Synthesis of 2,4,5-Triphenyl Imidazole Derivatives Using Diethyl Ammonium Hydrogen Phosphate as Green, Fast and Reusable Catalyst

Adel A. Marzouk*, Vagif. M. Abbasov, Avtandil H. Talybov, Shaaban Kamel Mohamed

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al Azhar University, Egypt

Abstract: A simple highly versatile and efficient synthesis of 2,4,5-trisubstituted imidazoles is achieved by three component cyclocondensation of 1,2-dicarbonyl compounds, aldehydes and ammonium acetate as ammonia source in thermal solvent free condition using Brønsted acidic ionic liquid diethyl ammonium hydrogen phosphate as catalyst. The key advantages of this process are cost effectiveness of catalyst, reusability of catalyst, easy work-up and purification of products by non-chromatographic methods, excellent yields and very short time reactions. Multicomponent reactions enjoy an outstanding status in organic and medicinal chemistry for their high degree of atom economy and application in the diversity-oriented convergent synthesis of complex organic molecules from simple and readily available substrates in a single vessel.

Keywords: 2, 4, 5-triarylimidazoles, benzyl and diethyl ammonium hydrogen phosphate

Received January 01, 2012; Revised February 4, 2013; Accepted March 17, 2013

Citation: Adel A. Marzouk, Vagif. M. Abbasov, Avtandil H. Talybov, Shaaban Kamel Mohamed, Synthesis of 2,4,5-Triphenyl Imidazole Derivatives Using Diethyl Ammonium Hydrogen Phosphate as Green, Fast and Reusable Catalyst. World Journal of Organic Chemistry, 1 (1). 6-10. January 2013. doi:10.12691/wjoc-1-1-2

1. Introduction

Imidazoles are a class of heterocyclic compounds that contain nitrogen and are currently under intensive focus due to their wide range of applications. [1] Synthetic study of imidazole units is very important due to their potent biological activity [2] and synthetic utility. [3] Imidazoles are an important class of heterocycles being the core fragment of different natural products and biological systems. Compounds containing imidazole moiety have many pharmacological properties and play important roles in biochemical processes.[4] The potency and wide applicability of the imidazole pharmacophore can be attributed to its hydrogen bond donor-acceptor capability as well as its high affinity for metals (e.g., Zn, Fe, Mg), which are present in many protein active sites3b [5,6].

Naturally occurring substituted imidazoles, as well as synthetic derivatives thereof, exhibit wide ranges of biological activities, making them attractive compounds for organic chemists. They act as inhibitors of p38 MAP kinase [7], B-Raf kinase [8], transforming growth factor b1 (TGF-b1) type 1 activin receptor-like kinase (ALK5) [9], cyclooxygenase-2 (COX-2) [10] and biosynthesis of interleukin-1 (IL-1) [11]. Appropriately substituted imidazoles are extensively used as glucagon receptors [12] and CB1 cannabinoid receptor antagonists [13], modulators of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) [14], antibacterial and antitumor agents [15] and also as pesticides [16]. Recent advances in green chemistry and organometallic catalysis has extended the application of imidazoles as ionic liquids [17] and N-heterocyclic carbenes [18].

Ionic liquid (IL) technology offers a new and environmentally benign approach toward modern synthetic chemistry. Ionic liquids have interesting advantages such as extremely low vapour pressure, excellent thermal stability, reusability, and talent to dissolve many organic and inorganic substrates. Ionic liquids have been successfully employed as solvents and catalyst for a variety of reactions which promise widespread applications in industry and organic syntheses [19].

