R2-H Cross-Coupling with

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Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

Recent Advances in Oxidative R1‑H/R2‑H Cross-Coupling with Hydrogen Evolution via Photo-/Electrochemistry Focus Review Huamin Wang,† Xinlong Gao,† Zongchao Lv,† Takfaoui Abdelilah,† and Aiwen Lei*,†,‡

Chem. Rev. Downloaded from pubs.acs.org by UNIV AUTONOMA DE COAHUILA on 05/10/19. For personal use only.

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Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, China ‡ National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, China ABSTRACT: Photo-/electrochemical catalyzed oxidative R1-H/R2-H cross-coupling with hydrogen evolution has become an increasingly important issue for molecular synthesis. The dream of construction of C−C/C−X bonds from readily available C− H/X−H with release of H2 can be facilely achieved without external chemical oxidants, providing a greener model for chemical bond formation. Given the great influence of these reactions in organic chemistry, we give a summary of the state of the art in oxidative R1-H/R2-H cross-coupling with hydrogen evolution via photo/electrochemistry, and we hope this review will stimulate the development of a greener synthetic strategy in the near future.

CONTENTS

1. INTRODUCTION

1. Introduction 2. C−C Bond Formation 2.1. C−H/C-H Homo-Coupling 2.2. C−H/C−H Cross-Coupling 3. C−X (X = O, N, S, P, B) Bond Formation 3.1. C−O Bond Formation 3.2. C−N Bond Formation 3.3. C−S Bond Formation 3.4. C−P Bond Formation 3.5. C−B Bond Formation 4. X−X/X−Y (X/Y = O, N, S, P, B) Bond Formation 4.1. X−H/X−H Homo-Coupling 4.2. X−H/Y−H Cross-Coupling 5. Annulation 5.1. Intermolecular Annulation 5.1.1. [4+2] Annulation 5.1.2. [3+2] Annulation 5.1.3. [4+1] Annulation 5.2. Intramolecular Annulation 6. Conclusions and Outlook Author Information Corresponding Author ORCID Notes Biographies Acknowledgments Abbreviations References

Employment of R1-H/R2-H cross-coupling has been recognized as a powerful and straightforward tool for the construction of C−C/C−X bonds.1−6 Over the past decades, significant progress has been made in this field. These reactions always need an external driving force. Therefore, a sacrificial chemical oxidant is always required for R1-H/R2-H cross-coupling, resulting in the difficult purification from a mass of undesired byproducts. A more dreamlike reaction pathway is to achieve oxidative R1-H/R2-H cross-coupling with hydrogen evolution without external oxidants. This bond formation with the release of H2 is one of the most atom-economical yet thermodynamically unfavorable methods owing to ΔGrxn > 0 (Scheme 1). The design of mild, straightforward, and environmentally friendly methods for C−C/C−X bond formation has attracted continuous interest in organic chemistry. Electricity has emerged as a good alternative to chemical oxidants to drive chemical reactions (ΔGrxn < 0, Scheme 1). Anodic oxidation along with cathodic proton reduction has been widely used in organic synthesis.7−13 On the other hand, integration of photocatalysis and hydrogen evolution catalysis has emerged as a promising strategy for achieving oxidative coupling with hydrogen evolution (ΔGrxn < 0, Scheme 1).14−19 Compared with classical synthetic methods, these dreamlike transformations feature mild conditions, high atom economy, and elimination of oxidants.

A B B B E E F G H H H H H H H H J L L O O O O O O O O P

Received: January 18, 2019

© XXXX American Chemical Society

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DOI: 10.1021/acs.chemrev.9b00045 Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 1. Oxidative R1-H/R2-H Cross-Coupling with Hydrogen Evolution via Photo-/Electrochemistry

dehydrogenative coupling of aryls, and a broad range of substrates were successfully converted. In the same year, the Han group developed an efficient electrochemical method for construction of bioheteroaryls (Scheme 3).28 Neither catalysts nor oxidants were necessary in this transformation. A series of bioactive biheteroaryl compounds were efficiently obtained from oxidative C(sp2)− H homocoupling reaction of imidazo[1,2-a]pyridines. 2.2. C−H/C−H Cross-Coupling

Nonsymmetrical biaryls are fundamental structures in a series of biologically active natural products.29,30 Therefore, the research into cross-coupling reactions for the synthesis of nonsymmetrical biaryls has been well investigated in contemporary organic chemistry. In electroorganic synthesis reaction, achieving cross-coupling instead of homo-coupling is a big challenge. A radical-cation-pool strategy, serving as a powerful tool for synthesis of unsymmetrical biaryls from unactivated electronrich aromatic compounds, has been developed by anology with the cation-pool method.31−33 In 2012, Yoshida and co-workers described a radical-cation-pool method for the construction of a C−C bond by C−H/C-H cross-coupling of two unactivated aromatic compounds (Scheme 4).33 This protocol consisted of two sequential steps. The first step was the generation and accumulation of an aromatic radical cation under oxidative conditions. Then, coupling of this radical cation species with another aromatic compound under nooxidative compounds occurred. This tansformation not only proceeded smoothly in the absence of metal complexes and chemical oxidants but also eliminated the nonselective oxidation of starting materials and overoxidation of the products. In the same year, Waldvogel and co-workers developed a metal-free electrochemical method for cross-coupling between phenols and arenes using boron-doped diamond (BDD) anodes in fluorinated media (Scheme 5A).34 Both yields and selectivity were dramatically enhanced when water or methanol was added to the electrolyte. In this metal-free and highly selective transformation, various nonsymmetrical biaryls were easily obtained. Only electrons were used as oxidants and no reagent waste was produced, according with the principle of green chemistry. Two years later, direct oxidative cross-coupling of two phenols has been described by the same group (Scheme 5B). BDD was also used as electrode because of its unique electrochemical properties.35 In 2016, one example was disclosed to generate partially protected 2,2′-biphenols with the use of a bulky silyl group on one coupling partner.36 In this work, twisted biaryl product and solvent effect played a key role in the outstanding selectivity. In addition, this protocol can be carried out on 30 mmol scale, highlighting the robust nature of the electrochemical conversion. Besides phenol−phenol cross-coupling, Waldvogel and coworkers developed an innovative and facile method for electrochemical dehydrogenative C−C cross-coupling to offer

This review will focus on recent advances (from 2011) in oxidative R1-H/R2-H cross-coupling with hydrogen evolution via photo-/electrochemistry.

