1

CHAPTER - I

INTRODUCTION TO THE

CHEMISTRY OF BENZIMIDAZOLES

2

GENERAL

Heterocyclic compounds posses a cyclic structure with two or more different kinds of

atoms in the ring. These type of compounds are very widely distributed in nature and

are essential to life, playing a vital role in the metabolism of all living cells e.g. the

pyrimidine and purine bases of the genetic material DNA, the essential amino acids,

proline, hisitidine, the vitamins and coenzymes etc. There are a vast number of

pharmacologically active heterocyclic compounds, many of which are in regular

clinical use. A wide range of synthetic and naturally occurring heterocyclic compounds

find their use in medicines and also in pesticides, agrochemicals, polymers etc. This

attracts the attention of scientists for carrying out more and more research leading to

novel heterocyclic molecules having useful biological activities.

Of the wide variety of heterocyclic systems known till date, the nitrogen heterocycles

are of great importance and benzimidazole is one amongst such important nitrogen

heterocyclic species because of its synthetic utility and broad spectrum of

pharmacological activity1-10. The benzimidazole nucleus is an important heterocyclic

ring since several of its derivatives have pharmacological properties and have been

marketed as commercial products. Most significantly, the benzimidazole ring system

has been found to be an integral part of Vitamin-B12 (Figure-1) and (Figure-2) in the

form of 5,6-dimethyl-1-(-D-ribofuranosyl) benzimidazole.

Many benzimidazole derivatives with different pharmacological properties such as

anthelmentic11, antiulcer12-14, cardiotonic15, antihypertensive16, etc., have already been

reported. The literature precedence revealed that the substitutions at 1, 2 and 5

positions of the benzimidazole moiety is crucial for the compounds to exhibit wide

range of pharmacological activities.

3

Figure-1: Chemical structure of Vitamin B12

Figure-2: Vitamin B12- 3D structure [C63H90CoN14O14P]

4

The benzimidazole ring system can be theoretically derived by fusion of an imidazole

ring through its 4 -5 bond to a benzene ring (Figure-3).

NH

N

NH

N

1

2

34

5

1

2

34

5

Figure-3

The numbering in the benzimidazole ring system is done as shown below (Figure-4).

NH

N

1

2

34

6

7

5

Figure-4

The two nitrogens present in the imidazole ring are different from one another in their

nature and this makes the properties of the ring system diverse in character. The

nitrogen bearing hydrogen atom is sp3 in character and is often referred as pyrrole

nitrogen and the other is sp2 in character and is often referred as pyridine nitrogen. The

hydrogen atom attached to the nitrogen in benzimidazole exhibits tautomerism as

shown below (Figure-5).

N

NH

NH

N

Figure-5

This tautomerism is analogous to that found in imidazoles and amidines. Due to this

tautomerism, certain benzimidazole derivatives that appear at first as isomers are in

reality the tautomers. The 4 and 5 positions are equivalent to 6 and 7 positions because

of this tautomerism. For example, 5-methylbenzimidazole is a tautomer of 6-methyl

benzimidazole (Figure-6). Although two non-equivalent structures can be written, the

two structures are tautomers and both structures represent the same compound.

CH3

N

NHCH3

NH

N 1

34

5

674

5

6

71

3

2 2

Figure-6

To prevent any confusion between the two tautomers, both the designating structures

are written with the second one in parenthesis, e.g., 5(6)-methylbenzimidazole. When

5

the group attached to the nitrogen in the 1-position is other than hydrogen, such

tautomerism is prevented and only isomeric forms exist. Thus, 1,5-

dimethylbenzimidazole and 1,6-dimethylbenzimidazole exist as distinct, isomeric

compounds (Figure-7).

N

NCH3

CH3CH3

N

N

CH3

1

2

345

6

7

1

2

345

67

Figure-7

IMPORTANCE OF BENZIMIDAZOLE RING SYSTEM

A wide range of benzimidazoles and their derivatives find use in pharmaceuticals and

veterinary drugs showing varied therapeutic activities. Some of the commercially

important benzimidazole derivatives are presented in Table-1.

