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Accepted Manuscript Original article Synthetic approaches to benzimidazoles from O- phenylenediamine: A literature review Shatha Ibrahim Alaqeel PII: DOI: Reference:

S1319-6103(16)30060-6 http://dx.doi.org/10.1016/j.jscs.2016.08.001 JSCS 833

To appear in:

Journal of Saudi Chemical Society

Received Date: Revised Date: Accepted Date:

17 December 2015 2 February 2016 5 August 2016

Please cite this article as: S.I. Alaqeel, Synthetic approaches to benzimidazoles from O- phenylenediamine: A literature review, Journal of Saudi Chemical Society (2016), doi: http://dx.doi.org/10.1016/j.jscs.2016.08.001

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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. 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.

Keywords - Benzimidazole nucleus, o-phenylenediamine, Pharmacological activity, Therapeutic compound

1. INTRODUCTION Amongst 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-dimethyl-1(α-D-ribofuranosyl)benzimidazole ring system was discovered in 1948 as the an integral part of the structure of vitamin B12 [1] (Fig. 1).

Figure 1. Some imidazole containing bioactive compounds Subsequently pharmaceutical, veterinary and agrochemical products 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 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].

ClH2CH2C

O N

ClH2CH2C

OCH3

N

N

NH

CH2CH2CH2CO2H N H

N H

Imet 3393 (Anticancer) S

1

Carbendazim (Fungicide)

OCH3

N 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 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). H 3C

NO2

NHCOCH3

H 3C

H 3C

NH 2

N

-H 2O

Sn HCl

NHCOCH3

CH3 N

H

Scheme 1 Almost all syntheses of benzimidazoles start with benzene derivatives possessing nitrogencontaining functions ortho to each other (Fig 3) that is, the starting material possesses the function designated by formula

H N R N H

H H

Figure 3. ortho di nitrogen compounds many methods have been reported for the synthesis of benzimidazols. Most of these methods involve the condensation of ortho-phenylenediamine, and its derivatives with carboxylic acids, or aldehydes. Various catalysed synthesis of benzimidazole derivatives are known condensation of ophenylenediamine 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], 2.1 By reaction with carboxylic acids Literature survey has revealed that o-phenylenediamines react readily with most carboxylic acids to give 2-substituted benzimidazoles, usually in very good yield. 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). NH2

O

N

OH

N

R

R NH2

+ 2H2O

H

Scheme 2 The most commonly used (Phillip’s method [14], involves the condensation of odiaminobenzenes 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.

O

NH2

HCl (4N) R

OH

H N R N

NH2

Scheme 3 Hollan et

al. who

have reported the reaction of the appropriate imidate ester

(trichloroacetimidate) with o-phenylenediamine

or its salt gives the 2-trichloromethyl

benzimidazole (Scheme 4) only at room temperature, and this is an important precursor for 2carboxylic benzimidazoles [15]. H N

CCl3

NH 2

AcOH +

O

NH

NH 2

CCl3 N

RT

Scheme 4 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 mole) and different aromatic acid ( 0.01 mole) in the presence of ammonium chloride as catalyst at 80-90°C (Scheme 5). The reaction is green and economically viable [16]. O

NH2

EtOH.NH4Cl R

NH2

OH

80-90 oC

H N R N

Scheme 5 Recently Saberi has synthesized of 2- benzimidazoles under microwave irradiation and solvent-free conditions is catalyzed by alumina, silica gel and zeolite HY As shown in Scheme 6, using 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].

MW Zeolite HY H N

O

NH2 R NH2

OH

R N

MW Silica gel

MW Alumina (acidic)

Scheme 6 2.2 By reaction with aldehydes Under the correct conditions aldehydes may react with o -phenylenediamines to yield 2substituted benzimidazoles (Scheme 7). NH2

N +

CHR

RCHO

NH2

-H2

NH2

N R N H

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.

NH2

N

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

R1 . Cu2Cl2

+ 4 CH3COOH + H2O

N

NH2

H

Scheme 8 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]. F

NH2

N

NH2

Cl

O

H N

N

N

Cl

H

+ O

F

Cl

Na2S2O5 DMF

Cl

O

Scheme 9 Suheyla et al. who have reported this reaction rely on pre-forming the bisulfite adduct of the aryl aldehyde to prepare benzimidazole, in which an ethanolic solution of aryl aldehyde was added seperately 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 adduct and the mixture was heated at 130oC for several hours affording benzimidazole (Scheme 10). NH2 H Ar-CHO

Ar

OH SO3Na

NH2

H N Ar N

Scheme 10 Or heating in the presence of nitro benzene [19]. Mann et al. using a mixture of unsubstituted or substituted phenylenediamine and appropriate aldehyde in nitrobenzene was heated at 140 °C. , the mixture was cooled and filtered after adding of water gives benzamidazole (Scheme 11).

