Synthesis of 5-substituted imidazo[4,5-b]pyridinones by annelation of 4-amino-5-ethoxalyl-1H-imidazole derivatives with active methylene compounds

Abstract

A new synthetic route to imidazo[4,5-b]pyridinones with a range of substituents at the 6-position has been developed. These compounds can be prepared in four steps from readily available 5-chloro-4-nitroimidazoles. The key step involves construction of the pyridine ring by annelation of 4-amino-5-ethoxalylimidazoles with active methylene compounds under dehydrating conditions or by acylation with substituted acetyl chlorides followed by spontaneous cyclisation. An exception is the reaction in which cyclisation of a phenylacetyl derivative occurs to give a seven-membered ring, forming an imidazo[4,5-b]azepinedione.

References

1. (a) G. Cristalli, S. Vittori, A. Eleuteri, R. Volpini, E. Camaioni, G. Lupidi, N. Mahmood, F. Bevilacqua and G. Palu, J. Med. Chem., 1995, 38, 4019; (b) G. Cristalli, A. Eleuteri, S. Vittori, R. Volpini, M. J. Lohse and K.-N. Kotz, J. Med. Chem., 1992, 35, 2363; (c) G. Cristalli, P. Franchetti, M. Grifantini, S. Vittori, T. Bordoni and C. Geroni, J. Med. Chem., 1987, 30, 1686; (d) G. Cristalli, P. Franchetti, M. Grifantini, S. Vittori, K.-N. Klotz and M. J. Lohse, J. Med. Chem., 1988, 31, 1179.
2. G. Tennant, C. J. Wallis and G. W. Weaver, J. Chem. Soc., Perkin Trans. 1, 1999, 629.
3. For a discussion of various synthetic approaches to imidazo[4,5-b]-pyridine derivatives see: (a) J. A. Montgomory and J. A. Secrist, in Comprehensive Heterocyclic Chemistry, ed. A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984, vol. 5, section 4.10.4.3; (b) P. C. Srivastava, R. K. Robins and R. B. Myer, in Chemistry of Nucleosides and Nucleotides, ed. L. B. Townsend, vol. 1, ch. 2, Plenum Press, New York, 1988.
4. F. Perandones and J. L. Soto, J. Heterocycl. Chem., 1997, 34, 107.
5. G. Tennant, C. J. Wallis and G. W. Weaver, J. Chem. Soc., Perkin Trans. 1, 1999, 817.
6. (a) F. L. Merchan, P. Merino and T. Tomas, Tetrahedron Lett., 1995, 38, 6949; (b) E. V. Dehmlow and E. Kunesch, Liebigs Ann. Chem., 1985, 1904.
7. G. Tennant, J. Chem. Soc., 1963, 2428.
8. D. Macleod and G. R. Proctor, J. Chem. Res. (S), 1990, 88.
9. H. Schaefer, K. Gewald and M. Seifert, J. Prakt. Chem., 1976, 318, 39.