Journal of Saudi Chemical Society (2017) 21, 229–237

King Saud University

Journal of Saudi Chemical Society

www.ksu.edu.sawww.sciencedirect.com

ORIGINAL ARTICLE

Synthetic approaches to benzimidazoles from

o-phenylenediamine: A literature review

E-mail address: shalaqeel@ksu.edu.sa

Peer review under responsibility of King Saud University.

Production and hosting by Elsevier

http://dx.doi.org/10.1016/j.jscs.2016.08.0011319-6103 � 2016 King Saud University. Production and hosting by Elsevier B.V.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Shatha Ibrahim Alaqeel

Department of Chemistry, College of Science, King Saud University (034), Riyadh 11495, Saudi Arabia

Received 17 December 2015; revised 2 February 2016; accepted 5 August 2016

Available online 13 August 2016

KEYWORDS

Benzimidazole nucleus;

o-Phenylenediamine;

Pharmacological activity;

Therapeutic compound

Abstract The methods for the synthesis of benzimidazoles have become a focus of synthetic

organic chemists, as they are useful building blocks for the development of important therapeutic

compounds in medicine. Benzimidazole nucleus plays a very important role as a therapeutic agent

e.g. antiulcer and anthelmintic drugs. Other benzimidazole derivatives exhibit pharmacological

activities such as antimicrobial, antiviral, anticancer, anti-inflammatory and analgesic.� 2016 King Saud University. Production and hosting by Elsevier B.V. This is an open access article under

the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Among heterocyclic pharmacophores, the benzimidazole ringsystem is quite common. These substructures are often called

‘privileged’ due to their wide recurrence in bioactive com-pounds. Although there is great interest in benzimidazoleligands and structural chemistry, the main interest is in theirbiological activities.

The early 1950s was an important period regarding discov-ery of the biological significance of benzimidazole-containingstructures and the closely-related purines (Fig. 1). The 5,6-di

methyl-1-(a-D-ribofuranosyl)benzimidazole ring system wasdiscovered in 1948 as an integral part of the structure of vita-min B12 [1] (Fig. 1).

Subsequently pharmaceutical, veterinary and agrochemicalproducts were discovered including thiabendazole, cimetidine,

azomycin, metronidazole, misonidazole, and chlotrimazole,

antihistamines, astemizole and the anti-ulcerative omeprazole)[2].

Benzimidazole-based drugs exhibit a wide range of different

biological activities as a result of changing the groups on thecore structure, as shown in Fig. 2. These biological activitiesinclude anti-cancer (1) [3], bactericidal (2), [4], fungicidal (3)

[5] and [6], analgesic (4) [7] and anti-viral properties (5) [8].Some have cardiovascular applications (6) [9] while somederivatives have been synthesized and evaluated for inhibition

of HIV-1 infectivity [10].

2. Synthesis of benzimidazoles

The first benzimidazole was prepared by Hoebrecker [11], whoobtained 2,5-dimethylbenzimidazole by the reduction anddehydration of 2-nitro-4-methylacetanilide (Scheme 1).

Almost all syntheses of benzimidazoles start with benzene

derivatives possessing nitrogen-containing functions ortho toeach other (Fig. 3) that is, the starting material possesses thefunction designated by formula many methods have been

reported for the synthesis of benzimidazols. Most of thesemethods involve the condensation of ortho-

N

N NH

N

Purine

NN

NN

Co

H3C

H3C

H3C

CH3

CH3N

N

CH3H

CH3CH3

CH3CO

CH2OHH

OP

-O

O

HOO

C

O

NH

H3CH

NC

H

CH3

NH2

O

NH2

O

NH2O

H2N

OH2N

O

vitamin B 12

Figure 1 Some imidazole containing bioactive compounds.

230 S.I. Alaqeel

phenylenediamine, and its derivatives with carboxylic acids, or

aldehydes.Various catalyzed synthesis of benzimidazole derivatives

are known condensation of o-phenylenediamine with orthoesters in the presence of various lewis acid catalyst is also

known such as ZrCl4, SnCl4, TiCl4, ZrOCl2�9H2O and HFCl4.Here a number of different synthetic methods for benzimi-

dazoles have been grouped according to the starting material

of o-phenylene diamines [12].

