An Efficient Protocol for Facile Synthesis of New 5-Substituted-1 H-Tetrazole Derivatives Using Copper-Doped Silica Cuprous Sulfate ( CDSCS ) as Heterogeneous Nano-Catalyst

A facile and highly efficient protocol for synthesis of new 5-substituted-1H-tetrazoles derivatives using copper-doped silica cuprous sulfate (CDSCS) is described. In this method, the cycloaddition reaction of sodium azide with structurally diverse nitriles involving bioactive N-heterocyclic cores exploiting CDSCS in refluxing H2O/i-PrOH (1:1, v/v) furnishes the corresponding 5-substituted1H-tetrazoles in good to excellent yields (up to 93%). The influence of parameters effective in progress of reaction including solvent type, temperature and catalyst was studied and discussed. In this protocol, CDSCS was proved to be an efficient heterogeneous nano-catalyst to easily achieve the new tetrazole derivatives. The advantages of CDSCS in current protocol known are its cheapness, thermal and chemical stability, ease of recyclability and reusability for several consecutive runs without significant decline in its reactivity.

The synthesis of tetrazole and its derivatives has attracted considerable attention since the broad utilities found for tetrazoles.In this context, the different preparative methods have been emerged so far. 37,38Among them, the [3 + 2]-cycloaddition reaction of nitriles with azides is a well-known and most extensively studied and used procedure for synthesis of diverse 5-substituted-1H-tetrazoles. 39,40In this regard, several homogeneous reagents or catalysts have been developed to synthesize 5-substituted-1H-tetrazoles. 41,42Although these methods exhibit some advantages to access 1H-tetrazoles, their scale up synthesis are restricted by one or more disadvantages such as harsh reaction conditions, low yields, long reaction times, the use of strong Lewis acids, the in situ generation of HN 3 as a highly dangerous volatile material with a great risk of eruption and toxicity, production of the stable metal-tetrazole complexes, the use of expensive and toxic metals or solvents, tedious work-up procedure and failure to undertake the recovery or reusability of the catalyst.
Nowadays, heterogeneous catalysts have gained considerable attention due to both economic and environmental standpoints.The successful applications of heterogeneous systems in various organic transformations are well documented.Employing the heterogeneous catalysts often leads to the simple experimental procedures, mild reaction conditions, recovery and reusability of the catalyst, the minimization of undesirable chemical wastes, and the production of large quantities of products by using a small amount of catalyst.Thus, the exploit of heterogeneous catalysis has an exact superiority over homogeneous catalyst.In recent decade, some heterogeneous catalytic systems were developed to promote the synthesis of 5-substituted-1H-tetrazoles; [43][44][45][46][47][48][49][50][51][52][53][54][55] nevertheless, drawbacks are usually accompanied with these heterogeneous catalysts comprising: (i) the strong acidic nature of some catalysts that largely aggravates the release of dangerous HN 3 ; (ii) the use of weakly bonded or none-bonded metal salts supported on mineral supports which normally lead to desorption of active metal species during the reaction progress or work-up procedure; (iii) the formation of stable metal-tetrazole complexes that makes the tedious work-up procedure and (iv) the thermal or chemical instability.Thus, the employment of a heterogeneous catalyst that obviates the above drawbacks is of particular interest.
Silica-based catalysts offer several advantages like cheapness, mild reaction conditions, high yields and selectivity, non-corrosive properties, ease of handling and preparation.In addition, they could be easily removed from the reaction mixture, recovered, and reused by a simple flash filtration.Recently, we have reported the synthesis, characterization, and application of copper-doped silica cuprous sulfate (CDSCS) as a novel and efficient heterogeneous nano-catalyst for the Cu I -catalyzed 'Click' synthesis of 1,4-disubstituted 1,2,3-triazoles 56 and also 3,5-disubstituted isoxazoles. 57In light of the unique biological activities of tetrazoles and also in continuation of our ongoing research in utilizing CDSCS in organic synthesis, [56][57][58] we herein report a practical and environmentally benign catalytic protocol for efficient synthesis of 5-substituted-1H-tetrazole derivatives using CDSCS (Scheme 1).In this synthesis, the desired nitriles 1 were primarily achieved by the reaction of diverse nucleophiles with 2-chloroacetonitrile or 3-chloropropanenitrile in the presence of an equimolar mixture of triethylamine (TEA)-K 2 CO 3 and catalytic amount of tetrabutylammonium iodide (TBAI) in MeCN at reflux condition.Then, to access tetrazoles 2, the cycloaddition reaction of nitriles 1 with sodium azide was carried out utilizing CDSCS in H 2 O/i-PrOH at reflux condition.

