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

Abstract

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.