A facile and efficient synthesis of tri- and tetrasubstituted imidazoles with potassium hydrogen sulfate and DB18C6 in an aqueous medium

Abstract

Potassium hydrogen sulfate in the presence of dibenzo-18-crown-6 (DB18C6) turns out to be a very efficient and effective catalyst for the facile synthesis of a wide variety of tri- and tetrasubstituted imidazoles in an aqueous medium at moderate temperature. The idea behind this is that the potassium ion, being trapped in the crown core, frees the hydrogen sulfate anion, which, because of its acidic nature, succeeds in the ready synthesis of the imidazoles.

Keywords:

• potassium hydrogen sulfate
• DB18C6
• tri- and tetrasubstituted imidazoles
• aqueous medium
• green reaction conditions

Introduction

The development of new methodologies to produce products of greater structural complexity from readily available simple starting materials with fewer synthetic steps but ensuring high yield under mild reaction conditions is the main challenge for the synthetic organic chemists 1 2. Again, because of global environmental legislation on chemical process industries, aqueous environment has been currently receiving considerable attention in organic chemistry (3–5) because water is abundant in nature, has virtually no cost, and is safest among all available solvents, thus leading to environmentally benign chemical processes 6.

Synthesis of imidazole ring system and its derivatives occupies an important place in the realm of natural and synthetic organic chemistry as the imidazole moiety, being a part of the side chain in histidine, plays a major role in the biological activity of many peptides and proteins. Several functionalized imidazole derivatives express many pharmacological properties and play important roles in biochemical processes 7 . The potency and wide applicability of the imidazole pharmacophore are largely because of its hydrogen-bond donor–acceptor capability as well as because of its high affinity for metals, which are present in many protein active sites 8 (e.g. Zn, Fe, Mg). Diverse substituted imidazoles act as inhibitors of p38 MAP kinase 9, B-Raf kinase 10, glucagon receptors 11, plant growth regulators 12, therapeutic agents 13, antibacterial 14, antitumor 15, and pesticides 16 . Recent advancements in green chemistry and organometallic chemistry expand the utility of imidazoles as ionic liquids (17–19) and N-heterocyclic carbenes 20 . Because of their widespread applications in various streams, there is an increasing interest in research on imidazoles.

2,4,5-Trisubstituted imidazoles are usually synthesized by a multicomponent reaction involving benzil (or a substituted benzil), an aldehyde, and ammonium acetate as an ammonia source 21, and many catalysts [silica/sulfuric acid 22 23, Yb(OTf)₃ 24, NiCl₂·6H₂O 25, oxalic acid 26, iodine 27, sulfanilic acid 28, tetrabutyl ammonium bromide 29, cerium ammonium nitrate 30, Zr(acac)₄ 31, InCl₃·3H₂O 32] as well as different activation modes [thermal activation, microwave irradiation 21 33, or ultrasounds 30 31] have been used to get the desired imidazoles in high yields. Most of the earlier methodologies are performed either in solution [AcOH 21 24, EtOH 25 27, EtOH–H₂O 26 34 35], under solventless conditions 22 33 36, or in ionic liquids 37 38 . But the synthesis of substituted imidazoles in an aqueous medium is rare. Actually there is only one report in this regard and that too under microwave irradiation at very high temperature (180–210°C) 39 . Therefore, room for green methodologies for the rapid construction of substituted imidazoles in an aqueous medium at milder conditions still remains quite open.

Cyclic polyethers such as 18-crown-6 (18C6) and dibenzo-18-crown-6 (DB18C6) have some unique ability to bind metal cations and small neutral or ionic molecules selectively. Two kinds of binding forces for complexation of cyclic polyethers are well established: ion–dipole interaction and hydrogen bonding 40 . Metal ions form complexes with crown ethers through ion–dipole electrostatic interactions, with the oxygen lone pairs being attracted to the cation positive charge (Scheme 1) and various organic molecules with acidic hydrogens binding to crown ethers via hydrogen bonding. Now, in the case of a salt, cyclic polyethers undergo complexation with the cations releasing the counter ion in the medium. Therefore, if the salt is an acid salt, say KHSO₄, K⁺ ion will be first trapped by the crown ether followed by the release of HSO₄ ⁻. Again, in the case of an aqueous medium, HSO₄ ⁻ will produce hydronium ion (H₃O⁺), thereby making the medium acidic (Scheme 1). We have very efficiently used this idea for the synthesis of various substituted imidazoles.

Scheme 1.  Potassium ion being trapped by the six oxygen atoms in the 18-crown-6 core and generation of hydronium ion in an aqueous medium.

In continuation of our search for the synthesis of biologically important heterocycles (41–44), here we describe the synthesis of 2,4,5-tri- and 1,2,4,5-tetrasubstituted imidazoles in an aqueous medium under moderate reaction condition.

Results and discussion

Initially, we started the condensation of benzil (1 mmol), benzaldehyde (1 mmol), and ammonium acetate (3 mmol) in water (5 mL) at room temperature for 24 h in the absence of catalyst but the desired product was not formed at all. Then the same reaction mixture was refluxed on an oil bath for an extended period of time (24 h) which led to very poor yield (15%) of 2,4,5-trisubstituted imidazole (Table 1, entry 2). Then, it was thought worthwhile to carry out the reaction in the presence of comparatively available crown ethers (18C6 and DB18C6) and acidic salts (KHSO₄ and NaHSO₄). After a thorough screening with the above-mentioned crown ethers and salts, it was revealed that heating the reaction mixture at 60°C for 4 h yields the best result (92% of isolated yield, Table 1, entry 6) in the presence of 15 mol% of both DB18C6 and KHSO₄. The details of the results obtained are given in Table 1.