2. C−C BOND FORMATION 2.1. C−H/C-H Homo-Coupling

C−C bond formation is an important research issue in organic synthesis. The construction of a C−C bond from readily available C−H compounds has attracted much attention and provided a powerful and straghitforward method for molecular synthesis.3,20−22 However, sacrificial chemical oxidants are necessary in these transformations, which does not accord with the principle of green chemistry. Recently, electroorganic synthesis has advanced a green and dreamlike method for the construction of a C−C bond with hydrogen evolution. Bio(hetero)arenes widely exist in a series of pharmaceutical molecules and natural products.23,24 Over the past decades, the most reported methods for the construction of bio(hetero)arenes often rely on expensive transition metals and a large excess of oxidants, resulting in a mass of undesired byproducts and difficult purification. Electroorganic synthesis has been a green alternative to typical synthetic strategies for the construction of bio(hetero)arenes. In this field, a significant breakthrough was made by Waldvogel and Yoshida et al. Homocoupling reactions of phenolic substrates play an important role in the synthesis of natural products. Waldvogel and co-workers have described several methods to efficiently achieve homocoupling reaction of phenolic substrates.25−27 It is worth mentioning that an active molybdenum-based anode was developed by Waldvogel and co-workers to access dehydrogenative coupling of aryls (Scheme 2).25 In HFIP, the molybdenum anode formed a compact, conductive, and electroactive layer of higher-valent molybdenum species, which either dissolved in the electrolyte or remained at the electrode to generate an active surface layer. This system could place MoV reagents for the Scheme 2. Dehydrogenative Coupling of Aryls

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Scheme 3. Regioselective Construction of Bioheteroaryls

Recently, photocatalysis has been widely used in organic synthesis.14−19,40−42 In 2013, Wu and co-workers described a photocatalytic dehydrogenation cross-coupling reaction to form a C−C bond by two different C−H bonds with concomitant release of H2 (Scheme 9A).43 No external oxidants were needed in this transformation. Combing eosin Y and a graphenesupported RuO2 nanocomposite (G-RuO2) as a photosensitizer and a catalyst, the desired cross-coupling products and H2 were achieved in quantitative yields under visible light irradiation at room temperature. Additionally, the combination of eosin Y and Co(dmgH)2Cl2 complex can achieve the similar reaction.44 In 2014, eosin Y was employed as a photosensitizer to initiate crosscoupling of amines with nucleophiles by the same group.44 In this work, Co(dmgH)2Cl2 complex was used as catalyst to capture the electrons and protons eliminating from the substrates, and H2 was the only byproduct. A similar oxidative strategy was used to develop a cascade cross-coupling along with in situ hydrogenation reaction.45 Amines were achieved from reductive hydrogenation of nitroarenes in good to excellent yields. Additionally, using Ru(bpy) 3 (PF 6 ) 2 and Co(dmgH)2pyCl as a photosensitizer and a catalyst, Wu and coworkers described visible light catalysis assisted site-specific modification of α-amino acid derivatives by C−H bond functionalization without the use of any oxidant or base (Scheme 9B).46 Coupling of glycine esters with β-keto esters or indole derivatives offered various amino acid derivatives in good efficiency. Because of its higher oxidation potential, the activation of a C−H bond adjacent to an O atom is much more challenging than well-established activation of a C−H bond adjacent to an N atom.3 It is noteworthy that Wu and co-workers disclosed an approach to forming C−C bonds through cross-coupling between oxonium species and nucleophiles under oxidant-free conditions.47 Catalytic enantioselective CDC of simple ketones has been extensively explored but with limited success due to fast product racemization processes. In 2017, Wu and Luo reported a visiblelight-promoted asymmetric CDC-type coupling of tertiary amines to ketones enabled by a chiral primary amine catalyst, photocatalyst, and cobalt catalyst (Scheme 10).48 The combination of photocatalyst and cobalt catalyst not only

Scheme 4. Radical-Cation-Pool Method for Cross-Coupling of Two Unactivated Aromatic Compounds

a series of 2,2′-diaminobiaryls (Scheme 6).37 The cosolvents of HFIP and methanol were essential for the high selectivity while no leaving groups were required. In addition, glassy carbon can significantly decrease the oligomerization of reaction substrates. Additionally, Waldvogel and co-workers developed the first example for C−C cross-coupling of thiophenes with phenols (Scheme 7).38 The use of excess thiophene provided desired single cross-coupling products. On the other hand, an excess of phenol preferred to form terarylic 2,5-bis(2-hydroxyphenyl)thiophenes. One year later, the first method that accessed arylation in position 2 or 3 of benzo[b]thiophenes via electrochemistry was reported by the same group.39 By only using electrons as oxidants, the described one-step construction of biaryls consisting of a benzothiophene and a phenol moiety was easy to conduct, scalable, and inherently safe. The cross-dehydrogenative coupling (CDC) reaction is one of the most powerful tools for the construction of C−C bonds through activation of the two different C−H bonds (Scheme 8).3 In regard to classical methods for the activation of this type of C−H bond, stoichiometric amounts of oxidants are necessary to remove electrons and hydrogen atoms, thereby leading to the formation of carbon radicals or reactive ion intermediates for subsequent transformations. However, stoichiometric oxidants lead to the limitation of the application in some way. Recently, visible light photocatalysis and electrochemical synthesis have attracted considerable attention in the activation of this type C− H bond without external oxidants.

