NaHSO4-SiO2-Promoted Solvent-Free Synthesis of Benzoxazoles, Benzimidazoles, and Benzothiazole Derivatives

An efficient protocol has been developed for the preparation of a library of benzoxazole, benzimidazole, and benzothiazole derivatives from reactions of acyl chlorides with o-substituted aminoaromatics in the presence of catalytic amount of silicasupported sodium hydrogen sulphate under solvent-free conditions. Simple workup procedure, high yield, easy availability, reusability, and use of ecofriendly catalyst are some of the striking features of the present protocol.


Introduction
Molecules with benzoxazole, benzimidazole, and benzothiazoles moieties are attractive targets for synthesis since they oen exhibit diverse and important biological properties.ese heterocycles have shown different pharmacological activities such as antibiotic [1], antifungal [2], antiviral [3], anticancer [4], antimicrobial [5], and anti-Parkinson [6] properties.ey have also been used as ligands for asymmetric transformations [7].Benzimidazole derivatives are a unique and broad spectrum class of antirhino/enteroviral agents such as antiulcerative [8] and antiallergic [9]; they are effective against the human cytomegalovirus [10] and are also efficient selective neuropeptide Y Y1 receptor antagonists [11].
In recent years, heterogeneous catalysts [40][41][42] have gained importance in several organic transformations due to their interesting reactivity as well as for economic and environmental reasons.In continuation of our work to develop new methodologies for organic transformations [43][44][45][46], we observed that silica-supported sodium hydrogen sulphate is highly efficient catalyst for the synthesis of substituted benzoxazole, benzimidazole, and benzothiazole derivatives through the reaction of o-substitued aminoaromatics with different acyl chlorides under solvent-free conditions.e catalyst NaHSO 4 -SiO 2 can easily be prepared [47] from the readily available NaHSO 4 and silica gel (230-400 mesh) and these are inexpensive and nontoxic.Besides, as the reaction is heterogeneous in nature, the catalyst can easily be removed by simple �ltration (Scheme 1).

Results and Discussions
In order to �nd the optimum reaction conditions for the condensation reaction, preliminary efforts were mainly focused on the evaluation of different solvents.e model reaction has been carried out between o-phenylenediamine and benzoyl chloride in the presence of NaHSO 4 -SiO 2 catalyst under different solvents and at different temperatures, and results are shown in Table 1.e effect of solvent, reaction temperature, and time on the reaction was systematically investigated, and the results were summarized in Table 1.e optimized reaction conditions for the reaction were found to be NaHSO 4 -SiO 2 under solvent-free condition for 12 hr at the temperature of 100 ∘ C. us, we used NaHSO 4 -SiO 2 as a catalyst in the present work.In order to elucidate the role of NaHSO 4 -SiO 2 as catalyst, a controlled reaction was conducted using o-phenylenediamine and benzoyl chloride under solvent-free condition in the absence of catalyst.is resulted in the formation of only 7% of the fused product aer 12 hr at 100 ∘ C.However, reaction with same substrate using 25%/wt of NaHSO 4 -SiO 2 at 100 ∘ C for 12 hr afforded the product in quantitative yield.Lower temperatures required more time for the completion of the reaction and obtained low yields compared to the optimized reaction condition.
As shown in Table 2, different acyl chlorides reacted with different o-substituted aminoaromatics without any signi�cant difference in the reaction time to give the corresponding 2-substituted benzoxazole, benzimidazole, and benzothiazole derivatives in good yield.e method has the ability to tolerate other functional groups such as methoxy, methyl, and halides.e products were synthesized in good to excellent yields and characterized by 1 H NMR, LCMS, and physical constant.Physical and spectral data of known compounds are in agreement with those reported in literature [48][49][50][51][52][53][54][55][56][57].
e reusability of catalyst is important for the largescale operation and industrial point of view.erefore, the recovery and reusability of NaHSO 4 -SiO 2 was examined.e catalyst was separated and reused aer washing with EtOAc and drying at 100 ∘ C. e reusability of catalyst was investigated in the reaction of o-phenylenediamine with benzoyl chloride (Figure 3).e results illustrated in Figure 3 showed that the catalyst can be used four times with consistent yield.

Conclusion
In conclusion, NaHSO 4 -SiO 2 was found to be an efficient catalyst for the formation of benzoxazole, benzimidazole, and benzothiazole derivatives.e use of this inexpensive, easily available, and reusable catalyst makes this protocol practical, environment friendly, and economically attractive.e simple workup procedure, high yields of products, and nontoxic nature of the catalyst are other advantages of the present method.

Experimental Section
All 1 H NMR spectra were recorded on 400 MHz Varian FT-NMR spectrometers.All chemical shis are given as  value with reference to Tetra methyl silane (TMS) as an internal standard.Melting points were taken in open capillaries.e IR spectra were recorded on a PerkinElmer 257 spectrometer using KBr discs.Products were puri�ed by �ash chromatography on 100-200 mesh silica gel.e chemicals and solvents were purchased from commercial suppliers either from Aldrich, Spectrochem, and they were used without puri�cation prior to use.

FT-IR Spectrum of NaHSO 4 -SiO 2
e FT-IR spectrum of the catalyst is shown in Figure 1.e catalyst is solid, and its solid-state IR spectrum was recorded using the KBr-disc technique.For silica (SiO 2 ), the major peaks are broad antisymmetric Si-O-Si stretching from 1000-1100 cm −1 and symmetric Si-O-Si stretching near 798 cm −1 , and bending modes of Si-O-Si lie around 467 cm −1 .e spectrum also shows a broad Si-OH stretching absorption from 3300 to 3500 cm −1 .

X-Ray Diffraction (XRD)
Spectrum of NaHSO 4 -SiO 2 Powder X-ray diffraction measurement was performed using D8 advance diffractometer.e strongest peaks of XRD pattern correspond to the SiO 2 plane with the other peaks indexed as the [22,23,32] planes of supported sodium hydrogen sulphate (Figure 2).

General Experimental Procedure
A mixture of 2-amino phenols or o-phenylenediamines (1 mmol) and acyl chloride (1 mmol) were place in a sealed vessel containing NaHSO 4 -SiO 2 (25%/wt) the reaction mixture was stirred at 100 ∘ C for 12 hrs.e progress of the    reaction was monitored by TLC Hexane: EtOAc (4 : 1) aer completion of the reaction, the reaction mixture was cooled and treated by dilution with EtOAc and the catalyst was removed by �ltration.Obtained �ltrate was evaporated under reduced pressure to get the crude product, which was puri�ed by column chromatography to give 2-substituted benzoxazoles, benzimidazole, and benzothioazole derivatives.8. Representative Spectral Data

F 2 :
XRD spectra of silica-supported sodium hydrogen sulphate.