Table 1. Condensation of benzil, benzaldehyde, and ammonium acetate in the presence of crown ethers and salts in an aqueous medium.

Entry	Crown ether (mol%)	Salt (mol%)	Temperature (°C)	Time (h)	Yield (%) (isolated)
1	–	–	25	24	Nil
2	–	–	100	24	15
3	18C6 (15)	KHSO4 (15)	25	24	Trace
4	18C6 (15)	KHSO4 (15)	60	6	75
5	DB18C6 (15)	KHSO4 (15)	25	24	Trace
6	DB18C6 (15)	KHSO4 (15)	60	4	92
7	DB18C6 (15)	NaHSO4 (15)	60	6	55

Once the reaction was standardized, our first attempt was the synthesis of various 2,4,5-trisubstituted imidazoles with DB18C6 and KHSO₄ in water (Scheme 2), and the results are depicted in Table 2.

Scheme 2.  Synthesis of 2,4,5-trisubstituted imidazoles in an aqueous medium using DB18C6 and KHSO₄ (15 mol%).

Table 2. Synthesis of 2,4,5-trisubstituted imidazoles in an aqueous medium using DB18C6 and KHSO₄ (15 mol%).

On examination of Table 2 we find that almost all of the 2,4,5-trisubstituted imidazoles were produced in high yields. A wide range of aromatic aldehydes bearing either electron donating or electron withdrawing substituents and different substituted benzils underwent this one-pot, three-component cyclocondensation to produce the products. Aliphatic aldehydes gave the corresponding imidazole in lower yield (52%) than did aromatic aldehydes while diacetyls gave lower yield of the product (65%) than that of other benzils. This is because of lower conjugation in the products than in the aromatic counterparts.

The same methodology was applied for the synthesis of 1,2,4,5-tetrasubstituted imidazoles via the one-pot, four-component condensation of an aldehyde, a benzil, a primary aromatic amine (as well as benzyl amine), and an ammonium acetate (Scheme 3), and the products were obtained in excellent yields in almost all cases except in the case of diacetyl where the yield is little lower (64%). The utility of this reaction was justified using various structurally different aldehydes and primary aromatic amines (Table 3).

Scheme 3.  Synthesis of 1,2,4,5-tetrasubstituted imidazoles in an aqueous medium using DB18C6 and KHSO₄ (15 mol%).

Table 3. Synthesis of 1,2,4,5-tetrasubstituted imidazoles in an aqueous medium using DB18C6 and KHSO₄ (15 mol%).

The mechanism of the formation of trisubstituted imidazoles involves protonation of the aldehydic carbonyl, diamine intermediate [A] formation with two molecules of ammonia from ammonium acetate and condensation with one molecule of diketone compound to form intermediate [B] that subsequently aromatized to produce the final products. In the case of tetrasubstituted imidazoles, the mechanism proceeds through the formation of the imine of the aromatic aldehydes with aromatic amines (as it is more stable than the imine of aldehydes and ammonia). This imine subsequently forms the diamine intermediate with ammonia and the rest of the mechanism remains the same. Because of the formation of the more stable imine intermediate in the case of four-component reaction of benzil, ammonium acetate, aromatic aldehydes, and aromatic primary amines, 1,2,4,5-tetrasubstituted imidazoles are exclusively formed (in place of the mixture of tri- and tetrasubstituted imidazoles). The detail of the mechanism is given in Scheme 4.

Scheme 4.  Proposed mechanism for the DB18C6-KHSO₄ catalyzed synthesis of substituted imidazoles formation.

After extraction by ethylacetate, the aqueous part containing DB18C6 and KHSO₄ can be recycled at least six times for imidazole synthesis without substantial loss in the yield of the reaction. Therefore, the catalytic efficiency is quite high.

Experimental

General procedure for the trisubstituted imidazole formation

To a mixture of aldehyde (1 mmol), benzil (1 mmol), and ammonium acetate (3 mmol) in water (5 mL) were added DB18C6 (15 mol%) and KHSO₄ (15 mol%), and the mixture was stirred at room temperature for 15 min. The resulting mixture was heated on a water bath at 60°C for the stipulated time mentioned in Table 2. When the reaction was complete as monitored by TLC, the reaction mixture was extracted with EtOAc (3×10 mL) and dried over anhydrous Na₂SO₄. After removal of the solvent in vacuo, the pure products were obtained by direct crystallization from ethanol.

After extraction by ethylacetate, the aqueous part containing DB18C6 and KHSO₄ can be reused at least six times for the imidazole synthesis. This recyclability of the catalyst increases its catalytic efficiency.

For large-scale preparation, aldehyde (10 mmol), benzil (10 mmol), ammonium acetate (30 mmol), water (20 mL), DB18C6 (15 mol%), and KHSO₄ (15 mol%) were taken in a round-bottom flask (100 mL) and stirred at room temperature for 30 min. The resulting mixture was heated on a water bath at 60°C until the reaction was completed (monitored by TLC). After the completion of the reaction, the reaction mixture was extracted with EtOAc (3×20 mL) and dried over anhydrous Na₂SO₄. After removal of the solvent in vacuo, the pure products were obtained by direct crystallization from ethanol.

