Molecular Diversity

, Volume 10, Issue 1, pp 17–22 | Cite as

Efficient library synthesis of imidazoles using a multicomponent reaction and microwave irradiation

  • E. Gelens
  • F. J. J. De Kanter
  • R. F. Schmitz
  • L. A. J. M. Sliedregt
  • B. J. Van Steen
  • Chris G. Kruse
  • R. Leurs
  • M. B. Groen
  • R. V. A. Orru
Full-length paper


Optimization of Radziszewski's four-component reaction employing a microwave-assisted protocol, led to a small library of 48 imidazoles with a success rate of 65% (conversion > 45%). All three diversity points of the four-component reaction were varied. Aromatic and aliphatic inputs were successfully implemented and mono-, di-, tri- and tetrasubstituted imidazoles with various substitution patterns were synthesized. Furthermore, unsymmetrical diketones could successfully be used which improved the intrinsic diversity of the method significantly. If the unsymmetrical diketone 1,2-phenylpropanedione (R1 and R2) was used two regioisomers were formed. Depending on the type of amine (R4) and aldehyde (R3) applied, regioselectivity was modest to good. Based on these results, a reaction mechanism is proposed.


imidazoles multicomponent reaction microwave diversity library synthesis combinatorial chemistry 





multicomponent reaction


electron withdrawing group


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kitbunnadaj, R., Zuiderveld, O.P., Christophe, B., Hulscher, S., Menge, W.M.P.B., Gelens, E., Snip, E., Bakker, R.A., Celanire, S., Gillard, M., Talaga, P., Timmerman, H. and Leurs, R., Identification of 4-(1H-imidazol-4(5)-ylmethyl)pyridine (immethridine) as a novel, potent, and highly selective histamine H-3 receptor agonist, J. Med. Chem., 10 (2004) 2414–2417.Google Scholar
  2. 2.
    Adams, J.L., Boehm, J.C., Gallagher, T.F., Kassis, S., Webb, E.F., Hall, R., Sorenson, M., Garigipati, R., Griswold, D.E. and Lee, J.C., Pyrimidinylimidazole inhibitors of p38: Cyclic N-1 imidazole substituents enhance p38 kinase inhibition and oral activity, Bioog. Med. Chem. Lett., 11 (2001) 2867–2870.Google Scholar
  3. 3.
    Dinsmore, C.J., Williams, T.M., O'Neill, A.B., Liu, D., Rands, E., Culberson, J.C., Lobell, R.B., Koblan, K.S., Kohl, N.E., Gibbs, J.B., Oliff, A.I., Graham, S.L. and Hartman, G.D., Imidazole-containing diarylether and diarylsulfone inhibitors of farnesyl-protein transferase Bioog. Med. Chem. Lett., 9 (1999) 3301–3306.Google Scholar
  4. 4.
    Khanna, I.K., Weier, R.M., Yu, Y., Xu, X.D., Kosyk, F.J., Collins, P.W., Koboldt, C.M., Veenhuizen, A.W., Perkins, W.E., Casler, J.J., Masferrer, J.L., Zhang, Y.Y., Gregory, S.A., Seibert, K. and Isakson, P.C., 1,2-Diarylimidazoles as potent, cycloogygenase-2 selective, and orally active antiinflammatory agents, J. Med. Chem., 40 (1997) 1634–1647.Google Scholar
  5. 5.
    Revesz, L., Bonne, F. and Makavou, P., Vicinal bromostannanes as novel building blocks for the preparation of di- and trisubstituted imidazoles, Tetrahedron Lett., 39 (1998) 5171–5174.CrossRefGoogle Scholar
  6. 6.
    Zhang, C., Woiwode, T.F., Short, K.S. and Mjalli, A.M.M., Synthesis of tetrasubstituted imidazoles via a-(N-acyl-N-alkylamino)-b-ketoamides on Wang resin, Tetrahedron Lett., 37 (1996) 751–754.Google Scholar
  7. 7.
    Orru, R.V.A. and de Greef, M., Recent advances in solution-phase multicomponent reactions for the synthesis of heterocyclic compounds, Synthesis, 10 (2003) 1471–1499.Google Scholar
  8. 8.
    Radziszewski, B., Ber., 15 (1882) 1493.Google Scholar
  9. 9.
    Drefahl, G. and Herma, H., Ubersuchungen uber stilbene 28. stilbenyl-imidazole, Chem. Ber., 93 (1960) 486.Google Scholar
  10. 10.
    Maduskuie Jr., T.P., Wilde, R.G., Billheimer, J.T., Cromley, D.A., germain, S., Gillies, P.J., Higley, C.A., Johnson, A.L., Pennev, P., Shimshick, E.J. and Wexler, R.R., Design, synthesis, and structure-activity relationship studies for a new imidazole series of J774 macrophages specific acyl-CoA: Cholesterol acyltransferase (ACAT) inhibitors., J. Med. Chem., 38 (1995) 1067–1083.Google Scholar
  11. 11.
