Carbon-14 labeled compounds play an integral role in the drug development process, allowing for investigation of metabolic pathways and support of drug disposition studies during late phase development. We outline a facile one-pot strategy for 13CN and 14CN exchange with aryl, heteroaryl, and vinyl nitriles using a Ni phosphine catalyst and BPh3. This late-stage carbon isotope exchange (CIE) strategy employs labeled Zn(CN)2 to facilitate enrichment using the non-labeled parent compound as the starting material, eliminating costly and time-consuming de novo synthesis for precursor development. This direct labeling approach is applicable to a broad substrate scope encompassing multiple pharmaceuticals, including the preparation of [14C]belzutifan to illustrate the exceptional functional group tolerance and utility of this method.

Late-stage carbon isotope exchange of aryl nitriles through Ni-catalyzed C–CN bond activation

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