General procedure for the tetrasubstituted imidazole formation

In the case of tetrasubstituted imidazoles, aldehyde (1 mmol), benzil (1 mmol), ammonium acetate (1.5 mmol), aromatic primary amines (1 mmol), DB18C6 (15 mol%), and KHSO₄ (15 mol%) were taken in water (5 mL), and the rest of the procedure remains the same. The final products were obtained by extraction with ethyl acetate, solvent removal in vacuo and crystallization from ethanol.

For large-scale preparation of tetrasubstituted imidazoles, aldehyde (10 mmol), benzil (10 mmol), primary amines (10 mmol), ammonium acetate (15 mmol), water (20 mL), DB18C6 (15 mol%), and KHSO₄ (15 mol%) were taken in a round- bottom flask (100 mL) and stirred at room temperature for 30 min. The resulting mixture was heated on a water bath at 60°C until the reaction was complete (monitored by TLC). After the completion of the reaction, the reaction mixture was extracted with EtOAc (3×20 mL) and dried over anhydrous Na₂SO₄. After removal of the solvent in vacuo, the pure products were obtained by direct crystallization from ethanol.

All the products gave satisfactory IR, ¹H NMR, ¹³C NMR, and analytical data as given below.

4,5-Bis-(4-chlorophenyl)-2-(3′-nitrophenyl)-1H-imidazole (Table 2, entry 7)

The titled compound was obtained as a yellow solid (420 mg, 93%); R _f=0.44 (25% ethylacetate/75% petroleum ether). M.P.: 314–315°C (MeOH); IR (KBr): 3072, 2964, 2376, 1527, 1348, 1091, and 834 cm⁻¹. ¹H NMR (300 MHz, d ₆-DMSO): 12.84 (s, 1H), 8.65 (s, 1H), 8.21 (d, J=7.2 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.40–7.10 (m, 8H). ¹³C NMR (75 MHz, d ₆-DMSO): 148.3, 143.9, 136.9, 133.5, 132.8, 131.6, 131.2, 130.3, 130.1, 129.3, 128.9, 128.4, 122.7, 119.5, 117.8. Anal. calcd. for C₂₁H₁₃N₃O₂Cl₂ (%): C 61.48, H 3.19, N 10.24. Found (%): C 61.36, H 3.27, N 10.28.

1-(4a-Chlorophenyl)-2-(4′-hydroxy-3′-methoxyphenyl)-4,5-diphenyl-imidazole (Table 3, entry 1)

The titled compound was obtained as a white solid (420 mg, 93%); R _f=0.54 (25% ethylacetate/75% petroleum ether). M.P.: 196–198°C (EtOAc); IR (KBr): 3411, 3058, 1600, 1490, 1438, 1380, 1272, 1228, 1090, 1027, and 698 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): 7.60 (dd, J=8.0, 1.5 Hz, 2H, C₄- and C₅-phenyl protons), 7.33–7.18 (m, 8H, C₄-, C₅-phenyl protons), 7.13 (dd, J=8.6, 1.5 Hz, 3H, C_2a-, C_6a-, C_2'–H), 6.99 (d, J=8.4 Hz, 2H, C_3a-, C_5a–H), 6.77–6.70 (m, 2H, C_5'-, C_6'–H), 3.74 (s, 3H, C_3'–OCH₃). ¹³C NMR (75 MHz, CDCl₃): [146.9, 146.5, 146.4 (C_4'-, C_3'-, and C₂)], 137.6 (C₄), 135.6 (C_1a), 134.2 (C_4a), 133.6 (C₅), 131.1 (2C, C₄- and C₅-phenyl carbons), [130.2, 130.1 (ipso to C₄- and C₅-, respectively)], 129.6 (2C, C_2a, C_6a), 129.3 (2C, C_3a, C_5a), 128.5 (2C, C₄-, and C₅-phenyl carbons), 128.2 (C₄- or C₅-phenyl carbon), 128.1 (2C, C₄- or C₅-phenyl carbons), 127.5 (2C, C₄- or C₅-phenyl carbons), 126.8 (C₄- or C₅-phenyl carbons), 122.5 (C_6'), 121.4 (C_1'), 114.3 (C_2'), 112.0 (C_5'), 55.8 (–OCH₃). Anal. calcd. for C₂₈H₂₁N₂O₂Cl (%): C 74.25, H 4.67, N 6.19. Found (%): C 74.13, H 4.79, N 6.24.