Imet 3393 (Anticancer)

(Bacte

Bezitramide (Analgesic)

NH

NCH2CH2CH2CO2H

NClH2CH2C

ClH2CH2C

(Anti-vira

2

1

4

5

S N

H

COOEt

NNO

N

N

Cl

NH

N

Figure 2 Some benzimida

2.1. By reaction with carboxylic acids

Literature survey has revealed that o-phenylenediamines reactreadily with most carboxylic acids to give 2-substituted benz-imidazoles, usually in very good yields. The reaction is carried

out usually by heating the reactants together on a steam bath,by heating together under reflux or at an elevated temperature,or by heating in a sealed tube [13] (Scheme 2).

The most commonly used (Phillip’s method [14], involves

the condensation of o-diaminobenzenes with carboxylic acidsor its derivatives, including heating the reagents together inthe presence of concentrated hydrochloric acid (Scheme 3), this

is the most common synthetic method for preparation of awide range of benzimidazoles.

Hollan et al. who have reported the reaction of the

appropriate imidate ester (trichloroacetimidate) with o-phenylenediamine or its salt gives the 2-trichloromethylbenzimidazole (Scheme 4) only at room temperature, and this

is an important precursor for 2-carboxylic benzimidazoles [15].Rithe et al. have reported various of 2-substituted benzim-

idazole derivatives in moderate to good yield have beenprepared in one-spot reaction by condensation of

o-phenylenediamine (0.01 mol) and different aromatic acid(0.01 mol) in the presence of ammonium chloride as catalystat 80–90 �C (Scheme 5). The reaction is green and economi-

cally viable [16].Recently Saberi has reported synthesis of 2-benzimidazoles

under microwave irradiation and solvent-free conditions which

is catalyzed by alumina, silica gel and zeolite HY As shown inScheme 6, o-phenylenediamine (2 mmol) with aromatic, ali-phatic and heterocyclic carboxylic (2 mmol) and 50 mg of Alu-mina or Silica gel or Zeolite were mixed thoroughly in a

mortar. The reaction mixture was then irradiated in a domesticmicrowave oven for 5–9 min at 160–560 W [17].

NH

NNH

OCH3

O

ricide)

Carbendazim (Fungicide)

Diabazole (Vasodilator spasmlytichypotensive)

l)

NH

HN

CH2PhCl

3

6

CH2CH2CO2H

SO

OCH3

S

zole containing drugs.

NH2

O

OHR

N

N

H

R + 2H2O

NH2

Scheme 2

NH2

NH2R OH

OHCl (4N)

N

HN

R

Scheme 3

NH2

NH2 NHO

CCl3AcOH

RT+

N

HN

CCl3

Scheme 4

NH2

NH2R OH

OEtOH.NH4Cl

N

HN

R80-90 oC

Scheme 5

NH2

NH2R OH

O

N

HN

R

MW

MW

MW

Zeolite HY

Silica gel

Alumina(acidic)

Scheme 6

NO2

NHCOCH3

H3CSn

HCl

NH2

NHCOCH3

H3C-H2O

N

NCH3

H3C

H

Scheme 1

HN

NH

H

HR

Figure 3 Ortho di nitrogen compounds.

Synthetic approaches to benzimidazoles from o-phenylenediamine 231

2.2. By reaction with aldehydes

Under the correct conditions aldehydes may react with o-phenylenediamines to yield 2-substituted benzimidazoles(Scheme 7).

Since an oxidation is involved, the reaction is best carriedout under oxidative conditions. This oxidation may be broughtabout by the air or, more conveniently, by the use of other oxi-dizing agents such as cupric acetate. This latter reagent was

first introduced by Weidenhagen [13]. Weidenhagen’s methodconsists in reacting the diamine and aldehyde in water or alco-holic solution in the presence of cupric acetate or a similar cup-

ric salt. The cuprous salt of the benzimidazole separates, andby means of hydrogen sulfide it may be readily decomposedto the free benzimidazole and cuprous sulfide. The sulfide

may be removed readily by filtration (Scheme 8). By meansof Weidenhagen’s method excellent yields of 2-substituted ben-zimidazoles may be obtained.

The condensation of phenylenediamines with aldehydes isachieved by various reported conditions. As shown inScheme 9, this can be achieved in the presence of sodiummetabisulphite [18].

