Research Article | Open Access
Synthesis of N-Alkyl-2-thiomethyl Benzimidazoles: A Green Approach
A green approach for the synthesis of N-alkyl-2-thiomethyl benzimidazoles 2 (R=CH3, C2H5, CH2Ph) under different conditions has been developed from N-alkyl-2-chloromethyl benzimidazole (i.e., CH3, C2H5, CH2Ph) 1 by reaction with thiourea by physical grinding, or by using green solvents like ethanol and PEG-600, or by using microwave irradiation technique.
Benzimidazoles are very useful intermediates/subunits for the development of molecules of pharmaceutical or biological interest [1, 2]. Benzimidazoles are an important class of bioactive molecules in the field of drugs and pharmaceuticals [3–7].
N-Methyl-o-phenylenediamine on treatment with thioacetic acid in HCl under reflux gave N-methyl-2-thiomethyl benzimidazole that was reported  by Casella et al. Rall et al. described  that N-methyl o-Phenylenediamine with S-benzyl thioacetic acid in aq. HCl under reflux gave N-benzyl-2-benzylthio methylbenzimidazole. Kato et al. reported  that 2-((methylthio)methyl)-1H-benzimidazole was prepared on treatment of S-methylthio acetic acid with o-phenylenediamine in aq. HCl under reflux for 16 hr. Reaction of S-methylthio methylbenzimidazole on treatment with methyl iodide in presence of sodium methoxide gave N-methyl-S-methylthio methylbenzimidazole that was reported by Haugwitz et al. . Zubenko et al. reported  that N-methyl-2-chloromethyl benzimidazole was reacted with thiomethane in ethanol in NaOMe and gave N-methyl-2-methylthio methylbenzimidazole. Rao et al.  reported that N-alkyl-2-chlorobenzimidazole was treated with thiourea green conditions and gave N-alkyl-2-thiomethyl benzimidazole in good yields. In continuation of our earlier studies , we now wish to report a green syntheses of N-alkyl-2-thiomethylbenzimidazoles.
2. Results and Discussion
Reaction of 1a–c, that is, N-alkyl-2-chloromethyl benzimidazole  (R=CH3, C2H5, or PhCH2), independently, each with thiourea by a simple physical grinding of the reaction mixture in a mortar with a pestle, under solvent-free conditions, for 10–15 min at RT, followed by simple processing, gave respectively (1-methyl-1H-benzimidazol-2-yl)methanethiol (2a, i.e., 2, R=CH3), (1-ethyl-1H-benzimidazol-2-yl)methanethiol (2b, i.e., 2, R=C2H5), and (1-benzyl-1H-benzimidazol-2-yl)methanethiol (2c, i.e., 2, R=CH2Ph) in excellent yields, matching the products identically with the ones reported  by the literature in all respects (m.p., m.m.p., and co-TLC) (Scheme 1).
The reaction of 1a, 1b, and 1c, independently, each with thiourea in ethanol under reflux for 3 hr, followed by simple processing, gave respectively 2a (i.e., 2, R=CH3), 2b (i.e., 2, R=CH2CH3), and 2c (i.e., 2, R=CH2Ph) identical with the same products obtained above (Scheme 1).
The reaction was also carried out in PEG-600 as the green solvent. Thus, heating a mixture of 1a, 1b, and 1c, independently, each with thiourea in PEG-600 for 3 hr without the use of any added base, followed by simple processing, gave, respectively, 2a (i.e., 2, R=CH3), 2b (i.e., 2, R=CH2CH3), and 2c (i.e., 2, R=CH2Ph) identical with the same products obtained above (Scheme 1).
Compounds 2a–c could also be prepared by an alternative, green method. Thus, 1a, 1b, and 1c, independently, each with thiourea under microwave irradiation conditions for 2 min and subsequent processing, gave respectively 2a (i.e., 2, R=CH3), 2b (i.e., 2, R=CH2CH3), and 2c (i.e., 2, R=CH2Ph) identical with the products obtained above (Scheme 1).
Thus, the above four methods have different yields with one suffering from relatively poor yields. Among in ethanol and PEG-600, ethanol gives more yields whereas PEG-600 gives lower yields. Due to high molecular weight and viscous nature of PEG-600 (135 cp at 25°C), it may lower reaction rates, reduce product yields, and cause the reaction to be mass-transfer limited. Because of this, three of the four methodologies result in the preparation of the compounds giving high yields whereas PEG-600 gives lower yields. Among these four methodologies, the microwave irradiation is superior to that of three methods because microwave dielectric heating is more energy efficient than classical conductive heat transfer methods.
