Transition Metal Catalyzed Oxidative Cross-Coupling Reactions

Lecture Notes in Chemistry 102

Aiwen Lei Editor

Transition Metal Catalyzed Oxidative Cross-Coupling Reactions

Lecture Notes in Chemistry Volume 102

Series editors Barry Carpenter, Cardiff, UK Paola Ceroni, Bologna, Italy Barbara Kirchner, Bonn, Germany Katharina Landfester, Mainz, Germany Jerzy Leszczynski, Jackson, USA Tien-Yau Luh, Taipei, Taiwan Eva Perlt, Bonn, Germany Nicolas C. Polfer, Gainesville, USA Reiner Salzer, Dresden, Germany

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Aiwen Lei Editor

Transition Metal Catalyzed Oxidative Cross-Coupling Reactions

Editor Aiwen Lei College of Chemistry & Molecular Sciences Wuhan University Wuhan, China

ISSN 0342-4901     ISSN 2192-6603 (electronic) Lecture Notes in Chemistry ISBN 978-3-662-58102-5    ISBN 978-3-662-58104-9 (eBook) https://doi.org/10.1007/978-3-662-58104-9 Library of Congress Control Number: 2018959849 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer-Verlag GmbH, DE part of Springer Nature. The registered company address is: Heidelberger Platz 3, 14197 Berlin, Germany

Contents

1 Introduction������������������������������������������������������������������������������������������������    1 Chao Liu 2 Transition Metal-Catalyzed Oxidative Coupling Involving Two Organometallic Compounds��������������������������������������������   11 Hua Zhang 3 Oxidative Coupling Reactions Between Hydrocarbons and Organometallic Reagents (The Second Generation) ����������������������   41 Chuan He 4 Oxidative Radical Couplings��������������������������������������������������������������������   99 Wei Liu 5 Fourth-Generation Oxidative Cross-­Coupling Reactions����������������������  155 Wenying Ai, Bin Li, and Qiang Liu

v

Chapter 1

Introduction Chao Liu

1.1  The Concept of Oxidative Coupling Synthetic chemistry has been considered as one of the central topics in modern novel material creations. Therefore, the development of novel synthetic concepts and synthetic methods is always appealing. Among various synthetic approaches, transition metal-catalyzed cross-coupling has been considered as one of the great discoveries in the last century. It has been demonstrated as a powerful tool for the construction of various chemical bonds [13]. Several named reactions in this field such as Heck reaction, Negishi reaction, Suzuki reaction, Stille reaction, Hiyama reaction, the Buchwald-Hartwig reaction, etc. have been explored [1, 4–6, 14, 15]. The Nobel Prize in chemistry has been awarded to this area in 2010. The model of those coupling reactions usually involves a nucleophile and an electrophile as the partner in the presence of a catalyst (Scheme 1.1, eq. 1). Overall, this is a redoxneutral process, and no extra redox reagents are required for achieving the bond formation (Scheme 1.1, eq. 1) [10]. In those classic cross-coupling, the electrophiles are usually obtained from the pre-functionalization of their corresponding nucleophiles, thus decreasing the reaction step-economy of the whole bond forming process. It restricted the development and application of those traditional cross-coupling reactions in organic synthesis. The traditional cross-couplings faced with great challenges for their inevitable drawbacks such as low atom economy, considerable useless by-products generation, etc.; thus, it gradually cannot meet the development of modern synthetic methodology and the urgent demand for green and economical synthesis. C. Liu (*) State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou, Gansu, China e-mail: [email protected] © Springer-Verlag GmbH Germany, part of Springer Nature 2019 A. Lei (ed.), Transition Metal Catalyzed Oxidative Cross-Coupling Reactions, Lecture Notes in Chemistry 102, https://doi.org/10.1007/978-3-662-58104-9_1

1

2 Scheme 1.1 Bond formation modes of classic cross-­coupling and oxidative cross-coupling

C. Liu Classic Cross Coupling: Nu

+

E

TM

Nu

E

(1)

Nu2

(2)

Oxidative Cross Coupling: Nu1

+

Nu2

TM/[O]

Nu1

Therefore, new form of coupling with higher atom economy and less overall reaction steps is highly demanding. Oxidative coupling, a concept which has been classically used in heterogeneous system for methane conversion, was introduced in homogeneous system for bond formations between two nucleophiles. Along with the development of synthetic chemistry and green chemistry, oxidative coupling reactions between two nucleophiles can meet the requirement of current development of chemical science; due to that both nucleophiles can be accessible from C-H, N-H, O-H, etc. compounds which are widely available. Conceptually, oxidative coupling, as stated in its name, is a coupling strategy through an oxidative process (Scheme 1.1, eq. 2) [10]. In this strategy, the coupling partners are usually two nucleophiles which are electron-rich. To make those nucleophiles forming chemical bonds, an extra oxidant has to be used to take two redundant electrons away to promote the bond formation. Therefore, to achieve a proper oxidative coupling, two aspects are needed to take into consideration. One is to find two suitable nucleophiles for bond formations; another is to provide a providential oxidant to accept the extra electrons. O2, H2O2, and high-valent metals and organohalides are usually used in oxidative coupling reactions. With the development of current catalysis science, transition metals were applied in the classic cross-coupling to improve the reaction efficiency. On this occasion, the oxidative cross-coupling reaction would be an ideal alternation. Compared with electrophiles, nucleophilic reagents are far more diverse than electrophilic reagents. Most of the organometal reagents, anions, amines, alcohols, and widely existing hydrocarbons are nucleophiles that can all be used in oxidative couplings for the construction of various chemical bonds (Scheme 1.2). It is worthy of note that the application of hydrocarbons, amines, and alcohols as the nucleophiles will provide an atom-economy strategy for bond formations, as usually only hydrogen atoms are lost in the whole process. Nowadays, more and more attentions are paid in this topic to make cross-couplings greener.

