Palladacarboxamide Capping Reagents for Carbon Isotope Labeling and Pharmaceutical Diversification

ABSTRACT Radiolabeling of bioactive molecules is essential for elucidating their pharmacokinetic and pharmacodynamic properties. Aryl carboxamides represent common constituents in a wide number of pharmaceuticals. Herein, we present a direct approach for the 14 C‐labeling of this functional group facilitated by organometallic carboxamide capping reagents, based on palladium. Near stoichiometric amounts of 14 CO are readily generated from a 14 CO surrogate and exploited to assemble a range of palladium oxidative addition complexes. When subjected to Suzuki cross‐coupling conditions with boronic acids or esters, structurally diverse high‐value aryl carboxamides can be accessed directly. The protocol's robustness is demonstrated by late‐stage modification of amine‐displaying small drug molecules with 14 C‐incorporation. Since the organometallic carboxamide complexes are air stable, this protocol provides a simple and direct means for carbon isotope labeling, which can easily be adapted to drug development programs.