A facile access to aliphatic trifluoromethyl ketones via photocatalyzed cross-coupling of bromotrifluoroacetone and alkenes

Abstract

Biological molecules incorporating trifluoromethyl ketones (TFMKs) have emerged as reversible covalent inhibitors, aiding in the management and treatment of inflammatory diseases, cancer, and respiratory conditions. TFMKs, renowned for their versatile binding properties and adaptability, are pivotal in the rational design of novel drugs for diverse diseases. The photocatalytic insertion of alkenes, abundant feedstocks, into the α-carbon of trifluoromethylacetone represents a highly effective and atom-economical method for synthesizing valuable TFMKs. However, these processes typically necessitate high-energy photoirradiation (λ > 300 nm, Hg lamp) and stoichiometric oxidants to generate the acetonyl radical from acetone. In our study, we demonstrate the visible-light photocatalytic radical addition into olefins using bromotrifluoroacetone as the trifluoroacetonyl radical precursor under mild conditions. Aliphatic trifluoromethyl ketones or the corresponding bromo-substituted products can be obtained by selecting an appropriate photocatalyst and solvent. Comprehensive experimental investigations, including cyclic voltammetry, Stern–Volmer quenching studies, and kinetic isotope effects, corroborate the synthesis of trifluoroacetonyl radical species from bromotrifluoroacetone under photoredox conditions. Further, we demonstrate the efficient synthesis of an oseltamivir derivative bearing a trifluoromethylketone moiety, which shows promising biological activity. Hence, this methodology will streamline the direct introduction of trifluoromethyl ketone into biological target molecules during drug discovery.