1.2  The History of Oxidative Coupling Actually, bond formations between two nucleophiles have been demonstrated for a long time. For example, the homo-coupling of terminal alkynes to prepare conjugated 1,3-diynes has been firstly demonstrated in 1869 [3]. In this transformation,

1 Introduction

3 RMgX, RZnCl RB(OH)2, etc. Anions Cl-, OH- etc.

Nucleophiles Amines Alcohols, etc.

Hydrocarbons

Scheme 1.2  Nucleophiles in oxidative couplings

CuCl was used as catalyst; ammonia and EtOH acted as the co-solvent, under O2 atmosphere; and phenyl acetylene transformed to 1,3-diynes. This transformation is now called Glaser coupling. However, the term “oxidative coupling” has been rarely used in homogeneous system during the twentieth century. Before the year of 2005, the term oxidative coupling was majorly used in heterogeneous catalytic system for the oxidative coupling of methane (OCM). As early as 1982, since the report by Keller and Bhasin on the oxidative coupling of methane reaction to synthesis ethylene and ethane [7]. Subsequently, more and more attention has been paid on the study of the catalysts’ preparation and reaction mechanism [2, 20]. It can be seen that both the homogeneous and heterogeneous systems have been majorly focused on the oxidative coupling between two identical nucleophiles. Those reactions can be termed as oxidative homo-couplings. In this case, it is highly restricted on the substrate scope. Therefore, the oxidative coupling was developed with a slow progress. The oxidative coupling between two different nucleophiles will obviously enlarge the scope of nucleophiles; thus, it can broaden the type of the products. However, the selectivity is difficult to control, for both homo-couplings and cross-­ couplings of two different nucleophiles may occur in one reaction system. It seemed unreachable for achieving the selective oxidative cross-couplings. Thanks to those early developments on the oxidative cross-couplings between two nucleophiles at the beginning of this century. Those breakthroughs bring the light of such appealing chemistry into the front of people. Since then, the oxidative cross-coupling between two different nucleophiles sprung up throughout the last 10 years, due to their great potential for green and economic synthesis as well as considerable advantages over traditional cross-couplings, especially for those cross-couplings between two C-H nucleophiles. Normally, nucleophiles could be divided into several classes: MX, C-M, CH, or X-H (X = N, O, S, etc.). In the MX group, salts such as metal halides are employed as reactants to form carbon-halogen bonds. In the C-M group, organometallic reagents serve as the efficient carbon nucleophiles which have been widely applied in transition metal-catalyzed coupling reactions.

4

C. Liu

R1

M1 + R 2

M2

R1

M + R2

H

R1

H + R2

H

R1

H + R2

H

[TM] [O] [TM] [O] [TM] [O] [TM]

R1

R2 +

M 1X

R1

R2 +

MX

R1

R2

R1

R2 +

+ M2X

(1)

(2) (3)

H2

(4)

Scheme 1.3  The development of oxidative cross-coupling reactions

The development of oxidative coupling can be divided into four generations (Scheme 1.3). At the beginning, oxidative couplings focused on the bond formations between two organometallic reagents (C-M, M = Zn, Mg, In, Sn, Cu, etc.) under transition metal catalysis (Scheme 1.3, eq. 1), and many excellent results with high selectivity and yield have been reported in this field. In this type of transformation, the organometallic reagents have high reactivity, the challenge is selectivity control, homo-coupling of the organometallic reagents that is often involved occurs, and the organometallic reagents can also react with oxidants that result in poor yields. And these organometallic reagents were sensitive to air and water; some of them are also very toxic. Besides, after the reaction complication, two kinds of metal salts were wastes. Therefore, this kind of bond formation mode does not meet the requirement of modern sustainable chemistry; more greener method is urgent to development [16]. While science is always in progress, in the following several years, taking the place of one of the organometallic reagents with a X-H compound is a greener design and makes the oxidative cross-coupling cleaner (Scheme 1.2, eq. 2), which is the second generation of oxidative cross-coupling. Notably, CH or XH (X = N, O, S, etc.) nucleophiles extensively exist in nature, which represent the most abundant nucleophiles. Thus, the best choice of oxidative coupling was the R1 − H/R2 − H coupling (Scheme  1.3, eq. 3), the third generation of oxidative cross-coupling, which can construct C-C and C-heteroatom bond toward sustainable synthesis; it can greatly enlarge the scope of organic synthesis, and numerous outstanding works have been reported [12]. Undoubtedly, air or O2 is a green oxidant, in the transition metal-catalyzed oxidative R1 − H/R2 − H coupling reactions; if air or O2 can be used as the oxidant, it will be an ideal approach for bond formations. Compared to the traditional cross-couplings, in oxidative R1 − H/R2 − H couplings, the substrates don’t need to be pre-functionalized, and the generation of waste is largely diminished with only H2O as the by-product; thus, the synthetic procedure is greatly shortened, and atom economy is considerably enhanced, demonstrating great potential for pharmaceutical and industrial application. However, in these transformations, noble transition metals such as Pd, Ru, Rh, and others were used as the catalysts. In recent years, there has been an increase in number of oxidative cross-­ coupling reactions with first-row transition metal salts (Fe, Co, etc.) as catalysts or even no metal. Since first-row transition metals often can go through multiple

5

1 Introduction

R1ZnCl 2.0 eq.

+ R2

SnBu3 1.2 eq.

Pd(dba)2 (2.5 mol%) THF, 60 °C Cl Ph Ph

R2

R1

O (Desyl Chloride) (1.0 eq.)