In recent years, ionic liquids (ILs) have become a rapidly expanding topic of chemical research on account of their unique properties that include a negligible vapor pressure, nonflammability, excellent thermal stability, reusability and ability to dissolve organic and inorganic compounds, and even polymeric materials [20,21]. These unusual properties mean that ionic liquids are superior media for a broad range of potential uses, for example, as environmentally friendly solvents for chemical synthesis [22], biocatalysis [23], separation technologies [24], and as solvents or “all-in-one” solvent/templates for nanomaterial preparation [25]. More recently, ILs with nitrogen, sulfur, or phosphorus as the central atom of cations have been extensively investigated. These include imidazolium, pyrrolidinium, tetraalkylammonium, pyridinium, piperidinium, sulfonium and phosphonium based ILs. Moreover, ILs consisting of large organic, asymmetrical ions, such as 1-ethyl-3-methylimidazolium, 1,3-dialkyl imidazolium, 1-alkyl-2,3-dimethylimidazolium, 1-alkylpyridinium, 1-alkyl pyrazolium, tetra alkyl ammonium, or tetra alkyl phosphonium cations and BF₄⁻, PF₆⁻, CF₃ SO₃, or N(SO₂CF₃)₂⁻ anions have been developed. The easy modification of the cations and anions in RTILs allows the development of task specific RTILs for catalysis organic synthesis, nanoparticles, extraction and dissolution. However, structural modifications affect RTIL physio-chemical properties. As a consequence, it is of great importance to understand the relationship between structural changes and the properties of ILs. This paper reports the synthesis of diethylammonium hydrogen phosphate that contain alkyl moiety with nitrogen and phosphorus atom [26,27].

We report here a simple, mild and efficient method for the preparation of the 2,4,5-triarylimidazoles using diethyl ammonium hydrogen phosphate as Brønsted acidic ionic liquid catalyst that is considered as efficient and reusable catalyst. The procedure reported herein is not cumbersome; consequently, the methodology represents a good addition to the list of methods available for the synthesis of highly substituted imidazoles.

2. Experimental

2.1. Chemicals and Instruments

All reagents were purchased from Aldrich and Merck and used without further purification. Products were characterized by spectroscopy data (FTIR, ¹H NMR and ¹³C NMR spectra and Mass) and melting points. SHIMADZU FT-IR-8400s spectrometer was used to record IR spectra using KBr pellets. NMR spectra were recorded on a Bruker (300-MHz) Ultrasheild NMR and DMSO-d₆ was used as a solvent. The purity of the substances and the progress of the reactions were checked on TLC and melting points that determined by open capillary method using a Galen Kamp melting point apparatus and are uncorrected.

2.2. General Methods for Synthesis of Ionic Liquid

Diethylamine (20mmol) was added into a 150ml three necked flask with a magnetic stirrer. Then equimolar concentrated phosphoric acid was added dropwise slowly into the flask at 0°C then stirring at 80°C for 12h. The mixture was washed with diethyl ether three times to remove non-ionic residues and dried in vacuum by a rotary evaporator to obtain the viscous clear diethyl ammonium hydrogen phosphate [19].

2.3. General Methods for Synthesis of 2,4,5-Trisubstituted Imidazoles

In rounded bottom flask Benzil (10mmol), aldehyde (10mmol), and ammonium acetate (40mmol) were added to diethyl ammonium hydrogen phosphate (0.513g, 3mmol) in an oil bath at room temperature as in . Then the reaction mixture was heated to 100°C for the stipulated period of time reported in Table 1. After completion of the reaction which was monitored by TLC, the mixture washed with water, the solid product purified by recrystallization from ethanol. All of the desired product(s) were characterized by comparison of their physical data with those of known compounds. Some characterization data for selected known products are given below.

Scheme 1. Diethylammonium hydrogen phosphate as Brønsted acidic ionic liquid for synthesis of 2,4,5-trisubstituted imidazoles.

Table 1.

3. Spectral and Analytical Data

1. 2,4,5-Triphenyl-1H-imidazole (1a). Mp. 271–272°C. FTIR (KBr, cm⁻¹): 3434 (NH), 2993, 2470, 1638 (C=C), 1510 (C=N); ¹H NMR (300 MHz, DMSO-d₆): 12.7 (s, 1H, NH), 8.1 (d, J¼7.8 Hz, 2H), 7.1–7.9 (m, 13H, Ar-H); ¹³C NMR (300 MHz, DMSO-d₆): d 146, 136, 135.4, 130.8, 130, 129, 128.75, 128.3, 127.5, 127, 125.6.

