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Indo American Journal of Pharmaceutical Research, 2015 ISSN NO: 2231-6876

SYNTHESIS, SPECTRAL AND PHYSICAL PROPERTIES OF BENZIMIDAZOLE

DERIVATIVES -AN REVIEW

Hamdan S. Al-Ebaisat Department of Chemistry, Faculty of Science, Tafila Technical University, Jordan.

Corresponding author

Hamdan S. Al-Ebaisat

Department of Chemistry,

Faculty of Science, Tafila Technical University,

Jordan.

Copy right © 2015 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical

Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ARTICLE INFO ABSTRACT

Article history

Received 20/01/2015

Available online

28/02/2015

Keywords

Benzimidazole,

Derivatives ,

Synthesis,

Pharmacological Activities.

Rapid and large scientific development of the heterocyclic compounds studied, whatever

makes an order and requires research in methods of synthesis and study their properties.

Increases the importance of this type of compounds every year, because of the many uses that

are recognized and try to apply in the areas of human life cost to take advantage of them.

Hence the interest in a comprehensive review of the procedures for studies and research that

has been know about this type of compounds. Interest in studying and identifying

characteristics have appeared in more than a hundred years. Exploit the properties and

transformations that occur in these compounds makes them subject deserves, addition to the

study of the interactions and logical access to new compounds suitable for use in the fields of

medicine, pharmacy, agriculture and industry with the aim of all the service of humanity. The

review of the literature shows that the benzimidazole derivatives are outstandingly effective

compound and number of reviews available for biochemical and pharmacological studies

conformed that their molecules are useful against a wide variety of microorganisms. Because

of their importance, the methods for their synthesis have become a focus of synthetic organic

chemists. Therefore in the present review tried to compile the chemistry of different

derivatives of substituted benzimidazoles as well as various pharmacological activities and

some of the important methodologies used for the synthesis. I hope that the benefit of all

interested, researchers in this area and have this as a reference for those who want to learn

more about this type of pleasant compounds .

Please cite this article in press as Hamdan S. Al-Ebaisat et al. Synthesis, spectral and physical properties of benzimidazole

derivatives -An review. Indo American Journal of Pharm Research.2015:5(02).

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Vol 5, Issue 02, 2015. Hamdan S. Al-Ebaisat et al. ISSN NO: 2231-6876

INTRODUCTION

Benzimidazole is a heterocyclic aromatic compound. Its molecular formula C7H6N2, molecular weight 118.14 g/mol. Also

known as :1H-Benzimidazole, 1,3-benzodiazole, o-benzimidazole, 3-azaindole and benzoglyoxaline. Benzimidazoles have only

limited solubility in water; consequently, minor differences in solubility tend to have a major effect on absorption. Benzimidazole's

production and use as a chemical intermediate in the production of agricultural fungicides may result in its release to the environment

through various waste streams. It is important pharmacophores and a privileged structure in medicinal chemistry. Benzimidazole is

bicyclic in nature which consists of the fusion of benzene and imidazole. Now a days is a moiety of choice which possesses many

pharmacological properties[1].The most prominent benzimidazole compound in nature N-ribosyldimethyl-benzimidazole, which

serve as an axial ligand for cobalt in vitamin B12 [1-3]. Benzimidazole derivatives play important role in medical field with so many

Pharmacological activities such as: analgesic [4-6], anti inflammatory [5-8] , antibacterial [9] , antifungal [10] , antiviral [11,12] ,

anti-helmenthic [13], anticonvulsant [14,15] , anticancer [16,17] , antiulcer [18] ,antihypertensive [19] ,. Historically, the first

benzimidazole was prepared in 1872 by Hoebrecker, who obtained 2,5(or 2,6)-dimethylbenzimidazole by the reduction of 2-nitro-4-

methyl acetanilide [20,21]. Hence the apparent importance of large uses of these compounds, also important to know the methods of

synthesis and characteristics in order to develop and reduce costs in the future. The aim of present review attempted to gather the

various developments in synthesis, spectral and physical properties of benzimidazole derivatives.