Scheme 1.4  The oxidative cross-coupling reaction between two different nucleophiles

c­ hemical valence changes, those oxidative cross-couplings can involve single-electron transfer processes. Radical oxidative coupling reactions represent a promising development in green chemistry [11]. Recently, an external oxidant-free oxidative coupling was developed, which no oxidant was needed and only H2 was generated as a side product (Scheme 1.3, eq. 4), which could be called the fourth-generation oxidative coupling reactions. In this transformation, no oxidants and proton acceptors were applied as the sacrificial reagents, with no wasteful by-products or oxidation side reactions. This was no doubt the most ideal mode to construct C-C and C-heteroatom bond. The field holds significant potential for the applications to a series of organic reactions, and scientists paid more and more attention on this field. In 2006, Lei firstly used the concept “oxidative cross-coupling” in a Csp-Csp3 bond formation between two different organometal nucleophiles (Scheme 1.4) [21]. In this transformation, alkynylstannanes and alkylzinc reagents were used as the two nucleophiles, 2-chloro-2-phenylacetophenone (Desyl chloride) was applied as the oxidant, and the desired Csp-Csp3 cross-coupled products were produced with high selectivity and yields in the presence of Pd(dba)2 without an extra ligand. In this reaction, the Csp3-Csp3 homo-coupling of alkylzinc reagent is very slow; the homo-­coupling of alkynylstannane did not occur under the standard conditions. The reaction started from the low-valent Pd(0), Desyl chloride used as the oxidant which was reoxidize Pd(0) to regenerate the Pd(II) species, and then two transmetalations of alkynylstannane and alkylzinc reagent with the Pd(II) species followed by reductive elimination to get the desired cross-coupling product. In addition, the mechanism was investigated by situ IR; the result indicated that the alkylzinc reagent transmetalated with the Pd-enolate bond and the alkynylstannanes reagent transmetalated with the Pd-Cl bond selectively. After that, this type of oxidative cross-­ coupling was further developed [9, 10, 12, 17]. At the same time, C-H functionalization has also developed. In 2006, Shi reported the C-H functionalization/halogenation of acetanilide (Scheme  1.5) [19]. In this reaction, acetanilide and halides (Cl or Br) can be considered as the two different nucleophiles; Pd(OAc)2 acted as the catalyst and Cu(OAc)2 as the oxidant; in DCE, acetanilides were transformed to halogenated acetanilides with high regioselectivity. In this transformation, the acetyl group was used as the directing group, which was important for this reaction; when changed to formyl, benzoyl, tosyl, and trifluoroacetyl, only trace amount of products (450 nm) r.t.

42a

43a

20 mol % eosin Y 0.3 mol % G-RuO2

43a

+

42a 42a : 42a-D = 1:1 Conv. of 42a: 94 % Conv. of 42a-D: 55 %

1)

+

D2

2)

N

NH 44a, 93 %

H N

+ N Ph D D 42a-D

H2

NH

D2O, hv, (λ>450 nm) r.t.

42a

+

44a, 94 %

H N

+

N

N Ph H H

20 mol % eosin Y 0.3 mol % G-RuO2

H N

+

N

20 mol % eosin Y 0.3 mol % G-RuO2

N +

H2O, hv, (λ>450 nm) r.t. 43a

H2

3)

NH 44a 44a: 93 % 44a-D: 92 % KH/KD = 1.7:1

Scheme 5.17  Deuterium experiments for the CCHE reaction between tetrahydroisoquinoline and indole

Scheme 5.18  Proposed mechanism for the CCHE reaction between tetrahydroisoquinoline and indole

169

5  Fourth-Generation Oxidative Cross-Coupling Reactions R'' +

N R

N

R'

42

H2O/CH3CN, 520 nm LEDs r.t.

43

N R N

R'

R''

+

H2

44

N Ph

N Ph H A

42a H

H+ + OH-

N Ph

H2O

Nuc

eosin Y*

eosin Y

CoII

ISC hv

3 mol % eosin Y 8 mol % Co(dmgH)2Cl2

Nuc:

-eN

eosin Y

CoI

CoIII

H2

B

Ph

C

Cl O N

H Co

O N

N O H Cl Co(dmgH)2Cl2

N O H

CoIII-H H+

Scheme 5.19  Cobaloxime-catalyzed CCHE reaction of tetrahydroisoquinoline with indole

improved catalytic system increased the reaction yield and widened the substrate scope. Mechanistic studies illustrated that the catalyst Co(dmgH)2Cl2 captured two electrons to generate a Co(I) intermediate, which reacted with a proton to afford a Co(III)-H species that reacted with another proton to realize H2 gas evolution. 5.2.1.2  C(sp3)-C(sp3) Cross-Coupling Reactions Wu’s group expanded the substrate scope from tertiary amines to secondary amines [12] (Scheme 5.20). The activation of secondary amines is much more challenging than that of primary amines for three reasons: (1) all the reported CCHE transformations proceeded in water or water-containing solutions, but imine intermediates generated from the oxidation of secondary amines are easily hydrolyzed into amines and aldehydes; (2) secondary amines are more difficult to oxidize than tertiary amines because of their lower relative oxidation potential; and (3) the stability of radical intermediates generated from secondary amines is low because of the highly acidic hydrogen atom adjacent to the N atom of secondary amines. Nevertheless, a variety of secondary amine glycine esters and β-keto esters were converted into the corresponding cross-coupling products using a Ru(bpy)3(PF)6/Co(dmgH)2pyCl catalytic system under water-free conditions. To obtain mechanistic insight, the proton source of H2 gas was identified. When CD3CN was used as the solvent, only H2 was observed. This result suggested that the released H2 gas originated from the substrates instead of the solvent in this reaction. When deuterated 45-D was reacted with 46 under the same conditions, the products 47 and 47-D were obtained with a ratio of 1.86, which means KH/KD = 1.86.

170

W. Ai et al.

Scheme 5.20  CCHE reaction of secondary amines with β-keto esters

This result indicated that the dissociation of a proton from 45 might be involved in the rate-determining step. When β-keto ester 46 was absent from the system, the yield of H2 evolved from secondary amine 45 decreased from 88% to 50%, implying that the proton from β-keto ester 46 also contributed to H2 gas evolution (Scheme 5.21). More recently, Wu’s group developed a novel dehydrogenative C-C coupling of isochromans and β-keto esters [13] (Scheme 5.22). Because of its higher oxidation potential, the direct functionalization of a C(sp3)-H bond adjacent to an O atom is more challenging than that of one adjacent to an N atom. By using the strongly oxidizing photosensitizer 9-mesityl-10-methylacridinium perchlorate (Mes-Acr+) and HEC Co(dmgH)2pyCl, oxocarbenium ions were generated from isochromans. The subsequent nucleophilic addition of oxocarbenium by β-keto esters promoted by Cu(OTf)2 furnished the target cross-coupling product in good yield. To shed light on the reaction mechanism, a series of deuterium labeling experiments were performed. When deuterated [D2]-50 reacted with [D2]-51 under the same conditions as described above, only D2 was detected along with the formation of cross-coupling product [D2]-52 in 75% yield. When CD3CN was used as the solvent, no deuterium incorporation of 52 or D2 was observed. These findings confirmed the sources of H atoms in the produced H2 gas were the α-proton of 50 and methylene proton of 51. The kinetic isotope effect was also studied for this transformation. The KH/KD ratio of 2.3 suggested that benzylic C-H bond cleavage might be the rate-determining step for this reaction (Scheme 5.23).