    Liverton, N.J., Butcher, J.W., Clayborne, C.F., Claremon, D.A., Libby, B.E., Nguyen, K.T., Pitzenberger, S.M., Selnick, H.G., Smith, G.R., Tebben, A., Vacca, J.P., Varga, S.L., Agarwal, L., Dancheck, K., Forsyth, A.J., Fletcher, D.S., Frantz, B., Hanlon, W.A., Harper, C.F., Hofsess, S.J., Kostura, M., Lin, J., Luell, S., O'Neill, E.A., Orevillo, C.J., Pang, M., Parsons, J., Rolando, A., Sahly, Y., Visco, D.M. and O'Keefe, S.J., Design and synthesis of potent, selective and orally active bioavailable tetrasubtituted imidazole inhibitors of p38 mitogen-activated protein, J. Med. Chem., 42 (1999) 2180–2190.Google Scholar
  12. 12.
    Santos, J., Mintz, E.A., Zehnder, O., Bosshard, C., Bu, X.R. and Günter, P., New class of imidazoles incorporated with thiophenevinyl conjunction pathway for robust nonlinear optical chromophores, Tetrahedron Lett., 42 (2001) 805–808.Google Scholar
  13. 13.
    Davies, J.R., Kane, P.D. and Moody, C.J., N-H insertion reactions of rhodium carbenoids. Part 5: A convenient route to 1,3-azoles, Tetrahedron, 60 (2004) 3967–3977.Google Scholar
  14. 14.
    Wolkenberg, S.E., Wisnoski, D.D., Leister, W.H., Wang, Y., Zhao, Z. and Lindsley, C.W., Efficient synthesis of imidazoles from aldehydes and 1,2-diketones using microwave irradiation, Org. Lett., 6 (2004) 1453–1456.CrossRefGoogle Scholar
  15. 15.
    Xu, Y., Liu, Y.Z., Rui, L. and Guo, Q.X., One-pot synthesis of tetra-substituted imidazoles on silicagel under microwave irradiation, Heterocycles, 63 (2004) 87.Google Scholar
  16. 16.
    Balalaie, S., Hashemi, M.M. and Akhbari, M., A novel one-pot synthesis of tetrasubstituted imidazoles under solvent-free conditions and microwave irradiation, Tetrahedron Lett., 44 (2003) 1709–1711.CrossRefGoogle Scholar
  17. 17.
    Usyatinsky, A.Y. and Khmelnitsky, Y.L., Microwave-assisted synthesis of substituted imidazoles on a solid support under solvent-free conditions, Tetrahedron Lett., 41 (2000) 5031–5034.CrossRefGoogle Scholar
  18. 18.
    Loupy, A., Petit, A., Hamelin, J., Texier-Boullet, F., Jacquault, P. and Mathe, D., New solvent-free organic synthesis using focused microwaves, Synthesis, (1998) 1213, and references cited herein.Google Scholar
  19. 19.
    Lew, A., Krutzik, P.O., Hart, M.E. and Chamberlin, R. Increasing rates of reaction: Microwave assisted organic synthesis for combinatorial chemistry, J. Comb. Chem., 4 (2002) 95–105 and references cited herein.Google Scholar
  20. 20.
    Perreux, L., Loupy, A. and Volatron, F., Solvent free preparation of amides from acids and primary amines under microwave irradiation, Tetrahedron, 58 (2002) 2155–2162.CrossRefGoogle Scholar
  21. 21.
    Goretski, C, Krlej, A., Steffens, C. and Ritter, H., Green polymer chemsitry: Microwave-assisted single-step synthesis of various (meth)acrylamides and poly(meth)acrylamides directly from (meth)acrylic acid, Macromol. Rapid Commun., 25 (2004) 513–516.Google Scholar
  22. 22.
    The isolated yield was determined by work-up via the following procedure. After the reaction, the reaction mixture was taken up in DCM. Water was added and the water layer was neutralized with Na2CO3. The layers were separated and the water layer was extracted twice more with DCM. The combined DCM layers were dried over Na2SO4 and reduced in vacuo. The crude mixture was analysed by 1H-NMR and was found to contain 71% of the expected imidazole 1. Flash chromatography with DCM as the eluent gave imidazole 1 in 70% yield and 95% purity.Google Scholar
  23. 23.
    The use of the optimised conditions for the MCR to produce imidazole 1 in ethanol, toluene, acetonitrile, dioxane, t-butylmethylether, or dichloroethane instead of chloroform results in all cases in > 80% conversion to 1. However, chloroform gave the best results: The highest conversions were obtained and the least side products were formed.Google Scholar
  24. 24.
    Yan, B., New combichem QC standards guard the supply of compounds and ensure HTS results, Modern Drug Discovery, (2004) 30–34.Google Scholar
  25. 25.
    This was established by NOESY-NMR analysis.Google Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • E. Gelens
    • 1
  • F. J. J. De Kanter
    • 1
  • R. F. Schmitz
    • 1
  • L. A. J. M. Sliedregt
    • 2
  • B. J. Van Steen
    • 2
  • Chris G. Kruse
    • 2
  • R. Leurs
    • 1
  • M. B. Groen
    • 1
  • R. V. A. Orru
    • 1
  1. 1.Department of Chemistry, Faculty of Exact SciencesVrije UniversiteitAmsterdamThe Netherlands
  2. 2.Solvay Pharmaceuticals Research LaboratoriesWeespThe Netherlands

Personalised recommendations