Arabian Journal of Chemistry (2015) 8, 685–691

King Saud University

Arabian Journal of Chemistry

www.ksu.edu.sawww.sciencedirect.com

ORIGINAL ARTICLE

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.E-mail addresses: nileshivraj@gmail.com (S.H. Nile), sewpark@

konkuk.ac.kr (S.W. Park).

Peer review under responsibility of the King Saud University.

Production and hosting by Elsevier

1878-5352 ª 2013 Production and hosting by Elsevier B.V. on behalf of King Saud University.

http://dx.doi.org/10.1016/j.arabjc.2012.12.006

Shivraj Hariram Nilea, Brajesh Kumar

b, Se Won Park

a,*

a Department of Molecular Biotechnology, School of Life and Environmental Sciences, Konkuk University, Seoul 143-701,South Koreab Department of Chemistry, TATA College, Kolhan University, Chaibasa-833202, Jharkhand, India

Received 24 September 2012; accepted 5 December 2012Available online 4 January 2013

KEYWORDS

Benzimidazoles;

Amberlite IR-120;

One-pot reaction;

Ultrasound irradiation

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 activ-

ity. The method provides several advantages such as green solvent, simple work-up procedure,

shorter reaction time and higher yield.ª 2013 Production and hosting by Elsevier B.V. on behalf of King Saud University.

1. Introduction

In modern organic chemistry the investigations are now direc-

ted to the discovery of methods that largely taken into accountthe criterion of sustainable chemistry because of increasingeconomic and ecological pressure for synthesis new drugs(Horvath and Anastas, 2007). In this context, multi compo-

nent reactions (MCRs) (Zhu and Bienaime, 2005), involvingdomino processes (Ramon and Yus, 2005), combining at leastthree different substrates in a one-pot operation, have emerged

as powerful tools and complementary substrate-directed syn-thetic alternatives to other well-known methods (Padwaet al., 2007; Vugts et al., 2006). Moreover, these transforma-

tions combine classical concerns such as efficiency, selectivity,molecular complexity and diversity (Ranu et al., 2000; Loupyand Perreux, 2001). Microwave-assisted organic synthesis

(MOREs) has received much attention in recent years becauseof its faster chemistry and the formation of cleaner productscompared 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 thatthe application of microwave technology to the rapid synthesis

of biologically significant molecules on the solid support wouldbe 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 develop-ing new protocols in liquid-phase combinatorial synthesis, we

explore the use of microwave irradiation as a heating source

Scheme 1 Ultrasound promoted one-pot synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles.

Table 1 Structures of synthesized 2-aryl-1-arylmethyl-1H-benzimidazoles from aldehydes in the presence of catalytic amount of

Amberlite IR-120.

Entry Aldehydes Benzimidazoles structures Reaction time (h) Yield (%) M.P./�C

C1 CHO

OHN

N

OH

HO

1.5 94 290–294

C2 CHO

ClN

N

Cl

Cl

1.8 87 240–245

C3 CHO

ClN

N

Cl

Cl

2 88 220–2224

C4 CHO

CH3N

N

CH3

H3C

1.6 96 272–274

C5 CHO

H3CN

N

H3C

CH3

2.5 84 280–284

C6 CHO

HON

N

HO

OH

3 93 230–235

(continued on next page)

686 S.H. Nile et al.

Table 1 (continued)

Entry Aldehydes Benzimidazoles structures Reaction time (h) Yield (%) M.P./�C

C7 CHO

OHN

N

OH

OH 1.8 88 265–268

C8 CHO

ClN

N

Cl

Cl 3.4 86 230–231

C9 CHO

CH3N

N

CH3

CH32.5 84 240–242

C10 CHO

N

N 2.2 82 202–204

Chemo selective one-pot synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles using Amberlite IR-120 687

in conformational rigid heterocycles’ synthesis. It has beennoted that microwave chemistry can provide access to syn-

