In this study, the CYTOS^® College System, a microreactor produced by CPC-Cellular Process Chemistry Systems GmbH [1], was used to produce imidazoles in a continuous way.

The imidazole core is an important unit in heterocyclic chemistry. It occurs in different natural products and in a variety of synthetic compounds. Some examples of imidazole-containing compounds in living organisms are the essential amino acid histidine and histamine. A lot of imidazoles show biological activities [2]. Known imidazole based drugs are ketoconazole, which has antifungal properties and losartan, a drug against hypertension. More recently, interest in imidazoles is still increasing due to applications as green solvents by means of ionic liquids [3] and in organometallic chemistry as N-heterocyclic carbenes [4].

Many procedures have been developed to generate a broad range of differently substituted imidazoles [5]. Although there is a wide variety of synthetic routes towards imidazoles, only a few studies exist for the synthesis of 1,2,4,5-tetrasubstituted imidazoles which are mostly performed via multistep routes or via a trisubstituted 1H-imidazole in which the nitrogen is substituted in the final step.

Using the modified Radziszewski reaction [6] (Figure 1), a procedure has been optimized for the generation of tri- and tetrasubstituted imidazoles via microreactor technology. Optimization included the search for a suitable solvent mixture, temperature and reaction time. Finally, the generality of the optimized reaction was tested using different starting materials.

It was possible to create a variety of tri- and tetrasubstituted imidazoles in moderate to good yields (up to 1.6 g/h) via a continuous procedure [7].

Figure 1: Imidazole formation through a 4-CR

References:

[1] CPC - Cellular Process Chemistry Systems GmbH: Heiligkreuzweg 90, D-55130 Mainz, Germany, www.cpc-net.com. T. Schwalbe, K. Golbig, M. Hohmann, P. Georg, A. Oberbeck, B. Dittmann, J. Stasna, S. Oberbeck, (Cellular Process Chemistry Inc., USA) Eur. Pat. Appl. 2001, EP 1 123 734, Chem. Abstr. 2001, 135, 154468b.

[2] (a) Laufer, S.A.; Zimmermann, W.; Ruff, K.J. J. Med. Chem. 2004, 47, 6311. (b) Mjalli, A.; Sarshar, S. U.S. Patent 1997, US 5,700,826, 19pp. (c) Cheung, D.W.; Daniel, E.E. Nature 1980, 283, 485. (d) Black, J.W.; Durant, G.J.; Emmett, J.C.; Ganellin, C.R. Nature 1974, 248, 65.

[3] Welton, T. Chem. Rev. 1999, 99, 2071.

[4] Herrmann, W.A. Angew. Chem. Int. Ed. 2002, 41, 1290.

[5] Gribble, G.W.; Joule, J.A.; Gilchrist, T.L. (Eds.) Progress in Heterocyclic Chemistry, volume 13 - 17, Elsevier, Oxford, 2001 - 2005.

[6] (a) Gelens, E.; De Kanter, F.J.J.; Schmitz, R.F.; Sliedregt, L.A.J.M.; Van Steen, B.J.; Kruse, C.G.; Leurs, R.; Groen, M.B.; Orru, R.V.A. Mol. Div. 2006, 10, 17. (b) Wolkenberg, S.E.; Wisnoski, D.D.; Leister, W.H.; Wang, Y.; Zhao, Z.; Lindsley, C.W. Org. Lett. 2004, 6, 1453.

[7] Acke, D.R.J.; Orru, R.V.A.; Stevens, C.V. QSAR Comb. Sci. 2006, in press.

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