Nickel-Catalyzed Reductive Cross-Couplings: New Opportunities for Carbon–Carbon Bond Formations through Photochemistry and Electrochemistry

Open AccessCCS ChemistryMINI REVIEW1 Jan 2022Nickel-Catalyzed Reductive Cross-Couplings: New Opportunities for Carbon–Carbon Bond Formations through Photochemistry and Electrochemistry Liang Yi†, Tengfei Ji†, Kun-Quan Chen, Xiang-Yu Chen and Magnus Rueping Liang Yi† Institute of Organic Chemistry, RWTH Aachen University, Aachen 52074 †L. Yi and T. Ji contributed equally to this work.Google Scholar More articles by this author , Tengfei Ji† Institute of Organic Chemistry, RWTH Aachen University, Aachen 52074 †L. Yi and T. Ji contributed equally to this work.Google Scholar More articles by this author , Kun-Quan Chen School of Chemical Sciences, University of the Chinese Academy of Sciences, Beijing 100049 Google Scholar More articles by this author , Xiang-Yu Chen *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] School of Chemical Sciences, University of the Chinese Academy of Sciences, Beijing 100049 Google Scholar More articles by this author and Magnus Rueping *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] King Abdullah University of Science and Technology (KAUST), Thuwal 23955 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202101196 SectionsAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Metal-catalyzed cross-electrophile couplings have become a valuable tool for carbon–carbon bond formation. This minireview provides a comprehensive overview of the recent developments in the topical field of cross-electrophile couplings, provides explanations of the current state-of-the-art, and highlights new opportunities arising in the emerging fields of photoredox catalysis and electrochemistry. Download figure Download PowerPoint Introduction Carbon–carbon bond formations have always been one of the most useful reactions in both industry and academia and have gained considerable attention from many synthetic chemists who developed novel strategies to achieve improved and sustainable transformations. Transition metal catalysis has continually provided new activation modes for C–C bond formations1–5 and fascinated synthetic chemists for a long time. Many named reactions have been associated with transition metal catalysis and become a powerful method for the cross-couplings of electrophiles with organometallic nucleophiles (Scheme 1a). Despite this progress, the use of organometallic reagents can cause undesired side reactions and chemical wastes. Alternatively, cross-nucleophile coupling has been developed as an efficient method for the synthesis of synthetically and biologically important compounds (Scheme 1b).6–8 However, the lower availability of carbon nucleophiles represents a limitation. Recently, transition metal-catalyzed cross-coupling reactions between two bench stable electrophiles under reductive conditions have emerged as a powerful tool for the construction of C–C bonds. In particular, nickel (Ni) catalysts, characterized by low reduction potential and electronegativity, can undergo rapid oxidative addition.9 As such, it is not surprising that nickel-catalyzed reductive cross-coupling represents a flourishing area in organic chemistry with characteristic advantages over classical synthesis, such as widely available carbon electrophiles and avoiding unstable organometallic reagents and time-consuming and costly prefunctional processes. Scheme 1 | (a–c) Transition metal-catalyzed cross-coupling. Download figure Download PowerPoint Thus, there has been significant progress in the development of new cross-electrophile couplings for constructing C–C bonds. The first example of cross-electrophile coupling was published about 100 years ago by Wurtz10 and Tollens and Fittig11 using sodium metal as the reductant and mediator for the cross-coupling of aryl halides with alkyl halides. Stoichiometric sodium metal and high temperatures are needed. Therefore, the functional group tolerance and application of this method are limited. Another classical cross-electrophile coupling strategy is electrosynthesis. Early explorations of electroreductive nickel-catalyzed cross-coupling include the cross/homo-coupling of organic halides, acyl, and carboxylation reductive cross-couplings.12 However, electroreductive cross-couplings can be difficult to achieve and specialized laboratory equipment is required. These limitations have restricted the further development of this method for the formation of C–C bonds for several years. However, electrosynthesis has recently seen a renaissance and emerged as a useful tool for reductive cross-couplings. The most popular strategy of reductive cross-coupling reactions