Ammonium Chloride: An Effective Catalyst For The One-Pot Synthesis Of 2,4,5-Trisubstituted Imidazoles

Introduction

Multicomponent reactions (MCRs) have drawn great interest enjoying an outstanding status in modern organic synthesis and medicinal chemistry because they are one-pot processes bringing together three or more components and show high atom economy and high selectivity [1, 2].  MCRs have great contribution in convergent synthesis of complex and important organic molecules from simple and readily available starting materials, and have emerged as powerful tools for drug discovery [3, 4]. The imidazole nucleus is a fertile source of biologically important molecules. Compounds containing imidazole moiety have many pharmacological properties and play important roles in biochemical processes. They are well known as inhibitors of P38MAP kinase, fungicides, herbicides, anti-inflammatory agents, antithrombotic agents, plant growth regulators and therapeutic agents. In addition, they are used in photography as photosensitive compounds. Some substituted triarylimidazoles are selective antagonists of the glucagons receptor and inhibitors of IL-1 biosynthesis [5]. Radziszewski and Jaap proposed the first synthesis of the imidazole core in 1882, starting from 1,2-dicarbonyl compounds, aldehydes and ammonia to obtain 2,4,5-triphenylimidazole [6, 7]. There are several methods for the synthesis of 2,4,5-triarylimidazoles using ZrCl4, zeolites HY/silica gel, NaHSO3, sulphanilic acid, iodine, ceric ammonium nitrate, oxalic acid, ionic liquids  and also by microwave irradiation using acetic acid. Each of the above methods for this reaction has its own merits, while some of the methods are plagued by the limitations of poor yield, longer reaction time, difficult work-up and effluent pollution [5]. Therefore, the development of a new mild method to overcome these disadvantages still remains a challenge for organic chemists. One of the aims we have in mind is to introduce a new catalyst for synthesis of 2,4,5-trisubstituted imidazoles with cost effectiveness and mild condition in high  yields.

In previous years the Ammonium chloride (NH₄Cl) was used as a catalyst for synthesis of organic compounds. For example, the Ammonium chloride was applied in the synthesis of pyrolo [3,4b] pyridines [8], the Claisen rearrangements of aliphatic compounds [9], the reduction of azo compounds to corresponding hydrazines [10] and the reduction of nitro phenols [11]. In 2009, Dr Maleki’s research group became successful to synthesize 2-aryl benzothiazoles by using Ammonium chloride as a catalyst [12]. In this work, we report the solvent-free synthesis of 2,4,5-trisubstituted imidazoles using Ammonium chloride (NH₄Cl) as a catalyst under classical heating (Figure 1 ).

We examined a wide variety of aromatic aldehydes with various substituents to establish the catalytic importance of NH₄Cl for this reaction. A wide range of ortho-, meta– and para-substituted aromatic aldehydes undergo this one-pot multicomponent synthesis with Benzil or Benzoin and ammonium acetate to afford 2,4,5-trisubstituted imidazoles in good yields.

 

Figure 1: Ammonium chloride catalysed synthesis of 2,4,5-trisubstituted imidazoles. Click here to View figure

Experimental

Melting points were measured with an Electrothermal 9100 apparatus. IR spectra were recorded with a Varian 3100 FTIR spectrometer. CHN analyses were performed on Exeter Analytical Inc. ‘Model CE-400 CHN Analyzer’. ¹H and ¹³C NMR spectra were recorded with a BRUKER DRX-400 AVANCE spectrometer at 298 ^oK and 75.47 MHz, respectively. NMR spectra were obtained on solutions in DMSO-d₆. All the products are known compounds, which were characterized by IR and ¹H NMR spectral data and their m.p.’s compared with literature reports.

General Procedure For Preparation Of 2a–L

A mixture of aldehyde (1 mmol), benzil or benzoin (1 mmol), ammonium acetate (5 mmol) and ammonium chloride (3 mmol, 30 mol %) as a catalyst in a 20 ml glass tube was stirred at 110 ^oC for 45-75 min. After completion of the reaction, the reaction was cooled to room temperature and solid materials washed with water and the solvent was evaporated to give the crude product. For further purification it was recrystallized from ethanol 96% to afford pure product.

