Silica Sulfuric Acid as an Efficient Heterogeneous Catalyst for the Solvent-Free Synthesis of 1-Substituted 1H-1,2,3,4-Tetrazoles

Application of the tetrazole compounds including 1substituted tetrazoles [1–3] has increased rapidly over the past few years for different purposes. For example they have been used in coordination chemistry, medicinal chemistry, agriculture, photography, and preparation of nitrogen-containing compounds [4, 5]. In general, the most direct and versatile method of the synthesis of tetrazoles is the cycloaddition between nitriles, cyanates and cyanamides, and azides [4, 6–11]. 1-substituted tetrazoles are generally synthesized by reaction of isocyanides with large excess amounts of dangerous and harmful hydrazoic acid [12, 13] or trimethyl azide [14]. e othermethods include addition of amines or their salts to sodium azide and orthocarboxylic acid ester in acetic acid or tri�uoroacetic acid [15, 16]. Su and coworkers have reported the synthesis of 1-substituted tetrazoles using Yb(OTf)3 in volatile organic solvents [17]. All of these known methods suffered from some limitations such as low yields, drastic reaction conditions, the use of expensive and toxic metal catalysts, tedious workup, complex isolation and recovery procedures, the use of excessive amounts of glacial acetic acid or tri�uoroacetic acid (an expensive solvent), the use of high boiling point solvent such as DMF (which is soluble in both organic solvents and water; thus its removing from the reaction mixture is difficult) and even the need for excess amounts of dangerous and harmful hydrazoic acid [4, 6–8, 15, 16]. erefore, the development of a more efficient and convenient method for the synthesis of 1-substituted tetrazoles under solvent-free conditions still remains an active research area. During the last decade many academic and industrial processes shied towards the development of new technologies in synthetic organic chemistry using solid acid catalysts [18–22]. Among various silica-based heterogeneous catalysts, silica sulfuric acid (SSA) has advantages of low cost, ease of preparation and recyclability, and is insoluble in all organic solvents.


Introduction
Application of the tetrazole compounds including 1substituted tetrazoles [1][2][3] has increased rapidly over the past few years for different purposes. For example they have been used in coordination chemistry, medicinal chemistry, agriculture, photography, and preparation of nitrogen-containing compounds [4,5].
1-substituted tetrazoles are generally synthesized by reaction of isocyanides with large excess amounts of dangerous and harmful hydrazoic acid [12,13] or trimethyl azide [14]. e other methods include addition of amines or their salts to sodium azide and orthocarboxylic acid ester in acetic acid or tri�uoroacetic acid [15,16]. Su and coworkers have reported the synthesis of 1-substituted tetrazoles using Yb(OTf) 3 in volatile organic solvents [17].
All of these known methods suffered from some limitations such as low yields, drastic reaction conditions, the use of expensive and toxic metal catalysts, tedious workup, complex isolation and recovery procedures, the use of excessive amounts of glacial acetic acid or tri�uoroacetic acid (an expensive solvent), the use of high boiling point solvent such as DMF (which is soluble in both organic solvents and water; thus its removing from the reaction mixture is difficult) and even the need for excess amounts of dangerous and harmful hydrazoic acid [4, 6-8, 15, 16]. erefore, the development of a more efficient and convenient method for the synthesis of 1-substituted tetrazoles under solvent-free conditions still remains an active research area.
During the last decade many academic and industrial processes shied towards the development of new technologies in synthetic organic chemistry using solid acid catalysts [18][19][20][21][22]. Among various silica-based heterogeneous catalysts, silica sulfuric acid (SSA) has advantages of low cost, ease of preparation and recyclability, and is insoluble in all organic solvents.

General Procedure for Preparation of the 1-Substituted
Tetrazoles. A mixture of amine (2.0 mmol), NaN 3 (2.0 mmol), triethyl orthoformate (2.4 mmol), and SSA (0.02 g) was taken in a 25 mL round bottom �ask e�uipped with a condenser under a well-ventilated fume hood and heated at 120 ∘ C for the appropriate time with vigorous stirring (Table 1). Aer completion (as monitored by TLC), the reaction mixture was diluted with cold water (5 mL) and extracted with ethyl acetate (3 × 10 mL). e catalyst was removed by �ltration, and the combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 . Aer concentration, a crystallization step was performed using EtOAc-hexane to afford the pure product. All the products are known compounds, and the spectral data and melting points were identical to those reported in the literature [14-16, 23, 24]. T 1: Synthesis of 1-substituted 1H-1,2,3,4-tetrazoles from the reaction of primary amines, sodium azide, and triethyl orthoformate in the presence of SSA at 120 ∘ C and in solvent-free conditions.
First, we examined a variety of structurally divergent aniline possessing a wide range of functional groups to understand the scope and generality of the SSA-promoted cycloaddition reaction to form the 1-substituted tetrazoles, and the results are summarized in Table 1.
Treatment of the heteroaromatic 3-aminopyridine with orthoformate and sodium azide at 120 ∘ C for 5 h also afforded the corresponding tetrazole in an excellent yield (Table 1, entry 10). Due to the presence of two NH 2 groups, 1h interestingly afforded the double-addition product ( Table 1, entry 8).
In a typical experiment, aer completion of the reaction, SSA was isolated from the reaction mixture by simple �ltration. e reusability of the catalyst was assessed aer activating the catalyst at 80 ∘ C for 5 h. en it was reused three times successively with consistent activity, indicating high activity of the catalyst. is reusability demonstrates the high stability and turnover of SSA under operating condition. e products were characterized by NMR, FT-IR, elemental analysis (CHN), and melting points. e 1-substituted tetrazoles are generally acidic substances and the relevant proton signal will be shied to down�eld (see 1 H NMR data), so the peak at = 7.80-8.30 ppm can be attributed to the proton of the tetrazole ring. 13 C NMR spectra displayed signals about = 147-157 ppm for C5 of the tetrazole ring [10,11,24].

Conclusion
We applied an efficient methodology for synthesis of the 1substituted tetrazoles using SSA as a heterogeneous catalyst. All reactions were performed under solvent-free conditions (from the standpoint of green chemistry and industry, both are important due to the reduced pollution, low cost, and simplicity in processing and handling) with high yields and a simple workup that no chromatographic procedure is necessary to get the pure compounds. e SSA catalyst can be recovered by simple �ltration and reused without the loss of activity. is methodology may �nd widespread application in organic synthesis for preparation of the tetrazoles. Further studies are in progress.