SYNTHESIS OF BENZIMIDAZOLES

Researches shows different methods synthesis of benzimidazole derivatives, some of these methods are simple and

inexpensive which can do in laboratory conditions. On the other side there are high costs methods, which need expensive raw

materials, high temperature, and long time. However, present review shows methods synthesis of benzimidazole derivatives including

the difference between them.

One of the most important techniques in the preparation of benzimidazole derivatives known as the Van Leusen method,

which react aldimines with tosylmethylisocynide (TosMIC).Reaction expanded in two step and named as the Van Leusen three-

component reaction (VL-3CR).

Mechanism of this reaction according to a publication by Van Leusen is driven by TosMIC, which contains a reactive

isocyanide carbon, an active methylene group and a leaving group [22a]

Under basic conditions (CH2N=C) moiety can undergo a stepwise cycloaddition to a polarized double bond .

1,5-disubstituted imidazole can be provided by elimination of p-toluenesulfinic acid (TosH) from the intermediate 4-tosyl-2-

imidazoline.

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To complete (VL-3CR) by generated aldimines in situ by condensation of an amine with an aldehydes for 30 minutes.

However (VL-3CR) is not a truemulticomponent reaction, as the components react stepwise. the reaction of aldehydes with

(TosMIC) leads to oxazoles [22b]

Synthesis of 4,5-disubstituted imidazoles can be provided by reaction 1,2-diketones and urotropine in the presence of

ammonium acetate, reaction undergoes rapidly (4 min.),105CO [23]

Another method for synthesis of 1,2,4-trisubstituted 1H-imidazoles was achieved in good yields by heating a mixture of a 2-

bromoacetophenone, an aldehyde, a primary amine, and ammonium acetate under solvent-free conditions, reaction need 2h. of heat

through 130CO [24]

The preparation of biologically active 2,4(5)-diarylimidazoles by parallel synthesis, by using a simple and efficient

approach, reaction undergoes in room temperature , side products depends on the reaction conditions employed [25]

synthesis of 2,4,5-triaryl imidazoles can be by using an improved and rapid one-pot reaction, through 25-120 min. in ionic

liquid,100CO. reaction does not need any added catalyst. This one-pot reaction offers very good isolated yields [26]

Multisubstituted imidazoles in good yields and high regioselectivity using oxygen as an oxidant without the addition of

expensive catalysts, using a copper-catalyzed [3 + 2] cycloaddition reaction,Its undergoes with DMF,90CO,about5h. needed [27]

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Using this type of reactions (copper-catalyzed) between two different isocyanides produces imidazoles, reaction conditions:

THF as solvent,24h. 80CO , products obtained in good yields [28]

Rapidly and simple reaction of stable and readily available 1-sulfonyl triazoles with nitriles gives the corresponding

imidazoles in good yields by rhodium(II)-catalyzed via rhodium iminocarbenoids intermediates, reaction undergoes through 15

minutes [29]

Another efficient reaction using copper-catalyzed regioselective diamination of terminal alkynes with amidines in the

presence of Na2CO3, pyridine, a catalytic amount of CuCl2·2H2O, and oxygen (1 atm), uses as a way to synthesis of diverse 1,2,4-

trisubstituted imidazoles in good yields [30]

Efficient and simple method synthesis asymmetric aryl imidazolium as triazolium salts in good yields using copper catalyst

allows the construction of aryl imidazolium salts from N-substituted imidazoles and diaryliodonium salts. Reaction undergoes in

DMF,100CO,(4-48h) [31]

A new class of substituted 2-aminoimidazoles via [3+2] annulations in good yields synthesized according to reactions of

propargylamines with carbodiimides, in the presence of 5 mol% of the titanacarborane monoamide, reaction uses toluene, heat

at115CO,

18h. [32]

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Readily accessible 2-azido acrylates and nitrones proceeded under mild conditions without any metal, acid, or base, used to

synthesized 1,2,4,5-tetrasubstituted imidazoles, heat to 66CO,48h.this method considered as highly efficient and convenient, excellent

yields obtained [33]