1-(4a-Chlorophenyl)-2-(2′,5′-dimethoxyphenyl)-4,5-diphenyl-imidazole (Table 3, entry 2)

The titled compound was obtained as a white solid (429 mg, 92%); R _f=0.75 (25% ethylacetate/75% petroleum ether). M.P.: 246–248°C (EtOAc); IR (KBr): 3341, 2936, 2372, 1602, 1522, 1484, 1441, 1221, 1178, 1045, and 694 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): 7.61 (dd, J=7.5, 1.2 Hz, 2H, C₄-, C₅-phenyl protons), 7.33–7.20 (m, 8H, C₄-, C₅-phenyl protons), 7.18–7.11 (m, 3H, C_2a, C_6a, and C_6'-H), 6.95–6.86 (m, 3H, C_3a, C_5a, and C_4'-H), 6.65 (d, J=9.0, 1H, C_3'-H), 3.82 (s, 3H, C_2'-OMe), 3.32 (s, 3H, C_5'-OMe). ¹³C NMR (75 MHz, CDCl₃): 153.4 (C_2'), 150.9 (C_5'), 145.0 (C₂), 137.8 (C₄), 135.6 (C_1a), 133.7 (C₅), 133.2 (C_4a), 130.9 (2C, C₄-, C₅-phenyl carbons), 130.2 (ipso to C₄), 129.4 (ipso to C₅), 128.5 (2C, C_2a, C_6a), 128.4 (2C, C_3a, C_5a), 128.3 (2C, C₄, C₅-phenyl carbons), 128.1 (C₄- or C₅-phenyl carbon), 128.0 (2C, C₄-, C₅-phenyl carbons), 127.5 (2C, C₄-, C₅-phenyl carbons), 126.7 (C₄- or C₅-phenyl carbon), 119.8 (C_1'), 117.1 (C_6'), 116.9 (C_4'), 111.8 (C_3'), 55.8 (C₂-OMe), and 55.0 (C₅-OMe). Anal. calcd. for C₂₉H₂₃N₂O₂Cl (%): C 74.59, H 4.96, N 5.99. Found (%): C 74.45, H 5.12, N 6.08.

1-(4a-Chlorophenyl)-2-(3′,4′-dimethoxyphenyl)-4,5-diphenyl-imidazole (Table 3, entry 3)

The titled compound was obtained as a white crystalline solid (401 mg, 86%); R _f=0.57 (25% ethylacetate/75% petroleum ether). M.P.: 172°C (EtOAc); IR (KBr): 3432, 3053, 2933, 2375, 1597, 1491, 1442, 1405, 1329, 1176, 1131, 1087, 1022, 845, 772, and 702 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): 7.62 (d, J=7.5 Hz, 2H, C₄- and C₅-phenyl protons), 7.26–7.17 (m, 8H, C₄-, C₅-phenyl protons), 7.14 (brd, J=5.7 Hz, 2H, C_2a-H and C_6a-H), 7.06 (s, 1H, C_2'-H), 7.00 (d,J=8.1 Hz, 2H, C_3a-H and C_5a-H), 6.91 (d, J=8.4 Hz, 1H, C_6'-H), 6.74 (d, J=8.4 Hz, 1H, C_5'-H), 3.85 (s, 3H, C_4'-OCH₃), 3.74 (s, 3H, C_3'-OCH₃).¹³C NMR (75 MHz, CDCl₃): 149.3 (C_4'), 148.4 (C_3'), 146.6 (C₂), 137.8 (C₄), 135.6 (C_1a), 134.0 (C_4a), 133.8 (C₅), 130.9 (2C, C₄-,C₅-phenyl carbons), 130.2 (ipso to C₄), 130.09 (ipso to C₅), 129.6 (2C, C_2a, C_6a), 129.2 (2C, C_3a, C_5a), 128.4 (2C, C₄-, C₅-phenyl carbons), 128.1 (C₄- or C₅-phenyl carbon), 128.0 (2C, C₄-, C₅-phenyl carbons), 127.2 (2C, C₄-, C₅-phenyl carbons), 126.6 (C₄- or C₅-phenyl carbon), 122.4 (C_1'), 121.7 (C_6'), 112.1 (C_2'), 110.6 (C_5'), (55.5 and 55.7) (2×OCH₃). Anal. calcd. for C₂₉H₂₃N₂O₂Cl (%): C 74.59, H 4.96, N 6.00. Found (%): C 74.43, H 5.04, N 6.07.

1-(4a-Chlorophenyl)-2-(4'-hydroxyphenyl)-4,5-diphenyl-imidazole (Table 3, entry 4)

The titled compound was obtained as an off-white solid (397 mg, 94%); R _f=0.37 (25% ethylacetate/75% petroleum ether). M.P.: 290°C (MeOH); IR (KBr): 3034, 2935, 2593, 2490, 1604, 1488, 1440, 1398, 1276, 1165, 1094, 836, and 698 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 9.72 (brs, 1H, –OH), 7.46 (d, J=7.2 Hz, 2H, C₄,C₅-phenyl protons), 7.33 (d, J=8.7 Hz, 2H, C_2'-H and C_6'-H), 7.27–7.25 (m, 3H, C_3a-H, C_5a-H, and one from either C₄- or C₅-phenyl protons), 7.21–7.11 (m, 9H, C_3'-H, C_5'-H, and seven from C₄-, C₅-phenyl protons), 6.67 (d, J=8.7H, 2H, C_2a-H and C_6a-H). ¹³C NMR (75 MHz, CDCl₃): 157.8 (C_4'), 146.7 (C₂), 136.7 (C₄), 135.9 (C₅), 134.5 (C_1a), 133.1 (C_4a), 131.2 (2C, C₄-, C₅-phenyl carbons), 130.6 (2C, C_2a, C_6a), 130.54 (ipso to C₄), 130.50 (ipso to C₅), 130.0 (2C, C_3a, C_5a), 129.3 (2C, C₄-, C₅-phenyl carbons), 128.6 (2C, C₄-, C₅-phenyl carbons), 128.5 (2C, C₄-, C₅-phenyl carbons), 128.2 (2C, C₄-, C₅-phenyl carbons), 126.4 (2C, C_2', C_6'), 121.1 (C_1'), 115.2 (C_3', C_5'). Anal. calcd. for C₂₇H₁₉N₂OCl (%): C 76.68, H 4.53, N 6.62. Found (%): C 76.79, H 4.66, N 6.51.

