R2-H Cross-Coupling with Hydrogen Evolution

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Oxidative R1-H/R2-H Cross-Coupling with Hydrogen Evolution Shan Tang, Li Zeng, and Aiwen Lei J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b07327 • Publication Date (Web): 27 Sep 2018 Downloaded from http://pubs.acs.org on September 27, 2018

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Journal of the American Chemical Society

Oxidative R1-H/R2-H CrossCross-Coupling with Hydrogen Evolution Shan Tang,† Li Zeng,† and Aiwen Lei†,‡,* †

College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, Wuhan 430072, People’s Republic of China

‡National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330027, People’s Republic of China 1

2

ABSTRACT: Oxidative R -H/R -H cross-coupling with

hydrogen evolution serves as one of the most atomeconomical methods for constructing new chemical bonds. This reaction strategy avoids substrate prefunctionalization steps in traditional cross-coupling reactions. Besides, hydrogen gas, which is recognized as a source of green energy, is the only byproduct during the reaction process. The major challenge in this reaction strategy is to achieve selective bond formation and hydrogen evolution at the same time. Over the past few years, novel synthetic techniques especially photochemistry and electrochemistry have provided possibilities for oxidative cross-coupling with H2 liberation. Both C-C and C-X bonds can be constructed without the use of any sacrificial reagents. In this perspective, we will discuss the concept of this reaction strategy and give an overview of its recent development.

organic halides and peroxides are used in most cases (Scheme 1b). It diminishes the atom economy of the overall transformation. A dream reaction pathway is to achieve oxidative R1-H/R2-H cross-coupling with hydrogen evolution (Scheme 1c). This bond formation strategy not only avoids the use of sacrificial reagent but also releases hydrogen gas as the only byproduct. Importantly, the generated hydrogen gas can be further used as an efficient and green energy source by storing in suitable hydrogen storage materials.7-11 Scheme 1. Bond Formation Strategies

INTRODUCTION Transition-metal-catalyzed cross-coupling has been recognized as a powerful tool for the construction of C-C and C-X bonds.1-2 A lot of name reactions including Kumada reaction, Stille reaction, Negishi reaction, Suzuki reaction, Heck reaction and Buchwald-Hartwig reaction have been developed through transition metal catalysis.1-2 These reactions successfully deal with the cross-couplings of organic halides with certain nucleophiles. Though these cross-couplings are reliable and efficient, the use of organic halides and organometallic reagents inevitably produces undesirable chemical wastes (Scheme 1a). Moreover, organic halides and organometallic reagents are not readily available substrates and required to be prepared through multiple prefunctionalization steps. Over the last decade, developments in C-H activation allow the construction of C-C and C-X bonds from readily available substrates. Oxidative R1H/R2-H cross-coupling has been considered as an ideal way for constructing new chemical bonds.3-6 However, sacrificial chemical oxidants are generally required to remove the hydrogen atoms in the bond formation processes. Stoichiometric amount of hypervalent metal salts,

The major challenge in oxidative R1-H/R2-H crosscoupling with hydrogen evolution is to achieve C-H/XH bond activation and hydrogen gas evolution at the same time. Thus, the development of novel catalytic systems is the key to realize this dream reaction pathway. In oxidative R1-H/R2-H cross-coupling reactions, CH/X-H bonds can be activated through transition metal catalysis12-13 or oxidation-induced bond activation.14-15 The major difference from traditional oxidative crosscoupling is the H2 elimination process. During the past few years, impressive achievements have been made by applying synthetic techniques including thermal transition metal catalysis16, photochemistry17 and electrochemistry18. Thermal H2 liberation of metal hydride, photoredox proton-reduction and cathodic protonreduction have all been used for the hydrogen evolution in oxidative R1-H/R2-H cross-coupling reactions. Con-

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sidering the fast development, it is necessary and significant to provide a conceptual understanding of this emerging area. With continuous interest in oxidative cross-coupling,3-4 we herein provide an overview of the recent developments of oxidative R1-H/R2-H crosscoupling with hydrogen evolution. This perspective focuses on the intermolecular oxidative R1-H/R2-H crosscoupling with hydrogen evolution. Instead of giving a comprehensive review, only representative examples in oxidative C-H/C-H or C-H/X-H cross-coupling will be discussed. The advantages and limitations by applying different synthetic techniques will also be discussed in this paper. OXIDATION-INDUCED FUNCTIONALIZATION EVOLUTION

OXIDATIVE C-H WITH HYDROGEN

Among the developed external chemical oxidant-free R1-H/R2-H cross-coupling reactions, transition metal catalysts are not required in most cases. Instead of metal-catalyzed C-H activation to afford C-M bonds, C-H bonds are usually activated by photochemical oxidation or electrochemical oxidation.14 Radicals, radical cations and cations can be generated through oxidation-induced C-H/X-H bond activation (eq. 1). This activation strategy enables the selective oxidative C-H functionalization of redox active substrates.

