Tetrahedron Letters 52 (2011) 4642–4645 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet Synthesis of 1,2,4,5-tetrasubstituted imidazoles using silica-bonded propylpiperazine N-sulfamic acid as a recyclable solid acid catalyst Khodabakhsh Niknam ⇑, Abdollah Deris, Fatemeh Naeimi, Fatemeh Majleci Chemistry Department, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran a r t i c l e i n f o Article history: Received 7 May 2011 Revised 21 June 2011 Accepted 27 June 2011 Available online 2 July 2011 Keywords: Silica-bonded propylpiperazine-N-sulfamic acid 1,2,4,5-Tetrasubstituted imidazoles Aldehydes Solvent-free Catalyst One-pot synthesis a b s t r a c t A simple and efficient procedure for the preparation of silica-bonded propylpiperazine-N-sulfamic acid (SBPPSA) by the reaction of 3-piperazine-N-propylsilica (3-PNPS) and chlorosulfonic acid in chloroform is described. Silica-bonded propylpiperazine-N-sulfamic acid is employed as a recyclable catalyst for the synthesis of highly substituted imidazoles from the reaction of benzil, aromatic aldehydes, ammonium acetate and amines under solvent-free conditions. The heterogeneous catalyst was recycled for five runs upon the reaction of benzil, 4-methylbenzaldehyde, benzylamine, and ammonium acetate without losing its catalytic activity. Ó 2011 Elsevier Ltd. All rights reserved. The imidazole ring system is one of the most important substructures found in a large number of natural products and pharmacologically active compounds.1–5 The members of this class of compounds are known to possess NO synthase inhibition and antifungal, antimycotic, antibiotic, antiulcerative, antibacterial, antitumor, and CB1 receptor antagonistic activities.6,7 Various substituted imidazoles act as inhibitors of p38 MAP kinase8 and B-Raf kinase,9 glucagon receptors,10 plant growth regulators,11 therapeutic agents,1 and pesticides.12 Industrial and academic studies for the preparation of 1,2,4,5-tetrasubstituted imidazoles have led to numerous methodologies for the synthesis of these compounds.13,14 The most wellknown and classical method for preparation of these compounds involves four-component condensations of a 1,2-diketone derivative with an aldehyde, primary amine, and ammonium acetate in refluxing HOAc, which is known to have poor yields and long reaction times.15 Improvements occurred using other acidic conditions, such as silica gel,16 zeolite,16 alumina,17 NaHSO4–SiO2,18 HClO4
SiO2,19 molecular iodine,20,21 FeCl3
6H2O,22 BF3
SiO2,23 InCl3
3H2O,24 K5CoW12O40
3H2O,25 copper acetate,26 trifluroacetic acid,27 L-proline,28 zeolite supported reagents,29 mercaptopropylsilica (MPS),30 Bronsted acidic ionic liquid,31 MCM-41 or p-TsOH,32 and 1-butyl-3-methylimidazolium bromide33 under microwave-irradiation, solvent-free or classical conditions. ⇑ Corresponding author. Fax: +98 771 4545188. E-mail addresses: niknam@pgu.ac.ir, khniknam@gmail.com (K. Niknam). 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.06.105 In continuation of our studies on the design and application of solid acid catalysts in organic transformations,34–38 herein, we describe the preparation of silica-bonded propylpiperazine-N-sulfamic acid (SBPPSA) and its application as a catalyst for the synthesis of 1,2,4,5-tetrasubstituted imidazoles. Silica-bonded propylpiperazine-N-sulfamic acid (SBPPSA) was prepared by the reaction of 3-piperazine-N-propylsilica (3-PNPS) with chlorosulfonic acid in chloroform as illustrated in Scheme 1. To study the effect of catalyst loading on the four component condensation reactions for the synthesis of 1,2,4,5-tetrasubstituted imidazoles, the reaction of benzil, 4-methylbenzaldehyde, benzylamine, and ammonium