Table-1: Some of the benzimidazole derivatives of commercial importance

Generic

Name

Brand

Name

Innovator

Company

Therapeutic

category Structure

Fuberidazole Voronit Bayer Fungicide N

N

O

H

Lansoprazole Agopton Takeda Anti

secretary

agent N

NS

N

O

OF

F

F

H

Astemizole

Hismanal Janssen Anti allergic

& anti

histaminic N

N

N

N

F

O

H

Tenatoprazole Protop Mitsubishi

pharma

Gastric Anti

secretory

drug NN

N O

SN

O

O

H

6

Rabeprazole

Sodium

Aciphex Janssen Antiulcer

agent

N

N

SN

O

OO

Na+

Pantoprazole

Sodium

Protonix

or

Apton

Altana

pharma

Antiulcer

drugs N

NN

S

O

O

O

O F

F

Na+-

Enviroxime --- --- Antiviral

OH

N

NNH2

SO2iPr

Thiabenda-

zole

Mintezol Merck,

Sharpe &

Dohme

Human anti

helmintic&

fungicide

N

N

N

S

H

Oxibenda-

zole

Anthel

cide EQ

Or

Filaribits

plus

Glaxo

Smith-

kline

Treatment of

helmintic

diseases N

NN

O

OO

H

7

METHODS FOR SYNTHESIS OF BENZIMIDAZOLES

Detailed reviews17 covering the synthesis and chemistry of both imidazoles and

benzimidazoles have been published. Generally, benzimidazoles can be synthesized

from a variety of starting materials and a few of them are listed below in detail.

1. o-Phenylenediamines

2. o-(N-acylamino and N–aryolamino)arylamines and nitroarenes

3. o-Nitroarylamines and o-dinitroarenes

4. o-substituted-N-benzylideneanilines

5. Amidines

6. Other heterocyclic compounds

1. From o-Phenylenediamine

o-Phenylenediamine (1) reacts with (a) carboxylic acids and their derivatives, (b)

imino-ethers, (c) carbonyl compounds and (d) nitriles to yield differently substituted

benzimidazoles.

a) By reaction with carboxylic acids and their derivatives

2-Substituted benzimidazoles may be synthesized in good yields by condensing o-

phenylenediamine (1) with carboxylic acids under a wide variety of conditions.

Ladenburg18 first prepared 2, 5 (or 2, 6)-dimethylbenzimidazole by refluxing 4-methyl-

o-phenylenediamine in glacial acetic acid. The parent benzimidazole (2) was prepared

in 1878 by heating (1) with formic acid19 (Scheme-1).

NH2

NH2

N

N

H

H-COOH

(1) (2)

+

Scheme-1

Since then, a large number of benzimidazoles have been synthesized from 1 and

aliphatic acids20-23. The most satisfactory method for the synthesis of 2-

alkylbenzimidazoles (3, R = alkyl) was developed by Phillips24-25, which involves

refluxing equimolar quantities of the diamine and the aliphatic carboxylic acid in 4N

hydrochloric acid for 3 to 4 hr (Scheme-2).

8

NH2

NH2

N

N

R

H

R-COOH

(1) (3)

+

(R = Alkyl)

4N HCl

Reflux, 3-4hr

(R = Alkyl)

Scheme-2

The mechanistic pathway for the formation of benzimidazoles by the reaction of 1 with

organic acids has already been studied26-29. Further, the role of hydrochloric acid in the

reaction has also been investigated30. The catalytic action of hydrochloric acid is

explained on the basis of activation of the carboxyl group by the protonation of oxygen.

The intermediate in the reaction is the addition product formed by the attack of the

unshared electron pair of one nitrogen onto the carbonyl group of the protonated acid.

However, Phillips25 concluded that the monoacyl derivative was the necessary key

intermediate for formation of benzimidazole ring.

