Chinese Chemical Letters  2014, Vol.25 Issue (01):155-158   PDF    
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Li-Ping Duan, Qiang Li, Ning-Bo Wu, Dong-Fang Xu, Hao-Bing Zhang.Synthesis of 2,5-disubstitued benzimidazole using SnCl2-catalyzed reduction system at room temperature[J]. Chin. Chem. Lett., 2014,25(01): 155-158   
Synthesis of 2,5-disubstitued benzimidazole using SnCl2-catalyzed reduction system at room temperature
Li-Ping Duana , Qiang Lia,b, Ning-Bo Wua, Dong-Fang Xub, Hao-Bing Zhanga    
* Corresponding authors at:a National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, WHO Collaborating Centre for Malaria, Schistosomiasis, and Filariasis, Key laboratory of Parasitology and Vector Biology at National Institute of Parasitic Diseases, Shanghai 200025, China;
b Shanghai Normal University, Shanghai 200005, China
Received:2013-9-2, Revised:2013-9-13, online:2013-11-8.
E-mail addresses:lipingduan@yahoo.com
Abstract: Stannous chloride dihydrate is used as an efficient catalyst in reductive cyclization of 2-nitro-5-substituted aniline Schiff base leading to stable 2,5-disubstitued benzimidazole derivatives in excellent yields with good purity. It provides a novelmethod of synthesis of 2,5-disubstitued benzimidazole under reductive system at room temperature.
Key words: Stannous chloride dihydrate     Reductive cyclization     Benzimidazole derivatives    
1. Introduction

The benzimidazole structural motif plays very important roles in numerous pharmaceutical molecules with a wide range of biological properties including anticancer, antihistaminic, antihypertensive, antifungal, and antiviral effects [1, 2, 3]. Consequently, the synthesis of the heterocyclic nucleus has gained great importance. Many methods for the synthesis of benzimidazoles have been discovered and reported. There are two general methods for the synthesis of benzimidazoles. One is oxidative cyclodehydrogenation of aniline Schiff base with various oxidative reagents [4, 5, 6]. The other method is the coupling of a carboxylic acid with phenylenediamine under high temperature [7, 8]. However, these synthetic protocols suffer from one or more disadvantages such as the use of dangerous or toxic oxide reagents, high temperature, strong acid conditions, prolonged reaction times, cumbersome multi-step processes, or the formation of side products. As a consequence, the introduction of new methods with technical improvements to overcome the limitations is still an important experimental challenge [9, 10]. To the best of our knowledge, few studies have related to the synthesis of benzimidazole derivatives under reductive atmosphere [11]. The advantages of using the reduction system include mild reaction conditions, elimination of toxic oxide reagents, operational simplicity, and high yields of products.

In the last decade, stannous chloride dihydrate has gained special attention as a mild and highly chemoselective reducing agent for various organic transformations. For example, SnCl2⋅2H2O is still popularly used to selectively reduce aromatic nitro group to amino for its eco-friendly nature, affordability, high reactivity, and safety profile. A significant breakthrough in the field of reductive cylization heterocyclic compounds was based on stannous chloride dihydrate. In 2002, Bates and Li reported cyclization products produced for nitroarene reduction to aminoarene using SnCl2⋅2H2O [12]. In 2006, Roy and co-workers reported that a one-step reductive transformation of 2-(2-nitrophenyl)- 3H-quinazolin-4-one in various alcohols furnished the desired tetracyclic product with SnCl2⋅2H2O [13]. Recently, the method of reductive cyclization of 2-nitrobenzamides with haloketones or keto acids mediated by SnCl2⋅2H2O was reported by Shi [14]. In this paper, we wish to describe a new route to synthesize benzimidazole derivatives via novel reductive cyclization of 2-nitro-5-substituted aniline Schiff base by SnCl2⋅2H2O at room temperature.