Reaction in a gold-catalyzed synthesis of bicyclic imidazoles with highly electrophilic α-imino gold carbene intermediate can

react with a weakly nucleophilic nitrile, which is used as the reaction solvent, to deliver the desired product rapidly in an overall

bimolecular [2 + 2 + 1] cycloaddition, good yields obtained at room temperature (for 6-20h.), by using AuCl3 as a catalyst [34]

Conversion of aromatic and heteroaromatic 2-nitroamines into bicyclic 2H-benzimidazoles employs formic acid, iron

powder, and NH4Cl as additive to reduce the nitro group and effect the imidazole cyclization with high-yielding conversions consider

one-pot procedure within(1-2 h.).The compatibility with a wide range of functional groups demonstrates the general utility of this

procedure [35]

Benzazoles can be synthesized from alkyl amines and o-hydroxy/amino/mercaptan anilines using of elemental sulfur as

traceless oxidizing agent enables a remarkably simple solvent-free and catalyst-free synthesis, reactions heat about 130CO,(16-20 h.)

good yields obtained [36]

Benzoxazole, benzothiazole, and benzimidazole derivatives in an efficient and connective methodology also synthesized by

the reaction of ortho-substituted anilines with functionalized orthoesters.The versatility of this approach enables the development of

new libraries of heterocycles containing multifunctional sites, reaction undergoes in DCM, at room tempruture,needs (2-4 h.) [37]

Benzimidazoles and imidazopyridines synthesized smoothly under mild conditions in isopropyl alcohol at 70°C,at 3-30 h.

using 2,2,2-trichloroethyl imidates as the acylating agents, by addition of sodium acetate proved to be beneficial in cases where

cyclization proceeded slowly. For substrates with poor nucleophilicity, using the more inert tert-amyl alcohol enabled superior

reactions [38]

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Synthesis of 2-substituted benzimidazoles and benzothizoles by using a convenient method for the offers short reaction time

(70 min.),through 50CO, large-scale synthesis, easy and quick isolation of the products, excellent chemo selectivity, and excellent

yields as main advantages for this method [39]

Another method one-pot, uses copper-catalyzed, three-component reaction of 2-haloanilines,aldehydes, and NaN3 enabled the

synthesis of benzimidazoles in good yields using catalytic a mounds of CuCl and TMEDA in DMSO at 120°C for 12 h. The reaction

tolerated many functional groups such as ester, nitro, bromo and chloro [40]

Synthesis of 1,2-disubstituted benzimidazoles by oxidative C-H amination of N-aryl-N-tosyl/ N-methylsulfonylamidines

and N,N-bis(aryl)amidines in the presence of mCPBA as terminal oxidant at room temperature,2-12h. by used iodobenzene as a

catalyst. The reaction is general, and the target products can be obtained in good yields [41]

Substituted 1H-benzimidazoles and 1,3-dihydrobenzimidazol-2-ones,obtaind in good yields using CuI/l-proline catalyzed

coupling of aqueous ammonia with 2-iodoacetanilides and 2-iodophenyl-carbamates affords aryl amination products at room

temperature, in DMSO,3-7 H. which undergo in situ additive cyclization under acidic conditions [42]

2-aminobenzimidazoles,2-aminobenzothiazoles, and benzoxazoles obtained via intramolecular cyclization of o-bromoaryl

derivatives is catalyzed by copper(II) oxide nanoparticles in DMSO under air. The heterogeneous catalyst can be recovered and

recycled without loss of activity, method very simple, efficient,at3-24 h. [43]

Transformation of N-benzyl bisarylhydrazones and bisaryloxime ethers to functionalized 2-aryl-N-benzylbenzimidazoles and

2-arylbenzoxazoles involves a copper(II)-mediated cascade C-H functionalization/C-N/C-O bond formation under neutral conditions.