is the combination of nickel catalysis and metallic reducing agents and number of nickel-catalyzed cross-electrophile couplings have been developed using Mn or Zn as reductants.13–20 Despite its success, in addition to scalability and efficiency problems, the utility of metal powders inevitably produces excess waste. Thus, photochemical alternatives for reductive cross-coupling reactions have been developed. Recently, impressive achievements have been made by merging nickel catalysis with photo- and electrochemistry to create new activation modes and avoid the use of metal powders. Considering the advantages of nickel-catalyzed cross-electrophile coupling for C–C bond construction, it is important to provide a conceptual understanding of this emerging area (Scheme 1c). Against this background, we attempt to give an overview of the current state-of-the-art of cross-electrophile couplings and highlight the new developments of reductive catalysis pathways. Alkyl–Aryl Reductive Cross-Coupling Nickel/metallic reducing agent system The viability of alkyl-aryl cross-coupling via the combination of transition metal catalysis and metallic reducing agents was initially demonstrated by the research groups of Durandetti,21 Lipshutz,22 and Wangelin23 (Scheme 2). Specifically, Durandetti and co-workers21 described an efficient nickel-catalyzed cross-coupling of aryl halides and α-chloroesters, as well as the Refortmatsky reaction in the presence of manganese as the reducing metal. Lipshutz and co-workers22 investigated the participation of zinc in palladium-catalyzed cross-coupling of alkyl halide and aryl bromide, and Wangelin and co-workers23 reported cobalt-catalyzed cross-coupling of aryl and alkyl halides. These early examples demonstrated the potential of the combined transition metal/reducing metal systems as a useful tool to construct C–C bonds under milder conditions. Scheme 2 | Early examples reporting the use of metallic reducing agents in transition metal catalysis. Download figure Download PowerPoint More recently, reductive cross-electrophile coupling was more widely recognized as a general concept and emerged as an actively researched and exciting area of transition metal catalysis. In 2010, Weix and co-workers24 developed a Ni/Mn system for the selective cross-coupling of equimolar quantities of alkyl and aryl halide. High cross-selectivities were achieved using both a bipyridyl and a phosphine ligand (Scheme 3a). Scheme 3 | (a–c) Overview of nickel-catalyzed alkyl–aryl reductive cross-couplings. Download figure Download PowerPoint In the developed protocol, stoichiometric organometallic reagents were not required, and a broad range of alkyl and aryl halides were tolerated. As a drawback, the use of secondary alkyl bromides resulted in mixed isomer products. Nevertheless, the direct reductive cross-coupling of alkyl halides with aryl halides without the formation of intermediate organomanganese species demonstrated the utility of this synthetic protocol. Regarding the mechanism (Scheme 3b), it is postulated that in the first key step the selective oxidative addition of aryl halides to low valent Ni(0) generates the Ar–Ni(II) intermediate I. Subsequent radical addition affords the Ar–Ni(III)–R species II. Finally, the reductive elimination of II affords the desired product and generates a Ni(I) species III, which could produce the alkyl radical from the alkyl halides via single-electron transfer (SET) or halogen-atom abstraction. Reduction of the Ni(I) species III by Mn finishes the catalytic cycle. Concurrently, similar results using cobalt/phosphine catalytic systems were disclosed by Amatore and Gosmini25 with electron-deficient aryl bromides. After these studies, great efforts from many research groups have focused on the different alkyl electrophiles for nickel-catalyzed reductive cross-couplings (Scheme 3c).26–38 Notably, Molander and co-workers39,40 successfully expanded this strategy for the installation of alkyl fragments onto pharmaceutically relevant heterocyclic motifs. A variety of secondary aliphatic halides or tosylates underwent the reductive cross-coupling reaction in moderate to good yields, furnishing substituted heteroaromatic compounds. Despite these achievements, the use of alkylamines, which are abundant natural feedstocks, had not been realized until more recently. In 2017, Watson and co-workers41 first reported the Suzuki–Miyaura cross-coupling of aryl boronic acids, employing Katritzky salts as C-centered-radical precursors. Very recently, the groups of Rueping,42 Watson,43 Martin,44 and Han45 independently applied Katritzky salts in nickel-catalyzed reductive cross-couplings of aryl halides. In these cases, Mn and Zn were