Selected Spectral Data

2,4,5-Triphenyl-1H-imidazole (2a).

Mp 273–275 ^oC. FTIR (KBr,cm^-1): 3451, 2856, 1636, 1490; ¹H NMR (400 MHz, DMSO-d₆): δ 12.69 (s, 1H), 8.09 (d, 2H), 7.56–7.22 (m, 13H); ¹³C NMR (75 MHz, DMSO-d₆): δ 145.6, 137.2, 135.2, 131.2, 130.4, 128.7, 128.5, 128.3, 128.2, 127.8, 127.2, 126.6, 125.3; Anal. Calcd for C₂₁H₁₆N₂: C, 85.11; H, 5.44; N, 9.45. Found: C, 85.18; H, 5.49; N, 9.33.

2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole (2b).

Mp 263 ^oC. FTIR (KBr, cm^-1): 3452, 3065, 1635, 1323; ¹H NMR (400 MHz, DMSO-d₆): δ 12.78 (s, 1H), 8.11 (d, 2H), 7.56–7.23 (m, 12H); ¹³C NMR (75 MHz, DMSO-d₆): δ 146.3, 130.3, 129.9, 129.2, 128.5, 127.4, 127.0, 126.4, 125.5, 125.2, 123.3, 116.3; Anal. Calcd for C₂₁H₁₅N₂Cl: C, 76.24; H, 4.57; N, 8.47. Found: C, 76.20; H, 4.61; N, 8.41.

4,5-Diphenyl-2-p-tolyl-1H-imidazole (2c).

Mp 231–233 ^oC. FTIR (KBr, cm^-1): 3449, 3034, 1611, 1495, 1320; ¹H NMR (400 MHz, DMSO-d₆): δ 12.59 (s, 1H), 7.98 (d, 2H), 7.54–2.21 (m, 12H), 2.35 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆): δ 145.6, 137.6, 136.9, 135.2, 131.1, 129.2, 128.6, 128.3, 128.1, 127.9, 127.6, 127.0, 126.4, 125.1, 20.8; Anal. Calcd for C₂₂H₁₈N₂: C, 85.13; H, 5.85; N, 9.03. Found: C, 85.23; H, 5.79; N, 8.97.

2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (2d).

Mp 229–233 ^oC. FTIR (KBr, cm^-1 ): 3425, 3029, 2956, 1610, 1495, 1249; ¹HNMR (400 MHz, DMSO-d₆): δ 12.50 (s, 1H), 8.03 (d, 2H), 7.50–7.33 (m, 10H), 7.05 (d, 2H), 3.82 (s, 3H); ¹³C NMR (75MHz, DMSO-d₆): δ 159.5, 145.7, 128.4, 127.7, 126.8, 123.1, 114.1, 55.2; Anal. Calcd for C₂₂H₁₈N₂O: C, 80.96; H, 5.56; N, 8.58. Found: C, 80.90; H, 5.51; N, 8.63.

4-(4,5-Diphenyl-1H-imidazol-2-yl)-phenol (2e).

Mp 265-269 ^oC. FTIR (KBr, cm^-1): 3590, 3454, 3284, 3064, 1701, 1283; ¹H NMR (400 MHz, DMSO-d₆): δ 12.40 (s, 1H), 9.70 (s, 1H), 7.90 (d,  2H), 7.54–7.21 (m, 10H), 6.86 (d, 2H); ¹³C NMR (75 MHz, DMSO-d₆): δ 157.7, 146.1, 136.6, 135.4, 131.3, 128.6, 128.3, 127.5, 127.3, 127.0, 126.8, 126.3, 121.6, 115.4; Anal. Calcd for C₂₁H₁₆N₂O: C, 80.75; H, 5.16; N, 8.97. Found: C, 80.79; H, 5.22; N, 8.91.

