Keto-Difluoromethylation of Aromatic Alkenes by Photoredox Catalysis: Step-Economical Synthesis of α-CF2H-Substituted Ketones in Flow

A step-economical method for synthesis of α-CF2H-substituted ketones from readily available alkene feedstocks has been developed. Radical difluoromethylation of aromatic alkenes combining DMSO oxidation and photoredox catalysis is a key to the successful transformation. Electrochemical analysis, laser flash photolysis (LFP), and density functional theory (DFT) calculations reveal that N-tosyl-S-difluoromethyl-S-phenylsulfoximine serves as the best CF2H radical source among analogous sulfone-based CF2H reagents. The present photocatalytic keto-difluoromethylation has been applied to flow synthesis and easily scaled up to gram-scale synthesis within a reasonable reaction time. Furthermore, potentials of the α-CF2H-substituted ketones for useful synthetic intermediates are shown; e.g., synthesis of the CF2H-containing α-hydroxyamide with the same carbon skeleton as that of the anticonvulsant active CF3-analogue, is disclosed. Additionally, mechanistic studies are also discussed in detail.