An Efficient One-Pot Three-Component Synthesis of Novel Sulfanyl Tetrazoles Using Ionic Liquids

Over the years, multicomponent reactions (MCRs) have become increasingly popular tools to ensure sufficientmolecular diversity and complexity. ey have gained signi�cant popularity in recent years due to their atom-economy and straightforward reaction design due to substantial minimization of waste, labour, time, and cost [1, 2]. Tetrazoles play an important role in coordination chemistry as ligands, in medicinal chemistry as stable surrogates for carboxylic acids and in materials applications, including explosives, rocket propellants, and agriculture [3– 13]. ere is a particular interest for the synthesis of 5alkyl/arylthiotetrazoles as these thiotetrazoles are having powerful activating property than the corresponding 5akyl/aryltetrazoles used for synthesis of DNA and RNA [14, 15]. e presence of alkylthio group makes the tetrazole ring more acidic than the corresponding 5-alkyltetrazoles which improves its ability to act asan activator [16]. On the other hand, coumarins are heterocyclic organic compounds which constitute an important group of natural products having varied biological activities such as antitumor, antiin�ammatory, antiviral, CNS, antioxidant, and anti-HIV activities [17–20]. us, in view of the diverse activity of coumarins and tetrazoles, as a part of our continuing research work on the synthesis of novel heterocyclic compounds, we thought to synthesize the compounds containing coumarin-substituted sulfanyl tetrazoles. e most convenient method of synthesizing tetrazoles is the addition of azide ions to nitriles. Earlier reported methods for the synthesis of 5-substituted tetrazoles suffer from drawbacks such as the use of strong Lewis acids, or expensive and toxic metals, and the in situ generated hydrazoic acid which is highly toxic and explosive [21–24]. Several syntheses of 5-substituted tetrazoles have been reported through the [2+3] cycloaddition of nitriles using NaN3 or TMSN3 in the presence of catalysts such as ZnCl2 [25], AlCl3 [26], BF3-OEt2 [27], Pd(PPh3)4 [28], FeCl3-SiO2 [29], TBAF [30], Zn/Al hydrotalcite [31], ZnO [32], and Cu2O [33]. Recently, LeBlanc and Jursic [34] and Demko and Sharpless [35] reported the synthesis of sulfanyl tetrazoles. Although these methods were quite useful, but having some limitations such as use of toxic solvents and use of homogeneous Lewis acid catalyst like ZnBr2 which could not be recycled from the reaction mixture. All the above methods require prolonged reaction times. erefore, we thought of developing more efficient and convenient method which is free from all the above drawbacks.


Introduction
Over the years, multicomponent reactions (MCRs) have become increasingly popular tools to ensure sufficient molecular diversity and complexity.ey have gained signi�cant popularity in recent years due to their atom-economy and straightforward reaction design due to substantial minimization of waste, labour, time, and cost [1,2].
us, in view of the diverse activity of coumarins and tetrazoles, as a part of our continuing research work on the synthesis of novel heterocyclic compounds, we thought to synthesize the compounds containing coumarin-substituted sulfanyl tetrazoles.
e most convenient method of synthesizing tetrazoles is the addition of azide ions to nitriles.Earlier reported methods for the synthesis of 5-substituted tetrazoles suffer from drawbacks such as the use of strong Lewis acids, or expensive and toxic metals, and the in situ generated hydrazoic acid which is highly toxic and explosive [21][22][23][24].

Results and Discussion
In recent times, ionic liquids have attracted increasing interest in the context of green synthesis.ese ILs have shown great promise as an alternative to conventional solvents due to their unique properties of nonvolatility, non�ammability, thermal stability, recyclability, and controlled miscibility [36][37][38][39][40]. Butylimidazolium salts ILs have already been demonstrated as efficient catalysts and solvents for various organic transformations [41][42][43][44].
Our literature survey revealed that till now there were no methods reported in the literature for the synthesis of sulfanyl tetrazoles via one-pot three-component reaction using ionic liquids.As part of our ongoing research work on the developments of new routes to heterocyclic system in ionic liquids [45,46], we, herein, wish to report a simple and efficient procedure for one-pot threecomponent synthesis of novel sulfanyl tetrazoles by using 3-(2-bromoacetyl)coumarins/phenacyl bromides, KSCN and NaN 3 in the presence of [Bmim]BF 4 ionic liquid at 100 ∘ C to afford title compounds in good yields.(Schemes 1 and 2).
Ionic liquids (ILs) based on butylimidazolium salts were tested as solvents.In order to optimize the reaction conditions, a model reaction was performed using 4chlorophenacyl bromide 5b, KSCN and NaN 3 using various ionic liquids.
A mixture of 4-chlorophenacyl bromide 5b and KSCN in ionic liquid was stirred at RT for 10 minutes.Aer completion of the reaction, NaN 3 was added and the reaction was continued for 12 h, there was no product formation as observed by TLC, whereas at 60 ∘ C the reaction proceeded but not to completion even aer 8 h.Consequently, the reaction temperature was optimized at 100 ∘ C, which gave the sulfanyltetrazole as the sole product.e results were summarized in Table 1.As can be seen from Table 1, the best result was obtained when the reaction was carried out in [Bmim]BF 4 at 100 ∘ C (Table 1, entry 4).e reaction using [Bmim]BF 4 proceeded in higher yield and shorter reaction time than that using another ionic liquids as reaction media.
e recyclability of the ionic liquid was also investigated using the above model reaction.Aer completion of the reaction, the mixture was poured into water and stirred thoroughly.e solid product was isolated by �ltration, and the �ltrate containing ionic liquid was extracted with ethyl acetate (2 × 20 mL) to remove nonionic organic impurities.en, the water was evaporated under reduced pressure and the recovered ionic liquid was dried at 80 ∘ C under vacuum for 2 h and reused in the next reaction.e procedure was repeated, and the results indicated that the ionic liquid could be reused for four times without evident loss in the yield of the product (Table 2).e scope and the generality of the present method were further demonstrated by the reaction of various phenacylbromides/3-(2-bromoacetyl)coumarins with KSCN and NaN 3 .In all cases, up to quantitative yields in reasonable reaction times were obtained (Table 3).All the synthesized compounds were characterized by m.p, elemental analysis, IR, 1 H NMR, mass, and 13 C NMR data.

Conclusion
In summary, we have developed an efficient, practically convenient, and ecologically safe method for the synthesis

T 1 :
Synthesis of 6b in various ILs at 100 ∘ C.