O NH2

H

+ O2N

NH2

PhNO2

H N

heat

N

NO2

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). NH2

CHO +

LaCl3

N

R

R

NH2

CH 3CN R.T

N H

R= H,Alkyl, Aryl

Scheme 12 The other way was synthesized by Lin et al. involves direct one step synthesis of various benzimidazoles from phenylenediamines and aldehydes that includes air as the oxidant [21] (Scheme 13). O NH2 H

air solvent

+ NH2

N N

reflux or 100 oC

H

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).

O

NH2

N

In(OTf)3 R

+

R

H N

NH2

H

Scheme 14 A series of benzimidasole derivatives were synthesized in good to high yields by reaction of ophenylenediamine and different aromatic aldehydes in the presence of sodium hexafluroaluminate, Na3AlF6, as an efficient catalyst at 50 ◦C [23] (Scheme 15). O

NH2

N

EtOH +

Ar

Ar

H N

Na3AlF6

NH2

H

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). O

NH2 +

R

H

N

Dioxane dibromide

R N

Acetonitrile 30-60 min. ,rt.

NH2

H

Scheme 16 Srinivasulu1 et al. one-pot synthesis of 2-substituted benzimidazole derivatives from ophynelyenediamine and substituted aldehydes were developed under zinc triflate in ethanol solvent at reflux temperature [25] as shown in Scheme 17 O

NH2 +

H

Zn (OTf)2 Ethanol

NH2

R

reflux, 8h

Scheme 17

N N H

R

Sehyun et al. have reported the reaction of o-phenylenediamine 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). O

NH2 R

+

N

O2 (from air)

H

NH2

R N

MeOH (0.1M) ,r.t

H

blue LEDs (7W)

R= aliphatic, aromatic

Scheme 18 Vishvanath et al. have used nickel acetate efficiently catalyzed the synthesis of benzimidazole derivatives [27] and this method has been involved a mixture of benzaldehyde (1mmol) and ophenylene diamine (1mmol) with Nickel Acetate (0.1mmol) was stirred magnetically with CHCl3 at room temperature as shown in Scheme 19 O

NH2 R'

+ R

N

Ni (OAc)2

H

NH2

CHCl3 ,RT

R' N

R

H

Scheme 19 Iodine catalyzed synthesis of 2-Aryl-1-arylmethyl-1H-benzimidazoles are demonstrated by Aniket et al. using phenylenediamine and aldehydes 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). O

NH2 + NH2

2

R

H

Iodine / Water 80-90 oC / 1.2-1.5 h

N R N

R

Scheme 20

Pardeshi et al. have synthesized a simple, efficient and selective method [29] for synthesis of 2aryl benzimidazole through reaction of ophenylenediamine with aryl aldehydes in aqueous media in presence of sodium dodecyl sulphate as shown in Scheme 21. O

NH2 + R

Ar

H

Water

NH2

N

sodium dodecyl sulfate (10 mol

Ar R

N

H

Scheme 21 2.3 By reaction with acid anhydrides Literature survey has revealed that the reaction of acid anhydrides and o -phenylenediamines will lead to benzimidazoles or to N,N'-diacylphenylenediamines depending on the conditions employed. It was formerly thought that o-phenylenediamine yield 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 yield. O-phenylenediamines when heated under reflux for several hours with acetic anhydride is completely converted to 2-methylbenzimidazole [13] (Scheme 22). 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 per cent yield from o-phenylenediamine and acetic anhydride on heating with 15 per cent hydrochloric acid . 2.4 By reaction with esters Reaction of o-phenylenediamines with esters also yields benzimidazoles. Von Niementowski who first was 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 hr. at 225°C. give 84 per cent of 5(or 6)methylbenzimidazole hydrochloride [13] (Scheme 23). H 3C

NH2

H 3C

N

.2HCl + HCOOC2H5

HCl

+ 2H2O + C2H 5Cl

N

NH2

H

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 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 benzimidazoles. However, good yields have been obtained in most cases. The amides that have been used are listed in Table 1.