Suheyla et al. who have reported this reaction rely on pre-forming the bisulfite adduct of the aryl aldehyde to preparebenzimidazole, in which an ethanolic solution of aryl aldehyde

was added separately to an aqueous solution of sodiummetabisulphite; the adduct formed precipitated from the reac-tion was filtered and dried. The o-phenylenediamine in DMF

was then added to the adduct and the mixture was heated at130 �C for several hours affording benzimidazole (Scheme 10).

Or heating in the presence of nitro benzene [19]. Mann et al.

used a mixture of unsubstituted or substituted phenylenedi-amine and appropriate aldehyde in nitrobenzene heated at140 �C., the mixture was cooled and filtered after adding waterwhich gives benzamidazole (Scheme 11).

Venkateswarlu et al. have reported the synthesis of benzim-idazole derivatives, with the use of lanthanum chloride as anefficient catalyst One-pot synthesis of 2-substituted benzimida-

zole derivatives from o-phenylenediamine and a variety ofaldehyde were carried out in the presence of lanthanum chlo-ride (10 mol%) in acetonitrile at room temperature [20]

(Scheme 12).The other way was synthesized by Lin et al. involving a

direct one step synthesis of various benzimidazoles fromphenylenediamines and aldehydes that includes air as oxidant

[21] (Scheme 13).Rushi et al. have reported 2-substituted benzimidazoles

have been synthesized in excellent yields in a single pot under

solvent-free conditions from o-phenylenediamine and aldehy-des in the presence of a catalytic amount of indium triflate[In(OTf)3] at room temperature [22] (Scheme 14).

A series of benzimidazole derivatives were synthesized ingood to high yields by reaction of o-phenylenediamine and dif-ferent aromatic aldehydes in the presence of sodium hex-

NH2

NH2

+ RCHONH

NR

-H2N

NH2

CHR

Scheme 7

NH2

NH2

.2HCl +R1CHO + 2(CH3COO)2CuN

N

H

+ 4 CH3COOH + H2OR1 . Cu2Cl2

Scheme 8

NH2

NH2

F

N

O

H

O

+

Cl

ClNa2S2O5DMF

N

HN

Cl

Cl

N

O

F

Scheme 9

Ar-CHO OH

H

Ar

SO3Na

NH2

NH2

N

HN

Ar

Scheme 10

+PhNO2

heat

NH2

NH2

O

H

O2N N

HN

NO2

Scheme 11

NH2

NH2+

N

N

H

CHO

R

LaCl3

CH3CN R.T

R

R= H,Alkyl, Aryl

Scheme 12

NH2

NH2+

N

N

H

air solventH

O

reflux or 100 oC

Scheme 13

232 S.I. Alaqeel

afluroaluminate, Na3AlF6, as an efficient catalyst at 50 �C [23](Scheme 15).

Birajdar et al. have synthesized a mild and efficientapproach for the synthesis of benzimidazole ring [24] through

oxidative cyclization of o-phenylenediamine and different alde-hydes using dioxane dibromide, as a user-friendly reagent. This

is a new, convenient and facile methodology for the synthesisof 2-substituted-1H-benzo[d]imidazoles (Scheme 16).

NH2

NH2+

N

N

H

In(OTf)3RR H

O

Scheme 14

NH2

NH2+

N

N

H

EtOHArAr H

O

Na3AlF6

Scheme 15

NH2

NH2+

N

N

H

Dioxane dibromide RR H

O

Acetonitrile 30-60 min. ,rt.

Scheme 16

NH2

NH2+

N

NIodine / Water RR H

O

80-90 oC / 1.2-1.5 h2

R

Scheme 20

Synthetic approaches to benzimidazoles from o-phenylenediamine 233

Srinivasulu1 et al. one-pot synthesis of 2-substituted benz-

imidazole derivatives from o-phynelyenediamine and substi-tuted aldehydes were developed under zinc triflate in ethanolsolvent at reflux temperature [25] as shown in Scheme 17.

Sehyun et al. have reported the reaction of o-phenylenediamine and a variety of aliphatic/aromatic aldehy-des [26] in methanol proceeds at room temperature with only

natural sources, molecular oxygen and visible light irradiationwith blue LEDs (Scheme 18).