5  Fourth-Generation Oxidative Cross-Coupling Reactions

PMP

HN H

O +

COOEt

H

PMP

D

H

COOEt 45-D

HN D

H

PMP COOEt 45

PMP

10 mol % Ru(bpy)3(PF6)2 10 mol % Co(dmgH)2pyCl

O HN H COOEt

CD3CN, blue LEDs r.t.

OEt

H

45

HN

O

171

O

47 (13 %)

O H

O HN H/D COOEt

CH3CN, blue LEDs r.t.

+

D2/HD/H2

COOEt 47/47-D KH /KD = 1.86

46 10 mol % Ru(bpy)3(PF6)2 10 mol % Co(dmgH)2pyCl CH3CN, blue LEDs r.t.

(15 %)

PMP

10 mol % Ru(bpy)3(PF6)2 10 mol % Co(dmgH)2pyCl

OEt

H2

COOEt

46

+

+

N H

PMP COOEt

49'

+

H2

(~50 %)

HN H

PMP COOEt

49

PMP = p-methoxphenyl

Scheme 5.21  Mechanistic study of the CCHE reaction of secondary amines with β-keto esters

Scheme 5.22  The CCHE reaction of isochromans with β-keto esters

172

W. Ai et al.

O D

O

+

D

D

[D2]-50

D

OEt

D

Cu(OTf)2, CH3CN blue LED, 24 h

+

50

O

Acr+-Mes Co(dmgH)2pyCl

O OEt

O

O

+

O + D

OEt

D

[D2]-50 0.2 mmol

OEt O O 52, 72 %

Acr+-Mes Co(dmgH)2pyCl

O

OEt

O

Cu(OTf)2, CD3CN blue LED, 24 h

51

O D

+

D2

+

H2

O O [D2]-52, 75 %

[D2]-51

O

50 0.2 mmol

Acr+-Mes Co(dmgH)2pyCl

O

Cu(OTf)2, CH3CN blue LED, 1 h

51

79 %

O + H2/HD/D2 H/D OEt O O 52/[D]-52 KH /KD = 2.3

Scheme 5.23  Deuterium experiment for the photocatalytic CCHE reaction of isochromans with β-keto esters

5.2.1.3  C(sp2)-C(sp2) Cross-Coupling Reactions In a further demonstration of the utility of CCHE reactions, Wu and co-workers extended this strategy to direct coupling of C(sp2)-H bonds. They developed a visible-­light-driven indole synthesis via the CCHE process. Using Ir(ppy)3 and Co(dmgH)2(4-CO2Mepy)Cl as a photocatalytic system, various N-aryl enamines were smoothly converted to the corresponding indoles under oxidant-free conditions [14] (Scheme 5.24). To probe the reaction mechanism, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was included as a radical scavenger. Adding two equivalents of TEMPO decreased the yields of the indole and H2. This result suggested that some radical intermediates might be involved in this transformation (Scheme 5.25). Based on the above results, the following mechanism for the reaction was proposed. Under visible-light irradiation, photosensitizer Ir(ppy)3 was activated to its excited state Ir(ppy)3*. Subsequent electron transfer from Ir(ppy)3* to the cobaloxime species afforded Ir(IV) and Co(II). Next, N-aryl enamine 55a was oxidized by the generated Ir(IV) species to form the cation radical 56a and ground-state Ir(III). With the release of a proton, cation radical 56a produced radical 57a, which was in resonance with 58a. The desired product indole 60a was formed from intermediate 58a through consecutive intramolecular radical addition, oxidation, and deprotonation processes. The electron and proton eliminated from substrate 55a were transformed to H2 promoted by the cobaloxime HEC (Scheme 5.26).

173

5  Fourth-Generation Oxidative Cross-Coupling Reactions R

H

COOEt Ph

N H 55

COOEt

Ir(ppy)3, Co(dmgH)2(COOMePy)Cl N2, 450 nm LED, 5 h

R

Ph +

N H

H2

60

COOEt

F

N H

COOEt

O

COOEt

N H

60a, 93 %

60b, 90 %

COOEt

N H 60c, 80 %

COOEt

CONHPh

OMe N H 60d, 93 %

N H

N H

60e, 95 %

60f, 55 %

Scheme 5.24  Synthesis of indoles via a photocatalytic CCHE strategy

Scheme 5.25  The reaction of 55a with a radical scavenger

5.2.2  Carbon-Heteroatom Cross-Coupling Reactions 5.2.2.1  C-S Cross-Coupling CCHE reactions are also a powerful tool to construct C-X bonds. In this respect, the study of C-S bond formation reactions is a fundamental research area, because the introduction of sulfur atoms is a crucial step in the synthesis of many pharmaceuticals and bioactive molecules. In 2014, Lei and Wu’s groups developed an efficient intramolecular CCHE reaction to synthesize benzothiazoles 64 from N-phenylbenzothioamides 61 without any oxidant (Scheme 5.27). This transformation was promoted by photosensitizer Ru(bpy)3(PF6)2 and HEC Co(dmgH)2pyCl

174

W. Ai et al.

H

COOEt

N H 55a

COOEt

Ir(ppy)3, Co(dmgH)2(COOMePy)Cl

Ph

N2, 450 nm LED, 5 h

Ph +

N

H2

60a

H H2 Co

N 60a

Ph

COOEt 54a (Z) CoIII

Co

-e-, -H+

H COOEt N 59a

N 55a H

Ph COOEt (E)