2. Experimental

From the starting material 2-nitro-5-substituted anilines (1), through the intermediate 2-nitro-5-substituted aniline Schiff bases (2), the target compounds 2,5-disubstitued benzimidazoles (3a-i) were obtained with stannous chloride dehydrate [15]. The details for the syntheses are shown in Scheme 1. The structures of 3a-i were characterized by mass spectrometry and NMR. The molecular structure of 2-methyl-5-phenylthio-benzimidazole was confirmed by X-ray analysis (Fig. 1). The crystallographic data have been assigned the deposition numbers at the Cambridge crystallographic data Centre (CCDC945241).

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Scheme 1.Synthesis of 3. Reaction conditions: (a) POCl3, R2CON(CH3)2, toluene, reflux; (b) SnCl2⋅2H2O, ethanol, 25℃.

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Fig. 1.Molecular structure of 2-methyl-5-phenylthio-benzimidazole.
Typical experimental procedure for synthesis 2,5-disubstitued benzimidazole derivatives: A solution of 2-nitro-5-substituted aniline (1 mmol), difference substituted N,N-dimethylamine (1.5 mmol) and phosphorus oxychloride (2.5 mL) in toluene (10 mL) was refluxed for 4 h at 120 ℃. The mixture was cooled and poured onto crushed ice, then made basic with sodium bicarbonate solution. The organic layer was washed with water, then dried over sodium sulfate and evaporated under vacuo. The crude material was purified by chromatography on silica gel column using ethyl acetate and petroleum ether (1:1 by volume) as the eluent. The solvent was removed under reduced pressure to afford the different substituted N,N-dimethyl-N0-(2-nitrophenyl) imidamide intermediates (2). Next, a mixture of 2 (1 mmol) and stannous chloride dihydrate (4 mmol) in ethanol (10 mL) was stirred at room temperature for 1 h. The solvent was removed under vacuo and the mixture was dissolved in dichloromethane and washed with sodium bicarbonate solution. The organic layer was then dried over sodium sulfate and evaporated in vacuo. The crude material was purified by chromatography on silica gel column using ethyl acetate and petroleum ether (1:2 by volume) as eluent. The solvent was removed under reduced pressure to give 2,5-disubstitued benzimidazoles 3.

3. Results and discussion

The reaction can usually be carried out effectively in various solvents such as ethanol, acetonitrile, acetic acid and acetone. So, we selected o-nitro aniline and N,N-dimethylacetamine as model substrates to optimize the experimental conditions for the proposed reductive cyclization reaction. The results showed that at room temperature in 1 h the best solvent was ethanol, and the reaction preceded smoothly in high yield (92.1%). Acetonitrile (76%) and acetic acid (75%) exhibited almost the same activity, and acetone showed poor activity (48%) in 1 h (Fig. 2). Additionally, the relationship between the molecules and spectral changes was discussed, and the reaction process was monitored using UV-vis spectroscopy. The resulting absorption is shown in Fig. 3. The addition of 4 equiv. of stannous chloride dihydrate to the solution of N,N-dimethyl-N'-(2-nitrophenyl)acetimidamide intermediate that is generated from the condensation of o-nitro aniline and N,N-dimethylacetamine caused a decrease in the absorbance at 275 nm. The absorption peak at 375 nm disappeared, which can be assigned to π-π* transition due to C=N bonds in conjugation with phenyl group. Meanwhile, a new increased absorption peak at 280 nm can be attributed to the 2-methylbenzimidazole. 1H NMR experiments were also carried out to confirm the formation of benzimidazole derivative (Fig. 4). The N,N-dimethyl resonance peak (3.01 ppm) of N,N-dimethyl-N'-(2-nitrophenyl)acetimidamide disappeared, and a new equal peak centered at 2.67 ppm appeared, which could be assigned to the NH protons of the benzimidazole. This result indicated that benzimidazole was formed.

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Fig. 2.Solvent effect for synthesis of 2-methylbenzimidazole using SnCl2⋅2H2O catalysts by HPLC.

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Fig. 3.The reaction process of N,N-dimethyl-N'-(2-nitrophenyl)acetimidamide with the addition of SnCl2⋅2H2O in ethanol at 25℃ was monitored using UV–vis spectroscopy in 1 h (the time interval is 15 min each trace in 1 h).

