1. Academic Validation
  2. Late-Stage Carbon Isotope Exchange of Aryl Nitriles through Ni-Catalyzed C-CN Bond Activation

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

  • J Am Chem Soc. 2021 Mar 31;143(12):4817-4823. doi: 10.1021/jacs.1c01454.
Sean W Reilly 1 Yu-Hong Lam 2 Sumei Ren 1 Neil A Strotman 1
Affiliations

Affiliations

  • 1 Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 2 Department of Computational and Structural Chemistry, Merck & Co., Inc. Rahway, New Jersey 07065, United States.
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 de novo 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.

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