2. 2-2-(4,5-Diphenyl-1H-imidazol-2-yl)-phenol (1b): Mp. 204–205°C. FTIR (KBr, cm⁻¹): 3596 (OH), 3432(NH), 2998, 2465, 1636 (C=C), 1216; ¹H NMR (300 MHz, DMSO-d₆): 12.74 (br. s. 1Н, NH), 7.17-7.23 (m, 10Н, Ar-H), 6.96-7.01 (d, J = 8.05Hz, 1Н), 6.8 - 6.95 (d, j=7.4 Hz, 2H); ¹³C NMR (300 MHz, DMSO-d₆): 146.0, 136.0, 130.08, 130.0, 129.0, 128.9, 128.4, 128.2, 127.6, 126.7, 125.6.

3. 4-(4,5-Diphenyl-1H-imidazol-2-yl)-phenol (1c): Mp 267–269°C. FTIR (KBr, cm⁻¹): 3590 (OH), 3454 (NH), 3284, 3064, 1701(C=C), 1283; ¹HNMR (300 MHz, DMSO-d₆): 12.20 (s, 1H, NH), 9.40 (s, 1H, OH), 7.90 (d, J¼8.4 Hz, 2H), 7.52–7.29 (m, 10H, Ar-H), 6.80 (d, J¼8.4 Hz, 2H); ¹³C NMR (300 MHz, DMSO-d₆): 157.6, 146.65, 127.12, 125.7, 124.3, 121.9, 114.75, 112.85, 98.55, 95.46ppm.

4. 2-(4-Methoxyphenyl)-4,5-diphenylimidazole (1d): Mp. 230–232°C. IR (KBr, cm⁻¹): 3400, 3060, 1611, 1490, 1179, 1028, 830, 761; ¹HNMR (DMSO-d₆, 300MHz): 12.52 (s, 1H, NH), 8.03 (d, J=8.80 Hz, 2.0 Hz, 2H), 7.70-7.10(m, 10H, Ar-H), 7.03 (dt, J=8.8 Hz, 2.0 Hz, 2H), 3.81 (s, 3H, CH₃); 13C NMR (300 MHz, DMSO-d₆): 158.32, 145.09, 136.01, 134.62, 131.38, 12130, 127.4, 126.01, 123,07, 113.89, 54.62ppm.

5. 4-[4-(4,5-Diphenyl-1H-imidazole-2-yl)-phenyl]-dimethylamine (1e): Mp 256–259°C. FTIR (KBr, cm⁻¹): 3447, 3061, 1614, 1501; ¹H NMR (300 MHz, DMSO-d₆): 12.31 (s, 1H, NH), 7.92 (d, J¼8.4 Hz, 2H), 7.7–7.11 (m, 10H, Ar-H), 6.80 (d, J¼8.4 Hz, 2H), 2.97 (s, 6H (CH₃)₂N); ¹³CNMR (300 MHz, DMSO-d₆): 150.46, 145.64, 137.4, 135.08, 131.85, 127.4, 126.38, 125.55, 117.4, 111.85, 30.00ppm.

6. 2-(3,4-Dimethoxyphenyl)-4,5-diphenylimidazole (1f): Mp 222-224°C. FTIR (KBr, cm⁻¹): 3381(NH), 3062(C-H), 3002, 2960, 1593 (C=N), 1512, 1265, 1023, 765. ¹HNMR (DMSO-d₆, 300MHz): 4.2(s., 6H, 2CH₃O), 7.02-7.60 (m., 13H, Ar-H), 10.4 (br. S., 1Н, NH); 13C NMR (300 MHz, DMSO-d₆): 149.769 148.931, 147.904, 136.733, 134.943, 131.467, 131.357, 129.900, 129.355, 129.107, 128.298, 126.696, 126.430, 123.772, 122.146, 113.294, 111.752, 55.747, 55.678ppm.

7. 2-(4-Nitrophenyl)-4,5-diphenyl-1H-imidazole (1g): Mp 241–242°C. (KBr, cm⁻¹): 3421(NH), 2928, 1596(C=N), 1515, 856; 1HNMR (DMSO-d₆, 300MHz): 11.7 (s. br., NH), 7.00-8.52 (m., 14H, Ar-H); 13C NMR (300 MHz, DMSO-d₆): 148.069, 147.460 145.633, 137.891, 134.737, 131.435, 131.103, 130.341, 129.631, 128.568, 126.862, 126.659, 124.165ppm.

