90
[63]
Ph
(CH2)5Me
94
[63]
Si Me
Unfunctionalized alk-1-enes (H2C=CHR1; R1 = alkyl) also lead to regioisomeric products (up to ~80:20), which is further complicated by competing - and ¢-hydride elimination (vide infra). N,N-Dimethyl-2-[2-(2-naphthyl)vinyloxy]ethanamine (41, R1 = 2-Naphthyl; Z = NMe2):[61]
To a stirred soln of 2-naphthyl trifluoromethanesulfonate (5.0 mmol) in DMF (20 mL) under a N2 atmosphere were added, in the following order, Pd(OAc)2 (0.0337 g, 0.15 mmol), Et3N (1.01 g, 10 mmol), and 2-(dimethylamino)ethyl vinyl ether (1.15 g, 10 mmol). The mixture was stirred magnetically and heated to 80 8C for 16 h. After cooling, the black mixture was diluted with pentane (100 mL), transferred to a separatory funnel, and washed with H2O (2 50 mL). Additional extraction of the aqueous phases was performed with pentane (50 mL). The combined organic portions were then treated with of 0.1 M HCl (5 50 mL). The aqueous extracts were combined and poured into a flask containing excess 1.0 M NaOH and pentane (100 mL). After 10 min of stirring, the phases were separated and the aqueous layer was extracted with additional pentane (100 mL). The combined organic phases were washed with brine (50 mL), dried (K2CO3), and concentrated by evaporation. This workup procedure afforded products of satisfactory purity (GLC/ MS analysis indicated a purity of >94%); yield: 93%.
Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.12.1
3.12.1.2
495
Intermolecular Reactions
Asymmetric Reactions
As outlined in Scheme 1, the sp3 carbon stereogenic center initially generated from the syn-insertion of the alkene, is converted into an sp2 carbon in the syn--hydride elimination to afford an achiral product.[1] Hence, the Mizoroki–Heck reaction had not been utilized to generate stereogenic centers until the first reports of intramolecular asymmetric reaction in the late 1980s.[18,19] Based on the mechanism of the Mizoroki–Heck reaction, if kinetic ¢-hydride elimination were more favorable than -hydride elimination, the sp3 carbon stereogenic center would be retained (Scheme 7). Since both the insertion and the elimination are syn-processes, rotation about the CÆ—C -bond is required before -hydride elimination can occur, which provides an opportunity to control this process. Scheme 7
- or ¢-Hydride Elimination R3
L 1
R Pd L
β
α
R3
R1 Hβ R3
R2
X 26
L X Pd L α R2 Hβ'
− HβPdX(L−L) 31
R1
R2 β
R1 − Hβ'PdX(L−L) 31
∗
R3
R2 β'
For example, the syn-palladation of endocyclic alkenes such as 42 provides complex 43, which is unable to undergo the necessary -bond rotation for conformational reasons, which drives the elimination with the ¢-hydride to retain the stereogenic center (Scheme 8). Another strategy to enforce the ¢-hydride elimination is through the intramolecular reaction manifold (vide infra). Scheme 8
Intramolecular Mizoroki–Heck Reaction of an Endocyclic Alkene R1 α
β
β'
L R1 Pd L X 26
42
R1
α
β
L
β'
//
X Pd L Hβ' Hβ
R1 β
H 43
∗
α
− Hβ'PdX(L−L) 31
β'
44
During the neutral process, the partial dissociation of the chiral ligand would seem to make it problematic for asymmetric induction (see Scheme 2, complex 34). Hence, in most of the asymmetric Mizoroki–Heck reactions, the cationic pathway affords the highest enantioselectivity. A further problem lies in the reversibility of the reaction, which can result in reinsertion of the product alkene 44 into the Pd—H bond in 31 to either regenerate 44 or form the regioisomer with the palladium atom attached to the ¢-carbon atom. If either of these substituents contains a suitably positioned hydrogen atom then the possibility exists for isomerization of the Æ,¢-alkene to the ¢,ª¢-position. For example, the reaction of 2,3-dihydrofuran using (R)-2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl as the ligand affords a mixture of Æ,¢- and ¢,ª¢-alkenes.[64] Very interestingly, the products are of opposite absolute configuration, which can be explained by a kinetic resolution of the products.[65] Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 510
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Stereoselective Synthesis
3.12
Mizoroki–Heck Reaction
When 4,5-dihydrooxazole-based P,N-ligands[66,67] are used as the ligand, no trace of the isomeric product (¢,ª¢-alkene) is formed, indicating that rapid dissociation of the catalyst from the initial product of ¢-hydride elimination occurs.[68,69] Remarkably, the resistance of the alkene to isomerization with this catalyst is so pronounced as to allow the arylation and/or alkenylation of cyclopentene, to afford regiodefined products with high yields and excellent enantioselectivities, albeit with trace amounts (99
95
[70]
Of major product. Proton-sponge = 1,8-bis(dimethylamino)naphthalene. GLC yield in parentheses. 16% of the vinyl trifluoromethanesulfonate recovered.
4,7-Dihydro-1,3-dioxepin is also a good substrate for the intermolecular asymmetric Heck reaction, and the resulting enol ethers (e.g., 48; Scheme 9) provide useful products since they are easily converted into chiral -aryl-ª-butyrolactones.[71] Again, the P,N-ligand 45 affords products such as 48 with high enantioselectivity.[68] Scheme 9 Asymmetric Mizoroki–Heck Reaction of 4,7-Dihydro1,3-dioxepin[68,71] 3 mol% Pd2(dba)3•dba
Ph
6 mol% 45
Ph
OTf
iPr2NEt, THF, 70
+ O
O
oC,
70%; 92% ee
7d
O
O 48
(R)-2-(Cyclohex-1-enyl)-2,5-dihydrofuran (46, R1 = Cyclohex-1-enyl, Z = O; n = 0):[68]
[Pd2(dba)3•dba] (77.5 mg, 0.135 mmol) and (S)-(–)-ligand 45 (104.6 mg, 0.270 mmol) were placed under argon in an ampule equipped with a magnetic stirrer bar and a Young valve and treated with a soln of cyclohex-1-enyl trifluoromethanesulfonate (1.048 g, 4.55 mmol) and tridecane (424 mg, 2.30 mmol) as internal GC standard in argon-saturated benzene (10 mL) (CAUTION: carcinogen), followed by 2,3-dihydrofuran (1.35 mL, 17.9 mmol), iPr2NEt (1.57 mL, 9.17 mmol), and argon-saturated benzene (40 mL). The ampule was sealed under argon and the mixture was stirred at 24 8C (red soln; precipitation of N,N-diisopropylethylammonium trifluoromethanesulfonate) until the reaction was complete according to GC analysis (65 h). The mixture was diluted with pentane (ca. 150 mL) and the resulting red suspension was filtered through a 2-cm layer of silica gel. Further elution with Et2O and concentration gave a red oil, which was purified by flash chromatography followed by Kugelrohr distillation (125 8C/12 kPa) to afford (R)-(+)-product as a colorless oil; yield: 629 mg (92%); 99% ee. 3.12.2
Intramolecular Reactions
Since the first successful examples of the asymmetric Mizoroki–Heck reaction were reported in 1989 (Schemes 10[18] and 11[19]), the reaction has been successfully applied to the construction of tertiary and quaternary centers. Although the enantioselectivities achieved in these preliminary studies were modest, they demonstrated the significant poMizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 510
498
Stereoselective Synthesis
3.12
Mizoroki–Heck Reaction
tential of the asymmetric intramolecular Mizoroki–Heck reaction, which inspired additional developments. These advances may be classified into two types of processes, namely (i) desymmetrization and (ii) enantiofacial selection. For example, the transformation of prochiral cyclohexadiene 49 into the chiral tetrahydronaphthalene 51 is a type i reaction [insertion of C=C bond a (50A) or b (50B)] (Scheme 10), whereas the reaction of vinyl trifluoromethanesulfonate 56 to give the spirocyclic ketone 57 is a type ii reaction (Re- or Si-face insertion of the C=C bond) (Scheme 11). As mentioned in Section 3.12.1.2, the cationic pathway generally affords a higher enantioselectivity than the neutral pathway. Under neutral conditions, the reaction is initiated by the dissociation of a phosphine from the bidentate ligand resulting in the 14-electron neutral species 53. Alkene complexation into the vacant coordination site affords the 16-electron neutral species 54, which promotes insertion of the alkene into the Pd—C bond followed by -hydride elimination to provide 51. Alternatively, the cationic pathway is initiated by the counteranion exchange of I– for X– to promote dissociation of X– from 52 to generate the tricoordinate 14-electron cationic complex 55 with the accompanying counterion X–. Alkene complexation into the vacant coordination site affords the 16-electron species 50, which gives 51 with the chiral bidentate ligand fully chelated throughout the process to enforce the necessary asymmetric environment. Therefore, silver(I) carbonate acts as both a base and halide scavenger.[47,48] However, a significant exception to this rule has been identified for a special aryl trifluoromethanesulfonate, i.e. a (Z)-2-(but-2-enamido)phenyl trifluoromethanesulfonate, in which the addition of halide salts to the reaction mixture results in a dramatic increase in enantiomeric excess for this process.[72] Alternatively, the corresponding aryl iodide provides excellent enantiomeric excess without the addition of additives. In this case, the neutral pathway involving a pentacoordinate intermediate without dissociation of one of the phosphines in the bidentate ligand was suggested. Intermolecular Asymmetric Mizoroki–Heck Reaction (Desymmetrization)[18]
Scheme 10
3 mol% Pd(OAc)2
CO2Me b
X−
b
a
+ Pd P P ∗
I 49
CO2Me
9 mol% (R)-BINAP Ag2CO3 (2 equiv) NMP, 60 oC
a
CO2Me
50A
or
+ P Pd P ∗
50B CO2Me a>b
H 51
Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
74%; 46% ee
3.12.2
499
Intramolecular Reactions CO2Me
I 49 Pd(0)
CO2Me
I
neutral pathway
Pd P P cationic pathway
∗
AgX
52 (16e−) CO2Me
Pd I P P ∗
53 (14e−)
CO2Me
Pd I P P ∗
− AgI
CO2Me
X−
+ Pd P P ∗
55 (14e−)
CO2Me
X−
+ Pd P P ∗
50 (16e−)
54 (16e−)
CO2Me
CO2Me
H
H 51
low ee
Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
51
high ee
for references see p 510
500
Stereoselective Synthesis
3.12
Mizoroki–Heck Reaction
Scheme 11 Intermolecular Asymmetric Mizoroki–Heck Reaction (Enantiofacial Selection)[19] TfO−
∗
P + P Pd H
10 mol% Pd(OAc)2
OTf
10 mol% (R,R)-Diop Et3N, benzene, rt
Re
H
Si
O
O 56
Re > Si
O 57
3.12.2.1
Formation of Tertiary Carbon Centers
3.12.2.1.1
6,6-Ring System Formation
90%; 45% ee
The modest asymmetric induction for the conversion of the prochiral alkenyl iodide 49 into the chiral tetrahydronaphthalene 51 (Scheme 10),[18] to facilitate the construction of adjacent quaternary and tertiary centers, is improved using alkenyl trifluoromethanesulfonates 58 (Scheme 12).[73] The application of this strategy to the preparation of bicyclic enones and dienones highlights the extension of the reaction scope and illustrates the potential synthetic utility.[74–76] Scheme 12
Enantioselective Synthesis of cis-1,2,4a,8a-Tetrahydronaphthalenes[73,74] 5 mol% Pd(OAc)2 10 mol% (R)-BINAP K2CO3 (2 equiv)
R1
R1
toluene, 60 oC
H
OTf 58
R1
ee (%) Yield (%) Ref
CO2Me
91
54
[73]
CH2OCOt-Bu
91
60
[73]
Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.12.2
501
Intramolecular Reactions But
O O
But
O
4.5 mol% Pd2(dba)3•CHCl3 11.3 mol% (R)-BINAP K2CO3 (2 equiv) t-BuOH (11 equiv) 1,2-dichloroethane, 60 oC
O
HO
HO
H
TfO
But
O O
O
H 76%; 86% ee
Allylsilanes (e.g., 59) provide high regioselectivity in the -hydride elimination step (Table 7),[77–79] wherein the conditions can be tailored to provide either vinyl- or (E)-silylvinyl-substituted compounds (i.e., 60 and 61, respectively). Table 7
Intramolecular Asymmetric Mizoroki–Heck Reaction of Allylsilanes[77]
R1
n
R1
Z
I
R2
n
R1
Z +
R2
n
Z
R2
TMS TMS 59
R1
R2
Z
H
H
OMe H
n Conditions
Ratio (60/61)
ee (%) Yield of 60 (%)
Ref
NCOCF3 1 Pd2(dba)3 (5 mol%), (S)-BINAP (7 mol%), AgOTf (1 equiv), DMF, 75 8C, 48 h
90:10
72
70
[77]
CH2
83:17
90
92
[77]
91:9
64
79
[77]
7:93
–
69
[77]
90%) using both sets of reaction conditions (Table 10). Table 10 Enantioselective Synthesis of Indolones with a Benzylic Quaternary Carbon Center[98–100]
R
1
X
OR
O
4
Pd catalyst BINAP
R
O N
N R2
R2
R3
(Z)-82
R1
R2
H
R3
OR4
R3 1
83
R4
X
Conditionsa
Me Me
TIPS
I
Pd2(dba)3 (5 mol%), (R)-BINAP (12 mol%), Ag3PO4 (2 equiv), DMA, 100 8C
H
Me Me
TIPS
I
H
Me Me
H
Me Me
Ratio (E/Z) in 83
ee (%)
Yield (%)
Ref
4:1
80
73
[98]
Pd2(dba)3 (5 mol%), (R)-BINAP (12 mol%), PMP (4 equiv), DMA, 100 8C
32:1
90
87
[98]
TBDMS I
Pd2(dba)3 (5 mol%), (R)-BINAP (12 mol%), PMP (4 equiv), DMA, 100 8C
24:1
92
80
[98]
Me
I
Pd2(dba)3 (5 mol%), (R)-BINAP (12 mol%), PMP (4 equiv), DMA, 100 8C
9:1
89
76
[98]
OMe Me Me
TIPS
I
Pd2(dba)3•CHCl3 (10 mol%), (S)-BINAP (23 mol%), PMP (4 equiv), DMA, 100 8C
98:2
95b
84
[99]
H
Me
OTf Pd(OAc)2 (5 mol%), (R)-BINAP (10 mol%), PMP (4 equiv), THF, 80 8C, 6 h
>10:1
82
86
[100]
Bn Ph
Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 510
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Stereoselective Synthesis
3.12
Mizoroki–Heck Reaction
Table 10 (cont.) R1
R2
H
R4
X
Bn 4-MeOC6H4
Me
OTf Pd(OAc)2 (5 mol%), (R)-BINAP (10 mol%), PMP (4 equiv), THF, 80 8C, 6 h
H
Bn 1-naphthyl
Me
H
Bn 3-pyridyl
Me
a b
R3
Conditionsa
Ratio (E/Z) in 83
ee (%)
Yield (%)
Ref
>10:1
79
81
[100]
OTf Pd(OAc)2 (5 mol%), (R)-BINAP (10 mol%), PMP (4 equiv), THF, 80 8C, 6 h
>10:1
92
92
[100]
OTf Pd(OAc)2 (5 mol%), (R)-BINAP (10 mol%), PMP (4 equiv), THF, 80 8C, 6 h
>10:1
88
77
[100]
PMP = 1,2,2,6,6-pentamethylpiperidine. (S)-83 predominates.
The methodology outlined in Table 10 has been further extended to a domino Mizoroki– Heck–cyanation sequence (Scheme 18).[101] The domino reaction proceeds efficiently when potassium hexacyanoferrate(II) is employed as the cyanide source to trap the -alkylpalladium intermediate. Scheme 18
Enantioselective Domino Mizoroki–Heck–Cyanation Sequence[101] 5 mol% Pd(dba)2 12 mol% (S)-DIFLUORPHOS K4[Fe(CN)6] (1.32 equiv)
MeO
I N Me
F
O
F
O
PPh2
F
O
PPh2
F
Ag3PO4 (2 equiv)
O
K2CO3 (1 equiv) DMA, 120 oC, 3 h 78%; 72% ee
MeO
CN ∗
O
N Me
O (S)-DIFLUORPHOS
(S)-1-Benzyl-3-(2-methoxyvinyl)-3-phenyl-1,3-dihydroindol-2-one (83, R1 = H; R2 = Bn; R3 = Ph; R4 = Me):[100]
A base-washed and oven-dried 10-mL sealable tube equipped with a magnetic stirrer bar was charged with trifluoromethanesulfonate (Z)-82 (R1 = H; R2 = Bn; R3 = Ph; R4 = Me; X = OTf; 98 mg, 0.19 mmol, 1.0 equiv), 1,2,2,6,6-pentamethylpiperidine (PMP; 0.14 mL, 0.78 mmol, 4.0 equiv), and THF (0.8 mL). This soln was deoxygenated by bubbling argon through a submerged needle for 20 min, and Pd(OAc)2 (2.2 mg, 9.7 mol, 5 mol%) and (R)-BINAP (12 mg, 19 mol, 10 mol%) were then added. Deoxygenation and vigorous stirring were continued for 15 min, during which time a red soln resulted. The tube was then sealed and heated at 80 8C for 6 h. After cooling to rt, the soln was diluted with EtOAc (10 mL) and washed with NaHCO3 (3 10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (hexanes/EtOAc 9:1) to give the product as an amorphous, colorless solid; yield: 59 mg (86%); 82% ee.
Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.12.2.2.3
509
Intramolecular Reactions
3.12.2
6,6,6-Ring System Formation
As demonstrated in Scheme 11, polyene cyclizations resulting from sequential intramolecular insertion of an organopalladium intermediate represent a highly effective method to construct quaternary carbon stereogenic centers.[19] The furans 84 undergo domino 6-exo-6-endo cyclizations with the chiral complex derived from tris(dibenzylideneacetone)dipalladium(0) and (R)-2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl to afford the tetracyclic compound 85 with good to high asymmetric induction (Scheme 19).[102–104] Enantioselective Polyene Cyclizations[103]
Scheme 19
5 mol% Pd2(dba)2
R1
OTf
10 mol% (R)-BINAP PMP (5 equiv) toluene, 110 oC, 48 h
R2
R2
R1
O
O O
O 84
85
PMP = 1,2,2,6,6-pentamethylpiperidine
R1
R2
ee (%) Yield (%) Ref
H
H
71
83
[103]
H
Me 90
78
[103]
96
71
[103]
Me Me 71
68
[103]
Me H
3.12.2.2.4
Spirocyclic System Formation
Spirocyclic compounds are readily prepared using cyclic alkenes, as exemplified in the formation of the spiroxindoles 88 (Scheme 20).[105,106] Treatment of the iodoanilides 87 with the chiral palladium complex derived from tris(dibenzylideneacetone)dipalladium(0) and (R)-2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl in the presence of silver(I) phosphate provides products (S)-88 in good yield and enantioselectivity. Surprisingly, if the reaction is carried out in the absence of silver salts using 1,2,2,6,6-pentamethylpiperidine as the base, the opposite enantiomer (R)-88 is obtained using the same enantiomer of 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl. Enantioselective Synthesis of Spiroxindoles[105]
Scheme 20
5 mol% Pd2(dba)2 11 mol% (R)-BINAP Ag3PO4 (2 equiv)
O NMe R1
O
NMe
DMA, 80 oC
I
R1
R1
R1 87
88
R1
R2
Temp (8C) Time (h) ee (%) Yield (%) Ref
H
H
60
Me
Me
80
O(CH2)2O
80
25 3.5 26
81
74
[105]
72
99
[105]
71
81
[105]
Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 510
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Stereoselective Synthesis
3.12
Mizoroki–Heck Reaction
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Mizoroki–Heck Reaction, Shibasaki, M., Ohshima, T., Itano, W. Science of Synthesis 4.0 version., Section 3.12 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
513 3.13
C—C Bond Formation by C—H Bond Activation H. M. L. Davies and D. Morton
General Introduction
The stereoselective formation of C—C bonds via C—H activation has attracted significant interest within the synthetic community for over 30 years.[1,2] This may be attributed to its potential to revolutionize chemical synthesis, by converting the relatively strong C—H bond from an otherwise inert bystander into a latent, flexible functional group equivalent, which represents a fundamentally distinct approach to the planning of chemical strategies. Over the course of the last 15–20 years the promise of this approach has begun to be realized and C—H activation has emerged as an important tool for the construction of strategically important C—C bonds.[3–8] Two primary modes of C—H activation have emerged (Scheme 1); (i) the more established direct addition of the C—H bond onto an active metal center, with subsequent functionalization of the bond, and (ii) the insertion of a transition metal coordinated carbene into the C—H bond to furnish the functionalized product directly. Scheme 1
The Two Main Classes of C—H Activation R3 N2
R1 N2 R2
H
R4
R5
R1 MLn
R1
R2
R3
H R2
R4
R5
(ii) metal carbenoid C−H functionalization
MLn
R4
R4
(i) oxidative addition C−H activation
R3
R5
MLn
H R4
X
R5
R3 H MLn
R3
X
R5
The principal challenge of C—H activation is the issue of selectivity. Thus, the high-energy nature of the species required for the activation of the relatively strong C—H bond has prompted the development of many innovative solutions to control the chemo-, regio-, and stereoselective outcome of the C—H activation event. The vast majority of modern techniques rely upon transition metals to mediate the reaction, which for the sake of cost, environmental impact, and practicality has driven the development of catalytic systems. The ability of many late transition metals to mediate C—H activation has been assessed; thus, ruthenium, platinum, iridium, nickel, and copper all catalyze C—H activation. However, the use of rhodium(I) and rhodium(II) as catalysts now dominates the
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 564
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Stereoselective Synthesis
3.13
C—C Bond Formation by C—H Bond Activation
field. The flexibility of the ligand environment of rhodium catalysts and its impact upon the reaction event is largely responsible for this prevalence. Scheme 2 displays representative examples of the many catalysts currently employed in this field. Scheme 2 Activation
Common Transition-Metal-Based Catalysts Employed in C—H
Cl Ph3P
PPh3
Rh
Ph3P
Rh
Cl
X X X
Rh Cl
[RhCl(coe)2]2
Rh Rh
X X X
X
X
1
X = O, N
Dirhodium(II) Carboxylate Catalysts:
O N O
O
Rh
O
Rh
N 1
R
H SO2Ar1
4
O
Rh
O
Rh 4
Rh2(S-PTPA)4 (R1 = Bn) Rh2(S-PTA)4 (R1 = Me)
Rh2(S-BSP)4 (Ar1 = Ph) Rh2(S-TBSP)4 (Ar1 = 4-t-BuC6H4)
Rh2(S-PTV)4 (R1 = iPr)
Rh2(S-DOSP)4 [Ar1 = 4-Me(CH2)11C6H4]
Rh2(S-PTTL)4 (R1 = t-Bu) Rh2(S-PTAD)4 (R1 = 1-adamantyl) Rh2(S-PTPG)4 (R1 = Ph)
Dirhodium(II) Carboxamidate Catalysts:
O
Rh
N
Rh
O
Rh
N
Rh
X
R1
4
Rh2(5S-MEPY)4 (R1 = CO2Me; X = CH2) Rh2(4S-MEOX)4 (R1 = CO2Me; X = O) Rh2(4R-BNOX)4 (R1 = Bn; X = O) Rh2(4S-PHOX)4 (R1 = Ph; X = O) Rh2(4S-MACIM)4 (R1 = CO2Me; X = NAc)
R1
4
Rh2(4S-MEAZ)4 (R1 = Me) Rh2(4S-IBAZ)4 (R1 = iBu) Rh2(4S-BNAZ)4 (R1 = Bn) Rh2(4S-CHAZ)4 (R1 = Cy) Rh2(4S-NEPAZ)4 (R1 = t-Bu)
Rh2(4S-MPPIM)4 [R1 = CO2Me; X = NCO(CH2)2Ph] Rh2(4S-MCHIM)4 (R1 = CO2Me; X = NCOEt)
The use of many of these catalysts will be discussed within the text, however, a discussion of the stability and handling of these catalysts is warranted. Wilkinsons catalyst [chlorotris(triphenylphosphine)rhodium(I), RhCl(PPh3)3] and associated rhodium(I) catalysts are air and moisture stable and are commonly employed under inert conditions, whereas -chlorobis(Å2-cyclooctene)rhodium dimer {[RhCl(coe)2]2} requires storage under argon at –5 8C to prevent discoloration. Alternatively, dirhodium(II) catalysts 1 are generally air and moisture stable solids, require no special handling, and can be stored indefinitely. With a growing emphasis on the environmental impact of synthetic chemistry, C—H activation provides an attractive prospect since not only does it remove many of the potentially toxic byproducts associated with functional group interconversions, but it can be carried out in a benign and catalytic fashion. C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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515
A number of recent reviews provide an extensive survey of the plethora of skeletons accessible through C—H activation, providing a detailed insight into how both the electronic and steric nature of the catalyst employed influences the reaction outcome.[3,6–10] A detailed discussion of these factors is outside the scope of this section; rather, it deals with the most synthetically useful transformations, highlighting the most efficient reports in each section in terms of their regio-, diastereo-, and enantioselectivity. The survey will be classified by the type of C—H bond being activated during a specific transformation and the product formed. 3.13.1
Intramolecular C—C Bond Formation by C—H Activation
Efficient C—C bond formation was first demonstrated in an intramolecular C—H activation reaction. This is due to the increased directing power and control offered by a rigid and geometrically defined insertion in an intramolecular process. Some general trends are observed. Activation occurs preferentially at the ª-position (Section 3.13.1.1.1.1, Scheme 5), forming five-membered rings. Nevertheless, this preference can be overcome through the introduction of an activating group with the ability to direct the insertion event to an alternative position. In the event that more than one five-membered ring can be formed, the reactivity of the C—H bonds follows the order of reactivity tertiary > secondary >> primary. 3.13.1.1
Intramolecular Activation of sp3 C—H Bonds
The stereoselective C—C bond formation via insertion into an unactivated sp3 bond represents a significant challenge. While sp2 C—H bonds and C—H bonds Æ to heteroatoms and activating groups are generally more reactive, the stereoelectronic effects governing the selection of these “unactivated” sp3 C—H bonds is much more subtle. 3.13.1.1.1
Synthesis of Carbocycles by Activation of sp3 C—H Bonds
The formation of carbocyclic compounds by intramolecular sp3 C—H insertion offers a highly reliable, substituent tolerant process for the selective formation of a fundamental chemical motif. 3.13.1.1.1.1
Dirhodium(II)-Catalyzed Carbene C—H Insertion
Early work on the transition-metal stabilized C—H insertion of carbenes derived from diazocarbonyl compounds revolved around the use of copper(II) and nickel(II) complexes.[11] However, these systems were only effective for the most rigid and geometrically defined substrates. The expansion of these findings can be attributed to the development of dirhodium(II) catalyst systems.[12–15] Diazocarbonyl compounds are commonly prepared in one of two ways. One method involves the treatment of -keto esters with methanesulfonyl azide under basic conditions to afford the diazocarbonyl compounds 2 (Scheme 3).[16] Scheme 3 Synthesis of Diazocarbonyl Compounds through Reactions with Methanesulfonyl Azide[16] O
O
MsN3, Na2CO3
O
O
MeCN, rt
R1O
R2
R 1O
R2 N2 2
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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An alternative method employs the diazo-transfer reagent 4-acetamidobenzenesulfonyl azide. Treatment of the acetates 3 with this reagent using 1,8-diazabicyclo[5.4.0]undec-7ene as the base efficiently affords the diazocarbonyl compounds 4, in generally good yield (Scheme 4).[17,18] Scheme 4 Synthesis of Diazocarbonyl Compounds through Reactions with 4-Acetamidobenzenesulfonyl Azide[17,18] O
O
AcHN R
R1O
2
DBU, MeCN, 0 oC to rt
+
R2
R1 O SO2N3
N2 4
3
The parallel and independent work of Taber[14] and Wenkert[15] laid the foundation and established many of the known trends for the dirhodium(II) intramolecular decomposition of diazocarbonyl compounds (e.g., diazo ketone 5 which gives the cyclopentanones 6 and 7) (Scheme 5),[19] with respect to both how the diazo compounds behave and the manner in which the catalyst influences the reaction outcome. Scheme 5
γ
The Effect of Catalyst Electronics on Reaction Selectivity[19]
O
1 mol% Rh2L4, CH2Cl2, 40 oC
α
O
N2
β
O
5
Rh2L4a
6
Ratio (6/7) Combined Yield (%) Ref 56
[19]
Rh2(OAc)4 44:56
97
[19]
Rh2(cap)4 100:0
76
[19]
Rh2(pfb)4
a
7
0:100
pfb = perfluorobutanoate; cap = caprolactam.
For example, the observation that the nature of the ligand on the catalyst has a decisive role in determining the reaction outcome prompted the rational design of new catalyst structures, with the aim of asserting control over these systems. The most effective catalyst systems developed for the intramolecular formation of cyclopentanes and cyclopentanones 9 (from the diazoacetates 8; Scheme 6) are dirhodium(II) N-phthaloyl complexes.[20,21] Indeed, the N-phthaloylphenylalanine catalyst Rh2(S-PTPA)4 (for structure, see Scheme 2) is the most general catalyst for this type of transformation.
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Intramolecular C—C Bond Formation by C—H Activation
Scheme 6 Dirhodium(II)-Catalyzed Carbene C—H Insertion of Æ-Diazo--keto Esters[20,21] O
O
O OR1
0.5−1 mol% Rh2(S-PTPA)4 CH2Cl2, 0 oC
CO2R1
N2 R2
R2 8
9
R1
R2
eea,b (%) Yield (%) Ref
Me
Me
24
76
[20]
(CH2)4Me 29
43
[20]
CH(iPr)2 (CH2)4Me 35
76
[21]
c
Me
c
CH=CH2
38
44
[20]
CH(iPr)2 CH=CH2
53
63
[21]
Me a
b
c
Enantioselectivity determined following hydrolysis/decarboxylation of cyclopentanones 9. Absolute configuration determined as (3R). Reaction performed in THF at –10 8C.
These reactions can be performed at or below room temperature, with catalyst loadings as low as 0.1 mol%, but typically between 0.5–1.0 mol%. The catalyst is also air stable and is an easily handled solid. The reaction is generally performed on a 0.2- to 1.0-mmol scale, although no scale-up issues have been observed, in dichloromethane or toluene. A variety of substituents are tolerated in this transformation and the yields (43–86%) are generally good (Scheme 6). Furthermore, Æ-phosphorylated diazo compounds can also undergo intramolecular C—H insertion reactions,[22,23] with similar modes of reaction, albeit with lower levels of efficiency in general. The excellent diastereoselectivity obtained with Æ-diazo ketones, which leads to the exclusive formation of the corresponding cyclopentane trans-isomer, is the subject of extensive experimental and computational studies.[24,25] The results of this work, depicted in a general form in Scheme 7, reveal that the formation of an n-membered ring proceeds via an [n + 1]-membered transition state 11. The eclipsed orientation of the Rh—C bond and the equatorial C—H bond in the cation 10 is favored, which leads to the formation of the trans-isomer 12. Scheme 7 H
Mechanistic Considerations of Intramolecular C—H Insertion into sp3 Bonds[24,25]
E
H
H N2
E
− N2
H
H Rh
E + H
Rh−
10
H
E + H
11
E Rh− 12
The enantioselectivity of the reaction is imparted by the chiral environment of the catalyst. It is clear that the chiral influence of Rh2(S-PTPA)4 affords only low levels of enantioselectivity (24–53% ee).[20,21] Moreover, the C2-symmetrical orientation of the dirhodium(II) catalyst ligands defines both the carbene orientation and the facial selectivity of the transformation.[21] Early work on the formation of cyclopentanes, e.g. 14, from the intramolecular C—H insertion of Æ-diazo esters, e.g. 13, determined that the competing -elimination to form C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
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C—C Bond Formation by C—H Bond Activation
cis-alkenes, such as 15, is a major obstacle to successful cyclopentane construction (Scheme 8).[26,27] The extent of this elimination is strongly dependent upon the catalyst employed.[28] Scheme 8
Dirhodium(II)-Catalyzed Reactions of Diazo Esters[27]
CO2Me CO2Me
1 mol% Rh2(O2CR1)4, CH2Cl2, rt
N2
+ 6
6
13
14
R1
Ratio (14/15) Combined Yield (%) Ref
Me
66:34
92
[27]
CF3
52:48
93
[27]
Ph
78:22
88
[27]
(CH2)7Me 78:22
90
[27]
t-Bu
97
[27]
85:15
CO2Me
6
15
These reactions are typically performed at room temperature in dichloromethane, on a 0.2- to 0.5-mmol scale with 1 mol% loading of dirhodium(II) catalyst. Alkyl- and aromaticsubstituted substrates are effective, and the transformation displays a strong diastereoselection for the trans-isomer,[28] in which the most successful enantioselective process to date employs the Rh2(S-PTTL)4 catalyst (for structure, see Scheme 2).[26] The reaction of a simple alkyl diazo ester catalyzed by the phthaloyl catalyst affords the trans-cyclopentane in 68% yield with 94% enantiomeric excess. SAFETY: Great care should be taken in the handling of diazo compounds as they are potentially toxic and may have explosive properties. Hence, diazo compounds should be handled carefully and all reactions should be carried out in a well-ventilated fume hood. Careful risk assessment should be conducted before the running of large-scale reactions of diazo compounds. Dimethyl Diazomalonate (2, R1 = Me; R2 = OMe); Typical Procedure:[16]
Methanesulfonyl azide (4.00 g, 33.0 mmol), was added to a soln of dimethyl malonate (3.45 g, 26.1 mmol) and Na2CO3 (8.50 g, 61.5 mmol), in MeCN (20 mL). The resulting mixture was stirred for 48 h at rt. The solid that precipitated was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc 9:1). Methyl 2-Phenyl-2-diazoacetate (4, R1 = Me; R2 = Ph); Typical Procedure:[17,18]
Methyl phenylacetate (3, R1 = Me; R2 = Ph; 1 equiv, 5–100 mmol), and 4-acetamidobenzenesulfonyl azide (1.2 equiv), were dissolved in MeCN and cooled to 0 8C under an argon atmosphere. DBU (1.2 equiv) was added in one portion to the stirred mixture, the ice bath was removed and the mixture was stirred for 2–4 h under argon. The reaction was quenched with sat. aq NH4Cl and the aqueous phase was extracted with Et2O (3 ). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was triturated with Et2O/petroleum ether (1:1) and the resulting solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, Et2O/petroleum ether 2:98). C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Intramolecular C—C Bond Formation by C—H Activation
trans-Methyl 2-Octylcyclopentanecarboxylate (14); Typical Procedure:[27]
The diazo ester 13 (86 mg, 0.26 mmol), in CH2Cl2 (2 mL), was added dropwise to Rh2[O2C(CH2)6Me]4 (1.3 mg, 1 mol%) in CH2Cl2 (1 mL) over 20 min at rt. The mixture was stirred for 12 h, and then the solvent was removed under reduced pressure. The residue was purified by flash chromatography. 3.13.1.1.2
Intramolecular Synthesis of Lactones by Activation of sp3 C—H Bonds
Intramolecular C—H bond insertion into unactivated sp3 bonds provides a chemo-, regio-, and stereoselective entry into lactones, which represents an important and ubiquitous structural motif. The extensive studies in this area have established methods to control the formation of both - and ª-lactones through the selective insertion into unactivated bonds, providing an efficient approach to a previously difficult disconnection. 3.13.1.1.2.1
Dirhodium(II)-Catalyzed Carbene C—H Insertion
The first systematic study of intramolecular C—H insertion for the preparation of lactones was performed in 1990 using diazomalonates.[29] This facile and flexible approach to form lactones has since been extensively explored, with applications for the preparation of fused ring systems,[30] sugar derivatives,[31] and natural product skeletons.[32] The product distribution of this transformation follows many of the same trends observed in the reactions of Æ-diazo- and Æ-diazo--keto esters, with five-membered ª-lactones 17 being formed preferentially. The activating nature of the oxygen atom in 16 is diminished due to conjugation with the adjacent carbonyl group, to such an extent that -lactones are rarely obtained. Dirhodium(II) carboxamidate catalysts are the most effective catalyst systems for these substrates. Although many of the initial studies employed the first-generation Rh2(MEPY)4 carboxamidate catalysts (see Scheme 2), which afforded good yields (34– 85%), and high chemo- and stereocontrol (45–91% ee), these results have been surpassed through the use of the second-generation Rh2(MPPIM)4 catalyst (see Scheme 2) that produce higher yields (50–>98%) and improved enantioselectivities (87–96% ee).[33,34] The reaction is a general one for a range of substituted cyclic and acyclic substrates (Scheme 9). Scheme 9
Scope of Enantioselective ª-Lactone Formation[34]
O
O
O
0.5−1 mol% Rh2(4S-MPPIM)4, CH2Cl2, 40
oC
O
N2 R1
R1 16
17
R1
ee (%) Yield (%) Ref
OMe
93
>98
[34]
Et
96
52
[34]
iBu
95
60
[34]
Bn
87
50
[34]
3-MeOC6H4CH2 91
66
[34]
4-ClC6H4
81
[33]
95
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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C—C Bond Formation by C—H Bond Activation
The reactions are generally performed on a 1- to 3-mmol scale with catalyst loadings of 0.5–1.0 mol%, in dichloromethane at either room temperature or 40 8C. A variety of substituents can be efficiently incorporated including alkyl, alkoxy, and aryl groups. The preference for reaction at the ª-position is so overwhelming that in the instance where benzylic activated C—H insertion could compete (i.e., 16, R1 = Bn), no trace of the possible six-membered insertion product is detected.[25] It is proposed that the increased size of the substituent at the N3 position of the catalyst ligand amplifies the influence on the orientation of the carbene intermediate,[30] hence increasing the enantiocontrol in comparison to the first-generation Rh2(MEOX)4 and Rh2(MEPY)4 catalysts (see Scheme 2).[34] The dirhodium(II)-mediated desymmetrization of cyclohexyl diazoacetate (18) is also strongly catalyst dependent and the diastereomers 19A and 19B are formed (Scheme 10).[35] Indeed, both the first- and second-generation dirhodium(II) carboxamidate catalysts promote the reaction giving reasonable product yields (30–70%) with exceptional enantiocontrol (95–97% ee), albeit with varying levels of diastereocontrol. Scheme 10
Desymmetrization via C—H Insertion of Cyclohexyl Diazoacetate[35]
O
O
O N2
H
H
0.5 mol% Rh2L4, CH2Cl2, 40 oC
18
O
O H 19A
O
+
H 19B
Rh2L4
Ratio (19A/19B) ee (%) of 19A ee (%) of 19B Combined Yield (%) Ref
Rh2(4S-MACIM)4
99:1
97
65
70
[35]
Rh2(5S-MEPY)4
75:25
97
91
65
[35]
Rh2(4S-MEOX)4
55:45
96
95
50
[35]
Rh2(OAc)4
40:60
–
–
46
[35]
Assuming that the diazoacetate and its corresponding metal carbene occupy the equatorial position there are four accessible C—H bonds for 1,5-C—H insertion in the diazoacetate 18. Insertion into the axial C—H bond affords the cis-isomer 19A, while insertion into the equatorial C—H bond furnishes the trans-isomer 19B. It is proposed that the increased steric bulk at the N3 position of the second-generation carboxamidate ligand increases the selectivity observed in this transformation.[35] These results demonstrate the importance of a close consideration of not only the substrate control but also an understanding of how the ligands on the metal catalyst can affect the outcome of the reaction. The dependence of product outcome upon the ligands surrounding the metal core has been highlighted in other systems,[31,36] including more sterically hindered tertiary centers[37,38] and related examples of desymmetrization of meso-diazoacetates.[36,39] The significance of this chemistry is demonstrated in the straightforward assembly of a number of natural products using the intramolecular C—H insertion step as an efficient method for the stereoselective construction of a critical skeletal motif. Targets such as the lignin lactones, including (+)-isodeoxypodophyllotoxin,[34,40] (–)-enterolactone,[32] (S)-(+)-imperanene,[32] and the GABA receptor antagonist (R)-(–)-baclofen,[33] have all been prepared using the dirhodium-catalyzed C—H insertion to form a lactone as the enantioinducing step, with exceptionally high levels of asymmetric induction (93–95% ee). The substituents adjacent to the diazo group can directly influence the product distribution. For instance, the intramolecular C—H insertion of cyclohexyl phenyldiazoacetate (20) (Scheme 11),[41] with a range of different dirhodium catalysts, preferentially afC—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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3.13.1
fords the -lactone 21, with only trace amounts of the normally observed ª-lactone 22. The products are formed in good yields (66–69%) and high chemoselectivity (>97% product selectivity), albeit with relatively low levels of enantioselectivity (50–63% ee). Scheme 11
Desymmetrization of Cyclohexyl Phenyldiazoacetate[41]
O
O Ph
O
O
1 mol% Rh2L4 CH2Cl2, 40 oC
O
Ph
N2
20
O +
21
Ph
22
Rh2L4 a
Ratio (21/22) ee (%) of 21 Combined Yield (%) Ref
Rh2(OAc)4
98:2
–
55
[41]
Rh2(4S-MEAZ)4 98:2
50
67
[41]
Rh2(4S-IBAZ)4
97:3
51
66
[41]
Rh2(S-DOSP)4
98:2
63
69
[41]
a
For catalyst structures, see Scheme 2.
These reactions are performed in refluxing dichloromethane, typically on a 0.5-mmol scale with a catalyst loading of 1 mol%. A similar preference for -lactone formation is observed in acyclic aryldiazoacetates.[41] However, if a tertiary C—H bond is available at the ª-position, the five-membered lactone is formed preferentially in high yield (79–94%) and with generally high asymmetric induction (56–90% ee).[41] 4-[(3-Methoxyphenyl)methyl]dihydrofuran-2(3H)-one (17, R1 = 3-MeOC6H4CH2); Typical Procedure:[34]
The diazoacetate 16 (R1 = 3-MeOC6H4CH2; 0.65 g, 2.8 mmol) in rigorously dried CH2Cl2 (20 mL) was added via a syringe pump at a rate of 2.0 mL • h–1 to a refluxing soln of Rh2(4S-MPPIM)4 (78 mg, 0.056 mmol, 2 mol%) in dry CH2Cl2 (40 mL) under N2. After the addition was completed, the mixture was allowed to cool to rt and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc 4:1); yield: 66%; 91% ee. cis/trans-Hexahydrobenzofuran-2(3H)-one (19A/19B); General Procedure:[35]
The diazo ester 18 (1.00 mmol) in CH2Cl2 (10 mL) was added via a syringe pump at a rate of 1 mL • h–1 to a light blue soln of the dirhodium(II) catalyst (0.005 mmol) in refluxing dry CH2Cl2 (50 mL). After the addition was completed, the mixture was allowed to cool to rt and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (silica gel, hexanes/EtOAc 9:1). 3-Phenyl-1-oxaspiro[3.5]nonan-2-one (21); Typical Procedure:[41]
A soln of cyclohexyl phenyldiazoacetate (20; 1 equiv, 0.5 mmol) in CH2Cl2 was added to Rh2(OAc)4 (1 mol%), in refluxing CH2Cl2 and the mixture was stirred for 1 h. The mixture was then allowed to cool to rt, before the solvent was removed under reduced pressure. The residue was purified by flash chromatography.
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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3.13.1.1.3
Intramolecular Synthesis of Lactams by Activation of sp3 C—H Bonds
3.13
C—C Bond Formation by C—H Bond Activation
The intramolecular C—C bond formed from the C—H insertion of nitrogen-containing structures provides rapid access to the corresponding lactams; both - and ª-lactams can be formed selectively using this approach. 3.13.1.1.3.1
Dirhodium(II)-Catalyzed Carbene C—H Insertion
The dirhodium(II)-catalyzed diazo decomposition of diazoacetamides can lead to the formation of both -and ª-lactams. In general, the five-membered lactams are formed preferentially; however, unlike the oxygen atoms in the diazoacetates employed for lactone formation, the nitrogen heteroatom electronically activates the position adjacent to the heteroatom toward the formation of the four-membered lactams. It is thus possible to be selective for the formation of -lactams, but only when access to the ª-C—H bond is sterically or electronically deactivated. Two factors are crucial in determining the selectivity of this transformation: (i) the nature of the ligands bound to the dirhodium(II) catalyst, and (ii) the electronic and conformational properties of the substrate. The additional substituent on the nitrogen presents a more sterically crowded environment adjacent to the active center, making the substrate conformation an important factor. The diazo decomposition of diazoamides for the construction of lactams was first described in 1965.[42] However, despite extensive investigation, the low yields and selectivities associated with the thermal and photochemical decomposition of the diazo compounds severely limited the development of this transformation.[43–46] It was not until the dirhodium(II)-catalyzed diazo decomposition was investigated in the mid-1980s that C—H activation was reconsidered as a strategy for constructing the lactam ring. An early report of the dirhodium(II)-mediated decomposition of diazoamides highlighted the significance of this transformation, which was utilized as a key step in the preparation of optically pure 1-methylcarbapenems, compounds that are of significant biological interest.[47] The first systematic examination of this chemistry[48] explored both the impact of catalyst structure and the nature of the N-substituents on the reaction outcome. The ability of this potentially chemo-, regio-, and stereoselective entry into the corresponding lactams prompted a number of groups to explore this area.[19,49–55] In general, the more electron-rich dirhodium(II) carboxamidate catalyst systems favor the formation of ª- over -lactams, relative to dirhodium(II) carboxylates, with the electrophilic carboxamidate carbenoid intermediates being more stabilized, which leads to increased selectivity in the transformation. The dirhodium(II) carboxamidate system has emerged as the most efficient catalyst for insertion into unactivated sp3 C—H bonds. A survey of the product distribution with the various carboxamidate catalysts clearly demonstrates the dependence of chemo- and regioselectivity on the nature of the catalyst and the nature of the substrate as illustrated by the conversions of the diazoamides 23 into mixtures of lactams 24–26 (Scheme 12).[56] Scheme 12 Effect of the Substrate Structure and Catalyst Environment on the Selectivity of Lactam Formation[56] O
O
ButN
1 mol% Rh2L4, CH2Cl2, 40 oC
ButN
+
N2 R1
R1 23
O
24
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
ButN
+
N O R1
R1 25
26
523
3.13.1
Intramolecular C—C Bond Formation by C—H Activation
R1
Rh2L4 a
Et
Rh2(4S-MEOX)4 91:9:0
71
80
82
[56]
Et
Rh2(4S-BNOX)4 92:8:0
99:1
97
–
67
[57]
Rh2(4S-MEOX)4 1
>99:1
92
–
68
[57]
Rh2(5S-MEPY)4 2
40:60
31
97
77
[57]
Rh2(4S-MEOX)4 2
26:74
15
98
95
[57]
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 564
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Stereoselective Synthesis
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C—C Bond Formation by C—H Bond Activation H
Rh2(4S-MACIM)4 CH2Cl2
N
N
86%; 96% de
O
H LiAlH4 87%
N
O N2
(−)-heliotridane
In general, lactam formation by insertion into sp3 C—H bonds proceeds in high yield (54– 95%) and, although the acyclic systems provide variable asymmetric induction (16–80% ee), the cyclic substrate affords exceptional levels of enantiocontrol (97–98% ee). The role of the nitrogen substituent has been extensively investigated, with respect to finding a substituent that not only does not interfere with the reaction pathway, but also can be removed in a straightforward fashion after the C—H insertion.[52,58] The robust nature of this transformation has also been demonstrated by its effective performance in water.[51,59] An elegant application of this transformation is the cyclization of an optically pure diazoacetopyrrolidine to afford a key heterobicyclic intermediate in 86% yield with 96% diastereomeric excess, which is a precursor to the natural product (–)-heliotridane (Scheme 13).[60] 1-tert-Butyl-4-ethoxypyrrolidin-2-one (24, R1 = OEt); General Procedure:[56]
A soln of the diazoamide 23 (R1 = OEt; 213 mg, 1.0 mmol) in CH2Cl2, was added dropwise over 10 h, to a soln of Rh2(4S-MEOX)4 or Rh2(4S-BNOX)4 (1.0 mol%) in refluxing CH2Cl2. Upon completion, the mixture was allowed to cool to rt and the solvent was removed under reduced pressure. The residue was purified by flash chromatography. 1-Azabicyclo[5.2.0]nonan-9-one (28, n = 1); General Procedure:[57]
A soln of the diazoamide 27 (139 mg, 1 mmol) in CH2Cl2, was added dropwise over 10 h to a soln of Rh2(5S-MEPY)4 or Rh2(4S-MEOX)4 (2 mol%) in refluxing CH2Cl2. Upon completion, the mixture was allowed to cool to rt and the solvent was removed under reduced pressure. The residue was purified by flash chromatography. 3.13.1.2
Intramolecular Activation of sp2 C—H Bonds
The activation of sp2 C—H bonds has particular significance for the fields of medicinal and materials chemistry, providing a means for facilitating the coupling and selective formation of strategic C—C bonds, while minimizing unwanted side products. 3.13.1.2.1
Synthesis of Carbocyclic Derivatives by Activation of sp2 C—H Bonds
The stereoselective construction of carbocycles containing (or fused to) an sp2 carbon provides a flexible entry into motifs that are not only central to many biologically significant molecules, but provide key intermediates that can easily be elaborated. 3.13.1.2.1.1
Directed sp2 C—H Bond Insertion
The major breakthrough for directed, chelation-assisted C—H activation of sp2 bonds was reported in 1993;[61] however, the intermolecular reaction suffered from a number of limitations. Foremost among these was that the substrate scope was narrow, with internal alkenes, dienes, and groups bearing electron-withdrawing and electron-donating groups showing low conversion. In 2001, the intramolecular activation of an sp2 C—H bond directed by an aromatic imine was disclosed.[62] The use of aromatic ketimines to direct intermolecular C—H activation was also reported.[63,64] C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Intramolecular C—C Bond Formation by C—H Activation
The increased control and entropic bias of an intramolecular system significantly expands the scope of this chemistry;[65] thus, employing Wilkinsons catalyst [RhCl(PPh3)3], a series of aromatic imines 30, with an alkene tethered at the 3-position, are cyclized selectively to the more hindered ortho site, affording the highly substituted bicyclic systems 31 (Scheme 14),[62,65] that represent motifs difficult to access via alternative strategies. Scheme 14 Cyclization of Aromatic Imines Using Wilkinson’s Catalyst To Synthesize Indane Derivatives[62,65] R1
R1
NBn
O R3
R3
1. 5 mol% RhCl(PPh3)3, toluene 2. 1 M HCl
R2
R2 31
30
R1 R2
R3 Temp (8C) Time (h) Yield (%) Ref
Me H
H 125
1
52a
[62]
Me Me
H 125
4
71
[62]
Me H
Ph 150
16
68
[65]
SiMe2Ph H 150
36
58
[65]
H
Me Me a
b
Ph 150
36
b
50
[65]
Competing alkene isomerization occurs, forming the styrenyl isomer in addition to the desired product (desired alkene/isomer 3:1). Isolated as a mixture of trans/cis-isomers (7:1).
This reaction promotes selective cyclization at the most substituted ortho position to provide the indane derivatives in good yields (50–71%). Wilkinsons catalyst is employed in a 5 mol% loading, using an inert atmosphere (glove box) on up to 3-mmol reaction scale (albeit typically performed on a 0.5-mmol scale). Alkyl, aryl, and silyl substituents have all been examined and the reactions are performed in toluene at 125–150 8C. The unsubstituted alkene side chain in 30 (R1 = Me; R2 = R3 = H) is the only one where a significant side reaction is observed. When two substituents are present on the side chain [e.g., 30 (R1 = R2 = Me; R3 = Ph)] the trans-isomer is the major adduct (trans/cis 7:1). While the transformation is possible with both the ketimines 30 (R1 = Me), and the aldimines 30 (R1 = H), the aldimines provide significantly lower conversions.[65] The reaction can also be applied to the preparation of tetrahydronaphthalene derivatives 33 from the imines 32 (Scheme 15). Here, the presence of various substituents on the alkene backbone directs the formation of the six-membered ring.
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
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C—C Bond Formation by C—H Bond Activation
Scheme 15 Cyclization of Aromatic Imines Using Wilkinson’s Catalyst To Synthesize Tetrahydronaphthalene Derivatives[62,65] R1
R1
NBn
O
1. 5 mol% RhCl(PPh3)3, toluene
R4
R4
2. 1 M HCl
R3
R3
R2
R2
32
R1
R2 R3
33
R4
2
85
[62]
Me 150
8
65
[62]
Me H
Me H
H
Me H H a
H
Ph Ph
Temp (8C) Time (h) Yield (%) Ref 125
Me H
a
150
48
50
[62]
Me 150
6
81
[65]
H
Isolated as a 1:1 mixture of the desired six-membered product and its five-membered analogue.
The syntheses of the tetrahydronaphthalenes are carried out in the same fashion as for the indane analogues. Normally the products are formed in moderate to high yields (50– 85%) and with excellent regioselectivity; however, when the unsubstituted substrate 32 (R1 = R2 = R3 = R4 = H) is employed, a 1:1 mixture of both the five- and six-membered fused bicyclic systems is obtained. A range of alternative imine directing groups has been examined, although the benzylimines prove to be most effective.[65] However, the electronic nature of the benzyl group affects the conversion, with electron-donating and electronaccepting groups on the ring reducing and increasing the yield, respectively.[65] A range of different transition-metal catalysts has also been investigated, although none are as efficient as Wilkinsons catalyst.[65] The mechanism for the intramolecular indane formation (Scheme 16) is based upon that proposed for the corresponding intermolecular transformation.[63,64] Imine precoordination, followed by C—H oxidative addition to the rhodium center generates the Rh–H complex, which allows coordination to the alkene. Migratory insertion into the Rh—H bond with subsequent reductive elimination then furnishes the product.
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Intramolecular C—C Bond Formation by C—H Activation
Scheme 16 Proposed Mechanism for the Intramolecular Annulation[63,64] NBn
NBn H H [Rh] pre-coordination
reductive elimination
Bn Bn
N
N
[Rh]
[Rh]
H
H alkene insertion
oxidative addition
Bn
Bn
N
N [Rh]H
[Rh]H alkene coordination
These reactions (e.g., 36 to give 37) can be performed asymmetrically, using the chiral monodentate phosphoramidite ligands 34 and 35 (Scheme 17).[66,67] Scheme 17
Asymmetric Intramolecular Cyclization of Aromatic Imines[66,67]
O O
34
P
NPri2
O O
Ph P
N Ph
35
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
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C—C Bond Formation by C—H Bond Activation
NBn
NBn 5 mol% [RhCl(coe)2]2 15 mol% ligand, toluene-d8
R1
R1 36
37
R1
Ligand Temp (8C) Time (h) ee (%) Yield (%) Ref
Me
34
125
98
This type of reaction proceeds highly efficiently with a catalyst loading of 2 mol% in dichloromethane at room temperature. The high yields (72–81%) and levels of enantioselectivity (73–81% ee) in the intramolecular insertions into benzylic C—H bonds prompted their incorporation into synthetic strategies toward (R)-(–)-baclofen[84] and (R)-(–)-rolipram,[85] a phosphodiesterase type IV inhibitor. Recent efforts demonstrate that a ruthenium catalyst that can promote the intramolecular insertion into benzylic C—H bonds; howC—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.13.1
Intramolecular C—C Bond Formation by C—H Activation
541
ever, the efficiency and chemo- and regioselectivity is analogous to the dirhodium(II)-catalyzed process.[86,87] 3.13.1.4
Intramolecular Activation of C—H Bonds Æ to Oxygen
The intramolecular insertion reaction into C—H bonds at the Æ-position to oxygen, benefits from the enhanced activating nature of the oxygen atom, to provide easy access to oxygen-containing heterocycles. 3.13.1.4.1
Dirhodium(II)-Catalyzed Carbene C—H Insertion
The most effective catalyst system for intramolecular C—H activation of the Æ-diazo ketones 65 to prepare 3,4-dihydro-2H-1-benzopyran-4-one (chroman-4-one) derivatives 66 is the dirhodium(II) prolinate complex Rh2(S-BSP)4 (Scheme 30; for catalyst structure, see Scheme 2).[88] The products are formed in excellent yield (90–98%), with a strong preference for the cis-isomers (48–86% de). While the enantioselectivities are variable (45–82% ee), the chemo- (76–94%) and regioselectivity are excellent, with the six-membered ring being formed preferentially in all cases, even in substrates with a double bond present. Scheme 30 Enantioselective Synthesis of 2H-1-Benzopyran-4-one Derivatives[88] R1
R2 O
1−2 mol% Rh2(S-BSP)4 CH2Cl2,
N2
O
40 oC
R2 R1
R3
R3
O
O
65
66
R1
R2
R3
H
Me
Me
75–89
82
>98
[88]
H
Ph
Me
75–89
62
>98
[88]
Me Me
Me
–
50
>98
[88]
de (%)
ee (%) Yield (%) Ref
H
CH=CH2 Me
86
60
>98
[88]
H
CH=CH2 Ph
>90
45
95
[88]
These reactions are routinely performed with a catalyst loading of 1–2 mol% in dichloromethane at reflux on a scale of 0.2–0.6 mmol. Unsubstituted, alkyl, and aromatic diazo compounds are all effective substrates. Intramolecular C—H insertions of ortho-alkoxy aryldiazoacetates 67 were explored independently by Davies and Hashimoto in 2001[89] and 2002,[90] respectively. The most effective catalyst for insertion into the tertiary sites of substrates of this type is the Rh2(S-DOSP)4 prolinate catalyst, affording the corresponding dihydrobenzofurans 68 in exceptional yield (93–98%) and with excellent levels of enantioinduction (90–94% ee) (Scheme 31). For methylene sites, the phthaloyl catalysts Rh2(S-PTTL)4 and Rh2(S-PTAD)4 prove the most efficient catalyst, furnishing the products in high yield (63–91%), diastereoselectivities (72–>98% de), and enantioselectivities (94–96% ee).
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Stereoselective Synthesis
3.13
C—C Bond Formation by C—H Bond Activation
Scheme 31 Dihydrobenzofuran Synthesis by Intramolecular C—H Insertion Æ to Oxygen[89–91] R1
R2 O
O
1−2 mol% Rh2L4
CO2Me
R2 CO2Me
N2 67
R1
R2
Rh2L4 a
68
Solvent Temp (8C) de (%) ee (%) Yield (%) Ref
Me Me Rh2(S-DOSP)4 hexane –50
–
hexane –50
–
(CH2)4 Rh2(S-DOSP)4
R1
b
94
98
[89]
90
93
[89]
Me H
Rh2(S-PTTL)4
toluene –78
72
97
91
[90]
H
Cy
Rh2(S-PTTL)4
toluene –78
92
96
63
[90]
H
Ph
Rh2(S-PTTL)4
toluene –78
>98
94
86
[90]
H
Ph
Rh2(S-PTAD)4 toluene –60
>98
95
79
[91]
a b
For catalyst structures, see Scheme 2. The anti-diastereomer was the major form.
These reactions are carried out at low temperature with catalyst loadings of between 1–2 mol%, in either hexane or toluene on typically a 0.10-mmol scale. A significant application of this chemistry is as the key step in the total synthesis of (–)-ephedradine A.[92,93] Here, the C—H insertion event is carried out with just 0.3 mol% of Rh2(S-DOSP)4, to facilitate the cyclization in 63% yield and with 86% diastereomeric excess. The cyclization of a more complex diazoacetamide, which exploits the activation conferred by insertion adjacent to oxygen, affords the ª-lactam in 75% yield and 85% enantiomeric excess, using Rh2(5S-MEPY)4 as the catalyst.[94] 3-Methyl-2-vinyl-3,4-dihydro-2H-1-benzopyran-4-one (66, R1 = H; R2 = CH=CH2; R3 = Me); Typical Procedure:[88]
The diazo ketone 65 (R1 = H; R2 = CH=CH2; R3 = Me; 120 mg, 0.56 mmol), was treated with Rh2(S-BSP)4 in refluxing CH2Cl2 to provide the crude product. This material was purified by flash chromatography; yield: >98%; 60% ee; 86% de. Methyl 2,2-Spirocyclobutyl-2,3-dihydrobenzofuran-3-carboxylate [68, R1,R2 = (CH2)4]; Typical Procedure:[89]
The methyl aryldiazoacetate 67, [R1,R2 = (CH2)4; 1 mmol], in hexanes (10 mL), was added, by syringe pump over 3 h to Rh2(S-DOSP)4 (0.01 mmol, 1 mol%) in hexanes (5 mL) cooled to –50 8C. The soln was maintained at –50 8C for 72 h, and then allowed to return to rt. The solvent was removed under reduced pressure and the residue was purified by flash chromatography; yield: 93%; 90% ee. 3.13.1.5
Intramolecular Activation of C—H Bonds Æ to Nitrogen
The efficient, selective, and flexible synthesis of azacycles has become a core focus for synthetic chemistry, not only for the preparation of the myriad of alkaloid natural products that have been isolated but for their incorporation into drug targets and pharmaceutically important motifs. The stereoelectronics of the nitrogen atom are such that C—H bonds located Æ to the heteroatom are significantly activated toward C—H insertion. C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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3.13.1.5.1
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Intramolecular C—C Bond Formation by C—H Activation
Dirhodium(II)-Catalyzed Carbene C—H Insertion
The dirhodium(II)-mediated carbene C—H insertion reaction is significantly improved when an activating group is present. For instance, C—H Bonds adjacent to nitrogen are particularly efficient at participating in these types of insertion events. Phthaloyl carboxylate dirhodium(II) catalysts are the most effective for this transformation. The Rh2(PTPA)4-catalyzed (see Scheme 2) intramolecular C—H insertions of N-alkyl-N-tertbutyl-3-(methoxycarbonyl)-Æ-diazoacetamides 69 afford the azetidin-2-ones 70 in an efficient manner as the cis-3,4-diastereomers (Scheme 32).[80] Scheme 32
Enantioselective Synthesis of Azetidin-2-ones[80]
O
O
R1
ButN
2 mol% Rh2(S-PTPA)4, CH2Cl2
CO2Me
ButN N2
R1
69
CO2Me 70
R1
Temp (8C) Time (h) ee (%) Yield (%) Ref
Ph
22
6
74
94
[80]
CH2CO2Me 22
8
56
98
[80]
Pr
5
60
97
[80]
16
These reactions proceed efficiently at or below room temperature in dichloromethane, typically employing 2 mol% of the catalyst. The azetidin-2-ones are formed in excellent yields (94–98%), albeit with modest asymmetric induction (56–74% ee). The conformation and nature of the nitrogen substituents play a key role in determining the favored pathway for these intramolecular processes. The tert-butyl group provides an efficient reaction, although it makes further elaboration challenging. Following the early work, the reactions of Æ-diazoacetamides tethered to a tetrahydro-1,3-oxazine system were investigated. These compounds provide excellent substrates for phthaloyl catalyst mediated intramolecular C—H insertion reactions (Scheme 33).[95] Thus, the reaction of Æ-diazoacetamides 71 furnish the 3,4-trans-azetidin-2-ones 72 in excellent yield (85–94%) and with exceptional levels of asymmetric induction (83–96% ee).
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis Scheme 33 R1 O
3.13
C—C Bond Formation by C—H Bond Activation
Enantioselective Cyclization of Æ-Diazoacetamides[95]
R2 O CO2Me
N
5 mol% Rh2L4, CH2Cl2, 0 oC
R1
R2
O
N
O
N2 CO2Me
H 71
R1
R2
Rh2L4 a
72
Time (h) ee (%) Yield (%) Ref
(CH2)5 Rh2(S-PTPA)4 3
90
89
[95]
(CH2)5 Rh2(S-PTV)4
3
92
86
[95]
(CH2)5 Rh2(S-PTPG)4 3
92
85
[95]
(CH2)5 Rh2(S-PTTL)4 4
93
85
[95]
(CH2)5 Rh2(S-PTA)4
2
96
94
[95]
Me Me Rh2(S-PTA)4
6
93
89
[95]
Et
8
83
89
[95]
a
Et
Rh2(S-PTA)4
For catalyst structures, see Scheme 2.
Not only do these substrates provide an N-substituent that is effective and noncompetitive, the procedure itself presents a convenient entry into biologically significant compounds. For example, this process has been used to great effect for the enantioselective synthesis of two important carbapenem antibiotics.[95–97] Methyl (3R,4R)-1-tert-Butyl-2-oxo-4-phenylazetidine-3-carboxylate (70, R1 = Ph); Typical Procedure:[80]
Rh2(S-PTPA)4 (2 mol%), was added to the Æ-diazoacetamide 69 (R1 = Ph; 1 mmol) in CH2Cl2 (0.1 M), at rt. The mixture was stirred for 3 h, and then concentrated under reduced pressure. The residue was purified using flash chromatography; yield: 94%; 74% ee. Methyl (6R,7R)-8-Oxo-3-oxa-1-azaspiro(bicyclo[4.2.0]octane-2,1¢-cyclohexane)-7-carboxylate [72, R1,R2 = (CH2)5]; Typical Procedure:[95]
Rh2(S-PTTL)4 (5 mol%), was added to a stirred soln of the Æ-diazoamide 71 [R1,R2 = (CH2)5; 1 mmol] in anhyd CH2Cl2 (2 mL) at 0 8C under argon. The mixture was stirred for 4 h, and then concentrated under reduced pressure. The residue was purified by flash chromatography; yield: 85%; 93% ee. 3.13.2
Intermolecular C—C Bond Formation by C—H Activation
Conceptually, intermolecular C—C bond formation through C—H activation significantly broadens the perspective of this chemistry, not only in terms of the substrates that can be employed but perhaps more importantly, the structures that can be accessed. The challenges associated with the selectivity in this process are quite different to those of intramolecular systems. No longer are reactions dependent so much on the ring size, or entropic issues, but rather steric and electronic factors become the most important considerations. With the removal of the entropic driving force favoring a particular ring size, the number of C—H bonds in the substrate that can participate significantly increases; thus, the other controlling factors must be finely balanced to provide a selective transformation.
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3.13.2.1
545
Intermolecular C—C Bond Formation by C—H Activation
Intermolecular Activation of sp3 C—H bonds
With the removal of the strong entropic driving force inherent to intramolecular systems, the ability to select a particular unactivated sp3 C—H bond in a system is significantly more challenging. However, the ability to selectively and efficiently facilitate a specific C—C bond formation provides an extremely powerful tool for planning novel synthetic strategies. 3.13.2.1.1
Dirhodium(II)-Catalyzed Carbene C—H Insertion
During the early development of catalysts for metallocarbenoid transformations, dirhodium tetracarboxylates were identified as being far superior to the then more prevalent copper catalysts at inducing intermolecular C—H activation.[13] However, the initial report was considered to be of little synthetic value due to the poor regioselectivity and multitude of side reactions that were observed, which primarily involved the dimerization of the carbene. The stigma surrounding intermolecular dirhodium-stabilized carbene C—H insertion remained up until the turn of this century, when the development of a more stable, inherently selective form of carbene, derived from the diazo decomposition of a compound containing both electron-donating and electron-withdrawing groups, made this feasible.[9] The extra stabilization of these carbenes, imparted by the donor group, renders these species significantly more selective and aids in the suppression of carbene dimerization. Indeed, work begun in 1997 established[17,98] that the decomposition of aryldiazoacetates 73 mediated by the dirhodium(II) prolinate catalyst Rh2(S-DOSP)4 (see Scheme 2) in the presence of cyclopentane or cyclohexane is the most effective way to effect this type of transformation and to afford the appropriate esters 74 (Scheme 34).[17] Scheme 34 C—H Activation of Cycloalkanes by Rh2(S-DOSP)4 Leading to the Catalyzed Diazo Decomposition of Aryldiazoacetates[17,98] N2 +
R1
CO2R2
1 mol% Rh2(S-DOSP)4
CO2R2
R1
n
n
73
74
R1
R2
Ph
Me 1 10
96
72
[17]
4-ClC6H4
Me 1 10
95
70
[17]
Ph
Me 2 10
95
80
[17]
4-ClC6H4
Me 2 10
94
76
[17]
4-MeOC6H4 Me 2 10
88
23
[17]
Ph
iPr
2 24
86
39
[17]
Ph
t-Bu 2 24
20
45
[17]
n Temp (8C) ee (%) Yield (%) Ref
These reactions are performed at or below room temperature, and the transformation can also be carried out in hexane, 2,2-dimethylbutane, or under solvent-free conditions. The anhydrous solvents used are degassed with argon in order to reduce side reactions with residual oxygen. The reactions are routinely performed on a 1- to 5-mmol scale, and no issues arise upon scale-up to 50 mmol. Catalyst loadings of 1 mol% are typically employed and the products are obtained in moderate to good yield (23–80%) and generally with high levels of enantiocontrol (20–96% ee). C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.13
C—C Bond Formation by C—H Bond Activation
Electron-donating aryl groups tend to decrease the efficiency of the insertion event, due to the associated decrease in the electrophilic character of the carbene, whereas the asymmetric induction decreases with increased steric size of the ester group. A range of both cyclic and acyclic unfunctionalized alkanes are suitable substrates for C—H insertion (Scheme 35).[17] General trends regarding the reactivity of intermolecular C—H activation have been developed. Tertiary C—H bonds are more activated than primary sites. Secondary positions are sensitive to their steric environment; hence, a methylene site adjacent to a tertiary centre is significantly less reactive than a less sterically encumbered position. Overall the reactions are markedly chemoselective, with the reactivity following the trend tertiary @ secondary >> primary C—H bonds. Scheme 35 Products of Rh2(S-DOSP)4-Catalyzed C—H Insertions of Methyl Phenyldiazoacetate into Various Alkanes[17] Ph
Ph
MeO2C
Et
Ph
MeO2C H
MeO2C H
H
27%; 66% ee
60%; 68% ee
Pri
Ph
MeO2C H
67%; 90% ee
Pri
H
31%; 86% ee
There is significant interest in providing a model for the rationalization and prediction of the selectivity associated with the C—H insertion event. A recent series of theoretical calculations and experimental comparisons support a model that closely correlates to the behavior of the prolinate Rh2(S-DOSP)4 catalyst (Scheme 36).[99] The C—H bond is thought to approach through a vector orthogonal to the carbene plane, such that a Newman projection can provide a visualization of how the incoming substituents interact with the chiral ligands on the catalyst, which orientate themselves to minimize steric interactions (RL = large, RM = medium, RS = small). Scheme 36 Predictive Model for Intermolecular C—H Insertion Mediated by Dirhodium(II) Prolinate Catalysts[99] RL RL
Ph N2 MeO2C
H RS
Ph
MeO2C RM
LnRh2
O
δ+
RL O
H Rh
RM RS
RM
RS H Rh − δ
L Ph R
MeO2C H
RM
RS
Methyl (R)-2-Cyclopentyl-2-phenylacetate (74, R1 = Ph; R2 = Me; n = 1); Typical Procedure:[98]
Methyl phenyldiazoacetate (73, R1 = Ph; R2 = Me; 304 mg, 1.72 mmol) in dry cyclopentane (30 mL), was added dropwise over 90 min to a soln of Rh2(S-DOSP)4 (28 mg, 0.015 mmol, 1 mol%), in dry cyclopentane (5 mL). The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography; yield: 72%; 96% ee.
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3.13.2
3.13.2.2
Intermolecular C—C Bond Formation by C—H Activation
547
Intermolecular Activation of sp2 C—H Bonds
The formation of C—C bonds via sp2 C—H functionalization has become an attractive alternative to cross coupling, since it not only provides a more atom-economical reaction, but it avoids the necessity for organo halide precursors, thereby reducing the production of toxic byproducts. 3.13.2.2.1
Heteroatom-Directed C—H Functionalization
The use of a proximal heteroatom to direct a selective C—H functionalization event has been the subject of extensive investigation. Two successful strategies are employed that either proceed by the transition metal chelating to the heteroatom to facilitate reactivity at a particular site, or through the coordination of a heteroatom to the metal to stabilize the complex with subsequent C—H insertion. A key breakthrough in the field of heteroatom-directed C—H functionalization is the demonstration that aromatic ketones can direct ruthenium-catalyzed C—H functionalization to the ortho position.[61] However, the scope of this discovery is limited to reactions with terminal, nonisomerizable alkenes, and the aromatic ketones employed require an ortho blocking group to prevent problems associated with over-alkylation. This work prompted others to investigate this system, and the exploratory investigations established pyridine motifs as suitable directing groups in palladium- and rhodium-catalyzed C—H alkylation chemistry.[100–104] These reactions, which demonstrate exceptional regioselectivity for the ortho position with suppressed levels of disubstituted products are, however, limited to terminal and nonisomerizable alkenes. Subsequently, the application of a palladium(II)/amino acid complex to pyridine-directed C—H insertion is illustrative of an extremely effective enantioselective C—C bond-forming transformation.[8,105] For example, extensive screening of chiral amino acids has identified the mono-protected N-menthyloxycarbonyl leucine derivative 76 as a suitable ligand, which forms a stable chiral complex with palladium(II). Thus, the reactions between a series of 2-benzylpyridines 75, the chiral mono-protected amine 76, a variety of boronic acids and palladium(II) to afford the monosubstituted products 77 has been reported (Scheme 37).[105] The reactions are typically carried out in refluxing tetrahydrofuran with 10 mol% loading of the air-stable compound palladium(II) acetate, on a scale of 0.2 mmol with 10–20 mol% of the chiral ligand. The products are isolated in high yield (43–96%), and with good to excellent levels of enantioinduction (72–95% ee), using a variety of substituted biphenyl pyridine compounds. The reaction is proposed to proceed through the complex 78 (Scheme 37), the conformation of which explains the observed asymmetric induction. The reactions can also be performed on alkylpyridines demonstrating that insertion is possible on sp3 C—H bonds, although both conversion and asymmetric induction are generally low.
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 564
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Stereoselective Synthesis
3.13
C—C Bond Formation by C—H Bond Activation
Palladium(II)-Catalyzed Enantioselective C—H Activation[105]
Scheme 37
10 mol% Pd(OAc)2 Bui 10−20 mol%
CO2H HN
Pri
O O
76 benzo-1,4-quinone o Ag2O, THF, 50−80 C, 20 h
N R1
R
1
+
2
R
R
R4B(OH)2
2
H H 3
R3
R
75
N R1 R2
R1
H R4
R3
R2 R3
77
R1 R2
R3 R4
Temp (8C) 76 (mol%) ee (%) Yield (%) Ref
Me H
H
Bu
50
20
95
50
[105]
Me H
H
Bu
60
10
88
96
[105]
H
H
H
Bu
80
20
79
47
[105]
Me H
H
60
10
89
61
[105]
H
Me H
Bu
60
10
84
58a
[105]
H
OAc H
Bu
80
10
72
43
[105]
H
H
Me Bu
80
10
78
61
[105]
a
Reaction performed over 40 h.
RS
RL
O O
H Pd
H
N
N PG 78
Aromatic aldimines and ketimines are now excellent substrates for rhodium(I)-catalyzed C—H functionalizations. The optimization of this transformation demonstrates that rhodium catalysts, in particular Wilkinsons catalyst [RhCl(PPh3)3], enjoy a broader reaction scope than the analogous transformations with ruthenium and rhenium catalysts. Hence, N-benzylaldimines and -ketimines react with alkenes that are electron deficient or have allylic hydrogen atoms, and even with internal alkenes that isomerize prior to reaction. For example, the ketimines 79 combine with a range of vinyl derivatives to afford the corresponding ketones 80 (Scheme 38).[63,64] C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.13.2
Intermolecular ortho-Alkylation with Functionalized Alkenes[63,64]
Scheme 38 Bn
O N 1. RhCl(PPh3)3, toluene, 2 h
R2 + R
549
Intermolecular C—C Bond Formation by C—H Activation
2. H3O+
R3
1
R1 R2
79
R3
80
R1
R2
R3
Temp (8C) Yield (%) Ref
H
Bu
H
135
94
[63]
H
CO2Me
H
150
94
[64]
CF3
CO2Me
H
150
95
[64]
OMe CO2Me
H
150
90
[64]
H
CO2Me
Me 150
81
[64]
H
CONMe2 H
150
75
[64]
H
SO2Ph
H
150
43
[64]
H
CN
H
150
32
[64]
While other intermolecular ortho-alkylation strategies tolerate only unsubstituted terminal alkenes, this system encompasses a much wider reaction scope,[64] which includes acrylamates. The reaction with methyl crotonate establishes that the alkene undergoes isomerization to the terminal alkene prior to C—H insertion, as the product is the straight-chain analogue. Functionalized alkenes are better substrates than their unfunctionalized counterparts, and it is proposed that this increase in reactivity is due to stabilization of the rhodium in the transition state by chelation to the carbonyl group. Subsequent acid hydrolysis of the imine furnishes the corresponding aromatic ketone. Aromatic primary alcohols[63] and amines[106] are all suitable substrates for this reaction system, using 3-methylpyridin-2-amine as an activating additive. Efforts have also focused on adapting this reaction system for industrial purposes by developing solvent-free reactions[107] and recyclable catalysts.[108] A very effective method for the palladium(II)-catalyzed enantioselective C—H alkenation of diphenylacetic acids has also been reported.[109,110] As an extension of the pyridinedirected reaction of chiral palladium(II)/amino acid complexes with boronic acids, the reaction of the acid-directed C—H activation and subsequent alkenation with styrenes has also been explored using the sodium salts 81 (Scheme 39).[109] The reactions are performed in 2-methylbutan-2-ol at 90 8C, employing 5 mol% of palladium(II) acetate as the catalyst with 10 mol% of a chiral amino acid ligand (Boc-Ile-OH). These reactions are typically carried out on a 0.5-mmol scale, and the products 82 are obtained in moderate to good yield (35–73%) with high levels of enantioselectivity (72–97% ee). The asymmetric induction is rationalized by a consideration of a presumed transition-state complex 83.
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 564
550
Stereoselective Synthesis Scheme 39 Acids[109]
3.13
C—C Bond Formation by C—H Bond Activation
Palladium(II)-Catalyzed Enantioselective C—H Alkenation of Diphenylacetic
R3
R3 5 mol% Pd(OAc)2
R1
10 mol% Boc-Ile-OH•0.5H2O 5 mol% benzo-1,4-quinone base, EtC(Me)2OH 90 oC, 48 h
CO2Na
R1 R2
CO2H
R2 R2 81
R1
R2
R3
Yield (%) ee (%) Ref
Me H
H
73
97
[109]
Me H
Me 71
97
[109]
Me H
Cl
74
96
[109]
Me Me H
63
90
[109]
Me Cl
H
35
87
[109]
Et
H
61
72
[109]
H
R2 82
RS
RL
O O
H Pd
H
O
ONa
N PG 83
(S)-2-[(2-Butyl-6-methylphenyl)(2-methylphenyl)methyl]pyridine (77, R1 = Me; R2 = R3 = H; R4 = Bu); Typical Procedure:[105]
CAUTION: Reactions carried out in sealed vessels are potentially hazardous. Operator protection is necessary, especially when the vessel is opened at the end of the procedure. The methylpyridine 75 (R1 = Me; R2 = R3 = H; 0.2 mmol, 1 equiv), Pd(OAc)2 (4.5 mg, 0.02 mmol, 10 mol%), butylboronic acid (R4 = Bu; 0.6 mmol, 3 equiv), Ag2O (46.3 mg, 0.2 mmol, 1 equiv), benzo-1,4-quinone (10.8 mg, 0.1 mmol, 0.5 equiv), and the chiral amino acid 76 (6.3 mg, 0.02 mmol, 10 mol%), were dissolved in THF (2 mL), under atmospheric air in a 20-mL Teflon cap-sealed tube. The tube was sealed with a Teflon-lined cap, and the mixture was stirred at 60 8C. After 20 h, the mixture was allowed to cool to rt and filtered through a pad of Celite, and washed with CH2Cl2 (20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography; yield: 96%; 88% ee.
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.13.2
551
Intermolecular C—C Bond Formation by C—H Activation
Methyl 3-(2-Acetylphenyl)propanoate (80, R1 = R3 = H; R2 = CO2Me); Typical Procedure:[64]
CAUTION: Reactions carried out in sealed vessels are potentially hazardous. Operator protection is necessary, especially when the vessel is opened at the end of the procedure. A screw-capped pressure vial (1 mL), equipped with a magnetic stirrer bar was charged with the aromatic ketimine 79 (R1 = H; 0.324 mmol), methyl acrylate (0.389 mmol), RhCl(PPh3)3 (16.2 mol, 5 mol%), and toluene. The vial was closed and heated at 150 8C with vigorous stirring for 2 h and then the mixture was allowed to cool to rt. 1 M HCl was added and the phases were separated; the aqueous layer was extracted with Et2O and the combined organic phases were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography; yield: 94%. (R,E)-2-Phenyl-2-(2-styrylphenyl)propanoic Acid (82, R1 = Me; R2 = R3 = H); Typical Procedure:[109]
CAUTION: Reactions carried out in sealed vessels are potentially hazardous. Operator protection is necessary, especially when the vessel is opened at the end of the procedure. The sodium salt 81 (R1 = Me; R2 = H; 0.5 mmol, 1 equiv), styrene (0.5 mmol, 1 equiv), Pd(OAc)2 (5.6 mmol, 0.025 mmol, 5 mol%), KHCO3 (0.25 mmol, 0.5 equiv), Boc-IleOH•0.5H2O (12.0 mg, 0.05 mmol, 0.1 equiv), and benzo-1,4-quinone (2.7 mg, 0.025 mmol, 0.05 equiv), were dissolved in anhyd 2-methylbutan-2-ol (3 mL) under O2 in a 50-mL Schlenk tube. The tube was sealed with a Teflon-lined cap, and the mixture was stirred at 90 8C for 48 h. The mixture was diluted with EtOAc and then it was acidified with 2 M HCl. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography; yield: 97%; 73% ee. 3.13.2.3
Intermolecular Activation of Benzylic C—H Bonds
Intermolecular benzylic C—H functionalization presents an attractive strategy for the convenient enantioselective preparation of alkylbenzene derivatives. 3.13.2.3.1
Dirhodium(II)-Catalyzed Carbene C—H Insertion
The most effective system for this transformation employs the Rh2(S-DOSP)4 prolinate catalyst[111,112] (see Scheme 2) and is exemplified by the conversions of ethylbenzenes 84 into the esters 86A and 86B by reactions with methyl 2-(4-bromophenyl)-2-diazoacetate (85) (Scheme 40).[111] The reactions generally proceed in modest to very good yield (38–86%), and with high levels of asymmetric induction (83–89% ee). However, only moderate diastereoselectivity is observed (36–68% de). These reactions are performed on a 1-mmol scale employing 1 mol% of the air-stable catalyst, at 50 8C in refluxing 2,2-dimethylbutane.
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.13
C—C Bond Formation by C—H Bond Activation
Scheme 40 Intermolecular Benzylic C—H Insertion into a Range of 4-Substituted Ethylbenzenes[111] N2 1 mol% Rh2(S-DOSP)4
+ R1
2,2-dimethylbutane, 50 oC
CO2Me Br 85
84
CO2Me
CO2Me R1
+
R1
Br
Br 86A
86B
R1
Ratio (86A/86B) ee (%) of 86A ee (%)of 86B Combined Yield (%) Ref
OMe
68:32
89
76
86
[111]
Et
75:25
89
70
71
[111]
Me
82:18
89
74
64
[111]
H
84:16
86
–
49
[111]
Br
73:27
88
58
38
[111]
OAc
78:22
86
53
77
[111]
CO2Me 80:20
83
58
56
[111]
The most electron-rich substituents provide the more effective ethylbenzene substrates. An examination of the steric and electronic factors involved in this reaction reveal that para-substituted substrates are required to prevent cyclopropanation of the aromatic ring.[112] Furthermore, the introduction of increased steric crowding at the benzylic site significantly decreases the efficiency of the reaction, with benzylic methylene sites being the most reactive. Indanes and tetrahydronaphthalenes are also suitable substrates for this reaction,[111,112] affording the appropriate products in good yield (43–72%) and with high levels of enantioinduction (67–94% ee), albeit with low levels of diastereoselectivity (14–60% de), which is attributed to the ring size. Vinyldiazoacetates also provide carbenes that readily undergo insertion into benzylic C—H bonds in moderate yields (51–53%), and with high levels of asymmetric induction (92–94% ee). These procedures provide a rapid entry to the skeletons of the natural products (+)-imperanene and (–)-Æ-conidendrin.[112] Methyl (2R,3R)-2-(4-Bromophenyl)-3-(4-methoxyphenyl)butanoate (86A, R1 = OMe); Typical Procedure:[111]
A degassed soln of methyl 2-(4-bromophenyl)-2-diazoacetate (85; 127.5 mg, 0.5 mmol), in 2,2-dimethylbutane (6 mL), was added by syringe pump over 1 h to a degassed soln of 1-ethyl-4-methoxybenzene 84 (R1 = OMe; 3.0 mmol) and Rh2(S-DOSP)4 (9.5 mg, 0.005 mmol) in 2,2-dimethylbutane (3 mL) at reflux. After the addition, the mixture was stirred for a further 0.5 h and then it was concentrated under reduced pressure. The residue was purified by flash chromatography.
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.13.2
3.13.2.4
553
Intermolecular C—C Bond Formation by C—H Activation
Intermolecular Activation of Allylic C—H Bonds
Double bonds also provide effective activating groups, a fact that is attributed to their hyperconjugative interactions with adjacent C—H bonds and the ability to stabilize an intermediate positive charge build up in the transition state of many of these transformations. The plethora of reactions a double bond can undergo makes C—H insertion at an allylic site particularly attractive for synthetic strategies seeking to further elaborate the C—H insertion product. 3.13.2.4.1
Dirhodium(II)-Catalyzed Carbene C—H Insertion
The common reaction pathway for a dirhodium(II)-stabilized carbene and a substrate containing a double bond is cyclopropanation. Indeed, for diazo compounds containing two pendant acceptor groups this is an extremely favorable process. Nonetheless, the dirhodium(II)-stabilized carbene derived from a diazo compound with a donor and an acceptor group, favors C—H insertion over cyclopropanation.[113,114] The reactions of donor/acceptor substituted diazoacetates 88 catalyzed by dirhodium(II) prolinate Rh2(S-DOSP)4 (see Scheme 2) proves to be the optimal system for insertions into allylic C—H bonds. For instance, this type of procedure was first examined on cyclohexenes 87 and affords the corresponding diastereomers 89A and 89B (Scheme 41).[115,116] Scheme 41
Allylic C—H Insertion into Cyclohexenes[115,116] R1
R1
R1 Rh2(S-DOSP)4
N2 +
R2
2,2-dimethylbutane, rt
H
CO2Me
CO2Me
88
H
CO2Me
R2
R2 87
+
89B
89A
R1
R2
Me
4-BrC6H4 17:83
94
98
53
[115]
Et
4-BrC6H4 25:75
90
94
46
[115]
iPr
4-BrC6H4 36:64
90
93
65
[115]
t-Bu
4-BrC6H4 62:38
91
81
46
[115]
Ph
4-BrC6H4 23:77
90
95
65
[115]
Cl
4-BrC6H4 65:35
96
91
58
[115]
TMS
4-BrC6H4 70:30
88
–
48
[115]
TBDPS 4-BrC6H4 94:6
95
–
64
[115]
Me
–
94
40
[116]
Ratio (89A/89B) ee (%) of 89A ee (%) of 89B Combined Yield (%) Ref
3-thienyl 25:75
The reaction is performed with 1 mol% catalyst in 2,2-dimethylbutane at room temperature. The products are isolated in moderate yield (40–65%), with excellent levels of asymmetric induction (88–98% ee), and display remarkable levels of regioselectivity. Although there are a number of allylic positions that could be functionalized in each substrate, reaction at an alternative position is only detected in one case (when R1 = Et; R2 = 4-BrC6H4). The scope of the reaction is also very general; for example, the reaction involving the thienyl-substituted diazoacetate 88 (R2 = 3-thienyl) is an interesting case considering that sulfur is known to poison dirhodium(II) catalysts.[16] Nevertheless, the diastereoselectivity of these transformations was generally only moderate (24–88% de). In order to achieve diaC—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 564
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Stereoselective Synthesis
C—C Bond Formation by C—H Bond Activation
3.13
stereoselectivity, the substituents at the site of insertion must be sterically differentiated, which is effectively demonstrated in the reactions of acyclic substituted allyl groups. For example, the reaction between the alkenes 90 and methyl 2-(4-bromophenyl)-2-diazoacetate (85) affords the diastereomers 91A and 91B (favoring 91A) (Scheme 42).[115,117] Scheme 42
Allylic C—H Insertion into Acyclic Substrates[115,117] N2
R2 +
R1
Rh2(S-DOSP)4 2,2-dimethylbutane, −30 oC
CO2Me Br
90
85 R2
R2 CO2Me
R1
CO2Me
R1 +
Br
Br
91A
R1 R2
91B
Ratio (91A/91B) ee (%) of 91A Combined Yield (%) Ref
Me Me
75:25
86
67
[115]
Et H
54:46
92
56
[115]
Ph Ph
85:15
96
33
Ph OTIPS
[115] a
[117] [117]
>95:5
71
66
Ph OTBDPS >95:5
84
65a
a
The conversion is essentially quantitative, with the mass balance being made up from a cyclopropanation product.
The significantly improved diastereoselectivity (>90% de) and good yields (33–67%) observed in the acyclic systems are thought to be due to the electronic activation of the differentially substituted allylic methylene site.[117] The C—H insertion of carbenes derived from aryldiazoacetates 92 into doubly allylic sites such as those of cyclohexa-1,4-diene is particularly efficient, furnishing the corresponding products 93 in good yield (50–98%), and with high asymmetric induction (65– 95% ee) (Scheme 43).[113,118] Indeed, the reaction is so efficient that it can be performed under solvent-free conditions at 0 8C using a catalyst loading of 0.01 mol% on a 50-mmol scale, furnishing a C—H insertion product in up to 96% yield and 81% enantiomeric excess.[119] Scheme 43 C—H Insertion of Aryldiazoacetates into Cyclohexa-1,4diene[113,118]
N2 +
R1
Rh2(S-DOSP)4, hexane, rt
CO2Me R1 92
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
CO2Me 93
3.13.2
Intermolecular C—C Bond Formation by C—H Activation
R1
ee (%) Yield (%) Ref
Ph
65a
98
[113]
Ph
b
71
50
[113]
4-ClC6H4
95
84
[118]
4-Tol
94
84
[118]
4-MeOC6H4 93
69
[118]
2-naphthyl
64
[118]
a b
92
555
The solvent was CH2Cl2. The solvent was pentane.
The reactions illustrated in Scheme 43 are carried out at room temperature with 2 mol% catalyst in dichloromethane, pentane, or hexane. The process is also highly efficient at effecting C—H insertion into cycloheptatrienes, thereby affording the appropriate products in 53–64% yield and 91–95% enantiomeric excess.[120] The scope of this transformation may be expanded to incorporate alternative diazo substituents, such as the electron-withdrawing phosphonate group. While the selectivity is low with Rh2(S-DOSP)4, the alternative complex Rh2(S-PTAD)4 affords high yield (83%) and enantioselectivity (92% ee).[91] The significance of this transformation is elegantly demonstrated in the straightforward preparation of (+)-cetiedil[116] and (+)-indatraline,[121] both of which incorporate allylic C—H insertions of aryldiazoacetates into cyclohexa-1,4-diene as the key asymmetry-inducing step. Vinyl groups prove effective as stabilizing electron-donating substituents on dirhodium(II)-stabilized carbenes, in which their reaction within allylic C—H insertion systems has also been examined.[118] The reaction of various (arylvinyl)diazoacetates 94, with cyclohexa-1,3-diene, furnishes products that are not the expected C—H insertion products, but rather those of a combined C—H activation/Cope rearrangement process that affords the esters 95 (Scheme 44).[118] In such cases the products are obtained in moderate to good yields (50–80%), but with outstanding enantiocontrol (96–99% ee). Since the product from direct C—H insertion is, in fact, thermodynamically more stable than the rearranged product, it probably arises through a C—H insertion process that is interrupted by a Cope rearrangement to provide the kinetic product, rather than via an initial C—H insertion, followed by a Cope rearrangement.[122]
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 564
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Stereoselective Synthesis
3.13
C—C Bond Formation by C—H Bond Activation
Combined C—H Activation/Cope Rearrangements[118]
Scheme 44
CO2Me
1 mol% Rh2(S-DOSP)4 hexane, rt
N2 R1
+
H
R1 R2
MeO2C R2
Rh
94 R2 R1 CO2Me 95
R1
R2
ee (%) Yield (%) Ref
H
4-MeOC6H4
99
58
[118]
H
3,4-Cl2C6H3
99
59
[118]
H
2-naphthyl
99
50
[118]
73
97
[118]
(E)-CH=CHPh 99
60
[118]
(CH2)3 H
The remarkable levels of asymmetric induction observed in these products is thought to be due to the rigidity provided in the transition state for the Cope rearrangement, which proceeds through the stable, well-defined, chair-form. The efficiency and enantioselectivity of this transformation with cyclohexa-1,3-diene is exploited in the rapid construction of an advanced precursor to the natural product (+)-sertraline, with the C—H insertion step proceeding in 59% yield with 99% enantiomeric excess.[118] The dirhodium(II)-catalyzed combined C—H activation/Cope rearrangement is the favored reaction pathway for a number of different types of allylic methylene sites.[122] A variety of substituted dihydropyranones provide excellent substrates for this transformation, affording the rearrangement products in 20–87% yield as single diastereomers and with characteristically high levels of enantioselectivity (98–99% ee). A similar level of reactivity is observed with various 1-substituted cyclohexenes 96 in reactions with the diazo ester 97, albeit giving a mixture of constitutional isomers 98 and 99 (Scheme 45).[122] Scheme 45
The C—H Activation/Cope Rearrangement of 1-Substituted Cyclohexenes[122] Ph
R1
CO2Me N2
CO2Me
R1
R1
Ph
1 mol% Rh2(S-DOSP)4
+
H
+ Ph
96
CO2Me
97
99
98
R1
Solvent
Temp (8C)
Ratio de (%) ee (%) Yield (%) Ref (98/99) of 98 of 99 of 98
Me
2,2-dimethylbutane
23
1.6:1
>98
99
40
[122]
Me
(trifluoromethyl)benzene
23
2.9:1
>98
97
53
[122]
Me
(trifluoromethyl)benzene
0
4.0:1
>98
97
68
[122]
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.13.2
557
Intermolecular C—C Bond Formation by C—H Activation
R1
Solvent
Temp (8C)
Ratio de (%) ee (%) Yield (%) Ref (98/99) of 98 of 99 of 98
Me
(trifluoromethyl)benzene
–20
4.5:1
>98
98
53
[122]
iPr
(trifluoromethyl)benzene
0
0.8:1
>98
95
31
[122]
OAc
(trifluoromethyl)benzene
0
2.2:1
>98
98
55
[122]
OTMS (trifluoromethyl)benzene
0
2.2:1
>98
99
44
[122]
The functionalized products are obtained in low to moderate yield (31–68%), as single diastereomers with high levels of enantioinduction (95–99% ee).[122] Major byproducts from these reactions are the direct C—H insertion products. Cyclopentene systems suffer significantly from low yields (~48 %), although the products are formed with excellent enantiomeric excess (95–96% ee). The reduced yields are a consequence of the direct C—H insertion and cyclopropanation reactions. Dihydronaphthalenes are excellent substrates for the C—H activation/Cope rearrangement.[123–125] The reaction of 1-substituted 3,4-dihydronaphthalenes 100 with (arylvinyl)diazoacetates such as the methyl diazoacetate 97 provides the formal C—H insertion products 102 as single diastereomers with exceptional enantioselectivity (>99% ee) (Scheme 46). This is unusual, since the direct intermolecular C—H insertion is known to suffer from low levels of diastereocontrol. This type of transformation appears to proceed through a C—H activation/Cope rearrangement, affording intermediate 101, followed by a retro-Cope rearrangement, in which the well-defined transition state explains the excellent levels of stereoselection observed in these reactions.
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.13
C—C Bond Formation by C—H Bond Activation
Scheme 46 Reactions of 1-Substituted 3,4-Dihydronaphthalenes with (Arylvinyl)diazoacetates[123] R3
CO2Me
R2
N2
Rh2(S-DOSP)4 2,2-dimethylbutane
+
Ph R2
CO2Me
R3
R1 R1
Ph 97
100
101 R3 R2
Ph
R1
H
CO2Me
102
R1
R2
R3
Catalyst Loading (mol%)
Temp (8C) de (%) ee (%) Yield (%) Ref
H
H
Me
1
23
>98
98.9
92
[123]
H
H
Me
0.1
23
>98
98.3
82
[123]
H
H
Me
0.5
0
>98
99.5
95
H
H
H
OMe Me
H
a
[123]
1
0–60
>98
99.3
60
[123]
1
0
>98
99.3
77
[123]
OMe H
Me
1
0
>98
98.9
90
[123]
H
H
OTMS
0.5
0
>98
97.5
55
[123]
H
H
OTBDMS
0.5
0
>98
95.2
78
[123]
H
H
OTIPS
0.5
0
>98
91.3
53
[123]
a
Heating to 60 8C is required to perform the retro-Cope rearrangement.
During the development of this selective transformation in the context of the total synthesis of the marine diterpene (+)-erogorgiaene[126] it was found that reactions of racemic dihydronaphthalenes involve enantiodivergent processes. For example, the dirhodium(II) prolinate catalyst Rh2(S-DOSP)4 effects the combined C—H activation/Cope rearrangement with the R-enantiomer of the substrate, whereas the S-enantiomer undergoes direct cyclopropanation. Both reaction pathways occur with high levels of diastereo- and enantioselectivity. The significance of this entry into highly stereochemically defined motifs has been elegantly demonstrated through its incorporation into the total syntheses of the natural products (+)-erogorgiaene,[126] (–)-colombiasin A, (–)-elisapterosin B, (+)-elisabethadione, and an unnamed (+)-benzo-1,4-quinone.[127,128] A recent systematic study outlines the fine balance in the factors that dictate the selection of reaction pathways in such cases.[125] The incorporation of a leaving group into the substrate provides a novel route for the enantioselective synthesis of substituted aromatic systems using the C—H activation/ Cope rearrangement. This methodology has been applied to the enantioselective synthesis of a diverse range of 4-aryl-4-(1-naphthyl)but-2-enoates,[129] furnishing the products in poor to excellent yield (14–92%) with exceptional enantioselectivity (>98% ee). The strategy is also effective in the synthesis of chiral 4-substituted indoles,[130] which are usually inaccessible due to the low reactivity of the 4-position. Thus, the acetate 103 readily undergoes a Rh2(S-DOSP)4-catalyzed C—H activation/Cope rearrangement with various (arylvinyl)diazoacetates 104 to afford the corresponding bicyclic allylic acetates 105, which C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.13.2
559
Intermolecular C—C Bond Formation by C—H Activation
undergo elimination to afford the substituted indoles 106 in good yields (45–65%) and with excellent enantioinduction (98–99% ee) (Scheme 47).[130] Scheme 47
Enantioselective Synthesis of 4-Substituted Indoles[130]
OAc
CO2Me N2
R1 1 mol% Rh2(S-DOSP)4 2,2-dimethylbutane, rt
CO2Me
AcO
+ N Boc
N Boc
R1
103
104
105 R1
CO2Me
N Boc 106
R1
ee (%) Yield (%) Ref
Ph
98.5
65
[130]
4-MeOC6H4
98.0
52
[130]
4-BrC6H4
98.7
53
[130]
3-indolyl
97.7
64
[130]
(E)-CH=CHPh 99.0
56
[130]
Me
61
[130]
98.6
The reactions of allyl silyl ethers with vinyldiazoacetates afford a mixture of direct C—H activation and C—H activation/Cope rearrangement products. In these systems the C—H activation/Cope rearrangement products are thermodynamically more stable. Hence on either heating or microwave irradiation the C—H activation/Cope rearrangement product is favored, which results in an improved yield.[131] Methyl 2-(4-Bromophenyl)-3-methylpent-4-enoates 91A/91B; General Procedure for C—H Activation of Allylic Sites:[115]
A degassed soln of a methyl (4-bromophenyl)diazoacetate (85; 0.5 mmol), in 2,2-dimethylbutane (6–10 mL) was added by syringe pump over 1 h at rt to a stirring and degassed soln of the alkene 90 (5.0 mmol), and Rh2(S-DOSP)4 (9.5 mg, 0.5 mol%) in 2,2-dimethylbutane (3 mL). The mixture was stirred for a further 1 h after the addition was complete, and then it was concentrated under reduced pressure, and the residue was purified by flash chromatography. Methyl 4-(Cyclohex-2-enyl)-4-phenylbut-2-enoates 98 and Methyl 2-(Cyclohex-2-enyl)-4phenylbut-3-enoates 99; General Procedure for a C—H Activation/Cope Rearrangement:[122]
Methyl [(E)-2-phenylvinyl]diazoacetate (203 mg, 1.0 mmol) in (trifluoromethyl)benzene (5 mL) at 0 8C was added via a syringe pump over 45 min to a cyclohexene (0.5 mmol) and Rh2(S-DOSP)4 (19 mg, 1 mol%), in (trifluoromethyl)benzene (2 mL). The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography.
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 564
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Stereoselective Synthesis
3.13.2.5
Intermolecular Activation of C—H Bonds Æ to Oxygen
3.13
C—C Bond Formation by C—H Bond Activation
As previously stated, C—H Bonds adjacent to oxygen are highly activated toward insertion, providing an effective means to regioselectively incorporate high functional group density in the products. 3.13.2.5.1
Dirhodium(II)-Catalyzed Carbene C—H Insertion
Substrates containing unprotected hydroxy groups readily undergo O—H insertion or ylide formation with dirhodium(II)-stabilized carbenes. However, suitably protected derivatives become very effective activating groups, providing efficient means for selective C—H insertion. The intermolecular C—H insertion of aryldiazoacetates 107 adjacent to the oxygen in tetrahydrofurans demonstrates why Rh2(S-DOSP)4 (see Scheme 2) has established itself as the most effective catalyst for this type of transformation. In the case of tetrahydrofuran itself the products are the diastereomers 108A and 108B (Scheme 48).[17] These reactions are performed at –50 8C, with 1 mol% catalyst, which affords the products in good yields (56–74%), and with excellent levels of enantioselectivity, albeit with modest diastereoselectivities. Scheme 48
C—H Insertion Æ to Oxygen in Tetrahydrofuran[17] 1 mol% Rh2(S-DOSP)4 hexanes, −50 oC
N2
O +
R1
CO2Me
O
O
CO2Me
+
CO2Me
H R1
H R1
108A
107
108B
R1
Ratio (108A/108B) ee (%) of 108A Combined Yield (%) Ref
Ph
74:26
97
67
[17]
4-ClC6H4
71:29
98
74
[17]
4-MeOC6H4 77:23
96
56
[17]
4-Tol
80:20
97
60
[17]
2-naphthyl
62:38
95
62
[17]
The scope of this transformation includes acyclic silyl ethers, which also exploit the double activation effect in the C—H functionalization to afford high yields and selectivities.[132] Rh2(S-DOSP)4 efficiently catalyzes the C—H insertion adjacent to oxygen in a range of aryldiazoacetates into silyl ethers[133] and allyl silyl ethers. The procedure is illustrated by the reaction of the allyl ether 109 with methyl (4-chlorophenyl)diazoacetate (110), which gives primarily the esters 111A and only minor amounts of the diastereomer 111B (Scheme 49).[134]
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Intermolecular C—C Bond Formation by C—H Activation
Scheme 49
C—H Insertion Æ to Silyl-Protected Oxygen[134] N2
OTBDMS
CO2Me
+
1 mol% Rh2(S-DOSP)4 hexanes, 23 oC
Cl
R1 109
110 Cl
Cl
OTBDMS
MeO2C
+
R1
R1
111A
R1
Ratio (111A/111B) ee (%) Yield (%) Ref
Me
98:2
80
72
[134]
Ph
98:2
85
70
[134]
CH=CH2 99:1
74
71
[134]
H
90
35
[134]
99:1
OTBDMS
MeO2C
111B
The reactions are generally performed at room temperature in hexanes, employing a 1 mol% catalyst loading to afford the products in low to high yields (35–72%), with high levels of enantioinduction (74–90% ee). The remarkably high levels of diastereoselectivity observed in these substrates (96–98% de) is especially impressive considering the diastereoselection with tetrahydrofuran. Furthermore, these substrates provide excellent examples of how the subtle electronic effects imparted by the oxygen-protecting group influence the C—H insertion event.[135] While the use of a triorganosiloxy ether activates the C—H bond adjacent to the oxygen toward insertion, the protection of the alcohol with an acetoxy group deactivates this C—H bond, due to the electron-withdrawing nature of the protecting group. Furthermore, the C—H bonds to an oxygen heteroatom are deactivated toward the insertion event, which is attributed to the inductive electron-withdrawing effect of the heteroatom. An understanding of these factors offers the potential for selective control of C—H activation adjacent to oxygen through the judicious choice of protecting groups. Methyl (S)-2-Phenyl-2-[(R)-tetrahydrofuran-2-yl]acetate (108A, R1 = Ph); Typical Procedure:[17]
A degassed soln of methyl phenyldiazoacetate (107, R1 = Ph; 1.04 mmol) in hexanes (10 mL), was added dropwise over 1 h, to a degassed, stirred soln of Rh2(S-DOSP)4 (20 mg, 1 mol%) and THF (144 mg, 2.0 equiv) in hexanes (5 mL), at –50 8C. The resulting soln was stirred for 10 h at –50 8C, and then allowed to warm to rt; it was concentrated under reduced pressure and the residue was purified by flash chromatography. Methyl (2R,3S,E)-3-(tert-Butyldimethylsiloxy)-2-(4-chlorophenyl)hex-4-enoate (111A, R1 = Me); Typical Procedure:[134]
A flame-dried, 50-mL round-bottomed flask equipped with a magnetic stirrer bar and a rubber septum was charged with the silyl ether 109 (R1 = Me; 1.5 mmol), Rh2(S-DOSP)4 C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.13
C—C Bond Formation by C—H Bond Activation
(14 mg, 1 mol%), and dry hexane (0.5 mL), and stirred under argon at rt to give a green soln. A soln of methyl 2-(4-chlorophenyl)-2-diazoacetate (110; 0.75 mmol) in dry hexane (7.5 mL) was then added dropwise via a syringe pump over 1 h. After this addition was complete, the mixture was stirred for a further 1 h and then concentrated under reduced pressure, and the residue was purified by flash chromatography; yield: 72%; 80% ee. 3.13.2.6
Intermolecular Activation of C—H Bonds Æ to Nitrogen
The activating nature of the nitrogen atom is such that C—H insertion adjacent to this heteroatom is extremely favorable, which provides a convenient entry to nitrogen-containing scaffolds. 3.13.2.6.1
Dirhodium(II)-Catalyzed Carbene C—H Insertion
Intermolecular C—H activation adjacent to nitrogen atoms, particularly with donor/acceptor carbenoids, is an extremely facile transformation, due to the activating nature of the nitrogen.[116,136–139] The products of this transformation are chiral -amino acid derivatives, traditionally prepared via asymmetric Mannich reactions. Davies and co-workers first investigated the C—H activation of the simple N-tert-butoxycarbonyl-protected pyrrolidine system 112 (N-protection is required to prevent N—H insertion), with a range of aryldiazoacetates 113. Following removal of the tert-butoxycarbonyl protecting group, the chiral -amino esters 114A can be obtained in good yields along with minor quantities of their diastereomers 114B. Again the Rh2(S-DOSP)4 catalyst system proves to be the most efficient for this type of transformation, in which the diastereo- and enantioselectivity for the products 114 are 92–94% de and 93–94% ee, respectively (Scheme 50).[136,139] C—H Insertion of N-tert-Butoxycarbonyl-Protected Cyclic Amines[136,139]
Scheme 50
1. 1 mol% Rh2(S-DOSP)4
Boc N +
1
R
H N
hexanes 2. TFA, CH2Cl2
N2
CO2Me
+
CO2Me
n
112
H N
CO2Me
n
113
H R1
n
114A
H R1 114B
R1
n Temp (8C) Ratio (114A/114B)
ee (%) of 114A Combined Yield (%)
Ref
Ph
1 –50
96:4
94
72
[136]
Ph
1
25
95:5
88
75
[139]
4-ClC6H4
1 –50
97:3
94
70
[136]
4-Tol
1 –50
97:3
93
67
[136]
2-naphthyl
1 –50
96:4
93
49
[136]
Ph
2
25
50:50
79
86
[139]
Ph
2 –50
64:36
89
44
[139]
Ph
3
25
>95:5
92
72
[139]
Ph
4
25
>95:5
90
74
[139]
These C—H insertion reactions are typically performed in hexane, at –50 8C, employing 1 mol% of catalyst. In the above cases N-tert-butoxycarbonyl-protected pyrrolidine was present in excess; however, the activating nature of the nitrogen is so great that if there is an excess of the aryldiazoacetate 113 present, a second C—H event occurs to afford the 2,5disubstituted N-tert-butoxycarbonyl pyrrolidine (78% yield, 97% ee).[136] Substituted sysC—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.13.3
Conclusions
563
tems are also suitable substrates for this chemistry, with C—H insertion occurring regioselectively at the least hindered site adjacent to the nitrogen atom. Furthermore, a kinetic resolution of racemic substrates is possible with this process.[138] The scope of this transformation includes the six-membered N-tert-butoxycarbonyl piperidine system, with the dirhodium(II) prolinate catalyst Rh2(S-biDOSP)2 affording a monofunctionalized product in good yield (73%), with high levels of enantioselection (86% ee), albeit with low diastereoselectivity (40% de). The Rh2(5R-MEPY)4 carboxamidate catalyst is also effective in the transformation, providing excellent diastereoselectivity (94% de) and moderate enantioselectivity (69% ee), albeit with only low conversion (22%).[137] Seven- and eight-membered rings display even higher levels of stereoselectivity in this reaction. The facility of C—H insertion next to nitrogen has led to its incorporation in the enantioselective preparation of a number of small molecules. Rh2(S-DOSP)4-mediated reactions are also used to prepare -peptides (77% yield, 93% ee),[139] C2-symmetric amines (60% yield, 90% ee),[140] and the antidepressant venlafaxine (62% yield, 93% ee).[141] Methyl (S)-2-Phenyl-2-[(R)-pyrrolidin-2-yl]acetate (114A, R1 = Ph; n = 1); Typical Procedure:[139]
Methyl phenyldiazoacetate (113, R1 = Ph; 176 mg, 1.0 mmol) in dry hexanes (10 mL), was added dropwise over 1 h to a soln of Rh2(S-DOSP)4 (19 mg, 1 mol%) and tert-butyl 1-pyrrolidinecarboxylate (112; 351 mg, 2 mmol) in dry hexanes (5 mL), at –50 8C. The mixture was allowed to warm slowly to rt overnight, before it was concentrated under reduced pressure, and the residue was treated with TFA (10 equiv) in CH2Cl2 (10 mL) at rt for 1 h, and the mixture was washed with H2O. The aqueous phase was basified with NaHCO3, extracted with CH2Cl2, dried (MgSO4), filtered, and concentrated under reduced pressure to give the crude product. 3.13.3
Conclusions
In the last ten years, C—C bond formation through C—H activation has matured significantly as a useful methodology, with excellent levels of chemo-, regio-, diastereo-, and enantioselectivity in a wide variety of chemical motifs. The development of transition-metal mediated asymmetric catalysis in this field, led by rhodium, has not only broadened the applicability of this methodology, but allowed the discovery of novel transformations. Emphasis on the environmental impact of a synthetic procedure has never been greater and the benign, mild nature of the catalytic C—H functionalization technology has never been more appropriate. The burgeoning application of C—H activation for the construction of strategically important C—C bonds in the synthesis of natural products and pharmaceutically important motifs, along with the discovery of novel transformations ensure that application and development of this field will enjoy significant attention in the years to come.
C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 564
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C—C Bond Formation by C—H Bond Activation
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C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.13
C—C Bond Formation by C—H Bond Activation
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C—C Bond Formation by C—H Bond Activation, Davies, H. M. L., Morton, D. Science of Synthesis 4.0 version., Section 3.13 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Cross Coupling M. Shimizu and T. Hiyama
General Introduction
Since the pioneering work independently reported by Kumada[1] and Corriu[2] on the nickel-catalyzed reaction of Grignard reagents with alkenyl and aryl halides, the transitionmetal-catalyzed cross-coupling reaction of organometallic reagents with organic (pseudo)halides has developed into one of the most powerful and straightforward methods for C—C bond formation (Scheme 1).[3–6] Scheme 1 Transition-Metal-Catalyzed Cross Coupling[3–6] R 1M +
Ni catalyst or Pd catalyst
R2X
R1 R2
R1 = alkenyl, alkynyl, aryl, alkyl; R2 = alkenyl, aryl, alkyl; M = Li, B, Mg, Al, Si, Cu, Zn, Zr, Sn; X = F, Cl, Br, I, OTf, OMs, OMe
A variety of complex molecules, which include natural products as well as a diverse range of functional organic materials, have been efficiently prepared with a cross-coupling reaction. The well-accepted mechanism involves a catalytic cycle that consists of an oxidative addition–transmetalation–reductive elimination sequence as illustrated in Scheme 2. Scheme 2
Catalytic Cycle for Cross Coupling
R1 R2
M 2 Ln
R2X
oxidative addition
reductive elimination
R1R2M2Ln
R2M2LnX
transmetalation
M1X
R1M1
Although the reaction and catalytic cycle outlined in Schemes 1 and 2 are very useful for understanding the general concept and mechanism of the cross-coupling reaction, it is difficult to appreciate what types of stereochemical issues can be solved by this process given that they do not include any stereochemical features. Hence, it is important to define the possible stereochemical elements in the cross-coupling reaction by including more specific structural details in the organometallic and/or organic (pseudo)halides to illustrate the synthetic utility of the reaction in stereoselective synthesis. As shown in Scheme 3, this chapter is divided into five sections with regard to the critical stereochemCross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
3.14
Cross Coupling
ical elements, namely asymmetric synthesis of tertiary carbon centers (Section 3.14.1; routes a and b correspond to Sections 3.14.1.1 and 3.14.1.2, respectively), stereoselective synthesis of multisubstituted alkenes (Section 3.14.2; routes c, d, e, and f correspond to Sections 3.14.2.1, 3.14.2.2, 3.14.2.3, and 3.14.2.4, respectively), stereoselective synthesis of alkenes bearing a stereogenic center at the allylic position (Section 3.14.3; route g), asymmetric synthesis of optically active allenes (Section 3.14.4; routes i and j correspond to Sections 3.14.4.1 and 3.14.4.2, respectively), and finally the asymmetric synthesis of biaryls (Section 3.14.5; routes k and l correspond to Sections 3.14.5.1 and 3.14.5.2, respectively). Allylic substitution reactions to form C—C, C—N, or C—O bonds are covered in Section 3.9 (route h). Further information, viewed from the perspective of enolate functionalization rather than cross coupling, can also be found in Section 3.15. Scheme 3
Overview of the Reactions in this Chapter
M R1
R3
R2
route a
R2X
+
R1
X
route b
R3
R1
R3
+ R2M
enantioselectivity (central chirality)
R1
M
R2
route d 1. R3M 2. R4M
route c 1. R3X 2. R4X
M
R
R1
R4
M
M
route e 1. R2X 2. R3X
1
R
R2
R1
X
R2
X
R1
R4
X
X
4
R3
route f 1. R2M 2. R3M
E/Z selectivity (alkene geometry)
R2
R1 2
R3
M
+ R X
R1
route g
route h
R1
R3
R3
X
+ R2M
enantioselectivity (central chirality)
R1 R4
X
+
R3M
R1
route i
R4
route j
R1
R2
R2
Br + R5 M
• R2
R3
enantioselectivity (axial chirality)
R3
R2 R3 enantioselectivity (axial chirality)
Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
route l 1. R3M 2. R4M
route k
M + X R2
R1 R4
R4
R1
(Customer-ID: 5907)
R1 X
R2 X
3.14.1
3.14.1
569
Asymmetric Synthesis of Tertiary Carbon Centers
Asymmetric Synthesis of Tertiary Carbon Centers
There are three approaches to enantioselective construction of a tertiary asymmetric carbon stereogenic center using the transition-metal-catalyzed cross-coupling reaction. The first is metal-catalyzed cross coupling of racemic secondary alkylmetal reagents with achiral organic halides using a chiral nickel or palladium complex, and the second involves a similar reaction of achiral organometallic reagents with racemic secondary alkyl halides. The third process involves transition-metal-catalyzed SE2¢-type coupling of allylic metal reagents with organic halides. The first two approaches are discussed in Section 3.14.1, while the third is discussed in Section 3.14.3. 3.14.1.1
Reaction of Secondary Organometallic Reagents with Organic Halides
Racemic secondary (1-arylethyl)magnesium chlorides react with vinyl bromide in the presence of a nickel complex bearing a chiral phosphine ligand, such as (R)-N,N-dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine (1), (R)-N,N-dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]propylamine (2), and [(S)-2-dimethylamino-3-methylbutyl]diphenylphosphine (3), to give the 3-arylbut-1-enyl derivatives 4 (Scheme 4).[7–9] The corresponding products are obtained in high yields and with good enantiomeric excesses (up to 86%). The presence of the dimethylamino group in the chiral phosphine is essential for this process, which is thought to involve a dynamic kinetic resolution wherein one enantiomer of the configurationally labile Grignard reagent is selectively coordinated by the amino group and preferentially undergoes transmetalation. The asymmetric cross-coupling reaction has been applied to the construction of enantioenriched 2-arylpropanoic acids, as exemplified by ibuprofen. The analogous asymmetric coupling may also be accomplished with the corresponding organozinc reagents in the presence of the complex derived from palladium(II) chloride and ligand 1, which provides improved enantioselectivities.[10] Scheme 4 Cross-Coupling Reactions of Racemic Secondary (1-Arylethyl)metals with Alkenyl Bromides[7–10] Et NMe2 Fe
PPh2
NMe2 Fe
Pri
PPh2 Ph2P
1
Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
2
NMe2 3
for references see p 613 (Customer-ID: 5907)
570
Stereoselective Synthesis
Ar
Cross Coupling
catalyst ligand
M +
3.14
∗
Br
1
Ar1 4
Ar1
M
Ph
MgCl NiCl2
1
Et2O, 0 8C
61
92 (>95)
[7]
Ph
MgCl NiBr2
2
Et2O, –20 8C
82
76
[9]
Ph
MgCl NiCl2
3
Et2O, 0 8C
81
(>95)
[8]
4-Tol
MgCl NiCl2
3
Et2O, 0 8C
83
94
[8]
2-naphthyl
MgCl NiCl2
3
Et2O, 0 8C
72
88
[8]
Ph
ZnCl PdCl2
1
THF/Et2O, 0 8C 85
(>95)
[10]
Ph
ZnI
PdCl2
1
THF/Et2O, 0 8C 86
80 (>95)
[10]
Ph
ZnBr PdCl2
1
THF, 10 8C
(51)
[10]
4-Tol
ZnI
1
THF/Et2O, 0 8C 86
(>95)
[10]
a
ee (%) Yielda (%) Ref
Catalyst Ligand Conditions
PdCl2
86
Yields in parentheses are determined by GC.
Chiral nonracemic allylsilanes 5 are readily available in good yield and with moderate enantioselectivity via the palladium-catalyzed cross coupling of (triorganosilyl)methyl Grignard reagents with alkenyl bromides using 0.5 mol% of the catalyst obtained from palladium(II) chloride and ligand 1 (Scheme 5).[11] The level of asymmetric induction is largely dependent on the alkene geometry of the bromide, wherein E-bromides afford higher enantioselectivity than the corresponding Z-derivatives. Scheme 5 Cross Coupling of Racemic Secondary Silylmethyl Grignard Reagents with Alkenyl Bromides[11]
NMe2 PdCl2,
R1 R2
Fe
R1 Si
MgBr
+
R4
Br
R3
PPh2
R1
1
Et2O
R2
R1 Si ∗
R4
R3
R5
R5 5
R1
R2
R3
R4
R5
Me
Me
Ph
H
H
0
95
42
[11]
Me
Me
Ph
Me
H
0
85
77
[11]
Me
Me
Ph
H
Me
0
24
38
[11]
Me
Me
Ph
Ph
H
0
95
93
[11]
Me
Me
Ph
H
Ph
15
13
95
[11]
Me
Me
Me
Ph
H
0
71
78
[11]
Me
Me
Me
H
Ph
–10
59
76
[11]
Me
Ph
Me
Ph
H
–10
68
92
[11]
Et
Et
Me
Ph
H
–10
93
88
[11]
55
78
[11]
85
36
[11]
Temp (8C) ee (%) Yield (%) Ref
Me
Me
Me
Me
H
–10
Et
Et
Me
Me
H
–20
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3.14.1
571
Asymmetric Synthesis of Tertiary Carbon Centers
In a related study, a series of secondary alkylzinc reagents undergo cross coupling with excellent diastereocontrol.[12] For example, the palladium-catalyzed cross coupling of 2-, 3-, and 4-substituted cyclohexylzinc chlorides with aryl halides, in tetrahydrofuran/1-ethylpyrrolidin-2-one, provides the 1,2-anti-, 1,3-cis-, and 1,4-anti-arylcyclohexanes 6–8 with selectivities ranging from 96:4 to ‡99:1 (Scheme 6). In each case the thermodynamically favored diastereomer is the major adduct, which is attributed to the diastereomeric zinc reagents being in equilibrium, and the preferential reaction of the equatorial organozinc species. Scheme 6
Cross Coupling of Substituted Cyclohexylzinc Halides with Aryl Iodides[12]
Pri
Ar1I (0.9 equiv) catalyst THF/1-ethylpyrrolidin-2-one, 25 oC
ZnX
Pri Ar1
6
X
Ar1
Catalysta
Cl
4-MeOC6H4
Pd(dba)2 (1 mol%), SPhos (1 mol%) >99:1 78
[12]
Cl
4-ClC6H4
Pd(dba)2 (1 mol%), SPhos (1 mol%)
98:2 71
[12]
Cl
3-F3CC6H4
Pd(dba)2 (1 mol%), SPhos (1 mol%)
96:4 63
[12]
Pd(PPh3)4 (5 mol%)
98:2 76
[12]
Pd(PPh3)4 (5 mol%)
98:2 81
[12]
N
I•LiCl
dr
Yield (%) Ref
N
I•LiCl O a
CO2Et
SPhos = 2-(dicyclohexylphosphino)-2¢,6¢-dimethoxybiphenyl.
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572
Stereoselective Synthesis R1
3.14
Cross Coupling R1
Ar1I (0.7 equiv) 2 mol% PdCl2(tmpp)2 THF/1-ethylpyrrolidin-2-one, −10 oC
Ar1
ZnCl 7 OMe tmpp =
MeO
P OMe 3
R1
Ar1
dr
iPr
4-MeO2CC6H4
96:4 86
[12]
iPr
3-EtO2CC6H4
97:3 71
[12]
CF3 4-MeO2CC6H4
96:4 74
[12]
Me 4-MeO2CC6H4
97:3 77
[12]
Me 4-BzC6H4
95:5 81
[12]
95:5 85
[12]
Yield (%) Ref
CF3
Me N
R1
R1
Ar1I (0.7 equiv) 2 mol% PdCl2(tmpp)2 THF/1-ethylpyrrolidin-2-one, –10 oC
Ar1
ZnCl
8
R1
Ar1
Yield (%) dr
Ref
Me
4-MeO2CC6H4
84
95:5
[12]
t-Bu 4-MeO2CC6H4
59
95:5
[12]
t-Bu 3-F3CC6H4
60
94:6
[12]
This diastereoselective cross coupling has been extended to cyclopentyl and steroidal zinc reagents with similar levels of stereocontrol, as illustrated in Scheme 7.[12]
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3.14.1
573
Asymmetric Synthesis of Tertiary Carbon Centers
Scheme 7 Iodides[12]
Cross Coupling of Substituted Cyclopentyl and Steroidal Zinc Reagents with Aryl
I
Pri
CO2Me
Pri
1 mol% Pd(dba)2 1 mol% SPhos THF/1-ethylpyrrolidin-2-one, 25 oC
ZnCl
CO2Me
96%; dr 96:4
SPhos =
PCy2 MeO
OMe
I 3
Pri
H
H
OMe
1 mol% Pd(dba)2 1 mol% SPhos THF/1-ethylpyrrolidin-2-one, 25 oC 86%; dr 97:3
H
ClZn
3
H
H
Pri
H
MeO
Enantiomerically enriched secondary boronic esters are available by rhodium-catalyzed asymmetric hydroboration of styrene derivatives with pinacolborane.[13] Palladium-catalyzed cross coupling of a chiral, nonracemic boronic ester of this type [(S)-4,4,5,5-tetramethyl-2-(1-phenylethyl)-1,3,2-dioxaborolane] with aryl iodides, using a tris(dibenzylideneacetone)dipalladium(0)/triphenylphosphine system with silver(I) oxide, proceeds with retention of configuration (Scheme 8).[14] Enantioenriched 1,1-diarylethanes such as 9 can thus be easily prepared by this protocol, although it should be noted that this type of coupling is not a stereoselective but a stereospecific one. Scheme 8
Cross Coupling of a 1-Arylethylboronic Ester with Aryl Iodides[14] 4 mol% Pd2(dba)3
Ac
99 mol% Ph3P Ag2O (1.5 equiv)
O
O B
THF, 70 oC
+
Ac
I
63%; 92% stereoretention
Ph 88% ee
Ph 9
3-Phenylbut-1-ene (4, Ar1 = Ph); Typical Procedure:[7]
A 100-mL, pressure-glass tube containing anhyd NiCl2 (13 mg, 0.10 mmol) and ligand 1 (44 mg, 0.10 mmol) was filled with argon after evacuation and cooling at –78 8C. To this system were added vinyl bromide (2.14 g, 20 mmol) using a precooled syringe and 1.5 M (1-phenylethyl)magnesium chloride in Et2O (27 mL, 40 mmol). The glass tube was stopped Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Cross Coupling
and allowed to warm to 0 8C. The mixture was left to stand at 0 8C for 24 h and then hydrolyzed with 10% HCl (20 mL). The organic layer and ethereal extracts from the aqueous layer were combined, washed with sat. NaHCO3 soln and H2O, and then dried (Na2SO4). After removal of the solvent, distillation through a short Vigreux column under reduced pressure (65 8C/20 Torr) gave the product; yield: 2.43 g [92% (>95% yield by GC)]. The product was further purified by preparative GC (Silicone DC 550).
