Cross-Electrophile Coupling through Direct Electrolysis

Conspectus Electrochemical reduction is a powerful means of generating reactive radical and anionic species with a degree of modularity and versatility that rivals other traditional chemical and photochemical reduction approaches. Our group has been motivated by the goal of using electrolysis as an enabling tool to develop reactivity and selectivity that are inaccessible using traditional reductants. In particular, we have leveraged the characteristics of direct electrolysis to promote sequential electron-transfer events that enable net-reductive radical-polar crossover, generating nucleophilic anionic intermediates from electrophilic reactants that undergo umpolung reactions with additional electrophiles. Guided further by physical organic principles, we identified systems that selectively activate a variety of common electrophiles to engage in a diverse array of formal cross-electrophile coupling (XEC) reactions. In this Account, we first describe the development of electroreductive cross-coupling of alkyl halides and its extension to silicon–silicon bond formation. This mechanistic framework was then applied to three-component dialkylation of alkenes using two distinct alkyl halides with high site- and chemoselectivity. Beyond alkyl halides, we further expanded the scope of electroreductive XEC to the deoxygenative functionalization of alcohols with a collection of heteroatom-based electrophiles. These transformations were enabled by in situ activation strategies that convert alcohols into reductively active intermediates, allowing them to behave analogously to alkyl halides and undergo borylation, silylation, and related coupling reactions. Finally, we recognized that an analogous activation logic could also enable the reductive functionalization of carbonyl compounds including ketones, aldehydes, and esters, which remains a major synthetic challenge that cannot be readily resolved by direct cathodic reduction. The continued evolution of activation methods ultimately enabled the formal geminal difunctionalization of electronically unbiased aldehydes and ketones that would otherwise require strongly reducing potentials to activate. These methods provided efficient access to densely functionalized sp3-carbon centers while demonstrating that product selectivity can be regulated through Faradaic control, a unique feature of electrochemistry.