Chinese Chemical Letters  2013, Vol.24 Issue (11):993-996   PDF    
An expedient one-pot synthesis of highly substituted imidazoles using supported ionic liquid-like phase (SILLP) as a green and efficient catalyst and evaluation of their anti-microbial activity
Maryam Saffari Joursharia, Manouchehr Mamaghania , Farhad Shirinia, Khalil Tabatabaeiana, Mehdi Rassab, Hadiss Langaria    
* Corresponding authors at:a Department of Chemistry, Faculty of Sciences, University of Guilan, P.O. Box 41335-1914, Rasht, Iran;
b Department of Biology, Faculty of Sciences, University of Guilan, P.O. Box 41335-1914, Rasht, Iran
Abstract: An efficient method for the synthesis of imidazole derivatives by a three-component condensation of benzil or 9,10-phenanthrenequinone, aldehydes and ammonium acetate using supported ionic liquidlike phase (SILLP) catalyst under ultrasonic irradiation or classical heating conditions is reported. The present methodology offers several advantages, such as excellent yields, simple procedures, short reaction times, simple work-up and mild conditions. The catalyst is easily separated from the products by filtration and also exhibits remarkable reusable activity. These highly substituted imidazoles were also evaluated for their anti-microbial activity.
Key words: SILLP     Imidazole     Phenanthroimidazole     Ionic liquid     Three-component reaction     Anti-microbial activities    
1. Introduction

Multi-substituted imidazoles,an important class of pharmaceutical compounds [1, 2, 3],exhibit a wide spectrum of biological activities such as nitric-oxide synthase inhibition [4],anti-inflammatory [5],anti-parasitic [6],antifungal [7],antidepressant [8], antitubercular [9],anticancer [10] and antiviral activities [11] as well as antileishmanial activity against Leshmaniadonovani [12]. Some of these compounds could also be used as organic optical materials in many fields,for example as signaling,fluorescent biosensory/chemosensory materials,molecular switches and organic light emitting diodes (OLEDs) [12, 13, 14, 15]. They can also be useful in asymmetric organic synthesis [16]and polymer and material science [17]. Therefore,preparation of substituted imidazoles has attracted considerable attention in recent years and numerous methods for their synthesis have been reported [17, 18, 19, 20, 21, 22, 23]. Some of these methods are associated with one or more disadvantages such as using expensive reagents,long reaction time,tedious work-up procedures and generation of largeamount of toxicwaste. However, there are few reports on the synthesis of phenanthroimidazole compounds due to their lower solubility in organic solvents and the steric hindrance in these molecules [24, 25, 26]. On the other hand one important aspect of clean technology is the use of environmentally friendly catalysts,typically a solid catalyst that can be easily recovered when the reaction is complete.

Due to the resistance of some microorganisms to imidazole action because of outer membrane modifications [27],development of new and different anti-microbial agents has become a prime objective of medicinal and synthetic chemists. Therefore much of the current research effort is oriented toward the design of new and readily available drugs [28].

2. Experimental

Melting points were measured on an Electrothermal 9100 apparatus and are uncorrected. 1H NMR spectra were obtained on a Bruker AVANCE III 400 MHz and 13C NMR spectra were collected on an AVANCE III 100 MHz advanced spectrometer. FT-IR spectra were recorded on a Shimadzu FT-IR 8400S spectrometer. Chemical shifts on 1H NMR and 13C NMR were expressed in ppm downfield from tetramethylsilane. Sonication was performed in an Elmasonic S 40H ultrasonic cleaning unit. Elemental analyses were conducted on a Carlo-Erba EA1110CNNO-S analyser and agreed with the calculated values. All chemicals were purchased from Merck and used without further purification.

A mixture of benzil or 9,10-phenanthrenequinone (1 mmol), corresponding aldehyde (1 mmol),ammonium acetate (4 mmol) and a catalytic amount of supported ionic liquid-like phase (SILLP) (0.1 g) in ethanol (3 mL) was stirred in an oil bath at 50 ℃ or under ultrasonic irradiations (40 kHz,50 ℃) for a specified period of time. The progress of the reaction was monitored by TLC analysis (petroleum ether/ethyl acetate,2/1). After the completion of the reaction,the crude product from the reaction mixture was dissolved in ethanol and the catalyst was separated by filtration. The filtrate was evaporated under reduced pressure to remove ethanol. The solid was then recrystallized from methanol to obtain the pure product. The data of some new compounds are listed below:

4,5-Diphenyl-2-(1,3-diphenyl-1H-pyrazol-4-yl)-1H-imidazole (3g): White solid,mp 239-240 ℃; 1H NMR (DMSO-d6): δ 7.23-7.58 (m,14H),7.96-8.11 (m,6H),9.01 (s,1H),12.52 (s,1H). 13C NMR (DMSO-d6): δ 113.4,119.7,126.9,127.1,127.2,127.4,128.6,128.7, 129,129.2,130.2,133.1,135.7,136.8,139.7,140,150.4. FT-IR (KBr, cm-1): v 3450,3010,2950,1665,1590,1520,1500,1440,1365, 1220,1120,1062,960,940,910,862,800,760,750,725,690,680. Anal. Calcd. for C30H22N4 (438.52): C 82.17,H 5.06,N 12.78; found: C 82.07,H 5.01,N 12.61.