Scheme 5. Cross-Coupling between Phenols and Arenes Using Boron-Doped Diamond (BDD) Anodes

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Scheme 6. Electrochemical Dehydrogenative C−C Cross-Coupling for Synthesis of 2,2′-Diaminobiaryls

Scheme 7. Cross-Coupling of Thiophene Derivatives with Phenols

Scheme 8. Cross-Dehydrogenative Coupling (CDC) Reaction

Scheme 9. Combination of Photocatalyst and Metal Catalyst for CDC Reaction

Scheme 10. Catalytic Enantioselective CDC of Simple Ketones

Scheme 11. Dehydrogenative Alkenylation of Aromatic Compounds

overcame the high barriers of direct oxidation of substrates but also avoided the undesired byproducts associated with typical oxidation processes. Moreover, Luo and co-workers developed an oxidant-free approach for the catalytic asymmetric oxidative

coupling of tertiary amines with simple ketones via the combination of electrochemical oxidation and chiral primary amine catalysis.49 D


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In 2016, Tung and co-workers developed photocatalytic amination and hydroxylation of benzene to produce aniline and phenol with hydrogen evolution (Scheme 14).53 QuCN+ with

In 2018, a method for the catalytic dehydrogenative alkenylation of aromatic compounds under external oxidantfree conditions was reported by Lei and co-workers (Scheme 11).50 In this work, a photo-/cobaloxime dual catalytic system was used. Various substituted aryl alkenes can be afforded in good to excellent yields, and H2 was the only byproduct of the reaction. Mechanism studies demonstrated that this transformation involved a key arene radical cation intermediate, which originated from electron transfer between excited-state photosensitizer and electron-rich arenes. The use of heterogeneous catalyst in construction of a C−C bond via C−H bond activation has been reported. A method for cyanomethylation of an aromatic compound by using acetonitrile was reported in 2013 (Scheme 12).51 Combination

Scheme 14. Photocatalytic Amination and Hydroxylation of Benzene

Scheme 12. Cyanomethylation of Aromatic Compounds high oxidation potential was used as photocatalyst in this reaction. Various substituted benzenes such as aryl ketones, benzoic acids, benzoates, benzamides, and aryl halides can also participate in this transformation. Mechanistically, benzene was oxidized by excited photocatalyst via single electron transfer to produce benzene radical cation. Subsequently, benzene radical cation was attacked by nucleophilic reagent to give a dienyl radical, which might be oxidized by cobalt(II) catalyst via single electron transfer to produce dienyl cation, followed by deprotonating to afford the final products. Afterward, in 2017, the same strategy was used to construct aryl ethers through direct esterification of benzene with alcohols.54 Meanwhile, Lei and co-workers developed photocatalytic anti-Markovnikov oxidation of β-alkyl styrenes to construct carbonyl compounds (Scheme 15).55 Compared with tradiof a heterogeneous palladium catalyst hybridized with a titanium dioxide photocatalyst promoted the transformation. On the basis of mechanistic studies, the authors speculated that the titanium dioxide was first photoexcited to produce an electron and a hole. Subsequently, an acetonitrile was oxidized to a cyanomethyl radical by the hole. The desired product was generated through radical substitution along with the formation of hydrogen radical. Then, hydrogen was formed as the only byproduct.

Scheme 15. Photocatalytic Anti-Markovnikov Oxidation of βAlkyl Styrenes

tional Wacker-type oxidation of alkenes to synthesize carbonyl compounds, various internal alkenes can participate in this transformation with high regioselectivity and functional group tolerance. In addition, using a photoredox catalytic system in no need of noble-metal catalysts and stoichiometric oxidants met the requirements of green chemistry. Mechanistically, alkene was activated by excited photocatalyst [Acr+-Mes ClO4−]* via single electron transfer to produce alkene radical cation, which was attacked by water and deprotonated to engender the antiMarkovnikov intermediate exclusively due to its better stability than the Markovnikov selective intermediate. Subsequently, by using a similar strategy, Lei and co-workers developed photocatalytic dehydrogenative C−H/O−H and C− H/N−H cross-coupling between alkenes with alcohols or azoles.56 Various alkyl alcohols were suitable in this transformation with good efficiency. Various azoled derivatives can also participate in this reaction to produce corresponding C−N bond-formation products in moderate to good yields. On the other hand, electroorganic synthesis has emerged as an efficient tool for C−O bond formation from simple available C− H/O−H. In 2017, Ackermann and co-workers reported electrochemical cobalt-catalyzed C−H oxygenation under

3. C−X (X = O, N, S, P, B) BOND FORMATION 3.1. C−O Bond Formation

In 2012, Boydston and co-workers demonstrated the organocatalyzed anodic oxidation of aldehydes to esters via construction of a C−O bond (Scheme 13).52 In this transformation, electroactive intermediates that can be viewed as catalytically generated electroauxiliaries could be formed. The authors found potentiostatic experiments to be more successful than using a constant current. A broad range of aldehyde and alcohol substrates were compatible with this protocol. Scheme 13. Organocatalyzed Anodic Oxidation of Aldehydes to Esters

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Scheme 16. Electrochemical Cobalt-Catalyzed C−H Oxygenation

Scheme 17. Electrochemical Hydroxylation of Arenes

Scheme 18. Electrochemical Oxidative Amination of Benzoxazoles with Alkyl Amines

Scheme 19. Electrochemical Coupling of Aromatic Compounds and Primary Alkylamines

mild conditions (Scheme 16).57 The inexpensive cobalt catalyst was applied for the first time in transition-metal-catalyzed C−H functionalization under electrolysis conditions. An RVC electrode was used as anode and a platinum plate was used as cathode. The electrolysis was conducted at constant current. Multifarious alkyl alcohols could participate in this reaction with good functional group tolerance and scale. According to the cyclic voltammetry curve, the oxidation potential of the substrate was significantly higher than cobalt(II), which might reveal that cobalt(II) was oxidized to cobalt(III) by anodic oxidation, followed by single electron transfer with substrate. Subsequently, Neumann and co-workers disclosed a method for electrochemical hydroxylation of arenes (Scheme 17).58 Under electrolytic conditions, benzene and its halogenated derivatives could be oxidized to aryl formats by using keggin polyoxometalate with a cobalt(IV) heteroatom as catalyst, which can be easily hydrolyzed to corresponding phenols. In the presence of [CoIIIW12O40]5−, the formylation reaction occurred on a Pt anode via formation of a formyloxyl radical as the reactive species, which can be trapped by a BMPO spin trap and identified by EPR.