2-(4'-Chlorophenyl)-1-(4a-nitrophenyl)-4,5-diphenyl-imidazole (Table 3, entry 5)

The titled compound was obtained as a yellow solid (428 mg, 95%); R _f=0.96 (25% ethylacetate/75% petroleum ether). M.P.: 218°C (EtOAc); IR (KBr): 3432, 3066, 2365, 1597, 1521, 1492, 1412, 1345, 1095, 852, and 699 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 8.10 (d, J=8.7 Hz, 2H, C_3a-H and C_5a-H), 7.56 (d, J=6.6 Hz, 2H, C₄-, C₅-phenyl protons), 7.33–7.09 (m, 14H, eight from C₄-, C₅-phenyl protons, C_2a-, C_6a-, C_2'-, C_3'-, C_5'-, and C_6'-H). ¹³C NMR (75 MHz, CDCl₃): 147.1 (C_4a), 145.6 (C₂), 142.0 (C_1a), 138.6 (C₄), 135.3 (C₅), 133.0 (C_4'), 131.0 (2C, C₄-, C₅-phenyl carbons), 130.6 (ipso to C₄), 130.3 (2C, C_2', C_6'), 129.4 (ipso to C₅), 129.1 (2C, C_2a, C_6a), 128.8 (3C, C_3', C_5', and one carbon from either C₄- or C₅-phenyl carbon), 128.7 (2C, C₄-, C₅-phenyl carbons), 128.3 (2C, C₄-, C₅-phenyl carbons), 127.6 (C_1'), 127.3 (2C, C₄-, C₅-phenyl carbons), 127.2 (C₄- or C₅-phenyl carbon), 124.5 (2C, C_3a and C_5a). Anal. calcd. for C₂₇H₁₈N₃O₂Cl (%): C 71.76, H 4.01, N 9.30. Found (%): C 71.85, H 4.23, N 9.21.

1-(4a-Nitrophenyl)-2-(4'-N,N-dimethylaminophenyl)-4,5-diphenyl-imidazole (Table 3, entry 6)

The titled compound was obtained as a brick red solid (396 mg, 86%); R _f=0.73 (25% ethylacetate/75% petroleum ether). M.P.: 280–282°C (EtOAc); IR (KBr): 3436, 3071, 2853, 2797, 2369, 1606, 1521, 1488, 1346, 1198, and 697 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 8.11 (d, J=8.7 Hz, 2H, C_3a-H and C_5a-H), 7.60 (dd, J=7.8 and 1.2 Hz, 2H, two protons from C₄-, C₅-phenyl protons), 7.33–7.21 (m, 8H, C₄-, C₅-phenyl protons), 7.18 (d, J=9.0 Hz, 2H, C_2'-H and C_6'-H), 7.11 (dd, J=8.1 and 1.8 Hz, 2H, C_2a-H and C_6a-H), 6.58 (d, J=9.0 Hz, 2H, C_3'-H and C_5'-H), 2.96 [s, 6H, –N(CH₃)₂]. ¹³C NMR (75 MHz, CDCl₃): 150.6 (C_4'), 147.7 (C_4a), 146.8 (C₂), 142.9 (C_1a), 138.1 (C₄), 133.5 (C₅), 131.1 (2C, C₄-, C₅-phenyl carbons), 130.2 (2C, C_2' and C_6'), (123.0 and 129.4) (ipso to C₄ and C₅), 129.3 (2C, C_2a and C_6a), 128.7 (2C, C₄-, C₅-phenyl carbons), 128.5 (C₄- or C₅-phenyl carbon), 128.2 (2C, C₄-, C₅-phenyl carbons), 127.5 (2C, C₄-, C₅-phenyl carbons), 127.0 (C₄- or C₅-phenyl carbon), 124.4 (2C, C_3a and C_5a), 116.4 (C_1'), 111.6 (2C, C_3' and C_5'), 40.1 [2C, –N(CH₃)₂]. Anal. calcd. for C₂₉H₂₄N₄O₂ (%): C 75.64, H 5.25, N 12.17. Found (%): C 75.51, H 5.33, N 12.29.

