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Electrochemical Nickel-Catalyzed C(sp3)–C(sp3) Cross-Coupling of Alkyl Halides with Alkyl Tosylates
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Electrochemical Nickel-Catalyzed C(sp3)–C(sp3) Cross-Coupling of Alkyl Halides with Alkyl Tosylates
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  • Malek Y. S. Ibrahim
    Malek Y. S. Ibrahim
    Institute of Chemistry, University of Graz, NAWI Graz, Graz 8010, Austria
    Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Graz 8010, Austria
    More by Malek Y. S. Ibrahim
  • Graham R. Cumming
    Graham R. Cumming
    Centro de Investigación Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas-Madrid, Spain
    More by Graham R. Cumming
  • Raquel Gonzalez de Vega
    Raquel Gonzalez de Vega
    TESLA-Analytical Chemistry, University of Graz, NAWI Graz, Graz 8010, Austria
    Institute of Chemistry, University of Graz, NAWI Graz, Graz 8010, Austria
    More by Raquel Gonzalez de Vega
  • Pablo Garcia-Losada
    Pablo Garcia-Losada
    Centro de Investigación Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas-Madrid, Spain
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  • Oscar de Frutos
    Oscar de Frutos
    Centro de Investigación Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas-Madrid, Spain
    More by Oscar de Frutos
  • C. Oliver Kappe
    C. Oliver Kappe
    Institute of Chemistry, University of Graz, NAWI Graz, Graz 8010, Austria
    Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Graz 8010, Austria
    More by C. Oliver Kappe
    Orcidhttps://orcid.org/0000-0003-2983-6007
  • David Cantillo*
    David Cantillo
    Institute of Chemistry, University of Graz, NAWI Graz, Graz 8010, Austria
    Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Graz 8010, Austria
    *Email for D.C.: [email protected]
    More by David Cantillo
    Orcidhttps://orcid.org/0000-0001-7604-8711
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Journal of the American Chemical Society

Cite this: J. Am. Chem. Soc. 2023, 145, 31, 17023–17028
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https://doi.org/10.1021/jacs.3c07313
Published July 26, 2023

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Abstract

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Formation of new C(sp3)–C(sp3) bonds is a powerful synthetic tool to increase molecular diversity, which is highly sought after in medicinal chemistry. Traditional generation of carbon nucleophiles and more modern cross-electrophile-coupling methods typically lack sufficient selectivity when cross-coupling of analogous C(sp3)-containing reactants is attempted. Herein, we present a nickel-catalyzed, electrochemically driven method for the coupling of alkyl bromides with alkyl tosylates. Selective cross-coupling transformations were achieved even between C(sp3)-secondary bromides and tosylates. Key to achieve high selectivity was the combination of the tosylates with sodium bromide as the supporting electrolyte, gradually generating small amounts of the more reactive bromide by substitution and ensuring that one of the reaction partners in the nickel-catalyzed electroreductive process is maintained in excess during a large part of the process. The method has been demonstrated for a wide range of substrates (>30 compounds) in moderate to good yields. Further expanding the scope of electroorganic synthesis to C(sp3)–C(sp3) cross-coupling reactions is anticipated to facilitate the switch to green organic synthesis and encourage future innovative electrochemical transformations.

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Over the past years, the development of novel methodologies for the selective formation of alkyl–alkyl bonds has become an important area of research. (1) Cross-coupling of sp3-hybridized carbons enables the rapid diversification of molecular structures, which is very relevant in the discovery and preparation of drug candidates. Traditional nickel- and palladium-catalyzed couplings using Grignard reagents (Scheme 1a) typically suffer from poor functional group tolerance due to the high reactivity of organometallic compounds. (2) Important efforts to circumvent the use of organometallic reagents have been made in the past years. Gong and co-workers coupled bromides using an excess amount of Zn or bis(pinacolato)diboron as reductant. (3) Successful cross-electrophile coupling between alkyl halides and tosylates was reported by Komeyama et al., (4) although the method required excess amounts of a metal reductant and cobalamin as cocatalyst (Scheme 1b). A similar strategy was described by Fu and Liu using a copper catalyst and stoichiometric amounts of magnesium and lithium methoxide. (5) An iridium/nickel dual photocatalyst system has been recently shown by MacMillan and co-workers to enable alcohol–bromide couplings. (6) Despite the recent advances, while metal-catalyzed cross-electrophile coupling reactions involving sp2 carbons are well established, formation of alkyl–alkyl bonds has remained a challenge. (7) Nickel-catalyzed methods are usually preferred over other metals due to their lower cost and ability to undergo oxidative addition with alkyl halides under mild conditions. Moreover, nickel species in solution can be reduced with ease using metal reductants such as Zn (8) or Mn. (9) Although this strategy is successful in driving the catalytic cycle, it often suffers from low selectivity due to the formation of homocoupling products. Additionally, the effective activation of the metal reductant might become complex in large-scale preparations.

Scheme 1

Scheme 1. Challenges in C(sp3)–C(sp3) Cross-Electrophile Coupling
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Electroorganic synthesis is rapidly growing as a safe and sustainable synthetic technology for the preparation of organic compounds, (10) including pharmaceutical ingredients. (11) Among the many redox transformations achieved electrochemically over the past years, (12) metal-catalyzed strategies for the formation of carbon–carbon bonds have been studied extensively. (13) Electrochemical cross-electrophile coupling of organic halides has been reported by using nickel catalysts. Yet, reports have mainly focused on C(sp2)–C(sp3) couplings, (14,15) as alkyl–alkyl bond-forming reactions lack selectivity versus undesired homocoupling (Scheme 1c). Lin and co-workers have recently achieved electroreductive C(sp3)–C(sp3) cross-coupling of alkyl halides by taking advantage of the fact that more substituted alkyl halides are more easily reduced to the corresponding carbanions. (16)

We envisaged that instead of selecting the thermodynamic properties of the reactants involved in the cross-coupling, altering the reaction kinetics by gradually generating one of the reactants within the reaction mixture during electrolysis could also be used to achieve high selectivity. In particular, cross-couplings between alkyl bromides that are not selective could be turned selective by generating the more reactive bromide from the corresponding tosylate by tosylate/bromide exchange with an inexpensive bromide source that also serves as supporting electrolyte (Scheme 1d).

To test our hypothesis, we initiated the investigation by studying the coupling of alkyl tosylate 1a with cyclohexyl bromide (1b) as a model reaction (Table 1). In a typical experiment, the reaction mixture was electrolyzed under an argon atmosphere under a constant current of 4 mA (ca. 2.7 mA cm–2), until 3.0 F mol–1 of charge had been passed, using a glassy-carbon cathode and an aluminum anode. Gratifyingly, the electrochemical reaction resulted in the formation of target cross-coupling product 1c with 79% yield (calibrated GC-FID) (Table 1, entry 1). Analysis of the reaction mixture revealed the presence of styrene and 1,4-diphenylbutane as the main side products formed from 1a by elimination and homocoupling, respectively. These results are in contrast with those obtained using (2-bromoethyl)benzene directly as substrate, which resulted in homocoupling as the major product (vide infra).

Table 1. Optimization of Cross-Coupling Conditions
entrydeviation from the above1c (%)b
1none79
210 mA53
32 mA8
4RVC cathode66
5graphite cathode74
6Zn anode24
7Mg anode46
830 mol % ligand45
9nBu4NPF6 as supporting electrolyte2
10nBu4NCl as supporting electrolyte42
11nBu4NI as supporting electrolyte66
12Et4NOTs as supporting electrolyte39
13L165
14L261
15L345
16L469
17L537
18complex 16

a

Conditions: 3 mL volume, 600 rpm, rt, under Ar.

b

Determined by calibrated GC-FID.

Notably, an increase or decrease of the current density resulted in a decrease in yield (Table 1, entries 2 and 3). Glassy carbon was the optimum cathode material, but satisfactory results were also achieved with RVC or graphite (entries 4 and 5). The choice of a sacrificial anode material proved to be very important. When zinc or magnesium (entries 6 and 7) were used, the formation of 1c dropped below 50%. In principle, the role of the sacrificial anode is to undergo oxidation as a counter electrode, and the reason for the improved performance of aluminum is not clear. No evidence was found for the direct participation of aluminum salts in the reaction mechanism. Solvents other than DMA did not perform well in the reaction (Table S2).

Increasing the ligand/nickel ratio to 3/1 had a negative effect (Table 1, entry 8), probably due to catalyst deactivation. As expected, when a nonhalide salt (nBu4NPF6) was used as supporting electrolyte (entry 9), the yield dropped to 2%. This observation is in line with the initial hypothesis that a tosylate–halide exchange initiates the reaction. The use of chloride- or iodide-containing supporting electrolytes also negatively impacted the reaction (entries 10 and 11). Iodide salts resulted in higher amounts of styrene, likely due to easier elimination. The use of chloride augmented the proportion of homocoupling (Table S3). A 0.1 M concentration of NaBr was found to be optimal (Table S4). Replacing NiBr2·dme with other nickel halide salts decreased the amount of 1c (Table S5). This is likely due to the fact that the halide anions from the catalyst can also participate in the exchange with tosylate. The ligand employed in the reaction had a lower impact on the reaction outcome than expected (entries 13–17). Although 4-methoxypicolinimidamide hydrochloride (L3) has shown good reactivity in other electrochemical Ni-catalyzed cross-coupling reactions, (11) only 45% of 1c was formed in this case (entry 15). 2,2′-Bipyridine (L4) gave analogous results, while 1,10-phenanthroline decreased the yield to 37% (entries 16 and 17). Surprisingly, complex 1 provided much poorer results than did L4 (entry 18).