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Substrates having either electron-donating or -withdrawing substituents undergo the cyclization at moderate temperature. Method also

simple ,efficient and can be used under laboratory conditions [44]

Ortho-diamines or ortho-aminothiophenol and aldehydes using chlorotrimethylsilane in DMF as a promoter and water-

acceptor agent, followed by oxidation with air oxygen using to preparation a set of benzimidazoles, 3H-imidazo[4,5-b]pyridines,

purines, xanthines and benzothiazole, reaction undergoes rapidly (2-4 h.),at 90CO . [45]

Reaction provides quick access to various substituted products, using a Pd-catalyzed amide coupling reaction enables a facile

synthesis of imidazo[4,5-b] pyridines and –pyrazines. A model system relevant to the natural product pentosidine has been

demonstrated, reaction is used on a large scale and the advantage of fast and appropriate heat [46]

Another excellent, highly efficient and versatile method for the synthesis of a series of 2-substituted N-H, N-alkyl, and N-aryl

benzimidazoles containing a wide range of functional groups was achieved in one step via the Na2S2O4 reduction of o-nitroanilines in

the presence of aldehydes. Alcohol is used as a solvent and the proper temperature as well as the appropriate time [47]

Synthesis of substituted benzimidazoles through a one-pot condensation of o-phenylenediamines with aryl aldehydes in the

presence of H2O2 and HCl in acetonitrile at room temperature features short reaction time, easy and quick isolation of the products,

using a simple and efficient method, in result good yields obtained [48]

Reaction between phenylenediamines and aldehydes via a one-step process using hypervalent iodine as oxidant gives 2-

arylbenzimidazoles.This method features mild conditions, short reaction times (3-5 min.),at room temperature, high yields, and a

simple procedure [49]

Formation of benzimidazoles under very mild conditions, when a mixture of a 1,2-phenylenediamine and an aldehyde in wet

DMF results added to oxone in rapid at room temperature. Products are isolated in high purity in most cases by simple aqueous

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precipitation. The reaction is applicable to a wide range of substrates but does not allow the conversion of aldehydes that are sensitive

to oxone under acidic reaction conditions [50]

The preparation of 2-substituted benzimidazoles from 1,2-phenylenediamines and triacyloxyborane intermediates generated

in situ from carboxylic acids and borane-THF.This protocol tolerates acid-labile functional groups. This is a mild and efficient one-pot

synthesis, which react at room temperature, but note the addition will be after 30 min. [51]

Reactions of o-aminoanilines or naphthalene-1,8-diamine with terminal alkynes and p-tolylsulfonyl azide allow a one-pot

synthesis of functionalized benzimidazoles and 1H-pyrimidines in good yields, reaction uses 3.7eq.H2SO4,at 4h [52]

Reaction of carbonitriles and N-methyl-1,2-phenylenediamine using a NaH -mediated allows the formation of N-

methylbenzimidazole and tolerates acid-labile acetal protective groups. Reaction undergoes with (120-180 CO), 3-23 h. Products were

further in good yields are pure crystalline [53]

A good, efficient, and sustainable method for intramolecular N-arylation provides a library of benzimidazoles in high yields

using Cu2O as the catalyst, DMEDA as the ligand, and K2CO3 as the base. Remarkably, the reaction was exclusively carried out in

water, rendering the methodology highly valuable from both environmental and economical points of view, reaction needs 30h. 100CO

to complete [54]

Common arylamino oximes in good yields depending upon the base used in the reaction gives N-aryl-1H-indazoles and

benzimidazoles. Triethylamine promoted the formation of benzimidazoles, where as 2-aminopyridine promoted the formation of N-

arylindazoles. Reaction conditions are easy, that make a possible synthesis in laboratory [55]

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Synthesis of a wide variety of 2-heterobenzimidazoles from o-haloarylcarbodiimides and N- or o-nucleophiles used by Cu(I)-

catalyzed cascade intermolecular addition/intramolecular C-N coupling process. Method consider as an efficient, uses dioxane, at

70Co, (20-30 h.)where good yields are obtained [56]

An efficient method preparation of 2-Imidazolines in good yields from the reaction of aldehydes and ethylenediamine with

iodine in the presence of potassium carbonate. The 2-imidazolines were smoothly oxidized to the corresponding imidazoles using