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Fig. 4.1H NMR spectra of N,N-dimethyl-N'-(2-nitrophenyl)acetimidamide (a) and 2-methylbenzimidazole (b) in CDCl3.

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Scheme 2.Potential mechanism for benzimidazole formation.

Table 1
Synthesis of 2,5-disubstitued benzimidazole (3a–3i).
Regarding the mechanism of the reductive cyclization reaction process, we speculated that 2-amino-5-substituted aniline Schiff base intermediate formed first through SnCl2⋅2H2O-assisted reduction (Scheme 2), followed by a very rapid elimination of HN(CH3)2 thus resulting in a stable imidazole ring. Finally, the generated base HN(CH3)2 is scavenged by the acid to produce salt in water. This catalyst SnCl2⋅2H2O promotes two different transformations in one pot: the conversion of nitro into amino through reduction, and catalytic 2-amino-5-substituted aniline Schiff base of benzimidazole intermediates leading to 2,5- disubstitued benzimidazole derivatives.

Furthermore, the process works well for the synthesis of various substituted benzimidazoles. As the results shown in Table 1, SnCl2 alcohol solution catalyst with various o-nitro anilines successfully afforded the corresponding benzimidazoles. Both 2-alkyl- and 2- aryl-substitued benzimidazoles were successfully produced in very high yields. In addition, 5-substituted derivatives were also produced successfully. 2-Nitroaniline containing electron donating substitution (such as phenylthio) shows a fast reaction time, because it increases amino nucleophilic character of 2-amino-5- substituted aniline Schiff base intermediate. In this protocol, all synthesized products were obtained in excellent yield.

4. Conclusion

In conclusion, treatment of 2-nitro-5-substituted aniline with difference substituted N,N-dimethylamine gives 2-nitro-5-substituted aniline Schiff base, and the adducts are readily converted into benzimidazoles by stannous chloride dihydrate in ethanol condition. It will possibly find wide application in organic synthesis.

Acknowledgments

This project is supported by Shanghai Municipal Natural Science Foundation (No. 12ZR1434900), International Collaboration on Drugs and Diagnostics Innovation of Tropical Diseases in China (International S&T Cooperation 2010DFB73280).