Interestingly, direct reuse of the glassy-carbon electrodes (after rinsing with solvent) resulted in a decrease in the reaction yield by ca. 10%. The yield did not decline any further upon reuse of the electrode for a third and fourth time. This issue was initially ascribed to grafting of the carbon surface to alkyl radicals. However, analysis of the electrode surface by SEM-EDX and LA-ICP-MS revealed that the carbon surface of the electrode had most likely been brominated (Figure S2). This layer could not be eliminated by polishing without damaging the electrode surface.

With the optimized conditions in hand, the scope of the cross-coupling reaction was investigated (Scheme 2). Alkylation of 1a with cyclopentyl, hexyl, and neopentyl bromide furnished the desired products 2c–4c in good yields. However, alkylation with bromocyclopropane or 2-bromoethyl methyl ether performed poorly (5c, 6c) due to rapid debromination of these reactants under the reaction conditions. The same issue was observed with 2-bromoethyl acetate (8c). Nitrogen-containing bromides could be used as coupling partners, giving moderate yields of 9c and 10c.

Scheme 2

Scheme 2. Scope of the Electrochemical Cross-Coupling of Alkyl Tosylates with Alkyl Bromidesd
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aConditions A: 3 mL volume, 0.1 M NaBr, 1.3 equiv alkyl bromide, 600 rpm, under Ar.

bConditions B: same as conditions A with 0.075 M NaBr and 2 equiv alkyl bromide.

cGC-FID yield using biphenyl as internal standard.

dIsolated yields are shown.

A variety of functionalized 2-ethylarene-tosylates were also tested. The method proved to be compatible with electron-rich aromatics (11c–14c). The presence of halides or nitro groups did not inhibit the reaction (15c–17c). However, partial nitro reduction was observed during the formation of 17c. Compounds containing naphthyl (18c) or methylaryl (19c) groups could also be prepared in good yields. As anticipated, when a reactant containing both an aryl- and alkyl-tosyl group was tested, the reaction proceeded selectively at the alkyl tosylate as only that position can undergo tosylate-bromide exchange (20c). Sulfur- and nitrogen-containing heterocycles could also be successfully incorporated into the coupling products (21c, 22c).

Surprisingly, a secondary tosylate resulted in a very low yield under the standard reaction conditions (24c). A relatively large amount of tosylate was still detected by GC analysis after the reaction. In contrast, other primary tosylates such as that resulting from citronellol (25c) gave large amounts of tosylate homocoupling. This variability was ascribed to different rates of tosylate–bromide exchange depending on the substrate. To shed light onto this issue, the reactivity of several tosylates toward NaBr was studied in the absence of current (Figure S3). It was found that substrates with a fast OTs–Br exchange rate perform better with a lower loading of NaBr (0.075 M instead of 0.1 M) and a larger excess of the alkyl bromide reaction partner (Conditions B in Scheme 2) (Tables S6 and S7).

Methylation is a very important structural modification often used in medicinal chemistry. (17) To our delight, our methodology could be used to realize methylation and ethylation of alkyl bromides using commercially available methyl and ethyl tosylates as alkylating agents (26c–29c). Additionally, the method was amenable to the preparation of compounds decorated with 2,2-difluorocyclopropane (30c) and phthalimide (31c). It was further confirmed that the method does not perform well with secondary tosylates (33c, 34c).

To confirm our hypothesis that gradual tosylate–bromide exchange is responsible for the cross-coupling selectivity obtained, the concentration of all components was monitored for the model reaction (Figure 1a). As expected, the formation of bromide 1f and its subsequent disappearance was observed. Furthermore, when 1f was used directly as substrate (Figure 1b) side product 1e, resulting from homocoupling of 1f, was observed as the main product, supporting the key role of the gradual tosylate–bromide exchange in the reaction selectivity. The more reactive cross-coupling alkyl bromide pair corresponds to the reactant that is added as tosylate (1a). In this manner, as the bromide is generated in small amounts, it encounters an excess of the other reactant (1b). The alkyl bromide that is less reactive (1b) can also undergo oxidative addition, although more slowly, and it is indeed consumed by the end of the reaction, partially generating bicyclohexyl as a side product. Tosylate/iodide exchange has been previously suggested as a step in reductive aryl–alkyl couplings. (18)

Figure 1

Figure 1. (a) Monitoring of the reaction mixture during the cross-coupling of 1a with 1b (Table 1, entry 1). (b) Control experiment using bromide 1f instead of tosylate 1a.

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Based on the experiments above and literature data on nickel-catalyzed reductive processes, (14,19,20) the reaction mechanism depicted in Figure 2 was proposed. The process is initiated by the cathodic reduction of C1, giving nickel(0) species C2. Tosylate–bromide exchange forms the more reactive alkyl bromide, which undergoes oxidative addition to C2, resulting in C3, (21) which is further oxidized to nickel(III) (C4) upon addition of the alkyl radical produced by reduction of the coupling partner. The cross-coupling product is released by the reductive elimination from C4. The catalytic cycle closes by the redox reaction between C5 and the alkyl halide coupling partner. Notably, no reaction occurred when the substrates were added after prereduction of the nickel, suggesting a short lifetime of the reduced Ni species in the absence of oxidants. (22)

Figure 2

Figure 2. Proposed mechanism for electrochemical cross-coupling.

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To summarize, we have demonstrated that selective electrochemical nickel-catalyzed C(sp3)–C(sp3) cross-coupling reactions are enabled when alkyl halides and tosylates are combined with a bromide supporting electrolyte. Key to achieving good selectivity is the progressive tosylate–bromide exchange taking place during the electrolysis, with a lower concentration of the reactive intermediate being sufficient for oxidative addition toward nickel(0), while disfavoring the homocoupling pathway. Utilization of Al as a sacrificial electrode instead of metal reductants such as Zn or Mg avoids the need for activation of the metal surface and enables the use of a less reactive and more cost-effective material. Given the growing importance of alkyl–alkyl bond forming reactions in medicinal chemistry, we anticipate that this contribution will further encourage the adoption of electroorganic synthesis in organic chemistry laboratories.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c07313.

  • Materials and methods, additional optimization data, characterization data for the cathode material, experimental procedures, characterization data, and NMR spectra (PDF)

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Author Information

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  • Corresponding Author
    • David Cantillo - Institute of Chemistry, University of Graz, NAWI Graz, Graz 8010, Austria;  Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Graz 8010, Austria;  Orcidhttps://orcid.org/0000-0001-7604-8711;  Email: [email protected]
  • Authors
    • Malek Y. S. Ibrahim - Institute of Chemistry, University of Graz, NAWI Graz, Graz 8010, Austria;  Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Graz 8010, Austria
    • Graham R. Cumming - Centro de Investigación Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas-Madrid, Spain
    • Raquel Gonzalez de Vega - TESLA-Analytical Chemistry, University of Graz, NAWI Graz, Graz 8010, Austria;  Institute of Chemistry, University of Graz, NAWI Graz, Graz 8010, Austria
    • Pablo Garcia-Losada - Centro de Investigación Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas-Madrid, Spain
    • Oscar de Frutos - Centro de Investigación Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas-Madrid, Spain
    • C. Oliver Kappe - Institute of Chemistry, University of Graz, NAWI Graz, Graz 8010, Austria;  Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Graz 8010, Austria;  Orcidhttps://orcid.org/0000-0003-2983-6007
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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The Research Center Pharmaceutical Engineering (RCPE) is funded within the framework of COMET–Competence Centers for Excellent Technologies by BMK, BMDW, Land Steiermark and SFG. The COMET program is managed by the FFG. We thank the Institute of Earth Science, NAWI Graz Geocenter for the SEM-EDX analyses.

