Ni-electrocatalytic Csp3-Csp3 doubly decarboxylative coupling

Cross-coupling between two similar or identical functional groups to form a new C-C bond is a powerful tool to rapidly assemble complex molecules from readily available building units, as seen with olefin cross-metathesis or various types of cross-electrophile coupling(1,2). The Kolbe electrolysis involves the oxidative electrochemical decarboxylation of alkyl carboxylic acids to their corresponding radical species followed by recombination to generate a new C-C bond(3-12). As one of the oldest known Csp(3)-Csp(3) bond-forming reactions, it holds incredible promise for organic synthesis, yet its use has been almost non-existent. From the perspective of synthesis design, this transformation could allow one to agnostically execute syntheses without regard to polarity or neighbouring functionality just by coupling ubiquitous carboxylates(13). In practice, this promise is undermined by the strongly oxidative electrolytic protocol used traditionally since the nineteenth century(5), thereby severely limiting its scope. Here, we show how a mildly reductive Ni-electrocatalytic system can couple two different carboxylates by means of in situ generated redox-active esters, termed doubly decarboxylative cross-coupling. This operationally simple method can be used to heterocouple primary, secondary and even certain tertiary redox-active esters, thereby opening up a powerful new approach for synthesis. The reaction, which cannot be mimicked using stoichiometric metal reductants or photochemical conditions, tolerates a range of functional groups, is scalable and is used for the synthesis of 32 known compounds, reducing overall step counts by 73%.

Automated summary

“Cross-coupling reactions are powerful tools for rapidly assembling complex molecules, but their use is limited by traditional oxidative electrolytic protocols. This study demonstrates a mildly reductive Ni-electrocatalytic system that enables coupling of different carboxylates through in situ generation of redox-active esters. This simple and versatile method offers a powerful new approach for synthesis by heterocoupling various levels of redox-active esters.”