For aromatic carboxylic acids, however, Phillips procedure fails to give any respectable

yields of 2-arylbenzimidazoles25. Aromatic carboxylic acids were reported31 to give

good yields of 2-arylbenzimidazoles (4, R = Ar) when heated with 1 in a sealed tube at

180-190 oC. A better procedure for the preparation of 2-arylbenzimidazoles (4), from 1

and aromatic carboxylic acid involves the use of polyphosphoric acid32,33 (PPA) or

polyphosphate ester34 (PPE) as dehydrating agent. Alternatively, phosphorus pentoxide

has also been reported as a dehydrating agent for the preparation of 2-

arylbenzimidazole derivatives35 (Scheme-3).

NH2

NH2

N

N

R

H

R-COOH

(1) (4)

+

(R = Aryl)

PPA or PPE

or P2O5

(R = Aryl)

Scheme-3

The methods described above have been utilized in recent years for the synthesis of a

variety of benzimidazoles carrying thiazolyl, thiadiazolyl and isothiazolyl substiutuents

at 2-position36-37. Similarly, the other benzimidazoles synthesized include 1-aryl-5-

amino38; 2-trifluoromethyl39; 2, 6-bis (trifluromethyl)-4-nitro40; 2--mercaptoethyl41; 2-

(1-amino-alkyl)42 and 2-(p-iodostyryl)43 benzimidazole etc.

The reaction between 4-methyl-o-phenylenediamine dihydrochloride (5) and esters was

first investigated by Niementowski44, who prepared 5(6)-methylbenzimidazole (6, X =

9

5(6)-methyl) by condensation of equimolar amounts of (5) and ethyl formate at 225oC

in a sealed tube for 3 hr (Scheme-4).

NH2

NH2CH3 N

N

H

H O

O

C2H5

X+

(5)

225°C

Sealed tube, 3 hrs

(6)

.2HCl

Scheme-4

2-Methylbenzimidazole (3, R = CH3) was obtained by prolonged treatment of 1 with

acetic anhydride, whereas treatment for a shorter period yielded only N, N’-diacetyl o-

phenylenediamine (7)45 (Scheme-5). Wagner46

reported improved yields of 2-

methylbenzimidazole from 1 and acetic anhydride by using dilute hydrochloric acid.

Similarly, it was also observed that treatment of the free base of 5 i.e., 4-methyl-o-

phenylenediamine with acetyl chloride in refluxing benzene yielded 2,5 (2,6)-

dimethylbenzimidazole whereas the corresponding 4-methyl-N,N’-diacetyl-o-

phenylenediamine was the sole product when the reaction was carried out at room

temperature47.

NH2

NH2

N

N

R

H

NHCOCH3

NHCOCH3

(1)

(3)Acetic anhydride

Prolongedheating

Shortheating

(R = Methyl)

(7)

Scheme-5

Niementowski obtained 2-substiuted 5(6)-methylbenzimidazoles (8, X=5(6)-methyl, R

= H, CH3 or Ph) by heating free base (5) with the corresponding amides48 (Scheme-6).

NH2

NH2CH3 N

N

R

H

R

O

NH2

X+

(5)(8)

(R = H, CH3, Ph)(R = H, CH3, Ph)

Scheme-6

10

Bisbenzimidazoles (10) were synthesized by heating OPDA (1) or its dihydrochloride

salt with aliphatic dicarboxylic acid amides in high boiling solvents like ethylene glycol

or glycerol49 (Scheme-7).

N

N(CH2)n

N

N

H H

NH2

NH2

(CH2)n(CONH2)2+

(1) (10)

Ethylene Glycol

OR Glycerol

Scheme-7

b) By reaction with imino-ethers (Imidates)

o-Phenylenediamine (1) on treating with imino-ethers in dilute acidic medium led to the

formation of benzimidazoles in high yields (Scheme-8).