thetic transformations, which may otherwise be time consum-ing or low yielding using conventional heating (De La Hozet al., 2004). Several microwave assisted organic reactions pro-

ceed at mild reaction conditions at much enhanced reactionrates with quick and simple optimization of reaction condi-tions relative to thermal reactions (Dewan et al., 1995). Hence

the decomposition of reactants and/or products is diminishedin these reactions leading to enhanced yields. Often, micro-wave assisted organic reactions proceed with low energyrequirements, less waste, and with no use of solvent. Also,

environmentally benign solid catalysts such as clays and zeo-lites, instead of mineral acids, are also employed for acid cat-alyzed microwave assisted synthetic transformations,

rendering them eco-friendly (Varma, 1999). Microwave irradi-ation has been utilized to effect organic reactions such as peri-cyclic (Srikrishna and Nagaraju, 1992), cyclization (Rama-Rao

et al., 1992), aromatic substitution (Laurent et al., 1994), oxi-dation (Gedye et al., 1986), alkylation (Yulin and Yuncheng,1994), decarboxylation (Jones and Chapman, 1993), radicalreactions and condensation (Villemin and Martin, 1994). The

benzimidazoles have received considerable attention in recenttimes because of their applications as antiulcers, antihyperten-

sives, antivirals, antifungals, anticancers and antihistaminesamong others (Perrux and Loupy, 2001; Shitole et al., in

press). In addition, they are important intermediates in manyorganic reactions and act as ligands to transition metals formodeling biological systems. Their utility in preparative organ-

ic chemistry led to the development of several methods for thesynthesis of benzimidazoles during the last few years capturingthe attention of medicinal chemists (Salehi et al., 2006). One of

the protocols often followed is the coupling of o-phenylenedi-amines with carboxylic acids or their derivatives and the otherinvolves the condensation of o-phenylenediamine and alde-hydes followed by oxidative cyclo-dehydrogenation. However,

the second approach has become more popular probably be-cause of the ease of accessibility of a variety of substitutedaldehydes (Varala et al., 2007). The reported procedures for

this protocol involved a wide spectrum of reagents including(bromodimethyl) sulfonium bromide/MeCN, iodobenzenediacetate/1,4-dioxane, H2O2/HCl in MeCN, chlorotrimethylsi-

lane/DMF, I2/KI/K2CO3/H2O, air/dioxane, ytterbium triflatein neat, p-TsOH/DMF, Na2S2O5 in neat under microwaveirradiation, [(NH4)H2PW12O14] in dichloroethane, H2O2/CAN, [Hbim]BF4, proline, p-TsOH/graphite, sodium hydro-

gen sulfite, p-TsOH/silica gel, ytterbium(III) perfluorooctane-sulfonate and [pmim]BF4 (Sharma and Konwar, 2009; Ji-Tai

Table 2 Role of catalyst, ultrasound and solvent for selective synthesis of 1-(4-methoxybenzyl)-2-(4-methoxyphenyl)-1H-1,

3-benzimidazole.

*Indicated in table.aIsolated yield based on the p-methoxy benzaldehyde.bReaction was carried out without sonication.

688 S.H. Nile et al.

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 forextraction and purifications (column chromatography) or forboth, which are not environmentally friendly. Several of these

reactions were carried out at higher temperatures and usingcostly 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 substitu-tion, resulting in the formation of two compounds (i.e., theformation of 2-substituted benzimidazole along with 1, 2-disubstituted benzimidazole as a mixture). We report the first

chemo selective ultrasound promoted one-pot synthesis ofultrasound 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 highlyefficient and more practical method for the preparation of thisimportant heterocyclic framework.