Æ-Substituted Allylic Silanes 5; General Procedure:[11] The following reaction was carried out under a dry N2 atmosphere. To a mixture of the alkenyl bromide (40 mmol) and the complex obtained from PdCl2/ligand 1 (0.20 mmol) was added a 0.6–1.0 M soln of [phenyl(trimethylsilyl)methyl]magnesium bromide in Et2O (80 mmol) at –78 8C. The mixture was stirred at the reported temperature for 2–5 d and then hydrolyzed with 10% HCl at 0 8C. The organic layer and the Et2O extracts from the aqueous layer were combined, washed with sat. NaHCO3 soln and H2O, and dried (MgSO4). The solvent was removed and the crude product was isolated by distillation. Further purification was carried out by preparative GC or preparative MPLC. 1-Aryl-2-isopropyl-5-methylcyclohexanes 6; General Procedure:[12]
A dry, argon-flushed, 10-mL Schlenk tube, equipped with a magnetic stirrer bar and a septum, was charged with a 1.0 M soln of ZnCl2 in THF (1.2 mL, 1.2 mmol) and 1-ethylpyrrolidin-2-one (1.2 mL, 10 vol%). A soln of the Grignard reagent (1.0 mmol) in THF (1.6 mL) was added at 25 8C, and the mixture was stirred for 10 min. In a second dry, argon-flushed, 10-mL Schlenk flask, a soln of Pd(dba)2 (5.75 mg, 0.01 mmol), 2-(dicyclohexylphosphino)2¢,6¢-dimethoxybiphenyl (SPhos; 4.11 mg, 0.01 mmol), and 4-iodoanisole (0.164 g, 0.7 mmol) in THF (0.7 mL) was stirred for 5 min, and the organozinc reagent was added. The reaction progress was monitored by GC analysis, and then the mixture was quenched with sat. aq NH4Cl (2 mL) and H2O (2 mL). The phases were separated and the aqueous phase was extracted with Et2O (3 10 mL). The combined organic layers were dried (Na2SO4) and the solvents were removed. The crude residue was purified via column chromatography (silica gel, pentane/Et2O 40:1). 1-Alkyl-3-arylcyclohexanes 7 and 1-Alkyl-4-arylcyclohexanes 8; General Procedure:[12]
A dry, argon-flushed, 10-mL Schlenk tube, equipped with a magnetic stirrer bar and a septum, was charged with a soln of ZnCl2 (1.2 mmol) in THF (1.2 mL) and 1-ethylpyrrolidin-2one (0.12 mL, 10 vol%). A 0.70 M soln of the Grignard reagent (1.0 mmol) in THF (1.43 mL) was added at 25 8C, and the mixture was stirred for 10 min. In a second dry, argon-flushed, 10-mL Schlenk flask a soln of PdCl2(tmpp)2 (25 mg, 0.02 mmol) and the aryl iodide (0.7 mmol) in THF (0.7 mL) was prepared and cooled to –10 8C. The organozinc reagent was subsequently added slowly, the progress of the reaction was monitored by GC analysis, and the mixture was quenched with sat. aq NH4Cl (2 mL) and H2O (2 mL). The phases were separated and the aqueous phase extracted with Et2O (3 10 mL). The combined organic layers were dried (Na2SO4) and the solvents were removed. The crude residue was purified via column chromatography (silica gel, pentane/Et2O 30:1) to give the product. (S)-1-[4-(1-Phenylethyl)phenyl]ethanone (9); Typical Procedure:[14]
4-Iodoacetophenone (24.6 mg, 0.100 mmol), (S)-4,4,5,5-tetramethyl-2-(1-phenylethyl)1,3,2-dioxaborolane (34.1 mg, 0.147 mmol), Ag2O (35.4 mg, 0.152 mmol), Pd2(dba)3 (3.69 mg, 0.0040 mmol, 8.1 mol% Pd), and Ph3P (26.0 mg, 0.099 mmol) were taken up in THF (1.9 g) under an inert atmosphere. The system was sealed, the mixture was stirred at 70 8C for 24 h, and then the product was isolated by column chromatography (hexanes/ EtOAc 20:1 to 10:1 gradient); yield: 63%. The enantiomeric ratio was determined by analysis using supercritical fluid chromatography (SFC) (AD-H column, 5% MeOH, 2 mL, 20 MPa). Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.14.1
Reaction of Organometallic Reagents with Secondary Organic Halides
The transition-metal-catalyzed cross coupling of alkyl halides that have -hydrogen atoms is significantly more difficult than with aryl and alkenyl halides, since the organometallic intermediate prepared upon oxidative addition into the aliphatic carbon—halogen bonds is prone to -hydride elimination. The ability to accomplish this challenging cross coupling has been the subject of extensive studies, from which several catalysts that tolerate alkyl halides as electrophiles are now available.[15–17] Indeed, this approach has been applied to asymmetric catalysis in the context of the nickel-catalyzed cross coupling of racemic secondary alkyl halides, which provides a convenient approach to the enantioselective construction of tertiary carbon stereogenic centers.[18] For example, the cross coupling of racemic, secondary Æ-bromo amides with alkylzinc reagents proceeds smoothly in 1,3-dimethylimidazolidin-2-one (DMI) at 0 8C, in the presence of the catalyst obtained from nickel(II) chloride–1,2-dimethoxyethane complex and ligand 10, to afford the Æ-alkylated amides 11 in good yield and with high to excellent enantiomeric excess (Scheme 9).[19] It is noteworthy that Æ-bromo amides are much more reactive than primary and secondary alkyl bromides (as exemplified by 1-bromooctane and bromocyclooctane). Moreover, the reaction is tolerant of a variety of functional groups, namely acetals, imides, nitriles, and alkenes. Furthermore, this work represents the first demonstration of enantioselective cross coupling of racemic secondary alkyl halides (see also Section 3.15.2.4.5). Scheme 9 Cross Coupling of Racemic Secondary Æ-Bromo Amides with Alkylzinc Reagents[19] 10 mol% NiCl2•DME
O
N
N Pri
O Bn
R1
N Ph
+
O
N
13 mol%
10
DMI/THF, 0 oC
R2ZnX
Pri
O Bn
R1
N R2
Ph
Br
11
R1
R2
Me
X ee (%) Yield (%) Ref O
3
Br 77
66
[19]
O
Et
(CH2)5Me
Br 96
90
[19]
Et
Me
I
91
90
[19]
Et
(CH2)2CH=CMe2
Br 95
78
[19]
Et
(CH2)5CN
Br 93
70
[19]
iBu
Me
I
78
[19]
87
Asymmetric synthesis of Æ-aryl or Æ-alkenyl esters 13 is readily accomplished by the coupling of racemic Æ-bromo esters with aryl- or alkenyl(trimethoxy)silanes using the catalyst prepared in situ from nickel(II) chloride–1,2-dimethoxyethane complex and the chiral ligand 12 (Scheme 10).[20] The reaction proceeds at room temperature in good yields and with high enantioselectivity. Interestingly, the 2,6-di-tert-butyl-4-methylphenyl ester and the silane activator tetrabutylammonium difluorotriphenylsilicate (BuN4SiPh3F2) are essential for good asymmetric induction. Reduction of the aryl ester with lithium alumiCross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Cross Coupling
num hydride and oxidative cleavage with ammonium cerium(IV) nitrate afford the hydroxymethyl and carboxylic acid derivatives, respectively, without racemization (see also Section 3.15.3.3.1). Scheme 10 Cross Coupling of Racemic Secondary Æ-Bromo Esters with Organosilicon Reagents[20] 10 mol% NiCl2•DME Ph
Ph
12 mol% MeHN
NHMe 12
But
O R1
O
+
R2Si(OMe)
Bu4N+ −SiPh3F2 (2.0 equiv) dioxane, rt 3
Br But But
O R1
O R2 But 13
R1
R2
ee (%) Yield (%) Ref
Me
Ph
89
84
[20]
iBu
Ph
93
64
[20]
(CH2)2CO2Me
Ph
92
80
[20]
CH2CH=CH2
Ph
80
78
[20]
Bn
Ph
84
72
[20]
Et
4-Tol
92
76
[20]
Bu
CH=CH2
93
66
[20]
Bu
(E)-CH=CHPh
92
72
[20]
The stereospecific sp3–sp3 coupling of optically active Æ-(trifluoromethylsulfonyloxy) esters with Grignard reagents is smoothly catalyzed by zinc(II) chloride (5–20 mol%) in tetrahydrofuran at 0 8C. The reaction proceeds with complete inversion of configuration, affording the enantiomerically enriched Æ-branched esters 14.[21] Various primary and secondary organomagnesium chlorides are applicable to this transformation, as outlined in Scheme 11. Interestingly, butylmagnesium bromide affords the desired products in low yield and systems free of magnesium salts are ineffective, illustrating the importance of the magnesium salts for this type of cross coupling. Scheme 11 Enantiospecific Cross Coupling of Optically Active Æ-(Trifluoromethylsulfonyloxy) Esters with Grignard Reagents[21] O ButO
O
5 mol% ZnCl2
R1
+
2
R MgCl
THF, 0 oC
R1
ButO R2
OTf 14
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Asymmetric Synthesis of Tertiary Carbon Centers
R1
R2
Bu
Me
99
92
[21]
Me
Bu
>99
>99
[21]
Bn
iPr
98
84
[21]
(S)-s-Bu
Bu
99
>99
[21]
CH2OBn
Et
97
95
[21]
99
74
[21]
ee (%) Yield (%) Ref
CH2CO2t-Bu Me
The nickel-catalyzed cross coupling of racemic Æ-bromo ketones with arylzinc reagents, using the chiral complex derived from nickel(II) chloride–1,2-dimethoxyethane complex and the chiral ligand 15, affords the corresponding Æ-aryl ketones 16 in high yields and with excellent enantioselectivities (Scheme 12).[22] The ability to affect this cross-coupling reaction without any racemization of the tertiary stereogenic center formed in the Æ-aryl ketone is particularly impressive and synthetically useful (see also Section 3.15.3.3.2). Scheme 12 Cross Coupling of Racemic Secondary Æ-Bromo Ketones with Arylzinc Reagents[22] 5 mol% NiCl2•DME O 6.5 mol%
O
N
Ph
Ph N
N MeO
OMe 15
O R1 +
Ar1
O
DME/THF, −30 oC
Ar2ZnI
R1
Ar1 Ar2
Br
16
R1
Ar1
Ar2
ee (%) Yield (%) Ref
Me
Ph
Ph
96
86
[22]
Me
Ph
4-MeOC6H4
96
93
[22]
(CH2)2Cl
Ph
Ph
92
90
[22]
Me
4-MeOC6H4
Ph
96
90
[22]
Me
4-F3CC6H4
Ph
87
76
[22]
Me
2-thienyl
Ph
96
81
[22]
Grignard reagents have also proved to be suitable coupling partners for the asymmetric nickel-catalyzed coupling of racemic Æ-bromo ketones to give Æ-aryl ketones 18 with high enantiocontrol (Scheme 13).[23] In this system, the optimal chiral ligand is the bis(4,5-dihydrooxazole) 17, and the reaction is conducted at –60 8C to afford the enantiomerically enriched Æ-aryl ketone without racemization (see also Section 3.15.3.3.3). Various functionalized Æ-aryl ketones are prepared using the protocol developed by Knochel for the generation of functionalized Grignard reagents.[24,25] The coupling of Æ-brominated dialkyl ketones requires a higher reaction temperature (–40 8C) and a different bis(4,5-dihydrooxazole) ligand to accomplish the asymmetric synthesis of Æ-arylated dialkyl ketones.
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Cross Coupling
Scheme 13 Cross Coupling of Racemic Secondary Æ-Bromo Ketones with Arylmagnesium Reagents[23] 7 mol% NiCl2•DME O
O
9 mol% N
O Ar
N
Ph
Ph
O
17
R1 +
1
DME, −60 C o
Ar2MgX
R1
Ar1
Ar2
Br 18
R1
Ar1
Ar2
ee (%) Yield (%) Ref
Me
Ph
3-BrC6H4
93
76
[23]
Me
Ph
4-EtO2CC6H4
95
91
[23]
Me
Ph
4-IC6H4
94
83
[23]
(CH2)2OAc
Ph
Ph
85
74
[23]
Me
3-MeOC6H4
Ph
92
81
[23]
Me
2-thienyl
Ph
87
91
[23]
Alkenylation of Æ-bromo ketones to give Æ-alkenyl ketones 20 is also possible using alkenylzirconium reagents with the chiral catalyst derived from nickel(II) chloride–1,2-dimethoxyethane complex and the chiral ligand 19 (Scheme 14).[26] The enantioselective alkenylation of Æ-bromo alkyl aryl and dialkyl ketones provides ,ª-unsaturated ketones without racemization of the Æ-carbon stereogenic center or isomerization to the Æ,-unsaturated ketone under these reaction conditions (see also Section 3.15.4.2.3). At present, the scope of the alkenylzirconium reagents is limited to those prepared by hydrozirconation of terminal alkynes using the Schwartz reagent [Zr(Cp)2ClH]. Scheme 14 Cross Coupling of Racemic Secondary Æ-Bromo Ketones with Alkenylzirconium Reagents[26] 3 mol% NiCl2•DME O
O
3.6 mol% N
O
Ph
Cl(Cp)2Zr
O
Ph
R2
19 DME/THF, 10 oC
R2 +
R1
N
R1
R3
Br
R3 20
R1
R2
R3
ee (%) Yield (%) Ref
Ph
Me
H
90
92
[26]
Ph
Me
Ph
91
89
[26]
Ph
Et
(CH2)4Cl
92
83
[26]
4-BrC6H4
Me
(CH2)3CN 90
74
[26]
2-thienyl
Me
CH2Cy
94
85
[26]
Et
Me
Bn
90
86
[26]
iPr
Et
Bn
98
82
[26]
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Asymmetric Synthesis of Tertiary Carbon Centers
Racemic 1-bromoindanes and related 1-bromo-1,2-dihydroacenaphthylenes react with alkylzinc reagents in the presence of nickel(II) bromide–diglyme complex and ligand 21 in dimethylacetamide at 0 8C to afford the 1-alkylindane derivatives 22 in good yields and with excellent enantioselectivity (91–99% ee) (Scheme 15).[27] The acyclic secondary benzylic bromides also undergo asymmetric alkylation, albeit with lower enantioselectivity. Alternatively, the alkynylation of benzyl bromides with trialkynylindium reagents proceeds with the same chiral catalyst at room temperature in moderate yield and with excellent enantioselectivity for a range of alkynyl groups.[28] Scheme 15 Cross Coupling of Racemic 1-Bromoindanes and Related Systems with Alkylzinc Reagents[27] 10 mol% NiBr2•diglyme
O
N
N
Br
Pri
+
DMA, 0
R3ZnBr
R3
Pri 21
R1
O
N
13 mol%
oC
R2
R1 R2 22
R1
R2
R3
ee (%) Yield (%) Ref
Me
H
(CH2)5Me
96
89
[27]
H
CN
(CH2)6Cl
91
47
[27]
H
H
(CH2)3CN
91
64
[27]
H
Cl
91
82
[27]
98
76
[27]
O O
(CH=CH)2 (CH2)3Ph
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Stereoselective Synthesis
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Cross Coupling
10 mol% NiBr2•diglyme
O
N
N Pri
Pri 21
Br R1
O
N
13 mol%
R3
o
R2
+
DMA, 0 C
R3ZnBr
R1
R2
R1
R3
ee (%) Yield (%) Ref
Bu
98
72
[27]
CH2Cy
96
39
[27]
Et
92
56
[27]
(CH2)3OBn
75
63
[27]
R2
O
4-Tol
Me
Alternatively, unactivated secondary halides undergo facile nickel-catalyzed cross coupling with organoboron reagents (Scheme 16).[29] For example, treatment of 1-aryl-2-bromoalkanes with 9-borabicyclo[3.3.1]nonyl-substituted alkanes, using the chiral complex derived from bis(cyclooctadiene)nickel(0) and the chiral diamine ligand 23, together with potassium tert-butoxide, affords the coupled alkanes 24 in good yield and with high enantioselectivity. The ability of the chiral nickel catalyst to discriminate between the arylmethyl group (CH2Ar1) and the alkyl group (R1) is particularly impressive given the level of asymmetric induction. A related coupling with Æ-chloro amides can be found in Section 3.15.3.3.4. Scheme 16 Cross Coupling of Racemic Unactivated Secondary Halides with Organoboron Reagents[29] 10 mol% Ni(cod)2 F3C
CF3
12 mol%
R1 +
Ar1
9-BBN R2
MeHN NHMe 23 t-BuOK (1.2 equiv), t-BuOH (2 equiv) iPr2O, 5 oC or rt
R1
Ar1 R2
Br
24
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3.14.1
581
Asymmetric Synthesis of Tertiary Carbon Centers
Ar1
R1
R2
ee (%) Yield (%) Ref
Ph
Me
(CH2)3Ph
90
78
[29]
Ph
Bu
(CH2)3Ph
94
84
[29]
Ph
iPr
(CH2)3Ph
88
74
[29]
4-MeOC6H4
Me
(CH2)3Ph
90
84
[29]
2-Tol
Me
(CH2)3Ph
86
86
[29]
Et
3,4-(MeO)2C6H3(CH2)3
85
74
[29]
O O
Asymmetric arylation of racemic secondary propargylic bromides with arylzinc reagents, to give propargylarenes 26, has been accomplished with a chiral catalyst derived from nickel(II) chloride–1,2-dimethoxyethane complex and the chiral ligand 25 (Scheme 17).[30] The preparation of the aryl(ethyl)zinc reagents by transmetalation of arylboronic acids with diethylzinc in 1,2-dimethoxyethane is critical for obtaining good yields and excellent asymmetric induction. The process is tolerant of a variety of common functional groups, namely acetals, alkoxycarbonyls, ethers, alkenes, and silyl groups. Scheme 17 Cross Coupling of Racemic Secondary Propargylic Bromides with Arylzinc Reagents[30] 3 mol% NiCl2•DME H
O
3.9 mol%
O
N
H
N
N H
H 25
R1 Br + Ar1ZnEt
R1
DME, −20 oC
Ar1
R2
R2 26
R1
R2
Ar1
ee (%) Yield (%) Ref
t-Bu (CH2)4Cl
4-Tol
92
81
[30]
Ph
Et
Ph
89
83
[30]
TMS Bu
Ph
92
90
[30]
TMS (CH2)4CO2Et
4-(t-BuOCH2)C6H4
94
76
[30]
93
71
[30]
88
81
[30]
TMS iBu
O O O
Me
Et O
The nickel-catalyzed asymmetric coupling of secondary allylic chlorides with alkylzinc reagents has also been developed.[31] The details of this type of cross coupling are discussed in Section 3.9, which deals specifically with allylic alkylation reactions. Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Cross Coupling
Æ-Branched Amides 11; General Procedure:[19] A 10-mL Schlenk flask was charged with NiCl2•DME (22.0 mg, 0.100 mmol), ligand 10 (39.2 mg, 0.130 mmol), and the Æ-bromo amide (1.00 mmol) in air (no special precautions were necessary). The flask was purged with argon for 5 min and then 1,3-dimethylimidazolidin-2-one (DMI; 2.2 mL) and THF (0.5 mL) were added. The resulting orange soln was stirred at rt for 20 min, and then the flask was placed into a 0 8C bath. The mixture was stirred for 10 min at this temperature, and then a 1.0 M soln of the organozinc reagent in DMI (1.3 mL, 1.3 mmol) was added. The resulting dark brown mixture was stirred for 12 h at 0 8C and then the excess organozinc reagent was quenched by addition of EtOH (0.5 mL). The resulting brown mixture was passed through a plug of silica gel, eluting with Et2O, to remove inorganic salts and most of the DMI. The filtrate was concentrated and the resulting orange oil was purified by flash chromatography. Æ-Branched Esters 13; General Procedure:[20] Dioxane (10 mL) was added to a mixture of ligand 12 (14.4 mg, 0.060 mmol), NiCl2•DME (11.0 mg, 0.050 mmol), and BuN4SiPh3F2 (539 mg, 1.00 mmol) in a 20-mL vial in a glovebox. The mixture was stirred for 10 min, and then the silane (0.65 mmol) and the Æ-bromo ester (0.50 mmol) were added. The mixture was stirred for 16 h and then a soln of 1 M HCl/acetone (1:1; 5 mL) was added. The mixture was stirred for 2 h and then poured into H2O (30 mL) and extracted with Et2O (2 30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography (silica gel, CH2Cl2/hexanes 1:19 to 1:4). tert-Butyl (S)-2-Methylhexanoate (14, R1 = Me; R2 = Bu); Typical Procedure:[21]
A soln of anhyd ZnCl2 (3.4 mg, 2.5 mol%) in dry THF (3 mL) at 0 8C was treated successively with MeCH(OTf )CO2t-Bu (278 mg, 1.00 mmol) and 2.0 M BuMgCl in THF (0.70 mL, 1.4 mmol, 1.4 equiv) under an argon atmosphere. The mixture was stirred for 3 h at 0 8C, diluted with pentane, and quenched by addition of sat. aq NH4Cl. The resulting mixture was extracted with pentane (3 ) and the combined organic layers were applied directly to a pad of silica gel. The filter was rinsed with pentane, the product was eluted with a mixture of pentane/Et2O (10:1), and the solvent was removed by distillation at atmospheric pressure to give the product; yield: 186 mg (>99%); >99% ee (determined by chiral-phase GC: Chiraldex G-TA column, 30 m 0.25 mm, 120 kPa He, isothermal 40 8C).
Æ-Aryl-Substituted Ketones 16; General Procedure:[22] A soln of arylmagnesium bromide (1.6 mmol, 1.6 equiv) was added to a soln of ZnI2 (510 mg, 1.6 mmol, 1.6 equiv) in THF under argon (final concentration of Ar2ZnI: 0.20 M). The mixture was stirred for 40 min at rt, with formation of a precipitate, and then cooled to –30 8C. NiCl2•DME (11.0 mg, 0.050 mmol, 0.050 equiv) and ligand 15 (29.9 mg, 0.065 mmol, 0.065 equiv) were added to an oven-dried, 50-mL flask. The flask was purged with argon and then the Æ-bromo ketone (1.0 mmol, 1.0 equiv) and DME (13.5 mL) were added in that order. The resulting mixture was stirred at rt for 20 min and then cooled to –30 8C. The suspension of Ar2ZnI (6.5 mL, 1.3 mmol, 1.3 equiv) was added dropwise over 3 min, and the mixture was stirred at –30 8C for 4 h. The reaction was then quenched with sat. NH4Cl soln (10 mL) and the mixture was diluted with Et2O (50 mL) and distilled H2O (10 mL). The organic layer was separated, washed with brine (10 mL), dried (MgSO4), and concentrated. The residue was purified by flash column chromatography to give the product. Æ-Aryl-Substituted Ketones 18; General Procedure:[23] A 20-mL vial equipped with a stirrer bar was capped with a septum and sealed with tape. The vial was purged with argon for 2 min and then DME (8 mL) was added by syringe, followed by the aryl iodide (Ar2I; 1.10 mmol). The resulting soln was cooled to –20 8C and a Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Asymmetric Synthesis of Tertiary Carbon Centers
583
2.0 M soln of iPrMgCl in Et2O (0.55 mL, 1.1 mmol) was added over 1 min. The resulting mixture was stirred at –20 8C for 1–2 h and then cooled to –60 8C. Ligand 17 (30.0 mg, 0.090 mmol) and NiCl2•DME (15.3 mg, 0.070 mmol) were added to a 4-mL vial equipped with a stirrer bar. The vial was capped with a septum, sealed with tape, and gently purged with argon for 1 min. DME (2.0 mL) was added and this catalyst soln was stirred at rt for 5 min. The Æ-bromo ketone (1.0 mmol) was then added, and the mixture was stirred at rt for 5 min before the resulting homogeneous dark pink soln was added dropwise over 3 min to the –60 8C soln of the Grignard reagent. The resulting yellow soln was stirred at –60 8C for 16–32 h before the reaction was quenched with EtOH (2 mL). The resulting mixture was filtered through a Bchner funnel containing a bed of silica gel. The silica gel was washed with Et2O (40 mL) and the combined filtrates were concentrated by rotary evaporation. The resulting residue was purified by flash chromatography.
,ª-Unsaturated Ketones 20; General Procedure:[26] Zr(Cp)2ClH (516 mg, 2.0 mmol) (CAUTION: moisture sensitive) was added to an oven-dried, 20-mL vial equipped with a magnetic stirrer bar. This vial was then closed with a screwcap containing a septum and purged with argon for 3 min. Anhyd THF (2.0 mL) was added followed by the alkyne (R3C”CH; 2.0 mmol; over 2 min). The mixture was stirred at rt for 60 min, after which time all of the white solids had been consumed and a homogeneous yellow soln was obtained. NiCl2•DME (6.6 mg, 0.030 mmol), ligand 19 (17.6 mg, 0.036 mmol), and anhyd DME (8.0 mL) were added under argon to an oven-dried, roundbottomed, 25-mL Schlenk flask equipped with a rubber septum and a magnetic stirrer bar. The pink catalyst soln was stirred for 10 min at rt and then cooled in an iPrOH bath at 10 8C. The bromo ketone (1.0 mmol) was added to the catalyst soln in one portion and then the soln of the alkenylzirconium reagent (2.0 mmol) was added over 3 min. The resulting mixture (yellow or orange) was stirred at 10 8C for 24 h and then the reaction was quenched by the addition of MeOH (2.0 mL). This soln was diluted with Et2O (20 mL) and washed with sat. aq NaHCO3 (15 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (2 15 mL). The organic fractions were combined, dried (MgSO4), and filtered through a bed of Celite. The filtrate was concentrated using a rotary evaporator and the residue was purified by flash chromatography (silica gel) to give the product. 1-Alkylindanes 22; General Procedure:[27]
A 4-mL glass vial was charged with NiBr2•diglyme (35.3 mg, 0.100 mmol), ligand 21 (39.2 mg, 0.130 mmol), and the benzylic halide (1.00 mmol) in air (no special precautions were necessary). The vial was fitted with a septum cap and purged with argon for 15 min. DMA (1.75 mL) was added and the resulting orange mixture was placed in a 0 8C bath and stirred for 15 min. A 1.6 M soln of the organozinc reagent in DMA (1.0 mL, 1.6 mmol) was added in a single portion and the resulting homogeneous brown soln was stirred at 0 8C for 24 h. The remaining organozinc reagent was then quenched by the addition of EtOH (0.3 mL), and the resulting orange soln was purified directly by flash chromatography. 2-Alkyl-1-arylalkanes 24; General Procedure:[29]
A soln of activated 9-alkyl-9-BBN (0.75 mmol) was added in a glovebox to a soln of Ni(cod)2 (13.8 mg, 0.050 mmol) and ligand 23 (22.6 mg, 0.060 mmol) in iPr2O (3.2 mL) in an 8-mL vial. The vial was capped with a septum, removed from the glovebox, and cooled to 5 8C. The alkyl bromide (0.50 mmol) was then added to this 5 8C soln, and the mixture was stirred vigorously for 18 h at 5 8C. It was then passed through a pad of silica gel (washed with hexane/Et2O 1:1), and the solvent was removed on a rotary evaporator. The resulting residue was purified by flash chromatography.
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Stereoselective Synthesis
3.14
Cross Coupling
Æ-Branched Alkynes 26; General Procedure:[30] A 4-mL vial was charged with NiCl2•DME (3.3 mg, 0.015 mmol), ligand 25 (7.7 mg, 0.020 mmol), and DME (1.3 mL) in a glovebox. The resulting soln was stirred for 10 min and then a 0.50 M soln of the arylzinc reagent in DME (2.0 mL, 1.0 mmol) was added. The vial was capped with a septum and removed from the glovebox, and the mixture was stirred for 10 min at rt, placed in a –20 8C bath, and stirred for a further 10 min. The propargylic bromide (0.50 mmol) was then added via syringe and the mixture was stirred for 14 h at –20 8C. The excess arylzinc reagent was then quenched with EtOH (0.3 mL), and the resulting mixture was passed through a short plug of silica gel (eluting with hexanes/Et2O 1:1) in order to remove inorganic salts and most of the DME. The filtrate was concentrated and the resulting oil was purified by flash chromatography. 3.14.2
Stereoselective Synthesis of Multisubstituted Alkenes
The metal-catalyzed cross coupling of alkenyl and alkyl organometallics with organic halides and alkenyl halides constitutes a convenient approach to stereodefined tri- and tetrasubstituted alkenes. The synthetic advantage of this strategy is nicely illustrated in the multicomponent coupling of 1,2-dimetallo- and 1,2-dihaloalkenes with electrophiles and organometallics, respectively. This provides a versatile approach to the stereocontrolled synthesis of multisubstituted alkenes, wherein both E- and Z-alkenes can be prepared by simply reversing the order of addition of the electrophile and/or the organometallic species. This section provides an overview of the stereoselective synthesis of multisubstituted alkenes. Selected examples are used to demonstrate the manner in which dimetalated or dihalogenated alkenes perform as key multifunctionalized coupling partners. 3.14.2.1
Reaction of gem-Dimetalated Alkenes with Organic Halides
The palladium-catalyzed cross coupling of 2-aryl-1,1-bis(pinacolatoboryl)alk-1-enes with aryl iodides occurs with the selective exchange of the boryl group cis to the alkyl (R1) group at room temperature, to afford the E-alkenylboronates 27 in good to high yields as a single geometrical isomer (Scheme 18).[32] The diborylalkenes are readily prepared by gem-diborylation of 2-aryl-1,1-dibromoalk-1-enes with bis(pinacolato)diboron [octamethyl-2,2¢-bi(1,3,2-dioxaborolane)][33,34] and the addition of tris(pinacolatoboryl)methyllithium[35] to alkyl aryl ketones. The discrimination of the two boryl groups is completely selective irrespective of the alkyl group and the process is tolerant of an array of functionality, including alkoxycarbonyl, alkoxy, amino, fluoro, and trifluoromethyl groups. Scheme 18 Cross Coupling of 2-Aryl-1,1-bis(pinacolatoboryl)alk-1-enes with Aryl Iodides[32]
O Ar1
B O +
R1
Ar2I
5 mol% Pd2(dba)3 20 mol% t-Bu3P 3 M aq KOH THF, rt
O Ar1 R1
B O O
R1
Ar1
B O Ar2 27
Ar2
Yield (%) Ref
Me Ph
4-MeOC6H4
70
[32]
Et
Ph
Ph
83
[32]
Et
Ph
4-Tol
87
[32]
Et
Ph
2-Tol
78
[32]
Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis of Multisubstituted Alkenes
R1
Ar1
Ar2
Yield (%) Ref
Et
4-Tol
4-FC6H4
67
[32]
Et
4-F3CC6H4
4-FC6H4
66
[32]
iPr
Ph
4-MeOC6H4
71
[32]
Ph
72
[32]
CF3 Ph
The E-alkenylboronates prepared from the first coupling may react further with a second aryl iodide, upon heating at 60 8C, to furnish the 1,1,2-triarylalk-1-enes 28 (which constitute a class of nonsteroidal anti-estrogens) (Scheme 19).[32] Both the E- and Z-isomers of tamoxifen can be prepared through this twofold coupling sequence, the latter of which is used clinically for breast cancer treatment. Both reactions can be accomplished in a onepot process, further illustrating the synthetic utility of this strategy. Scheme 19
Stereoselective Preparation of 1,1,2-Triarylalk-1-enes[32]
5 mol% Pd[P(t-Bu)3]2
O Ph
B O +
Et
Ar2I
3 M aq NaOH (1 equiv) THF, 60 oC
Ar2
Ph
Ar1
Ar1
Et 28
Ar1
Ar2
Yield (%) Ref
Ph
4-[Me2N(CH2)2O]C6H4
59
[32]
4-FC6H4
4-MeOC6H4
75
[32]
4-MeOC6H4
4-F3CC6H4
78
[32]
4-[Me2N(CH2)2O]C6H4
Ph
75
[32]
4-MeOC6H4
4-Tol
89
[32]
4-Tol
Ph
89
[32]
The stereoselective coupling of alkenyl- and aryl-substituted diborylethenes with aryl iodides has also been demonstrated.[36] The reaction again occurs selectively at the boryl group cis to the alkenyl group, as illustrated in Scheme 20. Further coupling of the dienylboronate with 2-phenyl-1-iodoethene gives (1E,3E,5E)-1,3,4,6-tetraphenylhexa-1,3,5-triene (29) with a high degree of geometrical selectivity [ratio (1E,3E,5E)/(1E,3Z,5E) 96:4]. The triene in chloroform does not exhibit detectable fluorescence upon ultraviolet irradiation, whereas in powder form it emits fluorescence in the blue region (459 nm) with a solid-state quantum yield of 0.25. This phenomenon is called aggregation-induced emission (AIE). Since substituted (1E,3E,5E)-1,3,4,6-tetraarylhexa-1,3,5-trienes also serve as AIEactive chromophores, the present synthesis is useful for the exploration and development of new light-emitting materials based on the hexatriene structure.[37]
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586
Stereoselective Synthesis Scheme 20 triene[36]
3.14
Stereoselective Synthesis of a (1E,3E,5E)-1,3,4,6-Tetraphenylhexa-1,3,5-
PhI (1.1 equiv) 5 mol% Pd(PPh3)4 3 M aq KOH (3 equiv) THF, rt
O Ph
Ph
Cross Coupling
B O B O O
O Ph
76% (single diastereomer)
B O Ph
Ph
I (1.5 equiv) Ph 8 mol% Pd[P(t-Bu)3]2
Ph
3 M aq KOH THF, 60 oC
Ph 98%
Ph Ph 29
(E)-2-(1,2-Diphenylbut-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27, R1 = Et; Ar1 = Ar2 = Ph); Typical Procedure:[32]
A mixture of the diborylalkene (R1 = Et; Ar1 = Ph; 38 mg, 0.10 mmol), iodobenzene (21 mg, 0.10 mmol), Pd2(dba)3 (4.6 mg, 5.0 mol), t-Bu3P (4.0 mg, 0.020 mmol), and 3 M aq KOH (0.10 mL, 0.30 mmol) in THF (1 mL) was stirred at rt for 5 h before quenching with sat. aq NH4Cl (1 mL). The resulting mixture was diluted with Et2O (10 mL) and washed with H2O (3 mL). The organic layer was separated, dried (MgSO4), and concentrated under reduced pressure. The crude product was purified by preparative TLC (hexane/EtOAc 10:1) to give the product as a colorless oil; yield: 27 mg (83%). (E)-1,2-Diphenyl-1-(4-tolyl)but-1-ene (28, Ar1 = 4-Tol; Ar2 = Ph); Typical Procedure:[32]
A mixture of the monoboryl alkene (Ar1 = 4-Tol; 18 mg, 0.054 mmol), iodobenzene (17 mg, 0.081 mmol), Pd[P(t-Bu)3]2 (1.4 mg, 2.7 mol), and 3 M aq NaOH (0.054 mL, 0.16 mmol) in THF (1 mL) was stirred at 60 8C for 24 h before quenching with sat. aq NH4Cl (1 mL). The resulting mixture was diluted with Et2O (10 mL) and washed with H2O (3 mL). The organic layer was separated, dried (MgSO4), and concentrated under reduced pressure. The crude residue was purified by column chromatography (hexane/EtOAc 10:1) to give the product as a colorless solid; yield: 14 mg (89%). (1E,3E,5E)-1,3,4,6-Tetraphenylhexa-1,3,5-triene (29); Typical Procedure:[36]
A soln of (1E,3E)-2,4-diphenyl-1,1-bis(pinacolatoboryl)buta-1,3-diene (0.10 g, 0.22 mmol), iodobenzene (47 mg, 0.23 mmol), Pd(PPh3)4 (13 mg, 0.011 mmol), and 3 M aq KOH (0.22 mL, 0.65 mmol) in THF (5 mL) was stirred at rt for 8 h before quenching with sat. aq NH4Cl (20 mL). The aqueous layer was extracted with EtOAc (3 20 mL), washed with sat. aq NaCl (20 mL), and dried (MgSO4). Removal of the organic solvents under reduced pressure followed by preparative TLC (hexane/EtOAc 10:1) gave the monocoupled product as a colorless solid; yield: 72 mg (76%). A soln of the monocoupled product (10 mg, 0.023 mmol), (E)-PhCH=CHI (8.0 mg, 0.035 mmol), Pd[P(t-Bu)3]2 (1.0 mg, 1.8 mmol, 8 mol%) and 3 M aq KOH (23 mL, 0.069 mmol) in THF (1 mL) was stirred at 60 8C for 12 h before quenching with sat. aq NH4Cl (10 mL). The aqueous layer was extracted with EtOAc (3 10 mL), and the organic extracts were washed with sat. aq NaCl (10 mL). The organic layer was separated, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/EtOAc 10:1) to give the product as a pale yellow solid; yield: 8.5 mg (98%); Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.14.2
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Stereoselective Synthesis of Multisubstituted Alkenes
ratio of isomers (1E,3E,5E)/(1E,3Z,5E) 96:4. The 1E,3E,5E-isomer could be obtained by recrystallization (hexane); mp 173.1 8C. 3.14.2.2
Reaction of gem-Dihalogenated Alkenes with Organometallic Reagents
Transition-metal-catalyzed cross coupling of 2-substituted 1,1-dibromo- and 1,1-dichloroalkenes provides one of the most versatile methods for the preparation of trisubstituted alkenes.[38] The dibromides and dichlorides are readily available via classical Wittig-type alkenation of the corresponding aldehydes with carbon tetrabromide and carbon tetrachloride, respectively. The cross coupling generally replaces the less hindered halogen to furnish the monocoupled product as a single geometrical isomer in a highly regioselective manner, albeit with some of the bis-coupled product. Coupling with a second organometallic reagent affords the trisubstituted alkene in a highly stereoselective manner. This strategy provides access to both the E- and Z-isomer of the trisubstituted alkene by arbitrarily reversing the order of addition of the organometallic reagents. Furthermore, the onepot, twofold coupling provides a very convenient protocol for the construction of this challenging motif, which is applicable to a variety of organometallic reagents, such as aryl, alkenyl, alkynyl, and alkylmetals. The first reported stereoselective coupling of dihaloalkenes used arylmagnesium and arylzinc reagents in the presence of a palladium catalyst [PdCl2(dppb)] to give the substituted alkenes 30 as outlined in Scheme 21.[39,40] The nature of the ligand is essential for the success of this process, since monocoupling is selective with the catalyst containing a bidentate ligand [PdCl2(dppb)], whereas the catalyst containing monodentate ligands [PdCl2(PPh3)2] furnishes the bis-coupled alkene as the major product. Arylstannanes may also be used but require the palladium catalyst derived from tris(dibenzylideneacetone)dipalladium and tri-2-furylphosphine [Pd2(dba)3/tri-2-furylphosphine] for optimal coupling,[41] whereas arylzinc reagents are efficiently catalyzed by an alternative system {PdCl2(DPEphos); DPEphos = bis[2-(diphenylphosphino)phenyl] ether} at room temperature.[42] Scheme 21 R1
Cross Coupling of 1,1-Dihaloalk-1-enes with Arylmetal Reagents[39,41,42]
X +
R1
catalyst
Ar1M
X Ar1
X 30
R1
X
Ar1
Ph
Cl Ph
M
Catalyst (mol%)
Conditions
Yield (%) Ref
MgBr
PdCl2(dppb) (1)
Et2O, reflux
98a
[39]
a
Ph
Cl Ph
ZnCl
PdCl2(dppb) (1)
Et2O, reflux
94
[39]
Ph
Cl 2-thienyl
MgBr
PdCl2(dppb) (1)
Et2O, reflux
80
[39]
2-thienyl
Cl Ph
MgBr
PdCl2(dppb) (1)
Et2O, reflux
76
[39]
Cl
Cl 4-ClC6H4
MgBr
PdCl2(dppb) (1)
Et2O, reflux
90
[39]
4-MeO2CC6H4
Br 2-furyl
SnBu3
Pd2(dba)3 (2.5), (2-furyl)3P (15)
toluene, 100 8C 80
[41]
2-NCC6H4
Br Ph
SnMe3 Pd2(dba)3 (2.5), (2-furyl)3P (15)
toluene, 100 8C 97
[41]
(CH2)5Me
Br Ph
ZnBr
PdCl2(DPEphos) (5) THF, 23 8C
94
[42]
(S)-s-Bu
Br 2-thienyl
ZnBr
PdCl2(DPEphos) (5) THF, 23 8C
91
[42]
TMS
Cl Ph
ZnBr
PdCl2(DPEphos) (5) THF, 23 8C
90
[42]
a
Yield determined by GC.
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Stereoselective Synthesis
3.14
Cross Coupling
Alkenylzinc reagents couple with 1,1-dibromoalk-1-enes in the presence of tetrakis(triphenylphosphine)palladium(0) to afford a variety of 2-bromo-1,3-dienes 31 in good to high yield and with excellent selectivity [(E,E) >98%] as illustrated in Scheme 22.[43,44] The bromodienes are important substrates for the asymmetric synthesis of axially chiral allenes via palladium-catalyzed coupling with malonate derivatives (see Section 3.14.4.2). Cross Coupling of 1,1-Dibromoalk-1-enes with Alkenylzinc Reagents[43,44]
Scheme 22 R1
Br
R1
R2
M
Br R2
catalyst
+ R3
Br
R3 31
R1
R2
R3
M
Ph
H
H
Ph
H
Ph
Catalyst (mol%)
Conditions
Yield (%)
Ref
ZnCl Pd(PPh3)4 (1.6)
THF, rt
84
[43]
(CH2)5Me
ZnBr Pd(PPh3)4 (5)
THF, 23 8C
63
[44]
H
C”CTMS
ZnBr Pd(PPh3)4 (5)
THF, 45 8C
86
[44]
(R)-CH(Me)CH2OTBDMS
H
Bu
ZnBr Pd(PPh3)4 (5)
THF, 45 8C
90
[44]
(R)-CH(Me)CH2OTBDMS
Bu
H
ZnBr Pd(PPh3)4 (5)
THF, 45 8C
72
[44]
(CH2)5Me
H
C”CTMS
ZnBr Pd(PPh3)4 (5)
THF, 45 8C
87
[44]
C”CTMS
H
Bu
ZnBr Pd(PPh3)4 (5)
THF, 45 8C
90
[44]
Although the palladium-catalyzed cross coupling of the bromodienes with organozinc reagents is a relatively smooth and efficient process, the stereochemical outcome is dependent upon the ligand used, as illustrated in Scheme 23. For example, the coupling may proceed with retention of configuration to give dienes 32A with certain catalysts {Pd[P(t-Bu)3]2 and Pd(dba)2/NHC},[44] whereas inversion to give dienes 32B is observed with others {Pd(PPh3)4, PdCl2(PPh3)2, PdCl2[P(2-furyl)3]2, PdCl2(dppf ), or PdCl2(DPEphos), particularly when R1 = alkyl and R2 = H}.[45] To account for this dichotomy, it is assumed that the inversion reaction proceeds via thermodynamically favorable alkenylidene-substituted -allylpalladium intermediates 33 (where R1CH= is E,syn) due to steric repulsion. Scheme 23 Cross Coupling of 2-Bromo-1,3-dienes with Organozinc Reagents[44,45]
R5
retention R5M catalyst THF, 23 oC
R4
R1
R3
Br
R3 R2
THF, 50 oC
R1
R3 R2
R2 32A
inversion R5M catalyst
R4
R1
R1
= alkyl
32B
>98% diastereomerically pure
>98% ds
R4 R5 >98% ds
R1
R2 R3
R4
R5
M
(R)-CH(Me)CH2OTBDMS
H Bu
H
Me
MeZn Pd[P(t-Bu)3]2 (2)
(R)-CH(Me)CH2OTBDMS
H Bu
H
Bu
ZnBr
C”CTMS
H Bu
H
Me
MeZn Pd[P(t-Bu)3]2 (2)
Ph
H Bu
H
Me
MeZn Pd[P(t-Bu)3]2 (2)
Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
Catalysta (mol%) Product Yield Ref (%) 32A
93
[44]
Pd2(dba)3 (5), 32A NHC (5),b Cs2CO3 (10)
94
[44]
32A
95
[44]
32A
94
[44]
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Stereoselective Synthesis of Multisubstituted Alkenes
R1
R2 R3
R4
R5
M
Catalysta (mol%) Product Yield Ref (%)
(R)-CH(Me)CH2OTBDMS
H C”CTMS
H
Ph
ZnBr
Pd[P(t-Bu)3]2 (2)
32A
91
[44]
Ph
H C”CTMS
H
Me
MeZn Pd[P(t-Bu)3]2 (2)
32A
94
[44]
(R)-CH(Me)CH2OTBDMS
Et Et
H
Me
MeZn Pd[P(t-Bu)3]2 (2)
32A
87
[44]
(R)-CH(Me)CH2OTBDMS
H Bu
Me
Me
MeZn Pd[P(t-Bu)3]2 (2)
32A
89
[44]
(R)-CH(Me)CH2OTBDMS
H C”CTMS
H
Me
MeZn PdCl2(DPEphos) (5)
32B
93
[45]
(R)-CH(Me)CH2OTBDMS
H C”CTMS
H
Bu
ZnBr
PdCl2(DPEphos) (5)
32B
91
[45]
(R)-CH(Me)CH2OTBDMS
H C”CTMS
H
Ph
ZnBr
PdCl2(DPEphos) (5)
32B
92
[45]
(R)-CH(Me)CH2OTBDMS
H C”CTMS
H
CH=CH2
ZnBr
PdCl2(DPEphos) (5)
32B
96
[45]
(R)-CH(Me)CH2OTBDMS
H C”CTMS
H
C”CH
ZnBr
PdCl2(DPEphos) (5)
32B
96
[45]
(R)-CH(Me)CH2OTBDMS
H Bu
H
Me
ZnBr
PdCl2(DPEphos) (5)
32B
85
[45]
(CH2)5Me
H CH2OTBDMS
H
Me
MeZn PdCl2(DPEphos) (5)
32B
88
[45]
(R)-s-Bu
H Ph
H
Me
MeZn PdCl2(DPEphos) (5)
32B
87
[45]
(R)-CH(Me)CH2OTBDMS
H H
Bu
Me
MeZn PdCl2(DPEphos) (5)
32B
92c
[45]
a b c
DPEphos = bis[2-(diphenylphosphino)phenyl] ether. NHC = N-heterocyclic carbene. Ratio (Z,E/E,E) = 50:50.
R3 R2 R
R4 PdBrLn
1
33
Alkenylboronic acids also undergo stereoselective coupling with 1,1-dibromoalkenes, in the presence of tetrakis(triphenylphosphine)palladium(0) and aqueous thallium(I) hydroxide at room temperature, to give dienes such as 34 (Scheme 24).[46,47] The process is tolerant of an array of functional groups, such as acetals, esters, and silyl ethers. Moreover, the one-pot synthesis of trisubstituted 1,3-dienes is also feasible by the sequential coupling of alkenyl- and alkyl(trifluoro)borates with 1,1-dibromoalk-1-enes.[48]
Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
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590
Stereoselective Synthesis Scheme 24
3.14
Cross Coupling
Cross Coupling of 1,1-Dibromoalk-1-enes with Alkenylboronic Acids[46,47] Br R1
(HO)2B
Br 10 mol% Pd(PPh3)4 0.4 M aq TlOH (1.0 equiv) THF, 23 oC
OH
Br R1
OH 34
R1
Yield (%) Ref
Cy
55–61
[46]
(S)-CH(OBz)CH2CH=CH2
75–80
[46]
80
[46]
O O
Ac
The trans-selective mono-alkynylation of 1,1-dihaloalk-1-enes is achieved by palladiumcatalyzed coupling with alkynylzinc reagents or the palladium/copper-cocatalyzed reaction with terminal acetylenes (Scheme 25).[49,50] Both reactions afford the corresponding enynes 35 in high yields, albeit with variable amounts of the bis-coupled products 36 depending on the reaction conditions. Scheme 25
Cross Coupling of 1,1-Dihalo-1-alkenes with Terminal Acetylenes and Alkynylzinc Reagents[49,50] R2
R1
X
R2 catalyst
M
R1
R1
X +
X R2
R1
R2
X M
Ph
TMS
Ph
R2 36
35
Conditions
Yieldb Ref Yieldb (%) of 35 (%) of 36
Br ZnCl PdCl2(dppf ) (5)
THF, 0 8C
89
3
[49]
TMS
Br ZnCl PdCl2(DPEphos) (5)
THF, 0 8C
90 (84)
8
[49]
Ph
TMS
Br H
89
8
[49]
Ph
TMS
Cl ZnCl PdCl2(dppf ) (5)
THF, 23 8C
87 (84)
10
[49]
(CH2)8Me
TMS
Br ZnCl PdCl2(DPEphos) (5)
THF, 0 8C
94 (87)
3
[49]
(CH2)8Me
TMS
Br H
92
6
[49]
C”CTMS
TMS
Cl ZnCl PdCl2(DPEphos) (5)
91 (88)
7
[49]
C”CTMS
TMS
Cl H
84
12
[49]
(R)-CH(Me)CH2OTBDMS
SiPh3 Br ZnBr PdCl2(DPEphos) (5)
99 (99)
99:1
82
47
[69]
C(CH2OBn)=CH2
>99:1
77
76
[69]
3-Substituted But-1-enes 49; General Procedure Using an Aryl Bromide:[69]
A flask charged with potassium (E)-but-2-enyl(trifluoro)borate (2.5 mmol), Pd(OAc)2 (3 mol%), ligand 48 (3.6 mol%), and K2CO3 (3.0 mmol) was flushed with N2. H2O/MeOH (9:1; 5 mL) and the aryl bromide (1.0 mmol) were then added. The resulting mixture was stirred at 80 8C for 22 h. The crude product was purified by chromatography (silica gel). Reaction of Chiral Allylic Metals with Organic Halides
3.14.3.2
Enantiomerically enriched allylic difluoro(phenyl)silanes undergo ª-selective coupling with aryl trifluoromethanesulfonates (such as 2-naphthyl trifluoromethanesulfonate) in the presence of a palladium catalyst and a source of fluoride anion to give functionalized alkenes (such as 51, Scheme 35). Interestingly, the absolute configuration of the newly formed allylic stereogenic center is controlled by a combination of the fluoride source and the solvent.[70] For example, tris(diethylamino)sulfonium difluoro(trimethyl)silicate in dimethylformamide affords the major product with an S configuration, presumably through an anti-SE2¢ transmetalation. In contrast, when the coupling is affected with cesium fluoride in tetrahydrofuran the major product is obtained with an R configuration with 74% enantiospecificity. This process is rationalized via a syn-SE2¢ mechanism involving a ternary complex of the silicon reagent with the palladium complex (vide infra). Scheme 35 Cross Coupling of an Enantiomerically Enriched Allylic Difluoro(phenyl)silane with an Aryl Trifluoromethanesulfonate[70] TfO
∗
Et
Et F2PhSi 69% ee
51
Conditions
Enantiospecificity (%) ee (%) Yield (%) Ref
Pd(PPh3)4 (4.3 mol%), (Et2N)3SSiF2Me3 (4.0 equiv), DMF, 60 8C
91
63 (S) 64
[70]
Pd(PPh3)4 (4.3 mol%), CsF (4.0 equiv), THF, 60 8C
74
51 (R) 50
[70]
Ar1 Et H F2PhSi
F Pd Ln H
Ar1
Et
H
Ar1
PdLn
anti-SE2'
Et S
Et H Ph
Si
F F F
H H Ln Pd F Ar1 Cs
syn-SE2'
Et
Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
PdLn
Ar1
Et
Ar1
R
for references see p 613 (Customer-ID: 5907)
602
Stereoselective Synthesis
Cross Coupling
3.14
The cross coupling of an enantiomerically enriched Æ-substituted allylic silanolate [(R,Z)-form, 88% ee] with aryl bromides, catalyzed by the complex generated from an allylpalladium chloride dimer and 4,4¢-bis(trifluoromethyl)dibenzylideneacetone, affords the (E)-2-arylalk-3-enes 52 in good yield, with high E,ª-selectivity and high enantiomeric excess (Scheme 36).[71] The stereochemical outcome indicates that the coupling proceeds in a syn-SE2¢ manner. In order to account for the stereochemical course, the formation of a palladium(II) silanolate obtained from the sodium silanolate and the arylpalladium bromide, has been envisioned to occur via an intramolecular transmetalation of the allylic moiety from palladium to silicon via a six-membered, chair-like transition state (vide infra). Scheme 36 Cross Coupling of an Enantiomerically Enriched Æ-Substituted Allylic Silanolate with Aryl Bromides[71] Ar1Br, 2.5 mol% Pd2(η3-C3H5)2Cl2 O 20 mol%
F3C
Bui NaO
CF3
toluene, 70 oC
Bui
Si
Me
Me
Ar1 52
94:6 er; (Z/E) 94:6
Ar1
Selectivity of 52 ee (%) of 52 Yield (%) Ref
Ph
98
96
76
[71]
2-Tol
95
96
70
[71]
1-naphthyl
90
96
78
[71]
4-MeOC6H4 97
96
67
[71]
4-ClC6H4
96
76
[71]
92
L
Me Bui
Me
Si
O
Ar1
Pd H
H
(E)-6-Methyl-2-phenylhept-3-ene (52, Ar1 = Ph); Typical Procedure:[71]
Pd2(Å3-C3H5)2Cl2 (3.7 mg, 0.010 mmol, 0.0050 equiv) and 4,4¢-(trifluoromethyl)dibenzylideneacetone (148 mg, 0.40 mmol, 0.20 equiv) were added to a 50-mL, single-necked, round-bottomed flask containing a magnetic stirrer bar and equipped with a three-way argon inlet capped with a septum. The flask was then sequentially evacuated and filled with argon three times and bromobenzene (314 mg, 2.0 mmol) was then added by syringe. The allylic silanolate (625 mg, 3.0 mmol, 1.5 equiv), preweighed into a 10-mL two-necked, round-bottomed flask in a drybox, was then dissolved in toluene (4.0 mL) and added by syringe. The mixture was heated in a preheated oil bath to 70 8C with stirring under argon. After 24 h, the mixture was allowed to cool to rt and filtered through silica gel (2 cm 1 cm) in a glass-fritted funnel (coarse, 2 cm 5 cm), and the filter cake was washed with Et2O (3 15 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography (silica gel, 30 mm 20 cm, hexane), C-18 reverse-phase chromatography (25 mm 16 cm, MeOH/H2O 9:1 to 20:1), and Kugelrohr distillation (70 8C/0.7 Torr) to afford the product as a clear, colorless oil; yield: 288 mg (76%). Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.14.4
3.14.4
603
Asymmetric Synthesis of Optically Active Allenes
Asymmetric Synthesis of Optically Active Allenes
There are few examples of the asymmetric synthesis of axially chiral allenes based on transition-metal-catalyzed cross-coupling reactions.[72] Successful approaches to optically active allenes via cross coupling are divided into two protocols, namely the palladium-catalyzed enantiospecific reaction of optically active propargylic (pseudo)halides with organometallic reagents, and the enantioselective palladium-catalyzed coupling of achiral 2-bromo-1,3-dienes with malonates. 3.14.4.1
Reaction of Propargylic Carbonates or Sulfonates with Organometallic Reagents
Enantiomerically enriched propargylic carbonates undergo palladium-catalyzed crosscoupling with arylboronic acids using tetrakis(triphenylphosphine)palladium(0) and potassium phosphate as the catalyst and base, respectively (Scheme 37). The 1,3-disubstituted allenes 53 are formed in good yields and with excellent chirality transfer. Among the propargylic carbonates and esters that have been examined, benzyl carbonates have proven to be the optimal leaving group.[73] Scheme 37
Cross Coupling of Propargylic Carbonates with Arylboronic Acids[73] Ar1B(OH)2 10 mol% Pd(PPh3)4 K3PO4 (5.0 equiv) 1,4-dioxane/H2O (2:1), 100 oC
CbzO
R1 • Ar1
R1 53
R1
Ar1
ee (%) of Substrate
ee (%) of 53
Yield (%)
Ref
Ph
Ph
96
94
64
[73]
Ph
2-Tol
96
94
93
[73]
Ph
4-MeOC6H4
96
90
71
[73]
Ph
2-methyl-1-naphthyl
96
86
99
[73]
(CH2)4Me
2-Tol
98
83
79
[73]
Me
1-naphthyl
99
74
75
[73]
Enantiomerically enriched fluoroalkyl-containing trisubstituted allenes 54 are readily prepared with excellent chirality transfer from fluoroalkylated propargylic methanesulfonates via palladium-catalyzed cross coupling with phenylzinc(II) chloride (Scheme 38).[74]
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604
Stereoselective Synthesis
Cross Coupling
3.14
Scheme 38 Cross Coupling of Fluoroalkyl-Substituted Propargylic Methanesulfonates with Phenylzinc(II) Chloride[74] PhZnCl 5 mol% Pd(PPh3)4
MsO R
THF, rt
5
•
5
1
R
1
Ph 54
R1
ee (%) of Substrate ee (%) of 54 Yield (%) Ref
CF3
96
96
77
[74]
CF2CF3 94
96
70
[74]
(R)-1-(2-Tolyl)-3-phenylpropa-1,2-diene (53, R1 = Ph; Ar1 = 2-Tol); Typical Procedure:[73]
2-TolB(OH)2 (32.6 mg, 0.240 mmol), K3PO4 (127 mg, 0.60 mmol), and Pd(PPh3)4 (13.9 mg, 0.012 mmol) were added at rt to a stirred soln of the benzyl carbonate (32.0 mg, 0.120 mmol) in 1,4-dioxane (0.8 mL) and H2O (0.4 mL). The mixture was stirred for 4 min at 100 8C and then filtered through a small amount of silica gel and concentrated. The residue was subjected to chromatography (silica gel, hexane) to give the product as a colorless oil; yield: 23.0 mg (93%); 94% ee. 3.14.4.2
Reaction of 2-Bromo-Substituted 1,3-Dienes with Organometallic Reagents
The enantioselective construction of axially chiral allenes 59 is accomplished via a formal SN2¢-type substitution of 2-bromo-1,3-dienes with the metalated malonates and related compounds 55 using the palladium complex derived from bis(dibenzylideneacetone)palladium(0) and one of the biaryl-based chiral bisphosphine ligands 56–58 (Scheme 39).[75,76] For example, 3-bromo-1-(trimethylsilyl)penta-2,4-diene provides enantiomerically enriched allenyl(methyl)silanes 59 (R1 = CH2TMS) in 79–87% enantiomeric excess.[77] The counterion, solvent, and the presence of dibenzylideneacetone from the palladium catalyst all affect the enantioselectivity. The bromodienes are readily prepared by trans-selective cross coupling of 1,1-dibromoalk-1-enes (see Section 3.14.2.2). The enantioselective synthesis of allenes has been applied to a formal total synthesis of methyl tetradeca2,4,5-trienoate, which is a male beetle sex pheromone.[78] Scheme 39
Cross Coupling of 2-Bromo-1,3-dienes with Malonates[75–78] TMS O PPh2
PPh2
O
PPh2
PPh2
PPh2
O
PPh2
O TMS 56
57
58
R2H 55 10 mol% Pd(dba)2
R2
10 mol% ligand
R1
• Br
R1 59
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3.14.5
605
Asymmetric Synthesis of Biaryls
R1
R2
Ligand Conditions
ee (%) Yield (%)
Ref
Ph
C(NHAc)(CO2Et)2
56
t-BuOCs, CH2Cl2, 20 8C
89
75
[75]
Ph
C(NHAc)(CO2Et)2
58
t-BuOCs, CH2Cl2, 20 8C
83
60
[78]
Ph
N(Boc)2
57
KH, THF, 23 8C
77
98
[76]
t-Bu
C(NHAc)(CO2Et)2
56
t-BuOCs, CH2Cl2, 20 8C
75
74
[75]
t-Bu
C(NHAc)(CO2Et)2
57
t-BuOCs, CH2Cl2, 23 8C
85
72
[76]
t-Bu
C(NHAc)(CO2Et)2
58
t-BuOCs, THF, 60 8C
89
87
[78]
t-Bu
CMe(CO2Me)2
57
NaH, THF, 23 8C
80
82
[76]
(CH2)7Me
C(NHAc)(CO2Et)2
58
t-BuOCs, THF, 40 8C
74
63
[78]
CH2TMS
C(NHAc)(CO2Et)2
58
t-BuOCs, THF, 50 8C
87
63
[77]
CH2TMS
CMe(CO2Me)2
58
NaH, THF, 40 8C
79
57
[77]
Diethyl (R)-2-Acetamido-2-(4-phenylbuta-2,3-dienyl)malonate [59, R1 = Ph; R2 = C(NHAc)(CO2Et)2]; Typical Procedure:[75]
A mixture of Pd(dba)2 (29 mg, 50 mol), ligand 56 (34 mg, 55 mol), and (Z)-2-bromo-1phenylbuta-1,3-diene (105 mg, 0.502 mmol) was dissolved in CH2Cl2 (5 mL) and the soln was added to a mixture of malonate 55 [R2 = C(NHAc)(CO2Et)2; 120 mg, 0.552 mmol] and t-BuOCs (125 mg, 0.607 mmol) in CH2Cl2 (2 mL) by cannula under N2. The mixture was stirred at 20 8C for 24 h and then filtered through a short pad of alumina to remove precipitated inorganic salts. The alumina pad was washed with small amounts of Et2O (3 ) and the combined soln was concentrated to dryness under reduced pressure. The orange-yellow residue was subjected to chromatography (alumina, hexane/Et2O 1:4) to give the product as a pale yellow oil that crystallized slowly; yield: 130 mg (75%); 89% ee. 3.14.5
Asymmetric Synthesis of Biaryls
The ubiquity of axially chiral biaryl groups in natural products, chiral auxiliaries, and chiral ligands has prompted the development of synthetic methods for atropselective construction of axially chiral biaryls.[79] In the context of cross coupling, two options are available, the first of which involves the enantioselective or diastereoselective formation of the biaryl axis through the direct coupling of arylmetals with aryl halides, and the second option involves the desymmetrization of achiral dihalobiaryl compounds (or equivalents) with organometallic reagents. 3.14.5.1
Reaction of Arylmetals with Aryl Halides
The first asymmetric cross-coupling approach to axially chiral biaryls involved the nickelcatalyzed coupling of arylmagnesium reagents with aryl bromides, using the ferrocenylphosphine 60 as the chiral ligand (Scheme 40).[80] Monocoordination of phosphine 60 to the nickel metal center is critical for the high catalytic reactivity, in which the methoxy group in 60 is assumed to coordinate to the magnesium metal in the transmetalation step to provide high enantiocontrol. Chiral binaphthalenes 61 are obtained in good yields and with excellent enantioselectivities, albeit from only a limited number of examples. The catalyst system is also applicable to the asymmetric synthesis of axially chiral ternaphthalenes.[81]
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606
Stereoselective Synthesis
3.14
Cross Coupling
Cross Coupling of Arylmagnesium Reagents with Aryl Bromides[80]
Scheme 40
4 mol% NiBr2 MeO 8 mol%
Ph2P
Fe
Br 60 Et2O/toluene (1:1), –5 oC
+
68%; 94% ee
MgBr 61
Functionalized chiral biaryls 63 are successfully prepared in excellent yield and with good enantioselectivity through the direct coupling of ortho-substituted phenylboronic acids with 1-bromo-2-naphthyl phosphonates using the chiral complex derived from tris(dibenzylideneacetone)dipalladium and the chiral ligand 62 (Scheme 41).[82] Excess potassium phosphate (2–3 equiv) accelerates the coupling and allows lower catalyst loadings. Since the phosphonate moiety is readily converted into the corresponding phosphine (PAr12), the method serves as a convenient approach to the construction of axially chiral monodentate phosphines. Scheme 41 Cross Coupling of ortho-Substituted Arylboronic Acids with ortho-Substituted Aryl Bromides[82] Pd2(dba)3
NMe2 PCy2
Br +
O P OR2 OR2
R1 O
62 K3PO4 (2 or 3 equiv), toluene
P OR2 OR2
R1 B(OH)2 63
R1
R2
Pd2(dba)3 (mol%) Ligand 62 (mol%) Temp (8C) ee (%) Yield (%) Ref
Me
Et
4
9.6
70
87
98
[82]
Et
Et
2
4.8
70
92
96
[82]
iPr
Et
2
4.8
80
85
83
[82]
Ph
Et
3
7.2
60
74
74
[82]
Me
Me
0.2
0.48
60
86
95
[82]
Alternatively, the enantioselective cross coupling of functionalized arylboronic acids with 1-bromonaphthalenes or related aryl compounds may be accomplished in an efficient manner using the palladium complex 64 containing a bis(hydrazone) chiral ligand (Scheme 42).[83] This catalyst is extremely robust, sufficiently so that the reaction may be performed open to air. Enantioenriched biaryls 65 and 66 are obtained in high yields and with good to excellent atropselectivities.
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3.14.5
607
Asymmetric Synthesis of Biaryls
Scheme 42
Cross Coupling of ortho-Substituted Arylboronic Acids with Aryl Bromides[83] Ph
Ph N
5 mol%
Pd Cl Ph
Br
N
R1
Cl Ph
64 Cs2CO3 (2 equiv), toluene, 20 oC
R1
R2
+ R2 R3
B(OH)2
R3 65
R1
R2
R3
H
OMe H
86
97
H
Me
95
80
ee (%) Yield (%) Ref
H
[83] [83]
a
[83]
H
Me
Me
89
85
H
Me
Me
>98
53
[83]
81
98
[83]
OMe OMe H a
Reaction performed at 80 8C.
Ph
Ph N
5 mol%
N Pd
Cl Ph
Cl Ph 64
Ar1Br, Cs2CO3 (2 equiv) toluene, 20 oC
R1
R1 1
Ar
B(OH)2
66
R1
Ar1
ee (%) Yield (%) Ref
Me
OMe
Me
Ph
Ph
>98
67
[83]
84
36
[83]
84
97
[83]
The diastereoselective coupling of planar chiral bromoarene(tricarbonyl)chromium complexes with ortho-substituted arylboronic acids is accomplished with tetrakis(triphenylphosphine)palladium(0) and an aqueous solution of sodium carbonate in methanol as Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
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608
Stereoselective Synthesis
3.14
Cross Coupling
the catalyst and base, respectively (Scheme 43).[84] The syn-diastereomer, syn-67, in which the ortho substituent in the boronic acid is orientated in the same direction as the chromium atom, is the major stereoisomer when the ortho substituents in both the boronic acid and chromium complex are anything other than a formyl group. In contrast, the diastereoselectivity is reversed with formyl-substituted boronic acids and chromium complexes, because the syn-diastereomers isomerize to the thermodynamically more stable anti-stereoisomers, anti-67, under the reaction conditions. Since the chromium metal is easily removed by photooxidation, this strategy can be applied to asymmetric synthesis of axially chiral biaryls by simply using enantiomerically pure chromium complexes. Scheme 43 Cross Coupling of Planar Chiral Bromoarene(tricarbonyl)chromium Complexes with ortho-Substituted Arylboronic Acids[84] 5 mol% Pd(PPh3)4
R1 Br
+ (HO)2B R2
(OC)3Cr
2 M aq Na2CO3 (2.7 equiv) MeOH, 75 oC
OMe
R1
R1
R2
+ (OC)3Cr
OMe R2 syn-67
R1
R2
Ratio (syn/anti) Yield (%) Ref
Me
Me
100:0
96
[84]
Me
100:0
81
[84]
CH2OH
Me
100:0
77
[84]
CH2OH
OMe
94:6
90
[84]
Me
OMe
97:3
94
[84]
Me
CHO
0:100
95
[84]
CHO
0:100
52
[84]
OMe
4:96
85
[84]
(OC)3Cr
OMe anti-67
O O
O O
CHO
(R)-2,2¢-Dimethyl-1,1¢-binaphthyl (61); Typical Procedure:[80]
The following reaction was carried out under a dry N2 atmosphere. A 0.2 M soln of MeMgBr in Et2O (5 mL, 1.0 mmol) was added to a mixture of ferrocenylphosphine ligand 60 (0.34 g, 0.80 mmol), anhyd NiBr2 (87 mg, 0.40 mmol), and 2-methyl-1-bromonaphthalene (2.92 g, 13 mmol), and the mixture was refluxed for 10 min during which time the orange soln turned dark brown. (2-Methyl-1-naphthyl)magnesium bromide (10 mmol), which was an orange slurry prepared in Et2O (15 mL) and diluted with toluene (15 mL), was added at –5 8C. The mixture was stirred at –5 8C for 96 h (monitoring by GLC) and hydrolyzed with dil HCl. The organic layer and Et2O extracts from the aqueous layer were combined, washed with sat. NaHCO3 and then H2O, dried (MgSO4), and stripped of solvent under reduced pressure. The residue was subjected to chromatography (silica gel, hexane) to give the product; yield: 1.91 g (68%); 94% ee. Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.14.5
609
Asymmetric Synthesis of Biaryls
2-Naphthylphosphonates 63; General Procedure:[82]
A flame-dried, resealable Schlenk tube was charged with the aryl bromide (0.2 mmol, 1.0 equiv), arylboronic acid (0.3 mmol, 1.5 equiv), and K3PO4 (90 mg, 0.4 mmol, 2 equiv). The Schlenk tube was capped with a rubber septum and twice evacuated and backfilled with argon. A soln of Pd2(dba)3 and ligand 62 (L/Pd = 1.2) in 1/2 to 1/3 of the total amount of toluene (total: 4–6 mL per mmol of aryl bromide) was sonicated for about 30 seconds and injected into the Schlenk tube followed by addition of the rest of toluene. The septum was replaced with a Teflon screwcap, and the Schlenk tube was sealed. The mixture was stirred at the indicated temperature (40–80 8C) for the required time (17–140 h) until the starting aryl bromide had been completely consumed (as monitored by GC analysis). The mixture was then allowed to cool to rt, diluted with EtOAc, filtered, and concentrated. The crude residue was purified by flash chromatography (silica gel) or preparative TLC. 1,1¢-Binaphthalenes 65 and Biaryl Derivatives 66; General Procedure:[83]
A dried Schlenk flask containing a magnetic stirrer bar was charged with Cs2CO3 (65.2 mg, 0.2 mmol), the boronic acid (0.15 mmol), and complex 64 (0.005 mmol) under an argon atmosphere. Dry toluene (0.5 mL) and the aryl bromide (0.1 mmol) were added via syringe (solid aryl bromides were added during the initial charge), and the mixture was stirred at 20 or 80 8C until consumption of the aryl bromide was observed (as monitored by TLC). The mixture was filtered through a short pad of Celite and the pad was washed with CH2Cl2. The combined organic layers were concentrated and the resulting residue was purified by flash chromatography and/or preparative TLC (hexane or hexane/EtOAc). Arene(tricarbonyl)chromium Complexes 67; General Procedure:[84]
A mixture of the (arene)chromium complex (0.60 mmol), boronic acid (1.20 mmol), and Pd(PPh3)4 (0.03 mmol) in 2 M aq Na2CO3 (0.8 mL) and MeOH (8 mL) was degassed by three freeze/vacuum/thaw cycles and heated at 75 8C for 30 min under argon. The mixture was quenched with sat. aq NH4Cl and extracted with Et2O. The extracts were washed with aq 10% NaOH and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography (silica gel) to give the coupling product. 3.14.5.2
Reaction of Dihalobiaryls with Organometallic Reagents
The desymmetrization of 2-aryl-1,3-bis(trifluoromethylsulfonyloxy)benzenes through an enantioselective cross-coupling reaction with Grignard reagents provides a unique approach to the asymmetric construction of axially chiral biaryls. Aryl- and alkynylmagnesium reagents react with achiral 2-(1-naphthyl)-1,3-bis(trifluoromethylsulfonyloxy)benzene in the presence of the chiral catalyst 68–70, which is derived from a palladium source and a 2-aminoethylphosphine ligand to afford enantioenriched monoarylated biaryls 71 in high yield and with very good enantioselectivity (Scheme 44).[85,86] The enantioselectivity of the products is improved in parallel with the amount of the bis-coupled biaryl 72 formed, which indicates that the minor enantiomer from the first coupling couples faster in the second reaction than the major isomer. The trifluoromethylsulfonyloxy group provides a very useful handle for incorporation of other functionality, for example, by palladium-catalyzed diphenylphosphinylation, alkynylation, and arylation.
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Stereoselective Synthesis
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Cross Coupling
Scheme 44 Cross Coupling of a 2-(1-Naphthyl)-1,3-bis(trifluoromethylsulfonyloxy)benzene with Grignard Reagents[85,86] Me Bn
Me
Me Cl Pd Cl P Ph Ph
Me Cl Pd Cl P Ph Ph N
N
69
68
TfO
Me Pri
OTf
Me Cl Pd Cl P Ph Ph N
70
R1MgBr/LiBr 5 mol% catalyst Et2O/toluene (1:1)
R1
OTf
+
R1
71
R1
72
R1
Catalyst Temp (8C) ee (%) of 71 Yield (%) of 71 Yield (%) of 72 Ref
Ph
68
–30
93
87
13
[85]
3-Tol
68
–20
90
83
11
[85]
C”CSiPh3 68
20
82
89
0
[86]
C”CSiPh3 69
20
92
88
10
[86]
C”CSiPh3 70
20
86
86
7
[86]
C”CPh
20
86
84
2
[86]
69
The palladium-catalyzed differentiation of enantiotopic trifluoromethylsulfonyloxy groups has also been extended to the asymmetric synthesis of quaternary carbon stereogenic centers, as outlined in Scheme 45. The enantioselective coupling of an arylboronic acid with 2-benzyl-2-methylcyclopenta-3,5-diene-1,3-diyl bis(trifluoromethanesulfonate), using the complex generated in situ from palladium(II) acetate and the chiral ligand 73, provides the monoarylated trifluoromethanesulfonate 74 in moderate yield and with good enantioselectivity.[87] Scheme 45 Cross Coupling of 2-Benzyl-2-methylcyclopenta-3,5-diene-1,3diyl Bis(trifluoromethanesulfonate) with Arylboronic Acids[87] Ar1B(OH)2 10 mol% Pd(OAc)2
OMe
11 mol%
Bn TfO
OTf
PPh2
73 CsF, 1,4-dioxane, rt
Bn Ar1
TfO
74
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Asymmetric Synthesis of Biaryls
3.14.5
Ar1
ee (%) Yield (%) Ref
4-AcC6H4
77
46
[87]
3-AcC6H4
86
51
[87]
2-OHCC6H4
82
41
[87]
4-HOC6H4
74
43
[87]
3-furyl
72
53
[87]
The asymmetric cross coupling of arylmagnesium bromides with dinaphthothiophene, using the chiral complex derived from bis(cyclooctadiene)nickel(0) and the chiral P,N-ligand 75, provides an unconventional route to enantioenriched binaphthylthiols 77 (Scheme 46).[88] For the coupling with methylmagnesium iodide, the chiral monophosphine 76 provides improved asymmetric induction. Since dinaphthothiophene is a chiral molecule, and the isolated yields are more than 50%, this asymmetric coupling is a dynamic kinetic resolution of the chiral thiophene, thereby making this a very attractive approach. Cross Coupling of Dinaphthothiophene with Grignard Reagents[88]
Scheme 46
O PPh2
PPh2 N Pri 75
76
R1MgX (10 equiv) 3 mol% Ni(cod)2 4.5 mol% ligand, THF
S
R1 SH
77
R1
X Ligand Temp (8C) ee (%) Yield (%) Ref
Ph
Br 75
20
95
92
[88]
4-Tol
Br 75
20
95
97
[88]
4-MeOC6H4
Br 75
20
93
96
[88]
Me
I
76
0
54
54
[88]
Me
I
76
10
68
97
[88]
2-(1-Naphthyl)-1,1¢-biphenyl-3-yl Trifluoromethanesulfonate (71, R1 = Ph); Typical Procedure:[85]
To a mixture of 2-(1-naphthyl)-1,3-bis(trifluoromethanesulfonyloxy)benzene (995 mg, 1.98 mmol), LiBr (174 mg, 2.00 mmol), and catalyst 68 (50 mg, 0.094 mmol) in toluene (2.6 mL) was added a 1.8 M soln of PhMgBr in Et2O (2.4 mL, 4.3 mmol) at –30 8C, and the mixture was stirred at –30 8C for 48 h (monitoring by GLC). The mixture was hydrolyzed with 10% HCl and extracted with Et2O. The ethereal extracts were washed with H2O, dried (Na2SO4), and stripped of solvent under reduced pressure. Short column chromatography Cross Coupling, Shimizu, M., Hiyama, T. Science of Synthesis 4.0 version., Section 3.14 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
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Cross Coupling
(silica gel, hexane/EtOAc 5:1) gave a mixture of the monocoupled product 71 (93% ee) and the bis-coupled product 72 (ratio 85:15). Recrystallization of the crude mixture (hexane) gave the enantiomerically pure monocoupled product 71; yield: 666 mg (78%). (S)-4-Aryl-5-benzyl-5-methylcyclopenta-1,3-dien-1-yl Trifluoromethanesulfonates 74; General Procedure:[87]
Dry, degassed 1,4-dioxane (2 mL) was added to a mixture of the bis(trifluoromethanesulfonate) (93.20 mg, 0.20 mmol), Ar1B(OH)2 (0.40 mmol), Pd(OAc)2 (4.50 mg, 0.02 mmol, 10 mol%), ligand 73 (10.30 mg, 0.022 mmol, 11 mol%), and CsF (91.40 mg, 0.60 mmol). This mixture was stirred for 6–10 h at rt, EtOAc (10 mL) and H2O (8 mL) were then added, and the aqueous layer was extracted with EtOAc (2 10 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Et2O/hexane 1:99 to 40:60 gradient) to give the product. (S)-2¢-(4-Tolyl)-1,1¢-binaphthyl-2-thiol (77, R1 = 4-Tol); Typical Procedure:[88]
A 1.1 M soln of 4-TolMgBr in THF (1.8 mL, 2.0 mmol) was added slowly at 0 8C under a N2 atmosphere to a soln of dinaphthothiophene (57 mg, 0.20 mmol), Ni(cod)2 (1.7 mg, 6 mol), and ligand 75 (6.7 mg, 18 mol) in dry THF (4 mL). The mixture was allowed to stir at 20 8C for 24 h, quenched with H2O, and diluted with CHCl3. The organic layer was washed with 10% HCl, sat. NaHCO3, and brine and the organic layer was dried (MgSO4) and concentrated under reduced pressure. Preparative TLC (silica gel, hexane/EtOAc 9:1) gave the product; yield: 73 mg (97%); 95% ee.
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References
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Cross Coupling
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Protonation, Alkylation, Arylation, and Vinylation of Enolates B. M. Stoltz and J. T. Mohr
General Introduction
The carbonyl is a pivotal functional group in organic synthesis due to the variety of methods that are available to readily convert it, and the peripheral atoms, into new derivatives. The ability to generate enolates by deprotonation of Æ-carbon atoms is particularly useful for carbon—carbon and carbon—heteroatom bond formation, and often generates new stereocenters in the process. Control over stereochemistry in these useful transformations has been a key advance in stereoselective synthesis and has enabled the preparation of many natural products and pharmaceutical agents. In many cases the solutions to enolate functionalization have been developed with the explicit purpose of addressing the specific challenges posed by particular synthetic targets. The strategy of target-driven methodology development has proven fruitful and many prized target molecules are now accessible due to these methods.[1] Moreover, the application of the new synthetic technologies developed during these efforts enables further exploration of synthetic chemistry in the context of target-directed synthesis. 3.15.1
Enantioselective Protonation of Enolates
Carbonyl compounds are moderately acidic, with pKa values ranging from ~10 for activated systems up to ~30 for unstabilized carbonyls. Since the corresponding enolates are quite basic and often protonate rapidly, a variety of organic and inorganic Brønsted acids are effective proton donors for exploring enantioselective protonation. Control of C—H bond formation is challenging due to epimerization of the products in the presence of Brønsted acids. Nonetheless, a number of approaches to enantioselective protonation are available.[2–6] Generally, these tactics focus either on controlling approach of the donor to the enolate (i.e., via a chiral Brønsted base) or on controlling the environment surrounding the donor proton (i.e., via a chiral Brønsted acid). Combination of these two tactics is also possible, and in some cases aggregation of the two components prior to C—H bond formation has been proposed. 3.15.1.1
Biocatalytic Enantioselective Protonation
Several naturally occurring enzymes carry out enantioselective protonations. The biomimetic nature of these transformations is appealing, particularly in cases where the enolate precursors (typically enol acetates or malonates) are easily prepared. Substrate specificity is often a limitation of biocatalytic processes; however, two particularly useful transformations are the hydrolysis of enol acetates and the decarboxylation/protonation of aryl malonates.[7,8]
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.15.1.1.1
Hydrolysis of Enol Esters
3.15
Enolate Protonation, Alkylation, Arylation, Vinylation
Enol esters are readily prepared from the corresponding ketones and are often isolable with minimal contamination from the isomeric -diketones. These characteristics present enol acetates as attractive enolate precursors for a number of transformations. Hydrolysis of cyclic enol esters (e.g., transformation of 1 into 2, Scheme 1) may be achieved directly by action of Pichia miso, and the products are highly enantioenriched.[9] Scheme 1 Enantioselective Hydrolysis/Protonation of an Enol Ester[9] O O
O Pichia miso IAM 4682 79%
1
2
90% ee
Yields of enantioenriched ketones are generally good, and product enantiomeric excess is dependent on both the nature of the Æ-substituent and the size of the cycloalkanone (Scheme 2). Interestingly, the asymmetric induction is very high for small rings, only moderate for medium-sized rings, and then returns to excellent levels for decanone and dodecanone derivatives. Further expansion of the ring furnishes products with low enantiomeric excess. Unexpectedly, the dodecanone-derived product is in the opposite enantiomeric series to the other products. This was attributed to some unique interaction of the dodecanone ring with the enzyme, but the details have not been forthcoming. Scheme 2
Enantioselective Hydrolysis of Enol Esters with Pichia miso[9]
O O
R2
O
R1
R1 Pichia miso IAM 4682
X
X
X
R1
R2
Substrate Concentrationa
Time (h)
Yield (%)
ee (%) Config Ref
CH2
Me
Et
1.0
24
71b
58
S
[9]
b
86
S
[9]
85
S
[9]
77
R
[9]
CH2
Pr
Et
0.2
3
78
CH2
(CH2)6Me
Et
1.0
24
80 b
CH2
CH2CH=CH2
Et
1.0
24
92
CH2
Bn
Et
0.2
3
75
84
R
[9]
(CH2)3 Me
Me 0.2
3
71
67
S
[9]
(CH2)5 Me
Et
0.2
3
83
89
S
[9]
(CH2)7 Me
Me 0.2
24
67
95
R
[9]
a b
Weight percent relative to medium. GC yield.
(S)-2-Methylcyclohexanone (2); Typical Procedure:[9]
The basal medium for hydrolysis with P. miso IAM 4682 was glucose (10 g), polypeptone (7 g), yeast extract (5 g), and K2HPO4 (5 g) in distilled H2O (1000 mL). The initial pH of the Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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medium was adjusted to 7.2 with 2 M HCl. Four 500-mL Erlenmeyer flasks, each containing sterilized basal medium (100 mL), were inoculated with a loopful of P. miso IAM 4682, and the mixture was shaken for 2 d at 30 8C. The combined grown cells were collected by centrifugation and washed with 0.2 M phosphate buffer (pH 6.5) to give ca. 14 g of wet cells of P. miso. These cells and acetate 1 (80 L, 78 mg, 0.5 mmol) were added to 0.2 M phosphate buffer (pH 6.5; 40 mL) in a 500-mL Sakaguchi flask, and the suspension was incubated for 3 h at 30 8C. The broth was extracted with Et2O and the extract was dried (Na2SO4). Concentration and purification by flash column chromatography (silica gel, hexane/Et2O 15:1) and Kugelrohr distillation (bath temperature 150 8C/20 Torr) afforded cyclohexanone 2 as a colorless oil; yield: 79%; 90% ee. 3.15.1.1.2
Decarboxylative Protonation of Malonic Acids
Arylmalonate decarboxylase (AMDase) has proven to be a useful biocatalyst for enantioselective decarboxylation/protonation cascades. The enzyme present in Alcaligenes bronchisepticus provides Æ-aryl carboxylic acids 4 with excellent enantiomeric excess from arylmalonic acids 3 (Scheme 3).[10,11] The acids 4 are generally not isolated and are converted directly into the corresponding methyl esters 5 with diazomethane. Yields are variable and the scope is rather limited as only examples with an Æ-methyl or Æ-fluoro group provide useful results. Decarboxylative Protonation Mediated by A. bronchisepticus[10,11]
Scheme 3 O
O
O
O
Alcaligenes bronchisepticus
HO
OH Ar1
− CO2
R1
CH2N2
R1
HO
R1
MeO
Ar1
3
Ar1 5
4
Ar1
R1
Substrate Concentrationa
Yield (%) ee (%) Configb Ref
Ph
Me 0.5
90
98
R
[10]
4-MeOC6H4
Me 0.1
48
99
R
[10]
4-Tol
Me 0.3
44
>95
n.r.
[11]
4-ClC6H4
Me 0.5
85
97
R
[10]
4-F3CC6H4
Me 0.3
88
97
n.r.
[11]
Me 0.5
96
>95
R
[10]
2-thienyl
Me 0.3
98
95
S
[10]
Ph
F
64
95
n.r.
[11]
MeO
a b
0.1
Weight percent relative to medium. n.r. = not reported.
A principle limitation of enzyme-based methodologies is that frequently only one enantiomer of the product compound is accessible. Ohta and coworkers formulated a mechanistic hypothesis based on the proposed enzyme active site, which provided a rationale for a mutation of the natural enzyme, to afford a modified decarboxylase that provides comparable levels of enantioselectivity, but favoring the opposite enantiomer.[12] Although this mechanistic hypothesis was successful in leading to an analogous enzyme, later studies have suggested that a substantially different mechanism may in fact be operating.[13,14] Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
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Enolate Protonation, Alkylation, Arylation, Vinylation
Methyl 2-Arylalkanoates 5; General Procedure:[10,11]
CAUTION: Diazomethane is explosive by shock, friction, or heat, and is highly toxic by inhalation. The composition of the basal medium was as follows: 1% (NH4)2HPO4, 0.2% K2HPO4, 0.03% MgSO4•H2O, 10 ppm FeSO4•7H2O, 8 ppm ZnSO4•7H2O, 8 ppm MnSO4•4H2O, 0.02% yeast extract, and 0.01 ppm d-biotin; pH 7.2. To a 500-mL Sakaguchi flask was added the sterilized basal medium (50 mL) containing phenylmalonic acid (250 mg) and peptone (50 mg). The mixture was inoculated with A. bronchisepticus and shaken for 4 d at 30 8C. The substrate 3 was then added to the resulting suspension and the incubation was continued for an additional 5 d. The broth was made acidic with 2 M HCl, saturated with NaCl, and extracted with Et2O (4 ). The Et2O layer was washed with brine and dried (Na2SO4). After removal of the solvent, the residue was esterified with CH2N2 and the ester was purified by preparative TLC (hexane/EtOAc 4:1). 3.15.1.2
Protonation of Enolates with Chiral Proton Donors
The utility of enantioselective enolate protonation is inexorably tied to the availability of the chiral protonating agent. Amino alcohols are particularly attractive for this reason and in some cases have proven quite effective. A particularly noteworthy example is the enantioselective protonation with ephedrine derivative 6 as a key step toward the naturally occurring fragrance compound Æ-damascone (7) (Scheme 4).[15–18] The scope of many protonation protocols is very limited and is sensitive to minute changes in reaction conditions. As a result, only a handful of methods have demonstrated general applicability. Scheme 4
Enantioselective Protonation in the Preparation of Æ-Damascone[15–17] Ph N Pri
5 mol% HO Me
•
O
O
6 PhSH (0.96 equiv) THF, −27 oC
O SPh
86%; 89% ee
3.15.1.2.1
7
α-damascone
Using -Hydroxy Sulfoxide Brønsted Acids
The availability of enantioenriched sulfoxides by means of enantioselective sulfide oxidation (see Section 3.22) provides access to a variety of useful methodologies. In one such application, -hydroxy sulfoxides were prepared in diastereomerically pure form, and these materials were subsequently investigated as chiral proton donors. When lithium enolates, formed in situ from the corresponding enol acetates, are exposed to the hydroxy sulfoxides 8 or 9 (Scheme 5) at low temperature, the ketone products 10 are formed in excellent yield and with high asymmetric induction (Table 1).[19,20] Scheme 5 Chiral Hydroxy Sulfoxides Used for Enantioselective Protonation[19,20] OH
O S
F3C 8
OH 4-Tol
O S
Pri
4-Tol
9
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Enantioselective Protonation of Enolates
Table 1
Enantioselective Protonation by Chiral Hydroxy Sulfoxides[19,20] 1. MeLi•LiBr (2 equiv) Et2O, 0 oC 2. sulfoxide (3 equiv) CH2Cl2, −100 to −40 oC
OAc R1
O R1
X
X 10
Starting Material
Sulfoxide
OAc
Yielda ee Config Ref (%) (%)
Product
O
9
Bn
OAc
Bn
n.r.
85
S
[20]
Bn
93
97
S
[19]
93
92
S
[19]
94
94
R
[19]
n.r.
87b S
[20]
97
87
[19]
O Bn
8
OAc
O
8
Ph
OAc
Ph
O
8
OAc
O Bn
OAc
O Ph
a b
Bn
9
8
Ph
S
n.r. = specific yield not reported; in general, 90–94% yield was observed. Reaction at –40 8C.
A specific application of enolate protonation with a chiral hydroxy sulfoxide is in the synthesis of the natural product epibatidine.[21] Enol acetate 11 is transformed into the Æ-aryl ketone 12 (82% ee) via enantioselective protonation using the chiral hydroxy sulfoxide 8, and the ketone 12 is then converted into the natural product in a further nine steps (Scheme 6).
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis Scheme 6
3.15
Enolate Protonation, Alkylation, Arylation, Vinylation
Enantioselective Protonation in the Synthesis of Epibatidine[21]
Cl
OAc N
1. MeLi, Et2O 0 oC, 15 min 2. 8 (2.5 equiv) CH2Cl2
Cl
O N
−90 to −60 oC 63%
O
O
O
O
11
12
82% ee
Cl
H N N H (−)-epibatidine
2-Alkylcycloalkanones 10; General Procedure:[20]
To a stirred soln of the corresponding enol acetate (1.0 mmol) in Et2O (9 mL) at 0 8C was added 1.5 M MeLi•LiBr in Et2O (2.1 mmol). The mixture was stirred at rt for 30 min. The lithium enolate soln was cooled to –75 8C and then slowly added over 7 min to a soln of the Æ-sulfinyl alcohol 8 or 9 (3.0 mmol) in CH2Cl2 (30 mL) at –100 to –40 8C.[20] The mixture was stirred for 1.5 h at the same temperature and then gradually warmed to 0 8C (temperature increase approximately 1.2 8C/min). The mixture was treated with phosphate buffer (pH 7.2) and extracted with hexane. After concentration of the hexane extracts, the residue was purified by column chromatography to give the corresponding ketone; yield: 90– 94%. 3.15.1.2.2
Using Lewis Acid Activated Brønsted Acids
Yamamoto and coworkers have developed chiral binaphthyl proton donors 13 and 14, activated by addition of tin(IV) chloride, as reactive Brønsted acids.[22] Using these complexes, protonations of silyl enol ethers 15 occurs with very high enantioselectivity for the products 16 (Scheme 7). Ketones bearing Æ-aryl or Æ-halogen substituents are also accessible by this method. In all cases, complete conversion of the starting material is achieved at low temperature. Scheme 7
Enantioselective Protonation of Silyl Enol Ethers[22]
OH
OH
OH
OMe
(R)-13
OTMS R1
15
(R)-14
proton donor (1.1 equiv) SnCl4 (1.0 equiv) toluene, −78
O R1
oC
16
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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R1
Proton Donor ee (%) Config Ref
Ph
(R)-14
94
S
[22]
4-MeOC6H4
(R)-13
96
S
[22]
2-naphthyl
(R)-13
91
S
[22]
Cl
(R)-14
87
R
[22]
Br
(R)-14
87
R
[22]
In addition to cyclic enol silanes, acyclic silyl ketene acetals 17 are competent proton acceptors (Scheme 8). A number of Æ-aryl carboxylic acids 18 may be formed in highly enantioenriched form through this transformation, including the nonsteroidal anti-inflammatory agents ibuprofen and naproxen. Additionally, Æ-aryl-Æ-alkoxy- and Æ-aryl-Æ-halo acids may be formed using the Lewis acid activated Brønsted acid reagent. Scheme 8
Enantioselective Protonation of Silyl Ketene Acetals[22] (R)-13 (1.1 equiv) SnCl4 (1.0 equiv)
OTMS TMSO
O
toluene or CH2Cl2
Ar1
−78 oC
Ar1
HO
R1
R1 18
17
Ar1
R1
ee (%) Config Ref
Ph
Me
92
S
[22]
4-iBuC6H4
Me
94
S
[22]
Me
92
S
[22]
Ph
OMe 87
S
[22]
Ph
F
–a
[22]
MeO
70
Ph
Cl
91
S
[22]
Ph
Br
83
S
[22]
4-BrC6H4
Cl
84
S
[22]
a
Config not reported.
An important advance in the application of Lewis acid activated Brønsted acids is the coupling of chiral protonating agents to achiral proton donors. Yamamoto and coworkers found that 2,6-dimethylphenol may be used as a stoichiometric Brønsted acid in the presence of a chiral tin complex of ligand (R)-14. This enables enantioselective protonation with a catalytic amount of the chiral binaphthyl compound and a substoichiometric amount of Lewis acid. Under these conditions, enantioselectivity is maintained and useful products such as ibuprofen are obtained (Scheme 9).
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Enolate Protonation, Alkylation, Arylation, Vinylation
Scheme 9 Catalytic Enantioselective Protonation with Lewis Acid Activated Brønsted Acids[22] 2−5 mol% (R)-14 50 mol% SnCl4 2,6-dimethylphenol (1.1 equiv) toluene, −80 oC
OTMS R1
R1
ee (%) Ref
Ph
90
[22]
2-naphthyl
91
[22]
O R1
5−10 mol% (R)-14 8 mol% SnCl4
OTMS TMSO
O
2,6-dimethylphenol (1.1 equiv) toluene, −80 oC
R1
HO
R1
ee (%) Ref
Ph
94
[22]
4-iBuC6H4
93
[22]
R1
Ketones 16 and Acids 18; General Procedure:[22]
A heat-gun-dried, 25-mL Schlenk flask containing (R)-13 (0.094 g, 0.33 mmol) was charged with anhyd toluene (distilled from CaH2; 6.6 mL). A 1.0 M soln of SnCl4 in CH2Cl2 (or hexane) (0.3 mL, 0.3 mmol) was added dropwise at rt. After being stirred for 5 min at this temperature, the mixture was cooled to –78 8C. Then, starting material 15 or 17 (0.3 mmol) was added dropwise. After being stirred for several h at –78 8C, the mixture was poured into sat. NH4Cl and extracted with Et2O (2 ). The organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. Purification of the crude product by chromatography (silica gel, hexanes/EtOAc 10:1 to 5:1) gave the pure product 16 or 18 as a white solid. The enantiomeric excess of ketones was determined by HPLC analysis. 3.15.1.3
Protonation of Enolates with Chiral Proton Acceptors
In contrast to the above strategies aimed at controlling the environment surrounding the electrophilic proton, another common tactic toward enantioselective protonation is to induce asymmetry through the proton acceptor. Given the wealth of effort and accomplishment in the area of enantioselective alkylation (see Section 3.15.2), one might expect a similar complement of methodologies with proton electrophiles. However, general protonation methodologies are comparatively uncommon. One factor contributing to the challenge of stereoselective protonation is the regioselective generation of a disubstituted enolate in geometrically pure form. To circumvent this issue, many methodologies have been developed around cyclic enolates. General stereoselective protonation in acyclic systems remains a challenging and unsolved synthetic problem. Many of the existing methods for enantioselective protonation rely on the pregeneration of an enolate/enol using powerful bases or Lewis acidic conditions. The necessity to employ stoichiometric reagents can, in turn, lead to a limited substrate scope. To obviate the need for such conditions, cleavable functional groups may be used to form substoichiometric amounts of an enolate in situ. The palladium-catalyzed conversion of allyl -keto esters into ketone enolates has been particularly successful in this manifold, Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.15.1
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Enantioselective Protonation of Enolates
since the putative palladium enolate is resistant to protonation by other acidic sites within the substrate.[23] Moreover, the variety of chiral ligands available for palladium-catalyzed transformations provides a degree of versatility for this process. A suitable stoichiometric reagent is required both to provide a proton and to turnover the -allylpalladium intermediate. Applying this tactic to the decarboxylative protonation of allyl -keto esters 21 using a complex derived from palladium(0) and phosphinodihydrooxazole (phosphinooxazoline) ligand 19[24,25] provides 2-methyltetralones 22 (R1 = Me) in high yield and with excellent enantioselectivity when formic acid is employed as the stoichiometric proton donor/reductant.[26] Notably, the products resist epimerization under the acidic reaction conditions. Key to the success of this method is the presence of molecular sieves, which serve an undetermined function (Scheme 10). Other tetralone-derived Æ-tertiary ketones are also accessible using this protocol. Using the same catalytic system, cyclohexanones 24 (X = CH2) can also be prepared in high yield and enantiomeric excess (Scheme 11). The facial selectivity of proton delivery for cyclohexanones is reversed relative to that for the tetralones. Scheme 10 Palladium-Catalyzed Enantioselective Protonation with Tetralone-Derived Allyl Keto Esters[26,27]
O
O
O Ph2P
O
N
O
But (S)-19
20
O R1
O
R4 O
Pd catalyst
O
R2
R1
R4
R2
R3
R3 21
22
R1
R2
R3
R4
Conditions
ee (%)
Configa Ref
H
H
H
Me
Pd(OAc)2 (10 mol%), (S)-19 (12.5 mol%), HCO2H 88 (5–8 equiv), 4-Å molecular sieves, 1,4-dioxane, 40 8C
94
S
[26]
H
H
H
CH2CH=CH2
Pd(OAc)2 (10 mol%), (S)-19 (12.5 mol%), HCO2H 88 (5–8 equiv), 4-Å molecular sieves, 1,4-dioxane, 40 8C
85
R
[26]
H
H
H
F
Pd(OAc)2 (10 mol%), (S)-19 (12.5 mol%), HCO2H 79 (5–8 equiv), 4-Å molecular sieves, 1,4-dioxane, 40 8C
88
S
[26]
H
OMe H
Me
Pd(OAc)2 (10 mol%), (S)-19 (12.5 mol%), HCO2H 91 (5–8 equiv), 4-Å molecular sieves, 1,4-dioxane, 40 8C
95
n.r.
[26]
H
OMe H
CH2CH=CH2
Pd(OAc)2 (10 mol%), (S)-19 (12.5 mol%), HCO2H 81 (5–8 equiv), 4-Å molecular sieves, 1,4-dioxane, 40 8C
88
n.r.
[26]
H
OMe H
Bn
Pd(OAc)2 (10 mol%), (S)-19 (12.5 mol%), HCO2H 95 (5–8 equiv), 4-Å molecular sieves, 1,4-dioxane, 40 8C
78
n.r.
[26]
Yield (%)
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
624 R1
Stereoselective Synthesis R2
R3
OMe OMe H
3.15
R4
Conditions
Me
Enolate Protonation, Alkylation, Arylation, Vinylation ee (%)
Configa Ref
Pd(OAc)2 (10 mol%), (S)-19 (12.5 mol%), HCO2H 62 (5–8 equiv), 4-Å molecular sieves, 1,4-dioxane, 40 8C
94
n.r.
[26]
Yield (%)
Me
H
Me Me
Pd(OAc)2 (10 mol%), (S)-19 (12.5 mol%), HCO2H 75 (5–8 equiv), 4-Å molecular sieves, 1,4-dioxane, 40 8C
92
n.r.
[26]
H
H
H
Me
Pd2(dba)3 (5 mol%), (S)-19 (12.5 mol%), 20 (2.5 equiv), 1,4-dioxane, 22 8C
86
77
S
[27]
H
H
H
CH2CH=CH2
Pd2(dba)3 (5 mol%), (S)-19 (12.5 mol%), 20 (2.5 equiv), 1,4-dioxane, 22 8C
83
77
R
[27]
Me
H
Me Me
Pd2(dba)3 (5 mol%), (S)-19 (12.5 mol%), 20 (2.5 equiv), 1,4-dioxane, 22 8C
77
77
n.r.
[27]
a
n.r. = not reported.
Later studies revealed that Meldrums acid 20 is also a suitable proton donor, and in this case heterogeneous additives are unnecessary (Scheme 10 and 11).[27] High yield and enantiomeric excess are again observed for a range of cyclic ketones, particularly cyclohexanone-derived keto esters 23 (X = CH2). Notably, acid-sensitive functional groups such as a -siloxy group survive the transformation. Scheme 11 Palladium-Catalyzed Enantioselective Protonation with Cyclohexanone-Derived Allyl Keto Esters[26,27] O
O
R1 O
X
R1
Pd catalyst
O
X
23
24
X
R1
Conditions
Yield (%)
ee (%)
Configa Ref
CH2
Me
Pd(OAc)2 (10 mol%), (S)-19 (12.5 mol%), HCO2H (5–8 equiv), 4-Å molecular sieves, 1,4-dioxane, 40 8C
99b
85
R
[26]
CH2
Bn
Pd(OAc)2 (10 mol%), (S)-19 (12.5 mol%), HCO2H (5–8 equiv), 4-Å molecular sieves, 1,4-dioxane, 40 8C
91
92
S
[26]
(CH2)2 Bn
Pd(OAc)2 (10 mol%), (S)-19 (12.5 mol%), HCO2H (5–8 equiv), 4-Å molecular sieves, 1,4-dioxane, 35 8C
69
74
n.r.
[26]
NBn
Et
Pd(OAc)2 (10 mol%), (S)-19 (12.5 mol%), HCO2H (5–8 equiv), 4-Å molecular sieves, 1,4-dioxane, 40 8C
81
84
n.r.
[26]
CH2
Me
Pd2(dba)3 (5 mol%), (S)-19 (12.5 mol%), 20 (2.5 equiv), 99b 1,4-dioxane, 22 8C
86
R
[27]
CH2
Et
Pd2(dba)3 (5 mol%), (S)-19 (12.5 mol%), 20 (2.5 equiv), 99b 1,4-dioxane, 22 8C
89
R
[27]
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.15.1
X
R1
Conditions
CH2
Bn
CH2 CH2 a b
625
Enantioselective Protonation of Enolates ee (%)
Configa Ref
Pd2(dba)3 (5 mol%), (S)-19 (12.5 mol%), 20 (2.5 equiv), 90 1,4-dioxane, 22 8C
78
S
[27]
CH2C(Me)=CH2
Pd2(dba)3 (5 mol%), (S)-19 (12.5 mol%), 20 (2.5 equiv), 87 1,4-dioxane, 22 8C
89
n.r.
[27]
CH2OTBDPS
Pd2(dba)3 (5 mol%), (S)-19 (12.5 mol%), 20 (2.5 equiv), 97 1,4-dioxane, 22 8C
80
n.r.
[27]
Yield (%)
n.r. = not reported. GC yield.
Together, these procedures offer convenient access to cycloalkanones bearing an Æ-tertiary stereogenic center. Complementary alkylation methodologies using identical substrates provide routes to the analogous Æ-quaternary cycloalkanones (see Section 3.15.2.4.2 and Section 3.15.2.4.3). Related palladium-catalyzed transformations of allyl and benzyl enol carbonates and esters have been reported; in these cases the stereocontrolling element is a chiral proton donor.[28,29] The conversion of allyl enol carbonates with a palladium complex with ligand 19 under the optimized protonation conditions gives lower enantioselectivity than the corresponding reaction with allyl -keto esters.[26] Additionally, silyl enol ethers are not appropriate substrates for the palladium/19/formic acid system, since they provide very low yields.[26] Nevertheless, other palladium-catalyzed protonations of enol silanes are available.[30] (S)-(–)-2-Methyl-3,4-dihydronaphthalen-1(2H)-one (22, R1 = R2 = R3 = H; R4 = Me); Typical Procedure:[26]
A glass tube (2.5 10 cm) with a ground glass joint equipped with a magnetic stirrer bar was charged with powdered 4- molecular sieves (540 mg) and then thoroughly flame dried under reduced pressure (3 , backfill with dry argon). After cooling to ambient temperature under dry argon, Pd(OAc)2 (6.7 mg, 0.030 mmol, 10 mol%), (S)-t-Bu-PHOX [(S)-19; 14.5 mg, 0.0375 mmol, 12.5 mol%], and freshly distilled 1,4-dioxane (4.5 mL) were added, and the resulting slurry was stirred vigorously at 40 8C for 30 min. At this point, neat HCO2H (68 L, 1.80 mmol, 6.0 equiv) was added to the mixture, followed immediately by addition of a soln of rac-21 (R1 = R2 = R3 = H; R4 = Me; 73.3 mg, 0.30 mmol, 1.0 equiv) in 1,4dioxane (4.5 mL). When the reaction was complete by TLC, the mixture was cooled to ambient temperature and then filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel, Et2O/pentane 1:9); yield: 42.1 mg (88%); 94% ee (chiral HPLC). 2-Alkylcycloalkanones 22 and 24; General Procedure Using Meldrums Acid:[27]
A 25-mL, round-bottomed flask equipped with a magnetic stirrer bar and a septum was flame dried under reduced pressure (3 , backfill with dry argon). After cooling to rt under dry argon, Pd2(dba)3 (13.7 mg, 0.015 mmol, 5 mol%), (S)-t-Bu-PHOX [(S)-19; 14.5 mg, 0.0375 mmol, 12.5 mol%], and freshly distilled 1,4-dioxane (4.5 mL) were added, and the resulting mixture was stirred vigorously at 40 8C for 30 min. A soln of -keto ester (0.30 mmol, 1.0 equiv) and Meldrums acid (20; 108.1 mg, 0.75 mmol, 2.5 equiv) in 1,4-dioxane (4.5 mL) was added to the mixture at 22 8C. When the reaction was complete by TLC, the mixture was filtered through a pad of silica gel and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, Et2O/pentane).
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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3.15.2
Alkylation of Enolates
3.15
Enolate Protonation, Alkylation, Arylation, Vinylation
Enolate alkylation provides one of the most important methods of functionalizing carbonyl-containing molecules. Many of the approaches that facilitate successful ketone alkylations are closely related to methods for enantioselective aldol reactions; the similarity arises from a shared requirement for control of facial selectivity for the enolate nucleophile. Chiral auxiliaries have proven particularly useful for enolate functionalizations and many different chiral controllers have been explored.[31] Among the most successful auxiliaries for acyclic enolate alkylation are oxazolidinone 25, camphorsultam 26, and pseudoephedrine (27) (Scheme 12). For cyclic enolates, imine- and hydrazine-type auxiliaries (derivatives of 28 and 29) are the most well-developed. Scheme 12
Chiral Auxiliaries for Enolate Alkylation
O OMe O
NH Pri 25
NH
Ph OH
S O
NHMe NH2
Bn
OMe N
NH2
O 26
27
28
(S)-29
Catalytic enolate alkylations have appeared more recently and now represent the forefront in enolate functionalization. A variety of approaches to catalysis are possible, including ligand-accelerated alkylation of enolates, in situ enolate generation with a catalyst, and cross-coupling strategies. The scope of effective electrophiles remains limited and the development of new methods is ongoing. 3.15.2.1
Alkylation of Amide Enolates via Chiral Auxiliaries
3.15.2.1.1
Using Oxazolidinone Auxiliaries
Evans and coworkers developed the enantioselective alkylation of imide enolates in the early 1980s.[32] The oxazolidinone auxiliaries (e.g., 25) are derived from readily available amino alcohols and provide a number of practical advantages including crystallinity, cleavability, and easy recovery following reaction. Several different oxazolidinones and the corresponding imides are commercially available in both enantiomeric forms. A general implementation of this technology is shown in Scheme 13. Deprotonation of the imide 30 with amide-type bases provides the Z-enolate with high selectivity. The enolate is presumably chelated to enforce the location of the steric-control element and block electrophile approach to one face of the enolate. In general, kinetic facial selectivity in alkylation is extremely high. If necessary, the diastereomeric ratio of the product 31 can often be improved through recrystallization. Activated electrophiles are much more successful in the transformation than unactivated electrophiles, and in the case of electrophiles prone to SN1 substitution the addition of different Lewis acids can lead to improved results.[33]
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.15.2
Diastereoselective Alkylation of N-Acyloxazolidinones[32,34]
Scheme 13 O O
627
Alkylation of Enolates
O R1
N
1. LDA (1.1 equiv) THF, −78 oC 2. R2X (1.1−5 equiv) 0 oC
O O
O R1
N R2
Pri
Pri
30
31
R1
R2
X
dr after Purification
Yielda (%)
Me
Bn
Ref
Br >99:1
>99:1
92
[32]
Me
CH2CH=CH2
Br
>99:1
71
Initial dr 98:2
[32]
b
Me
CH2OBn
Br
98:2
99:1
77
[32]
Me
Et
I
94:6
>99:1
36
[32]
Me
(E)-CH2CH=CHPh
Br
99:1
99:1
84
[34]
Et
Me
I
91:9
99:1
79c
[32]
>99:1
c
[32]
(CH2)7Me a b c
Me
I
93:7
77
Yield after purification. Reaction performed at –40 8C. Reaction performed with NaHMDS in place of LDA and 5 equiv of R2X.
All-carbon quaternary centers are not generally accessible using this technology due to the resistance of the initial alkylation products to deprotonation; the low acidity of the alkylation products is a key feature in preventing epimerization. A variety of methods are available for cleaving the auxiliaries to allow further functionalizations, including hydrolysis and reduction.[32] These transformations generally occur with minimal racemization and in most cases the auxiliary can be recovered and reused. Oxazolidinone-type auxiliaries have been used extensively in synthesis. The stereoselective alkylation technology, when combined with the auxiliary-controlled aldol transformation, is particularly suited to the synthesis of polyketide-type natural products. One such example is the use of alkylation product 32 toward the synthesis of the natural product ionomycin (Scheme 14).[34] In this instance, the stereoselective alkylation generates the stereocenter at C14 of the natural product. The Use of an Oxazolidinone Auxiliary in the Synthesis of Ionomycin[34]
Scheme 14
H O O
O
OH
OH 14
N
O
O
Ph
OH
Pri
OH
O
HO2C
14
32
dr 99:1
ionomycin
(S)-4-Isopropyl-3-[(R,E)-2-methyl-5-phenylpent-4-enoyl]oxazolidin-2-one [31, R1 = Me; R2 = (E)-CH2CH=CHPh]; Typical Procedure:[34]
To a cooled (0 8C) soln of iPr2NH (7.01 mL, 50.0 mmol) in THF was added 1.6 M BuLi in hexane (31.2 mL, 50.0 mmol) over a 20-min period. The resulting yellow soln was stirred at 0 8C for 30 min and then cooled to –78 8C. A soln of imide 30 (R1 = Me; 8.33 g, 45.0 mmol) Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Enolate Protonation, Alkylation, Arylation, Vinylation
in THF (8 mL) was then added over a 20-min period. The mixture was maintained at –78 8C for 1 h before cinnamyl bromide (13.3 g, 67.5 mmol) was added over a period of 10 min. The reaction temperature was maintained between –40 and –20 8C for 1 h, then allowed to rise to 0 8C and held at this temperature for an additional 2.2 h, producing an orange soln. Sat. aq NH4Cl (30 mL) was added, and the THF was removed under reduced pressure. H2O (30 mL) was added and the resulting mixture was extracted with Et2O (3 100 mL). The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting orange oil was flash chromatographed [silica gel (600g), EtOAc/ hexane 1:3] to afford the alkylated imide as a light yellow oil; yield: 11.43 g (84%). Diastereomer analysis before and/or after chromatography revealed a ratio of 1.3:98.7. 3.15.2.1.2
Using Camphorsultam Auxiliaries
Oppolzer and coworkers developed an alternative auxiliary derived from camphor in the late 1980s and applied the sultam 26 to enolate alkylation (Scheme 15).[35] Both enantiomeric forms of the auxiliary are now commercially available. The advantages of this auxiliary are similar to those of the oxazolidinones: alkylation of the acylsultams 33 occurs under standard conditions in which the products 34 are frequently crystalline and the procedure is scalable. The camphorsultam auxiliary performs somewhat better than the oxazolidinones when less active electrophiles are employed in the alkylation. Overall, excellent yields are observed and the diastereocontrol is outstanding. Substrates containing Æ-heteroatoms are useful for the preparation of Æ-alkoxy acids and unnatural amino acids, and undergo alkylation with comparable stereoinduction.[36] Scheme 15
Diastereoselective Alkylations of N-Acylcamphorsultams[35,36]
O R1
N
1. base (1 equiv) THF, −78 oC, 1 h 2. R2X (3 equiv) HMPA (3 equiv)
O
S O
R1
N
−78 oC to rt
R2
S O
O 33
O 34
R1
R2
X
Base
Initial dr
Me
Bn
I
NaHMDS
98.2:1.8
99.2:0.8
89
[35]
Me
(CH2)3iPr
I
NaHMDS
99.5:0.5
>99.5:0.5
81
[35]
Me
CH2C”CH
Br BuLi
99.1:0.9
>99.5:0.5
78
[35]
Bn
Me
I
NaHMDS
95.1:4.9
dr after Purification
>98.8:1.2
Yielda (%) Ref
b
[35]
c
83
OBn
Bn
I
LiHMDS
99.1:0.9
99.1:0.9
68
[35]
N=C(SMe)2
Bn
I
BuLi
97.3:2.7
>99.5:0.5
93
[36]
N=C(SMe)2
CH2CO2t-Bu Br BuLi
99.2:0.8
>99.5:0.5
96d
[36]
N=C(SMe)2
iBu
I
BuLi
97.8:2.2
>99.5:0.5
85
[36]
N=C(SMe)2
iPr
I
BuLi
98.9:1.1
>99.5:0.5
95
[36]
a b c d
Yield after purification. Alkylation at –78 8C for 16 h. Alkylation at –45 8C for 16 h. Alkylation conducted in the presence of TBAI.
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.15.2
629
Alkylation of Enolates
Æ-Alkylated N-Acylcamphorsultams 34; General Procedure:[35] CAUTION: Hexamethylphosphoric triamide is a possible human carcinogen and an eye and skin irritant. A 1 M soln of BuLi in hexane (1 equiv) was added over 1 h to a soln of camphorsultam 33 in THF (5 mL/mmol) at –78 8C (alternatively, 1 M NaHMDS or LiHMDS in THF was added over 10 min). The mixture was stirred at –78 8C for 1 h, and then the alkylating agent (3 equiv) in HMPA (3 equiv) was added. The mixture was then slowly warmed to rt and quenched with H2O. Extraction with Et2O followed by concentration afforded crude 34, which was usually crystallized (MeOH). 3.15.2.1.3
Using Pseudoephedrine Auxiliaries
Pseudoephedrine (27) is a readily available amino alcohol used in common nasal-decongestant formulations. In addition to its biological properties, it has been used as a chiral auxiliary and ligand in synthetic chemistry. Among the most useful of these applications is the alkylation of enolates derived from pseudoephedrine amides 35.[37,38] The nucleophilicity of these amide enolates is sufficient to allow relatively unactivated electrophiles to participate in the alkylation and therefore a wide range of functionalized products 36 are available. Halogens, aryl groups, and very bulky alkyl groups are all tolerated on the acylpseudoephedrine enolate (Scheme 16). Notably, the auxiliary is sufficient to control stereoinduction even when electrophiles contain existing stereocenters. Yields are usually very good and product diastereoselectivities are uniformly excellent. Cleavage of the auxiliary through hydrolysis, reduction to either an alcohol or aldehyde, and nucleophilic substitution (to form ketones) have been reported.[37,38] In each of these transformations, minimal racemization is observed. A resin-bound version of this auxiliary has been reported, but stereoselectivity is somewhat lower.[39] Alkylations of N-Acylpseudoephedrine Derivatives[37,38]
Scheme 16
1. LDA (1.95 equiv) LiCl (6 equiv), THF, 0 oC
O Ph
N OH
2. R2X (1.5−4 equiv), 0 oC
R1
O Ph
Me
OH
35
R2
X Isolated dr Yield (%) Ref
Me
Bu
I
Me
Me CH2CO2t-Bu
Me
R2
36
R1 Bu
R1
N
I Br
‡99:1a 98:2
80a
[37,38]
b
[37,38]
b
[38]
c
88
[37,38]
89
98:2
78 c
Cl
Bn
Br ‡99:1
Ph
Et
I
‡99:1
92
[37,38]
3-pyridyl
CH2CH=CH2
I
99:1
83b
[38]
Me
Bn
Br ‡99:1
90
[38]
t-Bu
Bn
Br ‡99:1a
84a
[38]
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Enolate Protonation, Alkylation, Arylation, Vinylation
R1
R2
X Isolated dr Yield (%) Ref
Me
(CH2)2OTIPS
I
98.5:1.5
89d
[38]
I
>99:1
97
[38]
I
1:58d
95e
[38]
Me
Me a b c
d e
Bn
Bn
Data after recrystallization. Alkylation performed at –78 8C. Alkylation performed at –45 8C. Data after two recrystallizations. Excess enolate (1.9 equiv) was employed. Reaction performed with the (R,R)-auxiliary; the inverted ratio indicates the opposite configuration at the newly formed stereocenter. Alkylation performed at 23 8C using excess enolate (2 equiv).
The pseudoephedrine auxiliary is also useful for the synthesis of amino acids when glycinamide substrates 37[40] are used (Scheme 17). Several methods have been employed for enolate generation with anhydrous glycinamide substrates.[41,42] However, the procedure exploiting the hydrate of the pseudoephedrine glycinamide offers several practical advantages in handling and isolation and is therefore recommended.[43] Excellent diastereoselection is observed for products 38 after alkylation with various electrophiles; however, the yields vary from moderate to good and are largely dependent on the electrophile. Scheme 17 Glycinamide Alkylations with the Pseudoephedrine Auxiliary[42,43] O Ph
NH2
N OH
1. base, LiCl, THF, 0 oC 2. R1X (1−1.2 equiv), 0 oC
O Ph
Me
OH
37
NH2
N Me
R1
38
Hydration of 37
R1
X
Base (equiv)
anhyd
Bn
Br
LDA (1.95) 6
Equiv of Time (h) for LiCl Alkylation Step
anhyd
CH2TMS
Br
LDA (1.95) 6
hydrate
CH2CH=CH2
Br
LiHMDS (3.2)c
4
hydrate
Me
I
LiHMDS (3.2)c
3.2
1
dr >99:1a a,b
Yield (%)
Ref
65a
[42]
a
22
>99:1
57
[42]
1
>99:1
71d
[43]
91
[43]
1.5
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
96.5:3.5
3.15.2
Hydration of 37
R1
X
Base (equiv)
Equiv of Time (h) for LiCl Alkylation Step
dr
Yield (%)
Ref
I
LiHMDS (3.2)c
3.2
3
98.5:1.5
65
[43]
Br
LiHMDS (3.2)c
3.2
2.5
96:4
84
[43]
Br
LiHMDS (3.2)c
3.2
0.5
O
hydrate
hydrate
O
631
Alkylation of Enolates
2
TBDMSO
TBDMSO
hydrate MeO a b c d
OMe
98.5:1.5a 80a
[43]
Data after recrystallization. Alkylation performed at 23 8C. Reaction performed with the (R,R)-auxiliary; the major product is enantiomeric to that shown in structure 38. Reaction on a 200-mmol scale; a yield of 77% was obtained on a 1-mmol scale.
Fluorinated acetamides have also been investigated with the aim of developing synthetic routes to potentially bioactive materials with stereodefined alkyl fluorides (Scheme 18).[44] Good stereoinduction is observed and product diastereoselectivity exceeds 96:4 in each case reported. Further enolization and alkylation of the secondary fluoride products has led to the first syntheses of fully substituted carbons using this technology. The tertiary fluorides formed in this process display very high diastereocontrol.[45] Recently, all-carbon quaternary stereogenic centers have been generated using the pseudoephedrine auxiliary.[46] The diastereomeric ratio of the Æ-quaternary amide products is highly dependent on the relative configuration of the amide starting materials.[46] Additionally, the optimal conditions require a limiting amount of electrophile (0.77 equiv relative to enolate). The scope for quaternary stereogenic center formation is much more limited than for the tertiary variant. Generally, activated electrophiles provide optimal results. The formation of all-carbon quaternary stereogenic centers in acyclic systems with chiral auxiliaries is a remarkable advance in synthetic technology, since many of the other auxiliaries are not amenable to the formation of these challenging stereocenters.
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.15
Enolate Protonation, Alkylation, Arylation, Vinylation
Scheme 18 Alkylation of Fluoroacetamides and Formation of Fully Substituted Carbons[44–46] 1. base, LiCl (6 equiv), THF −78 oC
O Ph
R1
N
2. R3X
O Ph
R2
R1
N
R3
Me
R1
R2
R3
X Base (equiv)
Conditions for Step dr 2
Yield (%)
Ref
F
H
Me
I
–50 8C, 0.5 h
>99:1
97
[44]
F
H
CH2C(Me)=CH2
Br LiHMDS (2.15)
–40 8C, 4 h
>97.5:2.5
91
[44]
Me F
CH2CH=CH2
I
LDA (2.1)
–78 8C, 4.5 h
>97:3
80
[45]
Me F
Bn
Br LDA (2.1)
–78 8C, 4.5 h
>99:1
71
[45]
Br LDA (1.95)
DMPU, –40 8C, 1 h
19:1
93a
[46]
a
Et
Me Bn
OH
2 Me R
OH
LiHMDS (2.15)
Bn Me CH2CH=CH2
Br LDA (1.95)
DMPU, –40 8C, 0.75 h
19:1
85
[46]
Bn Me Et
I
DMPU, –40 8C, 20 h
6.2:1
87a
[46]
a
LDA (1.95)
Yield based on amount of electrophile.
(R)-N-[(1S,2S)-1-Hydroxy-1-phenylpropan-2-yl]-N,2-dimethyl-3-phenylpropanamide (36, R1 = Me; R2 = Bn); Typical Procedure Using Limiting Nucleophile:[38]
A three-necked, 2-L flask equipped with a mechanical stirrer was charged with LiCl (25.0 g, 596 mmol, 6.00 equiv), iPr2NH (31.3 mL, 224 mmol, 2.25 equiv), and THF (120 mL). The resulting suspension was cooled to –78 8C and 2.43 M BuLi in hexanes (85.1 mL, 207 mmol, 2.08 equiv) was added via cannula. The suspension was warmed briefly to 0 8C and then cooled to –78 8C. An ice-cooled soln of amide 35 (R1 = Me; 22.0 g, 99.4 mmol, 1 equiv) in a minimal amount of THF (300 mL) was added to the reaction flask via cannula. The mixture was stirred at –78 8C for 1 h, at 0 8C for 15 min, and at 23 8C for 5 min and finally cooled to 0 8C, whereupon BnBr (17.7 mL, 149 mmol, 1.50 equiv) was added. The mixture was stirred at 0 8C for 15 min and then quenched by the addition of sat. aq NH4Cl (10 mL). The mixture was partitioned between sat. aq NH4Cl (800 mL) and EtOAc (500 mL), and the aqueous layer was separated and extracted with EtOAc (2 150 mL). The combined organic extracts were dried (Na2SO4) and concentrated to afford a yellow solid. Recrystallization of the product (hot toluene, 110 8C, 100 mL) furnished the amide 36 (R1 = Me; R2 = Bn) as a white, crystalline solid; yield: 27.8 g (90%). Amide 36 (R1 = Me; R2 = Bn; 30 mg, 0.096 mmol, 1 equiv) was silylated using TMSCl (34 L, 0.27 mmol, 2.8 equiv) and Et3N (49 L, 0.35 mmol, 3.6 equiv) in CH2Cl2 (1 mL) at 23 8C for 10 min, and chiral capillary GC analysis of the resulting TMS ether established that amide 36 was of ‡99% de. (R)-N-[(1S,2S)-1-Hydroxy-1-phenylpropan-2-yl]-N,2-dimethyl-4-(triisopropylsiloxy)butanamide [36, R1 = Me; R2 = (CH2)2OTIPS]; Typical Procedure Using Limiting Electrophile:[38]
A 2.55 M soln of BuLi in hexanes (27.4 mL, 69.9 mmol, 4.00 equiv) was added via cannula to a suspension of LiCl (9.39 g, 222 mmol, 12.7 equiv) and iPr2NH (10.6 mL, 75.3 mmol, 4.31 equiv) in THF (50 mL) at –78 8C. The resulting suspension was warmed briefly to 0 8C and then cooled to –78 8C. An ice-cooled soln of amide 35 (R1 = Me; 8.12 g, 36.7 mmol, 2.10 equiv) in THF (110 mL, followed by a 4-mL rinse) was added via cannula. The mixture was stirred at –78 8C for 1 h, at 0 8C for 15 min, and at 23 8C for 5 min. The mixture was cooled to 0 8C, and (2-iodoethoxy)triisopropylsilane (5.73 g, 17.5 mmol, 1 equiv) was added neat to the mixture via cannula. After being stirred for 18.5 h at 0 8C, the mixture Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.15.2
Alkylation of Enolates
633
was treated with half-sat. aq NH4Cl (180 mL), and the resulting mixture was extracted with EtOAc (4 110 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the residue by flash column chromatography (Et2O/hexanes 65:35) afforded a highly viscous, yellow oil; yield: 6.57 g (89%). Chiral capillary GC analysis of the corresponding trimethylsilyl ether established that the amide was of 97% de. (R)-2-Amino-N-[(1S,2S)-1-hydroxy-1-phenylpropan-2-yl]-N-methyl-3-phenylpropanamide (38, R1 = Bn); Typical Procedure Using Anhydrous Glycinamide:[42]
A 2.69 M soln of BuLi in hexanes (1.63 mL, 4.39 mmol, 1.95 equiv) was added to a soln of iPr2NH (630 L, 4.50 mmol, 2.00 equiv) in THF (4 mL) at 0 8C. After 10 min, the resulting soln of LDA was transferred via cannula over 5 min to a stirred slurry of anhyd 37 (500 mg, 2.25 mmol, 1 equiv) and flame-dried LiCl (572 mg, 13.5 mmol, 6.00 equiv) in THF (6 mL) at 0 8C. After stirring at 0 8C for 20 min, BnBr (281 L, 2.36 mmol, 1.05 equiv) was added dropwise to the bright yellow suspension. After 1 h, 1 M aq HCl (25 mL, 25 mmol) was added to the mixture, followed by EtOAc (50 mL). The organic layer was separated and extracted with a second portion of 1 M aq HCl (25 mL). The aqueous extracts were combined, and the resulting soln was cooled in an ice bath and carefully basified to pH 14 by addition of 50% aq NaOH. The basic aqueous soln was extracted with CH2Cl2 (3 40 mL). The combined organic extracts were dried (K2CO3), filtered, and concentrated under reduced pressure to provide a solid residue. The solid was recrystallized (hot toluene, 90 8C, ca. 5 mL). Upon cooling to 23 8C, the product crystallized rapidly. The recrystallization flask was cooled to 0 8C and held at that temperature for 1 h, at which time the crystals were isolated by filtration, washed with a small amount of Et2O (10 mL), and dried under reduced pressure (0.5 Torr); yield: 459 mg (65%). The diastereomeric excess of the product was determined by capillary GC analysis. The crude product was shown to be of 90% de, and the recrystallized product was shown to be of >99% de. (S)-2-Amino-N-[(1R,2R)-1-hydroxy-1-phenylpropan-2-yl]-N-methylpent-4-enamide (38, R1 = CH2CH=CH2); Typical Procedure Using Glycinamide Hydrate:[43]
An oven-dried, 3-L, three-necked, round-bottomed flask fitted with two glass stoppers and an inlet adapter connected to a source of vacuum and argon was charged with anhyd LiCl (33.9 g, 800 mmol, 4.00 equiv). The flask was evacuated, and a gentle flame was applied to further dry the solid LiCl. After cooling to 23 8C under vacuum, the flask was flushed with argon and then fitted with a mechanical stirrer and an oven-dried 1-L pressure-equalizing addition funnel, marked at 340 and 640 mL. THF (600 mL) was added to the flask, and the resulting suspension was stirred for 20 min at 23 8C. Solid (R,R)-(–)-pseudoephedrine glycinamide hydrate (ent-37•H2O; 48.1 g, 200 mmol, 1 equiv) was added to the suspension in eight portions over a period of 10 min through one of the necks by way of a powder funnel. The resulting slightly cloudy soln was cooled by immersing the reaction flask in an ice bath. The pressure-equalizing addition funnel was charged with a commercial 1 M soln of LiHMDS in THF (640 mL, 640 mmol, 3.20 equiv). The argon inlet adapter was transferred from the neck of the flask to the neck of the addition funnel, and the open neck was fitted with a septum pierced with a thermocouple to monitor the internal temperature of the mixture. Dropwise addition of the base was initiated when the substrate soln had cooled to 0 8C, ~35 min after the reaction flask had been immersed in an ice bath. The rate of addition of the first 300-mL portion of base (300 mmol, 1.5 equiv, to the 340 mL mark) was modulated such that the internal reaction temperature did not exceed 3 8C (addition time ~30 min). When the mixture had again cooled to 0 8C, the stopcock of the addition funnel was opened fully to allow for rapid addition of the second portion of base (340 mL, 340 mmol, 1.70 equiv). The latter addition produced a modest exotherm (8 8C maximum internal temperature). After 20 min, allyl bromide (18.2 mL, 210 mmol, 1.05 equiv) was injected slowly into the orange enolate soln over a period of 15 min. The internal temperature did not exceed 5 8C during the addition. After the addition of allyl bromide was comProtonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
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Enolate Protonation, Alkylation, Arylation, Vinylation
plete, the mixture was stirred at 0 8C for 1 h. H2O (500 mL) was added at this point, and the resulting biphasic mixture was carefully acidified to pH 0 by the addition of 6 M aq HCl (300 mL). The acidified aqueous soln was transferred to a 4-L separatory funnel and extracted with EtOAc (750 mL). The organic layer was separated and extracted sequentially with single 300-mL portions of 3 M and 1 M aq HCl, respectively. The aqueous layers were combined and cooled to an internal temperature of 5 8C by stirring in an ice–water bath. The cold soln was cautiously basified to pH 14 by the addition of 50% aq NaOH (200 mL). The temperature of the soln was maintained at or below 25 8C during basification. The basified soln was extracted sequentially with CH2Cl2 (800 mL then 3 250 mL). The combined organic extracts were dried (K2CO3), filtered, and concentrated under reduced pressure. The diastereomeric excess of the crude reaction product was shown to be 93% by capillary GC analysis of an acetylated sample. The oily, pale yellow residue solidified upon standing under reduced pressure (0.5 Torr). The solid was dissolved in hot toluene (100 mL); crystallization occurred upon cooling the resulting soln to 23 8C. After standing overnight at 23 8C, the crystallization flask was cooled to –20 8C for 6 h. The crystals were collected and washed sequentially with cold (0 8C) toluene (25 mL) and Et2O (4 100 mL). The crystals were dried under reduced pressure (0.5 Torr) at 23 8C for 14 h to provide diastereomerically pure product; yield: 32.7 g (62%). The mother liquors were concentrated, and the liquid residue was dissolved in hot toluene (25 mL). Cooling to 23 8C and then at –20 8C (3.5 d) afforded a second crop of product; yield: 4.4 g (8.4%); >99% de; mp 72–73 8C. 3.15.2.2
Alkylation of Enolates via Chiral Metalloenamines
The ability to control enolate alkylation in cyclic systems presents different challenges to the acyclic auxiliary-controlled cases discussed in Section 3.15.2.1. One successful tactic to access enantioenriched cyclic ketones is to convert the ketone into an imine or hydrazone having a chiral element. In addition to introducing a means of stereocontrol, the metalloenamines derived from the imines and hydrazones enjoy increased nucleophilicity relative to the corresponding enolates and therefore the scope of electrophiles is increased. 3.15.2.2.1
Using Imine-Type Auxiliaries
Enantiopure amino ethers (e.g., 28) are readily available from amino acids and readily condense with ketones to form imines 39 (Scheme 19). Deprotonation with lithium diisopropylamide followed by the introduction of alkyl halides at low temperature leads to excellent control of the configuration of the newly formed stereocenter.[47–49] Hydrolysis of the imine auxiliary may be completed during the reaction workup to afford the enantioenriched ketones 40. It is important to monitor the hydrolysis carefully, as some product racemization may occur over extended reaction times and with specific reagents. Product enantiomeric excesses are very high for Æ-alkylcyclohexanones 40 (Z = CH2) (Scheme 19), but decrease for larger rings.[50] Nevertheless, good asymmetric induction is obtained for very large ring cycloalkanones (e.g., cyclododecanone and cyclopentadecanone). Optimal results rely on the selective formation of the thermodynamic Z-enolate. Consequently, the large-ring alkylation products are in the opposite enantiomeric series to the small-ring cycloalkanones.