Little and Zeng developed electrochemical oxidative amination of benzoxazoles with alkyl amines (Scheme 18).59 A catalytic amount of nBu4NI was used as redox mediator and there was no need of any transition metal catalysts or oxidants. When using glassy carbon as anode and iron as cathode, the reaction between benzoxazole and morpholine proceeded effectively in a beakertype cell. Mechanistically, indirect electrochemical recycling mediated by I− might be involved in this transformation. Additionally, Zeng and co-workers developed an efficient and mild strategy for construction of 3-aminoquinoxalinones via the electrochemical dehydrogenative C-3 amination of quinoxalin2(1H)-ones.60 In 2016, Brown and co-workers disclosed a flow process for N-heterocyclic carbene (NHC)-mediated anodic oxidative amination of aldehydes.61 The flow mixing regimen played an important role in circumventing the competing imine formation between aldehyde and amine substrates. Unfortunately, only primary amines were able to access amides in this reaction. In 2015, Yoshida and co-workers disclosed a novel electrochemical oxidative coupling of aromatic compounds and primary alkylamines bearing a functional group (Scheme 19).62 Primary alkylamines first formed heterocycles. The aromatic radical cation resulting from oxidation of aromatic compounds would react with heterocycles to generate the corresponding cationic intermediates. Then, cross-coupling

3.2. C−N Bond Formation

Recently, important progress has been realized in the crosscoupling of C(sp2)-H/N−H with hydrogen evolution. In 2014, F


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Scheme 20. Amination of Arenes with Heterocyclic Amines

Scheme 21. C(sp2)-H Amination

products can be obtained from the cationic intermediates through a chemical reaction. Heterocyclization of functional primary alkylamines played a key role in this transformation. In 2017, Lei and co-workers achieved photoinduced oxidative selective C(sp2)-H amination of arenes with heterocyclic amines under mild conditions (Scheme 20).63 In this reaction, selective C(sp2)-H amination of methylarene can be achieved under oxidant-free conditions by using Co(dmgH)2Cl2 as the protonreduction catalyst. Under the optimal reaction conditions, a wide range of methylarenes can react with pyrazole in this transformation with satisfactory results. Unfortunately, the ortho- and para-position of methylarenes would participate in this reaction together without good chemoselectivity. Finally, the intermolecular kinetics of the isotopic effect experiment showed that C−H bond cleavage of arenes might not be involved during the rate-limiting step. Additionally, in 2018, the same catalytic system was used to achieved a site-selective amination of 2-arylimidazoheterocycles on the C3 position.64 One year later, Lei and co-workers achieved electrochemical dehydrogenative C−H/N-H cross-coupling between phenothiazines and phenols under undivided electrolytic conditions (Scheme 21).65 Under mild conditions, a series of triarylamine derivatives can be obtained with good functional-group tolerance and using neither metal catalysts nor chemical oxidants. Direct electrooxidative C−H amination of aromatic compounds would be appealing compared with traditional transition-metal-catalyzed C−H amination reactions. In 2018, Ackermann and co-workers developed electrochemical C−H amination by cobalt catalysis, which offered a step-economical approach toward aromatic amines by solely employing electricity as the green oxidant (Scheme 22).66 Electrochemical C−H bond amination products were efficiently obtained under mild conditions at 40 °C. Subsequently, the same group reported a method for nickel-catalyzed electrooxidative C−H amination.67 At the same time, Lei and co-

workers achieved cobalt(II)-catalyzed electrooxidative C−H amination between arenes and alkylamines, offering a simple way for the synthesis of arylamines (Scheme 22).68 Various arenes and secondary alkylamines can participate in this transformation with good functional group tolerance. Furthermore, this reaction can be extended to gram level. Intermolecular and intramolecular competition experiments indicated that C−H bond cleavage might not be involved during the rate-limiting step. To test the reaction mechanism, the authors also carried out chronoamperometry to prove the oxidation of Co(II) is occurring in the electrolysis. Subsequently, Mei and co-workers developed copper-catalyzed electrochemical C−H amination with extensive substrate applicability (Scheme 22).69 nBu4NI was used as a redox mediator in this transformation, which was necessary for the catalytic cycle of the copper catalyst. The radical inhibition experiments indicated that a single-electron-transfer (SET) process might be involved in this reaction. In addition to the C(sp2)-H amination mentioned above, C(sp3)-H amination is also an interesting research issue in organic chemistry.70,71 In 2016, Zeng and Sun developed electrochemically oxidative α-C(sp3)−H amination of ketones (Scheme 23A).72 Analogously, NH4I was used as redox catalyst to activate ketones, followed by nucleophilic substitution of amines to get the ultimate C−N formation products. Additionally, preparation of α-enaminones via electrochemical reaction of three components was reported by the Wang group in 2016.73 Subsequently, Lei and co-workers reported electrooxidative C(sp3)-H amination of azoles with tetrahydrofuran (Scheme 23B).74 The reaction could be restrained by adding stoichiometric radical inhibitor, which might reveal that the reaction involved a radical pathway. The kinetic isotopic effect (KIE) indicated that C−H cleavage of tetrahydrofuran might not be involved during the rate-determining step.

Scheme 22. Electrochemical C−H Amination by Cobalt/ Copper Catalysis

C−S bonds, important structural motifs, widely exist in various biologically active molecules and functional materials.75−77 In 2014, Boydston and co-workers described an efficient method for the formation of thioesters from various aldehyde and thiol substrates via integration of NHC catalysis and electrosynthesis (Scheme 24).78 By using DMAP as base, the formation of disulfide was strongly inhibited while thioesters were obtained in good to excellent yields. Later, Lei and co-workers developed electrocatalytic oxidantfree intermolecular C−H/S−H cross-coupling (Scheme 25).79 Varieties of electro-rich arenes and thiophenols can participate in this transformation with good efficiency and functional group

3.3. C−S Bond Formation

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Scheme 23. Electrochemical C(sp3)-H Amination

