Heterocyclic compounds are of particular interest in medicinal chemistry due to the range of biological properties they exhibit [1] [2] . Among the various heterocycles, the imidazole ring has attracted a lot of attention due to the wide range of biological activities exhibited by substituted imidazoles [3] [4] . The imidazole ring is found in many common drugs such as eprosartan 1 (hypertension) [5] , ketoconazole 2 (antimycotic) [6] , losartan 3 (hypertension) [7] , and olmesartan 4 (hypertension) (Figure 1) [8] .

2,4,5-trisubstituted imidazoles exhibit many biological activities and hence have attracted attention. 2-substituted-4,5-diphenylimidazoles have been shown to exhibit antinociceptive and anti-inflammatory properties [9] . Owing to their useful biological properties, several methods have been developed for the synthesis of 2,4,5-trisubstituted imidazoles. The first synthesis, which remains one of the most viable routes, involved a multicomponent reaction between an aldehyde 5, benzil 6 and ammonium acetate 7 to generate a 2,4,5-trisubstituted imidazole 8 (Scheme 1) [10] .

1 2

Since the early method suffered from harsh reaction conditions, considerable efforts have been directed towards improving the reaction to provide high yields under milder conditions. Methods for the synthesis of polysubstituted imidazoles have been reviewed [11] [12] . Several catalysts have been used for the synthesis of 2,4,5-trisubstituted imidazoles. A few representative examples are cited here and include Yb(OTf)₃ [13] , silica sulfuric acid [14] , NiCl₂×6H₂O [15] , microwave irradiation [16] , sodium bisulfite [17] , tetrabutylammonium bromide [18] , MoO₃/SiO₂ [19] , lipase [20] , mesoporous silica [21] , silica coated magnetite nanoparticles [22] , benzethonium chloride [23] , lactic acid [24] , magnetic nanoparticles [25] , CH₃SO₃H [26] , and mandelic acid [27] . While some of these catalysts are corrosive, a few others require preparation which detracts from their synthetic utility. In view of our continued interest in bismuth (III) salts, we investigated their use as catalysts for the synthesis of 2,4,5-trisubstituted imidazoles. Herein, we report a multicomponent synthesis of 2,4,5-trisubstituted imidazoles catalyzed by bismuth triflate, Bi(OTf)₃×xH₂O (1 < x < 4) (Table 1). Bismuth compounds are of interest because they are remarkably nontoxic and readily available [28] . Several reviews have summarized the applications of bismuth compounds in organic synthesis [29] [30] [31] [32] . The results of this study are summarized in Table 1.

^aRepresentative procedure (entry 4): A mixture of p-anisaldehyde (0.208 g, 1.528 mmol, 1.1 equiv), benzil (0.292 g, 1.389 mmol, 1.0 equiv), and ammonium acetate (0.428 g, 5.552 mmol, 4.0 equiv) in CH₃CN (4.0 mL) was stirred as Bi(OTf)₃ (0.182 g, 0.277 mmol, 20.0 mol%) was added. The reaction mixture was heated at 70˚C using a temperature controlled hot plate. Reaction progress was followed by TLC (CH₃OH/CH₂Cl₂, 3/97, v/v). After 24 h (disappearance of aldehyde), the mixture was concentrated on a rotary evaporator. Hot methanol (5.0 mL) was added to the residue and the mixture was stirred and cooled in ice. The resulting crystals were collected by suction filtration to yield 0.324 g (72%) of a white solid that was analyzed by ¹H, ¹³C NMR spectroscopy and TLC. ^bRefers to yield of isolated product that was deemed to be at least 98% pure by ¹H NMR spectroscopy. All products were characterized by ¹H and ¹³C NMR spectroscopy, TLC and by comparison to literature data. ^cAll products have been previously reported. Spectral data were compared to those reported in the literature. ^dSuperscript against yield refers to literature reference for spectral data of product. ^eWorkup was modified as follows: The reaction mixture was concentrated by rotary evaporation and the residue was loaded onto 30 g of silica gel. Product was isolated by elution with CH₂Cl₂/CH₃OH (10/90, v/v). ^fReaction was run for 45 h using 40.0 mol% catalyst.

We investigated the utility of a few different Lewis acids as catalysts for the multicomponent synthesis of 2,4,5-trisubstituted imidazoles. These included BiO(NO₃), BiBr₃, Bi(OTf)₃, FeCl₃, Fe(OTf)₃ in several solvents: CH₃OH, CH₃CH₂OH, CH₃COOH and CH₃CN. We also investigated the use of Fe(OTs)₃ as a catalyst for this reaction [33] . The best results were obtained with bismuth(III) triflate, Bi(OTf)₃, as a catalyst, in CH₃CN as the solvent. With all other catalysts significant amounts of starting material remained even after 24 h at 70˚C. Similar results were obtained in the absence of a catalyst. The multicomponent nature of this reaction allowed for the facile synthesis of the product in good to moderate yields in a single step that also eliminated the generation of an aqueous waste stream [34] . As can be seen from Table 1, good to moderate yields were obtained with a variety of aldehydes.

We have developed a bismuth (III) triflate catalyzed multicomponent synthesis of 2,4,5-trisubstituted imidazoles from a variety of substituted aldehydes, benzil, and ammonium acetate in CH₃CN as the solvent. The nontoxic nature of bismuth compounds, along with the multicomponent nature of this method, makes this an attractive route for the synthesis of 2,4,5-trisubstituted imidazoles.

This material is based upon work supported by the National Science Foundation under CHE-1229133, which funded the purchase of a 400 MHz NMR spectrometer. RM would like to acknowledge an Artistic and Scholarly grant from Illinois Wesleyan University.

The authors declare no conflicts of interest regarding the publication of this paper.

Thorp, S.C., Chisari, S.T., David, R.Q.V., Gjata, A., Good, A.L., Lopez, E. and Mohan, R.S. (2023) Bismuth (III) Triflate Catalyzed Multicomponent Synthesis of 2,4,5-Trisubstituted Imidazoles. Green and Sustainable Chemistry, 13, 209-215. https://doi.org/10.4236/gsc.2023.133011