Over the past several years, a fourth-generation oxidative cross-coupling strategy has been developed, which can construct C-C and C-X (X = heteroatom) bonds directly under external oxidant-free conditions and release hydrogen gas as the sole side product. Because of the thermodynamics difficulty of the loss of H2 in this reaction, input of external energy is required to provide a thermodynamic driving force. Based on the source of external energy in the cross-coupling reactions, the fourth-generation oxidative coupling reactions can be divided mainly into three types in this text, including thermal energy-driven cross-coupling reactions, visible-light-mediated cross-coupling reactions, and electrochemical dehydrogenative reactions.
Thermal energy Light energy Electrical energy Catalysis Hydrogen evolution oxidant-free
In the last chapter, we introduced the direct construction of a C-C or C-X (X = heteroatom) bond from two different C-H/C-H or C-H/X-H bonds via oxidative cross-coupling reactions. However, an external oxidant needs to be present in the system to remove excess protons and electrons generated during the formation of the C-C or C-X bond. To obviate the need for sacrificial oxidants and realize a more sustainable coupling reaction mode, a fourth-generation oxidative cross-coupling strategy has been developed in recent years, which is oxidant-free and yields hydrogen (H2) gas as the only by-product  (Scheme 5.1). This transformation is an ideal green coupling reaction process; however, the loss of H2 in this reaction is usually thermodynamically unfavorable. Therefore, input of external energy, including thermal energy, light energy, or electrical energy, is required to provide a thermodynamic driving force. In this chapter, we summarize the impressive progress of fourth-generation oxidative coupling reactions, which is divided into three parts: (1) thermal energy-driven cross-coupling reactions with H2 evolution, (2) visible-light-mediated cross-coupling reactions with H2 evolution, and (3) electrochemical dehydrogenative reactions with H2 evolution.
5.1 Thermal Energy-Driven Cross-Coupling Reactions with H2 Evolution
An oxidant-free Heck-type cross-coupling reaction between a vinyl C-H bond and X-H bond (X = carbon or heteroatom) with H2 evolution is a typical example of a thermal energy-driven cross-coupling reaction. A general mechanism of this reaction is shown in Scheme 5.2. The pathway begins with X-H activation to generate intermediate B via a deprotonation process. The subsequent insertion of an alkene into the M-X bond leads to the formation of alkyl metal complex C. The following β-H elimination of complex C leads to the target cross-coupling product and generates the metal hydride species D. Finally, intermediate D reacts with a proton to regenerate catalytically active species A along with the release of H2 gas. Based on this strategy, the following two types of reactions were realized under oxidant-free conditions: (1) construction of heterocyclic compounds with formation of both C-C and C-X bonds, which has been used to synthesize N- and O-containing heterocyclic compounds and (2) direct functionalization of C(sp2)-H bonds, including alkenylation, aromatization, and phosphorylation.
5.1.1 Construction of Heterocyclic Compounds
220.127.116.11 Synthesis of N-Containing Heterocyclic Compounds
In 2014, Wang’s group developed the annulation of imines and alkynes by C-H/N-H activation under oxidant-free conditions  (Scheme 5.3). In this work, isoquinolines were produced in good yields along with H2 gas as the sole by-product in the presence of manganese catalyst [MnBr(CO)5] at 105 °C.
To probe the mechanism, five-membered manganacycle 3a was prepared using stoichiometric amounts of [MnBr(CO)5] and imine 1a. Treatment of 3a with alkyne 2 generated annulation product 4a. Moreover, a catalytic amount of 3a promoted the annulation of imine 1a and alkyne 2 in good yield. These results suggested the involvement of species 3a in the catalytic cycle  (Scheme 5.4).
The above mechanistic study allowed a plausible mechanism to be proposed, as shown in Scheme 5.5. Cyclomanganation between imine 1 and catalyst [MnBr(CO)5] afforded species 3. Coordination of 2 to complex 3 and subsequent alkyne insertion led to reaction intermediate 6, which directly afforded isoquinolines 4 and manganese hydride species 7. There are two possible pathways for this process: (1) the σ-bond metathesis between C(sp2)-Mn and N-H bonds in species 6 leading to 4 and manganese hydride species 7 and (2) oxidative addition of the N-H bond followed by C-N reductive elimination to provide 4 and 7. Finally, complex 7 combined with 1 and then regenerated complex 3 along with the release of H2.
Later on, Li’s group developed a similar annulation reaction of imines and alkynes using a ruthenium (Ru) catalyst (Scheme 5.6). Primary mechanistic investigations suggested that the sequence of the reaction pathway involves C-H activation, alkyne insertion, and σ-bond metathesis .