Oxidative C-H functionalization of arenes. Oxidative arene-arene cross-coupling provides a straightforward way for the construction of nonsymmetrical biaryls.19-20 In 2008, Kita and co-workers reported a singleelectron-transfer oxidation-induced oxidative crosscoupling between naphthalenes and mesitylenes by using a hypervalent iodine(III) reagent as the oxidant.21 Anodic single-electron-transfer oxidation of arenes provides an environmentally friendly way for activating aromatic compounds. Since 2010, Waldvogel and coworkers have investigated the electrochemical crosscoupling between phenols and electron-rich arenes (Scheme 2a).22 Different electron-rich arenes including phenyl ethers,23 phenols24-25 and thiophenes26 were subsequently applied to couple with phenols under undivided electrolytic conditions. Boron-doped diamond (BDD) anodes and hexafluoroisopropanol (HFIP) solvent were both important for achieving a good reaction efficiency with phenols. The key step in these transformations was the anodic oxidation of phenols to generate oxyl radicals. Moreover, the same group also reported the electrochemical oxidative cross-coupling among different aniline derivatives.27 By using a radical cation pool strategy, the Yoshida group was able to achieve the oxidative cross-coupling of two unactivated aromatic compounds

under divided electrolytic conditions (Scheme 2b).28 One aromatic compound was oxidized by anode to generate radical cation while another aromatic compound was added under non-oxidative conditions. Scheme 2. Electrochemical Oxidative Arene-Arene CrossCoupling

Despite of C-C bond formation, electrochemical anodic oxidation was also applied to C-X bond formation reactions. In 2017, Lei and co-workers reported an oxidative C-H/S-H cross-coupling between electron-rich arenes and aromatic thiols under undivided electrolytic conditions (Scheme 3a).29 Both of the substrates were found to be redox active under the standard conditions. The C-S bond was proposed to be formed through the radical/radical cross-coupling between an arene radical cation and a sulfur radical. More recently, Lei and coworkers reported an electrochemical oxidative C-H amination of unprotected phenols with phenothiazine derivatives (Scheme 3b).30 Since phenothiazine demonstrated lower oxidation potential than phenols, the amine substrates were likely to be firstly oxidized to generate radical cations during electrolysis. This transformation was established before by using chemical oxidants while either high reaction temperature or strong chemical oxidants were used.31-32 In comparison, the electrochemical method could be conducted at room temperature without the use of any sacrificial reagents. Moreover, the reaction was scalable at ambient conditions. Scheme 3. Electrochemical Oxidative C-H Thiolation and Amination

Arene radical cations could also be generated under photochemical conditions. In 2015, Nicewicz and coworkers reported the generation of arene radical cation in a visible-light-mediated oxidative C(sp2)-H amination of arenes with azoles.33 A dual catalytic system of an acridinium photoredox catalyst and 2,2,6,6tetramethylpiperidine-1-oxyl (TEMPO) was used to fa-


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cilitate the C-N bond formation. Oxygen was used as the terminal oxidant. To further avoid the issue of possible over oxidation by oxygen, Lei and co-workers described a similar oxidative C(sp2)–H amination of arenes with azoles without the use of terminal oxidants (Scheme 4a).34 They utilized a synergistic photoredox and protonreduction catalytic system. 9-Mesityl-10methylacridinium perchlorate was used as the photoredox catalyst for the oxidative activation of arene while a cobaloxime complex was used as the proton-reduction catalyst for hydrogen evolution. Similar with the work of Nicewicz, arene radical cation was proposed to be the key intermediate for C-N bond formation. Unfortunately, only azoles could be utilized as the amination source in C(sp2)-N bond formation. At the same time, Wu and coworkers also reported a photochemical oxidative C(sp2)H amination and hydroxylation of benzene with water and ammonia (Scheme 4b).35 Compared with the work of Lei, stronger photo catalysts (quinolinum ions) were used, which allowed the direct oxidative functionalization of benzene and electron-deficient arenes. Using a similar catalytic system, they were also able to achieve a photochemical oxidative etherification of benzene with alcohols.36