8. 2-(2-Nitrophenyl)-4,5-diphenyl-1H-imidazole (1h): Mp 230-231°C. FTIR (KBr, cm⁻¹): 3421 (NH), 2928, 1596 (C=N), 1515, 1345, 856. ¹H NMR (300 MHz, DMSO-d₆): 12.10 (br. S., 1Н, NH), 7.9 - 8.2 (m, 14Н, Ar-H). ¹³C NMR (300 MHz, DMSO-d₆): 147.0, 141.0, 136.1, 130.6, 129.70, 128.4, 127.0, 126.9, 126.1, 125.4, 124.0, 122.0, 118.5ppm.

9. 4-(4,5-diphenyl-1H-imidazol-2-yl)benzaldehyde (1i): Mp 221-223°C. FTIR (KBr, cm⁻¹): 3300 (NH), 3052(C-H), 2980, 1593 (C=N), 1696 (C=O), 1504, 1345, 876. ¹H NMR (300 MHz, DMSO-d₆): 12.76 (br. S., 1Н, NH) 10.03 (br. S., 1Н, CHO), 7.22 - 8.19 (m, 14Н, Ar-H). ¹³C NMR (300 MHz, DMSO-d₆): 194.78, 135.50, 130.06, 129.56, 129.47, 128.72, 128.64, 128.57, 127.0, 128.51, 128.39, 128.22, 128.16, 128.08, 127.08ppm.

10. 2-(2,4-Dimethoxyphenyl)-4,5-diphenylimidazole (1j): Mp 217-219°C. FTIR (KBr, cm⁻¹): 3390 (NH), 3055(C-H), 3005, 2860, 1590 (C=N), 1515, 1274, 1028, 770. ¹HNMR (DMSO-d₆, 300MHz): 11.71 (br. S., 1Н, NH), 7.79-7.94 (m., 13H), 3.91(s., 3H, CH₃O), 3.83(s., 3H, CH₃O); 13C NMR (300 MHz, DMSO-d₆): 160.837157.204, 151.245, 143.350, 135.389, 134.512, 131.366, 129.792, 129.592, 129.506, 128.524, 128.315, 128.086, 127.437, 127.027, 126.865, 126.751, 126.265, 111.953, 105.584, 98.357, 55.890, 55.623ppm.

11. 2-(2,6-Dichlorophenyl)-4,5-diphenyl-1H-imidazole (1k): Mp 228-231°C. FTIR (KBr, cm⁻¹): 3390(NH), 3055(C-H), 2962, 2830, 1679 (C=N), 1559, 1194, 1096, 765, 695. ¹HNMR (DMSO-d₆, 300MHz): 11.82 (br. S., 1Н, NH), 7.79-7.94 (m., 13H); 13C NMR (300 MHz, DMSO-d₆): 160.737, 157.104, 151.345, 143.150, 135.289, 134.312, 131.166, 129.592, 129.392, 129.306, 128.224, 128.186, 128.115, 127.234, 127.122, 126.661, 126.453, 126.262, 111.751, 105.380, 98.151ppm.

12. 4-(4,5-diphenyl-1H-imidazol-2-yl)benzoic acid (1l): Mp 320-223°C. FTIR (KBr, cm⁻¹): 3400(NH), 3057(C-H), 2980, 2875, 1696(C=O), 1613(C=N), 1585, 1180, 1072, 721, 697. ¹HNMR (DMSO-d₆, 300MHz): 12.71 (br. S., 1Н, NH), 11.40 (br. S., 1Н, OH), 8.049-8.087 (d, J=8.8 Hz, 2.0 Hz, 2H), 8.191-8.229(d, J=8.8 Hz, 2.0 Hz, 2H), 7.32-7.74 (m, 10H, Ar-H); 13C NMR (300 MHz, DMSO-d₆): 167.359, 159.474, 154.258, 144.657, 136.104, 133.759, 131.919, 131.003, 130.879, 129.802, 129.230, 129.096, 128.772, 128.477, 128.181, 127.809, 127.704, 127.333, 126.570, 126.484, 126.141, 124.968ppm.