2-(1-(4-Bromophenyl)-3-phenyl-1H-pyrazol-4-yl)-4,5-diphenyl- 1H-imidazole (3h): White solid,mp 259-261 ℃; 1H NMR (DMSO-d6): δ 7.24-7.60 (m,13H),7.69 (d,2H),8.05 (d,2H), 8.15 (d,2H),9.03 (s,1H),12.54 (s,1H). 13C NMR (DMSO-d6): δ 113.4,118.9,122.1,128.2,128.6,128.8,129.2,130.1,130.3,130.8, 131.5,132.3,135.6,136.9,139.5,139.8,149.2. FT-IR (KBr,cm-1): v 3400,3010,2950,2068,1662,1586,1500,1465,1440,1362,1300, 1220,1065,1005,960,940,820,760,745,735,720,693; Anal. Calcd. for C30H21BrN4 (517.42): C 69.64,H 4.09,N 10.83; found: C 69.80,H 4.14,N 11.05.

2-(1-(4-Nitrophenyl)-3-phenyl-1H-pyrazol-4-yl)-4,5-diphenyl- 1H-imidazole (3i): Yellow solid,mp 248-250 ℃; 1H NMR (DMSO-d6): δ 7.32-7.65 (m,13H),7.98 (d,2H),8.36 (d,2H), 8.53 (d,2H),9.10 (s,1H),12.62 (s,1H). 13C NMR (DMSO-d6): δ 113.1,119.1,123.8,126.8,127.5,128.6,128.8,129.3,129.8,130.4, 130.5,131,135,139.4,145.1,145.9,147.4. FT-IR (KBr,cm-1): v 3450,3010,2990,2070,1710,1700,1625,1590,1518,1500, 1485,1338,1380,1180,1160,1100,1060,1020,960,920,850,835, 760,690. Anal. Calcd. for C30H21N5O2 (483.52): C 74.52,H 4.38, N 14.48; found: C 74.65,H 4.25,N 14.19.

2-(4-Chlorophenyl)-1H-phenanthro[9,10-d]imidazole (6b): Milky solid,mp > 300 ℃; 1H NMR (DMSO-d6): δ 7.76-7.64 (m,6H),8.33 (d,2H),8.53 (d,1H),8.58 (d,1H),8.85 (d,1H),8.88 (d,1H),13.55 (s, 1H). 13C NMR (DMSO-d6): δ 122.3,122.4,122.8,124.3,124.6,125.8, 126,127.3,127.7,128.1,128.3,129.5,129.7,134.2,148.4. FT-IR (KBr,cm-1): v 3450,3050,2950,2360,1610,1508,1468,1450, 1420,1370,1230,1100,1090,960,825,745,720,710,680. Anal. Calcd. for C21H13 ClN2 (328.79): C 76.71,H 3.98,N 8.52; found: C 76.45,H 4.22,N 8.33.

2-(4-Fluorophenyl)-1H-phenanthro[9,10-d]imidazole (6c): Milky solid,mp > 300 ℃; 1H NMR (DMSO-d6): δ 7.46 (t,2H),7.63 (t,2H), 7.74 (s,br. 2H),8.37 (dd,2H),8.57 (s,br.,2H),8.84 (d,2H),13.49 (s, 1H). 13C NMR(DMSO-d6): δ 116.3,116.6,122.4,122.9,124.5,125.7, 127.5,127.6,128.1,128.8,128.9,148.7,162,164.4. FT-IR (KBr, cm-1): v 3455,3050,2900,2070,1600,1520,1485,1450,1420, 1378,1347,1225,1132,1100,1038,830,750,690,610,505. Anal. Calcd. for C21H13FN2 (312.34): C 80.75,H 4.20,N 8.97; found: C 80.60,H 4.39,N 8.75.

2-(1,3-Diphenyl-1H-pyrazol-4-yl)-1H-phenanthro[9,10-d]imidazole (6d): Pale yellow solid,mp228-230 ℃; 1H NMR(DMSO-d6): δ 7.38-7.75 (m,10H),8.03 (m,4H),8.36 (d,1H),8.50 (d,1H),8.88 (m, 2H),9.20 (s,1H),13.42 (s,1H). 13C NMR (DMSO-d6): δ 113.4,119.3, 122.6,125.7,126,127.1,127.2,127.4,127.5,128.7,130.1,130.2, 130.4,131.7,132.3,141.3,143.5,149.8. FT-IR (KBr,cm-1): v 3455, 2900,2850,2065,1658,1620,1600,1540,1460,1378,1270,1180, 1080,1060,960,820,745,720,690. Anal. Calcd. for C30H20N4 (436.51): C 82.55,H 4.62,N 12.84; found: C 82.60,H 4.38,N 12.57.