employed as the optimal stoichiometric reductants and elevated temperatures were usually required. Notably, Han’s Ni/Zn system enabled wider substrate scope including bromoalkynes and alkyl bromides. Although the nickel-catalyzed reductive cross-couplings of aryl halides with primary or secondary electrophiles are well developed, the use of tertiary alkyl electrophiles in nickel catalysis is not easy due to the dominant β-hydride elimination side reaction. In 2015, Gong and co-workers46 resolved the issue by using pyridine (Py) or 4-(N,N-dimethylamino)pyridine (DMAP) and a carbene salt as the additives to suppress β-hydride elimination and enhance coupling efficiency (Scheme 4). The reaction tolerated various substituted aryl bromides and better results were obtained with electron-withdrawing substituents. Scheme 4 | Reductive cross-coupling of aryl bromides with tertiary alkyl halides. Download figure Download PowerPoint Until now, the cases described form C–C bonds at the ipso-carbon of alkyl halides, where the regioselectivity of these reductive cross-couplings has been less explored (Scheme 5a). An early example of migratory reductive cross-coupling was reported by Zhu and co-workers47 in 2017 (Scheme 5b). The reaction proceeded smoothly using Ni(ClO4)2(H2O)6/6,6′-dimethyl-2,2′-bipyridyl as the catalyst with different nonactivated alkyl electrophiles and aryl bromides affording 1,1-diarylalkane derivatives, which are widespread in natural products and biologically active molecules, in good to excellent yields and regioselectivity. Scheme 5 | (a–c) Nickel-catalyzed migratory reductive cross-couplings. Download figure Download PowerPoint A proposed mechanism for this transformation is provided in Scheme 5c. Initially, the oxidative addition of Ni(0) with the inactivated alkyl bromide leads to Ni(II) complex I. Reduction of Ni(II) by Mn and the following β-hydride elimination and migratory insertion steps deliver the thermodynamically stable benzylic-Ni(I) species III. Then, the oxidative addition of the aryl bromides with Ni(I) generates the Ni(III) complex IV. Finally, the reductive elimination of Ni(III) complex provides the desired product and Ni(I)-X species V. The Ni(I)-X species is then reduced by Mn powder to close the catalytic cycle. This class of transformation was also explored by Yin and co-workers,48 who demonstrated the utility of NiI2/bathocuproine as the cross-coupling catalyst and Zn as the reductant. Interestingly, an opposite mechanism is proposed. In the first key step, selective oxidative addition of aryl halides to Ni(0) rather than inactivated alkyl halides affords the Ar–Ni(II) complex I′. A radical chain process is proposed for the formation of the Ni(III) species II′ through the addition of alkyl radical generated from inactivated alkyl halides via a SET of Ni(I)−X ( IV′). Several control experiments and radical trapping experiments were carried out to support their mechanism. Although significant progress has been made in nickel-catalyzed reductive cross-coupling of aryl halides with alkyl electrophiles, the use of metal powders inevitably produces excess stoichiometric metal waste. Thus, the development of new types of reductive cross-couplings, which enable new activation modes, is still highly desirable. During the last few years, metal/photoredox dual catalysis has witnessed remarkable achievements and offered a broad range of unconventional transformations.49–65 To date, this field is strongly dominated by a redox neutral pathway, wherein the photoredox catalyst generates a radical species from the nucleophile partner and changes the oxidation state of the nickel catalyst for further transformations. A recently developed reductive nickel/photoredox system offers a valuable alternative for the construction of C–C bonds by using two electrophiles in the absence of a stoichiometric metal reductant (Scheme 6). Scheme 6 | A general representation of reductive cross-coupling pathway via nickel/photoredox dual catalysis. Download figure Download PowerPoint Nickel-photoredox dual catalysis In 2016, MacMillan and co-workers66–68 developed the first nickel/photoredox dual catalyzed reductive cross-coupling of aryl bromides and alkyl bromides in the absence of metal powder (Scheme 7a). This reaction proceeded smoothly with a broad scope of alkyl bromides and aryl bromides through Ni/photoredox dual catalysis. Regarding the mechanism, it is postulated that in the first step the oxidative addition of aryl bromide to Ni(0) results in the formation of Ni(II) complex I. Concomitantly, a hydrogen-atom abstraction of tris(trimethylsilyl)silane (TTMSS) via bromine radicals forms a stabilized silyl radical intermediate. The following