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Chemo selective one-pot synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles using Amberlite IR-120
⁎Corresponding author. Tel.: +82 2 450 3739 (Lab.); fax: +82 2 3436 5439. sewpark@konkuk.ac.kr (Se Won Park)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of the King Saud University.
Abstract
A simple, efficient and eco-friendly one pot synthesis method has been developed for ultrasound induced synthesis of biologically significant 2-aryl-1-arylmethyl-1H-benzimidazoles in EtOH/H2O solvent mixture using Amberlite IR-120. The catalyst is recyclable without loss of activity. The method provides several advantages such as green solvent, simple work-up procedure, shorter reaction time and higher yield.
Keywords
Benzimidazoles
Amberlite IR-120
One-pot reaction
Ultrasound irradiation
1 Introduction
In modern organic chemistry the investigations are now directed to the discovery of methods that largely taken into account the criterion of sustainable chemistry because of increasing economic and ecological pressure for synthesis new drugs (Horváth and Anastas, 2007). In this context, multi component reactions (MCRs) (Zhu and Bienaime, 2005), involving domino processes (Ramon and Yus, 2005), combining at least three different substrates in a one-pot operation, have emerged as powerful tools and complementary substrate-directed synthetic alternatives to other well-known methods (Padwa et al., 2007; Vugts et al., 2006). Moreover, these transformations combine classical concerns such as efficiency, selectivity, molecular complexity and diversity (Ranu et al., 2000; Loupy and Perreux, 2001). Microwave-assisted organic synthesis (MOREs) has received much attention in recent years because of its faster chemistry and the formation of cleaner products compared with conventional heating (Lidstrom et al., 2001). MOREs has become an expanding field in synthetic research, and there are very few areas of synthetic organic chemistry, which have not been covered by this technology. It is clear that the application of microwave technology to the rapid synthesis of biologically significant molecules on the solid support would be of great value for library generation (Brain and Brunton, 2001). This technology has recently been recognized as a useful tool for a drug-discovery program (Larhed and Hallberg, 2001). In conjunction with our continuous interest in developing new protocols in liquid-phase combinatorial synthesis, we explore the use of microwave irradiation as a heating source in conformational rigid heterocycles’ synthesis. It has been noted that microwave chemistry can provide access to synthetic transformations, which may otherwise be time consuming or low yielding using conventional heating (De La Hoz et al., 2004). Several microwave assisted organic reactions proceed at mild reaction conditions at much enhanced reaction rates with quick and simple optimization of reaction conditions relative to thermal reactions (Dewan et al., 1995). Hence the decomposition of reactants and/or products is diminished in these reactions leading to enhanced yields. Often, microwave assisted organic reactions proceed with low energy requirements, less waste, and with no use of solvent. Also, environmentally benign solid catalysts such as clays and zeolites, instead of mineral acids, are also employed for acid catalyzed microwave assisted synthetic transformations, rendering them eco-friendly (Varma, 1999). Microwave irradiation has been utilized to effect organic reactions such as pericyclic (Srikrishna and Nagaraju, 1992), cyclization (Rama-Rao et al., 1992), aromatic substitution (Laurent et al., 1994), oxidation (Gedye et al., 1986), alkylation (Yulin and Yuncheng, 1994), decarboxylation (Jones and Chapman, 1993), radical reactions and condensation (Villemin and Martin, 1994). The benzimidazoles have received considerable attention in recent times because of their applications as antiulcers, antihypertensives, antivirals, antifungals, anticancers and antihistamines among others (Perrux and Loupy, 2001; Shitole et al., in press). In addition, they are important intermediates in many organic reactions and act as ligands to transition metals for modeling biological systems. Their utility in preparative organic chemistry led to the development of several methods for the synthesis of benzimidazoles during the last few years capturing the attention of medicinal chemists (Salehi et al., 2006). One of the protocols often followed is the coupling of o-phenylenediamines with carboxylic acids or their derivatives and the other involves the condensation of o-phenylenediamine and aldehydes followed by oxidative cyclo-dehydrogenation. However, the second approach has become more popular probably because of the ease of accessibility of a variety of substituted aldehydes (Varala et al., 2007). The reported procedures for this protocol involved a wide spectrum of reagents including (bromodimethyl) sulfonium bromide/MeCN, iodobenzene diacetate/1,4-dioxane, H2O2/HCl in MeCN, chlorotrimethylsilane/DMF, I2/KI/K2CO3/H2O, air/dioxane, ytterbium triflate in neat, p-TsOH/DMF, Na2S2O5 in neat under microwave irradiation, [(NH4)H2PW12O14] in dichloroethane, H2O2/CAN, [Hbim]BF4, proline, p-TsOH/graphite, sodium hydrogen sulfite, p-TsOH/silica gel, ytterbium(III) perfluorooctanesulfonate and [pmim]BF4 (Sharma and Konwar, 2009; Ji-Tai et al., 2010). Although these methods are quite satisfactory, many of them employed considerable amounts of hazardous organic solvents either for carrying out the reactions or for extraction and purifications (column chromatography) or for both, which are not environmentally friendly. Several of these reactions were carried out at higher temperatures and using costly reagents (Rajesh and Joshi, 2007; Perumal et al., 2004). Furthermore, one of the major limitations of these methodologies is the poor selectivity in terms of N-1 substitution, resulting in the formation of two compounds (i.e., the formation of 2-substituted benzimidazole along with 1, 2-disubstituted benzimidazole as a mixture). We report the first chemo selective ultrasound promoted one-pot synthesis of ultrasound induced synthesis of biologically significant 2-aryl-1-arylmethyl-1H-benzimidazoles in EtOH/H2O mixture using Amberlite IR-120, as Amberlite IR-120 resin as a highly efficient and more practical method for the preparation of this important heterocyclic framework.
2 Materials and methods
All reagents were obtained from commercial sources and used without further purification. IR spectra were recorded on a Shimadzu FTIR-8300 spectrometer in Nujol/KBr and the 1H NMR and 13C NMR spectra were measured on a Bruker AVANCE 400 MHz spectrometer using tetramethylsilane (TMS, δ = 0 ppm) as an internal standard. Mass spectra (MALDI-TOF-MS) were determined on a Bruker BIFLEX III mass spectrometer. Elemental analysis was performed on a flash EA1112 analyzer. Sonication was performed in a Bransonic Ultrasonic Corporation; Model No. 5510E-DTH with a frequency of 42 kHz and a nominal power (135 W). Thin layer chromatography (TLC) was performed using the aluminum sheets coated with silica gel 60 (MERCK) containing fluorescent indicators, F254. The solvent for the development of the plate was hexane: ethyl acetate (7:3).
3 Experimental procedure
An appropriate aldehyde (1.0 mmol) and o-phenylenediamine (2.0 mmol) were dissolved in 66% EtOH in H2O (10 mL) at 25°C. To this solution (5 mg) of catalyst was added and the contents kept under sonication at 42 kHz for 90 min (Scheme 1). The completion of the reaction was monitored by TLC using hexane: ethyl acetate (7:3) as the eluent. The solution was filtered to recover the catalyst after completion of the reaction and after the recovery of the catalyst; the filtrate was concentrated under reduced pressure to furnish the crude product, which was re-crystallized from methanol to afford the pure form. The catalyst can be reused for fresh reactions without any loss of activity (Mohamed and Aatika, 2012).
Ultrasound promoted one-pot synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles.