2-(2′, 5′-Dimethoxyphenyl)-1-(4a-nitrophenyl)-4,5-diphenyl-imidazole (Table 3, entry 7)

The titled compound was obtained as a yellow solid (396 mg, 83%); R _f=0.64 (25% ethylacetate/75% petroleum ether). M.P.: 208–210°C (EtOAc); IR (KBr): 3426, 2940, 2375, 1598, 1522, 1492, 1347, 1223, 1040, and 698 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 8.02 (d, J=9.0 Hz, 2H, C_3a-H and C_5a-H), 7.61 (d, J=6.9 Hz, 2H, C₄-, C₅-phenyl protons), 7.36–7.20 (m, 6H, C₄-, C₅-phenyl protons), 7.16 (brd, J=5.7 Hz, 3H, C_2', and two other protons from C₄- and C₅-phenyl protons), 7.08 (d, J = 9.0 Hz, 2H, C_2a-H and C_6a-H), 6.93 (dd, J=9.0 and 3.0 Hz, 1H, C_4'-H), 6.64 (d, J=9.0 Hz, 1H, C_3'-H), 3.83 (s, 3H, C₂-OCH₃), 3.26 (s, 3H, C_5'-OCH₃). ¹³C NMR (75 MHz, CDCl₃): 153.7 (C_2'), 150.5 (C_5'), 146.3 (C_4a), 145.0 (C₂), 142.7 (C_1a), 138.3 (C₄), 133.3 (C₅), 130.9 (2C, C₄-, C₅-phenyl carbons), 129.7 (ipso to C₄), 129.2 (ipso to C₅), 128.8 (2C, C_2a, C_6a), 128.5 (C₄- or C₅-phenyl carbon), 128.1 (2C, C₄-, C₅-phenyl carbons), 127.7 (2C, C₄-, C₅-phenyl carbons), 127.5 (2C, C₄-, C₅-phenyl carbons), 127.0 (C₄- or C₅-phenyl carbon), 123.5 (2C, C_3a, C_5a), 119.2 (C_1'), 117.3 (C_6'), 117.1 (C_4'), 111.9 (C_3'), 55.8 (C_2'-OC¯H₃), 54.9 (C_5'-OC¯H₃). Anal. calcd. for C₂₉H₂₃N₃O₄ (%): C 72.95, H 4.85, N 8.80. Found (%): C 72.83, H 4.97, N 8.95.

2-(3′,4′-Dimethoxyphenyl)-1-(4a-methoxyphenyl)-4,5-diphenylimidazole (Table 3, entry 8)

The titled compound was obtained as a white solid (430 mg, 93%); R _f=0.29 (25% ethylacetate/75% petroleum ether). M.P.: 174–176°C (EtOAc); IR (KBr): 2945, 2834, 2374, 2040, 1601, 1515, 1471, 1442, 1247, 1026, and 699 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): 7.60 (d, J=7.2 Hz, 2H, C₄- and C₅-phenyl protons), 7.30–7.10 (m, 8H,C₄-_, C₅-phenyl protons), 7.05 (brs, 1H, C_2'-H), 6.97 (d, J=8.4 Hz, 3H, C_2a-H, C_6a-H, and C_6'-H), 6.76–6.69 (m, 3H, C_3a-H, C_5a-H, and C_5'-H), 3.80 (s, 3H, C_4a-OCH₃), 3.71 and 3.68 [2s, 6H, C_4'-OCH₃ and C_3'-OCH₃]. ¹³C NMR (75 MHz, CDCl₃): 159.0 (C_4a), 148.9 (C_4'), 148.2 (C_3'), 146.7 (C₂), 137.6 (C₄), 134.4 (C₅), 131.0 (2C, C₄-, C₅-phenyl carbons), (130.7, 130.6, and 129.9) (3C, C_1a, C₄ and C₅ ipso carbons), 129.4 (2C, C_2a, C_6a), 128.1 (2C, C₄-, C₅-phenyl carbons), 127.9 (2C, C₄-, C₅-phenyl carbons),127.7 (C₄- or C₅-phenyl carbon), 127.2 (2C, C₄-, C₅-phenyl carbons), 126.3 (C₄- or C₅-phenyl carbon), 123.1 (C_1'), 121.5 (C_6'), 114.0 (2C, C_3a, C_5a), 111.3 (C_2'), 110.6 (C_5'), 55.6 (C_4a-OMe), 55.5 (C_4'-OMe), and 55.2 (C_3'-OMe). Anal. calcd. for C₃₀H₂₆N₂O₃ (%): C 77.90, H 5.67, N 6.06. Found (%): C 77.81, H 5.75, N 6.14.

2-(4′-N,N-Dimethylaminophenyl)-1-(4a-methoxyphenyl)-4,5-diphenyl-imidazole (Table 3, entry 9)

The titled compound was obtained as an off-white solid (387 mg, 87%); R _f=0.67 (25% ethylacetate/75% petroleum ether). M.P.: 224°C (EtOAc); IR (KBr): 3436, 2899, 2375, 1610, 1510, 1441, 1365, 1248, 818, and 699 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 7.61 (d, J=7.5 Hz, 2H, C₄-, C₅-phenyl protons), 7.33 (d, J=8.7 Hz, 2H, C_2'-H and C_6'-H), 7.26–7.11 (m, 8H, C₄-, C₅-phenyl protons), 6.99 (d, J=8.7 Hz, 2H, C_2a-H and C_6a-H), 6.76 (d, J=8.7 Hz, 2H, C_3a-H and C_5a-H), 6.58 (d, J=8.7 Hz, 2H, C_3'-H and C_5'-H), 3.76 (s, 3H, C_4a-OCH₃), 2.93 [s, 6H, –N(CH₃)₂]. ¹³C NMR (75 MHz, CDCl₃): 158.9 (C_4a), 150.1 (C_4'), 147.7 (C₂), 137.5 (C₄), 134.7 (C₅), 131.2 (2C, C_4-, C₅-phenyl carbons), 131.1 (C_1a), 130.3, and 130.2 (C₄- and C₅-ipso carbons), 129.8 (2C, C_2', C_6'), 129.6 (2C, C_2a, C_6a), 128.2 (2C, C₄- and C₅- phenyl carbons), 128.0 (2C, from C₄- and C₅-phenyl carbons), 127.6 (C₄- or C₅-phenyl carbon), 127.4 (2C, from C₄- and C₅-phenyl carbons), 126.3 (C₄- or C₅-phenyl carbon), 118.3 (C_1'), 114.1 (2C, C_3a, C_5a), 111.6 (2C, C_3', C_5'), 55.3 (C_4a-OC¯H₃), 40.2 [2C, –N(CH₃)₂]. Anal. calcd. for C₃₀H₂₇N₃O (%): C 80.87, H 6.11, N 9.43. Found (%): C 80.74, H 6.22, N 9.52.