13. 2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole (1m): Mp 262-264°C. FTIR (KBr, cm⁻¹): 3148 (NH), 3082(C-H), 2959, 2912, 1601(C=N), 1502, 1128, 1072, 730, 694, 634. ¹HNMR (DMSO-d₆, 300MHz): 10.544 (br. S., 1Н, NH), 8.11 (d, J¼8.4 Hz, 2H, Ar-H), 7.294-7.562 (m, 12H, Ar-H); ¹³C NMR (300 MHz, DMSO-d₆): 144.428, 137.296, 135.008, 132.748, 130.927, 129.201, 128.772, 128.667, 128.562, 128.429, 128.200, 127.857, 127.075, 126.837, 126.598ppm.

14. 2-(2,5-Dimethoxyphenyl)-4,5-diphenyl-1H-imidazole (1n): Mp 181-183°C. FTIR (KBr, cm⁻¹): 3333(NH), 3059(C-H), 2962, 2834, 1648(C=N), 1524, 1221, 1175, 1047, 742, 696. ¹HNMR (DMSO-d₆, 300MHz): 11.90 (br. S., 1Н, NH), 7.43-8.132 (m, 13H, Ar-H), 3.91(s., 3H, CH₃O), 3.82(s., 3H, CH₃O); 13C NMR (300 MHz, DMSO-d₆): 159.435, 153.066, 150.235, 145.219, 142.950, 136.467, 136.076, 135.199, 131.156, 130.832, 128.725, 128.610, 128.543, 128.133, 127.666, 126.132, 126.446, 119.371, 115.014, 113.383, 112.764, 55.919, 55.470ppm.

15. 2-(3-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (1o): Mp 266-268°C. IR (KBr, cm⁻¹): 3390 (NH), 3054 (C-H), 2960, 2832, 1634(C=N), 1589, 1180, 1050, 889, 765, 697; ¹HNMR (DMSO-d₆, 300MHz): 10.97 (s, 1H, NH), 6.90-7.67 (m, 14H, Ar-H), 3.68 (s, 3H, CH₃); 13C NMR (300 MHz, DMSO-d₆): 166.424, 159.550, 158.940, 145.755, 142.010, 136.200, 134.300, 134.175, 131.623, 129.812, 128.667, 128.486, 128.191, 127.056, 119.667, 117.607, 114.213, 113.059, 112.335, 110.161, 55.203ppm.

16. 2-(4-Bromophenyl)-4,5-diphenyl-1H-imidazole (1p): Mp 249-252°C. FTIR (KBr, cm⁻¹): 3420(NH), 3027(C-H), 2924, 2835, 16034(C=N), 1501, 1126, 1069, 826, 728, 715, 696. ¹HNMR (DMSO-d₆, 300MHz): ) 11.54 (br. S., 1Н, NH), 8.057 (d, J¼ 8.2 Hz, 1.1 Hz, 2H), 7.702 (d, J¼ 8.2 Hz, 1.1Hz, 2H), 7.20-7.698 (m, 10H, Ar-H),; 13C NMR (300 MHz, DMSO-d₆): 144.457, 137.315, 134.970, 131.680, 131.356, 129.621, 129.516, 128.658, 128.410, 128.219, 127.876, 127.209, 127.094, 126.617, 121.392ppm.

4. Results and Discussion

As a result of the versatile biological activities of substituted imidazoles numerous classical methods for the synthesis of these compounds have been reported [28,29]. In a typical procedure, benzil or benzoin, aldehydes and ammonium acetate are condensed in the presence of strong protic acid such as H₃PO₄ [29], H₂SO₄ [30], HOAc [31] as well as organo catalyst in HOAc [32] under reflux conditions. These homogeneous catalysts present limitations due to the use of corrosive reagents and the necessity of neutralization of the strong acid media. In addition, the synthesis of these heterocycles in polar organic solvents such as ethanol, methanol, acetic acid, DMF and DMSO lead 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. Thus, design of solvent-free catalytic reaction has received tremendous attention in recent times in the area of green synthesis.[33]

2,4,5-Trisubstituted imidazole was prepared in quantitative yield by condensing benzyl (10mmol), ammonium acetate with benzaldehyde derivatives (10mmol), in the presence of brønsted ionic liquid diethylammonium hydrogen phosphate (0.513g, 3mmol), as a catalyst in solvent free condition at 100°C.

