Bromine radical-enhanced HAT activity leading to stoichiometric couplings of methylarenes with acid chlorides

The stoichiometric coupling of readily available methylarenes and diverse acid chlorides into alpha-aryl ketones, a valued structural motif present in pharmacologically relevant molecules, has been developed. The utility of this protocol is demonstrated by the late-stage acylation of biologically active molecules in a stoichiometric manner. Mechanistic investigation reveals that the photocatalytically generated bromine radical acts as a hydrogen atom abstraction reagent and delivers a nucleophilic benzyl radical, which is intercepted by nickel-catalyzed cross coupling to accomplish benzylic acylation.

Automated summary

This study developed a chemical method to couple readily available methylarenes and diverse acid chlorides into alpha-aryl ketones, a valuable structural motif in pharmacologically relevant compounds. The utility of this method was demonstrated through the stoichiometric acylation of biologically active molecules. Mechanistic investigation revealed that the photocatalytically generated bromine radical acts as a hydrogen atom abstraction reagent, releasing a nucleophilic benzyl radical that undergoes nickel-catalyzed cross coupling for benzylic acylation.