NH

N

R

NH2

NH2

R

NH

OMe

+

(1) (3)

( R = Alkyl)( R = Alkyl)

H+

Scheme-8

The main problem concerned with the Phillips procedure is that the diamine often

competes successfully for the proton of the acid catalyst, hence inhibiting nucleophilic

addition to the carbonyl group, this difficulty has been overcome by replacing the

carbonyl group by the more basic imino group, and very often the imidate method is

superior to the conventional Phillips procedure. For example, under Phillips conditions

the reaction of compound 1 with 2,4–dinitrophenylacetic acid takes place only under

drastic conditions and considerable resinification also occurs50, conversely, reaction of

the diamine with the hydrochloride of ethyl 2,4–dinitrophenylacetimidate (11) under

reflux gives the desired 2-(2,4-dinitrobenzyl)benzimidazole (12) in 84% yield50

(Scheme-9).

N

N

NO2

NO2

HNH2

NH2OC2H5

N

O2N

O2N H

+

(1) (12)

Solvent reflux

(11)

Scheme-9

11

Similarly 2-trichloromethylbenzimidazole (14) was synthesized in 95% yield by

reacting o-phenylenediamine hydrochloride (9) with ethyl trichloacetimidate (13) at

room temperture51, 52 (Scheme-10).

N

N

CCl3

HNH2

NH2 NH

CCl3O

RT

(9) (13) (14)

+.2HCl

Scheme-10

Other benzimidazoles like 2-nitroalkyl53, 2-aminoethyl54, 2-arylaminoethyl55, 2-

alkylesters of carbamic acids56, 57, 2-bromoalkyl58 and 2-heteroaryl benzimidazoles59

were also synthesized from 1 and the corresponding imino-ethers. In addition to this the

scope of imidates procedure for benzimidaoles synthesis has been assessed by King and

Acheson60.

c) By reaction with carbonyl compounds

(i) By reaction with aldehydes

The reaction between 1 and aldehydes as a method to synthesize benzimidazoles has

been reviewed independently by Rao and Ratnam61 and Smith and Ho62. Various 2-

substituted benzimidazoles (3, R = alkyl), (4, R = aryl) were synthesized by condensing

1 with aldehydes in the presence of oxidizing agents such as cupric acetate

(Weidenhagen procedure63), mercuric oxide (for 2-NHCOOMe)64, chloranil (for 2-

furyl)65, lead tetraacetate66, manganese dioxide67, nickel peroxide68 and nitrobenzene69.

An improvement in the conventional method is the use of the sodium bisulfite addition

product of the aldehyde70, which in boiling ethanol often results in good yields

(Scheme-11).

N

N

R

HNH2

NH2

R H

O

(1) (15)

+

Oxidising agent

(R = Alkyl, Aryl)(3, R = Alkyl)(4, R = Aryl) .

Scheme-11

The reaction of o-arylenediamines with formaldehyde gives rise to 1-methyl

benzimidazoles71,72 and these types of processes have been studied in detail73. Its

noteworthy to mention here that the reaction of 1 with aromatic aldehydes in methanol

12

medium gave monoanils (16) (Schiff bases, commonly known as monoanils in

benzimidazole chemistry) and in some cases the di-Schiff bases i.e., dianils61 (17)

depending on molar proportions of the aldehyde used in the reaction. The monoanils

when treated with acetic acid at room temperature resulted in the dehydrogenatively

cyclized products 2-arylbenzimidazoles (4, 1:1 products) and the dianils resulted in the

formation of 1-arylmethyl-2-arylbenzimidazoles (18, 1:2 product) in varying

proportions (Scheme-12).

NH2

NH2

N

NH

Ar

NH2

N=CH-Ar

N=CH-Ar

N=CH-Ar

N

N

Ar

CH2-Ar

(1)

(4)(16)

(17) (18)

Scheme-12

The monoanils (16) prepared separately could be converted to 2-substiuted

benzimidazoles (4) with the help of dehydrogenating agents68, 69, 74-76 (Scheme-13).