IrIV

H

CoI

COOEt

H

N H

H+ III-H

Ph

Ph

radical cyclization

II

IrIII

IrIII*

56a

N H

Ph COOEt -H+

H

COOEt

N 58a

Ph

H N 57a

Ph COOEt

Scheme 5.26  Photocatalytic intramolecular cross-coupling of N-aryl enamines

under visible-light irradiation. The selection of a suitable base is an important issue for the success of this transformation. The base needs to meet three requirements: (1) its pKb value must be low enough to capture a proton from the substrates; (2) it should act as a hydrogen atom donor to promote H2 evolution; and (3) it should be redox inert. When Na-Gly was used as the base in this reaction system, a range of desired benzothiazoles was efficiently afforded [15]. The transformation was also performed under oxidative conditions for comparison. The yields of oxidation by-products increased in the presence of oxidants. In contrast, the amide by-product was avoided completely under CCHE reaction conditions (Scheme 5.28). Subsequently, Lei, Wu, and co-workers developed an intermolecular dehydrogenative C-H bond thiolation reaction. Allylic sulfones were prepared in high efficiency from arylsulfinic acid and α-methylstyrene derivatives using TBA2-eosin Y/ Co(dmgH)2pyCl as the catalysts (Scheme 5.29). In the presence of pyridine as the base, deprotonation of the arylsulfinic acid afforded the corresponding sulfinate,

175

5  Fourth-Generation Oxidative Cross-Coupling Reactions

H N H

3 mol % Ru(bpy)3(PF6)2

R

S

8 mol % Co(dmgH)2(p-NMe2Py)Cl 1.0 equiv sodium-Gly 0.4 equiv DMAP CH3CN blue LEDs

S

61

H -e-, -H+

S

N 62

R

R + H2

N 64 -H+

S

-e63

R

N

Cl H

O N

O N Co N N O O H H N

Co(dmgH)2(p-NMe2Py)Cl

N

Scheme 5.27  Photocatalytic intramolecular annulation of N-phenylbenzothioamides

H

S

N H 61a entry 1b c

a

3 mol % Ru(bpy)3(PF6)2 2 equiv oxidant 1.0 equiv sodium-Gly 0.4 equiv DMAP CH3CN, blue LEDs oxidant -

S

H +

O

N H

N 64a

61a' yield (%)

b

64 a

61a'

99

0

O2

7

49

3

K 2S 2O 8

26

38

4

H 2O 2

16

17

2

a

Reaction conditions: 61a (0.35 mmol), Ru(bpy)3(PF6)2 (3 mol %), oxidant (2 equiv), sodium-Gly (1.0 equiv) and DMAP (0.4 equiv) were added in CH3CN (2 mL) under irradiation of 23W white fluorescent lamp for 12 h at rt. bCo(dmgH) (4-NMe Py)Cl (8 mol %) was used in place of oxidant. c1 atm O was used. 2 2 2

Scheme 5.28  Comparison between photo/cobalt and photo/oxidant systems

which was oxidized by excited eosin Y* to generate sulfonyl radical 68. This radical intermediate was trapped by an α-methylstyrene derivative to form the target product allylic sulfone via a series of electron and proton transfer processes [16].

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OH

+

65

PS Co(III)

O S

+ H2

O

66

67 -e-, -H+ O

O

-e-, -H+

S

S 68

O

O 69

Cl O N N O H

H Co

O N

N O H N

Co(dmgH)2 pyCl

Scheme 5.29  Photocatalytic dehydrogenative coupling to synthesize allylic sulfones

5.2.2.2  C-N and C-O Cross-Coupling Reactions Anilines and phenols are very useful raw materials for the production of dyes, agrochemicals, and polymers. However, industrial preparation methods suffer from harsh conditions, e.g., high temperature, high pressure, and strong acids. Moreover, multiple steps are required, generating a large amount of toxic waste [17–19]. Therefore, mild, one-step, and toxic waste-free methods to synthesize anilines and phenols are needed. In 2016, Wu’s group reported an unprecedented direct hydroxylation and amination of the inert C-H bonds of benzene produce to aniline and phenol using ammonia (NH3) and water under visible-light irradiation [20] (Scheme 5.30). This sustainable methodology generated H2 gas as the sole by-product without the need for a sacrificial oxidant [20]. In this reaction cycle, visible-light irradiation of the onium photocatalyst (QuH+ or QuCN+) generated its photoexcited state, which oxidized benzene to benzene radical cation 75 and generated the reduced form of the photocatalyst. Subsequently, the latter species delivered an electron to the Co(III) catalyst, regenerating the ground-state photosensitizer. The benzene radical cation intermediate reacted with an anionic nucleophile (X−) to produce an aromatic radical intermediate 76, which underwent electron transfer to reduce Co(II) to Co(I) and generate dienyl cation 77. The cation then quickly lost a proton to afford the desired product 78. Finally, the Co(I) species reduced two protons, releasing H2 gas as the sole by-product (Scheme 5.31). Very recently, Lei’s group reported another example of C-H/N-H cross-coupling via CCHE reaction under visible-light irradiation. As shown in Scheme  5.32, a series of N-arylazoles was readily synthesized using a catalytic system of Co(dmgH)2Cl2/Acr+-Mes ClO4−.

5  Fourth-Generation Oxidative Cross-Coupling Reactions

177

Scheme 5.30  Photocatalytic direct hydroxylation and amination of the inert C-H bonds of benzene

Scheme 5.31  Proposed mechanism for photocatalytic amination or hydroxylation of benzene

The above reaction has high selectivity for C(sp2)-H bond activation; on the contrary, C(sp3)-H bonds were not affected. This is because the arene radical cation intermediate plays an important role in the selective C(sp2)-H activation in this system. Under oxidative reaction conditions, very small amounts of amination products were generated in the presence of various oxidants. As a result, the CCHE reaction

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H + H N

R 79

80

N

N

N

R

CH3CN, blue LEDs N2, r.t.