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3.15.2
635
Alkylation of Enolates
Scheme 19
Alkylation of Cyclic Ketones via Chiral Metalloenamines[47,48,50]
OMe Bn
1. LDA (1.05 equiv) THF, −30 oC, 1 h 2. R1X (1.05 equiv), −78 oC, 1.5 h 3. AcOH, NaOAc, pentane/H2O
N
O R1
Z
Z
39
40
Z
R1
X Yield (%) ee (%) Config Ref
CH2
Et
I
82
94
S
[48]
CH2
Pr
I
76
99
S
[48]
CH2
CH2CH=CH2
Br 80
99
R
[48]
(CH2)2
(CH2)2OMe
I
77
81
R
[48]
(CH2)3
Me
I
65
20
S
[48]
a
(CH2)5
Me
I
77
30
S
[50]
(CH2)7
Me
I
83a
81
R
[50]
I
a
81
R
[50]
(CH2)10 Me a
78
Metalloenamine generated by addition of imine to LDA in THF at –40 8C, and subsequent heating to reflux for 1 h to afford a reported E/Z ratio of 0:100. The mixture was cooled to –78 8C prior to addition of the electrophile.
Based on the high diastereoselectivity obtained for the alkylation of large-ring cycloalkanones, acyclic ketones have also been investigated (Scheme 20).[50,51] In this case it is essential to control the geometry of the metalloenamine. Symmetrical dialkyl ketones perform well and provide products of high enantiomeric excess, whereas aryl alkyl ketones provide varied results. The method of enolization limits the methodology to symmetrical cases or to ketones that contain only one site for enolization. Imines formed from aldehydes afford only moderate enantioselectivity.[52] Scheme 20
Bn
Alkylation of Acyclic Ketones via Chiral Metalloenamines[50,51]
OMe
1. LDA (1.05 equiv), THF, −20 oC, 1 h
N
2. reflux, 1 h 3. R3I (1.05 equiv), −78 oC, 1 h 4. AcOH, NaOAc, pentane/H2O
R1
O R2
R1
R2
R3
R1
R2
R3
Et
Me Et
69
77
R
[50]
Et
Me Pr
60
88
R
[50]
Bu
Pr
Me 75
94
S
[50]
Ph
Me Et
71
58
R
[50]
4-MeOC6H4
Me Et
75
80
R
[50]
Yield (%) ee (%) Config Ref
2-Alkylcycloalkanones 40; General Procedure:[48]
An oven-dried, 50-mL flask equipped with a magnetic stirrer bar, a pressure-equalizing addition funnel, and a rubber serum cap was charged with anhyd THF (20 mL) under N2. Freshly distilled iPr2NH (1.47 mL, 1.06 g, 10.5 mmol) was added via syringe and the soln Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.15
Enolate Protonation, Alkylation, Arylation, Vinylation
was cooled to 0 8C. A 2.4 M soln of BuLi in hexane (4.4 mL, 10.6 mmol) was added and the soln was stirred at 0 8C for 15 min and then cooled to –30 8C. The chiral imine 39 (10 mmol) in anhyd THF (10 mL) was added over 15 min and the mixture was allowed to stir for 1–1.5 h. The soln was then cooled to –78 8C and a soln of the alkyl halide (10.5 mmol) in THF (3–4 volumes) was added over a period of 1 h and the mixture was allowed to stir at –78 8C for 1.5 h. The total volume of THF was such as to make the final concentration of the imine ~0.25 M. The light yellow cold soln was poured into sat. aq NaCl (100 mL) and the mixture was extracted with Et2O (3 ). The combined Et2O extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The amber oil was subjected to hydrolysis immediately. Delay of the hydrolysis step (e.g., overnight) resulted in ~10–15% racemization. A buffer soln composed of NaOAc (3.30 g), AcOH (7.5 mL), and H2O (35 mL) was added to the crude imine in pentane (50 mL) and the resulting mixture was shaken for 30 min. The aqueous layer was removed and saved to recover the chiral auxiliary. The aqueous layer was washed with pentane, and the organic solns were combined and washed with 1 M HCl (to remove any unhydrolyzed imine), H2O, 5% NaHCO3, H2O, and brine. The organic soln was then dried (Na2SO4), filtered, concentrated, and bulb-to-bulb distilled to yield the 2-substituted ketone. 3.15.2.2.2
Using Hydrazone-Type Auxiliaries
Hydrazones are easily formed by the condensation of hydrazines with ketones. The synthetic utility of the metalloenamines formed from these hydrazones was initially recognized in non-enantioselective transformations.[53,54] Taking advantage of the opportunity to introduce a chiral control element, hydrazines (R)-29 and (S)-29 (commonly referred to as RAMP and SAMP, respectively) derived from enantiopure prolinol have been prepared and examined (Scheme 21).[55] The hydrazones are useful for a number of applications including aldol reactions, conjugate addition, and Diels–Alder cyclizations.[56] Nevertheless, the first implementations were for the diastereoselective alkylation of ketones. Scheme 21
RAMP and SAMP Auxiliaries[56]
MeO H2N
OMe N
(R)-29 RAMP
N
NH2
(S)-29 SAMP
Metalation of the hydrazones 41 is effected with common amide bases such as lithium diisopropylamide.[57–61] Introduction of an electrophile at cryogenic temperature leads to efficient alkylation with high diastereoselectivity (Scheme 22). Cleavage of the hydrazone auxiliary may be achieved by several protocols, including ozonolysis, perborate oxidation, acidic hydrolysis, alkylation/hydrolysis sequences, and copper(II) chloride mediated hydrolysis.[62,63] Overall yields of the alkylated ketones 42 (hydrazone formation, alkylation, and auxiliary cleavage) are moderate but acceptable and the asymmetric induction is generally very high. The electrophile scope is good, including both activated and relatively inert alkyl halides. Quaternary stereogenic centers may also be prepared provided the substrate contains either an Æ-aryl[64] or Æ-cyano stabilizing group.[65]
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Alkylation of Enolates
3.15.2
Scheme 22
Alkylation of Cyclic Ketones via RAMP/SAMP Hydrazones[59,61,64,65]
OMe N
N R1
1. base, Et2O, −78 oC 2. R2I (1.05−1.5 equiv), −110 oC 3. O3, CH2Cl2, −78 oC
O R1
X
R2
X
41
42
X
R1
R2
Base Yield (%) ee (%) Config Ref
CH2
H
Me
LDA 66a
86
R
[59,61]
(CH2)2 H
Me
a
LDA 70
99
R
[59,61]
(CH2)3 H
Me
LDA 59b
94
R
[59,61]
(CH2)2 Ph Me
c
BuLi 43
93
R
[61,64]
(CH2)2 CN (CH2)5Me
LDA 63d
93
R
[65]
(CH2)5 CN Et
LDA 25
94
R
[65]
a b c d
Me2SO4 was used as the electrophile. Cleaved with MeI/5 M HCl. Cleaved with 12 M HCl/Et2O. Cleaved with 5 M HCl/Et2O.
Stereocontrol in acyclic systems is also excellent with the RAMP/SAMP auxiliaries (Scheme 23). Due to the enolization conditions, only hydrazones derived from symmetrical dialkyl ketones are suitable substrates. Alkylation of aryl alkyl ketones also provides good results. Metalloenamines stabilized by aryl groups (i.e., R2 = Ph) give comparable yields, but only 10–30% enantiomeric excess,[59] whereas the alkylation of aldehyde-derived hydrazones provides very good results. Scheme 23
RAMP/SAMP-Controlled Alkylations in Acyclic Systems[56,59–61,66]
OMe
1. LDA (1.05 equiv), Et2O, 0 oC 2. R3X (1.05 equiv), −110 oC to rt 3. MeI (5 equiv), 60 oC
N
N
R3
R3
X Yielda (%) ee (%) Config Ref
Et Me Et
I
61
94
S
[60]
Et Me
Br 61
‡97
S
[61]
Et Me CH2CO2t-Bu
Br 53b
‡94
S
[61]
Bu Pr
I
54
‡98
R
[60]
I
44
Me
Ph Me Et H H a b
Et
Me
Me (CH2)5Me
R2
R1
R2
R1
R1 R2
O
4. 3−4 M aq HCl
I I
‡97
S
[61]
b
95
R
[61]
b
‡95
S
[61]
65 52
Yield includes hydrazone formation. Hydrazone cleaved via ozonolysis.[59]
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.15
Enolate Protonation, Alkylation, Arylation, Vinylation
Some of the procedures for auxiliary removal lead to its degradation, thereby complicating the ability to recycle the chiral controller. Recently, a similar hydrazine auxiliary has been developed that provides similar stereocontrol and improved yields, and is more readily cleaved and recovered.[67] The RAMP/SAMP technology has been used frequently in synthesis.[56] For example, the SAMP-derived hydrazone 43 was used in the alkylation of the enantiomerically enriched alkyl iodide 44 (93% ee, dr >99:1). After cleavage of the auxiliary and the alcohol protective group, the naturally occurring pheromone serricornin (45) was obtained in 53% yield (Scheme 24).[68] Examination of the stereochemical distribution of products indicates that the newly formed stereocenter is generated as 97:3 mixture of epimers. Scheme 24
SAMP-Controlled Ketone Alkylation in the Synthesis of Serricornin[68] 1. LDA, Et2O, 0 oC O
OMe , −110 to −20 oC
2. I
OMe N
44 3. MeI, 60 oC
O
OH
4. 3 M aq HCl
N
53%
43
45 serricornin
2-Alkylcycloalkanones 42; General Procedure:[59]
A 1.6 M soln of BuLi (1.05 equiv) in hexane was added dropwise via syringe to a 0.25–0.5 M soln of iPr2NH (1.05 equiv) in Et2O under argon at 0 8C, and the mixture was stirred for 15 min to generate a soln of LDA (1.05 equiv). After dropwise addition of the hydrazone 41 (1.0 equiv), the mixture was stirred at 0 8C for 4 h and cooled to –110 8C, and a 2–3 M soln of the electrophile (1.05 equiv) in Et2O was added. The mixture was stirred at this temperature for 1–3 h, after which the mixture was allowed to warm to rt within 4–12 h. The mixture was then poured into Et2O/H2O (2:1) and the inorganic salts were removed by thorough washing with H2O. After drying of the organic layer (MgSO4), and concentration under reduced pressure, the crude oily product was purified by short-path distillation, Kugelrohr distillation, or column chromatography (silica gel, Et2O). Subsequent cleavage of the auxiliary[62,63] led to the pure ketone 42. 3.15.2.3
Alkylation of Enolates with Chiral Counterions
Alkylation of lithium enolates is a fairly general synthetic transformation in organic synthesis. The ligation environment around lithium is frequently taken for granted, despite its impact on the observed reactivity. Koga and coworkers have explored a number of chiral ligands bearing multiple Lewis basic atoms and have found that several provide a high degree of enantioselectivity in alkylation reactions (Scheme 25).[69,70] For example, the lithium amides 48 and 49 provide the enolizing base for the deprotonation of ketones. The conjugate acids (46 and 47) presumably serve as a chiral ligand for the lithium atom in the subsequent alkylation step.
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.15.2
639
Alkylation of Enolates
Scheme 25
Chiral and Achiral Amine Species for Enantioselective Enolate Alkylation[69–73]
Ph
Ph O
N H
N
OMe
Me N
N H
N
Me
46
47
Ph
Ph O
N N
Me
N
OMe
Me N
N
Li
Li
N
Me
N Me
48
49
Ph
Ph Me
N
N H
N H
50
Me N
N
N
Me
Me 51
Me
Me
N
N
Me
Me 52
Products of high enantiomeric excess are obtained for several activated electrophiles with enolates derived from cyclohexanones and tetralones 53 (Scheme 26). Lactams and lactones are also useful enolate precursors.[71] Due to the increased nucleophilicity of lactam enolates, only stoichiometric quantities of electrophile are employed. Although the yields are variable, the products 54 are generally formed with a high degree of enantioselectivity using this alkylation strategy.
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Stereoselective Synthesis Scheme 26
O Y1
3.15
Enolate Protonation, Alkylation, Arylation, Vinylation
Deprotonation/Alkylation of Ketones, Lactams, and Lactones[69–71] 1. base (1 equiv) LiBr (1.1 equiv) toluene, −20 oC 2. R1X (10 equiv) −45 oC
Y2
O R1
Y1 Y2
53
54
Y1
Y2
R1
X
CH2
CH2
Bn
Br 48
63
CH2
CH2
(E)-CH2CH=CHPh
Br 48
60
CH2
NMe
CH2
CH2
Base Yield (%)
b
ee (%) Configa
Ref
92
R
[69,70]
87
R
[69,70]
80
R
[69,70]
CH2CH=CH2
Br 48
41
Bn
Br 48
89
92
R
[69,70]
(E)-CH2CH=CHPh
Br 48
93
88
R
[69,70]
Me
I
71
88
S
[69,70]
Bn
Br 49
64c,d,e
98
R
[71]
Br 49
55
c,d,e
96
n.r.
[71]
(E)-CH2CH=CHPh
48
NMe
CH2
NMe
CH2
Br 49
55c,d,e
97
n.r.
[71]
O
CMe2 Bn
Br 49
74e
90
R
[71]
e
85
n.r.
[71]
90
n.r.
[71]
O
CMe2 (E)-CH2CH=CHPh
Br 49
64
O
CMe2
Br 49
63c,e
a b c d e
n.r. = not reported. Reaction performed at –50 8C. 1.2 equiv of R1Br. 2,2,4,4-Tetramethyltetrahydrofuran was used as solvent. Alkylation performed at –78 8C.
The lithium enolates may also be generated from silyl enol ethers 55 by action of methyllithium (Scheme 27).[70] Adding a chiral amine followed by an alkylating agent leads to alkylation with excellent stereoselectivity. The best enantioselectivities are obtained with amine 47, although 46 generally gives higher yield of the alkylated product 56. Importantly, enantiomerically enriched all-carbon quaternary stereogenic centers may be generated using this method; ligand 50 is the most effective for this task.[72]
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.15.2
641
Alkylation of Enolates
Scheme 27
Alkylation of Enolates Generated from Silyl Enol Ethers[70,72] 1. MeLi•LiBr (1 equiv) Et2O, rt, 1 h 2. chiral amine (1 equiv) toluene, −20 oC 3. R2X (10 equiv)
OTMS R1
Y1
O
R1
Y1
−45 C, 18 h o
Y2
R2
Y2 55
56
Y1
Y2
R1
R2
X
CH2
CH2 H
Bn
Br 46
68
92
R
[70]
H
Me
I
46
79
88
S
[70]
H
Me
I
47
64
98
S
[70]
H
Bn
Br 46
81
92
R
[70]
H
Bn
Br 47
56
97
R
[70]
Me Bn
Br 50
86
93
R
[72]
Me CH2CH=CH2
Br 50
63
97
–a
[72]
a
Chiral Amine
Yield (%) ee (%) Config Ref
Config not reported.
Alkylation of lithium enolates can be effected with a catalytic amount of the chiral amine 50, albeit in the presence of a superstoichiometric amount of an achiral amine additive, 51 or 52, to provide good yields (Scheme 28).[72,73] The enantioselectivity of the process is sensitive to the loading of chiral amine and the exact nature of the achiral amine. Both tertiary and quaternary carbon stereogenic centers are accessible through this process, and the enantioselectivity is comparable to the analogous alkylation with a stoichiometric chiral ligand. The success of alkylation reactions with catalytic chiral amine highlights the importance of activating enolates by appropriate ligation of a Lewis base to achieve the necessary reactivity.
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis Scheme 28
3.15
Enolate Protonation, Alkylation, Arylation, Vinylation
Catalytic Enantioselective Formation of Quaternary Carbon Stereocenters[72,73] 1. Me3Li•LiBr (1 equiv)
OTMS
O
2. chiral amine (cat.)
R1
additive (2 equiv)
Bn
3. BnBr (10 equiv)
R1
R1
Chiral amine (mol%) Additive
Time (h) Yield (%) ee (%) Config Ref
H
47 (20)
51
18
83
92
R
[73]
H
47 (5)
51
18
76
96
R
[73]
Me 50 (10)
51
48
66
80
R
[72]
Me 50 (10)
52
48
49
88
R
[72]
(R)-2-Benzylcyclohexanone (54, Y1 = Y2 = CH2; R1 = Bn); Typical Procedure:[70]
Under an argon atmosphere, LiBr (94.3 mg, 1.08 mmol) was dissolved in a soln of 46 (306 mg, 1.0 mmol) in toluene (7 mL) with the aid of ultrasonic vibration at rt. The resulting soln was cooled to –20 8C, and then mixed with 1.45 M BuLi in hexane (0.69 mL, 1.0 mmol), and the whole was stirred for 30 min. A soln of cyclohexanone (98 mg, 1.0 mmol) in toluene (3 mL) was added, and the whole was stirred at –20 8C for 30 min, and then cooled to –78 8C. A soln of BnBr (1.2 mL, 10 mmol) in toluene (2 mL) was added. The mixture was warmed to –45 8C, and stirred at this temperature for 18 h. After addition of 0.5 M aq HCl (10 mL) under vigorous stirring, the mixture was allowed to warm to rt, and then extracted with Et2O (3 20 mL). The organic extracts were combined, washed successively with H2O (10 mL), sat. aq NaHCO3 (10 mL), and brine (10 mL), and dried (MgSO4). Evaporation of the solvent gave the crude product, which was purified by column chromatography (silica gel, hexane/Et2O 15:1) followed by bulb-to-bulb distillation to give a colorless oil; yield: 118 mg (63%); bp 120 8C (bath temperature); 92% ee (HPLC). (R)-2-Benzyl-3,4-dihydronaphthalen-1(2H)-one (56, Y1,Y2 = 1,2-C6H4; R1 = H; R2 = Bn); Typical Procedure:[70]
Under an argon atmosphere, 1.50 M MeLi•LiBr in Et2O (0.67 mL, 1.0 mmol) was added to silyl enol ether 55 (Y1,Y2 = 1,2-C6H4; R1 = H; 218 mg, 1 mmol) at rt and the mixture was stirred for 1 h. Toluene (7 mL) was added, and the whole was cooled to –20 8C. After addition of a soln of 46 (306 mg, 1.0 mmol) in toluene (3 mL), the whole was stirred at –20 8C for 0.5 h and then cooled to –78 8C. A soln of BnBr (1.2 mL, 10 mmol) in toluene (2 mL) was added, and the whole was stirred at –45 8C for 18 h. After addition of 0.5 M aq HCl (10 mL) under vigorous stirring at –78 8C, the mixture was allowed to warm to rt, and then extracted with Et2O (3 20 mL). The organic extracts were combined, washed successively with H2O (10 mL), sat. aq NaHCO3 (10 mL), and brine (10 mL), and dried (MgSO4). Evaporation of the solvent under reduced pressure gave a residue, which was purified by column chromatography (silica gel, hexane/Et2O 15:1) followed by bulb-to-bulb distillation to give a colorless oil; yield: 191 mg (81%); bp 160 8C (bath temperature); 92% ee (HPLC). 3.15.2.4
Alkylation of Enolates via Chiral Transition-Metal Catalysts
Transition-metal catalysts are useful for many enantioselective reactions, and transitionmetal enolates display several useful characteristics that are attractive for synthetic applications. Among these advantages are that they tolerate acidic proton sources within substrates and that they are able to catalytically form enolates in situ during the course of the reaction. Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.15.2
3.15.2.4.1
643
Alkylation of Enolates
Decarboxylative Allylic Alkylation of Enol Carbonates and Silanes with Palladium Catalysts
Among the most successful implementations of enantioselective transition-metal catalysis is allylic alkylation catalyzed by palladium complexes.[74] The development of enantioselective alkylations of palladium -allyl complexes with unstabilized enolates has been a relatively recent accomplishment.[75–77] Early examples involved the preformation of the lithium enolate prior to reaction. Upon exposure to a palladium catalyst these enolates generate highly enantioenriched ketones bearing Æ-tertiary and Æ-quaternary stereocenters with excellent selectivity.[78–83] Selected ligands 19 and 57–60 for enolate alkylation are presented in Scheme 29. Although this approach is very successful in certain cases, the high basicity of the enolization conditions limits its utility somewhat. Scheme 29
Selected Ligands for Enantioselective Alkylation of Enolates CF3
O
O PPh2 N
P
PPh2
N
N But
But F 3C (S)-19
CF3 57
58
O O
O N H
N H
PPh2
Ph2P 59
O NH
HN
PPh2
Ph2P 60
Allyl enol carbonates facilitate the in situ formation of palladium enolates, which subsequently undergo enantioselective decarboxylative alkylation without isomerization of the enolate. Two particularly successful ligands enabling decarboxylative alkylation of unstabilized enolates are the phosphinodihydrooxazole (PHOX) framework 19[84] and the sterically-demanding bis(phosphine) 59 (Scheme 29).[85,86] The PHOX–palladium complex demonstrates broad scope for the formation of Æ-quaternary cyclic ketones 62 from carbonates and silyl enol ethers 61 (Scheme 30). The palladium/bis(phosphine) system is also effective for the generation of Æ-tertiary cycloalkanones, albeit with lower asymmetric induction. Alternatively, silyl enol ethers provide competent enolate precursors with the PHOX/palladium system. Furthermore, dioxanones are suitable substrates for the silyl enol ether variant of the decarboxylative alkylation; these provide access to Æ-oxygenated carbonyl compounds.[87]
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
644
Stereoselective Synthesis
3.15
Enolate Protonation, Alkylation, Arylation, Vinylation
Scheme 30 Palladium-Catalyzed Alkylation of Enolates from Allyl Enol Carbonates and Enol Silanes[84,85] OR1 R2
2.5 mol% Pd2(dba)3 6.5 mol% ligand additive, THF, 25 oC
O
X
R2
X 61
62
X
R1
R2
Ligand Additive
Yield (%)
ee (%)
Ref
CH2
CO2CH2CH=CH2
H
59
–
78a
78
[85]
CH2
CO2CH2CH=CH2
Me
59
–
88a
85
[85]
CH2
CO2CH2CH=CH2
Me
(S)-19 –
90
89
[84]
b
CH2
CO2CH2CH=CH2
Et
(S)-19 –
96
92
[84]
CH2
CO2CH2CH=CH2
(CH2)3OBn
(S)-19 –
87
88
[84]
c
t-Bu
(S)-19 –
55
82
[84]
(CH2)2 CO2CH2CH=CH2
Me
(S)-19 –
81
87
[84]
(CH2)3 CO2CH2CH=CH2
Me
(S)-19 –
90
79
[84]
CH2
TMS
Me
(S)-19 diallyl carbonate 95 (1.05 equiv), Bu4NSiF2Ph3 (35 mol%)
87
[84]
CH2
TMS
Et
(S)-19 diallyl carbonate 96 (1.05 equiv), Bu4NSiF2Ph3 (35 mol%)
92
[84]
Me
(S)-19 diallyl carbonate 94 (1.05 equiv), Bu4NSiF2Ph3 (35 mol%)
86
[84]
CH2
CO2CH2CH=CH2
(CH2)2 TMS
a b c
Performed in toluene with Pd2(dba)3•CHCl3 and 5.5 mol% ligand. Reaction performed at 12 8C; GC yield. 5 mol% Pd2(dba)3 and 12.5 mol% ligand.
The complex derived from palladium(0) and the bis(phosphine) 59 is also an effective catalyst for the preparation of acyclic Æ-tertiary ketones (Scheme 31).[86,88] Control of enol geometry in the substrate is critical, since in some cases one geometric isomer is significantly less reactive than the other and also leads to the enantiomeric product. Excellent yields and product enantiomeric excesses are obtained for a variety of substrates. Oxygen substituents are useful in some cases, although under certain conditions a different reaction pathway is observed.[89] Particularly useful derivatives are the 2-acylimidazolyl ketones, which are poised for further functionalization following enantioselective alkylation.[90] Scheme 31 Palladium-Catalyzed Allylic Alkylation of Acyclic Enol Carbonates[86,88–90] O O R1
O R2
2.5 mol% Pd2(dba)3•CHCl3 5.5 mol% 59 1,4-dioxane
O R1 R2
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.15.2
645
Alkylation of Enolates
R1
R2
Yield (%) ee (%) Ref
Ph
Et
94
94
[86,88]
Ph
(CH2)4Me
93
92
[86,88]
Ph
OAc
60
21
[89]
2-FC6H4
Me
80
94
[86,88]
4-BrC6H4
Me
94
93
[86,88]
2-MeOC6H4 Me
99
98
[86,88]
2-furyl
Me
89
88
[86,88]
Me
94
88
[86,88]
Me
99a
94
[86]
Me
a
99
88
[86]
Me
96
92
[90]
iPr Et N NPh a
Predominantly E-enol isomer of the starting material (‡18:1).
2-Allyl-2-methylcyclohexanone (62, X = CH2; R2 = Me); Typical Procedure:[84]
A 50-mL, round-bottomed flask equipped with a magnetic stirrer bar was flame dried under reduced pressure. After cooling under dry argon, Pd2(dba)3 (22.9 mg, 0.025 mmol, 0.025 equiv) and (S)-19 (24.2 mg, 0.0625 mmol, 0.0625 equiv) were added. After the flask had been flushed with argon, THF (30 mL) was added and the contents were stirred at 25 8C for 30 min, at which time allyl enol carbonate 61 (X = CH2; R1 = CO2CH2CH=CH2; R2 = Me; 196.2 mg, 1.0 mmol, 1.0 equiv) was added by syringe in one portion. When the reaction was complete by TLC, the mixture was concentrated under reduced pressure and the residue was chromatographed (silica gel, Et2O/pentane 2:98 to 3:97); yield: 129.6 mg (85%). 3.15.2.4.2
Decarboxylative Allylic Alkylation of -Keto Esters with Palladium Catalysts
Enol carbonate and enol silane substrates undergo decarboxylative alkylation under essentially neutral conditions; however, the substrate syntheses can involve strongly basic conditions, which in some cases provide poor selectivity for the desired enol isomer. To address this challenge, allyl -keto esters 63 were examined as enolate precursors. In this case the location of the C—C bond cleaved during decarboxylation determines the enolate isomer that is formed in situ. When the palladium complex using ligand 19 is employed in this transformation, high levels of regiochemical fidelity, yield, and enantiomeric excess are observed (Scheme 32).[91] The practical advantages of synthesis and handling afforded by the stable -keto ester substrates have facilitated the scope of this variant to be explored at length, and also enabled the scalable synthesis of the product ketones.[92] In addition to various Æ-quaternary cycloalkanones 64 (R1 = alkyl), tertiary fluorides 64 (R1 = F) are also readily accessible through this transformation.[91,93] Biaryl P,N-ligands (e.g., 58) are also useful for the preparation of these fluorinated compounds.[94]
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
646
Stereoselective Synthesis
Enolate Protonation, Alkylation, Arylation, Vinylation
Palladium-Catalyzed Decarboxylative Alkylation with Allyl -Keto
Scheme 32 Esters[91,94] O
3.15
2.5 mol% Pd2(dba)3 6.25 mol% ligand THF or Et2O 25−35 oC
R1 O
R2
O
R1
O
X
X R2 63
64
X
R1
R2
Ligand Yield (%) ee (%) Ref
CH2
Me
H
(S)-19 89
88
[91]
CH2
Me
Me (S)-19 87
92
[91]
a
CH2
Me
Cl
(S)-19 87
91
[91]
CH2
CH2CH=CMe2
H
(S)-19 97
91
[91]
a
CH2
CH2OTBDPS
H
(S)-19 86
81
[91]
CH2
(CH2)2CO2Et
H
(S)-19 96a
90
[91]
NBn
Et
H
(S)-19 91
92
[91]
CH2
F
H
(S)-19 80
(CH2)2 F
H
(CH2)2 F a
b
58
Me 58
91
[91]
b
86
[94]
b
88
[94]
92 82
Reaction performed with 4 mol% Pd2(dba)3 with 10 mol% ligand. Reaction performed with 5.5 mol% ligand in benzene at 40 8C.
The comparable yield and enantiomeric excess observed in products generated from enol carbonate, enol silane, and -keto ester substrates implies a common mechanism of bond formation in each of the three cases and ultimately this offers greater flexibility in synthetic planning.[95] The decarboxylative alkylation reactions have been applied in several synthetic endeavors. Notable successful implementations include the syntheses of terpenoids carissone (66) and cassiol (67) from enantioenriched vinylogous thioester 65 (Scheme 33),[96,97] and the synthesis of cyanthiwigin F (68) via a double enantioselective decarboxylative alkylation (Scheme 34).[98] Scheme 33 Enantioselective Syntheses of Carissone and Cassiol Using a Product of Decarboxylative Alkylation[96,97] OH
O 5 steps
10 steps
O
OH
O OH 66 carissone
PhS
OH 65
92% ee
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
67 cassiol
3.15.2
647
Alkylation of Enolates
Scheme 34 Double Enantioselective Decarboxylative Alkylation in the Synthesis of Cyanthiwigin F[98] O O
O
O
5 mol% Pd(dmdba)2 5.5 mol% (S)-19 Et2O
O O
O
78%
O 99% ee; dr 4.4:1
Pri
H H O
68
cyanthiwigin F
dmdba = bis(3,5-dimethoxybenzylidene)acetone
(S)-2-Allyl-2-methylcyclohexanone (64, X = CH2; R1 = Me; R2 = H); Typical Procedure:[84,91]
A 100-mL, round-bottomed flask was equipped with a magnetic stirrer bar and flame dried under reduced pressure. After cooling under dry N2, Pd2(dba)3 (22.9 mg, 0.025 mmol, 0.025 equiv) and (S)-t-BuPHOX [(S)-19; 24.2 mg, 0.0625 mmol, 0.0625 equiv] were added. The flask containing the solids was evacuated for 15 min and then refilled with dry N2. Anhyd THF (30 mL) was then added and the resulting soln was stirred at 25 8C for 30 min. At this point, allyl 1-methyl-2-oxocyclohexanecarboxylate (63, X = CH2; R1 = Me; R2 = H; 196.2 mg, 1.00 mmol) was added via syringe in one portion. When the reaction was complete by TLC, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, Et2O/pentane); yield: 129.6 mg (85%); 88% ee. When the reaction was performed in Et2O, a yield of 89% was obtained. 3.15.2.4.3
Decarboxylative Conjugate Addition/Allylic Alkylation Cascades with Palladium Catalysts
The putative chiral palladium enolate intermediate generated in the above cases is potentially useful for other enantioselective transformations. The first such application was enantioselective enolate protonation (see Section 3.15.1.3). Subsequently, carbon-based electrophiles have been examined (Scheme 35).[99] Benzylidenemalononitriles 70 effectively intercept the nucleophilic enolate derived from keto esters 69 to afford alkylated products bearing vicinal quaternary and tertiary stereocenters 71. The PHOX-type ligand 57, which has electron-withdrawing groups, is required for efficient reaction. Enantioselectivity is high across a range of electrophiles and enolate precursors, although diastereoselectivity is somewhat variable. These results indicate the potential of this method to enable general enolate functionalization beyond the confines of allyl electrophiles.
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
R1
5 mol% Pd2(dba)3
O X
Enolate Protonation, Alkylation, Arylation, Vinylation
Conjugate Addition/Allylation Cascades Catalyzed by Palladium[99]
Scheme 35 O
3.15
O
CN +
Ar1
O
R1 Ar1
12.5 mol% 57 1,4-dioxane, 40 oC
X NC
CN
R2 69
CN R2
70
71
X
R1
R2
Ar1
Yield (%)
dra
eeb (%)
Ref
CH2
Me
H
Ph
99
6.1:1
87
[99]
CH2
Et
H
Ph
91
3.5:1
99
[99]
CH2
Bn
H
Ph
65c
1.9:1
94
[99]
CH2
(CH2)2CO2Et
H
Ph
56
3.3:1
89
[99]
NBn
Me
H
Ph
97
>20:1
89
[99]
NBn
Et
H
Ph
99
>20:1
97
[99]
CH2
Me
H
3-MeOC6H4
78
8.2:1
86
[99]
CH2
Me
H
4-MeOC6H4
87
7.8:1
88
[99]
CH2
Me
H
4-Tol
76
6.2:1
87
[99]
CH2
Me
H
4-Me2NC6H4
54d
>20:1
99
[99]
CH2
Me
H
2-furyl
87
3.5:1
81
[99]
CH2
Et
H
2-furyl
92
2.3:1
96
[99]
CH2
Me
H
99
14.0:1
95
[99]
CH2
Me
83
9.4:1
82
[99]
O
a
b c d
O
H
(E)-CH=CHPh
In all cases the predominant minor diastereomer is epimeric at the benzylic position. The ee of the minor diastereomer ranged from 58 to 95%, when measurable. Value for major diastereomer. Reaction at 23 8C. Pd(dmdba)2 (10 mol%) was used instead of Pd2(dba)3; dmdba = bis(3,5-dimethoxybenzylidene)acetone.
2-Alkyl-2-(1-aryl-2,2-dicyanopent-4-enyl)cycloalkanones 71; General Procedure:[99]
A flame-dried, 50-mL Schlenk tube was charged with Pd2(dba)3 (13.7 mg, 0.015 mmol, 5 mol%) and ligand 57 (22.2 mg, 0.0375 mmol, 12.5 mol%) under argon and freshly distilled 1,4-dioxane (3 mL) was added. After stirring for 30 min at 23 8C, ester 69 (0.3 mmol, 1.0 equiv) and malononitrile 70 (0.3 mmol, 1.0 equiv) were added simultaneously. The resulting yellow-green soln was stirred at 40 8C for 16–72 h. The consumption of starting material was monitored by TLC (KMnO4 stain) or by NMR analysis of a small sample. The solvent was removed under reduced pressure and the dr was determined by crude 1H NMR spectroscopy. Isolation and separation of the diastereomers of 71 were achieved by flash chromatography (hexane/EtOAc). The enantiomeric excess was determined by either HPLC or supercritical fluid chromatography of the purified product.
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.15.2
3.15.2.4.4
649
Alkylation of Enolates
Alkylation of Tin Enolates Using Chromium Catalysts
In order to increase the scope of ketone alkylations to encompass simple alkyl electrophiles other than allyl derivatives, Jacobsen and Doyle have explored the combination of isolable tin enolates with chromium–salen catalysts (e.g., 72 and 73, Scheme 36).[100] Cyclic tin enolates 74 undergo efficient alkylation with a variety of electrophiles in the presence of catalyst 72 to afford of the Æ-quaternary ketones 75 in moderate to good yield and with excellent enantioselectivity (Scheme 37). Scheme 36
Chiral Chromium–Salen Catalysts for Ketone Alkylation[100,101]
N
N
N
Cr But
N Cr
But
O Cl O
O
Me
O Cl O
O
Si Me
But
But
But
(S,S)-72
Scheme 37
Me Si
But
But
But
Me
(R,R)-73
Chromium-Catalyzed Alkylation of Cyclic Ketones[100] 2.5−10 mol% catalyst R2X (4 equiv) benzene, 0 oC
OSnBu3 R1 Z
O R1 R2
Z 74
75
Z
R1
R2
CH2
Me CH2CH=CH2
Br (R,R)-72
2.5
84
94
S
[100]
CH2
Me CH2C”CH
Br (S,S)-72
2.5
81
96
R
[100]
CH2
Me CH2CO2Et
I
(R,R)-72
5.0
73
96
S
[100]
CH2
Me Bn
Br (S,S)-72
2.5
91
93
R
[100]
72
89
S
[100]
43
90
S
[100]
58
92
S
[100]
X
Catalysta
(CH2)2 Et
CH2CO2Et
I
(S,S)-72
(CH2)2 Et
Me
I
(S,S)-72
(CH2)3 Me CH2C”CH a
Br (R,R)-72
mol% of Catalyst Yield (%) ee (%) Config Ref
10 5.0 10
The different enantiomers of 72 gave opposite senses of stereoinduction.
Acyclic tin enolates are also viable substrates for this transformation using chromium complex 73 (Scheme 38).[101] Interestingly, mixtures of enolate isomers provide the Æ-quaternary ketones in very good yield, albeit with marginally lower enantioselectivity than in the cyclic system.
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.15
Enolate Protonation, Alkylation, Arylation, Vinylation
Scheme 38 Chromium-Catalyzed Alkylation of Acyclic Enolates[101]
OSnBu3
5 mol% (R,R)-73 5 mol% Bu3SnOMe R2X (2 equiv) o-xylene, −27 oC, 48 h
O R2 R1
R1
R1 R2
X Yielda (%) ee (%) Ref
Et CH2CH=CH2
I
83
82
[101]
Et Bn
Br 86
81
[101]
Et CH2CO2Et
I
73
76
[101]
Bu CH2CH=CH2
I
92
87
[101]
Bu Bn
Br 83
86
[101]
Bu CH2CO2Et
I
77
84
[101]
Bu CH2C”CTMS
Br 97
78
[101]
a
1
For starting enolate R = Et, E/Z = 1.8:1; for enolate R1 = Bu, E/Z = 1.5:1.
The chromium–salen catalyzed alkylation is unmatched in terms of electrophile scope, although the competent electrophiles are generally activated in some way. The use of stoichiometric tin enolates detracts from its practicality given the associated toxicity. 2-Allyl-2-methylcyclopentanone (75, Z = CH2; R1 = Me; R2 = CH2CH=CH2); Typical Procedure:[100]
CAUTION: Alkyltin compounds are highly toxic and should be handled with care. A 10-mL Schlenk flask was flame dried under reduced pressure, cooled to 23 8C, and charged with catalyst (R,R)-72 (7.9 mg, 0.0125 mmol, 2.5 mol%) under N2. The flask was evacuated and flushed with N2 (2 ) and then held under vacuum for an additional 10 min. Benzene (250 L) (CAUTION: carcinogen) and allyl bromide (173 L, 2 mmol, 4 equiv) were added, and the soln was cooled to 0 8C under N2 in a ice–water bath for 10 min. A soln of tin enolate 74 (Z = CH2; R1 = Me; 204 mg, 95% pure, 0.5 mmol, 1 equiv) in benzene (1.0 mL) was prepared in a flame-dried 2-dram vial. The soln was cooled in an ice bath with vigorous stirring under N2 for 5 min and then added dropwise by syringe to the Schlenk flask, followed by one benzene rinse (0.1 mL). The mixture was stirred at 0 8C for 2 h and then diluted with pentane (5 mL), transferred into a 18 150 mm borosilicate glass test tube containing sat. aq NaCl (1 mL), and cooled to 0 8C. Solid KF (~1–2 g) was added and formation of a white precipitate was observed. The mixture was filtered through a bed of Na2SO4 into a flask cooled to 0 8C and the filtrate was concentrated to ~1.5 mL by rotary evaporation in a 4 8C bath. The residue was purified by column chromatography (silica gel, Et2O/pentane 2:98). Concentration of the desired fractions was again performed in a 4 8C bath to give a clear oil; yield: 57.8 mg (84%); 94% ee (chiral GC). 3.15.2.4.5
Alkylation of Æ-Bromoamides Using Nickel Catalysts
Æ-Halo ketones are activated electrophiles that are useful in various alkylation reactions. These species are also activated toward oxidative addition in the presence of low-valent transition metals, a feature that provides the opportunity to develop enantioselective cross-coupling reactions of halo ketones with organometallics. Fu and Fischer demonstrated that nickel catalysts are particularly effective for sp3—sp3 cross-coupling reactions, Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
651
Alkylation of Enolates
3.15.2
which are enantioselective in the presence of the appropriate chiral ligands (Scheme 39).[102] For example, in the cross coupling of Æ-bromoamides 77 with alkylzinc reagents, the pybox ligand 76 is preferred. These reactions provide the alkylation products 78 in good yield and with excellent enantioselectivity. The scope of reaction partners is very good and the cross-coupling technique avoids some of the common pitfalls of traditional alkylations. This reaction is covered from a cross-coupling perspective in Section 3.14.1.2. Scheme 39 Nickel-Catalyzed Alkylation of Bromoamides with Alkylzinc Reagents[102]
O
O
N N
N Pri
Pri (R,R)-76
R2ZnX (1.3 equiv) 10 mol% NiCl2•DME 13 mol% (R,R)-76
O Bn
N Ph
O
1,3-dimethylimidazolidin-2-one THF, 0 oC, 12 h
R1
Bn
Br
R1
N R2
Ph
77
78
R1
R2
X Yield (%) ee (%) Ref
Et
(CH2)5Me
Br 90
96
[102]
Et
Me
I
90
91
[102]
Et
(CH2)3Ph
Br 84
96
[102]
Bu (CH2)5Me
Br 85
96
[102]
iBu Me
I
78
87
[102]
Et
(CH2)2CH=CMe2
Br 78
95
[102]
Et
(CH2)4OBn
Br 77
96
[102]
Br 60a
98a
[102]
Br 51
96
[102]
Br 70
93
[102]
O
Me
O
3
O N
Et
4
O
Et a
(CH2)5CN
Value obtained after recrystallization.
Although the fine mechanistic details remain unclear, the operative pathway allows for an enantioconvergent reaction wherein a racemic Æ-halo carbonyl compound is converted into a highly enantioenriched product with high efficiency. Several related transformations have been disclosed for enantioselective arylation and vinylation (see Sections 3.15.3.3, 3.15.4.2.2, and 3.15.4.2.3).
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
652
Stereoselective Synthesis
Enolate Protonation, Alkylation, Arylation, Vinylation
3.15
Æ-Alkylamides 78; General Procedure:[102] In the air (no special precautions are necessary), a 10-mL Schlenk flask was charged with NiCl2•DME (22.0 mg, 0.100 mmol), (R,R)-iPr-pybox [(R,R)-76, 39.2 mg, 0.130 mmol], and the Æ-bromoamide 77 (1.00 mmol). The flask was purged with argon for 5 min, and then 1,3dimethylimidazolidin-2-one (2.2 mL) and THF (0.5 mL) were added. The resulting orange soln was stirred at rt for 20 min, and then the flask was placed into a 0 8C bath. The mixture was stirred for 10 min, and then a 1 M soln of the organozinc reagent in 1,3-dimethylimidazolidin-2-one (1.3 mL, 1.3 mmol) was added. The resulting dark brown mixture was stirred for 12 h at 0 8C. Then, the excess organozinc reagent was quenched by the addition of EtOH (0.5 mL), and the brown mixture was passed through a plug of silica gel (eluted with Et2O) to remove inorganic salts and most of the 1,3-dimethylimidazolidin-2one. The filtrate was concentrated, and the resulting orange oil was purified by flash chromatography. 3.15.3
Arylation of Enolates
Carbonyl compounds bearing Æ-aryl substituents represent an important class of pharmaceuticals (e.g., the profen-type anti-inflammatory agents). Efforts by several research groups have culminated in a variety of cross-coupling-based tactics to achieve the arylation of enolates.[103] Control of stereoselectivity in C—C bond formation has proven particularly challenging since the technology for the arylation of enolates has not been explored as extensively as the corresponding alkylation reactions. Moreover, the arylation protocols often utilize transition-metal catalysts, which necessitate catalytic conditions to maintain cost efficiency. 3.15.3.1
Arylation of Enolates via Chiral Auxiliary Control
Analogous to enolate alkylation, chiral auxiliaries have proven useful for stereochemical control in enolate arylations. Silyl enol ethers (e.g., 79) derived from chiral imides provide moderate stereoselectivity in palladium-catalyzed cross-coupling reactions with aryl bromides (Scheme 40).[104] Lewis acidic zinc salts are beneficial additives to the reaction, wherein zinc(II) tert-butoxide permits the reaction to proceed at room temperature and in some cases gives an increase in diastereoselectivity for the products 80. Additionally, the more sterically demanding tert-butyl-substituted oxazolidinone provides a small increase in diastereocontrol, whereas increasing the steric demands on the propanoate fragment decreases the yield of product. Scheme 40
O O
Arylation of Enolates with Oxazolidinone Auxiliaries[104] 5 mol% Pd(dba)2 10 mol% t-Bu3P ZnF2 (0.5 equiv)
OTMS +
N
Ar1Br
O
Pri
O Ar1
N Pri
79
Ar1
O
DMF, 80 oC, 12 h
80
Yield (%) dr
Ref a
Ph
70
91:9
[104]
Ph
67
87:13
[104]
2-Tol
78
92:8
[104]
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Ar1
Yield (%) dr
Ref
3-AcC6H4
75b
84:16
[104]
4-NCC6H4
65
77:23
[104]
4-t-BuC6H4 57
83:17
[104]
a
b
Reaction at room temperature with Zn(Ot-Bu)2 (0.25 equiv) as additive. Combined yield of both diastereomers.
In the search for a more effective auxiliary, the chiral dioxanones popularized by Ley and coworkers[105] were found to serve as very effective stereochemical controllers with a variety of aryl halide coupling partners (Scheme 41). Using the enol silane 81, arylation proceeds cleanly to afford the arylated products 82 with very high diastereocontrol. Yields are optimal with electron-deficient aryl halides, and in some cases elevated temperatures are necessary for efficient coupling. The straightforward removal of the auxiliary in the arylated products using chlorotrimethylsilane and methanol affords the corresponding Æ-hydroxy esters with >99.5% enantiomeric excess. Arylation of Enolates with the Ley Auxiliary[104]
Scheme 41
5 mol% Pd(dba)2 10 mol% t-Bu3P additive
OMe
TMSO
O +
O
Ar1
OMe
O
DMF, 12 h
Br
Ar1
OMe
O
O
H
81
OMe 82
Ar1
Additive (equiv)
Temp (8C) Yield (%) dr
Ref
4-MeOC6H4
ZnF2 (0.5)
80
Ph
57
>50:1
[104]
Zn(Ot-Bu)2 (0.25) rt
73
>50:1
[104]
2-ClC6H4
ZnF2 (1.0)
80
78
20:1
[104]
3-AcC6H4
ZnF2 (1.0)
80
76
25:1
[104]
3-O2NC6H4
Zn(Ot-Bu)2 (0.5)
rt
89
>50:1
[104]
4-MeO2CC6H4
Zn(Ot-Bu)2 (0.5)
rt
95
>50:1
[104]
1-naphthyl
ZnF2 (1.0)
80
72
>50:1
[104]
2-naphthyl
ZnF2 (0.5)
80
58
>50:1
[104]
Dioxolanones such as 83, formed from enantiopure mandelic acid, are effective auxiliaries for preparing arylmandelic acid derivatives 84 (Scheme 42).[106] Yields and diastereoselectivities are uniformly high for electron-rich and electron-poor aryl bromide coupling partners. Two examples of cross coupling with hetaryl bromides have also been reported, but the selectivity is somewhat decreased. The arylation method is limited to Æ,Æ-diaryl acetates at this point, and the chiral component is used in more than twofold excess (2.3 equiv relative to the aryl bromide). Vinylations with this auxiliary are also highly stereoselective (see Section 3.15.4.1).
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Enolate Protonation, Alkylation, Arylation, Vinylation
Enolate Arylation with a Dioxolanone Auxiliary[106]
Scheme 42
O Ph
O
3.15
+
Ar
1Br
2 mol% Pd(OAc)2 8 mol% t-Bu3P•HBF4 LiHMDS (2.5 equiv) toluene, rt
O Ar1 O
O
O
But
Ph
But 83
Ar1
84
Yield (%) dr
Ref
4-t-BuC6H4
96
99.5:0.5
[106]
4-MeSC6H4
95
99:1
[106]
4-F3CC6H4
85
99.5:0.5
[106]
a
4-OHCC6H4
77
96.5:3.5
[106]
3-ClC6H4
90
98.5:1.5
[106]
3-EtO2CC6H4
93
98.5:1.5
[106]
3-MeOC6H4
95
99.5:0.5
[106]
98
99.5:0.5
[106]
92a
87:13
[106]
98
91:9
[106]
O O
3-pyridyl
Cl a
S
Reaction carried out at 50 8C for 12 h.
(R)-4-Isopropyl-3-[(R)-2-phenylpropanoyl]oxazolidin-2-one (80, Ar1 = Ph); Typical Procedure:[104]
To a screw-capped vial containing 0.50 M t-Bu3P in toluene (200 L, 0.10 mmol), Pd(dba)2 (29 mg, 0.050 mmol), ZnF2 (52 mg, 0.50 mmol), and PhBr (157 mg, 1.00 mmol) were added the trimethylsilyl enolate of the Evans imide 79 (370.0 mg, 1.44 mmol), followed by DMF (10 mL). The vial was sealed with a cap containing a PTFE septum and removed from the drybox. The heterogeneous mixture was stirred at 80 8C for 12 h. The crude mixture was then allowed to cool to rt and diluted with Et2O. The resulting soln was washed with H2O. The organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc/hexanes 2:98); yield: 67%. 5,6-Dimethoxy-5,6-dimethyl-3-(3-nitrophenyl)-1,4-dioxan-2-one (82, Ar1 = 3-O2NC6H4); Typical Procedure without Drybox:[104]
To a round-bottomed flask were added Pd(dba)2 (2.9 mg, 0.0050 mmol), Zn(Ot-Bu)2 (21.0 mg of commercial material, which is about 50% H2O by weight), the trimethylsilyl enolate of the Ley auxiliary 81 (34.0 mg calculated according to the purity, 0.130 mmol), and 3-bromonitrobenzene (20.2 mg, 0.100 mmol). The flask was purged with N2 for 5 min before addition of 0.5 M t-Bu3P in toluene (20 L, 0.010 mmol). DMF (1.0 mL) was then added, and the resulting mixture was stirred for 12 h. Trimethoxybenzene as an internal standard was then added to the soln, and the mixture was partitioned between Et2O (5.0 mL) and H2O (2.0 mL). The Et2O layer was washed with H2O, and the Et2O was evaporated under reduced pressure. The yield of 82 measured by NMR spectroscopy was determined with Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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an internal standard to be nearly quantitative, which is similar to the yield observed when the reactions are assembled in a drybox. 5,5-Diaryl-2-tert-butyl-1,3-dioxolan-4-ones 84; General Procedure:[106]
An oven-dried disposable test tube containing a magnetic stirrer bar was charged with (2S,5S)-2-tert-butyl-5-phenyl-1,3-dioxolan-4-one (83; 506 mg, 2.3 mmol, 2.3 equiv), Pd(OAc)2 (5.6 mg, 0.02 equiv), and t-Bu3P•HBF4 (23.1 mg, 0.08 equiv), capped with a Teflon septum, evacuated, and then backfilled with argon. The tube was brought into a N2-filled glovebox where LiHMDS (418 mg, 2.5 mmol, 2.5 equiv) was added. The test tube was removed from the glovebox and evacuated and backfilled with argon (2 ). The tube was placed in a bath at –10 8C (ice/acetone) and toluene (2 mL) was added. After 10 min of agitation at this temperature, the aryl bromide was added via syringe [if the aryl halide was solid, it was added dissolved in toluene (2 mL)]. Agitation at this temperature was continued for a further 10 min, and the mixture was allowed to warm to rt and stirred for 14– 18 h. At this point, the reaction was quenched with sat. aq NH4Cl (4 mL), and the mixture was stirred for 5 min. The layers were separated, and the aqueous layer was extracted with EtOAc (2 3 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (typically hexanes to hexanes/EtOAc 19:1) or preparative TLC. 3.15.3.2
Arylation of Enolates with Aryl Halides and Trifluoromethanesulfonates Using Chiral Transition-Metal Catalysts
The catalytic Æ-arylation of ketones is an important area of research, which has precipitated the development of several useful protocols for the construction of Æ-aryl carbonyl compounds.[103] In this context, chiral palladium complexes have proven particularly effective for Æ-arylation, using several chiral ligands 85–89 that typically bear at least one phosphine and often a chiral biaryl backbone (Scheme 43). Scheme 43
Phosphine Ligands for Arylation and Vinylation F PPh2 PPh2
F F F
(S)-85 (S)-BINAP
O O
PPh2
NMe2
O
PPh2
PPh2
O (R)-87
(S)-86 (S)-DIFLUORPHOS
But P O Pri P Pri
(S)-88
Ph
NMe2
(S,SP)-89
Arylations have also been successful with chiral nickel catalysts supported by chelating nitrogen-based ligands. These transformations are mechanistically distinct from the palladium-catalyzed methods since the polarity of the coupling partners is reversed.
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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3.15.3.2.1
Palladium- and Nickel-Catalyzed Arylation with Aryl Halides
3.15
Enolate Protonation, Alkylation, Arylation, Vinylation
Due to the strongly basic reaction conditions, the pioneering work on the enantioselective arylation of ketone enolates was primarily restricted to ketones that contain a single acidic site. Simple ketones may be alkylated by blocking one of the ketone Æ-positions through its condensation with benzaldehyde [e.g., 90 (R1 = Ph); Scheme 44]. The benzylidene moiety, though effective, is difficult to remove and the more amenable aminomethylene group was introduced to circumvent this problem. Biaryl ligands 85 and 88 have proven the most effective in these types of enolate arylations, providing the alkylated ketones 91 in good yield and with excellent enantiomeric excess for a range of substitutions and aryl coupling partners.[107,108] Increasing the size of the cycloalkanone leads to a substantial decrease in the level of enantioselectivity. Scheme 44
Enantioselective Arylation of Cyclic Enolates[107,108] R3
O R2 R1
R4
Pd2(dba)3, ligand t-BuONa (2 equiv)
O R2
toluene, rt
+
R3
R1 Br
R4 90
91
R1
R2
R3
R4
Pda (mol%)
Ligand
Yield (%)
ee (%)
Ref
Ph
Me
H
t-Bu
20b,c
(S)-85
75
98
[107]
Ph
Me
H
20c,d
(S)-85
86
95
[107]
H
10c
(S)-85
96
86
[108]
O O O
NMePh
Me O
NMePh
Me
H
Me
2
(S)-88
84
93
[108]
NMePh
Me
H
t-Bu
2
(S)-88
84
93
[108]
NMePh
Me
H
OMe
2
(S)-88
80
94
[108]
NMePh
Me
OMe
H
2
(S)-88
80
89
[108]
NMePh
Me
Me
H
2
(S)-88
85
94
[108]
NMePh
Pr
Me
H
2
(S)-88
85
88
[108]
NMePh
(CH2)4Me
Me
H
5
(S)-88
86
91
[108]
a b c d
Ratio Pd/ligand 1:1.2; 2 equiv of aryl bromide was employed. Pd(OAc)2 was used in place of Pd2(dba)3. Reaction carried out at 100 8C. NaHMDS was used in place of t-BuONa.
Similar methodology has been developed for the arylation of butyrolactones 92 using a catalyst derived from bis(cycloocta-1,5-diene)nickel(0) and binaphthyl ligand 85.[109] Using this catalyst system the Æ-aryl lactones 93 are readily available in good yield and with excellent enantiomeric excess from the asymmetric coupling of the butyrolactones 92 with aryl halides (Scheme 45). The choice of base is critical to the success of the reaction, since sodium tert-butoxide leads to reduction of the aryl halide and thus lower yield. Aryl bromides are competent coupling partners, but in general higher yields are observed with aryl chlorides. Additionally, a substoichiometric amount of zinc(II) bromide has a Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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beneficial effect on the reaction, which is presumably due to the ability of the zinc salt to accelerate the transmetalation step. Scheme 45
Enantioselective Arylation of Lactones[109]
R2
O R1
O
R3
5 mol% Ni(cod)2 8.5 mol% (S)-85 15 mol% ZnBr2 NaHMDS (2.3 equiv) toluene, 50 oC
O R1 R2
O
+ Cl
R3
92
93
R1
R2
R3
Yielda (%) ee (%) Ref
Me
OMe
H
86
96
[109]
Me
H
H
86
>97
[109]
Me
H
OTBDMS
67
95
[109]
b
Me
CO2t-Bu H
58
93
[109]
Me
H
73
CO2Et
90
[109]
c
Bn
NMe2
H
58
96
[109]
CH2CH=CH2
OMe
H
56c
95
[109]
H
c
98
[109]
Pr a b c
H
84
Relative to the aryl chloride, 2 equiv of ester was used. The aryl bromide was used. Performed with 10 mol% Ni(cod)2 and 17 mol% ligand.
2-Aryl-5-alkylidenecyclopentanones 91; General Procedure:[108]
An oven-dried Schlenk tube equipped with a rubber septum was evacuated and backfilled with argon. The tube was charged with Pd2(dba)3 (0.005 mmol), ligand (S)-88 (0.0125 mmol), and ketone 90 (0.50 mmol). The tube was evacuated and backfilled with argon (3 ). Toluene (2 mL) was added and the mixture was stirred for 15 min at rt. Aryl halide (1.00 mmol) and t-BuONa (96 mg, 1.00 mmol) were added to the tube. The tube was capped with a septum and purged with argon, and additional toluene (1 mL) was added through the septum. The mixture was stirred at rt until the starting ketone had been completely consumed as judged by GC analysis. The reaction was quenched with sat. aq NH4Cl (10 mL) and diluted with Et2O (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with Et2O (20 mL) and the combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude materials were purified by chromatography (silica gel, EtOAc/hexane 1:9 to 1:4). 3-Aryl-3-methyltetrahydrofuran-2-ones 93 (R1 = Me); General Procedure:[109]
An oven-dried, resealable Schlenk tube containing a magnetic stirrer bar was allowed to cool to rt and then charged with (S)-BINAP [(S)-85; 13.2 mg, 21.3 mol]. The tube was sealed, evacuated, and backfilled with argon. A freshly prepared, yellow, homogeneous 0.05 M stock soln of Ni(cod)2 in toluene (250 L, 12.5 mol) was added by syringe while purging with argon. The tube was sealed and heated to 60 8C for 5 min during which time the soln turned dark red. The reaction vessel was removed from the oil bath, and sequentially 3-methyltetrahydrofuran-2-one (92, R1 = Me; 47.0 L, 0.5 mmol), dodecane (50 L, internal standard), and NaHMDS (105.4 mg, 0.575 mmol) were added under argon. A 0.15 M stock soln of ZnBr2 in THF (250 L, 37.5 mol) was added by syringe Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Enolate Protonation, Alkylation, Arylation, Vinylation
while purging with argon; the mixture was then stirred for 5 min at rt. The aryl halide (0.25 mmol) was added by syringe or as a solid followed by the addition of toluene (500 L) while purging with argon. The tube was sealed and heated at 50 8C. After complete conversion had been accomplished, as judged by GC analysis, the mixture was allowed to cool to rt and then filtered through a pad of silica gel (3 0.5 cm), eluting with EtOAc. The eluate was concentrated under reduced pressure, and the residue was purified by chromatography [silica gel (1.5 30 cm) EtOAc/hexane]. Palladium- and Nickel-Catalyzed Arylation with Aryl Trifluoromethanesulfonates
3.15.3.2.2
Hartwig and coworkers also developed highly enantioselective palladium-catalyzed enolate arylations.[110] The complex of palladium and the chiral DIFLUORPHOS ligand (86) also catalyzes the arylation of cyclic ketones 94. Superior yields and enantiomeric excesses of Æ-aryl ketones 95 are obtained with aryl trifluoromethanesulfonate coupling partners rather than aryl halides (Scheme 46). The reaction is highly selective for electron-rich and electron-neutral aryl groups although electron-deficient aryl trifluoromethanesulfonates provide lower enantiomeric excesses with this catalyst. The corresponding nickel complex with ligand 86, however, proves effective for the arylation of tetralones and indanones with electron-poor aryl trifluoromethanesulfonates. Additionally, enantioselectivity in the palladium-catalyzed transformation is sensitive to ring size, whereas the nickel-catalyzed reaction gives uniformly high product enantioselectivity with both tetralone- and indanone-derived pronucleophiles. Scheme 46 Enantioselective Ketone Arylation with Aryl Trifluoromethanesulfonates[110] R1 R1
O
R2
O R2
+
X
TfO
94
X 95
X
R1
R2
Conditions
Yield (%) ee (%) Ref
CH2
H
H
Pd(dba)2 (10 mol%), 86 (12 mol%), t-BuONa (2 equiv), toluene, 60 8C
77
70
[110]
(CH2)2 H
H
Pd(dba)2 (10 mol%), 86 (12 mol%), t-BuONa (2 equiv), toluene, 60 8C
81
90
[110]
(CH2)2 H
Me
Pd(dba)2 (10 mol%), 86 (12 mol%), t-BuONa (2 equiv), toluene, 60 8C
79
92
[110]
(CH2)2 OMe OMe Pd(dba)2 (10 mol%), 86 (12 mol%), t-BuONa (2 equiv), toluene, 60 8C
79
91
[110]
CH2
H
CN
Ni(cod)2 (5 mol%), 86 (6 mol%), t-BuONa (2 equiv), toluene, 80 8C 84
95
[110]
CH2
H
CF3
Ni(cod)2 (5 mol%), 86 (6 mol%), t-BuONa (2 equiv), toluene, 80 8C 69
96
[110]
(CH2)2 H
CN
Ni(cod)2 (5 mol%), 86 (6 mol%), t-BuONa (2 equiv), toluene, 100 8C 55
97
[110]
(CH2)2 H
CF3
Ni(cod)2 (5 mol%), 86 (6 mol%), t-BuONa (2 equiv), toluene, 100 8C 40
98
[110]
Similar to the Buchwald system, the palladium-catalyzed arylation of ketones bearing benzylidene blocking groups is quite sensitive to the ketone ring size (Scheme 47). Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Arylation of Enolates Effect of Ring Size on Enolate Arylation[110]
Scheme 47
10 mol% Pd(dba)2 12 mol% 86
O
O
t-BuONa (2 equiv)
Ph
o
toluene, 60 C
+
Ph
PhOTf
X
Ph X
X
Yield (%) ee (%) Ref
CH2
70
95
[110]
(CH2)2 80
78
[110]
Other miscellaneous enolate arylations are available, but are somewhat limited in scope. Noteworthy examples include intermolecular arylation of keto esters with a copper catalyst,[111] intramolecular arylation of aldehydes,[112] intramolecular arylations to form indol2-ones,[113–115] and intermolecular arylations of indol-2-ones.[116] 2-Methyl-2-arylcycloalkanones 95; General Procedure Using Tris(dibenzylideneacetone)dipalladium(0):[110]
In a drybox, a screw-capped vial containing DIFLUORPHOS (86; 8.2 mg, 0.012 mmol), Pd(dba)2 (5.8 mg, 0.010 mmol), t-BuONa (19.2 mg, 0.200 mmol), and ketone 94 (0.100 mmol) in toluene (2.0 mL) was prepared. The aryl trifluoromethanesulfonate (0.200 mmol) was added and the vial was sealed with a cap containing a PTFE septum and removed from the drybox. The mixture was stirred at 60 8C for 48 h. The crude mixture was then cooled to rt, and the reaction was quenched with ice water. The resulting soln was then diluted with EtOAc (15 mL) and washed with brine. The organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by preparative TLC (hexane/Et2O 97:3). 2-Methyl-2-(4-cyanophenyl)indan-1-one (95, X = CH2; R1 = H; R2 = CN); Typical Procedure Using Bis(cycloocta-1,5-diene)nickel(0):[110]
In a drybox, a screw-capped vial containing DIFLUORPHOS (86; 10.3 mg, 0.0150 mmol), Ni(cod)2 (3.5 mg, 0.0127 mmol), t-BuONa (48.0 mg, 0.500 mmol), and 2-methylindan-1-one (94, X = CH2; 36.5 mg, 0.250 mmol) in toluene (2.0 mL) was prepared. 4-Cyanophenyl trifluoromethanesulfonate (188 mg, 0.750 mmol) was then added and the vial was sealed with a cap containing a PTFE septum and removed from the drybox. The mixture was stirred at 80 8C for 60 h. The crude mixture was then cooled to rt, and the reaction was quenched with ice water. The resulting soln was then diluted with EtOAc (20 mL) and washed with brine. The organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, hexane/Et2O 4:1); yield: 54.6 mg (84%). 3.15.3.3
Nickel-Catalyzed Arylations with Arylmetals
Fu and coworkers have examined the Æ-arylation of halo ketones with arylmetal nucleophiles, wherein the polarity of the cross-coupling reaction is reversed. To date, Hiyama, Negishi, Kumada, and Suzuki cross-coupling variants have been developed. Importantly, each of these methods is useful for preparing tertiary stereogenic centers, in contrast to the standard enolate arylations. Three classes of ligands have emerged for these reactions, namely the diarylethylenediamines 96, pybox derivatives 97, and bis(dihydrooxazoles) [bis(oxazolines)] 98 (Scheme 48).
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Enolate Protonation, Alkylation, Arylation, Vinylation
Scheme 48 Ligands for Enantioselective Arylation and Vinylation of Æ-Halocarbonyl Compounds R3 Ar1
Ar1
O R1
Me
NH
N
HN Me
O
N
O R1
N
R2
R1
R2
96
R3 O
N
R1
N
R2
R2
97
98
Although the mechanism of these nickel-catalyzed reactions has not been fully elucidated,[117,118] one plausible reaction pathway includes oxidative addition of the nickel species to the Æ-halo ketone to form a carbon-bound nickel enolate. The nature of the active nickel catalyst and the order of elementary steps remain unclear, and the degree of mechanistic analogy between reactions with different classes of nucleophiles and ligands is also uncertain. 3.15.3.3.1
Hiyama-Type Arylation of Esters
The first enantioselective Æ-arylation reported in this manifold was Hiyama-type cross coupling of Æ-bromo esters 99 with arylsilanes 100 (Scheme 49).[119] This transformation is most effective in the presence of diamine ligand 101. Electron-neutral and electron-rich aryl silanes are suitable pronucleophiles, which are activated with the fluoride donor tetrabutylammonium triphenyldifluorosilicate (TBAT). Potentially reactive groups, including esters, alkyl bromides, and benzylic chlorides, are compatible with the reaction conditions. Although the yields of the Æ-aryl esters 102 are somewhat variable, the enantiomeric excesses are excellent. This reaction is covered from a cross-coupling perspective in Section 3.14.1.2. Scheme 49
Nickel-Catalyzed Arylation of Bromo Esters with Arylsilanes[119] Ph
Ph
12 mol% Me
Bu
HN Me
10 mol% NiCl2•DME Bu4NSiF2Ph3 (2 equiv), 1,4-dioxane
O R1
O But
NH
(S,S)-101
t
+
Ar1Si(OMe)
3
Br 99
100 But O R1
O Ar1
But 102
R1
Ar1
Yield (%) ee (%) Ref
Me
Ph
84
89
[119]
Et
Ph
80
99
[119]
iBu
Ph
64
93
[119]
(CH2)2CO2Me
Ph
80
92
[119]
(CH2)2OMe
Ph
68
99
[119]
(CH2)2Br
Ph
70
86
[119]
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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R1
Ar1
Yield (%) ee (%) Ref
Et
2-naphthyl
74
89
[119]
Et
4-Tol
76
92
[119]
Et
4-MeOC6H4
64
87
[119]
Et
4-ClCH2C6H4 72
94
[119]
2,6-Di-tert-butyl-4-methylphenyl 2-Arylalkanoates 102; General Procedure:[119]
In a glovebox, dioxane (10 mL) was added to a mixture of (S,S)-101 (14.4 mg, 0.060 mmol), NiCl2•DME (11.0 mg, 0.050 mmol), and Bu4NSiF2Ph3 (TBAT; 539 mg, 1.00 mmol) in a 20-mL vial. The mixture was stirred for 10 min, and then the silane 100 (0.65 mmol) and the Æ-bromo ester 99 (0.50 mmol) were added. The mixture was stirred for 16 h at rt, and then a soln of 1 M HCl/acetone (1:1; 5 mL) was added. The mixture was stirred for 2 h, and then poured into H2O (30 mL) and extracted with Et2O (2 30 mL). The combined organic layer was washed with brine (30 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography (silica gel, CH2Cl2/hexanes 1:19 to 1:4). 3.15.3.3.2
Negishi-Type Arylation of Ketones
Arylation of the Æ-halo ketones 104 with organozinc nucleophiles is a highly effective protocol (Scheme 50).[120] In this case, the tridentate pybox framework 103 is optimal for the cross-coupling reaction (see also Section 3.14.1.2), which is tolerant to substituents on the aryl and Æ-alkyl groups of the electrophile 104 and the nucleophile 105, respectively. Steric encumbrance on the nucleophile (e.g., ortho-substitution) or branching at the carbon to the carbonyl on the electrophile leads to severely decreased yields. A single example of a heteroaromatic ketone has also been reported. The Æ-aryl ketones 106 are generally obtained in very good yield and with excellent enantiomeric excess. Scheme 50 Nickel-Catalyzed Arylation of Bromo Ketones with Arylzinc Reagents[120]
O Ph
O
N N
N
Ph OMe
MeO (+)-103
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
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6.5 mol% (+)-103 5 mol% NiCl2•DME DME/THF, −30 oC
O R1
Ar1
+
Enolate Protonation, Alkylation, Arylation, Vinylation
Ar2ZnI
O R1
Ar1 Ar2
Br 104
105
106
Ar1
R1
Ar2
Yield (%) ee (%) Ref
Ph
Me
Ph
86
96
[120]
Ph
Me
3-Tol
88
94
[120]
Ph
Me
4-FC6H4
74
96
[120]
Ph
Me
4-MeOC6H4
93
96
[120]
Ph
Me
4-MeSC6H4
71
96
[120]
Ph
Et
Ph
86
94
[120]
Ph
Bn
Ph
76
95
[120]
Ph
(CH2)2Cl
Ph
90
92
[120]
Ph
iBu
Ph
89a
95
[120]
b
4-MeOC6H4
Me
Ph
90
96
[120]
2-thienyl
Me
Ph
81
96
[120]
a b
Reaction performed at –20 8C. Ar22Zn (1.1 equiv) was used rather than Ar2ZnI.
Aryl Æ-Arylalkyl Ketones 106; General Procedure:[120]
A soln of the arylmagnesium bromide (1.6 mmol, 1.6 equiv) was added to a soln of ZnI2 (510 mg, 1.6 mmol, 1.6 equiv) in THF (final concentration of Ar2ZnI = 0.20 M) under argon. The mixture was stirred for 40 min at rt (a precipitate was immediately observed), and then cooled to –30 8C. NiCl2•DME (11.0 mg, 0.050 mmol, 0.050 equiv) and (+)-103 (29.9 mg, 0.065 mmol, 0.065 equiv) were added to an oven-dried 50-mL flask. The flask was purged with argon, and then the Æ-bromo ketone 104 (1.0 mmol, 1.0 equiv) and DME (13.5 mL) were added in that order. This soln was stirred at rt for 20 min, and then cooled to –30 8C. The suspension of Ar2ZnI (6.5 mL, 1.3 mmol, 1.3 equiv) was added dropwise over 3 min, and the mixture was stirred at –30 8C for 4 h. The reaction was then quenched with sat. NH4Cl (10 mL). The mixture was diluted with Et2O (50 mL) and distilled H2O (10 mL). The organic layer was separated, washed with brine (10 mL), dried (MgSO4), and concentrated. The residue was purified by flash column chromatography. 3.15.3.3.3
Kumada-Type Arylation of Ketones
Organomagnesium reagents are particularly attractive nucleophiles in cross-coupling reactions, owing to their highly developed preparative methods and synthetic applications. The aryl Grignard reagents 108 have been employed in the enantioselective nickel-catalyzed Kumada arylation of aryl Æ-haloalkyl ketones 107 using the bis(dihydrooxazole) ligand 109 (Scheme 51).[121] Despite the highly basic nature of organomagnesium species, very high enantiomeric excesses are obtained in the formation of stereochemically labile Æ-aryl ketones 110. A wide variety of coupling partners are effective in this transformation, including electron-rich and electron-deficient aryl groups, heteroaromatics, and sensitive functional groups, such as an alkyl azide. This reaction is covered from a cross-coupling perspective in Section 3.14.1.2.
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.15.3
663
Arylation of Enolates
Scheme 51 Nickel-Catalyzed Arylation of Alkyl Aryl Ketones with Arylmagnesium Reagents[121] O
O 9 mol%
N
N Ph
Ph (R,R)-109
O R1 +
Ar1
O
7 mol% NiCl2•DME DME, −60 oC
Ar2MgX
R1
Ar1 Ar2
Br 107
108
110
Ar1
R1
Ar2
Yield (%) ee (%) Ref
Ph
Me
Ph
81a
92
[121]
Ph
Me
2-EtO2CC6H4
79b
80
[121]
b
95
[121]
b
94
[121]
b
95
[121]
b
Ph Ph Ph
Me Me Me
3-NCC6H4 4-F3CC6H4 4-EtO2CC6H4
91 84 91
Ph
Me
4-IC6H4
83
94
[121]
Ph
Me
4-MeOC6H4
82b
91
[121]
Ph
Me
87b
91
[121]
73b
90
[121]
Ph
89a
72
[121]
Ph
a
92
[121]
a
O
Ph
Me N Boc
2-FC6H4 3-MeOC6H4
Me Me
81
4-BrC6H4
Me
Ph
80
80
[121]
4-BnOC6H4
Me
Ph
80a
90
[121]
a
2-thienyl
Me
Ph
91
87
[121]
Ph
(CH2)2Cl
Ph
73a
86
[121]
a
Ph
(CH2)2N3
Ph
72
80
[121]
Ph
(CH2)2OAc
Ph
74a
85
[121]
a b
Commercially available PhMgBr used. Grignard reagent formed in situ from Ar2I and iPrMgCl.
Complementary arylations of dialkyl ketones have also been developed with similar reaction conditions (Scheme 52). Bis(dihydrooxazole) ligand 113 enables the cross-coupling reaction of both symmetrical and unsymmetrical bromo ketones 111 with arylmagnesium reagents 112. This coupling provides access to arylated acyclic dialkyl ketones 114 in high enantiomeric excess for the first time.
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Enolate Protonation, Alkylation, Arylation, Vinylation
Scheme 52 Nickel-Catalyzed Arylation of Dialkyl Ketones with Arylmagnesium Reagents[121]
9 mol%
O
O N
N Ph
Ph (R,R)-113
O R2
R1
+
Ar1
111
112
Ar1
114
Yield (%) ee (%) Ref
Et Me Ph
90a
73
[121]
Bn Me Ph
a
74
85
[121]
Bn Me 4-ClC6H4
82b
90
[121]
Bn Me 4-EtO2CC6H4
b
79
81
[121]
Bn Me 4-MeOC6H4
73b
90
[121]
a
84
[121]
b
80
[121]
iPr Me Ph iPr Et a b
R2
R1
Br
R1 R2
O
7 mol% NiCl2•DME DME, −40 oC
Ar1MgX
4-EtO2CC6H4
83
78
Commercially available PhMgBr used. Grignard reagent formed in situ from Ar1I and iPrMgCl.
The Kumada-type coupling is one of the few cases of nickel-catalyzed sp3—sp3 coupling reactions where the kinetics have been examined. These studies have indicated that the process has a first-order dependence on nickel and arylmagnesium halide and is zeroorder with respect to the electrophile. The general mechanism proposed for related sp3—sp3 cross coupling is consistent with this rate law.[117,118] Aryl Æ-Arylalkyl Ketones 110; General Procedure:[121]
A 20-mL vial equipped with a stirrer bar was capped with a septum and taped. The vial was purged with argon for 2 min. DME (8 mL) was added by syringe, and then the vial was cooled to –20 8C and a soln of the Grignard reagent 108 (a soln in Et2O is preferred; 1.1 mmol) was added. The soln was stirred at –20 8C for 10 min, and then cooled to –60 8C. Ligand (R,R)-109 (30.0 mg, 0.090 mmol) and NiCl2•DME (15.3 mg, 0.070 mmol) were added to a 4-mL vial equipped with a stirrer bar. The vial was capped with a septum, taped, and gently purged with argon for 1 min. DME (2.0 mL) was added, and this soln of the catalyst was stirred at rt for 5 min. Next, the Æ-bromo ketone 107 (1.0 mmol) was added. The mixture was stirred at rt for 5 min, and then the resulting homogeneous dark pink soln was added dropwise over 3 min to the –60 8C soln of the Grignard reagent. The resulting yellow soln was stirred at –60 8C for 16 h (if Ar2MgX was electron rich, then the reaction was run for 32 h). Next, the reaction was quenched with EtOH (2 mL), and the resulting mixture was filtered through a Bchner funnel that contained a bed of silica gel (height: 3.0 cm). The silica gel was washed with additional Et2O (40 mL), and the combined filtrates were concentrated by rotary evaporation. The residue was purified by flash chromatography (silica gel).
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Arylation of Enolates
Alkyl Æ-Arylalkyl Ketones 114; General Procedure:[121]
A 20-mL vial equipped with a stirrer bar was capped with a septum and taped. The vial was purged with argon for 2 min. DME (8 mL) and a soln of the Grignard reagent 112 (1.2 mmol) were added in turn by syringe. The soln was stirred at rt for 2 min, and then cooled to –40 8C. Ligand (R,R)-113 (44.0 mg, 0.09 mmol) and NiCl2•DME (15.3 mg, 0.070 mmol) were added to a 4-mL vial equipped with a stirrer bar. The vial was capped with a septum, taped, and gently purged with argon for 1 min. DME (2.0 mL) was added, and this soln of the catalyst was stirred at rt for 5 min. Next, the Æ-bromo ketone 111 (1.0 mmol) was added. The mixture was stirred at rt for 5 min, and then the resulting homogeneous dark pink soln was added dropwise over 3 min to the –40 8C soln of the Grignard reagent. The resulting yellow soln was stirred at –40 8C for 48 h. Next, the reaction was quenched with EtOH (2 mL), and the resulting mixture was filtered through a Bchner funnel that contained a bed of silica gel (height: 3.0 cm). The silica gel was washed with additional Et2O (40 mL), and then the combined filtrates were concentrated by rotary evaporation. The resulting residue was purified by flash chromatography (silica gel). 3.15.3.3.4
Suzuki-Type Arylation of Amides
The nickel-catalyzed cross-coupling reaction of Æ-chloroamides 115 with the 9-aryl-9borabicyclo[3.3.1]nonane derivatives 116 (1.5 equiv) has also been described (Scheme 53).[122] The chiral ethylenediamine derivative 117 is the optimal ligand for this transformation, affording high yields and enantioselectivities. The dihydroindole moiety in the products 118 is convenient for further elaboration because it can be cleaved reductively (to form an alcohol) or oxidized to an indole and hydrolyzed (to yield a carboxylic acid). Nickel-Catalyzed Arylation of Chloroamides with Arylboron Reagents[122]
Scheme 53
F3C
CF3
10 mol% Me
B
O R1
N
NH
HN Me
(S,S)-117 8 mol% NiBr2•diglyme t-BuOK (1.3 equiv), iBuOH (1.5 equiv) toluene, −5 oC
Ar1
+
O
Ar1
Cl 115
116
118
R1
Ar1
Yield (%) ee (%) Ref
Me
Ph
88
87
[122]
Et
Ph
78
92
[122]
iBu
Ph
84
85
[122]
CH2CH=CH2
Ph
80
90
[122]
(CH2)2OTBDMS
Ph
80
84
[122]
a
a
Et
3-ClC6H4
76
92
[122]
Et
3-Tol
84
92
[122]
Et
4-MeOC6H4
80
90
[122]
Et
4-FC6H4
70
94
[122]
a
R1
N
Reaction with 10 mol% NiBr2•diglyme and 12.5 mol% (S,S)-117.
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
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Enolate Protonation, Alkylation, Arylation, Vinylation
In an analogous manner to the other cross-coupling reactions of Æ-halocarbonyls, this Suzuki-type reaction is stereoconvergent. However, in contrast to the other couplings, significant kinetic resolution is observed in the case of Æ-chloroamides. Control experiments with enantiopure chloroamides suggest that this stereochemical enrichment is due to moderate enantioselectivity in the oxidative addition step. The origin of the different behavior in this Suzuki-type reaction is unknown.
Æ-Arylamides 118; General Procedure:[122] In a N2-filled glovebox, NiBr2•diglyme (14.1 mg, 0.040 mmol, 0.08 equiv), ligand (S,S)-117 (18.8 mg, 0.050 mmol, 0.10 equiv), the electrophile 115 (0.50 mmol), and toluene (2.5 mL) were added to a 10-mL flask. The following materials were added in turn to a 4-mL vial: t-BuOK (73 mg, 0.65 mmol, 1.3 equiv), iBuOH (69 L, 0.75 mmol, 1.5 equiv), the aryl-9BBN reagent 116 (0.75 mmol, 1.5 equiv), and toluene (2.5 mL). The flask and the vial were each capped with a rubber septum, and the two mixtures were stirred for 10 min. Next, the vessels were removed from the glovebox and placed in a –5 8C bath, and the mixtures were stirred for 10 min. The soln in the vial was then transferred by syringe to the slurry in the 10-mL flask, which was attached to a N2-filled balloon. The mixture was stirred at –5 8C for 24 h (it turned orange after a few min). Next, the mixture was poured into a separatory funnel and washed with sat. aq Na2CO3 [5 mL; if the aqueous layer was very viscous, distilled H2O (3 mL) was added]. The aqueous phase was extracted with EtOAc (2 5 mL), and the organic layers were combined, washed with brine (5 mL), dried (Na2SO4), and concentrated. The resulting residue was purified by flash chromatography. It was sometimes difficult to remove 9-BBN-derived impurities by flash chromatography, necessitating the use of more than one chromatographic run. It was found to be more practical to run a preliminary flash chromatographic run and then a recrystallization; this effectively removed the impurity and simultaneously increased the ee of the product. 3.15.4
Vinylation of Enolates
Vinylation of enolates is conceptually similar to enolate arylation; however, the specific challenges that pertain to Æ-vinyl carbonyl compounds, such as the problem of the isomerization of the alkene into conjugation, render these transformations particularly difficult to develop. One straightforward strategy to avoid the problem of isomerization is to employ a fully substituted enolate that generates an Æ-quaternary stereocenter. This tactic imposes significant limitations on the scope of the transformation, and as such there remains a need for vinylation protocols that are compatible with labile ,ª-unsaturated carbonyl moieties. 3.15.4.1
Vinylation of Enolates via Chiral Auxiliary Control
The chiral auxiliary approach, utilizing a dioxolanone derived from mandelic acid, provides a convenient strategy for stereoselective enolate vinylation (Scheme 54).[106] The enolate of the dioxolanone 83 undergoes palladium-catalyzed cross-coupling reaction with the vinyl bromides 119 in the presence of tri-tert-butylphosphine to afford the vinylated adduct 120 in good yield and with excellent diastereocontrol. A range of substituted vinyl halides have been successfully applied. However, the method is limited since an excess (2 equiv) of dioxolane 83 is required. A similar auxiliary approach has been used for enolate arylation (see Section 3.15.3.1).
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Vinylation of Enolates Enolate Vinylation with a Dioxolanone Auxiliary[106]
Scheme 54
O
2 mol% Pd(OAc)2 8 mol% t-Bu3P•HBF4 LiHMDS (2.5 equiv) toluene
R1 Ph
O
+
R2
Br
O
R1
But
119
83
R2
R3
Yield (%) dr 97:3
[106]
99b
98:2
[106]
Ph
H
CF3 H
H
H
CF3 78
96.5:3.5
[106]
CH2TMS
H
H
75
95.5:4.5
[106]
Me
H
H
79
91:9
[106]
Me
Me Me 80
91.5:8.5
[106]
b
R3
R2
Ref
a
94
R1
120
H
a
H
Ph O O
R3
But
O
90:10 E/Z mixture in starting material and product; reaction with 2.3 equiv of dioxolane. Reaction at 50 8C.
5-Aryl-2-tert-butyl-5-vinyl-1,3-dioxolan-4-ones 120; General Procedure:[106]
An oven-dried disposable test tube containing a magnetic stirrer bar was charged with dioxolanone 83 (506 mg, 2.3 mmol, 2.3 equiv), Pd(OAc)2 (5.6 mg, 0.02 equiv) and t-Bu3P•HBF4 (23.1 mg, 0.08 equiv), capped with a Teflon septum, evacuated, and then backfilled with argon. The tube was brought into a N2-filled glovebox where LiHMDS (418 mg, 2.5 mmol, 2.5 equiv) was added. The test tube was removed from the glovebox and then evacuated and backfilled with argon (2 ). The tube was placed in a bath at –10 8C (ice/acetone) and toluene (2 mL) was added. After 10 min of agitation at this temperature, the vinyl bromide 119 (2 equiv) was added via syringe. Agitation at this temperature was continued for a further 10 min and the mixture was then allowed to warm to rt and stirred for 14–18 h. At this point the reaction was quenched with sat. NH4Cl (4 mL), and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted with EtOAc (2 3 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (typically hexanes then hexanes/EtOAc 19:1) or preparative TLC. 3.15.4.2
Vinylation of Enolates via Chiral Transition-Metal Catalysts
3.15.4.2.1
Palladium-Catalyzed Vinylation with Vinyl Halides
Enantioselective vinylation of ketone enolates with vinyl bromides 122 via palladium catalysis has been described with the vinylogous amides 121, which have the advantage of restricting the site of enolization while being able to be cleaved after the vinylation reaction has been performed (Scheme 55).[123] Binaphthyl P,N-ligand 87 is particularly effective for the vinylation reaction, in which the yields of vinylated ketones 123 are uniformly high with various substitutions on the enolate and vinyl coupling partners. The level of enantioselectivity is, however, quite sensitive to ketone ring size and the vinyl halide substitution. The enamine moiety is readily removed by hydrolysis to access the corresponding Æ-quaternary ketones in good yield. A few examples of the Æ-vinylation of indol-2-ones have been recently reported using a similar catalyst.[116] Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
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Enolate Protonation, Alkylation, Arylation, Vinylation
Palladium-Catalyzed Vinylation of Cyclic Ketones[123]
Scheme 55
NMe2
Pd2(dba)3,
PCy2
(R)-87
O Me
R1 N Ph
+
R
Br
2
t-BuONa (2 equiv) toluene
R3
X 121
122 O R1 Me
N Ph
X R3
R2
123
X
R1
R2
R3
Pd loadinga (mol%) Yield (%) ee (%) Ref
CH2
Me
H
H
2
94
92
[123]
CH2
Pr
H
H
5
86
90
[123]
CH2
(CH2)4Me
H
H
5
84
92
[123]
(CH2)2 Me
H
H
5
78
50
[123]
CH2
Me
H
Me 5
84
76
[123]
CH2
Me
Me H
2
95
90
[123]
CH2
Me
Ph H
2
92
89
[123]
CH2
Me
Me Me 5
95
71
[123]
a
Pd/ligand ratio = 1:1.25; 2 equiv of vinyl bromide was used relative to the vinylogous amide.
Æ-Alkyl-Æ¢-(N-methyl-N-phenylaminomethylene)-Æ-vinylcycloalkanones 123; General Procedure:[123] An oven-dried Schlenk tube equipped with a rubber septum was allowed to cool under an argon purge. The septum was removed and the tube was charged with Pd2(dba)3 (9.2 mg, 0.01 mmol, 1 mol%), ligand (R)-87 (12.4 mg, 0.025 mmol, 2.5 mol%), and the ketone 121 (1.0 mmol). Toluene (2 mL) was added and the mixture was stirred for 15 min at rt. Bromoalkene 122 (2.0 mmol) and t-BuONa (192 mg, 2.0 mmol) were added to the tube. The tube was capped with a septum and purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was stirred at rt until the starting ketone had been completely consumed as judged by GC analysis. The mixture was quenched with sat. aq NH4Cl (10 mL) and diluted with Et2O (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with Et2O (20 mL) and the combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude products were purified by chromatography (silica gel).
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.15.4
3.15.4.2.2
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Vinylation of Enolates
Nickel-Catalyzed Vinylation with Vinylsilanes
The nickel-catalyzed cross-coupling reaction of vinylsilanes 125 (1.3 equiv) with Æ-bromo esters 124 provides a convenient approach to the Æ-substituted ,ª-unsaturated esters 126 without isomerization of the alkene into conjugation (Scheme 56).[119] The complex derived from nickel(II) chloride and the ethylenediamine derivative 101 provides acceptable yields and excellent asymmetric induction, albeit for only three reported substrates. Reduction of the ester with lithium aluminum hydride or oxidative cleavage of the aryl ester with ammonium cerium(IV) nitrate provides the alcohol or acid, respectively, without racemization. Nickel-Catalyzed Vinylation with Vinylsilane Reagents[119]
Scheme 56
Ph
Ph
12 mol% Me
But
HN Me
10 mol% NiCl2•DME Bu4NSiF2Ph3 (2 equiv), 1,4-dioxane, rt
O R1
O But
NH
(S,S)-101
+
R2
Si(OMe)3
Br 125
124
But O
O R1
But R2 126
R1 R2 Yield (%) ee (%) Ref 66
93
[119]
Bu Ph 72
92
[119]
Et Bu 70
91
[119]
Bu H
2,6-Di-tert-butyl-4-methylphenyl Alk-3-enoates 126; General Procedure:[119]
In a glovebox, 1,4-dioxane (10 mL) was added to a mixture of (S,S)-101 (14.4 mg, 0.060 mmol), NiCl2•DME (11.0 mg, 0.050 mmol), and Bu4NSiF2Ph3 (TBAT; 539 mg, 1.00 mmol) in a 20-mL vial. The mixture was stirred for 10 min, and then the silane 125 (0.65 mmol) and the Æ-bromo ester 124 (0.50 mmol) were added. The mixture was stirred for 16 h at rt, and then a soln of 1 M HCl/acetone (1:1; 5 mL) was added. The mixture was stirred for 2 h, and then poured into H2O (30 mL) and extracted with Et2O (2 30 mL). The combined organic layer was washed with brine (30 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography (silica gel, CH2Cl2/hexanes 1:19 to 1:4). 3.15.4.2.3
Nickel-Catalyzed Vinylation with Vinylzirconocenes
The vinylzirconocene complexes 129, generated by hydrozirconation of alkynes, are also suitable coupling partners for Æ-alkenylation (Scheme 57).[124] Bis(dihydrooxazole) 127 was found to be the most effective ligand for the asymmetric cross-coupling reaction with Æ-bromo ketones 128. The broad substrate scope encompasses aryl alkyl ketones, unsymmetrical dialkyl ketones, and a variety of common functional groups. The retenProtonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
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Enolate Protonation, Alkylation, Arylation, Vinylation
tion of the ,ª-unsaturation in the product 130 is indicative of the compatibility of the reaction conditions with sensitive moieties of this nature. This reaction is covered from a cross-coupling perspective in Section 3.14.1.2. Scheme 57
Nickel-Catalyzed Vinylation with Organozirconium Species[124]
O Ph
O N
Ph
N
Ph
Ph (−)-127
3.6 mol% (−)-127 3 mol% NiCl2•DME
O R2
1
R
+
DME/THF, 10 oC
R3
O R2
R1
ZrCl(Cp)2
Br
R3 128
129
R3
130
R1
R2
Ph
Me H
92
90
[124]
Ph
Me CH2OTBDMS
81
90
[124]
Ph
Me
82
93
[124]
Ph
Et
83
92
[124]
Ph
iBu Bn
81
82
[124]
4-BnOC6H4
Me Bn
89
95
[124]
4-BrC6H4
Me (CH2)3CN
74
90
[124]
4-MeO2CC6H4
Me 4-MeOC6H4
83
87
[124]
2-thienyl
Me CH2Cy
85
94
[124]
Et
Me Bn
86
90
[124]
iPr
Et
Bn
82
98
[124]
Cy
Me Bn
87
91
[124]
(CH2)4Cl
Yield (%) ee (%) Ref
When a substrate bearing an existing stereocenter (e.g., 131) is exposed to the reaction conditions for vinylation, a high degree of catalyst control is observed in the diastereomeric products (e.g., 132) (Scheme 58). Kinetic experiments have demonstrated a first-order dependence on catalyst and organozirconium and zero-order dependence on bromo ketone. Although the details of the mechanism remain uncertain, these kinetic results are consistent with related nickel-catalyzed cross-coupling reactions and the general mechanism proposed for these transformations.[117,118]
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.15.4
671
Vinylation of Enolates
Scheme 58
Catalyst Control in Diastereoselective Vinylation[124] 6 mol% 127 5 mol% NiCl2•DME
O +
TIPSO
DME/THF, 10 oC
Bn
ZrCl(Cp)2
Br 131 O
O
TIPSO
+
TIPSO
Bn 132A
Bn 132B
Enantiomer of 127 Yield (%) dr (132A/132B) Ref (–)
83
(+)
80
15:1 1:10
[124] [124]
,ª-Unsaturated Ketones 130; General Procedure:[124] Zr(Cp)2ClH (516 mg, 2.0 mmol; note: moisture sensitive) was added to an oven-dried, 20-mL vial equipped with a magnetic stirrer bar. The vial was then closed with a septumcontaining screw cap and purged with argon for 3 min. Anhyd THF (2.0 mL) was added, followed by the alkyne (2.0 mmol) over 2 min. The mixture was stirred at rt for 1 h, at which time all of the white solid had been consumed and a homogeneous yellow soln was observed. Into an oven-dried, 25-mL round-bottomed Schlenk flask equipped with a rubber septum and a magnetic stirrer bar under argon was added NiCl2•DME (6.6 mg, 0.030 mmol), ligand (–)-127 (17.6 mg, 0.036 mmol), and anhyd DME (8.0 mL). The pink catalyst soln was stirred for 10 min at rt, and then cooled in a iPrOH bath at 10 8C. The Æ-bromo ketone 128 (1.0 mmol) was added to the catalyst soln in one portion, and then the soln of the alkenylzirconium reagent 128 (2.0 mmol) was added over 3 min. The reaction soln (yellow or orange) was stirred at 10 8C for 24 h, and then the reaction was quenched by the addition of MeOH (2.0 mL). The soln was diluted with Et2O (20 mL) and washed with sat. aq NaHCO3 (15 mL). The organic layer was separated, and the aqueous layer was extracted with Et2O (2 15 mL). The organic fractions were combined, dried (MgSO4), and filtered through a bed of Celite. The filtrate was concentrated by rotary evaporation, and the residue was purified by flash chromatography (silica gel).
Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. for references see p 672 Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Enolate Protonation, Alkylation, Arylation, Vinylation
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Protonation, Alkylation, Arylation, and Vinylation of Enolates, Stoltz, B. M., Mohr, J. T. Science of Synthesis 4.0 version., Section 3.15 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
675 3.16
Æ-Functionalization of Carbonyl Compounds D. W. C. MacMillan and A. J. B. Watson
General Introduction
The carbonyl functionality is perhaps the most synthetically versatile and broadly utilized functional group in organic molecules.[1,2] The abundance of both natural and commercially available carbonyl-containing compounds has rendered this substrate a widely employed starting material for a host of chemical processes. Additionally, the variety of chemical methods available for the installation of this functionality provides access to an even greater number of potential carbonyl-based materials. The chemistry of the carbonyl group is largely dominated by two distinct reactivity profiles. The carbon center is electrophilic and is therefore directly functionalizable through nucleophilic addition processes. Additionally, functionalization of adjacent C—H sites can be achieved by capitalizing on the reactivity imparted to these sites by virtue of the associated enol/enolate tautomerism. In the latter context, the Æ-functionalization of a carbonyl compound provides a convenient method for the elaboration of a particular molecule to a higher derivative while retaining the inherent utility of the parent carbonyl unit. Moreover, the generation of prochiral enolates can provide an opportunity to construct a new stereogenic center. The ability to exert control over enolate reactions has therefore been of considerable interest to synthetic chemists, resulting in a vast research effort culminating in a series of highly applicable methodologies allowing for stereocontrolled carbonyl Æ-functionalization.[3–5] These methodologies are typically based on the use of basic or Lewis acidic reagents or catalysts to activate either the parent carbonyl compound as its enolate or a preformed enolate derivative, such as an enol silane. Nevertheless, the activation of a carbonyl substrate under basic or Lewis acidic conditions precludes the use of substrates that are incompatible with such techniques. In addition, the preformation of a stoichiometric enolate or enolate equivalent has the associated ramifications on synthetic/reagent efficiency. Accordingly, the direct catalytic enantioselective Æ-functionalization of carbonyl compounds represents a valuable chemical strategy and key goal for the practitioners of asymmetric catalysis. Furthermore, the construction of a general platform from which a series of effective and meaningful asymmetric transformations may be launched would be of significant interest and broad-spectrum utility. In this regard, beginning first in the 1950s,[6] Gilbert Stork demonstrated the synthetic potential of enamines in the first of a series of seminal publications that established a solid basis for this new mode of reactivity.[7] The Hajos–Parrish–Eder–Sauer–Wiechert reaction (commonly truncated to the Hajos–Parrish reaction) proceeded to illustrate the power of enamine catalysis in an enantioselective format through the historic synthesis of the Wieland–Miescher ketone in 1971.[8–11] Although this represented a paradigm shift in asymmetric synthesis, the potential of enamine catalysis as a general concept for enantioselective catalysis remained largely unrecognized, although a few scattered examples were subsequently demonstrated, perhaps the most notable example arising in Woodwards seminal synthesis of erythromycin.[12–14] The realization of the general mode of organocatalytic reactivity that has become known as asymmetric enamine catalysis only occurred in 2000 following List, Lerner, -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
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Æ-Functionalization of Carbonyl Compounds
and Barbas demonstration of an enantioselective intermolecular proline-catalyzed aldol reaction.[15] This pivotal publication suddenly awakened the asymmetric catalysis community to a general method for direct catalytic enantioselective Æ-functionalization of carbonyl compounds and ignited an intense period of research generating a series of publications describing a host of new organocatalysts and asymmetric transformations.[16–19] Since then, efforts to expand upon this technology have produced single-electron based strategies that have significantly increased the synthetic scope of the enamine catalysis concept.[20–31] This section describes the application of enamine catalysis in the enantioselective installation of carbon–carbon and carbon–heteroatom bonds. Included in this are aldol and Mannich reactions (Section 3.16.1), Æ-functionalization with electrophilic heteroatomic species and alkylating agents (Section 3.16.2), SOMO-catalyzed processes (Section 3.16.3), and photoredox processes (Section 3.16.4). There are several general aspects of enantioselective enamine catalysis that should be noted and care should be directed toward these items when considering the use of a particular enamine reaction for a synthetic purpose; more specific details associated with a particular transformation are noted in the appropriate subject section.
Catalyst selection: The selection of an appropriate catalyst is crucial to the successful outcome of the reaction. There are aspects of many of the following transformations that require a particular catalyst type be employed. For example, many proline-based reactions will only operate with proline due to the proximity of the carboxylic acid motif. Similarly, SOMO processes are exclusively effective with imidazolidinone catalysts. Additionally, where relevant, the acid cocatalyst can have a profound effect on the reaction outcome and often the same amine catalyst will be used as a different acid salt for different reactions. A selection of the general catalyst types that have been shown to mediate effectively a particular transformation are provided for each reaction type. Many of the more broadranging catalysts are now commercially available while others must be prepared; these syntheses can vary substantially in difficulty. Catalyst loading: Organocatalyst loadings vary from transformation to transformation and can be as low as 1 mol% (0.01 equiv) to as high as 50 mol% (0.5 equiv). As a general rule of thumb, 20 mol% (0.2 equiv) would be a suitable starting point when attempting a transformation on an unknown substrate. Scale: Most enamine-catalyzed reactions are performed on millimole scale and typically below, although some, e.g. the Hajos–Parrish reaction, have been described on larger (gram) scale. Reagent economy: This can vary substantially depending on the transformation and care should be taken to note the relative quantities of a particular component. For example, many aldol and Mannich processes utilize the ketone substrate as the reaction solvent or cosolvent. Reaction temperature: Generally reaction specific, some reactions can be carried out conveniently at room temperature while many are cooled. When described, cooling is generally achieved in a solvent-filled cryocool although cold rooms have also been employed. Reaction time: Many enamine-catalyzed reactions are fast and are complete in minutes while some are in the order of days. Reactions are typically monitored by TLC, 1H NMR, GC, HPLC, and supercritical fluid chromatography (SFC) for consumption of the limiting reagent. -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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General Introduction
Product isolation: Where possible, the direct products of a particular transformation have been isolated, although occasionally it becomes necessary to derivatize immediately, for example reduce with a hydride reagent, to avoid loss of enantiointegrity. Analysis: Analysis of conversion and enantioselectivity has been achieved using a combination of NMR, GC, HPLC, and/or supercritical fluid chromatography (SFC) techniques. For convenience and where possible, the method of analysis of selectivity for a specific example has been noted. Utility: It is difficult to determine whether or not a transformation will be of broad-ranging utility beyond the examples provided in the parent publication. However, many contributors have provided examples with commonly encountered functional groups such as esters, carbamates, alkenes, and aromatic/heteroaromatic residues. Conversely, there are transformations where the tolerance cannot be readily ascertained and one could overanalyze whether the inclusion of some functionality will be detrimental or not, while it may be immediately obvious that a specific reagent will be incompatible with a given substrate. Waste output: Waste associated with enamine catalysis can be relatively high, especially when catalyst loadings are around 0.2 equivalents or greater, although many catalysts can be recovered at the end of the reaction and polymer-supported catalysts have been developed. Perhaps more significantly, many transformations operate with an excess of a particular reagent. However, the waste output of enamine catalysis should be placed in context with the alternative routes to the same molecules using more conventional chemical strategies. For illustrative purposes, a general enamine-catalyzed Æ-functionalization catalytic cycle, employing proline (1) as the organocatalyst, is shown in Scheme 1. Scheme 1 General Enamine-Catalyzed Enantioselective Æ-Functionalization O
O E
R1
R1
R2
R2
CO2H
N H 1
H2O
H2O
CO2H
N
E
R1
CO2H
N R1 R2
R2
CO2H
N
E+ R1
R2 E+
= electrophile
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
Æ-Functionalization of Carbonyl Compounds
678
Stereoselective Synthesis
3.16.1
Enamine-Mediated Enantioselective Aldol and Mannich Processes
3.16
The aldol and Mannich reactions represent some of the most important synthetic methods for stereoselective C—C bond formation and have been used extensively in the synthesis of both valuable intermediates and complex molecular targets.[32–39] Prior to the arrival of enamine catalysis, conventional enolate-based methods dominated this area of research and were the methods of choice for these powerful asymmetric transformations. Enamine catalysis provides an appealing alternative method for these processes, the attractiveness largely due to the operational simplicity and the fact that the majority of reactions can be performed with inexpensive (S)-proline (1) as the organocatalyst (Scheme 2). Scheme 2
General Enamine-Mediated Enantioselective Aldol and Mannich Processes
O CO2H
N H
+
R
− H2O
R2 1
CO2H
N
1
X R1
R3
R2
donor
R4
acceptor
O
XH R4
H2O
R1 −
CO2H
N H
R2
R3
1 X = O, NZ; Z = protecting group
3.16.1.1
Aldol Processes
The proline-catalyzed aldol reaction was the first publication of the new wave of enamine catalysis.[15] Since this initial publication, the aldol reaction has been the single most investigated topic in the organocatalysis domain with a considerable number of new catalysts described and substrates employed.[16–18,40,41] However, it should be noted that most aldol processes are conveniently carried out with proline (1), simple proline derivatives, and commercial imidazolidinone catalysts. Synthetic procedures are generally very straightforward and involve mixing the organocatalyst with the desired components and stirring, often at room temperature but occasionally below. Some more demanding reactions, for example aldehyde–aldehyde cross-aldol processes, require the slow addition of one of the aldehyde components to maintain efficiency, which is readily achieved with a common syringe pump. Both intra- and intermolecular enamine-catalyzed processes are known and use both aldehyde and ketones as the donors and acceptors. It should be noted that aldehydes are by far the most commonly employed acceptors with only suitably activated or intramolecularly disposed ketones performing in this role. In most cases, a particular component is used in excess and this can vary from, for example, 2 equivalents to cosolvent/solvent levels. Of course, intramolecular examples are a clear exception. Reaction times can be a constraining factor and it is common for transformations to require days to go to completion.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.1
679
Enamine-Mediated Enantioselective Aldol and Mannich Processes
3.16.1.1.1
Aldol Processes with Aldehyde Donors
3.16.1.1.1.1
Intramolecular Aldol Reactions
Dicarbonyl substrates with an aldehyde as the required donor readily take part in enamine-catalyzed intramolecular aldolizations to afford enantioenriched carbocycles (e.g., 3) (Table 1).[42–44] Proline (1) and proline-based amines (e.g., 2) are the catalysts of choice for these transformations and provide excellent levels of enantioinduction even when reactions are performed at room temperature. Nevertheless, care should be taken with some products since several have been found to be unstable for extended periods of time, albeit they have improved shelf life as the corresponding diols, which are usually obtained by reduction with sodium borohydride. Intramolecular Aldol Reactions with Aldehyde Donors[42–44]
Table 1
N H
CO2H
N H 1
N
2
O
O
R1
R1
OH O
H
H
n
n
3
Conditionsa
Entry Substrate
O
1
O
O
H
H
O
2
Product
ee (%)
H
CHO
Boc N
O
1 (0.2 equiv), toluene (0.1 M), rt
O
4 3
H
97
>20:1 75
[42]
99
2:1 92
[42]
86
1:1 91
[43]
H
BocN
OH
O O
Ref
O HO
1 (0.1 equiv), CH2Cl2 (0.1 M), H rt
OHC
Yield (%)
OH
1 (0.1 equiv), CH2Cl2 (0.1 M), H rt
O
3
dr
H
2b (0.3 equiv), NMP (0.1 M), 0 8C
89
–
89
[44]
O O a b
1 Equiv of dicarbonyl used in each case. TFA salt of 2 was used.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
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Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
(1S,2S)-2-Hydroxy-5,5-dimethylcyclohexanecarbaldehyde (Table 1, Entry 1); Typical Procedure:[42]
Note: the products are unstable over prolonged periods of time and should be derivatized as soon as possible. To a 0.1 M soln of 4,4-dimethylheptanedial (156.2 mg, 1 mmol, 1 equiv) in CH2Cl2 (10 mL) was added (S)-proline (1; 12 mg, 0.1 mmol, 0.1 equiv) at rt. The mixture was stirred until consumption of the starting material. The title compound was then isolated after standard aqueous workup (no details given); yield: 117.2 mg (75%); dr >20:1; 97% ee. The yield was based on the corresponding diol obtained by reduction with NaBH4 (no details given). The ee was determined by formation of the corresponding enone using LiOH and MeCOCH2PO(OMe)2 in THF (no details given) and HPLC analysis (no details given). tert-Butyl (1S,2S,3R,5S)- and tert-Butyl (1S,2R,3R,5S)-2-Formyl-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (Table 1, Entry 3); Typical Procedure:[43]
Note: the products are unstable over prolonged periods of time and should be derivatized as soon as possible. A mixture of tert-butyl (2R,5S)-2,5-bis(2-oxoethyl)pyrrolidine-1-carboxylate (216.5 mg, 0.85 mmol, 1 equiv) and (S)-proline (1; 24.5 mg, 0.21 mmol, 0.25 equiv) in toluene (8.5 mL) was stirred at rt for 24 h. The mixture was then diluted with Et2O and washed with H2O (2 ) and brine. The organic extract was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the products as a colorless oil; yield: 216.5 mg (91%); dr 1:1; 86% ee. The products were unstable and the ee was determined at the final stage of the total synthesis of (+)-cocaine following 3 steps. [Note: A discrepancy was noted between the quantity of proline 1 stated in the literature (0.2 equiv) and supporting information (0.25 equiv).] (7aS)-7a-Methyl-7-oxo-2,4,5,6,7,7a-hexahydro-1H-indene-3-carbaldehyde (Table 1, Entry 4); Typical Procedure:[44]
To a 0.1 M soln of 4-(1-methyl-2,6-dioxocyclohexyl)butanal (54.5 mg, 0.27 mmol, 1 equiv) in NMP (2.7 mL) at 0 8C was added the trifluoroacetic acid salt of (S)-1,2¢-methylenedipyrrolidine (2; 21.7 mg, 0.081 mmol, 0.3 equiv). The mixture was stirred at 0 8C for 56 h, then quenched with pH 7 phosphate buffer, and extracted with EtOAc (3 ). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative TLC; yield: 42.6 mg; (89%); 89% ee. The ee was determined by HPLC analysis (OB-H column, no details given). 3.16.1.1.1.2
Intermolecular Aldol Reactions
Intermolecular aldolizations present a potential problem in terms of ensuring the correct aldol product is obtained, i.e. that a specific carbonyl substrate functions solely in the desired donor or acceptor role. Methods to enforce this manifest themselves in several ways: (i) by employing a non-enolizable carbonyl as the acceptor, e.g. a benzaldehyde or isatin derivative; (ii) by using sterically differentiated aldehydes [in this case, catalyst condensation is more facile with the less-substituted aldehyde rendering this the donor and the more heavily substituted aldehyde (e.g., Æ,Æ-disubstituted) the acceptor]; (iii) by slow addition of the acceptor aldehyde via syringe pump addition; or (iv) by using an excess of the acceptor. Of course, dimerization of aldehydes can produce synthetically useful intermediates and, in this case, the above considerations are not necessary. Aldehyde–ketone reactions, where the ketone is the acceptor, are rare and only employ activated and non-enolizable ketones. Proline (1) and the proline- (e.g., 2 and 6) or imidazolidinone-based catalysts (e.g., 4) are generally optimal for these transformations and the substrate scope is fairly broad -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.1
681
Enamine-Mediated Enantioselective Aldol and Mannich Processes
with a variety of substituted donor aldehydes and acceptor carbonyls, which provide an array of densely functionalized adducts (e.g., 5 and 7) in good yield and diastereo- and enantioselectivity (Tables 2 and 3). Table 2
Intermolecular Aldol Reactions with Aldehyde Donors and Aldehyde Acceptors[45–51] O CO2H
N H 1
R2
H
N
Bn
4
O + H
R1
O
OH
R1
R2
R3
H
R3
5
acceptor
donor
But
N H
2
O
Me N
N H
R1
R2
R3
Conditions
Me
H
Ph
1 (0.1 equiv), DMF (0.2 M), 4 8C
99
Me
H
iPr
1 (0.1 equiv), DMF (0.2 M), 4 8C
OTBDPS
H
OTBDMS H
ee (%)
dr
Yield (%)
Ref
3:1a
81b
[45]
>99
24:1a
82b
[45]
a
61
[46,47]
62
[46,47]
CH2OTBDPS
1 (0.2 equiv), DMF/1,4-dioxane (1:1; 0.2 M), rt
96
9:1
CH2OTBDMS
1 (0.1 equiv), 1,4-dioxane (0.2 M), rt
88
3:1a
d
15:1
a
NPhth
H
Cy
1 (0.3 equiv), NMP (2 M), 4 8C
98
NPhth
H
CH(OMe)2
1 (0.3 equiv), NMP (2 M), 4 8C
86d
Bn
H
1 (0.1 equiv), DMF (0.05 M), rt
97 >20:1a
5:1a
b,c
73
[48]
69b,c
[48]
73d
[49]
S S
Pr
Me
4-O2NC6H4
2•TFA (0.1 equiv), DMSO (1 M), rt
89
66:34a 92e
[50]
Me
4-t-BuC6H4CH2
4-O2NC6H4
2•TFA (0.1 equiv), DMSO (1 M), rt
96
85:15
91f
[50]
4•TFA
h
58
[51]
84h
[51]
g
a
Me
H
CH2OCOt-Bu
(0.1 equiv), Et2O (0.67 M), 4 8C; then MeOH, Amberlyst-15
90
SBn
H
CH2SBn
4•TFA (0.1 equiv), Et2O (0.67 M), 4 8C; then MeOH, Amberlyst-15
97g 11:1a
a b c d e f g h
4:1
Ratio anti/syn. Ratio donor/acceptor (equiv) = 1:10. Of corresponding methyl ester derivative. Ratio donor/acceptor (equiv) = 1:5–10. Ratio donor/acceptor (equiv) = 2:1. Ratio donor/acceptor (equiv) = 10:1. Isolated as the dimethoxy acetal; config of 5 opposite to that shown. Ratio donor/acceptor (equiv) = 1:5.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
682
Stereoselective Synthesis
Æ-Functionalization of Carbonyl Compounds
3.16
Intermolecular Aldol Reactions with Aldehyde Donors and Ketone Acceptors[52–54]
Table 3
N CO2H
N H 1
HN N 6
O R2
H
N
N H
O
O +
R1 donor
R3
R3
HO
R4
H
R4
R1
R2 7
acceptor
Entry R1
R2
R3
R4
1
H
CO2Et
CO2Et 1 (0.5 equiv), CH2Cl2 (0.25 M), rt
Me
2
(CH2)5Me
H
3
Me
Me
ee (%)
dr
Yield (%)
Ref
90
–
90a
[52]
84
–
91
a
[52]
O
6 (0.15 equiv), H3PO4 (0.15 equiv), 84 H2O (1 equiv), iPrOH (0.25 M), 0 8C
–
92b
[53]
O
6 (0.15 equiv), H3PO4 (0.15 equiv), 98 H2O (1 equiv), iPrOH (0.25 M), 0 8C
3:2c 80b
[53]
CO2Et
CO2Et 1 (0.5 equiv), CH2Cl2 (0.25 M), rt
N H
4
Me
H N H
a b c
Conditions
Ratio donor/acceptor (equiv) = 1:1. Ratio donor/acceptor (equiv) = 5:1. Not specified, assumed anti/syn.
(2S,3R)-3-Hydroxy-2-methyl-3-phenylpropanal (5, R1 = Me; R2 = H; R3 = Ph); Typical Procedure:[45]
A soln of freshly distilled EtCHO (58.1 mg, 1 mmol, 1 equiv) in DMF (0.5 mL) precooled to 4 8C was added slowly over 16 h to a stirring suspension of PhCHO (1.06 g, 10 mmol, 10 equiv) and (S)-proline (1; 11.5 mg, 0.1 mmol, 0.1 equiv) in DMF (4.5 mL) at 4 8C. The mixture was stirred for 16 h, then diluted with EtOAc, and washed with H2O and brine. The combined aqueous layers were re-extracted with CH2Cl2 (3 ). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound as a colorless oil; yield: 132 mg (81%); dr 3:1; 99% ee (anti). The ee was determined by reduction to the corresponding alcohol with NaBH4 (no details given) and HPLC analysis (AD column, iPrOH/hexanes 1:99, 1 mL • min–1). (2S,3S)-2,4-Bis(tert-butyldimethylsiloxy)-3-hydroxybutanal (5, R1 = OTBDMS; R2 = H; R3 = CH2OTBDMS); Typical Procedure:[46]
A suspension of TBDMSOCH2CHO (176 mg, 1 mmol, 1 equiv) and (S)-proline (1; 11.5 mg, 0.1 mmol, 0.1 equiv) in 1,4-dioxane (1 mL) was stirred at rt for 48 h. The mixture was then diluted with Et2O (20 mL) and filtered through a pad (silica gel). The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the product as a colorless oil; yield: 109 mg (62%); dr 3:1; 88% ee (anti). The ee was determined by GC analysis (Bodman Chiraldex -DM column, 110 8C hold, 120 min then ramp 1 8C/min to 150 8C, 1.565 atm) of the corresponding acetonide derived by reduction of the product to the corresponding alcohol with NaBH4 (no details given) and formation of the acetonide with acetone (no details given). -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.1
Enamine-Mediated Enantioselective Aldol and Mannich Processes
683
(2S,3S)-3-Cyclohexyl-2-(1,3-dioxoisoindolin-2-yl)-3-hydroxypropanal (5, R1 = NPhth; R2 = H; R3 = Cy); Typical Procedure:[48]
To a mixture of 2-(1,3-dioxoisoindolin-2-yl)ethanal (378 mg, 2 mmol, 1 equiv) and cyclohexanecarbaldehyde (1.12 g, 20 mmol, 10 equiv) in NMP (1 mL) at 0 8C was added (S)-proline (1; 69 mg, 0.6 mmol, 0.3 equiv). The mixture was stirred at 4 8C for 36 h before being diluted with EtOAc and sat. aq NH4Cl. The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was quickly purified by flash chromatography to remove the excess aldehyde. Attempting to obtain the pure aldol product by chromatography led to lowered yield and dr. The dr of the aldol product (15:1) was determined by NMR spectroscopy. Yield and ee were based on the corresponding methyl ester derivative obtained in the following manner: The crude aldol product was dissolved in t-BuOH/H2O (5:1; 24 mL) and treated with NaH2PO4 (480 mg, 4 mmol), a 2 M soln of 2-methylbut-2-ene in THF (6.8 mL, 13.6 mmol), and NaClO2 (624 mg, 6.9 mmol). The resulting mixture was stirred at rt for 4 h before removal of the volatile components under reduced pressure to give a residue, which was extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was dissolved in toluene (2 mL) and MeOH (5 mL) and cooled to –20 8C. This mixture was treated with a 2 M soln of TMSCHN2 in hexane (no quantity given) dropwise until the yellow color persisted. The mixture was stirred for an additional 10 min and then quenched with AcOH (1 drop). The solvents were removed under reduced pressure to give a residue, which was purified by flash chromatography to afford methyl (2S,3S)-3-cyclohexyl-2-(1,3-dioxoisoindolin-2yl)-3-hydroxypropanoate; yield: 483.8 mg; (73%); dr 5:1; 98% ee (anti). The ee was determined by HPLC analysis (OD-H column, iPrOH/hexanes 1:19, 1 mL • min–1, 254 nm). (2S,3R)-2-Benzyl-3-(1,3-dithian-2-yl)-3-hydroxypropanal (5, R1 = Bn; R2 = H; R3 = 1,3-Dithian2-yl); Typical Procedure:[49]
A soln of freshly distilled 3-phenylpropanal (45 mg, 0.34 mmol, 1 equiv) in DMF (0.35 mL) was added slowly over 24 h to a stirring suspension of 1,3-dithiane-2-carbaldehyde (100 mg, 0.68 mmol, 2 equiv) and (S)-proline (1; 3.9 mg, 0.034 mmol, 0.1 equiv) in DMF (0.35 mL, 0.05 M overall) at rt. The mixture was stirred for 46 h, then diluted with Et2O, and washed with H2O and brine. The combined aqueous layers were extracted with EtOAc (5 ). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the product a colorless oil; yield: 71 mg (73%); dr >20:1; 97% ee (anti). The ee was determined on the corresponding acetal derived from 2,2-dimethylpropane-1,3-diol in the following manner: A soln of 2,2-dimethylpropane-1,3-diol (25 mg, 0.24 mmol) and PPTS (5 mg, 0.02 mmol) in MeCN (0.2 mL) was added to a soln of (2S,3R)-2-benzyl-3-(1,3-dithian-2-yl)-3hydroxypropanal (5, R1 = Bn; R2 = H; R3 = 1,3-dithian-2-yl; 26 mg, 0.092 mmol) in MeCN (0.2 mL) at rt. The mixture was stirred for 65 h before being filtered through a pad (silica gel, pentane/Et2O 10:1). The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the acetal as a colorless oil and as a mixture of diastereomers; yield: 31 mg (91%). The ee was determined by HPLC analysis (AD column, EtOH/hexanes 1:49, 1 mL • min–1, 254 nm). (2S)-2-[(S)-Hydroxy(4-nitrophenyl)methyl]-2-methylpentanal (5, R1 = Pr; R2 = Me; R3 = 4-O2NC6H4); Typical Procedure:[50]
A 1 M catalyst stock soln was prepared from 1-[(2S)-pyrrolidin-2-ylmethyl]pyrrolidine (2; 77.1 mg, 0.5 mmol) and TFA (57 mg, 0.5 mmol) in anhyd DMSO (0.5 mL) before use. To a soln of 4-nitrobenzaldehyde (75.6 mg, 0.5 mmol, 1 equiv) in DMSO (0.45 mL, 1 M overall) was added 2-methylpentanal (100.2 mg, 1 mmol, 2 equiv) and the catalyst stock soln (1 M -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
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Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
in DMSO, 0.01 mL, 0.05 mmol, 0.1 equiv). The mixture was stirred for 24 h and then purified directly by flash chromatography; yield: 115.6 mg (92%); dr 66:34; 89% ee (anti). The ee was determined by HPLC analysis (OJ-H column, iPrOH/hexanes 1:49, 1 mL • min–1, 254 nm). (2S,3R)-2-Hydroxy-3-methyl-4-oxobutyl 2,2-Dimethylpropanoate (5, R1 = Me; R2 = H; R3 = CH2OCOt-Bu); Typical Procedure:[51]
A soln of freshly distilled EtCHO (233.5 mg, 4.02 mmol, 5 equiv) and 2-oxoethyl 2,2-dimethylpropanoate (116 mg, 0.805 mmol, 1 equiv) in Et2O (0.6 mL) was added slowly over 36 h to a stirred soln of (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one (4; 0. 40 mg, 161 mmol, 0.2 equiv) and TFA (18.4 mg, 0.161 mmol, 0.2 equiv) in Et2O (0.6 mL) at 4 8C. After completion of the addition, MeOH (4 mL) and Amberlyst-15 (200 mg) were added in one portion and the mixture was stirred for 8 h. The Amberlyst-15 resin was removed by filtration through a fritted filter and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the dimethyl acetal of the title compound as a colorless oil and as a mixture of diastereomers; yield: 116 mg (58%); dr 4:1; 90% ee (anti). The ee was determined by GC analysis (Bodman Chiraldex -PH column, 120 8C isotherm, 0.95 atm). Diethyl Hydroxy[(2S)-1-oxopropan-2-yl]propanedioate (Table 3, Entry 1); Typical Procedure:[52]
An oven-dried test tube was charged with EtCHO (29 mg, 0.5 mmol, 1 equiv), diethyl ketomalonate (87.1 mg, 0.5 mmol, 1 equiv), and CH2Cl2 (2 mL, 0.25 M). (S)-Proline (1; 29 mg, 0.25 mmol, 0.5 equiv) was added and the test tube was sealed with a rubber stopper and stirred at rt for 3 h. The mixture was quenched with H2O and extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the crude title compound as a colorless oil; yield: 105 mg (90%); 90% ee. The ee was determined by GC analysis (Astec G-TA column, 120 8C). 2-[(3S)-3-Hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-methylpropanal (Table 3, Entry 3); Typical Procedure:[53]
To a mixture of 5-[(2S)-pyrrolidin-2-yl]-1H-tetrazole (6; 4.3 mg, 0.03 mmol, 0.15 equiv), iPrCHO (72.1 mg, 1 mmol, 5 equiv), H2O (3.6 mg, 0.2 mmol, 1 equiv), and H3PO4 (85%, 2.9 mg, 0.15 equiv) in iPrOH (0.5 mL, 0.4 M) at 0 8C was added isatin (30 mg, 0.2 mmol, 1 equiv) portionwise over 1 h. The resulting mixture was stirred at 0 8C for 24 h and then concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound; yield: 41 mg (92%); 84% ee. The ee was determined by HPLC analysis (no details given). 3.16.1.1.2
Aldol Processes with Ketone Donors
3.16.1.1.2.1
Intramolecular Aldol Reactions
The first example of ketone–ketone intramolecular aldolization was illustrated by the venerable Hajos–Parrish–Eder–Sauer–Wiechert reaction for the synthesis of enantioenriched bicycles, particularly the Wieland–Miescher ketone 10 (Table 4, Entry 2).[10,11] Considering the success of this transformation, it is unsurprising that diketone substrates have been revisited. Several aspects of this reaction type are worthy of note, particularly: (i) Aldol processes on open-chain diketones are notably less successful than cyclic counterparts and generate the corresponding aldol adducts in substantially diminished yield and selectivity.[55–57] (ii) Preparing 6,5-fused-ring systems via 5- or 6-endo cyclization is more efficient than the formation of analogous 6,6-systems. In this latter case, the aldolase antibody -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.1
685
Enamine-Mediated Enantioselective Aldol and Mannich Processes
Ab 38C2 is more effective than proline (1) for this transformation.[58] (iii) Typically one of the ketone substituents is a methyl group, while substrates containing substituents other than methyl generally result in lower levels of enantioinduction. However, phenylalanine (9) is a more effective catalyst in these cases (Table 4, Entry 5).[59] (iv) The catalysts (e.g., 1, 8, and 9) employed for these transformations are commercially available amino acids [proline (1) or phenylalanine (8)]. Additionally, several of these reactions can be carried out on larger (gram) scale than usually found in enamine-catalyzed processes, particularly the Hajos–Parrish reaction. Table 4
Intramolecular Aldol Reactions with Ketone Donors Aldol Reactions[10,11,59–63] TBDPSO Ph
CO2H
N H
CO2H NBu4
NH2
1
9
8
O
O
R1
CO2−
N H
R2
OH O
R2
R1
n
n
Conditionsa
Entry Substrate
O
Product
dr
Yield (%)
Ref
93
–
100
[10,11]
70
–
71
[60]
>95b
–
64
[61]
98.5:1.5
89
[62]
O
O
1 (0.03 equiv), DMF (1 M), rt
1
ee (%)
O
O
OH O
O
O
1 (0.05 equiv), DMSO (1 M), 18 8C
2
O
O
O
10
PhS
O
O
PhS
1 (0.05 equiv), DMF (0.3 M), 17 8C
3
O
O
OH
O OH
H
4
1 (0.3 equiv), DMF (0.1 M), rt
O
86 O
O
O
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
686 Table 4
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
(cont.) Conditionsa
Entry Substrate
Product
ee (%)
dr
Yield (%)
Ref
86
–
82
[59]
94
99:1
77
[63]
O O
O
5
O
8 (1.2 equiv), HClO4 (0.5 equiv), MeCN (0.37 M), reflux
O
N N
O
9 (0.05 equiv), MeCN (0.125 M), rt
6 CHO a b
HO
O
1 Equiv of substrate used in each case. After one recrystallization.
(3aS,7aS)-3a-Hydroxy-7a-methylhexahydro-1H-indene-1,5(4H)-dione (Table 4, Entry 1); Typical Procedure:[10]
A soln of 2-methyl-2-(3-oxobutyl)cyclopentane-1,3-dione (1.82 g, 10 mmol, 1 equiv) and (S)-proline (1; 34.5 mg, 0.3 mmol, 0.03 equiv) in DMF (10 mL, 1 M) was stirred at rt under argon for 20 h. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give an oil, which was seeded with a crystal of the pure title compound to afford a crystalline mass. The mass was broken up and placed under high vacuum to remove residual solvent and deliver the pure title compound; yield: 1.82 g (100%); 93% ee. The ee was determined by optical rotation. (7aS)-7a-Methyl-4-[2-(6-methylpyridin-2-yl)ethyl]-2,3,7,7a-tetrahydro-1 H-indene1,5(6H)-dione (Table 4, Entry 5); Typical Procedure:[59]
A soln of 2-methyl-2-[6-(6-methylpyridin-2-yl)-3-oxohexyl]cyclopentane-1,3-dione (516.2 mg, 1.71 mmol, 1 equiv), (S)-phenylalanine (8; 338 mg, 2.05 mmol, 1.2 equiv), and 1 M HClO4 (0.86 mL, 0.86 mmol, 0.5 equiv) in MeCN (4.6 mL, 0.37 M) was refluxed under N2 for 40 h. The mixture was cooled and then filtered and the collected (S)-phenylalanine (8) was washed thoroughly with CHCl3. The combined filtrate and washings were washed with 5% aq NaHCO3, H2O, and brine, then dried, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 397.3 mg (82%); 86% ee. The ee was determined by optical rotation. (1S,5R,8R)-8-Hydroxybicyclo[3.3.1]nonan-2-one (Table 4, Entry 6); Typical Procedure:[63]
A soln of 3-(4-oxocyclohexyl)propanal (100 mg, 0.648 mmol, 1 equiv) in MeCN (2.6 mL, 0.125 M overall) was added dropwise to a stirred soln of the tetrabutylammonium salt of (2S,4R)-4-(tert-butyldiphenylsiloxy)proline (10; 21.5 mg, 0.033 mmol, 0.05 equiv) in MeCN (2.6 mL) at rt. The mixture was stirred at rt for 3 h then concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound; yield: 77 mg (77%); dr 99:1; 94% ee. The dr was determined by 1H NMR spectroscopy and the ee was determined by 1H NMR spectroscopy and HPLC analysis (no details given).