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[15] 2-Methyl-5-phenylthio-benzimidazole (3a): white solid, mp: 159.6-162.6 ℃, IR (KBr, cm-1): v 3260, 3165, 2981, 1482, 1361. 1H NMR (400 MHz, CDCl3): δ7.490 (d, 2H, J = 8.0 Hz), 7.305-7.284 (m, 1H), 7.222 (d, 1H, J = 8.0 Hz), 7175-7.109 (m, 4H), 2.620 (s, 3H); 13C NMR (100 MHz, CDCl3): d154.6, 139.8, 122.4, 115.8, 14.1; LC-MS [M+H+]: 241.23. 2-Ethyl-5-phenylthio-benzimidazole (3b): white solid, mp: 135.3-137.8 ℃, IR (KBr, cm-1): v 3245, 3163, 3054, 2982, 1481, 1420. 1H NMR (400 MHz, CDCl3): δ7.280 (s, 1H), 7.236-7.109 (m, 5H), 7.087 (d, 1H, J = 8.0 Hz), 6.748 (d, 1H, J = 8.0 Hz), 2.426-2.370 (m, 2H), 1.243-1.206 (t, 3H); 13C NMR (100 MHz, CDCl3): δ151.6, 137.8, 122.4, 116.1, 22.4, 13.9; LC-MS[M+H+]: 255.25. 2-Phenyl-5-phenylthio-benzimidazole (3c): white solid, mp: 146.3-148.4 ℃. IR (KBr, cm-1): v 3268, 3174, 3054, 1452, 1420. 1H NMR (400 MHz, CDCl3): δ7.823 (d, 2H, J = 8.00 Hz), 7.645 (s, 1H), 7.512-7.254 (m, 9H), 7.131 (d, 1H, J = 8.00 Hz); 13C NMR (100 MHz, CDCl3): δ151.8, 138.8, 123.4, 115.8; LC-MS [M+H+]: 303.29. 2-Methyl-benzimidazole (3d): pale yellow solid, mp: 164.3-165.4 ℃, IR (KBr, cm-1): v 3260, 3174, 3054, 1452, 1420. 1H NMR (400 MHz, CDCl3): δ7.523 (d, 2H, J = 9.20 Hz), 7.222-7.178 (m, 2H), 2.671 (s, 1H), 2.612 (s, 3H); 13C NMR (100 MHz, CDCl3): δ151.6, 137.8, 122.4, 115.8, 13.9; LC-MS [M+H+]: 133.22. 2-Ethyl-benzimidazole (3e): pale yellow solid, mp: 122.7-125.6 ℃, IR (KBr, cm-1): v 3264, 3187, 3008, 1434, 1425, 1120. 1HNMR (400 MHz, CDCl3): δ7.527 (d, 2H, J = 9.20 Hz), 7.222-7.164 (m, 2H), 2.964-2.907 (m, 2H), 1.432-1.389 (t, 3H); 13C NMR (100 MHz, CDCl3): d151.9, 139.8, 125.4, 119.8, 20.8, 15.1; LC-MS [M+H+]: 147.24. 2-Phenyl-benzimida-zole (3f): pale yellow solid, mp 293.3-296.4 ℃. IR (KBr, cm-1): v 3256, 3174, 1452, 1444. 1H NMR (400 MHz, CDCl3): δ7.609 (d, 2H, J = 9.20 Hz), 7.481-7.438 (m, 2H), 7.397-6.958 (m, 5H); 13C NMR (100 MHz, CDCl3): d150.6, 139.3, 130.8, 129.3, 128.8, 123.9, 115.7; LC-MS [M+H+]: 195.30. 2-Methyl-5-chloro-benzimidazole (3g): white solid, mp 205.1-207.4 ℃. IR (KBr, cm-1): v 3420, 3000, 2987, 2931, 1465, 1399. 1HNMR (400 MHz, CDCl3): δ7.621 (d, 1H, J = 2.4 Hz), 7.552 (d, 1H, J = 8.6 Hz), 7.25 (dd, 1H, J = 8.6, 2.4 Hz), 2.604 (s, 3H); 13C NMR (100 MHz, CDCl3): δ151.3, 139.2, 138.6, 128.7, 123.4, 115.0, 114.8, 15.2; LC-MS [M+H+]: 167.24. 2-Ethyl-5-chloro-benzimidazole (3h): white solid, mp 185.1-186.2 ℃. IR (KBr, cm-1): v 3425, 3020, 2990, 1465, 1399. 1H NMR (400 MHz, CDCl3): δ7.622 (d, 1H, J = 2.4 Hz), 7.562 (d, 1H, J = 8.6 Hz), 7.23 (dd, 1H, J = 8.6, 2.4 Hz), 2.446-2.380 (m, 2H), 1.263-1.256 (t, 3H); 13C NMR (100 MHz, CDCl3): δ151.3, 139.2, 138.6, 128.7, 123.4, 115.0, 114.8, 24.6, 15.2; LC-MS [M+H+]: 181.55. 2-Phenyl-5-chloro-benzimidazole (3i): white solid, mp 212.1-213.0 ℃, IR (KBr, cm-1): v 3418, 3062, 3054, 1463, 1438, 1400. 1H NMR (400 MHz, CDCl3): δ 8.192 (d, 2H, J = 8.0 Hz), 7.653-7.492 (m, 5H), 7.22 (dd, 1H, J = 8.0, 2.4 Hz); 13C NMR (100 MHz, CDCl3): δ 154.2, 143.5, 139.1, 132.4, 130.1, 128.9, 128.1, 127.5, 123.3, 115.6; LC-MS [M+H+]: 244.65.
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Synthesis of 2,5-disubstitued benzimidazole using SnCl2-catalyzed reduction system at r...
Li-Ping Duan , Qiang Li, Ning-Bo Wu, Dong-Fang Xu, Hao-Bing Zhang