Regiocontrolled Synthesis of 1,2- Diaryl 1H imidazoles by Palladium and Copper Mediated Diorect Coupling of 1-Aryl-1H-Imidazoles with Aryl Halides under ligandless conditions

A large variety of 1,2-diaryl-1H-imidazoles, including a selective COX-2 inhibitor, have been regioselectively synthesised in moderate to high yields by direct coupling of 1-aryl- 1H-imidazoles with aryl iodides or bromides in DMF in the presence of CsF and catalytic amounts of Pd(OAc)2 under ligandless conditions. A possible mechanism for this new highly regioselective C-2 arylation reaction, involving the formation of an organocopper(I) derivatives followed by a transmetallation reaction with an arylpalladium(II) halide Introduction Imidazoles possessing two aryl substituents appear frequently in molecules that elicit important biological responses. Thus, some 1,5-diaryl-1H-imidazoles 1 (Figure 1) include substances that act as selective inhibitors of cyclooxygenase- 2 (COX-2)[1] and are cytotoxic against a variety of human cancer cell lines.[2] On the other hand, some 1,2- diaryl-1H-imidazoles 2 have been reported to be antagonists of the cannabinoid CB1 receptor[3,4] or to be able to inhibit COX-2 selectively.[5,6,7] The biological activities of compounds 1 and 2 have made them popular synthetic targets, and numerous methods for the synthesis of these heterocycles have been developed.[8,9] These synthetic methods, however, involve the construction of the imidazole ring by multi-step reaction sequences and, before our studies, no simple and straightforward synthesis of compounds 1 and 2 had been described, with the exception of that of com- [a] Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, 56126 Pisa, Italy Fax: +39-0502219260 E-mail: bellina@dcci.unipi.it, rossi@dcci.unipi.it [b] Dipartimento S.T.A.A.M., Universiy of Molise, 86100 Campobasso, Italy [c] Istituto di Metodologie Chimiche, CNR, via Salaria Km 29.300, 00016 Monterotondo Stazione, Roma, Italy [d] University of Provence, Jeune Equipe Traces, Centre de Saint- Jerome, Case 511, 13397 Marseille Cedex, France Supporting information for this article is available on the WWW under http://www.eurjoc.org or from the author. Eur. J. Org. Chem. 2006, 693–703 © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 693 species and a reductive elimination, is proposed. New onestep procedures for the synthesis of 1,2,5-triaryl-1H-imidazoles, based on palladium- and copper-mediated arylation of 1-aryl-1H-imidazoles, have also been developed. Interestingly, some imidazole derivatives prepared in this study have been found to exhibit significant cytotoxic activity against some human tumour cell lines.