1-(4a-Methoxyphenyl)-2-(4′-nitrophenyl)-4,5-diphenyl-imidazole (Table 3, entry 10)

The titled compound was obtained as a yellow solid (398 mg, 89%); R _f=0.85 (25% ethylacetate/75% petroleum ether). M.P.: 198°C (EtOAc); IR (KBr): 3436, 2932, 2378, 1597, 1511, 1336, 1247, 853, and 699 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): 8.11 (d, J=8.7 Hz, 2H, C_3'-H and C_5'-H), 7.65 (d, J=9.0 Hz, 2H, C_2'-H and C_6'-H), 7.59 (dd, J=8.1 and 1.5 Hz, 2H, C₄-, C₅-phenyl protons), 7.32–7.13 (m, 8H, 4,5-phenyl protons), 7.03 (d, J=8.7 Hz, 2H, C_2a-H and C_6a-H), 6.82 (d, J=8.7 Hz, 2H, C_3a-H and C_5a-H), 3.80 (s, 3H, C_4a-OCH₃). ¹³C NMR (75 MHz, CDCl₃): 159.7 (C_4a), 147.07 (C_4'), 144.3 (C₂), 138.9 (C₄), 136.2 (C_1'), 133.5 (C₅), 132.7 (C_1a), 131.0 (2C, C₄-, C₅-phenyl carbons), 129.8 (C₄- or C₅-ipso carbon), 129.3 (2C, C_2', C_6'), 129.1 (2C, C_2a, C_6a), 129.0 (C₄- or C₅-ipso carbon), 128.5 (2C, C₄-, C₅-phenyl carbons), 128.4 (C₄- or C₅-phenyl carbon), 128.3 (2C, C₄-, C₅-phenyl carbons), 127.3 (2C, C_2a, C_6a), 127.1 (C₄- or C₅-phenyl carbon), 123.4 (2C, C_3', C_5'), 114.6 (2C, C_3a, C_5a), 55.4 (C_4a–OC¯H₃). Anal. calcd. for C₂₈H₂₁N₃O₃ (%): C 75.16, H 4.73, N 9.39. Found (%): C 75.03, H 4.89, N 9.44.

2-(3,4′-Dimethoxyphenyl)-1-(4a-methylphenyl)-4,5-diphenyl-imidazole (Table 3, entry 11)

The titled compound was obtained as a white solid (410 mg, 92%); R _f=0.54 (25% ethylacetate/75% petroleum ether). M.P.: 162–164°C (EtOAc); IR (KBr): 3431, 3032, 2944, 2370, 1599, 1516, 1488, 1445, 1257, 1226, 1131, 1019, 770, and 699 cm⁻¹.¹H NMR (300 MHz, CDCl₃): 7.64 (d, J=7.2 Hz, 2H from C₄-, C₅-phenyl protons), 7.27–7.15 (m, 8H from C₄-, C₅-phenyl protons), 7.07–7.02 (m, 4H, C_2a-H, C_6a-H, C_2'-H, and C_6'-H), 6.95 (d, J=8.4 Hz, 2H, C_3a-H and C_5a-H), 6.72 (d, J=9.0 Hz, 1H, C_5'-H), 3.81 (s, 3H, C_4'-OCH₃), 3.67 (s, 3H, C_3'-OCH₃), 2.29 (s, 3H, C_4a-CH₃). ¹³C NMR (75 MHz, CDCl₃): 148.9 (C_4'), 148.1 (C_3'), 146.5 (C₂), 137.9 (C_4a), 137.5 (C₄), 134.5 (C_1a), 134.2 (C₅), 130.9 (2C, C₄-, C₅-phenyl carbons), 130.5, and 130.4 (2C, ipso to C₄ and C₅), 129.5 (2C, C_2a, C_6a), 128.1 (2C, C_3a, C_5a), 128.0 (2C, C₄-, C₅-phenyl carbons), 127.9 (2C, C₄-, C₅-phenyl carbons), 127.7 (C₄- or C₅-phenyl carbon), 127.1 (2C, C₄-, C₅-phenyl carbons), 126.3 (C₄- or C₅-phenyl carbon), 123.0 (C_1'), 121.5 (C_2'), 111.9 (C_6'), 110.5 (C_5'), 55.5 (C_4'–OC¯H₃), 55.3 (C_3'–OC¯H₃), 20.8 (C_4a–C¯H₃). Anal. calcd. for C₃₀H₂₆N₂O₂ (%): C 80.69, H 5.87, N 6.27. Found (%): C 80.54, H 5.99, N 6.35.