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    Chemistry - A European Journal (2014), 20 (47), 15334-15338CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    In the presence of copper iodide and bis(diphenylphosphino)methane (DPPM), alkyl mesylates and tosylates such as PhCH2CH2CH2OSO2R (R = Me, 4-MeC6H4) underwent chemoselective reductive coupling reactions with alkyl and aryl bromides such as cyclohexyl bromide and 4-bromo-N,N-dimethylaniline mediated by LiOMe and Mg metal to yield alkanes such as PhCH2CH2CH2R1 (R1 = cyclohexyl, 4-Me2NC6H4) in 25-89% yields. Coupling of a nonracemic pyrrolidinyl tosylate with bromocyclohexane under the reaction conditions yielded product of inverted configuration in 99.7% ee. Partially satd. benzo-fused oxacycles such as 2,3-dihydrobenzofuran were prepd. chemoselectively by reductive cyclizations of bromoaryloxyalkyl tosylates such as 2-BrC6H4OCH2CH2OTs (Ts = 4-MeC6H4SO2) in the presence of CuI and DPPM mediated by LiOMe and Mg metal. The structure and abs. configuration of (R)-3-cyclohexyl-1-(phenylsulfonyl)pyrrolidine [prepd. from the tosylate of (R)-1-phenylsulfonyl-3-pyrrolidinol] were detd. by X-ray crystallog.
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    Lyon, W. L.; MacMillan, D. W. C. Expedient Access to Underexplored Chemical Space: Deoxygenative C(sp3)–C(sp3) Cross-Coupling. J. Am. Chem. Soc. 2023, 145, 7736– 7742,  DOI: 10.1021/jacs.3c01488
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    Expedient Access to Underexplored Chemical Space: Deoxygenative C(sp3)-C(sp3) Cross-Coupling
    Lyon, William L.; MacMillan, David W. C.
    Journal of the American Chemical Society (2023), 145 (14), 7736-7742CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    An N-heterocyclic carbene (NHC)-mediated deoxygenative alkylation of alcs. and alkyl bromides via nickel-metallaphotoredox catalysis was reported. This C(sp3)-C(sp3) cross-coupling exhibited a broad scope and was capable of forming bonds between two secondary carbon centers, a longstanding challenge in the field. Highly strained three-dimensional systems such as spirocycles, bicycles, and fused rings were excellent substrates, enabling the synthesis of new mol. frameworks. Linkages between pharmacophoric satd. ring systems were readily forged, representing a three-dimensional alternative to traditional biaryl formation. The utility of this cross-coupling technol. was highlighted with the expedited synthesis of bioactive mols.
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    Weix, D. J. Methods and Mechanisms for Cross-Electrophile Coupling of Csp2 Halides with Alkyl Electrophiles. Acc. Chem. Res. 2015, 48, 1767– 1775,  DOI: 10.1021/acs.accounts.5b00057
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    Methods and Mechanisms for Cross-Electrophile Coupling of Csp2 Halides with Alkyl Electrophiles
    Weix, Daniel J.
    Accounts of Chemical Research (2015), 48 (6), 1767-1775CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. Cross-electrophile coupling, the cross-coupling of two different electrophiles, avoids the need for preformed carbon nucleophiles, but development of general methods has lagged behind cross-coupling and C-H functionalization. A central reason for this slow development is the challenge of selectively coupling two substrates that are alike in reactivity. This Account describes the discovery of generally cross-selective reactions of aryl halides and acyl halides with alkyl halides, the mechanistic studies that illuminated the underlying principles of these reactions, and the use of these fundamental principles in the rational design of new cross-electrophile coupling reactions. Although the coupling of two different electrophiles under reducing conditions often leads primarily to sym. dimers, the subtle differences in reactivity of aryl halides and alkyl halides with nickel catalysts allowed for generally cross-selective coupling reactions. These conditions could also be extended to the coupling of acyl halides with alkyl halides. These reactions are exceptionally functional group tolerant and can be assembled on the benchtop. A combination of stoichiometric and catalytic studies on the mechanism of these reactions revealed an unusual radical-chain mechanism and suggests that selectivity arises from (1) the preference of nickel(0) for oxidative addn. to aryl halides and acyl halides over alkyl halides and (2) the greater propensity of alkyl halides to form free radicals. Bipyridine-ligated arylnickel intermediates react with alkyl radicals to efficiently form, after reductive elimination, new C-C bonds. Finally, the resulting nickel(I) species is proposed to regenerate an alkyl radical to carry the chain. Examples of new reactions designed using these principles include carbonylative coupling of aryl halides with alkyl halides to form ketones, arylation of epoxides to form β-aryl alcs., and coupling of benzyl sulfonate esters with aryl halides to form diarylmethanes. Arylnickel(II) intermediates can insert carbon monoxide to form acylnickel(II) intermediates that react with alkyl halides to form ketones, demonstrating the connection between the mechanisms of reactions of aryl halides and acid chlorides with alkyl halides. The low reactivity of epoxides with nickel can be overcome by the use of either titanium or iodide cocatalysis to facilitate radical generation and this can also be extended to enantioselective arylation of meso-epoxides. The high reactivity of benzyl bromide with nickel, which leads to the formation of bibenzyl in attempted reactions with bromobenzene, can be overcome by using a benzyl mesylate along with cobalt phthalocyanine cocatalysis to convert the mesylate into an alkyl radical.
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    Li, Y.; Li, Y.; Peng, L.; Wu, D.; Zhu, L.; Yin, G. Nickel-catalyzed migratory alkyl-alkyl cross-coupling reaction. Chem. Sci. 2020, 11, 10461– 10464,  DOI: 10.1039/D0SC03217D
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    Nickel-catalyzed migratory alkyl-alkyl cross-coupling reaction
    Li, Yangyang; Li, Yuqiang; Peng, Long; Wu, Dong; Zhu, Lei; Yin, Guoyin
    Chemical Science (2020), 11 (38), 10461-10464CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    A migratory cross-coupling strategy, which can overcome this obstacle to access the desired cross-coupling products ArCH(R)(CH2)nCR1R2R3 (Ar = Ph, 4-fluorophenyl, indol-3-yl, etc.; R = cyclopentyl, cyclohexyl, cycloheptyl, N-benzyl-piperidin-4-yl, 2-methyl-propan-1-yl; R1 = H, D; R2 = H, D; R3 = H; n = 0-3, 5), 1-cyclopentyl-indan, 1-cycloheptyl-indan, (1-cyclopentyl-3-methyl-pentyl)benzene was described. Accordingly, a selective migratory cross-coupling of two alkyl electrophiles (RBr, ArCH(R)(CH2)nCR1R2R3 (R3 = Br or Cl), 2-bromoindan, (5-bromo-1-cyclopentyl-3-methyl-pentyl)benzene) has been accomplished by nickel catalysis. Remarkably, this alkyl-alkyl cross-coupling reaction provides a platform to prep. 2°-2° carbon-carbon bonds from 1° and 2° carbon coupling partners. Preliminary mechanistic studies suggest that chain-walking occurs at both alkyl halides in this reaction, thus a catalytic cycle with the key step involving two alkylnickel(II) species is proposed for this transformation.
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    Cherney, A. H.; Reisman, S. E. Nickel-catalyzed asymmetric reductive cross-coupling between vinyl and benzyl electrophiles. J. Am. Chem. Soc. 2014, 136, 14365– 14368,  DOI: 10.1021/ja508067c
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    Nickel-Catalyzed Asymmetric Reductive Cross-Coupling Between Vinyl and Benzyl Electrophiles
    Cherney, Alan H.; Reisman, Sarah E.
    Journal of the American Chemical Society (2014), 136 (41), 14365-14368CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A Ni-catalyzed asym. reductive cross-coupling between vinyl bromides and benzyl chlorides has been developed. This method provides direct access to enantioenriched products bearing aryl-substituted tertiary allylic stereogenic centers from simple, stable starting materials. A broad substrate scope is achieved under mild reaction conditions that preclude the pregeneration of organometallic reagents and the regioselectivity issues commonly assocd. with asym. allylic arylation.
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    (a) Zhu, C.; Ang, N. W. J.; Meyer, T. H.; Qiu, Y.; Ackermann, L. Organic Electrochemistry: Molecular Syntheses with Potential. ACS Cent. Sci. 2021, 7, 415– 431,  DOI: 10.1021/acscentsci.0c01532
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    Organic Electrochemistry: Molecular Syntheses with Potential
    Zhu, Cuiju; Ang, Nate W. J.; Meyer, Tjark H.; Qiu, Youai; Ackermann, Lutz
    ACS Central Science (2021), 7 (3), 415-431CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
    A review. Efficient and selective mol. syntheses are paramount to inter alia biomol. chem. and material sciences as well as for practitioners in chem., agrochem., and pharmaceutical industries. Org. electrosynthesis has undergone a considerable renaissance and has thus in recent years emerged as an increasingly viable platform for the sustainable mol. assembly. In stark contrast to early strategies by innate reactivity, electrochem. was recently merged with modern concepts of org. synthesis, such as transition-metal-catalyzed transformations for inter alia C-H functionalization and asym. catalysis. Herein, we highlight the unique potential of org. electrosynthesis for sustainable synthesis and catalysis, showcasing key aspects of exceptional selectivities, the synergism with photocatalysis, or dual electrocatalysis, and novel mechanisms in metallaelectrocatalysis until Feb. of 2021.
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    (b) Pollok, D.; Waldvogel, S. R. Electro-organic synthesis – a 21st century technique. Chem. Sci. 2020, 11, 12386– 12400,  DOI: 10.1039/D0SC01848A
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    Electro-organic synthesis - a 21st century technique
    Pollok, Dennis; Waldvogel, Siegfried R.
    Chemical Science (2020), 11 (46), 12386-12400CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    The severe limitations of fossil fuels and finite resources influence the scientific community to reconsider chem. synthesis and establish sustainable techniques. Several promising methods have emerged, and electro-org. conversion has attracted particular attention from international academia and industry as an environmentally benign and cost-effective technique. The easy application, precise control, and safe conversion of substrates with intermediates only accessible by this method reveal novel pathways in synthetic org. chem. The popularity of electricity as a reagent is accompanied by the feasible conversion of bio-based feedstocks to limit the carbon footprint. Several milestones have been achieved in electro-org. conversion at rapid frequency, which have opened up various perspectives for forthcoming processes.
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    (c) Horn, E. J.; Rosen, B. R.; Baran, P. S. Synthetic organic electrochemistry: an enabling and innately sustainable method. ACS Cent. Sci. 2016, 2, 302– 308,  DOI: 10.1021/acscentsci.6b00091
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    Synthetic Organic Electrochemistry: An Enabling and Innately Sustainable Method
    Horn, Evan J.; Rosen, Brandon R.; Baran, Phil S.
    ACS Central Science (2016), 2 (5), 302-308CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
    A review. While preparative electrolysis of org. mols. has been an active area of research over the past century, modern synthetic chemists have generally been reluctant to adopt this technol. In fact, electrochem. methods possess many benefits over traditional reagent-based transformations, such as high functional group tolerance, mild conditions, and innate scalability and sustainability. In this Outlook, we highlight illustrative examples of electrochem. reactions in the context of the synthesis of complex mols., showcasing the intrinsic benefits of electrochem. reactions vs. traditional reagent-based approaches. Our hope is that this field will soon see widespread adoption in the synthetic community.
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    (a) Shatskiy, A.; Lundberg, H.; Kärkäs, M. D. Organic Electrosynthesis: Applications in Complex Molecule Synthesis. ChemElectroChem. 2019, 6, 4067– 4092,  DOI: 10.1002/celc.201900435
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    Organic Electrosynthesis: Applications in Complex Molecule Synthesis
    Shatskiy, Andrey; Lundberg, Helena; Kaerkaes, Markus D.
    ChemElectroChem (2019), 6 (16), 4067-4092CODEN: CHEMRA; ISSN:2196-0216. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review on. Org. electrosynthesis is an enabling and sustainable technol., which constitutes a rapidly expanding field of research. Electrochem. approaches serve as convenient and green alternatives to stoichiometric and toxic chem. redox agents. Electrosynthesis constitutes a promising platform for harnessing the unique reactivity profiles of radical intermediates, expediting the development of new reaction manifolds. This review highlights both anodic and cathodic methods for the construction of various kinds of complex mols.
