biostudies-literatureLin LQHMinistry of Education - SingaporeWelch FoundationNational Institutes of HealthNIH HHSNIGMS NIH HHSe202317935https://www.ebi.ac.uk/biostudies/studies/S-EPMC11076007biostudies-literatureUnknown63(7)An emerging class of C-C coupling transformations that furnish drug-like building blocks involves catalytic hydrocarbonation of alkenes. However, despite notable advances in the field, hydrocarbon addition to gem-difluoroalkenes without additional electronic activation remains largely unsuccessful. This owes partly to poor reactivity and the propensity of difluoroalkenes to undergo defluorinative side reactions. Here, we report a nickel catalytic system that promotes efficient 1,2-selective hydroarylation and hydroalkenylation, suppressing defluorination and providing straightforward access to a diverse assortment of prized organofluorides bearing difluoromethyl-substituted carbon centers. In contrast to radical-based pathways and reactions triggered by hydrometallation via a nickel-hydride complex, our experimental and computational studies support a mechanism in which a catalytically active nickel-bromide species promotes selective carbonickelation with difluoroalkenes followed by alkoxide exchange and hydride transfer, effectively overcoming the difluoroalkene's intrinsic electronic bias.Angewandte Chemie (International ed. in English)Selective 1,2-Hydroarylation(Alkenylation) of gem-Difluoroalkenes to Access (-CF<sub>2</sub> H) Motifs.PMC11076007R35 GM137797A-2102-20220331A-8000034-00-00R35GM137797Lin LQHRenteria-Gomez AGutierrez OZhang YQParris ABOng KZWMartin RTKoh MJfalseSelective 1,2-Hydroarylation(Alkenylation) of gem-Difluoroalkenes to Access (-CF<sub>2</sub> H) Motifs.An emerging class of C-C coupling transformations that furnish drug-like building blocks involves catalytic hydrocarbonation of alkenes. However, despite notable advances in the field, hydrocarbon addition to gem-difluoroalkenes without additional electronic activation remains largely unsuccessful. This owes partly to poor reactivity and the propensity of difluoroalkenes to undergo defluorinative side reactions. Here, we report a nickel catalytic system that promotes efficient 1,2-selective hydroarylation and hydroalkenylation, suppressing defluorination and providing straightforward access to a diverse assortment of prized organofluorides bearing difluoromethyl-substituted carbon centers. In contrast to radical-based pathways and reactions triggered by hydrometallation via a nickel-hydride complex, our experimental and computational studies support a mechanism in which a catalytically active nickel-bromide species promotes selective carbonickelation with difluoroalkenes followed by alkoxide exchange and hydride transfer, effectively overcoming the difluoroalkene's intrinsic electronic bias.2024-01-01T00:00:00Z2024 Feb2025-04-18T13:01:21.83Z2025-04-06T22:29:38.035ZS-EPMC110760073811766210.1002/anie.202317935