2. Materials and methods

All reagents were obtained from commercial sources and used

without further purification. IR spectra were recorded on aShimadzu FTIR-8300 spectrometer in Nujol/KBr and the 1HNMR and 13C NMR spectra were measured on a Bruker

AVANCE 400 MHz spectrometer using tetramethylsilane(TMS, d = 0 ppm) as an internal standard. Mass spectra(MALDI-TOF-MS) were determined on a Bruker BIFLEXIII mass spectrometer. Elemental analysis was performed on

a flash EA1112 analyzer. Sonication was performed in a Bran-sonic Ultrasonic Corporation; Model No. 5510E-DTH with afrequency of 42 kHz and a nominal power (135 W). Thin layer

chromatography (TLC) was performed using the aluminumsheets coated with silica gel 60 (MERCK) containing fluores-cent indicators, F254. The solvent for the development of the

plate was hexane: ethyl acetate (7:3).

Figure 1 NMR Spectra for 2-aryl-1-arylmethyl-1H-benzimidazoles.

Chemo selective one-pot synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles using Amberlite IR-120 689

3. Experimental procedure

An appropriate aldehyde (1.0 mmol) and o-phenylenediamine(2.0 mmol) were dissolved in 66% EtOH in H2O (10 mL) at25�C. To this solution (5 mg) of catalyst was added and thecontents kept under sonication at 42 kHz for 90 min

(Scheme 1). The completion of the reaction was monitoredby TLC using hexane: ethyl acetate (7:3) as the eluent. Thesolution was filtered to recover the catalyst after completion

of the reaction and after the recovery of the catalyst; the fil-trate was concentrated under reduced pressure to furnish thecrude product, which was re-crystallized from methanol to af-

ford the pure form. The catalyst can be reused for fresh reac-

tions without any loss of activity (Mohamed and Aatika,2012).

4. Results and discussion

We have developed a speedy, clean and chemo selective pro-cess for the one-pot synthesis of 2-Aryl-1-arylmethyl-1H-benz-

imidazoles using Amberlite IR-120 and ultrasound waves inEtOH/H2O mixture. This process is environmentally benign,easy to manipulate and can be scaled up further for industrialprocesses. Benzimidazoles can be synthesized efficiently by

Figure 2 Mass spectra for 2-aryl-1-arylmethyl-1H-benzimidazoles.

690 S.H. Nile et al.

treating ortho-phenylenediamine with substituted aromaticaldehydes using commercially available Amberlite IR-20 re-agent using ethanol and water as solvent and at 5 �C for 30–

65 min. In all cases, the yields were good (Scheme 1) as conse-quently several substituted aromatic aldehydes were subjectedto the condensation reaction resulting in the desired products

with considerably good yields (Scheme 1). To summarize, a di-rect method has been developed for the synthesis of a series ofbenzimidazoles in a one-pot with environmentally friendly

conditions (‘green chemistry’) namely, microwave irradiation(Tables 1 and 2). Full assignment of all 1H and 13C NMRchemical shifts and molecular mass has been unambiguously

achieved (Figures 1 and 2). The 1H and 13C NMR spectra ofthe products are in consonance with benzimidazole structuresand their melting points are in agreement with those availablein 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 ofchlorosulfonic acid with L-proline (Varala et al., 2007) and sil-ica sulfuric acid (Salehi et al., 2006) also yields are excellent in

the synthesis of some substituted 2-aryl-1-arylmethyl-1H-benz-imidazoles previously in the literature and were characterizedby the comparison of IR and NMR spectra with authentic

samples. There is an urgent need to develop alternative sol-vents and technologies due to pressure from governmentalorganizations and other regulatory bodies to protect the envi-

ronment. To the best of our knowledge there is no previous re-port on the synthesis of 1, 2-disubstituted benzimidazoles inEtOH/H2O mixture at room temperature. Thus, we decided

to investigate the reaction in water for ultrasound induced syn-thesis. Unfortunately, the yield was not satisfactory even at re-flux, but the selectivity for the production of benzimidazoleswas high (Salehi et al., 2006; Berslow, 2004; Narayan et al.,

2005).

Chemo selective one-pot synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles using Amberlite IR-120 691

Acknowledgments

This research was supported by the 2014-‘‘Konkuk University

(KU), Research Professor Program-2014’’ Konkuk University,Seoul, South Korea.

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