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

Sean Reilly, Yu-hong Lam, Sumei Ren, Neil Strotman
2021 unpublished
<div> <p>A facile one-pot strategy for <sup>13</sup>CN and <sup>14</sup>CN exchange with aryl, heteroaryl, and vinyl nitriles using a Ni phosphine catalyst and BPh<sub>3</sub> is described. This late-stage carbon isotope exchange (CIE) strategy employs labeled Zn(CN)<sub>2</sub> to facilitate enrichment using the non-labeled parent compound as the starting material, eliminating <i>de novo</i> synthesis for precursor development. A broad substrate scope encompassing multiple pharmaceuticals is
more » ... sclosed, including the preparation of [<sup>14</sup>C]<a>belzutifan</a> to illustrate the exceptional functional group tolerance and utility of this labeling approach. Preliminary experimental and computational studies suggest the Lewis acid BPh<sub>3</sub> 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 <sup>14</sup>C labeled tracers for clinical development.</p> </div>
doi:10.26434/chemrxiv.13724023.v2 fatcat:buglqlkkz5cx7ep5n6ssvxwcoa