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    (b) Cantillo, D. Synthesis of active pharmaceutical ingredients using electrochemical methods: keys to improve sustainability. Chem. Commun. 2022, 58, 619– 628,  DOI: 10.1039/D1CC06296D
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    Synthesis of active pharmaceutical ingredients using electrochemical methods: keys to improve sustainability
    Cantillo, David
    Chemical Communications (Cambridge, United Kingdom) (2022), 58 (5), 619-628CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Org. electrochem. is receiving renewed attention as a green and cost-efficient synthetic technol. Electrochem. methods promote redox transformations by electron exchange between electrodes and species in soln., thus avoiding the use of stoichiometric amts. of oxidizing or reducing agents. The rapid development of electroorg. synthesis over the past decades has enabled the prepn. of mols. of increasing complexity. Redox steps that involve hazardous or waste-generating reagents during the synthesis of active pharmaceutical ingredients or their intermediates can be substituted by electrochem. procedures. In addn. to enhance sustainability, increased selectivity toward the target compd. has been achieved in some cases. Electroorg. synthesis can be safely and readily scaled up to prodn. quantities. For this pupose, utilization of flow electrolysis cells is fundamental. Despite these advantages, the application of electrochem. methods does not guarantee superior sustainability when compared with conventional protocols. The utilization of large amts. of supporting electrolytes, environmentally unfriendly solvents or sacrificial electrodes may turn electrochem. unfavorable in some cases. It is therefore crucial to carefully select and optimize the electrolysis conditions and carry out green metrics anal. of the process to ensure that turning a process electrochem. is advantageous.
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    (a) Yan, M.; Kawamata, Y.; Baran, P. S. Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance. Chem. Rev. 2017, 117, 13230– 13319,  DOI: 10.1021/acs.chemrev.7b00397
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    Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance
    Yan, Ming; Kawamata, Yu; Baran, Phil S.
    Chemical Reviews (Washington, DC, United States) (2017), 117 (21), 13230-13319CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. This review discusses advances in synthetic org. electrochem. since 2000. Enabling methods and synthetic applications are analyzed alongside innate advantages as well as future challenges of electroorg. chem.
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    (b) Wiebe, A.; Gieshoff, T.; Möhle, S.; Rodrigo, E.; Zirbes, M.; Waldvogel, S. R. Electrifying Organic Synthesis. Angew. Chem., Int. Ed. 2018, 57, 5594– 5619,  DOI: 10.1002/anie.201711060
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    Electrifying Organic Synthesis
    Wiebe, Anton; Gieshoff, Tile; Moehle, Sabine; Rodrigo, Eduardo; Zirbes, Michael; Waldvogel, Siegfried R.
    Angewandte Chemie, International Edition (2018), 57 (20), 5594-5619CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. The direct synthetic org. use of electricity is currently experiencing a renaissance. More synthetically oriented labs. working in this area are exploiting both novel and more traditional concepts, paving the way to broader applications of this niche technol. As only electrons serve as reagents, the generation of reagent waste is efficiently avoided. Moreover, stoichiometric reagents can be regenerated and allow a transformation to be conducted in an electrocatalytic fashion. However, the application of electroorg. transformations is more than minimizing the waste footprint, it rather gives rise to inherently safe processes, reduces the no. of steps of many syntheses, allows for milder reaction conditions, provides alternative means to access desired structural entities, and creates intellectual property (IP) space. When the electricity originates from renewable resources, this surplus might be directly employed as a terminal oxidizing or reducing agent, providing an ultra-sustainable and therefore highly attractive technique. This Review surveys recent developments in electrochem. synthesis that will influence the future of this area.
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    (a) Gandeepan, P.; Finger, L. H.; Meyer, T. H.; Ackermann, L. 3d Metallaelectrocatalysis for Resource Economical Syntheses. Chem. Soc. Rev. 2020, 49, 4254– 4272,  DOI: 10.1039/D0CS00149J
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    3d metallaelectrocatalysis for resource economical syntheses
    Gandeepan, Parthasarathy; Finger, Lars H.; Meyer, Tjark H.; Ackermann, Lutz
    Chemical Society Reviews (2020), 49 (13), 4254-4272CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    Resource economy constitutes one of the key challenges for researchers and practitioners in academia and industries, in terms of rising demand for sustainable and green synthetic methodol. To achieve ideal levels of resource economy in mol. syntheses, novel avenues are required, which include, but are not limited to the use of naturally abundant, renewable feedstocks, solvents, metal catalysts, energy, and redox reagents. In this context, electrosyntheses create the unique possibility to replace stoichiometric amts. of oxidizing or reducing reagents as well as electron transfer events by elec. current. Particularly, the merger of Earth-abundant 3d metal catalysis and electrooxidn. has recently been recognized as an increasingly viable strategy to forge challenging C-C and C-heteroatom bonds for complex org. mols. in a sustainable fashion under mild reaction conditions. In this review, we highlight the key developments in 3d metallaelectrocatalysis in the context of resource economy in mol. syntheses until Feb. 2020.
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    (b) Park, S. H.; Ju, M.; Ressler, A. J.; Shim, J.; Kim, H.; Lin, S. Reductive Electrosynthesis: A New Dawn. Aldrichimica Acta 2021, 54, 17– 27
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    Reductive electrosynthesis: a new dawn
    Park, Steve H.; Ju, Minsoo; Ressler, Andrew J.; Shim, Jiwoo; Kim, Hyunwoo; Lin, Song
    Aldrichimica Acta (2021), 54 (1Spec.Iss.), 17-27CODEN: ALACBI ISSN:. (Sigma-Aldrich Co. LLC.)
    A review. The renewed interest in synthetic org. electrochem. has led in recent years to a surge in literature reports on new electrochem. reaction methods and synthetic strategies. While oxidative electrochem. has been extensively studied in org. synthesis, reductive electrosynthesis in comparison remains substantially underexplored. Recent developments in this area have introduced innovative strategies to enable new transformations and control reaction selectivity. Here, we highlight examples of recent advances in direct reductive electrolysis, indirect reductive electrolysis, and reductive electrophotocatalysis.
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    (c) Malapit, C. A.; Prater, M. B.; Cabrera-Pardo, J. R.; Li, M.; Pham, T. D.; McFadden, T. P.; Blank, S.; Minteer, S. D. Advances on the Merger of Electrochemistry and Transition Metal Catalysis for Organic Synthesis. Chem. Rev. 2022, 122, 3180– 3218,  DOI: 10.1021/acs.chemrev.1c00614
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    Advances on the Merger of Electrochemistry and Transition Metal Catalysis for Organic Synthesis
    Malapit, Christian A.; Prater, Matthew B.; Cabrera-Pardo, Jaime R.; Li, Min; Pham, Tammy D.; McFadden, Timothy Patrick; Blank, Skylar; Minteer, Shelley D.
    Chemical Reviews (Washington, DC, United States) (2022), 122 (3), 3180-3218CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. This review discussed recent advances in the combination of electrochem. and homogeneous transition-metal catalysis for org. synthesis. The enabling transformations, synthetic applications, and mechanistic studies was presented alongside advantages as well as future directions to address the challenges of metal-catalyzed electrosynthesis.
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    (d) Novaes, L. F. T.; Liu, J.; Shen, Y.; Lu, L.; Meinhardt, J. M.; Lin, S. Electrocatalysis as an enabling technology for organic synthesis. Chem. Soc. Rev. 2021, 50, 7941– 8002,  DOI: 10.1039/D1CS00223F
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    Electrocatalysis as an enabling technology for organic synthesis
    Novaes, Luiz F. T.; Liu, Jinjian; Shen, Yifan; Lu, Lingxiang; Meinhardt, Jonathan M.; Lin, Song
    Chemical Society Reviews (2021), 50 (14), 7941-8002CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Electrochem. has recently gained increased attention as a versatile strategy for achieving challenging transformations at the forefront of synthetic org. chem. Electrochem.'s unique ability to generate highly reactive radical and radical ion intermediates in a controlled fashion under mild conditions has inspired the development of a no. of new electrochem. methodologies for the prepn. of valuable chem. motifs. Particularly, recent developments in electrosynthesis have featured an increased use of redox-active electrocatalysts to further enhance control over the selective formation and downstream reactivity of these reactive intermediates. Furthermore, electrocatalytic mediators enable synthetic transformations to proceed in a manner that is mechanistically distinct from purely chem. methods, allowing for the subversion of kinetic and thermodn. obstacles encountered in conventional org. synthesis. This highlights key innovations within the past decade in the area of synthetic electrocatalysis, with emphasis on the mechanisms and catalyst design principles underpinning these advancements. A host of oxidative and reductive electrocatalytic methodologies are discussed and are grouped according to the classification of the synthetic transformation and the nature of the electrocatalyst.
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    (a) Perkins, R. J.; Hughes, A. J.; Weix, D. J.; Hansen, E. C. Metal-Reductant-Free Electrochemical Nickel-Catalyzed Couplings of Aryl and Alkyl Bromides in Acetonitrile. Org. Process Res. Dev. 2019, 23, 1746– 1751,  DOI: 10.1021/acs.oprd.9b00232
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    Metal-Reductant-Free Electrochemical Nickel-Catalyzed Couplings of Aryl and Alkyl Bromides in Acetonitrile
    Perkins, Robert J.; Hughes, Alexander J.; Weix, Daniel J.; Hansen, Eric C.
    Organic Process Research & Development (2019), 23 (8), 1746-1751CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    While reductive cross-electrochem. coupling is an attractive approach for the synthesis of complex mols. at both small and large scale, two barriers for large-scale applications have remained: the use of stoichiometric metal reductants and a need for amide solvents. In this communication, new conditions that address these challenges are reported. The nickel-catalyzed reductive cross-coupling of aryl bromides with alkyl bromides can be conducted in a divided electrochem. cell using acetonitrile as the solvent and diisopropylamine as the sacrificial reductant to afford coupling products in synthetically useful yields (22-80%). Addnl., the use of a combination of the ligands 4,4',4''-tri-tert-butyl-2,2':6',2'-terpyridine and 4,4'-di-tert-butyl-2,2'-bipyridine is essential to achieve high yields.
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    (b) Perkins, R. J.; Pedro, D. J.; Hansen, E. C. Electrochemical Nickel Catalysis for Sp2-Sp3 Cross-Electrophile Coupling Reactions of Unactivated Alkyl Halides. Org. Lett. 2017, 19, 3755– 3758,  DOI: 10.1021/acs.orglett.7b01598
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    Electrochemical Nickel Catalysis for Sp2-Sp3 Cross-Electrophile Coupling Reactions of Unactivated Alkyl Halides
    Perkins, Robert J.; Pedro, Dylan J.; Hansen, Eric C.
    Organic Letters (2017), 19 (14), 3755-3758CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A const.-current electrochem. method for reducing catalytic Ni complexes in sp2-sp3 cross-electrophile coupling reactions was developed. The electrochem. redn. provides reliable Ni catalyst activation and turnover and offers a tunable parameter for reaction optimization, in contrast to more std. activated metal powder reductants. The electrochem. reactions give yields (i.e., 51-86%) and selectivities as high or superior to those using metal powder reductants and provide access to a wider substrate scope.
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  • Abstract