N

N

R

H

NH2

N CHAr

(16) (4)

DehydrogenatingAgent

Scheme-13

Similarly, the dianils (17) obtained from 1 with two moles of aldehyde were cyclised to

1,2-diarylsubstitutedbenzimidazoles (18) both under acidic as well as thermal

conditions73, 75, 77-79 (Scheme-14).

N=CH-Ar

N=CH-Ar

N

N

Ar

CH2

Ar(17) (18)

Acidic conditions/Thermal conditions

Scheme-14

Rao and co-workers80, reported the isolation, although in poor yields of other products,

1,3-diarylmethyl-2-arylbenzimidazolines (19, 1:3 product) in the condensation of 1

13

with o-chloro and m-nitrobenzaldehyde in acetic acid at room temperature (Scheme-

15).

N

N

Ar

CH2-Ar

N

NH

Ar

NH2

NH2 N

N

CH2-Ar

H

Ar

CH2-Ar

R H

O+ + +

(1)(R = Aryl)

(4) (18) (19)

Scheme-15

Obviously, the above reaction proceeds through the disproportionation of the initially

formed monoanils. The monoanils have been shown81 to exist in tautomeric equilibrium

with the corresponding dihydrobenzimidazoles (20) by NMR (Scheme-16).

NH

NH

H

Ar

N=CH-Ar

NH2

(16) (20)

Scheme-16

These dihydroderivatives could not be isolated in free state in the reaction of 1 with

aromatic aldehydes. However, the intermediate dihydroderivative 22 was isolated in

pure form, during the preparation of imidazo[4,5-b]pyridine 23 obtained from the

reaction of 2,3-pyridinediamine (21) with aromatic aldehydes82 (Scheme-17).

N

NH2

NH2 N

N

NH

ArAr H

O

N

NH

NH

OH

Ar

(21) (23)

+ Acetic acid

RT

(22)

Acetic acid

100°C

Scheme-17

(ii) By reaction with ketones

o-Phenylenediamine (1) has been reported83-85 to condense with ketones to form 2,2-

disubstitutedbenzimidazolines (24) which decomposes under the influence of heat to

give 2-substituted benzimidazole (3 or 4, R = R’=Variously substituted) and a

hydrocarbon. In several cases, the hydrocarbon was isolated and identified. In the

decomposition of an asymmetrically substituted benzimidazoline (24), it has been

14

observed84 that the C-C bond, which has greater degree of substitution, is generally

broken (Scheme-18).

NH

NH

R

R'

NH2

NH2

N

NH

R

R R'

O

R' > R R'-H+ +

(1) (R, R' = Variously substituted)

(24) (3, R = Alkyl)(4, R = Aryl)

Scheme-18

(d) By reaction with Nitriles

Nitriles when heated with o-phenylenediamine dihydrochloride (9) at 200°C gave 2-

substituted benzimidazoles (3). This reaction has been studied by Holljes and Wagner86

who have proposed the following mechanism for the reaction according to which the

reaction proceeds under acidic conditions and probably involves hydrogen–ion

catalysis (Scheme-19).

NH2

NH2

NH2

NH2

N

NH

R

NH2

H

N

N

R

NH3Cl

H

H

N

N

R

H

. .

.2HCl

RCN R-C=NH.Cl+

.HCl

+

NH4Cl+ -

+ +

+

(9)

(3, R = Alkyl)(4, R = Aryl)

Scheme-19

At this reaction temperature ammonium chloride will undergo decomposition to

generate additional hydrogen chloride and cause the reaction to proceed further. Using

this procedure 2-alkyl86, 2-aryl86, 2-heteroarylbenzimidazoles87, 2-guanidino

benzimidazoles88 and 2-alkylesters of carbamic acids89 have been synthesized.