halogen-atom abstraction mediated by silyl radical generates the alkyl radical, which binds to the Ni(II) complex I, leading to the formation of Ni(III) intermediate II. Reductive elimination from II affords the desired product and Ni(I) species III, which can be reduced by the reduced photo complex Ir(II). In this case, the photoexcited catalyst is reduced by bromide to generate a bromine radical. Scheme 7 | (a–d) Overview of nickel/photoredox dual catalyzed reductive cross-couplings of aryl halides. Download figure Download PowerPoint Lei and co-workers,69 independently from the studies of MacMillan, reported an alternative strategy employing Et3N as the terminal reductant. A proposed mechanism for this transformation is provided in Scheme 7b. Initially, the oxidative addition of Ni(0) with aryl bromides leads to the Ni(II) complex. At the same time, the alkyl radical is generated via a SET of photoexcited catalyst or a low-valent nickel intermediate. The resulting alkyl radical is then intercepted by Ni(II) to form the Ni(III) species. Finally, the reductive elimination of Ni(III) species provides the desired product and Ni(I)−X species, which is reduced by the Ir(II) to close both catalytic cycles. This strategy was also used by Vannucci and co-workers,70 who disclosed triethanolamine as the terminal reductant. Based on these previous developments, Jensen and co-workers71 developed a continuously stirred-tank reactor platform for the nickel/photoredox dual catalyzed cross-electrophile couplings in flow. Notably, gram-scale synthesis can be achieved after using their system for 13 h, which opened up potential applications of this system. A related approach was developed by Brill and co-workers72 for the assembly of complex drug-like compounds via cross-coupling of benzylic chlorides and (hetero)aryl bromides by using continuous flow and highlighting the industrial applicability. Furthermore, Yin and co-workers73 successfully expanded this strategy to reductive migratory cross-coupling of alkyl bromides and aryl bromides by using bathocuproine as a nickel ligand (Scheme 7c). Compared with alkyl bromides and iodides, simple alkyl chlorides are abundant, inexpensive, and readily available through simple synthetic methods. As such, they are widely used as electrophilic partners in nucleophilic and aromatic substitutions. The concept of nickel/photoredox dual activation modes was also successfully expanded to the coupling of inactivated alkyl chlorides. The reaction involving the inactivated alkyl chlorides and aryl chlorides as the substrates, aminosilane as the reductant, catalyzed by NiCl2(bim) and Ir-based photocatalyst, afforded the C(sp2)−C(sp3) coupled products in generally good yields (Scheme 7d).74 In the context of the development of alkyl electrophiles, a series of new nickel/photoredox dual catalyzed reductive cross-coupling reactions were developed using Katritzky salts, aziridines, and epoxides. In recent research by Molander and co-workers,75 Katritzky salts have been identified as C(sp3) electrophiles for the construction of C(sp2)−C(sp3) bonds. This reaction proceeded with good yields in the presence of 4CzIPN as the photocatalyst and NiBr2(DME)/4,4′-di-tert-butylbipyridine (dtbbpy) as the cross-coupling catalyst, with a broad scope of differently substituted substrates (Scheme 8a). Scheme 8 | (a–f) The development of alkyl electrophiles via nickel/photoredox dual catalysis. Download figure Download PowerPoint In 2017, Doyle and co-workers32 developed a nickel/Mn-catalyzed reductive cross-coupling of styrenyl aziridines and aryl iodides. A drawback in the substrate scope was that an aliphatic aziridine did not work under Mn conditions (Scheme 8b). A recent study by Doyle and co-workers76 constituted further progress in this field and resulted in a reductive nickel/photoredox strategy. Their study provided a new way for the reductive cross-coupling of alkyl aziridines and (hetero)aryl iodides. The newly developed system showed a broad substrate scope. A variety of substituted aryl iodides and alkyl aziridines underwent reductive cross-coupling to provide the desired products in moderate to good yields by using 4CzIPN as the photocatalyst and NiBr2(DME)/dtbbpy as the cross-coupling catalyst. Notably, they were able to use cyclic aziridines that could not be employed in classic methods, which opened up potential applications of this strategy (Scheme 8c). A proposed mechanism for this transformation is provided in Scheme 8d. Initially, the oxidative addition of Ni(0) with aryl iodide leads to Ni(II) complex I. The key β-iodoamine IV is formed via iodide ring-opening of aziridine. Subsequently, the alkyl radical is generated from β-iodoamine via a