Highly selective synthesis of 4(5)-aryl-, 2,4(5)-diaryl-, and 4,5-diaryl-1H-imidazoles via Pd-catalyzed direct C-5 arylation of 1-benzyl-1H-imidazole Fabio Bellina * , Silvia Cauteruccio, Annarita Di Fiore, Chiara Marchetti, Renzo Rossi * Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, I-56126 Pisa, Italy Received 27 August 2007; received in revised form 15 October 2007; accepted 17 October 2007 Available online 16 January 2008 Abstract Highly selective, practical, and efficient protocols for the preparation of 4(5)-aryl-1H-imidazoles 2, 2,4(5)-diaryl-1H-imidazoles 3, and 4,5- diaryl-1H-imidazoles 1 are described. A key step of these protocols is the regioselective synthesis of 5-aryl-1-benzyl-1H-imidazoles 9 by Pd-catalyzed direct C-5 arylation of commercially available 1-benzyl-1H-imidazole (8) with aryl halides. The three-step synthesis of compounds 3 from 8 also involves the Pd-catalyzed and Cu-mediated direct C-2 arylation of imidazoles 9 with aryl halides under base-free and ligandless conditions. On the other hand, the four-step synthesis of imidazoles 1 from 8 also involves the regioselective bromination of compounds 9 and a Suzuki reaction of the resulting 5-aryl-1-benzyl-4-bromo-1H-imidazoles 11 with arylboronic acids 5 under phase-transfer conditions, followed by N-debenzylation. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Imidazoles; Direct arylation; Regioselectivity; CeH bond activation; Biologically active compounds 1. Introduction Mono- and di-C-aryl substituted imidazoles are important compounds because of their significant pharmacological and biological activities. Monosubstituted 4(5)-aryl-1H-imidazoles, for example, include compounds with good in vitro antifungal activity, 1 potent inhibitors of b-glucosidase, 2 and substances which exhibit activin receptor like kinase 5 (ALK5) inhibitory activity, 3 and several 4(5)-aryl-2-heteroaryl-1H-imidazoles have been shown to possess antiinflammatory properties 4 as well as NPY5 receptor antagonist activity. 5 On the other hand, 2-alkyl-4(5)-aryl-1H-imidazoles are of interest as potent Na þ channel blockers 6 and several 5(4)-aryl-4(5)-(4-fluorophenyl)- 1H-imidazoles are p38 MAP kinase inhibitors. 7 Moreover, 2-tert-butyl-4(5)-(4-fluorophenyl)-5(4)-(4-pyridyl)-1H-imid- azole has been identified as a submicromolar inhibitor of B-Raf, 8 5(4)-aryl-4(5)-(3,4,5-trimethoxyphenyl)- and 5-aryl- 1-methyl-4-(3,4,5-trimethoxyphenyl)-1H-imidazoles have been shown to be potent cytotoxic agents able to mimic the ac- tivity of combretastatin A-4 against the polymerization of tubu- lin, 9 and 2-substituted 4,5-diaryl-1H-imidazoles have been identified as COX-2 inhibitors 10 and as human CB1 receptor in- verse agonists. 11 In light of this significance, mild and efficient methods for the synthesis of C-aryl substituted imidazoles have been devel- oped and a variety of synthetic procedures have been particu- larly devised for the synthesis of 4,5-diaryl-1H-imidazoles 1. 12 However, despite the progress, the state-of-the-art for the synthesis of these compounds remains less than ideal. N H N Ar 2 Ar 1 1 N H N Ar 1 2 N H N Ar 1 3 Ar 2 On the other hand, relatively few methods for the synthesis of 4(5)-aryl-1H-imidazoles 2 and 2,4(5)-diaryl-1H-imidazoles 3 have been reported in the literature and these synthetic * Corresponding authors. Tel.: þ39 050 2219282; fax: þ39 050 2219260 (F.B.); tel.: þ39 050 2219214; fax: þ39 050 2219260 (R.R.). E-mail addresses: bellina@dcci.unipi.it (F. Bellina), rossi@dcci.unipi.it (R. Rossi). 0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.01.051 Available online at www.sciencedirect.com Tetrahedron 64 (2008) 6060e6072 www.elsevier.com/locate/tet