Very recently, Zhang’s group developed an oxidant-free cobalt-catalyzed spiro annulation of maleimides with benzimidates to construct five-membered N-containing benzospirocyclic compounds  (Scheme 5.7). The pathway began with C-H activation to form cobaltacyclic intermediate 14 from species 13, which was generated by ligand exchange between catalyst 12 and AgOTf. The subsequent insertion of maleimide into the Co-C bond gave intermediate 15. Alkenylated product 16 and cobalt species 17 were then generated through elimination. The following aza-Michael addition of 16 gave the spirocyclic product 11. Finally, H2 gas was released by the reaction of species 17 with HOTf, and the active cobalt species 13 was regenerated.
18.104.22.168 Formation of O-Containing Heterocyclic Compounds
The benzofuran ring is an important structural motif in bioactive molecules and natural products. Existing strategies to synthesize benzofurans are limited in their scope and sustainability. In 2016, Liu’s group reported a dehydrogenative coupling of intramolecular C(sp2)-H bonds and phenolic hydroxyl groups through palladium metal (Pd(0))-catalyzed C-H bond functionalization, which could synthesize benzofurans from ortho-alkenylphenols in one step along with the release of H2 gas as the only by-product (Scheme 5.8) .
As shown in Scheme 5.9, the mechanism of this transformation is similar to a Heck reaction. The oxidative addition of Pd(0) with an O-H bond provided the Pd(II) intermediate 19, and then the migratory insertion of a C-C double bond into the Pd-O bond led to the formation of complex 20. After the subsequent β-H elimination of 20, the formation of the target benzofuran and palladium hydride species was realized. Finally, the Pd(0) species was regenerated along with the release of H2 via the reductive elimination of the HPdH complex.
5.1.2 Functionalization of Unsaturated C-H Bonds
22.214.171.124 Direct Alkenylation of Aromatic C-H Bonds
In 2015, Jeganmohan and co-workers described a Ru-catalyzed ortho alkenylation of aromatics with alkenes in the presence of AgSbF6 and CH3COOH. It is noteworthy that no oxidant was used in this reaction, and H2 gas was produced. The results of deuterium labeling experiments revealed that one hydrogen atom of the produced H2 gas came from CH3COOH and the other one originated from a ruthenium hydride species  (Scheme 5.10).
The proposed mechanism for this reaction is as follows  (Scheme 5.11). This transformation was initiated by C-H activation to form five-membered ruthenacycle intermediate 27 from cationic species 32, which was generated by ligand exchange between precatalyst 25 and AgSbF6. Coordinative insertion of alkene 28 into the Ru-C bond led to intermediate 29. Subsequent β-H elimination of 29 afforded target product 30 and ruthenium hydride species 31. Finally, species 31 reacted with AcOH, releasing H2 gas and regenerating the catalytically active species 32. The oxidation state of the metal did not change during the whole catalytic reaction process.
In 2016, Dong’s group reported a rhodium (Rh)-catalyzed H2-releasing ortho-alkenylation of N-aryl-substituted 7-azaindoles without the need for an oxidant (Scheme 5.12) . The reaction mechanism is similar to that of the above Ru-catalyzed ortho-alkenylation reaction .
126.96.36.199 Aromatization of Aromatic C-H Bonds
Biheteroaryl skeletons are widely distributed in many natural products, functional materials, and dyes. In general, biheteroaryl compounds are synthesized by transition metal-catalyzed cross-coupling of heteroaryl halides or pseudohalides with organometallic reagents. However, these methods require prefunctionalization of substrates and produce stoichiometric amounts of hazardous by-products. Very recently, Zhang’s group developed an H2-evolving cross-coupling between the β-site of indoles/pyrrole and the α-site of N-heteroarenes, which could efficiently generate N-containing biheteroarenes using an iridium (Ir) catalyst without the need for an external oxidant  (Scheme 5.13).
188.8.131.52 Phosphorylation of Aromatic C-H Bonds
In 2014, Yang’s group reported a copper-catalyzed phosphorylation of indoles with Ph2P(O)H to synthesize 3-phosphoindoles, which showed excellent bioactivity against NNRTI-resistant HIV-1 in vitro (Scheme 5.14) . The proposed reaction path followed the general mechanism for the dehydrogenative coupling reaction, as shown above (Scheme 5.2).
5.2 Visible-Light-Mediated Cross-Coupling Reactions with H2 Evolution
Another type of oxidant-free dehydrogenative cross-coupling reaction is those driven by light energy. This strategy allows the construction of a C-C or C-X bond directly from C-H and X-H bonds in the presence of photosensitizers and hydrogen-evolution catalysts (HEC) and is named the cross-coupling hydrogen evolution (CCHE) process. Compared with thermal energy-driven reactions, methodology using visible-light activation is more general and environmentally benign.
