The aza-ene reaction of heterocyclic ketene aminals with enones: an efficient and simple synthetic route to fused di- and tri-heterocycles

Abstract

Heterocyclic ketene aminals bearing a secondary amino moiety acted as hetero-ene components to react with a number of enones under very mild conditions. The reaction of five- and six-membered heterocyclic ketene aminals 5 and 8 with methyl vinyl ketone proceeded effectively through the aza-ene addition, imine–enamine tautomerization and intramolecular cyclization to give good yields of 8-aroyl-5-hydroxy-5-methyl-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridines 6 and 9-aroyl-6-hydroxy-6-methyl-1,2,3,4,7,8-hexahydroxy-6H-pyrido[1,2-a]pyrimidines 9, respectively. When methyl vinyl ketone was present in excess, preliminarily formed product 6 underwent a second aza-ene reaction followed by intramolecular cyclization and water-participating debenzoylation, to yield the cisoid-4,9-dihydroxy-4,9-dimethyl-1,2,5,6,6a,7,8,10α-octahydro-4H,9H-imidazo[1,2,3-ij][1,8]naphthyridin-10α-ylium benzoate 7 as the sole product. In refluxing acetonitrile, heterocyclic ketene aminals 5 underwent aza-ene addition and cyclocondensation reaction with a number of substituted α,β-unsaturated ketones to afford 1,2,3,7-tetrahydroimidazo[1,2-a]pyridine derivatives 23 while tricyclic imidazo[1,2-a]quinoline derivatives were easily obtained when 2-benzylidene-cyclohexanone and -cyclohexane-1,3-dione were used as enophiles. The effect of the structures of heterocyclic ketene aminals, particularly of the intramolecular hydrogen bond, on the aza-ene reactivity is also discussed.