2-(4-Fluorophenyl)-4,5-diphenyl-1H-imidazole (2f.)

Mp 248-251 ^oC. FTIR (KBr, cm^-1): 3316, 2993, 2470, 1660, 1210, 1169, 874, 719, 639; ¹H NMR (400 MHz, DMSO-d₆): δ 12.82 (s, 1H), 8.28 (d, 2H), 7.22-7.55 (m, 10H), 7.03 (d, 2H); ¹³C NMR (75 MHz, DMSO-d₆): δ 165.4, 137.3, 131.1, 129.8, 128.9, 127.7, 127.2, 126.6, 125.9, 125.5, 124.1, 117.4; Anal. Calcd for C₂₁H₁₅N₂F: C, 76.27; H, 4.54; N, 8.41. Found: C, 76.22; H, 4.60; N, 8.43.

2-(2-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (2g).

Mp 210-213 ^oC. FTIR (KBr, cm¹): 3437, 3033, 2950, 1615, 1498; ¹H NMR (400 MHz, DMSO-d₆): δ 11.82, (s, 1H), 8.02 (d, 1H), 7.53–7.07 (m, 13H), 3.92 (s, 3H); ¹³C NMR (75MHz, DMSO-d₆): δ 158.2, 146.2, 128.3, 127.5, 125.4, 123.8, 115.4, 55.3; Anal. Calcd for C₂₂H₁₈N₂O: C, 80.96; H, 5.56; N, 8.58. Found: C, 80.90; H, 5.63; N, 8.51.

2-(3-Nitrophenyl)-4,5-diphenyl-1H-imidazole (2i).

Mp 299-301 ^oC. FTIR (KBr, cm^-1): 3448, 3068, 1526, 1350; ¹H NMR (400 MHz, DMSO-d₆): δ 13.10 (s, 1H), 8.95 (s, 1H), 8.53 (d, 1H), 8.23 (d, 1H), 7.81 (d, 1H), 7.54–7.33 (m, 10H); ¹³C NMR (75 MHz, DMSO-d₆): δ 148.4, 143.4, 131.8, 131.2, 130.4, 128.7, 128.4, 127.1, 122.6, 119.4; Anal. Calcd for C₂₁H₁₅N₃O₂: C, 73.89; H, 4.43; N, 12.31. Found: C, 73.84; H, 4.47; N, 12.39.

Results and Discussions

Several methods are used in the synthesis of these trisubstituted imidazoles and their derivatives.In addition, the synthesis of these heterocycles has been usually carried out in polar organic solvents such as ethanol, methanol, acetic acid, DMF and DMSO leading to complex isolation and recovery procedures. These processes also generate waste containing catalyst and solvent, which have to be recovered, treated and disposed of. The toxicity and volatile nature of many organic solvents, particularly chlorinated hydrocarbons that are widely used in huge amounts for organic reactions have posed a serious threat to the environment [13]. Thus, design of solvent-free catalytic reaction has received tremendous attention in recent times in the area of green synthesis [14].

Efficiency of this reaction is mainly affected by the amount of catalyst, temperature and reaction time. For getting the best conditions, initially we started the condensation of benzil (1 mmol),4-chloro benzaldehyde (1 mmol) and ammonium acetate (5 mmol) in the presence of ammonium chloride (1 mmol, 10 mol %) as a catalyst at 100 ^oC for 1h, which led to low yield (50%) of 2,4,5-trisubstituted imidazole. To enhance the yield of the desired product the temperature of thereaction was increased to 130 ^oC. With increasing the temperature, the productivity of the reaction increased but was not very high, yet. Then, it was thought worthwhile to carry out the reaction in the presence of higher amount of the catalyst. As indicated in Table 1, Maximum yield was obtained (91%) when the reaction was loaded with 30 mol % of the catalyst at the 110  ^oC. A further increasing of catalyst loading does not affect the yield (entry 11, Table 1).

Table 1: Optimization one-pot synthesis of trisubstituted imidazoles under classical heating conditions^a

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