acetate was chosen as a model reaction (Table 1). The results show clearly that SBPPSA is an effective catalyst for this four component condensation reaction. The best catalytic loading of SBPPSA was 0.25 g in terms of reaction time and isolated yield. The optimized conditions were chosen as follows: benzil (1 mmol), aldehyde (1 mmol), amine (1 mmol), ammonium acetate (1 mmol), and SBPPSA (0.25 g, equal to 0.31 mmol of H+) and heated under solvent-free conditions at 140 °C (Scheme 2). The lower temperature gave the corresponding product in lower yield and longer reaction time (Table 1, entries 5–6). A wide range of aromatic aldehydes were employed and all imidazoles were obtained in high to excellent yields, which demonstrated that this is a general method that tolerates both electron-withdrawing and electron-donating constituents. Another important aspect is that various aliphatic and aromatic amines, such as aniline, benzyl, cyclohexyl, and ethyl amine were employed 4643 K. Niknam et al. / Tetrahedron Letters 52 (2011) 4642–4645 OH O Cl (MeO)3Si OH SiO2 toluene, reflux, 18 h OH Cl O Si SiO2 O (3-SPCl) H N N H O N-SO3H O O 1) ClSO3H/ CHCl3 /4 h N O Si SiO2 SiO2 2) wash with EtOH O Si N NH O (SBPPSA) (3-PNPS) Scheme 1. Preparation of silica-bonded propylpiperazine-N-sulfamic acid (SBPPSA). Table 1 Condensation reaction of benzil, 4-methylbenzaldehyde, benzylamine, and ammonium acetate in the presence of different amounts of SBPPSA as catalyst under solvent-free conditions and temperaturesa Entry Catalyst loading (g) Temperature (°C) Time (h) Conversionb,c (%) 1 2 3 4 5 6 7 0.05 0.1 0.2 0.25 0.25 0.25 0.3 140 140 140 140 100 80 140 7 4 1.5 1 2 3 1 70 80 85 95 75 70 95 (63) (74) (80) (90) (69) (65) (89) a Reaction conditions: benzil (1 mmol), 4-methylbenzaldehyde (1 mmol), benzylamine (1 mmol), and ammonium acetate (2 mmol) under solvent-free conditions at 140 °C. b Determined by GC analysis. c Isolated yields in parenthesis. in this four component condensation reaction under optimized conditions (Table 2). In each case, no side product formation (for example, 2,4,5-trisubstituted imidazoles) was observed, as is normally the case in such reactions under the influence of strong acids. This method not only affords the products in excellent yields but also avoids the problems associated with catalyst cost, handling, safety, and pollution. The results illustrate the high ability of this method for the synthesis of 1,2,4,5-tetrasubstituted imidazoles with different groups. To show the advantages of SBPPSA as a catalyst in this reaction, our results and reaction conditions for synthesis of 1-benzyl-2-(4methylphenyl)-4,5-diphenylimidazole (1a) were compared with previously reported data in Table 3. The results show that our method is quite comparable with the former methods in yields and reaction times. The possibility of recycling the catalyst was examined using the reaction of benzil, benzaldehyde, aniline, and ammonium acetate under optimized conditions. Upon completion, the reaction mixture was filtered and the solid was washed with ethanol, and the recycled catalyst was saved for the next reaction. The recycled catalyst could be reused five times without any further treatment. No observation of any appreciable loss in the catalytic activity of SBPPSA was observed (Fig. 1). In conclusion, we have shown that silica-bonded propylpiperazine-N-sulfamic acid (SBPPSA), which can be prepared from commercially available and cheap starting materials, catalyzed efficiently this four component condensation reactions for the synthesis of 1,2,4,5-tetrasubstituted imidazole derivatives. The simplicity of the procedure, eco-friendly, non-volatile, easy handling, safety