References

1. Part of this work has appeared as a preliminary communication: J.-H. Zhang, M.-X. Wang and Z.-T. Huang, Tetrahedron Lett., 1998, 39, 9237.
2. (a) H. M. R. Hoffmman, Angew. Chem., Int. Ed. Engl., 1969, 8, 556; (b) W. Oppolzer and V. Snieckus, Angew. Chem., Int. Ed. Engl., 1978, 17, 476; (c) G. V. Boyd, in The Chemistry of Double-bonded Functional Groups, ed. S. Patai, Wiley, New York, 1989, vol. 2, part 1, p. 477; (d) B. B. Snider, in Comprehensive Organic Synthesis, ed. B. M. Trost and I. Flemming, Pergamon, Oxford, 1991, vol. 5, p. 1; (e) W. Carruthers, Cycloaddition Reactions in Organic Synthesis, Pergamon, Oxford, 1990, p. 241.
3. B. B. Snider, in Comprehensive Organic Synthesis, ed. B. M. Trost and I. Flemming, Pergamon, Oxford, 1991, vol. 2, p. 527.
4. R. M. Borzilleri and S. M. Weinreb, Synthesis, 1995, 347.
5. (a) G. W. Kirby, Chem. Soc. Rev., 1977, 6, 1; (b) G. E. Keck, R. R. Webb and J. B. Yates, Tetrahedron, 1981, 37, 4007.
6. Y. C. Lai, S. E. Mallakpour, G. B. Butler and G. C. Palenic, J. Org. Chem., 1985, 50, 4378.
7. K. Mikami and M. Shimizu, Chem. Rev., 1992, 92, 1021.
8. B. B. Snider, Acc. Chem. Res., 1980, 13, 426.
9. (a) B. T. Gillis and F. A. Daniher, J. Org. Chem., 1962, 27, 4001; (b) E. Fahr and H. D. Rupp, Angew. Chem., Int. Ed. Engl., 1964, 3, 693; (c) J. E. Baldwin, R. M. Adlington, A. U. Jain, J. N. Kolhe and M. W. Perry, Tetrahedron, 1986, 42, 4247; (d) B. B. Snider, R. S. E. Conn and S. Sealfon, J. Org. Chem., 1979, 44, 218; (e) T. Shimizu, Y. Hayashi and Y. Kitora, Bull. Chem. Soc. Jpn., 1982, 55, 2450.
10. (a) M. Novak, J. Novak and C. A. Salemink, Tetrahedron Lett., 1991, 32, 4405; (b) S. Laschat and M. Grehl, Angew. Chem., Int. Ed. Engl., 1994, 33, 458; (c) Chem. Ber., 1994, 127, 2023; (d) J. Org. Chem., 1996, 61, 2829; (e) A. R. Ofial and H. Mayr, J. Org. Chem., 1996, 61, 5823.
11. (a) T. W. Mackewitz, C. Peters, U. Berstrasser, S. Leininger and M. Regitz, J. Org. Chem., 1997, 62, 7605; (b) A. Marinetti, L. Ricard and F. Mathey, Tetrahedron, 1993, 49, 10279; (c) T. W. Mackewitz and M. Regitz, Synthesis, 1998, 125.
12. (a) J. D'Angelo and A. Guingant, Tetrahedron Lett., 1988, 29, 2667; (b) J. D'Angelo, C. Ferrond, C. Riche and A. Chiaroni, Tetrahedron Lett., 1989, 30, 6511; (c) J. Cossy, A. Bouzide and M. Pfau, Tetrahedron Lett., 1992, 33, 4883; (d) J. D'Angelo, D. Desmaele, F. Dumas and A. Guingant, Tetrahedron: Asymmetry, 1992, 3, 459; (e) J. Cossy, A. Bouzide and M. Pfau, J. Org. Chem., 1997, 62, 7106.
13. P. C. Montevecchi and M. L. Navacchia, J. Org. Chem., 1995, 60, 6455.
14. (a) J. M. Conia and P. Le Perchec, Synthesis, 1975, 1; (b) J. Brocard, G. Moinet and J. M. Conia, Bull. Soc. Chim. Fr., 1973, 1711; (c) J. M. Conia and G. L. Lange, J. Org. Chem., 1978, 43, 564.
15. Z.-T. Huang and M.-X. Wang, in The Chemistry of Enamines, ed. Z. Rappoport, Wiley, Chichester, 1994, p. 889.
16. E. Campaigne, in The Chemistry of the Carbonyl Group, ed. S. Patai, Wiley, Chichester, 1966, p. 917.
17. Z.-T. Huang and M.-X. Wang, Heterocycles, 1994, 37, 1233.
18. M.-X. Wang, J.-M. Liang and Z.-T. Huang, J. Chem. Res. (S.), 1994, 166; J. Chem. Res. (M), 1994, 1001.
19. (a) R. C. F. Jones, P. Patel, S. C. Hirst and M. J. Smallridge, Tetrahedron, 1998, 54, 6191; (b) R. C. F. Jones and M. J. Smallridge, Tetrahedron Lett., 1988, 29, 5005; (c) Z.-T. Huang and Z.-R. Liu, Heterocycles, 1986, 24, 2247; (d) Z.-T. Huang and L.-H. Tzai, Chem. Ber., 1986, 119, 2208; (e) A. K. Gupta, H. Ila and H. Junjapa, Synthesis, 1988, 285; (f) Z.-T. Huang and H. Wamhoff, Chem. Ber, 1984, 117, 1856; (g) Z.-T. Huang and X.-J. Wang, Tetrahedron Lett., 1987, 28, 1527.
20. (a) R. C. F. Jones, P. Patel, S. C. Hirst and I. Turner, Tetrahedron, 1997, 53, 11781; (b) M.-X. Wang and Z.-T. Huang, J. Org. Chem., 1995, 60, 2807; (c) Z.-T. Huang and Z.-R. Liu, Chem. Ber., 1989, 122, 95.
21. Z.-T. Huang and M.-X. Wang, J. Org. Chem., 1992, 57, 184 and references therein.
22. Z.-T. Huang and M.-X. Wang, J. Chem. Soc., Perkin Trans. 1, 1993, 1085.
23. J.-H. Zhang, M.-X. Wang and Z.-T. Huang, J. Chem. Res. (S), 1998, 486.
24. J.-H. Zhang, M.-X. Wang and Z.-T. Huang, J. Chem. Soc., Perkin Trans. 1, 1999, 321.
25. J. H. Zhang, X.-A. Chen, Y. Li and Z.-T. Huang, Acta Crystallogr., Sec. C, 1998, 54, 140.
26. P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry, Pergamon, Oxford, 1983.
27. R. C. F. Jones and S. C. Hirst, Tetrahedron Lett., 1989, 30, 5361.
28. Z.-T. Huang and M.-X. Wang, in The Chemistry of Enamines, ed. Z. Rappoport, Wiley, Chichester, 1994, p. 1303.
29. A similar reaction has been reported: H. Meyer, F. Bossert and H. Horstmann, Justus Liebigs Ann. Chem., 1977, 1895.