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.1
3.16.1.1.2.2
Enamine-Mediated Enantioselective Aldol and Mannich Processes
687
Intermolecular Aldol Reactions
The initial disclosure of the proline-catalyzed intermolecular aldol reaction prompted a major research effort that has generated a series of new organocatalysts, several of which have desirable features that provide improved properties as compared to proline, for example improved solubility profile, greater substrate scope, etc.[16–19,40,41] Then again, considering proline (1) is readily available and inexpensive, this amino acid is an attractive starting point for a novel substrate class. Additionally, most newer catalyst architectures need to be prepared and these syntheses are not necessarily trivial, some requiring several steps. A variety of ketone donors and aldehyde acceptors have been investigated providing a host of interesting and synthetically useful products (e.g., 17) in typically excellent yield and selectivity, using convenient procedures that operate at room temperature (Table 5). Catalysts (e.g., 1, 6, and 11–16) have been designed to facilitate the selective formation of both syn- and anti-diastereomeric products, enabling simple access to all stereoisomers of a particular compound through judicious selection of organocatalyst. Usually one component is used in excess; however, in extreme cases this can be the solvent/cosolvent.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
688
Stereoselective Synthesis
Æ-Functionalization of Carbonyl Compounds
3.16
Intermolecular Aldol Processes with Ketone Donors and Aldehyde Acceptors[15,64–81]
Table 5
OBut
N CO2H
N H
N H
N HN N
H2N
6
1
CO2H
N
Pri
N H
9
NHTf
9
13
Pri
NH2
O
O R3
R2
Ph
O N H
Ph OH
OH
R1
H
NH2 16
15
+
R1
N H
14
O
NPr2 12
O N H
H 2N
11
R3 R2 17
R1
R2
R3
Ketonea Conditionsa (equiv)
Product
O
Me
H
4-O2NC6H4
1
ee Yield Ref (%) (%) OH
1 (0.3 equiv), DMSO/ acetone (4:1; 0.1 M), rt
76
68
[15]
92
85
[64,65]
97
40
[66–71]
93
48
[72]
NO2 O
CH2OH
OH
3-FC6H4
2
11 (0.2 equiv), 5methyl-1H-tetrazole (0.1. equiv), DMF (1 M), rt; then Ac2O
OAc
OAc
OAc F
dr 11:1 (syn/anti)
O
CH2OCMe2O
CH2OBn
1
1 (0.3 equiv), DMF (1.9 M), 2 8C
O
OH
O
OBn
dr >98:2 (syn/anti)
O
CH(OMe)2
H
iPr
5
1 (0.3 equiv), DMSO (2.5 M), 4 8C
OH
MeO
Pri OMe
(CH2)3
CCl3
2
6 (0.05 equiv), MeCN, H2O (0.5 M), 30 8C
O
OH CCl3
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
84b 85
[73,74]
3.16.1
Table 5
689
Enamine-Mediated Enantioselective Aldol and Mannich Processes
(cont.)
R1
R2
R3
Ketonea Conditionsa (equiv)
Product
O
OBn 4-O2NC6H4
Me
20
12•TfOH (0.1 equiv), rt
ee Yield Ref (%) (%) OH
OBn
97
98c
[75]
99
46
[76]
81
45
[77]
94
76
[78,79]
>99
45
[80]
>99
94
[81]
NO2
dr 9:1 (syn/anti)
O
(CH2)4
Ph
2
OH
13•TFA (0.1 equiv), H2O (0.5 M), rt
Ph
dr 9:1
O
Ph
H
3-O2NC6H4
5
14 (0.1 equiv), H2O (1 equiv), DMSO (0.67 M), rt
OH
Ph
NO2 O
Me
F
4-O2NC6H4
10
15 (0.2 equiv), CH2Cl2 (0.6 M), rt
OH
F
NO2
dr 5:1 (syn/anti)
(CH2)4
H
1
1 (0.1 equiv), HCHO gas (excess), DMSO (0.25 M), rt
O OH
O
(CH2)3
PO(OEt)2
–d
16 (0.05 equiv), 0 8C
OH P
OEt
OEt dr 95:5 a b c d
Relative to 1 equiv aldehyde used. 9:1 diastereomeric ratio. >20:1 regioisomeric ratio. 0.83 M ketone (hydrated form) used.
While the development of enamine-catalyzed aldol processes with aldehyde and ketone donors with aldehyde acceptors has been particularly rapid, development of the corresponding aldol transformations with ketone acceptors has been markedly slower. This is due to factors including the lowered electrophilicity of ketone acceptors and poorer discrimination of the enantiotopic faces compared to aldehydes. However, several catalysts (e.g., 18–21) and procedures have been developed providing the aldol products (e.g., 22) with varying levels of success (Table 6).
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
690
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
Intermolecular Aldol Processes with Ketone Donors and Ketone Acceptors[66,82–91]
Table 6
O O
O N H
N H
CO2H
N H
HN
N H
S HN S O O
SO2Ph
HN
N H
N O
H 2N
N
Ph 1
19
18
O
O
O R2
21
OH R4
+
R1
20
R3
R1
R4
3
R2
R
22
R1
R2
R3
R4
Amount of Donora
Conditions
Product
O
(CH2)4
Me
Me
H
H
CO2Me
Ph
1 (0.3 equiv), 9.6 equiv DMSO (1 M), rt
CF3
Ph
0.67 M
CF3
CH=CHPh
0.2 M
1 (0.1 equiv), –20 8C
O HO
H
O
0.068 M
Me
H
H
CH2iPr
Ph
CO2H
P(O)(OEt)2
–
0.2 M
18•TFA (0.1 equiv), 0 8C
O
a b c d
CH2OCMe2OCH2
1 equiv
98b 89
[82]
64c 98
[83]
CF3
92
93
[84]
97
93
[85–88]
Ph
19•TFA (0.05 equiv), H2O (10 equiv), 0 8C
O
HO O N H
20 (0.2 equiv), acetone/toluene (1:3, 0.125 M), 0 8C; then CH2N2
O HO
CO2Me
96d 96d
[89]
96
94
[90,81]
94
57
[66]
Pri O OEt O HO P OEt Ph
21•HCO2H (0.05 equiv), 0 8C
1 (0.3 equiv), DMF (1.9 M), 2 8C
CF3
HO
O
CH2OCMe2O
CO2Me
Ph
Br
N H
Me
HO
Ph
Br
Me
ee Yield Ref (%) (%)
OH O O
O
O
Relative to 1 equiv of ketone acceptor used. dr >20:1. Stereochemistry for example only, absolute configuration unknown. Of methyl ester.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.1
Enamine-Mediated Enantioselective Aldol and Mannich Processes
691
(1S,2R)-1-(3-Fluorophenyl)-3-oxobutane-1,2,4-triyl Triacetate (17, R1 = CH2OH; R2 = OH; R3 = 3-FC6H4); Typical Procedure:[64]
To a soln of 3-fluorobenzaldehyde (62.1 mg, 0.5 mmol, 1 equiv) in anhyd DMF (0.5 mL) at rt was added 1,3-dihydroxyacetone dimer [90.1 mg, 0.5 mmol, 1 equiv (2 equiv as monomer)], (2S,3R)-O-tert-butoxythreonine (11; 17.5 mg, 0.1 mmol, 0.2 equiv), and 5-methyl1H-tetrazole (4.2 mg, 0.05 mmol, 0.1 equiv). The resulting mixture was stirred at rt for 2.1 d, and then purified directly by flash chromatography to afford the aldol product. The aldol product was dissolved in anhyd CH2Cl2 (1 mL) and pyridine (0.5 mL). Then, Ac2O (0.3 mL) was added and the mixture was stirred overnight at rt, then diluted with CH2Cl2 (2 mL), and washed with 1 M aq HCl. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with sat. aq NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 144.6 mg (85%); dr 11:1; 92% ee. The ee was determined by HPLC analysis (AS column, iPrOH/hexanes 3:97, 1 mL • min–1, 254 nm). (3S,4R)-3-(Benzyloxy)-4-hydroxy-4-(4-nitrophenyl)butan-2-one (17, R1 = Me; R2 = OBn; R3 = 4-O2NC6H4); Typical Procedure:[75]
To 1-(benzyloxy)propan-2-one (821 mg, 5 mmol, 20 equiv) was added 4-nitrobenzaldehyde (37.8 mg, 0.25 mmol, 1 equiv) and the TfOH salt of (1R,2R)-N,N-dipropylcyclohexane-1,2-diamine (12; 8.7 mg, 0.025 mmol, 0.1 equiv). The resulting mixture was stirred at rt for 20– 72 h (not specified) and then purified directly by flash chromatography; yield: 77.3 mg (98%); dr 9:1, >20:1 regioisomeric ratio; 97% ee. The ee was determined by HPLC analysis (no details given). (3R,4S)-3-Fluoro-4-hydroxy-4-(4-nitrophenyl)butan-2-one (17, R1 = Me; R2 = F; R3 = 4-O2NC6H4); Typical Procedure:[78]
To a soln of 4-nitrobenzaldehyde (45.3 mg, 0.3 mmol, 1 equiv) and fluoroacetone (228 mg, 3 mmol, 10 equiv) in CH2Cl2 (0.5 mL) at rt was added (2S)-2-amino-N-[(2S)-1-hydroxy-3-methyl-1,1-diphenylbutan-2-yl]-4-methylpentanamide (15; 23 mg, 0.06 mmol, 0.2 equiv). The resulting mixture was stirred at rt for 48 h, then quenched with sat. aq NH4Cl, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine (3 10 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 51.8 mg (76%); dr 5:1; 94% ee. The ee was determined by HPLC analysis (AS column, iPrOH/hexanes 15:85, 1 mL • min–1, 254 nm). Methyl (2S)-Hydroxy(2-oxocyclohexyl)phenylacetate [22, R1,R2 = (CH2)4; R3 = CO2Me; R4 = Ph]; Typical Procedure:[82]
A mixture of methyl 2-oxo-2-phenylacetate (41 mg, 0.25 mmol, 1 equiv), cyclohexanone (942 mg, 2.41 mmol, 9.6 equiv), and (S)-proline (1; 8.7 mg, 0.075 mmol, 0.3 equiv) in DMSO (0.25 mL, 1 M) was stirred at rt for 72 h. The mixture was then poured into 15% aq NaCl and extracted with EtOAc (2 ). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 58.4 mg (89%); dr >20:1; 98% ee. The ee was determined by HPLC analysis (AD-H column, iPrOH/hexanes 1:9, 0.5 mL • min–1, 254 nm). (2S)-2-Hydroxy-4-methyl-2-(2-oxopropyl)pentanoic Acid (22, R1 = Me; R2 = H; R3 = CH2iPr; R4 = CO2H); Typical Procedure:[89]
CAUTION: Diazomethane is explosive by shock, friction, or heat, and is highly toxic by inhalation. To a mixture of anhyd acetone (1 mL) and toluene (3 mL) was added 4-methyl-2-oxopentanoic acid (65.1 mg, 0.5 mmol, 1 equiv) and (2S)-N-(6-methylpyridin-2-yl)pyrrolidine-2-car-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
692
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
boxamide (20; 20.5 mg, 0.1 mmol, 0.2 equiv). The resulting mixture was stirred at 0 8C for 48 h and then treated with a soln of CH2N2 in Et2O (no details given) and stirred for 20 min. The mixture was then concentrated under reduced pressure to give a residue, which was purified by flash chromatography to give the title compound as its methyl ester; yield: 97.1 mg (96%); 96% ee. The ee was determined by GC analysis (Supelco Beta DEX120 column, tinj = 240 8C, toven = 102 8C, tFID = 260 8C, 0.95 atm). 3.16.1.2
Mannich Processes
The Mannich reaction is a useful transformation for direct access to valuable amine-based intermediates.[36–39] Considering the similarity of the Mannich and aldol reactions, extension of enamine catalysis to encompass Mannich processes was quickly recognized, and has now generated two platforms for the enantiocontrolled synthesis of -amino carbonyl scaffolds using either preformed imines or the direct three-component process using an amine (typically an aniline) and two carbonyl substrates. 3.16.1.2.1
Mannich Processes with Preformed Imines
Directly analogous to the aldol reaction, the Mannich reaction with preformed imines represents a straightforward and robust method for the production of useful synthetic motifs and has been the subject of considerable interest.[16,17,40,92] Several catalyst structures (e.g., 1, 2, and 23–25) have been found to be effective in this area providing products (e.g., 26) with high diastereo- and enantioselectivity (Table 7). Importantly, both syn- and anti-diastereomers can be accessed with the appropriate catalyst. The classical and most extensively employed imine is derived from ethyl glyoxalate and 4-anisidine meaning products are usually substituted with a 4-methoxyphenyl (PMP) protecting group, although a variant of this transformation utilizes the more readily cleavable tert-butoxycarbonyl group.[93] The scope of the transformation is good as successfully illustrated with a range of imines and ketones.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.1
Mannich Processes with Preformed Imines[93–109]
Table 7
N
N H
CO2H
N H
693
Enamine-Mediated Enantioselective Aldol and Mannich Processes
1
N
N
N H
HN N
2
6 NHTf CO2H NH
N H
N H
OMe
24
23
O N
+
R1 R2
3
R
25
R5
O
HN
R5 R4
R
R1
4
R2
R3
26
Substrate Carbonyl
Conditions
Productb
N
H
–c CO2Et
O
1 (0.2 equiv), DMSO, rt
Ref
PMP
N
H
–c CO2Et
HN
95
82
[94]
>99
65
[95]
93
81
[96,97]
93
81d
[98]
>98
91
[93]
PMP CO2Et
O
O
ee Yield (%) (%)
Imine PMP
O
Carbonyl (equiv)a
HN
6 (0.05 equiv), CH2Cl2, rt
PMP CO2Et
dr >19:1 (syn/anti)
O
PMP
O N
1.5
H Pri
H
CO2Et
1 (0.05 equiv), 1,4-dioxane (0.1 M), rt
HN
H
PMP CO2Et
Pr
i
dr >10:1 (syn/anti)
PMP O
O
N
10
H
H
1 (0.3 equiv), DMF (0.1 M), 4 8C
Cl dr >10:1 (syn/anti)
O Boc
N
2
H H
Ph
PMP
H
Cl
O
HN
1 (0.2 equiv), MeCN (0.1 M), 0 8C
H
NHBoc Ph
dr >99:1 (syn/anti)
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
694
Stereoselective Synthesis
Table 7
3.16
Æ-Functionalization of Carbonyl Compounds
(cont.) Substrate
Carbonyl
Carbonyl (equiv)a
Conditions
Productb
86
42
[99]
99
62
[100]
>99
80
[101]
91
81
[102]
91
99
[103]
MeO O
N
O
–e
H
PMP
N
–c CO2Et
HN
1 (0.2 equiv), DMSO, rt
O
H
OH
Ref
Imine OMe
O
ee Yield (%) (%)
HN
1 (0.2 equiv), DMSO, rt
PMP CO2Et
OH dr >19:1 (syn/anti)
O
But
PMP
HN
H PMP
O
N
H
1.5 CO2Et
CO2Et
1 (0.3 equiv), DMSO (0.5 M), rt
H But dr 1.5:1 (syn/anti)
O N
N Ts
5
1 (0.05 equiv), CH2Cl2 (0.2 M), –2 8C
NH
N Ts Et O O
O O
O
N
–f
H Pri
CO2Et
2 (0.05 equiv), H2O (50 equiv), 0 8C
O
NH CO2Et CHO Pri
dr >20:1 (syn/anti)
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.1
Table 7
(cont.) Substrate
Carbonyl
Imine
O
PMP
Carbonyl (equiv)a
Conditions
Productb
O N
2
H Pri
695
Enamine-Mediated Enantioselective Aldol and Mannich Processes
H
CO2Et
23 (0.2 equiv), DMSO (0.1 M), rt
HN
H
ee Yield (%) (%)
Ref
82
52
[104,105]
>99
93
[106,107]
>97
72
[108,109]
PMP CO2Et
Pri dr 10:1 (anti/syn)
O
PMP
CO2Et
24 (0.01 equiv), 1,4-dioxane (0.1 M), rt
CO2Et
25 (0.05 equiv), DMSO (0.2 M), rt
N
3
H H
O
PMP
N
2
H H a b c d e f
O
HN
H
CO2Et
O H
PMP
HN
PMP CO2Et
Relative to 1 equiv of imine used. PMP = 4-methoxyphenyl. Using solvent/ketone (4:1; 0.1 M). Yield of alcohol after NaBH4 reduction. Using DMSO/ketone (4:1). Using Et2O/ketone (4:1; 0.06 M).
Ethyl (2S,3S)-3-Formyl-2-[(4-methoxyphenyl)amino]-4-methylpentanoate (26, R1 = R3 = H; R2 = iPr; R4 = CO2Et; R5 = 4-MeOC6H4); Typical Procedure:[96]
To a soln of ethyl (2E)-[(4-methoxyphenyl)imino]acetate (103.6 mg, 0.5 mmol, 1 equiv) in 1,4-dioxane (5 mL) at rt was added iBuCHO (84.1 mg, 1 mmol, 2 equiv) and (S)-proline (1; 2.9 mg, 0.025 mmol, 0.05 equiv). The mixture was stirred for 2–24 h (not specified) at rt and then quenched with half-sat. aq NH4Cl and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 118.8 mg (81%); dr >10:1; 93% ee. The ee was determined by HPLC analysis (AS column, iPrOH/hexanes 1:99, 1 mL • min–1, 254 nm). 1-[(1R)-9-Tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]butan-2-one (26, R1 = R3 = H; R2 = Me; R5,R4 = 3-Ethylene-indol-2-yl); Typical Procedure:[102]
To a soln of 9-tosyl-4,9-dihydro-3H-pyrido[3,4-b]indole (20 mg, 0.0617 mmol, 1 equiv) in DMSO (0.8 mL, 0.06 M overall) was added (S)-proline (1; 2.1 mg, 0.0185 mmol, 0.3 equiv). The resulting mixture was cooled to –2 8C before addition of butanone (0.2 mL). The mixture was stirred for 5 d at –2 8C and then quenched with sat. aq NaHCO3 and extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 19.8 mg (81%); 91% ee. The ee was determined by HPLC analysis (OD column, iPrOH/hexanes 1:2). Ethyl (2S,3R)-3-Formyl-2-[(4-methoxyphenyl)amino]hex-5-enoate (26, R1 = R3 = H; R2 = CH2CH=CH2; R4 = CO2Et; R5 = 4-MeOC6H4); Typical Procedure:[108]
To a soln of ethyl (2E)-[(4-methoxyphenyl)imino]acetate (103.6 mg, 0.5 mmol, 1 equiv) in DMSO (2.5 mL) at rt was added pent-4-enal (84.1 mg, 1 mmol, 2 equiv) and (3S,5S)-5-methylpyrrolidine-3-carboxylic acid (25; 3.2 mg, 0.025 mmol, 0.05 equiv). The mixture was stirred for 3 h at rt and then quenched with sat. aq NH4Cl and extracted with EtOAc (3 ). -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
696
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 104.9 mg (72%); dr 96:4; >97% ee. The ee was determined by HPLC analysis (AS-H column, iPrOH/hexanes 1:99, 1 mL • min–1, 254 nm). Direct (Three-Component) Mannich Processes
3.16.1.2.2
The three-component or direct Mannich reaction providing products (e.g., 30) with high diastereo- and enantioselectivity relies upon the in situ formation of the requisite imine prior to the introduction of organocatalyst (e.g., 1, 6, 27–29) and donor carbonyl species (Table 8). This approach operates as effectively as the preformed imine procedure and has the benefit of avoiding separate preparation (and purification) of the imine component. Significantly, both ketone and aldehyde donors can be employed; however, while good scope of the donor carbonyl has been demonstrated the amine component is always an aniline derivative, e.g. 4-anisidine. Reagent efficiencies are comparable to aldol processes, with most examples operating with an excess of a particular reagent. Direct (Three-Component) Mannich Processes[98,110–123]
Table 8
N CO2H
N H
N
N H
N
H2N
N
HN N
HN N 27
6
1
CO2H TBDMSO NH2 N H
CO2H N H
28
29
O
O
O +
R1
R3NH2
+ H
R2
R4
HN
R1
R3 R4
R2 30
R1
R2
R3
R4
Conditions
Me
H
4-MeOC6H4
iBu
1 (0.35 equiv), rt
Producta
O
Me
4-MeOC6H4
4-O2NC6H4
Ref
93
90
[110,111]
>99
85
[98]
PMP Bui
O
Me
HN
ee Yield (%) (%)
HN
PMP
1 (0.3 equiv), DMF (0.17 M), 4 8C
NO2 dr >10:1 (syn/anti)
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.1
Table 8
697
Enamine-Mediated Enantioselective Aldol and Mannich Processes
(cont.)
R1
R2
R3
R4
Conditions
Producta
ee Yield (%) (%)
Ref
Br
H
Me
4-BrC6H4
2-pyridyl
1 (0.1 equiv), DMF (1 M), –20 8C
O
HN N
H
>99
82b
[112]
>99
90c
[113–115]
95
80
[111–116]
98
91
[117–119]
99
96
[120]
90
83
[120]
96
87
[121]
96
63
[122]
dr >10:1 (syn/anti)
(CH2)4
4-MeOC6H4
H
1 (0.1 equiv), DMSO (0.25 M), rt
CH2OBn
1 (0.2 equiv), DMF (0.25 M), rt
O N H
O
H
OBn 4-MeOC6H4
HN
PMP
PMP
H OBn OBn dr 4:1 (syn/anti)
O
O
4-MeOC6H4
O
CH(OMe)2
1 (0.3 equiv), DMF (0.25 M), H2O (4 equiv), 2 8C
HN
PMP OMe
O
O
OMe
dr >99.5:0.5 (syn/anti)
O
Me
N3
4-MeOC6H4
CO2Et
6 (0.3 equiv), DMSO (0.5 M), rt
HN
PMP CO2Et
N3 dr 91:9 (syn/anti)
CH2NPhth H
4-MeOC6H4
CO2Et
6 (0.3 equiv), DMF (0.5 M), 4 8C, 40 h
O
HN
PMP CO2Et
NPhth
O
4-MeOC6H4
4-O2NC6H4
HN
PMP
27 (0.3 equiv), DMSO (0.23 M), rt
NO2 dr 4:1 (syn/anti)
Me
H
4-MeOC6H4
Ph
28 (0.05 equiv), DMF, –20 8C
O
HN
PMP Ph
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
698 Table 8 R1
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
(cont.) R2
R3
R4
Conditions
Producta
O
Me
OH
4-MeOC6H4
4-NCC6H4
29 (0.2 equiv), DMF (0.23 M), 4 8C
HN
ee Yield (%) (%)
Ref
90
[123]
PMP
OH
83
CN
dr >10:1 (syn/anti) a b c
PMP = 4-methoxyphenyl. Yield of alcohol after NaBH4 reduction. The experimental details provided in the literature did not include the necessary amine organocatalyst.
(4R)-4-[(4-Methoxyphenyl)amino]-6-methylheptan-2-one (30, R1 = Me; R2 = H; R3 = 4-MeOC6H4; R4 = iBu); Typical Procedure:[110]
A suspension of (S)-proline (1; 40 mg, 0.35 mmol, 0.35 equiv), 4-anisidine (135 mg, 1.1 mmol, 1.1 equiv), and iBuCHO (86.1 mg, 1 mmol, 1 equiv) in acetone (10 mL) at rt was stirred for 12–48 h (not specified). The mixture was then quenched with phosphate-buffered saline soln (pH 7.4) and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 224.4 mg (90%); 93% ee. The ee was determined by HPLC analysis (AS or AD column, iPrOH/hexanes, details not specified). Ethyl (2S)-5-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[(4-methoxyphenyl)amino]-4-oxopentanoate (30, R1 = CH2Phth; R2 = H; R3 = 4-MeOC6H4; R4 = CO2Et); Typical Procedure:[120]
A soln of ethyl 2-oxoacetate (51 mg, 0.5 mmol, 1 equiv) and 4-anisidine (61.6 mg, 0.5 mmol, 1 equiv) in DMSO (1 mL) was stirred until consumption of the starting materials (30–60 min). The mixture was cooled to 4 8C and 5-[(2S)-pyrrolidin-2-yl]-1H-tetrazole (6; 20.9 mg, 0.15 mmol, 0.3 equiv) and 2-(2-oxopropyl)-1H-isoindole-1,3(2H)-dione (152.4 mg, 0.75 mmol, 1.5 equiv) were added and the mixture was stirred at 4 8C for 40 h. The mixture was quenched with half-sat. aq NH4Cl and extracted with EtOAc. The organic layer was washed with H2O, dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound; yield: 170.3 mg (83%); 90% ee. The ee was determined by HPLC analysis (OD-H column, iPrOH/hexanes 1:9, 1 mL • min–1, 254 nm). 4-{(1R,2R)-2-Hydroxy-1-[(4-methoxyphenyl)amino]-3-oxobutyl}benzonitrile (30, R1 = Me; R2 = OH; R3 = 4-MeOC6H4; R4 = 4-NCC6H4); Typical Procedure:[123]
A mixture of 4-formylbenzonitrile (65.6 mg, 0.5 mmol, 1.1 equiv), 4-anisidine (55.4 mg, 0.45 mmol, 1 equiv), hydroxyacetone (370.4 mg, 5 mmol, 11 equiv), and (S)-tryptophan (29; 20.4 mg, 0.1 mmol, 0.2 equiv) in DMF (2 mL) was stirred vigorously at 4 8C for 16– 20 h (not specified). The mixture was diluted with EtOAc and half-sat. aq NH4Cl and then extracted with EtOAc (3 ). The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 115.9 mg (83%); dr >10:1; 90% ee (anti). The ee was determined by HPLC analysis (OJ-H column, iPrOH/hexanes 3:7, 1 mL • min–1, 254 nm). 3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization
The direct enantioselective Æ-functionalization of carbonyl compounds is an attractive method for the rapid preparation of versatile synthetic intermediates and is, therefore, of great interest to the synthetic chemist. The enamine catalysis platform provides an ef-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization
699
fective method for the introduction of a variety of functional groups in a stereoselective manner using a suitable electrophile.[16–19] The attractiveness of this enamine approach over contemporary methods lies in the simplicity of its operation, wherein an aldehyde or ketone and the electrophilic fragment are combined in the presence of a suitable amine catalyst to provide directly the enantioenriched product (Scheme 3). This circumvents auxiliary-based methods and provides the associated advantages of synthetic efficiency. General Enamine-Mediated Enantioselective Æ-Functionalization
Scheme 3
Me
O Me
O
N
O
N R1
N H
R2
+
R1 H
− H2O
R2
N
R3
E+ R3
O H2O Me
O N
− R1
N H
E
H R3
R2
E+ = electrophile
Since the arrival of modern enamine catalysis in 2000,[15] this area of research has been the subject of intense investigation and has led to a spectrum of new catalyst structures and procedures for the incorporation of carbon-, halogen-, oxygen-, nitrogen-, sulfur-, and selenium-based electrophiles. Nevertheless, a universal catalyst that can accommodate multiple reaction types with high stereoselectivity remains elusive, and generally the reactions are catalyst-specific. Additionally, some of these catalysts require multistep syntheses and the enantioselectivities of many of these processes can be lower than ideal for synthetic purposes. On the other hand, several of the most selective processes can be realized using commercially available and inexpensive catalysts such as proline (1). 3.16.2.1
Æ-Halogenation Reactions
The enantioselective Æ-halogenation of carbonyl compounds has been achieved with several catalysts using a range of electrophilic halogen sources. In general, Æ-fluorination and Æ-chlorination are highly enantioselective processes while Æ-bromination and Æ-iodination reactions suffer from lower levels of enantiocontrol, even with catalysts that are effective for the former transformations. The increased acidity of the Æ-protons in the halogenated product presents a potential problem with the preservation of the stereochemical integrity and, as such, the procedures typically involve a reduction step to ultimately afford the corresponding halogenated alcohol, although some Æ-halocarbonyl species can be isolated without racemization. 3.16.2.1.1
Æ-Fluorination Reactions
The importance of fluorine within many organic molecules is well documented and methods for the direct introduction of fluorine are highly desired.[124–129] The utility of enamine catalysis to provide a facile route to stereogenic fluorinated intermediates has been ex-
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
700
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
ploited in a series of very similar transformations that were reported almost consecutively. Using the convenient electrophilic fluorine source N-fluorobis(phenylsulfonyl)amine, highly enantioselective Æ-fluorination of aldehydes can be readily accomplished. The procedures are straightforward with N-fluorobis(phenylsulfonyl)amine added to a solution of the aldehyde and catalyst (e.g., 31 or 32) either at room temperature or below (Scheme 4). Upon completion of the reaction, the fluorinated aldehyde intermediate is reduced with sodium borohydride delivering the corresponding alcohol product (e.g., 33) (Scheme 4). Yields range from moderate to excellent and enantioselectivities are generally very high; however, these are substantially lower for more challenging Æ,Æ-disubstituted substrates.[130] Depending on the procedure, either the aldehyde or N-fluorobis(phenylsulfonyl)amine is used in excess. Æ-Fluorination of Aldehydes[131,132]
Scheme 4
F 3C O
CF3
Me
CF3
N Bn
N H TMSO
N H
CF3 31
32
O R1
H
+
PhO2S
N
SO2Ph
1. catalyst (0.01−0.2 equiv) 2. NaBH4
F
HO
F
R
1
33
R1
Catalyst
Conditions
ee (%)
Yield (%)
Ref
CH2Cl2/EtOH
91
77
[131]
THF/iPrOH, –10 8C
CH2Cl2/EtOH
98
85
[131]
31
THF/iPrOH, –10 8C
CH2Cl2/EtOH
99
54
[131]
32
t-BuOMe, rt
MeOH
93
74a
[132]
step 1
step 2
31
THF/iPrOH, –10 8C
31
Ph Bn
(CH2)3CO2Et
N Boc
(CH2)5Me
32
t-BuOMe, rt
MeOH
96
55
[132]
(CH2)3OBn
32
t-BuOMe, rt
MeOH
91
64a
[132]
a
Reaction performed using 1.5 equiv aldehyde and 1 equiv N-fluorobis(phenylsulfonyl)amine.
(2R)-2-Fluoro-2-phenylethanol (33, R1 = Ph); Typical Procedure:[131]
A 25-mL round-bottomed flask equipped with a magnetic stirrer bar was charged with the dichloroacetic acid salt of (5R)-5-benzyl-2,2,3-trimethylimidazolidin-4-one (31; 139 mg, 0.4 mmol, 0.2 equiv), N-fluorobis(phenylsulfonyl)amine (3.15 g, 10 mmol, 5 equiv), and THF/iPrOH (9:1; 10 mL). The mixture was stirred at rt until homogeneous and then cooled to –10 8C. Phenylacetaldehyde (240.3 mg, 2 mmol, 1 equiv) was added and the reaction was stirred for 12 h. The mixture was then cooled to –78 8C, diluted with Et2O (10 mL), and filtered through a pad (Davisil silica gel, Et2O). Me2S (5 mL) was then added forming a white precipitate. The resulting mixture was washed with sat. aq NaHCO3 (3 150 mL) and brine (1 150 mL), then dried (MgSO4), filtered, and concentrated under reduced pressure. The -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization
701
resulting oil was dissolved in CH2Cl2/EtOH (3:2; 8 mL) and treated with NaBH4 (189 mg, 5 mmol, 2.5 equiv). The mixture was stirred for 30 min before being cooled to 0 8C and quenched with sat. aq NH4Cl (150 mL). The resulting mixture was warmed to rt and stirred vigorously for 1 h. The mixture was then diluted with CH2Cl2 (75 mL) and extracted with CH2Cl2 (3 100 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound as a colorless oil; yield: 152 mg (54%); 99% ee. The ee was determined by GC analysis (Machery-Nagel Hydrodex-B-TBDAc column, 110 8C isotherm). (2S)-2-Fluorooctan-1-ol [33, R1 = (CH2)5Me]; Typical Procedure:[132]
A soln of (2S)-2-{bis[3,5-bis(trifluoromethyl)phenyl](trimethylsiloxy)methyl}pyrrolidine (32; 30 mg, 0.05 mmol, 0.01 equiv) and octanal (96.2 mg, 0.75 mmol, 1.5 equiv) in t-BuOMe (1 mL) at rt was stirred for 10 min before addition of N-fluorobis(phenylsulfonyl)amine (157.7 mg, 0.5 mmol, 1 equiv). The mixture was stirred for 4 h at rt before addition of pentane. The resulting precipitate was removed by filtration and the filtrate was treated with MeOH (4 mL) and NaBH4 (37.8 mg, 1 mmol, 2 equiv) at rt. The mixture was stirred for 30 min before being quenched with 1 M aq KHSO4 (3 mL). After standard workup (no details given), the crude product was purified by flash chromatography; yield: 40.8 mg (55%); 96% ee. The ee was determined by conversion of the alcohol into the corresponding 4-nitrobenzoyl ester following treatment with 4-nitrobenzoyl chloride in CH2Cl2/pyridine (1:1) (no specific details given) and HPLC analysis (AS column, iPrOH/hexanes 2:98). 3.16.2.1.2
Æ-Chlorination Reactions
Æ-Chlorinated carbonyl compounds provide synthetically flexible intermediates particularly suited to the preparation of valuable motifs including epoxides, aziridines, hydroxy acids, and amino acids.[133] The generation of enantioenriched Æ-chloro carbonyls provides ready access to these key materials. The enamine-catalyzed Æ-chlorination of aldehydes and ketones is a facile and highly selective transformation using a suitable organocatalyst and electrophilic chlorine source. In these chlorination reactions, the Æ-chloroaldehydes can be isolated either through careful chromatography[134] or an extraction procedure.[135] For aldehydes, an organocatalyst [e.g., 34 or (R,R)-35] with 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one[134] or N-chlorosuccinimide[135,136] provides the corresponding enantioenriched products (e.g., 36) (Scheme 5). The latter procedure also operates effectively for ketonic substrates using (4R,5R)-4,5-diphenylimidazolidine (37) as the organocatalyst, giving the Æ-chlorinated products 38 (Scheme 6).[136] Importantly, the chlorinating agents 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one and N-chlorosuccinimide are commercially available, which is convenient given they are used in excess (typically 1.2–2 equiv). It should be noted that an enantioselective Æ-chlorination process has also been realized under the SOMO catalysis platform (see Section 3.16.3.8).[29] Scheme 5 O
Æ-Chlorination of Aldehydes[134,135] Me
N Bn
N H 34
Ph
N H
Ph
(R,R)-35
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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702
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
catalyst (0.05−0.1 equiv) chlorinating agent (1.2−1.3 equiv) −30 oC or rt
O
O Cl
H
H
R1
R1
36
R1
Catalyst (equiv)
Chlorinating Agent Cl
34•TFA (0.05)
(CH2)4CH=CH2
Equiv Solvent
Temp (8C)
ee (%)
Yield (%)
Ref
1.2
acetone
–30
92
76
[134]
1.2
acetone
–40
80
92
[134]
1.2
acetone
–30
87
78
[134]
O Cl
Cl Cl
Cl Cl
Cl
34•TFA (0.05)
Bn
O Cl
Cl Cl
Cl Cl
Cl
34•TFA (0.05)
(CH2)3Ac
O Cl
Cl Cl
Cl Cl
Et
(R,R)-35 (0.1)
NCS
1.3
CH2Cl2
rt
97
90
[135]
(CH2)2OTBDMS
(R,R)-35 (0.1)
NCS
1.3
CH2Cl2
rt
81
95
[135]
Scheme 6
Æ-Chlorination of Ketones[136] Ph
H N
Ph
N H
(0.1 equiv)
O
O
37 NCS (2 equiv), CH2Cl2, −24 oC
R1
Cl R1
R2
R2 38
R1
Me a b c
R2
ee (%)
Yield a
Ref
CH2OCH2
98
50
[136]
CH2N(Boc)CH2
93
63b
[136]
86
c
[136]
Me
51
Yield of corresponding alcohol. Determined by NMR and GC analysis. Performed using 5 equiv of ketone and at –10 8C; yield of corresponding Æ-phenylsulfanyl ketone.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization
703
(2S)-2-Chloro-3-phenylpropanal (36, R1 = Bn); Typical Procedure:[134]
CAUTION: Products are alkylating agents and may be hazardous to health. Some products are volatile - care should be taken to avoid excess evaporation. A 10-mL round-bottomed flask equipped with a magnetic stirrer bar was charged with the TFA salt of (5S)-5-benzyl-2,2,3-trimethylimidazolidin-4one (34; 8.3 mg, 0.025 mmol, 0.05 equiv) and acetone-d6 (1 mL) and cooled to –30 8C for 5 min prior to addition of 2,3,4,5,6,6-hexachloro-2,4-cyclohexadien-1-one (180.5 mg, 0.6 mmol, 1.2 equiv). 3-Phenylpropanal (62 mg, 0.5 mmol, 1 equiv) was then added and the mixture was stirred for 6 h. The mixture was then filtered [Iatrobeads silica gel (8 g), Et2O]. The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash chromatography (Iatrobeads silica gel) to afford the title compound as a colorless oil; yield: 92% by NMR analysis; 92% ee before purification (80% ee after purification). The ee was determined by GC analysis (Bodman Chiraldex G-TA column, 60 8C isotherm, 1.0 mL • min–1). (2S)-2-Chlorobutanal (36, R1 = Et); Typical Procedure:[135]
CAUTION: Products are alkylating agents and may be hazardous to health. Some products are volatile - care should be taken to avoid excess evaporation. To a soln of PrCHO (36 mg, 0.5 mmol, 1 equiv) in CH2Cl2 (1 mL) at 0 8C was added (2R,5R)-2,5-diphenylpyrrolidine [(R,R)-35; 11.2 mg, 0.05 mmol, 0.1 equiv] and NCS (87 mg, 0.65 mmol, 1.3 equiv). The mixture was stirred at 0 8C for 1 h, then allowed to warm to rt and was stirred until consumption of the aldehyde (no time given). Pentane was added and the mixture was filtered to remove the precipitated catalyst and unreacted NCS. The filtrate was concentrated under reduced pressure to give a residue and the title compound was isolated by extraction into pentane (no specific details given); yield: 47.9 mg (90%); 97% ee. The ee was determined by GC analysis (Chrompak CP-Chirasil Dex CB column, 55 8C isotherm). (3R)-3-Chlorotetrahydro-4H-pyran-4-one (38, R1,R2 = CH2OCH2); Typical Procedure:[136]
CAUTION: Products are alkylating agents and may be hazardous to health. Some products are volatile - care should be taken to avoid excess evaporation. To a mixture of (4R,5R)-4,5-diphenylimidazolidine (37; 11.2 mg, 0.05 mmol, 0.1 equiv) and tetrahydro-4H-pyran-4-one (50 mg, 0.5 mmol, 1 equiv) in CH2Cl2 (1 mL) at –24 8C was added NCS (133.5 mg, 1 mmol, 2 equiv). The mixture was then stirred at –24 8C for 20 h. The yield and ee were determined by 1H NMR spectroscopy using an internal standard and GC analysis. An analytically pure sample was obtained by flash chromatography using neutral alumina (no specific details given); however, the product obtained was racemic. The ee was determined by GC analysis (Chrompak CP-Chirasil Dex CB, 70–120 8C, 10 8C/min then isotherm). (Note: Some discrepancies were noted between the quantity of organocatalyst and NCS employed in the literature and supporting information.) 3.16.2.1.3
Æ-Bromination Reactions
Enantioselective Æ-bromination of aldehydes and cyclic ketones to brominated compounds (e.g., 40) can be accomplished effectively with a cyclohexadienone-based brominating reagent 39 in an analogous manner to those employed for Æ-chlorination and organocatalysts (S,S)-35 and 37; the Æ-brominated carbonyl compounds are often reduced in situ to the corresponding alcohols (e.g., 41) (Table 9).[137] However, the overall effectiveness of this transformation is generally somewhat lower than that for both the Æ-fluorination and Æ-chlorination procedures. For example, the aldehyde and ketone components -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
704
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
are used in excess (typically 1.5–2 equiv). While Æ-iodination was also described in this publication, this procedure is much less effective and has very limited data, as such, this is not included in this discussion. Æ-Bromination Reactions of Aldehydes and Ketones[137]
Table 9
Ph
Ph
H N
Ph
N H
Ph
N H (S,S)-35
37
O O
But
R1
O
But
+
Br
R1
R2
Br
R2
Br 40
39
OH
NaBH4 (4 equiv) MeOH, −40 oC to rt
Br
R1 R2 41
Entry Substrate
Equiva Conditions
O
1
2
H Pri
(S,S)-35•PhCO2H (0.2 equiv), CH2Cl2/pentane (1:1; 0.25 M), –24 8C, then reduction
Product
2
H
(S,S)-35•PhCO2H (0.2 equiv), CH2Cl2/pentane (1:1; 0.25 M), –40 8C, then reduction
Ref
96
87
[137]
68
95
[137]
94
66b
[137]
73
67
[137]
Br
HO Pri
O
2
ee Yield (%) (%)
Br
HO 5
5
O
O
3
1.5
37•PhCO2H (0.2 equiv), EtOH (0.5 M), –30 8C
Br
O
O Br
4
1.5 O
a b
O
37•PhCO2H (0.2 equiv), THF (0.5 M), –30 8C O
O
Of substrate; 1 equiv 39 used. Conversion (%) determined by 1H NMR of the crude reaction mixture.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization
705
(2S)-2-Bromo-3-methylbutan-1-ol (Table 9, Entry 1); Typical Procedure:[137]
CAUTION: Products are alkylating agents and may be hazardous to health. Some products are volatile - care should be taken to avoid excess evaporation. To a soln of (2S,5S)-2,5-diphenylpyrrolidine [(S,S)-35; 22.3 mg, 0.1 mmol, 0.2 equiv), PhCO2H (12.2 mg, 0.1 mmol, 0.2 equiv), H2O (1 mmol, 18 mg, 18 L, 2 equiv), and iBuCHO (86.1 mg, 1 mmol, 2 equiv) in CH2Cl2/pentane (1:1; 2 mL) at –40 8C was added 4,4-dibromo2,6-di-tert-butyl-cyclohexa-2,5-dienone (39; 182.1 mg, 0.5 mmol, 1 equiv). The mixture was stirred at –40 8C for 1.5 h before addition of MeOH (4 mL) and NaBH4 (75.7 mg, 2 mmol, 4 equiv). The mixture was allowed to warm to rt and was stirred for 20 min before being quenched with sat. aq NH4Cl and extracted with Et2O (2 ). The combined organic phases were washed with H2O, sat. aq NaHCO3, and 1 M HCl, then dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 72.7 mg (87%); 96% ee. The ee of the aldehyde was determined by GC analysis (Chrompak CP Chirasil Dex CB column, 70 8C isotherm). (7R)-7-Bromo-1,4-dioxaspiro[4.5]decan-8-one (Table 9, Entry 4); Typical Procedure:[137]
CAUTION: Products are alkylating agents and may be hazardous to health. Some products are volatile - care should be taken to avoid excess evaporation. To a soln of (4R,5R)-4,5-diphenylimidazolidine (37; 22.4 mg, 0.1 mmol, 0.2 equiv), PhCO2H (12.2 mg, 0.1 mmol, 0.2 equiv), and 1,4-dioxaspiro[4.5]decan-8-one (117.1 mg, 0.75 mmol, 1.5 equiv) in THF (1 mL, 0.5 M) at –30 8C was added 4,4-dibromo-2,6-di-tert-butyl-cyclohexa2,5-dienone (39; 182.1 mg, 0.5 mmol, 1 equiv). The mixture was stirred at –30 8C for 40 h before being filtered through a pad (Iatrobeads silica gel, Et2O/CH2Cl2 1:9). The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 78.8 mg (67%); 73% ee. The ee of the aldehyde was determined by GC analysis (Chrompak CP Chirasil Dex CB column, 70–130 8C, 10 8C/min then isotherm). (Note: A discrepancy was noted in the use of benzoic acid as an additive. The literature includes this additive while the supporting information does not detail it in the experimental procedure. It has been included in both the scheme and experimental in this document.) 3.16.2.2
Æ-Oxidation Reactions
Æ-Oxygenated carbonyl compounds and derivatives are valuable building blocks for the production of a host of bioactive molecules.[138] The generation of these motifs has therefore become an important goal for asymmetric catalysis. The potential of enamine catalysis to provide a convenient method for the production of these key synthetic units has quickly been identified and has resulted in several procedures using various different oxygen sources. To date, nitrosobenzene has been the reagent of choice and was used in the first examples of this transformation.[139–142] However, dibenzoyl peroxide,[143] 2,2,6,6-tetramethylpiperidin-1-oxyl (see Section 3.16.3.7),[28] and even oxygen gas[144,145] have been subsequently employed as electrophilic oxygen sources with varying degrees of success. 3.16.2.2.1
Æ-Oxidation Reactions Using Nitrosobenzene
Nitrosobenzene serves as a convenient and commercially available source of both electrophilic oxygen (see below) and electrophilic nitrogen (see Section 3.16.2.3). Using proline (1) as the catalyst of choice, an exceptionally selective protocol is afforded proceeding with high overall efficiency. The products (e.g., 42) of aldehyde Æ-oxidation with nitrosobenzene are oligomeric and the products are more conveniently isolated as the corresponding alcohol, which is achieved by sodium borohydride reduction (Scheme 7). -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
706
Stereoselective Synthesis
Æ-Functionalization of Carbonyl Compounds
Æ-Oxidation of Aldehydes Using Nitrosobenzene[139–141]
Scheme 7 O +
H
3.16
N
Ph
1. 1 (0.05−0.3 equiv) 2. NaBH4
O
O
HO
NHPh
R1
R1
42
R1
Equiv of 1
Solvent (step 1)
Temp
Solvent (step 2)
ee (%)
Yield (%)
Ref
0.05
CHCl3
4 8C
EtOH
98
76
[139]
0.05
CHCl3
4 8C
EtOH
98
83a
[139]
CH2OBn
0.2
DMSO
rt
EtOH
99
54
[140]
(CH2)4NHBoc
0.2
DMSO
rt
(CH2)3OTIPS
NMe
Et
0.3
MeCN
–20 8C
Ph
0.3
MeCN
–20 8C
a
EtOH
94
61
[140]
MeOH
99
87
[141]
MeOH
99
62
[141]
Determined by NMR analysis.
In contrast, ketone products (e.g., 43) can be isolated cleanly as the parent compound (Scheme 8). Cleavage of the O—N bond has been achieved under a variety of conditions to reveal the free alcohol. Procedures using nitrosobenzene are very similar, with the reagents combined at reduced temperature and stirred until consumption of nitrosobenzene. In all cases, the aldehyde and ketone components are used in excess. Finally, a formal catalytic Æ-oxidation of ketones using nitrosobenzene has been achieved using stoichiometric achiral ketone-derived enamine, nitrosobenzene, and chiral diol as the catalyst.[146] Æ-Oxidation of Ketones Using Nitrosobenzene[142]
Scheme 8 O +
R1
Ph
N
O
1 (0.1 equiv) DMF, 0 oC
O
R1
O
R2
NHPh
R2 43
R1
ee (%) Yield (%) Ref
(CH2)4
>99
77
[142]
(CH2)2OCH2
96
53
[142]
40a
[142]
Me a
R2
Me >99
Reaction performed in DMSO at rt.
(2R)-2-(Phenylaminooxy)-5-(triisopropylsiloxy)pentan-1-ol [42, R1 = (CH2)3OTIPS]; Typical Procedure:[139]
A 2-dram vial equipped with magnetic stirrer bar was charged with (S)-proline (1; 5.8 mg, 0.05 mmol, 0.05 equiv) and CHCl3 (0.5 mL) and cooled to 4 8C. The mixture was stirred for 10 min before addition of PhNO (107.1 mg, 1 mmol, 1 equiv) and 5-(triisopropylsiloxy)pentanal (776 mg, 3 mmol, 3 equiv). The mixture was stirred for 2 h and then transferred to a soln of NaBH4 in EtOH at 0 8C. The mixture was stirred for 20 min before quenching with sat. aq NaHCO3 and extraction with CH2Cl2 (3 30 mL). The combined organic layers were -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization
707
dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound as a yellow oil; yield: 267.2 mg (76%); 98% ee. The ee was determined by HPLC analysis (AS column, EtOH/hexanes 0.2:99.8, 1.0 mL • min–1). (2S)-3-(Benzyloxy)-2-(phenylaminooxy)propan-1-ol (42, R1 = CH2OBn); Typical Procedure:[140]
To a soln of 3-(benzyloxy)propanal (197 mg, 1.2 mmol, 1.2 equiv) and PhNO (107 mg, 1 mmol, 1 equiv) in anhyd DMSO (2 mL) at rt was added (S)-proline (1; 23 mg, 0.2 mmol, 0.2 equiv). The mixture was stirred for 10–20 min (endpoint monitored by color change from orange to green) before pouring into a mixture of NaBH4 (151.3 mg, 4 mmol, 4 equiv) in EtOH (1 mL). After workup (no specific details given), purification by flash chromatography afforded the title compound; yield: 147.6 mg (54%); 99% ee. The ee was determined by HPLC analysis (AD column, iPrOH/hexanes 6:94, 1.0 mL • min–1, 254 nm). (2R)-2-(Phenylaminooxy)butan-1-ol (42, R1 = Et); Typical Procedure:[141]
To a soln of PrCHO (108.2 mg, 1.5 mmol, 3 equiv) and PhNO (53.5 mg, 0.5 mmol, 1 equiv) in MeCN (3 mL,) at –20 8C was added (S)-proline (1; 17.3 mg, 0.15 mmol, 0.3 equiv). The mixture was stirred for 24 h before addition of MeOH (1 mL) and NaBH4 (94.5 mg, 2.5 mmol, 5 equiv). The mixture was stirred for 10 min before quenching with a phosphate buffer (no specific details given) and extraction with EtOAc (3 ). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 78.8 mg; (87%); 99% ee. The ee was determined by HPLC analysis (no specific details given; a related compound was analyzed using an OD-H column, iPrOH/hexanes 2.5:97.5, 0.5 mL • min–1). (2R)-2-(Phenylaminooxy)cyclohexanone [43, R1,R2 = (CH2)4]; Typical Procedure:[142]
A soln of cyclohexanone (117.8 mg, 1.2 mmol, 2 equiv) and (S)-proline (1; 6.9 mg, 0.06 mmol, 0.1 equiv) in DMF (2.7 mL, 0.17 M overall) at 0 8C was added PhNO (64.2 mg, 0.6 mmol, 1 equiv) in DMF (0.9 mL) over 5.5 h by syringe pump. The mixture was stirred at 0 8C for 30 min, quenched with pH 7 phosphate buffer soln, and extracted with EtOAc (3 ). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 94.8 mg (77%); >99% ee. The ee was determined by HPLC analysis (no specific details given; a similar compound was analyzed using an OD-H column, iPrOH/hexanes 2.5:97.5). 3.16.2.2.2
Æ-Oxidation Reactions Using Dibenzoyl Peroxide
Dibenzoyl peroxide has been used in the enamine manifold to provide a simple route to Æ-hydroxy carbonyl functionality.[143] Unlike nitrosobenzene, which provides products that can require harsh conditions to cleave the N—O bond, this procedure provides the benzoyl ester (e.g., 45), which can be readily cleaved to the alcohol (Scheme 9). While dibenzoyl peroxide is a convenient and inexpensive oxidant, it is a known explosive hazard and care should be taken with this reagent. Nevertheless, the procedure is straightforward and has no special requirements for the use of dibenzoyl peroxide. The development of a new pyrrolidine-based organocatalyst 44 has been key to the development of this process, however this catalyst is not commercially available and synthesis requires several steps including a resolution. Considering this, even though the nitrosobenzene procedures (Section 3.16.2.2.1) provide products that may require a more challenging deprotection, ultimately these are generally more practical.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
708
Stereoselective Synthesis Scheme 9
3.16
Æ-Functionalization of Carbonyl Compounds
Æ-Oxidation of Aldehydes Using Dibenzoyl Peroxide[143]
N H
Tr
(0.1 equiv), THF, rt
O
44 hydroquinone (0.1 equiv), DBPO (1.1 equiv)
O
OBz
H
H
R1
R1
45
R1
ee (%) Yield (%) Ref
Bn
93
72
[143]
CH2CH=CH2
92
62
[143]
Cy
94
65
[143]
(2S)-1-Oxo-3-phenylpropan-2-yl Benzoate (45, R1 = Bn); Typical Procedure:[143]
CAUTION: Benzoyl peroxide is a potent oxidizing agent and a potential explosive hazard. A mixture of (2S)-2-tritylpyrrolidine (44; 3.1 mg, 0.01 mmol, 0.05 equiv), hydroquinone (1.1 mg, 0.01 mmol, 0.1 equiv), and 3-phenylpropanal (26.8 mg, 0.2 mmol, 1 equiv) in THF (1 mL, 0.2 M) at rt was treated with DBPO (25% hydrate; 71.1 mg, 0.22 mmol, 1.1 equiv). The mixture was stirred for 2 h and then poured onto 1 M HCl and extracted with EtOAc. The organic layer was washed with brine and sat. aq NaHCO3, and then dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 36.6 mg (72%); 93% ee. The ee was determined in the following manner: the title compound (13 mg, 0.05 mmol, 1 equiv) in MeOH (0.5 mL) and CH2Cl2 (0.5 mL) at 0 8C was treated with NaBH4 (1.9 mg, 0.05 mmol, 1 equiv). After being stirred for 10 min, the mixture was poured onto 1 M HCl and extracted with CH2Cl2 (3 ). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the alcohol product; yield: 13 mg (99%); 93% ee. The ee was determined by HPLC analysis (AD-H, IA, or OD-H column; no specific details given). 3.16.2.2.3
Æ-Oxidation Reactions Using Molecular Oxygen
A novel approach toward enamine-based Æ-oxidation has been reported that, unlike most oxidation protocols, which rely upon stoichiometric quantities of a pre-prepared electrophilic oxygen source, employs gaseous molecular oxygen in combination with a photosensitizer [e.g., 5,10,15,20-tetraphenylporphyrin (TPP)] and a light source to generate singlet oxygen in situ as the electrophilic oxygen source. While broad utility has not been demonstrated and the levels of stereochemical induction are lower than that of the preceding transformations, this provides a chemically more efficient method for accessing Æ-oxygenated carbonyl compounds. The products of aldehyde Æ-oxidation are isolated as the corresponding diols (e.g., 49) following in situ reduction with sodium borohydride, while ketone substrates are directly isolated as the Æ-hydroxy ketones (e.g., 50) (Scheme 10). This procedure requires the use of a high-pressure sodium lamp and gaseous reagents, which adds an element of practical difficulty. For the Æ-oxidation of aldehydes, organocatalyst 46 is used[144] while (S)-alanine (47) or (S)-valine (48) is the organocatalyst for the Æ-oxidation of ketones.[145]
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization
709
Scheme 10 Æ-Oxidation of Aldehydes and Ketones Using Molecular Oxygen[144,145] CO2H N H
CO2H 46
CO2H NH2
47
O H
NH2
Pri
46 (0.2 equiv), TPP, DMF O2, hν, 0 oC, then NaBH4
48
OH
HO
77%; 66% ee
2
Ph
Ph 49
O
46 (0.2 equiv), TPP, DMF O2, hν, 0 oC, then NaBH4
H
OH
HO
75%; 57% ee
Pri
Pri O
O 47 (0.2 equiv), TPP, DMSO O2, hν, rt
OH
93%; 56% ee
50
48 (0.2 equiv), TPP, DMSO O2, hν, rt
O
O
50%; 28% ee
4
4
OH
(2R)-3-Phenylpropane-1,2-diol (49); Typical Procedure:[144]
CAUTION: Oxygen gas is toxic in high concentration and a combustion hazard especially when used in proximity to combustible solvents/materials. 3-Phenylpropanal (134.2 mg, 1 mmol, 1 equiv) was added to a vial containing 5,10,15,20tetraphenylporphyrin (TPP; 30.5 mg, 0.05 mmol, 0.05 equiv) and (2S)-Æ-methylproline (46; 25.8 mg, 0.2 mmol, 0.2 equiv) in DMF (1 mL) at 0 8C. A continuous flow of O2 or air was bubbled through the vial while the reaction was exposed to a 250-W high-pressure sodium lamp. After 1–3.5 h (not specified), the light source was removed and MeOH (2 mL) and NaBH4 (383 mg, 10 mmol, 10 equiv) were added. The mixture was stirred for 5 min, then poured into a mixture of 1 M aq HCl and EtOAc, and stirred vigorously. The mixture was then extracted with EtOAc (3 ) and the combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 117.2 mg (77%); 66% ee. The ee was determined by HPLC analysis (AD column, iPrOH/hexanes 2:98, 0.5 mL • min–1, 242 nm). (2S)-2-Hydroxycyclohexanone (50); Typical Procedure:[145]
CAUTION: Oxygen gas is toxic in high concentration and a combustion hazard especially when used in proximity to combustible solvents/materials. Cyclohexanone (98.1 mg, 1 mmol, 1 equiv) was added to a vial containing tetraphenylporphyrin (TPP; 6.1 mg, 0.01 mmol, 0.01 equiv) and (S)-alanine (47; 17.8 mg, 0.2 mmol, 0.2 equiv) in DMSO (1 mL). A continuous flow of O2 or air was bubbled through the vial while the reaction was exposed to a 250-W high-pressure sodium lamp. After 1 h, the re-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
710
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
action was quenched with brine and extracted with EtOAc (no purification details given); yield: 106.2 mg (93%); 56% ee. The ee was determined by GC analysis [CP-Chirasil-Dex CB column, Tinj = 250 8C, Tdet = 275 8C, flow = 1.8 mL • min–1, Ti = 60 8C (9 min), rate = 85 8C/min, Tf = 200 8C (5 min)]. 3.16.2.3
Æ-Amination Reactions
The synthesis of nitrogen-based stereogenic centers has been a pre-eminent goal for asymmetric catalysis due to the ubiquity of this functionality within a host of medicinally relevant compounds and natural isolates.[147–150] Enamine catalysis provides a unique and direct route to these important synthons through the exploitation of suitable electrophilic nitrogen sources. In this context, azodicarboxylates have been quickly identified and adopted as the essential electrophilic nitrogen source that, in conjunction with a suitable organocatalyst, enable the facile synthesis of 1,2-amino alcohol and Æ-amino acid motifs.[151–153] For this transformation, proline and proline-derivatives provide the optimal catalysts, affording generally excellent levels of enantioinduction over a broad range of carbonyl substrates. One drawback is the atom economy of the transformation, in which, to gain access to the parent Æ-amino carbonyl (or carbonyl derivative), the carboxylates and N—N bond must be cleaved. In this regard, the selection of a suitable azodicarboxylate partner is key since, for example, the benzyloxycarbonyl and N—N bond of products derived from dibenzyl azodicarboxylate are readily cleaved by a single-step hydrogenation using Raney nickel[154] while others can require multiple steps. It should also be noted that a formal catalytic Æ-amination of ketones using nitrosobenzene has been achieved using stoichiometric achiral ketone-derived enamine, nitrosobenzene, and chiral diol catalyst.[146] 3.16.2.3.1
Æ-Amination Reactions Using Azodicarboxylates
The initial disclosure of enamine-catalyzed Æ-amination reactions focused on the use of widely available azodicarboxylates as the requisite source of electrophilic nitrogen. These studies resulted in processes that operated with high levels of efficiency, providing convenient access to enantioenriched Æ-amino carbonyl products (e.g., 52–54 and 56) that can be diversified in a number of useful ways (Schemes 11 and 12). (S)-Proline (1), 4-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]benzenesulfonamide (51), and (R)-proline (ent-1) have been used for the Æ-amination of aldehydes. For the Æ-amination of ketones (S)-proline (1) and the organocatalysts 28 and 55 have been employed. Scheme 11 Æ-Amination of Aldehydes Using Azodicarboxylates[154–159]
CO2H
N H 1
N H
HN 51
Ts
N H
CO2H
ent-1
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization
711 CO2R3
O rt
N R2 NH R1 CO2R3
H
52 O R2
H
CO2R3
R3O2C +
rt, then NaBH4
N N
R1
N R2 NH R1 CO2R3
HO
CO2R3
53 O rt, then NaBH4 aq NaOH
O
H N
N
CO2R3 R2
R1 54
R1
R2
R3
Catalyst
Solvent
Product
ee (%)
Yield (%)
Ref
CH2CH=CH2
H
Et
1
CH2Cl2
54
93
92
[155]
iPr
H
Et
1
CH2Cl2
54
91
70
[155]
Pr
H
Bn 1
MeCN
53
>95
93
[154]
Bn
H
Bn 1
MeCN
53
>95
95
[154]
Et
H
Et
51
CH2Cl2
54
85
77
[156]
iPr
H
Et
51
CH2Cl2
54
61
18
[156]
MeCN
52
>99
96
[157]
CH2Cl2
52
84
53
Bn ent-1 MeO2C
4-PhC6H4 4-MeOC6H4 a
Me Bn 1 Me Et
1
MeCN
52
88
a
85
[158] [159]
Reaction performed under microwave irradiation at 60 8C.
Scheme 12 Æ-Amination of Ketones Using Azodicarboxylates[160–162]
TBDMSO
CO2H
N H
N
H2N N H
CO2H N
1
28
55
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
712
Stereoselective Synthesis
O
3.16
Æ-Functionalization of Carbonyl Compounds
+
R1
CO2R3
O
R3O2C N N
R2
N
R1 CO2R3
R2
NH CO2R3
56
R1
R2 (CH2)4
84 (79)
Et 1
MeCN
rt
99 (99)a 69b
[160]
(CH2)2SCH2
Bn 28
1,2-dichloroethane
0 8C
89
72
[161]
(CH2)5
Bn 28
1,2-dichloroethane
0 8C
95
73
[161]
Et 55
iPrOH
40 8C 96c
63
[162]
iPrOH
c
63
[162]
iPr
Me CH2CO2Me
Et 55
40 8C 91
67
[160]
rt
4-ClC6H4
c
Yield (%) Ref a
1,2-dichloroethane
2-thienyl
b
Temp ee (%)
Et 1
Me
a
R3 Catalyst Solvent
After purification. Isolated as 76:24 mixture of regioisomers. Product has the opposite absolute configuration.
Ethyl [(4R)-4-Isopropyl-2-oxooxazolidin-3-yl]carbamate (54, R1 = iPr; R2 = H; R3 = Et); Typical Procedure:[155]
CAUTION: Certain azodicarboxylates are an explosive hazard. To a suspension of (S)-proline (1; 11.5 mg, 0.1 mmol, 0.1 equiv) in CH2Cl2 (2.5 mL) at rt was added iBuCHO (129.2 mg, 1.5 mmol, 1.5 equiv) and DEAD (174.2 mg, 1 mmol, 1 equiv). The mixture was stirred at rt until disappearance of the yellow color of the azodicarboxylate. The mixture was then treated with MeOH (2.5 mL) and NaBH4 (50 mg, 1.32 mmol, 1.32 equiv). The mixture was stirred for 20 min before addition of 0.5 M NaOH (2.5 mL). The resulting mixture was stirred for 2 h and then the organic solvents were removed under reduced pressure. The aqueous phase was diluted and extracted with EtOAc. The organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure to give the pure title compound (no physical description given); yield: 151.4 mg (70%); 91% ee. The ee was determined by GC analysis (Chrompak Chirasil Dex-C column). Dibenzyl 1-[(2R)-1-Hydroxy-3-phenylpropan-2-yl]hydrazine-1,2-dicarboxylate (53, R1 = R3 = Bn; R2 = H); Typical Procedure:[154]
CAUTION: Certain azodicarboxylates are an explosive hazard. CAUTION: Phosgene is a severe respiratory irritant and very toxic by inhalation. A mixture of (S)-proline (1; 11.5 mg, 0.1 mmol, 0.1 equiv) and dibenzyl azodicarboxylate (90%; 330 mg, 1 mmol, 1 equiv) in MeCN (10 mL) at 0 8C was added 3-phenylpropanal (129.2 mg, 1.5 mmol, 1.5 equiv). The mixture was stirred at 0 8C and then warmed to rt and stirred until the mixture became colorless. The mixture was then cooled to 0 8C and treated with MeOH (10 mL) and NaBH4 (40 mg, 1.6 mmol, 1.06 equiv). The mixture was stirred for 5 min before quenching with half-concd aq NH4Cl and extracting with EtOAc. The organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure to give the pure title compound (flash chromatography could be used as a purification method if necessary) as a colorless solid; yield: 412 mg (95%); >95% ee. The ee was determined by converting the alcohol into the corresponding oxazolidinone in the following manner: Dibenzyl 1-[(2R)-1-hydroxy-3-phenylpropan-2-yl]hydrazine-1,2-dicarboxylate (53, R1 = 3 R = Bn; R2 = H; 270 mg, 0.62 mmol, 1 equiv) was added to Raney nickel (ca. 300 mg, prewashed with anhyd MeOH) in anhyd MeOH (10 mL) and AcOH (12 drops). The mixture -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization
713
was hydrogenated (no specific details given) for 16 h at 20 8C, filtered through Celite, and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL), cooled to 0 8C and treated with Et3N (303.6 mg, 3 mmol, 4.8 equiv) and a 2 M soln of phosgene in toluene (350 L, 0.7 mmol, 1.13 equiv). The mixture was warmed to rt, quenched with half-concd aq NH4Cl and extracted with EtOAc. The organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford (4R)-(+)-4-benzyloxazolidin-2-one; yield: 70 mg (64%). The ee was determined by HPLC analysis [AD-RH column, 67.5% H2O (0.1% TFA)/32.5% MeCN]. Ethyl [(4R)-4-Ethyl-2-oxooxazolidin-3-yl]carbamate (54, R1 = R3 = Et; R2 = H); Typical Procedure:[156]
CAUTION: Certain azodicarboxylates are an explosive hazard. To a soln of PrCHO (108.2 mg 1.5 mmol, 1.5 equiv) and DEAD (174.2 mg, 1 mmol, 1 equiv) in CH2Cl2 (2.5 mL) at rt was added 4-methyl-N-[(2S)-pyrrolidin-2-ylmethyl]benzenesulfonamide (51; 2.5 mg, 0.01 mmol, 0.01 equiv). The mixture was stirred at rt until disappearance of the yellow color of the azodicarboxylate (3 h). The mixture was then treated with MeOH (2.5 mL) and NaBH4 (50 mg, 1.32 mmol, 1.32 equiv). The mixture was stirred for 20 min before addition of 0.5 M NaOH (2.5 mL). The resulting mixture was stirred for 2 h and then the organic solvents were removed under reduced pressure. The aqueous phase was extracted with EtOAc and the organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure to give the pure title compound; yield: 155.7 mg (77%); 85% ee. The ee was determined by GC analysis (no specific details given. A similar compound was analyzed using a CP Chirasil Dex CB column, 250 8C oven). Dibenzyl 1-[(1S)-Formyl-5-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-yl]hydrazine-1,2-dicarboxylate [52, R2,R1 = 2-(CH2)2-4-MeO2CC6H3; R3 = Bn]; Typical Procedure:[157]
CAUTION: Certain azodicarboxylates are an explosive hazard. To a suspension of (R)-proline (ent-1; 46.1 mg, 0.4 mmol, 0.2 equiv) in MeCN (5 mL) at rt was added dibenzyl azodicarboxylate (597 mg, 2 mmol, 1 equiv) and methyl 1-formyl-2,3-dihydro-1H-indene-5-carboxylate (572 mg, 2.8 mmol, 1.4 equiv). The mixture was stirred at rt until consumption of the azodicarboxylate (4 h). The mixture was then treated with sat. aq NH4Cl (10 mL) and extracted with EtOAc. The organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the pure title compound as a foam; yield: 964.8 mg (96%); >99% ee. The ee was determined by HPLC analysis (AD column, iPrOH/hexanes 1:4, 1.0 mL • min–1, 254 nm). (Note: An error was noted in the literature in the mass of aldehyde employed.) Diethyl 1-[(3R)-2-Methyl-4-oxopentan-3-yl]hydrazine-1,2-dicarboxylate (56, R1 = Me; R2 = iPr; R3 = Et); Typical Procedure:[160]
CAUTION: Certain azodicarboxylates are an explosive hazard. To a soln of 4-methylpentan-2-one (1.002 g, 10 mmol, 5 equiv) and DEAD (348.4 mg, 2 mmol, 1 equiv) in MeCN (1 mL) at rt was added (S)-proline (1; 23 mg, 0.2 mmol, 0.1 equiv). The mixture was stirred at rt until disappearance of the color of the azodicarboxylate. The mixture was then quenched with H2O and extracted with Et2O. The organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound, which was inseparable from its regioisomer; yield: 378.5 mg (69%); 76:24 ratio of regioisomers; 99% ee (major regioisomer). The enantiomeric excess was determined by HPLC analysis (AS column, iPrOH/hexanes 3:97, 1 mL • min–1). -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
714
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
Diethyl 1-[(1R)-2-Oxocycloheptyl]hydrazine-1,2-dicarboxylate [56, R1,R2 = (CH2)5; R3 = Et]; Typical Procedure:[161]
CAUTION: Certain azodicarboxylates are an explosive hazard. To a soln of cycloheptanone (84.1 mg, 0.75 mmol, 1.5 equiv), dibenzyl azodicarboxylate (149.1 mg, 0.5 mmol, 1 equiv), and H2O (81 mg, 81 L, 4.5 mmol, 9 equiv) in 1,2-dichloroethane (1 mL) at 0 8C was added (2S,4R)-4-(tert-butyldimethylsiloxy)pyrrolidine-2-carboxylic acid (28; 12.3 mg, 0.05 mmol, 0.1 equiv). The mixture was stirred at 0 8C for 20 h and then directly purified by flash chromatography; yield: 149.8 mg (73%); 95% ee. The ee was determined by HPLC analysis (IA column, iPrOH/hexanes 9:91, 1 mL • min–1). Diethyl 1-[(2S)-1-Oxo-1-(2-thienyl)propan-2-yl]hydrazine-1,2-dicarboxylate (56, R1 = 2-Thienyl; R2 = Me; R3 = Et); Typical Procedure:[162]
CAUTION: Certain azodicarboxylates are an explosive hazard. A mixture of 9-amino-9-deoxyepicinchonine (55; 5.9 mg, 0.02 mmol, 0.2 equiv), TsOH (6.9 mg, 0.04 mmol, 0.4 equiv), 1-(2-thienyl)propan-1-one (28 mg, 0.2 mmol, 2 equiv), and DEAD (17.4 mg, 0.1 mmol, 1 equiv) in anhyd iPrOH (0.3 mL) was stirred 40 8C for 72 h. The title product was isolated as a colorless oil after flash chromatography (no workup given); yield: 19.8 mg (63%); 96% ee. The ee was determined by HPLC analysis (AS column, iPrOH/ hexane 3:7, 1 mL • min–1, 254 nm). 3.16.2.3.2
Æ-Amination Reactions Using Nitrosobenzene
Nitrosobenzene has been used extensively in the development of enamine-catalyzed Æ-oxidation processes due to its propensity to protonate on nitrogen rendering the oxygen center more electrophilic. However, through the rational design of a new catalyst structure that promotes selective oxygen protonation, nitrosobenzene can be employed effectively as a source of electrophilic nitrogen.[163] The hydroxylamine motif of the (reduced) products (e.g., 58) is a potentially useful functionality (Scheme 13); however, if the parent amine is desired, deprotection is not trivial and as such, other methods may be favored. Additionally, the associated catalyst 57 for this transformation is highly specialized and its synthesis is lengthy. Considering these aspects, proline-catalyzed azodicarboxylate protocols (Section 3.16.2.3.1) may be the preferred Æ-amination approach at this juncture. Scheme 13 Æ-Amination of Aldehydes Using Nitrosobenzene[163] Ph
Ph OH NH
OH Ph
Ph
57
1. 57 (0.1 equiv) THF, 0 oC 2. NaBH4, MeOH
O +
H R1
Ph
N
OH
OH N
O
Ph
R1 58
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization
R1
ee (%) Yield (%) Ref
Bu
96
76
[163]
CH2Cy
99
86
[163]
(CH2)3OBn
97
86
[163]
715
(2R)-2-[Hydroxy(phenyl)amino]hexan-1-ol (58, R1 = Bu); Typical Procedure:[163]
To a mixture of organocatalyst 57 (13.2 mg, 0.02 mmol, 0.1 equiv) and PhNO (21.4 mg, 0.2 mmol, 1 equiv) in THF (1 mL) at 0 8C was added hexanal (60.1 mg, 0.6 mmol, 3 equiv). The mixture was stirred at 0 8C for 1 h before transferring it to a suspension of NaBH4 (23 mg, 0.6 mmol, 3 equiv) in MeOH at 0 8C. The mixture was stirred for 15 min and then treated with sat. aq NaCl and extracted with CH2Cl2 (3 5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound as a pale yellow oil; yield: 31.7 mg (76%); 96% ee. The ee was determined by HPLC analysis (AD-H column, EtOH/hexanes 9:91, 0.5 mL • min–1). 3.16.2.4
Æ-Sulfanylation Reactions
The strategic design of a new sulfur-based electrophilic reagent has been critical for the development of an enantioselective Æ-sulfanylation reaction.[164,165] 1-(Benzylsulfanyl)1H-1,2,4-triazole is the reagent of choice, leading to a highly effective strategy for aldehyde Æ-sulfanylation (Scheme 14). While this reagent is not commercially available, it is readily prepared in one step from commercial materials. The Æ-functionalization reaction is conveniently performed at room temperature using a readily accessible proline-derived organocatalyst (32 or 59). Upon completion of the reaction, reduction with sodium borohydride generates the corresponding enantioenriched sulfanylated alcohol product (e.g., 60). Fully substituted sulfur-containing stereocenters can be generated in this manner, albeit the enantioselectivity is lower than related processes. Scheme 14 Æ-Sulfanylation of Aldehydes[164] F3C
CF3 CF3
Ph
N H TMSO
Ph OTMS
N H CF3
32
59
1. catalyst (0.1 equiv) toluene, rt 2. NaBH4, MeOH
O R2
H
N
+
N
SBn
SBn HO
N
R1
R2 R1 60
R1
R2
Catalyst ee (%) Yield (%) Ref
Bn
H
32
97
94
CH2CH=CH2
H
32
96
64
Ph a
Me 59
61
84
a
[164] [164] [164]
The 2-O2NC6H4CO2H salt of catalyst 59 was used.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
716
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
(2S)-2-(Benzylsulfanyl)-3-phenylpropan-1-ol (60, R1 = Bn; R2 = H); Typical Procedure:[164]
A soln of (2S)-2-{bis[3,5-bis(trifluoromethyl)phenyl](trimethylsiloxy)methyl}pyrrolidine (32; 30 mg, 0.05 mmol, 0.05 equiv) and 3-phenylpropanal (67 mg, 0.5 mmol, 1 equiv) in toluene (1 mL) was stirred for 5 min before addition of 1-(benzylsulfanyl)-1H-1,2,4-triazole (115 mg, 0.6 mmol, 1.2 equiv). The mixture was stirred for 3 h and then diluted with MeOH (4 mL). NaBH4 (22.7 mg, 0.6 mmol, 1.2 equiv) was added and the mixture was stirred for 20 min. The mixture was then quenched with 1 M aq KHSO4 (3 mL) and subjected to standard aqueous workup (no details given). The crude product was purified by flash chromatography; yield: 121.4 mg (94%); 97% ee. The ee was determined by HPLC analysis (AD-H column, iPrOH/hexanes 1:99). (Note: A discrepancy was noted between the quantity of sulfanylating reagent employed in the literature and supporting information.) 3.16.2.5
Æ-Selanylation Reactions
The Æ-functionalization of aldehydes has been extended to encompass Æ-selanylation using a phthalimide-derived selenium source, which provides access to enantioenriched phenylselanyl alcohols (e.g., 61) (Scheme 15).[166–169] The procedure is a direct extension of the Æ-sulfenylation reaction and uses the same organocatalysts 32 and 59 and virtually the same reaction conditions, albeit with significantly higher levels of asymmetric induction. Scheme 15 Æ-Selanylation of Aldehydes[166,167] F3C
CF3 CF3
Ph
N H TMSO
Ph OTMS
N H CF3
32
59
O
O +
H
1. catalyst, toluene, 0 oC 2. NaBH4, MeOH
N SePh
R1
R1
O
61
R1
Catalyst ee (%) Yield (%) Ref
Me
32
95
99a
[166]
Bn
32
97
81a
[166]
CH2CH=CH2
59
93
90
[167]
iPr
59
95
93
[167]
a
SePh
HO
The 4-O2NC6H4CO2H salt of catalyst 32 was used.
(2S)-2-(Phenylselanyl)propan-1-ol (61, R1 = Me); Typical Procedure:[166]
CAUTION: Selenium-based compounds are potentially harmful. A vial equipped with a stirrer bar was charged with (2S)-2-{bis[3,5-bis(trifluoromethyl)phenyl](trimethylsiloxy)methyl}pyrrolidine (32; 12 mg, 0.02 mmol, 0.05 equiv), 4-nitrobenzoic acid (3.3 mg, 0.02 mmol, 0.05 equiv), and toluene (0.8 mL). EtCHO (34.8 mg, 0.6 mmol, 1.5 equiv) was added and the mixture was stirred at 0 8C for 10 min. N-(Phenyl-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization
717
selanyl)phthalimide (77% purity; 157 mg, 0.4 mmol, 1 equiv) was added and the mixture was capped with a rubber stopper and stirred for 40 h. MeOH (1.6 mL) and NaBH4 (26.5 mg, 0.7 mmol, 1.75 equiv) were added and the mixture was stirred for 30 min. The mixture was quenched with H2O (several drops). Brine (5 mL) was added and the mixture was extracted with EtOAc (3 10 mL). The combined organics were dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound as a colorless oil; yield: 85.2 mg (99%); 95% ee. The ee was determined by HPLC analysis (AD-H column, iPrOH/hexanes 1:9, 0.75 mL • min–1, 214 and 254 nm). 3.16.2.6
Æ-Alkylation Reactions
The stereoselective combination of two carbon-based components is a fundamental strategy in asymmetric synthesis. In addition to aldol and Mannich processes, the use of suitable electrophilic carbon species provides a convenient method for homologation and functionalization. In this regard, enamine catalysis has endeavored to provide a new enolate-mimic for this important bond formation using alkyl halides (and equivalents) and Michael acceptors. 3.16.2.6.1
Æ-Alkylation Reactions Using Alkyl Halides
Alkyl halides (and equivalents) present a particular problem for enamine catalysis due to competitive N-alkylation of the amine catalyst. However, a specific example of intramolecular aldehyde Æ-alkylation has been accomplished under the enamine manifold using the proline-derived organocatalyst 46 to generate a range of enantioenriched carbo- and heterocycles (e.g., 62) (Scheme 16).[170] Treatment of aldehydes containing a suitably disposed leaving group with this organocatalyst affords the corresponding cycloadducts in high yield and modest to excellent enantioselectivity. Recent studies have provided a new and general platform for the direct enantioselective Æ-alkylation of aldehydes with alkyl halides (see photoredox organocatalysis, Section 3.16.4).[30,31] Scheme 16 Æ-Alkylation of Aldehydes Using Alkyl Halides[170]
N H
O
(0.1 equiv) CO2H
46 Et3N (1 equiv), CHCl3, −30 oC
H
H Z
n
62
Z
n ee (%) Yield (%) Ref
C(CO2Et)2
3 95
92
[170]
NTs
3 91
52a
[170]
1 86
b
[170]
C(CO2Et)2 b
n
I
Z
a
O
70
Yield of the corresponding alcohol. Reaction performed at –15 8C using 0.2 equiv of catalyst 46 and mesitylene (0.2 M).
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
718
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
Diethyl (2R)-2-Formylcyclopentane-1,1-dicarboxylate [62, Y = C(CO2Et)2; n = 3]; Typical Procedure:[170]
CAUTION: Starting materials are potent alkylating agents and may be hazardous to health. A soln of diethyl (3-iodopropyl)(2-oxoethyl)propanedioate (185 mg, 0.5 mmol, 1 equiv) in anhyd CHCl3 (2.5 mL) was added to (S)-Æ-methylproline (46; 12.9 mg, 0.05 mmol, 0.1 equiv) and the mixture was cooled to –30 8C. Et3N (50.5 mg, 70 L, 0.5 mmol, 1 equiv) was added and the mixture was stirred at –30 8C for 24 h. The mixture was then concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound as a colorless oil; yield: 111 mg (92%); 95% ee. The ee was determined by conversion of the title compound into the corresponding methyl enone derivative via Horner–Wadsworth–Emmons alkenation using the following procedure: Dimethyl (2-oxopropyl)phosphonate (332 mg, 0.3 mL, 2 mmol, 4 equiv) was added to LiOH•H2O (21 mg, 0.5 mmol, 1 equiv) in THF (3 mL) and stirred for 30 min. The crude alkylation mixture was added and the resulting mixture was stirred for 30 min. The resulting enone was isolated through preparative TLC (no workup details given). The ee was determined by HPLC analysis (AS-RH column, H2O/MeCN 78:22). 3.16.2.6.2
Æ-Alkylation Reactions Using Michael Acceptors
A variety of Michael acceptors participate readily in enamine-catalyzed processes providing formal alkylation products without the requirement of alkyl halides or equivalents.[16] Both intra- and intermolecular processes have been developed providing a wide variety of products for both aldehyde and ketone substrates. Catalyst structures are imidazolidinone-based (e.g., 34) for intramolecular reactions (Scheme 17), and proline-derived (e.g., 2, 6, 14, 65, and 67) for intermolecular examples (Tables 10 and 11). Products, such as 64, derived from aldehydes or ketones (e.g. 63) via intramolecular processes are generally formed with high diastereo- and enantioselectivity (Scheme 17); however, while this area has been investigated extensively, products (e.g., 66 and 68) formed by intermolecular processes generally suffer from lower levels of enantioselection (Tables 10 and 11). Additionally, the intermolecular examples typically require the carbonyl component to be used in excess. Scheme 17 Intramolecular Æ-Alkylation of Aldehydes Using Michael Acceptors[171] O
O
R1
34•HCl (0.1 equiv) THF, rt
O
O
H R1
H X
X
64
63
R1
X
ee (%) dra
Yield (%) Ref
Ph CH2 97
24:1 99
[171]
H
CH2 80
49:1 85
[171]
Me NTs 93
8:1 90
[171]
a
Ratio anti/syn.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization
719
Table 10 Intermolecular Æ-Alkylation of Aldehydes Using Michael Acceptors[172–175]
N H
N
N H
R5
O R2
H
R3
+
R1
N
N H
Pri
Pri
65
14
2
N
N H
NHTf
ent-65
O
R3 R4 EWG
H
EWG
R1
R4
R2
R5
66
Entry
Substrates Aldehyde
Conditions
Product
O
H
SO2Ph SO2Ph
83b
71
[172]
80
78
[173]
12
59
[173]
91c
93d
[174]
75e
93d
[174]
90
67
[175]
Ph
H
PhO2S O
SO2Ph
H But
O
SO2Ph
65 (0.25 equiv), CHCl3 (0.11 M), rt
Et
H
ent-65 (0.15 equiv), CHCl3 (0.11 M), –25 8C
65 (0.25 equiv), CHCl3 (0.11 M), –60 8C
H But
3
Ref
NO2
O
2
NO2
Ph
Et
Yielda (%)
Michael Acceptor
O
1
ee (%)
SO2Ph
PhO2S O
SO2Ph
H Et O
O
4
H
Ph
NO2
2•TFA (0.3 equiv), iPrOH (0.5 M), 4 8C
Ph
H NO2 O
O H
H
5
Ph
6
a b c d e
NO2
2•TFA (0.3 equiv), iPrOH (0.5 M), 4 8C
NO2
O
O H
Ph
Pri
4-Tol
NO2
15 (0.2 equiv), iPrOH (0.22 M), 0 8C
4-Tol
H NO2
Ratio of aldehyde/Michael acceptor 10:1 (equiv), unless otherwise stated. dr 95:5; ratio anti/syn. Only syn-diastereomer detected. Ratio of aldehyde/Michael acceptor 2:1 (equiv). dr 84:16.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
720
Stereoselective Synthesis
Æ-Functionalization of Carbonyl Compounds
3.16
Table 11 Intermolecular Æ-Alkylation of Ketones Using Michael Acceptors[172,176–181]
N H
N H
N
N H
N
HN
NHTf
N N 6
2
14
N H N N
N H
Pri 65
N
Pri ent-65
67
R5
O R
N
N H
R3
+
1
R
2
O R3 R
EWG R
R4 EWG
1
4
R
2
R
5
68
Entry
Substrate Ketone
O
EtO
O
Product
OEt
2 (0.2 equiv), THF/ acetone (4:1; 0.1 M), rt
EtO2C O
Yield Ref (%)
70
–
46
[178,179]
O
O
53
9:1
61
[178]
51
4:1b 55
[172]
CO2Et
F 3C
F 3C
2
ee dra (%)
Michael Acceptor O
1
Conditions
O
EtO
OEt
2 (0.2 equiv), THF/ acetone (4:1; 0.1 M), rt
EtO2C O
CO2Et Ph
Ph
O
3 Et
Ph
ent-65•HCl (0.15 equiv), CHCl3 (0.11 M), rt
NO2
O
4
Ph
ent-65•HCl (0.15 equiv), CHCl3 (0.11 M), rt
NO2
O
NO2
5 OH
CF3
65•HCl (0.15 equiv), CHCl3 (0.11 M), rt
O
Ph
NO2 O
Ph
74
[172]
5:95 84
[180]
74 95:5 NO2
O
CF3
OH
NO2
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
99
3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization
721
Table 11 (cont.) Entry
Substrate Ketone
Conditions
ee dra (%)
Product
Michael Acceptor
O
NO2
6 S
OH
S
65•HCl (0.15 equiv), CHCl3 (0.11 M), rt
O
OH
O
6 (0.15 equiv), iPrOH/EtOH (1:1, 0.25 M), rt
7
[180]
–c
74
[181]
96 99:1
95
[177]
94 >50:1
82
[176]
NO2
93
O
NO2
NO2 O Ph
96 22:78 66
OMe
OMe
8
Yield Ref (%)
NO2
S
67•2,4O2NC6H3SO3H (0.1 equiv), CHCl3 (0.125 M), 0 8C
O
NO2 S O
Cl
Ph
Ph
O O
14 (0.1 equiv), iPrOH (0.22 M), rt
9 Ph
O Cl
a b c
Ratio syn/anti. Regioisomeric ratio = 74:26 (internal/terminal). Only syn-diastereomer detected.
(1S,2R)-2-(2-Oxo-2-phenylethyl)cyclopentanecarbaldehyde (63, R1 = Ph; X = CH2); Typical Procedure:[171]
A soln of (6E)-8-oxo-8-phenyloct-6-enal (173 mg, 0.8 mmol, 1 equiv) in anhyd THF (8 mL) at rt was treated with the hydrochloric acid salt of (5S)-5-benzyl-2,2,3-trimethylimidazolidin4-one (34; 20.4 mg, 0.08 mmol, 0.1 equiv) and the resulting mixture was stirred at rt for 15 h. The solvent was then removed under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound; yield: 171.3 mg (99%); dr 24:1; 97% ee (anti). No details were provided as to the determination of ee. (2S,3R)-2-Methyl-4-nitro-3-phenylbutanal (Table 10, Entry 1); Typical Procedure:[172]
A soln of propanal (30 vol%) and (2R,2¢R)-1-isopropyl-2,2¢-bipyrrolidine (ent-65; 9.1 mg, 0.05 mmol, 0.15 equiv) in CHCl3 (3 mL, 0.11 M) at –25 8C was treated with (E)-(2-nitrovinyl)benzene (50 mg, 0.335 mmol, 1 equiv) and the resulting mixture was stirred at –25 8C for 2 d. The mixture was quenched with 1 M aq HCl (3 mL) at 0 8C and extracted with CH2Cl2 (3 3 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound; yield: 49.3 mg (71%); 95:5 dr; 83% ee (syn). The ee was determined by GC analysis (Hydrodex-B-3P column, 135 8C isotherm). -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
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Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
(2S)-2-[2,2-Bis(phenylsulfonyl)ethyl]-3,3-dimethylbutanal (Table 10, Entry 2); Typical Procedure:[173]
A soln of (2S,2¢S)-1-isopropyl-2,2¢-bipyrrolidine (65; 14.6 mg, 0.08 mmol, 0.25 equiv) in anhyd CHCl3 (filtered through basic alumina; 3 mL) at –60 8C was treated with 1,1-bis(phenylsulfonyl)ethylene (103 mg, 0.335 mmol, 1 equiv) and 3,3-dimethylbutanal (335.5 mg, 3.35 mmol, 10 equiv) and the resulting mixture was stirred at –60 8C for 2 h. The mixture was quenched with sat. aq NH4Cl (2 mL) and extracted with CH2Cl2 (3 3 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound as a pale yellow oil; yield: 106 mg (78%); 80% ee. The ee was determined by supercritical fluid chromatography analysis (OB-H column, 2 mL • min–1, 20 MPa, 10–25% MeOH, 30 8C). Diethyl {(1S)-3-Oxo-1-[2-(trifluoromethyl)phenyl]butyl}propanedioate (Table 11, Entry 1); Typical Procedure:[178]
A soln of diethyl 2-[2-(trifluoromethyl)benzylidene]propanedioate (79.1 mg, 0.25 mmol, 1 equiv) in THF/acetone (4:1; 2.5 mL) was treated with (S)-1,2¢-methylenedipyrrolidine (2; 7.7 mg, 0.05 mmol, 0.2 equiv) at rt and the resulting mixture was stirred at rt for 4 d. The mixture was then treated with 1 M aq HCl (4 mL) and stirred vigorously before being extracted with CH2Cl2 (3 2 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 43.1 mg (46%); 70% ee. The ee was determined by HPLC (AD column, no specific details given). (3R,4S)-3-Methyl-5-nitro-4-phenylpentan-2-one (Table 11, Entry 3); Typical Procedure:[172]
A soln of butanone (30 vol%) and the HCl salt of (2R,2¢R)-1-isopropyl-2,2¢-bipyrrolidine (ent65; 10.9 mg, 0.05 mmol, 0.15 equiv) in CHCl3 (3 mL) at rt was treated with (E)-(2-nitrovinyl)benzene (50 mg, 0.335 mmol, 1 equiv) and the resulting mixture was stirred at rt for 6 d. The mixture was quenched with 1 M aq HCl (3 mL) at 0 8C and extracted with CH2Cl2 (3 3 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 40.8 mg (55%); dr 4:1; 51% ee (syn). The ee was determined by supercritical fluid chromatography analysis (AD column, 2% MeOH for 2 min then increasing 1%/min to 15%, 30 8C). (2S)-2-[(1R)-1-(4-Methoxyphenyl)-2-nitroethyl]cyclohexanone (Table 11, Entry 7); Typical Procedure:[181]
A suspension of 5-[(2S)-pyrrolidin-2-yl]-1H-tetrazole (6; 11.5 mg, 0.075 mmol, 0.15 equiv) and 1-methoxy-4-[(E)-2-nitrovinyl]benzene (89.6 mg, 0.5 mmol, 1 equiv) in iPrOH/EtOH (1:1; 2 mL) at rt was treated with cyclohexanone (73.6 mg, 0.75 mmol, 1.5 equiv) and the resulting mixture was stirred at rt for 24 h. The mixture was quenched with sat. aq NH4Cl (2 20 mL) and extracted with EtOAc (2 25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography; yield: 102.6 mg (74%); 93% ee. The ee was determined by HPLC analysis (no specific details given, a similar compound was analyzed using an ADH column). 3.16.2.7
Æ-Arylation Reactions
Quinones provide viable electrophiles for enamine-catalyzed processes (e.g., with organocatalyst 59) to afford the corresponding Æ-arylated products (e.g., 69) (Table 12).[182] Additionally, anilines can be oxidized in situ using hypervalent iodine reagents or electrochemical conditions to the corresponding quinone imines, which react with enamine-activated aldehydes to provide similar Æ-arylated products (Table 12).[183] The effectiveness of -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.2
Enamine-Mediated Enantioselective Æ-Functionalization
723
this transformation is high, however the substrate scope is limited with only a small selection of quinones employed using very basic aldehydes with limited functionality. These procedures provide products analogous to those obtained from SOMO-catalyzed arylation (Section 3.16.3.6).[25–27] Table 12
Æ-Arylation Reactions[183,182] Ph
X O
R3
R4
R1
XH R3
R4
59
+
H
Ph OTMS
N H
R2
R1
R2 O
O
OH 69
R1 R2 R3
R4 X
Equiv of 59
Conditionsa
ee (%)
Yield (%)
Ref
iPr (CH=CH)2 H O
0.2
7% H2O/DMSO (7:93; 1 M), rt
99
90
[182]
Bn H Cl
0.2
EtOH (1 M), 4 8C
99
76
[182]
Cl O
b
Et H H
H NTs 0.1
anodic oxidation, 1 M NaClO4 in MeCN/H2O (1:1; 0.28 M)
94
83
[183]
Cy H H
H NTs 0.1
PhI(OAc)2 (1 equiv), MeCN/H2O (1:1; 0.28 M)
93
79c
[183]
a b
c
Ratio aldehyde/alkylating reagent = 5:1. Undivided cell, current density = 10 mA • cm–2; alkylating agent formed in situ from N-(4-hydroxyphenyl)-4-toluenesulfonamide and NaClO4. Alkylating agent formed in situ from N-(4-hydroxyphenyl)-4-toluenesulfonamide and PhI(OAc)2.
(2R,3R)-3-Isopropyl-2,3-dihydronaphtho[1,2-b]furan-2,5-diol [69, R1 = iPr; R2,R3 = (CH=CH)2; R4 = H; X = O]; Typical Procedure:[182]
To a soln of (2S)-2-[diphenyl(trimethylsiloxy)methyl]pyrrolidine (59; 19.5 mg, 0.06 mmol, 0.2 equiv), and iBuCHO (129.2 mg, 1.5 mmol, 5 equiv) in H2O/DMSO (7:93; 0.3 mL) at rt was added naphthalene-1,4-dione (47.4 mg, 0.3 mmol, 1 equiv). The resulting mixture was stirred at rt until consumption of the quinone as indicated by 1H NMR spectroscopy. The mixture was then directly purified by flash chromatography to afford the title compound as a viscous brown oil; yield: 66 mg (90%); 99% ee. The ee was determined by HPLC analysis of the corresponding alcohol obtained by NaBH4 reduction in MeOH (OD column, iPrOH/ hexanes 1:9, 1.0 mL • min–1). N-{(2R,3R)-3-Ethyl-2-hydroxy-2,3-dihydrobenzo[1,2-b]furan-5-yl}-4-toluenesulfonamide (69, R1 = Et; R2 = R3 = R4 = H; X = NTs); Typical Procedure:[183]
To a 5-mL two-necked flask containing a 0.1 M NaClO4 soln in MeCN/H2O (1:1; 2 mL) was added N-(4-hydroxyphenyl)-4-toluenesulfonamide (147 mg 0.56 mmol, 1 equiv), (2S)-2-[diphenyl(trimethylsiloxy)methyl]pyrrolidine (59; 18.2 mg, 0.056 mmol, 0.1 equiv), and butanal (201.9 mg, 2.8 mmol, 5 equiv). The flask was equipped with a Pt-net (cathode) and C-rod (anode; area = 2.5 cm2) with a distance of 0.8 cm. The anodic oxidation was carried out at rt with magnetic stirring under galvanostatic electrolysis conditions (applied current = 25 mA; current density = 10 mA • cm–2) for 5 h. The mixture was then diluted with H2O and extracted with EtOAc (3 ). The organic extracts were dried, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound as a colorless oil; yield: 155 mg (83%); 94% ee. The ee was determined by HPLC analysis of the corresponding alcohol obtained by NaBH4 reduction in MeOH (AD column, iPrOH/hexanes 3:7, 1.0 mL • min–1). -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
724
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
N-[(2R,3R)-3-Cyclohexyl-2-hydroxy-2,3-dihydrobenzofuran-5-yl]-4-toluenesulfonamide (69, R1 = Cy; R2 = R3 = R4 = H; X = NTs); Typical Procedure:[183]
To a mixture of MeCN/H2O (1:1; 2 mL, 0.28 M) was added N-(4-hydroxyphenyl)-4-toluenesulfonamide (147 mg, 0.56 mmol, 1 equiv) and PhI(OAc)2 (147 mg, 0.59 mmol, 1.05 equiv). The mixture was stirred for 2 h before addition of (2S)-2-[diphenyl(trimethylsiloxy)methyl]pyrrolidine (59; 18.2 mg, 0.056 mmol, 0.1 equiv) and cyclohexylacetaldehyde (353.4 mg, 2.8 mmol, 5 equiv). The resulting mixture was stirred at rt overnight and then directly purified by flash chromatography to afford the title compound as a colorless oil; yield: 171.4 mg (79%); 93% ee. The ee was determined by HPLC analysis of the corresponding alcohol obtained by NaBH4 reduction in MeOH (AD column, iPrOH/hexanes 3:17, 1.0 mL • min–1). 3.16.3
OrganoSOMO Mediated Enantioselective Æ-Functionalization
Enantioselective enamine catalysis provides a highly efficient platform for the direct asymmetric Æ-functionalization of carbonyl compounds with electrophilic reagents, generating a host of valuable products.[16–19] The synthetic utility of enamine catalysis has also been expanded beyond its original domain through the development of organoSOMO catalysis (singly occupied molecular orbital).[20–29] Here, a transiently generated chiral enamine 71, arising from condensation of a chiral amine organocatalyst 70 and aldehyde, is oxidized in situ using a stoichiometric quantity of a single-electron metal oxidant to generate an enamine cation-radical species 72 (Scheme 18). This effectively renders the carbonyl Æ-position electrophilic, enabling the direct stereoselective coupling of 72 with nucleophilic species (SOMOphiles), a process that cannot take place under conventional (nucleophilic) enamine reactivity (i.e., with 71). The OrganoSOMO Catalysis Platform[20–25]
Scheme 18
Me
O Me
O
N
O
N R1
N H
R2
+
R1 H
− H2O
R2
N
R3
E+ R3
70
71 Me
O N oxidant − 1e−
R1
R2
N
So R3 72 E+ = electrophile; So = SOMOphile.
Since its disclosure in 2007,[20] a number of new transformations have been developed with a variety of nucleophilic (or SOMOphilic) components, producing an array of novel and synthetically useful products with usually high levels of enantioselectivity. Experimentally, the synthetic procedures are generally very similar and typically employ commercially available ammonium cerium(IV) nitrate as the stoichiometric oxidant,[20–27] although others have emerged that rely on iron- {e.g., tris(1,10-phenanthroline)iron(III) hexafluorophosphate [Fe(phen)3(PF6)3] or iron(III) chloride}[25,28] or copper-based [e.g., copper(II) trifluoroacetate] reagents.[28,29] -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.3
OrganoSOMO Mediated Enantioselective Æ-Functionalization
725
The nature of the mechanism of these transformations requires the strict absence of oxygen to maintain synthetic efficiency, although this is typically readily achieved using oven-dried glassware and evacuation/inert gas back-filling procedures. The majority of transformations operate under cryogenic conditions, and, in most cases, employ at least 2 equivalents of metal oxidant, although substoichiometric examples have been described.[28,29] The quantity of water present has a profound effect on the reaction outcome and, as such, the levels of added water are carefully controlled based on optimized conditions. Additionally, imidazolidinone organocatalysts (generation 1 and 2) are the catalysts of choice for this mode of activation, with proline- or pyrrolidine-based catalysts being markedly less effective in terms of synthetic efficiency and enantioinduction.[26–28] 3.16.3.1
Æ-Allylation Reactions
The initial communication of this new catalytic transformation described the enantioselective Æ-allylation of aldehydes using organocatalyst 4 (Scheme 19).[20] Typically, the aldehyde substrate is introduced to the cooled oxidizing reaction mixture containing the nucleophile, which is stirred at constant temperature until it is consumed. While in many cases the aldehyde product (e.g., 73) is stable to isolation, it is often more convenient to isolate the corresponding alcohol. This is generally achieved by filtration of the reaction mixture and direct reduction with sodium borohydride prior to purification. This transformation uses the aldehyde as the limiting reagent with excess of allylsilane (2.5 equiv). Although ammonium cerium(IV) nitrate is a potent oxidant, substantial latitude in functional-group tolerance toward the oxidizing media has been demonstrated, since alkenes, ketones, esters, and carbamates are inert under the reaction conditions and provide the products in good yield and with excellent selectivity. Scheme 19 Æ-Allylation of Aldehydes[20] R2
O H
O
4•TFA (0.2 equiv), CAN (2.0 equiv) NaHCO3 (1.5 equiv), DME, −20 oC
+
R2
H
R1
R1
TMS
73
R1
R2
ee (%) Yield (%) Ref
(CH2)8OBz
H
95
72
[20]
H
93
70
[20]
(CH2)5Me
Ph
90
87
[20]
(CH2)5Me
CO2Et 90
81
[20]
N Boc
(9R)-9-Formyldodec-11-enyl Benzoate [73, R1 = (CH2)8OBz; R2 = H]; Typical Procedure:[20]
CAUTION: Ammonium cerium(IV) nitrate (CAN) is a powerful oxidizing agent. An oven-dried 25-mL round-bottomed flask equipped with a magnetic stirrer bar was charged with the TFA salt of (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one (4; 36 mg, 0.1 mmol, 0.2 equiv), CAN (685 mg, 1.25 mmol, 0.2 equiv), oven-dried NaHCO3 (63 mg, 0.75 mmol, 1.5 equiv), and bench-grade DME (2 mL). The mixture was cooled to –50 8C and deoxygenated by stirring vigorously under vacuum for 3–5 min before back-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
726
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
filling with argon (3 ). Allyltrimethylsilane (143 mg, 199 L, 1.25 mmol, 2.5 equiv) was added followed by 10-oxodecyl benzoate (138 mg, 0.5 mmol, 1 equiv). The resulting mixture was stirred at –20 8C under argon for 24 h. The mixture was then cooled to –50 8C and quickly filtered through a pad (silica gel), rinsing the residue out with a minimal quantity of DME and eluting with Et2O. The filtrate was concentrated under reduced pressure to afford a residue, which was purified by flash chromatography to afford the title compound as a colorless oil; yield: 114 mg (72%); 95% ee. The ee was determined by formation of the acetal adduct of the title compound with (2R,4R)-(–)-pentane-2,4-diol (no details given) and supercritical fluid chromatography analysis (OD-H column, 5–10% MeCN, 1.0 mL • min–1, 214 nm). 3.16.3.2
Æ-Enolation Reactions
Silyl enol ethers are also compatible with the SOMO catalysis strategy, offering a straightforward route to enantioenriched 1,4-diketones (e.g., 74) (Scheme 20).[21] This process requires a slightly modified procedure that employs a different base; however, the experimental set-up and workup is almost identical to the Æ-allylation procedure. Additionally, the same imidazolidinone organocatalyst 4, albeit a different acid salt, has been employed as for the aldehyde Æ-allylation. In these reactions, the aldehyde is the limiting reagent and an excess of the silyl enol ether is employed (typically 1.5–2 equiv). The transformation is chemoselective based on the observation that the rate of intermolecular enolation is much greater than the corresponding rate of intramolecular radical cyclization of a pendent alkene onto the in situ generated radical cation. This method is complementary to the Æ-enolation of aldehydes employing photoredox organocatalysis (described in Section 3.16.4.1) and provides similar products.[30] Scheme 20 Æ-Enolation of Aldehydes[21]
O
4•TfOH (0.2 equiv), CAN (2 equiv) 2,6-di-tert-butylpyridine (2 equiv), H2O (2 equiv)
OR3
H
R2
H
R2
R1
O
−20 oC
+
R1
O
74
R1
R2
R3
Solvent
ee (%) Yield (%) Ref
Cy
Ph
TMS
acetone
93
74
[21]
Bn
Ph
TMS
acetone
91
77
[21]
(CH2)5Me
2-thienyl
TBDMS DME
93
70a
[21]
(CH2)5Me
CH=CH2
TMS
DME
90
61
[21]
(CH2)5Me
Me
TBDPS DME
86
67
[21]
a
Reaction performed at –50 8C using 1.5 equiv of the silyl enol ether.
(2S)-2-Cyclohexyl-4-oxo-4-phenylbutanal (74, R1 = Cy; R2 = Ph); Typical Procedure:[21]
A scintillation vial equipped with a magnetic stirrer bar was charged with the TfOH salt of (4; 20.3 mg, 0.051 mmol, (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one 0.2 equiv) and acetone (4 mL) and cooled to –78 8C under argon. Cyclohexylacetaldehyde (32.3 mg, 0.256 mmol, 1 equiv), trimethyl(1-phenylvinyloxy)silane (98.5 mg, 0.512 mmol, 2 equiv), H2O (9 mg, 9 L, 0.512 mmol, 2 equiv), CAN (281 mg, 0.512 mmol, 2 equiv), and 2,6-di-tert-butylpyridine (98 mg, 115 L, 0.512 mmol, 2 equiv) were added and the soln was purged with argon for 1 min. The mixture was then stirred at –20 8C for 24 h before being -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.3
OrganoSOMO Mediated Enantioselective Æ-Functionalization
727
poured into Et2O and filtered (Davisil silica gel, Et2O). The filtrate was concentrated under reduced pressure to afford a residue, which was purified by flash chromatography to afford the title compound as a white solid; yield: 46 mg (74%); 93% ee. The ee was determined by supercritical fluid chromatography analysis (OJ-H column, 5–9.5% MeCN, linear gradient, 10 MPa, 35 8C oven, 4.0 mL • min–1). 3.16.3.3
Æ-Vinylation Reactions
Potassium trifluoro(vinyl)borates provide excellent coupling partners in SOMO-catalyzed processes (e.g., with organocatalyst 4) which facilitate the construction of enantioenriched Æ-vinyl aldehyde adducts.[22] A range of alkyl- and aryl-substituted trifluoro(vinyl)borates, in addition to several aldehydes, are tolerated delivering products that are isolated as the alcohol (e.g., 75) following reduction with sodium borohydride (Scheme 21). Yields are based on the aldehyde substrate using a substantial excess (3–5 equiv) of the potassium trifluoro(organo)borate. A degree of specificity has been noted, which has prompted the development of two different procedures, i.e. one employing acetone and the other using dimethyl ether as the reaction solvent. Scheme 21 Æ-Vinylation of Aldehydes[22] 1. 4•TFA (0.2 equiv) CAN (2.5 equiv), NaHCO3 (2 equiv)
O
H2O (4 equiv), −50 oC 2. NaBH4, CH2Cl2, EtOH
R2 +
H
KF3B
OH R2
R3
R1
R1
R3 75
R1
R2
R3
Solvent
ee (%) Yield (%) Ref
(Z)-(CH2)4CH=CHEt
Ph
H
acetone
95
78
[22]
(CH2)3OBn
Ph
H
acetone
93
78
[22]
(CH2)5Me
4-FC6H4 H
DME
93
63a
[22]
Me DME
94
a
93
[22]
H
93
73
[22]
(CH2)5Me
(CH2)5Me
a
Ph
acetone
Reaction performed using 3 equiv of the potassium trifluoroborate salt.
(2R)-2-[(E)-4-Fluorostyryl]octan-1-ol [75, R1 = (CH2)5Me; R2 = 4-FC6H4; R3 = H]; Typical Procedure:[22]
A 2-dram vial equipped with a Teflon septum and magnetic stirrer bar was charged with the TFA salt of (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one (4; 18 mg, 0.05 mmol, 0.2 equiv), potassium (E)-trifluoro(4-fluorostyryl)borate (171 mg, 0.75 mmol, 3 equiv), CAN (342 mg, 0.625 mmol, 2.5 equiv), and NaHCO3 (42 mg, 0.5 mmol, 2 equiv). The vessel was cooled to –78 8C before addition of DME (1 mL) and H2O (18 mg, 18 L, 1 mmol, 4 equiv). The mixture was deoxygenated by evacuating and back-filling with argon (3 ). Octanal (32 mg, 0.25 mmol, 1 equiv) was added the mixture was stirred at –50 8C for 24 h before addition of cold Et2O and stirring for 15 min. The mixture was then filtered (Iatrobeads silica gel) and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 (10 mL) and EtOH (1 mL) and treated with NaBH4 (95 mg, 2.5 mmol, 10 equiv). Upon consumption of the aldehyde, the mixture was -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
728
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
quenched with sat. aq NH4Cl (10 mL) and extracted with CH2Cl2 (3 20 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried (MgSO4), and concentrated under reduced pressure to afford a residue, which was purified by flash chromatography to afford the title compound as a colorless oil; yield: 39.4 mg (63%); 93% ee. The ee was determined by supercritical fluid chromatography analysis (AD-H column, 5–15% iPrOH, linear gradient, 10 MPa, 35 8C oven, 4.0 mL • min–1). 3.16.3.4
Æ-Homobenzylation Reactions
Styrenes also provide potent nucleophiles that react with enamine radical cations derived from organocatalyst 76 to deliver carbonyl Æ-homobenzylation products (e.g., 77) (Scheme 22).[23] The benzylic carbocation, generated upon initial nucleophilic attack and second oxidation, is also a viable electrophile and, in this procedure, it is quenched with the nitrate produced in situ from the ammonium cerium(IV) nitrate oxidant. This second stereocenter is created with moderate diastereocontrol and acts as a suitable functionalgroup handle to enable the synthesis of heterocyclic adducts such as 2,4-disubstituted tetrahydropyrans, 2,4-disubstituted pyrrolidines, and cis- and trans-3,5-disubstituted ª-lactones through conventional synthetic manipulations. For this transformation, the styrene is the limiting reagent and the procedure requires 2 equivalents of the aldehyde component. Scheme 22 Æ-Homobenzylation of Aldehydes[23] O
Me N But
N H 76
76•TFA (0.2 equiv) CAN (2.5 equiv), DME NaHCO3 (2 equiv), H2O (2 equiv)
O
−40 oC
+
H
R2
R3
R1
R3
R2
O
R4
H R1
R4
ONO2 77
Entry R1 1
(CH2)6C”CEt
2
R2
R3
R4
ee (%) dr
Yield (%) Ref
H
H
H
96
3:1
94
[23]
H
H
H
94
2:1
82
[23]
OMe 96
3:1
94
[23]
3:1
95
[23]
83
[23]
N Boc
3
(CH2)5Me
H
H
4
(CH2)5Me
H
NO2 H
5 a
(CH2)5Me
Me H
H
92 89
a
4:1
Æ,-anti.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.3
OrganoSOMO Mediated Enantioselective Æ-Functionalization
729
(1S,3S)-3-Formyl-1-(3-methoxyphenyl)nonyl Nitrate [77, R1 = (CH2)5Me; R2 = R3 = H; R4 = OMe]; Typical Procedure:[23]
A 10-mL round-bottomed flask equipped with a magnetic stirrer bar and septum was charged with the TFA salt of (2R,5R)-2-tert-butyl-3,5-dimethylimidazolidin-4-one (76; 28.4 mg, 0.1 mmol, 0.2 equiv), CAN (684 mg, 1.25 mmol, 2.5 equiv), and NaHCO3 (84 mg, 1 mmol, 2 equiv) and cooled to –78 8C under argon. DME (3 mL) and H2O (18 mg, 18 L, 1 mmol, 2 equiv) were added and the mixture was deoxygenated by evacuating and back-filling with argon (3 ). 3-Methoxystyrene (67 mg, 0.5 mmol, 1 equiv) was then added, followed by octanal (128 mg, 156 L, 1 mmol, 2 equiv). The mixture was stirred at –40 8C for 12 h before addition of Et2O. The mixture was then filtered (Florisil silica gel, Et2O) and the filtrate was concentrated under reduced pressure to afford a residue, which was purified by flash chromatography to afford the title compound as a mixture of diastereomers as a colorless oil; yield: 151.2 mg (94%); dr 3:1; 96% ee (major diastereomer). The ee was determined by conversion of the title compound into the corresponding lactone derivative using the following procedure: A soln of (1S,3S)-3-formyl-1-(3-methoxyphenyl)nonyl nitrate [76, R1 = (CH2)5Me; R2 = 3 R = H; R4 = OMe; 151.2 mg, 0.47 mmol, 1 equiv] in THF/AcOH/H2O (8:1:1; 5 mL) was treated with Zn dust (100 mg, 1.52 mmol, 3.23 equiv). The mixture was stirred at rt for 4 h before being quenched with sat. aq NaHCO3 and extracted with EtOAc (3 ). The combined organics were washed with H2O and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the crude lactols, which were dissolved in acetone (10 mL), cooled to 0 8C, and treated with 2.5 M Jones reagent (0.3 mL, 0.75 mmol, 1.6 equiv). The mixture was stirred for 1 h and then quenched with iPrOH (1 mL) and stirred at rt for 30 min. The mixture was filtered (Florisil, EtOAc) and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford (3S,5S)-3hexyl-5-(3-methoxyphenyl)dihydrofuran-2(3H)-one [yield: 92 mg (71%); 96% ee] and (3S,5R)-3-hexyl-5-(3-methoxyphenyl)dihydrofuran-2(3H)-one [yield: 29.9 mg (23%); 78% ee] as colorless solids. The ee was determined by HPLC analysis (AS-H column, EtOH/hexanes 3:97, 1.0 mL • min–1, 214 nm. 3.16.3.5
Æ-Nitroalkylation Reactions
In an analogous fashion to the SOMO Æ-enolation of aldehydes (Section 3.16.3.2),[21] silyl nitronates can be employed as the SOMOphilic species, which provides products that are useful precursors to -amino acids.[24] Interestingly, in this transformation, the alternative silyl protecting groups (tert-butyldimethylsilyl and triisopropylsilyl) on the silyl nitronate 78 result in two different mechanistic pathways, leading to either syn- (e.g., 80) or anti-diastereomeric products (e.g., 79) (Scheme 23). This aspect provides a convenient method for accessing both diastereomers, and the enantiomers of a particular -nitroaldehyde through judicious selection of silyl nitronate and organocatalyst (e.g., 4 or ent-4). In this regard, two different sets of reaction conditions are described, each of which is tailored for a specific silyl nitronate and thus a specific diastereomer. The silyl nitronate is the limiting reagent and requires 2 equivalents of the aldehyde with yields slightly more moderate than in the previous SOMO protocols. Scheme 23 Æ-Nitroalkylation of Aldehydes[24] O
O
Me
Me
N Bn
N H 4
N But
Bn
N H
But
ent-4
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
730
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds 4•TFA or ent-4•TFA (0.2 equiv), CAN (2 equiv) NaHCO3 (2 equiv), H2O (2 equiv) THF, −40 oC
O
NO2 R2
H R1
R2
O +
H
H
N
R1
79
O
OR3 78
4•TFA or ent-4•TFA (0.2 equiv), CAN (2 equiv) NaO2CCF3 (3 equiv), H2O (2 equiv) acetone, −40 oC
O
NO2 R2
H R1 80
R1
R2
R3
Catalyst Product ee (%) dra Yield (%) Ref
Cy
Et
TIPS
4
79
97
3:1 65b
[24]
Cy
Et
TBDMS 4
80
96
1:4 55
[24]
Et
TIPS
4
79
95
9:1 71
[24]
Et
TBDMS 4
80
94
1:5 67
[24]
(CH2)4OBz
(CH2)2CO2Me
TIPS
ent-4
79
91
6:1 79
[24]
(CH2)4OBz
(CH2)2CO2Me
TBDMS ent-4
80
91
1:6 68
[24]
(CH2)4OBz
(CH2)2CH=CH2
TIPS
79
80
2:1 73
2
MeO2C CO2Me
2
MeO2C CO2Me
(CH2)4OBn a b
(CH2)2CH=CH2
ent-4
TBDMS ent-4
80
91
b
1:5 91
[24] [24]
Ratio anti/syn. Reaction performed at –50 8C.
(5S,6S)-5-Formyl-9-methoxy-6-nitro-9-oxononyl Benzoate [79, R1 = (CH2)4OBz; R2 = (CH2)2CO2Me]; Typical Procedure:[24]
A 10-mL round-bottomed flask equipped with a magnetic stirrer bar and septum was charged with the TFA salt (2R,5R)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one (ent-4; 29 mg, 0.08 mmol, 0.2 equiv), CAN (450 mg, 0.82 mmol, 2.05 equiv), and NaHCO3 (67 mg, 0.8 mmol, 2 equiv). The vessel was cooled to –78 8C before addition of THF (3 mL) and H2O (14.4 mg, 14.4 L, 0.8 mmol, 2 equiv). The mixture was deoxygenated by evacuating and back-filling with N2 (2 ) before addition of 6-oxohexylbenzoate (0.8 mmol, 176 mg, 2 equiv) followed by methyl 4-[oxido(triisopropylsiloxy)imino]butanoate (121 mg, 0.4 mmol, 1 equiv). The mixture was deoxygenated once again by evacuating and back-filling with N2 and then stirred at –40 8C for 24 h. Upon completion of the reaction, cold Et2O (20 mL) was added and the mixture was stirred at –78 8C for 10 min and then filtered through a pad of Florisil silica gel eluting with Et2O (125 mL). The filtrate was concentrated under reduced pressure to afford a residue, which was purified by flash chromatography to afford the title compound as a mixture of diastereomers; yield: 117 mg (80%); dr 6:1 (anti/syn); 91% ee (anti). The ee was determined by reduction of the diastereomeric aldehydes to the corresponding alcohols with NaBH4 in Et2O/EtOH (10:1, no specific conditions given) and HPLC analysis (AD-H column, iPrOH/hexanes 1:4, 1.0 mL • min–1, 225 nm). (Note: The literature and supporting information report different enantiomers of this material. Characterization data is presented for the enantiomer of the material shown here.) -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.3
OrganoSOMO Mediated Enantioselective Æ-Functionalization
731
(5S,6R)-5-Formyl-9-methoxy-6-nitro-9-oxononyl Benzoate [80, R1 = (CH2)4OBz; R2 = (CH2)2CO2Me]:[24]
A 10-mL round-bottomed flask equipped with a magnetic stirrer bar and septum was charged with the TFA salt of (2R,5R)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one (4; 29 mg, 0.08 mmol, 0.2 equiv), CAN (450 mg, 0.8 mmol, 2.0 equiv), and NaO2CCF3 (109 mg, 0.8 mmol, 2 equiv). The vessel was cooled to –78 8C before addition of acetone (3 mL) and H2O (14.4 mg, 14.4 L, 0.8 mmol, 2 equiv). The mixture was deoxygenated by evacuating and back-filling with N2 (2 ) before addition of 6-oxohexyl benzoate (176 mg, 0.8 mmol, 2 equiv) followed by methyl 4-[(tert-butyldimethylsiloxy)oxidoimino]butanoate (105 mg, 0.4 mmol, 1 equiv). The mixture was deoxygenated once again by evacuating and back-filling with N2 and then stirred at –40 8C for 16 h. Upon completion of the reaction, cold Et2O (25 mL) was added and the mixture was stirred at –78 8C for 10 min and then filtered through a pad of Florisil silica gel eluting with Et2O (125 mL). The filtrate was concentrated under reduced pressure to afford a residue, which was purified by flash chromatography to afford the title compound as an inseparable mixture of diastereomers; yield: 99 mg (68%); dr 1:6 (anti/syn); 92% ee (syn). The ee was determined by reduction of the diastereomeric aldehydes to the corresponding alcohols with NaBH4 (no specific conditions given) and HPLC analysis (AS-H column, iPrOH/hexanes 1:9, 1.0 mL • min–1, 220 nm). (Note: The authors report the use of 2 equiv of CAN in the literature and 2.05 equiv in the supporting information.) 3.16.3.6
Æ-Arylation Reactions
Several carbocyclic and heterocyclic arenes provide suitable SOMOphilic species to facilitate the construction of a range of enantioenriched Æ-aryl aldehydes (e.g., 82) or alcohols (e.g., 83 and 84) after reduction with sodium borohydride (Scheme 24).[25–27] This process is currently only known in the intramolecular manifold, using an appropriate tether to provide a number of bi- and tricyclic scaffolds. Two groups have contributed to the development of this transformation. In one example, the discovery of a new organocatalyst 81 via automated screening processes has led to, in many cases, much improved reactivity and selectivity over the traditionally employed catalysts (e.g., 4).[25] Several different sets of reaction conditions are described (with variation of oxidant, base, and other additives) indicating a considerable substrate-dependence. On the other hand, from the experimental results, it appears that there is an optimum set of conditions for a specific arene substrate class, i.e. phenyl derivatives, naphthalenes, and heteroarenes, perhaps suggesting that reaction conditions may be extrapolated to unknown substrates based on the substrate type.[25] Some considerable differences are noted in the spread of product yields between the two studies. This may be attributable to slight differences in the experimental procedures, where the rigorous deoxygenation appears to be the critical factor in the overall efficiency of this process.[26,27] This method provides products analogous to those generated through enamine-catalyzed Æ-arylation as described in Section 3.16.2.7.[183,182] Scheme 24 Æ-Arylation of Aldehydes[25–27]
O
Me
O
Me
N Bn
N H 4
N But
N H
But
81
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
732
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds R2 O H
R2 O
R1
R1
R3
∗ Z
X
R3
82
H
R2
Z
X
R1
R3
HO X
Z
83
R2
R3
Conditionsa
Product ee Yield (%) (%)
Ref
NTs CH2 OMe H
H
81•TFA (0.2 equiv), [Fe(phen)3]•3PF6 (2.5 equiv), pivalic acid (0.3 equiv), NaHCO3 (5 equiv), MeCN (0.15 M), H2O (1 equiv), –20 8C; then NaBH4, EtOH
83
95
86
[25]
81•TFA (0.2 equiv), [Fe(phen)3]•3PF6 (2 equiv), NaH2PO4 (1 equiv), acetone (0.4 M), H2O (1 equiv), –30 8C; then NaBH4, EtOH
83
96
73
[25]
OMe 4•TFA (0.2 equiv), CAN (2 equiv), 82 DME (0.4 M), H2O (2 equiv), –30 8C
86
76
[26,27]
OMe OMe 4•TFA (0.2 equiv), CAN (2 equiv), 82 DME (0.4 M), H2O (2 equiv), –30 8C
94
58
[26,27]
X
R1
Z
CH2 CH2 (CH=CH)2 H
CH2 O
OMe H
CH2 CH2 H
a
phen = 1,10-phenanthroline.
