One-pot synthesis of trifluoromethyl ketone-containing heterocycles via tandem photocatalytic haloalkylation of olefins and intramolecular cyclisation

Abstract

Trifluoromethyl ketone (TFMK) is an important functional group in reversible covalent inhibitors. However, synthetic strategies to incorporate TMFK into heterocyclic compounds are limited. In this study, we report a novel protocol for tandem photoredox-catalysed difunctionalisation of olefins bearing internal nucleophiles using bromotrifluoroacetone, followed by intramolecular cyclisation. The protocol involves the use of 1.0 mol% organophotocatalyst and zinc acetate as a bromide ion scavenger. Subsequent intramolecular cyclisation of the brominated intermediate is promoted by basic alumina or K₂CO₃. This method provides straightforward access to a wide range of TFMK-containing heterocycles, including oxazolines, benzoxazines, γ-lactones, and pyrrolidones, and can be feasible for designing reversible covalent inhibitors.