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    Scheme 1

    Scheme 1. Challenges in C(sp3)–C(sp3) Cross-Electrophile Coupling
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    Scheme 2

    Scheme 2. Scope of the Electrochemical Cross-Coupling of Alkyl Tosylates with Alkyl Bromidesd
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    aConditions A: 3 mL volume, 0.1 M NaBr, 1.3 equiv alkyl bromide, 600 rpm, under Ar.

    bConditions B: same as conditions A with 0.075 M NaBr and 2 equiv alkyl bromide.

    cGC-FID yield using biphenyl as internal standard.

    dIsolated yields are shown.

    Figure 1

    Figure 1. (a) Monitoring of the reaction mixture during the cross-coupling of 1a with 1b (Table 1, entry 1). (b) Control experiment using bromide 1f instead of tosylate 1a.

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    Figure 2

    Figure 2. Proposed mechanism for electrochemical cross-coupling.

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  • References

    This article references 22 other publications.

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      Liu, Jing-Hui; Yang, Chu-Ting; Lu, Xiao-Yu; Zhang, Zhen-Qi; Xu, Ling; Cui, Mian; Lu, Xi; Xiao, Bin; Fu, Yao; Liu, Lei
      Chemistry - A European Journal (2014), 20 (47), 15334-15338CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      In the presence of copper iodide and bis(diphenylphosphino)methane (DPPM), alkyl mesylates and tosylates such as PhCH2CH2CH2OSO2R (R = Me, 4-MeC6H4) underwent chemoselective reductive coupling reactions with alkyl and aryl bromides such as cyclohexyl bromide and 4-bromo-N,N-dimethylaniline mediated by LiOMe and Mg metal to yield alkanes such as PhCH2CH2CH2R1 (R1 = cyclohexyl, 4-Me2NC6H4) in 25-89% yields. Coupling of a nonracemic pyrrolidinyl tosylate with bromocyclohexane under the reaction conditions yielded product of inverted configuration in 99.7% ee. Partially satd. benzo-fused oxacycles such as 2,3-dihydrobenzofuran were prepd. chemoselectively by reductive cyclizations of bromoaryloxyalkyl tosylates such as 2-BrC6H4OCH2CH2OTs (Ts = 4-MeC6H4SO2) in the presence of CuI and DPPM mediated by LiOMe and Mg metal. The structure and abs. configuration of (R)-3-cyclohexyl-1-(phenylsulfonyl)pyrrolidine [prepd. from the tosylate of (R)-1-phenylsulfonyl-3-pyrrolidinol] were detd. by X-ray crystallog.
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    6. 6
      Lyon, W. L.; MacMillan, D. W. C. Expedient Access to Underexplored Chemical Space: Deoxygenative C(sp3)–C(sp3) Cross-Coupling. J. Am. Chem. Soc. 2023, 145, 7736– 7742,  DOI: 10.1021/jacs.3c01488
      6
      Expedient Access to Underexplored Chemical Space: Deoxygenative C(sp3)-C(sp3) Cross-Coupling
      Lyon, William L.; MacMillan, David W. C.
      Journal of the American Chemical Society (2023), 145 (14), 7736-7742CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      An N-heterocyclic carbene (NHC)-mediated deoxygenative alkylation of alcs. and alkyl bromides via nickel-metallaphotoredox catalysis was reported. This C(sp3)-C(sp3) cross-coupling exhibited a broad scope and was capable of forming bonds between two secondary carbon centers, a longstanding challenge in the field. Highly strained three-dimensional systems such as spirocycles, bicycles, and fused rings were excellent substrates, enabling the synthesis of new mol. frameworks. Linkages between pharmacophoric satd. ring systems were readily forged, representing a three-dimensional alternative to traditional biaryl formation. The utility of this cross-coupling technol. was highlighted with the expedited synthesis of bioactive mols.
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    7. 7
      Weix, D. J. Methods and Mechanisms for Cross-Electrophile Coupling of Csp2 Halides with Alkyl Electrophiles. Acc. Chem. Res. 2015, 48, 1767– 1775,  DOI: 10.1021/acs.accounts.5b00057
      7
      Methods and Mechanisms for Cross-Electrophile Coupling of Csp2 Halides with Alkyl Electrophiles
      Weix, Daniel J.
      Accounts of Chemical Research (2015), 48 (6), 1767-1775CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. Cross-electrophile coupling, the cross-coupling of two different electrophiles, avoids the need for preformed carbon nucleophiles, but development of general methods has lagged behind cross-coupling and C-H functionalization. A central reason for this slow development is the challenge of selectively coupling two substrates that are alike in reactivity. This Account describes the discovery of generally cross-selective reactions of aryl halides and acyl halides with alkyl halides, the mechanistic studies that illuminated the underlying principles of these reactions, and the use of these fundamental principles in the rational design of new cross-electrophile coupling reactions. Although the coupling of two different electrophiles under reducing conditions often leads primarily to sym. dimers, the subtle differences in reactivity of aryl halides and alkyl halides with nickel catalysts allowed for generally cross-selective coupling reactions. These conditions could also be extended to the coupling of acyl halides with alkyl halides. These reactions are exceptionally functional group tolerant and can be assembled on the benchtop. A combination of stoichiometric and catalytic studies on the mechanism of these reactions revealed an unusual radical-chain mechanism and suggests that selectivity arises from (1) the preference of nickel(0) for oxidative addn. to aryl halides and acyl halides over alkyl halides and (2) the greater propensity of alkyl halides to form free radicals. Bipyridine-ligated arylnickel intermediates react with alkyl radicals to efficiently form, after reductive elimination, new C-C bonds. Finally, the resulting nickel(I) species is proposed to regenerate an alkyl radical to carry the chain. Examples of new reactions designed using these principles include carbonylative coupling of aryl halides with alkyl halides to form ketones, arylation of epoxides to form β-aryl alcs., and coupling of benzyl sulfonate esters with aryl halides to form diarylmethanes. Arylnickel(II) intermediates can insert carbon monoxide to form acylnickel(II) intermediates that react with alkyl halides to form ketones, demonstrating the connection between the mechanisms of reactions of aryl halides and acid chlorides with alkyl halides. The low reactivity of epoxides with nickel can be overcome by the use of either titanium or iodide cocatalysis to facilitate radical generation and this can also be extended to enantioselective arylation of meso-epoxides. The high reactivity of benzyl bromide with nickel, which leads to the formation of bibenzyl in attempted reactions with bromobenzene, can be overcome by using a benzyl mesylate along with cobalt phthalocyanine cocatalysis to convert the mesylate into an alkyl radical.
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    8. 8
      Li, Y.; Li, Y.; Peng, L.; Wu, D.; Zhu, L.; Yin, G. Nickel-catalyzed migratory alkyl-alkyl cross-coupling reaction. Chem. Sci. 2020, 11, 10461– 10464,  DOI: 10.1039/D0SC03217D
      8
      Nickel-catalyzed migratory alkyl-alkyl cross-coupling reaction
      Li, Yangyang; Li, Yuqiang; Peng, Long; Wu, Dong; Zhu, Lei; Yin, Guoyin
      Chemical Science (2020), 11 (38), 10461-10464CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      A migratory cross-coupling strategy, which can overcome this obstacle to access the desired cross-coupling products ArCH(R)(CH2)nCR1R2R3 (Ar = Ph, 4-fluorophenyl, indol-3-yl, etc.; R = cyclopentyl, cyclohexyl, cycloheptyl, N-benzyl-piperidin-4-yl, 2-methyl-propan-1-yl; R1 = H, D; R2 = H, D; R3 = H; n = 0-3, 5), 1-cyclopentyl-indan, 1-cycloheptyl-indan, (1-cyclopentyl-3-methyl-pentyl)benzene was described. Accordingly, a selective migratory cross-coupling of two alkyl electrophiles (RBr, ArCH(R)(CH2)nCR1R2R3 (R3 = Br or Cl), 2-bromoindan, (5-bromo-1-cyclopentyl-3-methyl-pentyl)benzene) has been accomplished by nickel catalysis. Remarkably, this alkyl-alkyl cross-coupling reaction provides a platform to prep. 2°-2° carbon-carbon bonds from 1° and 2° carbon coupling partners. Preliminary mechanistic studies suggest that chain-walking occurs at both alkyl halides in this reaction, thus a catalytic cycle with the key step involving two alkylnickel(II) species is proposed for this transformation.
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    9. 9
      Cherney, A. H.; Reisman, S. E. Nickel-catalyzed asymmetric reductive cross-coupling between vinyl and benzyl electrophiles. J. Am. Chem. Soc. 2014, 136, 14365– 14368,  DOI: 10.1021/ja508067c
      9
      Nickel-Catalyzed Asymmetric Reductive Cross-Coupling Between Vinyl and Benzyl Electrophiles
      Cherney, Alan H.; Reisman, Sarah E.
      Journal of the American Chemical Society (2014), 136 (41), 14365-14368CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A Ni-catalyzed asym. reductive cross-coupling between vinyl bromides and benzyl chlorides has been developed. This method provides direct access to enantioenriched products bearing aryl-substituted tertiary allylic stereogenic centers from simple, stable starting materials. A broad substrate scope is achieved under mild reaction conditions that preclude the pregeneration of organometallic reagents and the regioselectivity issues commonly assocd. with asym. allylic arylation.
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    10. 10
