Selective synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles in water at ambient temperature Peyman Salehi, a, * Minoo Dabiri, b Mohammad Ali Zolfigol, c Somayeh Otokesh b and Mostafa Baghbanzadeh b a Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, PO Box 19835-389, Evin, Tehran, Iran b Department of Chemistry, Faculty of Sciences, Shahid Beheshti University, Evin, Tehran, Iran c Department of Chemistry, Faculty of Sciences, Bu-Ali Sina University, Hamadan, Iran Received 22 November 2005; revised 1 February 2006; accepted 9 February 2006 Abstract—A highly selective synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles from the reaction of o-phenylenediamines and aromatic aldehydes in the presence of silica sulfuric acid is reported. The reactions were performed in ethanol or water and the cat- alyst could be reused for several runs. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction The benzimidazole nucleus is of significant importance to medicinal chemistry. Several publications report benzimidazole-containing compounds showing biologi- cal activities such as selective neuropeptide YY1 recep- tor antagonism, 1 and as 5-lipoxygenase inhibitors for use as novel antiallergic agents, 2 factor Xa (FXa) inhib- itors, 3 poly (ADP-ribose) polymerase (PARP) inhibi- tors 4 and as human cytomegalovirus (HCMV) inhibitors. 5 Substituted benzimidazole derivatives have found commercial applications in veterinarian medicine as anthelmintic agents and in diverse human therapeutic areas such as treatment of ulcers and as antihistaminics. 6 In light of the affinity they display towards a variety of enzymes and protein receptors, medicinal chemists would certainly classify them as ‘privileged sub-struc- tures’ for drug design. 7 The traditional synthesis of benzimidazoles involves the reaction between an o-phenylendiamine and a carboxylic acid or its derivatives (nitriles, amidates, orthoesters) under harsh dehydrating conditions. 8 Benz- imidazoles have also been prepared on solid-phase to provide a combinatorial approach. 9 The most popular strategies for their synthesis utilise o-nitroanilines as intermediates or resort to direct N-alkylation of an unsubstituted benzimidazole. 10 A number of synthetic protocols that involve intermediate o-nitroanilines have evolved to include the synthesis of benzimidazoles on solid support. 11–17 Another method for the synthesis of these compounds is the reaction of o-phenylenediamine with aldehydes in the presence of acidic catalysts under various reaction conditions. 18–22 In continuation of our interest in catalysed solid support reactions, 23 we report a selective synthesis of 2-aryl-1- arylmethyl-1H-1,3-benzimidazoles in ethanol and water. When o-phenylenediamine derivatives 1 and aromatic aldehydes 2 in the presence of silica sulfuric acid 24 and different organic solvents, were allowed to react at room temperature, both expected products were obtained whose ratios depended on the nature of the solvent (Scheme 1, 3 and 4). As can be seen in Table 1, the best overall yields and selectivities were obtained in ethanol, in which only N-substituted benzimidazoles 3 were pro- duced. Consequently several aromatic aldehydes with different substituents on the aromatic ring were sub- jected to the condensation reaction. In all cases the yields were high and 3 was formed selectively rather than 4 (Table 2). 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.02.049 Keywords: Heterocycles; Benzimidazole; Heterogenous catalysis; Water; Silica sulfuric acid. * Corresponding author. Tel./fax: +98 21 2241 8679; e-mail: p-salehi@ sbu.ac.ir Tetrahedron Letters 47 (2006) 2557–2560