Synthetic approaches to benzimidazoles from o ...

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

King Saud University

Journal of Saudi Chemical Society www.ksu.edu.sa www.sciencedirect.com

ORIGINAL ARTICLE

Synthetic approaches to benzimidazoles from o-phenylenediamine: A literature review 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. Ó 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 ring system is quite common. These substructures are often called ‘privileged’ due to their wide recurrence in bioactive compounds. Although there is great interest in benzimidazole ligands and structural chemistry, the main interest is in their biological activities. The early 1950s was an important period regarding discovery of the biological significance of benzimidazole-containing structures and the closely-related purines (Fig. 1). The 5,6-di methyl-1-(a-D-ribofuranosyl)benzimidazole ring system was discovered in 1948 as an integral part of the structure of vitamin B12 [1] (Fig. 1). Subsequently pharmaceutical, veterinary and agrochemical products were discovered including thiabendazole, cimetidine, E-mail address: [email protected] Peer review under responsibility of King Saud University.

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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 the core structure, as shown in Fig. 2. These biological activities include 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 some derivatives have been synthesized and evaluated for inhibition of HIV-1 infectivity [10]. 2. Synthesis of benzimidazoles The first benzimidazole was prepared by Hoebrecker [11], who obtained 2,5-dimethylbenzimidazole by the reduction and dehydration of 2-nitro-4-methylacetanilide (Scheme 1). Almost all syntheses of benzimidazoles start with benzene derivatives possessing nitrogen-containing functions ortho to each other (Fig. 3) that is, the starting material possesses the function designated by formula many methods have been reported for the synthesis of benzimidazols. Most of these methods involve the condensation of ortho-

http://dx.doi.org/10.1016/j.jscs.2016.08.001 1319-6103 Ó 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/).

230

S.I. Alaqeel 2.1. By reaction with carboxylic acids

N

N

N H

N

Literature survey has revealed that o-phenylenediamines react readily with most carboxylic acids to give 2-substituted benzimidazoles, 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 acids or its derivatives, including heating the reagents together in the presence of concentrated hydrochloric acid (Scheme 3), this is the most common synthetic method for preparation of a wide range of benzimidazoles. Hollan et al. who have reported the reaction of the appropriate imidate ester (trichloroacetimidate) with ophenylenediamine or its salt gives the 2-trichloromethyl benzimidazole (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 benzimidazole derivatives in moderate to good yield have been prepared 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 catalyst at 80–90 °C (Scheme 5). The reaction is green and economically 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 in Scheme 6, o-phenylenediamine (2 mmol) with aromatic, aliphatic and heterocyclic carboxylic (2 mmol) and 50 mg of Alumina or Silica gel or Zeolite were mixed thoroughly in a mortar. The reaction mixture was then irradiated in a domestic microwave oven for 5–9 min at 160–560 W [17].

Purine O NC

NH2

NH2 H3C

O

NH2 H3 C

N

O

N

H2N

Co

H3C H

O H2N

CH3

N

N

CH3 O O

CH3

CH3

CH3 N

CH3

N

CH3

NH -

O

C

H3C

O

H

HO P

C

O

O

H O

H CH2 OH vitamin B 12

Figure 1

Some imidazole containing bioactive compounds.

phenylenediamine, and its derivatives with carboxylic acids, or aldehydes. Various catalyzed synthesis of benzimidazole derivatives are known condensation of o-phenylenediamine with ortho esters 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 benzimidazoles have been grouped according to the starting material of o-phenylene diamines [12].

ClH2CH2C

O N

OCH3

N

N

ClH2CH2C

NH

CH2CH2CH2CO2H N H

N H

Imet 3393 (Anticancer) S

1

OCH3

N

Carbendazim (Fungicide)

O N H

3

S

(Bactericide) COOEt O

2

N

H N

N S

CH2PhCl

N

N

N H

CH2CH2CO2H

H N

Diabazole (Vasodilator spasmlytic hypotensive)

Bezitramide (Analgesic) 4

6 Cl

(Anti-viral) 5

Figure 2

Some benzimidazole containing drugs.