2) From o-(N-acylamino and N-aroylamino) arylamines and nitroarenes

The formation of benzimidazoles by the reaction of 1 with carboxylic acids and related

compounds90 is presumed to involve the formation of (monoaroylamino) arylamines. A

number of benzimidazole compounds (27) have been synthesized by cyclisation of N-

15

monoacyl-o-phenylenediamines (25), under acid catalysed conditions or in uncatalysed

thermal conditions91-98. Compound 27 can also be generated in situ from the appropriate

o-nitroarylamine (26) by using a variety of reducing agents such as Sn/AcOH99,

Na2S2O4100, H2/Pd/C101, Raney-Ni102, SnCl2/HCl103, Fe/AcOH104, sodium sulfide105 etc.

(Scheme-20).

NCOR2

NH2

R1

N

R2

N

R1

NCOR2

R1

NO2

Reductantaq. HCl

or heat

(25) (26)(27)

Scheme-20

Thus, differently substituted benzimidazoles (27) and related compounds106,107 have

been synthesized by the cyclisation of N-monoacyl-o-phenylenediamines (25).

3) From o-Nitroarylamines and o-dinitroarenes

Benzimidazoles have been synthesized in a single step from o-nitroarylamine or

o-dinitroarenes by using reductants such as NaHSO3108, BaSO4/Pd/H2

109, Zn110,

Na2S2O5111 and Na2SO3

112. Benzimidazoles are also obtained by the thermolysis of

nitroarenes and alcohol mixtures in the gas phase. Since reasonable yields are obtained,

these processes have got commercial importance. When o-nitroanilines are used in

thermolysis, a secondary reaction occurs which converts the 2-alkylbenzimidazoles into

1,2-dialkylbenzimidazoles113. o-Dinitroarenes behave in a similar fashion with alcohols

over alumino–copper or vanadium, but in this case the products are exclusively 2-

alkylbenzimidazoles (3).

The direct reductive method from the carbanilic acid derivatives (28) leading to alkyl

esters of 2-amino-1-benzimidazolecarboxylic acids (29) is of commercial value, since

products of the latter type are transformed thermally into alkyl esters of benzimidazole-

2-carbamic acids (30)114 (Scheme-21).

16

NO2

N

N

O

O

R

N

N

NH2

OO

R

N

N

N

H

O

O R

HH2/Raney Ni

(28) (29) (30)

Scheme-21

4) From o-substituted-N-benzylideneanilines

The reduction of aromatic nitro compounds by triethylphosphite and related reagents

has been widely used as a simple and effective route to a variety of nitrogen containing

heterocycles115. Derivatives of N-benzylidene-2-nitroaniline (31) were converted into

substituted 2-phenylbenzimidazoles116 (4) in this manner and the yields were slightly

higher than those obtained by the use of classical Weidenhagen aldehyde method63

(Scheme-22).

N=CH-Ph

NO2

N

N

Ph

H

(EtO)3P/t-BuC6H5

reflux

(31) (4)

Scheme-22

Good yields of benzimidazoles can be obtained by heating N-benzylidene-2-

azidoanilines (32) in 1,2–dichlorobenzene117 or dimethylformamide118 and the method

can be used to prepare 2-substituted benzimidazoles (Scheme-23).

N=CH-Ph

N3

N

N

Ph

H(32) (4)

Scheme-23

5) From Amidines

Generally benzimidazoles are synthesized from 1 and its derivatives. Their

preparation119 from N’-aryl-N-hydroxylamidines (33) is unusual in the sense that both

nitrogen atoms of the imidazole ring arise from one side chain (Scheme-24).

17

N R

N

H

OH

N

N

R

H

(33) (4)

PhSO2Cl / Et3N

or Pyridine

(R = Aryl)

Scheme-24

The reactions are carried out under mild conditions using benzene sulfonyl chloride in

pyridine or triethylamine giving good yields .This method has been used to prepare a

variety of compounds with substiutuents in the aryl ring119.

6) From other heterocyclic compounds

Benzimidazole derivatives can be prepared by reductive cyclisation of o-

benzoquinonedibenzimide by using triphenylphosphine120. Benzimidazoles are also

formed during the photolysis of indazoles121.

18

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