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

Carbon isotope labelling of bioactive molecules is essential for accessing the pharmacokinetic and pharmacodynamic properties of new drug entities. Aryl carboxylic acids represent an important class of structural motifs ubiquitous in pharmaceutically active molecules and are ideal targets 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 catalysts. Herein, we report the development of a practical and affordable Pd-catalysed electrocarboxylation setup. This approach enables the use of near-stoichiometric CO₂ generated from the primary carbon-14 source Ba¹⁴CO₃, facilitating late-stage and single-step carbon-14 labelling of pharmaceuticals and representative precursors. The proposed isotope-labelling protocol holds significant promise for immediate impact on drug development programmes.

Gabriel M. F. Batista, Ruth Ebenbauer, Craig Day, Jonas Bergare, Karoline T. Neumann, Kathrin H. Hopmann, Charles S. Elmore, Alonso Rosas-Hernández, Troels Skrydstrup