Silica Sulfuric Acid : An Eco-Friendly and Reusable Catalyst for Synthesis of Benzimidazole Derivatives

Benzimidazole derivatives are found in many biologically active compounds possessing antiviral, antihypertension, and anticancer properties [1, 2]. Compounds possessing the benzimidazole moiety exhibit signi�cant activity against several viruses such as HIV [3, 4], herpes (HSV-1) [5], RNA [6], in�uenza [7], and human cytomegalovirus (HCMV) [3, 4]. Speci�cally, the 2-substituted analogs of benzimidazoles are known to be potent biologically active compounds [8]. ere are several methods for benzimidazole synthesis; these compounds are conventionally prepared using condensation of o-phenylenediamine with carbonyl compounds in the presence of strong acids such as Me2S BrBr, P-TsOH [9], Alumina-methanesulfnic acid [10], BF3⋅OEt2 [11], ceric(IV) ammonium nitrate [12]. However, many of the synthetic protocols reported so far suffer from disadvantages, such as a requirement for anhydrous conditions, use of organic solvents, harsh reaction conditions, expensive reagents, and low-to-moderate yields. erefore, the development of a simple, mild, and efficient method is still needed. Solid supported reagents have improved activity and selectivity than individual reagents, because the surface area of the reagent is increased manifold [14]. Silica sulfuric acid (SiO2-OSO3H), a solid acid, is a versatile catalyst that makes reaction processes more convenient, more economic, and environmentally benign. Owing to the numerous advantages associated with this cheap and nonhazardous catalyst, under mild conditions, silica sulfuric acid has been explored as a powerful catalyst for various organic transformations [15, 16].is solid acid has also been used in synthesis of oxazolines and imidazolines [17], synthesis of 2,3-dihydroquinazolin-4(1H)-ones [18], synthesis of substituted pyrroles [19], chemoselective detritylation of 5-tritylated nucleosides [20], and deprotection of oxime to carbonyls [21]. In this paper, we wish to report an efficient and versatile procedure for the synthesis of 2-substituted benzimidazole derivatives in the presence of silica sulfuric acid. We nowwish to describe our efforts towards the synthesis of 2-substituted benzimidazole derivatives in the prescence of solid acid catalyst see Scheme 1.

Solid supported reagents have improved activity and selectivity than individual reagents, because the surface area of the reagent is increased manifold [14].
Silica sulfuric acid (SiO 2 -OSO 3 H), a solid acid, is a versatile catalyst that makes reaction processes more convenient, more economic, and environmentally benign.Owing to the numerous advantages associated with this cheap and nonhazardous catalyst, under mild conditions, silica sulfuric acid has been explored as a powerful catalyst for various organic transformations [15,16].is solid acid has also been used in synthesis of oxazolines and imidazolines [17], synthesis of 2,3-dihydroquinazolin-4(1H)-ones [18], synthesis of substituted pyrroles [19], chemoselective detritylation of 5 � -tritylated nucleosides [20], and deprotection of oxime to carbonyls [21].In this paper, we wish to report an efficient and versatile procedure for the synthesis of 2-substituted benzimidazole derivatives in the presence of silica sulfuric acid.
We now wish to describe our efforts towards the synthesis of 2-substituted benzimidazole derivatives in the prescence of solid acid catalyst see Scheme 1.

Experimental
e products were known and were characterized by IR and NMR and by comparing their physical properties with those reported in the literature.IR spectra were run on a Shimadzu IR-470 spectrometer.NMR was obtained using a Bruker Avans 400 MHz spectrometer.Melting points were determined with a Barnstead Electrothermal melting point apparatus.Elemental analyses were performed using a Costech ECS 4010 CHNS-O analyzer.Benzonitrile or aldehyde (1 mmol), o-phenylenediamine (1 mmol), and ethanol in the presence of SiO 2 -OSO 3 H (0.1 g) were placed in a round bottom �ask.e materials were mixed and heated at re�ux for 20 min.e progress of the reaction was followed by TLC (3 : 1:n-hexane:ethylacetate).Aer the completion of the reaction, the mixture was �ltered to remove the catalyst.By evaporation of the solvent, the crude product was recrystallized from hot aq.ethanol to obtain the pure compound.All products are known and were identi�ed by comparison of their physical or spectral data with those of authentic samples.

Results and Discussion
In continuation of our investigation about application of solid acids in organic synthesis [22,23], we herein report a simple and efficient protocol for benzimidazole synthesis using a cheap and readily available SiO 2 -OSO 3 H catalyst. e efficiency of this acid is comparable with some other catalysts such as Me 2 S + BrBr − , P-TsOH, alumina-methanesulfunic acid, and BF 3 ⋅OEt 2 .Most of these methods have limitations such as organic solvents, fuming catalyst, and harsh reaction condition.To optimize the catalytic system, the synthesis of 2-(phenyl)benzimidazole was used as a model reaction.e catalytic activity and efficiency of this method can be in�uenced by various parameters such as the employed catalyst, catalyst amount, and temperature.
Silica sulfuric acid, owing to the numerous advantages such as solid acid, nonhazardous, and available was selected for this protocol.
It is worthwhile to mention that the minimum amount of the catalyst was optimized to be 0.1 g. e effect of temperature was studied by carrying out the model reaction in the presence of silica sulfuric acid (0.1 g) in ethanol (10 mL) and solvent-free at different temperatures (room temperature, 45 and 80 ∘ C).It was observed (Table 1, entries 6, 7, and 8) that the yield was increased as the reaction temperature was raised.From these results, 80 ∘ C is selected as the best temperature for all future studies.e reusability of the SiO 2 -OSO 3 H catalyst was also examined.Aer each run, CHCl 3 was added and the product was �ltered, the solvent evaporated and the residue (catalyst) was washed with CHCl 3 and reused.Apparently, treatment with CHCl 3 removes tars more efficiently from the catalyst surface (Table 1, entries 11 and 12).is catalyst was reusable, although a gradual decline in activity was observed.We also tried to use benzonitrile instead of benzaldehyde in the model reaction (Table 2, entry 15).We can mention fortunately, that our attempts to carry out the reaction in the presence of benzonitrile were successful.
To show the generality of this method, the optimized conditions used for the synthesis of other benzimidazoles and all results are summarized in Table 2.As shown in Table 2, this method is effective for the preparation of benzimidazoles from both benzonitrile derivatives as well as benzaldehydes.
e work-up procedure of this reaction is very simple.A�er completion of reaction the mixture was �ltered off to separate the catalyst and then the solvent was evaporated to dryness under reduced pressure.e pure products were obtained by recrystallization from a mixture of ethanol and water.

Conclusion
In summary, silica sulfuric acid is an efficient catalyst for the synthesis of benzimidazoles.In addition, as a water stable solid acid, reusable, and green catalyst, the handling of this catalyst is easy, it makes this catalyst suitable for the largescale operation.e reaction appears to be heterogeneously catalyzed.High yields, relatively short reaction times, simplicity of operation, and easy work-up procedure are some other advantages of this protocol.
T 2: Synthesis of benzimidazoles catalyzed by silica sulfuric acid a .Molar ratio of aldehyde or benzonitrile: 2-amino aniline: SiO 2 -OSO 3 H(g) was 1: 1 : 0.1.b Isolated yield.c All products are known and were identi�ed by their melting points, IR, 1 H NMR, and 13 C NMR spectra. a