Development, Application, and Mechanistic Interrogation of a Dual Ni Catalysis Approach to Photoredox-Based C(sp3)–C(sp3) Cross-Coupling

The installation of alkyl substituents, such as methyl groups, is a crucial tactic for the synthesis and diversification of medicinal compounds with improved pharmacological profiles. However, strategies that leverage methyl radical for C(sp3) methylation remain underdeveloped due to the challenge of obtaining cross-selectivity between fleeting aliphatic radicals and alkyl electrophiles. We report the development, application, and interrogation of a conceptually-novel mechanistic framework for C(sp3)–Me bond formation using two distinct Ni catalysts capable of cross-coupling sterically and electronically diverse alkyl halides (chlorides and bromides) with methyl radical generated photocatalytically from benzaldehyde dimethyl acetal. Furthermore, by modifying the alkyl substituents on the acetal coupling partner, we demonstrate cross-couplings beyond methylation to access an array of 1°–1° and 1°–2° alkyl–alkyl bonds. Experimental and computational mechanistic studies provide support for cooperativity between an in situ-generated (bpy)NiI(X) catalyst that facilitates XAT and inner-sphere C–C bond formation and a (Tp*)NiII(acac) co-catalyst that captures methyl radical and engages in concurrent outer-sphere SH2 coupling.