Cobalt/Photoredox-Catalyzed, Phosphine-Mediated Carbon Isotope Exchange of Unactivated Alkyl Carboxylic Acids

Carbon isotope exchange (CIE) reactions have emerged as a useful isotope labeling strategy, offering an expedient alternative to traditional routes for synthesizing compounds needed in drug and agrochemical development, as well as in medical imaging. Effective CIE processes of alkyl carboxylic acids using isotopically labeled CO2 are generally restricted to substrates bearing an anion-stabilizing group adjacent to the carboxylate (i.e., benzylic, imino, or keto acids) or require preactivation to undergo decarboxylation and exchange. To expand the repertoire of CIE methods, we sought to develop a mechanistically distinct process using photoredox catalysis in conjunction with a phosphine mediator to enable direct labeling of unactivated alkyl carboxylic acids. Here we report that in the presence of a Co catalyst, alkyl carboxylic acids undergo Co/photoredox-catalyzed, phosphine-mediated CIE under low pressures of 13CCO2 (1 atm, ∼3 equiv). Contrary to our initial mechanistic hypothesis, born out of established phosphine-mediated carboxylic acid radical deoxygenation methods, the reaction appears to proceed via decarboxylation of the acid substrate followed by Co-catalyzed carboxylation. Notably, control experiments revealed that significant amounts of CO are generated during the CIE reaction through the photoredox-catalyzed, phosphine-mediated reduction of CO2.