4. X−X/X−Y (X/Y = O, N, S, P, B) BOND FORMATION

Scheme 24. Formation of Thioesters from Aldehydes and Thiol Substrates

4.1. X−H/X−H Homo-Coupling

Recently, N−N homo-coupling has been used in complex moleculer synthesis.82 An impressive and convincing example for the total synthesis of the N,N-linked dimeric indole alkaloid dixiamycin B was reported by Baran and co-workers (Scheme 28).83 Moreover, several other simple carbazole derivatives, including an ester, an alkyl group, and a sulfone group, were tested, which further highlighted good functional tolerance of this protocol. 4.2. X−H/Y−H Cross-Coupling

Phosphorus-based nucleophiles have been widely used in molecular synthesis.84−86 In 2017, Wang and co-workers reported electrochemical N−H/P−H cross-coupling, providing an effective method for the synthesis of phosphinic amides (Scheme 29).87 Compared with traditional synthetic methods between phosphorus halides and amines, it was more convenient and environmentally friendly. Stoichiometric KI was used as electrolyte as well as redox mediator for the activation of diphenylphosphine oxide in this transformation. Various secondary amines can participate in this reaction and give moderate to good yields. Unfortunately, primary amines can not be tolerated in this transformation, which might result from the overoxidation of products and the weak nucleophilicity of primary amines. Large amounts of metals are necessary in metal-catalyzed S− H/S−H cross-coupling reactions, which is because of the strong coordination ability of sulfur atom to metal.88,89 Design of mild and green methods for construction of S−S bonds via crosscoupling is necessary. In 2018, Lei and co-workers developed an oxidant-free and catalyst-free S−H/S−H cross-coupling with hydrogen evolution via electroorganic chemistry (Scheme 30).90 A series of aryl mercaptans and alkyl mercaptans were suitable substrates for this transformation. On the basis of experiment results, the authors proposed that oxidative dimerization of aryl mercaptan was significant for achieving this transformation.

tolerance. Gram-scale reaction between indole and thiophenol was also tested in good yields, which showed great potential of this electrocatalytic intermolecular C−H/S-H cross-coupling. In the proposed mechanism, direct coupling or radical substitution between indole radical-cation intermediate and sulfur radical (disulfide) might be involved. 3.4. C−P Bond Formation

To avert the employment of oxidants, Wu and co-workers first developed photocatalytic C−H/P−H cross-coupling with hydrogen evolution between thiazole derivatives and diarylphosphine oxides at room temperature in 2016 (Scheme 26).80 Mechanistically, excited state eosin B+• was reductively quenched by diarylphosphine oxide to produce a P-centered radical-cation intermediate. Then the P-centered radical was obtained by deprotonation of the P-centered radical-cation intermediate, followed by nucleophilic addition to thiazole and deprotonation to get the final product. 3.5. C−B Bond Formation

In 2015, Darcel and co-workers first achieved iron-catalyzed C− H borylation of arenes under the irradiation of UV (Scheme 27).81 When using Fe(Me)2(dmpe)2 as catalyst precursor, various arylboronates could be obtained in moderate isolated yields without any additives. To explore the reaction mechanism, the authors tested the activity of iron complexes with pinacolborane and found hydrido-(boryl)iron complex Fe(H)(Bpin)(dmpe)2 was obtained under UV irradiation, which might react with arene to afford the final C−H/B−H coupling product.

5. ANNULATION 5.1. Intermolecular Annulation

5.1.1. [4+2] Annulation. The heterocyclic compounds commonly exist in many natural products, pharmaceuticals, and

Scheme 25. Formation of C−S Bond from Electrorich Arenes and Thiophenols

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Scheme 26. Formation of a C−P Bond from Thiazole Derivatives with Diarylphosphine Oxides

Scheme 27. Iron-Catalyzed C−H Borylation of Arenes

Scheme 28. Electrochemical-Catalyzed N−N Bond Formation

Scheme 29. Electrochemical-Catalyzed N−P Bond Formation

Scheme 30. Electrochemical-Catalyzed S−S Bond Formation

Scheme 31. Photocatalyzed Dehydrogenative [4+2] Annulation

bioactive molecules.91,92 Among the methods of building valuable five/six-membered heterocyclic compounds, intermolecular or intramolecular annulation reaction is a versatile synthetic protocol. In 2018, Lei and co-workers developed a photocatalyzed dehydrogenative [4+2] annulation reaction between aromatic N−H ketimines and alkenes to form 3,4-dihydroisoquinoline

derivatives by using the dual catalytic system (Scheme 31A).93 The reaction proceeded smoothly at room temperature, giving the 3,4-dihydroisoquinolines with high regioselectivity and diastereoselectivity. Additionally, the same system was successfully used to synthesize polysubstituted aromatics from reaction between styrene derivatives with electron-rich dienophiles (Scheme 31B).94 Through an in situ-generated alkene radical I


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Scheme 32. Electrochemical-Catalyzed Dehydrogenative [4+2] Annulation

Scheme 33. [4+2] Annulation of Tertiary Anilines and Alkenes

(Scheme 32D).99 Mechanistic studies revealed the existence of a facile organometallic C−H ruthenation and the process of an effective electrochemical reoxidation of the key ruthenium(0) intermediate. Lei and co-workers described electrochemical oxidative [4+2] annulation of tertiary anilines and alkenes for the synthesis of tetrahydroquinolines (Scheme 33).100 In this reaction, a N,Ndimethylaniline radical cation was detected by EPR. Further experiments showed that the radical cation can be stabilized by acetic acid. In the same year, the Xu group described an organocatalyzed electrochemical [4+2] annulation reaction of alkenes with 1,2and 1,3-diols (Scheme 34).101 A series of 1,4-dioxane and 1,4-

