Copper-Catalyzed Enantioselective Three-Component Fluoroalkylalkynylation of Unactivated Alkenes

Abstract

The enantioselective three-component dicarbonfunctionalization of electronically unactivated alkenes continues to pose a significant challenge. In this work, a copper-catalyzed highly regio- and enantioselective fluoroalkylalkynylation of unactivated alkenes with diverse terminal alkynes and fluoroalkyl halides under mild conditions is developed. In addition to fluoroalkyl halides, Togni’s reagent can also participate in the reaction, delivering chiral β-trifluoromethyl alkynes with high enantioselectivities. This method exhibits good functional group tolerance, facilitating the late-stage derivatization of a variety of biologically active molecules. The success of this chemistry was achieved by using a bulky indene-substituted BOPA ligand. DFT calculations indicate that the radical fluoroalkylalkynylation is achieved through a fluorine-directed outer-sphere pathway. Mechanistic studies reveal that the amide group is crucial for achieving high stereoselectivities because the exclusive F···H hydrogen bonding between the fluoroalkyl group and the Mes group on the amide can be formed to stabilize the Si-radical coupling transition state.