Synthetic approaches to benzimidazoles from o-phenylenediamine H3C

231

H 3C

NO2

NHCOCH3

H 3C

NH2

N

-H2O

Sn HCl

NHCOCH3

CH3 N H

Scheme 1

2.2. By reaction with aldehydes

H N H R

H N H

Ortho di nitrogen compounds.

Figure 3

NH2

O

N

OH

N

R + 2H2O

R NH2

H

Scheme 2

H N

O

NH2

HCl (4N) R

R

OH

N

NH2

Scheme 3

CCl3

NH2

AcOH +

O

RT

NH

NH2

H N CCl3 N

Scheme 4

O

NH2

EtOH.NH4Cl R

OH

NH2

80-90 oC

H N R N

Scheme 5

MW Zeolite HY

R NH2

H N

O

NH2

OH

R MW Silica gel

MW Alumina (acidic)

Scheme 6

N

Under the correct conditions aldehydes may react with ophenylenediamines to yield 2-substituted benzimidazoles (Scheme 7). Since an oxidation is involved, the reaction is best carried out under oxidative conditions. This oxidation may be brought about by the air or, more conveniently, by the use of other oxidizing agents such as cupric acetate. This latter reagent was first introduced by Weidenhagen [13]. Weidenhagen’s method consists in reacting the diamine and aldehyde in water or alcoholic solution in the presence of cupric acetate or a similar cupric salt. The cuprous salt of the benzimidazole separates, and by means of hydrogen sulfide it may be readily decomposed to the free benzimidazole and cuprous sulfide. The sulfide may be removed readily by filtration (Scheme 8). By means of Weidenhagen’s method excellent yields of 2-substituted benzimidazoles may be obtained. The condensation of phenylenediamines with aldehydes is achieved by various reported conditions. As shown in Scheme 9, this can be achieved in the presence of sodium metabisulphite [18]. Suheyla et al. who have reported this reaction rely on preforming the bisulfite adduct of the aryl aldehyde to prepare benzimidazole, in which an ethanolic solution of aryl aldehyde was added separately to an aqueous solution of sodium metabisulphite; the adduct formed precipitated from the reaction was filtered and dried. The o-phenylenediamine in DMF was then added to the adduct and the mixture was heated at 130 °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 phenylenediamine and appropriate aldehyde in nitrobenzene heated at 140 °C., the mixture was cooled and filtered after adding water which gives benzamidazole (Scheme 11). Venkateswarlu et al. have reported the synthesis of benzimidazole derivatives, with the use of lanthanum chloride as an efficient catalyst One-pot synthesis of 2-substituted benzimidazole derivatives from o-phenylenediamine and a variety of aldehyde were carried out in the presence of lanthanum chloride (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 from phenylenediamines 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 aldehydes 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 in good to high yields by reaction of o-phenylenediamine and different aromatic aldehydes in the presence of sodium hex-

232

S.I. Alaqeel NH2

N

NH2

N

-H2

CHR

RCHO

+

R N H

NH2

Scheme 7

NH2

N

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

R1 . Cu2Cl2

+ 4 CH3COOH + H2O

F

H N

N

N

N

NH2

H

Scheme 8

F

NH2

N

NH2

Cl

O H

+

Cl

Na2S2O5 DMF

Cl

O

Cl

O

Scheme 9

NH2 H

H N

NH2

Ar-CHO

Ar

OH

Ar N

SO3Na

Scheme 10

O NH2

H

PhNO2

H N

heat

N

NO2

+ O 2N

NH2

Scheme 11

NH2

CHO +

LaCl3

N

R

R

NH2

CH3CN R.T

N H

R= H,Alkyl, Aryl

Scheme 12

O NH2 + NH2

air solvent

H

N N

reflux or 100 oC

H

Scheme 13

afluroaluminate, Na3AlF6, as an efficient catalyst at 50 °C [23] (Scheme 15). Birajdar et al. have synthesized a mild and efficient approach for the synthesis of benzimidazole ring [24] through

oxidative cyclization of o-phenylenediamine and different aldehydes using dioxane dibromide, as a user-friendly reagent. This is a new, convenient and facile methodology for the synthesis of 2-substituted-1H-benzo[d]imidazoles (Scheme 16).

