Solvent Free One-Pot Synthesis of 1,2,4,5-Tetrasubstituted Imidazoles Catalyzed by Secondary Amine Based Ionic Liquid and Defective Keggin Heteropoly Acid

Secondary amine based ionic liquid and defective Keggin type heteropoly acid (HPA) are separately used for efficient one-pot four-component synthesis of 1,2,4,5-tetrasubstituted imidazoles assisted by microwave (MW). Eco-friendly solvent free procedure, short reaction time, high yield of products and reusability of catalysts are important features of the synthesis. A comparative study on the efficiency of the two catalysts is reported. This work further demonstrates the alternate use of urea, instead of often used ammonium acetate, as source of nitrogen.


Introduction
Tetrasubstituted imidazoles are important heterocycles with wide biological applications.Their synthesis and reactions form a significant part of the study of heterocycles with medicinal use [1].Tetrasubstituted imidazole scaffold is the most active constituent in many biological systems and drug molecules such as olmesartan medoxomil, losartan, eprosartan and trifenagrel [2][3][4] as well as other natural products of pharmaceutical importance [5][6][7].Multicomponent reaction (MCR) is a powerful tool in generating molecules with diverse functionality in a single synthetic protocol [8][9][10] and forms the basis of the synthesis of 1,2,4,5-tetrasubstituted imidazoles.Important synthetic methods include one-pot thiazolium catalyzed addition of an aldehyde to an acyl imine followed by ring closure to the imidazole [11], condensation of arylglyoxal, 1˚-amine, carboxylic acids and isocyanates on Wang resin followed by cyclization in the presence of acetic acid [12], by a hetero-Cope rearrangement [13], a direct synthesis from alkenes involving two step ketoiodonation/cyclization protocol [14], Domino reaction of 2-azido acrylates and nitrones [15].
Other synthetic methods include the condensation of benzoin and benzoin acetate with aldehyde, 1˚-amine, ammonia in the presence of copper acetate [16], one-pot synthesis using BF 3 -SiO 2 as catalyst [17], cyclization of sulphonamide with mesoionic 1,3-oxazolinium-5-olates [18], condensation of β-carbonyl-N-acyl-N-alkylamines with NH 4 OAc in refluxing acetic acid [19,20], conversion of N-2-oxoamides with ammonium triflate [21] besides others [22][23][24][25].Several catalysts have been explored for performing the four components' reaction to give the target product notably the use of L-proline [26], zeolite HY and silica gel [27], Keggin type heteropolyacid [28], LaCl 3 catalyzed synthesis using urea as a source of ammonia [29].Shaterian et al. reported the synthesis of tetrasubstituted imidazole used Brønsted acidic ionic liquid, N-methyl-2-pyrrolidonium hydrogen sulphate, as catalyst, but long reaction time, high amount of catalyst used and the time-consuming procedure for the preparation of the IL (12 hrs) are some of the disadvantages [30].Most of the procedures reported are associated with one or more disadvantages such as use of expensive reagents and catalysts, mineral acids and requirement of large amount of catalysts which eventually results in generation of toxic wastes, longer reaction time and tedious work-up.

