Asymmetric difluorocarbonylation reactions of non-active imines catalyzed by Bi(OAc)3/chiral phosphoric acid

Abstract

Difluorinated carbonyl has been identified as the basic skeleton of multitudinous biologically active molecules. However, development of strategies for asymmetrically introducing such an important moiety remains a formidable challenge. Herein, we reported a practical and efficient asymmetric difluorocarbonylation reaction of non-active imines with difluoroenoxysilane. In the presence of Bi(OAc)₃/chiral phosphoric acid (2 mol%), excellent efficiency (up to 99%) and high enantioselectivity (up to 99 : 1 e.r.) were obtained. The reaction could be scaled up, and the synthetic utility of the desired chiral difluorocarbonylation product was proved by diverse transformations. In addition, the catalytic strategy can also be well applied to other imines, oxocarbenium ions and monofluorinated enol silyl ether. A possible mechanism is proposed to illustrate the reaction process and density functional theory calculation is conducted to interpret the enantioselectivity.