Synthetic approaches to benzimidazoles from o-phenylenediamine O

NH2

H

R

R

N Iodine / Water

H

+ 2 R

N

NH2

O

NH2

N

In(OTf)3 +

233

80-90 oC / 1.2-1.5 h

NH2

H

R

Scheme 14

Scheme 20

O

NH2

N

EtOH

H

Ar

+

Ar N

Na3AlF6

NH2

H

Scheme 15 O

NH2 + NH2

R

H

N

Dioxane dibromide

R N

Acetonitrile 30-60 min. ,rt.

H

Scheme 16

(0.1 mmol) that was stirred magnetically with CHCl3 at room temperature as shown in Scheme 19. Iodine catalyzed synthesis of 2-Aryl-1-arylmethyl-1Hbenzimidazoles is demonstrated by Aniket et al. using phenylenediamine and aldehydes which are carried out at 80–90 °C. New approach is promising and giving moderate yields with high purity and selectively single product in aqueous media [28] (Scheme 20). Pardeshi et al. have synthesized a simple, efficient and selective method [29] for the synthesis of 2-aryl benzimidazole through the reaction of ophenylenediamine with aryl aldehydes in aqueous media in the presence of sodium dodecyl sulfate as shown in Scheme 21. 2.3. By reaction with acid anhydrides

Srinivasulu1 et al. one-pot synthesis of 2-substituted benzimidazole derivatives from o-phynelyenediamine and substituted aldehydes were developed under zinc triflate in ethanol solvent at reflux temperature [25] as shown in Scheme 17. Sehyun et al. have reported the reaction of ophenylenediamine and a variety of aliphatic/aromatic aldehydes [26] in methanol proceeds at room temperature with only natural sources, molecular oxygen and visible light irradiation with blue LEDs (Scheme 18). Vishvanath et al. have used nickel acetate efficiently catalyzed 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

Literature survey has revealed that the reaction of acid anhydrides and o-phenylenediamines will lead to benzimidazoles or to N,N0 -diacylphenylenediamines depending on the conditions employed. It was formerly thought that ophenylenediamine yields benzimidazoles with acids and diacyl derivatives with acid anhydrides; however, this was shown to be incorrect. Time appears to be a decisive factor and if the refluxing is continued long enough benzimidazoles may be obtained, usually in good yields. o-Phenylenediamines when heated under reflux for several hours with acetic anhydride is completely converted to 2-methylbenzimidazole [13] (Scheme 22).

O

NH2 +

N

Zn (OTf)2

H

reflux, 8h

R

R

N

Ethanol

NH2

H

Scheme 17

O

NH2

N O2 (from air)

H

R

+ NH2

R N

MeOH (0.1M) ,r.t

H

blue LEDs (7W)

R= aliphatic, aromatic

Scheme 18

O

NH2 + R

R N

NH2

R'