cation intermediate, the reaction can be carried out under room temperature with good regioselectivity. In the same year, Li and co-workers described visible-light photoredox-catalyzed iminyl radical formation by N−H bond cleavage for the synthesis of isoquinolines and related polyaromatics.95 Mechanistic investigations demonstrated that generated iminyl radical initiated cascade C−N/C−C bond construction. In 2018, the first electrochemical cobalt-catalyzed C−H/N− H activation for [4+2] annulation using internal alkynes as coupling partners was reported by the Ackermann group (Scheme 32A).96 A series of decorated isoquinolones were efficiently synthesized. Mechanism studies provided strong support for a facile C−H activation by a catalytically component cobalt(III) species. Meanwhile, the same group developed a strategy for electrochemical cobalt-catalyzed C−H/N−H annulation with allenes (Scheme 32B).97 This allene annulation featured excellent levels of chemoselectivity, position selectivity, and regioselectivity. Computational studies were supportive of a non-rate-determining C−H cleavage and gave key insights into the regioselectivity of this allene annulation. Meanwhile, an example of cobalt-catalyzed electrooxidative C−H/N-H [4+2] annulation between aryl/vinyl amides and ethylene/ethyne was demonstrated by Lei and co-workers (Scheme 32C).98 In this protocol, the desired [4+2] annulation products can be facilely obtained in good to high reaction yields. On the basis of a preliminary mechanistic study, the authors speculated that electrochemical oxidation of coordinated Co(II) complex may be the key step during the reaction process. In the same year, Ackermann and co-workers developed the first example of electrochemical C−H bond activation by weak O-coordination

Scheme 34. [4+2] Annulation of Alkenes with 1,2- and 1,3Diols

dioxepane derivatives were facilely obtained in good efficiency. Gram-scale synthesis demonstrated the potential ultility of this protocol. Triarylamine catalyst was needed for the formation of alkenes radical cation. 5.1.2. [3+2] Annulation. In 2017, Lei and co-workers reported a green and efficient electrooxidative [3+2] annulation between phenols and N-acetylindoles to achieve the selective synthesis of benzofuro[3,2]indolines (Scheme 35).102 Utilizing n Bu4NBF4 as the electrolyte and 1,1,1,3,3,3-hexafluoroisopropyl J


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Scheme 35. [3+2] Annulation of Phenols and N-Acetylindoles

Scheme 36. Ruthenium-Catalyzed Electrochemical Dehydrogenation Alkyne Annulation

Scheme 37. Cobalt-Catalyzed Electrochemical Oxidative C−H/N−H Carbonylation

Scheme 38. Electrooxidative C−H Alkenylations

Scheme 39. Cp2Fe as Redox Catalyst

the corresponding benzofuro[3,2-b]indoline in a high reaction efficiency with a 87% yield. Afterward, Xu and co-workers reported a method for ruthenium-catalyzed electrochemical dehydrogenation alkyne annulation (Scheme 36).103 Various indole derivatives were facilely offered from easily accessible alkynes and aniline

alcohol (HFIP)/CH2Cl2 as cosolvents, benzofuro[3,2-b]indolines were obtained under 10 mA constant current for 1.8 h in an undivided cell. The great potential application of the electrooxidative [3+2] annulation was demonstrated by a 5 mmol scale reaction under atmospheric conditions that afforded K


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Scheme 40. C−H/N−H Intramolecular Annulations via N-Radical Addition

Scheme 41. Construction of N−N Bond via N−H/N−H Cross-Coupling

of Cp2Fe as redox catalyst, Xu and co-workers developed a series of great methods for the formation of indole derivatives via intramolecular annulation. In 2016, Xu and co-workers reported an unprecedented electrochemical synthesis of highly functionalized indoles and azaindoles by C−H/N-H functionalization of (hetero)-arylamines using tethered alkynes (Scheme 39A).109 The noblemetal reagent- and oxidant-free reaction employed inexpensive ferrocene ([Cp2Fe]) as the redox catalyst. A broad range of diverse sensitive functional groups were well tolerated in this protocol and only gave H2 as the theoretical byproduct. The synthetic utility of the methodology was demonstrated by the construction of the bioactive natural isocryptolepine compounds. Subsequently, by using Cp2Fe as the redox catalyst, Xu and co-workers developed an electrochemical cascade cyclization reaction to form three rings in a single operation (Scheme 39B).110 This protocol provided an efficient approach to the construction of nitrogen-doped polycyclic aromatic hydrocarbons (PAH), which exist widely in material sciences. Additionally, an unprecedented strategy for cross-dehydrogenative coupling of C(sp3)−H and C(sp2)−H bonds from malonate amides by employing Cp2Fe as the redox catalyst to synthesize C3-fluorinated oxindoles was reported (Scheme 39C).111 In this transformation, the in situ generation of the requisite oxidant and base at relatively low temperature and in a continuous fashion allowed the base- and heat-sensitive fluorinated oxindoles to be formed with high efficiency. Moreover, C−H/N−H intramolecular annulations via Nradical addition have been developed by Xu. In 2016, Xu developed the first example that amidinyl radicals can be generated conveniently through anodic cleavage of N−H bonds (Scheme 40A).112 Mechanistic studies provided strong evidence for the existence of nitrogen-centered radical in this transformation. Later, a metal- and reagent-free, electrochemical intramolecular oxidative amination reaction of tri- and tetrasubstituted alkenes was described (Scheme 40B).113 This electrosynthetic method had good functional tolerance, and a wide range of carbamate, amide, and urea substrates were compatible with this protocol. The similar annulation reaction

derivatives. This protocol featured simple and convenient operation because it was carried out under an undivided cell, proceeded efficiently in an aqueous solution, and was insensitive to air. 5.1.3. [4+1] Annulation. Carbon monoxide is an abundant C1 building block for the carbonylation industry. In 2018, the Lei group disclosed cobalt-catalyzed electrochemical oxidative C−H/N−H carbonylation without external oxidants (Scheme 37).104 A series of the intra- and intermolecular carbonylation products can be facilely achieved using carbon monoxide as carbon source under a divided cell. Mechanistically, the CoII/ CoIII/CoI catalytic cycle was proposed by the studies of XANES and CV. In 2018, Ackermann and co-workers reported the first unprecedented iridium-catalyzed electrooxidative C−H activation within a cooperative action of a redox catalysis, setting the stage for electrooxidative C−H alkenylations through weak Ocoordination (Scheme 38).105 The iridium-catalyzed electrochemical C−H activation featured a broad substrate scope and excellent tolerance of various functional groups. Detailed mechanistic insights provided strong support for a fast organometallic C−H iridation by a BIES (base-assisted internal electrophilic-type substitution) mode of action and a synergistic iridium (III/I)/redox catalyst regime, enabling the use of sustainable electricity as the terminal oxidant. In the same year, the same group reported the first electrochemical rhodiumcatalyzed similar cross-dehydrogenative alkenylation via C−H activation.106 The desired esterification products were accomplished with weakly coordinating benzoic acids and benzamides, employing electricity as the terminal oxidant and generating H2 as the sole byproduct. Oxidative 2-fold C−H functionalizations set the stage for chemoselective and site-selective C−H alkenylations with ample scope. Mechanistic studies provided strong support for a facile organometallic C−H rhodation by a BIES mode of action. 5.2. Intramolecular Annulation