and reusability of catalyst are the advantages of this method. All the products were characterized by comparison of their IR, 1 H NMR and 13C NMR spectroscopic data and their melting points with reported values.11–32 3-piperazine-N-propylsilica (3-PNPS) was prepared according to the procedure reported by Dey.39 Synthesis of silica-bonded propylpiperazine-N-sulfamic acid (SBPPSA): To a magnetically stirred mixture of 3-piperazine-N-propylsilica (3-PNPS) (25 g) in CHCl3 (50 mL), chlorosulfonic acid (25 mL) was added dropwise at 0 °C over 2 h. After the addition was complete, the mixture was stirred for another 2 h and then, the mixture was filtered and washed with ethanol (50 mL) and dried at room temperature to afford silica-bonded propylpiperazine-N-sulfamic acid (SBPPSA) as a cream powder (26.8 g). Elemental analysis showed the S content to be 2.85%; C, 8.70%; H, 2.4%; N, 2.1%. The number of H+ sites of SBPPSA was determined by pH-ISE conductivity titration (Denver Instrument Model 270) and found to be 1.25 H+ sites per 1 g of solid acid at 25 °C (pH 2.30). General procedure: To a mixture of benzil (1 mmol), aldehyde (1 mmol), amine (1 mmol), and ammonium acetate (2 mmol) was added SBPPSA (0.25 g, equal to 0.31 mmol of H+) and heated at SiO2 Ph N N-SO3H O (0.25 g) + Ar-CHO + R-NH2 + NH4OAc Ph O O Si O O (1 mmol) (1 mmol) (2 mmol) Solvent-free Ph N Ph N R Ar 140 oC (1 mmol) 1 Scheme 2. Synthesis of 1,2,4,5-tetrasubstituted imidazoles catalyzed by SBPPSA. 4644 K. Niknam et al. / Tetrahedron Letters 52 (2011) 4642–4645 Table 2 Preparation of various 1,2,4,5-tetrasubstituted imidazoles in the presence of SBPPSA under solvent-free conditions at 140 °Ca Entry Ar R Product Time (min) Yieldb (%) Mp (°C) Lit. mp (°C) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 4-Me-C6H44-Cl-C6H42-Cl-C6H43,4,5-(MeO)3-C6H23-HO-C6H44-MeS-C6H44-NC-C6H44-O2N-C6H43-Br-C6H44-NC-C6H44-Me-C6H4C6H54-Me-C6H44-MeO-C6H44-Cl-C6H44-O2N-C6H44-HO-C6H44-Cl-C6H44-NC-C6H4- C6H5-CH2– C6H5-CH2– C6H5-CH2– C6H5-CH2– C6H5-CH2– C6H5-CH2– C6H5-CH2– C6H5– C6H5– C6H5– 4-Br-C6H4– C6H11– C6H11– C6H11– C6H11– C6H11– C6H11– Et– Et– 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m 1n 1o 1p 1q 1r 1s 60 70 90 85 75 60 75 120 150 150 150 300 240 120 90 320 260 90 90 90 92 90 90 89 86 87 89 85 72 88 70 75 75 78 77 78 72 73 165–167 162–164 140–142 185–187 232–235 164–166 208–210 212–214 143–145 194–196 219–221 168–170 164–166 217–219 197–199 215–217 283–285 310–312 155–157 165–16622 162–16423 140–14223 184–18619 — — — 159–16027 — — — 167–16922 162–16422 — — — — — — a Reaction conditions: benzil (1 mmol), aromatic aldehyde (1 mmol), amine (1 mmol), ammonium acetate (2 mmol), SBPPSA (0.25 g, equal to 0.31 mmol of H+), solvent-free at 140 °C. b Isolated yield. Table 3 Synthesis of 1-benzyl-2-(4-methylphenyl)-4,5-diphenyl-imidazole 1a using different catalysts and reaction conditions a Entry Solvent and catalyst (loading) Time (min) Yielda (%) Ref. 1 2 3 4 5 6 7 8 9 MW, solvent-free, zeolite HY (5 mol %) Solvent-free, 140 °C, NaHSO4–SiO2 (18.6 g) Solvent-free, 140 °C, HClO4.SiO2 (1 mol %) MeOH, rt, InCl3.3H2O (10 mol %) Solvent-free, 140 °C, K5CoW12O40.3H2O (0.1 mol %) MeOH, 60 °C, L-proline (15 mol %) Reflux in AcOH, MCM-41(0.04 g) [Bmim]Br (0.5 g, 2.28 mmol), solvent-free, 140 °C Solvent-free, 140 °C, SBPPSA (equal to 0.31 mmol H+) 6 120 6 480 120 540 32 120 60 85 92 90 75 95 88 82 90 90 16 18 19 24 25 28 32 33 This work Isolated yield. Acknowledgment We are thankful to Persian Gulf University Research Council for partial support of this work. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2011.06.105. References and notes Figure 1. 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