3. Experimental Section
Melting points were determined in open capillaries in sulfuric acid bath and are uncorrected. IR spectra were recorded with Jasca FT-IR 5300. 1H NMR and 13C NMR were recorded in CDCl3/DMSO using Varian 400 MHz instrument. Mass spectra were recorded on an Agilent LC-MS instrument giving only M+ values in Q+1 mode. Thin-layer chromatography (TLC) analyses were carried out on glass plates coated with silica gel GF-254 and visualization was achieved using iodine vapors or UV lamp. Experiments under microwave irradiation were carried out by using the commercially available CEM Discover Microwave Reactor.
3.1. Preparation of 2 from 1
3.1.1. Physical Grinding Method
A mixture of 1a–c (10 mM) and thiourea (0.76 g, 10 mM) was ground for about 10–15 min in a mortar with a pestle at RT to obtain a homogeneous mixture. The completion of the reaction was monitored by TLC on silica gel-G plates using authentic samples of the starting material and the target compounds as references. The mixture was then treated with ice-cold water (≈30–40 mL). The separated solid was filtered, washed with water (2 × 10 mL), and dried to obtain crude 2a–c. Yields are shown in Table 1. Recrystallization of the crude product from ethyl acetate gave pure 2a–c. IR, 1H NMR, and LC-MS spectra for the compounds 2a–c were found to be in agreement with the structures assigned to them.
|Yield refers to recrystallized products.|
3.1.2. In Ethanol
A mixture of 1a–c (10 mM) and thiourea (0.76 g, 10 mM) in ethanol was refluxed on water bath for 3 hr. The progress of the reaction was monitored on TLC for the disappearance of 1. After the completion of the reaction (≈3 hr), the excess ethanol was rotary evaporated and the residue poured into ice-cold water (30 mL). The separated solid was filtered, washed with water (2 × 10 mL), and dried. For yields, please see Table 1. The crude products were purified by recrystallization from ethyl acetate to obtain pure 2a–c, identical with the same products obtained above.
3.1.3. In PEG-600
A mixture of 1a–c (10 mM), thiourea (0.76 g, 10 mM), and PEG-600 (20 mL) was heated on a steam-bath at 100°C for 3 hr. At the end of this period, the mixture was cooled to RT and poured into ice-cold water (≈50 mL). The separated solid was filtered, washed with water (2 × 10 mL), and dried. Yields are shown in Table 1. The crude product was purified by recrystallization from ethyl acetate to obtain pure 2a–c, identical with the same products obtained above.
3.1.4. Under Microwave Condition
A mixture of 1a–c (10 mM) and thiourea (0.76 g, 10 mM) was taken in a 10 mL CEM-reaction tube sealed by rubber stopper and subjected to microwave irradiation for 2 min at 130°C in a commercial microwave reactor. After that, the tube was cooled and the completion of reaction was checked by TLC. Then, the reaction mixture was poured into ice-cold water (50 mL). The separated solid was filtered, washed with water (2 × 10 mL), and dried. Yields are shown in Table 1. The crude products were purified by recrystallization from ethyl acetate to obtain pure 2a–c, identical with the same products obtained above.
3.2. Characterization Data
(1-Methyl-1H-benzimidazol-2-yl)methanethiol, 2a. M.P. 141–45°C (Lit.(7) m.p. 139–43°C); IR (KBr): 2418–2396 cm−1 (–SH); 1H NMR (400 MHz, DMSO-d6/TMS): δ 3.66 (s, 3H, –NCH3), 9.24 (s, 1H, –SH), and 7.35–8.47 (complex, m, and 4H aryl protons); 13C NMR: δ 172.2, 138.8, 132.5, 125.4, 118.4, and 25.9 ppm; MS (CI): m/z 179 [M•++1].
(1-Ethyl-1H-benzimidazol-2-yl)methanethiol, 2b. M.P. 118–22°C (Lit.(7) m.p. 120–24°C); IR (KBr): 2485–2312 cm−1 (–SH); 1H NMR (400 MHz, DMSO-d6/TMS): δ 2.75 (q, 2H, and –NCH2 of ethyl), 2.45 (t, 3H, and –CH3 of ethyl), 8.98 (s, 1H, and –SH), and 7.29–8.45 (complex, m, and 4H aryl protons); 13C NMR: δ 170.6, 136.5, 130.2, 124.3, 116.4, 26.9, and 22.8 ppm; MS (CI): m/z 193 [M•++1].