N

+

81

N AN

N

B N

H2

N

B tBu

A 97 % 1:13 CA: CB

70 %

71 %

N

N

N

N N

Ph 95 %

95 % 19:1 CA: CB

64 %

N

N B

N B A 98 % 1:7.6 CA: CB

A 81 % 1:11.5 CA: CB

Scheme 5.32  Photocatalytic C-H/N-H cross-coupling of arenes and azoles

system showed superior performance over the oxidant-containing system for this transformation. We believe that this methodology could be used for the amination of sensitive substrates that cannot tolerate oxidative conditions (Scheme 5.33) [21]. Along similar lines, Wu and Tung’s groups reported the direct cross-coupling between a benzene C-H bond and alcohol O-H bond in the presence of QuCN+/ Co(dmgBF2)2(CH3CN)2 as catalysts [22] (Scheme 5.34). Both intermolecular and intramolecular etherification reactions were investigated to construct aryl ether and chromane compounds in high yield. Furthermore, Lei’s group developed an anti-Markovnikov oxidation of alkenes to ketones and aldehydes using water as the terminal oxidant (Scheme 5.35) [23]. In this transformation, an alkene substrate was oxidized by the excited photosensitizer to form radical cation intermediate 90. Subsequently, the nucleophilic attack of this radical cation species by water gave a distonic radical cation 91, which could generate the anti-Markovnikov radical intermediate 92 instead of Markovnikov intermediate 93 because of the high stability of the benzylic radical. The target product was generated from 92 through sequential electron transfer, deprotonation, and tautomerization processes. More recently, Lei’s group extended this methodology to synthesize a range of enol ethers and N-vinylazoles using an alcohol or azole as the nucleophile instead of water under very similar reaction conditions [24] (Scheme 5.36).

5  Fourth-Generation Oxidative Cross-Coupling Reactions

Scheme 5.33 C(sp2)-H activation via an arene radical cation

Scheme 5.34  Photocatalytic etherification of arenes

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W. Ai et al. R2 H

R1

+

R3

7 mol % Acr+-Mes ClO48 mol % Co(dmgH)2Cl2

H2O

87

O R1

CH3CN, blue LEDs N2, r.t.

88

R2 R3 89

-eR2 H R1

R2

H2O R1

R3

H

red favo + -H

H O H

-H +

R3

90

91

OH

disfa

vored

R2 R1

Cl O N N O H

Me

H Co

O N

N O H N

Co(dmgH)2pyCl

R3

Me Me N ClO4 Acr+-Mes ClO4-

Scheme 5.35  Photocatalytic anti-Markovnikov oxidation of styrenes

Scheme 5.36  Visible-light-driven synthesis of enol ethers and N-vinylazoles

92

OH R3

H2 -e-

R2

R1

+

93

-H+ tautomerism

5  Fourth-Generation Oxidative Cross-Coupling Reactions N

R

S

+

H

99 N

O H P 1 Ar2 Ar 100

CHCl3, hv N2, r.t., 24 h

O P

S Ph

N Ph

N

R

O

P S Ph Ph

Ph

+

H2

101

O

N

O P Ph

S Ph 69 %

54 %

N

O

P S Ar2 Ar1

P S Ph Ph

MeO

87 %

73 %

5 mol % Esoin B

181

N

O

N

P

S Ph

Ph

F

77 %

O

P S Ph Ph

83 %

Scheme 5.37  Photocatalytic dehydrogenative C-H/P-H cross-coupling of thiazole derivatives and diarylphosphine oxides

5.2.2.3  C-P Cross-Coupling Reactions In 2016, Wu’s group reported a direct dehydrogenative cross-coupling between heteroaryl C-H and P-H bonds in the presence of the photocatalyst eosin B under visible-­light irradiation (Scheme 5.37). A series of heteroaryl-P bonds was formed via this transformation without any oxidant or metal catalyst [25].

5.3  E  lectrochemical Dehydrogenative Reactions with Hydrogen Evolution Electrochemical synthesis is recognized as an effective and environmentally friendly method for various transformations and has attracted increasing attention in recent years. In electrochemical synthesis, radical cations and radical anions can be easily generated under mild conditions from neutral organic compounds [26]. Recently, remarkable advances have been made using electrochemical processes to replace chemical oxidants in dehydrogenative cross-coupling reactions. In this section, typical examples in this research field from the following three categories are summarized: (1) electrochemical N-H/C-H cross-coupling reactions, (2) electrochemical C-S bond formation reactions, and (3) electrochemical C-H/C-H cross-coupling reactions.

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W. Ai et al. H R3

A N O

N

H RVC

B N

C

R1

R2

Pt

R3

Et4NPF6 (1 equiv.) MeOH, reflux

N

A N O

B N

R2

C

+

H2

R1 103

102 CN

TBSO

N N

76% TsBocN

Bn

N

O

N

O 79%

N

81% N

Br

Bn

O 82%

Bn N

N N

N

O

88%

N

N

O

N N

O

O

N

N N Bn

O

N

N

59%

Scheme 5.38  Synthesis of benzimidazoles via electrolysis

5.3.1  Electrochemical N-H/C-H Cross-Coupling Reactions N-Heterocycles are an important class of organic compounds because of their wide-­ ranging applications in both medicinal chemistry and chemical biology. An electrochemical approach to synthesize N-heterocycles without an oxidant has been developed as an alternative strategy to classical synthetic methods. Recently, Xu and co-workers developed an efficient intramolecular cyclization of (hetero)arenes to produce polycyclic benzimidazoles 103 and pyridoimidazoles 105 through anodic cleavage of N-H bonds and aromatic C-H bond functionalization [27]. These reactions were performed using a reticulated vitreous carbon anode and platinum cathode under a constant current of 10 mA (the anode current density was 0.13 mA cm−2) in an electrolyte solution containing 1 equiv. of Et4NPF6 in MeOH heated under reflux. Numerous examples of benzimidazoles 103 bearing alcohol, ester, carbamate, sulfonamide, tert-butylcarbonyl (Boc)-protected amine, and amino ester groups were prepared with isolated yields of up to 92% (Scheme 5.38). In addition, 12 functionalized pyridoimidazoles 105 were synthesized in moderate to good yields through this electrolysis process without any metal catalyst or oxidant [27] (Scheme 5.39). When this electrolysis reaction was performed in a mixture of hexafluoro-2-­ propanol (HFIP) and MeOH (5:1) at room temperature, a C-H/N-H cross-coupling reaction between biaryl aldehydes and NH3 as the nitrogen source successfully led to various pyridine fused polycyclic N-heteroaromatic compounds [28] 107