N H

Ni (OAc)2 CHCl3 ,RT

Scheme 19

R' R

N H

234

S.I. Alaqeel O

NH2 + R

Ar

H

N

sodium dodecyl sulfate (10 mol Water

NH2

Ar N

R

H

Scheme 21

NH2

N CH3

+ 2 ( CH3CO)2O

+ 3 CH3COOH

N

NH2

H

Scheme 22

The reaction of o-phenylenediamines with acetic anhydride has been carried out with acetic anhydride alone or with acetic anhydride to which has been added sodium acetate, mineral acids, or acetic acid. Excellent results have been obtained by employing the modification of Phillips involving the addition of dilute mineral acids (usually about 4 N hydrochloric acid) to the reaction mixture. Thus, 2-methylbenzimidazole may be obtained in 93.3% yield from o-phenylenediamine and acetic anhydride on heating with 15% hydrochloric acid. 2.4. By reaction with esters Reaction of o-phenylenediamines with esters also yields benzimidazoles. Von Niementowski first investigated the reaction of esters and o-phenylenediamines to give benzimidazoles. Equimolecular amounts of 3,4-diaminotoluene dihydrochloride and ethyl formate when heated in a sealed tube for 3 h at 225 °C give 84% of 5(or 6)-methylbenzimidazole hydrochloride [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 poor yields of benzimidazoles would probably be obtained from esters of acids of higher molecular weight. A good yield of 2methylbenzimidazole 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 benzimidazoles. However, good yields have been obtained in most cases. The amides that have been used are listed in Table 1. Equimolecular amounts of o-phenylenediamine dihydrochloride and benzamide when heated to 240–250 °C give an almost quantitative yield of 2-phenylbenzimidazole. 2.6. by reaction with urea Rathod et al. have used o-phenylenediamine dihydrochloride and 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 ophenylenediamine and urea under reflux in amyl alcohol solu-

tion until the evolution of ammonia ceased, Mistry and Guha have 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 ophenylenediamines, depending upon experimental conditions. Acetyl chloride with 3,4-diaminotoluene in benzene solution yields 2,5 (or 2, 6)-dimethylbenzimidazole if the reaction is carried out without cooling and diacetyl-o-phenylenediamine when the reaction is cooled (Scheme 25). Most reactions between o-phenylenediamines and acid chlorides to give benzimidazoles have been carried out with aroyl chlorides. The reactions are carried out usually by heating the components together at about 200–220 °C., by heating under reflux, or by heating on a steam bath in the presence of pyridine or a similar basic substance. Since benzimidazoles which possess no grouping in the l-position may undergo acylation with acid chlorides, most reactions have been carried out with N-substituted o-phenylenediamines. Table 2 lists the compounds that have been prepared by the reaction of acid chlorides 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, 2aminobenzimidazole may be prepared from cyanogen bromide and o-phenylenediamine (Scheme 26). The reaction is carried out by mixing equimolecular amounts of the reactants in aqueous suspension. Pellizzari has obtained benzimidazole derivatives by treatment of o-aminophenylurea with cyanogen bromide (Scheme 27). O-phenylene-a-guanylurea is unstable and tends to hydrolyze to 2-aminobenzimidazole. Heating the monohydrochloride of o-phenylenediamine with an aliphatic or an aromatic nitrile at 200 °C results in the formation of a 2-substituted benzimidazoles. oPhenylenediamine, itself, fails to react with benzonitrile at 200 °C, indicating that benzimidazole formation depends upon the presence of acid. Formation of a mixture of an imino chloride and o-phenylenediamine may be the rate-determining step of the reaction. The combination of these two substances could

Synthetic approaches to benzimidazoles from o-phenylenediamine H 3C

235

NH2

H 3C

N

.2HCl + HCOOC2H5

HCl

+ 2H2O + C2H5Cl

N

NH2

H

Scheme 23

Table 1

Benzamidazoles from amides.

Diamine

Amide

Product

NH2

H 3C

H 3C

.2HCl

N

HCONH2

NH2

N H

NH2

H 3C

H3C

.2HCl

N CH3

CH3 CONH2

NH2

N H H 3C

NH2

H 3C

.2HCl

N C 6H 5

C6 H5 CONH2

NH2

N H

H N

NH2 .2HCl + NH2CONH2

CO

NH2

+ 2NH4HCl

N H

Scheme 24 NH2

O

H 3C

C 6H 6

N CH3

Cl N

NH2

H

Scheme 25 NH2

Table 2 Benzamidazoles from acid chlorides and N-substituted-o-phenylenedimines. Diamine

Acid chloride NH2

N +

BrCN

NH2

NH2 .HBr N H

Product

Scheme 26

N CH3

NHC2H5

CH3 COCl

N

Nitriles that have been used in the synthesis of benzimidazoles are listed in Table 3.

