Synthesis of some benzimidazole-substituted benzotriazoles

RESEARCH ARTICLE A. Mobinikhaledi, N. Foroughifar, P. Mohammadlu and M. Kalhor, S. Afr. J. Chem., 2008, 61, 141–143, <http://journals.sabinet.co.za/sajchem/>. 141 Synthesis of Some Benzimidazole-substituted Benzotriazoles Akbar Mobinikhaledi*, Naser Foroughifar, Parvin Mohammadlu and Mehdi Kalhor Department of Chemistry, University of Arak, Dr. Beheshti Avenue, Arak, Iran. Received 20 April 2008, revised 30 September 2008, accepted 10 October 2008. ABSTRACT 2-Alkylsubstituted benzimidazoles (3a–h) were prepared from the acid-catalyzed reaction of 4-methyl-1,2-phenylenediamine with corresponding carboxylic acids. Addition of these benzimidazoles to N-chloromethylbenzotriazole in the presence of sodium amide under reflux conditions gave the novel benzimidazole-substituted benzotriazoles (5a–f). IR and 1H NMR spectroscopy and elemental analysis were used for the identification of these compounds. KEYWORDS Phenylenediamine, benzimidazole, benzotriazole. 1. Introduction Benzimidazoles are of special interest because of their diverse biological activity and clinical applications.1 This heterocyclic system has been subjected to a large variety of structural modifications in order to synthesize derivatives with different biological activities. It is well documented that several benzimidazoles show chemotherapeutic2–7 and biological8–10 effects. Compounds containing a benzotriazole moiety11–13 attached to a heterocyclic system are of wide interest because of their diverse biological activities. Several heterocycles containing a benzotriazole moiety have been reported in the literature.11–17 However benzimidazole systems containing a benzotriazole moiety are not well represented. Preparation of the (benzimidazole)methylbenzotriazoles is often carried out using a three-component reaction of benzotriazole, formaldehyde and benzimidazole.18,19 Instead, preparation of the (benzimidazole)methylbenzotriazoles using N-hydroxy-methylmethylbenzotriazole or N-chloromethylbenzotriazole is more convenient and eliminates the use of formaldehyde.14,20 As part of ongoing studies17,21 to explore the versatile biological properties of benzotriazoles and benzimidazoles, we have modified and extended these methods in order to synthesize some novel benzimidazole-substituted benzotriazoles. 2. Experimental All chemicals were of reagent grade quality and used without further purification. 1-Chloromethybenzotriazole was prepared by reaction of 1-hydroxymethyl-benzotriazole and thionyl chloride.20 Melting points were determined on an Electrothermal digital melting point apparatus and were uncorrected. 1H NMR spectra were recorded using Bruker 300 and 500 MHz spectrometers. IR spectra were recorded using a Galaxy 500 FTIR spectrophotometer. Microanalyses were performed on an Elemental Vario EL III elemental analyser at the University of Arak. Reaction progress was routinely monitored by thin layer chromatography (TLC) on silica gel plates. The structures of all novel compounds reported below were confirmed by spectroscopic methods and the corresponding elemental analyses are reported below. Compounds 3a, 3b and 3d are known.22,23 * To whom correspondence should be addressed. E-mail: 2.1. General Procedure for the Preparation of Benzimidazoles and Benzimidazole-substituted Benzotriazoles For the preparation of substituted 5-methylbenzimidazoles (3a–h) a mixture of 4-methyl-1,2-phenylenediamine (1.0 mmol) and the corresponding carboxylic acid (1.0 and 0.5 mmol for monofunctional and bifunctional acids respectively) in hydrochloric acid (10 mL, 4 mol L–1) was refluxed for 4 to 9 h. The mixture was cooled and neutralized slowly with NaOH (1 mol L–1). The precipitate was filtered to give crude benzimidazoles (3a–h), which were then recrystallized from a mixture of ethanol and water (50:50). Adipic acid and succinic acid were used as bifunctional acids for the syntheses of 3f and 3g, respectively. The reaction was monitored by TLC (n-hexane/ethyl acetate, 2:1). For the preparation of benzimidazole-substituted benzotriazoles (5a–f) a mixture of sodium amide (1 mmol) and the corresponding synthesized benzimidazole 3 (1 mmol) in dry toluene (5 mL) was refluxed for 4 to 6 h. Chloromethylbenzotriazole (1 mmol) was added to the hot suspension and refluxed for 8 to 9 h. After cooling, crystals formed which were collected in a funnel. The crude product was recrystallized from water. The reaction was monitored by TLC (n-hexane/ethyl acetate, 2:1). 2.2. 2,5-Dimethyl-1H-1,3-benzimidazole (3a) Cream crystals, yield 60%, m.p. 160–162 °C, 1 H NMR (DMSO-d6, 500 MHz), δ: 2.37 (s, 3H, CH3phenyl), 2.44 (s, 3H, CH3), 6.91–7.32 (m, 3H, phenyl), 12.01 ppm (bs, 1H, NH). IR (KBr) ν: 3038 (N-H), 2717, 2912 (C-Haliphatic), 1030, 1224 (C-N), 858, 804 cm–1. 2.3. 2-Ethyl-5-methyl-1H-1,3-benzimidazole (3b) Brown crystals, yield 75%, m.p. 170–172 °C, 1H NMR (DMSO d6, 500 MHz), δ: 1.28–1.31 (t, 3H, J = 7.6 Hz, CH3ethyl), 2.76–2.81 (q, 2H, J = 7.6 Hz, CH2ethyl), 2.38 (s, 3H, CH3phenyl), 6.91–7.32 (m, 3H, phenyl), 12.01 ppm (bs, 1H, NH). IR (KBr) ν: 3040 (N-H), 2727, 2846, 2974 (C-Haliphatic), 1041 (C-N), 808 cm–1. 2.4. 5-Methyl-2-(trichloromethyl)-1H-1,3-benzimidazole (3c) Brown crystals, yield 75%, m.p. 187–189 °C, 1 H NMR (DMSO-d6, 500 MHz), δ: 2.31 (s, 3H, CH3), 7.07–7.62 (m, 3H, phenyl), 13.33 ppm (bs, 1H, NH). IR (KBr) ν: 3043 (N-H), 2957 RESEARCH ARTICLE A. Mobinikhaledi, N. Foroughifar, P. Mohammadlu and M. Kalhor, S. Afr. J. Chem., 2008, 61, 141–143, <http://journals.sabinet.co.za/sajchem/>. (C-Haliphatic), 1029, 1132, 1190 (C-N), 833, 707 cm–1. Anal. calcd. for C9H7N2Cl3: C, 43.32; H, 2.83; N, 11.23. Found: C, 43.51; H, 2.98; N, 10.88. 2.5. 5-Methyl-2-(2-pyridyl)-1H-1,3-benzimidazole (3d) Grey crystals, yield 85%, m.p. 230–232 °C, 1H NMR (DMSO-d6, 500 MHz), : 2.68 (s, 3H, CH3), 6.67–8.67 (m, 7H, aromatic), 12.09 ppm (bs, 1H, NH). IR (KBr) ν: 3041 (N-H), 2950 (C-Haliphatic), 1120 (C-N), 806, 700 cm–1. Anal. calcd. for C13H11N3: C, 74.62; H, 5.30; N, 20.08. Found: C, 74.36; H, 5.56; N, 20.32. 2.6. 5-Methyl-2-(3-pyridyl)-1H-1,3-benzimidazole (3e) Cream crystals, yield 80%, m.p. 240–242 °C, 1 H NMR (DMSO-d6, 500 MHz), : 2.29 (s, 3H, CH3), 7.06–9.32 (m, 7H, aromatic), 12.99 ppm (bs, 1H, NH). IR (KBr) ν: 3047 (N-H), 2910 (C-Haliphatic), 1132, 1229 (C-N), 812, 707 cm–1. Anal. calcd. for C13H11N3: C, 74.62; H, 5.30; N, 20.08. Found: C, 74.87; H, 5.38; N, 20.24. 2.7. 5-Methyl-2-[4-(5-methyl-1H-1,3-benzimidazole2-yl)butyl]-1H-1,3-benzimidazole (3f) Red crystals, yield 70%, m.p. 270–271 °C, 1H NMR (DMSO-d6, 500 MHz), : 1.81 (m, 4H, CH2), 2.37 (s, 6H, CH3), 2.82 (m, 4H, CH2), 6.91–7.33 (m, 6H, phenyl), 12.00 ppm (s, 2H, NH). IR (KBr) ν: 3038 (N-H), 2756, 2870, 2933 (C-Haliphatic), 1129 (C-N), 798 cm–1. Anal. calcd. for C20H22N4: C, 75.44; H, 6.96; N, 17.60. Found: C, 75.68; H, 6.69; N, 17.68. 2.8. 5-Methyl-2-[2-(5-methyl-1H-1,3-benzimidazole2-yl)ethyl]-1H-1,3-benzimidazole (3g) Pink crystals, yield 70%, m.p. 260–262 °C, 1H NMR (D (...truncated)