1. 81•TFA (0.2 equiv), CAN (2 equiv) NaHCO3 (2 equiv), NaO2CCF3 (2 equiv) H2O (1 equiv), acetone, −30 oC 2. NaBH4, EtOH
OHC 3
96%; 90% ee
O
O HO 84
(4R)-5,7-Dimethoxy-3,4-dihydro-2H-benzopyran-4-carbaldehyde (82, X = CH2; Z = O; R1 = R3 = OMe; R2 = H); Typical Procedure:[26,27]
An oven-dried 10-mL vial equipped with a stirrer bar was charged with the TFA salt of (2S,5S)-2-tert-butyl-5-benzyl-3-methylimidazolidin-4-one (4; 18 mg, 0.05 mmol, 0.2 equiv) in DME (4 mL) and cooled to –78 8C. 4-(3,5-Dimethoxyphenoxy)butanal (56.1 mg, 0.25 mmol, 1 equiv), H2O (9 mg, 9 L, 0.5 mmol, 2 equiv), and CAN (274 mg, 0.5 mmol, 2 equiv) were added and the mixture was stirred vigorously for 1 min under argon. The mixture was then warmed to –30 8C and stirred for 24 h. The mixture was quenched with sat. aq NaHCO3 (10 mL), extracted with Et2O (2 25 mL), dried (MgSO4), and concentrated under reduced pressure to give a residue, which was purified by flash chromatog-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.3
OrganoSOMO Mediated Enantioselective Æ-Functionalization
733
raphy to afford the title compound as a colorless oil; yield: 42.2 mg (76%); 86% ee. The ee was determined by reduction to the corresponding alcohol with NaBH4 (no details given) and HPLC analysis (OD-H column, iPrOH/hexanes 2:98, 1.0 mL • min–1). [(4S)-5-Methoxy-2-tosyl-1,2,3,4-tetrahydroisoquinolin-4-yl]methanol (83, X = NTs; Z = CH2; R1 = OMe; R2 = R3 = H); Typical Procedure:[25]
An oven-dried 10-mL round-bottomed flask equipped with a magnetic stirrer bar and septum was charged with the TFA salt of (2S,5S)-2-tert-butyl-3-methyl-5-(1-naphthylmethyl)imidazolidin-4-one (81; 16.4 mg, 0.04 mmol, 0.2 equiv), [Fe(phen)3]•3PF6 (515 mg, 0.5 mmol, 2.5 equiv), pivalic acid (6.13 mg, 0.06 mmol, 0.3 equiv), and NaHCO3 (84 mg, 1 mmol, 5 equiv). The vessel was deoxygenated by evacuating and back-filling with argon (5 ) before being cooled to –78 8C. Deoxygenated MeCN (1.3 mL) and H2O (3.6 mg, 3.6 L, 0.2 mmol, 1 equiv) were added followed by addition of N-(3-methoxybenzyl)-4methyl-N-(3-oxopropyl)benzenesulfonamide (69.5 mg, 0.2 mmol, 1 equiv). The mixture was deoxygenated once again by evacuating and back-filling with N2 (5 ) and then stirred at –20 8C for 24 h. Upon completion of the reaction, cold Et2O was added and the mixture was stirred at –78 8C for 5 min. The mixture was then filtered through a glass frit funnel into a 100-mL flask containing excess NaBH4 (76 mg, 2 mmol, 10 equiv). EtOH (10 mL) was added to the mixture at –40 8C and the reaction temperature was gradually increased to –10 8C. Upon consumption of the aldehyde, the mixture was quenched with sat. aq NH4Cl and extracted with Et2O. The combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound as a colorless oil; yield: 59.5 mg (86%); 95% ee. The ee was determined by HPLC analysis (OD-H column, iPrOH/hexanes 1:9). (Note: Some discrepancy was noted in the reaction conditions for this transformation. The literature notes the addition of various additives while these are missing in the relevant general procedure in the supporting information.) (4R)-1,2,3,4-Tetrahydrophenanthren-4-ylmethanol [83, X = Z = CH2; R1,R2 = (CH=CH)2; R3 = H]; Typical Procedure:[25]
A Schlenk tube equipped with a magnetic stirrer bar was charged with the TFA salt of (81; 16.4 mg, (2S,5S)-2-tert-butyl-3-methyl-5-(1-naphthylmethyl)imidazolidin-4-one 0.04 mmol, 0.2 equiv) and cooled to –78 8C. A soln of 5-(2-naphthyl)pentanal (42.5 mg, 0.2 mmol, 1 equiv) and H2O (3.6 mg, 0.2 mmol, 3.6 L, 1 equiv) in acetone (0.5 mL) was added followed by deoxygenating the mixture by evacuating and back-filling with argon (5 ). [Fe(phen)3]•3PF6 (430 mg, 0.42 mmol, 2.1 equiv) and Na2HPO4 (28 mg, 0.2 mmol, 1 equiv) were then added against the flow of argon. The mixture was deoxygenated once again by evacuating and back-filling with argon (5 ) and then stirred at –30 8C for 24 h. Upon completion of the reaction, cold Et2O (no volume given) was added and the mixture was stirred at –78 8C for 5 min. The mixture was then filtered through a glass frit funnel into a 100-mL flask containing excess NaBH4 (76 mg, 2 mmol, 10 equiv). EtOH (10 mL) was added to the mixture at –40 8C and the reaction temperature gradually increased to –10 8C. Upon consumption of the aldehyde, the mixture was quenched with sat. aq NH4Cl and extracted with Et2O. The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound as a colorless oil; yield: 31 mg (73%); 96% ee. The ee was determined by HPLC analysis (OD-H column, iPrOH/hexanes 1:19). (7S)-4,5,6,7-Tetrahydrobenzo[b]furan-7-ylmethanol (84); Typical Procedure:[25]
A Schlenk tube equipped with a magnetic stirrer bar was charged with the TFA salt of (81; 16.4 mg, (2S,5S)-2-tert-butyl-3-methyl-5-(1-naphthylmethyl)imidazolidin-4-one 0.04 mmol, 0.2 equiv) and cooled to –78 8C. A soln of 5-(3-furyl)pentanal (30.5 mg, 0.2 mmol, 1 equiv) and H2O (3.6 mg, 3.6 L, 0.2 mmol, 1 equiv) in acetone (1.3 mL) was -Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
734
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
added followed by deoxygenating the mixture by evacuating and back-filling with argon (5 ). CAN (230 mg, 0.42 mmol, 2.1 equiv), NaHCO3 (33.6 mg, 0.4 mmol, 2 equiv), and NaO2CCF3 (55.6 mg, 0.4 mmol, 2 equiv) were then added against the flow of argon. The mixture was deoxygenated once again by evacuating and back-filling with argon (5 ) and then stirred at –30 8C for 24 h. Upon completion of the reaction, cold Et2O was added and the mixture was stirred at –78 8C for 5 min. The mixture was then filtered through a glass frit funnel into a 100-mL flask containing excess NaBH4 (76 mg, 2 mmol, 10 equiv). EtOH (10 mL) was added to the mixture at –40 8C and the reaction temperature gradually increased to –10 8C. Upon consumption of the aldehyde, the mixture was quenched with sat. aq NH4Cl and extracted with Et2O. The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography to afford the title compound as a colorless oil; yield: 29.4 mg (96%); 90% ee. The ee was determined by HPLC analysis (OD-H column, iPrOH/hexanes 2:98). (Note: The quantity of oxidant employed varies from 2 equiv to 2.1 equiv for some examples.) 3.16.3.7
Æ-Oxidation Reactions
The enamine radical cation that is generated in situ (e.g., from organocatalyst 34) can be readily trapped with other radical species, such as 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) to facilitate the enantioselective synthesis of synthetically important Æ-oxyaldehydes or the corresponding alcohols (e.g., 85) after reduction with sodium borohydride (Scheme 25).[28] This reaction provides the first example of the use of catalytic quantities of a metal oxidant [iron(III) chloride], which uses sodium nitrite and oxygen as co-oxidants. This requirement for oxygen gas may present a technical obstacle, and considering that methods to cleave the N—O bond derived from 2,2,6,6-tetramethylpiperidin-1-oxyl are similar to the ones used for nitrosobenzene-derived products, the simpler nitrosobenzene approach (Section 3.16.2.2.1) is likely to be the preferred method. This method provides products analogous to those generated through enamine-catalyzed Æ-oxidation as described in Section 3.16.2.2.[139,140] Scheme 25 Æ-Oxidation of Aldehydes[28] 1. 34•HBF4 (0.2 equiv), FeCl3 (0.2 equiv) O• N
(2 equiv), NaNO2 (0.3 equiv), O2, DMF, −10 oC or rt
R1
HO O H
2. NaBH4, THF, 0 oC
O
R1
85
R1
Temp (8C) ee (%) Yield (%) Ref
Bn
–10
82
68a
[28]
3,4-(MeO)2C6H3CH2
rt
72
76
[28]
CH2CH=CH2
–10
90
58
[28]
a
Performed using 4 equiv of TEMPO.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
N
3.16.3
OrganoSOMO Mediated Enantioselective Æ-Functionalization
735
(2S)-3-Phenyl-2-[(2,2,6,6-tetramethylpiperidin-1-yl)oxy]propan-1-ol (85, R1 = Bn); Typical Procedure:[28]
CAUTION: Oxygen gas is toxic in high concentration and a combustion hazard especially when used in proximity to combustible solvents/materials. A mixture of 3-phenylpropanal (67 mg, 0.5 mmol, 1 equiv), TEMPO (312.4 mg, 2 mmol, 4 equiv), NaNO2 (10.4 mg, 0.15 mmol, 0.3 equiv), and (5S)-5-benzyl-2,2,3-trimethylimidazolidin-4-one salt 34•HBF4 (30.6 mg, 0.1 mmol, 0.2 equiv) in DMF (0.5 mL) was stirred at rt for 5 min. FeCl3 (0.1 mmol, 0.2 equiv) and O2 (introduced via 10 mL-syringe) were added and the mixture was stirred at –10 8C for 24 h. Upon completion of the reaction, sat. aq NH4Cl (5 mL) was added and the mixture was extracted with CH2Cl2 (3 10 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to afford a residue, which was dissolved in THF (5 mL) and cooled to 0 8C. NaBH4 (37.8 mg, 1 mmol, 2 equiv) was added and the mixture was warmed to rt and stirred for 1 h. The mixture was then poured into sat. aq NH4Cl (10 mL) and extracted with CH2Cl2 (3 10 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to afford a residue, which was purified by flash chromatography to afford the title compound as a colorless oil; yield: 99.3 mg (68%); 82% ee. The ee was determined by HPLC analysis (OD-H column, iPrOH/hexanes 2:98, 1.0 mL • min–1). 3.16.3.8
Æ-Chlorination Reactions
By using organocatalyst 86, simple alkali metal chlorides can function effectively as SOMOphilic components providing a straightforward and highly enantioselective Æ-chlorination process for the synthesis of Æ-chlorinated aldehydes and the corresponding alcohols (e.g., 87) after reduction with sodium borohydride (Scheme 26).[29] Unlike most other SOMO methodology (with the exception of the Æ-oxidation described in Section 3.16.3.7),[28] this transformation utilizes substoichiometric quantities of metal oxidant, assisted by an equivalent of sodium persulfate. This methodology has enabled the one-pot synthesis of enantioenriched terminal epoxides from aldehydes, which provides a convenient alternative to the more conventional asymmetric epoxidation of terminal alkenes. This method provides products analogous to those generated through enamine-catalyzed Æ-chlorination as described in Section 3.16.2.1.2.[134,135] Scheme 26 Æ-Chlorination of Aldehydes[29] O
Me N N H
But
86
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
736
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
1. 86•TFA (0.2 equiv) Cu(O2CCF3)2 (0.5 equiv), Na2S2O8 (1 equiv) LiCl (1.5 equiv), H2O (2.2 equiv), MeCN, 10 oC
O H
2. NaBH4, 0 oC
R1
HO
R1
Cl 87
R1
ee (%) Yield (%) Ref
(Z)-(CH2)3CH=CHEt
96
89
[29]
(CH2)3OMOM
94
84
[29]
91
75
[29]
NBoc
tert-Butyl 3-[(2S)-2-Chloro-3-hydroxypropyl]-1H-indole-1-carboxylate {87, R1 = [N-(tertButoxycarbonyl)indol-3-yl]methyl}; Typical Procedure:[29]
A 10-mL pear-shaped round-bottomed flask (at 10 8C) equipped with a magnetic stirrer bar was charged with the TFA salt of (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one (86; 34 mg, 0.12 mmol, 0.2 equiv), LiCl (38 mg, 0.9 mmol, 1.5 equiv), Cu(O2CCF3)•H2O (87 mg, 0.3 mmol, 0.5 equiv), and Na2S2O8 (143 mg, 0.6 mmol, 1 equiv). MeCN (4.8 mL) and H2O (24 mg, 24 L, 1.32 mmol, 2.2 equiv) were added and the mixture was stirred for 5 min before addition of tert-butyl 3-(3-oxopropyl)-1H-indole-1-carboxylate (164 mg, 0.6 mmol, 1 equiv). The mixture was stirred vigorously for 4 h at 10 8C and then cooled to 0 8C before addition of NaBH4 (136 mg, 3.6 mmol, 6 equiv). After 15 min, the mixture was warmed to rt and stirred for 5 min before quenching with sat. aq NH4Cl (40 mL) and EtOAc (40 mL). The resulting mixture was stirred vigorously until the aqueous layer had turned deep blue. The layers were then separated and the aqueous soln was extracted with EtOAc (3 40 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated to give a residue, which was purified by flash chromatography to afford the title compound as a colorless oil; yield: 139 mg (75%); 91% ee. The ee was determined by HPLC analysis (AD-H column, EtOH/hexanes 1:19). 3.16.4
Photoredox Organocatalysis Mediated Enantioselective Æ-Functionalization
The direct enantioselective Æ-alkylation of carbonyl compounds has remained a considerable challenge for enamine catalysis. While alkylation can be readily achieved through the use of suitable Michael acceptors (as described in Section 3.16.2.6.2), the use of general alkylating agents presents a significant problem for enamine catalysis, largely due to competing N-alkylation of the amine catalyst, albeit the intramolecular variant has been described (see Section 3.16.2.6.1).[170] Nevertheless, a more general strategy toward the asymmetric Æ-alkylation[30] and perfluoroalkylation[31] of aldehydes has been devised, which utilizes a dual catalyst system that consists of a chiral amine organocatalyst with a transition-metal photoredox catalyst. This process provides access to a range of functionalized products with high levels of efficiency and moderate enantioselectivities. Mechanistically, the photoredox catalyst acts as a powerful single-electron reductant that produces electrophilic alkyl radicals, which are readily intercepted by the transient chiral enamine produced from condensation of the organocatalyst and the substrate aldehyde (Scheme 27). The photoredox catalysts employed are very efficient, which is exemplified by the very low catalyst loading (0.5 mol%).
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.16.4
Photoredox Organocatalysis Mediated Enantioselective Æ-Functionalization 737
Scheme 27
Radical Generation with Photoredox Catalysts[30]
photoredox catalyst
hν
photoredox catalyst*
R1X
reductant
R1 • electrophilic radical
Considering this mechanistic aspect, the presence of oxygen is detrimental to the photoredox procedures, which require the exclusion of any oxygen. Similar to SOMO catalysis (see Section 3.16.3), this is readily achieved with evacuation/refilling and purging techniques. 3.16.4.1
Æ-Alkylation Reactions
The enantioselective Æ-alkylation of aldehydes is optimal for the imidazolidinone organocatalyst 86 in combination with the commercially available photoredox catalyst tris(bipyridine)ruthenium(II) dichloride [Ru(bipy)3Cl2] (Table 13).[30] While many photochemical procedures require the use of high-intensity light sources, this photoredox catalyst operates effectively in the visible-light region[184,185] meaning that reactions can be carried out using simple light sources, such as fluorescent household light bulbs. The catalytic system is mild and tolerates a wide range of functionality in the aldehyde component, including linear and branched alkyls, esters, carbamates, alkenes, and arenes. In the initial disclosure, the demonstrated alkylating agents were a series of Æ-bromo carbonyl compounds, which furnished products (e.g., 88) with the 1,4-dicarbonyl motif. This was extended to encompass fluorinated alkyl chains that do not possess the activating carbonyl unit (see Section 3.16.4.2).[31] Several Æ-bromo carbonyl compounds are commercially available while others must be prepared. Racemic Æ-bromo carbonyl compounds can also be employed in diastereoselective applications of this process. Notably, this method allows the straightforward enantioselective synthesis of all-carbon quaternary stereocenters. The procedure is straightforward in its execution, conveniently taking place at room temperature in dimethylformamide. The only restraints being the use of previously dried solvent and deoxygenation of the reaction mixture, which is achieved by bubbling nitrogen gas through the reaction medium. Upon completion of the reaction, the products are isolated through standard aqueous workup and purification procedures. This method provides products analogous to those generated via the SOMO-catalyzed Æ-enolation protocol (Section 3.16.3.2).[21]
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
738
Stereoselective Synthesis Table 13
3.16
Æ-Functionalization of Carbonyl Compounds
Æ-Alkylation of Aldehydes[30] 86•TfOH (0.2 equiv) Ru(bipy)3Cl2 (0.005 equiv)
O
O +
H
hν, DMF, 23 oC
Br
R1
R2
O
2,6-lutidine (2 equiv)
R3
R3
H
R2
R1
O
88
Entry
Substrates Aldehyde
ee (%)
Yield (%)
Ref
90
92
[30]
91
66
[30]
93
63a
[30]
96
87
[30]
95
84
[30]
99b
70
[30]
Bromo Carbonyl
O
1
Product
EtO2C
H
O
CO2Et H
Br
Bn
CO2Et CO2Et Bn
O
O
H
EtO2C
2
CO2Et
H
CO2Et
CO2Et
Br N Boc
N Boc
O
O EtO2C
H
3
CO2Et
CO2Et
H
CO2Et
Br
O
OMe
O
H
O
4
5
H
4
Br
O
OMe O
NO2
5
5
H
4
Br
NO2
O 5
Br H
b
O
O
O
6
a
O
H
O
4
CO2Bu
O t
CO2
Using 0.4 equiv of catalyst 86. dr 5:1.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
But
3.16.4
Photoredox Organocatalysis Mediated Enantioselective Æ-Functionalization 739
Diethyl [(2R)-1-Oxo-3-phenylpropan-2-yl]propanedioate (Table 13, Entry 1); Typical Procedure:[30]
CAUTION: Æ-Bromo carbonyl derivatives are potent alkylating agents. An oven-dried 8-mL vial equipped with a septum and magnetic stirrer bar was charged with Ru(bipy)3Cl2•6H2O (1.4 mg, 1.9 mol, 0.005 equiv), diethyl bromomalonate (91.3 mg, 0.385 mmol, 66 L, 1 equiv), and the TfOH salt of (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one (86; 24.6 mg, 76.9 mol, 0.2 equiv). The vial was purged with a stream of N2 before addition of anhyd DMF (0.8 mL), 3-phenylpropanal (103.2 mg, 101 L, 0.769 mmol, 2 equiv), and 2,6-lutidine (82.4 mg, 90 L, 0.769 mmol, 2 equiv). The resulting mixture was deoxygenated by bubbling N2 gas through the reaction medium for 10 min. The vial was sealed with Parafilm and placed approximately 8 cm from a 15-W fluorescent lamp. After 7 h, the mixture was poured into a separatory funnel containing H2O (5 mL) and Et2O (5 mL). The layers were separated and the aqueous layer was extracted with Et2O (3 5 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (Davisil Grade 643 silica gel) to afford the title compound as a colorless oil; yield: 105 mg (93%); 90% ee. The ee was determined in the following manner: the title compound (20 mg, 68 mol, 1 equiv) was added to a mixture of (2S,4S)-(+)-pentanediol (>99% ee; 8.4 mg, 82 mol, 1.2 equiv) and p-toluenesulfonic acid monohydrate (1.5 mg, 8 mol, 0.12 equiv) in CH2Cl2 (1 mL) at rt. Upon completion of the reaction (no time given), the mixture was concentrated under reduced pressure and the ee of the title compound was determined by 1 H NMR spectroscopic analysis. 3.16.4.2
Æ-Perfluoroalkylation Reactions
The photoredox aldehyde alkylation procedure (described in Section 3.16.4.1) has been extended to encompass Æ-perfluoroalkylation.[31] This transformation is mechanistically and operationally similar to the original procedure and requires the same organocatalyst 86 (albeit a different acid salt). The mild reaction conditions enable facile access to functionalized fluorinated compounds (e.g., 89) of particular synthetic value in a number of important research areas (Scheme 28).[124–129] Importantly, the scope of the reaction is not limited to conventionally favored trifluoromethylation and can be readily applied to higher homologues. In the case of trifluoromethylation, trifluoro(iodo)methane gas is used as the trifluoromethyl synthon, resulting in a technically more demanding procedure, which requires the condensation of the gaseous reagent, although this is not necessary when using higher-order reagents. The transformation is performed under cryogenic conditions, requiring careful reaction set-up and some degree of specialized equipment, namely a glass-sheathed UV light source compatible with solvent-cooled cryogenic vessels. Unlike the alkylation process detailed in Section 3.16.4.1, the required photoredox catalyst for this transformation is not commercially available, although it is readily prepared following literature methods.[186] Employing dried solvents and maintaining a deoxygenated reaction medium remains a necessary element with this protocol. The perfluoroalkylated products are generally isolated as the alcohol (e.g., 89) after reduction with sodium borohydride although examples of diversification through oxidation to carboxylic acid, reductive amination, and oxidation/Curtius rearrangement of a specific Æ-trifluoromethyl aldehyde have also been described.
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 741
740
Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
Scheme 28 Æ-Perfluoroalkylation of Aldehydes[31] 1. 86•TFA (0.2 equiv) Ir(ppy)2(dtb-bipy)PF6 (0.005 equiv) 2,6-lutidine (1.1 equiv), hν, DMF, −20 oC
O +
H
F
F
R2
I
F
2. NaBH4, CH2Cl2, MeOH, −78 oC
R2
HO R
R1
F
1
89 dtb-bipy = 4,4'-di-tert-butyl-2,2'-bipyridyl; ppy = 2-phenylpyridine
R1
R2
ee (%) Yield (%) Ref
(CH2)3OBn
F
95
71
[31]
4-MeOC6H4
F
93
61
[31]
(R)-CH(Me)Ph
F
99a
68
[31]
(CH2)4Me
(CF2)2CF3
96
67
[31]
(CH2)4Me
C6F5
98
85
[31]
(CH2)4Me
Br
99
68
[31]
a
dr >20:1.
(2S)-5-(Benzyloxy)-2-(trifluoromethyl)pentan-1-ol [89, R1 = (CH2)3OBn; R2 = F]; Typical Procedure:[31]
CAUTION: Haloperfluorohydrocarbon derivatives are potent alkylating agents. This procedure requires the use of a fluorescent lamp under cryogenic conditions (solvent-filled cryocool) and extreme care should be taken when using electrical apparatus in close proximity to flammable solvents. When using an electrical device near a cooling bath, be certain the outlet is equipped with a proper ground fault circuit interrupter (GFI or GFCI) to prevent severe or fatal electric shock. An oven-dried 13 mm 100 mm borosilicate test tube equipped with a septum and magnetic stirrer bar was charged with the TFA salt of (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one (86; 43.4 mg, 0.15 mmol, 0.2 equiv) and Ir(ppy)2(dtb-bipy)PF6 (3.5 mg, 0.004 mmol, 0.005 equiv). The test tube was purged by alternating vacuum/argon gas backfill (3 ) before cooling to –78 8C. DMF (2.53 mL) was added and the resulting soln was purged further by alternating vacuum/argon gas backfill (3 ). CF3I (1.2 g, 6.13 mmol, 8.1 equiv) was condensed into the tube using a cold finger fitted with an 18-gauge needle. 5-(Benzyloxy)pentanal (162 mg, 0.76 mmol, 1 equiv) and 2,6-lutidine (97.4 L, 0.84 mmol, 1.1 equiv) were then added and the test tube was placed in a –20 8C acetone cryocool at approximately 3 cm from a 26-W fluorescent light source (daylight GE Energy Smart 1600 lumens) that was inserted in a Pyrex glass tube. After 7.5 h, the test tube was removed, cooled to –78 8C and transferred via precooled pipet to a round-bottomed flask containing CH2Cl2 (4 mL) at –78 8C using cold CH2Cl2 (8 mL) to transfer the remaining residue. NaBH4 (288 mg, 7.6 mmol, 10 equiv) was added followed by cold MeOH (10 mL) and the mixture was stirred for 1 h before quenching with aq NH4Cl (10 mL). The mixture was allowed to warm to rt before extracting with Et2O (3 ). The combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to afford a residue, which was purified by flash chromatography to afford the title compound as a colorless oil; yield: 156 mg (71%); 95% ee. The ee was determined by HPLC analysis of the alcohol product (AS column, EtOH/hexanes 3:97, 1.0 mL • min–1, 214 nm).
-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
References
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[51]
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[77]
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Stereoselective Synthesis
3.16
Æ-Functionalization of Carbonyl Compounds
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Æ-Functionalization of Carbonyl Compounds
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-Functionalization of Carbonyl Compounds, MacMillan, D. W. C., Watson, A. J. B. Science of Synthesis 4.0 version., Section 3.16 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
747 3.17
Baeyer–Villiger Reactions S. Levinger
General Introduction
The peroxide-mediated insertion of an oxygen atom into the bond between a carbonyl carbon atom and another carbon or hydrogen atom is known as the Baeyer–Villiger reaction or Baeyer–Villiger oxidation (Scheme 1). Although this definition includes the oxidation of aldehydes and Æ-oxo ketones to give carboxylic acids and acid anhydrides respectively, it is the transformation of acyclic ketones (and some aldehydes) into esters, and that of cyclic ketones into lactones, that constitutes the main field of application. Scheme 1
The Baeyer–Villiger Reaction
O R3
R1
O
O
R4 or O 2
O
R2
R1
OR2
R1 = R2 = alkyl, cycloalkyl, aryl, hetaryl, H, acyl; R3 = acyl, aroyl, alkyl, silyl, H; R4 = H, silyl
Since it was first reported in 1899 the Baeyer–Villiger reaction has developed into an important method in organic synthesis, characterized by an exceptionally broad scope of applicability and high degree of tolerance toward different functional groups. The topic has been surveyed in Science of Synthesis, Vol. 20b [Three Carbon—Heteroatom Bonds: Esters and Lactones; Peroxy Acids and R(CO)OX Compounds; R(CO)X, X = S, Se, Te (Sections 20.5.1.3.2, 20.5.1.6.1, 20.6.1.10.5, and 20.6.1.10.6)] for the synthesis of esters and lactones, and the reader is referred to these sections for a detailed discussion of experimental conditions, including many examples. The mechanistic aspects of the Baeyer–Villiger reaction have been reviewed in depth.[1,2] There exists a wide consensus in favor of a twostep mechanism based on Criegees proposal[3] and later refinements[4–7] (Scheme 2). Scheme 2
Mechanism of the Baeyer–Villiger Reaction[1–7] O
O R
1
R3
O
O
H
2
R
R1
OH O
O R3
R2
O
O
− R3CO2H
R
1
O
R2
The first step is a nucleophilic addition of the oxidant (as exemplified by a peroxycarboxylic acid in Scheme 2) to the carbonyl function of the substrate to form a peroxidic hemiacetal. This species, known as the Criegee intermediate, subsequently undergoes a concerted 1,2-migration of a carbonyl substituent (R2) to the neighboring electrophilic oxygen, with concomitant cleavage of the peroxide bond and reforming of the carbonyl group. The desired ester is thus obtained along with a byproduct which, depending on the nature of the oxidizing agent, may be a carboxylic acid (as in Scheme 2) or another hydroxy compound (e.g., water or an alcohol). Conservation of orbital symmetry during the thermal 1,2-sigmatropic shift of the second step dictates retention of configuration at the migrating carbon with the resultant stereospecificity being an inherent trait for all Baeyer–Villiger Reactions, Levinger, S. Science of Synthesis 4.0 version., Section 3.17 sos.thieme.com © 2014 Georg Thieme Verlag KG
for references see p 757 (Customer-ID: 5907)
748
Stereoselective Synthesis
3.17
Baeyer–Villiger Reactions
Baeyer–Villiger transformations. However, in the context of the Baeyer–Villiger reaction the classification of “stereoselective”, as opposed to “nonstereoselective”, does not refer to this general property, but rather to the discriminatory effect the chiral environment of a reacting system has on the reaction rate of enantiomeric reactants (kinetic resolution) or production rate of enantiomeric products (asymmetric synthesis). Stereoselectivity in Baeyer–Villiger oxidations has also been discussed in Science of Synthesis, Vol. 20b [Three Carbon—Heteroatom Bonds: Esters and Lactones; Peroxy Acids and R(CO)OX Compounds; R(CO)X, X = S, Se, Te (Sections 20.6.1.10.5 and 20.6.1.10.6)] as part of the general treatment of the method and is presented here as a special topic. 3.17.1
Chemical Methods
3.17.1.1
Reactions Promoted by Chiral Metal Catalysts
Moderate to good enantioselectivity in metal-mediated oxidation is achieved mainly with strained systems. Chiral copper complex 1 and 1,1¢-bi-2-naphthol (BINOL) complexes of zirconium 2 and aluminum 3 have been used in the Baeyer–Villiger oxidation of racemic bicyclo[4.2.0]octan-7-one (4) to give (3aR,7aS)-hexahydrobenzo[c]furan-1(3H)-one (5) and (3aR,7aR)-hexahydrobenzo[b]furan-2(3H)-one (6) (Scheme 3).[8,9] The reaction is regiospecific, in that each enantiomer of the substrate is specifically (and with its own rate) diverted to a different regioisomeric lactone, and enantioselective in that each of the regioisomers obtained is enantiomerically enriched. The low activity of the zirconium reagent requires its use in stoichiometric quantities, whereas the aluminum complex (prepared in situ from the same ligand) performs similarly with lower loadings (25 mol%). Scheme 3
Regiodivergent Kinetic Resolution of Bicyclo[4.2.0]octan-7-one[8–10] But
But O N
NO2
O
O
Cu N
O
O2N But
O
O Zr
O
But (S,S)-1
(R)-2
O O
Al Cl
(R)-3
H
H
O
O
H O
[O]
O H rac-4
Baeyer–Villiger Reactions, Levinger, S. Science of Synthesis 4.0 version., Section 3.17 sos.thieme.com © 2014 Georg Thieme Verlag KG
O
+
H 5
(Customer-ID: 5907)
H 6
O
3.17.1
749
Chemical Methods
Conditions
ee (%) Yield (%) Ref 5
O2, t-BuCHO, (S,S)-1 (0.01 equiv), benzene, rt t-BuOOH (1.5 equiv), (R)-2 (1 equiv), toluene
6
5
92 67 15 46
[8]
84 16 –a –a
[8,10]
c
t-BuOOH (1 equiv), Me2AlCl (0.25 equiv), (R)-BINOL 90 25 – a b c
6
b
–
b
[8]
The products are obtained in the ratio (5/6) 1:6. Conversion is given as 98
70
[26]
Et
Et
93
83
[26]
(CH2)3
97
80
[26]
(CH2)4
>98
78
[26]
(CH2)5
>98
57
[26]
(CH2)6
87
55
[26]
CH2OCH2 >98
74
[26]
Lactones 24; General Procedure:[26]
Ketone 23 (ca. 1 mmol) was subjected to oxidation in the presence of the enzyme cyclohexanone oxygenase (E.C. 1.14.13.-, ca. 30 units, ca. 10 mg) and a catalytic amount of NADP+ [the oxidized form of nicotinamide adenine dinucleotide phosphate (NADPH)] in a pH 8.0 soln of glycine/NaOH (80 mL). The glucose-6-phosphate disodium salt (1.25 mmol)/glucose-6-phosphate dehydrogenase (1.10 mg) cofactor recycling protocol was utilized to regenerate the required NADPH.[27] Chromatography gave the isolated product. 3.17.2.3
Reactions Using Engineered Organisms
With the advent of methods for genetic engineering there is the possibility for useful enzymes to be expressed in microorganisms other than those possessing the enzymes naturally. This strategy combines the benefits of both whole-cell enzyme and isolated enzyme techniques. The recombinant organism can be grown to provide a constant source of both the enzyme and the cofactor, without producing harmful enzymes typical of the natural organism, which avoids the problem of product overmetabolism. The designed organism is chosen to be nonpathogenic and can be prepared in large quantities. An assortment of Baeyer–Villiger monooxygenases (BVMOs) have been overexpressed in bakers yeast and in a variety of E. coli strains, the latter having the additional advantage of reduced biomass production. The overexpression of the genes for synthetically useful enzymes in benign and amenable organisms is at present the most attractive and promising biochemical method of synthesis available.[21] Various racemic 2-substituted cyclohexanones rac-25 have been kinetically resolved using bakers yeast engineered to produce cyclohexanone monooxygenase to give the resolved (unreacted) ketones 25 and the 6-substituted lactones 26 with excellent enantiomeric purities (Scheme 9).[24,28] The selectivity of the enzyme is in all cases for the same configuration at the ketone Æ-position (regardless of its nominal R/S designation, which is dependent on the particular substituent). It is noteworthy that the allylic substituent (R1 = CH2CH=CH2) remains unaffected under these oxidation conditions.
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3.17.2
755
Biochemical Methods
Scheme 9 Kinetic Resolution of 2-Substituted Cyclohexanones by Asymmetric Oxidation with Engineered Baker’s Yeast[24,28] O
O
O R1
engineered baker's yeast O2
R
1
O +
rac-25
R1
25
R1
ee (%) (Config) 25
26
Yield (%) Ref 25 26
Et
‡98 (R)
95 (S)
69 79
[28]
Pr
92 (R)
97 (S)
66 54
[28]
iPr
96 (S) ‡98 (R)
46 41
[28]
‡98 (S) ‡98 (R)
58 59
[28]
98 (R) ‡98 (S)
64 59
[28]
CH2CH=CH2 Bu
26
The stereospecificity of the Baeyer–Villiger reaction, resulting from the retention of configuration at the migrating center, makes it possible to convert the residual, enantiopure ketones into enantiopure lactones by oxidation with achiral peroxy acids. As such, a combination of enzymatic resolution followed by chemical oxidation gives access to both enantiomers of a target lactone. For example, racemic 2-butylcyclopentanone (rac-27) is kinetically resolved by a biochemical Baeyer–Villiger oxidation to give the residual ketone (R)-27 (47% yield, 98% ee) and the lactone (S)-28 (47% yield and 95% ee). Chemical oxidation of the residual ketone gives the lactone (R)-28 with no loss of enantiopurity (98% ee) (Scheme 10).[29] Scheme 10 Biochemical Resolution and Subsequent Chemical Oxidation To Provide Both Enantiomers of a Lactone[29] O
O
O Bu
engineered E. coli O2
Bu
O + Bu
rac-27
(R)-27
47%; 98% ee
(S)-28
47%; 95% ee
O
O Bu
O
chemical oxidation
Bu (R)-27
(R)-28
98% ee
Enantiocomplementary lactones from the same substrate may also be accessed employing different Baeyer–Villigerases chosen from a growing list of available enzymes.[30,31] 2-Substituted Cyclohexanones 25 and 6-Substituted Lactones 26; General Procedure:[28]
A portion of frozen, washed 15C(pKR001) cells (0.20 g) was added to YEP-2% galactose (100 mL) along with the racemic ketone rac-25 (1.0 mmol) in a sterile, 500-mL Erlenmeyer flask. If required for solubility, -cyclodextrin (1.0 equiv) was also added to the mixture. The culture was shaken at 200 rpm at 30 8C and sampled periodically for GC analysis. After Baeyer–Villiger Reactions, Levinger, S. Science of Synthesis 4.0 version., Section 3.17 sos.thieme.com © 2014 Georg Thieme Verlag KG
for references see p 757 (Customer-ID: 5907)
756
Stereoselective Synthesis
3.17
Baeyer–Villiger Reactions
half of the substrate had been consumed (approximately 20 h after the start of fermentation), the cells were removed by centrifugation at 4000 g for 10 min at 4 8C. The supernatant was extracted with CH2Cl2 (4 50 mL) and the combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was subjected to chromatography (silica gel) to give the kinetically resolved ketone 25 and the lactone 26.
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References
References [1] [2] [3] [4] [5] [6] [7] [8]
[9] [10] [11]
[12] [13] [14] [15] [16]
[17] [18]
[19] [20] [21] [22] [23]
[24] [25] [26] [27] [28] [29]
[30] [31]
Krow, G. R., Org. React. (N. Y.), (1993) 43, 251. Renz, M.; Meunier, B., Eur. J. Org. Chem., (1999), 737. Criegee, R., Justus Liebigs Ann. Chem., (1948) 560, 127. Noyori, R.; Sato, T.; Kobayashi, H., Tetrahedron Lett., (1980) 21, 2569. Noyori, R.; Kobayashi, H.; Sato, T., Tetrahedron Lett., (1980) 21, 2573. Noyori, R.; Sato, T.; Kobayashi, H., Bull. Chem. Soc. Jpn., (1983) 56, 2661. Chandrasekhar, S.; Roy, C. D., Tetrahedron Lett., (1987) 28, 6371. Bolm, C., In Peroxide Chemistry: Mechanistics and Preparative Aspects of Oxygen Transfer, Adam, W., Ed.; Wiley-VCH: Weinheim, Germany, (2000); p 494. ten Brink, G. J.; Arends, I. W. C. E.; Sheldon, R. A., Chem. Rev., (2004) 104, 4105. Bolm, C.; Beckmann, O., Chirality, (2000) 12, 523. Bolm, C.; Beckmann, O., In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin, (1999); Vol. 2, p 803. Bolm, C.; Beckmann, O.; Cosp, A.; Palazzi, C., Synlett, (2001), 1461. Bolm, C.; Schlingloff, G.; Bienewald, F., J. Mol. Catal. A: Chem., (1997) 117, 347. Peng, Y.; Feng, X.; Yu, K.; Li, Z.; Jiang, Y.; Yeung, C.-H., J. Organomet. Chem., (2001) 619, 204. Uchida, T.; Katsuki, T., Tetrahedron Lett., (2001) 42, 6911. Murahashi, S.-I.; Ono, S.; Imada, Y., Angew. Chem., (2002) 114, 2472; Angew. Chem. Int. Ed., (2002) 41, 2366. Peris, G.; Miller, S. J., Org. Lett., (2008) 10, 3049. Xu, S.; Wang, Z.; Zhang, X.; Zhang, X.; Ding, K., Angew. Chem., (2008) 120, 2882; Angew. Chem. Int. Ed., (2008) 47, 2840. Xu, S.; Wang, Z.; Li, Y.; Zhang, X.; Wang, H.; Ding, K., Chem.–Eur. J., (2010) 16, 3021. Aoki, M.; Seebach, D., Helv. Chim. Acta, (2001) 84, 187. Kayser, M. M., Tetrahedron, (2009) 65, 947. Mazzini, C.; Lebreton, J.; Alphand, V.; Furstoss, R., Tetrahedron Lett., (1997) 38, 1195. Gagnon, R.; Grogan, G.; Groussain, E.; Pedragosa-Moreau, S.; Richardson, P. F.; Roberts, S. M.; Willetts, A. J.; Alphand, V.; Lebreton, J.; Furstoss, R., J. Chem. Soc., Perkin Trans. 1, (1995), 2527. Stewart, J. D., Curr. Org. Chem., (1998) 2, 195. Alphand, V.; Archelas, A.; Furstoss, R., Biocatalysis, (1990) 3, 73. Taschner, M. J.; Peddada, L., J. Chem. Soc., Chem. Commun., (1992), 1384. Chenault, H. K.; Whitesides, G. M., Appl. Biochem. Biotechnol., (1987) 14, 147. Stewart, J. D.; Reed, K. W.; Zhu, J.; Chen, G.; Kayser, M. M., J. Org. Chem., (1996) 61, 7652. Wang, S.; Chen, G.; Kayser, M. M.; Iwaki, H.; Lau, P. C. K.; Hasegawa, Y., Can. J. Chem., (2002) 80, 613. Mihovilovic, M. D.; Rudroff, F.; Mller, B.; Stanetty, P., Bioorg. Med. Chem. Lett., (2003) 13, 1479. Mihovilovic, M. D.; Rudroff, F.; Groetzl, B.; Kapitan, P.; Snajdrova, R.; Rydz, J.; Mach, R., Angew. Chem., (2005) 117, 3675; Angew. Chem. Int. Ed., (2005) 44, 3609.
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759 3.18
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides J. B. Johnson
General Introduction
Strained ring systems, particularly epoxides and aziridines, are well established as versatile synthetic intermediates. The electrophilic nature of these compounds dictates their reactivity, and nucleophiles readily attack to open the strained ring and produce 1,2-difunctionalized compounds. Cyclic anhydrides display similar characteristics, as they are also subject to nucleophilic attack and ring opening to generate the corresponding tethered acid–carbonyl compounds. While ring-opening reactions of these groups are well established, enantioselective methods represent a more recent development. Due to the stereospecific nature of the majority of ring-opening reactions of epoxides and aziridines, well-developed asymmetric epoxidation and aziridination methods are often used to set the stereochemistry for the generation of the corresponding enantioenriched 1,2-difunctionalized species.[1–4] A complementary approach, the enantioselective desymmetrization of meso starting materials, represents an attractive means of transforming readily available and inexpensive chemicals into useful asymmetric intermediates. The enantioselective ring opening of epoxides and aziridines results in the simultaneous formation of two contiguous stereocenters, while the analogous reaction with meso cyclic anhydrides has been utilized to set one or two stereocenters in a single transformation. The value of these processes is increased with the scope of nucleophiles that have been utilized to perform the ring-opening reactions, which provide access to a broad variety of enantioenriched difunctionalized materials. 3.18.1
Ring Opening of Epoxides
The utility of any synthetic method is dictated not only by the products generated, but also by the availability of the starting materials. The preparation of epoxides has been covered in Houben–Weyl, Vol. 6/3 and Vol. E 21, pp 4599–4697, and Science of Synthesis, Vol. 37 [Ethers (Section 37.2)]. The ready preparation of these species makes them highly versatile functional groups. This portion of the chapter covers three general strategies for the use of epoxides in asymmetric synthesis. The first section outlines methods for the desymmetrization of meso-epoxides. Although inherently limited by the availability of meso-epoxides, the value of these transformations lies in the simultaneous formation of two contiguous stereocenters from an achiral starting material via the enantioselective ring opening of symmetrical epoxides. The second section describes methods for the kinetic resolution of racemic epoxides. While these methods only utilize one enantiomer of the racemic starting materials, the simple epoxides utilized in these transformations are often readily available and inexpensive, making kinetic resolution a viable option for organic synthesis. The final section will briefly outline methods for the ring opening of epoxides via stereospecific pathways. These methods provide the means of generating a broad range of highly enantioenriched 1,2-difunctionalized compounds from appropriately enriched asymmetric starting materials. Within each section, methods will be arranged by the type of nucleophile utilized for the ring-opening reaction.
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 825
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Stereoselective Synthesis
3.18.1.1
Enantioselective Ring Opening of meso-Epoxides
3.18.1.1.1
Reaction with Oxygen Nucleophiles
3.18.1.1.1.1
Using Water
3.18
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
The enantioselective construction of chiral 1,2-diols is of great interest, due to their inherent synthetic utility. While numerous methodologies exist for the production of these materials, the enzymatic hydrolysis of meso-epoxides has proven to be both efficient and highly selective. A useful method for this process has been reported utilizing epoxide hydrolases to produce the desired (S,S)-1,2-diols 1 with enantiomeric excesses of 81–96% for cyclic epoxides (Scheme 1).[5] The hydrolysis of cis-stilbene-derived epoxides has proven to be remarkably selective, providing the corresponding diol in greater than 97% enantiomeric excess. However, the corresponding process with linear aliphatic epoxides has not been reported. Scheme 1
Epoxide Hydrolase Catalyzed Desymmetrization of meso-Epoxides with Water[5] epoxide hydrolase sodium phosphate buffer (pH 7.5)
R1
R1
OH
O R2
R2
OH 1
R1
R2
Epoxide Hydrolase TOFa Yieldb (%) eec (%) Ref BD10 721
5.0 84
90
[5]
CH2N(CO2Bn)CH2
BD9884
0.1 78
93
[5]
(CH2)4
BD9883
5.1 75
96
[5]
CH2CH=CHCH2
BD9883
7.2 74
91
[5]
(CH2)3
Ph
Ph
BD8877
4.9 83
99
[5]
3-ClC6H4
3-ClC6H4 BD8877
7.6 78
98.5
[5]
4-ClC6H4
4-ClC6H4 BD8877
2.6 90
>99.5
[5]
2-pyridyl
2-pyridyl BD8877
16.5 78
99
[5]
3-pyridyl
3-pyridyl BD8877
7.3 80
97
[5]
4-pyridyl
4-pyridyl BD8877
0.3 88
98
[5]
a
TOF = turnover frequency = mol(product) × mol–1(catalyst) × s–1.
b
Isolated yield. Determined by GC or HPLC analysis using a chiral stationary phase.
c
(1R,2R)-1,2-Di(3-pyridyl)ethane-1,2-diol (1, R1 = R2 = 3-Pyridyl); Typical Procedure:[5]
To a soln of (2R,3S)-2,3-di(3-pyridyl)oxirane (0.1 g, 0.50 mmol) in a 0.02 M sodium phosphate buffer (10 mL) at pH 7.5 with MeCN (5% v/v) was added epoxide hydrolase BD8877 (0.28 mg, enzyme content estimated by PAGE and protein assay). The reaction was stirred at 22 8C and monitored by withdrawing aliquots for HPLC analysis. The reaction was complete after 18 h and H2O was removed by lyophilization. The residual solid was purified by flash column chromatography (silica gel); yield: 80%; 97% ee.
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.18.1
3.18.1.1.1.2
761
Ring Opening of Epoxides
Using Alcohols
Additional advances have been made in the enantioselective ring opening of epoxides with alcohols to generate asymmetric (R)-hydroxy ether compounds. The gallium heterobimetallic complex 2 has been utilized to catalyze the addition of phenolic nucleophiles to a range of meso-epoxides to form -hydroxy ethers 4 (Scheme 2).[6] While most examples are cyclic epoxides, a single example of a highly selective ring opening of a linear epoxide is also reported. A second generation catalyst 3 with tethered ligands provides the products 4 in comparable enantioselectivity but with higher yields. Scheme 2
Desymmetrization of meso-Epoxides with Phenolic Nucleophiles[6] O O
O
O Ga
O
O
O
O
Li
Li
2
3
R1 O
O Ga
+ MeO
OH
10−20 mol% catalyst toluene 4-Å molecular sieves
R2
R1
OH
R2
O
OMe
4
R1
R2
Catalyst Yielda (%) eeb (%) Ref
(CH2)4
2
48
93
[6]
(CH2)4
3
72
91
[6]
(CH2)3
2
75
86
[6]
(CH2)3
3
88
85
[6]
CH2CH=CHCH2
2
69
92
[6]
CH2CH=CHCH2
3
80
91
[6]
CH2N(SO2Mes)CH2 2
51
90
[6]
CH2N(SO2Mes)CH2 3
77
78
[6]
Me
72
91
[6]
a b
Me
3
Isolated yield. Determined by HPLC using a chiral stationary phase.
In more recent work, a series of lanthanide catalysts have been examined for the addition of alcohols to epoxides.[7,8] A scandium(III) trifluoromethanesulfonate precatalyst with bipyridine-derived ligand 5 provides optimum selectivity, promoting the desymmetrization of meso-stilbene epoxides with a wide range of alcohols to produce the corresponding -hydroxy ethers 6 in high yields and enantioselectivities typically above 95% (Scheme 3). The extension of the substrate scope to nonstilbene-derived epoxides provides the desired products in excellent yields, albeit with significantly diminished enantioselectivities (44–65% ee).
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 825
762
Stereoselective Synthesis
3.18
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
Scheme 3 Scandium-Catalyzed Desymmetrization of meso-Epoxides with Alcohols[7,8] 10 mol% Sc(OTf)3
N
12 mol%
N
But
But OH
R1
HO 5
O
+
R2OH
CH2Cl2, rt
R1
R1
OH
R1
OR2 6
R1
R2
Yielda (%) eeb (%) Ref
Ph
Me
81
92
[7]
Ph
Et
75
96
[7]
Ph
CH2CH=CH2 78
95
[7]
Ph
CH2C”CH
73
91
[8]
Ph
iPr
72
89
[8]
Ph
PMB
82
97
[8]
2-naphthyl Me
83
98
[7]
3-Tol
Me
75
96
[7]
4-ClC6H4
PMB
75
92
[8]
Me
PMB
93
49
[8]
iBu
PMB
33
45
[8]
a b
Isolated product. Determined by HPLC analysis using a chiral stationary phase.
(1R,2R)-2-(4-Methoxyphenoxy)cyclopentanol [4, R1,R2 = (CH2)3]; Typical Procedure:[6]
A mixture of powdered 4- molecular sieves (400 mg), dried at 180 8C under reduced pressure (~5 Torr) for 6 h prior to use, and a 0.05 M soln of Ga catalyst 2 in THF (4.0 mL, 0.20 mmol) were combined in a flask. The solvent was removed under reduced pressure. A soln of 4-MeOC6H4OH (149 mg, 1.2 mmol) in toluene (2.0 mL) and cyclopentene oxide (87.5 L, 1.0 mmol) were added to the residue at rt, and the mixture was stirred at 50 8C for 72 h. The resultant mixture was diluted with Et2O (30 mL) and filtered over a pad of Celite to remove the molecular sieves. The filtrate was washed successively with 5% aq citric acid (10 mL), 1 M aq NaOH (10 mL), sat. aq NH4Cl (10 mL), and brine (10 mL) and then dried (MgSO4). The soln was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, hexane/acetone 10:1); yield: 75%; 86% ee. (1R,2R)-2-[(4-Methoxybenzyl)oxy]-1,2-diphenylethanol (6, R1 = Ph; R2 = PMB); Typical Procedure:[7]
Under N2, a soln of Sc(OTf )3 (49 mg, 0.10 mmol) and chiral ligand 5 (33 mg, 0.10 mmol) in CH2Cl2 (5 mL) was stirred for 5 min at rt. Subsequently, cis-stilbene oxide (196 mg, 1.00 mmol) and 4-MeOC6H4CH2OH (275 mg, 2.00 mmol) were added, and the soln was stirred for 12 h at rt. The solvents were removed under reduced pressure and the crude product was purified by flash column chromatography (silica gel, Et2O/pentane 1:3); yield: 82%; 97% ee. Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.18.1
3.18.1.1.1.3
763
Ring Opening of Epoxides
Using Carboxylic Acids
The ring opening of epoxides with carboxylate salts to generate the corresponding hemiesters has also been examined. For example, the enantioselective ring opening of a series of meso-epoxides has been demonstrated with benzoic acid, using cobalt–salen catalyst 7 (Scheme 4).[9] These reactions provide the corresponding products 8 in high yield and with modest to excellent enantioselectivity (73–93% ee), which can be improved through recrystallization to afford enantiomerically pure compounds. Scheme 4
Desymmetrization of meso-Epoxides with Carboxylic Acids[9]
H
H N
N Co
But
O
But
O
But
But 7
R1
O O
Ph
R1
7, iPr2NEt, t-BuOMe
+ OH
R2 O
HO
R2
O Ph 8
R1
R2 (CH2)4
Catalyst Loading (mol%) Temp (8C) Yielda (%) eeb (%) Ref 2.5
0
98
77
[9]
Me
Me
2.5
0
97
73
[9]
Ph
Ph
5.0
rt
92
92
[9]
5.0
rt
96
93
[9]
a b
Isolated yield. Determined by HPLC using a chiral stationary phase.
(1R,2R)-2-Hydroxycyclohexyl Benzoate [8, R1,R2 = (CH2)4]; Typical Procedure:[9]
A soln of Co–salen catalyst 7 (0.62 g, 1.0 mmol) and PhCO2H (13.4 g, 110 mmol) in t-BuOMe (20 mL) was stirred under O2 for 30 min. Volatile materials were then removed under reduced pressure. The flask was recharged with N2, iPr2NEt (14.21 g, 19.16 mL, 110 mmol) was added, and the stirred mixture was cooled to 4 8C. Cyclohexene oxide (9.82 g, 10.12 mL, 100 mmol) was added and the resulting soln was stirred at 4 8C for 40 h. The product mixture was then diluted with Et2O (250 mL), washed with 1 M aq HCl (5 100 mL) and sat. aq NaHCO3 (2 100 mL), dried (MgSO4), and filtered. The soln was concentrated under reduced pressure; yield: 98%; 77% ee. Recrystallization (CH2Cl2/heptanes) afforded the pure product; yield: 75%; 98% ee.
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for references see p 825
764
Stereoselective Synthesis
3.18.1.1.2
Reaction with Nitrogen Nucleophiles
3.18.1.1.2.1
Using Amines
3.18
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
Enantiopure -amino alcohols are of great interest to the chemical community given their synthetic utility in the preparation of biologically active compounds, such as in their use as chiral auxiliaries and ligands. Methods that utilize scandium catalysts to promote the addition of aromatic amines to meso-stilbene-derived epoxides in high yields and with enantioselectivities in excess of 90% ee have been independently described.[7,10] These methodologies differ primarily in the choice of solvent and in catalyst loading, but both utilize bipyridine ligand 5 with scandium(III) to provide very comparable yields and selectivities of a range of -amino alcohols 9 (Scheme 5). Comparable results have also been achieved with indium(III) trifluoromethanesulfonate and niobium methoxide catalysts.[11,12] While deviation from cis-stilbene-derived substrates maintains excellent catalyst activity in both cases, the resulting products are generated with significantly decreased enantioselectivity. Scheme 5 Enantioselective Opening of meso-Epoxides with Aromatic Amine Nucleophiles[7,10]
N
N
But
R1 O
+
R3
H N
But OH
HO
R1
OH
R2
N
5
R4
R2
R4
R3 9
R1
R2
R3
R4 Conditions
Yielda (%)
eeb (%)
Ref
Ph
Ph
Ph
H
Sc(OTf )3 (10 mol%), 5 (10 mol%), CH2Cl2, 12 h, rt
95
93
[7]
Ph
Ph
Ph
H
Sc[OSO3(CH2)11Me]3 (1 mol%), 5 (1.2 mol%), H2O, 22 h, rt
89
91
[10]
Ph
Ph
Ph
Me Sc(OTf )3 (10 mol%), 5 (10 mol%), CH2Cl2, 12 h, rt
85
97
[7]
Ph
Ph
Ph
Me Sc[OSO3(CH2)11Me]3 (1 mol%), 5 (1.2 mol%), H2O, 22 h, rt
88
96
[10]
Ph
Ph
2-MeOC6H4 H
Sc[OSO3(CH2)11Me]3 (1 mol%), 5 (1.2 mol%), H2O, 22 h, rt
81
93
[10]
Ph
Ph
OBn
H
Sc(OTf )3 (10 mol%), 5 (10 mol%), CH2Cl2, 12 h, rt
85
86
[7]
4-Tol
4-Tol
Ph
H
Sc[OSO3(CH2)11Me]3 (1 mol%), 5 (1.2 mol%), H2O, 22 h, rt
81
90
[10]
3-Tol
3-Tol
Ph
H
Sc(OTf )3 (10 mol%), 5 (10 mol%), CH2Cl2, 12 h, rt
93
91
[7]
2-naphthyl 2-naphthyl Ph
H
Sc[OSO3(CH2)11Me]3 (1 mol%), 5 (1.2 mol%), H2O, 22 h, rt
75
91
[10]
H
Sc(OTf )3 (10 mol%), 5 (10 mol%), CH2Cl2, 12 h, rt
96
54
[7]
(CH2)4
Ph
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.18.1
765
Ring Opening of Epoxides
R1
R2
R3
R4 Conditions
Yielda (%)
eeb (%)
Ref
Me
Me
Ph
H
Sc(OTf )3 (10 mol%), 5 (10 mol%), CH2Cl2, 12 h, rt
92
60
[7]
(CH2)2Ph
(CH2)2Ph
Ph
H
Sc[OSO3(CH2)11Me]3 (1 mol%), 5 (1.2 mol%), H2O, 22 h, rt
61
60
[10]
Bu
Bu
Ph
H
Sc[OSO3(CH2)11Me]3 (1 mol%), 5 (1.2 mol%), H2O, 22 h, rt
89
71
[10]
a b
Isolated yield. Determined by HPLC using a chiral stationary phase.
The ring opening of cyclic meso-epoxides with aromatic amine nucleophiles has been achieved with lanthanide binaphtholate complexes (Scheme 6).[13] While several lanthanide complexes demonstrate catalytic activity, the samarium(III) binaphtholate complex 10 provides a range of desired -amino alcohols 11 with excellent enantioselectivity (up to 93% ee), when the reaction is performed at –40 8C. Despite the promise of these reactions, no general methodology currently exists for the efficient and stereoselective desymmetrization of acylic meso-epoxides with alkyl substitution and with alkylamino nucleophiles. Scheme 6 Samarium-Catalyzed Desymmetrization Using Aromatic Amine Nucleophiles[13]
O O
Sm
I(THF)2
10
R1 O
+ R3NH2
10 mol% 10 4-Å molecular sieves, CH2Cl2 −40 oC, 18 h
R2
R1
OH
R2
NHR3 11
R1
R2
R3
Yielda (%) eeb (%) Ref
(CH2)4
Ph
79
91
[13]
(CH2)4
2-MeOC6H4 85
91
[13]
(CH2)4
4-MeOC6H4 82
85
[13]
(CH2)3
2-MeOC6H4 80
93
[13]
(CH2)3
4-MeOC6H4 79
93
[13]
68
83
[13]
CH2CH=CHCH2 2-MeOC6H4 75
92
[13]
CH2CH=CHCH2 4-MeOC6H4 79
92
[13]
CH2CH=CHCH2 Ph
a b
Yield of isolated product. Determined by HPLC using a chiral stationary phase.
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 825
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Stereoselective Synthesis
3.18
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
(1S,2S)-1,2-Diphenyl-2-(phenylamino)ethanol (9, R1 = R2 = R3 = Ph; R4 = H); Typical Procedure:[7]
In a flame-dried flask under N2, a soln of Sc(OTf )3 (25 mg, 0.05 mmol) and chiral bipyridine 5 (17 mg, 0.05 mmol) in CH2Cl2 (2 mL) was stirred for 5 min at rt. Subsequently, cis-stilbene oxide (98 mg, 0.50 mmol) and PhNH2 (47 mg, 0.50 mmol) were added and the soln was stirred at rt for 12 h. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (silica gel, Et2O/pentane 1:2); yield: 95%; 93% ee. (1S,2S)-1,2-Diphenyl-2-(phenylamino)ethanol (9, R1 = R2 = R3 = Ph; R4 = H); Typical Procedure:[10]
Under argon, chiral bipyridine ligand 5 (0.012 equiv) was added to a stirred soln of scandium(III) dodecyl sulfate (0.01 equiv) in H2O (1 M concentration with respect to substrates). The reaction was stirred for 1 h at rt at which time the amine (1 equiv) and epoxide (1 equiv) were added. The reaction was stirred for 30–48 h at rt and subsequently quenched with sat. aq NaHCO3. The resultant mixture was extracted with EtOAc and the combined organic layers were dried (Na2SO4) and filtered. The solvents were removed under reduced pressure and the residue was purified by preparatory TLC (silica gel, Et2O/ hexane); yield: 89%; 91% ee. (1R,2R)-2-(Phenylamino)cyclohexanol [11, R1,R2 = (CH2)4; R3 = Ph]; General Procedure:[13]
In an inert atmosphere glove box, 4- molecular sieves (50 mg) were added to a soln of Sm(III) complex 10 (0.05 mmol) in CH2Cl2 (6 mL). The flask was sealed with a septum and removed from the glove box. Amine (0.6 mmol) was added via microsyringe and after stirring for 15 min, the mixture was cooled to –40 8C. The desired epoxide (0.5 mmol) was added via syringe. After stirring at –40 8C for 18 h, the mixture was quenched with 1 M aq HCl, neutralized, and extracted with CH2Cl2. Removal of the solvent under reduced pressure provided a crude product which was purified by preparative TLC (silica gel, heptane/EtOAc 4:1); yield: 79%; 91% ee. 3.18.1.1.2.2
Using Azides
The enantioselective reaction of an epoxide with an azide, which is typically delivered as an azidotrialkylsilane, results in the formation of an azido trialkylsilyl ether (e.g., 12) with two contiguous stereocenters. For example, a zirconium-catalyzed process has been described that utilizes the asymmetric 1,1¢,1¢¢-nitrilotripropan-2-ol ligand to control the delivery of bulky azidosilanes to a range of epoxides with enantioselectivities greater than 87% (Scheme 7).[14] While cyclic epoxides are the primary substrates, the desymmetrization of an acylic substrate, cis-butene oxide, proceeds in 87% enantiomeric excess. Scheme 7 Zirconium-Catalyzed Asymmetric Addition of an Azidosilane to meso-Epoxides[14] R1 O
+
PriMe
2
R
2SiN3
4 mol% (LZrOH)2•t-BuOH CF3CO2TMS (0.02 equiv)
R1
OSiMe2Pri
R2
N3 12
OH
N
L= HO
OH
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.18.1
767
Ring Opening of Epoxides
R1
R2
Yielda (%) eeb (%) Ref 86
93
[14]
CH2CH=CHCH2 79
89
[14]
Me
59
87
[14]
64
83
[14]
(CH2)4 Me
(CH2)3 a b
Isolated yield. Determined by GC or HPLC using a chiral stationary phase.
Similar results have been reported utilizing chromium–salen complex 13 to catalyze the ring opening of epoxides with azidotrimethylsilane to give -azido alcohols 14, in excellent enantioselectivities for epoxides containing a variety of functionality (Scheme 8).[15,16] The reaction of only a single acyclic substrate is described, namely cis-butene oxide, which affords the corresponding product in 65% yield and 82% enantiomeric excess. Scheme 8 Chromium–Salen Catalyzed Asymmetric Addition of Azidosilanes to meso-Epoxides[15,16]
H
H N
N Cr
But
But
O Cl O But
But 13
R1
1. 2 mol% 13, Et2O 2. CSA, MeOH
O R
+
N3 14
R2
Yielda (%) eeb (%) Ref
(CH2)4
80
88
[15]
(CH2)3
97
93
[16]
CH2OCH2
96
97
[16]
CH2N(COCF3)CH2 90
95
[15]
CH2N(Fmoc)CH2 80
95
[15]
82
[15]
Me b
OH
R2
2
R1
a
R1
TMSN3
Me
65
Isolated yield. Determined by GC or HPLC using a chiral stationary phase.
(1S,2S)-2-Azido-1-(isopropyldimethylsiloxy)cyclopentane [12, R1,R2 = (CH2)3]; Typical Procedure:[14]
CAUTION: Organic and metal azides are potentially explosive. Under N2, a soln of (S,S,S)-1,1¢,1¢¢-nitrilotripropan-2-ol (19 mg, 0.1 mmol) in anhyd THF was added to a soln of Zr(Ot-Bu)4 (38 mg, 0.10 mmol) in anhyd THF (1 mL). After 5 min, the THF was removed under reduced pressure. Hexanes (1 mL) were added and removed to aid in Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 825
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Stereoselective Synthesis
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
3.18
the removal of t-BuOH, and the residue was placed in a glass vial. CF3CO2TMS (6.0 L) was added. A soln of cyclopentene oxide (0.20 g, 2.4 mmol) and iPrMe2SiN3 (0.29 g, 2.5 mmol) in 1,2-dichlorobutane (3.0 mL) was added all at once and the mixture was allowed to stand for 48 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, hexane/Et2O 98:2); yield: 64%; 83% ee. (1S,2S)-2-Azidocyclopentanol [14, R1,R2 = (CH2)3]; Typical Procedure:[16]
CAUTION: Organic and metal azides are potentially explosive. A 100-mL flask was charged with Cr–salen complex 13 (632 mg, 1.00 mmol), flushed with N2, and sealed. Cyclopentene oxide (4.40 mL, 50.0 mmol) and TMSN3 (6.90 mL, 52.5 mmol) were added sequentially at rt. The mixture was allowed to stir for 12 h and excess TMSN3 was removed under reduced pressure. The product was isolated by vacuum distillation (90% enantiomeric excess. Scheme 18 Kinetic Resolution of Terminal Epoxides with Oxygen Nucleophiles[27–29]
H
H N
N Co
But
O
But
O
X
But
But 29
O
O
O
H
O
But N
But
O
O
O
O
Co H
N
N
H
Co But
N
But
O
H
O O
O 30
n
n = 1−3
OH
O +
R2OH
R2O
R1
R1 31
R1
R2
Conditions
Me
H
29 (X = OAc) (0.5 mol%), H2O (0.45 equiv), 0 8C, 12–14 h
>99
99
[27]
CH2Cl
H
29 (X = OAc) (0.5 mol%), H2O (0.45 equiv), 0 8C, 12–14 h
89
95
[27]
CF3
H
29 (X = OAc) (0.5 mol%), H2O (0.45 equiv), 0 8C, 12–14 h
93
>99
[27]
Ph
H
29 (X = OAc) (0.5 mol%), H2O (0.45 equiv), 0 8C, 12–14 h
93
98
[27]
Ac
H
29 (X = OAc) (0.5 mol%), H2O (0.45 equiv), 0 8C, 12–14 h
89
97
[27]
Bu
Ph
29 [X = OC(CF3)3] (4 mol%), t-BuOMe, 3-Å molecular sieves
97
98
[28]
CH2Cl
Ph
29 [X = OC(CF3)3] (4 mol%), t-BuOMe, 3-Å molecular sieves
97
99
[28]
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
Yielda (%) eeb (%) Ref
3.18.1
R1
Conditions
Yielda (%) eeb (%) Ref
CO2Me Ph
29 [X = OC(CF3)3] (4 mol%), t-BuOMe, 3-Å molecular sieves
98
96
[28]
Bu
4-MeOC6H4
29 [X = OC(CF3)3] (4 mol%), t-BuOMe, 3-Å molecular sieves
75
99
[28]
Bu
3-Tol
29 [X = OC(CF3)3] (4 mol%), t-BuOMe, 3-Å molecular sieves
99
99
[28]
Bu
4-BrC6H4
29 [X = OC(CF3)3] (4 mol%), t-BuOMe, 3-Å molecular sieves
92
99
[28]
Bu
Bn
30 (0.25 mol%), MeCN, 4 8C
91
99
[29]
Bu
(CH2)2TMS
30 (0.25 mol%), MeCN, 4 8C
97
99
[29]
Bu
2-ClC6H4
30 (0.25 mol%), MeCN, 4 8C
95
99
[29]
a b
R2
779
Ring Opening of Epoxides
Isolated yield. In all cases, yields are based on the use of 1 equiv of nucleophile. Determined by HPLC analysis using a chiral stationary phase.
(S)-Propane-1,2-diol (31, R1 = Me; R2 = H); Typical Procedure:[27]
A 100-mL flask equipped with a stirrer bar was charged with (R,R)-N,N¢-bis(3,5-di-tert-butylsalicylidene)cyclohexa-1,2-diaminocobalt(II) (242 mg, 400 mol, 0.002 equiv). The complex was dissolved in toluene (5 mL) and treated with AcOH (240 L, 4.2 mmol). The soln was allowed to stir at rt open to air for 30 min over which time the color changed from orange-red to dark brown. The soln was concentrated under reduced pressure to leave Co catalyst (R,R)-29 (X = OAc) as a brown solid. This residue was dissolved in 2-methyloxirane (propylene oxide; 14.0 mL, 11.6 g, 200 mmol) at rt. The reaction flask was cooled to 0 8C and H2O (1.62 mL, 90 mmol, 0.45 equiv) was added. After 12 h, the residual 2-methyloxirane was removed from the mixture by distillation and subsequent vacuum distillation (50 8C, 0.25 Torr) gave the product; yield: >99%; 99% ee. (S)-1-Phenoxyhexan-2-ol (31, R1 = Bu; R2 = Ph); Typical Procedure:[28]
A 10-mL flask was charged with Co catalyst 29 [X = OC(CF3)3; 86 mg, 0.100 mmol] and 3- molecular sieves (100 mg). 2-Butyloxirane (0.501 g, 5.00 mmol), PhOH (0.212 g, 2.25 mmol), and t-BuOMe (200 L) were added at 25 8C and the mixture was stirred for 12 h. The soln was concentrated under reduced pressure and the residue was subjected to Kugelrohr distillation (100 8C, 2 Torr); yield: 97%; 98% ee. (R)-1-(Benzyloxy)hexan-2-ol (31, R1 = Bu; R2 = Bn); Typical Procedure:[29]
BnOH (243 mg, 2.25 mmol), 2-butyloxirane (500 mg, 5.00 mmol), and MeCN (0.2 mL) were added to Co catalyst (R,R)-30 (as a mixture of oligomers with n = 1–3; 4.8 mg, 0.0056 mmol) at 4 8C and the soln was stirred for 8 h. The reaction was diluted with Et2O (5 mL) and filtered through a silica gel plug. The silica gel was washed with additional Et2O (20 mL) and the filtrate was concentrated under reduced pressure; yield: 91%; 99% ee. 3.18.1.2.2
Reaction with Nitrogen Nucleophiles
The kinetic resolution of epoxides with nitrogen nucleophiles represents a versatile route to synthetically versatile 1,2-amino alcohols. Although the use of nitrogen nucleophiles has not been developed to the extent of oxygen nucleophiles, methods have been developed for the highly selective addition of azides to terminal epoxides. A procedure has been established for the preparation of trimethylsiloxy azides 33 in excellent yield and with enantioselectivities over 95% ee for a variety of epoxides using the chromium– salen catalyst 32 (Scheme 19).[30]
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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780
Stereoselective Synthesis Scheme 19 Azide[30]
3.18
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
Kinetic Resolution of Terminal Epoxides with an
H
H N
N Cr
But
But
O N3 O But
But 32
O R1
OTMS
1−5 mol% 32, 0 oC
+ TMSN3
N3
R1 33
R1
Yielda (%) eeb (%) Ref
Me
98
97
[30]
CH2OTBDMS
96
96
[30]
CH2Cl
94
95
[30]
(CH2)2CH=CH2 94
98
[30]
Bn
93
[30]
a
b
94
Isolated yield. In all cases, yields are based on the use of 1 equiv of nucleophile. Determined by HPLC analysis using a chiral stationary phase.
More recently, the cobalt-catalyzed addition of carbamates to terminal epoxides has been reported to afford the amido alcohols 34 with excellent enantioselectivities (>99% ee) (Scheme 20).[31] Scheme 20
Kinetic Resolution of Terminal Epoxides with Carbamates[31]
H
H N
N Co
But
O
But
O
But
But 7
O + R1
R2NH2
2−5 mol% 7 2 mol% 4-nitrobenzoic acid t-BuOMe, 23 oC
OH NHR2
R1 34
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.18.1
781
Ring Opening of Epoxides
R1
R2
Me
CO2t-Bu 99
99
[31]
(CH2)2CH=CH2 CO2t-Bu 99
>99
[31]
4-BrC6H4
CO2t-Bu 76
>99
[31]
CH2Cl
CO2Bn
87
>99
[31]
CH2OPh
CO2Bn
93
>99
[31]
a
b
Yielda (%) eeb (%) Ref
Isolated yield. In all cases, yields are based on the use of 1 equiv of nucleophile. Determined by HPLC analysis using a chiral stationary phase.
(R)-1-Azido-2-(trimethylsiloxy)propane (33, R1 = Me); Typical Procedure:[30]
CAUTION: Contact of metal azides with acids liberates the highly toxic and explosive hydrazoic acid. Under N2, a 10-mL flask cooled to 0 8C in an ice bath was charged with Cr catalyst (R,R)-32 (64 mg, 0.10 mmol) and 2-methyloxirane (290 mg, 5.00 mmol). TMSN3 (330 L, 2.50 mmol) was then added via syringe. The mixture was stirred for 18 h at 0 8C and then placed under vacuum (at 0 8C) to remove the unreacted epoxide. The residue was subjected to vacuum distillation (24 8C/ 90% ee). Scheme 24
Kinetic Resolution of Racemic Epoxides to Allylic Alcohols[34] 1. 10 mol%
NH N 42
LDA (2 equiv) DBU (5 equiv), THF, 0 oC 2. NH4Cl
O
R1 R2 R3
R1 R2
OH
R3
n
n
43
R1
R2
R3
n
Conversiona (%) Yieldb (%) eec (%) Ref
Me H
H
1
43
30
96
[34]
Et
H
H
1
63
47
90
[34]
t-Bu H
H
1
58
40
99
[34]
Me Me 1
52
43
94
[34]
41
34
94
[34]
H
t-Bu H a
b
c
H
2
Conversion determined by GC on the basis of epoxide consumption as compared to an internal standard. Isolated yield. Yields are based on the use of 1 equiv of epoxide. Determined by GC analysis with a chiral stationary phase.
(R)-1-Methylcyclohex-2-en-1-ol (43, R1 = Me; R2 = R3 = H; n = 1); Typical Procedure:[34]
Under N2, a 1.6 M soln of BuLi in hexane (0.38 mmol) was added dropwise over 5 min to a soln of (1S,3R,4R)-3-(pyrrolidin-1-ylmethyl)-2-azabicyclo[2.2.1]heptane (42; 15 mol), iPr2NH (0.36 mmol), and DBU (3.0 mmol) in THF (1.5 mL) at 0 8C. The resulting soln was stirred at 0 8C for 30 min and 1-methylcyclohexene oxide (40 mg, 0.36 mmol) in THF (1.0 mL) containing dodecane (ca. 10 mg, as internal standard for GC analysis) was then added dropwise over a period of 5 min. The mixture was stirred at 0 8C for 4 h (43% conversion). The mixture was partitioned between sat. aq NH4Cl (5 mL) and Et2O (10 mL). The phases were separated and the organic layer was washed with 10% aq citric acid (2 5 mL), H2O (5 mL), and brine (5 mL), and then dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, pentane/Et2O 99:1); yield: 30%; 96% ee.
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 825
786
Stereoselective Synthesis
3.18.1.3
Stereospecific and Regioselective Ring Opening of Epoxides
3.18
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
The stereospecific ring opening of epoxides provides a useful method for the construction of carbon—carbon and carbon–heteroatom bonds, which serve as important intermediates in the synthesis of complex organic molecules. A variety of nucleophiles have been utilized for these reactions, in which heteroatom nucleophiles primarily attack the epoxides at the least hindered carbon atom. While a significant number of methods have been developed for the stereospecific ring opening of epoxides with particularly common substitution patterns, the examples outlined herein are based on their simplicity, generality, and synthetic utility. These methods are organized with regard to the nucleophile utilized for ring opening, and, when available, methods that proceed efficiently with a range of substitution patterns are provided. It should be noted that with stereospecific ring-opening reactions, the well-established methods provided herein are often representative of significant numbers of related reaction conditions. 3.18.1.3.1
Reaction with Oxygen Nucleophiles
The ring opening of epoxides with oxygen nucleophiles is a particularly attractive method for the preparation of 1,2-diols and 1,2-hydroxy ether compounds. The stereospecific opening of epoxides, e.g. (R)-2-tert-butyloxirane to -hydroxy ether 44, proceeds efficiently with a wide range of alkoxides in aprotic solvents.[35] For substrates containing base-sensitive functionality (e.g., 45), Lewis acid mediated processes proceed in excellent yield with complete retention of stereochemistry for the formed -hydroxy ethers 46.[36] Representative examples of these procedures are provided in Scheme 25. Scheme 25 Stereospecific Ring Opening of Epoxides with Oxygen Nucleophiles[35,36] OBn
OBn O
OH Bu
t
K2CO3, DMF, 105 oC
+
OH O
But
84%
But
But
44
OH
O
BnO
OH BF3•OEt2, CH2Cl2 76%
45
BnO
O 46
(R)-1-[2-(Benzyloxy)-5-tert-butylphenoxy]-3,3-dimethylbutan-2-ol (44); Typical Procedure:[35]
To a stirred soln of 2-(benzyloxy)-5-tert-butylphenol (1.03 g, 4.0 mmol, 1.0 equiv) in anhyd DMF (15 mL) was added K2CO3 (1.11 g, 8.0 mmol, 2.0 equiv). After stirring for 10 min, (R)-2tert-butyloxirane was added (800 mg, 8.0 mmol, 2.0 equiv) and the mixture was heated at 105 8C for 24 h. The mixture was poured into H2O (10 mL), treated dropwise with 1 M aq HCl until acidic, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine (3 5 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes/Et2O 3:1); yield: 84%.
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.18.1
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Ring Opening of Epoxides
(R)-1-(Allyloxy)-3-(benzyloxy)propan-2-ol (46); Typical Procedure:[36]
To a stirred soln of (R)-benzyl glycidol (45; 261 mg, 1.6 mmol) and allyl alcohol (1.1 mL, 16 mmol) in CH2Cl2 (10 mL) was added BF3•OEt2 (50 L, 0.4 mmol). After 1 h, the soln was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 9:1); yield: 76%. 3.18.1.3.2
Reaction with Nitrogen Nucleophiles
Nitrogen-containing nucleophiles have also been widely utilized in the stereospecific ring opening of epoxides. While the precise conditions required for this transformation vary based on the nature of the substrate, many primary and secondary amines react with epoxides to give amino alcohols (e.g., 47–50) in the absence of any catalyst or in the presence of weakly Lewis acidic complexes (Scheme 26).[37–39] Other nitrogen nucleophiles, including imides,[40] sulfonamides,[41] and azides[42] have also been utilized for ring opening of epoxides (e.g., 53) to generate a variety of difunctionalized compounds (e.g., 51, 52, and 54) in a regioselective and stereoretentive manner (Scheme 27). Stereospecific Opening of Asymmetric Aziridines with Amines[37–39]
Scheme 26 O
OH
EtOH, 60 oC
NH4OH
+
NH2
>99%
9
9
47
O
OH
iPrOH, 82 oC
+ BnNH2
NHBn
86%
9
9
48
O Ph
+ Ph
Ph
HO
LiClO4, 120 oC
H2N
Ph
Ph
97%
Ph N H 49
Ph Ph
HO
H N
O
LiClO4, 100 oC
+
98%
Ph
Ph
Ph Ph N
50
Scheme 27 Stereospecific Opening of Asymmetric Aziridines with Nitrogen Nucleophiles[40–42] O
O
phthalimide DMF, 90 oC
O +
NK
CO2Et
OH N
80%
O
CO2Et
O 51
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 825
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Stereoselective Synthesis
O
O +
H2N
3.18
OH
TEBAC, K2CO3
O S
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
1,4-dioxane, 90 oC
Bu
t
H N
85%
S
O
But O
52
O
ButO2C
OH NaN3, NH4Cl EtOH/H2O, 60 oC
ButO2C
N3
96%
Ph 53
Ph 54
(R)-1-Aminododecan-2-ol (47); Typical Procedure:[37]
(R)-1,2-Epoxydodecane (58 mg, 0.31 mmol) and 25% aq NH4OH (2 mL) were heated in EtOH (2 mL) in a sealed tube at 60 8C for 16 h. After cooling, the mixture was concentrated under reduced pressure to afford the product as a pure white crystalline compound; yield: >99%. (R)-1-(Benzylamino)dodecan-2-ol (48); Typical Procedure:[37]
(R)-1,2-Epoxydodecane (370 mg, 2.01 mmol) and BnNH2 (655 mg, 6.11 mmol) were refluxed in iPrOH (1 mL) for 17 h. After cooling, the soln was concentrated under reduced pressure and purified by column chromatography (silica gel, CHCl3/MeOH/Et3N 95.5:2.5:2); yield: 86%. (R)-2-(Allylamino)-1,1,2-triphenylethanol (49); Typical Procedure:[38]
A glass pressure tube equipped with a stirrer bar was charged with (S)-2,2,3-triphenyloxirane (500 mg, 1.84 mmol), LiClO4 (391 mg, 3.67 mmol), and prop-2-enamine (1.4 mL, 18.40 mmol). The suspension was then stirred at 120 8C overnight. The resulting soln solidified when cooled to rt. This solid was dissolved in CH2Cl2 and the organic layer was washed with brine. The organics were dried (MgSO4), filtered, and concentrated under reduced pressure; yield: 97%. (R)-2-Piperidino-1,1,2-triphenylethanol (50); Typical Procedure:[39]
Under N2, a mixture of (S)-2,2,3-triphenyloxirane (272 mg, 1.00 mmol), LiClO4 (214 mg, 2.0 mmol), and piperidine (1.0 mL, 10.0 mmol) was heated at 100 8C. After 24 h, excess amine was removed under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL), washed with H2O (2 100 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel pretreated with Et3N, hexane/EtOAc); yield: 98%. Ethyl (S)-2-Hydroxy-3-phthalimidopropanoate (51); Typical Procedure:[40]
Ethyl (S)-glycidate (200 mg) in DMF (2 mL) was added to a mixture of phthalimide (220 mg) and potassium phthalimide (40 mg) in DMF (50 mL). The mixture was heated to 90 8C and stirred for 12 h. The mixture was diluted with H2O (500 mL) and extracted with CHCl3 (3 150 mL). The extracts were washed with H2O (50 mL) and brine (50 mL), dried (MgSO4), and filtered. The solvent was removed under low pressure to yield a yellow oil. Recrystallization (Et2O) provided the product; yield: 80%. More recent reports have demonstrated the stereospecificity of this reaction.[43] (R)-N-(2-Hydroxypropyl)-2-methylpropane-2-sulfonamide (52); Typical Procedure:[41]
TEBAC (0.1 equiv) was added to a stirred suspension of (R)-2-methyloxirane (1 equiv), t-BuSO2NH2 (1.5 equiv), and K2CO3 (0.1 equiv) in 1,4-dioxane (0.25 mL per mmol of epoxide). The suspension was heated at 90 8C for 16 h, cooled to rt, and CH2Cl2 (25 mL) was added. Following filtration through a short plug of Celite and washing with CH2Cl2 (2 20 mL), Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Ring Opening of Epoxides
the sample was concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, petroleum ether/Et2O) gave the product; yield: 85%. tert-Butyl (2R,3S)-4-Azido-2-benzyl-3-hydroxybutanoate (54); Typical Procedure:[42]
CAUTION: Contact of metal azides with acids liberates the highly toxic and explosive hydrazoic acid. To a soln of epoxide 53 (0.50 g, 2 mmol) in 60% EtOH were added NaN3 (0.65 g, 10 mmol) and NH4Cl (0.22 g, 4 mmol). The mixture was heated at 60 8C for 2 h and the solvent was removed under reduced pressure. The residue was suspended in Et2O and washed with H2O. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was recrystallized (Et2O/hexane); yield: 96%. 3.18.1.3.3
Reaction with Sulfur Nucleophiles
The ring opening of epoxides with thiols provides an efficient means for the production of 1,2-difunctionalized thioethers (e.g., 55 and 57) from readily available starting materials (e.g., 56). The nucleophilicity of the anionic sulfides is sufficient to result in the uncatalyzed ring opening of epoxides at the most sterically accessible carbon in a stereospecific manner.[44,45] These reactions typically proceed with very high yields and excellent regioselectivity and have been utilized in a number of asymmetric syntheses. Scheme 28 provides some representative examples of this type of transformation. Scheme 28 Stereospecific Ring Opening of Epoxides with Sulfur Nucleophiles[44,45] OH O
PhSH, NaH, THF, 0 oC 95%
Pr
SPh
Pr 55
NHBoc
NHBoc NaSMe, MeOH, reflux
Bn
O
92%
Bn
SMe OH
56
57
(S)-1-(Phenylsulfanyl)pentan-2-ol (55); Typical Procedure:[45]
NaH (2.31 g, 96.4 mmol) was suspended in THF (200 mL) and cooled to 0 8C. PhSH (7.62 mL, 74.2 mmol) was carefully added dropwise and the mixture was stirred for 30 min. After dropwise addition of (S)-2-propyloxirane (10 mL, 96.4 mmol), the mixture was allowed to warm to rt and stirred for 4 h. Upon recooling to 0 8C, the reaction was carefully quenched with MeOH until no additional gas evolution was observed. The mixture was poured into a separatory funnel containing a half-sat. aq NH4Cl soln (200 mL). The layers were separated and the aqueous layer was extracted with Et2O (2 100 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated under reduced pressure; yield: 95%. (2S,3S)-3-(tert-Butoxycarbonylamino)-1-(methylsulfanyl)-4-phenylbutan-2-ol (57); Typical Procedure:[44]
A soln of epoxide 56 (105 mg, 0.40 mmol) and NaSMe (34 mg, 0.50 mmol) in anhyd MeOH (5 mL) was heated at reflux for 1 h. The soln was concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica gel pretreated with Et3N, hexane/EtOAc); yield: 92%. Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 825
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Stereoselective Synthesis
3.18.1.3.4
Reaction with Halide Nucleophiles
3.18
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
The significant synthetic utility of halohydrins makes the stereospecific ring opening of epoxides with halides an important process. The use of chloride,[46] bromide,[47,48] and iodide[49] nucleophiles is well established, and alkali metal salts of these species are generally of sufficient nucleophilicity to regioselectively and stereospecifically ring open epoxides (e.g., 58, 60, 62, and 64) to halohydrins (e.g., 59, 61, 63, and 65) without the use of additional reagents (Scheme 29). More recently developed methods have also utilized fluoride nucleophiles for the ring opening of asymmetric epoxides (e.g., 45) to fluoro alcohols (e.g., 66). In addition, newly developed protocols further improve the efficiency of this transformation, to facilitate the ring-opening reactions under very mild reaction conditions.[50] Stereospecific Ring Opening of Epoxides with Halides[46–50]
Scheme 29 O
O LiCl, TiCl4, THF, −78 C o
O
HO
89%
Cl 58
59
OH Li2NiBr4, THF, 30 oC
O
96%
Br 61
60
OH
O
LiBr, AcOH, THF, 23 oC
Br
75%
62
63
LiI, H2O, THF AcOH, 0 oC
O I
OH I
I
93%
64
O
BnO
65
iPr2NH•3HF, 110 oC 70%
45
OH BnO
F 66
(2R,3R,5R)-3-Chloro-2-hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclohexanone (59); Typical Procedure:[46]
Under N2, TiCl4 (540 L, 4.95 mmol, 1.1 equiv) was added to THF (15 mL) at –78 8C. This mixture was warmed to –20 8C and a 0.5 M soln of LiCl in THF (10 mL, 4.95 mmol, 1.1 equiv) was added slowly over 6 min. After addition, the mixture was cooled to –78 8C and a soln of carvone oxide (58; 748 mg, 4.5 mmol, 1.0 equiv) in THF (6 mL) was added. The mixture was then warmed to –20 8C and stirring was continued. After 6 h, the reaction was quenched by pouring into sat. aq NaHCO3 (50 mL). The mixture was extracted with Et2O (3 30 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), and filtered. The solvent was removed under reduced pressure; yield: 89%. Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Ring Opening of Epoxides
(1S,2S,4E)-2-Bromo-1-methyl-4-(6-methylhept-5-en-2-ylidene)cyclohexan-1-ol (61); Typical Procedure:[47]
Under argon, an excess of a soln of Li2NiBr4 in THF (16 mmol, 40 mL) was added to a soln of epoxide 60 (2.20 g, 10.0 mmol) in THF (8 mL). After stirring for 72 h at 30 8C, the mixture was treated with phosphate buffer (30 mL, 10%, pH 7) and extracted with Et2O (3 25 mL). The combined organic layers were washed with 2% aq HCl (2 25 mL) and sat. aq NaHCO3 (2 25 mL) and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, hexane/EtOAc 97:3); yield: 96%. More recent reports have demonstrated the stereospecificity of this reaction.[51] (R)-1-Bromooctan-2-ol (63); Typical Procedure:[48]
To a soln of (R)-2-octyloxirane (62; 5.0 g, 39 mmol) in AcOH (10 mL) and THF (50 mL) was added LiBr•H2O (6.5 g, 62 mmol), and the mixture was stirred for 1 h. H2O was added, and the product was extracted with t-BuOMe. The organic layer was washed with H2O and brine and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel); yield: 75%. (2R,7E)- and (2R,7Z)-1,8-Diiodooct-7-en-2-ol [(2R,7E)- and (2R,7Z)-65]; Typical Procedure:[49]
To a soln of epoxide 64 (1.36 g, 5.4 mmol) in THF (20 mL) were added LiI (613 mg, 22 mmol) and H2O (6 mL) at 0 8C. AcOH was added (30 mL) and after stirring for 1 h at 0 8C, the reaction was quenched with sat. aq NaHCO3 (80 mL). The mixture was extracted with Et2O (2 50 mL) and the extract was washed with H2O and brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EtOAc 5:1); yield: 93%. 1-(Benzyloxy)-3-fluoropropan-2-ol (66); General Procedure:[50]
Under N2, a flask was charged with epoxide 45 (0.38 g, 2.31 mmol) and iPr2NH•3HF (0.75 g, 4.63 mmol). The flask was tightly sealed with a plastic cap and heated at 110 8C for 7 h. The resulting semisolid mass was extracted with 20 portions of Et2O (or by using a Soxhlet extractor for 12 h). The combined Et2O extracts were washed with H2O, dried (MgSO4), and passed through a silica gel plug. The sample was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, hexanes/EtOAc 2:1); yield: 70%. More recent reports have demonstrated the stereospecificity of this reaction.[52] 3.18.1.3.5
Reaction with Carbon Nucleophiles
A wide range of carbon pronucleophiles have been utilized in the stereospecific ring opening of asymmetric epoxides (e.g., 67 and 69) to alcohols (e.g., 68 and 70). These species include alkyl,[53,54] dithiane,[55] propargyl,[56] vinyl,[57] alkynyl,[58] and cyanide[59] nucleophiles (Schemes 30 and 31). The majority of these reactions proceed in excellent yield and selectivity using only the appropriate lithium or magnesium reagent, whereas less nucleophilic species require conversion to the corresponding cuprate and/or the addition of a suitable Lewis acid. Where possible, a general reference containing numerous examples has been identified; however, when no such reference has been available, a recent example of a representative procedure has been selected. Each procedure, with minor variations in temperature and/or concentration, has been successfully utilized in a number of asymmetric total syntheses.
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 825
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Stereoselective Synthesis
3.18
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
Scheme 30 Stereoselective Ring Opening of Epoxides with Alkyl Nucleophiles[53–56,60–62] OH O
R1
R1 R2
R3
R2 R3
67
R4 68
R1
R2
R3 R4
Conditions
Me
H
Ph Bu
CuCN (1.45 equiv), BuLi (2.66 equiv), THF, –20 8C 96
[53]
Pr Pr
CuCN (1.45 equiv), PrLi (2.66 equiv), THF, –20 8C 86
[53]
Me Et
CuCN (1.45 equiv), EtLi (2.66 equiv), THF, –20 8C 98
[53]
(CH2)3
Yielda (%)
Ref
But
(CH2)2CH=CMe2
CH2OH Me Me
CuI, MeLi (8.5 equiv), Et2O, –5 8C
76
[54]
(CH2)2OTBDPS
H
H
Bu
CuI, BuLi (8.5 equiv), Et2O, –5 8C
78
[60]
CH2OH
H
H
CH2C”CH
HC”CCH2MgBr, Et2O, –78 8C
94
[56]
(S)-CH(Et)OCH2OBn
H
H
CH2C”CH
HC”CCH2MgBr, Et2O, –78 8C
71
[61]
Me
H
H
S
S
1,3-dithiane (1 equiv), HMPA (2 equiv), BuLi (1 equiv), THF, –78 8C
96
[55]
Ph
H
H
S
S
1,3-dithiane (1 equiv), HMPA (2 equiv), BuLi (1 equiv), THF, –78 8C
87
[62]
a
Isolated yield.
Scheme 31
Ring Opening of Epoxides with Unsaturated Carbon Nucleophiles[57–59] OH
O R1
R2
R1 69
70
R1
R2
Conditions
CH2OPMB
CH=CH2
H2C=CHMgBr, THF, –78 8C
Yielda (%)
Ref
99
[57]
CH2Cl
C”CPh
THF, –78 8C
>99
[58]
CH2Cl
C”C(CH2)4Me Me(CH2)4C”CH, BuLi, BF3•OEt2, THF, –78 8C
74
[58]
CH2O2CC(Me)=CH2 C”CPh
PhC”CH, BuLi, BF3•OEt2, THF, –78 8C
93
[58]
Et
KCN (2 equiv), LiClO4 (2 equiv), MeCN, 70 8C
87
[59]
a
CN
PhC”CH, BuLi,
BF3•OEt2,
Isolated yield.
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Ring Opening of Epoxides
While most ring-opening reactions of epoxides proceed via nucleophilic attack at the least hindered carbon of the epoxides, some structural motifs, particularly aryl-substituted epoxides (e.g., 71), lead to alcohols (e.g., 72) arising from regioselective attack at the more substituted carbon atom, as outlined in Scheme 32.[63,64] Scheme 32
Ring Opening of Epoxides with Attack at the More Hindered Carbon Atom[63,64] OH
O R1
R3
+
R3
THF, 0 oC to rt
R4MgBr
R1
n
R2
n
R2
71
R4
72
R1
R2
R3
R4
n
Yielda (%) Ref
H
H
4-MeOC6H4
CH2CH=CH2
2
86
[63]
H
H
4-Tol
CH2CH=CH2
2
65
[63]
2
88
[63]
OCH2CH2O 3,4-(MeO)2C6H3 CH2C(Me)=CH2 2
88
[63]
OCH2CH2O 3,4-(MeO)2C6H3 Bn H
H
C”CPh
CH2CH=CH2
3
83
[64]
H
H
C”CPh
CH2CH=CH2
1
88
[64]
H
H
C”CPh
Bn
2
84
[64]
H
H
C”CPh
CH2C(Me)=CH2 2
76
[64]
a
Isolated yield.
(S)-2-Phenylheptan-2-ol (68, R1 = Me; R2 = H; R3 = Ph; R4 = Bu); Typical Procedure:[53]
CAUTION: Cyanide salts can be absorbed through the skin and are extremely toxic. CuCN (0.10 g, 1.1 mmol) was placed in a two-necked, 25-mL round-bottomed flask equipped with a magnetic stirrer bar. The salt was azeotropically dried with toluene (2 2.0 mL) and the flask was purged with argon. Anhyd THF (2.0 mL) was added and the slurry was cooled to –78 8C. A 2.17 M soln of BuLi in hexane (0.98 mL, 2.0 mmol) was added dropwise and warmed to –20 8C. 2-Methyl-2-phenyloxirane (Æ-methylstyrene oxide, 67; R1 = Me; R2 = H; R3 = Ph; 0.10 g, 0.75 mmol) was dissolved in THF (1.0 mL), cooled to –20 8C, and transferred to the cuprate soln via cannula with a subsequent wash of cold THF (0.5 mL). The reaction was stirred at –20 8C for 2 h and then quenched with a NH4Cl/NH4OH soln (9:1; 5 mL). After stirring at rt for 30 min, the soln was transferred to a separatory funnel and brine (5 mL) was added. This was extracted with Et2O (3 7 mL) and the extracts were combined and dried (K2CO3), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, Et2O/pentane 3:7); yield: 96%. (2R,3S)-2,3,7-Trimethyloct-6-ene-1,3-diol [68, R1 = (CH2)2CH=CMe2; R2 = CH2OH; R3 = Me; R4 = Me]; Typical Procedure:[54]
Under argon, a 1.4 M soln of MeLi in Et2O (18.6 mL) was added to a –5 8C soln of CuI (2.22g, 11.7 mmol) in Et2O (10 mL) over 30 min. At the same temperature, a soln of epoxide 67 [R1 = (CH2)2CH=CMe2; R2 = CH2OH; R3 = Me; 0.520 g, 2.94 mmol] in Et2O (5 mL) was added over 30 min. The reaction was stirred at –5 8C for 12 h, and was then warmed to rt and stirred for an additional 30 min. The reaction was quenched by slow addition of sat. aq NH4Cl and the separated aqueous layer was extracted with hexane/EtOAc (4:1; 2 20 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/hexanes 3:2); yield: 76%. Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 825
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Stereoselective Synthesis
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Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
(S)-Hex-5-yne-1,2-diol (68, R1 = CH2OH; R2 = R3 = H; R4 = CH2C”CH); Typical Procedure:[56]
CAUTION: Mercury(II) chloride is a poison by ingestion and is toxic by skin contact. When heated to decomposition it emits toxic fumes of mercury. Under argon, a mixture of Mg turnings (4.756 g, 195.2 mmol), HgCl2 (269.1 mg, 0.991 mmol), and a single crystal of I2 in Et2O (100 mL) was carefully treated with a small portion of propargyl bromide (80% in toluene, 10.5 mL, 11.59 mg, 97.4 mmol) dissolved in Et2O (40 mL). After the reaction had started, the mixture was cooled to 0 8C and the remainder of the propargyl bromide was added slowly over 1 h. The reaction was stirred for 1 h, and then warmed to rt and stirred for 1 h. (R)-Glycidol (67, R1 = CH2OH; R2 = R3 = H; 1.0 mL, 1.077 g, 14.53 mmol) was dissolved in Et2O and cooled to –78 8C. Under vigorous stirring the soln of propargylmagnesium bromide (112.5 mL, 72.8 mmol) was added slowly over 1 h. The soln was allowed to stir and slowly warm to rt over 14 h. The reaction was quenched with sat. aq NH4Cl and a small amount of potassium sodium tartrate was added. The soln was extracted with Et2O (4 ) and with EtOAc (4 ) and the combined extracts were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, hexane/EtOAc 10:1) provided the product; yield: 94%. (R)-1-(1,3-Dithian-2-yl)propan-2-ol (68, R1 = Me; R2 = R3 = H; R4 = 1,3-Dithian-2-yl); Typical Procedure:[55]
CAUTION: Hexamethylphosphoric triamide is a possible human carcinogen and an eye and skin irritant. Under argon, HMPA (25.6 mL, 204 mmol, 2 equiv) and a 2.4 M soln of BuLi in hexanes (42.5 mL, 102 mmol, 1 equiv) were added to a soln of 1,3-dithiane (12.22 g, 102 mmol) in anhyd THF (50 mL) at –78 8C. The mixture was slowly warmed to 0 8C and stirred for 2 h. The soln was recooled to –78 8C and (R)-2-ethyloxirane (67, R1 = Me; R2 = R3 = H; 6.212 g, 107 mmol) was added. After stirring for 1 h at –78 8C, the reaction was quenched with sat. aq NH4Cl and the mixture was warmed to rt. The mixture was extracted with EtOAc (3 80 mL) and concentrated under reduced pressure. The residue was dissolved in EtOAc (150 mL), washed with H2O (3 20 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes/ EtOAc 4:1); yield: 96%. (R)-1-(4-Methoxybenzyloxy)pent-4-en-2-ol (70, R1 = CH2OPMB; R2 = CH=CH2); Typical Procedure:[57]
Epoxide 69 (R1 = CH2OPMB; 23.0 g, 119 mmol) was dissolved in THF (500 mL) and cooled to –78 8C, followed by addition of CuI (5.67 g, 29.7 mmol). A 1 M soln of vinylmagnesium bromide in THF (143 mL, 143 mmol) was added over 1 h. The soln was stirred for 3 h at –78 8C and then warmed to rt. A sat. aq NH4Cl/NH3 soln (4:1; 150 mL) was added. The organic layer was separated and the aqueous layer was extracted with t-BuOMe (3 100 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, pentane/Et2O 2:1); yield: 99%. (R)-1-Chloro-5-phenylpent-4-yn-2-ol (70, R1 = CH2Cl; R2 = C”CPh); Typical Procedure:[58]
Under N2, a soln of BuLi (0.96 mL, 1.5 mmol) in hexane was added to a soln of phenylacetylene (153 mg, 1.5 mmol in 2 mL THF) at –78 8C and the mixture was stirred for 10 min. BF3•OEt2 (0.2 mL) was then added and stirring was continued for an additional 10 min. A soln of (R)-2-(chloromethyl)oxirane (69, R1 = CH2Cl; 1 mmol) in THF was added and after stirring for 30 min at –78 8C, the reaction was quenched by the addition of aq NH4Cl. The Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Ring Opening of Epoxides
organic materials were extracted with EtOAc, dried (Na2SO4), filtered, and concentrated under reduced pressure; yield: quant. (S)-3-Hydroxypentanenitrile (70, R1 = Et; R2 = CN); Typical Procedure:[59]
CAUTION: Cyanide salts can be absorbed through the skin and are extremely toxic. To a soln of (S)-2-ethyloxirane (69, R1 = Et; 6.0 mL, 69.6 mmol) in anhyd MeCN (50 mL) were added KCN (9.0 g, 138 mmol) and LiClO4 (14.8 g, 139 mmol) at rt. The mixture was sealed and heated to 70 8C. After 12 h, the mixture was diluted with EtOAc and washed with sat. NaHCO3, H2O, and brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/EtOAc 2:1) afforded the product; yield: 87%. (1R,2S)-2-Allyl-2-(4-methoxyphenyl)cyclohexanol (72, R1 = R2 = H; R3 = 4-MeOC6H4; R4 = CH2CH=CH2; n = 2); Typical Procedure:[63]
Under N2, a soln of allylmagnesium bromide in THF (10 mmol, 5 equiv) was added to a soln of epoxide 71 (R1 = R2 = H; R3 = 4-MeOC6H4; 1 equiv) in THF (15 mL) over 2 min at 0 8C. The mixture was warmed slowly to rt and stirred overnight. The mixture was partitioned between sat. aq NH4Cl and Et2O. The combined organic extracts were dried (Na2SO4), filtered, concentrated, and purified by column chromatography (silica gel); yield: 86%. 3.18.1.3.6
Reaction with Miscellaneous Nucleophiles
A number of additional nucleophiles have been utilized in the stereospecific ring opening of asymmetric epoxides. Epoxides can be efficiently reduced to the corresponding alcohols (e.g., 73) with the use of lithium triethylborohydride in excellent yield and regioselectivity (Scheme 33).[65] Likewise, phosphides also react with epoxides to generate -phosphino alcohols (e.g., 74) in excellent yield (Scheme 33).[66] Scheme 33 Stereospecific Ring Opening of Epoxides with Hydride and Phosphide Nucleophiles[65,66] O
OH
LiBEt3H THF, 25 oC 82%
73
O + LiPPh2
THF, −5 oC
OH PPh2
90%
74
In more recent developments, the ring opening/elimination sequence utilizing sulfonium ylides has provided an efficient means of generating enantioenriched allylic alcohols 75 from the enantiomerically enriched epoxides (Scheme 34).[67]
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 825
796
Stereoselective Synthesis
3.18
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
Scheme 34 Stereospecific Conversion of Epoxides to Allylic Alcohols[67] Me3S+I−, BuLi THF, −10 oC
O
R1
OH R1 R2 75
R2
R1
R2
Yielda (%) Ref
Bu
H
80
[67]
CH2OPh
H
96
[67]
(CH2)2OBn Me 89
[67]
CH=CH2
Me 93
[67]
89
[67]
(CH2)6 a
Isolated yield.
In related reactions, a ring-opening/ring-closing reaction has been demonstrated with sulfoxonium ylides to generate tetrahydrofuran derivatives 76 in excellent yield (Scheme 35).[68] Alternatively, the rhodium-catalyzed reductive coupling of epoxides with aldehydes provides a novel approach to -alkoxy alcohol derivatives 77 (Scheme 36).[69] In both cases, the reactions proceed with complete retention of epoxide stereochemistry. Scheme 35 Stereospecific Synthesis of Tetrahydrofurans from Asymmetric Epoxides[68] O I− S+ Me Me NaH, DMSO, 85 oC, 36 h Me
O
R2
R3
R1
OH
R2 O
R1 HO R3 76
R1
R2
R3
Yielda (%) Ref
CH2OBn
H
H
96
[68]
CH2OPMB H
H
86
[68]
(CH2)2OBn H
H
91
[68]
H
(CH2)2OBn H
85
[68]
CH2OBn
H
Me 33
[68]
a
Isolated yield.
Scheme 36
Stereospecific Reductive Coupling of Epoxides and Aldehydes[69]
+ R1
2.5 mol% RhCl(PPh3)3 BEt3 (2 equiv), 23 oC
O
O R2
H
OH R1
O 77
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
R2
3.18.1
797
Ring Opening of Epoxides
Method R1
R2
Additive Yielda (%) Ref
A
Me
Ph
–
82
[69]
A
Et
Ph
–
90
[69]
B
iPr
Ph
Et3N
96
[69]
B
Et
2-naphthyl Et3N
70
[69]
B
(CH2)5Me 2-furyl
57
[69]
a
Et3N
Isolated yield.
1-Methylcyclohexanol (73); Typical Procedure:[65]
CAUTION: Lithium triethylborohydride (Super Hydride) can ignite upon exposure to protic solvents or air. This reagent should be handled with the utmost care under an inert atmosphere with predried and deoxygenated solvents. An oven-dried 200-mL flask equipped with a side arm fitted with a septum, a stirrer bar, and a reflux condenser connected to a bubbler was cooled to rt under anhyd N2. The flask was immersed in a water bath at 25 8C, and then a 1.5 M soln of LiBEt3H in THF (25 mL, 37.5 mmol) was added, followed by 1-methylcyclohexene oxide (3.1 mL, 2.8 g, 25 mmol). The mixture was stirred vigorously. After 2 min, H2O was added to quench the reaction and the layers were separated. The aqueous phase was extracted with Et2O (2 20 mL). The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure; yield: 82%. (S)-1-(Diphenylphosphino)propan-2-ol (74); Typical Procedure:[66]
Under N2, (S)-2-methyloxirane (1 g, 17 mmol) was added dropwise at –5 8C to a soln of LiPPh2 (4.8 g, 17 mmol) in THF (35 mL). A color change from red to light brown indicated complete conversion. The reaction was stirred for an additional 20 min, then deoxygenated H2O (20 mL) was slowly added. The mixture was allowed to warm to rt and the sample was concentrated under reduced pressure. The resulting aqueous emulsion was extracted with CH2Cl2 (3 10 mL). The combined organic phase was passed through a column (MgSO4/alumina/MgSO4), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by distillation (168–172 8C/0.3 Torr); yield: 90%. (R)-Hept-1-en-3-ol (75, R1 = Bu; R2 = H); Typical Procedure:[67]
Under N2, a 1.6 M soln of BuLi in hexane (2.56 mL, 4.1 mmol) was added to a suspension of trimethylsulfonium iodide (857 mg, 4.2 mmol) in anyhd THF (13 mL). After 30 min, (R)-hex-1-ene oxide (140 mg, 1.40 mmol) in THF (2 mL) was added, producing a milky suspension. The reaction was allowed to warm to 0 8C over about 30 min and then to rt and stirred for 2 h. The reaction was quenched with H2O at 0 8C, extracted with Et2O and the combined organic layers were dried (MgSO4) and filtered. The soln was concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica gel); yield: 80%. (2S,3S)-2-[(Benzyloxy)methyl]tetrahydrofuran-3-ol (76, R1 = CH2OBn; R2 = R3 = H); Typical Procedure:[68]
Trimethylsulfoxonium iodide was dried overnight at rt under high vacuum. Dimethylsulfoxonium methylide was prepared fresh for each reaction. NaH (4.0 g as a 60% dispersion in mineral oil, 100 mmol, washed twice with pentane) was placed in a flame-dried flask and anhyd DMSO (100 mL) was added via syringe. Trimethylsulfoxonium iodide (22.0 g, 100 mmol) was added in small portions over 20 min. After addition of the trimethylsulfoxonium iodide was complete, the mixture was stirred for an additional 30 min until bubbling ceased. {(2S,3R)-3-[(Benzyloxy)methyl]oxiran-2-yl}methanol (1.94 g, 10 mmol) disRing Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 825
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Stereoselective Synthesis
3.18
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
solved in a small amount of DMSO was added dropwise and the flask was covered with aluminum foil and heated to 80 8C for 36 h. The dark brown mixture was cooled and diluted with two times the volume of H2O and sat. NH4Cl (1 mL). The mixture was extracted several times with EtOAc and the combined organics were washed with brine, dried (Na2SO4), and filtered. The soln was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, hexane/EtOAc); yield: 96%. (R)-1-(Benzyloxy)propan-2-ol (77, R1 = Me; R2 = Ph); Typical Procedure:[69]
Method A: Under argon, (R)-2-methyloxirane (0.30 mL, 4.28 mmol), PhCHO (0.20 mL, 1.96 mmol), and BEt3 (0.60 mL, 4.14 mmol) were added to RhCl(PPh3)3 (47 mg, 0.05 mmol). The mixture was stirred at rt for 16 h and then purified by column chromatography (silica gel, 0–20% EtOAc/hexane); yield: 82%. (R)-1-(Benzyloxy)-3-methylbutan-2-ol (77, R1 = iPr; R2 = Ph); Typical Procedure:[69]
Method B: Under argon, Et3N (0.28 mL, 0.21 mmol), (S)-2-isopropyloxirane (0.20 mL, 1.88 mmol), PhCHO (0.10 mL, 0.98 mmol), and BEt3 (0.28 mL, 1.93 mmol) were added to RhCl(PPh3)3 (47 mg, 0.05 mmol). The mixture was stirred at rt for 16 h and then purified by column chromatography (silica gel, 0–20% EtOAc/hexane); yield: 96%. 3.18.2
Ring Opening of Aziridines
Vicinal diamines and -amino acids are compounds of great interest to the chemical community, given their synthetic utility and ubiquity in biologically significant agents. While several methods exist for their preparation, these 1,2-difunctionalized compounds can be prepared directly from achiral starting materials via the enantioselective ring opening of aziridines. The preparation of aziridines has been covered in Houben–Weyl, Vol. E 16c and Science of Synthesis, Vol. 40a [Amines, Ammonium Salts, Amine N-Oxides, Haloamines, Hydroxylamines and Sulfur Analogues, and Hydrazines (Section 40.1.5)]. Although ring strain considerations of aziridines and epoxides would lead one to anticipate similar reactivity, particularly with electron-deficient N-substitution, the desymmetrization of aziridines has proven significantly more challenging than analogous reactions with epoxides. As such, methodology for the enantioselective ring opening of these compounds remains largely underdeveloped. To date, major advances center on the use of electron-withdrawing substitution coupled with highly nucleophilic substrates such as azide and cyanide. Nevertheless, efforts continue toward the development of general methods for the incorporation of new nucleophiles and aziridine N-substitution to produce 1,2-difunctionalized intermediates in synthetically useful yields and selectivities. In addition to the desymmetrization methodology, the ring opening of asymmetric aziridines has developed proportionately with the development of methods for the preparation of enantioenriched aziridines. A variety of methods are presented for the stereospecific ring opening of these compounds with a range of nucleophiles.
3.18.2.1
Enantioselective Ring Opening of meso-Aziridines
3.18.2.1.1
Reaction with Nitrogen Nucleophiles
3.18.2.1.1.1
Using Amines
A highly selective method has been recently reported for the desymmetrization of N-(2-methoxyphenyl)aziridines with anilines.[70] The ring opening is applicable to a number of anilines, using titanium(IV) isopropoxide with the tridentate 1,1¢-bi-2-naphthol ligand 78, to provide the 1,2-diamines 79 in high yields and with excellent enantioselectivities (up to 93% ee) (Scheme 37). While variation of the N-aryl substituent leads to reduced Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.18.2
799
Ring Opening of Aziridines
selectivity, a wide range of anilines are compatible with this methodology. The use of a zirconium-based catalyst has also been described, using the same 1,1¢-bi-2-naphthol derivative (Scheme 37).[71] A series of linear and cyclic aziridines with N-benzyl substitution undergo the enantioselective reaction with anilines to provide enantioenriched 1,2-diamines 80. These reactions proceed most selectively at 0 8C in toluene in the presence of pentanol. Scheme 37 Enantioselective Addition of Anilines to meso-Aziridines Catalyzed by Titanium and Zirconium Complexes[70,71]
Pri OH
OH
OH
78
+ R1NH2
N
2−10 mol% Ti(OiPr)4 2−10 mol% 78 10 mol% H2O, MgSO4 toluene, −10 oC
H N MeO NHR1
MeO
79
R1
Catalyst Loading (mol%) Yielda (%) eeb (%) Ref 2
88
92
[70]
10
81
93
[70]
3-ClC6H4 10
84
93
[70]
4-IC6H4
10
69
89
[70]
3-FC6H4
10
82
91
[70]
4-Tol
10
63
90
[70]
4-BrC6H4 10
62
89
[70]
Ph 3-Tol
a b
Isolated yield. Determined by HPLC analysis using a chiral stationary phase.
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 825
800
Stereoselective Synthesis
R1
R3NH2
+
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
10 mol% Zr(Ot-Bu)4 11 mol% 78 50 mol% pentanol toluene, 0 oC
Ph N
R2
3.18
Ph
R1
H N
R2
Ph NHR3
Ph
80
R1
R2
R3
Yielda (%) eeb (%) Ref
(CH2)4
3-ClC6H4
80
86
[71]
(CH2)4
3-F3CC6H4
73
86
[71]
(CH2)4
3,5-(F3C)2C6H3 81
92
[71]
CH2CH=CHCH2
3,5-(F3C)2C6H3 96
93
[71]
3,5-(F3C)2C6H3 93
92
[71]
3,5-(F3C)2C6H3 51
86
[71]
(CH2)3 Me
Me
3,5-(F3C)2C6H3 77
93
[71]
Et
Et
3,5-(F3C)2C6H3 56
80
[71]
a b
Isolated yield. Determined by HPLC analysis using a chiral stationary phase.
A titanium–1,1¢-bi-2-naphthol catalyst system has also been recently reported for the desymmetrization of a series of meso-N-aryl aziridines with anilines (Scheme 38).[72] This highly efficient procedure provides the desired 1,2-diamines 81 in good yields (75–90%) and enantioselectivities generally in excess of 90%. Scheme 38 Desymmetrization of meso-Aziridines Catalyzed by a Titanium–1,1¢-Bi-2naphthol Complex[72] R1 N R3
+
R4NH2
10 mol% Ti(Ot-Bu)4 22 mol% (R)-BINOL CH2Cl2, −40 oC
R1
NHR3
R2
R2
NHR4 81
R1
R2
R3
R4
Yielda (%) eeb (%) Ref
(CH2)4
Ph
Ph
92
98
[72]
(CH2)4
Ph
4-MeOC6H4 86
98
[72]
(CH2)4
Ph
4-Tol
85
99
[72]
(CH2)4
4-MeOC6H4 Ph
89
98
[72]
(CH2)4
4-MeOC6H4 4-MeOC6H4 86
98
[72]
(CH2)3
Ph
Ph
90
99
[72]
(CH2)3
Ph
4-MeOC6H4 96
99
[72]
(CH2)3
4-MeOC6H4 4-MeOC6H4 75
99
[72]
CH2CH=CHCH2 Ph
Ph
78
89
[72]
Me
Ph
87
90
[72]
a b
Me Ph
Isolated yield. Determined by HPLC using a chiral stationary phase.
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.18.2
801
Ring Opening of Aziridines
(1S,2S)-N-(2-Methoxyphenyl)-N¢-phenylcyclohexane-1,2-diamine (79, R1 = Ph); Typical Procedure:[70]
Under argon, Ti(OiPr)4 (7.1 mg, 0.025 mmol) and ligand 78 (10.8 mg, 0.025 mmol) in toluene (1.25 mL) were stirred at 60 8C for 3 h. After cooling to rt, the resulting yellow soln was added to a 10-mL flask charged with the aziridine (0.25 mmol) and anhyd MgSO4 (50 mg). The yellow suspension was stirred at 0 8C for 30 min and then a 3.0 M soln of H2O in iPrOH (16.5 L) was added. The mixture turned a dark red color and was stirred for another 30 min. The mixture was cooled to –10 8C and an aniline (0.30 mmol) in toluene (0.25 mL) was added over 22.5 h using a syringe pump. After complete addition, the mixture was stirred for an additional 17.5 h and then quenched with sat. aq NaHCO3 (10 mL). The mixture was extracted with CH2Cl2 (3 10 mL). The organic extracts were combined, dried (Na2SO4), and filtered, and the solvent was removed under reduced pressure. The crude product was purified by preparative TLC [silica gel, benzene (CAUTION: carcinogen)/hexane/EtOAc 19:10:1]; yield: 88%; 92% ee. (1S,2S)-N-[3,5-Bis(trifluoromethyl)phenyl]-N¢-(diphenylmethyl)cyclohexane-1,2-diamine [80, R1,R2 = (CH2)4; R3 = 3,5-(F3C)2C6H3]; Typical Procedure:[71]
Under argon, Zr(Ot-Bu)4 (0.015 mmol) and ligand 78 (0.0165 mmol) were added into a flame-dried 10-mL reaction tube. After toluene (0.2 mL) was added, the mixture was stirred at 60 8C for 2 h. The mixture was cooled to rt and pentanol (0.075 mmol) was added and the mixture was stirred for 1 h. The mixture was cooled to 0 8C and the aziridine (0.15 mmol) in toluene (15 mL) and aniline (0.18 mmol) in toluene (0.15 mL) were successively added. After 24 h, H2O was added to quench the reaction. After addition of CH2Cl2 (10 mL), the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 15 mL). The organic layers were combined, dried (NaSO4), and filtered, and the solvent was removed under reduced pressure. The crude product was purified by preparative TLC (silica gel, hexane/EtOAc 4:1); yield: 81%; 92% ee. (1S,2S)-N,N¢-Diphenylcyclohexane-1,2-diamine [81, R1,R2 = (CH2)4; R3 = R4 = Ph]; General Procedure:[72]
Under argon, Ti(Ot-Bu)4 (19 L, 0.05 mmol) was added to a soln of (R)-BINOL (31.5 mg, 0.11 mmol) in CH2Cl2 (1 mL) and the mixture was stirred for 1 h at rt. Aniline (50 L) was then added to the deep red soln and the soln was stirred for an additional 30 min. The mixture was cooled to –40 8C and the aziridine (0.50 mmol) was added dropwise. After the soln had been stirred for 5 h at –40 8C, the reaction was quenched by the addition of Et3N (0.50 mL) at –40 8C and then warmed to rt. The mixture was purified by column chromatography (silica gel, petroleum ether/EtOAc 20:1 containing 1% Et3N); yield: 92%; 98% ee. 3.18.2.1.1.2
Using Azides
The enantioselective addition of azide nucleophiles to achiral aziridines provides an important method for generating asymmetric 1,2-diamines. This process was inspired by Jacobsens asymmetric ring opening of meso-aziridines with a chromium/tridentate Schiff base complex.[73] The most widely applicable methodology of this type utilizes an yttrium species with glucose-derived ligand 82 to catalyze the ring opening of a broad series of aziridines with azidotrimethylsilane.[74] Cyclic, linear, and stilbene-derived aziridines are all compatible with this transformation, which provides the corresponding 1,2-difunctionalized products 83 in excellent yield (>93%) and enantioselectivities typically in excess of 90% (Scheme 39).
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 825
802
Stereoselective Synthesis
3.18
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
Scheme 39 Yttrium-Catalyzed Desymmetrization of meso-Aziridines with Azidotrimethylsilane[74] Ph
O
Ph P O HO
O
F
HO
F
82
R2
NO2
NO2
R1
1−10 mol% Y(OiPr)3, 2−20 mol% 82 TMSN3 (1.5 equiv), EtCN
N
R1
H N
NO2
NO2 R2
O
N3
O 83
R1
R2 Temp (8C) Catalyst Loadinga (mol%) Yieldb (%) eec (%) Ref (CH2)4
0
CH2CH=CHCH2 rt
1
97
92
[74]
2
96
91
[74]
(CH2)3
rt
5
>99
94
[74]
(CH2)5
40
10
94
86
[74]
CH2OCH2
40
10
>99
96
[74]
5
>99
94
[74]
CH2N(Cbz)CH2 rt Me
Me rt
1
94
95
[74]
Pr
Pr rt
5
>99
87
[74]
Ph
Ph rt
2
>99
93
[74]
a b c
For 82, 2 × mol% of Y(OiPr)3 (i.e., 2–20 mol%) was used. Isolated yield. Determined by HPLC analysis of crude reaction mixtures using a chiral stationary phase.
In a related approach that avoids the use of transition metals, the desymmetrization of aziridines is accomplished using the asymmetric phosphoric acid 84 to catalyze the addition of azidotrimethylsilane to a series of 3,5-bis(trifluoromethyl)benzoyl-substituted aziridines.[75] The addition reactions are relatively mild, occuring at room temperature in 1,2dichloroethane to generate the ring-opened products 85 with enantioselectivity over 90% ee for many cyclic aziridines and near 85% ee for linear and cis-stilbene-derived aziridines (Scheme 40). Scheme 40
Brønsted Acid Catalyzed Desymmetrization of Aziridines[75]
Ph Ph
O
O P
HO
O 84
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.18.2
803
Ring Opening of Aziridines CF3 O
R1
10 mol% 84
CF3
N
1,2-dichloroethane, rt
R1
H N
+ TMSN3 R2
R2 CF3
R1
R2
85
Yielda (%) eeb (%) Ref 97
95
[75]
CH2CH=CHCH2 84
92
[75]
(CH2)4 (CH2)5
64
91
[75]
(CH2)3
68
84
[75]
Me
Me 88
86
[75]
Ph
Ph
95
83
[75]
49
87
[75]
CH2OCH2 a b
N3
CF3 O
Isolated yield. Determined by HPLC using a chiral stationary phase.
The most recent addition to this area utilizes discrete yttrium–salen complex 86 for the enantioselective delivery of azide to N-acylaziridines to generate enantiopure -amino azides 87.[76] The reaction of cyclic and linear aziridines, which occurs in 1,2-dichloroethane (or dichloromethane) at room temperature, generally proceeds with yields and enantiomeric excesses over 95%, albeit very slowly (Scheme 41). Scheme 41 Complex[76]
Desymmetrization of N-Acylaziridines Catalyzed by a Clearly Defined Yttrium
OMe N
O Y
N
O N O Me Me OMe
2
86
Ring Opening of Epoxides, Aziridines, and Cyclic Anhydrides, Johnson, J. B. Science of Synthesis 4.0 version., Section 3.18 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
for references see p 825
804
Stereoselective Synthesis
3.18
Ring Opening of Epoxides, Aziridines, Cyclic Anhydrides
O R1
NO2
N
+
TMSN3
5 mol% 86 1,2-dichloroethane, rt
NO2
R2
R
1
R2
H N N3
O 87
R1
R2
99
97
[76]
CH2CH=CHCH2 ‡99
99
[76]
(CH2)4
Pr a b
Yielda (%) eeb (%) Ref
(CH2)5
47
97
[76]
(CH2)3
99
98
[76]
73
92
[76]
Pr
Isolated yield. Determined by HPLC analysis with a chiral stationary phase.
N-[(1S,2S)-2-Azidocyclohexyl]-3,5-dinitrobenzamide [83, R1,R2 = (CH2)4]; Typical Procedure:[74]
CAUTION: Organic and metal azides are potentially explosive. Under N2, a 0.2 M soln of Y(OiPr)3 in THF (25 L, 0.005 mmol, 2 mol%) was added to a soln of ligand 82 (4.6 mg, 0.01 mmol, 4 mol%) in THF (0.15 mL) at rt. The mixture was stirred at 45–60 8C for 1 h and the solvent was removed under reduced pressure. After drying the resulting precatalyst under reduced pressure (99.5
37
98
96
[65]
87
>99.5
95
[65]
(1R,4S)-4-Hydroxycyclopent-2-enyl Benzoate (43, R1 = H); Typical Procedure:[65]
Catalyst 5 (5.4 mg, 0.025 mmol) in PrCN (3 mL), Et3N (858 mg, 8.48 mmol) in PrCN (30 mL), cis-1,3-diol 42 (R1 = H; 500 mg, 4.99 mmol) in PrCN (30 mL), and BzCl (1.20 g, 8.54 mmol) in PrCN (3 mL) were added sequentially at –78 8C under an argon atmosphere to 4- molecular sieves (670 mg). After 3 h at –78 8C, the reaction was quenched by the addition of a phosphate buffer (pH 7). The organic materials were extracted with Et2O, and the combined extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexanes 1:15) to give the product; yield: 326 mg (32%); 98% ee; [Æ]D20 +126 (c 1.7, CHCl3). (R)-4-Oxocyclopent-2-enyl Benzoate (44, R1 = H); Typical Procedure:[65]
CAUTION: Preparative hazard! Explosions have occurred during the preparation of pyridinium dichromate. A soln of benzoate ester 43 (R1 = H; 22.6 mg, 0.111 mmol) in CH2Cl2 (5 mL) was added to 4- molecular sieves (83.6 mg) and PDC (85.2 mg, 0.227 mmol), and the mixture was stirred for 3 h at rt. The resulting mixture was diluted with Et2O and filtered through a plug of silica gel. The filtrate was concentrated in vacuo and the residue was purified by TLC (silica gel, Et2O/hexanes 2:1) to give the product without loss of ee; yield: 21.6 mg (96%). Acylation of Alcohols and Amines, Oriyama, T. Science of Synthesis 4.0 version., Section 3.19 sos.thieme.com © 2014 Georg Thieme Verlag KG
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844
Stereoselective Synthesis
3.19.1.2.4
Asymmetric Acylation of meso-1,5-Diols
3.19
Acylation of Alcohols and Amines
Scheme 19 illustrates the efficient desymmetrization of meso-1,5-diol 45 with catalyst (–)-3, in the presence of acetic anhydride and triethylamine in 2-methylbutan-2-ol, to afford the monoacetate 46 in 91% yield and with excellent enantiomeric excess (>99% ee).[26] Scheme 19
Desymmetrization of a meso-1,5-Diol[26] Me2N
1 mol%
N Ph
Fe
Ph
Ph
OH
OH
Ph
Ph (−)-3
OH
OAc
Ac2O, Et3N, 2-methylbutan-2-ol, 0 oC 91%; >99% ee
46
45
3.19.2
Asymmetric Acylation of Amines
Amines represent a much more challenging class of substrates for kinetic resolution using achiral acylation agents than alcohols, as highly basic amines are easily acylated without the influence of the chiral catalyst, leading to significant undesired background reactions. 3.19.2.1
Asymmetric Acylation of Primary Amines
The enzymatic enantioselective acylation of amines is well known.[66] Unfortunately, there has been relatively little significant progress in the development of nonenzymatic acylation catalysts for the kinetic resolution of amines, although some advances have recently been made in the discovery of enantioselective stoichiometric acylating reagents.[67] In particular, a stoichiometric amount of planar-chiral catalyst 11 has served as an effective reagent for the enantioselective acylation of racemic primary amines to provide the corresponding amides with high enantioselectivity (66–91% ee).[68] One of the issues in developing a useful catalyst for kinetic resolution is how to counter the nucleophilicity of the amine substrate, and its tendency to react directly with the acylating reagent without the intervention of the chiral catalyst. The O-acylated azlactone 47 reacts much more rapidly with catalyst (–)-10 than with a primary amine.[69] As such a significant degree of stereoselectivity is observed in the kinetic resolution of racemic primary amines to give enantiomerically enriched amines 48 and carbamates 49 (Scheme 20). The stereoselectivity can be enhanced by conducting the reaction at –50 8C and by adding the acylating agent in two batches. Various amines can be resolved and higher selectivity factors are obtained for amines in which the aromatic group bears an ortho-substituent.
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3.19.2
845
Asymmetric Acylation of Amines Kinetic Resolution of Primary Amines[69]
Scheme 20
N 10 mol%
O O But
NH2 + Ar1
N Fe
OMe (−)-10
O
CHCl3, −50 oC
N
R1 rac
O
47 NH2
HN
OMe
+ Ar1
R1 48
Ar1
R1
Selectivity (s) Ref
Ph
Me
12
[69]
1-naphthyl
Me
27
[69]
2-Tol
Me
16
[69]
4-MeOC6H4 Me
11
[69]
4-F3CC6H4
Me
13
[69]
3-MeOC6H4 Me
22
[69]
Ph
16
[69]
Et
Ar1
R1 49
A proposed mechanism for acylation of amines using catalyst (–)-10 is illustrated in Scheme 21.[69] The catalyst reacts rapidly with the acylating agent, O-acylated azlactone 47, producing an ion pair which is the resting state of the catalytic cycle. In the subsequent stereochemistry-determining step, the methoxycarbonyl group is transferred to the amine, thus furnishing the carbamate 49 and regenerating the catalyst.
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846
Stereoselective Synthesis
3.19
Acylation of Alcohols and Amines
Proposed Mechanism for Acylation of Amines[69]
Scheme 21
O O
O
N
NH2 HN
+ Ar1
But
OMe N
R1 Ar1
O N
Fe
R1
OMe
49 slow
fast
(−)-10
47
NH2 Ar1
R1 rac
O−
N But N MeO
O N
O Fe
(R)-1-Phenylethylamine (48, Ar1 = Ph; R1 = Me); Typical Procedure:[69]
Catalyst (–)-10 (5.2 mg, 0.014 mmol), 1-phenylethylamine (17.0 mg, 0.140 mmol), and CHCl3 (2.5 mL) were added to a Schlenk flask under argon. The resulting purple soln was cooled in a –50 8C bath, and a soln of O-acylated azlactone 47 (13.5 mg, 0.0420 mmol) in CHCl3 (0.15 mL) was added by syringe. After 4 h, additional azlactone (13.5 mg, 0.0420 mmol) in CHCl3 (0.15 mL) was added and, after a total of 24 h, the carbamate 49 was isolated using flash chromatography (EtOAc/hexanes 1:3); yield: 7.3 mg; 79% ee (by HPLC). The unreacted amine was acylated (Et3N, Ac2O, CH2Cl2, rt) and then purified by flash chromatography (EtOAc) to furnish the amide; yield: 11.4 mg; 42% ee (by GC). These ee values correspond to a selectivity factor (s) of 12 at 35% conversion. 3.19.2.2
Asymmetric Acylation of Secondary Amines
The kinetic resolution of 2-substituted indolines catalyzed by a planar-chiral catalyst derived from 4-(pyrrolidin-1-yl)pyridine proceeds smoothly to afford the corresponding chiral indolines bearing a stereocenter at the 2-position (90–98% ee).[70] Enantioselective Nacylation of secondary amides using enzymes or synthetic catalysts has never been reported. However, the kinetic resolution of various racemic oxazolidin-2-ones using catalyst (+)-31 proceeds smoothly at room temperature to afford the corresponding enantiomerically enriched secondary amides 50 and tertiary amides 51 (Scheme 22).[71] Investigation into the effects of substrate structure reveals that replacement of the phenyl group (Ar1 = Ph) with a 1-naphthyl group leads to increased enantioselectivity. Asymmetric acylation of geminal dimethyl substrates (R1 = Me) proceeds more slowly than for unsubstituted substrates. In these cases, higher conversions are obtained on a convenient time scale by doubling the catalyst and anhydride loadings.
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Asymmetric Acylation of Amines
3.19.2
Scheme 22
Kinetic Resolution of Secondary Amides[71] S 4 mol% N
O HN Ar1
N
Ph (+)-31 (iPrCO)2O, iPr2NEt, Na2SO4, CHCl3, rt
O R1
O HN Ar1
R1
O
+
Pri
R1
R1
Ph
H
1-naphthyl
H
2-naphthyl
H
2-furyl
H
8.5
2-thienyl
H
Ph 1-naphthyl 2-naphthyl a b c
R1 R1
Time (h) Selectivitya,b (s) eea (%) Conversion (%) Ref 98.3
36
[71]
21
450
99.1
42
[71]
14
260
97.8
47
[71]
96
95.7
42
[71]
6
430
98.2
49
[71]
Me 12
340
99.1
33c
[71]
99.1
c
[71]
c
[71]
Me
O
51
200
Me
N Ar1
R1 50
Ar1
O
O
8.5
7 8.5
520 200
98.2
45 37
Values determined for product 51. The selectivity factors (s) are averages of two runs. 8 mol% of (+)-31 was used.
