A practical photocatalytic strategy for radical (deuterio)difluoromethylation using imidazolium reagents

Abstract

The difluoromethyl group (CF₂H) has garnered significant interest in medicinal chemistry owing to its unique biochemical and physicochemical properties. Its deuterated counterpart (CF₂D), building on the established utility of CF₂H, exhibits multifaceted potential for advancing biomedical research and therapeutic development. While the incorporation of the difluoromethyl group (CF₂H) into drug molecules has matured, efficient installation of its deuterated counterpart (CF₂D) remains a formidable challenge in medicinal chemistry. This study reports a novel (deuterio)difluoromethyl imidazolate reagent IMDN-SO₂CF₂X (X = D, H), which is used to successfully construct various highly selective (deuterio)difluoromethyl compounds in the form of (deuterio)difluoromethyl radicals while maintaining high deuteration rates, achieving >99% isotopic purity in deuterium incorporation. The reagent enables precise CF₂D and CF₂H installation in natural products and synthetic bioactive compounds, showing broad substrate compatibility. This establishes a robust deuteration platform for drug discovery.