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Synthesis of pyrimidines by direct condensation of amides and nitriles

Abstract

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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Figure 1
Figure 2: Scheme for the synthesis of pyrimidine 3a.

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Acknowledgements

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.

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Correspondence to Mohammad Movassaghi.

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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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