Selective Ni(I)/Ni(III) Process for Consecutive Geminal C(sp3)–C(sp2) Bond Formation

Ni-catalyzed multicomponent cross-couplings have emerged as a powerful strategy for efficiently constructing complex molecular architectures from a diverse array of organic halides. Despite its potential, selectively forming multiple chemical bonds in a single operation, particularly in the realm of cross-electrophile coupling catalysis, remains a significant challenge. In this study, we have developed a consecutive open-shell reductive Ni catalysis, enabling the formation of two geminal C(sp³)–C(sp²) bonds from two stereoelectronically similar C(sp²)–I reactants in conjunction with a methylene electrophile. Using zirconaaziridine and elemental Mg⁰ as reductants, this protocol exhibits broad applicability across a wide range of (hetero)aromatic, alkenyl, and glycal halides, allowing for the rapid assembly of medicinally relevant scaffolds with excellent functional group tolerance. Further kinetic studies suggest a dual “sequential reduction” catalytic process facilitated by a zirconaaziridine-mediated redox-transmetalation process in Ni catalysis. Notably, the concerted oxidative addition of Ni(I)–I across a C(sp²)–I bond, as well as the halide atom abstraction among various C(sp³) electrophiles by an open-shell C(sp²)-Ni(I) species, can proceed with high selectivity. The use of an unsymmetrical methylene electrophile with exceptionally high reactivity in XEC resulted in the rapid accumulation of a benzylic or allylic electrophile intermediate at the outset of reaction, thereby finely controlling the coupling sequence.