Vishvanath et al. have used nickel acetate efficiently cat-alyzed the synthesis of benzimidazole derivatives [27] and in

this method is involved a mixture of benzaldehyde (1 mmol)and o-phenylene diamine (1 mmol) with Nickel Acetate

NH2

NH2+

Zn (H

O

Ethreflu

R

Scheme 1

NH2

NH2+

O2R H

O

Me

blu

Scheme 1

NH2

NH2+

NR' H

O

CR

Scheme 1

(0.1 mmol) that was stirred magnetically with CHCl3 at roomtemperature as shown in Scheme 19.

Iodine catalyzed synthesis of 2-Aryl-1-arylmethyl-1H-

benzimidazoles is demonstrated by Aniket et al. usingphenylenediamine and aldehydes which are carried out at80–90 �C. New approach is promising and giving moderate

yields with high purity and selectively single product in aque-ous media [28] (Scheme 20).

Pardeshi et al. have synthesized a simple, efficient and selec-tive method [29] for the synthesis of 2-aryl benzimidazole

through the reaction of ophenylenediamine with aryl aldehydesin aqueous media in the presence of sodium dodecyl sulfate asshown in Scheme 21.

2.3. By reaction with acid anhydrides

Literature survey has revealed that the reaction of acid anhy-

drides and o-phenylenediamines will lead to benzimidazolesor to N,N0-diacylphenylenediamines depending on the condi-tions employed. It was formerly thought that o-

phenylenediamine yields benzimidazoles with acids and diacylderivatives with acid anhydrides; however, this was shown tobe incorrect. Time appears to be a decisive factor and if therefluxing is continued long enough benzimidazoles may be

obtained, usually in good yields. o-Phenylenediamines whenheated under reflux for several hours with acetic anhydride iscompletely converted to 2-methylbenzimidazole [13]

(Scheme 22).

N

N

H

OTf)2

anolx, 8h

R

7

N

N

H

(from air) ROH (0.1M) ,r.t

e LEDs (7W)

R= aliphatic, aromatic

8

N

N

H

i (OAc)2 R'

HCl3 ,RT R

9

NH2

NH2+

N

N

H

sodium dodecyl sulfate (10 molArAr H

O

WaterRR

Scheme 21

NH2

NH2+ 2 (CH3CO)2O

N

NCH3

H

+ 3 CH3COOH

Scheme 22

234 S.I. Alaqeel

The reaction of o-phenylenediamines with acetic anhydridehas been carried out with acetic anhydride alone or with acetic

anhydride to which has been added sodium acetate, mineralacids, or acetic acid.

Excellent results have been obtained by employing the

modification of Phillips involving the addition of dilute min-eral acids (usually about 4 N hydrochloric acid) to the reactionmixture. Thus, 2-methylbenzimidazole may be obtained in

93.3% yield from o-phenylenediamine and acetic anhydrideon heating with 15% hydrochloric acid.

2.4. By reaction with esters

Reaction of o-phenylenediamines with esters also yields benz-imidazoles. Von Niementowski first investigated the reactionof esters and o-phenylenediamines to give benzimidazoles.

Equimolecular amounts of 3,4-diaminotoluene dihydrochlo-ride and ethyl formate when heated in a sealed tube for 3 hat 225 �C give 84% of 5(or 6)-methylbenzimidazole hydrochlo-

ride [13] (Scheme 23).The product is not further alkylated by the ethyl chloride

formed. Ethyl acetate under the same conditions gives only a

poor yield of 2,5(or 2,6)-dimethylbenzimidazole, and pooryields of benzimidazoles would probably be obtained fromesters of acids of higher molecular weight. A good yield of 2-methylbenzimidazole may be obtained by allowing a mixture

of o-phenylenediamine and ethyl acetate to stand.

2.5. By reaction with amides

Relatively few amides have been used for the synthesis of ben-zimidazoles. However, good yields have been obtained in mostcases. The amides that have been used are listed in Table 1.

Equimolecular amounts of o-phenylenediamine dihy-drochloride and benzamide when heated to 240–250 �C givean almost quantitative yield of 2-phenylbenzimidazole.

