Efficient conversion of nitrogen-containing methylheteroarenes into their corresponding nitrile derivatives

Very recently, Y. Yuan and Coll. reported an original conversion of methylheteroarenes to their corresponding nitriles using sodium nitrite as the nitrogen source. [1] This direct C-H bond activation is illustrated in the Scheme below through a gram-scale preparation of an intermediate of Topiroxostat (a selective xanthine oxidase inhibitor developed for treatment and management of hyperuricemia and gout).

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Based on mechanistic study, it has been proposed that a nitroso radical reacts on an imino ene-type species (resulted from isomerization of the starting nitrogen-containing methylheteroarene) to provide an aldoxime ester intermediate leading to the nitrile derivative by activation with the second equivalent of AcCl. It should be pointed out that the scope of this methodology is limited to substrates containing a methyl group which could be isomerized to an imino ene-type intermediate.

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[1] C. Jiang, Y. Chen, P. Gao, S. Zhang, X. Jia, Y. Yuan, Org. Lett. 2022, 24, 6341-6345.