2-(4′-N,N-Dimethylaminophenyl)-1-(4a-methylphenyl)-4,5-diphenyl-imidazole (Table 3, entry 12)

The titled compound was obtained as a white solid (399 mg, 93%); R _f=0.95 (25% ethylacetate/75% petroleum ether). M.P.: 234–236°C (EtOAc); IR (KBr): 2902, 1894, 1608, 1484, 1365, 1198, 816, 776, and 698 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): 7.62 (d, J=7.0 Hz, 2H, C₄-, C₅-phenyl protons), 7.34 (d, J=8.9 Hz, 2H, C_2'-H and C_6'-H), 7.30–7.13 (m, 8H, C₄-, C₅-phenyl protons), 7.07 (d, J=8.1 Hz, 2H, C_2a-H and C_6a-H), 6.96 (d, J=8.2 Hz, 2H, C_3a-H and C_5a-H), 6.59 (d, J=8.9 Hz, 2H, C_3'-H and C_5'-H), 2.95 [s, 6H, –N(CH₃)₂], 2.34 (s, 3H, C_4a-CH₃). ¹³C NMR (75 MHz, CDCl₃): 150.1 (C_4'), 147.6 (C₂), 137.8 (C_4a), 137.5 (C₄), 134.8 (C_1a), 134.6 (C₅), 131.2 (2C, C₄-, C₅-phenyl carbons), 131.0 (ipso to C₄), 130.1 (ipso to C₅), 129.8 (2C, C_2' and C_6'), 129.6 (2C, C_2a and C_6a), 128.2 (2C, C_3a and C_5a), 128.2 (2C, C₄- and C₅-phenyl carbons), 128.0 (2C, C₄-, C₅-phenyl carbons), 127.6 (C₄- or C₅-phenyl carbon), 127.4 (C₄- or C₅-phenyl carbon), 126.3 (C₄- or C₅-phenyl carbon), 118.2 (C_1'), 111.5 (2C, C_3' and C_5'), 40.1 [2C, –N(CH₃)₂], 21.1 (C_4a-C¯H₃). Anal. calcd. for C₃₀H₂₇N₃ (%): C 83.88, H 6.34, N 9.78. Found (%): C 83.75, H 6.51, N 9.89.

1-(4a-Aminophenyl)-2-(4'-chlorophenyl)-4,5-diphenyl-imidazole (Table 3, entry 13)

The titled compound was obtained as a grey solid (379 mg, 90%); R _f=0.64 (25% ethylacetate/75% petroleum ether). M.P.: 236–238°C (EtOAc); IR (KBr): 3382, 3051, 2275, 1623, 1515, 1293, 1092, 834, and 699 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): 7.41 (dd, J=8.1 and 1.8 Hz, 2H, C₄-, C₅-phenyl protons), 7.27 (dd, J=6.9 and 1.8 Hz, 2H, C_2'-H and C_6'-H), 7.14–6.90 (m, 10H, C_3'-H, C_5'-H, and eight protons from C₄- and C₅-phenyl protons), 6.62 (dd, J=6.8 and 2.1 Hz, 2H, C_2a-H and C_6a-H), 6.34 (dd, J=6.8 and 2.4 Hz, 2H, C_3a-H and C_5a-H), 3.84 (s, 2H, –NH₂). ¹³C NMR (75 MHz, CDCl₃): (146.7 and 145.5) (2C, C_4a, C₂), 137.3 (2C, C₄, C₅), (134.5 and 133.4 (2C, C_1a, C_4'), 131.5 (2C, ipso to C₄, C₅), 131.1 (2C, C₄-, C₅-phenyl carbons), 130.1 (2C, C_2', C_6'), 129.0, and 128.3 (6C, C_2a, C_6a, C_3', C_5', and two from C₄- and C₅-phenyl carbons), 128.2 (2C, C₄-, C₅-phenyl carbons), 128.1 (C₄- or C₅-phenyl carbon), 127.4 (2C, C₄-, C₅-phenyl carbons), 126.9 (C₄- or C₅-phenyl carbons), 126.8 (C_1'), 115.1 (2C, C_3a, C_5a). Anal. calcd. for C₂₇H₂₀N₃Cl (%): C 76.86, H 4.78, N 9.96. Found (%): C 76.75, H 4.91, N 9.82.

Conclusion

We have for the first time utilized potassium hydrogen sulfate in the presence of dibenzo-18-crown-6 (DB18C6) as an efficient and highly effective catalyst for the facile synthesis of a wide variety of tri- and tetrasubstituted imidazoles in an aqueous medium at moderate temperature. Mild reaction conditions, easy work-up procedure, excellent overall yield, and use of water as the green reaction medium are the major advantages of this methodology.

Acknowledgements

One of the authors (P.K.T.) thanks the University Grants Commission, New Delhi, for his fellowship (SRF). We thank the CAS Instrumentation Facility, Department of Chemistry, University of Calcutta, for spectral data. We also acknowledge the grant received from UGC-funded Major project, F. No. 37-398/2009 (SR) dated 11 January 2010.