Late-Stage Carbon Isotope Exchange of Aryl Nitriles through Ni-Catalyzed C–CN Bond Activation

Abstract

A facile one-pot strategy for ¹³CN and ¹⁴CN exchange with aryl, heteroaryl, and alkenyl nitriles using a Ni phosphine catalyst and BPh₃ is described. This late-stage carbon isotope exchange (CIE) strategy employs labeled Zn(CN)₂ to facilitate enrichment using the nonlabeled parent compound as the starting material, eliminating <i>de novo</i> synthesis for precursor development. A broad substrate scope encompassing multiple pharmaceuticals is disclosed, including the preparation of [¹⁴C] belzutifan to illustrate the exceptional functional group tolerance and utility of this labeling approach. Preliminary experimental and computational studies suggest the Lewis acid BPh₃ is not critical for the oxidative addition step and instead plays a role in facilitating CN exchange on Ni. This CIE method dramatically reduces the synthetic steps and radioactive waste involved in preparation of ¹⁴C labeled tracers for clinical development.