As shown in Scheme 5.15, the initial step of this transformation is an intermolecular photo-induced electron transfer process from R-H to the excited state photosensitizer, resulting in the formation of electron transfer state [PC]•− and cation radical [R-H]•+. The generated [R-H]•+ further releases a proton and electron to produce a cation intermediate [R]+. Nucleophilic addition to [R]+ gives the cross-coupling product. The radical anion [PC]•− is restored to its ground state by reacting with HEC+ and produces an HEC intermediate. Further reduction of HEC by [R-H]•+ leads to the formation of HEC•−, which reacts with a proton to afford HEC+-H. Protonation of HEC+-H finishes the H2 evolution process and completes this catalytic cycle. The photosensitizer can be a Ru(II), Pt(II), Ir(III)-based complex, organic dye, or other chromophore. HECs including graphene-supported RuO2 nanocomposites and cobaloximes have been reported . The CCHE reaction is a very efficient and sustainable method to construct different C-C and C-X bonds. The recent advances of CCHE reactions are summarized in the following two parts: (1) C-C cross-coupling via CCHE reactions, including C(sp3)-C(sp3), C(sp3)-C(sp2), and C(sp2)-C(sp2) bond formation reactions, and (2) C-X cross-coupling via CCHE reactions, including C-S, C-N, C-O, and C-P bond formation reactions.
5.2.1 Carbon-Carbon Cross-Coupling
The design of efficient, mild, and general methods for C-C bond construction is an essential topic in organic chemistry. In an ideal C-C cross-coupling reaction via the CCHE process, visible light could activate two different C-H bonds to form a C-C bond directly and afford H2 gas as the only by-product at ambient temperature without an oxidant.
184.108.40.206 C(sp3)-C(sp2) Cross-Coupling Reactions
In 2013, Wu’s group reported the first example of a visible-light-driven CCHE reaction : the direct cross-coupling reaction of N-phenyl-1,2,3,4-tetrahydroisoquinoline (1) and indole (2) promoted by visible light in the absence of any oxidant. In this work, the organic dye eosin Y was used as a photosensitizer to trigger this dehydrogenative cross-coupling reaction. A graphene-supported RuO2 nanocomposite (G-RuO2) was employed as a HEC to remove the extra electrons and protons generated in the bond formation process. Optimization of the reaction conditions revealed that water was better than other solvents for this reaction. This is because water provided more protons than other solvents for H2 evolution from the metal hydride intermediate (Scheme 5.16).
To identify the proton source of H2 in this reaction, a deuterium labeling experiment was carried out. When D2O was used as the solvent, D2 was generated as the sole gas-phase product instead of H2, which suggested that the protons released from substrates exchanged quickly with D2O. The kinetic isotope effect was then investigated by competition experiments. The experimental results suggested that the benzylic C-H bond of compound 42 cleavage was the rate-limiting step for this reaction. In addition, the electron transfer process from [eosin Y]•− to G-RuO2 was demonstrated by a flash photolysis study (Scheme 5.17).
On the basis of the above results, a mechanism for this reaction was proposed, as shown in Scheme 5.18 First, eosin Y was excited to its singlet excited state 1eosin Y* under visible-light irradiation, which quickly transformed to the triplet state 3eosin Y*. Subsequent electron transfer from 42a to 3eosin Y* generated the radical anion [eosin Y]•− and radical cation A. Following release of a proton and further oxidation, radical cation A afforded iminium ion intermediate B. Subsequent nucleophilic addition to B afforded the target cross-coupling product C. The radical anion [eosin Y]•− was oxidized to its ground state by G-RuO2 in water, and the electron and proton transfer catalyzed by G-RuO2 led to a simultaneous H2 evolution process.
Subsequently, the same group developed a base metal-catalyzed homogeneous visible-light-driven CCHE reaction for the same transformation  (Scheme 5.19). In this work, the heterogeneous noble metal HEC G-RuO2 was replaced by base metal complex Co(dmgH)2Cl2, and eosin Y was used as a photosensitizer. The 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.
220.127.116.11 C(sp3)-C(sp3) Cross-Coupling Reactions
Wu’s group expanded the substrate scope from tertiary amines to secondary amines  (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. 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  (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).
18.104.22.168 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  (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).
5.2.2 Carbon-Heteroatom Cross-Coupling Reactions
22.214.171.124 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 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 .
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, 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 .
126.96.36.199 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, 18, 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  (Scheme 5.30). This sustainable methodology generated H2 gas as the sole by-product without the need for a sacrificial oxidant .
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−.
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 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) .
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  (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) . 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  (Scheme 5.36).
188.8.131.52 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 .
5.3 Electrochemical 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 . 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.
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 . 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  (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  107 (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 phenanthridine product was produced  (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 . 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  (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  (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 conditions . 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  (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  (Scheme 5.46). C-S bond formation products were obtained in isolated yields of up to 99% from 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  (Scheme 5.47).
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.
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 . 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  (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  (Scheme 5.50).
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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