2.6. by reaction with urea

Rathod et al. have used o-phenylenediamine dihydrochlorideand when it was heated with urea at 130 �C. gives 2(3H)-

benzimidazolone (Scheme 24).This general method has been used also for the preparation

of substituted benzimidazolones [13]. By heating o-

phenylenediamine and urea under reflux in amyl alcohol solu-

tion until the evolution of ammonia ceased, Mistry and Guhahave obtained a 95% yield of 2(3H)-benzimidazolone.

2.7. By reaction with acid chlorides

The action of acid chlorides on o-phenylenediamines leads to

benzimidazoles or monoacylated or diacylated o-phenylenediamines, depending upon experimental conditions.Acetyl chloride with 3,4-diaminotoluene in benzene solution

yields 2,5 (or 2, 6)-dimethylbenzimidazole if the reaction is car-ried out without cooling and diacetyl-o-phenylenediaminewhen the reaction is cooled (Scheme 25).

Most reactions between o-phenylenediamines and acid

chlorides to give benzimidazoles have been carried out witharoyl chlorides. The reactions are carried out usually by heat-ing the components together at about 200–220 �C., by heating

under reflux, or by heating on a steam bath in the presence ofpyridine or a similar basic substance. Since benzimidazoleswhich possess no grouping in the l-position may undergo acy-

lation with acid chlorides, most reactions have been carried outwith N-substituted o-phenylenediamines. Table 2 lists the com-pounds that have been prepared by the reaction of acid chlo-

rides and N-substituted o-phenylenediamines.

2.8. By reaction with nitriles

Cyanogen bromide will react with o-phenylenediamines to

yield 2-aminobenzimidazoles in good yields; for example, 2-aminobenzimidazole may be prepared from cyanogen bromideand o-phenylenediamine (Scheme 26).

The reaction is carried out by mixing equimolecularamounts of the reactants in aqueous suspension.

Pellizzari has obtained benzimidazole derivatives by treat-

ment of o-aminophenylurea with cyanogen bromide(Scheme 27).

O-phenylene-a-guanylurea is unstable and tends to hydro-

lyze to 2-aminobenzimidazole.Heating the monohydrochloride of o-phenylenediamine

with an aliphatic or an aromatic nitrile at 200 �C results inthe formation of a 2-substituted benzimidazoles. o-

Phenylenediamine, itself, fails to react with benzonitrile at200 �C, indicating that benzimidazole formation depends uponthe presence of acid. Formation of a mixture of an imino chlo-

ride and o-phenylenediamine may be the rate-determining stepof the reaction. The combination of these two substances could

NH2

NH2

H3C

.2HCl + HCOOC2H5N

N

H

H3C

HCl + 2H2O + C2H5Cl

Scheme 23

Table 1 Benzamidazoles from amides.

Diamine Amide Product

NH2

NH2

H3C

.2HClHCONH2 N

N

H

H3C

NH2

NH2

H3C

.2HClCH3CONH2 N

N

H

H3C

CH3

NH2

NH2

H3C

.2HClC6H5CONH2 N

N

H

H3C

C6H5

NH2

NH2

.2HCl + NH2CONH2NCO

HN

H

+ 2NH4HCl

Scheme 24

NH2

OCl

C6H6

N

N

H

H3C

CH3

NH2

Scheme 25

Table 2 Benzamidazoles from acid chlorides and N-substi-

tuted-o-phenylenedimines.

Diamine Acid chloride Product

NH2

NHC2H5CH3COCl N

N

C2H5

CH3

NH2

NHC6H5C6H5COCl N

N

C6H5

C6H5

NH2

NH2+ BrCN

NH

NNH2 .HBr

Scheme 26

Synthetic approaches to benzimidazoles from o-phenylenediamine 235

lead to formation of hydrochloride of an o-aminophenyl sub-stituted amidine, which could lose the elements of ammonium

chloride to give the 2-substituted benzimidazole (Scheme 28).This scheme is supported by the observation that N-

phenylbenzimino chloride react with o-phenylenediamine to

give 2-phenylbenzimidazole.

Nitriles that have been used in the synthesis of benzimida-zoles are listed in Table 3.

2.9. By reaction with ketones

The reaction of o-phenylenediamines with a number of ketones

has been investigated by Elderfield and Kreysa. The reactionoccurs as indicated in Scheme 29.

