Pushing the boundaries of trifluoroacetylation: development of masked acyl reagents for the synthesis of trifluoromethyl ketones

Due to its impressive ability promoting biological activity as a carboxylic acid bioisostere and untapped potential as a covalent enzymatic inhibitor, the synthesis of trifluoromethyl ketones (TFMKs) has become an important and growing area of research. Although various protocols have been developed to access TFMKs, the direct installation of trifluoromethylacyl radicals remains challenging due to the potential for decarbonylation and inherent electrophilicity, limiting widespread synthetic application. To address these challenges, we have developed a novel method for masked radical trifluoroacetylation of electron-deficient alkenes through the use of a masked acyl reagent, leveraging an umpolung approach to yield a complementary nucleophilic acetal radical, which, once coupled, can be deketalized to reveal the TFMK. We further expanded this masked trifluoroacetylation strategy towards installing TFMKs directly onto nitrogen-containing heterocycles in a photomediated Minisci-type reaction. The utility of our methodology is highlighted by large-scale, late-stage reactions of bioactive molecules, such as sclareolide, loratadine, and nicotine.