(diacetoxyiodo)benzene, DMSO, at room temperature through 24h [57]

Reactions of IBX with heteroatom-containing substrates were discovered and their utility was demonstrated. IBX was used

for the generation of imines from secondary amines in notably high yields, for the oxidative aromatization of nitrogen heterocycles

and for the cleavage of dithianes. This is a new type of reactions, which it can be used easy, with DMSO,45Co,for 14 h. [58]

An efficient one-pot method in good yields can allows the preparation of differently substituted symmetrical and

unsymmetrical imidazolium salts from readily available formamidines and α-halo ketones. For many substitution patterns of the

imidazolium salt products, this efficient strategy compares favorably with well-known processes in terms of yield, easy of synthesis,

and uses toluene, and nearly 90Co [59]

Synthesis of 3-methyl-2-arylimidazo[1,2-a]pyridine derivatives from amino pyridines and 2-methyl-nitroolefins,when using

an iron-catalyzed denitration reaction in good yields, using DMF as solvent. The procedure is simple and inexpensive and tolerates

various functional groups. [60]

Methylimidazo[1,2-a]pyridines, imidazo[1,2-a]pyrazines, and imidazo[2,1-a] isoquinolines without any addition of catalyst

synthesized in aqueous, using acetonitrile as solvent, when used Ag-catalyzed intramolecular amino oxygenation produced

imidazo[1,2-a] pyridine-3-carbaldehydes [61]

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Afforded therapeutically important versatile N-fused imidazoles were synthesized when a mixed Cu(I)-Cu(II) system in situ

generated by partial reduction of CuSO4 with glucose, an efficient and eco-friendly multicomponent cascade reaction of A3-coupling

of heterocyclic amidine with aldehyde and alkyne,5-exo dig cycloisomerization, and prototropic shift. Reaction has been done

refluxing in EtOH [62]

Corresponding imidazo[1,2-a]pyridines in high yields also synthesized by using one-pot reaction of aldehydes, 2-aminopyridines, and

terminal alkynes, in the presence of the copper(I) iodide-CuI-NaHSO4. SiO2 combination catalyst in refluxing toluene, for (12-14 h.)

[63]

Corresponding imidazo[1,2-a]pyridines in excellent yields, also synthesized by reaction N-Phenacylpyridinium bromides,

which were prepared in situ from the addition of pyridines to α-bromoketones, undergo nucleophilic addition of ammonium acetate

under microwave irradiation and solvent-free conditions, reaction needs two step to complete rapidly, products are useful in

pharmacies studies [64]

3-arylimidazo[1,2-a]pyridines was synthesized by a catalyst-free cascade process from 2-aminopyridine and 1-bromo-2-

phenylacetylene or 1,1-dibromo-2-phenylethene in yields up to 86%. Reaction undergoes with DMF,120CO,(24-48h.) [65]

Affords imidazo[1,5-a]pyridines in good yields, obtained by using metal-free sequential dual oxidative amination of C(sp3)-H

bonds under ambient conditions. The reaction involves two oxidative C-N couplings and one oxidative dehydrogenation process with

six hydrogen atoms removed, used DMF as solvent at room temperature for 12 h [66]

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One-pot procedure enables the synthesis of imidazo[1,2-a] pyridines with amino pyridines and nitro olefins using air as

oxidant in copper-catalyzed. This general reaction appears to be very suitable for the construction of various imidazo[1,2-a] pyridines

in DMF, at 80Co,for 4 h [67]

One of the important reactions in this field is that the regioselective and high-yielding Groebke-Blackburn-Bienaymé

reaction, glyoxylic acid is used as formaldehyde equivalent leading to a regioselective, mild, convenient, and effective synthesis of 3-

aminoalkyl imidazoazines.Reaction undergoes at room temperature, using MeOH, for 12 h. [68]

Affords various 2,8-diaryl-6-aminoimidazo[1,2-a]pyridines in good yield and easy conditions;(R2NH as solvent,80Co,10-30

min.) were synthesized by using an efficient microwave-assisted metal-free amino benzannulation of aryl(4-aryl-1-(prop-2-ynyl)-1H-

imidazol-2-yl)methanone with dialkylamines [69]

Coupling three-component reaction of substituted picolinaldehydes, amines, and formaldehyde produces imidazo[1,5-

a]pyridinium ions in high yields under mild conditions, allowing the incorporation of diverse functionality and chiral substituents.