Heck-type reaction of electron-rich arenes with styrenes (Scheme 5c).40 Electron-rich arenes was proposed to act as nucleophiles in this transformation. Instead of oxidative activation of alkenes, the other coupling partner could also be activated in the oxidative C-H functionalization of alkenes. In 2016, Lei and co-workers also reported a sulfonylation of α-methyl-styrene derivatives with sulfinic acids (Scheme 5d).41 Eosin Y was used as the photocatalyst instead of acridines. As a consequence, sulfinic acids were found to be oxidized instead of alkenes. A series of allylic sulfones could be synthesized in good to high yields. Scheme 5. Photochemical Oxidative C-H Functionalization of Alkenes

Scheme 4. Photochemical Oxidative C-H Functionalization of Arenes

Oxidative C-H functionalization of alkenes. Nicewicz and co-workers have shown that alkene radical cations can also be generated by using acridinium photocatalysts.37 Since there was a lack of oxidation protocols, they were only able to achieve the hydrofunctionalization and difunctionalization of alkenes. In 2016, Lei and co-workers reported an anti-Markovnikov oxidation of alkenes with H2O as the oxygenation source under external chemical oxidant-free conditions (Scheme 5a).38 Similar with their work on photochemical oxidative C-H functionalization of arenes, a synergistic photoredox and proton-reduction catalytic system was applied. C-O bonds were formed through the nucleophilic addition of water to the in situ generated alkene radical cation. Using alcohols or azoles instead of water, they were also able to synthesize multi-substituted enol ether derivatives and N-vinylazoles from simple alkenes under similar reaction conditions (Scheme 5b).39 Importantly, this reaction strategy was also applicable to the oxidative

Oxidative C-H functionalization of aldehydes. Scheidt42 and Studer43 studied the N-heterocyclic carbene-catalyzed oxidative esterification between aldehydes and alcohols in the presence of chemical oxidants including MnO2 and quinone. In 2012, Boydston and coworkers reported a N-heterocyclic carbene-catalyzed oxidative esterification between aldehydes and alcohols under undivided electrolytic conditions (Scheme 6a).44 Instead of oxidation by chemical oxidants, anodic oxidation of the in situ generated Breslow intermediate was the key for this electrochemical transformation. Electrophilic 2-acylazolium species were proposed to be formed. By using thiols instead of alcohols, they were also able to synthesize a series of thioesters.45 As for the synthesis of amides, they needed to prepare the Breslow intermediate at first since amines could directly react with aldehydes in the presence of N-heterocyclic carbenes. In a flow reaction system, they were able to pre-



pare amides in high reaction yields (Scheme 6b).46 Obviously, stoichiometric amount of N-heterocyclic carbene was required in this transformation. Scheme 6. Electrochemical N-Heterocyclic CarbenePromoted Oxidative Esterification and Amidation with Aldehydes

Oxidative C(sp3)-H functionalization. In 2007, Jørgensen and co-workers reported an organocatalytic enantioselective α-arylation of aldehydes with quinones.47 Since quinones could be synthesized from corresponding phenols by electrochemical oxidation, the same group reported the combination of electrochemical oxidation and chiral amine catalysis in the asymmetric oxidative cross-coupling between aliphatic aldehydes and protected 4-aminophenols (Scheme 7a).48 Anodic oxidation of 4-aminophenols and enamine activation of aliphatic aldehydes by chiral amine catalyst worked synergistically for the asymmetric C(sp3)-C(sp2) bond formation. It has been reported that tertiary amines can be oxidized by chemical oxidants to generate iminium cation intermediates.49 By using a similar reaction strategy with Jørgensen, Luo and co-workers achieved the asymmetric oxidative C(sp3)-H/C(sp3)-H cross-coupling between aliphatic ketones and tertiary amines (Scheme 7b).50 Tentative mechanism involved anodic oxidation of tertiary amines and enamine activation by a primary chiral amine catalyst.