4 Results and discussion
We have developed a speedy, clean and chemo selective process for the one-pot synthesis of 2-Aryl-1-arylmethyl-1H-benzimidazoles using Amberlite IR-120 and ultrasound waves in EtOH/H2O mixture. This process is environmentally benign, easy to manipulate and can be scaled up further for industrial processes. Benzimidazoles can be synthesized efficiently by treating ortho-phenylenediamine with substituted aromatic aldehydes using commercially available Amberlite IR-20 reagent using ethanol and water as solvent and at 5 °C for 30–65 min. In all cases, the yields were good (Scheme 1) as consequently several substituted aromatic aldehydes were subjected to the condensation reaction resulting in the desired products with considerably good yields (Scheme 1). To summarize, a direct method has been developed for the synthesis of a series of benzimidazoles in a one-pot with environmentally friendly conditions (‘green chemistry’) namely, microwave irradiation (Tables 1 and 2). Full assignment of all 1H and 13C NMR chemical shifts and molecular mass has been unambiguously achieved (Figures 1 and 2). The 1H and 13C NMR spectra of the products are in consonance with benzimidazole structures and their melting points are in agreement with those available in the literature (Perrux and Loupy, 2001; Shitole et al., in press). To show the merit of the present work in comparison with reported results in the literature we compared results of chlorosulfonic acid with l-proline (Varala et al., 2007) and silica sulfuric acid (Salehi et al., 2006) also yields are excellent in the synthesis of some substituted 2-aryl-1-arylmethyl-1H-benzimidazoles previously in the literature and were characterized by the comparison of IR and NMR spectra with authentic samples. There is an urgent need to develop alternative solvents and technologies due to pressure from governmental organizations and other regulatory bodies to protect the environment. To the best of our knowledge there is no previous report on the synthesis of 1, 2-disubstituted benzimidazoles in EtOH/H2O mixture at room temperature. Thus, we decided to investigate the reaction in water for ultrasound induced synthesis. Unfortunately, the yield was not satisfactory even at reflux, but the selectivity for the production of benzimidazoles was high (Salehi et al., 2006; Berslow, 2004; Narayan et al., 2005). ∗Indicated in table. aIsolated yield based on the p-methoxy benzaldehyde. bReaction was carried out without sonication.
Entry
Aldehydes
Benzimidazoles structures
Reaction time (h)
Yield (%)
M.P./°C
C1
1.5
94
290–294
C2
1.8
87
240–245
C3
2
88
220–2224
C4
1.6
96
272–274
C5
2.5
84
280–284
C6
3
93
230–235
C7
1.8
88
265–268
C8
3.4
86
230–231
C9
2.5
84
240–242
C10
2.2
82
202–204
NMR Spectra for 2-aryl-1-arylmethyl-1H-benzimidazoles.
Mass spectra for 2-aryl-1-arylmethyl-1H-benzimidazoles.
Acknowledgments
This research was supported by the 2014-“Konkuk University (KU), Research Professor Program-2014” Konkuk University, Seoul, South Korea.
References
- Acc. Chem. Res.. 2004;37:471.
- Synlett. 2001;3:382.
- Curr. Org. Chem.. 2004;8:903.
- J. Chem. Res., Synop.. 1995;1:21.
- Tetrahedron Lett.. 1986;27:279.
- Chem. Rev.. 2007;107:2167.
- Ultrason. Sonochem.. 2010;17:356.
- J. Org. Chem.. 1993;58:5558.
- Drug Discovery Today. 2001;6:406-416.
- Organometallics. 1994;13:2493.
- Tetrahedron.. 2001;57:9225-9283.
- Tetrahedron. 2001;57:9199.
- Saudi Chem. Soc.. 2012;16:237.
- Angew. Chem. Int. Ed.. 2005;44:3275-3279.
- Tetrahedron. 2007;63:5341.
- Tetrahedron. 2001;57:9199.
- ARKIVOC. 2004;8:46.
- E-J. Chem.. 2007;4:606.
- Tetrahedron. 1992;3:859.
- Angew. Chem. Int. Ed.. 2005;44:1602.
- Green Chem.. 2000;2:5.
- Tetrahedron Lett.. 2006;47:2557.
- Synth. Commun.. 2009;39:980.
- Shitole, N.V., Niralwad, K.S., Shingate, B.B., Shingare, M. S., 2012. Arabian J. Chem., in press. doi: http://dx.doi.org/10.1016/j.arabjc.2011.09.015.
- Chem. Soc., Perkin Trans.. 1992;1:311.
- Tetrahedron Lett.. 2007;48:69.
- Clean Prod. Processes. 1999;1:132.
- J. Chem. Res., Synop. 1994:146.
- Chem. Eur. J.. 2006;12:7178.
- Synth. Commun.. 1994;24:1045.
- Multicomponent Reactions. Weinheim: Wiley-VCH; 2005.