Higher order condensations are also described that provide access to multidentate NHC ligands useful for a variety of applications.

Reaction uses EtOH at room temperature, for 1-12h. [70]

SPECTRAL PROPERTIES OF BENZIMIDAZOLES

1) Nuclear magnetic resonance (NMR) spectroscopy: An important feature of this work is that the protonation parameters derived

from simple five and six membered heterocycles can be used to predict chemical shift changes resulting from nitrogen

protonation and deprotonation in more complex molecules (7-9ppm) values shows multiplet indicates the presence of

benzimidazole aryl ring.

2) 13Carbon( NMR): The spectra shows different carbon peaks at range of δ(0-200ppm) compared to TMS. For benzimidazoles the

range starts from δ(115-145ppm).Overlapping is easily confirmed by triplet, doublet peaks obtained. Low intensity peaks show

the presence of proton less carbons. So carbonyl group at which position is recognized [21].

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3) Infra red (IR) spectroscopy: The absorption spectra of benzimidazole near the 2850cm-1 indicates the presence of the aryl ring ,

absorption near the 3170cm-1 indicates the presence of N -H stretch and 1690cm-1 indicates the presence of C-N stretch.

4) Mass spectroscopy: The fragmentation pathways of simple benzimidazoles are similar to those of imidazoles. The spectrum of

benzimidazole indicates a sequential loss of two molecules of hydrogen cyanide from the molecular ion, the first of which is

nonspecific as evidenced by deuterium labeling procedures. A characteristic feature in the fragmentation of 2-n-propyl-

benzimidazole is the elimination of ethylene from the molecular ion, 2-acylthiophenes,2-acyl and 2-benzoylbenzimidazoles are

characterized by loss of carbon monoxide from the molecular ion.

PHYSICAL PROPERTIES OF BENZIMIDAZOLES

Benzimidazole, molecular formula C7H6N2 - C, stable, combustible,

Incompatible with strong oxidizing agent, sparingly soluble in water [20]. The melting point of number of the benzimidazoles

indicated that the introduction of a substituent into 1-position in general lowers the melting point. Benzimidazoles with the imide

nitrogen are usually soluble in polar solvents and less soluble in organic solvents. With introduction of other non-polar substituents in

various positions of the benzimidazole ring, the solubility in nonpolar solvents is increased. Conversely, the introduction of polar

C. Benzimidazoles

are weakly basic, being somewhat less basic than the imidazoles and are in general soluble in dilute acids. Benzimidazoles are also

sufficiently acidic to be generally soluble in aqueous alkali and form N-metallic compounds. The acidic properties of the

benzimidazoles, like those of the imidazoles, seem to be due to stabilization of ion by resonance. The more acidic benzimidazoles may

be soluble in less basic solution, such as potassium carbonate solution [21,22].

CONCLUSION

Through different studies of benzimidazole derivatives, it is clear that there is considerable interest from chemists and

pharmacists. The reason is due to their characteristics and multiple reactions of these compounds. Derivatives have many uses in

various fields of life such as medicine, pharmacy, agriculture, industry and others. They are a large number of researches and studies

of properties, methods of preparation of benzimidazoles derivatives since the middle of the last century. There were good results in the

knowledge of the properties and there were multiple methods of preparation that have aims to facilitate and reduce costs in the process

of preparation of these compounds. Rapid and large scientific development has to be a comprehensive review of the methods of

preparation of this type of compounds. The goal of which is to know what has been studied, as well as to pave the methods in terms of

finding new methods to serve researchers in the future. This was the goal of this report.

ACKNOWLEDGEMENT The author gratefully acknowledges to the assistant Dr. Shadi H. in reviewing this article (University Culture Center, Aqaba-

Jordan)

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