C2 Homologation of Alkenes with Programmable Substitution

Alkene homologation represents an efficient strategy for upgrading commodity olefins and expediting the synthesis of their longer homologues. However, current alkene homologation methodologies are limited to the access to terminal alkenes. Herein, we report a radical‑based approach that enables C2 homologation of alkenes with programmable substitution patterns. This transformation features a radical hydro-alkylation of alkenes using bromomethylphosphonium hexafluorophosphate as an electrophilic carbon radical precursor. The resulting phosphonium salt, bearing a C1-extended chain, undergoes Wittig olefination with inexpensive aldehyde/ketone to deliver C2-elongated terminal/1,2-/1,1,2-substituted alkenes (>40 examples, up to 99% yield; Z/E up to >20:1, with photocatalytic access to the E-isomers). This protocol exhibits broad functional group tolerance and is applicable to the late-stage modification of bioactive compounds, pharmaceuticals, and liquid crystals. Furthermore, by iteratively combining this C2 method with our previously established C1 homologation, the olefinic chains of complex molecules can be precisely elongated by three, four, or more carbon atoms. Comprehensive mechanistic studies, including DFT calculations and experimental probes, support a radical pathway and identify hydrogen bonding between HFIP and triethylamine, which raises the competing HAT barrier from 8.5 to 13.1 kcal/mol, as the key element that suppresses reductive debromination and channels the radical toward C–C bond formation.