Synthesis of gem‐Difluoroalkenes via Ni‐Catalyzed Three‐Component Defluorinative Reductive Cross‐Coupling of Organohalides, Alkenes and Trifluoromethyl Alkenes

Comprehensive Summary gem ‐Difluoroalkenes are considered ideal isosteres for metabolically susceptible carbonyl groups in modern drug discovery and medicinal chemistry. In addition, gem ‐difluoroalkenes are used as versatile precursors for the synthesis of difluoroalkylated compounds and monofluoroalkenes. Therefore, a great deal of effort has been devoted to developing efficient methods for their preparation. The catalytic defluorinative functionalization of trifluoromethyl alkenes represents a useful strategy for the preparation of chiral gem ‐difluoroalkenes. However, most of these catalytic processes are still essentially limited to two‐component defluorinative cross‐couplings to form single C—C bonds. Due to the challenge of controlling chemoselectivity in the carbon‐carbon bond forming events, three‐component defluorinative cross‐coupling involving multiple C—C bond formations has rarely been studied. We report a nickel‐catalyzed three‐component defluorinative reductive cross‐coupling of organohalides, alkenes and trifluoromethyl alkenes. A variety of electron‐rich and electron‐deficient alkenes, as well as aryl and alkyl halides can efficiently participate in the formation of three‐component cross‐coupling products. This reaction proceeds under mild conditions and exhibits excellent functional group compatibility without requiring a pendant chelating group, providing a variety of functionalized gem ‐difluoroalkenes in good yields with excellent chemoselectivity.