(R)-4-Aryloxazolidin-2-ones 50 and (S)-4-Aryl-3-(2-methylpropanoyl)oxazolidin-2-ones 51; General Procedure:[71]
A stock soln was prepared by dissolving catalyst (+)-31 (20 mg, 0.080 mmol) and iPr2NEt (0.26 mL, 1.50 mmol) in CHCl3 in a 10.0-mL volumetric flask, and bringing the volume up to the mark. Two 1-dram vials were each charged with the racemic oxazolidin-2-one (0.10 mmol) and the stock soln (0.50 mL). After the substrate was dissolved Na2SO4 (100 mg) was added, and the resulting mixture was magnetically stirred at rt before being treated with (iPrCO)2O (12.4 L, 0.075 mmol). This mixture was stirred at rt and the reaction was monitored by 1H NMR and quenched by addition of MeOH (0.5 mL) when no further progress was observed (less than 1% change in the level of conversion in 2 h). The resulting soln was concentrated and subjected to flash chromatography (EtOAc/hexanes 35:65). The unreacted substrate and the N-acylated derivative thus separated were analyzed by chiral stationary phase HPLC.
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Stereoselective Synthesis
3.19
Acylation of Alcohols and Amines
References [1]
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Litvinenko, L. M.; Kirichenko, A. I., Dokl. Akad. Nauk SSSR, (1967) 176, 97; Chem. Abstr., (1968) 68, 68 325. Steglich, W.; Holfe, G., Angew. Chem., (1969) 81, 1001; Angew. Chem. Int. Ed. Engl., (1969) 8, 981. Guibe-Jampel, E.; Bram, G.; Vilkas, M., Bull. Soc. Chim. Fr., (1973), 1021. Vedejs, E.; Diver, S. T., J. Am. Chem. Soc., (1993) 115, 3358. Chen, C.-S.; Sih, C. J., Angew. Chem., (1989) 101, 711; Angew. Chem. Int. Ed. Engl., (1989) 28, 695. Klibanov, A. M., Acc. Chem. Res., (1990) 23, 114. Burgess, K.; Jennings, L. D., J. Am. Chem. Soc., (1991) 113, 6129. Drueckhammer, D. G.; Hennen, W. J.; Pederson, R. L.; Barbas, C. F., III; Gautheron, C. M.; Krach, T.; Wong, C.-H., Synthesis, (1991), 499. Vedejs, E.; Daugulis, O.; Diver, S. T., J. Org. Chem., (1996) 61, 430. France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T., Chem. Rev., (2003) 103, 2985. Dalko, P. I.; Moisan, L., Angew. Chem., (2004) 116, 5248; Angew. Chem. Int. Ed., (2004) 43, 5138. Vedejs, E.; Jure, M., Angew. Chem., (2005) 117, 4040; Angew. Chem. Int. Ed., (2005) 44, 3974. Vedejs, E.; Daugulis, O., J. Am. Chem. Soc., (1999) 121, 5813. MacKay, J. A.; Vedejs, E., J. Org. Chem., (2004) 69, 6934. Ruble, J. C.; Fu, G. C., J. Org. Chem., (1996) 61, 7230. Oriyama, T.; Hori, Y.; Imai, K.; Sasaki, R., Tetrahedron Lett., (1996) 37, 8543. Sano, T.; Imai, K.; Ohashi, K.; Oriyama, T., Chem. Lett., (1999), 265. Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K., J. Am. Chem. Soc., (1997) 119, 3169. Kawabata, T.; Yamamoto, K.; Momose, Y.; Yoshida, H.; Nagaoka, Y.; Fuji, K., Chem. Commun. (Cambridge), (2001), 2700. Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M., J. Am. Chem. Soc., (1998) 120, 1629. Copeland, G. T.; Jarvo, E. R.; Miller, S. J., J. Org. Chem., (1998) 63, 6784. Spivey, A. C.; Fekner, T.; Spey, S. E., J. Org. Chem., (2000) 65, 3154. Spivey, A. C.; Leese, D. P.; Zhu, F.; Davey, S. G.; Jarvest, R. L., Tetrahedron, (2004) 60, 4513. Fu, G. C., Acc. Chem. Res., (2004) 37, 542. Wurz, R. P.; Lee, E. C.; Ruble, J. C.; Fu, G. C., Adv. Synth. Catal., (2007) 349, 2345. Ruble, J. C.; Tweddell, J.; Fu, G. C., J. Org. Chem., (1998) 63, 2794. Bellemin-Laponnaz, S.; Tweddell, J.; Ruble, J. C.; Breitling, F. M.; Fu, G. C., Chem. Commun. (Cambridge), (2000), 1009. Tao, B.; Ruble, J. C.; Hoic, D. A.; Fu, G. C., J. Am. Chem. Soc., (1999) 121, 5091. Terakado, D.; Oriyama, T., Org. Synth., (2006) 83, 70. Sano, T.; Miyata, H.; Oriyama, T., Enantiomer, (2000) 5, 119. Nunno, L. D.; Franchini, C.; Nacci, A.; Scilimati, A.; Sinicropi, M. S., Tetrahedron: Asymmetry, (1999) 10, 1913. Ogawa, C.; Wang, N.; Kobayashi, S., Chem. Lett., (2007) 36, 34. Chen, Y.-J.; Chen, C., Tetrahedron: Asymmetry, (2007) 18, 1313. Sun, J.; Yuan, F.; Yang, M.; Pan, Y.; Zhu, C., Tetrahedron Lett., (2009) 50, 548. Cho, B. T.; Kim, D. J., Tetrahedron, (2003) 59, 2457. Cho, B. T., Tetrahedron, (2005) 61, 6959. Kawamata, Y.; Oriyama, T., Chem. Lett., (2010) 39, 382. Shiina, I.; Nakata, K., Tetrahedron Lett., (2007) 48, 8314. Birman, V. B.; Li, X., Org. Lett., (2006) 8, 1351. Shiina, I.; Nakata, K.; Sugimoto, M.; Onda, Y.; Iizumi, T.; Ono, K., Heterocycles, (2009) 77, 801. Mukaiyama, T.; Tomioka, I.; Shimizu, M., Chem. Lett., (1984), 49. Mukaiyama, T.; Tanabe, Y.; Shimizu, M., Chem. Lett., (1984), 401. Ichikawa, J.; Asami, M.; Mukaiyama, T., Chem. Lett., (1984), 949. Suzuki, T.; Uozumi, Y.; Shibasaki, M., J. Chem. Soc., Chem. Commun., (1991), 1593. Ishihara, K.; Kubota, M.; Yamamoto, H., Synlett, (1994), 611. Kinugasa, M.; Harada, T.; Oku, A., J. Am. Chem. Soc., (1997) 119, 9067. Fujioka, H.; Nagatomi, Y.; Kitagawa, H.; Kita, Y., J. Am. Chem. Soc., (1997) 119, 12 016. Oriyama, T.; Imai, K.; Sano, T.; Hosoya, T., Tetrahedron Lett., (1998) 39, 3529. Mizuta, S.; Sadamori, M.; Fujimoto, T.; Yamamoto, I., Angew. Chem., (2003) 115, 3505; Angew. Chem. Int. Ed., (2003) 42, 3383.
Acylation of Alcohols and Amines, Oriyama, T. Science of Synthesis 4.0 version., Section 3.19 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Kndig, E. P.; Enriquez Garcia, A.; Lomberget, T.; Perez Garcia, P.; Romanens, P., Chem. Commun.
(Cambridge), (2008), 3519. [51] Theil, F., Chem. Rev., (1995) 95, 2203. [52] [53] [54] [55] [56] [57]
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Schoffers, E.; Golebiowski, A.; Johnson, C. R., Tetrahedron, (1996) 52, 3769. Davis, A. P., Angew. Chem., (1997) 109, 609; Angew. Chem. Int. Ed. Engl., (1997) 36, 591. Oriyama, T.; Taguchi, H.; Terakado, D.; Sano, T., Chem. Lett., (2002), 26. Trost, B. M.; Corte, J. R., Angew. Chem., (1999) 111, 3947; Angew. Chem. Int. Ed., (1999) 38, 3664. Itoh, T.; Ohara, H.; Takagi, Y.; Kanda, N.; Uneyama, K., Tetrahedron Lett., (1993) 34, 4215. Harre, M.; Raddatz, P.; Walenta, R.; Winterfeldt, E., Angew. Chem., (1982) 94, 496; Angew. Chem. Int. Ed. Engl., (1982) 21, 480. Noyori, R.; Suzuki, M., Angew. Chem., (1984) 96, 854; Angew. Chem. Int. Ed. Engl., (1984) 23, 847. Laumen, K.; Schneider, M., Tetrahedron Lett., (1984) 25, 5875. Knight, S. D.; Overman, L. E.; Pairaudeau, G., J. Am. Chem. Soc., (1995) 117, 5776. Sugai, T.; Mori, K., Synthesis, (1988), 19. Wong, C.-H.; Chen, S.-T.; Hennen, W. J.; Bibbs, J. A.; Wang, Y.-F.; Liu, J. L.-C.; Pantoliano, M. W.; Whitlow, M.; Bryan, P. N., J. Am. Chem. Soc., (1990) 112, 945. Curran, T. T.; Hay, D. A.; Koegel, C. P., Tetrahedron, (1997) 53, 1983. Duhamel, L.; Herman, T., Tetrahedron Lett., (1985) 26, 3099. Oriyama, T.; Hosoya, T.; Sano, T., Heterocycles, (2000) 52, 1065. van Rantwijk, F.; Sheldon, R. A., Tetrahedron, (2004) 60, 501. Kondo, K.; Kurosaki, T.; Murakami, Y., Synlett, (1998), 725. Ie, Y.; Fu, G. C., Chem. Commun. (Cambridge), (2000), 119. Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C., Angew. Chem., (2001) 113, 240; Angew. Chem. Int. Ed., (2001) 40, 234. Arp, F. O.; Fu, G. C., J. Am. Chem. Soc., (2006) 128, 14 264. Birman, V. B.; Jiang, H.; Li, X.; Guo, L.; Uffman, E. W., J. Am. Chem. Soc., (2006) 128, 6536.
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Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions
3.20
V. Gouverneur and O. Lozano
General Introduction
In recent years, fluorine chemistry has established itself as an important area of research, which benefits agrochemical, medicinal, and material science.[1–3] The properties of the C—F bond assist in interpreting the behavior of organofluorine compounds.[4,5] For instance, fluorine is the most electronegative element (å = 4) and has the smallest atomic radius of the second row of the periodic table. Its ionization energy (I) is highly endothermic (–401.2 kcal • mol–1) but its electron affinity (Eea) is a very favorable exothermic process (+78.3 kcal • mol–1). The fluorine atom is intermediate in size between hydrogen and oxygen but closer to oxygen [van der Waals radii (): H (1.20); O (1.52); F (1.47)]. Fluorine forms the strongest bond to carbon in organic chemistry (109.9 kcal • mol–1 for CH3F) and is highly polarized with the electron density located mainly on fluorine. The substantial ionic nature of the C—F bond is reflected in its large dipole moment, which, combined with other effects (hyperconjugation, weak hydrogen-bond acceptor, charge dipole interactions C—F…X+), accounts for the conformational behavior of many fluorinated compounds. These unique characteristics have encouraged direct fluorination, in the context of mono-, di-, and trifluoromethylation, as a means of tailoring the physical properties of organic compounds to demand. Selected characteristics of fluoromethanes are given in Table 1. Table 1
Properties of Fluoromethanes[4] C—F Bond Length (Å)
C—F Bond Energy (kcal • mol–1)
bp (8C)
Dipole Moment (D)
Ref
CH4
–
–
–161
0.0
[4]
CH3F
1.385
109.9
–78
1.85
[4]
CH2F2
1.357
119.5
–52
1.97
[4]
CF3H
1.332
127.5
–83
1.65
[4]
CF4
1.319
130.5
–128
0.0
[4]
More recent progress in organofluorine chemistry has led to the development of numerous novel catalytic methods for the fluorination of organic molecules, such as aromatics and alkenes.[6] Various transition-metal-catalyzed and organocatalytic strategies for the stereoselective introduction of a fluorine atom or fluorine-containing substituent into activated substrates have also been disclosed.[7,8] This chapter covers the stereoselective synthesis of compounds containing a fluorine bonded to an sp3-carbon atom (i.e. monofluoromethyl, difluoromethyl, or trifluoromethyl substituents). The emphasis is on highlighting previously discussed asymmetric routes inclusive of catalytic strategies of broad synthetic scope, and on disclosing key new developments that have not been presented in previous volumes of Science of Synthesis for the fluorination of aldehydes {see Science of Synthesis, Vol. 25 [Aldehydes (Section 25.4.1.1.1.1)]}, ketones {see Science of Synthesis, Vol. 26 [Ketones (Section 26.6.1)]}, acids and esters {see Science of Synthesis, Vol. 20 [Three Carbon—Heteroatom Bonds: Acid Halides; Carboxylic Acids and Acid Salts; Esters, and Lactones; Peroxy Acids and R(CO)OX Compounds; R(CO)X, X = S, Se, Te (Sections 20.2.8.1.1.1
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Stereoselective Synthesis
3.20
Asymmetric Fluorination and Fluoroalkylation
and 20.5.11.1.1.1)]}, and substrates other than carbonyl derivatives [see Science of Synthesis, Vol. 34 (Fluorine)]. For each subcategory of fluorinated compounds, the material is organized around the reactivity profile of the fluorinating reagent and the generic mode of activation and induction used to facilitate stereoselective fluorination. 3.20.1
Stereoselective Fluorination
3.20.1.1
Stereoselective Electrophilic Fluorination
For the stereoselective synthesis of monofluorinated compounds, electrophilic fluorination processes outnumber methods that use nucleophilic fluorinating reagents. Common reagents for electrophilic fluorination are the user-friendly N-fluoro reagents, such as 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1, Selectfluor), N-fluorobenzenesulfonimide [2, NFSI, N-fluorobis(phenylsulfonyl)amine], N-fluorobenzene-1,2-disulfonimide (3, NFOBS, 2-fluoro-1,3,2-benzodithiazole 1,1,3,3teroxide),[9] and N-fluoropyridinium salts (e.g., 4)[10] (Scheme 1). The preparation of N-fluorobenzene-1,2-disulfonimide (3) is outlined in Scheme 2. Scheme 1
Electrophilic Fluorinating Reagents[9,10] O Cl
N N
2BF4−
O O O O S S Ph N Ph
F 1
Scheme 2 O S
O
N S
F
O
2
3
O
F
TfO−
N F 4
Synthesis of N-Fluorobenzene-1,2-disulfonimide[9]
O NH
S
O
S
10% F2 in N2, NaF CHCl3/CFCl3 (1:1) −40 oC
O S
N
>90%
O
O
S O
F
O
3
N-Fluorobenzene-1,2-disulfonimide (3, NFOBS):[9]
CAUTION: Pure fluorine gas is a very powerful oxidizing reagent and reacts violently or explosively with a wide range of materials. It is a severe irritant of the eyes, mucous membranes, skin, and lungs. F2(g) (10% in N2) was passed through a soln of 1,3,2-benzodithiazole 1,1,3,3-tetroxide (4 mmol) and vacuum-dried (20 8C) NaF (40 mmol) in CFCl3/CHCl3 (1:1; 360 mL) at –40 8C for 4 h. After the reaction was complete, N2 was passed through the soln for 30 min. The soln was filtered, washed with H2O and brine, and dried under reduced pressure. Removal of the solvent afforded crude material, which was crystallized (Et2O/hexane) to give the product as a stable, white, crystalline solid; yield: >90%; mp 139–140 8C; 19F NMR (CFCl3, ): –12.
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3.20.1
3.20.1.1.1
853
Stereoselective Fluorination
Diastereoselective Electrophilic Fluorination
For the preparation of complex fluorinated molecules featuring multiple stereocenters, the fluorination typically relies on the presence of existing stereocenters to induce stereocontrol. This strategy is most often used for installing the fluorine substituent Æ to a carbonyl group that is preactivated as a silyl enol ether or metal enolate. Various biologically important fluorinated compounds, e.g. steroids, -lactams, ketone peptide isosteres, and nucleosides have been prepared using this approach. The diastereoselective fluorination of ketones and carboxylic acids bearing either a chiral auxiliary or a removable stereodirecting group is also a reliable route to access enantioenriched Æ-fluoro carbonyl derivatives. This method provides fluorinated building blocks amenable to further functional manipulation. Functionalized organosilanes also provide suitable templates for diastereoselective fluorination reactions.[11] 3.20.1.1.1.1
Preparation of Æ-Fluoro Ketones from Æ-Silyl Ketones
A regio- and diastereoselective electrophilic fluorination of enantiopure Æ-silyl ketones with N-fluorobenzenesulfonimide (2) followed by racemization-free removal of the silyldirecting group has been reported. This is a rare example of asymmetric fluorination of ketones with broad synthetic scope.[12,13] The enantiopure silylated ketones 5, prepared by diastereoselective silylation of the corresponding (S)- or (R)-1-amino-2-(methoxymethyl)pyrrolidine hydrazones followed by ozonolytic cleavage of the chiral auxiliary, are subjected to electrophilic fluorination. Lithium enolates of ketones 5 generated with lithium diisopropylamide or lithium hexamethyldisilazanide in tetrahydrofuran react with N-fluorobenzenesulfonimide (2) to give the expected Æ-fluoro-Æ¢-silyl ketones 6 in good yields and high diastereomeric excesses (Scheme 3). Lithium diisopropylamide and lithium hexamethyldisilazanide induce the formation of differing enolate geometries with acyclic ketones [LDA (E), LiHMDS (Z)], resulting in the formation of epimeric fluorinated ketones 6. For ketones substituted by a branched alkyl group (e.g., R1/R2 = Me/Pr, Me/iBu, or Bn/Pr), the fluorinated products are formed in good yields but with lower diastereoselectivity. Scheme 3
Electrophilic Fluorination of Enantiopure Æ-Silyl Ketones[13] 1. base, THF 0 oC, 4 h
O
R1
TBDMS
R2
F R1
(R)-5
syn-6
R1
R2
Base
Et
Et
LDA
79b
syn
79
[13]
Et
Et
LiHMDS
89b
anti
80
[13]
‡98
anti
81
[13]
(CH2)4 LDA
‡98
anti
85
[13]
syn
81
[13]
a
b
Pr
LDA
R2
+
TBDMS
F R1
R2
anti-6
dea (%) Major Config Yield (%) Ref
(CH2)3 LDA Pr
O
O
2. (PhSO2)2NF 2 −78 oC
TBDMS
b
65
Diastereoselectivities determined by 19F NMR or 13 C NMR spectroscopy of crude material. Isolated with ‡98% de.
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Asymmetric Fluorination and Fluoroalkylation
The enantiomerically enriched Æ-fluoro ketones (e.g., 8) are formed from the diastereomerically pure Æ-fluoro-Æ¢-silyl ketones (e.g., 7) after racemization-free desilylation using a mixture of fluoride sources (Scheme 4). Scheme 4
Desilylation of Æ-Fluoro-Æ¢-silyl Ketones[13] O
TBDMS
F
NH4F, KH2PO4, TBAF, HF THF, −78 oC to rt
O F
92%; 93% ee
(3R,5S)-7
8
Æ-Fluoro-Æ¢-silyl Ketones 6; General Procedure for Electrophilic Fluorination of Enantiopure Æ-Silyl Ketones Using Lithium Diisopropylamide:[12,13] To a soln of iPr2NH (0.8 mL, 5.5 mmol) in THF (25 mL) at 0 8C was added a 1.5 M soln of BuLi in hexane (3.7 mL). Ketone 5 (5 mmol) was added after 30 min. After stirring at 0 8C for 4 h, the soln was cooled to –78 8C and a soln of N-fluorobenzenesulfonimide (2; 1.58 g, 5 mmol) in THF (20 mL) was added dropwise. The mixture was stirred at –78 8C for 2 h, slowly warmed to rt overnight, and quenched with sat. NH4Cl. The mixture was extracted with CH2Cl2 or Et2O (3 20 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude oily solid was purified by distillation and/or column chromatography (silica gel, Et2O/pentane). Æ-Fluoro-Æ¢-silyl Ketones 6; General Procedure for Electrophilic Fluorination of Enantiopure Æ-Silyl Ketones Using Lithium Hexamethyldisilazanide:[12,13] To (TMS)2NH (1.15 mL, 5.5 mmol) in Et2O (10 mL) was added a 1.5 M soln of BuLi in hexane (3.7 mL) at 0 8C. The soln was warmed to rt and the solvent was removed under high vacuum. The remaining colorless solid was dissolved in THF (25 mL), the soln was cooled to 0 8C, and a soln of ketone 5 (5 mmol) in THF (5 mL • mmol–1) was added dropwise. After 16 h at 0 8C, the mixture was cooled to –78 8C and N-fluorobenzenesulfonimide (2; 1.58 g, 5 mmol) in THF (20 mL) was added. After a slow return to rt, the reaction was quenched with sat. aq NH4Cl. The mixture was extracted with CH2Cl2 or Et2O (3 20 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude oily solid was purified by distillation and/or column chromatography (silica gel, Et2O/pentane). (3S)-3-Fluoroheptan-4-one (8); Typical Procedure:[12,13]
CAUTION: Hydrogen fluoride fumes are severely irritating and extremely destructive to the respiratory system. NH4F (10 equiv), KH2PO4 (10 equiv), a 1 M soln of TBAF in THF (1 mL), and 48% aq HF (1 equiv) were suspended in THF (20 mL) and the mixture was cooled to –78 8C. A soln of the Æ-fluoro-Æ¢-silyl ketone 7 (1 mmol) in THF (10 mL) was added dropwise and the mixture was slowly warmed to rt before being quenched with sat. NH4F. The soln was poured into H2O (10 mL), the resulting mixture was extracted with CH2Cl2 (3 10 mL), and the combined extracts were dried (Na2SO4). After removal of the solvent under reduced pressure, the crude brown-red product was purified by column chromatography (silica gel, Et2O/ pentane 1:40) to give the corresponding Æ-fluoro ketone 8 as a colorless liquid. The product was stored at –20 8C under argon without detectable racemization; yield: 92%; 93% ee.
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.20.1
3.20.1.1.1.2
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Stereoselective Fluorination
Preparation of Æ-Fluoro Carboxylic Acids, -Fluoro Alcohols, Æ-Fluoro Aldehydes, Æ-Fluoro Ketones, and ª-Lactones from Carboxylic Acids
The asymmetric Æ-fluorination of carboxylic acids is best performed using an oxazolidinone auxiliary with either N-fluorobenzenesulfonimide (2) or N-fluorobenzene-1,2-disulfonimide (3) as the fluorinating reagent. The chiral imide enolates are generated at –78 8C in tetrahydrofuran with lithium diisopropylamide or sodium hexamethyldisilazanide. Fluorination leads to Æ-fluoro carboximides 10 in good to excellent diastereoselectivities, with the fluorinating agent approaching the less hindered Si-face of the imide enolate derived from (4S,5R)-oxazolidinones 9 (Scheme 5). Diastereoselective Fluorination of (4S,5R)-Imide Enolates[14–16]
Scheme 5 O O
O
O 1. base 2. fluorinating reagent
R3
N
O
O R3
N F
R1
R2
R1
R2
9
10
R1
R2
R3
Base
Fluorinating Reagent de (%) Yield (%) Ref
Ph
Me
Bu
LDA
NFOBS (3)
97
88
[16]
H
iPr
Bu
LDA
NFOBS (3)
96
85
[16]
Ph
Me
t-Bu
LDA
NFOBS (3)
96
86
[16]
H
iPr
t-Bu
LDA
NFOBS (3)
97
80
[16]
Ph
Me
Bn
LDA
NFOBS (3)
89
84
[16]
Pha Me
Ph
NaHMDS
NFSI (2)
‡97
85
[15]
Me
NaHMDS
NFSI (2)
‡97
77
[15]
CH2OBn
NaHMDS
NFSI (2)
94
78
[14]
a
Ph
Me
Pha Me a
(+)-(4R,5S)-4-Methyl-5-phenyloxazolidinone was used.
Upon hydrolytic cleavage of the auxiliary, the Æ-fluoro carboxylic acids (e.g., 12) are obtained with partial racemization, but this is minimized using lithium hydroperoxide (78–90% ee) instead of lithium hydroxide (69–87% ee). Alternatively, the reductive cleavage of the chiral auxiliary in the Æ-fluoro carboximides (e.g., 11) affords the corresponding -fluoro alcohols (e.g., 13) without compromising the stereochemical integrity (Scheme 6).[14,16] The -fluoro alcohols (e.g., 14) can be oxidized to Æ-fluoro aldehydes (e.g., 15) without significant erosion of enantiomeric excess using the Dess–Martin periodinane reagent in dichloromethane at room temperature (Scheme 6).[14] When ,ª-unsaturated Æ-fluoro oxazolidinones (e.g., 16) are treated with osmium(VIII) oxide and trimethylamine N-oxide, the enantioenriched ª-lactones (e.g., 17 and 18) are obtained as a separable mixture of diastereomers in excellent overall yield (Scheme 6).[17]
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Asymmetric Fluorination and Fluoroalkylation
Scheme 6 Access to Æ-Fluoro Carboxylic Acids, -Fluoro Alcohols, Æ-Fluoro Aldehydes, Ketones, and ª-Lactones[14,16,17] O LiOOH
O O
Bu
HO
86%; 90% ee
O
F
Bu
N
12
F Ph LiBH4, Et2O
11
Bu
HO
83%; >95% ee
F 13
BnO
OH
O
Dess−Martin periodinane CH2Cl2, 10 min
BnO
95%; 94% ee
F
H F 15
14
O O
O
OBn
N
OsO4 TMANO
O
+
BnO
96%
O
O
F
HO
Ph
16
O
BnO HO
F
17
1:2.3
F
18
Alternatively, Æ-fluoro ketones (e.g., 20) can be obtained from Æ-fluoro oxazolidinone carboximides via conversion into the Æ-fluoro N-methoxy-N-methylamides (e.g., 19) by Weinreb amide formation, followed by Grignard reagent addition. This process also occurs without epimerization at the fluorinated stereogenic center (Scheme 7).[15] Conversion of Æ-Fluoro Oxazolidinone Carboximides into Æ-Fluoro Ketones[15]
Scheme 7 O O
O R1
N
MeNH(OMe)•HCl Me3Al
F
MeO
R1
N Me
Ph
R2MgBr THF, 0 oC
O
R1
R2
F
F 20
19
R1
R2
Yield (%) of 19 eea (%) of 20 Yield (%) of 20 Ref
Ph
Me
77
>97
77
[15]
Me
Ph
80
>97
80
[15]
Ph
Ph
77
96
85
[15]
Ph
CH=CH2
77
>97
76
[15]
a
O
19
Determined by F NMR spectroscopy and comparison with racemic Æ-fluoro ketones 20.
Æ-Fluoro Carboximides 10; General Procedure for Diastereoselective Fluorination of Chiral Imide Enolates:[16]
Chiral imide enolates were generated at –78 8C in THF by treatment of the chiral imides 9 (0.3–3.0 mmol) with LDA (1.1 equiv) for 20 min. Æ-Fluorination was performed by addition of a THF soln of N-fluorobenzene-1,2-disulfonimide (3; 1.2 equiv) to the enolate, stirring for 2.5 h, and warming to 0 8C for 20 min prior to quenching with NH4Cl. The Æ-fluoro car-
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Fluorination
857
boximides 10 were purified by flash chromatography (silica gel, EtOAc/pentane 8:92). For reactions employing NaHMDS as the base, reverse addition of the enolate to the N-fluorobenzenesulfonimide (2) soln avoids enolate quenching by the more acidic Æ-fluorinated proton in the product. (2S)-2-Fluorohexan-1-ol (13):[16]
(4S,5R)-3-[(2S)-2-Fluorohexanoyl]-4-methyl-5-phenyloxazolidin-2-one (11) in THF or Et2O was treated with LiBH4 (1.2 equiv) and the resulting mixture was stirred for 1–2 h. The mixture was quenched with H2O to provide the enantiopure product; yield: 83%; >95% ee. (2R)-3-(Benzyloxy)-2-fluoropropanal (15):[14]
A soln of Dess–Martin periodinane (900 mg, 2.17 mmol) in CH2Cl2 (10 mL) was stirred at rt. (2S)-3-(Benzyloxy)-2-fluoropropan-1-ol (14; 363 mg, 1.97 mmol) in CH2Cl2 (10 mL) was added, and after 10 min the soln was diluted with Et2O (20 mL), sat. NaHCO3 (10 mL), and sat. Na2S2O3 (10 mL). After stirring until the organic phase was clear, the organic phase was washed with sat. NaHCO3 (2 10 mL) and sat. Na2S2O3 (2 10 mL), dried, and concentrated; yield: 341 mg (95%); 94% ee. 5-O-Benzyl-2-deoxy-2-fluoro-d-ª-xylonic Lactone (17) and 5-O-Benzyl-2-deoxy-2-fluoro-l-ªlyxonic Lactone (18):[17]
CAUTION: Exposure to osmium(VIII) oxide can result in acute conjunctivitis, and dermatitis with painful skin eruptions. To a soln of (4R,5S)-3-[(2R,3E)-5-(benzyloxy)-2-fluoropent-3-enoyl]-4-methyl-5-phenyloxazolidin-2-one (16; 0.957 g, 2.5 mmol) in acetone and H2O (20:1, 12.5 mL), were added TMANO (0.659 g, 6.25 mmol) and a 2.5% (w/w) soln of OsO4 in t-BuOH (2.5 mL). After 2 h at rt, solid NaHSO3 (excess) was added and the soln was stirred for 10 min, diluted with EtOAc (20 mL), dried (MgSO4), and concentrated. Purification by column chromatography (silica gel, EtOAc/hexane 1:1) afforded 0.115 g of 5-O-benzyl-2-deoxy-2-fluoro-d-ª-xylonic lactone (17), 0.322 g of 5-O-benzyl-2-deoxy-2-fluoro-l-ª-lyxonic lactone (18), and a mixture of both diastereomers (0.137 g), which was further purified; overall yield: 96%. Both lactones were initially obtained as slightly glassy yellow solid, but on standing 5-O-benzyl-2deoxy-2-fluoro-l-ª-lyxonic lactone (18) solidified.
Æ-Fluoro Ketones 20; General Procedure:[15] CAUTION: Neat trimethylaluminum is highly pyrophoric.
N,O-Dimethylhydroxylamine hydrochloride (5.28 mmol, 3 equiv) and Me3Al (3 equiv) were mixed at rt in CH2Cl2. After stirring for 15 min at rt and cooling to 0 8C, the Æ-fluoro oxazolidinone carboximide (1 equiv) was added. The yellow soln was stirred for 2–3 h at 0 8C until completion (TLC). After quenching with 1% HCl, the Æ-fluoro-N-methoxy-N-methylamides 19 were isolated as oils by column chromatography (silica gel); yield: 77–95%. The amides were then treated with the Grignard reagents (MeMgBr, PhMgBr, or H2C=CHMgBr) (0.28 mmol, 1.1 equiv) at 0 8C in THF for 10–15 min. After quenching with sat. NH4Cl soln, the corresponding (R)-Æ-fluoro ketones 20 were isolated by preparative TLC; yield: 75–85%. The enantiomeric purity of the ketones was judged to be >96% using 19 F NMR spectroscopy with the chiral shift reagent Eu(hfc)3. 3.20.1.1.1.3
Preparation of Æ-Fluoro Phosphonic Acids
The importance of hydrolytically stable fluorinated phosphonic acids as inhibitors of protein phosphatases has inspired the development of synthetic routes for their preparation. Æ-Carbanions of phosphonamides (e.g., 21) and phosphonamidates (e.g., 23) bearing the
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Stereoselective Synthesis
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Asymmetric Fluorination and Fluoroalkylation
chiral auxiliaries (1R,2R)-N,N¢-dimethylcyclohexane-1,2-diamine and (–)-ephedrine, respectively, undergo electrophilic fluorination with N-fluorobenzenesulfonimide (2) in tetrahydrofuran to give Æ-fluorinated phosphonamides (e.g., 22) and Æ-fluorinated phosphonamidates (e.g., 24) (Schemes 8 and 9). The diastereomeric ratio is highly dependent on the nature of the base and the counterion, and the stereocontrol approaches 9:1 in the best cases. Diastereoselective Fluorination of Phosphonamides[18]
Scheme 8 Me N
O
Me N
O
P
P
F
1. base, THF 2. (PhSO2)2NF 2 (1.1 equiv)
N Me
N Me
R
21
22
dra
Base (equiv)
Yield (%) Ref
LiHMDS (0.95) 85:15 81
[18]
BuLi (0.95)
[18]
a
84:16 68
Diastereoselectivities were determined by 19F NMR spectroscopy of the crude material.
Scheme 9
Diastereoselective Fluorination of Phosphonamidates[18]
Me N
O P
O
Me N
O 1. NaHMDS, THF 2. (PhSO2)2NF 2 (1.1 equiv)
Ph
P
F S
O
Ph
54%; dr 79:21
cis-23
cis-24
F
Me N
1. NaHMDS, THF 2. (PhSO2)2NF 2 (1.1 equiv)
P O trans-23
O
Ph
62%; dr 86:14
R
O
Me N P O
Ph
trans-24
The Æ-fluoro phosphonamidates (e.g., 24) can be isolated in diastereomerically pure form after purification by silica gel column chromatography. Removal of the ephedrine auxiliary using trifluoroacetic acid/methanol followed by treatment with bromotrimethylsilane affords the Æ-monofluoroalkylphosphonic acids (e.g., 25) in modest to good yield without any detectable racemization (Scheme 10).[18]
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.20.1
859
Stereoselective Fluorination
Scheme 10
Cleavage of the Chiral Auxiliary[18] F R
O trans-24
P O
F
1. 10% TFA/MeOH 2. TMSBr (10 equiv) 3. MeOH/H2O
Me N Ph
R
PO3H2
62%
25
(3aR,7aR)-2-[(R)-Fluoro(2-naphthyl)methyl]-1,3-dimethyloctahydro-1H-1,3,2-benzodiazaphosphole 2-Oxide (22); Typical Procedure:[18]
The base (0.95 equiv) was added to a soln of phosphonamide 21 in THF (ca. 5–10 mL THF/ mmol of phosphonamide) at –78 8C over a period of 2 min. The resulting orange soln was stirred for 2 h at –78 8C. A soln of N-fluorobenzenesulfonimide (2; 1.1 equiv) in THF [ca. 2–4 mL THF/mmol N-fluorobenzenesulfonimide (2)] was added over a period of 2 min, during which time the soln turned from orange to yellow-brown. After addition, the soln was stirred for 2 h at –78 8C; a precipitate may form. The reaction was quenched with a 10% NH4Cl soln and the resulting soln (precipitate dissolved) was extracted with CHCl3. The combined organic layers were washed with brine, dried (MgSO4), and concentrated under reduced pressure to give a yellow residue. Column chromatography (silica gel) of the crude residue gave the phosphonamide 22 as a mixture of two diastereomers. (2S,4S,5R)-2-[(R)-Fluoro(2-naphthyl)methyl]-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine 2-Oxide (trans-24):[18]
NaHMDS (1.1 equiv) was added to phosphonamidate trans-23 (1 equiv) and N-fluorobenzenesulfonimide (2; 1.1 equiv) over a period of 1 h at –78 8C. After stirring for an additional 2 h at –78 8C, the mixture was warmed to rt and quenched with a 10% NH4Cl soln, and the resulting soln was extracted with CHCl3. The combined organic layers were washed with brine, dried (MgSO4), and concentrated under reduced pressure. Column chromatography (silica gel) of the crude residue gave the phosphonamidate trans-24 as a mixture of two diastereomers; yield: 62%; dr 86:14. [(R)-Fluoro(2-naphthyl)methyl]phosphonic Acid (25); General Procedure:[18]
A soln of the fluorinated oxazaphospholidinone trans-24 in 10% TFA/MeOH (ca. 1 mL/ mmol starting material) was stirred at rt overnight. The soln was then concentrated under reduced pressure, dissolved in benzene (CAUTION: carcinogen), and concentrated (3 ) prior to being placed under high vacuum for 2 h. The resulting product was dissolved in anhyd CH2Cl2 (approx 3–5 mL/mmol) and stirred at rt for 24 h in the presence of TMSBr (10 equiv). The soln was concentrated under reduced pressure and placed under high vacuum for several h. Anhyd Et2O was then added followed by filtration and concentration of the filtrate (if a precipitate formed during evaporation, more anhyd Et2O was added and the suspension filtered). The residue was dissolved in MeOH, containing 1 drop of H2O, and stirred for 15 min. The soln was then concentrated under reduced pressure and the resulting product obtained pure after washing extensively with benzene and CH2Cl2; yield: 62%. 3.20.1.1.1.4
Preparation of Monofluoro Ketomethylene Dipeptide Isosteres
Monofluorinated ketopeptide isosteres (e.g., 27) have therapeutic potential as protease inhibitors. These compounds are accessible by stereoselective electrophilic fluorination of derivatized N-tritylated amino acids (e.g., 26). The nature of the nitrogen-protecting group on the amino acid residue is critical for the preparation of fluorinated ketomethylene dipeptide isosteres with high diastereoselectivity. Various trimethylsilyl enol ethers (Z-isomer), prepared from syn-(2R,5S)-N-tritylated ketone dipeptides using sodium hexamethyl-
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
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Asymmetric Fluorination and Fluoroalkylation
disilazanide and chlorotrimethylsilane, have been fluorinated with Selectfluor (1) in the presence of tetrabutylammonium fluoride (Scheme 11). The resulting products are isolated in synthetically useful yields (up to 76%). The cooperative stereocontrol induced by the N-tritylamino group and the substituent at C2 (relative to the ester) leads to excellent diastereoselectivities (de >95%). The anti-(2S,5S)-N-tritylated ketone dipeptides can be fluorinated but these reactions are not stereoselective (dr ~1:1).[19] Scheme 11 Electrophilic Fluorination of Enantiopure (2R,5S)-N-Tritylated Ketone Dipeptides[19] O
R2
R1
OMe
TrHN
1. NaHMDS, then TMSCl, THF 2. Selectfluor (1), TBAF, DMF
TrHN
O 26
OMe F
O
27
R1
R2
dea (%) Yield (%) Ref
iBu
Me
>95
76
[19]
iBu
CH2Cy >95
73
[19]
(CH3)2SMe
Bn
>95
65
[19]
Me
iBu
>95
75
[19]
Bn
Pr
>95
68
[19]
a
R2
O R1
Determined by 1H NMR spectroscopy of the crude material.
Monofluorinated Ketopeptide Isosteres 27; General Procedure for Electrophilic Fluorination of Enantiopure N-Tritylated Ketone Dipeptide Isosteres:[19]
At –78 8C, a 2.0 M soln of NaHMDS in THF (0.27 mL, 0.54 mmol) was added to a soln of the (2R,5S)-N-tritylated dipeptide isostere 26 (190 mg, 0.41 mmol) in THF (20 mL). After 3.5 h at –78 8C, TMSCl (0.1 mL, 0.51 mmol) in THF (10 mL) was added. The resulting soln was warmed to rt for 1 h and taken up into hexanes (150 mL), washed with ice-cold sat. NaHCO3 (20 mL), dried (Na2SO4), filtered, and concentrated. 1H NMR spectroscopy of the yellow residue showed that only a single enol ether isomer was formed. Under N2, the residue was suspended into DMF (3 mL), cooled to –50 8C, and treated with Selectfluor (1; 150 mg, 0.42 mmol) in DMF (3 mL). After 15 min, the soln was reacted with a 1.0 M soln of TBAF in THF (0.42 mL, 0.42 mmol). The resulting mixture was warmed to rt for 45 min, treated with cold 0.5 M NaHCO3 (10 mL), and extracted with Et2O (2 50 mL). The combined extracts were dried (MgSO4) and concentrated to provide the fluorinated dipeptide isostere 27 as a colorless oil. Diastereoselectivities were determined by 1H NMR spectroscopy of the crude product. 3.20.1.1.1.5
Preparation of Allylic Fluorides
Chiral allylic fluorides are readily available from the corresponding allylsilanes with electrophilic fluorinating reagents. The fluorination proceeds with full transposition of the double bond, an observation consistent with an SE2¢ mechanism.[11,20] Various chiral acyclic and cyclic allylsilanes react stereoselectively with Selectfluor (1) in acetonitrile at room temperature to furnish a series of valuable fluorinated building blocks with the fluorine substituent as a stereogenic allylic center.[21–25] Schemes 12 and 13 illustrate, with representative allylsilanes, the scope of this methodology. For cyclic precursors, the level of stereocontrol is dependent on both the structural and stereochemical features of the allylsilanes. The electrophilic fluorodesilylation
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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861
Stereoselective Fluorination
of cyclic enantioenriched protected syn--hydroxysilanes has been conducted with Selectfluor (1) in acetonitrile at room temperature to afford fluorinated cyclopentenes or cyclohexenes 28 with up to 90% yield (Scheme 12). The level of diastereocontrol is consistently high [anti approach of Selectfluor (1) with respect to the silyl group] and independent of the nature of the silyl group and the ring size. The protecting group of the secondary alcohol is important for efficient stereocontrol with the benzoyl group being optimal (Scheme 12). Scheme 12 Diastereoselective Fluorodesilylation of Cyclic Allylsilanes[26] Selectfluor (1; 1.1 equiv) NaHCO3 (1.2 equiv)
SiMe2R1
MeCN, rt
OR2
OR2 F
n
n
28
R1
R2 n Time (h) dr
Ph
Ac 2 72
94:6a 69
[26]
Me
Ac 2 72
92:8
a
90
[26]
Ph
Bz 2 72
>98:2
75
[26]
Me
Bz 2 72
>98:2
75
[26]
Me
Bz 1 72
>98:2
79
[26]
a
Yield (%) Ref
Inseparable mixture of diastereomers.
Interestingly, the diastereoselective fluorination of cyclic allylsilanes, prepared by asymmetric Diels–Alder reactions, is excellent for endo-adducts but only moderate for the exoadducts (Scheme 13).[27] Excellent transfer of chirality has also been observed for the fluorination of acyclic allylsilanes which have a stereogenic silylated carbon. The sense of selectivity is consistent with an anti SE2¢ addition of the fluorinating reagent with respect to the silyl group, in which the allylsilane adopts a conformation that minimizes A(1,3) strain (Scheme 13).[27–29] Scheme 13
Diastereoselective Fluorodesilylation of Cyclic and Acyclic Allylsilanes[27,29]
TMS Selectfluor (1; 1.1−1.3 equiv) MeCN, rt, 2−4 h 69%; dr 9:1
F Ph
OH
Ph
OH
Selectfluor (1; 1.5 equiv)
TMS
NaHCO3 (1 equiv) MeCN, rt, 16 h
BnO
OH OBn 2R,3R,4E
F BnO
OH
90%; 93% ee; dr >95:5
OBn 2S,3E,5R; (E/Z) 6:1
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Asymmetric Fluorination and Fluoroalkylation
Selectfluor (1; 1.5 equiv) NaHCO3 (1 equiv) MeCN, rt, 16 h
TMS BnO
OH
F BnO
OH
83%; 93% ee
OBn
OBn
2R,3S,4E
2S,3E,5S; (E/Z) 12:1
Fluorinated Cyclopentenes and Cyclohexenes 28; General Procedure for Diastereoselective Fluorodesilylation of Allylsilanes:[27,29]
To a soln of the allylsilane (1 equiv) in anhyd MeCN was added NaHCO3 (1.1–1.2 equiv) and Selectfluor (1; 1.1–1.5 equiv) and the mixture was stirred at rt for the time indicated in Scheme 12. The solvent was removed and the residue was fractioned between Et2O and sat. NaHCO3. The organic phase was dried (MgSO4), filtered, and concentrated to dryness to afford the crude product, which was purified by column chromatography (silica gel). Diastereoselectivities were determined on the crude material by 1H NMR and 19F NMR spectroscopy. 3.20.1.1.1.6
Preparation of Fluorinated Tetrahydrofurans
The stereoselective synthesis of cis- and trans-fluorinated tetrahydrofurans (e.g., 30) can be achieved by electrophilic fluoroetherification of allylsilanes that contain a pendant alcohol pronucleophile (Scheme 14). For this process, it is important to prevent competitive fluorodesilylation, which restricts the process to alkenes activated by silyl groups other than trimethylsilyl to provide a reactivity profile necessary to facilitate fluorocyclization with Selectfluor (1). The allylsilane functions as a 1,2-dipole and the resulting silane is amenable to oxidative cleavage after the cyclization. The reaction is also stereospecific with respect to the alkene geometry. Thus, the E- and Z-isomers afford the corresponding cis- and trans-diastereomers, respectively. For the allylsilanes 29 [R1,R2 = (CH2)4; R3 = H; R4 = iPr] and 29 [R1,R2 = (CH2)4; R3 = H; R4 = 4-Tol], the stereoselectivity in formation of the two newly formed stereogenic centers (relative stereochemistry) is excellent but the level of stereocontrol observed with respect to the two existing stereogenic centers is modest. Scheme 14
R1 R2
Electrophilic Fluorocyclization of Allylsilanes[30] Selectfluor (1; 1 equiv) NaHCO3 (1 equiv)
R3 SiPri2R4
R3 R1
MeCN, rt
R2
OH 29
F SiPri2R4
O 30
R1
R2
R3
R4
Ratio (E/Z) Ratio (cis/trans) Yield (%) Ref
Me
H
Me
iPr
>20:1
>20:1
72
[30]
Me
H
Me
4-Tol >20:1
>20:1
(CH2)4 (CH2)4 a b
H H
iPr
>20:1
4-Tol >20:1
>20:1
47
[30]
a
83
[30]
b
55
[30]
>20:1
Ratio [trans/cis (C3, C4)] 1.7:1. Ratio [trans/cis (C3, C4)] 1.6:1.
The reaction of the prochiral trisubstituted allylsilane 31 with the chiral N-fluoro reagent derived from the cinchona alkaloid derivative (DHQ)2PHAL (dihydroquinine phthalazine1,4-diyl diether) affords the expected anti-fluoro tetrahydrofuran 32 in 70% yield, albeit
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Fluorination
with modest enantioselectivity (45% ee) (Scheme 15). This is the only example of asymmetric electrophilic fluorocyclization reported to date.[30] Scheme 15 Electrophilic Fluorocyclization of Allylsilanes with an N-Fluoro Reagent Derived from a Cinchona Alkaloid[30] Et
Et N
N
N N O
O
H
H OMe
MeO N
N (DHQ)2PHAL
SiPri2(4-Tol) HO
F
Selectfluor (1)/(DHQ)2PHAL NaHCO3, MeCN, −20 oC, 4 d
Ph
70%; 45% ee; (trans/cis) >20:1
Ph 31
(Z/E) >20:1
O
SiPri2(4-Tol) 32
cis-3-Fluoro-2-(silylmethyl)tetrahydrofurans 30; General Procedure for Electrophilic Fluorocyclization of Allylsilanes:[30]
To a 0.1 M soln of the allylsilane (1 equiv) and NaHCO3 (1 equiv) in MeCN was added Selectfluor (1; 1 equiv). The mixture was stirred for 6 h, after which time the solvent was removed under reduced pressure, the residue was dissolved in Et2O, and sat. NaHCO3 was added. The aqueous phase was extracted with Et2O. The combined organic extracts were dried (MgSO4) and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane/Et2O). 3.20.1.1.2
Enantioselective Electrophilic Fluorination
3.20.1.1.2.1
Reagent-Controlled Enantioselective Fluorination
Pioneering work has demonstrated that chiral N-fluoro reagents can effect asymmetric fluorination.[31,32] Although the level of enantiocontrol is relatively modest with the firstgeneration reagents derived from camphor and 2,3-dihydrobenzisothiazole,[33] a dramatic improvement was observed with the quaternary N-fluoroammonium salts derived from cinchona alkaloids.[34] Two commonly used chiral N-fluoro reagents for enantioselective fluorination are prepared from the monoalkaloid dihydroquinidine acetate (33, DHQDA) and the bisalkaloid derivative dihydroquinine 2,5-diphenylpyrimidine-4,6-diyl diether [34, (DHQ)2PYR] (Scheme 16). These electrophilic fluorinating reagents are accessible by transfer fluorination from Selectfluor (1) to the commercially available cinchona alkaloid derivatives. Using this approach, a wide range of substrates undergo fluorination with high facial enantiocontrol. A very practical approach involves the preparation of the reagent in situ by mixing Selectfluor (1) and the cinchona alkaloid derivative (e.g., 33 or 34) prior to addition of the starting material.[35] For synthetic applications, extensive optimization studies are typically required to identify the optimal alkaloid for each substrate.
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Asymmetric Fluorination and Fluoroalkylation
Scheme 16 Representative Examples of Cinchona Alkaloid Derivatives Used in Enantioselective Fluorination Et
Et
Et N AcO
N H
O
MeO
N
N 33
34
H
N Ph
N
DHQDA
N
O
H
MeO
3.20.1.1.2.1.1
Ph
OMe N
(DHQ)2PYR
Preparation of Æ-Fluorinated Æ-Cyano Esters
The Æ-cyano methyl and ethyl esters 35 are fluorinated to give Æ-fluoro-Æ-cyano esters 36 in moderate to good yields using dihydroquinidine acetate (33, DHQDA)/Selectfluor (1) (Scheme 17). The level of enantiocontrol is excellent with this particular alkaloid but the methodology is only synthetically useful for arylated precursors.[35] Scheme 17 Esters[35]
Enantioselective Fluorination of Acyclic Cyano
DHQDA (33)/Selectfluor (1) MeCN/CH2Cl2 (3:4), −80 oC, 3−6 h
CO2R2 R1
R1
CN 35
R2
eea (%) Yield (%) Ref
4-Tol
Et
87
80
[35]
2-naphthyl
Me
76
87
[35]
Ph
Et
83
81
[35]
4-iPrC6H4
Me
87
82
[35]
4-ClC6H4
Me
68
56
[35]
79
[35]
a
b
CO2R2 CN 36
R1
4-Tol
F
Et
b
85
The absolute configuration was determined only for 36 (R1 = 4-Tol; R2 = Et). The reaction was carried out using recovered DHQDA.
Ethyl Cyano(fluoro)(4-tolyl)acetate (36, R1 = 4-Tol; R2 = Et); Typical Procedure:[35]
A soln of ethyl cyano(4-tolyl)acetate (35, R1 = 4-Tol; R2 = Et; 50 mg, 0.246 mmol) in CH2Cl2 (4 mL) was added at –80 8C to DHQDA (33)/Selectfluor (1) [prepared in situ from DHQDA (33; 181 mg, 0.493 mmol) and 95% Selectfluor (1; 138 mg, 0.370 mmol) in MeCN (3 mL) in the presence of 3- molecular sieves at rt for 1 h]. After the mixture had been stirred for 2 h, H2O was added, and the mixture was extracted with EtOAc. The organic phase was washed with 5% HCl, sat. NaHCO3, and brine, and dried (Na2SO4). The solvent was removed under reduced pressure to give a crude oil, which was purified by preparative TLC (silica gel); yield: 43.5 mg (80%); 87% ee [by HPLC (Chiralcel OJ column, iPrOH/hexane 1:99)].
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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3.20.1.1.2.1.2
Stereoselective Fluorination
865
Preparation of Fluorinated Keto Esters, Indolones, and Allylsilanes
The reagent-controlled asymmetric fluorination of keto esters, indolones, and allylsilanes is also possible using in situ generated chiral N-fluoro reagents derived from cinchona alkaloids. The level of enantiocontrol is highly dependent on the structural features within the starting material. A selection of substrates 37 that perform well in the asymmetric fluorination with these reagents is outlined in Table 2. The fluorination reaction is typically high yielding with selectivities ranging from 76 to 96% enantiomeric excess. As for the previously described Æ-cyano esters 35, -keto esters (Table 2, entries 1 and 2), indolones (entries 5 and 6), and substituted phthalimido esters and nitriles (Table 2, entries 3 and 4) are sufficiently reactive to be fluorinated without preactivation as either a silyl enol ether or enolate. Interestingly, this is not the case for Æ-substituted indanones (Table 2, entry 7), which require enolization and silylation prior to fluorination. A series of indene- and naphthalene-derived allylsilanes also undergo fluorination under mild conditions with up to 96% enantiomeric excess (Table 2, entries 8–10).[21]
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Asymmetric Fluorination and Fluoroalkylation
3.20
Table 2 Enantioselective Fluorination of Cyclic -Keto Esters, Phthalimido Esters and Nitriles, Indolones, Silyl Enol Ethers, and Allylsilanes[21,35,36] Et
Et
Et N
N
N
O O
H
MeO
MeO
H
O
OMe
O N
N
Cl
N
O
O
H
(DHQ)2AQN
DHQB
Et
Et N
N
Ph O
H MeO
O N Ph
N
H
N
OMe N
(DHQD)2PYR
X R1
X R2
R1
F R2
37
Entry Starting Material
Conditions
Product
O
1
ee (%)
Yield (%)
Ref
78a
89
[35]
80a
92
[35]
76
86
[36]
92
65
[36]
78a
100
[35]
O CO2Et
DHQDA (33)/Selectfluor (1), MeCN/CH2Cl2, –80 8C
CO2Et F
O
O
2
CO2Et
DHQDA (33)/Selectfluor (1), MeCN/CH2Cl2, –80 8C
CO2Et
O
O CO2Et
3
N Ph
1. LiHMDS, THF 2. isolated N-fluoro DHQB, –78 8C
F Ph O
O
O CN
N Ph
1. LiHMDS, THF 2. isolated N-fluoro DHQB, –78 8C
F Ph O
Bn
F O
N H
CN
N
O
5
CO2Et
N
O
4
F
O
O
Bn
(DHQ)2AQN/Selectfluor (1), MeCN, 0 8C
O N H
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.20.1
Table 2
867
Stereoselective Fluorination
(cont.)
Entry Starting Material
Conditions
PMB
6
F
O
ee (%)
Yield (%)
Ref
O
82a
79
[35]
Bn
89
99
[35]
96
>95b
[21]
83
>95b
[21]
87a
>95b
[21]
PMB
(DHQD)2PYR/Selectfluor (1), MeCN, 0 8C N H
N H OTMS
7
Product
Bn
O
DHQB/Selectfluor (1), MeCN, –20 8C
F
TMS
8 Bn
(DHQ)2PYR (34)/Selectfluor (1), MeCN, –20 8C
Bn F
TMS
9
Bn
(DHQ)2PYR (34)/Selectfluor (1), MeCN, –20 8C
Bn F
SiPh3
10
a b
(DHQ)2PYR (34)/Selectfluor (1), MeCN, –20 8C
F
Absolute configuration was not determined. Conversion.
Fluorinated Indenes and Naphthalenes (Table 2, Entries 8–10); General Procedure for Enantioselective Fluorodesilylation of Allylsilanes:[21]
A soln of the alkaloid derivative (0.09 mmol) in anhyd MeCN (2 mL) containing 4- molecular sieves was treated at rt with Selectfluor (1; 32 mg, 0.09 mmol). The resulting soln was stirred at rt for 1 h, and then placed in a cryostat at –20 8C. A soln of the allylsilane (0.075 mmol) in MeCN (2 mL), also at –20 8C, was added dropwise to the alkaloid/Selectfluor (1) reagent. The resulting soln was allowed to stir at –20 8C and the reaction was followed by TLC and HPLC. The mixture was poured into a separating funnel containing sat. NaHCO3 (10 mL). The product was extracted into Et2O (3 10 mL) and the combined organic phases were dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was subjected to chiral HPLC and the conversion and enantiomeric excesses were determined by comparison to racemic references. 3.20.1.1.2.2
Catalytic Enantioselective Fluorination
Complementing strategies relying on the use of chiral reagents, catalytic asymmetric fluorinations have been developed using either transition-metal complexes or organocatalysts.
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.20.1.1.2.2.1
Catalytic Asymmetric Fluorination Mediated by Chiral Metal Complexes
3.20
Asymmetric Fluorination and Fluoroalkylation
Various substrates that undergo two-point binding with chiral metal complexes successfully undergo asymmetric fluorination reactions. Pioneering work has demonstrated that titanium(IV)–Æ,Æ,Æ¢,Æ¢-tetraphenyl-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol (TADDOL) complexes of -keto esters undergo electrophilic fluorination with Selectfluor (1) in acetonitrile, to provide the fluorinated products in up to 90% enantiomeric excess.[37] This method paved the way for the development of numerous metal-mediated asymmetric protocols. The most commonly employed transition-metal catalysts for asymmetric fluorination are palladium (e.g., 38–45),[38–44] nickel (e.g., 46),[45,46] and copper (e.g., 47)[47] complexes (Scheme 18). Chiral Palladium, Nickel, and Copper Complexes[38–47]
Scheme 18
Ar1 Ar1 P 2+ OH2 Pd HP OH2 Ar1 Ar1 38
Ph Ph P 2+ OH2 Pd P OH2 Ph Ph 39
Ar1 = 3,5-Me2C6H3
Ar1 Ar1
H O
O
Ar1 Ar1
P + + P Pd Pd P P O H Ar1 Ar1 Ar1 Ar1
2X−
Ar1 Ar1
H O
Ar1 Ar1
P + + P Pd Pd P P O H Ar1 Ar1 Ar1 Ar1
O O O
40
O
41
O
Ar1 Ar1 H P + O + P Pd Pd P P O H Ar1 Ar1 Ar1 Ar1
O O
2X−
O
Ar1 = 3,5-t-Bu2-4-MeOC6H2
Ar1 Ar1
O
Ar1 Ar1 H P + O + P Pd Pd P P O H Ar1 Ar1 Ar1 Ar1
2X−
O
O
O
O
Ar1 = 3,5-Me2C6H3
Ar1 Ar1
O
2X−
O 42
44
Ar1 = 3,5-Me2C6H3
43
Ar1 = 3,5-Me2C6H3
Ar1 Ar1
Ph Ph
P 2+ OH2 2X− Pd P NCMe Ar1 Ar1
P 2+ OH2 2X− Pd P NCMe Ph Ph 45
Ar1 = 3,5-Me2C6H3
Ph Ph Cl
P Ni P Ph Ph 46
Cl
O
O N
Cu
Ph TfO
N OTf Ph
47
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Fluorination
Additional work has demonstrated that catalytic palladium–2,2¢-bis(diphenylphosphino)1,1¢-binaphthyl (BINAP) complexes[48] are superior to titanium(IV)–TADDOL complexes for the fluorination of -keto esters, tert-butoxycarbonyl lactones, -keto phosphonates, and indolones. Acetonitrile(aqua){(R)-2,2¢-bis[bis(3,5-dimethylphenyl)phosphino]-1,1¢-binaphthyl}palladium(II) Tetrafluoroborate (44, X = BF4):[41]
To a soln of PdCl2[(R)-XylBINAP] (99.1 mg, 0.1086 mmol) in CH2Cl2 (6 mL) was added AgBF4 (52.8 mg, 0.2715 mmol) in MeCN (3.0 mL) at rt and the mixture was stirred for 21 h. The precipitated AgCl was filtered off (Celite), and the filtrate was concentrated under reduced pressure. The product was recrystallized (CH2Cl2/Et2O) to afford the palladium complex 44 (X = BF4) as a yellow powder; yield: 72.8 mg (62%); mp 159–160 8C; [Æ]D20 +512 (c 0.5, CHCl3); 1H NMR (200 MHz, CDCl3, ): 1.98 (br s, 15H), 2.43 (s, 12H), 3.70 (br s, 2H), 6.38–6.58 (m, 4H), 7.12–7.77 (m, 20H). 3.20.1.1.2.2.1.1
Fluorination of -Keto Esters and Lactones with Palladium Catalysts
The reactions of -keto esters (e.g., 48) with N-fluorobenzenesulfonimide (2), in the presence of 2.5 mol% of palladium catalyst 38, 40, or 41, provide the Æ-fluoro -keto esters (e.g., 49) in high yield and with excellent levels of enantiocontrol (Scheme 19).[38] Importantly, the palladium complexes can be immobilized in ionic liquids with no loss of efficiency, which permits the catalysts to be recycled (up to 10 times).[39] Scheme 19
Catalytic Enantioselective Fluorination of -Keto Esters[38]
O CO2But
R1
2.5 mol% Pd catalyst (PhSO2)2NF 2 (1.5 equiv) EtOH (1 M)
O
R2
R2 48
R1
CO2But
R1
F 49
R2
Catalyst
Temp (8C) Time (h) ee (%) Yield (%) Ref
(CH2)3
41 (X = OTf )
20
18
92
90a
[38]
(CH2)4
40 (X = BF4) –10
20
94
91
[38]
40 (X = OTf ) –20
36
83b
85
[38]
[38]
Ph
Me
40 (X = BF4)
20
40
91
92
Me
Et
40 (X = OTf )
20
42
87
88
(CH2)4 Ph a b c d
Me
c
[38]
40 (X = BF4)
0
20
91
82
[38]
38 (X = OTf )
20
48
91
96d
[38]
iPrOH was used instead of EtOH. The absolute configuration was determined to be R. 1 mol% of the catalyst and a 2.5 M soln of the substrate were used. 1-g scale.
tert-Butoxycarbonyl ª-lactones [e.g., 50 (n = 1)] are amenable to enantiocontrolled palladium-catalyzed fluorination to afford the corresponding Æ-fluoro ª-lactones [e.g., 51 (n = 1)] in good yield and with moderate enantiomeric excess. For tert-butoxycarbonyl ª-lactams, both the yields and the enantioselectivity are much less satisfactory. Although the facial
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Asymmetric Fluorination and Fluoroalkylation
selectivity for the asymmetric fluorination of tert-butoxycarbonyl -lactone [50 (n = 2)] is excellent with palladium catalyst 41 (X = OTf ), the yield does not exceed 35%, which diminishes its synthetic utility (Scheme 20).[40] Scheme 20 Catalytic Enantioselective Fluorination of tert-Butoxycarbonyl Lactones[40] O CO2But
O
Pd catalyst (PhSO2)2NF 2 (1.5 equiv) iPrOH (1 M), rt
O F O
CO2But
n
n
50
51
n
Catalyst (mol%)
1
38 (X = OTf ) (5)
6
79
96
1
39 (X = OTf ) (5)
6
77
79
2 a
b
Time (h) ee (%) Yield (%) Ref
41 (X = OTf ) (2.5) 27
a
97
35
[40] [40] a,b
[40]
Isolated yield and ee value after reductive ring opening. The reaction was carried out in t-BuOH.
Æ-Fluoro--keto Esters 49; General Procedure for Catalytic Enantioselective Fluorination of -Keto Esters:[38] To a soln of the palladium complex 38 (0.01 mmol), 40 (0.005 mmol), or 41 (0.005 mmol) in EtOH (0.2 mL) was added the -keto ester 48 (0.2 mmol) at rt and the mixture was stirred for 5 min at the temperature indicated in Scheme 19. N-Fluorobenzenesulfonimide (2; 95 mg, 0.3 mmol) was added and the mixture was allowed to stir for the designated time in Scheme 19. After completion of the reaction (TLC, benzene/Et2O 5:1) (CAUTION: carcinogen), the reaction was quenched with sat. NH4Cl (3 mL). The aqueous layer was extracted with Et2O (3 10 mL) and the combined organic layers were washed with H2O and brine. After drying (Na2SO4), the solvent was removed under reduced pressure. Further purification was performed by flash column chromatography (silica gel, hexane/Et2O 10:1) to give the pure product 49. The ee was determined by chiral stationary phase HPLC analysis.
Æ-(tert-Butoxycarbonyl)-Æ-fluoro Lactones 51; General Procedure for Catalytic Enantioselective Fluorination of Æ-(tert-Butoxycarbonyl) Lactones:[40] Lactone 50 (0.2 mmol), N-fluorobenzenesulfonimide (2; 0.3 mmol), and the palladium complex listed in Scheme 20 (0.01 mmol or 0.005 mmol) were dissolved in EtOH (0.2 mL). To this suspension was added 2,6-lut (0.1 mmol) and the mixture was stirred at rt for the time indicated in Scheme 20. The reaction was monitored by TLC analysis. The reaction was quenched with sat. NH4Cl and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried (Na2SO4). Removal of the solvent followed by column chromatography (silica gel, hexane/EtOAc) afforded the product 51. The ee was determined by chiral stationary phase HPLC analysis. 3.20.1.1.2.2.1.2
Fluorination of -Oxo Phosphonates with Palladium Catalysts
-Oxo phosphonates constitute an additional class of substrates that allow two-point binding with a chiral metal complex for enantioselective fluorination. Treatment of several acyclic and cyclic substrates (e.g., 52) with N-fluorobenzenesulfonimide (2) in the presence of 5 mol% of palladium catalyst 44 furnished the Æ-fluoro--oxo phosphonates
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.20.1
871
Stereoselective Fluorination
(e.g., 53) in good yield and with excellent enantiomeric excess (Scheme 21).[41] Various other palladium complexes can also be used for this process with analogous results.[42] Scheme 21
Enantioselective Fluorination of -Oxo Phosphonates[41] 5 mol% 44 ( X = BF4)
O
O P(OEt)2
R1
O
(PhSO2)2NF 2 (1.5 equiv) solvent
O P(OEt)2
R1 R
R2 52
2
F 53
R1
R2
Solvent Time (h) ee (%) Yield (%) Ref
MeOH
8
97
93
[41]
MeOH
10
95
92
[41]
MeOH
3
97
91
[41]
MeOH
11
95
86
[41]
(CH2)3
MeOH
45
95
67
[41]
(CH2)4
MeOH
86
95
73
[41]
MeO
MeO MeO
4-ClC6H4
Me
THF
94
91
68
[41]
4-O2NC6H4
Me
THF
90
87
78
[41]
(E)-CH=CHMe
Me
THF
58
93
79
[41]
Æ-Fluoro--oxo Phosphonates 53; General Procedure for Catalytic Fluorination of -Oxo Phosphonates:[41] To a stirred soln of -oxo phosphonate 52 (0.3 mmol) and palladium catalyst 44 (X = BF4; 16.1 mg, 0.015 mmol) in MeOH or THF (3 mL) was added N-fluorobenzenesulfonimide (2; 141.9 mg, 0.45 mmol) at rt. The mixture was stirred for the time designated in Scheme 21 at rt. The mixture was diluted with sat. NH4Cl (30 mL) and extracted with Et2O (2 30 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and purified by column chromatography (silica gel) to afford the Æ-fluoro--oxo phosphonate 53. The ee was determined by chiral stationary phase HPLC analysis. 3.20.1.1.2.2.1.3
Fluorination of Æ-Cyano tert-Butyl Esters with Palladium Catalysts
The catalytic asymmetric fluorination of Æ-cyano esters (e.g., 54) has been investigated, using the palladium–2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl (BINAP) catalyst 45 and N-fluorobenzenesulfonimide (2) as the electrophilic fluorine source.[43] Various tertbutyl Æ-cyano-Æ-fluoro esters 55 are obtained in moderate to excellent yield and with similar enantioselectivity (Scheme 22). The tert-butyl ester is crucial for obtaining optimal lev-
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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els of asymmetric induction, since the selectivity with methyl, ethyl, and benzyl esters is significantly lower. Importantly, although the Æ-aryl derivatives react under these reaction conditions, the Æ-alkyl cyanoacetates are unreactive. Scheme 22
Catalytic Enantioselective Fluorination of tert-Butyl Æ-Cyano Esters[43] 5 mol% 45 (PhSO2)2NF 2 (1 equiv) MeOH
CO2But Ar1
CO2But CN
Ar1
CN 54
F 55
Ar1
Catalyst
Ph
45 (X = PF6) 0
60
99
83
[43]
4-ClC6H4
45 (X = PF6) rt
17
85
94
[43]
4-Tol
45 (X = PF6) 0
60
93
85
[43]
4-MeOC6H4
45 (X = BF4) 0
72
99
85
[43]
2-naphthyl
45 (X = PF6) 0
60
93
88
[43]
Temp (8C) Time (h) ee (%) Yield (%) Ref
tert-Butyl Æ-Cyano-Æ-fluoro Esters 55; General Procedure for Catalytic Enantioselective Fluorination of tert-Butyl Æ-Cyano Esters:[43]
To a stirred soln of the tert-butyl Æ-cyano ester 54 (0.3 mmol), catalyst 45 (X = PF6 or BF4; 16.2 mg, 0.015 mmol) in MeOH (3 mL) was added N-fluorobenzenesulfonimide (2; 94.6 mg, 0.3 mmol) at the temperature indicated in Scheme 22. The mixture was stirred for 17–72 h at the same temperature. The mixture was diluted with sat. NH4Cl (20 mL) and extracted with Et2O (2 20 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and purified by column chromatography (silica gel, EtOAc/hexane 1:15). 3.20.1.1.2.2.1.4
Fluorination of Indolones with Palladium Catalysts
Chiral, nonracemic Æ-fluorinated indolones have many applications in the field of medicinal chemistry.[49] In this context, the palladium catalyst 43 has proven optimal for the enantioselective fluorination of various indolones (e.g., 56) to the corresponding Æ-fluoroindolones (e.g., 57) (Scheme 23). The nitrogen-protecting group is critical for achieving high levels of enantiocontrol, in which the asymmetric fluorination of the N-tert-butoxycarbonyl derivatives is considerably better than the unprotected indolones. The reaction tolerates both aryl and alkyl substituents at C3, and the reactions are operationally simple, so they can be performed without exclusion of air and moisture.[44] Scheme 23
Catalytic Enantioselective Fluorination of Indolones[44] 2.5 mol% 43 (X = OTf) (PhSO2)2NF 2 (1.5 equiv) iPrOH (1 M)
R1
R1
F
O N
O N
Boc 56
(rac)
Boc 57
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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R1
Temp (8C) Time (h) ee (%) Yield (%) Ref
Ph
0
4-Tol
18
90
96
[44]
3
86
97
[44]
18
88
92
[44]
20–23
4-Tol
0
4-FC6H4
20–23
3
84
94
[44]
Me
20–23
5
95
86
[44]
18
96
85
[44]
Me
0
Et
20–23
10
92
85
[44]
CH2C(O)Me
20–23
2
86
85
[44]
3-Fluoro-1,3-dihydro-2H-indol-2-ones 57; General Procedure for Catalytic Enantioselective Fluorination of 1,3-Dihydro-2H-indol-2-ones:[44]
Racemic indolones 56 (0.2 mmol) were dissolved in iPrOH (0.2 mL). To this soln was added the palladium complex 43 (X = OTf; 0.005 mmol), followed by N-fluorobenzenesulfonimide (2; 0.3 mmol) at 0 8C or rt. The mixture was stirred at the same temperature for the time indicated in Scheme 23. The reaction was quenched with sat. NH4Cl (3 mL) and the aqueous layer was extracted with EtOAc (3 10 mL). The combined organic layers were washed with H2O and brine. After drying (Na2SO4), the solvent was removed under reduced pressure. Further purification by column chromatography (silica gel, hexane/ EtOAc) gave the pure product. The ee was determined by chiral stationary phase HPLC analysis. 3.20.1.1.2.2.1.5
Fluorination of Æ-Aryl Acetic Acid Derivatives with Nickel Catalysts
A catalytic asymmetric fluorination of Æ-arylacetic acids derivatized with an ancillary thiazolidinone, using the nickel-based triadic system nickel(II)/2,2¢-bis(diphenylphosphino)1,1¢-binaphthyl (BINAP)/trimethylsilyl trifluoromethanesulfonate/2,6-lutidine, has also been developed.[45] The fluorination of N-acyloxazolidinones [e.g., 58 (X = O)] and -thiazolidinones [e.g., 58 (X = S)] with N-fluorobenzenesulfonimide (2) proceeds in excellent yields and with high enantiofacial control for a wide range of Æ-aryl-substituted derivatives (Table 3). The subsequent conversion of the fluorinated products 59 into the corresponding carboxylic acids, esters, and Weinreb amides proceeds without any racemization as shown in Scheme 24 for 3-[(R)-fluoro(phenyl)acetyl]thiazolidin-2-one. Nevertheless, this method is particularly inefficient with 3-alkanoylthiazolidin-2-ones (Table 3, entry 7), probably due to their inability to enolize under the reaction conditions.[45] Table 3
Catalytic Enantioselective Fluorination of Æ-Arylacetic Acid Derivatives[45]
R1
NiCl2(BINAP) 46 (PhSO2)2NF 2 (1.5 equiv), TESOTf toluene, −20 oC, 10 min
O
O N
O
O R
1
N
X
X
F 58
59
(rac)
Entry X R1
Catalyst 46 (mol%)
TESOTf (equiv)
ee (%)
Yield (%)
Ref
1
S Ph
5
0.75
88
99
[45]
2
S 4-FC6H4
5
0.75
83
90
[45]
3
S 3-MeOC6H4
10
1.5
82
95
[45]
4
S 2-naphthyl
10
1.5
83
99
[45]
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis Table 3
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Asymmetric Fluorination and Fluoroalkylation
(cont.)
Entry X R1
Catalyst 46 (mol%)
TESOTf (equiv)
ee (%)
Yield (%)
Ref
5
0.75
87
94
[45]
5
S 1-naphthyl
6
O Ph
10
1.5
87
95
[45]
7
S Pr
10
1.5
11
15
[45]
Scheme 24 Racemization-Free Conversion of Fluorinated Products into Carboxylic Acids, Esters, and Weinreb Amides[45] MeNH(OMe)•HCl (3 equiv) Me3Al (3 equiv), CH2Cl2
O
O
0 oC, 3 h
Ph
N
S
O OMe
Ph
N
88%
F
F
1. LiOH, H2O2, THF, H2O 0 oC, 2 h
O
O
2. TMSCHN2, MeOH, rt
Ph
N F
S
Me
O Ph
OMe
83%
F
3-[(2R)-2-Fluoro-2-phenylacetyl]thiazolidin-2-one (Table 3, Entry 1); Typical Procedure:[45]
CAUTION: Triethylsilyl trifluoromethanesulfonate causes burns. 3-(2-Phenylacetyl)thiazolidin-2-one (58, R1 = Ph; 22 mg, 0.1 mmol), the nickel complex 46 (3.8 mg, 0.005 mmol, 5 mol%), and N-fluorobenzenesulfonimide (2; 47.4 mg, 0.15 mmol) were placed in a dry reaction tube. Toluene (0.1 mL) and TESOTf (17 mL, 0.75 equiv) were added at –20 8C under N2. After 10 min, 2,6-lut (18 mL, 0.15 mmol) was added and the resulting mixture was stirred at –20 8C for 24 h. Brine was then added to quench the reaction and the aqueous layer was extracted with EtOAc (3 5 mL). The combined organic layers were washed with brine and dried (Na2SO4). The solvent was removed and the crude product was purified by column chromatography (silica gel, hexane/CHCl3/EtOAc 5:1:1) to afford the product as a white solid; yield: 99%; 88% ee. 3.20.1.1.2.2.1.6
Enantioselective Fluorination of 1,3-Dicarbonyl Derivatives Capable of Two-Point Binding with Nickel Catalysts
The combination of the chiral tridentate ligand (R,R)-dibenzofuran-4,6-diyl-2,2¢-bis(4-phenyl-4,5-dihydrooxazole) [(R,R)-DBFOX-Ph], nickel(II) perchlorate hexahydrate, and N-fluorobenzenesulfonimide (2) promotes the enantioselective electrophilic fluorination of various cyclic carbonyl compounds (e.g., 60), which are capable of undergoing twopoint binding with the catalyst. The asymmetric fluorination of a series of -keto esters and tert-butoxycarbonyl-protected indolones affords the desired products 61 in high yield and with excellent enantioselectivity. MaxiPost, an effective opener of maxi-potassium channels by cleavage of the tert-butoxycarbonyl group has been prepared successfully in high enantiomeric excess using this method (Table 4, entry 9).[46]
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Table 4 Catalytic Enantioselective Fluorination of 1,3-Dicarbonyl Derivatives Capable of Two-Point Binding with Nickel Catalysts[46]
O
∗
(R,R)-DBFOX-Ph (0.11 equiv) Ni(ClO4)2 (0.1 equiv) CH2Cl2, 4-Å molecular sieves rt, 2−35 h
BS
R1
∗
L
L Ni
O
BS
R1 R2
R3 R2
60
R3
O (PhSO2)2NF 2 (1.2 equiv)
R1
F
BS
∗
R2
R3 61
O O
N
N
Ph
Ph
O
(R,R)-DBFOX-Ph BS = Binding site
Entry Reactant
Product
Time (h)
ee (%)
Yield (%)
Ref
3
99
76a
[46]
6
99
93a,b
[46]
3
95
88
[46]
2
93
84
[46]
2
99
86
[46]
O
O
F
1
CO2But
CO2But O
O
F
2
CO2But CO2 O
But
O O O
F
O
3
O
O
4
O F
But
CO2
CO2But O
5
O CO2But
F CO2But
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis Table 4
3.20
(cont.)
Entry Reactant
O
6
Asymmetric Fluorination and Fluoroalkylation
Product
O
Et
Ph O
O Ph
O
Et
Time (h)
ee (%)
Yield (%)
Ref
18
83
75
[46]
35
93
73
[46]
5
96
72
[46]
14
93
71a
[46]
Ph O
Ph
F F
7
O
O
N
N
Boc
Boc
Ph
8
F
Ph O
O N
N
Boc
Boc Cl
MeO
Cl
F
MeO
9 O O F3C
N
F3C
N Boc
Boc a b
The (S)-isomer was obtained. (R,R)-DBFOX-Ph (0.02 equiv) and Ni(ClO4)2•6H2O (0.02 equiv) were used.
2-Fluoro-1,3-dicarbonyl Compounds (Table 4, Entries 1–6) and 3-Fluoro-1,3-dihydro2H-indol-2-ones (Table 4, Entries 7–9); General Procedure for Catalytic Enantioselective Fluorination of 1,3-Dicarbonyl Derivatives Capable of Two-Point Binding with a Nickel Catalyst:[46]
CAUTION: Nickel(II) perchlorate is a strong oxidant and it should be handled with care when the reaction is performed on a very large scale. Ni(ClO4)2•6H2O (10 mol%) and (R,R)-DBFOX-Ph (11 mol%) were stirred under reduced pressure for 2 h at rt. Anhyd CH2Cl2 (1 mL) and 4- molecular sieves (50–100 mg) were added under N2 and stirred for 1 h. Then, a soln of the substrate (0.10–0.20 mmol) in anhyd CH2Cl2 (2 mL) was added to the catalyst soln. After stirring for another 30 min, N-fluorobenzenesulfonimide (2; 1.2 equiv) was added directly to the mixture. The mixture was stirred at rt for 1 h to overnight (TLC); it was quenched by addition of H2O. The mixture was then diluted with CH2Cl2, washed with sat. NaHCO3, brine, and dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EtOAc) to give the fluorinated product. The ee of the product was determined by chiral HPLC. 3.20.1.1.2.2.1.7
Sequential Nazarov–Fluorination with Copper Catalysts
Copper(II) complexes have proven to be effective for a series of Nazarov cyclizations followed by electrophilic fluorination with N-fluorobenzenesulfonimide (2), to provide the Æ-fluoroindanones (e.g., 62) with high levels of enantio- and diastereocontrol. In the absence of a chiral ligand the trans-diastereomers are formed preferentially (dr >49:1) in
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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good yield (Scheme 25). Preliminary attempts to extend this protocol to a catalytic enantioselective transformation are promising as the enantioenriched fluoroindanones are formed with up to 95.5% enantiomeric excess in the presence of copper catalyst 47 (Scheme 26).[47] Scheme 25
Catalytic Diastereoselective Sequential Nazarov–Fluorination[47] O
O
R3
10 mol% Cu(OTf)2
OR1
R4
O
(PhSO2)2NF 2 (1.2 equiv) 1,2-dichloroethane, 80 oC, 8 h
R3
R2
F O
R4 R2
OR1
62
R1
R2
Me
4-MeOC6H4
OCH2O
32:1
95
[47]
Me
3,4,5-MeOC6H2
OCH2O
>49:1
82
[47]
Me
2,4,6-MeOC6H2
OCH2O
32:1
78
[47]
Me
2-MeOC6H4
OCH2O
24:1
67
[47]
Me
4-ClC6H4
H
H
24:1
82
[47]
Me
4-O2NC6H4
H
H
19:1
84
[47]
Et
2,4,6-MeOC6H2
OMe H
19:1
85
[47]
a
R3
1
R4
Ratio (trans/cis)a Yield (%) Ref
19
Determined by H NMR or F NMR spectroscopy.
Scheme 26
Catalytic Enantioselective Tandem Nazarov–Fluorination[47] O
O
O O
OMe
10 mol% 47 (PhSO2)2NF 2 (1.2 equiv) 1,2-dichloroethane, 80 oC, 8 h
O O O
Ar1
F O Ar1 OMe
Ar1
Ratio (trans/cis) eea (%) Yield (%) Ref
2,4,6-MeOC6H2
>49:1
95.5
80
[47]
19:1
43.5
69
[47]
2-MeOC6H4 a
For the trans-isomer.
Methyl (5R,6S)-6-Fluoro-5-(4-methoxyphenyl)-7-oxo-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxole-6-carboxylate (62, R1 = Me; R2 = 4-MeOC6H4; R3, R4 = OCH2O); Typical Procedure:[47]
Under a positive pressure of argon at rt, Cu(OTf )2 (8.0 mg, 0.022 mmol), methyl (2Z)-2-(1,3benzodioxol-5-ylcarbonyl)-3-(4-methoxyphenyl)prop-2-enoate (75.3 mg, 0.22 mmol), and N-fluorobenzenesulfonimide (2; 83.7 mg, 0.27 mmol) were dissolved in 1,2-dichloroethane (3 mL) in a 15-mL Schlenk flask. The resulting mixture was stirred at 80 8C. After 8 h, the mixture was cooled to rt and purified by column chromatography [silica gel, EtOAc/ petroleum ether (60–90 8C) 1:9 to 1:4 gradient] to furnish the product as a white solid; yield: 75.3 mg (95%).
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3.20.1.1.2.2.2
Catalytic Enantioselective Fluorination Mediated by Organocatalysts
3.20.1.1.2.2.2.1
Organocatalytic Fluorination of Aldehydes: Preparation of Æ-Fluoro Aldehydes, -Fluoro Alcohols, and Propargylic Fluorides
Asymmetric Fluorination and Fluoroalkylation
3.20
Enamine catalysis provides an organocatalytic strategy for the enantioselective fluorination of aldehydes to generate Æ-fluoro aldehydes, in addition to the corresponding Æ-fluoro alcohols and propargylic fluorides. These reactions are currently not applicable to the fluorination of less activated substrates (e.g., ketones, esters, and aldehydes). Pioneering work validated the feasibility of this strategy using Selectfluor (1) as the fluorine source and proline as the organocatalyst,[50] albeit with a level of enantiocontrol that was rather poor. Subsequent contributions have demonstrated that N-fluorobenzenesulfonimide (2) is a better fluorinating reagent than Selectfluor (1) using organocatalysts (S)-63, (R)-63, and (S)-64 (Scheme 27). Scheme 27
Organocatalysts for Asymmetric Fluorination[50–53] F3C
CF3 CF3
O
O MeN
NMe
Ph
Ph N H •Cl2CHCO2H
N H (S)-63
N H OTMS
CF3
(S)-64
(R)-63
The enantiofacial control has been attributed to a closed transition state, which involves sulfone–proton bonding and concomitant fluorine/enamine activation (Scheme 28).[51] Scheme 28 Proposed Mechanism for the Organocatalytic Direct Æ-Fluorination of Aldehydes[51] O H
R
1
+
O
secondary amine enamine catalysis
O O O O S S Ph Ph N
R1
H
F
F
2
secondary amine
N
X H O
R1
(PhSO2)2NF 2
R1 O O N F O S H Ph N S O O X Ph
Organocatalyst (R)-63 has been used for the enantioselective Æ-fluorination of several aldehydes bearing a wide variety of functional groups, including alkenes, esters, amines, carbamates, and aryl substituents. The reactions are typically performed at either –10 8C or room temperature using a 2.5–20 mol% catalyst loading. Due to the volatility of some of these chiral fluorinated aldehydes, they are reduced with sodium borohydride to facilitate isolation as the corresponding (R)--fluorinated alcohols (R)-65 (Scheme 29). In all cases, good yields and excellent enantioselectivities are obtained. Various solvent systems are suitable for the fluorination, including tetrahydrofuran, acetonitrile, acetone, and ethyl acetate, but only in the presence of propan-2-ol (10%).[51] Similar data have been reported using 1 mol% of the silylated prolinol catalyst (S)-64; in this case, the (S)--fluorinated alco-
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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hols (S)-65 are formed (Scheme 29).[52] This strategy has been extended to the enantioselective organocascade catalysis of several Æ,-unsaturated aldehydes to afford the corresponding chiral Æ-fluorinated aldehydes in moderate yield with excellent enantioselectivities (up to 99% ee). This process involves the creation of two stereogenic centers in a onepot process, making it an attractive synthetic strategy.[54] Scheme 29
Enantioselective Æ-Fluorination of Several Aldehydes[51,52] 1. 20 mol% (R)-63, (PhSO2)2NF 2 (5 equiv) THF/iPrOH, −10 oC 2. NaBH4, CH2Cl2
R1
HO F (R)-65
O R1
H
1. 1 mol% (S)-64, (PhSO2)2NF 2 (1 equiv) t-BuOMe, rt 2. NaBH4, MeOH
R1
HO F (S)-65
R1
Organocatalysta
Time (h)
Product eeb (%)
Yieldc (%)
Ref
(CH2)8Me
(R)-63
10
(R)-65
94
70
[51]
(CH2)7CH=CH2
(R)-63
10
(R)-65
94
79
[51]
CH4CH=CHEt
(R)-63
10
(R)-65
94
81
[51]
96
[51]
85
[51]
71
[51]
Cy
(R)-63
12
(R)-65
99
N-(tert-butoxycarbonyl)piperidin-4-yl
(R)-63
12
(R)-65
98
d
d
Bn
(R)-63
12
(R)-65
96
1-adamantyl
(R)-63
12
(R)-65
98
82
[51]
Pr
(S)-64
6
(S)-65
96 >95
[52]
Bu
(S)-64
28
(S)-65
91 >90
[52]
t-Bu
(S)-64
2
(S)-65
97 >90
[52]
a b
c d
Conditions for each organocatalyst as indicated in the scheme. Enantiomeric excess determined by chiral HPLC of the 2-naphthoyl derivative (Chiralcel OJ) unless otherwise indicated. Yields based on GC analysis of the crude product. Enantiomeric excess determined by chiral GLC analysis.
The direct enantioselective Æ-fluorination of several linear aldehydes has also been studied, with imidazolidinone (S)-63 as the chiral promoter and N-fluorobenzenesulfonimide (2) as the source of fluorine. In all cases, the yields and enantiomeric excesses are excellent (>86%). This methodology has also been applied to branched aldehydes, which afford quaternary Æ-fluoro aldehydes in high yield but with modest enantioselectivity (up to 66% ee). Finally, the enantioselective fluorinations can be conducted in an array of solvents, such as tetrahydrofuran, dimethylformamide, methanol, and 1,4-dioxane.[55] A synthetically useful extension of the catalytic asymmetric fluorination of aldehydes is to couple the fluorination event with an alkynylation or alkenylation of the resulting enantioenriched fluoro aldehyde. This strategy provides a convenient approach for the preparation of various chiral, nonracemic propargylic and allylic fluorides, respectively.[53] The one-pot organocatalytic Æ-fluorination of aldehydes followed by in situ treatment with the Ohira–Bestmann reagent (dimethyl 1-diazo-2-oxopropylphosphonate) pro-
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Asymmetric Fluorination and Fluoroalkylation
vides the optically active propargylic fluorides (e.g., 66) using the silylated prolinol catalyst (S)-64 (Scheme 30). In all cases, the enantioselectivities are excellent, although the yields are relatively modest. Scheme 30 Formation of Optically Active Propargylic Fluorides from Aldehydes[53] 1. 1 mol% (S)-64 Ohira−Bestmann reagent (1.32 equiv) (PhSO2)2NF 2 (1 equiv), t-BuOMe, rt
O R1
R1
2. MeOH, K2CO3, rt
H
F 66 O
O P(OMe)2
Ohira−Bestmann reagent = N2
R1
Time (h) ee (%) Yield (%) Ref
(CH2)7Me
4
93
67
[53]
(CH2)13Me
5
99
65
[53]
4-MeOC6H4CH2
8
91
65
[53]
4-BrC6H4CH2
8
92
69
[53]
2-MeOC6H4CH2
8
99
58a
[53]
a
Contaminated with 5% difluorinated product.
These optically active propargylic fluorides provide interesting intermediates that can be further functionalized. For example, click reactions with organic azides provide enantioenriched heterocycles.[53] These catalytic asymmetric protocols complement alternative routes to enantioenriched propargylic fluorides, e.g. the stereospecific fluorination of enantioenriched allenylsilanes using Selectfluor (1), an SE2¢ process that occurs with clean transfer of chirality (up to 96% ee).[56] The concept has also been extended to the formation of an enantioenriched allylic fluoride using a Wittig reaction, albeit with limited reaction scope. (2R)-2-Fluoroalkan-1-ols 65; General Procedure for Enantioselective Æ-Fluorination of Aldehydes Followed by Reduction with Sodium Borohydride:[51]
To a 25-mL flask charged with the dichloroacetic acid salt of organocatalyst (5R)-5-benzyl2,2,3-trimethylimidazolidin-4-one [(R)-63; 139 mg, 0.400 mmol] and N-fluorobenzenesulfonimide (2; 3.15 g, 10.0 mmol) were added THF (9.0 mL) and iPrOH (1.0 mL). The mixture was stirred at rt until homogeneous and then cooled to –10 8C. The aldehyde (2.0 mmol) was added and the mixture was stirred for 12 h. The mixture was cooled to –78 8C, diluted with Et2O (10 mL), and filtered through a pad (Davisil silica gel, Et2O). DMS (5.0 mL) was added, forming a white precipitate. The resulting mixture was washed with sat. NaHCO3 (3 150 mL) and brine (1 150 mL), dried (MgSO4), filtered, and concentrated. The resulting oil was dissolved in CH2Cl2 (12 mL) and EtOH (8 mL) and NaBH4 (189 mg, 5.0 mmol) was added. After 30 min, the mixture was cooled to 0 8C and sat. NH4Cl (150 mL) was added. The mixture was warmed to rt and stirred vigorously for 1 h. The suspension was allowed to separate and CH2Cl2 (75 mL) was added. The soln was extracted with CH2Cl2 (3 100 mL) and the combined organics washed with sat. NaHCO3 (3 150 mL) and brine (1 150 mL), dried (Na2SO4), filtered, and concentrated. Purification of the resulting oil by forced flow chromatography afforded the enantioenriched -fluoro alcohols. The enantioselectivity
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Fluorination
881
was determined either by chiral GLC analysis, or chiral stationary phase HPLC analysis after acylation of the alcohol with 2-naphthoyl chloride. Propargylic Fluorides 66; General Procedure:[53]
An 8-mL glass vial was charged with the aldehyde (0.22 mmol, 1.1 equiv), (2S)-2-{bis[3,5bis(trifluoromethyl)phenyl](trimethylsiloxy)methyl}pyrrolidine [(S)-64; 0.002 mmol, 0.01 equiv] and t-BuOMe (0.4 mL). After 10 min of stirring at rt, N-fluorobenzenesulfonimide (2; 0.2 mmol, 1 equiv) was added. Stirring was maintained at rt for the time required for full conversion of N-fluorobenzenesulfonimide (2) (see Scheme 30 for specific reaction times). Upon completion of the reaction, MeOH (4.5 mL), the Ohira–Bestmann reagent (0.26 mmol, 1.32 equiv), and K2CO3 (0.53 mmol, 2.64 equiv) were added sequentially. After 18 h of stirring, the crude mixture was diluted with pentane and filtered through a short pad [silica gel, Et2O/pentane 1:1 (100 mL)]. The excess solvents were carefully removed under reduced pressure (note: the products are volatile) and the products were purified by column chromatography (silica gel). 3.20.1.1.2.2.2.2
Catalytic Asymmetric Fluorodesilylation of Allylsilanes, Silyl Enol Ethers, and Indolones
The first examples of reagent-controlled asymmetric electrophilic fluorodesilylation have been reported.[21] For instance, the catalytic variant of this transformation has been applied to both allylsilanes [e.g., 68 (X = CH2)] and silyl enol ethers [e.g., 68 (X = O)],[57] using N-fluorobenzenesulfonimide (2) in combination with a catalytic amount of either dihydroquinine 2,5-diphenylpyrimidine-4,6-diyl diether [34, (DHQ)2PYR] (Table 5, entries 1–5) or dihydroquinine phthalazine-1,4-diyl diether [67, (DHQ)2PHAL] (Table 5, entries 6–9). These reactions provide the desired allylic fluorides [e.g., 69 (X = CH2)] and Æ-fluoro ketones [e.g., 69 (X = O)], respectively, in good yield and with moderate to high levels of enantiocontrol (up to 95% ee). Notably, the presence of a large substituent (R1) in the C2 position of the substrates is a prerequisite for high enantiomeric excess, and the reactions typically require several days to go to completion.
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Table 5 Enantioselective Fluorodesilylation of Allylsilanes and Silyl Enol Ethers Catalyzed by Bis-cinchona Alkaloid Derivatives[57] Et
Et N
N
N N O
H
O H OMe
MeO N
N 67
X TMS R1
(DHQ)2PHAL
(PhSO2)2NF 2 (1.2 equiv) bis-cinchona alkaloid K2CO3 (6 equiv), MeCN
X F
n
n
68
Entry X
R1
69
R1
n Bis-cinchona Alkaloida
Temp (8C)
Time ee (%)
Yield (%)
Ref
1
CH2 Bn
1 (DHQ)2PYR (34)
–40
3d
94
75
[57]
2
CH2 4-TolCH2
1 (DHQ)2PYR (34)
–20
12 h
95
75
[57]
3
CH2 4-ClC6H4CH2
1 (DHQ)2PYR (34)
–20
18 h
94
81
[57]
4
CH2 2-naphthylmethyl
1 (DHQ)2PYR (34)
–20
34 h
91
69
[57]
36 h
81
71
[57]
5
CH2 4-TolCH2
2 (DHQ)2PYR (34)
–20
6
O
4-TolCH2
2 (DHQ)2PHAL (67)
–40
8d
86
79
[57]
7
O
4-ClC6H4CH2
2 (DHQ)2PHAL (67)
–40
8d
86
74
[57]
8
O
PMB
2 (DHQ)2PHAL (67)
–40
6d
85
84
[57]
9
O
2-naphthylmethyl
2 (DHQ)2PHAL (67)
–40
6d
84
88
[57]
a
For (DHQ)2PYR, 10 mol% was used; for (DHQ)2PHAL, 20 mol% was used.
The catalytic asymmetric fluorination of indolones to the fluorinated derivatives 72 was accomplished using N-fluorobenzenesulfonimide (2) in the presence of a catalytic amount of one of the bis-cinchona alkaloid derivatives, namely dihydroquinidine 9,10-dioxo-9,10dihydroanthracene-1,4-diyl diether [70, (DHQD)2AQN] and dihydroquinine 9,10-dioxo9,10-dihydroanthracene-1,4-diyl diether [71, (DHQ)2AQN] (Scheme 31). This approach is limited to 3-aryl-substituted indolones to achieve high enantioselectivity, since indolones with methyl, ethyl, isopropyl, and an ethyl ester at C3 provide low levels of asymmetric induction.[35]
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Fluorination Enantioselective Fluorination of Indolones[57]
Scheme 31
Et
Et
N
N O
O
H
H
MeO
O
OMe
O N
N 70
(DHQD)2AQN
Et
Et N
N O
O
H
H
MeO
O
OMe
O N
N 71
Ar1 R1 O
(DHQ)2AQN
(PhSO2)2NF 2 (1.2 equiv) 5 mol% bis-cinchona alkaloid CsOH•H2O (6 equiv) MeCN/CH2Cl2, −80 oC
Ar1
F
R1
O N Boc
N Boc
72
Ar1
R1
Bis-cinchona Alkaloid Time (d) ee (%) Yield (%) Ref
Ph
H
(DHQD)2AQN (70)
5
87
87
[57]
4-Tol
H
(DHQD)2AQN (70)
5
83
86
[57]
4-Tol
Me
(DHQD)2AQN (70)
5.5
81
81
[57]
Ph
OMe (DHQD)2AQN (70)
5
84
92
[57]
4-Tol
OMe (DHQD)2AQN (70)
5
79
86
[57]
4-FC6H4 OMe (DHQD)2AQN (70)
5
81
86
[57]
a
Ph
H
(DHQ)2AQN (71)
5
85
99
[57]
4-Tol
H
(DHQ)2AQN (71)
5
86a
94
[57]
a
4-Tol
Me
(DHQ)2AQN (71)
7
84
86
[57]
4-Tol
OMe (DHQ)2AQN (71)
5
85a
99
[57]
a
(R)-Fluorinated indolones were obtained.
Allylic Fluorides 69 (X = CH2; Table 5, Entries 1–5); General Procedure for Catalytic Enantioselective Fluorination of Allylsilanes:[57]
A soln of cinchona alkaloid derivative (DHQ)2PYR (34; 10 mol%) and N-fluorobenzenesulfonimide (2; 1.2 equiv) in MeCN (1.0 mL) was stirred under N2 at rt for 30 min. K2CO3 (6.0 equiv) was then added to the soln, and the mixture was stirred for 30 min at –20 8C or –40 8C. A soln of the corresponding allylsilane (0.084–0.131 mmol) in MeCN (1.0 mL) was added to the catalyst soln. The mixture was stirred at the temperature indicated in Table 5 with monitoring by TLC. The mixture was filtered through alumina and the sol-
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Asymmetric Fluorination and Fluoroalkylation
vent was removed. The residue was purified by preparative TLC (alumina) or column chromatography (alumina, hexane). The ee was determined by chiral HPLC (Chiralcel OD-H or OJ, or Chiralpak AD-H column).
Æ-Fluoro Ketones 69 (X = O; Table 5, Entries 6–9); General Procedure for Catalytic Enantioselective Fluorination of Silyl Enol Ethers:[57]
A soln of cinchona alkaloid (DHQ)2PHAL (67; 20 mol%) and N-fluorobenzenesulfonimide (2; 1.2 equiv) in MeCN (1.0 mL) was stirred under N2 at rt for 30 min. K2CO3 (6.0 equiv) was then added to the soln, and the mixture was stirred for 30 min at –40 8C. A soln of the silyl enol ether (0.075–0.123 mmol) in MeCN (1.0 mL) was added to the catalyst soln. The mixture was stirred at the temperature indicated in Table 5 with monitoring by TLC. The reaction was quenched by the addition of 1 M HCl. The mixture was then diluted with EtOAc, washed with sat. NaHCO3, brine, and dried (Na2SO4), and the solvent was removed. The residue was purified by column chromatography (silica gel, hexane/EtOAc or hexane/ CH2Cl2). The ee was determined by chiral HPLC (Chiralcel OJ-H or OB-H column). 3-Aryl-3-fluoro-1,3-dihydro-2H-indol-2-ones 72; General Procedure for Catalytic Enantioselective Fluorination of 3-Aryl-1,3-dihydro-2H-indol-2-ones:[57]
A soln of (DHQD)2AQN (70; 5 mol%) and N-fluorobenzenesulfonimide (2; 1.2 equiv) in MeCN/CH2Cl2 (3:4; 1.0 mL) was stirred under argon at rt for 30 min. CsOH•H2O (6.0 equiv) was then added to the soln, and the mixture was stirred for 30 min at –80 8C. A soln of the 3-arylindolone (0.100–0.145 mmol) in MeCN/CH2Cl2 (3:4, 1 mL) was added to the catalyst soln and the mixture was stirred at –80 8C for 5–7 d with monitoring by TLC. The reaction was quenched by addition of H2O. The mixture was diluted with EtOAc, washed with 2 M HCl, sat. NaHCO3, brine, and dried (Na2SO4), and the solvent was removed. The residue was purified by column chromatography (silica gel, hexane/EtOAc containing 1% Et3N). The ee was determined by chiral HPLC (Chiralcel OD-H column). 3.20.1.1.2.2.2.3
Preparation of Fluorinated Flavanones
An organocatalytic intramolecular oxa-Michael addition followed by an electrophilic fluorination provides a convenient route to fluorinated flavanone derivatives (e.g., 75). The optimal organocatalyst for this transformation is the trifluoromethylated bifunctional quinidine derivative 73 (Scheme 32).[58] In the first stage of this one-pot process, the activated Æ,-unsaturated keto esters 74 undergo asymmetric oxa-Michael addition in the presence of 15 mol% of the cinchona alkaloid derivative 73, this is followed by fluorination with N-fluorobenzenesulfonimide (2) and sodium carbonate to afford the enantioenriched fluoro flavanones as single diastereomers. -Aryl-substituted Æ,-unsaturated keto esters provide optimal enantioselectivities.[58] Scheme 32
Sequential Oxa-Michael Addition–Fluorination Reaction[58]
CF3
OH O N H
N 73
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Fluorination
1. 15 mol% 73
OH
R1
O
O
toluene, rt, t1 2. Na2CO3 (1.2 equiv) (PhSO2)2NF 2 (1.5 equiv), rt, t2
F CO2R2
CO2R2
O
R1
75
74
R1
R2
t1 (h) t2 (h) ee (%) Yield (%) Ref
Ph
Et
12
6
93
99
[58]
4-NCC6H4
Et
12
7
92
99
[58]
3-BrC6H4
Et
12
7
93
99
[58]
4-PhC6H4
Et
15
12
93
97
[58]
Ph
t-Bu 24
6
96
94
[58]
Ethyl (2R,3R)-3-Fluoro-4-oxo-2-phenyl-3,4-dihydro-2H-1-benzopyran-3-carboxylate (75, R1 = Ph; R2 = Et); Typical Procedure:[58]
A mixture of ethyl (2E)-2-[(2-hydroxyphenyl)carbonyl]-3-phenylprop-2-enoate (74, R1 = Ph; R2 = Et; 0.1 mmol) and cinchona alkaloid derivative 73 (7 mg, 0.015 mmol) in toluene (1.0 mL) was stirred at rt for 12 h (TLC). Then, Na2CO3 (12.7 mg, 0.12 mmol) and N-fluorobenzenesulfonimide (2; 47.3 mg, 0.15 mmol) were added and the mixture was stirred at rt for 6 h (TLC). The mixture was then concentrated and the residue was purified by column chromatography (silica gel, EtOAc/petroleum ether 1:20) to give the product as a white solid; yield: 31.1 mg (99%); 93% ee. 3.20.1.1.2.2.2.4
Asymmetric Fluorination with Chiral Bifunctional Phase-Transfer Catalysts
Chiral bifunctional phase-transfer catalysts can be used for the asymmetric fluorination of -keto esters. Several cyclic -keto esters (e.g., 77) have been treated with N-fluorobenzenesulfonimide (2) and the thiomorpholine-derived phase-transfer catalyst (S)-76 (2 mol%) in diethyl ether with aqueous potassium carbonate to afford the corresponding fluorinated compounds 78 with excellent yield and with very good enantiomeric excess (Scheme 33). Furthermore, only cyclic tert-butyl -keto esters 77 are amenable to the asymmetric fluorination with satisfactory levels of enantioselectivity. The transitionstate model for enantiocontrol invokes the in situ formation of Z-enolate stabilized by both ionic interactions and hydrogen bonding with the bifunctional catalyst.[59]
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Asymmetric Fluorination and Fluoroalkylation
Scheme 33 Enantioselective Fluorination with a Chiral Bifunctional PhaseTransfer Catalyst[59] CF3
CF3
F3C
CF3 OH N
S Br−
OH F3C
CF3
CF3
CF3
(S)-76
O
2 mol% 76 (PhSO2)2NF 2 (1.1 equiv) 0.5 M aq K2CO3, Et2O, −20 oC
O
R1
OBut
O
O
R2
F
R1
R2
OBut
77
78
R1
R2 Time (h) ee (%) Yield (%) Ref
0.5
98
99
[59]
2
90
99a
[59]
2
90
99
[59]
(CH2)3
2
98
99a
[59]
(CH2)4
8
95
99
[59]
MeO
O
a
0.5 M aq K3PO4 used as base.
Cyclic Æ-Fluoro--keto Esters 78; General Procedure for Enantioselective Fluorination with a Chiral Bifunctional Phase-Transfer Catalyst:[59]
To a reaction vessel containing the -keto ester 77 (0.1 mmol) and the chiral ammonium salt (S)-76[59] (0.002 mmol, 2 mol%) was added Et2O (4.0 mL). After the mixture had been cooled to –20 8C, 0.5 M aq K2CO3 (1.0 mL) was added dropwise. After stirring for 10 min at the same temperature, N-fluorobenzenesulfonimide (2; 36 mg, 0.11 mmol, 1.1 equiv) was added in a single portion. The mixture was then stirred vigorously at the same temperature for 0.5–8 h. The reaction was quenched with sat. NH4Cl (10 mL) and the mixture was extracted with Et2O (10 mL). The organic phase was dried (Na2SO4) and concentrated. Purification of the residue by column chromatography (silica gel, hexane/EtOAc) afforded the fluorination product 78. The ee was determined by chiral stationary phase HPLC.
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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3.20.1.1.2.2.3
887
Stereoselective Fluorination
Catalytic Enantioselective Fluorination Mediated by Metals and Organocatalysts
The combination of a metal catalyst, an organocatalyst, and a fluorinating agent provides a unique catalytic asymmetric approach to enantiopure Æ-fluorinated carboxylic acid derivatives (e.g., 81) from acid chlorides (e.g., 80) (Scheme 34). “Dual-Activation” Electrophilic Fluorination[60]
Scheme 34
OMe
N N OBz 79
O R1
1. 10 mol% 79, 3 mol% metal catalyst (PhSO2)2NF 2 (1 equiv), iPr2NEt (1 equiv) 2. NuH (excess)
F
O
R1
Cl 80
Nu 81
R1
Nu
Metal Catalyst
4-MeOC6H4
OMe
NiCl2(dppp)
99
83
[60]
NiCl2(dppp)
>99a
90b
[60]
NiCl2(dppp)
>99a
80b
[60]
ee (%) Yield (%) Ref
O
4-MeOC6H4
NBoc
S
1-naphthyl MeO2C
NHBoc
CH2NPhth
OMe
trans-PdCl2(PPh3)2
>99
72
[60]
CH2NPhth
N
trans-PdCl2(PPh3)2
>99
79b
[60]
a b
Diastereomeric excess. 1.1 equiv of nucleophile was used.
The reaction exploits a “dual-activation” strategy in which the benzoylquinidine (79, BQd) chiral nucleophile in conjunction with a transition-metal-based Lewis acid cocatalyst affords metal-coordinated chiral ketene enolates 82 (Scheme 35).[61] These doubly activated enolates are efficiently fluorinated with commercially available N-fluorobenzenesulfonimide (2) to produce configurationally stable Æ-fluorinated carboxylic acid derivatives in high yield and with excellent enantiomeric excess. The advantage of this method is the ability to prepare a broad range of carboxylic acid derivatives by simply modifying the nucleophile employed after fluorination. For example, fluorinated carboxylic acids, amides, esters, thioesters, peptides, and even natural product analogues are all accessible via this method.[60,62]
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis Scheme 35
3.20
Asymmetric Fluorination and Fluoroalkylation
Mechanism of “Dual-Activation” Electrophilic Fluorination[60] BQd H
O R1
79 LnMCln
Cl
BQd
O R1
PhO2S
− BQd
F N
MLnCln
F
O R1
82 − LnMCln
SO2Ph
F
O
R1
N(SO2Ph)2
PhO2S
R2H
N
SO2Ph
F
O
R1
R2
Æ-Fluorinated Carboxylic Acid Derivatives 81; General Procedure for “Dual-Activation” Electrophilic Fluorination:[60]
Benzoylquinidine (79; 0.04 mmol) and trans-PdCl2(PPh3)2 (0.012 mmol) were placed into a 10-mL flask and THF (1 mL) was added. The mixture was cooled to –78 8C and iPr2NEt (0.4 mmol) was added followed by N-fluorobenzenesulfonimide (2; 0.4 mmol) as a soln in THF (1 mL). The acid chloride 80 (0.4 mmol) was added dropwise as a soln in THF (1 mL) and the mixture was kept at –78 8C for 6–8 h. The reaction was quenched with MeOH (3 mL) or with the nucleophile indicated in Scheme 34 and the mixture was allowed to warm to rt overnight. The mixture was concentrated and purified by column chromatography (silica gel, EtOAc/hexanes). 3.20.1.2
Stereoselective Nucleophilic Fluorination
The most commonly used nucleophilic fluorinating reagents are hydrogen fluoride complexes, diethylaminosulfur trifluoride (DAST), and bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor). The fluorination of chiral allyl halides, alcohols, and epoxides by nucleophilic displacement (typically SN2) has been well documented {see Science of Synthesis, Vol. 34 [Fluorine (Sections 34.1.4.1, 34.1.4.2, and 34.9)]}. The enantioselective nucleophilic fluorination of achiral compounds is much more challenging with only one useful catalytic asymmetric process described to date. SAFETY: Hydrogen fluoride fumes are severely irritating and extremely destructive to the respiratory system. Diethylaminosulfur trifluoride can undergo exothermic decomposition above 50 8C and decomposes violently above 90 8C, e.g. during removal of solvent or attempted vacuum distillation. Contact with water causes explosive decomposition and produces hydrogen fluoride, which is highly corrosive and irritating to all tissues. 3.20.1.2.1
Prins Cyclization To Access Fluorinated Tetrahydropyrans, Tetrahydrothiopyrans, and Piperidines
Fluorinated tetrahydropyrans, tetrahydrothiopyrans, and piperidines are accessible by treating homoallylic alcohols, thiols, and amines with aldehydes in the presence of boron trifluoride–diethyl ether complex, which serves as both a Lewis acid and a fluorine source. Boron trifluoride–diethyl ether complex has been employed with chiral nonracemic homoallylic alcohols to obtain the expected enantiopure fluorinated tetrahydropyrans as single all-syn-diastereomers.[63] The modest yield was attributed to the competition between fluoride and water in the conversion of the oxocarbenium ion intermediate into the cyclized tetrahyropyran. The coupling of homoallylic alcohols and aldehydes has been studied with ionic liquid hydrogen fluoride salts, e.g. tetraethylammonium fluoride pentahydrofluoride
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Fluorination
(Et4NF•5HF), which acts both as a supporting electrolyte and a fluorine source, to provide access to cis-4-fluorinated tetrahydropyrans 83 (X = O), tetrahydrothiopyrans 83 (X = S), and piperidines 83 (X = NTs) in excellent yield.[64,65] The cis-isomers are formed predominantly, although some trans-product has been detected for the nitrogen- and sulfur-containing heterocycles (Scheme 36). Fluorinated Heterocycles by Prins Cyclization[64]
Scheme 36
neat Et4NF•5HF rt
O + R
1
X
HX
H
R1
F 83
R1
X
Time (h) Ratio (cis/trans) Yield (%) Ref
Cy
O
0.33
>98:2a a
[64]
quant
[64]
Ph
O
0.33
Cy
S
1
95:5
98
[64]
Ph
S
1
96:4
quant
[64]
(CH2)6Me
NTs 1
88:12
quant
[64]
Cy
NTs 2
92:8
quant
[64]
a
>98:2
93
Only the cis-isomer was observed.
O
O R1
H
H+
H
R1
H
− H2O
R1
X
HX
R1
X
F−
X R1
F
Fluorinated Heterocycles 83; General Procedure for Prins Cyclization of Homoallylic Alcohols and Aldehydes:[64]
The Prins cyclization of various aldehydes (0.2 mmol) and homoallylic alcohols, thiols, or amines (0.2 mmol) was carried out at rt in Et4NF•5HF (3 mL) in a plastic cell. After complete conversion of the starting materials (TLC), the mixture was passed through a short column (silica gel, EtOAc) to remove the fluoride salt. The eluent was concentrated under reduced pressure to yield the product. For the thia- (X = S) or aza-Prins (X = NTs) cyclization, the products were obtained as stereoisomeric mixtures of cis- and trans-isomers. The dr was determined by 19F NMR spectroscopy. The products were separated and purified by column chromatography (silica gel, hexane/EtOAc). 3.20.1.2.2
Catalytic Asymmetric Ring Opening of Achiral Epoxides
A catalytic enantioselective desymmetrization of cyclic meso-epoxides (e.g., 85) with fluoride has been reported. The method involves the amine-catalyzed generation of hydrogen fluoride in situ from benzoyl fluoride and an alcohol, such as 1,1,1,3,3,3-hexafluoropropan-2-ol. This protocol not only provides a convenient fluoride source for catalytic C—F bond-forming reactions,[66,67] but allows for development of an enantioselective process through the intermediacy of a chiral amine hydrofluoride salt or by chiral Lewis acid/
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
890
Stereoselective Synthesis
3.20
Asymmetric Fluorination and Fluoroalkylation
amine cocatalysis. This latter strategy has proven optimal for the synthesis of -fluoro alcohols (e.g., 87) using (salen)cobalt(II) complex 84 and (–)-tetramisole (86) (Scheme 37). The scope of the reaction is quite general, as various functional groups such as alkenes, esters, and protected amines are tolerated. However, acyclic substrates and those containing more Lewis basic groups undergo fluorination with lower selectivity.[68] Scheme 37
Enantioselective Catalytic Ring Opening of Epoxides[68]
N
N Co
But
O
But
O
But
But 84
N
8 mol% Ph N 86
O
S
10 mol% 84 BzF (2 equiv), (F3C)2CHOH (4 equiv) t-BuOMe or EtMe2COH, rt, 24−120 h
F
OH
X
X
85
87
X
Time (h) Solvent
ee (%) Yield (%) Ref
(CH2)2
24
EtMe2COH
93
65a
[68]
(CH2)3
72
t-BuOMe
90
82
[68]
(Z)-CH2CH=CHCH2
72
t-BuOMe
95
87
[68]
120
EtMe2COH
90
75b
[68]
120
t-BuOMe
86
88
[68]
120
EtMe2COH
80
84
[68]
CO2Me
NCOCCl3 a
b
Reaction conducted with the Co(III)OTs complex on a 5-mmol% scale. Epoxide is a 10:1 mixture of diastereomers.
-Fluoro Alcohols 87; General Procedure for Catalytic Enantioselective Fluorination of Epoxides:[68]
CAUTION: Benzoyl fluoride is a flammable liquid that can cause burns. CAUTION: 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) can cause burns. To an undried 10-mL flask were added (–)-(1R,2R)-cyclohexane-1,2-diamino-N,N¢-bis(3,5-ditert-butylsalicylidene)cobalt(II) (84; 60.4 mg, 0.10 mmol, 10 mol%) and (–)-tetramisole (86; 16.3 mg, 0.08 mmol, 8 mol%). (F3C)2CHOH (0.416 mL, 4.0 mmol) was added and the brown slurry was diluted with Et2O, t-BuOMe, or 2-methylbutan-2-ol (5 mL). The epoxide (1.0 mmol) was then added, followed by BzF (0.218 mL, 2.0 mmol). The mixture was stirred
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3.20.2
891
Stereoselective Fluoroalkylation
open to air for 1 min. The flask was sealed with a Teflon cap, which was secured with Parafilm, and stirred at rt for the time indicated in Scheme 37. For some substrates, the general procedure was modified. 3.20.2
Stereoselective Fluoroalkylation
Stereoselective fluoroalkylation is an important area of research which complements the direct fluorination processes. Monofluoromethylation, difluoromethylation, and trifluoromethylation have been thoroughly investigated using readily available and easy to handle reagents, which are synthetic equivalents of monofluoro-, difluoro-, and trifluoromethanide anions, respectively. 3.20.2.1
Monofluoromethylation Reactions
The instability of fluoromethyllithium and the corresponding Grignard derivative has precluded their suitability and encouraged the development of new reagents for fluoromethylation. Fluoromethyl phenyl sulfone (88) and fluorobis(phenylsulfonyl)methane (89, FBSM) are the most commonly used reagents for stereoselective monofluoromethylation. Fluoromethyl phenyl sulfone (88) is commercially available and fluorobis(phenylsulfonyl)methane (89) can easily be prepared in good yield from bis(phenylsulfonyl)methane by monofluorination with Selectfluor (1) or with molecular fluorine (Scheme 38).[69] SAFETY: Both fluoromethyl phenyl sulfone and bis(phenylsulfonyl)methane are irritant solids. Avoid contact with skin, eyes, and respiratory system. Scheme 38
Monofluoromethylating Reagents[69]
O Ph
S O
F
88
O O O O S S Ph Ph
1. NaH, THF, 0 oC 2. Selectfluor 1, MeCN, rt 60%
O O O O S S Ph Ph
F 89
Fluorobis(phenylsulfonyl)methane (89):[69]
To a stirred suspension of NaH (60% oil dispersion; 270 mg, 6.75 mmol) in THF (25 mL) was added bis(phenylsulfonyl)methane (2.00 g, 6.75 mmol) at 0 8C under N2. After 30 min stirring at rt, a soln of Selectfluor (1; 2.39 g, 6.75 mmol) in MeCN (5 mL) was added at 0 8C, and the mixture was stirred for 3 h at rt. The reaction was quenched by addition of sat. NH4Cl. The mixture was then extracted with CH2Cl2 and the organic phase was washed with brine and dried (Na2SO4). The solvent was removed and the residue was purified by column chromatography (silica gel, hexane/CH2Cl2 1:4) to give fluorobis(phenylsulfonyl)methane (89) as colorless needles; yield: 1.28 g (60%); mp 114–114.5 8C (hexane); 1H NMR (200 MHz; CDCl3, SiMe4 reference, ): 5.70 (1H, d, J = 45.8 Hz, CH), 7.55–7.65 (4H, m, Ar), 7.70–7.80 (2H, m, Ar), 7.95–8.05 (4H, d, J = 7.6 Hz, Ar); 13C NMR (50 MHz; CDCl3, ): 105.3 (d, J = 263.4), 129.2, 129.8, 134.9, 135.4; 19F NMR (188 MHz; CDCl3, CFCl3 reference, ): –167.2 (d, J = 45.8 Hz); IR (KBr): ~max: 1354, 1174 cm–1.
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
892
Stereoselective Synthesis
3.20.2.1.1
Diastereoselective Nucleophilic Monofluoromethylation
3.20.2.1.1.1
Preparation of Chiral Æ-Monofluoromethyl Amines Using Fluoromethyl Phenyl Sulfone
3.20
Asymmetric Fluorination and Fluoroalkylation
Chiral Æ-monofluoromethylated amines (e.g., 92) are accessible via the fluorination of Ellman-type N-(tert-butylsulfinyl)imines 90. For example, treatment of the homochiral (RS)N-(tert-butylsulfinyl)imines 90 with the fluoromethyl phenyl sulfone (88) in the presence of a base affords the fluoro(phenylsulfonyl)methylated products 91 in high yields and with excellent facial selectivity. These products are formed as mixtures of epimers (91A and 91B) at the fluorinated stereogenic center, however this is not a drawback as this stereocenter is generally removed in the conversion of the primary adducts into the corresponding enantiopure monofluoromethylated amine hydrochlorides 92 (Scheme 39). The amine is obtained as the hydrochloride salt by the reductive cleavage of both the phenylsulfonyl and tert-butylsulfinyl groups with sodium amalgam in methanol followed by treatment with hydrogen chloride in dioxane.[70] Monofluoromethylation of Ellman-Type (RS)-N-(tert-Butylsulfinyl)imines[70]
Scheme 39
PhSO2CH2F 88 (1 equiv) LiHMDS (1.05 equiv), THF, −78 oC
O But
S
R1
N
But
(RS)-90
O But
S
F
SO2Ph
N H
R1
O S
+
91A
F
SO2Ph + R1
N H
91B
(RS,1S,2S)
F
SO2Ph
N H
R1
91C
(RS,1R)
O But
S
(RS,1S,2R)
1. Na/Hg, MeOH 2. HCl, dioxane
F Cl− R1
H3N
(S)-92
R1
Ratio [(91A + 91B)/91C)] Yield (%) of 91A + 91B Yield (%) of 92 Ref
Ph
99:1
99
77
[70]
4-ClC6H4
99:1
98
73
[70]
2-naphthyl
99:1
95
74
[70]
4-MeOC6H4 99:1
99
76
[70]
4-Me2NC6H4 98:2
99
75
[70]
2-furyl
99:1
98
71
[70]
t-Bu
99:1
99
73
[70]
Pr
99:1
94
70
[70]
The application of this protocol to (RS,2S)-Æ-amino-N-(tert-butylsulfinyl)imines 93 provides a direct route to the chiral diamines 94 with excellent yield and selectivity. The cooperative stereodirecting effect of the two stereogenic centers accounts for the high level of diastereocontrol observed in the fluorination. The cleavage of the tert-butylsulfinyl group can again be performed using sodium amalgam followed by treatment with hydrogen chloride (Scheme 40).[71]
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.20.2
Scheme 40
Monofluoromethylation of (RS,S)-Æ-Amino-N-(tert-butylsulfinyl)imines[71]
O But
S
893
Stereoselective Fluoroalkylation
NBn2
N R
PhSO2CH2F 88 (1 equiv) NaHMDS (1.4 equiv) THF, −78 oC, 2−3 h
But
S
94A
O But
S
94B
F N H H
SO2Ph NBn2
+
R1
(RS,1S,2S,3S)
SO2Ph NBn2 R1
(RS,1R,2S,3S)
O +
But
S
F
SO2Ph
N H H
94C
NBn2 R1
(RS,2R,3S)
Ratio [(94A + 94B)/94C)]a Yield (%) of 94A + 94B Ref
Bn >99:1
99
[71]
iBu >99:1
97
[71]
iPr >99:1
87
[71]
a
N H H
1
(RS,2S)-93 (1.1 equiv)
R1
F
O
Diastereomeric ratios were determined by 19F NMR spectroscopy of the crude product.
The fluoromethylation of (RS)-N-tert-butylsulfinyl ketimines using in situ generated fluoro(phenylsulfonyl)methanide anion is inefficient. Hence, for less electrophilic ketimines (e.g., 95), it is necessary to pregenerate the fluoro(phenylsulfonyl)methanide anion with butyllithium prior to addition of the ketimines (Scheme 41). Interestingly, opposite facial selectivity is observed for aldimines and ketimines, indicating that the reaction paths to the fluoro(phenylsulfonyl)methylated products 96 involve divergent transition states. The authors postulate the formation of a cyclic six-membered transition state for ketimines and a non-chelation-controlled open transition state for the aldimines to explain this stereochemical divergence.[72]
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894
Stereoselective Synthesis Scheme 41
Asymmetric Fluorination and Fluoroalkylation
Monofluoromethylation of (RS)-N-(tert-Butylsulfinyl) Ketimines[72] PhSO2CH2F 88 (1.2 equiv) BuLi (1.3 equiv) THF, −78 oC, 1 h
O S
But
3.20
N
O R1 S N H
But
R1
(RS)-95
96A
O R1 S But N H 96B
SO2Ph F (RS,1R,2R)
SO2Ph
+
F
96C
Ratio [(96A + 96B)/96C)]a Yield (96A + 96B) (%) Ref
Ph
95:5
90
[72]
4-FC6H4
96:4
81
[72]
4-MeOC6H4
96:4
85
[72]
4-Tol
95:5
93
[72]
2-furyl
95:5
81
[72]
t-Bu
95:5
77b
[72]
b
O R1 S But N H
(RS,1R,2S)
R1
a
+
SO2Ph F (RS,1S)
19
Diastereomeric ratios were determined by F NMR spectroscopy of the crude product. Yield determined by 19F NMR using PhCF3 as an internal standard.
The cleavage of both the phenylsulfonyl and tert-butylsulfinyl groups leads to enantiopure monofluoromethylated diamines (e.g., 97) and amines (e.g., 98) (Scheme 42). Scheme 42 Preparation of Monofluoromethylated Amines and Diamines[70–72]
O But
S
F N H H
1. Na/Hg, MeOH, rt 2. HCl, dioxane
SO2Ph NBn2
F
MeOH, rt 59%
NBn2
H2N
Bn
Bn (2S,3S)-97
OMe O But
S
N H
SO2Ph F
1. Mg, AcOH/NaOAc DMF, rt 2. HCl, dioxane MeOH, rt
OMe
80%
F
H2N 98
(R)-N-[(1S,2R)-2-Fluoro-1-phenyl-2-(phenylsulfonyl)ethyl]-2-methylpropane-2-sulfinamide (91A, R1 = Ph) and (R)-N-[(1S,2S)-2-Fluoro-1-phenyl-2-(phenylsulfonyl)ethyl]-2-methylpropane-2-sulfinamide (91B, R1 = Ph); Typical Procedure:[70]
Fluoromethyl phenyl sulfone (88)[73,74] and (RS)-N-(tert-butylsulfinyl)aldimines[75,76] were prepared using known procedures. Under N2, into a 20-mL Schlenk flask containing (RS)-(E)-N-benzylidene-2-methylpropane-2-sulfinamide [(RS)-90, R1 = Ph; 188 mg, 0.90 mmol] and PhSO2CH2F (88; 157 mg,
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3.20.2
Stereoselective Fluoroalkylation
895
0.90 mmol) in THF (6 mL) at –78 8C was added a 1 M soln of LiHMDS in THF (0.95 mL, 0.95 mmol). The mixture was stirred at this temperature for 40 min, followed by addition of sat. NH4Cl (10 mL). The mixture was extracted with EtOAc (3 15 mL) and the combined organic phases were dried (MgSO4). After removal of the solvents under reduced pressure, the crude product was purified by column chromatography (silica gel); yield: 342 mg (99%); ratio (91A/91B) 1:2. (1S)-2-Fluoro-1-phenylethanamine Hydrochloride [(S)-92, R1 = Ph]; Typical Procedure:[70]
CAUTION: Mercury vapor is readily absorbed by inhalation and is neurotoxic. To a mixture of (R)-N-[(1S,2R)-2-fluoro-1-phenyl-2-(phenylsulfonyl)ethyl]-2-methylpropane2-sulfinamide (91A, R1 = Ph) and (R)-N-[(1S,2S)-2-fluoro-1-phenyl-2-(phenylsulfonyl)ethyl]2-methylpropane-2-sulfinamide (91B, R1 = Ph) and Na2HPO4 (510 mg, 3.60 mmol) in anhyd MeOH (5 mL) at –20 8C, was added Na amalgam (10 wt% Na in Hg; 3.60 mmol net Na content). The mixture was stirred at –20 8C for 1 h. The liquid phase was decanted, and most of the organic phase was removed under reduced pressure. Then, brine (20 mL) was added, followed by extraction of the mixture with EtOAc. The combined organic phases were dried (MgSO4) and the solvent was removed to give a mixture which was dissolved in anhyd MeOH (5 mL) and a 4 M soln of HCl in dioxane (0.5 mL). The mixture was stirred at rt for 30 min and concentrated to near dryness. Et2O was added to precipitate out the amine hydrochloride and the precipitate was collected by filtration and washed with Et2O; yield: 61 mg (77%). N-{1-[1-(Dibenzylamino)alkyl]-2-fluoro-2-(phenylsulfonyl)ethyl}-2-methylpropane-2sulfinamides 94; General Procedure for Monofluoromethylation of (RS,S)-Æ-AminoN-(tert-butylsulfinyl)imines:[71]
Under N2, into a 50-mL Schlenk flask containing chiral (RS,S)-Æ-amino-N-(tert-butylsulfinyl)imine 93 (1.1 mmol) and PhSO2CH2F (88; 1.0 mmol) in THF (10 mL) at –78 8C was added a 1.0 M soln of NaHMDS in THF (1.4 mL, 1.4 mmol). The mixture was then stirred at this temperature until the reaction was complete (usually 3–5 h), followed by addition of brine (10 mL) at this temperature. After warming to rt, the mixture was extracted with EtOAc (3 25 mL), and the combined organic phases were dried (MgSO4). After removal of solvents under reduced pressure, the crude product was further purified by column chromatography (silica gel, petroleum ether/EtOAc); yield: 87–99%. N-[1-Fluoro-1-(phenylsulfonyl)propan-2-yl]-2-methylpropane-2-sulfinamides 96; General Procedure for Monofluoromethylation of (RS)-N-(tert-Butylsulfinyl) Ketimines:[72]
Under N2, a soln of BuLi (1.3 mmol) in hexane was added dropwise into a soln of PhSO2CH2F (88; 209 mg, 1.2 mmol) in THF (8 mL) at –78 8C and, after 30 min at this temperature, the N-tert-butylsulfinyl ketimine 95 (1.0 mmol) in THF (2 mL) was added slowly into the soln. The mixture was then stirred vigorously at –78 8C for 1 h, followed by addition of brine (10 mL). The mixture was extracted with Et2O (3 10 mL), and the combined organic phases were dried (MgSO4). After the removal of volatile solvents under reduced pressure, the crude product was further purified by column chromatography (silica gel); yield: 77– 93%. 3.20.2.1.2
Catalytic Enantioselective Nucleophilic Monofluoromethylation
3.20.2.1.2.1
Preparation of Æ-Monofluoromethylated Amines
An alternative method for accessing enantioenriched Æ-monofluoromethylated amines is the catalytic asymmetric monofluoromethylation of in situ generated achiral imines with fluorobis(phenylsulfonyl)methane (89) in the presence of a chiral phase-transfer catalyst.
