Russian Chemical Bulletin

, Volume 55, Issue 5, pp 907–919 | Cite as

N-alkylation of 2,3-dihydroimidazo[2,1-b]quinazolin-1(10)H-5-one. On the cryptoanionic mechanism of N-substitution

  • A. S. Morkovnik
  • L. N. Divaeva
  • T. A. Kuz’menko


Quantum chemical methods involving studies of transition states of the reaction showed that the main products of N-alkylation of prototropic 2,3-dihydroimidazo[2,1-b]quinazolin-1(10)H-5-one (1) in the gas phase and under neutral conditions in solution occurring via the SN2 mechanism should be N(10)-alkyl-substituted derivatives formed from the 1H-tautomer. Minor N(1)-substituted derivatives in solution can be produced from both tautomers. For the alkylation of the free N-anion of compound 1, position 1 is attacked first. Validity of conclusions concerning the overall regioselectivity of the reaction was confirmed experimentally. In the absence of solvent, the alkylation proceeds abnormally with a sharp increase in the content of the 1-substituted isomers up to inversion of the regioselectivity of the reaction, which is explained by the participation in the process of the H-bonded dimer of the substrate (1a)2, which undergoes alkylation via the cryptoanionic mechanism.

Key words

2,3-dihydroimidazo[2,1-b]quinazolin-1(10)H-5-one quantum chemical calculations density functional method transition states prototropic tautomerism N-alkylation H-bonded dimers cryptoanionic reaction mechanism mechanism of alkyltransferase action 


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  1. 1.
    G. H. Hardtmann, G. Koletar, and O. R. Pfister, J. Med. Chem., 1975, 18, 447.CrossRefGoogle Scholar
  2. 2.
    G. H. Hardtmann, US Pat. 3833652;
  3. 3.
    G. H. Hardtmann, US Pat. 3912731;
  4. 4.
    G. H. Hardtmann, US Pat. 3919210;
  5. 5.
    G. H. Hardtmann, US Pat. 3969506;
  6. 6.
    N. P. Peet and Sh. Sunder, US Pat. 4871732;
  7. 7.
    G. H. Hardtmann, US Pat. 3598823;
  8. 8.
    T. Jen, B. Dienel, H. Bowman, J. Petta, A. Helt, and B. Loev, J. Med. Chem., 1972, 15, 727.CrossRefGoogle Scholar
  9. 9.
    E. Takeuchi and T. Sato, Jpn Pat. 61115083;
  10. 10.
    M. O. Sinnokrot and C. D. Sherrill, J. Am. Chem. Soc., 2004, 126, 7690.CrossRefGoogle Scholar
  11. 11.
    H.-S. Lee, D.-Y. Cheong, S.-D. Yoh, W.-S. Kim, Y.-W. Kwak, Y.-T. Park, and J.-K. Lee, Bull. Korean Chem. Soc., 2001, 22, 633.Google Scholar
  12. 12.
    G. S. Hammond, J. Am. Chem. Soc., 1955, 77, 334.CrossRefGoogle Scholar
  13. 13.
    T. N. Truong, T.-T. T. Truong, and E. V. Stefanovich, J. Chem. Phys., 1997, 107, 1881.CrossRefGoogle Scholar
  14. 14.
    J. Gao and X. Xia, J. Am. Chem. Soc., 1993, 115, 9667.CrossRefGoogle Scholar
  15. 15.
    S. P. Webb and M. S. Gordon, J. Phys. Chem. A, 1999, 103, 1265.CrossRefGoogle Scholar
  16. 16.
    M. Sola, A. Lledos, M. Duran, J. Bertran, and J. M. Abboud, J. Am. Chem. Soc., 1991, 113, 2873.CrossRefGoogle Scholar
  17. 17.
    J. March, Advaced Organic Chemistry, Reactions, Mechanisms and Structure, Wiley-Interscience Publication, New York, 1985.Google Scholar
  18. 18.
    D. K. Bohme and A. B. Raksit, J. Am. Chem. Soc., 1984, 106, 3447.CrossRefGoogle Scholar
  19. 19.
    E. Humeres, R. J. Nunes, V. G. Machado, M. D. G. Gasques, and C. Machado, J. Org. Chem., 2001, 66, 1163.CrossRefGoogle Scholar
  20. 20.
    K. C. Westaway, Y. Gao, and Y. Fang, J. Org. Chem., 2003, 68, 3084.CrossRefGoogle Scholar
  21. 21.
    M. L. Glowka, A. Olczak, and L. Korzycka, J. Chem. Crystallogr., 1994, 24, 725.CrossRefGoogle Scholar
  22. 22.
    W. J. Le Noble, Synthesis, 1970, 1.Google Scholar
  23. 23.
    K. Hori, J.-L. M. Abboud, C. Lim, M. Fujio, and Y. Tsuno, J. Org. Chem., 1998, 63, 4228.CrossRefGoogle Scholar
  24. 24.
    S. D. Yoh, M.-K. Lee, K.-J. Son, D.-Y. Cheong, I. Han, and K.-T. Shim, Bull. Korean Chem. Soc., 1999, 20, 466.Google Scholar
  25. 25.
    Y. Takata, Y. Huang, J. Komoto, T. Yamada, K. Konishi, H. Ogawa, T. Gomi, M. Fujioka, and F. Takusagawa, Biochemistry, 2003, 42, 8394.CrossRefGoogle Scholar
  26. 26.
    J. Komoto, T. Yamada, Y. Takata, K. Konishi, H. Ogawa, T. Gomi, M. Fujioka, and F. Takusagawa, Biochemistry, 2004, 43, 14385.Google Scholar
  27. 27.
    P. Velichkova and F. Himo, J. Phys. Chem. B, 2005, 109, 8216.CrossRefGoogle Scholar
  28. 28.
    P. Velichkova and F. Himo, J. Phys. Chem. B, 2005, 109; ASAP Web Release, Date: 07-Dec-2005.Google Scholar
  29. 29.
    W. Schmidt, K. K. Baldridge, J. A. Boatz, S. T. Elbert, M. S. Gordon, J. H. Jensen, S. Koseki, N. Matsunaga, K. A. Nguyen, S. J. Su, T. L. Windus, M. Dupuis, and J. A. Montgomery, J. Comput. Chem., 1993, 14, 1347.CrossRefGoogle Scholar
  30. 30.
    M. N. Glukhovstev, A. Pross, M. P. McGrath, and L. Radom, J. Chem. Phys., 1995, 103, 1878.CrossRefGoogle Scholar
  31. 31.
    K. K. Irikura, R. D. Johnson III, and R. N. Kacker, J. Phys. Chem. A, 2005, 109, 8430.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • A. S. Morkovnik
    • 1
  • L. N. Divaeva
    • 1
  • T. A. Kuz’menko
    • 1
  1. 1.Research Institute of Physical and Organic ChemistryRostov-on-Don State UniversityRostov-on-DonRussian Federation

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