Palladacarboxamide Capping Reagents for Carbon Isotope Labeling and Pharmaceutical Diversification

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 ¹⁴C-labeling of this functional group facilitated by organometallic carboxamide capping reagents, based on palladium. Near stoichiometric amounts of ¹⁴CO are readily generated from a ¹⁴CO 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 ¹⁴C-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.