Results and Discussion
The first step of this synthetic approach was initiated by the preparation of the essential nitriles 1.In this context, various nucleophiles comprising azole derivatives, purine and pyrimidine nucleobases and phenols underwent the N-or O-alkylation reaction with 2-chloroacetonitrile or 3-chloropropanenitrile through the S N 2-type reaction.The reaction of the selected nucleophiles with above chloronitriles was carried out using TEA-K 2 CO 3 (1:1) in the presence of TBAI (cat.) in refluxing MeCN (anhyd.) to gain 1. Afterward, to assess the optimized reaction condition for [3 + 2]-cycloaddition of 1 with NaN 3 , the influence of various parameters including temperature, solvent, and catalyst was studied.In this regard, the cycloaddition reaction of 2-(1H-benzo[d]imidazol-1-yl)acetonitrile (1a) with NaN 3 was selected as a sample reaction.
To progress the reaction efficiently, the choice of an appropriate solvent is crucial.Among tested solvents, the use of water has attracted enormous interest in organic transformations, since water is a cheap, clean, and universal solvent exhibiting extraordinary physical properties and enviro-economic benefits. 59In this regard, the model reaction was carried out in an aquatic media at room temperature.However, the corresponding tetrazole 2a was obtained only in 19% yield (Table 1, entry 1).To increase the reaction yield, the model reaction was investigated at varied temperatures (Table 1).As indicated in Table 1, the use of pure water at different temperatures failed to afford the satisfactory results even at reflux condition.This can be attributed to the lack of solubility of nitrile 1a in pure water.Consequently, the influence of several 1:1 (v/v) solutions of H 2 O with some water miscible organic solvents were examined (Table 1).
It is well understood that cycloaddition reaction between nitrile and azide is very slowly achieved in the absence of a suitable catalyst and thus it is unsuitable for large scale synthesis.In this connection, the choice of an efficient catalyst is critically essential for progress of the reaction.To investigate the catalytic potency of CDSCS, the effect of different catalysts was studied and compared with CDSCS (Table 2).To this end, we examined the potency of several heterogeneous or homogeneous catalysts including Lewis and proton acids, solid supports, and ammonium salts which are often applied in synthesis of tetrazole derivatives.As the results in The optimized stoichiometric ratio of nitrile/sodium azide to access 2a using CDSCS (0.05 mol%) was determined to be 1:1.5.
The generality and versatility of current protocol was screened by applying the optimized condition to various structurally diverse nitriles 1a-1o (Table 3).Due to Table 3, CDSCS proved to be a convenient and efficient heterogeneous nano-catalyst for cycloaddition reaction of sodium azide with different nitriles tethered to bioactive cores.As shown in Table 3, nitriles bearing azole derivatives (Table 3, entries 1-4, 10, 11), xanthine (Table 3, entry 9), purine and pyrimidine nucleobases (Table 3, entries 5 and 6) were employed to produce their corresponding 5-substituted-1H-tetrazole derivatives in good to excellent yields.Moreover, nitriles involving amine ( cycloaddition reaction with azide to obtain the desired tetrazole derivatives.The structures of all synthesized compounds were confirmed by 1 H and 13 C NMR, elemental analysis, mass and infrared (IR) spectroscopy techniques.
The applicability of the present protocol in preparative scale was also examined.In this context, the cycloaddition reaction of nitrile 1a with NaN 3 was performed on a 100-mmol scale.Interestingly, 2a was obtained in an excellent yield (89%) after 4 h which is comparable to smaller scale synthesis (Table 3, entry 1).
The recoverability and reusability of the catalyst is an important issue from different aspects like commercial applications and environmental concerns.In this connection, the reusability of CDSCS was investigated for sample reaction (Table 4).
The separation of the catalyst from the reaction media was conducted using a sintered glass funnel.The catalyst was then washed with ethyl acetate (2 × 15 mL) and dried in a vacuum oven at 90 ºC for 20 min.The catalyst was sequentially applied for 5 runs without the addition of the fresh catalyst to the reaction media.As shown in Table 4, the catalyst can be reused for many consecutive times without considerable decline in its catalytic activity.To determine the amount of leached Cu from CDSCS, the copper content of catalyst was determined using inductively coupled plasma (ICP) analysis for both fresh and reused catalyst (after 5 runs).Based on the ICP results, the leached Cu was found to be 0.014%, which is negligible.

