p -TsOH Catalyzed synthesis of 2-arylsubstituted benzimidazoles

p -TsOH (20 mol%) was used to be a catalyst for the synthesis of


Introduction
Benzimidazole derivatives exhibit significant activity against several viruses such as HIV, 1 herpes (HSV-1), 2 RNA, 3 influenza, 4a and human cytomegalovirus (HCMV) 1 .The widespread interest in benzimidazole-containing structures has promoted extensive studies for their synthesis.While many strategies are available for benzimidazole synthesis, [7][8][9][10][11][12][13][14][15][16] there are two general methods for the synthesis of 2-substituted benzimidazoles.One is the coupling of phenylenediamines and carboxylic acids 4b or their derivatives (nitriles, imidates, or orthoesters), 5 which often requires strong acidic conditions, and sometimes combines with very high temperatures or microwave irradiation. 6The other way involves a two-step procedure that includes the oxidative cyclo-dehydrogenation of Schiff bases, which are often generated from the condensation of phenylenediamines and aldehydes.Various oxidative and catalytic reagents such as sulfamic acid, 7 I 2 , 8 DDQ, 9 Air, 10 Oxone, 11 FeCl 3 •6H 2 O, 12 In(OTf) 3 , 13 Yb(OTf) 3 , 14 Sc(OTf) 3 , 15 KHSO 4 , 16 IL, 17 have been employed.Because of the availability of a vast number of aldehydes, the condensation of phenylenediamines and aldehydes has been extensively used.While many published methods are effective, some of these methods suffer from one or more disadvantages such as high reaction temperature, prolonged reaction time, and toxic solvents etc.Therefore, the discovery of mild and practicable routes for synthesis of 2-substituted benzimidazoles continues to attract the attention of researchers.
In recent times, we have shown KHSO 4 16 and IL 17 can be used as promoters and catalysts for the synthesis of benzimidazoles.So we tried to synthesize benzimidazoles using an organocatalyst.In this paper, p-TsOH 18 was used for the synthesis of 2-arylsubstituted benzimidazoles by the condensation of aryl aldehyde with o-phenylenediamine (Scheme 1).

Scheme 1
In order to establish the optimum condition for this reaction, various ratios of p-TsOH were examined.Using o-phenylenediamine and p-chlorobenzaldehyde as a model, p-TsOH was added in various ratios in DMF at 80°C.As shown in Table 1, very little of the desired products was obtained in the absence of p-TsOH and the best yields were obtained with 20% p-TsOH.Next the effect of solvent was examined.As shown in Table 2, different solvents can result in different yields.Clearly DMF stands out as the solvent of choice, with its fast conversion, high yield and low toxicity.
To test the general scope and versatility of this procedure in the synthesis of a variety of 2substituted benzimidazole, we examined a number of differently substituted arylaldehydes.We were pleased to find that moderate to high yields were obtained in the condensation of ophenylenediamine with aldehydes.As Table 3 shows that aryl aldehydes bearing both electrondonating and electron-withdrawing substituents gave the desired benzimidazoles in good yields.Heteroaryl aldehyde (Entry 8) and α,β-unsaturated cinnamicaldehyde (Entry 9) also gave acceptable yields.Whereas little product was obtained when aliphatic aldehydes were used.In conclusion, we have developed a simple, one-pot synthesis of 2-arylsubstituted benzimidazoles by the condensation of o-phenylenediamine with arylaldehyde catalyzed by p-TsOH.Simple and convenient procedure, easy purification and shorter reaction time are the advantageous features of this method

Table 2 .
Effect of solvent in condensation of o-phenylenediamine with 4-chlorobenzaldehyde a All yields refer to isolated product.b Reaction time: 10 min.

Table 3 .
Synthesis of benzimidazoles catalyzed by p-TsOH All yields refer to isolated product, characterized by melting points, 1 H NMR. a