      (a) Zhu, C.; Ang, N. W. J.; Meyer, T. H.; Qiu, Y.; Ackermann, L. Organic Electrochemistry: Molecular Syntheses with Potential. ACS Cent. Sci. 2021, 7, 415– 431,  DOI: 10.1021/acscentsci.0c01532
      10a
      Organic Electrochemistry: Molecular Syntheses with Potential
      Zhu, Cuiju; Ang, Nate W. J.; Meyer, Tjark H.; Qiu, Youai; Ackermann, Lutz
      ACS Central Science (2021), 7 (3), 415-431CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      A review. Efficient and selective mol. syntheses are paramount to inter alia biomol. chem. and material sciences as well as for practitioners in chem., agrochem., and pharmaceutical industries. Org. electrosynthesis has undergone a considerable renaissance and has thus in recent years emerged as an increasingly viable platform for the sustainable mol. assembly. In stark contrast to early strategies by innate reactivity, electrochem. was recently merged with modern concepts of org. synthesis, such as transition-metal-catalyzed transformations for inter alia C-H functionalization and asym. catalysis. Herein, we highlight the unique potential of org. electrosynthesis for sustainable synthesis and catalysis, showcasing key aspects of exceptional selectivities, the synergism with photocatalysis, or dual electrocatalysis, and novel mechanisms in metallaelectrocatalysis until Feb. of 2021.
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      (b) Pollok, D.; Waldvogel, S. R. Electro-organic synthesis – a 21st century technique. Chem. Sci. 2020, 11, 12386– 12400,  DOI: 10.1039/D0SC01848A
      10b
      Electro-organic synthesis - a 21st century technique
      Pollok, Dennis; Waldvogel, Siegfried R.
      Chemical Science (2020), 11 (46), 12386-12400CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      The severe limitations of fossil fuels and finite resources influence the scientific community to reconsider chem. synthesis and establish sustainable techniques. Several promising methods have emerged, and electro-org. conversion has attracted particular attention from international academia and industry as an environmentally benign and cost-effective technique. The easy application, precise control, and safe conversion of substrates with intermediates only accessible by this method reveal novel pathways in synthetic org. chem. The popularity of electricity as a reagent is accompanied by the feasible conversion of bio-based feedstocks to limit the carbon footprint. Several milestones have been achieved in electro-org. conversion at rapid frequency, which have opened up various perspectives for forthcoming processes.
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      (c) Horn, E. J.; Rosen, B. R.; Baran, P. S. Synthetic organic electrochemistry: an enabling and innately sustainable method. ACS Cent. Sci. 2016, 2, 302– 308,  DOI: 10.1021/acscentsci.6b00091
      10c
      Synthetic Organic Electrochemistry: An Enabling and Innately Sustainable Method
      Horn, Evan J.; Rosen, Brandon R.; Baran, Phil S.
      ACS Central Science (2016), 2 (5), 302-308CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      A review. While preparative electrolysis of org. mols. has been an active area of research over the past century, modern synthetic chemists have generally been reluctant to adopt this technol. In fact, electrochem. methods possess many benefits over traditional reagent-based transformations, such as high functional group tolerance, mild conditions, and innate scalability and sustainability. In this Outlook, we highlight illustrative examples of electrochem. reactions in the context of the synthesis of complex mols., showcasing the intrinsic benefits of electrochem. reactions vs. traditional reagent-based approaches. Our hope is that this field will soon see widespread adoption in the synthetic community.
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    11. 11
      (a) Shatskiy, A.; Lundberg, H.; Kärkäs, M. D. Organic Electrosynthesis: Applications in Complex Molecule Synthesis. ChemElectroChem. 2019, 6, 4067– 4092,  DOI: 10.1002/celc.201900435
      11a
      Organic Electrosynthesis: Applications in Complex Molecule Synthesis
      Shatskiy, Andrey; Lundberg, Helena; Kaerkaes, Markus D.
      ChemElectroChem (2019), 6 (16), 4067-4092CODEN: CHEMRA; ISSN:2196-0216. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review on. Org. electrosynthesis is an enabling and sustainable technol., which constitutes a rapidly expanding field of research. Electrochem. approaches serve as convenient and green alternatives to stoichiometric and toxic chem. redox agents. Electrosynthesis constitutes a promising platform for harnessing the unique reactivity profiles of radical intermediates, expediting the development of new reaction manifolds. This review highlights both anodic and cathodic methods for the construction of various kinds of complex mols.
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      (b) Cantillo, D. Synthesis of active pharmaceutical ingredients using electrochemical methods: keys to improve sustainability. Chem. Commun. 2022, 58, 619– 628,  DOI: 10.1039/D1CC06296D
      11b
      Synthesis of active pharmaceutical ingredients using electrochemical methods: keys to improve sustainability
      Cantillo, David
      Chemical Communications (Cambridge, United Kingdom) (2022), 58 (5), 619-628CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Org. electrochem. is receiving renewed attention as a green and cost-efficient synthetic technol. Electrochem. methods promote redox transformations by electron exchange between electrodes and species in soln., thus avoiding the use of stoichiometric amts. of oxidizing or reducing agents. The rapid development of electroorg. synthesis over the past decades has enabled the prepn. of mols. of increasing complexity. Redox steps that involve hazardous or waste-generating reagents during the synthesis of active pharmaceutical ingredients or their intermediates can be substituted by electrochem. procedures. In addn. to enhance sustainability, increased selectivity toward the target compd. has been achieved in some cases. Electroorg. synthesis can be safely and readily scaled up to prodn. quantities. For this pupose, utilization of flow electrolysis cells is fundamental. Despite these advantages, the application of electrochem. methods does not guarantee superior sustainability when compared with conventional protocols. The utilization of large amts. of supporting electrolytes, environmentally unfriendly solvents or sacrificial electrodes may turn electrochem. unfavorable in some cases. It is therefore crucial to carefully select and optimize the electrolysis conditions and carry out green metrics anal. of the process to ensure that turning a process electrochem. is advantageous.
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    12. 12
      (a) Yan, M.; Kawamata, Y.; Baran, P. S. Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance. Chem. Rev. 2017, 117, 13230– 13319,  DOI: 10.1021/acs.chemrev.7b00397
      12a
      Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance
      Yan, Ming; Kawamata, Yu; Baran, Phil S.
      Chemical Reviews (Washington, DC, United States) (2017), 117 (21), 13230-13319CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. This review discusses advances in synthetic org. electrochem. since 2000. Enabling methods and synthetic applications are analyzed alongside innate advantages as well as future challenges of electroorg. chem.
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      (b) Wiebe, A.; Gieshoff, T.; Möhle, S.; Rodrigo, E.; Zirbes, M.; Waldvogel, S. R. Electrifying Organic Synthesis. Angew. Chem., Int. Ed. 2018, 57, 5594– 5619,  DOI: 10.1002/anie.201711060
      12b
      Electrifying Organic Synthesis
      Wiebe, Anton; Gieshoff, Tile; Moehle, Sabine; Rodrigo, Eduardo; Zirbes, Michael; Waldvogel, Siegfried R.
      Angewandte Chemie, International Edition (2018), 57 (20), 5594-5619CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. The direct synthetic org. use of electricity is currently experiencing a renaissance. More synthetically oriented labs. working in this area are exploiting both novel and more traditional concepts, paving the way to broader applications of this niche technol. As only electrons serve as reagents, the generation of reagent waste is efficiently avoided. Moreover, stoichiometric reagents can be regenerated and allow a transformation to be conducted in an electrocatalytic fashion. However, the application of electroorg. transformations is more than minimizing the waste footprint, it rather gives rise to inherently safe processes, reduces the no. of steps of many syntheses, allows for milder reaction conditions, provides alternative means to access desired structural entities, and creates intellectual property (IP) space. When the electricity originates from renewable resources, this surplus might be directly employed as a terminal oxidizing or reducing agent, providing an ultra-sustainable and therefore highly attractive technique. This Review surveys recent developments in electrochem. synthesis that will influence the future of this area.
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    13. 13
      (a) Gandeepan, P.; Finger, L. H.; Meyer, T. H.; Ackermann, L. 3d Metallaelectrocatalysis for Resource Economical Syntheses. Chem. Soc. Rev. 2020, 49, 4254– 4272,  DOI: 10.1039/D0CS00149J