The stoichiometric amount of ammonium acetate in the preparation of 2,4,5-trisubstituted imidazoles is two. We can prepare 2,4,5-trisubstituted imidazoles using two equivalents of ammonium acetate but we observed in our experiment and other published papers, if we use inexpensive and available ammonium acetate having more than two equivalents, the reaction will show better results. Thus, a slight excess of the ammonium acetate was found to be advantageous and hence the molar ratio of benzil to ammonium acetate was kept at 1:4. The efficiency and versatility of the ionic liquid as a catalyst for the preparation of 2,4,5-trisubstituted imidazoles were demonstrated by the wide range of substituted and structurally diverse aldehydes to synthesize the corresponding products in high to excellent yields (Table 2).

Table 2.Comparison between our catalyst diethylammonium hydrogen phosphate and the other used catalyst

The presence of electron withdrawing groups afforded the corresponding 2,4,5-trisubstituted imidazoles in shorter reaction time with higher yields, however the presence of electron donating groups () on the aromatic aldehyde resulted in the corresponding products in low yields and the reaction was sluggish.

Scheme 2. Mechanism of Condensation Reaction between Benzil, Benzaldehyde, and Ammonium Acetate in the Presence of Diethylammonium Hydrogen Phosphate as Brønsted Acidic Ionic Liquid

5. Conclusion

Multicomponent reactions enjoy an outstanding status in organic and medicinal chemistry for their high degree of atom economy and application in the diversity-oriented convergent synthesis of complex organic molecules from simple and readily available substrates in a single vessel.

A simple highly versatile and efficient synthesis of 2,4,5-trisubstituted imidazoles is achieved by three component cyclocondensation of 1,2-dicarbonyl compounds, aldehydes and ammonium acetate as ammonia source in thermal solvent free condition using Brønsted acidic ionic liquid diethyl ammonium hydrogen phosphate as catalyst. The key advantages of this process are cost effectiveness of catalyst, reusability of catalyst, easy work-up and purification of products by non-chromatographic methods, excellent yields and very short time reactions.