SET of photoexcited catalyst 4CzIPN−• or a low-valent nickel intermediate or halogen-atom abstraction from Ni(I)−I ( III). The resulting alkyl radical is then intercepted by I to form Ni(III) species II. Finally, the reductive elimination of II provides the desired product and Ni(I)−I species III. Then Ni(I)−I species III is reduced by the reduced state of [4-CzIPN]−• to close both catalytic cycles. Notably, the classic nickel/Mn system gave the MnI2 salt instead of β-iodoamine; thus, no desired products were obtained. Continued efforts by Doyle and co-workers77 expanded this strategy to cross-coupling of epoxides and (hetero)aryl iodides (Scheme 8e). Compared with the classic methods, the newly developed Ni/Ti/photoredox system has a wider substrate scope. Various styrene oxides, cyclic epoxides, and terminal aliphatic epoxides all reacted well to provide the desired products in moderate to good yields and high regioselectivities. Allylic carbonates have also been proven to be suitable electrophiles for reductive cross-couplings.78–80 Another nice example of cross-electrophile coupling via nickel/photoredox dual catalysis was described by Chu and co-workers81 by employing allylic carbonates and vinyl triflates as the substrates (Scheme 8f). In this case, both E- and Z-configured 1,4-dienes could be achieved by the choice of photocatalysts. When Ir(ppy)2(dtbbpy)+ was used as the photocatalyst, a photoinduced contra-thermodynamic E→Z isomerization process would occur to give the (Z)-1,4-diene product.81 Despite the utility of these strategies, all of them rely on the redox potentials of the photocatalysts to furnish the cycle. In addition, many of these reactions become less appealing when considering the potential toxicity and high cost of the photocatalysts. The photoactive electron-donor-acceptor (EDA) complex allows for the generation of alkyl radicals under mild conditions without using metal based-photocatalysts and organic dyes. In the context of the development of milder nickel/photoredox strategy, Molander and co-workers82 reported the application of the EDA concept in nickel/photoredox dual catalyzed reductive cross-coupling of aryl bromides and N-hydroxyphthalimide (NHPI) esters. The reaction proceeds via the formation of an EDA complex between NHPI ester and Hantzsch ester (HE), which upon radiation-induced SET forms the alkyl radical (eq 1).82 Download figure Download PowerPoint Electrochemical nickel catalysis Electrochemistry may offer an economical and efficient alternative to classical transformations. Recent studies have demonstrated the ability of electrochemistry for various synthetically important bond-forming reactions. Within this research area, electrochemically induced metal catalysis has emerged as a powerful tool by integrating electrosynthesis and metal catalysis (Scheme 9). The seminal work of nickel-catalyzed reductive cross-coupling reaction between chloroesters and aryl halides was developed by an electrochemical strategy.12 A breakthrough for nickel-catalyzed electroreductive cross-coupling as a general concept had not been achieved until very recently. In 2017, Hansen and co-workers83 reported the nickel-catalyzed electroreductive cross-coupling of alkyl bromides with aryl bromides (Scheme 10a). In this case, the sacrificial zinc anode was employed as the reductant and tuning of the current was found to be crucial to the reaction. The cooperative combination of nickel catalysis and electrochemistry circumvented the need of stoichiometric metal powders and high temperatures. Thus, this method exhibited good functional group tolerance and substrate generality. Scheme 9 | A general representation of electroreductive cross-coupling. Download figure Download PowerPoint Scheme 10 | (a–d) Nickel-catalyzed electroreductive aryl–alkyl cross-couplings. Download figure Download PowerPoint Further efforts by Bio and co-workers84 resulted in a more economical strategy. Compared with Hansen’s method, the newly developed strategy used NHPI esters as the radical source and tertiary amine as the reductant under mild conditions in a divided electrochemical cell (Scheme 10b). Later, a one-pot electroreductive C(sp2)–C(sp3) cross-coupling reaction was developed by Loren and co-workers85 (Scheme 10c), wherein the redox-active esters were generated in situ from alkyl carboxylates and NHPI tetramethyluronium hexafluorophosphate. Sevov and co-workers86 developed a more general strategy and found that the redox-active shuttles can protect the nickel catalyst from over reduction, thus improving the yields and suppressing the side-product pathway (Scheme 10d). The reactions gave good yields across a wide range of substrates, including aryl, heteroaryl, or