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Great achievements have been made on the photoinduced oxidative C(sp3)-H of tertiary amines in the presence of chemical oxidants.51-55 By using a dual catalytic system, Wu and co-workers reported the first photo-induced oxidative C(sp3)-H/C(sp2)-H cross-coupling of tertiary amines with indoles under external chemical oxidant-free conditions (Scheme 8a).17 Eosin Y was used as a photoredox catalyst and graphene-supported RuO2 was used as a proton-reduction catalyst. Hydrogen gas was produced as the only byproduct in quantitative yields. Later on, they found that a homogenous protonreduction catalyst, Co(dmgH)2Cl2, was able to replace graphene-supported RuO2 for the same transformation (Scheme 8a).56 In both cases, photocatalyst would deliver electrons to proton-reduction catalyst after reductive quenching. Synergistic cooperation of substrate oxidation and proton-reduction was the key for the success of this reaction. An iminium cation intermediate was proposed to be generated during the reaction. Besides tertiary amines, the same group expanded the method to the oxidative C(sp3)-H/C(sp2)-H cross-coupling with benzylic ethers.36 In a collaborative study by Wu and Luo, a visible-light-promoted asymmetric C(sp3)-H/C(sp3)-H cross-coupling of tertiary amines with ketones was achieved by using a synergistic multiple catalytic system (Scheme 8b).57 Despite of photoredox catalyst and proton-reduction catalyst, a primary chiral amine catalyst was used for the enamine activation of ketones. The mild reaction conditions enabled high chemoselectivity and regioselectivity in the C(sp3)-C(sp3) bond formation. Scheme 8. Photochemical Oxidative C-H/C-H CrossCoupling with Tertiary Amines cat. eosin Y 1 cat. G-ReO2 or R Co(dmgH)2Cl2

H R1

(a)

N

Ar+

H

R2 N R3 2.0-3.0 equiv

Ar

2

R

N R3

R4

up to 98% yield n Pr Nn Pr

cat.

Scheme 7. Electrochemical Asymmetric Oxidative C-H/CH Cross-Coupling

N

R4 H2O or CH3CN/H2O, r.t. green LEDs

O

R1

(b)

N H

Ar

+

H

3

R 2

R

3.0 equiv

NH2

R1

N Ar O cat.Ru(bpy)3Cl2 6H2O R2 cat. Co(dmgH)2Cl2 R3 CH3CN, - 10 C blue LEDs up to 92% yield, 99% ee (10 mol%)

Besides C-C bond formation, considerable efforts were paid to C-N bond formation reactions. In 2016, Zeng, Sun and co-workers reported an electrochemical oxidative cross-coupling of aliphatic ketones with amines (Scheme 9a).58 Actually, the same reaction was achieved by the using NH4I as the catalyst and sodium percarbonate as the oxidant.59 In the electrochemical transformation, NH4I was used as a redox mediator. A series of α-amino ketones could be synthesized in moderate to good yields. Mechanistic studies revealed that αiodination of ketone was the key step for the C-N bond ACS Paragon Plus Environment

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formation. In the same year, Huang and Gong developed an electrochemical oxidative C-H/N-H cross-coupling between γ-lactams and anilines. No redox mediator was used in this transformation and an iminum cation was found to be the key intermediate for C-N bond formation. Next year, Lei and co-workers reported an electrochemical oxidative C(sp3)-H amination with azoles under undivided electrolytic conditions (Scheme 9c).61 C(sp3)−H bonds adjacent to oxygen, nitrogen, sulfur, benzyl and allyl groups were all suitable in this transformation. Different from the work of Huang, nitrogen radicals were proposed to be generated through direct anodic oxidation.

R1 H +

H

cat. [M]

R2

R1

R2 +

H2

or (heat)

(electricity)

(a) Thermal H2 liberation of metal hydride (b) Electrochemical recycling of metal catalyst R1 H

[M]

H2

H2

H+

H+

R1

H [M]

R1

H+

R1 H

[M] -

+ H+

- 2 e-

H+

[M]

R1

H [M] R2

H

R2

R1

R2

H

[M]

R2

3

Scheme 9. Electrochemical Oxidative C(sp )-H Amination

TRANSITION-METAL-DIRECTED C-H TO C-M AND OXIDATIVE FUNCTIONALIZATION WITH HYDROGEN EVOLUTION

Oxidation-induced C-H/X-H bond activation is only applicable to the oxidative cross-coupling with redox active substrates. In order to deal with redox inactive substrates, it is necessary to develop transition-metaldirected C-H to C-M and oxidative functionalization with hydrogen evolution. A big challenge in this transformation is to recycle the transition metal catalysts without the use of external chemical oxidants. Up to now, thermal H2 liberation of metal hydride (Scheme 10a) and electrochemical recycling of metal catalyst (Scheme 10b) have been used for achieving this goal. We will discuss the representative reports of these two reaction strategies in this section. Scheme 10. Transition-Metal-Directed Oxidative R1-H/R2H Cross-Coupling with Hydrogen Evolution