References

[1]   | Saikat Das Sharma, Parasa Hazarika, Dilip Konwar An efficient and one-pot synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles catalyzed by InCl₃_3H₂O, Tetrahedron Letters 49, 2216-2220, 2008.
[2]   | Prisinano, T.; Law, H.; Dukat, M.; Slassi, A.; MaClean, N.; Demchyshyn, L.; Glennon, R. A. Bioorg. Med. Chem., 9, 613, 2001.
[3]   | Bhor, S.; Anilkumar, G.; Tse, M. K.; Klawonn, M.; Döbler, C.; Bitterlich, B.; Grotevendt, A.; Beller, M. Org. Lett., 7, 3393, 2005.
[4]   | Lambardino, J. G.; Wiseman, E. H. J. Med. Chem., 17, 1182, 1974.
[5]   | Takle, A. K.; Brown, M. J. B.; Davies, S.; Dean, D. K.; Francis, G.; Gaiba, A.; Hird, A. W.; King, F. D.; Lovell, P. J.; Naylor, A.; Reith, A. D.; Steadman, J. G.; Wilson, D. M. Bioorg. Med. Chem. Lett., 16, 378, 2006.
[6]   | Hojat Veisi, Ardashir Khazaei, Leila Heshmati, and Saba Hemmati, Convenient One-Pot Synthesis of 2,4,5-Triaryl-1H-imidazoles Bull. Korean Chem. Soc., 33, 4, 1231, 2012.
[7]   | Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. F.; Kumar, S.; Green, D.; McNulty, D.; Blumenthal, M. J.; Keys, J. R.; Vatter, S. W. L.; Strickler, J. E.; McLaughlin, M. M.; Siemens, I. R.; Fisher, S. M.; Livi, G. P.; White, J. R.; Adams, J. L.; Young, P. R. Nature, 372, 739, 1994.
[8]   | Takle, A. K.; Brown, M. J. B.; Davies, S.; Dean, D. K.; Francis, G.; Gaiba, A.; Hird, A. W.; King, F. D.; Lovell, P. J.; Naylor, A.; Reith, A. D.; Steadman, J. G.; Wilson, D. M. Bioorg. Med. Chem. Lett., 16, 378, 2006.
[9]   | Khanna, I. K.; Weier, R. M.; Yu, Y.; Xu, X. D.; Koszyk, F. J.; Collins, P. W.; Koboldt, C. M.; Veenhuizen, A. W.; Perkins, W. E.; Casler, J. J.; Masferrer, J. L.;Zhang, Y. Y.; Gregory, S. A.; Seibert, K.; Isakson, P. C. J. Med. Chem., 40, 1634, 1997.
[10]   | Lange, J. H. M.; Van Stuivenberg, H. H.; Coolen, H. K. A. C.; Adolfs, T. J. P.; McCreary, A. C.; Keizer, H. G.; Wals, H. C.; Veerman, W.; Borst, A. J. M.; de Loof, W.; Verveer, P.C.; Kruse, C. G. J. Med. Chem., 48, 1823, 2005.
[11]   | Gallagher, T. F.; Fier-Thompson, S. M.; Garigipati, R. S.; Sorenson, M. E.; Smietana, J. M.; Lee, D.; Bender, P. E.; Lee, J. C.; Laydon, J. T.; Griswold, D. E.; Chabot-Fletcher, M. C.; Breton, J. J.; Adams, J. L. Bioorg. Med. Chem. Lett., 5, 1171, 1995.
[12]   | de Laszlo, S. E.; Hacker, C.; Li, B.; Kim, D.; MacCoss, M.; Mantlo, N.; Pivnichny, J. V.; Colwell, L.; Koch, G. E.; Cascieri, M. A.; Hagmann, W. K. Bioorg. Med. Chem. Lett., 9, 641, 1999.
[13]   | Eyers, P. A.; Craxton, M.; Morrice, N.; Cohen, P.; Goedert, M. Chem. Biol., 5, 321, 1998.
[14]   | Newman, M. J.; Rodarte, J. C.; Benbatoul, K. D.; Romano, S. J.; Zhang, C.; Krane, S.; Moran, E. J.; Uyeda, R. T.; Dixon, R.; Guns, E. S.; Mayer, L. D. Cancer Res. 60, 2964, 2000.
[15]   | Antolini, M.; Bozzoli, A.; Ghiron, C.; Kennedy, G.; Rossi, T.; Ursini, A. Bioorg. Med. Chem. Lett. 9, 1023, 1999.
[16]   | Wang, L.; Woods, K. W.; Li, Q.; Barr, K. J.; McCroskey, R. W.; Hannick, S. M.; Gherke, L.; Credo, R. B.; Hui, Y.-H.; Marsh, K.; Warner, R.; Lee, J. Y.; Zielinsky- Mozng, N.; Frost, D.; Rosenberg, S. H.; Sham, H. L. J. Med. Chem., 45, 1697, 2002.
[17]   | Maier, T.; Schmierer, R.; Bauer, K.; Bieringer, H.; Buerstell, H.; Sachse, B. U.S. Patent 4820335, 1989; Chem. Abstr., 111, 19494w, 1989.
[18]   | Chowdhury, S.; Mohan, R. S.; Scott, J. L. Reactivity of ionic liquids, Tetrahedron, 63, 2363, 2007.
[19]   | Adel A. Marzouk, Vagif M. Abbasov and Avtandil H. Talybov, Short Time One-Spot Synthesis of 2, 4, 5-Trisubstituted-Imidazoles Using Morpholinium Hydrogen Sulphate as Green and Reusable Catalysts, Chemistry Journal, 02, 05, 179-184, 2012.