      13a
      3d metallaelectrocatalysis for resource economical syntheses
      Gandeepan, Parthasarathy; Finger, Lars H.; Meyer, Tjark H.; Ackermann, Lutz
      Chemical Society Reviews (2020), 49 (13), 4254-4272CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      Resource economy constitutes one of the key challenges for researchers and practitioners in academia and industries, in terms of rising demand for sustainable and green synthetic methodol. To achieve ideal levels of resource economy in mol. syntheses, novel avenues are required, which include, but are not limited to the use of naturally abundant, renewable feedstocks, solvents, metal catalysts, energy, and redox reagents. In this context, electrosyntheses create the unique possibility to replace stoichiometric amts. of oxidizing or reducing reagents as well as electron transfer events by elec. current. Particularly, the merger of Earth-abundant 3d metal catalysis and electrooxidn. has recently been recognized as an increasingly viable strategy to forge challenging C-C and C-heteroatom bonds for complex org. mols. in a sustainable fashion under mild reaction conditions. In this review, we highlight the key developments in 3d metallaelectrocatalysis in the context of resource economy in mol. syntheses until Feb. 2020.
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      (b) Park, S. H.; Ju, M.; Ressler, A. J.; Shim, J.; Kim, H.; Lin, S. Reductive Electrosynthesis: A New Dawn. Aldrichimica Acta 2021, 54, 17– 27
      13b
      Reductive electrosynthesis: a new dawn
      Park, Steve H.; Ju, Minsoo; Ressler, Andrew J.; Shim, Jiwoo; Kim, Hyunwoo; Lin, Song
      Aldrichimica Acta (2021), 54 (1Spec.Iss.), 17-27CODEN: ALACBI ISSN:. (Sigma-Aldrich Co. LLC.)
      A review. The renewed interest in synthetic org. electrochem. has led in recent years to a surge in literature reports on new electrochem. reaction methods and synthetic strategies. While oxidative electrochem. has been extensively studied in org. synthesis, reductive electrosynthesis in comparison remains substantially underexplored. Recent developments in this area have introduced innovative strategies to enable new transformations and control reaction selectivity. Here, we highlight examples of recent advances in direct reductive electrolysis, indirect reductive electrolysis, and reductive electrophotocatalysis.
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      (c) Malapit, C. A.; Prater, M. B.; Cabrera-Pardo, J. R.; Li, M.; Pham, T. D.; McFadden, T. P.; Blank, S.; Minteer, S. D. Advances on the Merger of Electrochemistry and Transition Metal Catalysis for Organic Synthesis. Chem. Rev. 2022, 122, 3180– 3218,  DOI: 10.1021/acs.chemrev.1c00614
      13c
      Advances on the Merger of Electrochemistry and Transition Metal Catalysis for Organic Synthesis
      Malapit, Christian A.; Prater, Matthew B.; Cabrera-Pardo, Jaime R.; Li, Min; Pham, Tammy D.; McFadden, Timothy Patrick; Blank, Skylar; Minteer, Shelley D.
      Chemical Reviews (Washington, DC, United States) (2022), 122 (3), 3180-3218CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. This review discussed recent advances in the combination of electrochem. and homogeneous transition-metal catalysis for org. synthesis. The enabling transformations, synthetic applications, and mechanistic studies was presented alongside advantages as well as future directions to address the challenges of metal-catalyzed electrosynthesis.
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      (d) Novaes, L. F. T.; Liu, J.; Shen, Y.; Lu, L.; Meinhardt, J. M.; Lin, S. Electrocatalysis as an enabling technology for organic synthesis. Chem. Soc. Rev. 2021, 50, 7941– 8002,  DOI: 10.1039/D1CS00223F
      13d
      Electrocatalysis as an enabling technology for organic synthesis
      Novaes, Luiz F. T.; Liu, Jinjian; Shen, Yifan; Lu, Lingxiang; Meinhardt, Jonathan M.; Lin, Song
      Chemical Society Reviews (2021), 50 (14), 7941-8002CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Electrochem. has recently gained increased attention as a versatile strategy for achieving challenging transformations at the forefront of synthetic org. chem. Electrochem.'s unique ability to generate highly reactive radical and radical ion intermediates in a controlled fashion under mild conditions has inspired the development of a no. of new electrochem. methodologies for the prepn. of valuable chem. motifs. Particularly, recent developments in electrosynthesis have featured an increased use of redox-active electrocatalysts to further enhance control over the selective formation and downstream reactivity of these reactive intermediates. Furthermore, electrocatalytic mediators enable synthetic transformations to proceed in a manner that is mechanistically distinct from purely chem. methods, allowing for the subversion of kinetic and thermodn. obstacles encountered in conventional org. synthesis. This highlights key innovations within the past decade in the area of synthetic electrocatalysis, with emphasis on the mechanisms and catalyst design principles underpinning these advancements. A host of oxidative and reductive electrocatalytic methodologies are discussed and are grouped according to the classification of the synthetic transformation and the nature of the electrocatalyst.
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    14. 14
      (a) Perkins, R. J.; Hughes, A. J.; Weix, D. J.; Hansen, E. C. Metal-Reductant-Free Electrochemical Nickel-Catalyzed Couplings of Aryl and Alkyl Bromides in Acetonitrile. Org. Process Res. Dev. 2019, 23, 1746– 1751,  DOI: 10.1021/acs.oprd.9b00232
      14a
      Metal-Reductant-Free Electrochemical Nickel-Catalyzed Couplings of Aryl and Alkyl Bromides in Acetonitrile
      Perkins, Robert J.; Hughes, Alexander J.; Weix, Daniel J.; Hansen, Eric C.
      Organic Process Research & Development (2019), 23 (8), 1746-1751CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
      While reductive cross-electrochem. coupling is an attractive approach for the synthesis of complex mols. at both small and large scale, two barriers for large-scale applications have remained: the use of stoichiometric metal reductants and a need for amide solvents. In this communication, new conditions that address these challenges are reported. The nickel-catalyzed reductive cross-coupling of aryl bromides with alkyl bromides can be conducted in a divided electrochem. cell using acetonitrile as the solvent and diisopropylamine as the sacrificial reductant to afford coupling products in synthetically useful yields (22-80%). Addnl., the use of a combination of the ligands 4,4',4''-tri-tert-butyl-2,2':6',2'-terpyridine and 4,4'-di-tert-butyl-2,2'-bipyridine is essential to achieve high yields.
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      (b) Perkins, R. J.; Pedro, D. J.; Hansen, E. C. Electrochemical Nickel Catalysis for Sp2-Sp3 Cross-Electrophile Coupling Reactions of Unactivated Alkyl Halides. Org. Lett. 2017, 19, 3755– 3758,  DOI: 10.1021/acs.orglett.7b01598
      14b
      Electrochemical Nickel Catalysis for Sp2-Sp3 Cross-Electrophile Coupling Reactions of Unactivated Alkyl Halides
      Perkins, Robert J.; Pedro, Dylan J.; Hansen, Eric C.
      Organic Letters (2017), 19 (14), 3755-3758CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      A const.-current electrochem. method for reducing catalytic Ni complexes in sp2-sp3 cross-electrophile coupling reactions was developed. The electrochem. redn. provides reliable Ni catalyst activation and turnover and offers a tunable parameter for reaction optimization, in contrast to more std. activated metal powder reductants. The electrochem. reactions give yields (i.e., 51-86%) and selectivities as high or superior to those using metal powder reductants and provide access to a wider substrate scope.
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      (c) Hamby, T. H.; Lalama, M. J.; Sevov, C. C. Controlling Ni redox states by dynamic ligand exchange for electroreductive Csp3–Csp2 coupling. Science 2022, 376, 410– 416,  DOI: 10.1126/science.abo0039
      14c
      Controlling Ni redox states by dynamic ligand exchange for electroreductive C(sp3)-C(sp2) coupling
      Hamby, Taylor B.; LaLama, Matthew J.; Sevov, Christo S.
      Science (Washington, DC, United States) (2022), 376 (6591), 410-416CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
      Cross-electrophile coupling (XEC) reactions of aryl and alkyl electrophiles are appealing but limited to specific substrate classes. Here, electroreductive XEC of previously incompatible electrophiles including tertiary alkyl bromides, aryl chlorides, and aryl/vinyl triflates are reported. The reactions rely on the merger of an electrochem. active complex that selectively reacts with alkyl bromides through 1e- processes and an electrochem. inactive Ni0(phosphine) complex that selectively reacts with aryl electrophiles through 2e- processes. Accessing Ni0(phosphine) intermediates is crit. to the strategy but is often challenging. Here, a previously unknown pathway for electrochem. generating these key complexes at mild potentials through a choreographed series of ligand-exchange reactions has been uncovered. The mild methodol. is applied to the alkylation of a range of substrates including natural products and pharmaceuticals.
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    15. 15