183

5  Fourth-Generation Oxidative Cross-Coupling Reactions H R2

Het

N

H RVC

N

Et4NPF6 (1 equiv.) MeOH, reflux

N

O

R2

Pt

N

Het

R1 105

104 N

N

N

N

N O

H2

N

O

R1

N

+

N

F

N N

O

Bn

51%

60%

N N N

O

N

Bn 53%

Bn

Scheme 5.39  Synthesis of pyridoimidazoles via electrolysis

R2 R1

O

R2

RVC R1

NH3, HFIP/MeOH RT

CH2CH2OH

CH2CH2OTBS MeO

MeO N

MeO

N

MeO

81%

H2

107

106

MeO

+

N

S N

MeO 53%

70%

OMe N Ts

MeO MeO

N 77%

N N 43%

N 45%

Scheme 5.40  Synthesis of N-heteroaromatics from biaryl aldehydes and NH3 via electrolysis

(Scheme 5.40). It is noteworthy that no metal catalyst, oxidizing agent, or salt additive was added to produce N-heteroaromatic compounds under these scalable electrochemical reaction conditions. Based on the experimental results and density functional theory calculations, the following mechanism for the electrolysis reaction was proposed. Radical cation B was generated by losing an electron at the anode from aldimine intermediate A generated in situ. After losing another electron and two protons, the desired

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MeO NH

MeO A

+ NH3

MeO

- H 2O

MeO

O H2 O 2

+• MeO MeO B

OH CF3

•

MeO NH

F3C

C

F 3C

CF3 MeO

N

MeO

2

H H

-e

MeO

N

Scheme 5.41  Proposed mechanism for synthesis of N-heteroaromatics through electrolysis

phenanthridine product was produced [28] (Scheme 5.41). Meanwhile, H2 gas was produced at the cathode from protons and electrons. Later on, Xu and co-workers developed the electrochemical intramolecular annulation of anilides with tethered alkynes by C-H/N-H functionalization to synthesize functionalized indoles and azaindoles [29]. Various indole and azaindole derivatives with a broad range of sensitive functional groups were synthesized with yields of 43%–94% in the presence of 5  mol% ferrocene ([Cp2Fe]) as the redox catalyst and an electrolyte of Na2CO3 and nBu4NBF4 in a mixture of MeOH and THF (1:5). This reaction was conducted using a reticulated vitreous carbon anode and Pt cathode under a constant current of 5 mA (Scheme 5.42). A plausible mechanism for this process involves the initial anodic oxidation of [Cp2Fe] to [Cp2Fe]+ and concomitant cathodic reduction of MeOH to form methoxide (MeO−) and release H2. After transfer of a single electron, 6-exo-dig cyclization and rearomatization of anion A to give radical D, the desired product would be finally generated from D through loss of another electron and proton [29] (Scheme 5.43). Under similar electrochemical reaction conditions, nitrogen-doped polycyclic aromatic hydrocarbons (PAHs) 111 were readily synthesized from various substituted urea-tethered diynes 110 via the electrochemical cascade cyclization reaction. PAHs are widely used in material sciences because of their unique electronic and physicochemical characteristics [30] (Scheme 5.44).

5.3.2  Electrochemical C-S Bond Formation Reactions C-S bonds are important structural motifs in various biologically active molecules and functional materials. However, the dehydrogenative C-S bond formation reactions of C-H bonds under non-oxidative conditions have seldom been studied. Very recently, Lei and co-workers developed an external oxidant-free intramolecular dehydrogenative C-S cross-coupling reaction under undivided electrolytic

5  Fourth-Generation Oxidative Cross-Coupling Reactions

H R1

R2

R2 RVC

H

Pt constant current, 5mA

N R3

[Cp2Fe] (5 mol%) MeOH/THF (1:5), Na2CO3 nBu4NBF4, reflux

N O

185

R1

+

N N R3 109

O

108 CO2Me

OH

Ph

O N N

O

71%

N

N O

O

Ph

86%

O

Ph

N N

N N

N

80%

66%

N

N

O

N

N

N

H2

N 92%

N O

N 78%

Scheme 5.42  Electrochemical C-H/N-H functionalization for the synthesis of functionalized (aza)indoles

conditions [31]. These reactions were performed in a mixture of MeCN and H2O (9:1) containing nBu4NBF4 at 70 °C without addition of any oxidant or catalyst. The transformation was conducted using a graphite rod anode and Pt plate cathode under a constant current of 7 mA (the current density of the anode was ~11.7 mA cm−2). Various 2-aminobenzothiazoles 114 were obtained with high isolated yields from the direct combination of aryl isothiocyanates 112 with amines 113 under these conditions (Scheme 5.45a). When PhCOONa was added to this reaction system, various N-arylthioamides 116 could also be cyclized under non-oxidative conditions to furnish benzothiazoles 115 in good to high yields. H2 gas was released via the concomitant cathodic reduction of water during the reaction [31] (Scheme 5.45b). Furthermore, Lei’s group reported an electrocatalytic oxidant- and catalyst-free dehydrogenative C-H/S-H cross-coupling of N-methylindole derivatives 117 and thiophenols 118 in the presence of 4 equiv. of LiClO4 in MeCN at room temperature using a Pt anode and Pt cathode under a constant current of 12 mA [32] (Scheme 5.46). C-S bond formation products were obtained in isolated yields of up to 99% from

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W. Ai et al.