In several cases the product represented by R00H was iso-

lated and identified.Ladenburg and Rugheimer have obtained 2-phenyl-5 (or

6)-methylbenzimidazole by heating 3,4-diaminotoluene withacetophenone at 180 �C for some time. Here again the methyl

group is the one that is eliminated preferentially (Scheme 30).

NHCONH2

NH2+ BrCN

NHCN

NHCONH2 moist air

or water N

NNH2

CONH2

NH

NNH2

Hydrolysis

o-Phenylene-a-guanylurea

Scheme 27

NH2

NH2

.HCl + RCND

NH2

NH2

+ CHN R

Cl

HN

N

HN

RNH4Cl + C R

NH2ClNH2

Scheme 28

Table 3 Benzimidazoles from nitriles.

Diamine Nitrile Product

o-Phenylenediamine HCN Benzimidazole

o-Phenylenediamine CH3CN 2-Methylbenzimidazole

o-Phenylenediamine C2H5CN 2-Ethylbenzimidazole

o-Phenylenediamine C6H5CN 2-phenylbenzimidazole

NH2

NHR+ R1COR11

R = H or alkyl

Scheme 2

NH2

NH2

+ CH3COC6H5

H3C H

Scheme 3

NH2

NH2+ CO

R

R1 NC

HN

H

R

R1

Scheme 3

236 S.I. Alaqeel

o-Phenylenediamine reacts with ketones to form 2-disubstituted benzimidazolines, these decompose under the

influence of heat with the formation of a 2-substituted benzim-idazole and a hydrocarbon. The decomposition of unsymmet-rically substituted benzimidazoline may lead to formation of

two different benzimidazoles depending upon whether the sub-stituent R or the substituent R0 is eliminated preferentially(Scheme 31).

N

HN

R

-R11HN

N

R

R1CR1R11

9

NH

NC6H5

3C

+ CH4 + H2O

0

heatN

HN

R

N

HN

R1 R H+

R1 H

1

NH2

NHC6H5 N

NO2N

HC(OC2H5)3O2N

C6H5

+ 3C2H5OH

Scheme 32

Synthetic approaches to benzimidazoles from o-phenylenediamine 237

2.10. By reaction with potassium hydroxide and chloroform

Grassi-Cristaldi and Lambarbi have reported the synthesis ofbenzimidazole by heating o-phenylenediamine with chloro-

form and potassium hydroxide (dissolved in ethanol). Thisconvenient method for the preparation of benzimidazole isrelated to the method involving the use of ethyl orthoformate.

Ethyl orthoformate was first used for the preparation ofbenzimidazoles by von Walther and Kessler who have synthe-sized 1-phenyl-5-nitrobenzimidazole by the reaction between

ethyl orthoformate and 4-nitro-2-aminodiphenylamine(Scheme 32).

Very recently, the use of ethyl orthoformate has been inves-tigated more fully by Mamalis, Petrow, and Sturgeon who

have reported o-phenylenediamines or N-alkylated o-phenylenediamines which may be converted to the correspond-ing benzimidazoles in almost quantitative yields by the use of

an excess of ethyl orthoformate at an elevated temperature orin a solvent such as ethanol or ethyl acetate.

3. Conclusion

Benzimidazoles possess one of the most useful biological activ-ities. Benzimidazoles are utilized in many therapeutic applica-

tions such as anti-inflammatory, anti anxiety and antimicrobialcompounds.

The efficient and economical methods of synthesizing ben-zimidazole by condensation reaction between ortho phenylene

diamine and various compounds in the presence of variousconditions presented in this review helps chemists to get thefirst hand information for the synthesis of benzimidazole and

become very useful for chemists and workers in this field, todevelop protocols for the large production of benzimidazolesand this can be developed from year to year to produce new

economical and environmental clean protocols for the largescale production of important pharmacophores based on syn-thesized benzimidazoles in the future.

Acknowledgement

This research project was supported by a Grant from the‘‘Research Center of the Female Scientific and Medical Col-leges”, Deanship of Scientific Research, King Saud University.

References

[1] R. Bonnett, Chem. Rev. 63 (6) (1963) 573–605.

[2] H. Al-Muhaimeed, J. Int. Med. Res. 25 (1997) 175–181.

[3] S. Kurakata, K. Fujiwara, T. Fujita, 2001. 2000-JP4858

2001005402, 20000719.