(1-Benzyl-1H-benzimidazol-2-yl)methanethiol, 2c. M.P. 134–38°C (Lit.(7) m.p. 136–39°C); IR (KBr): 2229–2258 cm−1 (–SH); 1H NMR (400 MHz, DMSO-d6/TMS): δ 3.60 (s, 2H, and –NCH2 of benzyl), 8.63 (s, 1H, and –SH), and 7.28–8.48 (complex, m, 9H, and 5 aromatic benzyl + 4H aryl protons); 13C NMR: δ 170.4, 137.8, 135.3, 134.5, 126.4, 123.4, 118.4, and 44.9 ppm; MS (CI): m/z 255 [M•++1].
In conclusion, we have developed simple and green synthesis of N-alkyl-2-thiomethyl benzimidazole under different conditions.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors are indebted to the authorities of Jawaharlal Nehru Technological University Hyderabad for providing facilities.
- A. Spasov, I. N. Yozhitsa, L. I. Bugaeva, and V. A. Anisimova, “Benzimidazole derivatives: spectrum of pharmacological activity and toxicological properties,” Pharma Chemica Journal, vol. 33, pp. 232–243, 1999.
- P. N. Preston, The Chemistry of Heterocyclic Compounds, Benzimidazoles and Congeneric Tricyclic Compounds, Part-2, vol. 10, John Wiley & Sons, New York, NY, USA, 1980.
- D. A. Horton, G. T. Bourne, and M. L. Smythe, “The combinatorial synthesis of bicyclic privileged structures or privileged substructures,” Chemical Reviews, vol. 103, no. 3, pp. 893–930, 2003.
- P. N. Preston, “Synthesis, reactions, and spectroscopic properties of benzimidazoles,” Chemical Reviews, vol. 74, no. 3, pp. 279–314, 1974.
- X. Han, H. Ma, and Y. Wang, “p-TsOH catalyzed synthesis of 2-arylsubstituted benzimidazoles,” Arkivoc, vol. 2007, no. 13, pp. 150–154, 2007.
- M. T. Migawa, J.-L. Girardet, J. A. Walker II et al., “Design, synthesis, and antiviral activity of α-nucleosides: D- and L-isomers of lyxofuranosyl- and (5-deoxylyxofuranosyl)benzimidazoles,” Journal of Medicinal Chemistry, vol. 41, no. 8, pp. 1242–1251, 1998.
- A. R. Porcari, R. V. Devivar, L. S. Kucera, J. C. Drach, and L. B. Townsend, “Design, synthesis, and antiviral evaluations of 1-(substituted benzyl)- 2-substituted-5,6-dichlorobenzimidazoles as nonnucleoside analogues of 2,5,6- trichloro-1-(β-D-ribofuranosyl)benzimidazole,” Journal of Medicinal Chemistry, vol. 41, no. 8, pp. 1252–1262, 1998.
- L. Casella, M. Gullotti, E. Suardi, M. Sisti, R. Pagliarin, and P. Zanello, “Blue copper models. Synthesis and characterization of copper(II) enethiolate complexes derived from (1R)-3-hydroxymethylenebornane-2-thione and 2-aminothia-alkyl-1-methylbenzimidazoles (donor set N2SS*) or diamines (donor set N2S2),” Journal of the Chemical Society, Dalton Transactions, no. 9, pp. 2843–2851, 1990.
- J. Rall, M. Wanner, M. Albrecht, F. M. Hornung, and W. Kaim, “Sensitive valence tautomer equilibrium of paramagnetic complexes [(L)()] ( or 2; Q = Quinones) related to amine oxidase enzymes,” Chemistry, vol. 5, no. 10, pp. 2802–2809, 1999.
- J. Y. Kato, Y. Ito, R. Iluin, H. Aoyama, and T. Yokomastu, “Novel strategy for synthesis of substituted benzimidazole[1,2-a] quinolines,” Organic Letters, vol. 15, pp. 3794–3797, 2013.
- R. D. Haugwitz, B. V. Maurer, and V. L. Narayanan, “Synthesis and anthelmintic activity of some sulfonylbenzimidazoles,” Journal of Medicinal Chemistry, vol. 15, no. 8, pp. 856–858, 1972.
- A. A. Zubenko, L. N. Fetisov, L. D. Popov, and E. Vihzila, “Preparation of pyrido[1,2-a]benzimidazole derivatives having antibacterial activity and process for their preparation,” Russian Patent no. 2394824, Chemical Abstract 151859, 2008.
- S. S. Rao, P. K. Dubey, and Y. B. Kumari, “A Green and Simple synthesis of N-substituted-2-mercapto benzimidazoles,” Indian Journal of Chemistry, vol. 52, pp. 1210–1213, 2013.
- S. S. Rao, Ch. V. R. Reddy, and P. K. Dubey, “A facile and green synthesis of N-substituted-2-chlorobenzimidazoles,” Der Pharma Chemica, vol. 5, pp. 69–72, 2013.
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