Table 1. Benzamidazoles from amides Amide

Diamine H 3C

NH2

Product H 3C

HCONH2

N

.2HCl N

NH2

H H 3C

NH2

H 3C

CH3CONH2

N CH 3

.2HCl N

NH2

H H 3C

NH2

H 3C

C6H5CONH2

N C 6H 5

.2HCl N

NH2

H

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 when it was heated with urea at 130°C. gives 2(3H)-benzimidazolone (Scheme 24). H N

NH 2 .2HCl + NH2CONH 2

CO

NH 2

+ 2NH4HCl

N

H

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 solution until the evolution of ammonia ceased, Mistry and Guha have obtained a 95 per cent 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 carried out without cooling and diacetyl-o-phenylenediamine when the reaction is cooled (Scheme 25). NH 2

O

C 6H 6

H 3C

N CH3

Cl N

NH2

H

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 200-220oC., 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. Table 2. Benzamidazoles from acid chlorides and N-substituted-o-phenylenedimines Diamine NH2

Acid chloride CH3COCl

Product N CH3 N

NHC2H5

C 2H 5 NH2

C6H5COCl

N C 6H 5

NHC6H5

N C 6H 5

2.8 By reaction with nitriles Cyanogen bromide will react with o-phenylenediamines to yield 2-aminobenzimidazoles in good yield; for example, 2-aminobenzimidazole may be prepared from cyanogen bromide and o -phenylenediamine (Scheme 26).

NH 2

N +

BrCN

NH2 .HBr

NH 2

N H

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). NHCONH2 + NH2

BrCN

NHCONH2 NHCN

moist air or water

N NH 2 N CONH2 o-Phenylene-a-guanylurea Hydrolysis

N NH2 N H

Scheme 27 O-phenylene-α-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. O-phenylenediamine, it self ,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 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).

NH2 .HCl

NH2

D

+ RCN

NH2

NH4Cl +

Cl +

HN

C

R

NH2

H N

H N

C

R N

NH2

R

NH2Cl

Scheme 28 This scheme is supported by the observation that N-phenylbenzimino chloride react with ophenylenediamine to give 2-phenylbenzimidazole. Nitriles that have been used in the synthesis of benzimidazoles are listed in Table 3. 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

2.9 By reaction with ketones 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 H N

NH2 +

CR 1R11

R 1COR 11

NHR

N -R 11H

R1

N

N

R

R

R = H or alkyl

Scheme 29 In several cases the product represented by R″H was isolated and identified.

Ladenburg and Rugheimer have obtained 2-phenyl-5 (or 6)-methylbenzimidazole by heating 3,4diaminotoluene with acetophenone at 180°C. for some time. Here again the methyl group is the one that is eliminated preferentially (Scheme 30). H 3C

NH2

H 3C +

N

CH3COC 6H5

C 6H 5

NH2

+ CH4 + H2O

N H

Scheme 30 o-phenylenediamine reacts with ketones to form 2- disubstituted 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 led to formation of two different benzimidazoles depending upon whether the substituent R or the subtituent R′ is eliminated preferentially (Scheme 31). H N NH2

R + O

NH2

R C

C R1

N

R1 H

R

H N

D

N

R1

H

H N R1

+

R

N

Scheme 31 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).

H

O 2N

NH2

HC(OC2H5)3

O 2N

N + 3C2H5OH

NHC 6H5

N C 6H 5

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 may be converted to the corresponding benzimidazoles in almost quantitative yield 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 posses 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.

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Figure 1. Some imidazole containing bioactive compounds ClH2CH2C

O N

ClH2CH2C

OCH3

N

N

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

CH2CH2CO 2H

H

N H

N

Diabazole (Vasodilator spasmlytic hypotensive)

Bezitramide (Analgesic) 4

6 Cl

(Anti-viral) 5

Figure 2. Some benzimidazole containing drugs

H N R N H

H H

Figure 3. ortho di nitrogen compounds

Table 1. Benzamidazoles from amides Diamine H 3C

Amide

NH2

HCONH2

Product H 3C

N

.2HCl N

NH2

H H 3C

NH2

CH3CONH2

H 3C

N CH3

.2HCl N

NH2

H H 3C

NH2

C6H5CONH 2

H 3C

N C 6H 5

.2HCl N

NH2

H

Table 2. Benzamidazoles from acid chlorides and N-substituted-o-phenylenedimines Diamine NH2

Acid chloride

Product

CH3COCl

N CH3 N

NHC2H5

C2H 5 NH2

C6H5COCl

N C 6H 5 N

NHC6H5

C 6H 5

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