Results and Discussion
In a broad programme of developing efficient, selective and eco friendly synthetic methods for pharmacologically important heterocycles, we explored the applicability of green promoters namely the simple acidic ionic liquids (IL) as well as the defective Keggin type heteropolyacids (HPA) in the synthesis of 1,2,4,5 tetrasubstituted imidazoles using microwave (MW) heating in both procedures.Combination of two green techniques is reported to give better results in terms of short reaction time and high yield of products.Catalytic efficiencies of both the ionic liquid and heteropolyacid are well documented.The unique thermodynamic properties of both are increasingly enticing chemists to explore their use as media as well as promoters in organic synthesis [31][32][33], however, high cost of the often used imidazole based ILs and the heteropoly acids deter their use in industrial processes.Herein, we explored the possibility of using simple and cost effective secondary amine based IL namely di-n-propylammonium hydrogensulphate in the synthesis of imidazoles in a solvent free multicomponent reaction (MCR) using MW heating.In a related study, the efficiency of this IL vis a vis a heteroploy acid as an alternative catalyst for the synthesis was examined under identical experimental conditions.Initially the IL and the HPA used were prepared by adopting a simple atom economy procedure using cheap and easily available substrates.The IL used herein was prepared by the action of conc.H 2 SO 4 on di-n-propylamine [34] and the lacunary and defective Keggin type HPA namely H 6 PAlMo 11 O 40 was prepared by a reported procedure [35] albeit with minor modification.Microwave heating was used while preparing the HPA instead of conventional heating which resulted in less reaction time and high yield of the HPA.
For the purpose of optimization of the amount of catalyst and the reaction time, representative reaction using benzil, benzaldehyde, benzylamine and NH 4 OAc as the substrates was performed by varying the concentration of the catalyst from 5 mol% to 10 mol% and concomitant variation of reaction time from 2 mins to 10 mins.In case of IL as the catalyst, yield of the desired product 4a improved by 20% when mol% was increased from 5% to 10% and in case of HPA 5 mol% of catalyst and 10 min reaction time gave the best results.No improvement in yield was apparent with increase in mol% of catalyst and/or the reaction time.Results summarized in Table 1 indicated best results with 10 mol% of IL as catalysts and in case of HPA it was 5 mol%.
These two catalysts were used in turn for performing a one-pot four component reaction involving 1,2-diketone, aromatic aldehyde, 1˚-amine and NH 4 OAc to give the target 1,2,4,5-tetrasubstituted imidazole under solvent free condition mediated by MW.In a typical procedure, the reactants and the catalyst in the form of either HPA or IL, are thoroughly mixed and exposed to MW irradiation.In order to establish the generality of the synthetic procedure, several diversified examples were studied by varying the 1˚-amine and the aldehyde.The yields obtained by using both HPA and the IL are good to excellent with very little or no side products which is a significant improved over other reported procedures.Further good results have been obtained with both the aliphatic as well as the aromatic amines.Reactions with the IL as promoter required 2 -3 min for completion and reactions catalyzed by HPA required 10 -13 min.These results are indicative of better efficiency of IL over HPA in this synthesis.The reaction is shown in Scheme 1 and the results summarized in Table 2. Work up was accomplished by extraction of the reaction mixture with CH 2 Cl 2 to separate out the target product.The CH 2 Cl 2 solution was washed with water (3x 50 mL) to remove any trace of the impurity.Since both the catalysts are insoluble in CH 2 Cl 2 the catalysts were precipitated out after addition of CH 2 Cl 2 to the reaction mixture and recovered by simple filtration.The recovered IL was stored in desiccator for reuse and HPA was dried at 85˚C for 24 hours and reused.Both the catalysts retained their activity after two subsequent reuses.
In order to preclude other possibilities, the reaction was examined using related catalyst namely tetra-npropylammonium bromide and NaHSO 4 under MW irradiation.With tetra-n-propylammonium bromide, the reaction did not proceed at all whereas with NaHSO 4 about  3. In this study benzil, 2-anisaldehyde, benzyl amine and ammonium acetate were taken as the reference reactants and 10 mol% amounts of catalysts were used.Investigations were also carried out using urea as the source of nitrogen in the reaction.It was observed that the reaction proceeded equally well with urea in the presence of both IL and HPA.Here efficiency was examined in some model reactions in presence of either IL or HPA.The results obtained by using urea instead of NH 4 OAc are summarized in Table 4.
All products obtained were characterized by spectroscopic method such as IR, 1 H NMR, 13 C NMR, Mass spectrometry and by comparing their melting points with those reported in literature.Some new compounds are also reported.Single crystal X-ray analysis of one of the new products namely 1-ethyl-2-(2', 6'-dichlorophenyl)-4, 5-di(4'-methylphenyl)-imidazole (4p) confirms the structure (Figure 1).Crystals were obtained from ethanol in which case the results indicate the presence of residual solvent in the crystal.Attempt to remove the solvent destroyed crystallinity of the product and no worthwhile data could be obtained.Crystallographic data are given in Table 5. CCDC reference number for the compound is CCDC 892443.

Conclusion
In conclusion, a one-pot solvent free MCR promoted by the combined use of microwave and IL or HPA offer easy access to tetrasubstituted imidazoles in excellent yield.Procedural simplicity, short reaction time, solvent

General
Melting points were recorded in a VMP-D model melting point apparatus and are uncorrected. 1H NMR and 13 C NMR spectra were recorded on a Bruker advance digital 300 MHz spectrometer in CDCl 3 .TMS was used as in- ternal standard.IR spectra were obtained on a Perkin Elmer FT-IR 1600 spectrophotometer using KBr pallets.Mass spectra were recorded on a Waters Micromass ZQ TM 400 Mass spectrometer system.The XRF analysis was carried out in Axios XRF Spectrometer.Microwave irradiation of the reaction mixture was performed in a reactor procured from Catalyst TM (India) reactor.The single crystal X-ray diffraction data for compound 1ethyl-2-(2', 6'-dichlorophenyl)-4, 5-di(4'-methylphenyl) imidazole (4p) was collected on a SMART Bruker Apex-II diffractometer.The structure was solved by direct method and refined by full-matrix least squares based on F 2 using the SHELXTL 5.1 software package.The hydrogen atoms residing in the carbon atoms were located geometrically.All non-hydrogen atoms were refined anisotropically.

Synthetic
-II free condition and the use of non toxic and environmentally benign promoters are some of the important features of this new methodology.An added advantage is the simple recovery and efficient reusability of the catalyst.The reaction proceeds equally well with urea as a source of nitrogen instead of NH 4 OAc which result in cost reduction of the transformation.

Table 2 . Solvent free MW induced one-pot synthesis of 1, 2, 4, 5-tetrasubstituted imidazole promoted by [n-Pr 2 NH 2 ][HSO 4 ] or HPA using ammonium acetate as nitrogen source.
4NBr and in absence of catalyst for a model reaction are summarized in Table