C 2H 5 NH2

N C6H5

NHC6H5

C6 H5 COCl

2.9. By reaction with ketones

N C 6H 5

lead to formation of hydrochloride of an o-aminophenyl substituted 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 Nphenylbenzimino chloride react with o-phenylenediamine to give 2-phenylbenzimidazole.

The reaction of o-phenylenediamines with a number of ketones has been investigated by Elderfield and Kreysa. The reaction occurs as indicated in Scheme 29. In several cases the product represented by R00 H was isolated and identified. Ladenburg and Rugheimer have obtained 2-phenyl-5 (or 6)-methylbenzimidazole by heating 3,4-diaminotoluene with acetophenone at 180 °C for some time. Here again the methyl group is the one that is eliminated preferentially (Scheme 30).

236

S.I. Alaqeel NHCONH2

NHCONH2

BrCN

+ NH2

N

moist air

NH2

or water

NHCN

N CONH2 o-Phenylene-a-guanylurea Hydrolysis

N NH2 N H

Scheme 27

NH2

NH2

D .HCl

Cl

+ RCN

HN

+

NH2

R

C

NH2

H N

H N

NH4Cl +

C

R N

NH2

R

NH2Cl

Scheme 28

Table 3

o-Phenylenediamine reacts with ketones to form 2disubstituted benzimidazolines, these decompose under the influence of heat with the formation of a 2-substituted benzimidazole and a hydrocarbon. The decomposition of unsymmetrically substituted benzimidazoline may lead to formation of two different benzimidazoles depending upon whether the substituent R or the substituent R0 is eliminated preferentially (Scheme 31).

Benzimidazoles from nitriles.

Diamine

Nitrile

Product

o-Phenylenediamine o-Phenylenediamine o-Phenylenediamine o-Phenylenediamine

HCN CH3CN C2H5CN C6H5CN

Benzimidazole 2-Methylbenzimidazole 2-Ethylbenzimidazole 2-phenylbenzimidazole

H N

NH2

CR1R11

R1COR11

+ NHR

N

-R11H

R1

N

N

R

R

R = H or alkyl

Scheme 29 H3C

NH2

H3C +

N

CH3COC6H5

C 6H 5

NH2

+ CH4 + H2O

N H

Scheme 30 H N NH2

R +

NH2

O

R C

C R1

N

R1 H

R

H N

heat

N

R1

H

H N R1 N

Scheme 31

+

R

H

Synthetic approaches to benzimidazoles from o-phenylenediamine O2N

NH2

237 O 2N

HC(OC2H5)3

N + 3C2H5OH

NHC6H5

N C 6H 5

Scheme 32

2.10. By reaction with potassium hydroxide and chloroform Grassi-Cristaldi and Lambarbi have reported the synthesis of benzimidazole by heating o-phenylenediamine with chloroform and potassium hydroxide (dissolved in ethanol). This convenient method for the preparation of benzimidazole is related to the method involving the use of ethyl orthoformate. Ethyl orthoformate was first used for the preparation of benzimidazoles by von Walther and Kessler who have synthesized 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 investigated more fully by Mamalis, Petrow, and Sturgeon who have reported o-phenylenediamines or N-alkylated ophenylenediamines which may be converted to the corresponding benzimidazoles in almost quantitative yields by the use of an excess of ethyl orthoformate at an elevated temperature or in a solvent such as ethanol or ethyl acetate. 3. Conclusion Benzimidazoles possess one of the most useful biological activities. Benzimidazoles are utilized in many therapeutic applications such as anti-inflammatory, anti anxiety and antimicrobial compounds. The efficient and economical methods of synthesizing benzimidazole by condensation reaction between ortho phenylene diamine and various compounds in the presence of various conditions presented in this review helps chemists to get the first hand information for the synthesis of benzimidazole and become very useful for chemists and workers in this field, to develop protocols for the large production of benzimidazoles and this can be developed from year to year to produce new economical and environmental clean protocols for the large scale production of important pharmacophores based on synthesized benzimidazoles in the future. Acknowledgement This research project was supported by a Grant from the ‘‘Research Center of the Female Scientific and Medical Colleges”, 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. UriaNickelsen, 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.