      For a review, see:

      Yi, L.; Ji, T.; Chen, K.-Q.; Chen, X.-Y.; Rueping, M. Nickel-Catalyzed Reductive Cross-Couplings: New Opportunities for Carbon–Carbon Bond Formations through Photochemistry and Electrochemistry. CCS Chem. 2022, 4, 9– 30,  DOI: 10.31635/ccschem.021.202101196
      15
      Nickel-catalyzed reductive cross-couplings: new opportunities for carbon-carbon bond formations through photochemistry and electrochemistry
      Yi, Liang; Ji, Tengfei; Chen, Kun-Quan; Chen, Xiang-Yu; Rueping, Magnus
      CCS Chemistry (2022), 4 (1), 9-30CODEN: CCCHB2 ISSN:. (Chinese Chemical Society)
      A review. 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 electrochem.
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    16. 16
      Zhang, W.; Lu, L.; Zhang, W.; Wang, Y.; Ware, S. D.; Mondragon, J.; Rein, J.; Strotman, N.; Lehnherr, D.; See, K. A.; Lin, S. Electrochemically Driven Cross-Electrophile Coupling of Alkyl Halides. Nature 2022, 604, 292– 297,  DOI: 10.1038/s41586-022-04540-4
      16
      Electrochemically driven cross-electrophile coupling of alkyl halides
      Zhang, Wen; Lu, Lingxiang; Zhang, Wendy; Wang, Yi; Ware, Skyler D.; Mondragon, Jose; Rein, Jonas; Strotman, Neil; Lehnherr, Dan; See, Kimberly A.; Lin, Song
      Nature (London, United Kingdom) (2022), 604 (7905), 292-297CODEN: NATUAS; ISSN:1476-4687. (Nature Portfolio)
      Here, electrochem. were used to achieve the differential activation of alkyl halides e.g., 2-(2-bromopropan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (I) by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic redn. of a more substituted alkyl halide (I) gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimol. nucleophilic substitution to forge a new carbon-carbon bond. This protocol enables efficient cross-electrophile coupling of a variety of functionalized and unactivated alkyl electrophiles in the absence of a transition metal catalyst, and shows improved chemoselectivity compared with existing methods.
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    17. 17
      Chen, Y. Recent Advances in Methylation: A Guide for Selecting Methylation Reagents. Chem. Eur. J. 2019, 25, 3405– 3439,  DOI: 10.1002/chem.201803642
      17
      Recent Advances in Methylation: A Guide for Selecting Methylation Reagents
      Chen, Yantao
      Chemistry - A European Journal (2019), 25 (14), 3405-3439CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Methylation is a well-known structural modification in org. and medicinal chem. This review summarizes recent advances in methylation by categorizing specific methylation reagents. The challenges of mono N-methylation of aliph. amines and N-methylation of peptides are discussed. This review will be useful for chemists wanting to select the appropriate reagents for methylation chem. Based on the large diversity of methylation reagents and their wide scope, this review also broadens perspectives on which strategies to select for utilizing a particular methylation, resulting in an increased flexibility in synthetic route planning.
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    18. 18
      Molander, G. A.; Traister, K. M.; O’Neill, B. T. Engaging Nonaromatic, Heterocyclic Tosylates in Reductive Cross-Coupling with Aryl and Heteroaryl Bromides. J. Org. Chem. 2015, 80, 2907– 2911,  DOI: 10.1021/acs.joc.5b00135
      18
      Engaging Nonaromatic, Heterocyclic Tosylates in Reductive Cross-Coupling with Aryl and Heteroaryl Bromides
      Molander, Gary A.; Traister, Kaitlin M.; O'Neill, Brian T.
      Journal of Organic Chemistry (2015), 80 (5), 2907-2911CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      A method has been developed for the introduction of nonarom. heterocyclic structures onto aryl and heteroaryl bromides using alkyl tosylates in a reductive cross-coupling manifold. This protocol offers an improvement over previous methods by utilizing alkyl tosylate coupling partners that are bench-stable, cryst. solids that can be prepd. from inexpensive, com. available alcs. E.g., in presence of NiBr2.glyme and 4,4'-di-tert-butyl-2,2'-bipyridine, cross-coupling of tosylate (I) with N-Boc-5-bromoindole gave 73% II.
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    19. 19
      Barman, K.; Edwards, M. A.; Hickey, D. P.; Sandford, C.; Qiu, Y.; Gao, R.; Minteer, S. D.; White, H. S. Electrochemical Reduction of [Ni(Mebpy)3]2+: Elucidation of the Redox Mechanism by Cyclic Voltammetry and Steady-State Voltammetry in Low Ionic Strength Solutions. ChemElectroChem. 2020, 7, 1473– 1479,  DOI: 10.1002/celc.202000171
      19
      Electrochemical Reduction of [Ni(Mebpy)3]2+: Elucidation of the Redox Mechanism by Cyclic Voltammetry and Steady-State Voltammetry in Low Ionic Strength Solutions
      Barman, Koushik; Edwards, Martin A.; Hickey, David P.; Sandford, Christopher; Qiu, Yinghua; Gao, Rui; Minteer, Shelley D.; White, Henry S.
      ChemElectroChem (2020), 7 (6), 1473-1479CODEN: CHEMRA; ISSN:2196-0216. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Bipyridine complexes of Ni are used as catalysts in a variety of reductive transformations. Here, the electroredn. of [Ni(Mebpy)3]2+ (Mebpy=4,4'-dimethyl-2,2'-bipyridine) in DMF is reported, with the aim of detg. the redox mechanism and oxidn. states of products formed under well-controlled electrochem. conditions. Results from cyclic voltammetry, steady-state voltammetry (SSV) and chronoamperometry demonstrate that [Ni(Mebpy)3]2+ undergoes two sequential 1e redns. at closely sepd. potentials (E10'=-1.06±0.01 V and E20'=-1.15±0.01 V vs Ag/AgCl (3.4 M KCl)). Homogeneous comproportionation to generate [Ni(Mebpy)3]+ is demonstrated in SSV expts. in low ionic strength solns. The comproportionation rate const. is detd. to be >106 M-1 s-1, consistent with rapid outer-sphere electron transfer. Consequentially, on voltammetric time scales, the 2e redn. of [Ni(Mebpy)3]2+ results in formation of [Ni(Mebpy)3]+ as the predominant species released into bulk soln. We also demonstrate that [Ni(Mebpy)3]0 slowly loses a Mebpy ligand (∼10 s-1).
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    20. 20
      Everson, D. A.; Shrestha, R.; Weix, D. J. Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with Alkyl Halides. J. Am. Chem. Soc. 2010, 132, 920– 921,  DOI: 10.1021/ja9093956
      20
      Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with Alkyl Halides
      Everson, Daniel A.; Shrestha, Ruja; Weix, Daniel J.
      Journal of the American Chemical Society (2010), 132 (3), 920-921CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The direct reductive cross-coupling of alkyl halides with aryl halides is described. The transformation is efficient (equimolar amts. of the starting materials are used), generally high-yielding (all but one between 55 and 88% yield), highly functional-group-tolerant [OH, NHBoc, NHCbz, Bpin, C(O)Me, CO2Et, and CN are all tolerated], and easy to perform (uses only benchtop-stable reagents, tolerates small amts. of water and oxygen, changes color when complete, and uses filtration workup). The reaction appears to avoid the formation of intermediate organomanganese species, and a synergistic effect was found when a mixt. of two ligands was employed.
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    21. 21
      Greaves, M. E.; Johnson Humphrey, E. L. B.; Nelson, D. J. Reactions of nickel(0) with organochlorides, organobromides, and organoiodides: mechanisms and structure/reactivity relationships. Catal. Sci. Technol. 2021, 11, 2980– 2996,  DOI: 10.1039/D1CY00374G
      21
      Reactions of nickel(0) with organochlorides, organobromides, and organoiodides: mechanisms and structure/reactivity relationships
      Greaves, Megan E.; Johnson Humphrey, Elliot L. B.; Nelson, David J.
      Catalysis Science & Technology (2021), 11 (9), 2980-2996CODEN: CSTAGD; ISSN:2044-4753. (Royal Society of Chemistry)
      A review. The reactions of nickel(0) complexes with organohalides have been reviewed. The review is divided according to the class of ligand that is present on nickel: phosphine, N-heterocyclic carbene, or bidentate nitrogen ligand. The preferred mechanism of reaction is often detd. by a delicate balance of ligand and substrate structure, and relatively small changes can lead to large differences in behavior. This will have an impact on the progress of catalytic reactions that use organohalide substrates, and may influence ligand selection and/or the scope and limitations of the reaction.
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    22. 22
      Till, N. A.; Tian, L.; Dong, Z.; Scholes, G. D.; MacMillan, D. W. C. Mechanistic Analysis of Metallaphotoredox C-N Coupling: Photocatalysis Initiates and Perpetuates Ni(I)/Ni(III) Coupling Activity. J. Am. Chem. Soc. 2020, 142, 15830– 15841,  DOI: 10.1021/jacs.0c05901
      22
      Mechanistic Analysis of Metallaphotoredox C-N Coupling: Photocatalysis Initiates and Perpetuates Ni(I)/Ni(III) Coupling Activity
      Till, Nicholas A.; Tian, Lei; Dong, Zhe; Scholes, Gregory D.; MacMillan, David W. C.
      Journal of the American Chemical Society (2020), 142 (37), 15830-15841CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The combined use of reaction kinetic anal., ultrafast spectroscopy, and stoichiometric organometallic studies has enabled the elucidation of the mechanistic underpinnings to a photocatalytic C-N cross-coupling reaction. Steady-state and ultrafast spectroscopic techniques were used to track the excited-state evolution of the employed iridium photocatalyst, det. the resting states of both iridium and nickel catalysts, and uncover the photochem. mechanism for reductive activation of the nickel cocatalyst. Stoichiometric organometallic studies along with a comprehensive kinetic study of the reaction, including rate-driving force anal., unveiled the crucial role of photocatalysis in both initiating and sustaining a Ni(I)/Ni(III) cross-coupling mechanism. The insights gleaned from this study further enabled the discovery of a new photocatalyst providing a >30-fold rate increase.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c07313.

    • Materials and methods, additional optimization data, characterization data for the cathode material, experimental procedures, characterization data, and NMR spectra (PDF)


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