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

摘要

A facile one-pot strategy for ~(13)CN and ~(14)CN exchange with aryl, heteroaryl, and alkenyl nitriles using a Ni phosphine catalyst and BPh_3 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 de novo synthesis for precursor development. A broad substrate scope encompassing multiple Pharmaceuticals is disclosed, including the preparation of [~(14)C] belzutifan to illustrate the exceptional functional group tolerance and utility of this labeling approach. Preliminary experimental and computational studies suggest the Lewis acid BPh_3 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 ~(14)C labeled tracers for clinical development.