A protocol for the single-step synthesis of pyrimidine derivatives by condensation of N-vinyl or N-aryl amides with nitriles is described. Gram-scale synthesis of 4-tert-butyl-2-phenyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimidine serves as a representative procedure for this methodology for azaheterocycle synthesis. This chemistry involves amide activation with trifluoromethanesulfonic anhydride in the presence of 2-chloropyridine and the necessary nitrile. Nucleophilic addition of the nitrile to an activated intermediate followed by annulation affords the pyrimidine product in a single step. The total time necessary for the completion of this procedure is approximately 3 h. This chemistry has been applied to a wide range of amides and nitriles including optically active derivatives.
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M.M. is a Firmenich Assistant Professor of Chemistry and a Beckman Young Investigator. We acknowledge generous financial support by NSF (547905), Damon Runyon Cancer Research Foundation, GlaxoSmithKline, Merck Research Laboratories, Amgen and Boehringer Ingelheim Pharmaceutical Inc.
The authors declare no competing financial interests.
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Movassaghi, M., Hill, M. Synthesis of pyrimidines by direct condensation of amides and nitriles. Nat Protoc 2, 2018–2023 (2007). https://doi.org/10.1038/nprot.2007.280
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