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Synthesis of pyrimidines by direct condensation of amides and nitriles


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.


  1. Undheim, K. & Benneche, T. Pyrimidines and their benzo derivatives. In Comprehensive Heterocyclic Chemistry II Vol. 6 (eds. Katritzky, A.R., Rees, C.W., Scriven, E.F.V. & McKillop, A.) 93–231, 1177–1307 (Pergamon, Oxford, 1996).

    Chapter  Google Scholar 

  2. Lagoja, I.M. Pyrimidine as constituent of natural biologically active compounds. Chem. Biodivers. 2, 1–50 (2005).

    CAS  Article  Google Scholar 

  3. Michael, J.P. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 22, 627–646 (2005).

    CAS  Article  Google Scholar 

  4. Erian, A.W. The chemistry of β-enaminonitriles as versatile reagents in heterocyclic synthesis. Chem. Rev. 93, 1991–2005 (1993).

    CAS  Article  Google Scholar 

  5. Sakai, N., Youichi, A., Sasada, T. & Konakahara, T. New approach to the practical synthesis of tri- or tetrasubstituted pyrimidine derivatives: a four-component coupling reaction from a functionalized silane, two types of aromatic nitriles, and acetals. Org. Lett. 7, 4705–4708 (2005).

    CAS  Article  Google Scholar 

  6. Yoon, D.S. et al. Efficient synthesis of 4-aminoquinazoline and thieno[3,2-d]pyrimidin-4-ylamine derivatives by microwave irradiation. Org. Lett. 6, 4775–4778 (2004).

    CAS  Article  Google Scholar 

  7. Kakiya, H., Yagi, K., Shinokubo, H. & Oshima, K. Reaction of α,α-dibromo oxime ethers with Grignard reagents: alkylative annulation providing a pyrimidine core. J. Am. Chem. Soc. 124, 9032–9033 (2002).

    CAS  Article  Google Scholar 

  8. Kotsuki, H., Sakai, H., Morimoto, H. & Suenaga, H. A new quinazoline synthesis. Synlett 1993–1995 (1999).

  9. Ghosez, L., Jnoff, E., Bayard, P., Sainte, F. & Beaudegnies, R. A highly efficient multicomponent synthesis of pyridones and pyrimidones by a [2 + 2 + 2] strategy. Tetrahedron 55, 3387–3400 (1999).

    CAS  Article  Google Scholar 

  10. Martínez, A.G., Fernández, A.H., Fraile, A.G., Subramanian, L.R. & Hanack, M. On the mechanism of the reaction between ketones and trifluoromethanesulfonic anhydride. An improved and convenient method for the preparation of pyrimidines and condensed pyrimidines. J. Org. Chem. 57, 1627–1630 (1992).

    Article  Google Scholar 

  11. Chinchilla, R., Nájera, C. & Yus, M. Metalated heterocycles and their applications in synthetic organic chemistry. Chem. Rev. 104, 2667–2722 (2004).

    CAS  Article  Google Scholar 

  12. Turck, A., Plé, N., Mongin, F. & Quéguiner, G. Advances in the directed metalation of azines and diazines (pyridines, pyrimidines, pyrazines, pyridazines, quinolines, benzodiazines and carbolines). Part 2. Metalation of pyrimidines, pyrazines, pyridazines and benzodiazines. Tetrahedron 57, 4489–4505 (2001).

    CAS  Article  Google Scholar 

  13. Movassaghi, M. & Hill, M.D. Single-step synthesis of pyrimidine derivatives. J. Am. Chem. Soc. 128, 14254–14255 (2006).

    CAS  Article  Google Scholar 

  14. Muci, A.R. & Buchwald, S.L. Practical palladium catalysts for C–N and C–O bond formation. Top. Curr. Chem. 219, 131–209 (2002).

    CAS  Article  Google Scholar 

  15. Hartwig, J.F. Palladium-catalyzed amination of aryl halides and related reactions. In Handbook of Organopalladium Chemistry for Organic Synthesis (ed. Negishi, E.) 1051–1096 (Wiley-Interscience, New York, 2002).

    Chapter  Google Scholar 

  16. Dehli, J.R., Legros, J. & Bolm, C. Synthesis of enamines, enol ethers, and related compounds by crosscoupling reactions. Chem. Commun. 8, 973–986 (2005).

    Article  Google Scholar 

  17. Beletskaya, I.P. & Cheprakov, A.V. Copper in cross-coupling reactions. Coordin. Chem. Rev. 248, 2337–2364 (2004).

    CAS  Article  Google Scholar 

  18. Jiang, L., Job, G.E., Klapars, A. & Buchwald, S.L. Copper-catalyzed coupling of amides and carbamates with vinyl halides. Org. Lett. 5, 3667–3669 (2003).

    CAS  Article  Google Scholar 

  19. Bose, D.S. & Jayalakshmi, B. A practical method for the preparation of nitriles from primary amides under non-acidic conditions. Synthesis 64–65 (1999).

  20. Movassaghi, M. & Hill, M.D. Synthesis of substituted pyridine derivatives via the ruthenium-catalyzed cycloisomerization of 3-azadienynes. J. Am. Chem. Soc. 128, 4592–4593 (2006).

    CAS  Article  Google Scholar 

  21. Hill, M.D. & Movassaghi, M. Synthesis of substituted pyridines and quinolines. Synthesis 1115–1119 (2007).

  22. Charette, A.B. & Grenon, M. Spectroscopic studies of the electrophilic activation of amides with triflicanhydride and pyridine. Can. J. Chem. 79, 1694–1703 (2001).

    CAS  Article  Google Scholar 

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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.

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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).

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