Ni-catalyzed distal-selective gem-difluorovinylation of unactivated alkenes with 2,2-difluorovinyl benzoates

Abstract

The gem-difluoroalkene is a bioisostere of the carbonyl group, used for improving the bioavailability of drug candidates. Here, we present an intermolecular Ni-catalyzed strategy for the distal-selective hydro gem-difluorovinylation of unactivated alkenes, utilizing 2,2-difluorovinyl benzoates (BzO–DFs) as building blocks for the synthesis of a wide array of gem-difluoroenol ethers that are otherwise challenging to produce. Diverse BzO–DF derivatives bearing sensitive functional groups, strained carbocycles, and natural products are prepared from inexpensive bromodifluoroacetates by using metallic zinc as a reductant. The cross-coupling reaction is initiated by Ni(0) oxidative addition to BzO–DFs to form the difluorovinyl Ni(II) complexes as the resting state. The vinyl Ni(II) complexes have been characterized by ESI-MS. The precoordination of the picolinimide auxiliary facilitates the migratory insertion of the difluorovinyl Ni(II) into alkenes, exhibiting exceptional regiocontrol and broad functional group tolerance. Complementary to the methods involving organometallic nucleophiles, this approach employs alkenes as abundant nucleophiles, achieving high distal-selectivity without chain-walked isomerization. The synthetic utility is further demonstrated through late-stage modifications with complex, medicinally relevant molecules.