[20]   | Kühl, O., The chemistry of functionalised N-heterocyclic carbenes, Chem. Soc. Rev., 36, 592, 2007.
[21]   | Zhi-Bin Zhou, Hajime Matsumoto, and Kuniaki TatsumiChem., Cyclic Quaternary Ammonium Ionic Liquids with Perfluoroalkyltrifluoroborates: Synthesis, Characterization, and Properties, Eur. J., 12, 2196-2212, 2006.
[22]   | R. D. Rogers, K. R. Seddon, Ionic Liquids IIIA: Fundamentals, Progress, Challenges, and Opportunities (ACS Symposium Series 901), American Chemical Society, Washington, DC, 2005.
[23]   | J. Dupont, R. F. de Souza, P. A. Z. Suarez, Ionic Liquid (Molten Salt) Phase Organometallic Catalysis., Chem. Rev., 102, 3667-3692, 2002.
[24]   | R. A. Sheldon, R. M. Lau, M. J. Sorgedrager, F. van-Rantwijk, K. R. Seddon, Biocatalysis in ionic liquids, Green Chem., 4, 147-151, 2002.
[25]   | C.C. Tzschucke, C. Markert, W. Bannwarth, S. Roller, A. Hebel, R. Haag, Modern separation techniques for the efficient workup in organic synthesis, Angew. Chem., 114, 4136-4173, 2002.
[26]   | E. R. Cooper, C. D. Andrews, P. S. Wheatley, P. B. Webb, P. Wormald & R. E. Morris, Ionic liquids and eutectic mixtures as solvent and template in synthesis of zeolite analogues. Nature, 430, 1012-1016, 2004.
[27]   | Tzi-Yi Wu, Shyh-Gang Sua, Shr-Tusen Gung, Ming-Wei Lina, Yuan-Chung Linc, Chao-Anx Lai, I-Wen Suna Ionic liquids containing an alkyl sulfate group as potential electrolytes, Electrochimica Acta 55, 4475-4482, 2010.
[28]   | Freedman J., Loscalzo J. New Therapeutic Agent in Thrombosis and Thrombolysis, Third Edition, Taylor and Francis, 2009.
[29]   | Shaterian H. R., Mohammad R., An environmental friendly approach for the synthesis of highly substituted imidazoles using Brønsted acidic ionic liquid, N-methyl-2-pyrrolidonium hydrogen sulfate, as reusable catalyst, Journal of Molecular Liquids, 160, 40-49, 2011.
[30]   | Shaterian H. R., Oveisi A. R., PPA-SiO₂ as a Heterogeneous Catalyst for Efficient Synthesis of 2-Substituted-1,2,3,4-tetrahydro-4-quinazolinones under Solvent-free Conditions, Chin. J. Chem., 27, 2418, 2009.
[31]   | Shaterian H.R., A. Hossienian, M. Ghashang, Ferric Hydrogen Sulfate as an Efficient Heterogeneous Catalyst for Environmentally Friendly Greener Synthesis of 1,8-Dioxo-Octahydroxanthenes, Turk. J. Chem. 2, 233, 2009.
[32]   | Freemantle M., Introduction to Ionic Liquids, Royal Society of chemistry, Cambridge CB4 OWF, UK, 2009.
[33]   | Ali M., Hossein K., Reza S., Behrooz M., Hamed R., Hassanali M., Zeinalabedin S., Saman D., A highly efficient and reusable heterogeneous catalyst for the one-pot synthesis of tetrasubstituted imidazoles, Applied Catalysis A: General, 429-430, 73-78, 2012.
[34]   | Sharma S. D., Hazarika P., Konwar D. An efficient and one-pot synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles catalyzed by InCl₃.3H₂O, Tetrahedron Letters, 49, 2216-2220, 2008.
[35]   | Joshi R. S., Mandhane P. G., Shaikh M. U., Kale R. P., Gill C.H. Chin. Chem. Lett. 21,429, 2010.
[36]   | Khosropour R., Ultrasound-promoted greener synthesis of 2,4,5-trisubstituted imidazoles catalyzed by Zr(acac)₄ under ambient conditions" Ultrason.Sonochem., 15, 659, 2008.
[37]   | Samai S., Nandi G. C., Singh M. S., L-Proline: an efficient catalyst for the one pot synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles. Tetrahedron, 65, 10155, 2009.
[38]   | Siddiqui S. A., Narkhede U. C., Palimkar S. S., Daniel T., Lahoti R. J., Srinivasan K.V., Room temperature ionic liquid promoted improved and rapid synthesis of 2,4,5-triaryl imidazoles from aryl aldehydes and 1,2-diketones or α-hydroxyketone, Tetrahedron, 61, 3539, 2005.