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.