Since indole derivatives are important structural moieties, strategies allowing for direct efficient synthesis of such molecules have been paid much attention by chemists.107,108 On the base L


Chemical Reviews

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Scheme 42. Electrochemical Oxidative Hofmann−Löffler−Freytag (HLF) Reactions

Scheme 43. Synthesis of Indoles

was developed by Moeller in 2014.114 This difunctionalization of alkenes has proven to be a powerful tool for moleculer synthesis, and significant breakthroughs have been made by Moeller, Lin, and Lei et al. In 2017, Waldvogel and co-workers developed an electrochemical oxidative intramolecular annulation for the construction of N−N bond via N−H/N-H cross-coupling (Scheme 41).115 Mechanism studies demonstrated that the N−N bond formation involved a diradical as intermediate. Subsequently, the same group reported an electrochemicalcatalyzed access to N-aryl-phenanthredin-6-ones through directly generated amidyl radical.116 This protocol featured a high current efficiency and operated without the necessity of a mediator. A variety of N-arylphenanthridin-6-one derivatives with valuable functional groups and substitution patterns at the aniline moiety and the biphenyl entity were achieved with good yields. Up-scaling of this method was easily possible. Additionally, the direct C(sp3)-H functionalization represents a powerful and straightforward protocol for constructing carbon−carbon or carbon−heteroatom bonds.3 In particular, the selective crosscoupling amination of C(sp3)−H and N−H enables the efficient synthesis of saturated nitrogen-containing heterocycles, which are important structural motifs in various biologically active compounds.117,118 In 2018, Lei and co-workers reported electrochemical oxidative Hofmann−Löffler−Freytag (HLF) reactions. The intramolecular remote inert δ-C(sp3)−H amination of amides can be achieved through a 1,5-HAT process in an undivided cell under constant-current electrolysis conditions (Scheme 42).119 Tetrabutylammonium acetate was not only employed as an electrolyte but also formed the intermolecular hydrogen bond with amide and promoted cleavage of the N−H bond. A variety of benzylic and nonactivated tertiary, secondary, primary C(sp3)-H aminations were achieved with good yields. Additionally, the reaction was easily scaled up. An electrocatalytic reaction protocol for achieving intramolecular dehydrogenative annulation of N-aryl enamines was demonstrated by the Lei group (Scheme 43A).120 KI not only served as the electrolyte but also participated in the redox processes of the oxidative annulation. Good to excellent yields were obtained under oxidant-free and transition-metal-free

conditions. Additionally, an oxidant-free intramolecular annulation strategy for the synthesis of indoles was developed by the Wu group (Scheme 43B).121 A series of indoles were obtained under mild reaction conditions along with the release of H2. Mechanistically, enamines were oxidized by IrIv originating from Ir(ppy)3 through single electron transfer to Co(dmgH)2(4CO2Mepy)Cl, followed by intramolecular radical addition to yield the indoles smoothly under ambient conditions, and the cobaloxime complex served as a catalyst to capture the protons and electrons eliminating from the substrate for H2 production. In 2017, the Zhang group reported an efficient transitionmetal-free photoinduced intramolecular dehydrogenative annulation of 4H-chromen-4-ones for the synthesis of complicated fused-ring heteroaromatics (Scheme 44).122 Meanwhile, similar intramolecular aromatic C−H/C-H annulation to form C−C bond via electrochemical oxidative protocol was achieved by Hilt. Scheme 44. Photoinduced Dehydrogenative Annulation of 4H-chromen-4-ones

Additionally, C−H/S−H intramolecular annulations via Sradical addition have been developed by the Lei, Wu, and Xu groups. In 2015, an external oxidant-free C−H functionalization/C−S bond formation reaction to form the benzothiazoles was described by Lei and Wu. This strategy could be carried out on a larger scale and applied to the synthesis of biologically active molecules bearing benzothiazole structural scaffolds (Scheme 45A).123 Later, a TEMPO-catalyzed electrochemical C−H bond thiolation reaction for the synthesis of benzothiazoles and thiazolopyridines was developed by the Xu group (Scheme 45B).124 Mechanistic studies suggested that the thioamide substrate was oxidized through an inner-sphere electron transfer by the electrochemically generated TEMPO+ to afford a thioamidyl radical, which underwent homolytic M


Chemical Reviews

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Scheme 45. Annulation for Synthesis of Thiazolopyridines and 4H-1,3-benzoxazines

Scheme 46. Intramolecular Annulation for C−O Bond Formation

practical intramolecular phosphonic Kolbe oxidative cyclization electrochemical method for the synthesis of ethoxy dibenzooxaphosphorin oxides (Scheme 46B).129 A series of ethoxy dibenzooxaphosphorin oxides were obtained readily in moderate to good yields. The competitive experiments demonstrated that the anodic oxidation of phosphonic acids was not likely a rate-determining step in this cyclization reaction, and the ratedetermining step probably involved the trapping of phosphonic acid radicals by the Ar2 ring. In the same year, Xu and co-workers reported an efficient electrochemical method for the direct synthesis of aromatic lactones through dehydrogenative C−O cyclization of 2-(hetero)arylbenzoic acids (Scheme 46C).130 The direct electrochemical C−O cyclization was scalable to 100 g under mild conditions. Additionally, drug molecule telmisartan analogue was isolated in 64% yield by applying the electrochemical C−H functionalization/C−O cyclization reaction. A similar reaction was achieved by Zeng.131 In 2017, Lei and co-workers reported the first electrooxidative tandem cyclization reaction of alkynes with sulfinic acids to construct sulfonated indenones in an oxidant-free and simple undivided cell under constant current conditions (Scheme 47A).132 The experimental investigation of reaction mechanism