[4] D. Carcanague, Y.-K. Shue, M.A. Wuonola, M. Uria-

Nickelsen, C. Joubran, J.K. Abedi, J. Jones, T.C. Kuehler, J.

Med. Chem. 45 (2002) 4300–4309.

[5] M. Lezcano, W. Al-Soufi, M. Novo, E. Rodriguez-Nunez, J.V.

Tato, J. Agric. Food. Chem. 50 (2002) 108–112.

[6] N.M. Aghatabay, M. Somer, M. Senel, B. Dulger, F. Gucin,

Eur. J. Med. Chem. 42 (2007) 1069–1075.

[7] S. Demirayak, A.C. karaburun, I. Kayagil, U. Ucucu, R. Beis,

Phosphorous Sulfur Silicon 180 (2005) 1841–1848.

[8] A.K. Tewari, A. Mishra, Indian J. Chem Sect. B: Org. Chem.

Inci. Med. Chem. 45 (2006) 489–493.

[9] V. Austel, K. Noll, W. Eberlein, J. Heider, J. Van Meel, W.

Diederen, W. Haarmann, 1989. 87-3728244, 3728244, 19870825.

[10] J.M. Gardiner, C.R. Loyns, A. Burke, A. Khan, N. Mahmood,

Bioorg. Med. Chem. Lett. 7 (1995) 1251–1254.

[11] F. Hoebrecker, Ber. 5 (1872) 920–926.

[12] John B. Wright, The chemistry of the Benzimidazoles, Research

Laboratories, The Upjohn Company, Kalamazoo, Michigan,

1951.

[13] C.P. Rathod, R.M. Rajurkar, S.S. Thonte, Indo Am. J. Pharm.

Res. 3 (2) (2013) 2323–2329.

[14] M. Phillip, J. Chem. Soc. C. (1971) 1143–1145.

[15] G. Hollan, L. Samuel, B. Ennis, R. Hinde, J. Chem. Soc. C.

(1967) 20–26.

[16] S.R. Rithe, R.S. Jagtap, S.S. Ubarhande, RASA-YAN J. Chem.

8 (2) (2015) 213–217.

[17] A. Saberi, Iran. J. Sci. Technol. 39A1 (2015) 7–10.

[18] O. Suheyla, F. Betul, K. Canan, G. Hakan, Acta Cryst. E58

(2002) 1062–1064.

[19] J. Mann, A. Baron, Y. Opoku-Boahen, E. Johansson, G.

Parkinson, L.R. kelland, S. Neidle, J. Med. Chem. 44 (2001)

138–144.

[20] Y. Venkateswarlu, S.R. Kumar, P. Leelavathi, Organ. Med.

Chem. Lett. 3 (7) (2013) 2–8.

[21] S. Lin, L. Yang, Tetrahedron Lett. 46 (2005) 4315–4319.

[22] T. Rushi, K.De Surya, A.G. Richard, J. Mol. Catal. A: Chem.

245 (2006) 8–11.

[23] P. Sehyun, J. Jaehun, J.C.E. Eun, J. Org. Chem. (2014) 4148–

4154;

A. Mobinikhaledi, A. Hamta, M. Kalhor, M. Shariatzadeh,

Iran. J. Pharm. Res. 13 (1) (2014) 95–101.

[24] S.S. Birajdar, G.D. Hatnapure1, A.P. Keche1, V.M. Kamble1,

Res. J. Pharm. Biol. Chem. Sci. 5 (1) (2014) 487–493.

[25] R. Srinivasulu, K.R. Kumar, P.V.V. Satyanarayana, Green

Sustainable Chem. 4 (2014) 33–37.

[26] P. Sehyun, J. Jaehun, J.C.E. Eun, J. Org. Chem. (2014) 4148–

4154.

[27] D.P. Vishvanath, P.P. Ketan, Int. J. ChemTech Res. 8 (11)

(2014) 457–465.

[28] P. Aniket, D.S. Shantanu, O.B. Anagha, P.S. Ajinkya, Int. J.

ChemTech Res. 8 (2) (2015) 496–500.

[29] S.D. Pardeshi, S.N. Thore, Int. J. Chem. Phys. Sci. 4 (2015) 300–

307.