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
896
Stereoselective Synthesis
3.20
Asymmetric Fluorination and Fluoroalkylation
For example, Æ-(tert-butoxycarbonylamino) sulfones 100 have been treated with cesium hydroxide monohydrate and fluorobis(phenylsulfonyl)methane (89) in the presence of catalytic amounts of N-benzylquinidinium chloride (99) in dichloromethane at –80 8C (Scheme 43). After 24–48 hours, the resulting fluorinated products 101 are isolated in good to excellent yield with excellent enantioselectivities (>90% ee). Interestingly, the nature of the solvent and inorganic base are critical, since their modification results in poor conversion and lower enantioselectivity. Scheme 43 Monofluoromethylation of Æ-(tert-Butoxycarbonylamino) Sulfones[77]
+ N
Ph
HO
Cl−
H MeO N 99
(PhSO2)2CHF 89 (1.05 equiv) 5 mol% 99 CsOH•H2O (1.2 equiv) CH2Cl2, −80 oC, 1−2 d
NHBoc R1
NHBoc SO2Ph
R1
SO2Ph
F
100
R1
ee (%) Yield (%) Ref
Ph
96
92
3-ClC6H4
97
98
[77]
4-MeOC6H4
95a
88
[77]
a
96
[77]
2-furyl
a
93
81
[77]
(CH2)6Me
95a
95
[77]
iPr
a
99
93
[77]
t-Bu
96a
70
[77]
2-naphthyl
b
90
b
[77]
a
a
SO2Ph 101
The absolute stereochemistry was assigned by analogy. Yield using 10 mol% of catalyst.
Reductive desulfonylation of bis(phenylsulfonyl) carbamates (e.g., 102) to the fluoro carbamates (e.g., 103) with magnesium in methanol proceeds without significant racemization (Scheme 44).[77] Scheme 44
Reductive Desulfonylation[77]
NHBoc SO2Ph
Ph
84%; 95% ee
F
SO2Ph 102
NHBoc
Mg, MeOH, 0 oC, 2 h
F
Ph 103
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.20.2
897
Stereoselective Fluoroalkylation
N-(tert-Butoxycarbonyl)-1-fluoro-1,1-bis(phenylsulfonyl)alkan-2-amines 101; General Procedure for Monofluoromethylation of Æ-(tert-Butoxycarbonylamino) Sulfones:[77]
To a mixture of the Æ-(tert-butoxycarbonylamino) sulfone (0.35 mmol), N-benzylquinidinium chloride (99; 0.018 mmol) and CsOH•H2O (0.42 mmol) in CH2Cl2 (1.0 mL), was added fluorobis(phenylsulfonyl)methane (89; 0.38 mmol) in one portion at –80 8C. The mixture was then vigorously stirred at the same temperature. After 1 or 2 d, the reaction was quenched with sat. NH4Cl soln and the aqueous layer was extracted with EtOAc (2 5 mL). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The crude product was purified by column chromatography on (silica gel, acetone/hexane 1:5). The ee of the products was determined by chiral HPLC. (1S)-N-(tert-Butoxycarbonyl)-2-fluoro-1-phenylethylamine (103); Typical Procedure:[77]
Under N2, a flask containing Mg (145.8 mg, 6.0 mmol) was dried by heating. The flask was cooled to 0 8C, and then MeOH (0.28 mL) and (S)-N-(tert-butoxycarbonyl)-2-fluoro-1-phenyl2,2-bis(phenylsulfonyl)ethylamine [102 (96% ee); 103.7 mg, 0.20 mmol] were added. The mixture was stirred for 2 h. The reaction was quenched with sat. NH4Cl and the mixture was extracted with CH2Cl2. The combined organic phases were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, EtOAc/hexane 1:10); yield: 40.2 mg (84%); 95% ee. 3.20.2.1.2.2
Preparation of -Monofluoromethylated Ketones and ª-Monofluoromethylated Alcohols
Fluorobis(phenylsulfonyl)methane (89) has been used successfully as a monofluoromethanide anion equivalent in catalytic enantioselective Michael additions to Æ,-unsaturated ketones (e.g., 106). Cinchona alkaloid derived ammonium salts (e.g., 104 and 105) catalyze this process in dichloromethane in the presence of 3 equivalents of cesium carbonate over a period of 24–48 hours to furnish the Michael adducts (e.g., 107) in high yields and with excellent enantioselectivities. The reaction is best applied to Æ,-unsaturated ketones flanked by two aryl substituents that can presumably interact with the catalyst via a – stacking interaction (Scheme 45). Scheme 45
Monofluoromethylation of Æ,-Unsaturated Ketones[78] F 3C
OMe
CF3 CF3
OH +
+ N
CF3
HO
N H
F3C
Br−
H
N Br−
MeO CF3 F3 C
N 104
CF3 105
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
898
Stereoselective Synthesis
3.20
Asymmetric Fluorination and Fluoroalkylation
(PhSO2)2CHF 89 (1.0 equiv) 5 mol% ammonium salt Cs2CO3 (3.0 equiv) CH2Cl2, −40 oC, 1−2 d
O
O R1
SO2Ph
F
SO2Ph
R2 R1
R2
106 (1.1 equiv)
107
R1
R2
Ammonium Salt ee (%) Yield (%) Ref
Ph
Ph
104
97
80 (S)
[78]
Ph
3-ClC6H4
104
98
85 (S)
[78]
Ph
4-BrC6H4
104
97
86 (S)
[78]
4-BrC6H4
Ph
104
95
82 (S)
[78]
Ph
Me
104
85
91 (R)
[78]
Ph
3-ClC6H4
105
82
77 (R)
[78]
Ph
4-BrC6H4
105
94
90 (R)
[78]
4-ClC6H4
Ph
105
89
90 (R)
[78]
The conjugate addition adducts (e.g., 108) are converted into -monofluoromethylated ketones (e.g., 109) without detectable racemization using a three-step sequence, namely, reduction with sodium borohydride, followed by reductive desulfonylation with magnesium metal in methanol, and then oxidation with pyridinium chlorochromate (Scheme 46).[78] Scheme 46
O
F
Reductive Desulfonylation[78]
SO2Ph SO2Ph
1. NaBH4, THF/MeOH (8:1) 2. Mg, THF/MeOH (1:3.75) 3. PCC, H5IO6, MeCN
F
O
48%; 97% ee
Ph
Ph 108
Ph
Ph 109
A very similar conjugate addition to Æ,-unsaturated aryl ketones has been reported, which provides the fluorinated products in high yield and enantiomeric excess, using 9-amino-9-deoxyepicinchona alkaloids as the organocatalyst and fluorobis(phenylsulfonyl)methane (89) as the fluoromethylating agent.[79] The catalytic enantioselective conjugate addition of fluorobis(phenylsulfonyl)methane (89) to the enals 110, using 20 mol% of diarylprolinol silyl ethers 111 in toluene at room temperature in the presence of benzoic acid (Table 6),[80] affords the fluorinated products in good yield and with excellent enantioselectivity, albeit with lengthy reaction times (up to 96 hours). Interestingly, when R1 is a propyl group, the yield decreases significantly but the enantioselectivity remains excellent (98% ee). This limitation was circumvented by replacing catalyst 111 (R2 = TBDMS) with a less sterically encumbered catalyst 111 (R2 = TMS) and carrying out the reaction in the absence of benzoic acid (Table 6, entries 7 and 8). Reduction of the aldehyde to the bis(phenylsulfonyl) alcohol (e.g., 112) with sodium borohydride (Table 6) followed by reductive desulfonylation (e.g., of 113) with activated magnesium in methanol furnishes the corresponding ª-fluoromethylated alcohols (e.g., 114) without any detectable racemization (Scheme 47).[80]
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Fluoroalkylation
3.20.2
Table 6 Monofluoromethylation of Æ,-Unsaturated Aldehydes and Reductive Desulfonylation[80] 1. (PhSO2)2CHF 89 (1.0 equiv) Ph 20 mol%
Ph OR2
N H 111
20 mol% BzOH, toluene, 0 oC 2. NaBH4
CHO
R1
F
PhO2S
SO2Ph
R1
OH
110
112
Entry R1
R2
Aldehyde (equiv) Time (h) ee (%) Yielda (%) Ref
1
4-O2NC6H4
TBDMS 1.5
72
99
83
[80]
2
4-BrC6H4
TBDMS 3.0
72
>99
81
[80]
3
4-F3CC6H4
TBDMS 3.0
70
>99
80
[80]
4
3-O2NC6H4
TBDMS 2.0
59
97
75
[80]
5
2-FC6H4
TBDMS 2.4
70
>99
74
[80]
6
Ph
TBDMS 5.0
72
>99
71
[80]
7
Pr
TBDMS 5.0
96
98
17
[80]
8
Pr
TMS
79
92
81b
[80]
a b
5.0
Isolated yields based on two steps. Reaction carried out in the absence of BzOH.
Scheme 47 Alcohol[80] PhO2S
F
Reductive Desulfonylation of a Bis(phenylsulfonyl)
SO2Ph
F Mg, MeOH, rt 79%
Ph (S)-113
OH >99% ee
Ph (S)-114
OH 98% ee
(3S)-4-Fluoro-1,3-diphenyl-4,4-bis(phenylsulfonyl)butan-1-one (107, R1 = R2 = Ph); Typical Procedure:[78]
1,3-Diphenylprop-2-en-1-one (106, R1 = R2 = Ph; 80.2 mg, 0.385 mmol) was added to a stirred mixture of fluorobis(phenylsulfonyl)methane (89; 110 mg, 0.350 mmol), cinchona alkaloid derivative 104 (16.1 mg, 0.0175 mmol), and Cs2CO3 (342.1 mg, 1.05 mmol) in anhyd CH2Cl2 (1.0 mL) at –40 8C. After completion of the reaction (1–2 d, monitored by TLC), the mixture was diluted with CH2Cl2 and washed with H2O and brine. The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, acetone/hexane 1:4); yield: 145.7 mg (80%); 97% ee. The ee was determined by HPLC analysis (Daicel Chiralcel AD-H column). (3S)-4-Fluoro-1,3-diphenylbutan-1-one (109); Typical Procedure:[78]
CAUTION: Pyridinium chlorochromate can cause cancer by inhalation. It is very toxic to aquatic organisms and may cause long-term adverse effects in the aquatic environment. To a soln of (S)-4-fluoro-1,3-diphenyl-4,4-bis(phenylsulfonyl)butan-1-one (108; 100.8 mg, 0.193 mmol) in THF (0.8 mL) and MeOH (0.1 mL) was added NaBH4 (8.8 mg, 0.231 mmol)
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.20
Asymmetric Fluorination and Fluoroalkylation
at 0 8C. After 1 h, the reaction was carefully quenched with sat. NH4Cl and diluted with CH2Cl2. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, EtOAc/hexane 1:1) to give the corresponding alcohol as a white solid; yield: 99.6 mg (98%). Under N2, a flask containing Mg (46.2 mg, 1.90 mmol) was dried by heating. The flask was cooled to 0 8C, and then MeOH (1.5 mL) and a soln of the alcohol (97% ee; 99.6 mg, 0.190 mmol) in THF (0.4 mL) were added. The mixture was stirred for 3 h. The reaction was quenched with sat. NH4Cl and the mixture was extracted with CH2Cl2. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, EtOAc/ hexane 1:4) to give the corresponding desulfonylated alcohol as a colorless oil; yield: 23.1 mg (50%). To MeCN (0.7 mL) was added H5IO6 (21.4 mg, 0.0993 mmol) and the soln was stirred vigorously at rt for 15 min. The desulfonylated alcohol (23.1 mg, 0.0946 mmol) was added at 0 8C, followed by addition of PCC (0.4 mg, 0.00189 mmol). The mixture was stirred for 1 h, then diluted with EtOAc, washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, EtOAc/hexane 1:9) to give the product as a white solid; yield: 23.1 mg (97%); 97% ee. 4-Fluoro-4,4-bis(phenylsulfonyl)butan-1-ols 112; General Procedure for Catalytic Enantioselective Monofluoromethylation of Æ,-Unsaturated Aldehydes Followed by Reduction with Sodium Borohydride:[80]
A mixture of the Æ,-unsaturated aldehyde 110 (0.10 mmol), fluorobis(phenylsulfonyl)methane (89; 31.4 mg, 0.10 mmol), (2S)-2-[(tert-butyldimethylsiloxy)diphenylmethyl]pyrrolidine (111, R2 = TBDMS; 0.02 mmol), and BzOH (2.4 mg, 0.02 mmol) in toluene (0.8 mL) was stirred at 0 8C for the time indicated in Table 6. The mixture was then directly purified by column chromatography (silica gel, hexane/EtOAc, 3:1) to give the desired aldehyde. The resulting residue was dissolved in MeOH (1.0 mL) and the soln was cooled to 0 8C. NaBH4 (11 mg, 0.30 mmol) was added in three portions and the mixture was stirred at 0 8C for 20 min. The mixture was poured into H2O and extracted with CH2Cl2. The combined organic layers were washed with H2O and brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (silica gel, pentane/EtOAc 2:1). (S)-4-Fluoro-3-phenylbutan-1-ol [(S)-114]; Typical Procedure:[80]
(S)-4-Fluoro-3-phenyl-4,4-bis(phenylsulfonyl)butan-1-ol [(S)-113; 15 mg, 0.033 mmol] was dissolved in MeOH (1 mL). Activated Mg (16 mg, 0.66 mmol) (prepared from Mg and BrCH2CH2Br in Et2O) was added to this soln and the mixture was stirred at rt for 2 h. Then, 1 M HCl (5 mL) was added and the mixture was extracted with Et2O. The combined organic layers were washed with H2O and brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (silica gel, hexane/EtOAc 3:1); yield: 4.5 mg (79%); 98% ee. 3.20.2.1.2.3
Asymmetric Allylic Monofluoromethylation
Homochiral monofluoromethylated allylic derivatives are accessible using palladium-catalyzed allylic substitution reactions with fluorobis(phenylsulfonyl)methane (89) and a chiral palladium complex. The asymmetric fluorobis(phenylsulfonyl)methylation of several (2E)-prop-2-enyl acetates 116 with fluorobis(phenylsulfonyl)methane (89) is typically carried out in dichloromethane at 0 8C in the presence of cesium carbonate and catalytic amounts of both the palladium catalyst diallyldi--chlorodipalladium(II) [{Pd(Å3-C3H5)Cl}2] (2.5 mol%) and the chiral ligand (4S)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-4,5-di-
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3.20.2
hydrooxazole [(S)-115, (S)-PHOX] (5 mol%). Under these conditions, the reaction affords the enantioenriched fluorobis(phenylsulfonyl)methylated derivatives 117 in good to excellent yield with very high enantioselectivity (up to 96% ee) (Scheme 48). As expected, the enantiomeric products are accessible using (R)-PHOX as the chiral ligand. The scope of this reaction has been investigated with several acyclic allylic substrates that are doubly flanked by aryl groups. One cyclic system (meso-cyclopent-4-ene-1,3-diyl diacetate) is desymmetrized successfully using ligand 118, delivering allylic acetate 119 in 95% ee (Scheme 49). Palladium-Catalyzed Monofluoromethylation of Allylic Acetates[69]
Scheme 48
O N
PPh2
Pri (S)-115
(S)-PHOX
(PhSO2)2CHF 89 (1.1 equiv) 5 mol% (S)-115 2.5 mol% [Pd(η3-C3H5)Cl2] Cs2CO3 (1.1 equiv) CH2Cl2 (1 M), 0 oC, 6 h
OAc R1
F
SO2Ph SO2Ph
R1
R1
R1
116
(R)-117
R1
Config of Product ee (%) Yield (%) Ref
Ph
R
96
92 a
[69]
4-MeOC6H4
R
91
74
[69]
4-BrC6H4
R
94
69b
[69]
2-naphthyl
R
92
89
[69]
6-methoxy-2-naphthyl
R
91
72
[69]
4-iBuC6H4
R
94
83
[69]
91
89
[69]
c
4-iBuC6H4 a b
c
S
Reaction carried out at rt. Conditions: (PhSO2)2CHF (1.0 equiv), 116 (R1 = 4-BrC6H4; 2.0 equiv), Cs2CO3 (2.0 equiv), [{Pd(Å3-C3H5)Cl}2] (2.5 mol%), (S)-PHOX [(S)-115; 5 mol%], rt, 6 h. Yield based on 116 (R1 = 4-BrC6H4). (R)-PHOX [(R)-115] was used instead of (S)-PHOX [(S)-115].
Scheme 49 Palladium-Catalyzed Monofluoromethylation of a meso-Allylic Diacetate[69]
O
O NH
HN
PPh2 Ph2P 118
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
AcO
3.20
Asymmetric Fluorination and Fluoroalkylation
(PhSO2)2CHF 89 (1.0 equiv) 5 mol% 118 2.5 mol% [Pd(η3-C3H5)Cl2] Cs2CO3 (1.5 equiv) CH2Cl2, (1 M), 0 oC, 3 h
OAc
PhO2S F
OAc
PhO2S
87%; 95% ee
(1R,4S)-119
(1.5 equiv)
The reductive desulfonylation was accomplished with magnesium in methanol to remove the phenylsulfonyl groups to provide the corresponding enantioenriched monofluoromethylated compounds without any erosion of stereochemical integrity. The method has been applied to the preparation of fluoromethylated analogues of (S)- and (R)-ibuprofen, and 5-deoxy-5-fluoro--d-carbaribofuranose.[69] (1E,3R)-4-Fluoro-1,3-bis(4-isobutylphenyl)-4,4-bis(phenylsulfonyl)but-1-ene [(R)-117, R1 = 4-iBuC6H4]; Typical Procedure:[69]
A soln of (2E)-1,3-bis(4-isobutylphenyl)allyl acetate (116; R1 = iBuC6H4; 249 mg, 0.68 mmol), (S)-PHOX [(S)-115; 12.7 mg, 0.034 mmol, 5 mol%], and [{Pd(Å3-C3H5)Cl}2] (6.2 mg, 0.017 mmol, 2.5 mol%) in CH2Cl2 (0.7 mL) was stirred at rt for 5 min. Fluorobis(phenylsulfonyl)methane (89; 236 mg, 0.75 mmol) and Cs2CO3 (244 mg, 0.75 mmol) were added to the soln at 0 8C. The resulting soln was stirred at 0 8C for 6 h. The mixture was poured into sat. NH4Cl and the mixture was extracted with CH2Cl2. The organic phase was dried (Na2SO4) and, after removal of the solvent under reduced pressure, the product was purified by column chromatography (silica gel) to give the product as a colorless solid; yield: 350 mg (83%); 94% ee. 3.20.2.2
Difluoromethylation Reactions
Since difluoromethyllithium (F2CHLi) and difluoromethyl Grignard reagents (F2CHMgX) are prone to undergo Æ-elimination of a fluoride ion, the use of other organometallic reagents, e.g. difluoromethylcadmium, -zinc, and -copper reagents, has been examined. Unfortunately, the reactivity profile of these reagents limits the range of substrates that can be difluoromethylated and this limitation has prompted the development of alternative reagents. Difluorobis(trimethylsilyl)methane, (difluoromethyl)dimethyl(phenyl)silane, and (difluoromethyl)trimethylsilane have all been prepared, however, these reagents have not been used in the context of stereoselective difluoromethylation. Difluoromethyl phenyl sulfone (120) was first prepared in 1960,[81,82] but its utility as a powerful nucleophilic difluoromethylation reagent had been overlooked until recently (Scheme 50). [Difluoro(phenylsulfanyl)methyl]trimethylsilane (121)[83] is another reagent used for nucleophilic difluoromethylation (Scheme 50). This section details how difluoromethyl phenyl sulfone (120) has advanced the field of stereoselective difluoromethylation.[84,85] Scheme 50
Ph
S
F F
Difluoromethylating Reagents[81,83] H2O2, AcOH 105 oC 58%
O Ph
O S
F F
120
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.20.2
903
Stereoselective Fluoroalkylation 1. Mg, DMF, rt
TMSCl
2. PhSCF2Br 85%
Ph
S
TMS
F
F
121
Difluoromethyl Phenyl Sulfone (120):[81]
CAUTION: Hydrogen peroxide of concentration greater than 50% is highly corrosive and can explode violently, especially in the presence of certain metal salts and organic compounds. Difluoromethyl phenyl sulfide (21.5 g., 0.13 mol) was dissolved in glacial AcOH (60 g) and kept at 105 8C, while 90% H2O2 (12 g, 0.33 mol) was added dropwise over a period of 4 h. After most of the AcOH had been removed by distillation, the mixture was poured into H2O and the organic layer was taken up in Et2O. The Et2O soln was washed with alkali, dried (Drierite), and distilled (115–120 8C/7 Torr); yield: 15 g (58%); nD27 1.4999; mp 24.7– 25.0 8C. Other methods of preparation are available.[82–86] [Difluoro(phenylsulfanyl)methyl]trimethylsilane (121):[83]
To a mixture of Mg turnings (220 mg, 9.2 mmol), TMSCl (1.99 g, 18.3 mmol), and DMF (20 mL) at rt was added bromo(difluoro)methyl phenyl sulfide (1.1 g, 4.6 mmol). The mixture was stirred at rt for 1 h and excess TMSCl was removed under reduced pressure. The residue was washed with ice water and extracted with CH2Cl2 (3 20 mL). The combined organic phases were washed successively with brine and H2O, and dried (MgSO4). After removal of the solvent, the crude product was further purified by column chromatography (silica gel, pentane) to give the product as a colorless liquid; yield: 905 mg (85%); bp 86– 87 8C/4 Torr; 1H NMR (500 MHz, CDCl3, ): 0.25 (s, 9H), 7.37 (m, 3H), 7.59 (d, 2H); 13C NMR (125 MHz, CDCl3, ): –4.2, 126.3 (t, J = 4.1 Hz), 128.8, 129.3, 134.0 (t, J = 300.1 Hz), 136.2; 19 F NMR (470 MHz, CDCl3, ): –88.1 (s); 29Si NMR (99 MHz, CDCl3, ): 7.7 (t, J = 31.28 Hz); IR (neat): ~max: 3064, 2965, 2904, 1884, 1585, 1475, 1441, 1414, 1307, 1255, 1076, 1025, 962, 884, 850, 825, 744, 703, 690, 631, 607, 496 cm–1. 3.20.2.2.1
Diastereoselective Nucleophilic Difluoromethylation
3.20.2.2.1.1
Preparation of Homochiral Æ- and -Difluoromethyl Amines
Homochiral Æ-difluoromethyl amines (e.g., 124) are accessible from enantiopure Ellmantype N-(tert-butylsulfinyl)imines (e.g., 122) and difluoromethyl phenyl sulfone (120) (Schemes 51 and 52). The difluoro(phenylsulfonyl)methanide anion, generated in situ with either lithium hexamethyldisilazanide or potassium tert-butoxide, is sufficiently nucleophilic to add to optically active (RS)-N-(tert-butylsulfinyl)aldimines. The Cram addition products 123 are isolated in high yields and are formed as single diastereomers. The sense of induction for the newly formed stereogenic center is rationalized by a non-chelationcontrolled addition.
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Stereoselective Synthesis
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Asymmetric Fluorination and Fluoroalkylation
Scheme 51 Stereoselective Nucleophilic Difluoromethylation of (RS)N-(tert-Butylsulfinyl)imines[87] PhSO2CF2H 120 (1 equiv) LiHMDS (1.2 equiv) THF, −78 oC, 10−20 min
O But
S
R1
N
(RS)-122 (1.1 equiv)
SO2Ph R1
(RS,S)-123
R1
dra
Ph
>99:1 95
[87]
4-ClC6H4
>99:1 95
[87]
2-naphthyl
>99:1 98
[87]
2-furyl
>99:1 90
[87]
Et
>99:1 95
[87]
iPr
>99:1 94
[87]
a
F O F S But N H
Yield (%) Ref
Diastereoselectivities were determined by 19F NMR spectroscopy of the crude product.
The adducts are converted into the corresponding enantiomerically pure (S)-Æ-difluoromethyl amines (e.g., 124) in two steps, through a desulfonylation with sodium amalgam followed by acid methanolysis (Scheme 52).[87] Difluoromethylated vicinal diamines are accessible from chiral (RS,S)-Æ-amino-N-(tert-butylsulfinyl)imines [e.g., (RS,2S)-125] using a similar strategy (Scheme 53).[71] Scheme 52 F O F S But N H
Preparation of Difluoromethylated Amines[87] SO2Ph
1. Na/Hg, Na2HPO4, MeOH, −15 oC, 0.5−1 h 2. HCl, dioxane, MeOH, rt, 10−30 min
F
F Cl−
R1
R1
H3N
124
(RS,S)
R1
Yield (%) Ref
Ph
83
[87]
2-naphthyl
97
[87]
Scheme 53 Stereoselective Nucleophilic Difluoromethylation of (RS,S)-N-(tertButylsulfinyl)imines[71]
O But
S
NBn2
N R1
(RS,2S)-125 (1.1 equiv)
PhSO2CF2H 120 (1 equiv) NaHMDS (1.4 equiv) THF, −78 oC, 3−5 h
F O F S But N H
SO2Ph NBn2 R1
(RS,2S,3S)
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
R1
dra
Bn
>99:1 80
[71]
iBu
>99:1 83
[71]
s-Bu >99:1 83
[71]
Me
[71]
a
905
Stereoselective Fluoroalkylation
3.20.2
Yield (%) Ref
>99:1 95
Diastereoselectivities were determined by 19 F NMR spectroscopy of the crude product.
An interesting variation of this chemistry is the conversion of (RS)-N-(tert-butylsulfinyl)imines into chiral 2,4-disubstituted 3,3-difluoropyrrolidines using a selective nucleophilic addition/radical cyclization strategy. The diastereoselective difluoromethylation of (RS)N-(tert-butylsulfinyl)imines with [difluoro(phenylsulfanyl)methyl]trimethylsilane (121)[83] leads to the corresponding (RS,S)-difluoro(phenylsulfanyl)methylated sulfinamides 126 in good yield and with high diastereoselectivites (dr >98:2) (Scheme 54). Several Lewis initiators can be used for this addition, e.g. lithium acetate and cesium fluoride, but the optimal results are obtained with tetrabutylammonium difluorotriphenylsilicate (TBAT). Acid-catalyzed methanolysis followed by N-allylation afford the intermediates 127 required for the 5-exo radical cyclization. Treatment with tributyltin hydride and a catalytic amount of 2,2¢-azobisisobutyronitrile provides the 2,4-disubstituted 3,3-difluoropyrrolidines 128 as a mixture of diastereomers (up to 11:1) (Scheme 54).[88] The (RS,S)-difluoro(phenylsulfanyl)methylated sulfinamides are also precursors to the corresponding chiral Æ-(difluoromethyl) amines. This transformation requires reductive cleavage with tributyltin hydride/2,2¢-azobisisobutyronitrile followed by acid-catalyzed methanolysis. Overall, the construction of chiral (S)-Æ-(difluoromethyl) amines using this route is lower yielding than the one based on the difluoromethylation reagent, difluoromethyl phenyl sulfone (120).[88] Difluoromethylation Followed by Addition/Radical Cyclization[88]
Scheme 54
But
S
F
TMSCF2SPh 121 (1.1 equiv) TBAT (0.5 equiv), DMF −40 oC, 1 h, then −20 oC, 4 h
O
O F S But N H
R1
N
1. HCl, MeOH, rt 2. H2C=CHCH2Br K2CO3, DMF, rt
SPh R1
126 F
SPh
N H
Bu3SnH, AIBN
TBAT = Bu4
F
F +
R1
N H
127 N+(Ph
F
F
toluene
F
R1
N H
trans-128
R1
cis-128
)−
3SiF2
R1
Yield (%) of 126
dr of 126
Yield (%) of 127
Ratio (trans-128/cis-128)
Yield (%) of 128
Ref
Ph
75
>99:1
78
11:1
75
[88]
2-naphthyl
85
>98:2
75
10:1
77
[88]
An alternative strategy to prepare -difluoromethylated amines and alcohols utilizes 1,2cyclic sulfamidates and sulfates, respectively. Sulfamidates and sulfates are more reactive
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
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Asymmetric Fluorination and Fluoroalkylation
than the less electrophilic aziridines and epoxides, which that do not afford the expected ring-opened products in the presence of the difluoro(phenylsulfonyl)methanide anion.[89] The reaction of the anion generated in situ from difluoromethyl phenyl sulfone (120) and lithium hexamethyldisilazanide reacts with several enantiopure (S)-N-protected 1,2-cyclic sulfamidates 129[90,91] to afford, after acidic hydrolysis, the homochiral (S)--difluoro(phenylsulfonyl)methylated amines 130 in very good yield and without detectable stereochemical erosion at the existing stereogenic center (>99.5% ee) (Table 7, entry 1). Difluoromethylation of Optically Pure (S)-1,2-Cyclic Sulfamidates[89]
Table 7
R
R
1
2
O N S O
1. PhSO2CF2H 120 (1.1 equiv) LiHMDS (1.2 equiv) THF/HMPA, −78 oC, 30 min
O
R2HN
2. 20% aq H2SO4
F
F
R1
SO2Ph
(S)-129
130
R1
Entry
R2
Yield (%)
Ref
a
1
Bn
Bn
96
[89]
2
Bn
PMB
98
[89]
3
iBu
Bn
99
[89]
4
iBu
PMB
98
[89]
5
iPr
Bn
93
[89]
6
Ph
Bn
90
[89]
a
>99.5% ee.
The (S)--difluoro(phenylsulfonyl)methylated amines (e.g., 131) are converted into either the enantiomerically pure (S)--difluoromethylated amines (e.g., 132) upon reductive desulfonylation or the chiral (S)--difluoromethylenated amines (e.g., 133) via the basemediated Æ,-elimination of benzenesulfinic acid (Scheme 55). This protocol also provides access to difluoromethylated alcohols from the corresponding sulfates; however, this has only been validated on racemic substrates. Scheme 55 Reductive Desulfonylation and Æ,-Elimination of (S)--Difluoro(phenylsulfonyl)methylated Amines[89] BnHN
F
Bn
F SO2Ph
Mg, AcOH/NaOAc DMF, rt 81%
BnHN Bn
F
131 BnHN
F
Bn
132
F SO2Ph
131
F
LiHMDS, THF, rt 70%
BnHN Bn
F F
133
(RS)-N-[(S)-2,2-Difluoro-1-phenyl-2-(phenylsulfonyl)ethyl]-2-methylpropane-2-sulfinamide [(RS,S)-123, R1 = Ph]; Typical Procedure:[87]
Under N2, into a 20-mL Schlenk flask containing (RS)-(E)-N-benzylidene-2-methylpropane2-sulfinamide [(RS)-122, R1 = Ph; 440 mg, 2.1 mmol] and difluoromethyl phenyl sulfone (120; 385 mg, 2.0 mmol) in THF (10 mL) at –78 8C was added a 1.06 M soln of LiHMDS in THF soln (2.2 mL, of 2.4 mmol). The mixture was stirred at this temperature for 20 min,
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3.20.2
Stereoselective Fluoroalkylation
907
prior to the addition of brine (10 mL). The mixture was extracted with EtOAc (25 mL) and the combined organic phases were dried (MgSO4). After the removal of solvents under reduced pressure, the crude product was further purified by column chromatography (silica gel) to give the product as a white solid; yield: 763 mg (95%). The dr was determined by 19 F NMR spectroscopy of the crude product. (1S)-2,2-Difluoro-1-phenylethanamine Hydrochloride (124, R1 = Ph); Typical Procedure:[87]
CAUTION: Mercury vapor is readily absorbed by inhalation and is neurotoxic. Under N2, into a 10-mL flask containing (RS)-N-[(S)-2,2-difluoro-1-phenyl-2-(phenylsulfonyl)ethyl]-2-methylpropane-2-sulfinamide [(RS,S)-123, R1 = Ph; 180 mg, 0.45 mmol] and Na2HPO4 (510 mg, 3.6 mmol) in anhyd MeOH (5 mL) at –20 8C was added Na amalgam (10 wt% Na in Hg, 3.6 mmol net Na content). The mixture was stirred at –15 8C for 1 h. The liquid phase was decanted and most of the organic phase was removed under reduced pressure. Brine (20 mL) was added, followed by extraction with EtOAc. The combined organic phases were dried (MgSO4), and the solvent was removed to give a residue, which was dissolved in anhyd MeOH (5 mL), followed by addition of 4 M HCl in dioxane (1 mL). The mixture was stirred at rt for 30 min and concentrated to near dryness. Et2O was added to precipitate out the amine hydrochloride. The precipitate was collected by filtration and washed with Et2O; yield: 72 mg (83%). (2S)-N-Benzyl-4,4-difluoro-1-phenyl-4-(phenylsulfonyl)butan-2-amine (130, R1 = R2 = Bn); Typical Procedure:[89]
CAUTION: Hexamethylphosphoric triamide is a possible human carcinogen and an eye and skin irritant. Under N2, into a Schlenk flask containing (4S)-3,4-dibenzyl-1,2,3-oxathiazolidine 2,2-dioxide [(S)-129, R1 = R2 = Bn; 1.0 mmol] and difluoromethyl phenyl sulfone (120; 211 mg, 1.1 mmol) in THF (5 mL) and HMPA (0.5 mL) at –78 8C was added a 1.0 M soln of LiHMDS in THF (1.2 mL, 1.2 mmol) over a period of 10 min. The mixture was stirred at this temperature for 30 min, followed by the addition of 20% H2SO4 soln (5 mL). The mixture was stirred at rt for 1 h. The aqueous phase was adjusted to pH 10–12 using aq NaOH. The product was extracted with Et2O (3 10 mL) and the combined organic phases were washed with sat. NaHCO3 and dried (Na2SO4). After removal of the volatile solvents under reduced pressure, the crude product was purified by column chromatography (silica gel) to give the product as a colorless oil; yield: 399 mg (96%). (2S)-N-Benzyl-4,4-difluoro-1-phenylbutan-2-amine (132); Typical Procedure:[89]
To a 50-mL Schlenk flask containing (2S)-N-benzyl-4,4-difluoro-1-phenyl-4-(phenylsulfonyl)butan-2-amine (131; 160 mg, 0.385 mmol) in DMF (4 mL) at rt was added 8 M AcOH/ NaOAc (1:1) buffer soln (2.5 mL). Mg turnings (166 mg, 6 mmol) were added in portions. The mixture was stirred at rt for 3 h, followed by the addition of H2O (30 mL) and adjustment of the pH to 10–12 with aq NaOH. The mixture was extracted with Et2O (3 20 mL), and the combined organic phases were washed with brine and dried (Na2SO4). After removal of Et2O, the crude product was purified by column chromatography (silica gel, petroleum ether/EtOAc 5:1); yield: 86 mg (81%). (2S)-N-Benzyl-4,4-difluoro-1-phenylbut-3-en-2-amine (133); Typical Procedure:[89]
Under N2, a Schlenk flask was charged with (2S)-N-benzyl-4,4-difluoro-1-phenyl-4-(phenylsulfonyl)butan-2-amine (131; 145 mg, 0.35 mmol) in THF (3 mL). A 1.0 M soln of LiHMDS in THF (1.4 mL, 1.4 mmol) was added dropwise at 0 8C. The mixture was stirred at rt for 6 h, and the reaction was monitored by TLC. After completion, the reaction was quenched with sat. NH4Cl and the mixture was extracted with Et2O (3 15 mL). The combined organ-
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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ic phases were dried (Na2SO4) and filtered, and the solvent was removed. The crude product was purified by column chromatography (silica gel, petroleum ether/EtOAc 10:1); yield: 67 mg (70%). 3.20.2.2.1.2
Preparation of Chiral Difluoromethylated 1,3-Diols
Difluoromethyl phenyl sulfone (120) is a versatile reagent which can react stepwise with two electrophiles when used in combination with an appropriate alkoxide that acts both as a base and as a nucleophile. In this case, the reagent can be regarded as a difluoromethylene dianion (CF2–) or a linchpin synthon (Scheme 56).[92] Scheme 56 O Ph
Double Functionalization of Difluoromethyl Phenyl Sulfone[92]
O S
O
RO− M+
F
Ph
O S
F
O
E+
F
Ph
F
F
E
E
F
F
E+
−OR1
E F
O O E S Ph R1O F F
E F
O S
F
The synthetic utility of this synthon has been demonstrated by the treatment of excess benzaldehyde (134, R1 = Ph) with difluoromethyl phenyl sulfone (120) in the presence of potassium tert-butoxide in dimethylformamide to afford the C2-symmetrical disubstituted 1,3-diol 135 (R1 = Ph) in excellent yield and with high diastereoselectivity (anti/syn 97:3). The observed diastereoselectivity was attributed to a charge–charge repulsion effect during the second addition rather than steric control based on Crams model. The method is optimal for electron-deficient and non-enolizable aldehydes (Scheme 57). Scheme 57 Stereoselective Synthesis of anti-2,2-Difluoropropane-1,3-diols from Aldehydes[92] PhSO2CF2H 120 (1 equiv) t-BuOK (4 equiv) DMF, −50 oC to rt
O R1
OH R1
H
R1 F
134 (3 equiv)
F 135
R1
dr (anti/syn)a Yield (%) Ref
Ph
97:3
82
[92]
4-ClC6H4
94:6
78
[92]
4-BrC6H4
96:4
70
[92]
4-MeOC6H4
94:6
52
[92]
2-naphthyl
97:3
69
[92]
4-PhC6H4
96:4
75
[92]
2-furyl
93:7
63
[92]
a
OH
19
Ratios were determined by F NMR spectroscopy.
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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This methodology also allows the construction of unsymmetrical anti-2,2-difluoropropane-1,3-diols (e.g., 136), as illustrated by the coupling of difluoromethyl phenyl sulfone (120) with benzaldehyde and 4-chlorobenzaldehyde (Scheme 58). Scheme 58
OH O O S Ph Ph F F
PhSO2CF2H 120 NaOH/H2O/CH2Cl2
O Ph
Synthesis of an Unsymmetrical anti-2,2-Difluoropropane-1,3-diol[92]
H
90%
Cl
OH
CHO (2 equiv)
t-BuOK (3 equiv), DMF, −50
oC
76%; dr 96:4
to rt
OH
Ph F
F Cl 136
(1R*,3R*)-2,2-Difluoro-1,3-diphenylpropane-1,3-diol (135, R1 = Ph); Typical Procedure:[92]
The reaction was carried out in a Schlenk flask under argon. To a DMF soln (5 mL) of PhSO2CF2H (120; 480 mg, 2.5 mmol) and PhCHO (134, R1 = Ph; 800 mg, 7.5 mmol) at –50 8C was added a DMF soln (5 mL) of t-BuOK (1.12 g, 10 mmol). The reaction flask was sealed and the mixture was stirred at –50 8C for 1 h, followed by stirring at –50 8C to rt overnight. The reaction was quenched with iced water (20 mL) and the mixture was extracted with Et2O (20 mL). The combined organic phases were washed with sat. NH4Cl followed by H2O. After drying (MgSO4), Et2O was removed under reduced pressure. The crude product was further purified by column chromatography (silica gel, hexane/EtOAc 9:1 to 1:1) to give the product as a white, crystalline solid; yield: 541 mg (82%); dr (anti/syn) 97:3, determined by 19F NMR spectroscopy. 3.20.2.2.2
Electrophilic and Radical Difluoromethylation
Although asymmetric nucleophilic difluoromethylation is by far the best method for preparing difluoromethylated compounds, other strategies have also been examined. For example, the electrophilic difluoromethylation of oxygen, nitrogen, sulfur, phosphorus, and carbon nucleophiles using dibromo(difluoro)methane as a precursor of difluorocarbene has been described.[93–95] The reaction of lithium enolates of chiral N-acyloxazolidinones with bromo(difluoro)methane affords the Æ-difluoromethyl carboximides with modest yields (~ 45%) and diastereomeric ratios (up to 28:1). These reactions involve insertion of the in situ generated difluorocarbene rather than a more conventional nucleophilic attack.[96] Sporadic examples of stereoselective radical difluoromethylation have been explored in the context of carbohydrate chemistry. The addition of bromo(difluoro)methane and dibromo(difluoro)methane to glycals has been studied using sodium dithionite as the radical initiator and the addition products are then subjected to reductive debromination with tributyltin hydride and 2,2¢-azobisisobutyronitrile.[97] Similarly, several 2-acyloxy glycal derivatives undergo free-radical difluoromethylation with bromo(chloro)difluoromethane followed by selective hydrodechlorination to afford difluoromethylated monosaccharides. This method suffers from modest yields and stereoselectivities.[98,99]
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3.20.2.3
Trifluoromethylation Reactions
3.20
Asymmetric Fluorination and Fluoroalkylation
As for other fluorine-containing substituents, the incorporation of a trifluoromethyl group confers valuable physiological properties on drug-like molecules by enhancing binding selectivity, improving metabolic stability, and modulating lipophilicity. The introduction of a trifluoromethylated stereogenic center has been the subject of considerable research, with a focus on nucleophilic 1,2-trifluoromethylation of ketones and sulfinylimines. The reagent most commonly employed for stereoselective nucleophilic trifluoromethylation is trimethyl(trifluoromethyl)silane (137, Ruppert–Prakash reagent), which typically requires in situ activation with a fluoride source (Scheme 59). Other nucleophilic initiators may be used, for example alkoxides, amines, N-oxides, dimethylformamide, dimethyl sulfoxide, carbonates, acetates, and phosphates. Stereoselective electrophilic trifluoromethylations are less well developed despite the ready availability of trifluoro(iodo)methane (138) (Scheme 59). This reagent suffers from several drawbacks, including toxicity, flammability, and high volatility. Building on some pioneering work,[100] a variety of S-(trifluoromethyl)dibenzothiophenium salts (e.g., 139) are commercially available and are effective in the electrophilic trifluoromethylation of heteronucleophiles (Scheme 59). Scheme 59 Most Commonly Used Commercially Available Trifluoromethylating Reagents Me Me Si CF3 Me 137
Ruppert−Prakash reagent
F
I
F
F
S CF3
138
139
BF4−
Umemoto's reagent
It has been reported that a hypervalent trifluoromethyl iodine(III) reagent is also a suitable and mild electrophilic trifluoromethylating reagent for both carbon- and heteroatom-centered nucleophiles.[101,102] More recently, [(oxido)phenyl(trifluoromethyl)-º4-sulfanylidene]dimethylammonium tetrafluoroborate has been prepared, a reagent suitable for the electrophilic trifluoromethylation of selected carbon nucleophiles.[103] SAFETY: Trimethyl(trifluoromethyl)silane (TMSCF3) is a highly flammable liquid (bp 54–55 8C). It should be stored between 2–8 8C and inhalation of its vapor should be avoided. Trifluoro(iodo)methane is supplied as a compressed gas (bp 22.5 8C). It is a mutagen and chronic exposure may lead to irreversible effects. 3.20.2.3.1
Diastereoselective Nucleophilic Trifluoromethylation
3.20.2.3.1.1
Trifluoromethylation of Carbohydrates
In the context of carbohydrate chemistry, the replacement of a methyl group with a hydrophobic trifluoromethyl group is valuable for molecular recognition.[104] In addition, the electron-withdrawing effect of the trifluoromethyl group can increase resistance to hydrolysis, which provides longer half-lives for the carbohydrates. This is an important characteristic for applications in biomedical sciences, for example in vivo 19F NMR spectroscopy.[105] The trifluoromethyl group may also be used to control the equilibrium between pyranose and furanose forms. Table 8 illustrates representative diastereoselective trifluoromethylations of various carbohydrates: ribofuranose 140 to trifluoromethylated derivative 141 (entry 1),[106] pentodialdoses 142 and 144 to trifluoromethylated carbohydrates 143 and 145 (entries 2 and 3, respectively),[107] 3-oxoglucose 146 to trifluoromethylated alcohol 147 (entry 4), ketone ribose 148 to trifluoromethylated alcohol 149 (entry 5),[108] pentodialdose 150 to trifluo-
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romethylated derivative 151 (entry 6),[109] and pentopyranosid-2-uloses 152 and 154 to trifluoromethylated compounds 153 and 155 (entries 7 and 8, respectively).[110] All reactions employ trimethyl(trifluoromethyl)silane (137) activated with either tetrabutylammonium fluoride or tetrabutylammonium difluorotriphenylstannate (less nucleophilic compared with tetrabutylammonium fluoride)[111,112] to provide the corresponding trifluoromethylated species with excellent levels of diastereocontrol. Trifluoromethylation of Carbohydrates with Trimethyl(trifluoromethyl)silane[106–110]
Table 8
Entry Starting Material
Product
BzO
1
70
[106]
80:20 95
[107]
88:12 98
[107]
O
HO 140
141
HO
O
O
O
O
F3C
2
H
O
BnO
O
BnO 142
143 HO
O
O
O
O
F3C
H
O
O
O
O 144
145 O
O O
O
O
O
O
4
O
F3 C O
O
88
[107]
100:0
45
[108]
147
Cl
Cl O
Cl
OMe
O
Cl
OMe
O
O Cl
100:0 O
HO
146
5
100:0
O F 3C
O
O
3
Ref
O
O
OHC
Yield (%)
BzO
O
OHC
dr
O
O
Cl
CF3 O
Cl
Cl
148
149
OH
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis Table 8
3.20
Asymmetric Fluorination and Fluoroalkylation
(cont.)
Entry Starting Material
TBDMSO
Product
TBDMSO
O
O
HO
150
O
7
O F3C O
152
OH
OBn
O F3C
O
154
[109]
100:0
64
[110]
100:0
65
[110]
OBn
O
O O
86
153
O
8
100:0
OMe
O O
O
O
151
OMe
O
Ref
O F3C
O
Yield (%)
O
O
6
dr
O
OH
155
Trifluoromethylated Carbohydrate Derivatives 143 and 145 (Table 8, Entries 2 and 3, Respectively); General Procedure for Trifluoromethylation of Carbohydrates:[107]
Pentodialdose 142 or 144 (2–10 mmol) was dissolved in anhyd CH2Cl2 (5 mL • mmol–1) and the soln was cooled to 0 8C. Then, TMSCF3 (137; 1.1 equiv) and a catalytic amount of tetrabutylammonium difluorotriphenylstannate were added. The reaction was warmed to rt and stirred until completion. The mixture was treated with 2 M HCl. After partition between sat. NH4Cl and CH2Cl2, the organic layer was dried (MgSO4), filtered, and concentrated. The crude product was analyzed by 1H NMR spectroscopy to determine the dr. Separation of the epimers was performed using column chromatography (silica gel). 5-O-(tert-Butyldimethylsilyl)-1,2-O-isopropylidene-3-C-(trifluoromethyl)-Æ-d-ribofuranose (151; Table 8, Entry 6):[109]
5-O-(tert-Butyldimethylsilyl)-1,2-O-isopropylidene-Æ-d-erythro-pentofuranos-3-ulose (150) was dehydrated by azeotropic distillation from a soln in toluene before use. To a stirred soln of the nonhydrated keto compound (1 mmol) in THF (5 mL) was added TMSCF3 (137; 1.1 mmol) and a catalytic amount of TBAF (20 mg for 10 mmol) at rt. When the reaction was complete, the mixture was washed with sat. NH4Cl. The aqueous layer was extracted with Et2O (2 10 mL) and the organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. To the crude product dissolved in MeOH was added a catalytic amount (0.1 equiv) of metallic Na at 0 8C. The reaction was complete within 1 h; the mixture was then treated with sat. NH4Cl and the aqueous layer was extracted with Et2O. The combined organic layers were dried (Na2SO4). After purification by column chromatography (silica gel, petroleum ether/EtOAc 97:3), the product was obtained as an oil; yield: 86%. 3.20.2.3.1.2
Trifluoromethylation of Steroidal Derivatives
One of the most versatile methods for the trifluoromethylation of steroidal ketones (e.g., 156) uses trimethyl(trifluoromethyl)silane (137) and tetrabutylammonium fluoride (Scheme 60). The corresponding trifluoromethylcarbinols (e.g., 157) are typically formed
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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as single diastereomers.[113] For hindered ketones (e.g., 158 and 160), the replacement of tetrabutylammonium fluoride with tetramethylammonium fluoride (smaller ammonium cation) gives superior conversions. The O-silylated intermediates are readily converted into unprotected trifluoromethylated carbinols (e.g., 159 and 161) with 40% aqueous hydrogen fluoride (Scheme 60).[114] Scheme 60
Trifluoromethylation of Steroidal Derivatives[113,114] OH
O 1. TMSCF3 137 (2.4 equiv) TBAF (2 equiv), THF 2. aq HCl
H H
H
CF3
H H
62%; dr >99:1
H
MeO
MeO 156
157
OH
O
CF3
1. TMSCF3 137 Me4NF (cat.), THF 2. 40% aq HF 83%; dr >99:1
AcO
AcO 158
159
OH
O
CF3
1. TMSCF3 137 Me4NF (cat.), THF 2. 40% aq HF 88%; dr >99:1
HO
HO 160
161
3-Methoxy-17-(trifluoromethyl)estra-1,3,5(10)-trien-17-ol (157); Typical Procedure:[113]
A mixture of 3-methoxyestra-1,3,5(10)-trien-17-one (10 mmol) and TMSCF3 (24 mmol, 2.4 equiv) in THF (10 mL) cooled to 0 8C was treated with TBAF (2 equiv). Instantaneously, a yellow color developed with release of fluorotrimethylsilane, and the mixture was brought to rt and stirred. The mixture was periodically analyzed by GC. The resulting siloxy compound was hydrolyzed with aq HCl. The mixture was extracted with Et2O (75 mL), and the combined Et2O extracts were washed with H2O (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. The residue was purified; yield: 62%; dr >99:1. Steroidal Trifluoromethylcarbinols 159 and 161; General Procedure:[114]
CAUTION: Hydrogen fluoride fumes are severely irritating and extremely destructive to the respiratory system. To an ice-cooled soln of the keto steroid 158 or 160 (200 mg) in THF (1.5 mL) was added TMSCF3 (137; 0.3 mL) and Me4NF (10 mg). The mixture was stirred at 0 8C for 30 min and at rt for 4 h. After removal of THF, the residue was dissolved in MeCN (2 mL), followed by the addition of 40% aq HF (1 mL). The soln was stirred at rt for 30 min. The mixture was extracted with Et2O (75 mL), and the combined Et2O extracts were washed with H2O (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography (silica gel).
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3.20.2.3.1.3
Asymmetric Synthesis of Trifluoromethylated Aldehydes, Diols, Amino Alcohols, and Triols
3.20.2.3.1.3.1
Trifluoromethylated Aldehydes, 1,2-Diols, and 1,2-Amino Alcohols
3.20
Asymmetric Fluorination and Fluoroalkylation
A protocol[115] has been developed for the preparation of enantiomerically enriched trifluoromethylated 1,2-diols and 1,2-amino alcohols, which involves the diastereoselective addition of trimethyl(trifluoromethyl)silane (137) to chiral 2-acylperhydro-1,3-benzoxazines (e.g., 162) derived from (–)-menthol.[116] This method is applicable to the synthesis of diols and amino alcohols in which the trifluoromethyl group is a quaternary stereocenter. The feasibility of the reaction was demonstrated with various aromatic and aliphatic derivatives (Scheme 61). In all cases, excellent 1,2-stereoinduction is observed in agreement with the Felkin–Anh model, in which the alcohols (e.g., 163) are formed as essentially single diastereomers. The optimal reaction conditions employ tetrahydrofuran and anhydrous cesium fluoride. Interestingly, the nucleophilic activator, tetrabutylammonium fluoride, provides lower chemical yields and diastereoselectivities, in which the former is presumably a consequence of its hygroscopic character.[117] Scheme 61
Trifluoromethylation of 2-Acylperhydro-1,3-benzoxazines[115] 1. TMSCF3 137 (1.5 equiv) CsF (0.025 equiv), THF, 0 oC
N
O
O
2. TBAF (1 equiv), rt, 1 h
N
R1
Bn
HO CF3 R1
Bn
162
163
R1
dra
Ph
>50:1 95
[115]
4-MeOC6H4
>50:1 93
[115]
2-furyl
>50:1 96
[115]
iPr
>50:1 95
[115]
Bu
>50:1 94
[115]
Et
>50:1 90
[115]
a
O
Yield (%) Ref
Diastereoselectivities determined by 1H and 19F NMR spectroscopy.
The chiral auxiliary of the alcohols (e.g., 164 and 166) can be cleaved hydrolytically (hydrochloric acid/ethanol) or reductively (hydrochloric acid/ethanol then sodium borohydride/ethanol), leading to enantiopure trifluoromethylated aldehydes (e.g., 165) or diols (e.g., 167), respectively, in moderate yields (Scheme 62). Alternatively, reductive ring opening of the alcohols (e.g., 166) with aluminum trihydride followed by oxidation with pyridinium chlorochromate and treatment with sodium hydroxide leads to trifluoromethylated 1,2-amino alcohols (e.g., 168) (Scheme 62).
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Fluoroalkylation
Scheme 62 Synthesis of Trifluoromethylated Aldehydes, 1,2-Diols, and 1,2Amino Alcohols[115] OMe
N
O
2% HCl/EtOH reflux, 1 h
HO CF3
64%
Bn
OH OHC
OMe 164
CF3
165
1. 2% HCl/EtOH reflux, 1 h 2. NaBH4, EtOH 0 oC, 1.5 h 62%
Ph OH
HO
CF3 167 N
O
HO CF3
Bn 166
Ph
1. AlH3, THF, −10 oC to rt 2. PCC, CH2Cl2 3. NaOH 4. HCl
Ph 44%
OH
HCl• BnHN
CF3 168
1-(3-Benzyl-4,4,7-trimethyloctahydro-2H-1,3-benzoxazin-2-yl)-2,2,2-trifluoroethanols 163; General Procedure for Trifluoromethylation of 2-Acylperhydro-1,3-benzoxazines:[115]
To a soln of the ketone (2 mmol) and CsF (0.05 mmol) in THF (50 mL), cooled to 0 8C under argon was added dropwise a soln of TMSCF3 (137; 3 mmol) in THF (1.5 mL). The mixture was stirred at this temperature until the reaction was complete (TLC). Subsequently, TBAF (2 mmol) was added, and the mixture was stirred for 1 h at rt. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, hexane/EtOAc). (2S)-3,3,3-Trifluoro-2-hydroxy-2-(4-methoxyphenyl)propanal (165); Typical Procedure:[115]
A soln of trifluoromethylated perhydrobenzoxazine 164 (4 mmol) in EtOH (60 mL) and 2% aq HCl (30 mL) was refluxed until the hydrolysis was complete (TLC, 1 h). After removal of EtOH by distillation at atmospheric pressure, the aqueous layer was extracted with hexane (3 60 mL). The organic extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The product was obtained as a white solid and was purified by sublimation (90 8C/0.5 Torr); yield: 64%. (2S)-3,3,3-Trifluoro-2-phenylpropane-1,2-diol; (167); Typical Procedure:[115]
A soln of trifluoromethylated perhydrobenzoxazine 166 (4 mmol) in EtOH (60 mL) and 2% aq HCl (30 mL) was refluxed until the hydrolysis was complete (TLC, 1 h). After removal of EtOH by distillation at atmospheric pressure, the aqueous layer was extracted with hexane (3 60 mL). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue from the hydrolysis was dissolved in EtOH (15 mL) and powdered NaBH4 (1.5 mmol) was added in portions at 0 8C. The mixture was stirred at 0 8C for 1.5 h (TLC) and quenched by addition of 5% HCl (3 mL). After removal of EtOH, the aqueous layer was extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine,
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.20
Asymmetric Fluorination and Fluoroalkylation
dried (MgSO4), and concentrated. The residue was purified by column chromatography (silica gel, hexane/CH2Cl2 4:1). The product was further purified by sublimation (125 8C/ 5 Torr); yield: 62%. (2S)-3-(Benzylamino)-1,1,1-trifluoro-2-phenylpropan-2-ol Hydrochloride (168); Typical Procedure:[115]
CAUTION: Aluminum trichloride dust is a severe irritant to all tissues and reacts violently with water. CAUTION: Solid lithium aluminum hydride reacts vigorously with a variety of substances, and can ignite on rubbing or vigorous grinding. CAUTION: Pyridinium chlorochromate can cause cancer by inhalation. It is very toxic to aquatic organisms and may cause long-term adverse effects in the aquatic environment. Dry AlCl3 (1.3 mmol) was added in portions to a stirred suspension of LiAlH4 (5.3 mmol) in THF (26 mL) cooled to –10 8C. The mixture was stirred for 10 min and a soln of trifluoromethylated perhydrobenzoxazine 166 (1.3 mmol) in THF (13 mL) was added slowly. The mixture was stirred at rt until the reduction was complete (TLC, 5–20 h) and subsequently quenched by slow addition of H2O. The solid was filtered and washed with hot EtOAc, the organic layer was dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EtOAc) and the product was obtained as a white solid; yield: 95%; mp 104–105 8C (hexane). A soln of the aminomenthol derivative (1.64 mmol) and PCC (1.41 g, 6.56 mmol) in CH2Cl2 (40 mL) and 3- molecular sieves (1 g) was stirred under argon until the oxidation was finished (TLC, 1–2 d). The solvent was removed under reduced pressure. The residue was dissolved in 10% aq NaOH until pH 12 (30 mL) and the resulting soln was stirred for 6 h at rt. The solids were filtered off and washed with CHCl3 and the organic layer was decanted. The aqueous layer was extracted with CHCl3 (5 35 mL). The combined organic extracts were washed with brine and dried (MgSO4), and the solvents were removed. The free amino alcohol was purified by flash chromatography (silica gel, hexanes/EtOAc). The amino alcohol was transformed into its hydrochloride by slow bubbling of HCl through a soln of the amino alcohol in Et2O and filtration. The hydrochloride 168 was obtained as a white solid; yield: 44%; mp 251–252 8C (Et2O). 3.20.2.3.1.3.2
Asymmetric Synthesis of 2-(Trifluoromethyl)-1,2,3-triols
A convenient approach to enantiopure 2-trifluoromethylated 1,2,3-triols has been developed via the diastereoselective trifluoromethylation of alkylated dioxanones (e.g., 169) followed by simple deprotection. The starting enantiomerically pure Æ-alkylated dioxanones have been prepared through the condensation of 2,2-dimethyl-1,3-dioxan-5-one with (S)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP), followed by alkylation and subsequent racemization-free oxidative cleavage of the auxiliary.[118–122] The trifluoromethylation of (S)-169 is successfully performed with excellent levels of diastereocontrol (dr ‡98:2) using trimethyl(trifluoromethyl)silane (137) activated with either catalytic or stoichiometric amounts of tetrabutylammonium fluoride to afford the trifluoromethylated dioxanols (4S,5S)-170 in moderate to high yields (Table 9). The enantiomeric Æ-trifluoromethylated dioxanols (4R,5R)-170 are obtained from the corresponding R-configured dioxanones 169 in an analogous manner. The trifluoromethylation of enantiopure dioxanone 169 [R1 = R3 = Me; R2 = (CH2)5Me); Table 9, entry 6] bearing substituents on both Æ- and Æ¢-positions is equally successful, creating two vicinal quaternary stereogenic centers; however, this method is not applicable to dioxanones that have two side chains of similar steric demand (low dr).
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.20.2
917
Stereoselective Fluoroalkylation Trifluoromethylation of Enantiopure Alkylated Dioxanones[123]
Table 9 O
R2
R1
R3 O
CF3 R2
HO
TMSCF3 137 (1.5 equiv)
R1
TBAF, THF, 0 oC
O
O
(4S,5S)-170
(S)-169
Entry R1
R2
R3
dra
1
Me
H
H
‡98:2 69b
[123]
2
Et
H
H
‡98:2 86c
[123]
b
Yield (%) Ref
3
iPr
H
H
‡98:2 75
[123]
4
Bu
H
H
‡98:2 64c
[123]
H
c
[123]
c
[123]
5
(CH2)5Me
6 a b c
R3
O
H
Me
(CH2)5Me 1
Me
‡98:2 94 ‡98:2 77
13
Determined by H and C NMR spectroscopy. Stoichiometric amounts of TBAF used. Catalytic amounts of TBAF used.
The trifluoromethylated triols (e.g., 172) are prepared via the deprotection of the acetonide group of the trifluoromethylated dioxanols (e.g., 171) using freshly activated Dowex 50 in ethanol without any erosion of stereochemical integrity (Scheme 63).[123] Scheme 63 HO
Cleavage of the Acetonide Protecting Group[123] CF3
HO
CF3
Dowex 50, EtOH, rt
4
O (4S,5S)-171
O
90%; dr >98:2
4
OH
OH
172
2,2-Dimethyl-5-(trifluoromethyl)-1,3-dioxan-5-ols 170; General Procedure for Trifluoromethylation of Enantiopure Dioxanones with a Catalytic Amount of Tetrabutylammonium Fluoride:[123]
TBAF (0.05–0.1 equiv) was added to a stirred soln of dioxanone 169 (1.0 equiv) and TMSCF3 (137; 1.5 equiv) in THF (5–6 mL/mmol dioxanone 169) at 0 8C. The mixture was warmed to rt. After completion (TLC), TBAF (1.5 equiv) was added and the mixture was stirred for 1 h and then quenched with H2O. The aqueous layer was extracted with Et2O and the combined organic layers were washed with H2O and brine. The organic layer was dried (MgSO4) and concentrated. The crude product was purified by column chromatography (silica gel). 2,2-Dimethyl-5-(trifluoromethyl)-1,3-dioxan-5-ols 170; General Procedure for Trifluoromethylation of Enantiopure Dioxanones with Stoichiometric Amounts of Tetrabutylammonium Fluoride:[123]
TBAF (1.5 equiv) was added to a soln of dioxanone 169 (1.0 equiv) and TMSCF3 (1.5 equiv) in THF (5–6 mL/mmol dioxanone 169) at 0 8C. The mixture was warmed to rt. After completion (TLC), the mixture was quenched with H2O. The aqueous layer was extracted with Et2O and the combined organic layers were washed with H2O and brine. The organic layer was dried (MgSO4) and concentrated. The crude product was purified by column chromatography (silica gel).
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
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Asymmetric Fluorination and Fluoroalkylation
(2S,3S)-2-(Trifluoromethyl)nonane-1,2,3-triol (172):[123]
(4S,5S)-4-Hexyl-2,2-dimethyl-5-(trifluoromethyl)-1,3-dioxan-5-ol [(4S,5S)-171; 0.107 g, 0.38 mmol] was dissolved in EtOH (0.3 mL). After addition of freshly activated Dowex 50, the mixture was stirred until completion of the reaction (TLC). The solid was removed by filtration and washed with Et2O and the organic layer was dried (MgSO4) and concentrated under reduced pressure. After purification by column chromatography (silica gel, pentane/Et2O 4:1 then Et2O), the product was obtained as a colorless oil; yield: 0.084 g (90%); dr ‡98:2. 3.20.2.3.1.4
Asymmetric Synthesis of Trifluoromethylated Amines and Diamines
Chiral trifluoromethylated amines and diamines are accessible through the stereoselective nucleophilic trifluoromethylation of chiral N-sulfinylimines with trimethyl(trifluoromethyl)silane (137). The trifluoromethylation of various (RS)-N-(tert-butylsulfinyl)imines (e.g., 173 and 175) with soluble fluoride activator tetrabutylammonium difluorotriphenylsilicate (TBAT) provides excellent diastereocontrol. In this process, tetrabutylammonium difluorotriphenylsilicate reacts with trimethyl(trifluoromethyl)silane (137) to form a trifluoromethylated pentavalent silicon intermediate with a large tetrabutylammonium counterion. This species approaches the less sterically hindered Re face of the (RS)-sulfinylimines (e.g., 173 and 175) to afford the Cram addition products (e.g., 174 and 176) (Schemes 64 and 65). The trifluoromethylated chiral (RS)-sulfinamides (e.g., 177) can be transformed to the corresponding chiral trifluoromethylated amines (e.g., 178) with hydrochloric acid in methanol (Scheme 66).[124] The method has also been applied to the preparation of partially protected diamines (Scheme 66).[125] Scheme 64
Trifluoromethylation of (RS)-Sulfinylimines[124] TMSCF3 137 (1.2 equiv) TBAT (1.1 equiv) THF, −55 oC, 0.5−1 h
O But
S
N
R1
O But
(RS)-173
S
CF3 R1
N H
(RS,S)-174
TBAT = Bu4N+(Ph3SiF2)−
R1
dr
Yield (%) Ref
97:3 80
[124]
4-BrC6H4
>99:1 90
[124]
4-ClC6H4
>99:1 95
[124]
2-pyridyl
99:1 95
[124]
2-naphthyl
96:4 83
[124]
Cy
99:1 88
[124]
Ph
Scheme 65 Trifluoromethylation of (RS,2S)-Æ-Amino-N-(tertbutylsulfinyl)imines[125]
O But
S
NBn2
N R1 (RS,2S)-175
TMSCF3 137 (1.5 equiv) Me4NF (1.2 equiv) THF, −35 oC, 1−2 h
O But
S
CF3 N H
NBn2 R1
(RS,2S,3S)-176
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.20.2
R1
dr (%) Yield (%) Ref
Me >99:1 86
[125]
Pr
>99:1 85
[125]
Bn >99:1 81
[125]
iBu >99:1 71
[125]
Scheme 66 O But
919
Stereoselective Fluoroalkylation
S
Synthesis of Trifluoromethylated Amines and Diamines[124–126]
CF3
CF3
4 M HCl/dioxane, MeOH rt, 30 min
N H
>99% ee
Cl−
H 3N Br
Br 178
(RS)-177
O But
S
CF3 N H
NBn2
1. HCl (10 equiv), dioxane/MeOH 2. sat. NaHCO3 3. Pd/C, H2, MeOH/CH2Cl2 83%
Bn
(RS,2S,3S)
CF3 NH2
H2N Bn (2S,3S)
The trifluoromethylation of the structurally related chiral (SS)-N-(4-tolylsulfinyl)imines with trimethyl(trifluoromethyl)silane (137) activated with the Lewis base tetrabutylammonium acetate has also been studied. The diastereomeric products are formed in high yield and with excellent selectivity (typically >95:5). As for the previous sulfinamides, the chiral auxiliary was removed from the diastereomerically pure product with 1 M hydrochloric acid to furnish the enantiopure trifluoromethylated amine.[127] N-(2,2,2-Trifluoroethyl)-2-methylpropane-2-sulfinamides (RS,S)-174; General Procedure for Diastereoselective Trifluoromethylation of (RS)-Sulfinylimines:[124]
TMSCF3 (137; 0.6 mmol) in THF (2 mL) was added to a mixture of the (RS)-sulfinylimine (RS)173 (0.5 mmol) and TBAT (0.55 mmol) in THF (8 mL) at –55 8C. The soln was stirred for 0.5– 1 h. Disappearance of the white slurry of TBAT indicated completion of the reaction. Sat. NH4Cl (2 mL) was added at the same temperature and the mixture was then warmed to rt. The mixture was extracted with EtOAc, and the combined organic layers were dried (Na2SO4). Removal of the solvent followed by column chromatography (silica gel) gave the products. N-[1-(Dibenzylamino)-3,3,3-trifluoropropan-2-yl]-2-methylpropane-2-sulfinamides (RS,2S,3S)-176; General Procedure for Diastereoselective Trifluoromethylation of (RS,2S)-Æ-Aminosulfinylimines:[125]
Into a 25-mL dry flask containing THF (5 mL) was placed the (RS,2S)-Æ-aminosulfinylimine (RS,2S)-175 (0.5 mmol) and Me4NF (1.2 equiv). The resulting soln was cooled to –35 8C and a soln of TMSCF3 (137; 1.5 equiv) in THF (5 mL) was added slowly via syringe. The mixture was stirred at –35 8C until the reaction was complete. The mixture was warmed to –10 8C and the reaction was quenched with sat. NH4Cl (2 mL). The mixture was extracted with EtOAc, dried (Na2SO4), and concentrated. The crude product was purified by column chromatography (silica gel, hexane/EtOAc).
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
920
Stereoselective Synthesis
3.20
Asymmetric Fluorination and Fluoroalkylation
(1S)-1-(4-Bromophenyl)-2,2,2-trifluoroethanamine Hydrochloride (178); Typical Procedure:[126]
To a soln of (RS)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-2-methylpropane-2-sulfinamide [(RS)-177; 0.82 mmol] in MeOH (0.42 mL) was added 4 M HCl in dioxane (0.41 mL, 1.64 mmol). The mixture was stirred at rt for 30 min. Et2O was added to precipitate the amine hydrochlorides. The precipitate was collected by filtration and washed with Et2O or hexanes; yield: not given; >99% ee. 3.20.2.3.2
Enantioselective Trifluoromethylation
3.20.2.3.2.1
Nucleophilic Trifluoromethylation of Aryl Ketones, Aryl Aldehydes, and Azomethine Imines
Enantiopure Æ-trifluoromethylated alcohols (e.g., 180) are readily available from prochiral aryl ketones using trimethyl(trifluoromethyl)silane (137) in the presence of catalytic amounts of tetramethylammonium fluoride and chiral ammonium salts (e.g., 179) derived from cinchona alkaloids. The reactions are typically performed at low temperatures (–40 8C to –80 8C), with stirring for up to 30 hours prior to addition of an aqueous solution of tetrabutylammonium fluoride. The resulting tetrasubstituted trifluoromethylated aryl alcohols 180 are isolated in good yield and with good to excellent enantioselectivity (Scheme 67).[128] A similar transformation has been reported using a fluoride-free catalytic system consisting of the cinchona alkaloid derivatized as a quaternary ammonium bromide (5 mol%) and sodium hydride (50 mol%).[129] Scheme 67
Enantioselective Nucleophilic Trifluoromethylation of Aryl Ketones[128] Br−
N
Br−
HO H
H
N
N HO
N 179
1. TMSCF3 137 (2 equiv), 10 mol% 179 10 mol% Me4NF, toluene/CH2Cl2 (2:1) −60 to −50 oC 2. TBAF/H2O (2:1), THF, rt, 1 h
O R1
R2
HO
CF3
R1
R2 180
R1
R2
2-naphthyl
Me
6
85
87
[128]
6-methyl-2-naphthyl
Me
30
88
74
[128]
4-BrC6H4
Me
3
86
81
Time (h) ee (%) Yield (%) Ref
[128] a
[128] [128]
4-BrC6H4
Et
12
93
84
4-MeOC6H4
Me
7
89
84b
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.20.2
921
Stereoselective Fluoroalkylation
R1
R2
4-FC6H4
Me
7
87
96
[128]
4-Tol
Me
12
88
94
[128]
24
86
82b,c
[128]
Time (h) ee (%) Yield (%) Ref
MeO a b c
Reaction carried out at –80 to –70 8C. 20 mol% of tetramethylammonium fluoride was used. Reaction carried out at –50 to –40 8C.
The preparation of Æ-trifluoromethylated alcohols from aryl aldehydes is significantly more challenging, with only a few reported cases to date. This reaction is performed with either chiral ammonium fluorides derived from cinchona alkaloids or chiral triamino sulfonium salts as reported by Prakash and Iseki, respectively.[130] The trifluoromethylation of aromatic aldehydes has been examined using a catalytic system featuring a chiral quaternary ammonium salt combined with a chiral binaphtholate but the enantioselectivity is modest (up to 71%).[131] The asymmetric catalytic nucleophilic trifluoromethylation of ketones or aldehydes using trimethyl(trifluoromethyl)silane (137) activated by chiral Lewis bases has been attempted but has not proven very successful. A catalytic asymmetric reaction has been developed for the preparation of trifluoromethylated amines based on an enantioselective trifluoromethylation of azomethine imines (e.g., 182) with trimethyl(trifluoromethyl)silane (137) and a chiral phase-transfer catalyst (e.g., 181) derived from a cinchona alkaloid. Azomethine imines are advantageous as they are significantly more reactive than N-tosylimines. The optimum conditions consist of treating the azomethine imine with excess trimethyl(trifluoromethyl)silane (137) and potassium hydroxide in the presence of a chiral ammonium bromide catalyst (e.g., 181) (10 mol%) in toluene/dichloromethane to afford trifluoromethylated pyrazolidines (e.g., 183) (Scheme 68). Azomethine imines derived from aromatic aldehydes are optimal substrates for this process. Scheme 68 Catalytic Enantioselective Trifluoromethylation of Azomethine Imines[132]
HO N
Br−
R1
H N R1 181
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
922
Stereoselective Synthesis
3.20
Asymmetric Fluorination and Fluoroalkylation
TMSCF3 137 (4 equiv) 10 mol% 181 KOH (6 equiv)
O N
O HN
toluene/CH2Cl2 (2:1) −50 oC
N
N
R2
R1
R2
CF3
182
(S)-183
R2
Time (h) ee (%) Yield (%) Ref 17
90
94
[132]
t-Bu 4-Tol
8
90
87
[132]
t-Bu 3-MeOC6H4
3
92
73
[132]
t-Bu 4-MeOC6H4
8
95
84
[132]
t-Bu 4-t-BuC6H4
3
98
88
[132]
t-Bu 4-FC6H4
12
89
89
[132]
t-Bu 4-ClC6H4
9
86
81a
[132]
t-Bu 2-naphthyl
4
90
95
[132]
CF3 Ph
t-Bu Cy a
b
7
71
b
[132]
85
Reaction was carried out at –50 8C and warmed to –40 8C over 2 h. Reaction was carried out at –70 8C and warmed to –60 8C over 2 h.
Following enantioselective trifluoromethylation, the trifluoromethylated amine (e.g., 184) is prepared by the treatment of the trifluoromethylated pyrazolidine (e.g., 183) with Raney nickel in methanol at 180 8C for 16 hours followed by addition of concentrated hydrochloric acid for two days at 100 8C. Amazingly, this process occurs without loss of enantiopurity. Nevertheless, the harsh reaction conditions required for the preparation of the free amine means that this method will be restricted in substrate scope (Scheme 69).[132] Scheme 69 O
1. Raney Ni, MeOH 180 oC, 16 h 2. concd HCl, 100 oC, 2 d
HN N Ph
Preparation of a Trifluoromethylated Amine[132]
72%
NH3 Ph
Cl−
CF3
CF3
(S); 90% ee
184
(S); 90% ee
Æ-Trifluoromethylated Alcohols 180; General Procedure for Enantioselective Trifluoromethylation of Aryl Ketones:[128] To a stirred soln of the aryl ketone (30.0 mg, 0.180 mmol), finely ground cinchona alkaloid derivative 179 (15.0 mg, 0.018 mmol), and Me4NF (1.6 mg, 0.018 mmol) in toluene/CH2Cl2 (2:1; 0.5 mL) was added TMSCF3 (137; 52.2 L, 0.350 mmol) at –80 8C under N2. After stirring for 6 h at the same temperature, the reaction was quenched with sat. NH4Cl. The aqueous layer was extracted with EtOAc (2 5 mL), and the combined organic layers were washed with brine, dried (MgSO4), and concentrated under reduced pressure to furnish the crude product as the trimethylsilyl ether. The trimethylsilyl ether was treated with TBAF (50.6 mg, 0.19 mmol) in THF (1.5 mL) at rt for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatogra-
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.20.2
Stereoselective Fluoroalkylation
923
phy (silica gel, acetone/hexanes 10:1); yield: 74–96%. The ee of the products were determined by chiral HPLC (Chiralcel OD-H or AD-H column) or GC analysis. 5,5-Dimethyl-1-(2,2,2-trifluoroethyl)pyrazolidin-3-ones 183; General Procedure for Enantioselective Trifluoromethylation of Azomethine Imines:[132]
To a stirred soln of azomethine imine 182 (0.10 mmol; prepared by a modified literature procedure[133]), alkaloid derivative 181 (0.01 mmol, 10 mol%), and KOH (33.7 mg, 0.60 mmol) in toluene/CH2Cl2 (2:1; 1.0 mL) was added TMSCF3 (137; 59.1 L, 0.40 mmol) at –50 8C under N2. After stirring at the same temperature for the time indicated in Scheme 68, the reaction was quenched with sat. NH4Cl. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes/EtOAc 1:1); yield: 73–95%. (1S)-2,2,2-Trifluoro-1-phenylethanamine Hydrochloride (184):[132]
To an aqueous suspension of Raney nickel (900 mg) in H2O (12.6 mL) was added NaOH (1.7 g) at rt (note: this process is exothermic). The stirred mixture was heated at 70 8C for 20 min. After cooling down to rt, the suspension was washed with H2O (3 9 mL) and MeOH (5 6 mL). A mixture of 5,5-dimethyl-[(1S)-1-(2,2,2-trifluoro-1-phenylethyl]pyrazolidin-3-one (90% ee; 100 mg, 0.367 mmol) and activated Raney nickel in MeOH (5.0 mL) was heated at 180 8C for 16 h in a sealed tube. After cooling to rt, the mixture was filtered (Celite), washing with hot MeOH, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EtOAc 3:7) to obtain the diamine intermediate as a white solid; yield: 73.1 mg (73%). A soln of this residue (30.0 mg, 0.109 mmol) in concd HCl (2.5 mL) was stirred at 100 8C for 2 d. After cooling down to rt, the soln was concentrated. The solid was collected by filtration, washed with Et2O (10 mL), and freeze-dried to give the product as a white solid; yield: 22.7 mg (98%). 3.20.2.3.2.2
Electrophilic Trifluoromethylation of -Keto Esters
Asymmetric electrophilic trifluoromethylation reactions are rare and very little progress has been made since the early studies in this area.[134] The trifluoromethylation of the potassium enolate derived from ethyl phenyl ketone has been performed with 5-(trifluoromethyl)dibenzo[b,d]thiophenium tetrafluoroborate (139) in the presence of a stoichiometric amount of chiral borepin, leading to the corresponding enantioenriched Æ-trifluoromethylated ketone in 41% yield and with 42% ee.[134] More recently, the trifluoromethylation of -keto esters has been performed using the same trifluoromethylating reagent, albeit using a stoichiometric amount of a chiral guanidine base 185. Although the enantiomeric excesses for the trifluoromethylated -keto esters 186 do not exceed 70%, this work stands out for advancing the field of asymmetric electrophilic trifluoromethylation (Scheme 70).[135]
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
924
Stereoselective Synthesis Scheme 70
Asymmetric Fluorination and Fluoroalkylation
3.20
Electrophilic Trifluoromethylation of -Keto Esters[135]
BF4− (1.2 equiv)
S CF3 139 Ph
H N
Ph
N H
N
O
(1.1 equiv)
Ph
O
185
CO2R1
CF3
solvent (0.1 M), 1−2 h
CO2R1 186
R1
Solvent
Me
CHCl3/CH2Cl2 (1:1) –80
70
63
[135]
Et
CHCl3/CH2Cl2 (1:1) –80
67
59
[135]
Bn
CHCl3
–40
63
56
[135]
CH2CF3 CHCl3
–40
66
49
[135]
Temp (8C) ee (%) Yield (%) Ref
Alkyl 1-Oxo-2-(trifluoromethyl)-2,3-dihydro-1H-indene-2-carboxylates 186; General Procedure for Asymmetric Electrophilic Trifluoromethylation:[135]
To a stirred 0.1 M soln of the -keto ester (10 mg, 0.0526 mmol) in the solvent indicated in Scheme 70 (0.5 mL) was added the chiral guanidine 185 (19.8 mg, 0.0579 mmol), and the mixture was stirred for 10 min at rt and for 5 min at –40 8C. 5-(Trifluoromethyl)dibenzo[b,d]thiophenium tetrafluoroborate (139; 21.5 mg, 0.0631 mmol) was added, and the mixture was stirred for 1 h at the temperature indicated in Scheme 70. The reaction was quenched with sat. NH4Cl and the mixture was extracted with EtOAc (3 3 mL). The combined organic phases were concentrated, and the residue was purified by column chromatography (silica gel). The ee was determined by HPLC (Chiralcel OD-H or AD-H column); yield: 49–63%. 3.20.2.3.2.3
Asymmetric Radical Æ-Trifluoromethylation of Aldehydes
A conceptually new strategy has been developed which combines enamine and organometallic photoredox catalysis to provide a catalytic asymmetric route to Æ-trifluoromethylated aldehydes using trifluoro(iodo)methane (138) as the trifluoromethylating reagent. This remarkable transformation relies on the propensity of the electrophilic radical derived from the reduction of trifluoro(iodo)methane (138) by the iridium-based photoredox catalyst 187, to combine with facially biased chiral enamine intermediates generated with the trifluoroacetic acid salt of organocatalyst (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one (188•TFA) (Scheme 71). The reaction has broad scope and tolerates a range of substrates inclusive of Æ-arylated aldehydes. Moderate to high yields and excellent levels of enantiocontrol are key features of this trifluoromethylation process (Scheme 71). The trifluoromethylated aldehydes can be converted into the corresponding alcohols (e.g., 189) by reduction (Scheme 71), Æ-trifluoromethylated carboxylic acids (e.g., 190) by oxidation, -trifluoromethylated amines (e.g., 191) via reductive amination, and Æ-trifluoromethylated carbamates (e.g., 192) via Curtius rearrangement (Scheme 72).[136]
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.20.2
925
Stereoselective Fluoroalkylation Enantioselective Radical Æ-Trifluoromethylation of Aldehydes[136]
Scheme 71
+ But N O
N BF6−
Ir N
NMe •TFA
N H
N
But
But 187
188•TFA
1. 0.5 mol% photocatalyst 187 20 mol% organocatalyst 188•TFA 2,6-lut, DMF, 26-W household light, −20 oC 2. NaBH4, MeOH, −78 oC
O + CF3I
H
OH CF3
H
R1
R1 189
138
R1
ee (%) Yielda (%) Ref
(CH2)5Me
99
79
[136]
(CH2)3OBn
95
72
[136]
(CH2)3CO2Et
97
86
[136]
(CH2)3NPhth
98
78
[136]
Cy
99
70
[136]
98
70
[136]
97
75
[136]
N Boc
Bn a
Isolated yields of the corresponding alcohol.
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
926
Stereoselective Synthesis Scheme 72
3.20
Asymmetric Fluorination and Fluoroalkylation
Access to Enantioenriched Trifluoromethylated Derivatives[136] O TEMPO, PhI(OAc)2
CF3
HO Bn 190 O CF3
H
BnNH2•AcOH NaBH3CN, CH2Cl2
94%; 96% ee
CF3
BnHN Bn
Bn 191
97% ee 1. TEMPO, PhI(OAc)2 2. DPPA, t-BuOK, 110 oC, 10 h
95%; 87% ee
NHBoc Bn 192
CF3 88%; 92%ee
DPPA = (PhO)2P(O)N3
Trifluoromethylated Alcohols 189; General Procedure for Enantioselective Radical Æ-Trifluoromethylation of Aldehydes Followed by Reduction with Sodium Borohydride:[136]
CAUTION: Trifluoro(iodo)methane iodide is supplied as a compressed gas (bp 22.5 8C).It is a mutagen and chronic exposure may lead to irreversible effects. To an oven-dried 13 mm 100 mm borosilicate test tube was added the TFA salt of (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one (188; 43.2 mg, 0.200 equiv) and iridium complex 187[137] (3.5 mg, 0.005 equiv). The tube was fitted with a septum, degassed through alternating vacuum evacuation/argon backfill cycles (3 ), and cooled to –78 8C before DMF (2.5 mL) was added. The resulting yellow soln was further degassed by alternating vacuum evacuation/argon backfill cycles (3 ) at –78 8C. CF3I (138; ca. 1.20 g, 8.1 equiv) was then condensed using a cold finger fitted with an 18 gauge needle. The aldehyde (0.76 mmol, 1.0 equiv) and 2,6-lut (97.4 L, 1.1 equiv) were added by syringe and the test tube was placed in a –20 8C acetone-containing cryocool approximately 3 cm from a 26-W compact fluorescent light bulb (daylight GE Energy Smart 1600 lumens) that was inserted into a Pyrex glass tube insert. After 7.5–8 h, the test tube was removed, cooled to –78 8C, and transferred by precooled pipet to a round-bottomed flask containing CH2Cl2 (4.0 mL) at –78 8C. Cold CH2Cl2 (8.0 mL, –78 8C) was then used to transfer the remaining residue and NaBH4 (288 mg, 10 equiv) was added followed by cold MeOH (10 mL, –78 8C). The mixture was stirred for 1 h at –78 8C before being quenched with sat. NH4Cl (10 mL). The resulting soln was warmed to rt and extracted with Et2O, and the combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The crude oil was then purified by column chromatography (silica gel) to furnish the desired alcohol product; yield: 70–86%. (2S)-2-Benzyl-3,3,3-trifluoropropanoic Acid (190); Typical Procedure:[136]
Cold CH2Cl2 (4.0 mL, –20 8C) was used to transfer (2S)-2-benzyl-3,3,3-trifluoropropanal. PhI(OAc)2 (0.490 g, 2 equiv) was added, followed by TEMPO (0.024 g, 0.2 equiv) and cold H2O (3.8 mL). The mixture was stirred for 2 h at –20 8C before being quenched with 1 M aq Na2SO3 (10 mL). The resulting soln was warmed to rt and poured into a separating funnel containing 1 M NaOH (25 mL) and CH2Cl2 (25 mL), and the organic materials were removed by extraction with CH2Cl2. The remaining aqueous layer was then acidified with 1 M HCl and extracted with CH2Cl2 (3 30 mL). The combined organic layers were dried
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.20.2
Stereoselective Fluoroalkylation
927
(MgSO4) and concentrated under reduced pressure. The crude oil was purified by column chromatography (silica gel, Et2O/pentanes 1:1); yield: 94%; 96% ee. (2S)-N,2-Dibenzyl-3,3,3-trifluoropropan-1-amine (191); Typical Procedure:[136]
Crude (2S)-2-benzyl-3,3,3-trifluoropropanal was taken up in CH2Cl2 (2.5 mL) and cooled to –40 8C before NaBH3CN (0.095 g, 2.0 equiv) and BnNH2•AcOH (0.762 g, 6.00 equiv) were added. The reaction flask was kept at –40 8C for 2 h before being allowed to warm to rt overnight. The reaction was quenched by addition of sat. NaHCO3 followed by brine. The aqueous layer was then extracted with CH2Cl2 and EtOAc. The organic layers were combined, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification of the product was achieved using flash chromatography (basic silica packed as a slurry in 3% Et3N in hexanes, CH2Cl2/EtOAc/hexanes 10:5:85); yield: 95%; 87% ee tert-Butyl [(2R)-1,1,1-Trifluoro-3-phenylpropan-2-yl]carbamate (192); Typical Procedure:[136]
CAUTION: Diphenylphosphoryl azide is toxic by inhalation, in contact with skin and if swallowed. Crude (2S)-2-benzyl-3,3,3-trifluoropropanoic acid (190) was subjected to Curtius rearrangement by transfer with t-BuOH (7.6 mL, 0.1 M) to a sealed Pyrex tube containing t-BuOK (94 mg, 1.1 equiv) and 4- molecular sieves (1.0 wt equiv). After addition of diphenylphosphoryl azide (DPPA; 0.36 mL, 2.2 equiv) and purging with argon before sealing the tube, the reaction was stirred for 10 h at 110 8C, then cooled to rt and quenched with a 1 M citric acid soln (20 mL). The resulting soln was extracted with CH2Cl2, and the combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated under reduced pressure. The crude oil was then purified by column chromatography (silica gel, Et2O/pentane 15:85); yield: 88%; 92% ee.
Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo for references see p 928 Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Asymmetric Fluorination and Fluoroalkylation
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Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions, Gouverneur, V., Lo Science of Synthesis 4.0 version., Section 3.20 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Asymmetric Fluorination and Fluoroalkylation
[88]
Li, Y.; Hu, J., Angew. Chem., (2007) 119, 2541; Angew. Chem. Int. Ed., (2007) 46, 2489. Ni, C.; Liu, J.; Zhang, L.; Hu, J., Angew. Chem., (2007) 119, 800; Angew. Chem. Int. Ed., (2007) 46, 786. [90] Posakony, J. J.; Tewson, T. J., Synthesis, (2002), 766. [91] Williams, A. J.; Chakthong, S.; Gray, D.; Lawrence, R. M.; Gallagher, T., Org. Lett., (2003) 5, 811. [92] Prakash, G. K. S.; Hu, J.; Mathew, T.; Olah, G. A., Angew. Chem., (2003) 115, 5374; Angew. Chem. Int. Ed., (2003) 42, 5216. [93] Kirsch, P., Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Wiley-VCH: Weinheim, Germany, (2004). [94] Brahms, D. L. S.; Dailey, W. P., Chem. Rev., (1996) 96, 1585. [95] Burton, D. J.; Hahnfeld, J. L., Fluorine Chem. Rev., (1977) 8, 119. [96] Iseki, K.; Asada, D.; Takahashi, M.; Nagai, T.; Kobayashi, Y., Tetrahedron: Asymmetry, (1996) 7, 1205. [97] Miethchen, R.; Hein, M.; Reinke, H., Eur. J. Org. Chem., (1998), 919. [98] Wegert, A.; Miethchen, R.; Hein, M.; Reinke, H., Synthesis, (2005), 1850. [99] Wegert, A.; Hein, M.; Reinke, H.; Hoffmann, N.; Miethchen, R., Carbohydr. Res., (2006) 341, 2641. [100] Yagupolskii, L. M.; Kondratenko, N. V.; Timofeeva, G. N., Zh. Org. Khim., (1984) 20, 115; J. Org. Chem. USSR (Engl. Transl.), (1984) 20, 103. [101] Eisenberger, P.; Gischig, S.; Togni, A., Chem.–Eur. J., (2006) 12, 2579. [102] Kieltsch, I.; Eisenberger, P.; Togni, A., Angew. Chem., (2007) 119, 768; Angew. Chem. Int. Ed., (2007) 46, 754. [103] Noritake, S.; Shibata, N.; Nakamura, S.; Toru, T.; Shiro, M., Eur. J. Org. Chem., (2008), 3465. [104] Bansal, R. C.; Dean, B.; Hakomori, S.-i.; Toyokuni, T., J. Chem. Soc., Chem. Commun., (1991), 796. [105] Welch, J. T.; Eswarakrishnan, S., Fluorine in Bioorganic Chemistry, Wiley: New York, (1991). [106] Johnson, C. R.; Bhumralkar, D. R., Nucleosides Nucleotides, (1995) 14, 185. [107] Lavaire, S.; Plantier-Royon, R.; Portella, C., Tetrahedron: Asymmetry, (1998) 9, 213. [108] Schmit, C., Synlett, (1994), 241. [109] Lavaire, S.; Plantier-Royon, R.; Portella, C., J. Carbohydr. Chem., (1996) 15, 361. [110] Eilitz, U.; Bçttcher, C.; Hennig, L.; Burger, K.; Haas, A.; Gockel, S.; Sieler, J., J. Heterocycl. Chem., (2003) 40, 329. [111] Gingras, M., Tetrahedron Lett., (1991) 32, 7381. [112] Brigaud, T.; Doussot, P.; Portella, C., J. Chem. Soc., Chem. Commun., (1994), 2117. [113] Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S., J. Org. Chem., (1991) 56, 984. [114] Wang, Z.; Ruan, B., J. Fluorine Chem., (1994) 69, 1. [115] Pedrosa, R.; Sayalero, S.; Vicente, M.; Maestro, A., J. Org. Chem., (2006) 71, 2177. [116] He, X.-C.; Eliel, E. L., Tetrahedron, (1987) 43, 4979. [117] Prakash, G. K. S.; Yudin, A. K., Chem. Rev., (1997) 97, 757. [118] Hoppe, D.; Schmincke, H.; Kleemann, H.-W., Tetrahedron, (1989) 45, 687. [119] Vorbrggen, H., Acta Chem. Scand., Sect. B, (1982) 36, 420. [120] Enders, D.; Bockstiegel, B., Synthesis, (1989), 493. [121] Enders, D.; Voith, M., Synthesis, (2002), 1571. [122] Enders, D.; Voith, M.; Ince, S. J., Synthesis, (2002), 1775. [123] Enders, D.; Herriger, C., Eur. J. Org. Chem., (2007), 1085. [124] Prakash, G. K. S.; Mandal, M.; Olah, G. A., Angew. Chem., (2001) 113, 609; Angew. Chem. Int. Ed., (2001) 40, 589. [125] Prakash, G. K. S.; Mandal, M., J. Am. Chem. Soc., (2002) 124, 6538. [126] Liu, G.; Cogan, D. A.; Ellman, J. A., J. Am. Chem. Soc., (1997) 119, 9913. [127] Kawano, Y.; Mukaiyama, T., Chem. Lett., (2005) 34, 894. [128] Mizuta, S.; Shibata, N.; Akiti, S.; Fujimoto, H.; Nakamura, S.; Toru, T., Org. Lett., (2007) 9, 3707. [129] Hu, X.; Wang, J.; Li, W.; Lin, L.; Liu, X.; Feng, X., Tetrahedron Lett., (2009) 50, 4378. [130] Kuroki, Y.; Iseki, K., Tetrahedron Lett., (1999) 40, 8231. [131] Zhao, H.; Qin, B.; Liu, X.; Feng, X., Tetrahedron, (2007) 63, 6822. [132] Kawai, H.; Kusuda, A.; Nakamura, S.; Shiro, M.; Shibata, N., Angew. Chem., (2009) 121, 6442; Angew. Chem. Int. Ed., (2009) 48, 6324. [133] Sibi, M. P.; Rane, D.; Stanley, L. M.; Soeta, T., Org. Lett., (2008) 10, 2971. [134] Umemoto, T.; Adachi, K., J. Org. Chem., (1994) 59, 5692. [135] Noritake, S.; Shibata, N.; Nomura, Y.; Huang, Y.; Matsnev, A.; Nakamura, S.; Toru, T.; Cahard, D., Org. Biomol. Chem., (2009) 7, 3599. [136] Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C., J. Am. Chem. Soc., (2009) 131, 10 875. [137] Slinker, J. D.; Gorodetsky, A. A.; Lowry, M. S.; Wang, J.; Parker, S.; Rohl, R.; Bernhard, S.; Malliaras, G. G., J.Monofluoromethylation, Am. Chem. Soc., (2004)Difluoromethylation, 126, 2763. Asymmetric Fluorination, and Trifluoromethylation Reactions, Gouverneur, V., Lo [89]
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Stereoselective Polymerization J.-F. Carpentier and E. Kirillov
General Introduction
Previously published information regarding this topic can be found in part in Houben– Weyl, Vol. E 20, and more recently in Science of Synthesis, Vol. 48 [Alkanes (Section 48.5)]. Among the various criteria that define individually and collectively macromolecular chains contained in a polymer, main-chain stereoregularity, also referred to as tacticity, is arguably a major parameter in determining material properties and its applications. Chemists have therefore continuously made efforts to develop even more stereoselective synthetic protocols, to manipulate the intrinsic properties of polymers and provide scientists and engineers with materials with even greater performance. A myriad of macromolecular compounds have been prepared over the past two centuries, and probably several dozen are eligible for inclusion in this chapter; thus, in this contribution, a selection of the most important classes of tactic polymers has been made. The focus here is also only on polymer classes for which highly stereoselective (typically >90%) syntheses are available. Monomer enchainments to create macromolecules can proceed in a variety of fundamentally different chemical pathways: ionic (anionic or cationic), free-radical, and coordinative–catalytic polymerizations. Although the former types, i.e. anionic and free-radical polymerizations, are probably the most common and traditional techniques, they are arguably not as selective as coordinative–catalytic polymerizations in terms of stereocontrol.[1] The past decades have witnessed major breakthroughs in metal-catalyzed polymerizations, with the revolution of “single-site” catalysis.[2] This has allowed not only a deeper understanding of fundamental processes but has also resulted in the achievement of unprecedented levels of stereocontrol for a variety of tactic polymers, with many new classes being accessible for the first time. Accordingly, a prominent position has been reserved for “single-site” catalysis in this chapter. However, more classical synthetic techniques (often based on more readily available reagents/initiators) are also considered whenever they offer comparable performance. 3.21.1
Stereoselective Polymerization of Propene: Isotactic Polypropene; Syndiotactic Polypropene
Polypropene (PP) is an inexpensive engineering thermoplastic with a global production of ca. 45 Mt • year–1 worldwide. A myriad of microstructures, featuring different relative configuration at adjacent stereogenic methine carbon atoms, have been reported for polypropene (Scheme 1).[3] The most commercially valuable material is isotactic polypropene (1, iPP) (see experimental procedure in Section 3.21.1.1), a highly crystalline material (Tm = 160–165 8C) with attractive physical properties (e.g., strength, toughness, chemical and heat resistance). Highly stereoregular syndiotactic propene (2, sPP) (see experimental procedure in Section 3.21.1.2) also shows an interesting range of specific properties (e.g., Tm up to 154 8C, toughness, clearness, and stability to gamma irradiation). Polypropenes with mixed, controlled stereochemistry are also available (Scheme 1). For instance, isotactic-
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Stereoselective Polymerization
atactic and isotactic-hemiisotactic stereoblock (e.g., 3) polypropene homopolymers are also reported to have potential applications owing to their thermoplastic elastomeric properties. Scheme 1
Principal Microstructures for Poly(propene)s isospecific catalyst n
1
isotactic
syndiospecific catalyst n
2
syndiotactic
6n n
hemiisotactic
n−m
m
isotactic-atactic stereoblock
n−m
3
3.21.1.1
m
isotactic-hemiisotactic stereoblock
Isotactic Polypropene
Isotactic polypropene was first obtained by Natta and Ziegler using a heterogeneous polymerization catalyst.[4] Commercial isotactic polypropene, with [m]4 up to 99%, is traditionally either produced in bulk (liquid propene) or in the gas phase, using so-called “fourthgeneration” heterogeneous Ziegler–Natta catalytic systems, namely, the combination of titanium(IV) chloride/magnesium chloride/phthalate ester–triethylaluminum–dimethoxydiorganosilane.[5] Highly isospecific polymerization of propene can also be achieved using two different families of homogeneous metallocene catalysts (Scheme 2) and methylaluminoxane (MAO) as activator ([Al]/[Zr] = 500–15 000 equiv). The sophisticated, bulky C2-symmetric metallocene 4 yields isotactic polypropene with [m]4 of 99.1% and Tm = 161 8C.[6] The simpler, fluorenyl-based, C1-symmetric precursor 5 affords isotactic polypropene with [m]4 = 98.1% and Tm = 162 8C.[7] Very high polymerization stereoselectivity requires that these reactions are conducted in liquid propene (Tpolym = 60–70 8C, P >10 atm). In a related study, a rather simple and highly isospecific catalytic system is composed of titanium(III) chloride as a precatalyst and bis(Å5-cyclopentadienyl)dimethyltitanium(IV) as the cocatalyst.[8] The polymerization takes place at 40 8C in heptane at atmospheric propene pressure and affords virtually pure isotactic polypropene with [m]4 = 99.2%; Tm = 165.2 8C; Mw = 1 130 000 g • mol–1; Mw/Mn = 7.8 [Mw: weight-average molecular weight; Mn: number-average molecular weight; Mw/Mn: molecular weight distribution (polydispersity)].
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Stereoselective Polymerization of Propene
Scheme 2 Metallocene Precatalysts for Highly Isospecific Propene Polymerization[6–8]
But
But
Me Si
ZrCl2
ZrCl2
Me
But
5
4
Isotactic Polypropene (1); Typical Procedure:[8]
Heptane (92 mL) and TiCl3 (154 mg, 1.0 mmol) were introduced under an inert atmosphere into a 200-mL glass reactor equipped with a magnetic stirrer. The reactor was purged under reduced pressure, and propene (1 atm) was introduced. After the mixture had stirred for 20 min at 40 8C, the polymerization was started by adding a soln of Ti(Me)2(Cp)2 (416 mg, 2.0 mmol) in heptane (8 mL). The polymerization was carried out at 40 8C for 15 min, and then the reactor was vented in air and an excess of MeOH/HCl soln was added to precipitate the polymer. The polymer was collected by filtration, washed with MeOH, and dried under reduced pressure. The crude polymer was fractionated with hot heptane to afford pure isotactic polypropene; yield: 1.12 g. 3.21.1.2
Syndiotactic Polypropene
Preferential formation of syndiotactic polypropene was first disclosed by Natta, using heterogeneous catalytic systems derived from vanadium salts and dialkylaluminum monohalides, e.g. vanadium(IV) chloride–diethylaluminum chloride–anisole (Tpolym 98.0% and Tm = 151–153 8C) are achieved with metallocenes 7 in toluene[13] and 8.[14] Polymerizations are carried out with methylaluminoxane ([Al]/[Zr] = 1000–2500) at 0 8C in liquid propene and give syndiotactic polypropene with the following characteristics (using precatalyst 7): [r]4 >99%; Tm = 153.0 8C; Mw = 961 000 g • mol–1; Mw/Mn = 2.1; or (with precatalyst 8); [r]4 = 98.9%; Tm = 151.0 8C. Scheme 3 Metallocene Precatalysts for Highly Syndiospecific Propene Polymerization[12–14] Pri
Me ZrCl2
Ph
ZrCl2
Ph
Si SiMe2 ZrCl2 Me
Pri Pri
6
7
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Stereoselective Polymerization
Syndiotactic Polypropene (2); Typical Procedure:[13]
CAUTION: All polymerization procedures should be performed behind a blast shield. A 100-mL glass pressure reactor was charged under an inert atmosphere with dry methylaluminoxane (75 mg, 1.3 mmol Al; obtained immediately prior to use from a commercial toluene soln by removal of all volatiles under reduced pressure). Propene (30 mL, 437 mmol; dried through a Matheson 6410 drying system equipped with an OXYSORB column) was condensed in at 0 8C using an ice–water bath. A soln of metallocene 6 (0.6 mol) in toluene (1.0 mL) was injected by syringe and the mixture was stirred at 0 8C for 10 min. The reactor was vented and the reaction was quenched with dilute HCl/MeOH. Syndiotactic polypropene was separated from hydrolyzed aluminoxanes by precipitation from MeOH, followed by filtration and drying in vacuo; yield: 0.48 g. 3.21.2
Stereoselective Polymerization of Higher Alk-1-enes: Isotactic Poly(hex-1-ene) and Poly(oct-1-ene); Syndiotactic Poly(hex-1-ene) and Poly(oct-1-ene)
Despite the potential availability of the same stereoregular configurations as for polypropenes, only isotactic and syndiotactic poly(alk-1-ene)s are documented to date. Due to the presence of long hydrocarbyl tails, these polymers typically feature rather low crystallinity and melting temperature (Tm 95
76 500
[20]
95
155 000
[21]
Range of molecular weights obtained using different concentrations of hex-1-ene (0.15– 1.5 M).
Isotactic Poly(hex-1-ene) (9, R1 = Bu); Typical Procedure:[18]
Hex-1-ene (7.5 mL, 60.4 mmol) and then toluene (50 mL) were added under an inert atmosphere to a 50-mL glass reactor equipped with a magnetic stirrer bar. B(C6F5)3 (24.6 mg, 0.048 mmol) was added to the soln. In a separate flask the precatalyst was obtained by dissolving racemic complex 11 (X = Me; 8.1 mg, 0.048 mmol) in toluene (2 mL). The polymerization was started by injection of the precatalyst soln held at 0 8C into the toluene soln of hex-1-ene. After the mixture had been stirred at 0 8C for 2 min, the polymerization was quenched by the addition of 5 M MeOH in toluene (1 mL). The polymer soln was then passed through an activated alumina column to remove byproducts generated from the quenched catalysts. The volatiles were evaporated from the eluent and the purified polymer was weighed; yield: 0.51 g (10%). Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.21.2.2
Syndiotactic Poly(alk-1-ene)s
3.21
Stereoselective Polymerization
Highly syndiotactic polymers 10 from pent-1-ene, hex-1-ene, and oct-1-ene (see Scheme 4) are prepared using Cs-symmetric metallocenes, such as the precatalyst 6 (Scheme 6), activated by methylaluminoxane (MAO).[16] However, the bulkier analogue 15 provides better results in terms of stereoselectivity (see Table 2).[22] Scheme 6 Precatalysts for Highly Syndiospecific Alk-1-ene Polymerization[16,22] But
But Ph
ZrCl2
ZrCl2 Ph
6
Table 2
15
Syndiospecific Polymerizations of Alk-1-enes[16,22]
Precatalyst
R1
Polymerization Conditions
[r]4 (%) Ref Mw (g • mol–1)
6
Pr
bulk, MAO (1000 equiv vs Zr), 25 8C
56 000
89
[16]
6
Bu
bulk, MAO (1000 equiv vs Zr), 25 8C
42 500
86
[16]
6
(CH2)5Me
bulk, MAO (1000 equiv vs Zr), 25 8C
45 000
79
[16]
15
Pr
toluene, MAO (7800 equiv vs Zr), 25 8C
–
91
[22]
15
Bu
toluene, MAO (7800 equiv vs Zr), 25 8C
–
89
[22]
15
(CH2)5Me
toluene, MAO (7800 equiv vs Zr), 25 8C
–
88
[22]
Syndiotactic Poly(alk-1-ene)s 10; General Procedure:[22]
A 170-mL glass reactor equipped with a heat jacket and a magnetic stirrer was evacuated under reduced pressure for 60 min at 95 8C and then flushed several times with argon. After cooling to 25 8C, the reactor was charged with dry methylaluminoxane (0.40 g, 7.8 mmol Al; obtained from a commercial toluene soln prior to use by the removal of all volatiles under reduced pressure), the alk-1-ene (100 mmol; to provide a 1.0 M soln), and toluene (100 mL). The polymerization was started by injection of a soln of the precatalyst 15 (1.0 mol) in toluene (1 mL). After 20 min, the reaction was quenched by the addition of a 1:1 mixture of 2 M HCl and EtOH (5 mL). The resulting polymer soln was stirred overnight at rt with a 1:1 mixture of 2 M HCl and EtOH (60 mL). After phase separation, the organic phase was washed with sat. aq NaHCO3 (1 ) and with H2O (2 ). The soln was evaporated to dryness and the polymer was dried overnight in vacuo at 60 8C; yield: 0.84 g (10%). 3.21.3
Stereoselective (Co)Polymerization of Styrene: Isotactic and Syndiotactic Polystyrenes
Polystyrene (PS) can be prepared in atactic (aPS), isotactic (iPS) 16, and syndiotactic (sPS) 17 configurations. While atactic polystyrene is commonly produced by radical (thermic) polymerization, highly stereoregular isotactic and syndiotactic polystyrenes can be prepared using early transition metal catalysts (Scheme 7).[23] In contrast to atactic polystyrene, which is an amorphous material, isotactic and syndiotactic polystyrenes are semiStereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective (Co)Polymerization of Styrene
crystalline polymers, with Tm up to 240 8C and 265–275 8C, respectively, while maintaining a glass transition temperature (Tg) of 100 8C. In practice, the crystallinity of isotactic polystyrene is very low due to the slow crystallization rate. On the other hand, syndiotactic polystyrene crystallizes at a relatively high rate and up to four crystalline forms have been observed. Stereoregular copolymers of styrene, including long syndiotactic sequences alternated with monomer units such as ethene and isoprene, to eventually break the crystallinity while maintaining other inherent advantages of syndiotactic polystyrene, have also been developed.[24] Scheme 7
Main Microstructures for Polystyrene Ph
Ph
Ph
Ph
catalyst n
16
isotactic (racemic)
4n Ph Ph
Ph
Ph
Ph
catalyst n
17
syndiotactic
Experimental procedures for the preparation of isotactic and syndiotactic polystyrenes can be found in Sections 3.21.3.1 and 3.21.3.2, respectively. 3.21.3.1
Isotactic Polystyrene
Isotactic polystyrene was discovered in 1955 by Natta using heterogeneous catalysts based on titanium(IV) chloride/trialkylaluminum binary systems.[15,25] Other simple related systems such as titanium(III) chloride/trialkylaluminum,[26] titanium(III) chloride/methylaluminoxane,[27] and vanadium(III) chloride/aluminum trichloride[28] are also effective, affording fractions of isotactic polystyrene with isotacticity [m]4 up to 95%. One obvious advantage of these Ziegler–Natta type catalyst systems is their simplicity and availability. However, they all lead to polymers with a broad molecular weight distribution (Mw/Mn » 5–10) and require tedious time- and solvent-consuming fractionation procedures to isolate the highly isotactic ([m]4 up to 99%) polystyrene fraction from the significant amount of atactic polymer produced systematically. More recently, a highly isospecific polymerization of styrene with homogeneous single-site catalysts has been described (Scheme 8). Dichlorotitanium complexes 18 (R1 = t-Bu, CMe2Ph), based on tetradentate dianionic dithia-bis(phenolate) ligands activated by methylaluminoxane, generate highly active catalysts that give isotactic polystyrene with Tm up to 225 8C, high molecular weights up to 2 600 000 g • mol–1, and relatively narrow molecular weight distributions (Mw/Mn ~2), albeit fractionation is still required to isolate pure isotactic polystyrene.[29] With an enantiomerically pure variant 19 of such catalyst precursors, optically active isotactic oligostyrenes terminated by few hexene units are obtained.[30] (Allyl)yttrocenes 20 (R1 = H; n = 1) or 20 (R1 = TMS; n = 0), supported by an isopropylidenebis(indenyl) ligand, are single-component catalysts (i.e., they do not require any activator) that are even more isospecific for the polymerization of styrene. Isotactic polystyrene with Mn up to 100 000 g • mol–1, Mw/Mn ~2, and [m]6 up to 99% on the unfractionated material is obtained; no fractionation of the crude polymer is required in this case.[31]
Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Polymerization
Single-Site Precatalysts for Isospecific Styrene Polymerization[29–31]
Scheme 8
But
R1 R1
But
O
S
Cl
S
R
Cl
Ti
O
S
Ti
R
Y Cl Cl
S
O
R1
(THF)n
R1
O 1
R R1
But But
18
19
20
Isotactic Polystyrene (16); Typical Procedure Using -Titanium(III) Chloride/Trimethylaluminum:[26]
CAUTION: Neat trimethylaluminum is highly pyrophoric. A Schlenk flask was charged under an inert atmosphere with a magnetic stirrer bar, -TiCl3 (0.065 g, 0.42 mmol), toluene (25 mL), Me3Al (0.23 mL, 3.2 mmol), and then styrene (5.00 mL, 4.54 g, 43 mmol). The mixture was stirred and heated at 95 8C. The reaction was stopped with EtOH after 30 h, and the polymer was coagulated with acidified EtOH, washed with fresh EtOH until neutrality was attained, and dried in vacuo at 60 8C. The polystyrene was then fractionated by sequential exhaustive extraction in a Kumagawa or a Soxhlet apparatus for 12 h with boiling methyl ethyl ketone. The methyl ethyl ketone insoluble fraction (isotactic polystyrene, ca. 90%) was dried in vacuo; yield: 0.70 g (15%). Isotactic Polystyrene (16); Typical Procedure Using an (Allyl)yttrocene Catalyst:[31]
A 50-mL Schlenk flask containing a magnetic stirrer bar was charged with the (allyl)yttrium complex 20 (R1 = H; n = 1; 10.0 mg, 21.0 mol) under an inert atmosphere, and then styrene (1.10 g, 10.6 mmol) was introduced. The flask was immediately placed in an oil bath heated to 80 8C and its contents were vigorously stirred. After 30 min, the Schlenk flask was opened to the air and 10% HCl in MeOH (ca. 1 mL) was added to quench the reaction. The mixture was then poured into a large quantity (200 mL) of MeOH, and the polymer that precipitated was washed repeatedly with MeOH (ca. 500 mL), collected by filtration, and dried in vacuo; yield: 1.05 g (95%). 3.21.3.2
Syndiotactic Polystyrene
Highly syndiotactic polystyrene was first prepared using homogeneous methylaluminoxane-activated half-titanocenes of the type TiCp¢Xn (Cp¢ = substituted or unsubstituted cyclopentadienyl ligand; X = halo, alkoxy, alkyl; n = 2, 3).[32,33] In the TiCp¢X3 series, fluorides are the most active,[34] followed by alkoxides[35,36] and chlorides.[34] Pentamethylcyclopentadienyl derivatives often give a higher degree of syndiospecificity along with higher molecular weights than systems based on the unsubstituted cyclopentadienyl ligands. Thus, the triisopropoxy(Å5-pentamethylcyclopentadienyl)titanium(IV)/methylaluminoxane system provides a good compromise for the synthesis of syndiotactic polystyrene, in terms of simplicity and availability of the catalyst precursors on the one hand, and catalytic performance on the other. This system affords, within short reaction times, more than 95% syndiotactic polystyrene with a Tm of ca. 270 8C. Many modified half-titanocenes are reported that demonstrate somewhat enhanced catalytic performances (i.e., activity and/or syndiospecificity) and/or higher molecular Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Polymerization of Cycloalkenes
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weights.[23] However, the most appreciable breakthrough came from using group 3 metal complexes. With these systems, the crude polymers contain neither atactic nor isotactic polystyrene. Therefore, solvent fractionation is not required to obtain pure syndiotactic polystyrene ([r]4 >99% for all polymers obtained). An (allyl)neodymocene complex supported by an isopropylidene-bridged cyclopentadienyl-fluorenyl ligand [Nd(C5H4-CMe2Flu)(Å3-C3H5)(THF)] is a single-component catalyst that affords pure syndiotactic polystyrene with a narrow molecular weight distribution (Mw/Mn 90% cis) has been prepared to date. This is obtained with C2-symmetric rac-metallocene 10 (R1 = Cl) (see Scheme 5) activated by methylaluminoxane ([Al]/[Zr] = 250–300; 25–60 8C). Scheme 9
Main Microstructures for Poly(cycloalkene)s
n
21
cis-cis isotactic
n
cis-cis syndiotactic
4n
+ n
cis-trans heterotactic
cis-trans heterotactic
trans-trans isotactic
n
n
n
trans-trans syndiotactic
cis-cis Isotactic Poly(cyclopentene) (21); Typical Procedure:[42]
A soln of Zr complex 10 (R1 = Cl; 2.7 mg, 6.5 mol) in toluene (11.8 mL) and then cyclopentene (6.2 mL, 70.2 mmol) were added to a 100-mL round-bottomed flask containing dry methylaluminoxane (105 mg, 1.62 mmol Al; obtained, prior to use, from a commercial toluene soln by the removal of all volatiles under reduced pressure). The mixture was stirred at 25 8C under N2 for 24 h, prior to being quenched with MeOH. The quenched mixture Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.21.5
Stereoselective Polymerization of Linear Conjugated Dienes
941
was filtered and the insoluble product was washed with MeOH and dried in vacuo; yield: 2.80 g (59%). 3.21.5
Stereoselective Polymerization of Linear Conjugated Dienes: cis- and trans-1,4-Polybutadiene and -Polyisoprene; Syndiotactic 1,2-Polybutadiene; Isotactic 3,4-Polyisoprene
Polymerization of conjugated linear dienes leads to a variety of stereoregular structures, provided not only the stereoselectivity, but also chemo- and regioselectivity is achieved during the polymerization. Macromolecules feature iso-syndio isomerism (as observed for alk-1-enes) if only one double bond is polymerized. On the other hand, if a conjugate (1,4-) polymerization takes places, macromolecules with a double bond in the polymer backbone are produced, giving rise to cis/trans-isomers. Scheme 10 depicts the common stereoregular polymers 22–25 that can be accessed from the two of the most common monomers in this class, namely buta-1,3-diene (BD) and isoprene (Ip). Scheme 10 Structures of Common Stereoregular Polymers Derived from Buta-1,3-diene and Isoprene R1
n
22
R1 = H cis-1,4-PBD R1 = Me cis-1,4-PI
R1
n
23 n
R1 = H trans-1,4-PBD R1 = Me trans-1,4-PI
R1
R1
R1 n/2
24
R1 = H 1,2-syndiotactic PBD R1 = Me 3,4-syndiotactic PI
R1
R1 n/2
25
R1 = H 1,2-isotactic PBD R1 = Me 1,2-isotactic PI
Out of these polymers, cis-1,4-polybutadiene (PBD) (22, R1 = H) and cis-1,4-polyisoprene (PI) (22, R1 = Me) have a major industrial importance as technical rubbers and they are traditionally obtained by using Ziegler–Natta binary, ternary, and quaternary catalyst systems based on rare earth metals (most often neodymium).[45] The nature of the rare earth precursors, cocatalysts, halide donors, and other additives, as well as the molar ratios of these catalyst components, and technological aspects (solvents, catalyst addition order, catalyst preformation and aging, polymerization temperature, etc.) all play a significant role in determining the characteristics of the polymer. Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.21
Stereoselective Polymerization
Experimental procedures for the preparation of isotactic cis-1,4-polyisoprene, trans1,4-polyisoprene, syndiotactic 1,2-polybutadiene, and isotactic 3,4-polyisoprene can be found in Sections 3.21.5.1, 3.21.5.2, 3.21.5.3, and 3.21.5.4, respectively. 3.21.5.1
cis-1,4-Polybutadiene and -Polyisoprene
The most controlled polymerizations of buta-1,3-diene and isoprene are achieved with rare-earth-based systems, in particular with neodymium, which also provides the highest cis stereoselectivity. Binary and ternary combinations trichloro(ligand)neodymium(III)/triisobutylaluminum (ligand = THF, py, etc.) and neodymium(III) carboxylate/diethylaluminum chloride (or Al2Et3Cl3)/triisobutylaluminum (or DIBAL-H) generate very active catalysts that afford polybutadiene and polyisoprene with up to 99% 1,4-cis content [see 22 (R1 = H) and 22 (R1 = Me), respectively (Scheme 10)].[45,46] However, these systems lead to rather broad polydispersities (Mw/Mn >2). Polybutadiene and polyisoprene with narrower molecular weight distributions (Mw/Mn ~1.2–1.4) and very high 1,4-cis contents are obtained with neodymium–allyl precursors such as bis(Å3-allyl)neodymium(II)[47,48] and the bis(Å3-allyl)neodymium–magnesium complex [Nd(C3H5)2Cl(MgCl2)(THF)4] [which is readily prepared from NdCl3(THF)n and the allyl Grignard reagent],[49] combined with methylaluminoxane or an alkylaluminum. cis-1,4-Polyisoprene (22, R1 = Me) Using an (Allyl)neodymium Catalyst; Typical Procedure:[49]
A Schlenk flask was placed in a glovebox and charged with [Nd(C3H5)2Cl(MgCl2)(THF)4] (11.0 mg, 17.0 mol) and a stirrer bar, and then a soln of methylaluminoxane in toluene (5.0 mL) was transferred into the flask by syringe. The mixture was stirred at rt for 60 min, and a soln of isoprene (1.36 g, 20 mmol) in hexane (3.0 mL) was added under vigorous stirring. After 60 min at rt, the reaction was quenched by adding a MeOH soln acidified with 10% HCl (ca. 1 mL), and more MeOH (ca. 10 mL) was then added. The supernatant liquids were removed by pipet, and the polymer was washed with acetone/EtOH and then dried under reduced pressure at 40 8C for 8 h; yield: 1.35 g (99%); Mn = 188 000 g • mol–1; Mw/Mn = 1.4; cis-1,4-polyisoprene = 98.5%, 3,4-polyisoprene = 1.5%. 3.21.5.2
trans-1,4-Polybutadiene and -Polyisoprene
Highly trans-stereospecific polymerization of buta-1,3-diene and isoprene is achieved by using either a tris(allyl)neodymium compound as a single-component catalyst[50] or a binary catalytic combination of a neodymium alkoxide, aryloxide,[51] or borohydride[52] with a dialkylmagnesium. The dialkylmagnesium is the key component to achieve trans-stereoselective polymerization (as opposed to alkylaluminums for cis-stereoselective polymerization). These systems afford polybutadiene and polyisoprene with a 1,4-trans content higher [see 23 (R1 = H) and 23 (R1 = Me), respectively (Scheme 10)] than 95% and relatively narrow molecular weight distribution (Mw/Mn = 1.1–1.8). The combination [NdCp¢(BH4)2(THF)2]/dibutylmagnesium [Cp¢ = tetramethyl(propyl)cyclopentadienyl] is particularly efficient.[52] trans-1,4-Polyisoprene (23, R1 = Me); Typical Procedure:[52]
[NdCp¢(BH4)2(THF)2] (20 mg, 0.041 mmol) under N2 was introduced into a 20-mL flask. Dry toluene (0.5 mL), a 1.0 M soln of Bu2Mg in heptane (0.036 mL, 0.036 mmol), and freshly distilled isoprene (0.50 mL, 5.0 mmol) were added in this order via syringes into the flask. The mixture was magnetically stirred at 50 8C for 2.75 h. Then, the viscous mixture was diluted with toluene (1 mL), and the resulting soln was poured into EtOH (50 mL). The white powder was collected by filtration, and dried under reduced pressure for 24 h; yield: 0.338 g Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.21.5
Stereoselective Polymerization of Linear Conjugated Dienes
943
(99%); Mn = 9500 g • mol–1; Mw/Mn = 1.15; trans-1,4-polyisoprene = 98.5%, 3,4-polyisoprene = 1.5%. 3.21.5.3
Syndiotactic 1,2-Polybutadiene
Highly crystalline syndiotactic 1,2-polybutadiene (sPBD) (24, R1 = H) (Scheme 10) having a Tm up to 208–216 8C can be obtained by using a tris(acetylacetonato)cobalt(III)/triethylaluminum/carbon disulfide catalyst.[53,54] This system offers syndiotactic 1,2-polybutadiene with 99.7% 1,2-content and 99.6% syndiotacticity, as determined by 1H and 13C NMR spectroscopy. The presence of carbon disulfide is essential for the polymerization to syndiotactic 1,2-polybutadiene, and the polydispersity of the resulting polymers (Mw/Mn = 2.2) reflects the single-site character of this catalyst. Syndiotactic 1,2-Polybutadiene (24, R1 = H); Typical Procedure:[53]
CAUTION: Carbon disulfide is extremely flammable, and toxic by inhalation, skin absorption, and ingestion. A catalyst soln was prepared by mixing Co(acac)3 (13.8 mg, 38.7 mol), Et3Al (0.295 g, 2.58 mmol), H2O (35 L, 1.93 mmol), and CS2 (8.5 L, 112 mol) in benzene (10 mL) (CAUTION: carcinogen) under N2. The polymerization was also carried out under N2 in a 2-L separate glass flask equipped with an anchor-type stirrer, a thermometer, and an inlet tube. The flask was placed in a water bath at 40 8C and charged with dry benzene (850 mL), and the previously prepared catalyst soln was syringed into it. Then, buta-1,3-diene (85.0 g, 1.57 mol) was progressively introduced via the inlet tube. The reaction was continued at 40 8C for 30 min, before it was quenched by adding MeOH (ca. 10 mL) dropwise. The polymer was recovered by filtration, washed thoroughly with MeOH, and dried under reduced pressure; yield: 14.7 g (17%). 3.21.5.4
Isotactic 3,4-Polyisoprene
Isospecific 3,4-polymerization of isoprene takes place with extremely high regio- and stereoselectivity (3,4-selectivity: 100%, [m]4 >99%) in the presence of cationic yttrium catalysts.[55] The catalyst is typically generated in situ from a neutral silylene-linked cyclopentadienyl–phosphidoyttrium alkyl complex 26 (Scheme 11) and 1 equivalent of triphenylcarbenium tetrakis(pentafluorophenyl)borate. The reaction is best conducted at low temperature (–20 8C) to provide optimal selectivity, which yields the isospecific 3,4-polyisoprene (25, R1 = Me) (Scheme 10) with a high Tm of 162 8C. Scheme 11 Yttrium Precatalyst for Isospecific 3,4-Polymerization of Isoprene[55]
Me Me Si
TMS
Y P
P Y
Si Me Me
TMS
26
Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.21
Stereoselective Polymerization
Isotactic 3,4-Polyisoprene (25, R1 = Me); Typical Procedure:[55]
A 100-mL flask equipped with a magnetic stirrer bar and a dropping funnel was placed within a glovebox and isoprene (1.022 g, 15.0 mmol), phosphidoyttrium complex 26 (0.024 g, 0.025 mmol), and PhCl (8 mL) were added. [Ph3C][B(C6F5)4] (0.023 g, 0.025 mmol) in PhCl (2 mL) was introduced into the dropping funnel. The apparatus was then moved outside the glovebox and placed in a cooling bath (–20 8C). After 10 min, the [Ph3C][B(C6F5)4] soln was added dropwise to the mixture of the yttrium complex and isoprene with rapid stirring. After the mixture had been stirred at –20 8C for 48 h, MeOH was injected into it to terminate the polymerization. The mixture was then poured with stirring into a large quantity (200 mL) of MeOH containing a small amount of HCl and BHT (as a stabilizing agent). The precipitated polymer was isolated by decantation, cut into small pieces, washed with MeOH, and then dried under reduced pressure at 60 8C to constant weight to afford isotactic 3,4-polyisoprene; yield: 0.889 g (87%); Mn = 50 000 g • mol–1; Mw/Mn = 1.6; Tg = 33 8C. 3.21.6
Stereoselective Polymerization of Cyclic Conjugated Dienes: cis-1,4-Poly(cyclohexa-1,3-diene)
Stereoselective polymerization of cyclic conjugated dienes has focused on cyclohexa-1,3diene (CHD). As for noncyclic conjugated dienes, 1,4- and 1,2- polymers are known, in which the former 1,4-linked poly(cyclohexadiene) has four stereoisomers (Scheme 12). Various initiators (anionic, cationic, radical) and metal-based catalysts (Ti-, Mo-, W-, Ni-, Pd-) have been reported for the polymerization of cyclohexa-1,3-diene, but most afford a mixture of 1,4- and 1,2-poly(cyclohexa-1,3-diene) or insoluble polymers.[2] Nickel-catalyzed poly(cyclohexa-1,3-diene), which is insoluble, is believed to be 1,4-cis-syndiotactic rich (>90%).[56] Very high regio- and stereoselectivity (1,4-selectivity: 100%; cis selectivity: 99%) for the polymerization of cyclohexa-1,3-diene, to afford soluble crystalline (Tm up to 254 8C) cis-1,4-poly(cyclohexa-1,3-diene) (28), is achieved with a cationic rare earth hydride catalyst conveniently prepared in situ from the neutral precursor 27 and 1 equivalent of triphenylcarbenium tetrakis(pentafluorophenyl)borate (Scheme 13).[57] The tacticity of the resulting cis-1,4-poly(cyclohexa-1,3-diene) reaches ca. 70–80%, but is not unequivocally characterized (as either diisotactic or disyndiotactic). Scheme 12 diene)
Possible Stereochemistries of 1,4-Poly(cyclohexa-1,3-
R S
H
H
H
H
R
R S
S
H
H
n
cis-disyndiotactic
H
H R
H
S S S
H
H
n
cis-diisotactic
H
S
R
H trans-diisotactic
S
H S n
R S
H trans-disyndiotactic
Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
H n
3.21.7
Stereoselective Cyclopolymerization of Nonconjugated Dienes
945
Scheme 13 Regio- and Stereoselective cis-1,4-Polymerization of Cyclohexa-1,3-diene[57]
n
[Y4(C5Me4TMS3)4H8(THF)] 27 [Ph3C][B(C6F5)4] (1 equiv) toluene, 25 oC n
28
cis-1,4-Poly(cyclohexa-1,3-diene) (28); Typical Procedure:[57]
A soln of [Ph3C][B(C6F5)4] (37 mg, 40 mol) in toluene (1 mL) was added to Y4(C5Me4TMS)4H8(THF) (27; 48 mg, 40 mol) in toluene (1 mL) in a 10-mL Schlenk flask that was kept in a glovebox. The mixture was stirred at rt for 5 min, and then cyclohexa1,3-diene (0.80 g, 10 mmol) was added with vigorous stirring. Within 5 h at rt an orange precipitate formed and, after 15 h, the flask was removed from the glovebox and MeOH (ca. 1 mL) was added to terminate the polymerization. The mixture was poured into MeOH (200 mL, containing 1% BHT) to precipitate the polymeric product. The polymer, a white powder, was collected by filtration and dried in vacuo at 60 8C to a constant weight; yield: 0.40 g (50%). The product obtained was soluble in 1,2-dichlorobenzene and 1,1,2,2-tetrachloroethane at 120 8C; Mn = 6100 g • mol–1; Mw/Mn = 2.2. 3.21.7
Stereoselective Cyclopolymerization of Nonconjugated Dienes: Isotactic and Syndiotactic cis/trans-Poly(hexa-1,5-diene)
Æ,ø-Dienes such as hexa-1,5-diene (1,5-HD), hepta-1,6-diene, and octa-1,7-diene cyclopolymerize in the presence of group 4 metallocenes and related catalysts to provide stereoregular poly(methylene-1,3-cycloalkane)s. The microstructure of these cyclopolymers is considerably more complicated than for the simple vinyl polymers since, analogous to the polymerization of cycloalkenes (Section 3.21.4), this process provides cis/trans-stereoisomers for the rings and relative stereochemistry between the individual rings. Although four types of microstructures can be envisaged (Scheme 14), to date only the trans-isotactic forms 29 can be prepared with moderate selectivity.
Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis Scheme 14
3.21
Stereoselective Polymerization
Main Microstructures for Poly(methylene-1,3-cycloalkane)s
m
m
m
n
cis-isotactic
m
m
m
n
m
n
cis-syndiotactic
3n m
m
m
29
m
trans-isotactic
m
m
n
trans-syndiotactic
An experimental procedure for the preparation of trans-isotactic poly(methylene-1,3-cyclopentane) (29, n = 0) can be found in Section 3.21.7.1. 3.21.7.1
Poly(methylene-1,3-cyclopentane) from Hexa-1,5-diene
Most attention has been focused on the polymerization of hexa-1,5-diene using simple metallocenes [e.g., Zr(Cp)2X2 and Zr(Cp*)2X2 (X = Cl, Me)], which upon activation with methylaluminoxane, selectively cyclopolymerize (>99% cyclization) hexa-1,5-diene to poly(methylene-1,3-cyclopentane) (PMCP) with trans-atactic (up to ca. 90% trans) and cisatactic (up to 93% cis) microstructures, respectively.[58,59] Atactic poly(methylene-1,3-cyclopentane) is also obtained with high trans selectivity (91–98%) using a bis(ferrocenyl)zirconocene.[60] In these systems, low polymerization temperatures (–78 8C < T < –25 8C) favor stereoselectivity but at the expense of monomer conversions, i.e. turnover. Highly isotactic poly(methylene-1,3-cyclopentane) with up to 73% trans rings is obtained by regioselective cyclopolymerization of 1,5-HD using chiral metallocenes of the Britzinger type, such as rac-dichloro[1,1¢-(ethane-1,2-diyl)bis(4,5,6,7-tetrahydroindenyl)]zirconium(IV) [30, rac-Zr(EBTHI)Cl2] (Scheme 15).[59] The enantiopure catalyst precursor 31 [(R,R)-Zr(EBTHI)(BINOL)] yields optically active poly(methylene-1,3-cyclopentane) with a molar optical rotation of [F]40528 +51. Scheme 15
Precatalysts for Isospecific Polymerization of Hexa-1,5-diene[59]
ZrCl2
30
Zr(EBTHI)Cl2
O
Zr O
31
Zr(EBTHI)[(S,S)-BINOL]
Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.21.8
Stereoselective Ring-Opening Metathesis Polymerization of Cyclic Alkenes
947
trans-Isotactic Poly(methylene-1,3-cyclopentane) (29, n = 0); Typical Procedure:[59]
rac-Zr(EBTHI)(BINOL) (31; 5.0 mg, 7.8 mol), dry methylaluminoxane (500 mg, 8.6 mol; obtained before use by the removal of all volatiles from a commercial toluene soln in vacuo), and a magnetic stirrer bar were placed in a 100-mL Schlenk flask within a glovebox. Then, the flask was sealed with a rubber septum, removed from the glovebox, and connected to a vacuum line. Toluene (100 mL) was added to the flask via a cannula and, after the homogeneous soln had been stirred for 5 min, hexa-1,5-diene (5 mL, 42 mmol) was added via a syringe. The reaction was allowed to proceed at rt for 3 h, the polymerization was stopped by carefully adding MeOH (10 mL), and the mixture was stirred for another 8 h, before all the volatiles were removed in vacuo. The resulting solid was washed with 4 M HCl/MeOH (1:1) and then with MeOH. After drying, the solid was extracted with boiling toluene (4 25 mL), passed over a medium glass frit prepared with a Celite filtering agent, and dried under reduced pressure to constant weight; yield: 3.1 g (90%); Mn = 16 000 g • mol–1; Mw/Mn = 3. 3.21.8
Stereoselective Ring-Opening Metathesis Polymerization of Cyclic Alkenes: cis-Isotactic and cis-Syndiotactic Poly(norbornene) and Poly(endo-dicyclopentadiene); Tactic trans-Poly(3-substituted cyclopropene)
3.21.8.1
Polymers of Cyclic Alkenes
Ring-opening metathesis polymerization (ROMP) enables the conversion of alkenic molecules into particular types of polyalkenes featuring regular distribution of double bonds within the polymeric chain.[61] The primary microstructural units in these polymers are double bonds with cis and/or trans configurations. Additionally, if the monomers have a stereocenter the stereochemistry of the resultant polymers becomes fairly complex. The traditional monomers used for ring-opening metathesis polymerization are norbornenes, since substitution (asymmetric) in these molecules at different positions gives rise to different types of stereoconfigurations and microstructures (and, therefore, physical properties) of the final polymers. The stereoselective ring-opening metathesis polymerization of norbornadienes and endo-dicyclopentadiene has been intensively studied. More recently, the highly stereoselective polymerization of 3-methyl-3-phenylcyclopropene has also been reported. 3.21.8.1.1
Poly(norbornene)s and Poly(norbornadiene)s
The microstructure of stereoregular metathesis polymers of norbornene (NB, bicyclo[2.2.1]hept-2-ene) and norbornadiene (NBD, bicyclo[2.2.1]hepta-2,5-diene) obtained by ring-opening polymerization (ROP) can be represented by four different diad structures (Scheme 16). A variety of polymers with cis/trans sequences combined with different tacticities are potentially available, especially when considering possible additional substitution in five-membered rings.
Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.21
Stereoselective Polymerization
Scheme 16 Main Stereochemistries for Poly(cycloalkene)s Obtained by RingOpening Polymerization, and Numbering Schemes in Poly(norbornene) and Poly(norbornadiene)
n
cis-isotactic
n
cis-syndiotactic
2n
n
trans-isotactic
n
trans-syndiotactic
5
3
4
6 7
1
3 4 2
2 7
1
n
n
poly(norbornene)
poly(norbornadiene)
Highly stereoselective formation of cis-syndiotactic (>95% cis; [r] >90%) poly(norbornene), poly(5,5¢-dimethylnorbornene), and poly(norbornadiene) (32) may be achieved using a simple osmium(III) chloride/phenylacetylene catalyst in tetrahydrofuran (the polymerization of norbornene using this system is depicted in Scheme 17).[62,63] However, well-defined molybdenum catalysts, such as 33 and 34 (Scheme 17), promote the highly stereoselective cis-isotactic polymerization of 2,3-bis(trifluoromethyl)norbornadiene and dimethyl norbornadiene-2,3-dicarboxylate (35).[64–66] The latter polymerizations proceed in a “living” manner, affording polymers, such as 36, with the following characteristics: >99% cis; [m] >99%; Mn = 7400–35 000 g • mol–1 (range of molecular weights obtained using different [monomer]/[Mo] ratios); Mw/Mn = 1.02–1.28. Highly stereotactic trans polymerization of both norbornene and norbornadiene has not been reported to date. Scheme 17 Precatalysts for the Stereoselective Ring-Opening Metathesis Polymerization of Norbornadienes[64–66] , THF
1. OsCl3, Ph
30 oC, 48 h 2. TsNHNH2, xylene, 120 oC, 2 h
2n
3. MeOH 20% n
32
Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.21.8
949
Stereoselective Ring-Opening Metathesis Polymerization of Cyclic Alkenes
But
But
R1 R2
O O
Mo
But
O O Mo
N
N
But
R1
But
R2 Ph
Ph 33
34
1. 33 (R1 = Ph; R2 = Me) THF, 4 h 2. PhCHO (trace), 12 h 3. MeOH
MeO2C 2n
CO2Me
CO2Me
CO2Me
CO2Me
91%
MeO2C 35
36
n
cis-Syndiotactic Poly(norbornadiene) (32); Typical Procedure:[63]
OsCl3 (15.0 mg, 50.6 mol) and phenylacetylene (100 mg, 0.98 mmol) in dry THF (2 mL) at 20 8C were reacted under an inert atmosphere for 2 h, before a soln of norbornadiene (0.50 g, 5.3 mmol) in THF (3 mL) was added. The mixture was stirred for 48 h at 30 8C and then dissolved in xylene (10 mL). Tosylhydrazine (500 mg) was then added and the mixture was heated at 120 8C with stirring for 2 h, before it was cooled and added to MeOH (250 mL). The precipitated polymer was collected by centrifugation, washed with MeOH (2 ), and dried under reduced pressure; yield: 0.10 g (20%). cis-Isotactic Poly(dimethyl norbornadiene-2,3-dicarboxylate) (36); Typical Procedure:[66]
Dimethyl norbornadiene-2,3-dicarboxylate (35; 100 mg, 0.481 mmol, 50 equiv) was diluted with THF (ca.1 mL) and added in one portion to a rapidly stirred soln of the initiator 33 (R1 = Ph; R2 = Me; 8.2 mg, 9.6 mol) in THF (ca. 7 mL) protected under an inert atmosphere. The mixture was stirred for 4 h, before being capped with PhCHO (2 drops), followed by stirring for 12 h. Following precipitation from MeOH, the resulting fine, white polymer was isolated by centrifugation and dried overnight under high vacuum; yield: 94 mg (91%). 3.21.8.1.2
Poly(endo-dicyclopentadiene)s
Metathesis polymerization of endo-dicyclopentadiene (DCPD) can afford stereoregular polymers featuring similar microstructural patterns to those described for poly(norbornene) and poly(norbornadiene). However, there are only a few examples of highly stereoselective syntheses of poly(endo-dicyclopentadiene) (Scheme 19). Stereoselective cis-isotactic polymerization of endo-dicyclopentadiene can be achieved with the precatalyst 37 and butyllithium (Scheme 18) to afford poly(endo-dicyclopentadiene) (38) with the following properties: 91% cis; [m] = 96%; Tm = 264 8C; Mn = 3900 g • mol–1; Mw/Mn = 2.4.[67] The tungsten complex 38 promotes cis-syndiotactic ring-opening metathesis polymerization to yield poly(dicyclopentadiene) (40) with the following characteristics: 93% cis; [r] = 80%; Tg = 151 8C; Mn = 10 000 g • mol–1; Mw/Mn = 3.5.[68]
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950
Stereoselective Synthesis
3.21
Stereoselective Polymerization
Scheme 18 Precatalysts for the Stereoselective RingOpening Metathesis Polymerization of Dicyclopentadiene[67,68] But
But O
O
O
W O
N
O
But
Cl Cl
But
Cl Cl
Et2O 38
37
Ring-Opening Metathesis Polymerization of Dicyclopentadiene[67,68]
Scheme 19
n
W
H H
37, BuLi, toluene cyclohexane, 80 oC, 2 h
H
H
n
39
2n
H H
38, Et2Al(OEt), toluene cyclohexane, 50 oC, 3 h
poly(endo-DCPD)
H
H
100%
H
H n
40
cis-Isotactic Poly(endo-dicyclopentadiene) (39); Typical Procedure:[67]
The polymerization was carried out under an inert atmosphere in a prebaked ampule tube equipped with a rubber septum. Polymerization catalyst solns were prepared as follows: the tungsten complex 37 (51.5 mg, 56.4 mol) in toluene was mixed with BuLi (2 equiv) at –78 8C, and the resulting deep blue soln was allowed to warm to rt. The mixture was aged for an additional 15 min, resulting in a reddish-orange soln. A soln of dicyclopentadiene (7.50 g, 56.7 mmol) and oct-1-ene (0.127 g, 1.13 mmol) in cyclohexane (25 mL) was added to the mixture at 80 8C and, after stirring for 2 h, the polymerization was quenched by the introduction of a small amount of iPrOH. The polymer was precipitated in MeOH (100 mL), isolated by filtration, and dried in vacuo; yield: 7.50 g (100%). cis-Syndiotactic Poly(endo-dicyclopentadiene) (40); Typical Procedure:[68]
The polymerization was carried out in a prebaked ampule tube equipped with a rubber septum. A toluene soln of complex 38 (27.8 mg, 56.7 mol) (green soln) was mixed with Et2Al(OEt) (3 equiv) at rt, and the mixture was stirred for 15 min (resulting in a brown soln). A soln of dicyclopentadiene (7.50 g, 56.7 mmol) and oct-1-ene (0.245 g, 2.18 mmol) in cyclohexane (25 mL) was added to the mixture at 50 8C, and, after stirring for 3 h, the polymerization was quenched with a small amount of iPrOH. The polymer was precipitated in MeOH (100 mL), isolated by filtration, and dried in vacuo; yield: 7.50 g (100%).
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3.21.9
3.21.8.1.3
951
Stereoselective Polymerization of Alkynes
Poly(3-substituted cyclopropene)s
There is only one example of the highly stereospecific synthesis of poly(3-methyl-3-phenylcyclopropene)s 41 and 42 (Scheme 20), utilizing the bis(phenoxy)molybdenum–alkylidene complexes 43 and 44 (Scheme 21).[69] The NMR spectroscopic data and physical properties of these polymers are in agreement with a highly tactic microstructure (>99% tactic; Tg = 100–107 8C; Mn = 9000–14 000 g • mol–1; Mw/Mn = 1.18–2.2), although the relative configuration of the stereogenic centers is still under investigation. Scheme 20 Stereochemistries of Ring-Opening Metathesis Polymerization Products from 3-Methyl-3-phenylcyclopropene[69] Ph
Ph Ph
Ph n
Ph
41
4n
trans-isotactic
Ph
Ph Ph
Ph n
42
trans-syndiotactic
Scheme 21 Precatalysts for Stereoselective Ring-Opening Metathesis Polymerization of 3-Methyl-3-phenylcyclopropene[69]
R1 But
R1
Pri
Pri
N
C6F5
N
THF
THF
O Mo F3C
O Mo Ph
O
Ph
O
But
C6 F 5
F3C 43
R1 = Me, iPr, 1-adamantyl
44
Tactic Poly(3-methyl-3-phenylcyclopropene) 41/42; Typical Procedure:[69]
A soln of 3-methyl-3-phenylcyclopropene (132 mg, 1.00 mmol) in CH2Cl2 (2 mL) was added in one portion under an inert atmosphere to a stirred soln of the catalyst 43 (10.0 mg, 10.0 mol) in CH2Cl2 (4 mL) and the mixture was stirred for 2 h. PhCHO (500 L) was then introduced and the mixture was stirred at rt for an additional 1 h. The polymer was precipitated in MeOH (100 mL), isolated by filtration, and dried in vacuo; yield: 130 mg (98%). 3.21.9
Stereoselective Polymerization of Alkynes
The discovery of conducting organic polymers based on poly(acetylene)s launched a new area in the field of organic materials.[70–72] Poly(acetylene)s are linear conjugated molecules with alternating C=C bonds along the polymeric chain, in which a microstructure of poly(acetylene)s can adopt one of four configurations (Scheme 22). Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis Scheme 22
3.21
Stereoselective Polymerization
Main Stereochemistries of Poly(acetylene)s
n
45
cis-cisoid
cis-transoid
n
n
46
trans-cisoid
trans-transoid
Apart from the ring-opening metathesis polymerization of cyclooctatetraenes,[73] poly(acetylene)s can be prepared from the corresponding alkynes by metathesis or using Ziegler–Natta or rhodium-based coordination/insertion catalysts. 3.21.9.1
Poly(acetylene)
Acetylene is efficiently and stereoselectively homopolymerized to poly(acetylene) utilizing a concentrated 1:4 mixture of titanium(IV) butoxide and triethylaluminum aged at room temperature for 1 hour.[74,75] Highly cis-transoid (98.1%) poly(acetylene) 45 (Scheme 23) forms at –78 8C, whereas virtually 100% trans-transoid poly(acetylene) 46 is obtained at 150 8C. Scheme 23
Synthesis of cis-transoid and trans-transoid Poly(acetylene)s[75] Ti(OBu)4, Et3Al toluene, −78 oC n
45 4n H
H Ti(OBu)4, Et3Al toluene, 150 oC n
46
cis-transoid Poly(acetylene) (45); Typical Procedure:[75]
Acetylene was purified before use by passing it successively through a NaHSO3 soln, a dry ice/MeOH trap, a CaCl2 column, a P2O5 column, and finally a soln of Et3Al in Tetralin. Ti(OBu)4 (5.1 g, 15 mmol) and Et3Al (8.2 mL, 60 mmol), in that order, were added to toluene (60 mL) while protected under an inert atmosphere. After the mixture had been stirred for a few minutes at rt, a 30-mL aliquot was transferred into a Schlenk-type flask. The flask was cooled at –78 8C and gaseous acetylene was introduced. The formation of a red-colored poly(acetylene) film was observed immediately after the introduction of the acetylene gas. The polymerization was interrupted by evacuating the system, and the catalyst soln remaining under the film formed was removed by syringe, then the film was washed repeatedly with toluene or hexane until the washings became colorless. The purification was carried out at the temperature of the polymerization in order to prevent cisStereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Polymerization of Alkynes
trans isomerization of the polymers. The washed film was dried by blowing N2 on it for a minute at rt, and then stored under N2 at –30 8C; yield: not reported. trans-transoid Poly(acetylene) (46); Typical Procedure:[75]
trans-transoid poly(acetylene) was prepared by following the same procedure as the one applied for synthesis of its cis-transoid isomer (vide supra). The acetylene polymerization reaction was conducted in hexadecane at 150 8C (instead of –78 8C) to afford a blue poly(acetylene) film; yield: not reported. 3.21.9.2
Substituted Poly(acetylene)s
Stereoselective cis-transoid polymerization of monosubstituted acetylenes takes place in a “living” manner. For example, the polymerization of tert-butylacetylene (TBA) is achieved at –30 8C using the molybdenum-based ternary catalytic system tetrachlorooxomolybdenum(VI)/tetrabutylstannane/ethanol, to isolate poly(tert-butylacetylene) (49) (Scheme 24) with the following properties: cis 97%; Mn = 149 000 g • mol–1; Mw/Mn = 1.12.[76] The rhodium complex 47 activated by (triphenylvinyl)lithium/triphenylphosphine promotes a highly stereoselective polymerization of phenylacetylene (PA) ([PA]/[Rh] = 250–4000, toluene; 30 8C, 1 h) to give the cis-transoid polymer 50 (cis ‡99%; Mn = 25 000–401 000 g • mol–1; Mw/ Mn = 1.04–1.12).[77] Similarly, the discrete rhodium complexes 48 produce poly(phenylacetylene) ([PA]/[Rh] = 100, toluene or THF; 30 8C, 0.5–4 h) having a cis-transoid microstructure, with the following characteristics: cis >99%; Mn = 16 000–1 420 000 g • mol–1; Mw/Mn = 1.12–2.87.[78] Scheme 24 Synthesis of cis-transoid Poly(tert-butylacetylene) and Poly(phenylacetylene)[76–78] F F F
Rh F
F
Cl
Rh
Cl
47
P
F
−
Rh
F
BF4
Z
48
diene = cod, norbornadienetetrafluorobenzabarralene Z = OMe, SMe, NMe2
But 4n But
Ph
Ph
F
But
MoCl4, Bu4Sn, EtOH toluene, −30 oC, 10 min 100%
But
But
n
49
Ph
Ph 47, Ph2C=C(Ph)Li, Ph3P toluene, 30 oC, 1 h
4n Ph Ph
Ph n
50
cis-transoid Poly(tert-butylacetylene) (49); Typical Procedure:[76]
While protected under an inert atmosphere MoOCl4 (25.4 mg, 0.1 mmol) was mixed with Bu4Sn (34.7 mg, 0.1 mmol) in toluene (5 mL) in a Schlenk flask. The soln was left to age at 30 8C for 15 min, before EtOH (6 L, 0.1 mmol) was added to the soln and the resultant mixture was aged at 0 8C for an additional 15 min. Polymerization was initiated at –30 8C by Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.21
Stereoselective Polymerization
adding tert-butylacetylene (0.62 mL, 5 mmol) in toluene (5 mL) to the catalyst soln. After 10 min, the reaction was quenched by adding a MeOH/toluene mixture (1:4; 2 mL). This mixture was diluted with toluene (20 mL) and poured into MeOH (1 L). The precipitated polymer was collected by filtration, washed with MeOH, and dried to constant weight under reduced pressure; yield: 0.41 g (100%). cis-transoid Poly(phenylacetylene) (50); Typical Procedure:[77]
Catalyst 47 (3.6 mg, 5.0 mol) was dissolved in toluene (3.0 mL) in a Schlenk flask while the mixture was protected under an inert atmosphere, and a soln of triphenylvinyllithium (50 L, 25 mol) in toluene was then added. A soln of phenylacetylene (0.27 mL, 2.5 mmol) in toluene (2.0 mL) was added to the catalyst soln together with Ph3P (13.1 mg, 50 mol). Polymerization was carried out at 30 8C for 1 h, and the polymer that formed was isolated by precipitation in a large amount of MeOH, filtered using a glass filter, and dried under reduced pressure to constant weight; yield: 0.251 g (100%). 3.21.10
Stereoselective Copolymerization of Alk-1-enes and Carbon Monoxide: Isotactic and Syndiotactic Polyketones Derived from Propene and Styrene
3.21.10.1
Polyketones
Stereoregular polyketones are alternating copolymers of carbon monoxide and an alk-1ene; they are typically produced by a palladium-catalyzed coordination/insertion reaction.[79–81] All these polymers have very high melting points, which are as high as their decomposition temperatures. Only three types of highly stereoregular alkene/carbon monoxide copolymers have been reported to date: isotactic poly(propene-alt-carbon monoxide) (51), isotactic poly(styrene-alt-carbon monoxide) (52), and syndiotactic poly(styrenealt-carbon monoxide) (53) (Scheme 25). Isotactic copolymers are produced by a site-control mechanism utilizing precatalysts bearing chiral ligands. Alternatively, the syndiotactic poly(styrene-alt-carbon monoxide) polymer is prepared via the syndiospecific alternating enchainment of styrene and carbon monoxide using a chain-end control mechanism. Scheme 25 Main Stereoselectivities of Polyketones Prepared from Alternating Copolymerization of Alk-1-enes and Carbon Monoxide CO Pd catalyst
4n
O
O
O
O n
51
isotactic poly(propene-alt-CO)
Ph
Ph
O
Ph
O
O n
CO Pd catalyst
4n
O
Ph
52
Ph Ph
isotactic poly(styrene-alt-CO)
Ph
O
O
Ph
O
Ph
O n
53
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syndiotactic poly(styrene-alt-CO)
3.21.10
Stereoselective Copolymerization of Alk-1-enes and Carbon Monoxide
955
Experimental procedures for the preparation of isotactic poly(propene-alt-carbon monoxide) and of isotactic and syndiotactic poly(styrene-alt-carbon monoxide)s can be found in Sections 3.21.10.1.1 and 3.21.10.1.2, respectively. 3.21.10.1.1
Isotactic Poly(propene-alt-carbon monoxide)
Highly stereoregular and enantioselective (100% head-to-tail, 93–96% isotactic l-diads), but poorly productive [1.7–5.6 g(polyketone) • g(Pd)–1 • h–1, 42 8C, 80 atm, 170 h] copolymerization of propene and carbon monoxide takes place using the chiral complexes derived from (R or S)-54 with palladium(II) acetate (Scheme 26).[82] Another palladium-based system derived from the Josiphos-type ligands 55 is more stereoselective (>97% isotactic diads) and much more productive [up to 1800 g(polyketone) • g(Pd)–1 • h–1, 50 8C, 76 atm, 3 h].[83] Another highly active and stereoselective cationic system, {Pd(Me)(MeCN)[L]}{[3,5(F3C)2C6H3]4B}, is based on the (R,S)-BINAPHOS ligand (L = 56), which produces isotactic poly(propene-alt-carbon monoxide) with the following properties: [F]D +40; Mn = 65 300 g • mol–1; Mw/Mn = 1.6; Tg = 8 8C; Tm = 164 8C.[84,85] Scheme 26 Ligands for Palladium-Catalyzed Isospecific Copolymerization of Propene and Carbon Monoxide[82–85]
PCy2 MeO
PR12
MeO
PR1
54
O Fe
2
R1 = iPr, Cy
PPh2
55
P
O
O
PAr12
56
Ar1 = Ph, 3-F3CC6H4, 4-F3CC6H4, 3,5-(F3C)2C6H3
Isotactic Poly(propene-alt-carbon monoxide) (51); Typical Procedure:[85]
CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. A soln of the phosphite 56 (8.7 mg, 11 mol) in benzene (0.5 mL) (CAUTION: carcinogen) was added under an inert atmosphere to a soln of PdMe(Cl)(cod) (3.0 mg, 11 mol) in benzene (1.0 mL). The mixture was stirred at 20 8C for 1 h and then concentrated under reduced pressure. The product was redissolved in CH2Cl2 (1.0 mL) and sodium tetrakis[3,5bis(trifluoromethyl)phenyl]borate (10.0 mg, 11 mol) in MeCN (1.0 mL) was added. After the soln had been stirred at 20 8C for 1 h, the solvents were removed and the residue was redissolved in CH2Cl2 (2.0 mL), and then degassed by freeze–vacuum–thaw cycles (3 ). The soln was added to a stainless steel autoclave, exposed to CO (1 atm) and then treated with propene (3 atm, 50 mL). The mixture was stirred under CO (20 atm) for 4 d at 20 8C. After the pressure had been released, MeOH (0.2 mL) was added under inert atmosphere, and the mixture repressurized with CO (20 atm) in order to cleave Pd—C bonds by methoxycarbonylation. After 1 h, the autoclave was depressurized and the mixture was poured into MeOH (100 mL) under air to precipitate poly(propene-alt-carbon monoxide); yield: 0.333 g (76%).
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Stereoselective Synthesis
3.21.10.1.2
Isotactic and Syndiotactic Poly(styrene-alt-carbon monoxide)s
3.21
Stereoselective Polymerization
A series of cationic palladium complexes promote the stereospecific copolymerization of styrene and carbon monoxide (Scheme 27). Highly isospecific copolymerization between 4-tert-butylstyrene and carbon monoxide is catalyzed by the complexes 57 [R1 = Me, iPr; Ar1 = 3,5-(F3C)2C6H3] (Scheme 27) under mild conditions (25 8C, 1 atm, 72 h) to give >98% isotactic poly(styrene-alt-carbon monoxide) with [F]58925 –536; Mn = 26 000 g • mol–1; Mw/ Mn = 1.4; Tm = 145 8C.[86] Slightly modified catalytic systems yield similar highly isotactic copolymers.[87] Thus, the dicationic palladium complex 58 produces highly isotactic styrene/carbon monoxide copolymer at 50 8C and 320 atm.[88] The cationic system {Pd(Me)(NCMe)[L]{[3,5-(F3C)2C6H3]4B} (where L = 56; see Scheme 26, Section 3.21.10.1.1) is also highly isospecific at 20 8C and 20 atm.[89] Examples of highly syndiospecific and regioregular head-to-tail copolymerization of styrene and carbon monoxide are more limited. Cationic catalyst 59 provides up to 90% of syndiotactic triads,[86] while similar complex 60 affords a polymer with higher stereocontrol (ca. 92% of uu triads) and Mn = 7000 g • mol–1; Mw/Mn = 1.2.[90] Scheme 27 Complexes for Stereospecific Copolymerization of Styrene and Carbon Monoxide[86,90] 2+
O
O N
57
N Pd
R1
O
Me
Ph
−BAr1
4
R1 NCMe
Ph2P N Pd H2O OH2
R1 = Me, iPr; Ar1 = 3,5-(F3C)2C6H3
N
N
N
N
−
BAr14
59
OMe
58
Pri
N Pri
N
−BAr1
Pd
Pd Me
2 −OTf
Me
4
NCMe
NCMe
Ar1 = 3,5-(F3C)2C6H3
60
Ar1 = 3,5-(F3C)2C6H3
Isotactic Poly(styrene-alt-carbon monoxide) (52); Typical Procedure:[86]
CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. The reaction was carried out as described above for the synthesis of isotactic poly(propene-alt-carbon monoxide), except styrene was used instead of propene. The copolymerization reaction was carried out in a thermostated Schlenk flask equipped with a CO gas line and a tank for CO. In a typical copolymerization, a soln of compound 57 [R1 = iPr; Ar1 = 3,5-(F3C)2C6H3; 0.129 g, 0.1 mmol] in styrene (6.3 mL, 54.8 mmol) was stirred under CO (1 atm) at 25 8C for 72 h, followed by the addition of MeOH (100 mL) to precipitate the polymer; yield: 1.3 g.
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3.21.11
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Stereoselective Polymerization of Acrylates
Syndiotactic Poly(styrene-alt-carbon monoxide) (53); Typical Procedure:[90]
CAUTION: Carbon monoxide is extremely flammable and toxic, and exposure to higher concentrations can quickly lead to a coma. Compound 60 [Ar1 = 3,5-(F3C)2C6H3; 0.195 g, 0.167 mmol] was dissolved at 0 8C in CH2Cl2 (10 mL) in a thermostated Schlenk flask equipped with a CO gas line and the soln was saturated with CO (1 atm). The mixture was stirred for 30 min during which time the color of the soln changed from pale yellow to orange-yellow. Styrene (4.8 mL, 41.7 mmol) was added and the soln was stirred under CO (1 atm) at 0 8C. Within 6 h the soln darkened slightly; after 24 h, the flask was vented in air, and a gray polymer was precipitated by adding MeOH (30 mL). The polymer was collected by filtration and washed with MeOH. To remove metallic palladium traces the polymer was redissolved in 1,1,1,3,3,3-hexafluoropropan-2-ol, diluted with CH2Cl2 and the mixture was filtered through Celite. After precipitation with MeOH, washing with MeOH and Et2O, and drying under reduced pressure the product was collected; yield: 1.75 g of copolymer [98 g of polymer • g(Pd)–1]. 3.21.11
Stereoselective Polymerization of Acrylates: Syndiotactic, Isotactic, and Heterotactic Poly(alkyl methacrylate)s
Poly(acrylate)s and poly(methacrylate)s belong to a common class of polymers, in which several are commercially important products, as exemplified by poly(methyl methacrylate) (PMMA). Three major stereoregular microstructures exist: isotactic 61, syndiotactic 62, and heterotactic 63 (Scheme 28). The stereoregularity in these polymers is readily analyzed by 1H NMR spectroscopy and is commonly determined at the triad level. Variation in stereoregularity is known to affect the materials properties. For instance, in poly(methyl methacrylate), the glass transition temperatures increase from isotactic (Tg = ca. 50 8C) < heterotactic (Tg = ca. 91 8C) < syndiotactic (Tg up to ca. 140 8C), while melting temperatures increase in the order isotactic (Tm = 150 8C) < syndiotactic (Tm = 159 8C) < heterotactic (Tm = 166 8C). Scheme 28
Stereoregular Microstructures of Poly(acrylate)s
R1 CO2R2
R1 CO2R2 R1 CO2R2 R1 CO2R2 m
+
R1 CO2R2 R1 CO2R2 R1 CO2R2
m
r
r
n
61
+
n
isotactic (mm triad)
62
syndiotactic (rr triad)
R1 CO2R2 R1 CO2R2 R2O2C R1 r
m n
63
heterotactic (mr triad)
Although poly(alkyl methacrylate)s are conveniently prepared by free-radical polymerization, only modest stereocontrol can be achieved via this process, even using controlled free-radical systems.[1] Most of poly(alkyl methacrylate)s produced by free-radical polyStereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.21
Stereoselective Polymerization
merization exhibit a moderate syndiotactic enrichment (typically 60–85% rr content). High levels of stereoregularity, and more generally good control over the polymerizations, are achieved with classical systems based on group 1–3 organometallic compounds,[91] albeit these procedures are prone to side reactions, which become particularly acute with acrylate monomers. Some well-defined initiators based on group 1–5 and 12, 13 metals stabilized by bulky ancillary ligands perform much better, both in terms of stereocontrol and molecular weight control.[2] Notably, these initiators include simple alkyl- and hydride-samarocene complexes, which give highly syndiotactic poly(methyl methacrylate) (up to 95% rr at –95 8C, and still 83% rr at 0 8C),[92] and chiral C1-symmetric ansa-lanthanidocenes that produce highly isotactic poly(methyl methacrylate) (up to 94% mm at –35 8C).[93] Stereocontrolled polymers with higher molecular weight (Mn = 20 000–820 000 g • mol–1) are produced, which are more difficult to achieve with the classical systems that operate at low temperatures (typically T 90% rr) (see Scheme 28) with narrow molecular weight distributions (Table 3). Poly(tertbutyl methacrylate)s obtained by these initiators are significantly less syndiotactic. Table 3 Syndiospecific Polymerization of Alkyl Methacrylates with tert-Butyllithium/Tributylaluminum (1:3) in Toluene at –78 8C[91,95] R2
Yielda (%) Mn (g • mol–1) Mw/Mn
Me
100
4730
1.17
92 7.5 0.5
[91,95]
Et
100
6050
1.07
90 8
2
[91,95]
iPr
92
7200
1.14
92 5
3
[91,95]
Tacticity (%) rr
mr
Ref
mm
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3.21.11
959
Stereoselective Polymerization of Acrylates
Table 3
(cont.)
R2
Yielda (%) Mn (g • mol–1) Mw/Mn
rr
mr
mm
Bu
76
7020
1.07
92
7
1
[91,95]
iBu
91
8690
1.06
93
5
2
[91,95]
t-Bu 87
7140
1.64
57 33
10
[91,95]
a
Tacticity (%)
Ref
Conditions: monomer (10 mmol), t-BuLi (0.2 mmol), Bu3Al (0.6 mmol), toluene (10 mL), 24 h.
As described in the following section (Section 3.21.11.3), the polymerization of trimethylsilyl methacrylate with the tert-butyllithium/bis(2,6-di-tert-butylphenoxy)methylaluminum combination affords the corresponding highly syndiotactic polymers (up to 98% rr). These polymers can be converted into various kinds of syndiotactic poly(alkyl methacrylate)s through the poly(methacrylic acid)s. 3.21.11.3
Heterotactic Poly(alkyl methacrylate)s
The most convenient and effective system for the preparation of heterotactic poly(alkyl methacrylate)s 63 [R1 = C(Me)=CH2] (see Scheme 28) uses a combination of tert-butyllithium with bis(2,6-di-tert-butylphenoxy)methylaluminum.[91,96] This living system affords polymers with narrow polydispersities and heterotactic contents that strongly depend on the nature of the alkyl residues, but which are often in the range 80–96% mr (Table 4). The poly(allyl methacrylate) can be converted into the highly heterotactic poly(methyl methacrylate) via poly(methacrylic acid), by deprotecting the allyl esters with tetrakis(triphenylphosphine)palladium(0) in the presence of pyrrolidine and re-esterifying with diazomethane.[97] Table 4 Heterospecific Polymerization of Alkyl Methacrylates with tert-Butyllithium/ Bis(2,6-di-tert-butylphenoxy)methylaluminum (1:5) in Toluene[91,96] R2
Temp (8C)
Yielda (%)
Mn (g • mol–1)
Mw/Mn
rr
mr
mm
Me
–78
100
5940
1.24
21
68
12
[91,96]
Et
–78
100
5680
1.07
6
87
7
[91,96]
Et
–95
100
8100
1.11
1
92
7
[91,96]
Pr
–78
100
6040
1.13
3
91
6
[91,96]
Bu
–78
98
9300
1.07
5
87
8
[91,96]
iPr
–78
50
4730
1.07
29
69
2
[91,96]
iBu
–78
84
6350
1.07
10
78
12
[91,96]
CH=CHMe
–78
94
7610
1.13
4
90
6
[91,96]
b
Tacticity (%)
Ref
CH=CHMe
–95
85
8760
1.15
1
96
3
[91,96]
TMS
–78
100
7030
1.16
96
3
99% mm) polyethers in quantitative yields (Scheme 30).[99] Using as little as 0.025 mol% of the racemic catalyst 64 and 0.050 mol% bis(triphenylphosphoranylidene)ammonium acetate ([PPN][OAc]), neat propene oxide (2-methyloxirane) is polymerized almost instantaneously at room temperature. On the other hand, the enantiopure form of catalyst 64 enables the kinetic resolution of racemic epoxides, giving in ca. 50% yield highly isotactic, optically active polyethers 66B with high molecular weights and relatively narrow molecular weight distributions; a 50% yield of an enantiomer of the appropriate starting monosubstituted epoxide is also obtained. This latter catalyst system is applicable to a wide range of terminal epoxides (alkyl, aryl, alkoxymethyl, or fluoroalkyl substituents) (see Table 5). Scheme 30
Isospecific Polymerization of Racemic Propene Oxides[98,99]
N
N Co
But
O
But
O
AcO But
But 65
O
catalyst 65 or rac-64 >99% conversion
R1 rac
R
O
R1
S
+ n
66A
O
R1
n
66B
rac-isotactic polyether
Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
O
3.21
Stereoselective Polymerization
enantiopure catalyst 64 R 100% conversion
R1
O
S
+
R1
of S-enantiomer
rac
O
R
1
in racemate
66B
n
enantiopure isotactic polyether
Table 5 Enantioselective Polymerization of Racemic Epoxides Catalyzed by a Chiral Mixed Binaphthol–Salen Cobalt Complex/Bis(triphenylphosphoranylidene)ammonium Acetate[98,99] R1
[epoxide]/[64]a
Temp (8C)
Time (h)
Conversion (%)
ee (%)
[mm]b (g • mol–1)
Mnb
Mw/Mnb
Ref
99.1
98.6
26 400
1.8
[98,99]
n.d.
n.d.
n.d.
[98,99]
Me 4000
0
0.25
34
Me 4000
22
1.5
51
0.25
22
99.2
98.8
61 400
2.0
[98,99]
51
99
n.d.
n.d.
n.d.
[98,99]
19
99.1
98.6
76 800
2.1
[98,99]
n.d.
n.d.
n.d.
[98,99]
94.4
98 900
1.9
[98,99]
n.d.
n.d.
n.d.
[98,99]
Et
1000
0
Et
1000
22
Bu
667
0
Bu
1000
22
15
52
Ph
1000
0
17
20
Ph
500
22
15
55
a b
52 0.33
>99
>99 96.1 >99
General Conditions: [PPN][OAc]/[64] = 2:1, [epoxide] = 2.0 M in toluene, except for styrene oxide (neat), 0 8C. n.d. = not determined.
Racemic Isotactic Poly(propene oxide) (66A/66B, R1 = Me); Typical Procedure:[98]
CAUTION: Propene oxide should be handled with extreme care. It is a carcinogen, a mutagen, irritating, and highly flammable. A Schlenk tube was placed in a glovebox and charged with the complex 65 (9.4 mg, 0.014 mmol) and a Teflon-coated stirrer bar. The flask was then sealed and removed from the glovebox. Toluene (6.6 mL) was added under N2 and the soln was cooled to 0 8C. Propene oxide (0.50 mL, 7.2 mmol; previously dried over CaH2 and vacuum transferred before use) was added via an airtight syringe, and the mixture was stirred for 2 h at 0 8C. After this time, the mixture was quenched with 1 M aq HCl (5.0 mL) and unreacted propene oxide was removed in vacuo, before CH2Cl2 (20 mL) was added to redissolve the precipitated polymer. The organic layer was separated and the solvent was removed by rotary evaporation at 22 8C; yield: 370 mg (89%). The polymer was purified by dissolving it in hot acetone (5.0 mL), and then adding the resulting soln dropwise to acetone (150 mL) at 25 8C. The polymer soln was cooled to 0 8C for 3 h and the white precipitate that formed was filtered and dried in vacuo to constant weight; yield: 360 mg (86%). Enantiomerically Pure Isotactic Poly(propene oxide) (66B, R1 = Me); Typical Procedure:[99]
CAUTION: Propene oxide should be handled with extreme care. It is a carcinogen, a mutagen, irritating, and highly flammable. (R,R)(S)(R,R)-64 (8.0 mg, 7 mol), [PPN][OAc] (8.4 mg, 14 mol), and toluene (12 mL) under N2, were added to a 50-mL Schlenk tube with a Teflon-covered stirrer bar. After the flask had been cooled to 0 8C, racemic propene oxide (2.00 mL, 1.69 g; previously dried over CaH2 and vacuum transferred before use), also cooled to 0 8C, was added to the soln. After the mixture had been stirred for 90 min at 0 8C, the unreacted propene oxide was evaporated to a trap cooled by liq N2, and CH2Cl2 (30 mL) was added to the polymer/catalyst residue. The polymer/catalyst soln was transferred to a 250-mL flask, concentrated using rotary evaporation, and then dried under reduced pressure. Crude poly(propene Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.21.12
Stereoselective Polymerization of Racemic and Meso Epoxides
963
oxide) was obtained; yield: 849 mg (50%). The crude polymer was purified by crystallization from hot acetone and washed with cold acetone; Mn = 89 000 g • mol–1; Mw/Mn = 1.6. 3.21.12.2
Stereoregular Polycarbonates
3.21.12.2.1
Isotactic Poly(cycloalkene carbonate)s
Optically active poly(cycloalkene carboxylate)s, typically poly(cyclohexene carboxylate), with 100% carbonate linkages and highly isotactic structures such as 68 are prepared from cycloalkene oxides and carbon dioxide with chiral zinc-based catalysts (Scheme 31).[102,103] The most effective system is a zinc complex 67 that is supported by a C1-symmetric imine-dihydrooxazole ligand; it affords relatively high molecular weight highly isotactic polymers with up to 72% enantiomeric excess and with narrow molecular weight distributions. This system is also applicable to the alternating isospecific copolymerization of cyclopentene oxide with carbon dioxide (up to 76% ee). Scheme 31 Enantioselective Isospecific Copolymerization of Cyclohexene Oxide and Carbon Dioxide with a Zinc Catalyst[102,103] But
O N
Zn N(TMS)2 N
67
O n
+
n CO2
catalyst 67
O
O
R
R
O n
68
isotactic
Enantiomerically Enriched Isotactic Poly(cyclohexene carbonate) (68); Typical Procedure:[102]
The zinc complex 65 (60 mg, 0.10 mmol), cyclohexene oxide (1.0 mL, 1.0 g, 10.0 mmol), toluene (3 mL), and a magnetic stirrer bar were placed in a 60-mL Fischer–Porter bottle kept in a glovebox. The vessel was pressured with CO2 (7 atm) and its contents were stirred at rt for 24 h. After the toluene had been evaporated, the product was redissolved in CH2Cl2 (1 mL) and precipitated from MeOH (5 mL). The polymer was collected by filtration and dried in vacuo to constant weight; yield: 1.0 g (100%); Mn = 14 700 g • mol–1; Mw/Mn = 1.35; [Æ]D20 –14.7 (c 2.0, CHCl3). 3.21.12.2.2
Syndiotactic Poly(cycloalkene carbonate)s
Syndiospecific alternating copolymerization of cyclohexene oxide with carbon dioxide leading to the polymer 70, with 86–90% carbonate linkages and 80% r diads, is mediated by the chiral racemic cobalt–salen complex 69 (Scheme 32).[104]
Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.21
Stereoselective Polymerization
Scheme 32 Enantioselective Syndiospecific Copolymerization of Cyclohexene Oxide and Carbon Dioxide with a Cobalt–Salen Catalyst[104]
N
N Co
But
O
But
O Br But
But 69
O +
2n
2n CO2
catalyst 69
O
O
O
O
R
R
S
S
O
O n
70
syndiotactic
Syndiotactic Poly(cyclohexene carbonate) (70); Typical Procedure:[104]
Complex 69 (15.6 mg, 0.0201 mmol) and cyclohexene oxide (1.00 mL, 9.88 mmol) under an inert atmosphere (typically in a glovebox), were placed in a glass sleeve with a Teflon stirrer bar inside a 100-mL autoclave. The autoclave was pressurized with CO2 (54 atm) and its contents were left to stir at 22 8C for 3 h. The reactor was vented at 22 8C, and the polymerization mixture was then dissolved in CH2Cl2 (5 mL), quenched with 5% HCl in MeOH (0.2 mL), and precipitated from MeOH (30 mL). The polymer was collected and dried in vacuo to constant weight; yield: 0.799 g (57%); Mn = 22 300 g • mol–1; Mw/Mn = 1.35. 3.21.13
Stereoselective Ring-Opening Polymerization of Lactones: Isotactic, Stereoblock, Syndiotactic, and Heterotactic Poly(lactide)s; Syndiotactic Poly(3-Hydroxybutanoate)
3.21.13.1
Poly(lactide)s
Poly(lactic acid)s (PLAs) are important biodegradable materials for biomedical, pharmaceutical, and packaging applications. They are most conveniently prepared by the ringopening polymerization of the cyclic dimer of lactic acid [3,6-dimethyl-1,4-dioxane-2,5dione, which is referred to as lactide (LA)]. Lactide exists as three isomers: (S,S)-l, (R,R)-d, and (S,R)-meso. Among these, l-lactide is the most readily available, since it is derived from naturally occurring l- or d-lactic acid, prepared by fermentation from biomass. Also available is a racemic mixture of lactic acid dimer known as racemic lactide (rac-LA). Starting from these monomers, a variety of poly(lactide)s 71–74 with different tacticities can be produced (Scheme 33).[105] These polymers feature significantly different physicochemical properties, such as melting point and rate of degradation by living organisms. Scheme 33
Common Microstructures of Stereoregular Poly(lactide)s
O O
Nu
S S
2n
O
S
O
O S
O
S
O
S
O
O
O
O
n
O 71
PLLA (isotactic)
Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
H
965
Stereoselective Ring-Opening Polymerization of Lactones
3.21.13
O
O
Nu R
O
O R
O n
O
S
O
m
S
O +n
O
O
R
72
O
O
S
O
O
H p
PLLA-b-PDLA (isotactic stereoblock)
S
R
O
O
O Nu
rac-lactide
R
O R
O
O
O
S
S
O
O 73
O
H n
hPLA (heterotactic)
O 2n
O
R
O
Nu R
O S
O S
O
O R
O
O
O
H
O
O meso-lactide
S
n
74
sPLA (syndiotactic)
Experimental procedures for the preparation of isotactic poly(l-lactide) (71), stereoblock isotactic poly(lactide) (72), syndiotactic poly(lactide) (74), and heterotactic poly(lactide) (73) can be found in Sections 3.21.13.1.1, 3.21.13.1.2, 3.21.13.1.3, and 3.21.13.1.4, respectively. 3.21.13.1.1
Isotactic Poly(lactide)
Ring-opening polymerization of l-lactide gives rise to the formation of isotactic poly(l-lactide) (71, PLLA) without epimerization of the stereocenters [similar polymerization of d-lactide gives poly(d-lactide) (PDLA)]. This can be achieved with most of the reported metal coordination catalysts (avoiding the most active ones, such as organolithium and -magnesium initiators), or combinations of a nucleophilic organocatalyst (tertiary amines, phosphines, and N-heterocyclic carbenes) with the requisite alcohol. Ring-opening polymerization of l-lactide using strong Lewis bases, such as the commonly used 4-(dimethylamino)pyridine, with a primary alcohol initiator (EtOH, BnOH) proceeds in a living fashion, affording poly(l-lactide) with narrow polydispersity and molecular weight that can be adjusted by varying the amount of primary alcohol.[106] High monomer conversions are obtained for monomer to initiator ratios up to 140 both in dichloromethane solution (35 8C, a few days) and in bulk (melted monomer, 185 8C, a few minutes). Isotactic Poly(l-lactide) (71); Typical Procedure:[106]
A round-bottomed flask equipped with a stirrer bar and sealed with a septum was flamedried under reduced pressure, and purged with N2. l-Lactide (1.00 g, 6.94 mmol) and DMAP (0.56 g, 0.46 mmol; for DP = 30) were added to the flask while it was kept in a glovebox. CH2Cl2 (5 mL; distilled from CaH2) and EtOH (14 L, 0.23 mmol) were added, and the flask was heated to 35 8C. The polymer was isolated by adding cold MeOH, filtering, and drying to a constant weight; yield: 1.00 g (100%). 3.21.13.1.2
Stereoblock Isotactic Poly(lactide)
Stereoblock isotactic poly(lactide), [PLLA-b-PDLA]n, was first prepared by the kinetic resolution of rac-lactide using aluminum catalysts [enantiomerically pure or racemic; typically, complex 75 (Scheme 34)] via a site-control mechanism.[107] Later studies demonstrated Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
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Stereoselective Synthesis
3.21
Stereoselective Polymerization
that this type of material can be accessed by ring-opening polymerization of rac-lactide via a chain-end control mechanism using achiral, intrinsically more simple salen-type catalysts.[108] With complex 76 (Scheme 34), combined with 1 equivalent of benzyl alcohol, the stereoblock isotactic poly(lactide)s prepared are almost monodisperse (Mw/Mn = 1.08– 1.12), and have a high stereoregularity (Tm = 192 8C; Pm = probability of meso linkage = 0.91).[107–113] Scheme 34 Catalysts and Precatalysts for Stereospecific Ring-Opening Polymerization of Racemic Lactide[107–113]
N
N N
O Al
N
Al But
OPri
But
O
O Et
O
But
But
75
76
H B N N
Zn
N
N Bu
OPri
t
N N Ca
N N But
But
N(TMS)2 77
78
R2
R2 N
THF O Y R1 (Me2HSi)2N 79
O O Me
R1
R1= R2 = CMe2Ph, adamantyl, t-Bu R1 = Tr; R2 = Me
Stereoblock Isotactic Poly(lactide) (72); Typical Procedure:[108]
A 0.050 M soln of the catalyst 75 or 76 in toluene (1.0 mL, 0.050 mmol) was added under N2 via a cannula to rac-lactide (0.72 g, 5.0 mmol) and 0.10 M soln of BnOH in toluene (0.50 mL, 0.050 mmol) at rt. The catalyst flask was rinsed with toluene (1 2.0 mL; 1 1.5 mL). The yellow mixture was heated at 70 8C and the progress of the polymerization was monitored by 1H NMR and SEC analysis of a small amount (ca. 5 mg) of the mixture. When the conversion was >90%, the mixture was cooled at 20 8C, and [PLLA-b-PDLA]n (72) was obtained by precipitation of the mixture with cold MeOH (ca. 100 mL); yield: 0.70 g (96%). 3.21.13.1.3
Syndiotactic Poly(lactide)
An efficient synthesis of syndiotactic poly(lactide) (74, sPLA) involves the ring-opening polymerization of meso-lactide, employing the enantiomerically pure (R)-SalBinap–aluminum catalyst 75 (Scheme 34).[109] This complex leads to more syndiotactic PLAs ([r]3 up to 96%) than those obtained by chain-end control with the achiral -diiminate zinc complex Stereoselective Polymerization, Carpentier, J.-F., Kirillov, E. Science of Synthesis 4.0 version., Section 3.21 sos.thieme.com © 2014 Georg Thieme Verlag KG (Customer-ID: 5907)
3.21.13
Stereoselective Ring-Opening Polymerization of Lactones
967
77 ([r]3 up to 76%), although the latter compound is catalytically more active than the aluminum compound. Syndiotactic Poly(lactide) (74); Typical Procedure:[109]
(R)-SalBinap–Al catalyst 76 (8.0 mg, 14.0 mol), meso-lactide (0.201 g, 1.4 mmol), toluene (7.0 mL), and a magnetic stirrer bar were placed in a Schlenk flask held within a glovebox. The flask was heated to the desired temperature (50 or 70 8C), and stirred for 40 h. An aliquot was taken for determining the conversion by 1H NMR. The solvent was removed in vacuo and the polymer was redissolved in CH2Cl2 and precipitated from cold MeOH. The white, crystalline solid was collected by filtration and dried in vacuo to constant weight; yield: 0.165 g (82%). 3.21.13.1.4
Heterotactic Poly(lactide)
Preparation of heterotactic poly(lactide) (hPLA) from rac-lactide can be achieved with some discrete metal complexes supported by ligands having bulky substituents. Among the most efficient systems are the -diiminate zinc complex 77,[110] the tris(pyrazolyl)borate calcium complex 78,[111] and amino–alkoxy–bis(phenolate)yttrium complexes 79[112] (Scheme 34). These complexes efficiently promote the ring-opening polymerization of rac-lactide to produce poly(lactide) with heterotactic levels up to 90–95%. However, the preparation of these catalysts (and sometimes of the proligands) is quite tedious. A more efficient and convenient catalyst system for the preparation of heterotactic poly(lactide) is based on the simple combination of indium(III) chloride, benzyl alcohol, and triethylamine.[113] This generates a catalyst in situ for the ring-opening polymerization of rac-lactide under mild conditions (0–60 8C), affording highly heterotactic poly(lactide) (Pr = 0.94 at 25 8C, increased up to 0.97 at 0 8C) of controlled molecular weight and narrow molecular weight distribution. Heterotactic Poly(lactide) (73); Typical Procedure:[113]
The appropriate amount of initiator (as a 0.276 M BnOH soln in CH2Cl2) was added under an inert atmosphere, to a stirring suspension of InCl3 in a 1.0 M soln of rac-lactide. After 10 min of stirring, Et3N (as a 0.276 M soln in CH2Cl2) was added (2 equiv with respect to BnOH), after which the indium salt began to dissolve. Once the reaction reached near complete conversion (96–99% conversion, as indicated by 1H NMR monitoring), the polymer was precipitated out of soln by dropwise addition to cold, wet MeOH (0 8C, 20 mL of MeOH/1.38 mL of the reaction soln). The polymer was isolated and dried under high vacuum for 48 h; yield: 95%. 3.21.13.2
Poly(3-hydroxybutanoate)
The most common poly(hydroxyalkanoate) (PHA) is natural poly(3-hydroxybutanoate) [poly(3-hydroxybutyrate), PHB], which is a pure isotactic, highly crystalline thermoplastic polyester produced by various bacteria and algae. Beside this natural polymerization process, which only gives isotactic poly(3-hydroxybutanoate), the controlled ring-opening polymerization of racemic -butyrolactone (rac-BBL) can potentially provide access to a variety of poly(3-hydroxybutanoate) microstructures. Only a few metal-based initiators are known to imbue the ring-opening polymerization of rac-butyrolactone with significant activity, and even less provide stereocontrol, so as to afford high molecular weight tactic poly(3-hydroxybutanoate)s. The most effective systems to date are amino–alkoxy– bis(phenolate)yttrium complexes 79[114] (Schemes 34 and 35). These catalysts lead to poly(3-hydroxybutanoate)s with high molecular weight, narrow polydispersity (Mw/Mn 90% ee). Oxidation of Sulfides, Lattanzi, A. Science of Synthesis 4.0 version., Section 3.22 sos.thieme.com © 2014 Georg Thieme Verlag KG
for references see p 1012 (Customer-ID: 5907)
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Stereoselective Synthesis
3.22.1
Oxidation of Sulfides Using Achiral Reagents
Oxidation of Sulfides
3.22
The oxidation of sulfides bearing stereogenic centers generally proceeds with moderate diastereocontrol. Common oxidizing reagents such as 3-chloroperoxybenzoic acid,[7–9] sodium periodate,[10] alkyl hydroperoxides,[11] and hydrogen peroxide[12,13] can be used. The highly diastereoselective oxidation of some 2-substituted 1,3-dithianes and 1,3-dithiolanes or sulfides having stereogenic centers in their scaffold can be accomplished using common organic or inorganic oxidants and peroxometal complexes. The stereocontrol is attributed to the steric bias created by the incipient stereogenic center and neighboring-group participation. The stereoselective oxidation of 2-phenyl-1,3-dithiane, as a representative compound, is highlighted in Table 1.[14–16] Table 1
Diastereoselective Oxidation of 2-Phenyl-1,3-dithiane[14–16] oxidation
S
S
S
Ph
S
+ O
Ph trans-1
S
S
O
Ph cis-1
Conditions
Yield (%)
dr (trans/ cis)
Ref
MCPBA, CH2Cl2, –25 8C, overnight
63a
92:8
[14]
NaIO4, MeOH/dioxane, 0 8C, overnight
94a
92:8
[14]
Ti(Cp)2Cl2 (5 mol%), t-BuOOH, 4-Å molecular sieves, CH2Cl2, 0 8C, 5h
86
98:2
[15]
1,3-bis[bis(3,5-trifluoromethyl)phenyl]thiourea (1 mol%), t-BuOOH, CH2Cl2, rt, 40 h
92
96:4
[16]
a
Yield after recrystallization.
The stoichiometric employment of strong oxidants, such as 3-chloroperoxybenzoic acid or sodium periodate, requires subambient temperatures to chemoselectively furnish trans-2-phenyl-1,3-dithiane 1-oxide (trans-1) in good yield and stereoselectivity.[14] Catalytic metal-promoted oxidation using dichlorobis(Å5-cyclopentadienyl)titanium(IV) [Ti(Cp)2Cl2] in conjunction with tert-butyl hydroperoxide as the oxidant provides trans-1 in high yield and with excellent diastereocontrol.[15] The organic promoter 1,3-bis[3,5-bis(trifluoromethyl)phenyl]thiourea efficiently catalyzes the process at low catalytic loadings, affording almost exclusively the trans-isomer at room temperature.[16] High diastereocontrol in favor of trans-1 is a consequence of the less hindered equatorial approach of the oxidant. In the oxidation of 2,2-disubstituted 1,3-dithianes or 1,3-dithiolanes the level of diastereoselectivity is generally lower, due to the lower differentiation between the equatorial and axial positions. Hydroxy groups present in a substrate provide a useful tool to preferentially deliver the electrophilic oxygen atom of a peracid or peroxometal complex to the prochiral sulfide, in a similar manner to that observed in the epoxidation of allylic alcohols with the same reagents.[17,18] The oxidation of methyl (E)-3-({(1R,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-1-yl}methylsulfanyl)acrylate with 3-chloroperoxybenzoic acid affords the sulfoxide in good yield and high diastereocontrol (Scheme 1).[19] Similarly, the bis(acetylacetonato)oxovanadium(IV)/tert-butyl hydroperoxide system facilitates the oxidation of (R)-3-(4-tolylsulfanyl)butan-1-ol with modest diastereocontrol.[11]
Oxidation of Sulfides, Lattanzi, A. Science of Synthesis 4.0 version., Section 3.22 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.22.1
975
Oxidation of Sulfides Using Achiral Reagents Diastereoselective Oxidations of Hydroxy Sulfides[11,19]
Scheme 1
OH
MCPBA, CH2Cl2, 0 oC
O
73%
O
S
S
CO2Me
H
OH
+
S O
CO2Me
CO2Me 92:8
4-Tol
4-Tol
VO(acac)2
S
t-BuOOH, CH2Cl2, −20 oC
S
O
OH
OH dr 83:17
The use of hydrogen peroxide conveniently and stereospecifically affords the sulfoxide product starting from the penicillin derivative (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenoxyacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (Scheme 2).[20] The polar protic secondary amide portion near the sulfur atom, directs the oxygen delivery to provide the cis-diastereomer. This finding has been ascribed to hydrogen-bonding interactions between hydrogen peroxide and the amide portion as previously observed in the oxidation of hydroxy sulfides with 3-chloroperoxybenzoic acid. Scheme 2 Diastereoselective Oxidation of (2S,5R,6R)-3,3-Dimethyl-7-oxo-6(2-phenoxyacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic Acid with Hydrogen Peroxide[20] H N
PhO O
H
H N
PhO S
S
H2O2, CH2Cl2
O
90%
N O
O
H N
O CO2H
CO2H
The oxidations of phenyl sulfides with stereogenic centers that do not bear groups capable of neighboring-group participation and without particular steric features generally proceed with modest diastereoselectivity. Indeed, sodium periodate and 3-chloroperoxybenzoic acid lead to moderate diastereocontrol in this type of oxidation. Nevertheless, an appropriate choice of oxidant, such as tert-butyl hypochlorite, enables the formation of branched alkyl phenyl sulfoxides with good to excellent diastereocontrol, depending on the type of substitution at the stereocenters (Scheme 3).[21] Scheme 3 Diastereoselective Oxidation of Alkyl Phenyl Sulfides Bearing a Chiral Center with tert-Butyl Hypochlorite[21] t-BuOCl, CH2Cl2, −78 oC, 1 h
R1
S
Ph
R1
S O anti
R1
Yield (%) dr (anti/syn) Ref
4-ClC6H4
85
99:1
[21]
iPr
84
85:15
[21]
Oxidation of Sulfides, Lattanzi, A. Science of Synthesis 4.0 version., Section 3.22 sos.thieme.com © 2014 Georg Thieme Verlag KG
Ph
+
R1
S
Ph
O syn
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Stereoselective Synthesis
3.22
Oxidation of Sulfides
trans-2-Phenyl-1,3-dithiane 1-Oxide (trans-1):[16]
A soln of 2-phenyl-1,3-dithiane (39.3 mg, 0.2 mmol) and 1,3-bis[3,5-bis(trifluoromethyl)phenyl]thiourea (1 mg, 2 mol) in anhyd CH2Cl2 (400 L) was stirred at rt in a capped vial. A 5–6 M soln of t-BuOOH in decane (44 L, 0.24 mmol) was then added. The mixture was kept at rt for 40 h, then the solvent was removed under reduced pressure, and the crude mixture was analyzed by 1H NMR to determine the trans/cis ratio (dr 96:4). Purification of the residue by flash chromatography (petroleum ether/EtOAc 4:1 to 0:1) afforded a white solid; yield: 39 mg (92%). 3.22.2
Chiral Metal Complex Catalyzed Oxidation of Sulfides
An array of stoichiometric or catalytic chiral metal-based protocols are available for the synthetic chemist to perform the asymmetric oxidation of sulfides. Some of them operate under relatively strictly controlled reaction conditions for the generation of the active species, whereas an ever-increasing number of methods work under more environmentally friendly conditions in terms of oxidant, reaction medium, cost, and efficiency.[5,6,22,23] Although the chemoselective oxidation of sulfides to sulfoxides is often complicated by overoxidation to the sulfone, the process can be utilized to provide a stereoconvergent kinetic resolution and thereby improve the enantioenrichment of the sulfoxide product. Many of the ligands suitable for the asymmetric process, such as diols, -amino alcohols, and 1,2-diamines, are either commercially available or are readily prepared from commercially available compounds. 3.22.2.1
Catalysis Using Titanium/Chiral Diols
3.22.2.1.1
Using Titanium(IV) Isopropoxide/(R,R)-Diethyl Tartrate
In 1984, a modification of the Sharpless–Katsuki reagent for the asymmetric epoxidation of allylic alcohols was independently reported by the groups of Kagan and Modena.[24–26] The Sharpless–Katsuki asymmetric epoxidation of allylic alcohols with the titanium(IV) isopropoxide/diethyl tartrate/tert-butyl hydroperoxide system is described in Science of Synthesis, Vol. 37 [Ethers (Section 37.2.1.1.2)]. Under molar ratios optimized for the epoxidation, i.e. titanium(IV) isopropoxide/diethyl tartrate (1:2), the oxidation of prochiral sulfides is unselective. In contrast to the Sharpless–Katsuki oxidation of allylic alcohols, the stoichiometric oxidation of prochiral sulfides developed by Kagan requires a controlled amount of water in order to maintain a homogeneous system that results in high enantiocontrol. The reaction temperature and aging times for the generation of the catalytically active species are also found to be important parameters. Hence, a ratio of 1:2:1:1.1 titanium(IV) isopropoxide/diethyl tartrate/water/tert-butyl hydroperoxide is employed at –20 8C in dichloromethane to ensure an efficient and asymmetric oxidation (Scheme 4).[24,25] Scheme 4
Kagan’s Protocol for the Asymmetric Oxidation of Sulfides[24,25] Ti(OiPr)4 (1 equiv), (R,R)-DET (2 equiv), H2O (1 equiv)
R1
S
O
t-BuOOH (1.1 equiv), CH2Cl2, −21 oC
R2
R1
S
R2
The optimal results in terms of yield and asymmetric induction are observed for aryl methyl sulfoxides (91% ee), although lower enantioselectivity is obtained for substrates where the carbon chain of the alkyl group of the alkyl aryl sulfide is increased. This reaction tolerates various functional groups in the alkyl chain including esters, cyclopropane rings, amines, alkynes, and alkenes, albeit this type of substitution significantly affects the level of asymmetric induction. Dialkyl sulfoxides are obtained with lower enantioOxidation of Sulfides, Lattanzi, A. Science of Synthesis 4.0 version., Section 3.22 sos.thieme.com © 2014 Georg Thieme Verlag KG
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977
Chiral Metal Complex Catalyzed Oxidation of Sulfides
selectivity (50–71% ee). The process is highly chemoselective and the sulfone is not detected at the end of the process. The absolute configuration of sulfoxide is predictable, since the (R)-sulfoxide is obtained with (R,R)-diethyl tartrate. Kagan also investigated the oxidation of labile sulfur containing compounds.[27] Disulfides, sulfenamides, and sulfenates are less easily oxidized to the corresponding thiosulfinates, sulfinamides, and sulfinates and provide modest levels of enantioselectivity, as illustrated in Scheme 5. Scheme 5 Stoichiometric Asymmetric Oxidation of Labile Sulfides Using Kagan’s Protocol[27]
R1
S
X
R2
Ti(OiPr)4, (R,R)-DET, H2O t-BuOOH, CH2Cl2, −20 oC, 1−7 d
O R
R1
X
R2
Yield (%) ee (%) Config Ref
iPr
S
iPr
43
52
S
[27]
t-Bu 29
23
S
[27]
t-Bu S
4-Tol NEt Et
60
35
S
[27]
4-Tol O
Me
88
36
R
[27]
Ph
Me
86
29
R
[27]
O
1
S
X
R2
The optimum reagent ratio for Modenas oxidation protocol is 1:4:2 of titanium(IV) isopropoxide/diethyl tartrate/tert-butyl hydroperoxide in toluene or 1,2-dichloroethane at –20 8C. Scheme 6 illustrates this reaction for the synthesis of methyl 4-tolyl sulfoxide (2).[26] Similar results in terms of asymmetric induction are achieved under these conditions to those obtained using Kagans method. Interestingly, the addition of molecular sieves provides racemic sulfoxides, indicating that water is critical for asymmetric induction. The excess of tartrate ligand is thought to introduce water, which would give rise to a catalytic species identical to that formed under Kagans conditions. Scheme 6 Oxidation of Methyl 4-Tolyl Sulfide Using Modena’s Protocol[26]
4-Tol
S
Ti(OiPr)4 (1 equiv), (R,R)-DET (4 equiv) t-BuOOH (2 equiv), 1,2-dichloroethane −20 oC, 14 h
Me
60%; 88% ee
O 4-Tol
S
Me
2
The level of enantiocontrol for oxidations using Kagans protocol has been further improved using cumene hydroperoxide, which proves to be a superior oxidant compared to tert-butyl hydroperoxide (Scheme 7).[28] A variety of aryl methyl sulfoxides and some dialkyl sulfoxides 3 are chemoselectively obtained in good to high yield and with excellent enantioselectivity.
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Stereoselective Synthesis
Oxidation of Sulfides
3.22
Scheme 7 Stoichiometric Asymmetric Oxidation of Prochiral Sulfides with Kagan’s Protocol Using Cumene Hydroperoxide[28] Ti(OiPr)4, (R,R)-DET, H2O PhCMe2OOH (2 equiv), CH2Cl2
Me
S
O
−20 oC, overnight
R1
S
Me
R1
3
R1
Yield (%) ee (%) Config Ref
4-Tol
75
>99.5
R
[28]
4-MeOC6H4
78
99.5
R
[28]
1-naphthyl
91
91.2
R
[28]
Bn
87
95.4
R
[28]
(CH2)7Me
63
85.1
R
[28]
In another example, (R)-ethyl 4-tolyl sulfoxide is prepared in 82% yield and with 87% enantiomeric excess. Nevertheless, alkyl aryl sulfides with longer alkyl chains are only oxidized with modest asymmetric induction. The asymmetric oxidation of racemic -hydroxy sulfides has been studied by Modena.[29] A critical factor in this reaction is the necessity to protect the hydroxy group as a sterically encumbered silyl derivative, which magnifies the difference between the two groups linked to the thioether, as exemplified in the oxidation of {[1-(methylsulfanyl)-1phenylpropan-2-yl]oxy}triphenylsilane (Scheme 8). Oxidation with tert-butyl hydroperoxide under the same conditions provides the sulfoxide in 90% yield, with an 88:12 anti/syn ratio and with 70% enantiomeric excess for the major isomer. Scheme 8 Oxidation of {[1-(Methylsulfanyl)-1-phenylpropan-2-yl]oxy}triphenylsilane under Modena’s Conditions[29] Ti(OiPr)4, (R,R)-DET PhCMe2OOH (2 equiv)
Ph Me
S
OSiPh3
CH2Cl2 −20 oC, overnight 91%
Ph Me
S
Ph OSiPh3
+
O anti; 78% ee
Me
S
OSiPh3
O 91:9
syn; 70% ee
NMR and IR studies have been carried out to elucidate the nature of the catalytic species involved in the process, but the identification of this species is challenging due to the lability of the reactive species in solution.[30] Kagan explained the stereochemical outcome of the asymmetric oxidation of sulfides by suggesting the transition state illustrated in Scheme 9.[31] A bimetallic electrophilic species is formed where one tartrate acts as a tridentate ligand. The sulfide approaches along the O—O bond of the coordinated peroxide through an orientation that is dictated by the stereoelectronic preference imparted by the largest (RL) and smallest (RS) substituents. The larger the difference in size of RL and RS, the higher the enantioselectivity, which is generally optimal for aryl methyl sulfoxides.
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Chiral Metal Complex Catalyzed Oxidation of Sulfides
3.22.2
979
Scheme 9 Transition State Proposed for the Oxidation Using Kagan’s System[31] O O R1 O
O
RL S
OEt
O
Ti O
OEt O
Ti
RS
Scettri has investigated the influence of the structure of the alkyl hydroperoxide under Modenas conditions.[32] In this case, cumene hydroperoxide (1.2 equiv), with a stoichiometric amount of the chiral titanium complex [titanium(IV) isopropoxide/diethyl tartrate 1:4], is a superior oxidant compared to tert-butyl hydroperoxide (Scheme 10). Scheme 10 Stoichiometric Asymmetric Oxidation of Prochiral Sulfides with Modena’s Protocol Using Cumene Hydroperoxide[32] Ti(OiPr)4, (R,R)-DET PhCMe2OOH (1.2 equiv), CH2Cl2
Me
S
O
−20 oC, 24 h
R1
Me
R1
Yield (%) ee (%) Config Ref
4-Tol
84
90
R
[32]
2-MeOC6H4a
99
92
R
[32]
2-naphthyl
90
92
R
[32]
4-O2NC6H4
60
87
R
[32]
(CH2)7Me
73
91
R
[32]
a
S
R1
Reaction time 40 h.
Aryl methyl sulfoxides are chemoselectively obtained in good to high yield and enantioselectivity, with a particularly notable result for the preparation of methyl octyl sulfoxide. Nevertheless, the necessity for stoichiometric loadings of the titanium complex, the timings for reagent mixing to generate the catalytically active species, the addition of water, the mode of stirring in addition, and the issues involved with the removal of titanium salts affect the cost and practicality of the Kagan and Modena protocols. In the course of initial investigations to develop a catalytic version of the oxidation, Kagan observed that under catalytic loading (20 mol%) of the chiral titanium complex [titanium(IV) isopropoxide/diethyl tartrate/water 1:2:1], the addition of activated 4- molecular sieves before all the other components had a beneficial effect on the enantioselectivity.[33,34] Molecular sieves likely regulate the extra amount of water, present in the reaction vessel, which is presumable deleterious for the formation of the correct titanium catalyst responsible for the highly enantioselective pathway. It was also observed that the replacement of water by propan-2-ol affords comparable results with respect to standard stoichiometric conditions using cumene hydroperoxide. Moreover, even in this case, the initial addition of molecular sieves had a positive effect. Hence, a truly catalytic procedure for the oxidation of sulfides with cumene hydroperoxide (2 equiv) has been established by adding molecular sieves (1 wt equivalent with respect to the sulfide) and 10 mol% of the
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Stereoselective Synthesis
Oxidation of Sulfides
3.22
reagent [titanium(IV) isopropoxide/diethyl tartrate/propan-2-ol 1:4:4] at –20 8C in dichloromethane. The best result achieved in the case of methyl 4-tolyl sulfoxide is a 77% yield and with 96% enantiomeric excess.[33] The oxidation of 2-alkyl-substituted 1,3-dithianes and 1,3-dithiolanes has also been investigated with the titanium(IV) isopropoxide/diethyl tartrate system.[35] Indeed, enantiomerically enriched monosulfoxides of cyclic dithioacetals provide chiral acyl anion equivalents and are therefore interesting targets. Modenas conditions generally afford better results in the oxidation of 2-alkyl-1,3-dithiolanes.[36,37] The stoichiometric process is highly substrate dependent and moderate to good diastereo- and enantioselectivities are obtained for the monosulfoxides (trans/cis 60:40 to >90:10; 30–80% ee). The oxidation of 2-acyl-1,3-dithianes, under the same conditions, generally proceeds with high stereocontrol, as illustrated in Scheme 11.[38–41] Using stoichiometric amounts of the titanium(IV) isopropoxide/tartrate reagent with the Modena or Kagan protocol, (1R,2R)-configured sulfoxides are isolated as the major products in good yield with satisfactory diastereoselectivity for the trans-isomer 4A and with high enantiomeric excess. The reaction is not completely chemoselective, since the trans-1,3-dioxide 5 is obtained in the oxidation of 1-(2-ethyl-1,3-dithian-2-yl)butan-1-one and tert-butyl 1,3-dithiane-2-carboxylate in 4 and 11% yield, respectively. In both cases, the trans-1,3-dioxide is highly enantiomerically enriched as expected. This oxidation provides a convenient method to prepare a trans(1R,3R)-1,3-dithiane 1,3-dioxide using Modenas protocol in >99% enantiomeric excess (Scheme 11).[41] Scheme 11 Stoichiometric Asymmetric Oxidation of 2-Acyl-1,3-dithianes with Titanium(IV)/(R,R)-Diethyl Tartrate Systems[38,40,41]
S R
Ti(OiPr)4, (R,R)-DET R3OOH, CH2Cl2
S 1
S
S 1
O
R
R2
O O
S
+
R
R2
S 1
O O
+
S
S
O
R1 R2
R2
4A
O
O 5
4B
R1
R2
Conditions
Yield (%)
Ratioa (4A/4B)
eea (%) of 4A
eea (%) of 4B
Ref
H
t-Bu
Ti(OiPr)4/DET/PhCMe2OOH (1:4:1.2), –37 8C
63
75:25
92
88
[40]
Ph Me
Ti(OiPr)4/DET/H2O/t-BuOOH (1:2:1:1.2), –20 8C 71
91:9
99
99
[38]
Me Ph
Ti(OiPr)4/DET/H2O/t-BuOOH (1:2:1:1.2), –20 8C 58
>99:1
86
n.d.
[40]
Et
Pr
Ti(OiPr)4/DET/H2O/t-BuOOH (1:2:1:1.2), –20 8C 66
91:9
90
n.d.
[38]
H
Ot-Bu Ti(OiPr)4/DET/H2O/PhCMe2OOH (1:2:1:2), –35 8C, 48 h
79
n.d.
95
n.d.
[41]
a
n.d. = not determined.
Ti(OiPr)4 (1 equiv) (R,R)-DET (4 equiv) PhCMe2OOH (4 equiv)
S
S
CH2Cl2, −22 oC, 24 h 62%
CO2Et
O
S
NaOH, H2O 70 oC
S
O
83%
CO2Et (R,R); >97% ee
O
S
S
O
>99% ee
The direct double oxidation of 1,3-dithiane under Kagans conditions affords trans(1R,3R)-1,3-dithiane 1,3-dioxide with modest enantiomeric excess (59% ee). Oxidation of Sulfides, Lattanzi, A. Science of Synthesis 4.0 version., Section 3.22 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.22.2
Chiral Metal Complex Catalyzed Oxidation of Sulfides
981
Attempts to make the titanium/tartrate system more practical have led to the immobilization of the catalyst using soluble polymers; these systems bring the advantages of homogeneous solution chemistry, such as high reactivity, lack of diffusion phenomena, and the fact that products may be readily analyzed, isolated, and purified.[42] Poly(ethylene glycol) monomethyl ether (MeOPEGOH) provides a soluble support for a small library of tartrate esters (e.g., 6), which are readily available via a one-pot reaction using (R,R)-tartaric acid, poly(ethylene glycol) monomethyl ether (MW 2000), and various alcohols (Scheme 12). The oxidation using cumene hydroperoxide and the metal complex at substoichiometric loading (50 mol%) in dichloromethane at –20 8C, furnishes the (S)-aryl methyl sulfoxides in good yield and with high enantioselectivity. The tartrate polymer has been recycled up to four times with >97% recovery without compromising the level of asymmetric induction in the oxidation, and the catalyst can be easily recovered by simple precipitation and filtration. Scheme 12 Enantioselective Oxidation of Sulfides Using a Soluble-Polymer-Supported Tartrate System[42] O HO
OPEGOMe O
HO
6
O 6
Me
S
50 mol% Ti(OiPr)4/6 (1:4) PhCMe2OOH, CH2Cl2, −20 oC, 16 h
Ar
1
O Me
Ar1
Yield (%) ee (%) Ref
4-Tol
66
90
[42]
4-ClC6H4
91
99
[42]
S
Ar1
Titanium(IV)/diethyl tartrate catalyzed oxidation of sulfides has proven to be a powerful transformation for the preparation of highly enantioenriched sulfoxides with important biological activity. One example is the industrial production of esomeprazole by AstraZeneca [esomeprazole, the S-enantiomer of omeprazole, is registered as Nextium]. This sulfoxide is a member of a highly potent class of gastric acid secretion inhibitors, and is successfully used as an anti-ulcer agent.[43] A modified catalytic version of Kagans protocol was devised to produce this agent. This represents one of the most efficient large-scale asymmetric oxidations developed to date in the pharmaceutical industry (Scheme 13).[44,45]
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Stereoselective Synthesis
3.22
Oxidation of Sulfides
Enantioselective Oxidation To Give Esomeprazole[45]
Scheme 13
1. 30 mol% Ti(OiPr)4
OMe
OMe
60 mol% (S,S)-DET 20 mol% H2O toluene, 50 oC 2. 30 mol% iPr2NEt
N
PhCMe2OOH (1 equiv) 35 oC
S
N HN
N
O S
N
78%; 97% ee
HN
OMe
pyrmetazole
OMe
esomeprazole
The standard oxidation protocol provides almost racemic sulfoxide, presumably due to the comparable size of the sulfide substituents. The new protocol, besides aging of the catalyst, requires the introduction of N,N-diisopropylethylamine (Hnigs base) to achieve excellent enantioselectivity. Indeed, esomeprazole is isolated in 78% yield and with 97% enantiomeric excess using substoichiometric loadings of the titanium catalyst (4–30 mol%).[45] Moreover, a variety of related sulfides with the imidazole NH group are oxidized with high enantioselectivity. A mechanistic rationale for the oxidation of pyrmetazole and structurally similar sulfides based on MS, NMR, and DFT modeling studies has been proposed. This rationale suggests that the most important interaction governing asymmetric induction in the out-of-sphere oxidation is hydrogen bonding between the NH of the imidazole ring and the chiral tartrate ligand on the titanium (Scheme 14).[45] Scheme 14 Transition State Suggested in the Oxidation of a Model Methyl Imidazole Sulfide[45] R1 Pri CO2Et O N Et O Ti Pri O OL S Me EtO2C H N N
The kinetic resolution of racemic methyl sulfoxides has been examined using Modenas protocol using (R,R)-diethyl tartrate as ligand. The S-enantiomer is selectively oxidized to the sulfone, thereby affording the enantiomerically enriched (R)-sulfoxide.[46,47] The (R)-sulfoxide is also formed preferentially during the oxidation of sulfides under analogous conditions. Kinetic resolution provides an alternative approach to the construction of enantioenriched sulfoxides, albeit the maximum yield is only 50%. Although cumene hydroperoxide is a superior oxygen donor to tert-butyl hydroperoxide, the furyl hydroperoxides 7 and 8 are the oxidants of choice for this process, affording the sulfoxides with optimal yield and asymmetric induction (Scheme 15).
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3.22.2
983
Chiral Metal Complex Catalyzed Oxidation of Sulfides
Scheme 15
Kinetic Resolution of Methyl Sulfoxides[46,47] Pri 3
H
EtO2C O Pri
O
H O
OOH
HOO
H
O
7
8
Ti(OiPr)4 (1 equiv), (R,R)-DET (4 equiv) oxidant (1.6 equiv), CH2Cl2, −20 oC
O S
Me
H
R1
O Me
S
O R1
+
Me
O S
R1
rac
R1
Oxidant
Yield (%) of Sulfoxide ee (%) Config sa
Ref
4-Tol
PhCMe2OOH
40
83
R
8.6
[46]
4-Tol
7
38
>95
R
n.r.
[46]
4-ClC6H4
7
40
95
R
15.7
[46]
4-O2NC6H4
8
58
>95
R
n.r.
[47]
(CH2)7Me
8
31
94
R
7.8
[47]
a
s = ln[(1 – C)(1 – ee)]/ln[(1 – C)(1 – ee)];[48] n.r. = not reported.
The stereoconvergent oxidation/kinetic resolution of aryl methyl sulfides and dialkyl sulfides, using an excess of furyl hydroperoxide 7 (1.6 equiv) under stoichiometric conditions [titanium(IV) isopropoxide/diethyl tartrate 1:4] in dichloromethane at –23 8C, provides various sulfoxides in modest yield (31–58%) and with good to excellent enantioselectivity (83–95% ee). (R)-Methyl 4-Tolyl Sulfoxide (2); Typical Procedure:[26]
To a stirred soln of Ti(OiPr)4 (1.9 g, 6.7 mmol) and (R,R)-DET (5.6 g, 27 mmol) in anhyd 1,2dichloroethane (50 mL) cooled to –20 8C were added successively t-BuOOH (1.2 g, 13.3 mmol, as reported) and methyl 4-tolyl sulfide (0.93 g, 6.7 mmol). The mixture was stirred at –20 8C for 14 h, and then washed with 5% aq Na2SO3 (3 15 mL) and sat. aq NaCl. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, CHCl3); yield: 0.62 g (60%); 88% ee [determined after further distillation (bp 85–87 8C/0.5 Torr)]. (R)-Methyl 4-Tolyl Sulfoxide (3, R1 = 4-Tol); Typical Procedure:[28]
Ti(OiPr)4 (0.83 g, 3 mmol) was added rapidly (10 s) to a soln of (R,R)-DET (1.24 g, 6 mmol) in CH2Cl2 (10 mL) under N2 at 16 8C. After 2.5 min, H2O (54 L, 3 mmol) was added slowly using a microliter syringe with vigorous stirring and an interruption of 15 s after each drop. The mixture was stirred for 20 min at 16 8C, followed by cooling in a freezer (–22 8C) without stirring for an additional 20 min. Rapid addition of methyl 4-tolyl sulfide (415 mg, 3 mmol) and precooled (–22 8C) cumene hydroperoxide (6 mmol) was followed by storage of the flask in the freezer without stirring. The mixture was poured into a soln of FeSO4•7H2O (3 g, 10.8 mmol) and citric acid (presumably the monohydrate; 1 g, 4.8 mmol) in H2O (30 mL), 1,4-dioxane (15 mL), and Et2O (25 mL), and the resulting mixture was stirred for 15 min. The aqueous phase was extracted with Et2O (3 20 mL). The combined Oxidation of Sulfides, Lattanzi, A. Science of Synthesis 4.0 version., Section 3.22 sos.thieme.com © 2014 Georg Thieme Verlag KG
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984
Stereoselective Synthesis
3.22
Oxidation of Sulfides
organic phases were vigorously stirred with 2 M aq NaOH (50 mL) for 1 h. The aqueous phase was then extracted with Et2O (3 20 mL). The combined organic phases were washed with brine (25 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. Purification of the residue by chromatography (silica gel, EtOAc) afforded a colorless solid; yield: 347 mg (75%); >99.5% ee; [Æ]D +145 (c 2, acetone). 2-(2,2-Dimethyl-1-oxopropyl)-1,3-dithiane 1-Oxide (4, R1 = H; R2 = t-Bu); Typical Procedure:[40]
Ti(OiPr)4 (0.146 mL, 139 mg, 0.49 mmol, 1 equiv) was added to a soln of (R,R)-DET (0.34 mL, 0.404 g, 1.96 mmol, 4 equiv) in CH2Cl2 under N2. The resulting pale yellow soln was stirred at rt for 5 min. 2-(2,2-Dimethyl-1-oxopropyl)-1,3-dithiane (0.10 g, 0.49 mmol) was dissolved in CH2Cl2 and added by syringe to the mixture. The soln was stirred at rt for a further 5 min and then at between –40 and –20 8C for 30 min. Cumene hydroperoxide (91 L, 93.2 mg, 0.61 mmol, 1.2 equiv) was added and the mixture was stirred at –37 8C for 1 d. H2O (10 equiv) was added to the mixture, which was then stirred at –40 to –20 8C for 1 h and allowed to reach rt over a further 1 h with stirring. Celite was added together with additional CH2Cl2, and the mixture was stirred for a further 5 min. The mixture was filtered under reduced pressure and the Celite was rinsed with several portions of CH2Cl2. The filtrate was washed with 5% aq Na2S2O3 saturated with NaCl and then with 5% aq NaOH saturated with NaCl, and then dried (MgSO4), and the solvents were removed under reduced pressure to give a crude oily residue. Flash column chromatography furnished the 1,3-dithiane 1-oxide product; yield: 69.4 mg (63%). 3.22.2.1.2
Using Titanium(IV) Isopropoxide/1,1¢-Bi-2-naphthol or Diols
In 1993, Uemura reported a modified version of the Kagan and Modena protocols, which replaced diethyl tartrate with (R)-1,1¢-bi-2-naphthol (BINOL) as the chiral ligand.[49] The most notable feature of this methodology is the catalytic loading of the chiral metal complex, which makes the process more economical and practical. Hence, under the optimized reaction conditions, a ratio of 0.1:0.2:2:2 titanium(IV) isopropoxide/(R)-1,1¢-bi-2naphthol/water/tert-butyl hydroperoxide (70% aqueous solution) is employed for the oxidation of aryl methyl sulfides in carbon tetrachloride (or aromatic solvents) at 25 8C or at lower temperatures. Using 5 mol% of the catalyst, (R)-methyl 4-tolyl sulfoxide is isolated in up to 96% enantiomeric excess but the yield is only 43%, due to the formation of the sulfone. Large, positive nonlinear effects are observed in the oxidation, indicating that more than one molecule of 1,1¢-bi-2-naphthol is coordinated to the titanium. The enantiomeric excess of the sulfoxide increases with reaction time and with the formation of the sulfone. All these findings are in agreement with the kinetic resolution of the enantioenriched sulfoxide, in which the S-enantiomer is preferentially converted into the sulfone (Scheme 16). Scheme 16
Enantioselective Oxidation/Kinetic Resolution under Uemura’s Conditions[49] 5 mol% Ti(OiPr)4, 10 mol% (R)-BINOL H2O (1 equiv), t-BuOOH (2 equiv)
Me
S
O
CCl4, 25 oC
4-Tol
Me
S
4-Tol
50% ee
O
O
kinetic resolution
Me
S
4-Tol
43%; 96% ee
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+
Me
O S
4-Tol
3.22.2
985
Chiral Metal Complex Catalyzed Oxidation of Sulfides
Some (sulfanylmethyl)phosphonates have been oxidized under similar conditions, without the necessity for kinetic resolution, to afford the sulfoxides 9 in good yield and with excellent enantioselectivity (>90% ee).[50] In these sulfoxides, the methylphosphonate residue behaves as a removable auxiliary, which can be replaced upon treatment with various Grignard reagents. Hence, an array of dialkyl, alkyl aryl, and diaryl sulfoxides 10 may be prepared via the Andersen-type process in an enantiospecific manner (Scheme 17). Scheme 17 Sulfoxides Bearing the Diethyl Methylphosphonate Groups as an Auxiliary in an Andersen-Type Approach to Chiral Sulfoxides[50] O
O
O
S
P OEt OEt
[O]
R1
S
P OEt OEt
R
1
9
R1
R2
R1
S
R2
Yield (%) from 9 ee (%) Configa Ref 54
>98
R
[50]
Me Cy
50
>96
n.d.
[50]
Me (CH2)17Me 49
>98
n.d.
[50]
4-Tol
36
91
R
[50]
Ph 4-Tol
42
94
R
[50]
a
O
10
Me (CH2)7Me
Et
R2MgBr (1.5 equiv) benzene, 0 oC
n.d. = not determined.
Although the yields of the sulfoxides 10 are modest, this approach provides a convenient strategy for the construction of particularly challenging dialkyl and diaryl sulfoxides with excellent enantiocontrol. The structure of the alkyl hydroperoxide is a critical component for the level of enantiocontrol in the Uemura protocol. For instance, 2-(2-hydroperoxypropan-2-yl)furan, which is the furyl analogue of cumene hydroperoxide, facilitates the formation of (R)-methyl 4-tolyl sulfoxide in toluene at 0 8C in 63% yield and with 87% enantiomeric excess.[51] Under identical conditions, but using tert-butyl hydroperoxide as oxidant, (R)-methyl 4-tolyl sulfoxide is recovered in 66% yield and with 72% enantiomeric excess.[49] Modified 1,1¢-bi-2-naphthols provide improved chemoselectivity in sulfide oxidation.[52] C2-Symmetric diols have been explored as ligands with a view to improve both the chemo- and enantioselectivity. For example, in the presence of (R,R)-1,2-diphenylethane1,2-diol (11), tert-butyl hydroperoxide chemoselectively oxidizes sulfides to sulfoxides that are more difficult to prepare by the aforementioned procedures, namely linear alkyl aryl and aryl benzyl sulfides.[53] In contrast to Uemuras protocol, the oxidation with a ratio of 0.05:0.1:1:2 titanium(IV) isopropoxide/(R,R)-1,2-diphenylethane-1,2-diol/ water/tert-butyl hydroperoxide (70% aqueous solution) in carbon tetrachloride at 0 8C leads to chemoselective oxidation. Moreover, diols bearing different aryl groups (e.g., 12) can also be used as ligands and hexane can be employed as the solvent.[54] Functionalized substrates, namely -keto sulfides, also undergo effective and highly enantioselective oxidation to the sulfoxides 13 under these conditions (Scheme 18).[55]
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986
Stereoselective Synthesis Scheme 18 HO
3.22
Oxidation of Sulfides
Catalytic Asymmetric Oxidation of Sulfides with Rosini’s Protocol[53–55] HO
OH
OH
But
But
11
1
R
S
12
5 mol% Ti(OiPr)4, 10 mol% ligand H2O (1 equiv), t-BuOOH (2 equiv), CCl4, 0 oC, 2 h
R
O
2
R1
S
R2
13
R1
R2
Ligand Yield (%) ee (%) Config Ref
Me
4-Tol
12
70
90
S
[54]
Me
Ph
11
63
80
S
[53]
Bu
Ph
11
69
80
S
[53]
Bn
Ph
11
73
>99
S
[53]
a
Bn
4-MeOC6H4
12
72
>99
S
[54]
2-naphthyl
CH2Bz
11
90b
>98
R
[55]
11
b
>98
R
[55]
4-BrC6H4 a b
CH2Bz
75
Performed in hexane. Performed at rt with (S,S)-1,2-diphenylethane-1,2-diol. Reaction time 48 h.
A strategy for the immobilization of catalysts to give heterogeneous chiral titanium catalysts for the asymmetric oxidation of sulfides has been reported by Ding.[56] This protocol involves the use of homochiral metal-organic coordination polymers, formed by the selfassembly of chiral multitopic ligands and catalytically active metal ions as “self-supported” chiral catalysts.[57] The oxidation of aryl methyl sulfides with a heterogenized 1,1¢-bi-2naphthol/titanium catalyst, e.g. 14 (5 mol%), and cumene hydroperoxide in carbon tetrachloride at 25 8C provides the sulfoxides 15 in modest yield and with excellent enantioselectivity (Scheme 19). The level of enantiomeric enrichment is the result of a further kinetic resolution of the resulting sulfoxide, which is reflected in the low yield (99
R
13.1
[79]
4-FC6H4
4-Tol
21
S
9.9
[79]
Ph
4-BrC6H4
31
>99
S
17.6
[79]
Ph
Ph
21
86
S
4.6
[79]
Ph
Me
51
4
S
1.1
[79]
a
98.3
s = ln[(1 – C)(1 – ee)]/ln[(1 – C)(1 – ee)].
Subtle steric and electronic factors affect the efficiency of the kinetic resolution of aryl benzyl sulfoxides. For example, replacing the aryl group with an alkyl derivative leads to an unselective process. Sulfoxides 31; General Procedure:[78]
A soln of VO(acac)2 (159.0 mg, 0.60 mmol) in CHCl3 (15 mL) was added to a soln of (R)-30 (425.8 mg, 0.90 mmol) in CHCl3 (15 mL) and the mixture was stirred for 2 h. A soln of the sulfide (60.0 mmol) in CHCl3 (30 mL) was added and the mixture stirred for 30 min at rt before cooling it to 0 8C. After 30 min, 30% H2O2 (7.36 mL, 72.0 mmol) was added to the mixture, which was then stirred vigorously at 0 8C for 48 h. The reaction was quenched with 10% aq Na2S2O3 (200 mL) and the mixture was extracted with CHCl3 (3 100 mL). The extracts were combined, washed with brine (3 100 mL), and dried (MgSO4), and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (EtOAc/petroleum ether 1:1) and then analyzed by chiral HPLC. 3.22.2.4
Catalysis Using Iron/Chiral Schiff Base Ligands
Bolm reported the development of an environmentally friendly oxidation methodology that has outstanding ecological sustainability using iron as the metal source. Iron-based complexes are generally less toxic, less expensive, and easier to access than other metals. Among them, tris(acetylacetonato)iron(III) has proven a convenient catalyst that can be employed with low loadings, e.g. 2 mol% metal complex with 4 mol% of (S)-30 as the ligand, in the presence of 30% aqueous hydrogen peroxide in dichloromethane at room temperature.[80] Although sulfoxides can be obtained with excellent asymmetric induction (up to 90% ee) under these conditions, the conversions are modest (91% ee).[90] Solvent-free or highly concentrated reactions reduce the “E factor” (deOxidation of Sulfides, Lattanzi, A. Science of Synthesis 4.0 version., Section 3.22 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Stereoselective Synthesis
3.22
Oxidation of Sulfides
fined as the waste per kg of product produced) of a chemical process, while also reducing the cost and enhancing the rate of reaction.[91] A plausible catalytic cycle has been proposed, which invokes an Å2-hydroperoxo complex 38 as the active species (Scheme 35).[90] The hydroperoxo complex, formed from the aluminum complex with hydrogen peroxide, oxidizes the sulfide and produces an aluminum hydroxide complex that reacts with hydrogen peroxide to regenerate the active hydroperoxo complex. Scheme 35 Plausible Catalytic Cycle for the Aluminum/Salalen Catalyzed Oxidation of Sulfides[90] L∗AlCl H2O2, buffer
L∗Al
H 2O
O OH
R1
S
R2
38 O H2O2
R1
L∗Al-OH
S
R2
Methyl Sulfoxides 37; General Procedure:[88]
The sulfide (0.20 mmol), 67 mM phosphate buffer (pH 7.4; 20.0 L), and 30% H2O2 (24 L, 0.22 mol) were added sequentially to a soln of complex 36 (3.6 mg, 4.0 mol) in MeOH (2.0 mL), and the resulting soln was stirred at rt for 24 h. The mixture was then concentrated under reduced pressure, and the residue was purified by chromatography (silica gel, hexane/acetone 4:1 to 1:1) to give the sulfoxide. The ee was determined by chiral HPLC analysis. 3.22.2.6
Catalysis Using Chiral Molybdenum- and Niobium-Based Catalysts
The application of molybdenum- and niobium-based catalysts to the asymmetric oxidation of sulfides has also been relatively underexplored. In 2006, Yamamoto described the successful catalytic enantioselective oxidation of sulfides utilizing catalytic amounts of a chiral molybdenum complex (2 mol%) with trityl hydroperoxide in dichloromethane at 0 8C.[92] Alkyl aryl sulfoxides 40 are generally obtained in good yields with up to 86% enantiomeric excess. Moreover, the same system provides a stereoconvergent kinetic resolution wherein a combined asymmetric oxidation/kinetic resolution provides higher enantioselectivities, albeit with moderate yield (Scheme 36).[93] The sterically demanding bis(hydroxamic acid) chiral ligands (e.g., 39) are also effective in the vanadium-catalyzed enantioselective epoxidation of cis- and trans-allylic alcohols.[94] Scheme 36 Catalytic Asymmetric Oxidation/Kinetic Resolution with a Chiral Molybdenum Complex/Trityl Hydroperoxide[93]
O 4-Tol
O N
N
OH
4-Tol 4-Tol
4-Tol
OH
4-Tol 4-Tol
39
Oxidation of Sulfides, Lattanzi, A. Science of Synthesis 4.0 version., Section 3.22 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.22.2
R1
S
1001
Chiral Metal Complex Catalyzed Oxidation of Sulfides
2 mol% MoO2(acac)2, 4 mol% 39 TrOOH (1.5 equiv) CH2Cl2, −40 to 0 oC, 43 h
O
R2
R1
+
S
R2
O R1
O S
R2
40 kinetic resolution
R1
R2
Yield (%) of 40 ee (%) Config Ref
Me Ph
66
92
S
[93]
Me 4-Tol
55
94
S
[93]
Et
51
96
S
[93]
50
93
S
[93]
Ph
Me 2-naphthyl
The oxidation of di-tert-butyl disulfide with a similar ligand and a stoichiometric amount of trityl hydroperoxide furnishes the synthetically useful thiosulfinate ester in 79% yield and with 90% enantiomeric excess.[92] Katsuki described the first asymmetric oxidation of sulfides with a chiral niobium– salen complex in 2003.[95] A variety of aryl methyl sulfides are oxidized with 8 mol% of the niobium(III) complex and 12 mol% of the salen ligand 41 using urea–hydrogen peroxide complex as terminal oxidant in dichloromethane at –10 8C in the presence of molecular sieves. Although the niobium–salen complex is less reactive than the complexes previously described for the asymmetric oxidation of sulfides, the reaction is highly chemoselective, providing the sulfoxides in high yield and with good enantioselectivity (Scheme 37). The oxidation of a dialkyl sulfide, namely benzyl methyl sulfide, also proceeds with similar selectivity, albeit in lower yield. Scheme 37 Catalytic Asymmetric Oxidation with Niobium–Salen/ Urea–Hydrogen Peroxide Complex[95]
N
N
OH HO Ph Ph
41
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1002
Stereoselective Synthesis
3.22
Oxidation of Sulfides
8 mol% NbCl3(DME), 12 mol% 41 H2O2•urea (1.1 equiv)
Me
S
O
4-Å molecular sieves, CH2Cl2, −10 oC, 2 d
R1
Me
R1
Yield (%) ee (%) Config Ref
4-MeOC6H4
94
81
S
[95]
4-ClC6H4
92
84
S
[95]
4-BrC6H4
94
83
S
[95]
2-BrC6H4
65
83
S
[95]
Bn
61
80
S
[95]
S
R1
Mechanistic studies indicate a positive nonlinear effect, which suggests that the chiral complex exists as an equilibrium between the monomer and a series of oligomers. FABMS analysis indicates that the niobium–salen complex is a 1:1 adduct, in which niobium(III) is oxidized to niobium(V) during complex formation or mass spectrometric analysis. Hence, the salen presumably serves as an Å4 ligand for the metal center. Sulfoxides 40; General Procedure:[93]
To a soln of ligand 39 (0.03 mmol) in CH2Cl2 (3 mL) was added MoO2(acac)2 (5 mg, 0.015 mmol), and the mixture was stirred for 1 h at rt. The resulting soln was cooled to –40 8C, then the sulfide (0.75 mmol) and TrOOH (1.13 mmol) were added, and stirring was maintained at the same temperature for 19 h. Then, the mixture was stirred for 24 h at 0 8C. The progress of oxidation was monitored by TLC. Sat. aq Na2SO3 was added, and the mixture was stirred for 30 min at 0 8C. The mixture was then allowed to warm to rt and extracted with CH2Cl2. The extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography to provide the sulfoxide 40. The ee was determined by chiral HPLC analysis. 3.22.3
Organocatalytic Oxidation of Sulfides
Organocatalysts provide a number of advantages over the corresponding metal-based asymmetric catalysts, namely availability from the chiral pool, stability under aerobic conditions, and low toxicity. Additionally, the reactions are operationally simple to perform under more environmentally friendly conditions.[96] Applications for both small- and large-scale production of chiral compounds will obviously benefit from these advantages as this area continues to develop. Although only a few effective organocatalytic systems have been disclosed for the asymmetric oxidation of sulfides, these generally have relatively wide substrate scope. Nevertheless, this process is currently limited to the use of stoichiometric chiral promoters. 3.22.3.1
Using Chiral Oxaziridines and Oxaziridinium Salts
Metal-free asymmetric oxidation reactions of sulfides are dominated by chiral oxaziridines, which were developed by Davis in the early 1990s. A variety of oxaziridines (e.g., 42) have been prepared and examined as stoichiometric oxidants, providing variable results in terms of asymmetric induction.[97] The most effective oxygen source is prepared in three steps from readily available (+)- or (–)-camphor in 50% overall yield. Alkyl aryl and dialkyl sulfides, including functionalized derivatives, undergo smooth oxidation in carbon tetrachloride or dichloromethane at room temperature, to afford the corresponding sulfoxides 43 in excellent yield and enantiomeric excess (Scheme 38).[98] Oxidation of Sulfides, Lattanzi, A. Science of Synthesis 4.0 version., Section 3.22 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.22.3
1003
Organocatalytic Oxidation of Sulfides
Scheme 38 Stoichiometric Asymmetric Oxidation of Sulfides with Davis’ Oxaziridine[98] Cl
N O
Cl Ph (1 equiv) S O O
42
R1
S
O
CCl4, 20 oC, 2−48 h
R2
R1
S
R2
43
R1
R2
Yield (%) ee (%) Config Ref
Me
4-Tol
95 a
>95
S
[98]
9-anthryl
Me
90
95
S
[98]
Bn
4-Tol
88
94
S
[98]
cyclopropyl
Ph
90
92
S
[98]
Bu
4-Tol
90
91
S
[98]
Me
t-Bu
84
94
S
[98]
Ph
CH2CO2Me
65
94
S
[98]
a
In CH2Cl2 as solvent.
Optimal asymmetric induction for the oxidation of sulfides is generally achieved where there is a large difference in size between the groups directly bonded to the sulfur atom, analogous to the model outlined for the Kagan reagent.[31] For example, the oxidation of methyl 4-tolyl sulfide affords the sulfoxide in 95% yield and with >95% enantiomeric excess, whereas methyl octyl sulfoxide is obtained in a modest yield (60%) and with poor asymmetric induction (15% ee) under analogous conditions. Enantiomerically enriched sulfoxides of both absolute configurations are accessible using the appropriately configured camphor-derived oxaziridine. Steric effects are primarily responsible for the molecular recognition and are predictable using an active-site model based on the crystal structure of the oxaziridine. It is suggested that the oxaziridine behaves as an electrophilic oxidant, a proposal which is supported by the low reactivity of the corresponding dehalogenated oxaziridine and the fact that electron-withdrawing groups at the oxaziridine carbon accelerate oxygen transfer. The mechanism of oxygen transfer from the N-sulfonyloxaziridine involves an SN2-type displacement of the sulfonylimine by the nucleophilic sulfide, a process which is facilitated by a relatively weak N—O bond. The corresponding sulfonylimine side product is isolated in >90% yield and may be conveniently recycled by treating it with 3-chloroperoxybenzoic acid. Oxaziridinium salts are electrophilic oxygen transfer reagents that have primarily been applied to the epoxidation of alkenes.[99,100] Boh and coworkers have prepared an oxaziridinium salt from cholesterol that serves as an efficient reagent for the stoichiometric oxidation of various sulfides in dichloromethane.[101] This process is highly chemoselective and the sulfoxides are isolated in high yield and with excellent enantiomeric excess (up to >99% ee; Scheme 39). Although the electronic effects of the substituents on the phenyl ring have minimal influence on selectivity, the steric effects are very important. Nevertheless, such effects are not easily predictable as the effective size of an aryl group in the transition state may be quite different from its actual size. Linear and more sterically demanding alkyl substituents on phenyl sulfides are well tolerated; however, dialkyl sulfides are poor substrates for this system. For example, the oxidation of benzyl methyl sulfide provides an almost racemic sulfoxide. Oxidation of Sulfides, Lattanzi, A. Science of Synthesis 4.0 version., Section 3.22 sos.thieme.com © 2014 Georg Thieme Verlag KG
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1004
Stereoselective Synthesis
3.22
Oxidation of Sulfides
Scheme 39 Stoichiometric Asymmetric Oxidation of Sulfides with a Cholesterol-Derived Oxaziridinium Salt[101] Pri 3
(1 equiv)
TBDPSO
R1
R1
S
O
+ N
BF4− Me
O
CH2Cl2, −70 oC to rt, 3 h
R2
R2
R1
S
R2
Yield (%) ee (%) Config Ref
Me 4-Tol
88
>99
R
[101]
Me 2-Tol
85
98
R
[101]
Me 4-O2NC6H4
73
84
R
[101]
Pr
Ph
76
90
R
[101]
iPr Ph
76
94
R
[101]
Bn Ph
83
85
R
[101]
The camphor-derived sulfonylimines (1 equiv) can also be employed in the asymmetric oxidation of sulfides under basic conditions using 1,8-diazabicyclo[5.4.0]undec-7-ene (4 equiv) and aqueous hydrogen peroxide (4 equiv) in dichloromethane at low temperature.[102] Unfortunately, the level of asymmetric induction is generally quite poor, except for the oxidation of 2-phenyl-1,3-dithiane, which affords the trans-monosulfoxide in quantitative yield and with 83% enantiomeric excess. The identity of the oxidizing species is still uncertain, but two possible parallel pathways for the oxygen transfer to sulfur have been postulated. The first proposes that the reaction proceeds via the hydroperoxyamine obtained by addition of the oxidant to the C=N bond of the imine, whereas the second pathway is thought to involve the oxaziridine produced by cyclodehydration of the hydroperoxyamine. Sulfoxides 43; General Procedure:[98]
In a 5-mL, round-bottomed flask equipped with a magnetic stirrer bar and an argon inlet was placed oxaziridine 42 (0.25 mmol) in CH2Cl2 (5 mL) or CCl4 (10 mL) (CAUTION: toxic) followed by the addition of a soln of the sulfide (0.28 mmol) in solvent (5 mL). The progress of the reaction was monitored by TLC (CH2Cl2/pentane 4:1), and the sulfoxide was isolated by preparative TLC (Et2O). The enantiomeric excess was determined either by chiral HPLC analysis or by 1H NMR analysis employing tris[3-(heptafluoropropylhydroxymethylene)(+)-camphorato]europium(III) [Eu(hfc)3] as chiral shift reagent in CDCl3. 3.22.3.2
Using a Chiral Ketone/Oxone System
Ketones derived from sugars have been successfully employed by Shi as precursors to chiral dioxiranes for the highly enantioselective epoxidation of unfunctionalized and functionalized alkenes.[103,104] The d-fructose-derived ketone 45 with Oxone has also proven to be an interesting organocatalytic system for the oxidation of functionalized, sterically hindered, symmetrical disulfides 44.[105] For example, treatment of the disulfides with substoichiometric amounts of the ketone 45 (30 mol%) in the presence of Oxone (1.4 equiv), under buffered conditions in acetonitrile/dimethoxymethane (1:2) at 0 8C, furnishes the thiosulfinate esters 46 in good yield and with good to high enantiocontrol Oxidation of Sulfides, Lattanzi, A. Science of Synthesis 4.0 version., Section 3.22 sos.thieme.com © 2014 Georg Thieme Verlag KG
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3.22.4
1005
Biological Oxidation of Sulfides
(Scheme 40). The oxidation of di-tert-butyl disulfide with this system is also an effective process. However, substrates with free hydroxy groups give lower asymmetric induction. The Bolm–Ellman vanadium-based catalysts are inefficient in the oxidation of these disulfides. Scheme 40 Asymmetric Oxidation of Disulfides with a D -Fructose-Derived Ketone/Oxone System[105]
O
O
O
30 mol% O
O O 45
R2
R2 S
R1
buffer (pH 9.3) Oxone (1.4 equiv), MeCN/CH2(OMe)2 0 oC, 13 h
R1 S R2
R1
S
2 O R
R2
46
R1
R2
Yield (%) ee (%) Ref
H
Me
97
84a
[105]
OH
Et
80
72
[105]
OAc
Et
89
89
[105]
OAc
(CH2)4Me
57
96
[105]
89
93
[105]
a
R1
R2 S
R2
44
OCOBn Et
R2
S Configuration determined by [Æ]D measurement.
Thiosulfinates 46; General Procedure:[105]
A soln of Bu4NHSO4 (15 mg, 0.04 mmol) and ketone 45 (77 mg, 0.3 mmol) in an alkaline buffer (pH 9.3; 10 mL) was added to a soln of the corresponding disulfide 44 (1 mmol) in MeCN/CH2(OMe)2 (1:2; 15 mL) under stirring at 0 8C. A mixture of Oxone (0.85 g, 1.38 mmol) in Na2(edta) soln (6.5 mL) and K2CO3 (0.8 g, 5.8 mmol) dissolved in distilled H2O (6.5 mL) were added dropwise separately and slowly over the course of 1 h. After stirring for an additional 12 h at 0 8C, the resulting mixture was diluted with H2O and extracted with Et2O, and the extracts were dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography. 3.22.4
Biological Oxidation of Sulfides
The number of processes that involve biocatalysts is steadily increasing since enzymes allow reactions to be performed under mild conditions using water as a convenient medium, and also avoid the need to employ hazardous reagents.[106] This is a positive step toward the development of ideal synthetic processes that respect environmental and safety concerns, which are of ever-increasing importance for industrial applications. Enzymes are also highly regio-, chemo-, and stereoselective catalysts, although they have high substrate specificity, which may significantly limit the scope and access is generally restricted to only one absolute configuration of the product. Moreover, the modification of the reaction conditions often leads to decreased enzyme stability and poor selectivity.
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1006
Stereoselective Synthesis
3.22.4.1
Oxidation Using Isolated Enzymes
3.22.4.1.1
Using Peroxidases and Monooxygenases
3.22
Oxidation of Sulfides
There are two main types of enzymes used for sulfide oxidation reactions, namely peroxidases and monooxygenases. Peroxidases are redox enzymes that are able to catalyze sulfide oxidation by the addition of a chemical oxidant, such as hydrogen peroxide or alkyl hydroperoxides.[107] The native enzymes contain heme [Fe(III) protoporphyrin IX] as the prosthetic group, which is oxidized by the peroxide to a formally iron(V) oxo species that is responsible for the oxygen transfer to the sulfide. Horseradish peroxidase (HRP) has been the most thoroughly investigated to date, and moderate levels of asymmetric induction have been observed for the oxidation of aryl methyl sulfides using this enzyme.[108] Modification of the active site of native horseradish peroxidase by site-directed mutagenesis, e.g. replacement of the phenylalanine-41 by a leucine residue, can lead to significantly improved enantiocontrol (>99% ee).[109] Colonna has reported that heme-containing chloroperoxidase (CPO), isolated from the marine fungus Caldariomyces fumago, facilitates sulfoxidation reactions using hydrogen peroxide.[110,111] In order to achieve excellent chemo- and enantioselectivity it is necessary to suppress the uncatalyzed oxidation promoted by hydrogen peroxide and trace metal.[112,113] The slow addition of hydrogen peroxide to the reaction mixture is necessary to reduce enzyme deactivation and also to limit the uncatalyzed oxidation to sulfoxide as demonstrated in the case of a vanadiumcontaining bromoperoxidase (VBrPO)[114] from the alga Corallina officinalis (Scheme 41). Scheme 41 Asymmetric Oxidation of Sulfides with Chloroperoxidase and Vanadium-Containing Bromoperoxidase at Room Temperature[112,114,115] O R
1
S
R
2
R1
S
R2
R1
R2
Conditions
Me
Ph
CPO, H2O2, buffer/t-BuOH (1:1)
Me
Ph
CPO, H2O2, buffer
Et
Ph
Et
ee (%)
Config Ref
73
99
R
[112]
100
99
R
[112]
CPO, H2O2, buffer/t-BuOH (1:1)
52
99
R
[112]
Ph
CPO, H2O2, buffer
83
99
R
[112]
Pr
Ph
CPO, H2O2, buffer/t-BuOH (1:1)
1
60
R
[112]
Pr
Ph
CPO, H2O2, buffer
3
27
R
[112]
Me
4-MeOC6H4
CPO, H2O2, buffer/t-BuOH (1:1)
50
99
R
[112]
Me
4-MeOC6H4
CPO, H2O2, buffer
53
99
R
[112]
Me
2-MeOC6H4
CPO, H2O2, buffer/t-BuOH (1:1)
2
99
R
[112]
Me
2-MeOC6H4
CPO, H2O2, buffer
3
99
R
[112]
Me
4-O2NC6H4
CPO, H2O2, buffer/t-BuOH (1:1)
17
99
R
[112]
Me
4-O2NC6H4
CPO, H2O2, buffer
19
99
R
[112]
Me
4-ClC6H4
CPO, H2O2, buffer/t-BuOH (1:1)
73
99
R
[112]
Me
4-ClC6H4
CPO, H2O2, buffer
78
99
R
[112]
Me
2-thienyl
CPO, H2O2, buffer/t-BuOH (1:1)
91
99
R
[112]
Me
2-thienyl
CPO, H2O2, buffer
100
99
R
[112]
Oxidation of Sulfides, Lattanzi, A. Science of Synthesis 4.0 version., Section 3.22 sos.thieme.com © 2014 Georg Thieme Verlag KG
Conversion (%)
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3.22.4
R1
Me
R2
CH2Ac
1007
Biological Oxidation of Sulfides Conditions
Conversion (%)
ee (%)
Config Ref
VBrPO, H2O2 (slow addition, 16 h), buffer (pH 6.5)
99
90
S
[114]
VBrPO, H2O2 (slow addition, 16 h), buffer (pH 6.5)
84
91
S
[114]
100
>99
R
[115]
CPO, H2O2 (slow addition, 1 h), buffer (pH 5)
The chloroperoxidase and vanadium containing bromoperoxidase enzymes are highly substrate specific, in which well-defined steric requirements in the sulfide alkyl chain and the substituents on the phenyl ring impact the conversion and enantioselectivity. Various heme peroxidases can also catalyze the enantioselective oxidation of alkyl aryl sulfides, namely cytochrome c peroxidase,[116] microsome peroxidase,[117] lactoperoxidase,[118] and dioxygenase,[119] albeit with lower turnover numbers and enantioselectivity compared to chloroperoxidase. The cost of heme peroxidases and their reduced activity in organic solvents, coupled with their thermal instability and susceptibility to degradation in the presence of hydrogen peroxide, has limited industrial applications. With this in mind, Strukul and coworkers incorporated chloroperoxidase into a solid matrix to enable the enzyme to be used and recycled on a large scale, thereby reducing the cost of this process.[120] The use of a microencapsulated chloroperoxidase in a solid matrix of microporous silica gel facilitates the oxidation of aryl methyl sulfides with hydrogen peroxide to allow the chemoselective formation of sulfoxides with high enantioselectivity (>99% ee). The oxidation occurs with minimal leaching of the enzyme, which permits the catalyst to be recycled (up to four times) without loss of enantiocontrol, albeit with decreased activity. The low solubility of sulfides in water can be improved, without affecting the stereocontrol, through the addition of short-chain poly(ethylene glycols)[121] or hydrophilic ionic liquids to the chloroperoxidase/hydrogen peroxide buffered reaction mixture.[122] Monooxygenases, classified according to their redox cofactor as cytochrome P450-dependent, flavin-dependent, copper-dependent, and iron–pterin enzymes insert one oxygen atom from dioxygen into the substrate leaving the remaining oxygen atom to be reduced to water.[123] Under physiological conditions, the enzyme prosthetic group is regenerated in the catalytic cycle by the oxidized form of nicotinamide adenine dinucleotide phosphate (NADP+) and the reduced nicotinamide adenine dinucleotide phosphate (NADPH). These enzymes are limited by the necessity to employ stoichiometric amounts of this expensive cofactor and the poor stability of the isolated enzymes. Flavin-dependent monooxygenases from Acinetobacter calcoaceticus have been employed to catalyze the enantioselective Baeyer–Villiger oxidation of ketones to esters.[124] Colonna and coworkers have investigated the oxidation of sulfides using the nicotinamide adenine dinucleotide phosphate dependent cyclohexanone monooxygenase (CMO).[125] The oxidation with cyclohexanone monooxygenase is coupled to a second enzymatic reaction that involves the regeneration of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) with glucose 6-phosphate dehydrogenase (G6PDH; Scheme 42).
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Oxidation of Sulfides
Catalytic Cycle of Oxidation Mediated by Cyclohexanone Monooxygenase[125]
Scheme 42
R1
S
O
CMO, O2
R2
R1
NADPH
+
H
NADP
+
S
R2
H2O OH
OH
OH
OH
HO CO2H glucose 6-phosphate dehydrogenase
HO HO
P
O
OH
O
OH HO
O
HO
P
OH
O
O
Cyclohexanone monooxygenase promotes the highly chemo- and enantioselective oxidation of a variety of sulfides, including functionalized derivatives with polar groups. The process is highly substrate specific in terms of the asymmetric induction and absolute configuration of the product (Scheme 43).[126,127] An active-site model of the enzyme has been proposed to explain the observed stereoselectivity. Scheme 43 Asymmetric Oxidation of Aryl Alkyl Sulfides with Cyclohexanone Monooxygenase[126,127] O 1
R
S
CMO, O2
Ar
1
R1
S
Ar1
R1
Ar1
Yield (%) ee (%) Config Ref
Me
Ph
88
99
R
[126]
Me
4-FC6H4 91
92
R
[126]
Me
2-Tol
90
87
R
[126]
CH2CN
Ph
90
92
R
[127]
(CH2)2Cl
Ph
75
93
S
[127]
Et
Ph
86
47
R
[126]
iPr
4-Tol
99
86
S
[126]
Cyclohexanone monooxygenase has been employed to facilitate the oxidation of challenging dialkyl sulfides to sulfoxides 47 (Scheme 44).[128] The more sterically hindered alkyl methyl sulfoxides are obtained in a highly chemo- and enantioselective manner, in which only the sulfur atom is oxidized in the case of allyl methyl sulfide. Nevertheless, minor substrate modifications strongly influence the performance of the enzyme. This is nicely exemplified in the oxidation of tert-butyl ethyl sulfide, which affords the R-configured sulfoxide in low conversion (30%) and with poor enantiocontrol (35% ee). Similarly, linear acyclic alkyl groups are not well tolerated.
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Scheme 44 Asymmetric Oxidation of Dialkyl Sulfides with Cyclohexanone Monooxygenase[128] CMO, O2, NADPH, D-glucose 6-phosphate, buffer (pH 8.6)
Me
S
O
glucose 6-phosphate dehydrogenase, overnight, rt
S
1
R
Me
R1
47
R1
Conversion (%) ee (%) Config Ref
cyclopentyl
80
‡98
R
[128]
Cy
86
‡98
R
[128]
CH2CH=CH2 82
‡98
R
[128]
t-Bu
85
‡98
R
[128]
(CH2)4Me
58
60
S
[128]
(CH2)7Me
50
50
S
[128]
Although simple 1,3-dithanes, dithiolanes, and acyclic dithioacetals are oxidized with low enantiocontrol using chiral metal catalysts, enzymes provide excellent selectivity. Cyclohexanone monooxygenase mediated oxidation is the preferred oxidation, since it provides the monosulfoxides in high yield and with excellent enantioselectivity (Scheme 45).[129] Scheme 45 Asymmetric Oxidation of Dithioacetals and Di-tert-Butyl Disulfide with Cyclohexanone Monooxygenase[129,130]
R1S
CMO, O2, NADPH, D-glucose 6-phosphate, buffer glucose 6-phosphate dehydrogenase
SR2
O R1
R1
R2
81
‡98
R
[129]
(CH2)2
94
‡98
R
[129]
Me Me 92
‡98
R
[129]
S
S
R2
Yield (%) ee (%) Config Ref
(CH2)3
But
S
S
CMO, O2, NADPH, D-glucose 6-phosphate, buffer glucose 6-phosphate dehydrogenase
Bu
t
90% conversion; 97% ee
O But
S
S
But
The overoxidation of the sulfoxide to the sulfone in the case of 1,3-dithiane contributes to the enhancement of sulfoxide enantioselectivity due to stereoconvergent kinetic resolution. Finally, the enzymatic oxidative approach to (R)-tert-butyl 2-methylpropane-2-thiosulfinate is a useful alternative to the Bolm–Ellman vanadium–Schiff base catalyzed oxidation described earlier (see Scheme 27, Section 3.22.2.3).[130] In related work, 4-hydroxyacetophenone monooxygenase, isolated from Pseudomonas fluorescens, provides excellent substrate scope for sulfoxidation, in which (S)-methyl phenyl sulfoxide and (S)-methyl 4-tolyl sulfoxide provide the highest enantiomeric excess (up to 99% ee).[131] Other enzymes such as toluene dioxygenase and naphthalene dioxygenase efficiently catalyze the oxidation of some alkyl aryl sulfides in high yield and enantioselectivity (>98% ee).[132,133] In addition to site-directed mutagenesis, which is applicable when the structure of an enzyme is known, another way to improve the activity and stereoselectivity of enzymes is to randomly change the sequence via mutagenesis and Oxidation of Sulfides, Lattanzi, A. Science of Synthesis 4.0 version., Section 3.22 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Oxidation of Sulfides
then screen the libraries of modified proteins. The optimal enzymes are then selected and subjected to another mutation cycle in an evolutionary manner. Reetz and coworkers have successfully applied this strategy to cyclohexanone monooxygenase from Acinetobacter sp. NCIMB 9871 to dramatically improve the enantioselectivity in the oxidation of methyl 4-tolyl sulfide (from 14 to >95% ee).[134] Methyl Sulfoxides 47; General Procedure:[128]
The sulfide (0.1 mmol) was magnetically stirred overnight in 0.05 M Tris-HCl buffer (pH 8.6; 4 mL) containing NADPH (2 mol), glucose 6-phosphate (0.4 mmol), CMO (5 units), and glucose 6-phosphate dehydrogenase (10 units). The soln was extracted with Et2O (4 4 mL) and the organic extract was dried and concentrated under reduced pressure. The enantiomeric excess of sulfoxide was determined by chiral HPLC. The absolute configuration was established by comparison of optical rotation and chiral HPLC elution order with the literature. 3.22.4.2
Oxidation Using Whole-Cell Systems
The ability to utilize whole-cell biocatalysis is a very attractive option because it circumvents the need to isolate and add the enzyme, in addition to the cofactors and oxidants to the reaction mixture. Several microorganisms, such as bacteria,[135] yeasts,[136] and fungi[137] are commonly exploited in this manner. Being a complex system, a whole-cellmediated oxidation can lead to unpredictable results in terms of yield and asymmetric induction due to the modified activity of the enzyme or parallel processes affecting the substrate and final product. Nevertheless, preparative-scale oxidations are more conveniently performed using whole-cell systems rather than using isolated enzymes. Interesting examples of the highly enantioselective oxidation of substrates such as metallocene and hetaryl sulfides have been reported using various bacterial strains.[138,139] For example, Holland and coworkers have extensively studied the oxidation of prochiral sulfides to sulfoxides 48 by the fungus Helminthosporium sp. NRRL 4671, as illustrated in Scheme 46. Scheme 46 Asymmetric Oxidation of Methyl Sulfides with the Fungus Helminthosporium[140–142]
Me
S
O
Helminthosporium sp. NRRL 4671
R1
Me
S
R1
48
R1
Yield (%) ee (%) Config Ref
4-NCC6H4
80
92
S
[140]
4-BrC6H4
69
90
S
[140]
4-MeOC6H4
83
80
S
[140]
4-ClC6H4CH2
71
90
S
[141]
2-BrC6H4CH2
58
64
S
[142]
4-O2NC6H4CH2
95
92
S
[141]
Benzyl and phenyl methyl sulfides are generally chemoselectively oxidized with good to high enantioselectivity, although substitution on the phenyl ring significantly affects the stereocontrol. 1,3-Dithiane and 1,3-dithiolane and their 2-monosubstituted and 2-disubstituted analogues are not good substrates. In these cases, the conversion and stereocontrol are modest at best. In contrast, the oxidation of N-[ø-(methylsulfanyl)alkyl]phthalimides proceeds in moderate yield but excellent enantioselectivity (Scheme 47).[143] Oxidation of Sulfides, Lattanzi, A. Science of Synthesis 4.0 version., Section 3.22 sos.thieme.com © 2014 Georg Thieme Verlag KG
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Scheme 47 Asymmetric Oxidation of N-[ø-(Methylsulfanyl)alkyl]phthalimides with the Fungus Helminthosporium[143] O
O SMe N
O S Me
Helminthosporium sp. NRRL 4671
N
n
n
O
O
n Yield (%) ee (%) Ref 3 47
‡95
[143]
5 50
‡95
[143]
6 62
‡95
[143]
These compounds are synthetic precursors of biologically active isothiocyanate containing methyl sulfoxides, such as (S)-sulforaphane. Predictive models have been established by Holland based on the oxidation of over 100 sulfides using whole-cell systems.[144,145] These models predict the stereochemical outcome for a wide range of substrates, thereby making it a very useful synthetic tool. (S)-Sulforaphane is a potent inducer of phase II detoxification enzymes in mammalian metabolism that also shows anticancer activity in rats. Holland has prepared this compound in 45% yield and 93% enantiomeric excess by enantioselective oxidation of the corresponding sulfide using the fungus Helminthosporium sp. NRRL 4671 (Scheme 48).[143] Interestingly, the opposite enantiomer of sulforaphane and its analogues can be obtained with slightly lower efficiency using the fungus Mortierella isabellina ATCC 42 613. Scheme 48
Synthesis of (S)-Sulforaphane with Helminthosporium[143] O
SCN
S
Helminthosporium sp. NRRL 4671
Me
45%; 93% ee
S
SCN
Me
sulforaphane
Methyl Sulfoxides 48; General Procedure:[141]
Two slopes of Helminthosporium species NRRL 4671 were used to inoculate 15 1-L Erlenmeyer flasks each containing autoclaved medium [200 mL; composed of V8 vegetable juice (200 mL) and CaCO3 (3 g) per L of distilled H2O, adjusted to pH 7.2 by the addition of 1 M NaOH prior to sterilization]. The flasks were allowed to stand overnight at 27 8C, then placed on a rotatory shaker at 180 rpm and growth was allowed to continue for a further 72 h at 27 8C. The fungus was then harvested by vacuum filtration and resuspended in 15 1-L Erlenmeyer flasks containing H2O (200 mL), resulting in ca. 90 g (wet weight) of mycelian growth per flask. Sulfide (1 g) in 95% EtOH (30 mL) was then distributed among the flasks. The contents of the flasks were then separated by filtration as before, the aqueous medium was extracted with CH2Cl2 (continuous extraction, 72 h), and the fungus was discarded. Concentration of the medium extract gave the crude product. The mixture was purified by chromatography [silica gel, benzene (CAUTION: carcinogen)/Et2O 10% stepwise gradient, then Et2O/MeOH 5% stepwise gradient]. The absolute configuration and ee of the sulfoxide were determined by 1H NMR analysis in the presence of the chiral shift reagent (S)-(+)-methoxy(phenyl)acetic acid. The chemical shifts were correlated with data obtained from both (R)- and (S)-sulfoxides of known absolute configuration.
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Oxidation of Sulfides
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Stereoselective Synthesis
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Oxidation of Sulfides
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