Oxidative C(sp3)-H functionalization. Esterification and amidation are among the most fundamental transformations in chemistry.62 Traditional methods for synthesizing esters and amides largely depend on nucleophilic substitution to obtain carboxylic acid derivatives. In most cases, the carboxylic acid derivatives used in esterification and amidation are acyl halides and anhydrides which are synthesized by multiple steps. In comparison, alcohols and aldehydes are readily available substrates. In 2005, Milstein and co-workers developed a ruthenium-catalyzed reaction system for the selfesterification of primary alcohols with hydrogen evolution.63 A dearomatized PNP-Ru complex was used as the catalyst. The alcohol was activated by the dearomatized PNP-Ru complex and an aromatized complex was formed. A ruthenium hydride complex could be generated through β-H elimination. Hydrogen gas could be released from the generated ruthenium hydride complex upon heating. By using the aromatizationdearomatization strategy, the same group reported a ruthenium-catalyzed oxidative cross-esterification between primary alcohols and secondary alcohols in 2012 (Scheme 11a).64 In order to achieve a good reaction selectivity, 2.5 equiv of secondary alcohol was required. Besides oxidative esterification, they also applied this reaction strategy to achieve the oxidative amidation between primary alcohols and primary amines (Scheme 11b).65 Notably, excellent reaction selectivity and efficiency could be achieved with 1:1 ratio of alcohols and amines. After this pioneering work with ruthenium catalysis, Milstein and co-workers also utilized manganese as the metal center for the oxidative amidation between alcohols and amides.66 Another way for directly converting amines to amides is the oxygenation of aliphatic amines. In 2014, Milstein and co-workers reported the synthesis of lactams from cyclic amines with water as the oxygenation source (Scheme 11c).67 An acridinebased PNP-Ru complex was used as the catalyst. Mechanistic studies indicated that the actual catalyst was the dearomatized form of the precatalyst.68 Coordinated imine was proposed to be generated through β-H elimi-



nation. Water not only acted as the oxygenation source but also played a role in catalyzing the H2 evolution. Scheme 11. Ruthenium-Catalyzed Oxidative Esterification and Amidation PtBu2

cat. H H

(a)

1

R

R3

+

OH

R

toluene, reflux

2.5 equiv

R3

O

(0.1 mol%) 2

HO

H Ru CO N

R1

O

R2

up to 98% yield

PtBu2 cat. H H

(b)

1

R

R3

+

OH

R2

H2N

H Ru CO NEt2 (0.1 mol%)

toluene, reflux

1.0 equiv

R

n

N H

H H

+

H

O

large excess

N H

R2

PiPr2 Cl N Ru CO H PiPr2 (1-5 mol%)

H

R

up to 99% yield

cat.

(c)

R3

O 1

dioxane, 150 C

n

O

R

Besides electrochemical recycling of metal catalysts, acid could also promote the recycling of metal catalysts in oxidative Heck reactions. In 2016, Jeganmohan reported a ruthenium-catalyzed oxidative Heck reaction of aromatic amides, ketoximes and anilides (Scheme 13a).72 Interestingly, hydrogen gas could be detected by GC under room temperature. Mechanistic study indicated that acetic acid could react with ruthenium hydride generated after β-hydride elimination to form H2. Later on, Dong and co-workers reported a similar strategy for rhodium-catalyzed oxidative Heck reaction of 7azaindoles (Scheme 13b).73 In both cases, stoichiometric amount of acetic acid was used to recycle the metal catalysts.

