Nickel Catalyzed Markovnikov Hydrodifluoromethylation Of Alkynes

The difluoromethyl group is an important fluorine-containing group,which can be used as a bioisostere of hydroxyl,sulfhydryl,amino and a weak hydrogen bond donor in bioactive compounds.Therefore,the selective introduction of difluoromethyl group into organic molecules has attracted wide attention of scientists.In the past few decades,the difluoromethylation reaction of aromatic compounds has made significant progress,but there are few reports on the construction of difluoromethylated olefins,especially the synthesis ofα-difluoromethylated olefins.In recent years,transition metal-catalyzed hydroalkylation of alkynes has become a powerful strategy for the construction of substituted olefins with different regioselectivity and stereoselectivity.Nevertheless,the correspond hydrodifluoromethylation reaction of alkynes with electrophilic difluoromethylating reagents to constructα-CF₂H olefins has not been reported.Therefore,it is of great interest to explore theα-CF₂H hydro-difluoromethylation reaction of alkynes with fluorine-containing electrophiles via nickel catalysis to constructα-CF₂H olefins.Based on the strategy of Ni H-catalyzed hydroalkylation of alkynes,we used Br CF₂H as the difluoromethylation reagent,Ni Cl₂·（PCy₃）₂ as the nickel catalyst,dtbbpy as the ligand,（Et O）₂Me Si H as the hydrogen source,K₂HPO₄·3H₂O as the base and NMP/Et OAc as the mixed solvent to successfully achieve the Markovnikov-selective hydrodifluoromethylation of alkynes with bromodifluoromethane.The reaction conditions are mild and shows good substrate applicability to aliphatic and（hetero）aryl alkynes.This method efficiently synthesizes skeleton-rich CF₂H-olefins with moderate to excellent yields,providing regioselectivity and reactivity complementary to the classical radical addition pathway.Furthermore,late-stage functionalization of drug-derived complex molecules and synthetic manipulations of the resulting branched CF₂H-alkenes for highly valued fluorine-containing compounds have been demonstrated to highlight the synthetic valueness of this method.