aromatic substitution to form the key C−S bond. Additionally, an unprecedented electrochemical method for synthesis of benzothiazoles and thiazolopyridines in continuous flow was reported in 2018.125 This protocol not only reduced the need for supporting electrolyte but also allowed the reaction to proceed at room temperature. In the same year, Xu and co-workers described an electrochemical C−H oxidation reaction for preparation of 4H-1,3-benzoxazines via O-radical addition (Scheme 45C).126 This reaction can also be carried out in an electrochemical microreactor. In early 2012, an electrochemical oxidative method was successfully applied for the cyclization reaction of N-benzyl-2piperidine alcohols and 3-dialkylamino-1-phenylpropanols.127 The ultility of iodide ions significantly increased the yields of these reactions. Five years later, an efficient electrochemical C(sp3)−H esterification reaction for the synthesis of bioactive α-acyloxy lactones with hydrogen evolution was developed by Xu and Zhang (Scheme 46A).128 nBu4NI acted as mediator to promote the transformation. A scaled-up reaction demonstrated that this protocol opened a practical route to bioactive α-acyloxy lactones. As for C(sp2)−O bond formation via intramolecular annulation, Mo and co-workers developed a simple, novel, and N


Chemical Reviews

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Scheme 47. Electrooxidative Tandem Cyclization Reaction

indicated that the reaction probably involved a radical process and sulfonyl iodine ought to be the reaction intermediate. Subsequently, Lei and co-workers developed electrochemical dehydrogenative C−S cross-coupling under catalyst- and oxidant-free conditions (Scheme 47B).133 Graphite rod was used as anode, and platinum plate was used as cathode. Various secondary amines were applied as substrates with phenyl isothiocyanate in good yields. At the same time, the intramolecular dehydrogenative C−S cross-coupling can also be achieved by using N-aryl thioamides as substrates.

research focuses on oxidative cross-coupling reactions and addition reactions of unsaturated bonds. Xinlong Gao obtained his B.S. degree (2016) from Wuhan University. He joined Prof. Aiwen Lei’s group during his second year of undergraduate studies and started his Ph.D. studies in September 2016 in the same group. He is currently a third-year Ph.D. student whose research focuses on electrocatalysis. Zongchao Lv received his B.S. degree from Zhengzhou University of Light Industry in 2014. Then, he studied in Wuhan University of Technology and obtained his M.S. degree in 2017. He joined Prof. Aiwen Lei’s group in September 2018 and started his Ph.D. studies at Wuhan University. He is currently a first-year Ph.D. student whose research focuses on oxidative cross-coupling reactions and electroorganic synthesis.

6. CONCLUSIONS AND OUTLOOK R1 −H/R 2 −H cross-coupling has been a powerful and straightforward tool for the construction of C−C/C−X bonds. However, sacrificial chemical oxidants are needed to force these oxidative coupling reactions, leading to a mass of undesired products. Recently, electroorganic synthesis and photocatalysis have attracted increasing attention in the cross-coupling of R1− H/R2−H with hydrogen evolution, which not only eliminates the requirement of chemical oxidants but also offers an option toward opening up a new perspective for molecular synthesis. This review provides an updated summary (from 2011) of this rapidly developing area. In this developing field, design of efficient and general methods for selective inert C−H bond activation still remains a challenge. In terms of the synthesis of important and complicated units in pharmaceuticals, natural products, and agrochemicals, using these hydrogen evolution methods to achieve this goal is at a primary stage. Despite these challenges, these hydrogen evolution reactions from readily available R−H compounds demonstrate high potential application in complex molecule synthesis and will undoubtedly witness improvement in the future.

Takfaoui Abdelilah obtained his Ph.D. under the supervision of Prof. Rachid Touzani at the University of Mohammed 1st, Morocco, in collaboration with Prof. Henri Doucet and Prof. Pierre Dixneuf at the University of Rennes 1, France. Then he joined Aiwen’s group as a postdoctoral researcher working on the field of photo- and electrocatalytic hydrogen evolution. Aiwen Lei obtained his Ph.D. (2000) under the supervision of Prof. Xiyan Lu at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences (CAS). He then moved to Pennsylvania State University, U.S.A., and worked with Prof. Xumu Zhang as a postdoctoral fellow. He joined Stanford University in 2003, working with Prof. James P. Collman as a research associate. He then became a full professor (2005) at the College of Chemistry and Molecular Sciences, Wuhan University, China. His research focuses on novel approaches and understanding bond formation reactions.

ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21520102003) and the Hubei Province Natural Science Foundation of China (2017CFA010). The Program of Introducing Talents of Discipline to Universities of China (111 Program) is also appreciated.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

ABBREVIATIONS BDD Boron-doped diamond BDE Bond dissociation energy BIES Base-assisted internal electrophilic-type substitution CFL Compact fluorescent light DDQ 2,3-Dichloro-5,6-dicyanobenzoquinone DCE 1,2-Dichloroethane DFT Density functional theory DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide EPR Electron paramagnetic resonance

ORCID

Aiwen Lei: 0000-0001-8417-3061 Notes

The authors declare no competing financial interest. Biographies Huamin Wang obtained his B.S. degree (2014) from Wuhan University. He joined Prof. Aiwen Lei’s group during his second year of undergraduate studies and started his Ph.D. studies in September 2014 in the same group. He is currently a fifth-year Ph.D. student whose O


Chemical Reviews HFIP KIE NHC QuCN+ SET TBAI TEMPO THF

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1,1,1,3,3,3-Hexafluoro-2-propanol Kinetic isotope effect N-Heterocyclic carbene 3-Cyano-1-methylquinolinium ion Single-electron transfer Tetrabutylammonium iodide 2,2,6,6-Tetramethylpiperidine-1-oxyl Tetrahydrofuran

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