2-(1-(4-Bromophenyl)-3-phenyl-1H-pyrazol-4-yl)-1H-phenanthro[ 9,10-d]imidazole (6e): Pale yellow solid,mp 122-124 ℃; 1H NMR (DMSO-d6): δ 7.46 (t,1H),7.61-7.76 (m,6H),7.74 (m,2H), 8.04 (d,2H),8.09 (d,2H),8.39 (d,1H),8.52 (d,1H),8.88 (d,1H),8.92 (d,1H),9.24 (s,1H),13.43 (s,1H). 13C NMR (DMSO): δ 113.6,119.1, 122.2,122.4,124.7,125.8,127.5,127.6,127.7,127.9,128.1,130.3, 130.7,130.9,131.7,132.1,139.5,143.4,149.6. FT-IR (KBr,cm-1): v 3450,2900,2850,2360,1735,1580,1500,1460,1400,1245,1220, 1160,1140,1080,960,820,750,720,680. Anal. Calcd. for C30H19BrN4 (515.4): C 69.91,H 3.72,N 10.87; found: C 69.75,H 3.50,N 11.04. 3. Results and discussion

In the course of our search for the development of efficient and environmentally friendly protocols for the synthesis of biologically important heterocyclic products [29],we studied the synthesis of highly substituted imidazole derivatives as potential drug candidates,over a supported ionic liquid-like phase (SILLP) catalyst (Scheme 1). Initially the SILLP was prepared by using Merrifield resin (1% cross linked,200-400 mesh,1-1.3 mmol/g) and the procedure employed by Luis et al. [30]. In order to optimize the effect of the amount of catalyst on the efficiency of the reaction,the condensation of benzil (1 mmol),4-chlorobenzaldehyde (1 mmol) and ammonium acetate (4 mmol) in the presence of SILLP was selected as a model reaction (Scheme 1). This study gave the optimized amount of the catalyst (0.1 g per mmol of substrate). The effect of different solvents was also examined for the model reaction in the presence of SILLP and we obtained the maximum yield of the product in shortest reaction time,when ethanol was used as solvent. Therefore all the reactions described in this report were carried out under these optimized conditions. The results of this study using various aryl- and heteroaryl aldehydes are given in Table 1.

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Scheme 1. Synthesis of tri-substituted imidazoles (3a-j).

Table 1
One-pot synthesis of highly substituted benzimidazoles (3a-j) in the presence of supported ionic liquid-like phases as a solid green catalyst at 50 ℃,under ultrasonic irradiation and conventional condition.

Table 2 compares efficiency of SILLP with other catalysts in the synthesis of 3b. It is clear from the results that SILLP is more efficient,and less time-consuming for the synthesis of the desired product (3b).

Table 2
Comparison of efficiency of the catalysts in one-pot synthesis of 3b in ethanol at 50 ℃ under conventional heating.

In order to determine the scope of this protocol,the reaction of 9,10-phenanthrenequinone was also carried out in the presence of SILLP with various aromatic and heteroaromatic aldehydes under the optimized conditions (Scheme 2). The results are summarized in Table 3. It can be easily seen that in all cases,regardless of the nature of the substituents,the reactions gave the products in very high yields.

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Scheme 2. Synthesis of tri-substituted phenantroimidazoles (6a-e).

Table 3
One-pot synthesis of highly substituted phenanthroimidazoles (6a-e) in the presence of SILLP at 50 ℃,under ultrasonic irradiation and conventional heating.

Due to environmental concerns,ultrasonic reactions have attracted more and more attention as clean,green and benign routes for the preparation of organic compounds of synthetic and biological value [31].

To improve the efficiency of the present method for the synthesis of highly substituted imidazole derivatives,we also carried out the reaction under ultrasonic irradiation (40 Hz,EtOH, 50 ℃). The results are presented in Tables 1 and 3. Using ultrasound gave comparable yields of products but with shorter reaction time (3-6 min),compared to conventional heating.

In this study the catalyst was separated simply by filtration from the reaction mixture,washed by ethanol and used in the next run. The high catalytic activity was maintained even after fourth reuse of the catalyst.

The antibacterial activity of synthesized compounds 3a-i and 6a-e was examined against Escherichia coli (EC),Micrococcus luteus (ML),Bacillus subtillis (BS) and Pseudomonas aeruginosa (PS). For comparison,two routinely used antibiotics,tetracycline and erythromycin,were also included (Table 4). Although nearly all the compounds exhibited antimicrobial activity,the most active ones were compounds 3g,3h,3i,6d and 6e. Compared to the control antibiotics used,these compounds showed much improved activity.

Table 4
Antimicrobial activity of compounds 3a-i and 6a-e.
4. Conclusion

In summary the work reported here offers an efficient one-pot multicomponent route for the synthesis of trisubstituted imidazole derivatives in the presence of supported ionic liquid-like phase (SILLP) as a green catalyst. The simple procedures combined with easy recovery and reuse of the catalyst make this method an economical,environmentally benign and user-friendly process for the synthesis of highly substituted imidazoles. Furthermore,some of the synthesized products (3g,3h,3i,6d and 6e) exhibited highly potent antimicrobial activity,which needs further investigation. Acknowledgments

The authors are grateful to the Research Council of University of Guilan for the financial support of this research work.

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