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

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 s...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2021-03, Vol.143 (12), p.4817-4823
Main Authors: Reilly, Sean W, Lam, Yu-hong, Ren, Sumei, Strotman, Neil A
Format: Article
Language:English
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Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.1c01454