Conclusions
In conclusion, we have described a convenient protocol for facile and high yield synthesis of the new structurally diverse 5-substituted-1H-tetrazoles utilizing CDSCS as a highly efficient heterogeneous nano-catalyst.CDSCS was proved to be a useful catalyst for cycloaddition reaction of sodium azide with different nitriles involving bioactive cores in H 2 O/i-PrOH (1:1, v/v) at reflux condition, which affords the corresponding tetrazole derivatives in good to excellent yields.The use of ecofriendly solvent, the reusability of the catalyst, the simplicity of the process, cheapness, and applicability in preparative scale are benefits that can be mentioned for current synthetic protocol.

General
All chemicals were purchased from either Fluka or Merck.Reactions were followed by TLC using  Table 3. Synthesis of 5-substituted-1H-tetrazole derivatives using CDSCS a (cont.)SILG/UV 254 silica-gel plates.The fresh CDSCS was prepared according to our previous reported procedure. 56,58olumn chromatography was performed on silica gel 60 ( General procedure for synthesis of alkyl nitriles 1a-1o In a double-necked round bottom flask (100 mL) equipped with a condenser, it was added a mixture, consisting of nucleophile (including: N-heterocyclic compounds or phenolic derivatives) (0.01 mol), 2-chloroacetonitrile or 3-chloropropanenitrile (0.013 mol), Et 3 N (0.01 mol), K 2 CO 3 (0.01 mol), and a catalytic amount of TBAI (0.1 g) in anhydrous MeCN (40 mL).The mixture was refluxed until TLC monitoring indicates no further improvement in the reaction.The solvent was evaporated in vacuo and the remaining foam was dissolved in CHCl 3 (100 mL) and subsequently washed with water (2 × 100 mL).The organic layer was dried (Na 2 SO 4 ) and evaporated.The crude product was purified by column chromatography on silica gel.

General procedure for synthesis of 5-substituted-1Htetrazole 2a-2o
In a double-necked round bottom flask (100 mL) equipped with a condenser, it was added a mixture, consisting of alkyl nitrile (0.01 mol), NaN 3 (0.015 mol), and CDSCS (0.3 g, 0.05 mol%) in H 2 O/i-PrOH (1:1 v/v, 50 mL).The mixture was heated at reflux until TLC monitoring indicates no further improvement in the conversion (Table 3).The reaction mixture was then cooled to room temperature, vacuum-filtered using a sinteredglass funnel and the residue was washed with ethyl acetate (2 × 20 mL).The filtrate was treated with 5 N HCl to reach pH = 3 and it was allowed to stir for 30 minutes.Subsequently, the organic layer was separated, dried over anhydrous Na 2 SO 4 and evaporated.The crude product was purified by recrystallization and/or column chromatography on silica gel eluted with proper solvents.

Table 2
indicate, higher yield of 2a in shorter reaction time were observed utilizing CDSCS in comparison with other tested catalysts.The use of other catalysts yielded 2a in moderate to reasonable amounts in variable times.

Table 4 .
The reusability of CDSCS in successive trails for synthesis of 2a a Reaction conditions: nitrile (0.01 mol), NaN 3 (0.015 mol), recovered CDSCS, H 2 O/i-PrOH (50 mL); b the entry number corresponds to the trial number; c isolated yield.