N H up to 85% yield

Oxidative C(sp2)-H functionalization. Oxidative Heck reaction has been well established by using the combination of transition metal catalysis and oxidants.69 In 2007, Jutand and co-workers reported an electrochemical palladium-catalyzed oxidative Heck reaction of N-acetylanilines (Scheme 12a).70 Instead of using stoichiometric amount of benzoquinone to recycle the palladium catalyst, they used a catalytic amount of benzoquinone in a divided cell. The hydroquinone generated after each catalytic cycle was oxidized by anode to regenerate benzoquinone. At the same time, protons were reduced at the nickel foam cathode to release hydrogen gas. More recently, Ackermann and co-workers reported an electrochemical rhodium-catalyzed oxidative Heck reaction of benzoic acids (Scheme 12b).71 Instead of using redox mediators, rhodium catalyst was directly recycled by anodic oxidation in a simple undivided cell. In these two cases, anodic oxidation both played a key role in the recycling of metal catalysts. Scheme 12. Electrochemical Oxidative Heck Reaction

Scheme 13. Acid-Promoted Oxidative Heck Reaction

Electrochemical recycling of cost-efficient cobalt catalyst in oxidative C(sp2)-H functionalization of arenes has also been explored. Actually, a big problem for cobalt-catalyzed oxidative C-H functionalization is that stoichiometric amount of high-valent metal salts especially silver salts and manganese salts are generally required to recycle the cobalt catalysts.74-79 For example, Song and co-workers have achieved the cobalt-catalyzed oxidative C(sp2)-H etherification and amination by using silver salts as oxidants.78-79 In 2017, Ackermann and coworkers reported an electrochemical cobalt-catalyzed CH etherification of phenyl amides with aliphatic alcohols (Scheme 14a).80 The reactions could be conducted both in divided and undivided cells. The cobalt catalyst was directly recycled by electrochemical anodic oxidation during electrolysis. Later on, they also achieved the electrochemical cobalt-catalyzed C-H amination of aromatic amides with cyclic secondary amines (Scheme 14b).81


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Renewable g-valerolactone (GLV) was found to be the optimized solvent for the amination reaction. Almost at the same time, Lei and co-workers reported an electrochemical cobalt-catalyzed oxidative C-H amination of aromatic amides with secondary amines (Scheme 14c).82 The major difference with the work of Ackermann group was that inexpensive carbon cloth anode and nickel plate were used instead of reticulated vitreous carbon (RVC) anode and platinum plate cathode. Scheme 14. Electrochemical Cobalt-Catalyzed Oxidative C-H etherification and Amination

Electrochemistry, direct anodic oxidation or anodic oxidation promoted transition metal catalysis is used for CH/X-H bond activation while cathodic reduction of protons can release hydrogen gas; 3) Thermal transition metal catalysis, the same transition metal is used both for C-H/X-H bond activation and hydrogen evolution. Due to the diversity of catalytic systems, photochemistry and electrochemistry are applicable to a lot of oxidative R1-H/R2-H cross-coupling reactions. Hopefully, further developments in new catalytic systems will allow oxidative R1-H/R2-H cross-coupling with hydrogen evolution to take the place of oxidative R1-H/R2-H cross-coupling reactions using oxidants. AUTHOR INFORMATION Corresponding Author

*[email protected] ORCID

Aiwen Lei: 0000-0001-8417-3061 Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS ACKNOWLEDGMENTS

CONCLUSION Oxidative R1-H/R2-H cross-coupling with hydrogen evolution provides an environmentally friendly way for the construction of new chemical bonds. Due to the fast development of synthetic techniques especially photochemistry and electrochemistry, this dream reaction pathway has been proven to be feasible for selective bond formation. No sacrificial reagent is required and hydrogen gas is produced as the only byproduct. Moreover, good functional group tolerance can be achieved in the cross-coupling reaction since no external chemical oxidant is used. This environmentally friendly synthetic strategy is one of the future directions in organic synthesis. Increasing attention has been paid to this emerging research area. The key in this synthetic strategy is to achieve C-H/XH bond activation and hydrogen gas evolution in a single reaction system. In the developed methods, C-H/X-H bonds are activated either by oxidation-induced bond activation or by transition metal catalysis. At the same time, hydrogen gas can be liberated by thermal H2 elimination of metal hydride, photoredox proton-reduction or cathodic proton-reduction. Based on the types of energy sources applied, three reaction protocols have been utilized in oxidative R1-H/R2-H cross-coupling with hydrogen evolution: 1) Photochemistry, a photoredox catalyst is used for C-H/X-H bond activation while a protonreduction catalyst is used for hydrogen evolution; 2)

This work was supported by the National Natural Science Foundation of China (Grants 21390402 and 21520102003) and the Hubei Province Natural Science Foundation of China (Grant 2017CFA010). The Program of Introducing Talents of Discipline to Universities of China (111 Program) is also appreciated. This paper is dedicated to Professor Xiyan Lu on the occasion of his 90th birthday.

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R2-H Cross-Coupling with Hydrogen Evolution

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