Ph

e

MeOH

NH N

O

Ph

Ph e

MeO- + 1/2 H2

N FeIII

N

O

N

Pt cathode

N

O

A

e ,

Ph C anode

H Ph

Ph

FeII N

•

•

•

N

N

N

O

H+

O B

N

O

N

D

C

Scheme 5.43  Proposed mechanism for the electrochemical synthesis of functionalized (aza) indoles

R1 R2

R4

NH

R3

N

O

R1 RVC Pt constant current [Cp2Fe] (5 mol%) MeOH/THF (1:5) Na2CO3 (1 equiv.), 65 oC

R4 R2

N N

O

111

110 Ph

R3

Ph

Ph

S

F3C N O

N

N N

64%

O

N 67%

N

O

82%

Scheme 5.44  Electrochemical synthesis of polycyclic N-heteroaromatics

+ H2

5  Fourth-Generation Oxidative Cross-Coupling Reactions

N R

C

S +

H N

H

113

112 H

R2

N R1

187

H S 115

C (+) Pt (-) nBu4NBF4, CH3CN/H2O undivided cell C (+) Pt (-) nBu4NBF4, CH3CN/H2O PhCOONa undivided cell

N R

S

N

+

H2

(a)

+

H2

(b)

114 N

R1

S

R2

116

Scheme 5.45  Electrochemical intramolecular dehydrogenative C-S bond formation for the synthesis of benzothiazoles

H

R

N 117

R H

S

Ar 118

Pt anode, Pt cathode constant current = 12 mA

S Ar N

119

36 - 99% yields

LiClO4, CH3CN, rt, 3h Ar H 120

Ar S

+

H2

Cl 121

24 - 74% yields

Scheme 5.46 Electrochemical dehydrogenative C-H/S-H cross-coupling of N-methylindole derivatives and thiophenols

various aryl/heteroaryl thiols and electron-rich arenes. Aryl radical cation intermediates are an important feature of this C-S bond transformation. In the proposed mechanism of this cross-coupling reaction, a sulfur radical and indole radical-cation intermediate were generated at the same time via a single-­ electron transfer oxidation process at the anode. This step was followed by direct coupling with the sulfur radical or its substituted disulfide to generate hydroindole cation intermediate B. The C-S bond formation product was afforded after a final deprotonation step [32] (Scheme 5.47).

5.3.3  Electrochemical C-H/C-H Cross-Coupling Reactions Transition metal-catalyzed oxidative dehydrogenative cross-coupling reactions between two C-H bonds have become a fast-growing research area in organic chemistry during the past decade. In particular, the use of electrochemical anodic oxidation to replace classical chemical oxidants in C-H/C-H dehydrogenative cross-coupling reactions has received increasing attention very recently.

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Scheme 5.47  Proposed mechanism for electrochemical dehydrogenative C-H/S-H cross-coupling

In 2017, Xu and co-workers reported a Cp2Fe-catalyzed C(sp3)-H and C(sp2)-H bond dehydrogenative cross-coupling reaction using an undivided cell equipped with a reticulated vitreous carbon anode and Pt plate cathode [33]. Various C3-fluorinated oxindole derivatives 123 with diverse functional groups, such as -OH, -OTBS, -CH=CH2, and -C ≡ CH, were synthesized in high yield. It is noteworthy that the in situ generation of the requisite oxidant and base as well as LiCp as the additive plays important roles to improve the yield of C3-fluorinated oxindole derivatives 123 (Scheme 5.48). A mechanism involving functionalized monofluoroalkyl radical intermediate generation by electrochemical activation of C-H bonds has been proposed. Lei’s group developed an electrocatalytic intramolecular oxidative annulation of N-aryl enamines 124 via C(sp2)-H functionalization to provide substituted indole derivatives 125. This reaction proceeded in an undivided cell with Pt plate anode and cathode under a constant current of 7  mA at room temperature [34] (Scheme  5.49). Indole derivatives 125 were synthesized in yields of 56%–96% without any oxidant or transition metal. Notably, KI not only acted as the electrolyte but also participated as an electron transfer mediator in the redox process of this oxidative annulation. The mechanism proposed for this reaction involves the in situ generation of a hyperiodide intermediate (I+) from iodide ions through two anodic oxidation steps. Then, an N-iodo intermediate was generated by the reaction of the N-aryl enamine with I+. Following sequential intramolecular radical addition, oxidation, and deprotonation processes, the final product indole was formed [34] (Scheme 5.50).

5  Fourth-Generation Oxidative Cross-Coupling Reactions

H

F R1 N

O

122 F

N

Pt

CO2Me N

+

O

N

F N

O

O

76%

72%

CO2Me N

OH

O

75%

O

O

75%

O

CO2Me

CO2Me N

F

H2

123

NHBoc

O

CO2Me

R2

F

CO2Me N

R1

MeO2C

79% F

F

[Cp2Fe] (10 mol%) LiCp (30 mol%) MeOH/THF (1:2),nBu4NBF4 0 or -30 oC

R2

H

RVC

CO2Me

189

F NHPh

CO2Me O

N

O

80%

Scheme 5.48  Electrochemical dehydrogenative coupling synthesis of C3-fluorinated oxindoles

HH R1

N H 124

R3 R2

R3

Pt (+) Pt (-) : I = 7 mA KI (0.15 M), DMF/H2O, rt, 3 h undivided cell

R1

CO2Me

CO2Et N H

N H

96%

61%

N H 125

R2

+

CO2Et N H 80%

H2

COPh

Ph N H 62%

Scheme 5.49  Electrocatalytic intramolecular oxidative annulation of N-aryl enamines

Ph

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Scheme 5.50  Proposed mechanism for electrocatalytic intramolecular oxidative annulation of N-aryl enamines

5.4  Conclusion In conclusion, fourth-generation oxidative cross-coupling reactions have been developed in recent years, which represent a useful and environmental friendly strategy to form a C-X bond from the corresponding C-H and X-H (X = carbon or heteroatom) bonds. In this reaction system, no external oxidant is required, and H2 gas is released as the only by-product. Therefore, we believe this sustainable bond construction methodology will become an interesting alternative to well-established cross-coupling reactions.

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