Simple practical method for synthesis of trisubstituted imidazoles: an efficient copper catalyzed multicomponent reaction

A rapid practical process has been developed for synthesis of 2,4,5-trisubstituted-imidazoles in excellent yields up to 95% from readily available starting materials. In this CuI catalyzed synthesis, trisubstituted imidazoles were afforded in short reaction times, wherein the substrate scope is well explored with benzoin as well as benzil reacting with different aldehydes in the presence of ammonium acetate as the nitrogen source.


Introduction
The ve-membered aromatic imidazole ring is an important heterocycle broadly present in various natural products and synthetic molecules with a broad range of medicinal applications. [1][2][3][4][5][6][7] Furthermore, they possess diverse biological properties such as antibacterial, antifungal, anticancer, anti-inammatory, antihistaminic, antitubercular, antihypertensive, antiviral, antineuropathic, anti-obesity, antiparasitic and have possible applications in pathology and diagnostics. 6 The imidazole core is an important aromatic heterocycle which has broad therapeutic interest due to its two nitrogen atoms leading to hydrogen bond creation for improving water solubility properties. Further, the imidazole nucleus has been recognized as an important isostere of amide, thiazole, tetrazole, pyrazole, oxazole and triazole with an attractive binding site available for interacting with various biomolecules, anions and cations in biological systems offering potential in imidazole-based drug discovery and developments. 8 Furthermore, imidazole has good photophysical properties, [9][10][11][12][13][14][15][16][17] and is used as a ligand in homogeneous catalysis [18][19][20] and functionalized materials. [21][22][23][24][25][26][27][28][29][30] Several imidazole-based scaffolds have been widely utilized in the clinic for treatment of different diseases with great therapeutic potency, which have proved the great development signicance. Imidazole-based medicinal chemistry research is rapidly becoming an active area, and chemists are encouraged by these imidazole-linked drugs as enormous therapeutic assets. Moreover, it is gaining importance in agrochemicals, solar cell dyes, and functional materials; the process development has good functional group tolerance and substrate exibility is increasing. Several methods have been reported for synthesis of trisubstituted imidazoles. 31 But, alternative method development for regiocontrolled substituted imidazoles has strategic importance due to a few shortcomings such as complex starting materials, use of strong oxidants, requirement of stoichiometric amounts of toxic metals, microwave conditions, byproducts formation and tedious work up procedures. The importance of economic viability and nature balance means the development of environmentally benign, simple and fast protocols for synthesis of polysubstituted imidazoles still has signicant scope. To continue efforts towards synthesis of nitrogen containing heterocycles, 32-36 herein we are going to report an alternative simple and efficient method for the synthesis of polysubstituted imidazoles.

Results and discussion
We started by investigating 4-chlorobenzaldehyde 1a (1 mmol), benzoin 2a (1 mmol) and ammonium acetate 3 (3 mmol) as model substrates in the presence of (20 mol%) Cu(I) catalysts. We screened CuCl, CuBr and CuI catalysts; where 75% yield of the anticipated product 4a was obtained aer 90 min in DMSO as reaction medium with CuI catalyst at 140 C ( Table 1, entries 1-3). From these results, the reaction was further optimized by using CuI (20 mol%) with various solvents. Initially, the reaction was carried out in DMF at 140 C temperature which afforded desired product 4a in 65% yield (Table 1, entry 4). By considering green chemistry principles and keeping in mind their pharmaceutical importance, the reaction conditions were further optimized using green solvents to nd the best conditions. Gratifyingly, when it was optimized to use butanol solvent at reux, the product 4a was afforded in 85% yield within 20 min (Table 1, entry 5). Aer that, the reaction was investigated with ethanol solvent at reux; where the anticipated product 4a was obtained in 76% yield in a slightly greater time up to 70 min (Table 1, entry 6). Moreover, the reaction studied with methanol solvent reuxed at 65 C procured the product 4a in 74% yield aer 90 min (Table 1, entry 7).
In the next step, the reaction was examined with water solvent under reuxed conditions; but 4a product formation was observed only in up to 10% yield with 90 min reaction time ( Table 1, entry 8). Then, the reaction conditions were optimized with nonpolar solvents such as toluene (at 110 C) and chlorobenzene (at 120 C) which afforded the product 4a in yields of 67% and 56% respectively (Table 1, entries 9-10). Furthermore, the reaction carried out in CH 3 CN solvent at reux obtained a yield of product 4a of up to 68% in 90 min (Table 1, entry 11). To nd out the best optimized conditions, the catalyst loading was examined, and the same results were reproduced with 15 mol% CuI catalyst (Table 1, entry 12). Further, the reaction was also studied in the presence of 10 mol% and 5 mol% CuI catalyst, which resulted in slightly lower yields of the desired product in 25 min and 30 min reaction times respectively ( Table  1, entry [13][14]. Next, we investigated the temperature effects and the product 4a was obtained in lower yields of 80% and 78% aer 80 min for 90 C and 70 C respectively (Table 1, entries [15][16]. Aer that, the reaction was studied in neat reaction conditions; where the anticipated product 4a formed in up to 64% yield (Table 1, entry 17). Therefore, the reaction conditions described in entry 12 were noted to be optimal, tolerating for maximum conversion to the desired trisubstituted imidazole product 4a.
The plausible mechanism for the trisubstituted imidazole synthesis is summarized in Scheme 1. From the relevant literature and experimental results, different pathways have been proposed for benzil and benzoin as starting materials. [40][41][42][43][44][45] Initially, the condensation of 4-chlorobenzaldehyde with ammonia produced from ammonium acetate generates intermediate A. 42

Conclusion
In conclusion, we have developed a practical method for synthesis of 2,4,5-trisubstituted imidazoles. The present method has a great advantage of substrate scope with a-hydroxy ketone (benzoin) as well as 1,2-diketone (benzil). This three component reaction is effective due to good yields in a short time and simple reaction conditions.

General information
All solvents used in the reactions were distilled for purity. The reagents were commercially available and used directly without purication unless otherwise stated. Melting points were recorded with a Thomas-Hoover capillary melting point apparatus. The thin layer chromatography (TLC) was performed using silica gel plates (GF254) with 100-120 mesh size and visualization was effected with a short-wavelength UV lamp (254 nm). 1 H and 13 C NMR spectra were recorded using Jeol as well as Bruker NMR instruments at 400 and 100 MHz using DMSO and CDCl 3 solvents. The chemical shis are expressed in d, parts per million (ppm) with reference to internal standard TMS. The spin multiplicities are represented by the symbols s   (singlet), d (doublet), t (triplet), q (quartet), p (pentet), and m (multiplet) and coupling constants (J) are reported in hertz (Hz).
General procedure for synthesis of imidazoles (4) In a round bottom ask, the mixture of aldehyde 1 (1 mmol), benzoin 2a or benzil 2b (1 mmol), NH 4 OAc (3 mmol), CuI (15 mol%) and BuOH (7 mL) was reuxed. The progress of the reaction was monitored using thin layer chromatography (TLC) technique. Aer completion of the reaction, the mixture was cooled to room temperature and poured into crushed ice. The precipitated solid product was stirred at room temperature and ltered to obtain sufficient pure crude product 4. The product was recrystallized by using ethanol solvent.