Efficient palladium-catalyzed electrocarboxylation enables late-stage carbon isotope labelling

Abstract

Carbon isotope labelling of bioactive molecules is a critical step for accessing the pharmacokinetic and pharmacodynamic properties of new drug entities. Aryl carboxylic acids represent an important class of structural motifs commonly found in many pharmaceutically active molecules and are ideal target structures for the installation of a radioactive tag employing isotopically labelled CO2. However, direct isotope incorporation via the reported catalytic reductive carboxylation (CRC) of aryl electrophiles relies on excess CO2, which is incompatible with carbon-14 isotope incorporation. Furthermore, the application of some CRC reactions for late-stage carboxylation is limited because of the low tolerance of molecular complexity by the catalytic systems. Herein, we report the development of a practical and affordable electrochemical CRC setup based on palladium catalysis. This approach enables the use of near-stoichiometric 14CO2 generated from the primary carbon-14 source Ba14CO3, facilitating late-stage and single-step carbon-14 labelling of pharmaceuticals and representative precursors. Further studies provide more details in the mechanistic understanding of this process, allowing CRC to be performed in solvents alternative to DMF. The proposed isotope-labelling protocol holds significant promise for immediate impact on drug development programmes.