vinyl bromides with primary or secondary alkyl bromides. Given the importance of 1,1-diarylalkane derivatives, independently and concurrently, the research groups of Rueping87 and Mei88 reported the migratory electroreductive cross-coupling of alkyl halides and aryl halides (Scheme 11a). Both methods showed good functional group tolerance and wide substrate scope, giving rise to the corresponding 1,1-diarylalkane derivatives in moderate to good yields. Based on the experimental results and density functional theory (DFT) studies, Rueping and co-workers87 proposed a plausible mechanism for this transformation (Scheme 11b). Scheme 11 | (a and b) Nickel-catalyzed migratory electroreductive cross-couplings. Download figure Download PowerPoint In the first step, the Ni(0) species is generated at the cathode surface. Subsequent oxidative addition of Ni(0) to aryl bromide gives Ni(II) complex I, which is reduced at the cathode giving rise to the Ar−Ni(I) intermediate II. A SET then occurs to generate alkyl radical and Ar−Ni(II)−Br species III. The following single-electron cathodic reduction and alkyl radical addition will give the Ni(II) intermediate IV. The β-hydride elimination and migratory insertion steps deliver the thermodynamically stable benzylic-Ni(II) species V. Finally, the reductive elimination of benzylic-Ni(II) species would release the desired product and regenerate the Ni(0). Aryl–Aryl Reductive Cross-Couplings In comparison to cross-electrophile coupling for the construction of C(sp2)–C(sp3) bonds, the corresponding C(sp2)–C(sp2) bond formations are more challenging as a result of the subtle difference between the two aryl electrophiles. In 2008, Amatore and Gosmini89 reported a cobalt-catalyzed reductive cross-coupling of two aryl electrophiles for the synthesis of unsymmetrical biaryl compounds in the presence of Mn as the reductant. The key to success was the different reactivity profiles of two aryl electrophiles, which allowed the selective oxidative addition of these species. Later, this concept was extended to nickel-catalyzed cross-coupling of aryl halides with 2-halopyridine by the same group.90 In 2015, Weix and co-workers91 developed a different method to construct C(sp2)–C(sp2) bonds, wherein the selectivities were controlled by the catalysts rather than the electronic properties of the substrates as previous reports (Scheme 12a). Mechanistically, aryl bromides undergo selective oxidative addition with Ni(0) to give Ni(II) species I. At the same time, aryl triflates react exclusively with Pd(0) to form Pd(II) species III. The transmetalation then occurs between Ni(II) and Pd(II) complex, leading to the key Ar1–Pd(II)–Ar2 intermediate IV, which allows for the reductive elimination to give the asymmetrical biaryls. Notably, the additive potassium fluoride (KF) is crucial to achieving high selectivity, presumably by improving the selectivity of the palladium catalyst for aryl triflate over aryl bromide. Continued efforts by Olivares and Weix92 and other groups expanded this method for the coupling of vinyl bromides with vinyl triflates, aryl chlorides with aryl triflates,93 aryl triflates with aryl tosylates,94 aryl chlorides with ortho-fluoro-substituted aromatic amides,95 aryl iodides with difluoromethyl 2-pyridyl sulfone,96 aryl bromides, and 2,2-difluorovinyl tosylate.97 Scheme 12 | (a–c) Nickel-catalyzed aryl–aryl reductive cross-couplings via different methods. Download figure Download PowerPoint Very recently, Rueping and co-workers98 realized the reductive cross-coupling of polyfluorinated arenes with aryl halides using nickel/photoredox dual catalysis (Scheme 12b). This protocol opens up a new entry to multifluorinated biaryls. The reaction process starts with the oxidative addition of aryl halides with Ni(0) generating Ni(II) species I′. Concomitantly, the [C5F5N]•− is generated via a SET process of Ir(II) to C5F5N, which can be trapped with Ni(II) to give Ni(III) intermediate II′. The following reductive elimination affords the desired product and Ni(I) species III′, which can be reduced by Ir(II). Also, a Ni(0)/Ni(I)/Ni(III)/Ni(I) cycle is possible, a pathway that involves the trapping of Ni(0) and selective addition of Ni(I)–C5F4N ( IV′) to the aryl halides. Besides these achievements, the nickel-catalyzed electrochemical method was also applied to aryl-heteroarybond formation reactions. In this regard, Léonel and co-workers99–102 reported several electroreductive nickel-catalyzed cross-coupling reactions of aryl halides and heteroaryls, such as 3-chloro-6-methoxypyridazines, 3-amino-6-chloropyridazines, and chloropyrimidines (Scheme 12c). Alkyl–Alkyl Reductive Cross-Couplings As discussed above, the reductive