Direct Generation of Carboxyl Radicals from Carboxylic Acids Catalyzed by Photoactivated Ketones

Carboxyl radicals are reactive intermediates, which potentially offer opportunities to develop unique transformations in radical chemistry, yet their straightforward generation from carboxylic acids has largely relied on the use of environmentally less benign methods, and their application has been mainly limited to decarboxylative functionalizations. Here, we present a photoactivated ketone-catalyzed direct generation of carboxyl radicals via hydrogen atom transfer (HAT) from the O-H bond of carboxylic acids. An integrated approach combining theoretical predictions and experimental validation guided the development of this simple, chemoselective O-H HAT catalysis, which is facilitated by hydrogen-bonding interaction between the ketone photocatalyst and the carboxylic acid and leaves weaker C-H bonds intact. Our protocol has a broad substrate scope with high functional group tolerance and is applicable to direct decarboxylative functionalization of primary, secondary, and tertiary aliphatic carboxylic acids, including bioactive molecules. Benzoyloxy radicals were also prepared, enabling site-selective C(sp3)-H alkylation of ortho-alkyl-substituted benzoic acids via a 1,5-HAT process.