12

CHAPTER-I

INTRODUCTION TO THE CHEMISTRY OF BENZIMIDAZOLES

General:- In the past decades, the literature seems to brim over with

research work on nitrogen containing heterocycles, as they are

present in nucleic acids, vitamins, proteins and biologically important

molecular systems. Benzimidazole is one such leading nitrogen

heterocycles containing potential pharmacological properties. The

discovery of 5, 6-dimethyl-1-(α-D-ribofuranosyl) benzimidazole1 is

fundamental structure of the vitamin-B12.

When a benzene ring (I) is fused to an imidazole ring (II)

through its 4, 5-bond, a benzimidazole ring (III) is formed.

N

N

N

N

HH

12

34

5

(II) (III)(I)

N

N

H

(III)

1

2

345

6

7

The two nitrogens present in the imidazole ring are different from

one another in their nature, and makes the properties of the ring

system diverse in character. The hydrogen attached to the nitrogen in

tautomerism with the other nitrogen.

13

N

NH

N

N

H(III) (IIIa)

Due to this tautomerism, certain benzimidazole derivatives, which

appear at first as isomers, are in reality tautomers.

N

N

H

H3C

N

NH3CH

1

2

3456

7

12

345

67

(IV) (IVa)

To prevent any confusion between the two tautomers, both the

designating structures are written with the second one in

parentheses, e.g., 5(6)-methylbenzimidazole, and 4(7)-

methylbenzimidzole.

N

N

HN

NH

12

3456

12

3

67

(V) (Va)

CH3

5CH3

4 7

When a group attached to nitrogen in the 1-position is larger than

hydrogen, such tautomerism is prevented and isomeric forms exist.

Thus, 1, 5-dimethylbenzimidazole (VI) and 1, 6-dimethylbenzimidazole

(VII) exist as distinct, isomeric compounds.

14

N

NH3C

CH3

12

345

67

N

NCH3

H3C 12

3456

7

(VI) (VII)

IMPORTANCE OF BENZIMIDAZOLE RING SYSTEM:-

A large number of benzimidazole derivatives find use as

pharmaceuticals. Some of the commercially important benzimidazole

derivatives, are shown in Table-1.

S.

N0

Structure Importance

1 N

N

F

NH

N

OCH3

Astemizole

Antihistam

inic

2 N

NO

CH3O

NCN

Bezitramide

Analgesic

15

3 N

N

COOH

O CH3

NNN

N H

Candesartan

Antihypert

ensive

4

N

NH

O

NN

NO

H

Cl

Domperidone

Antiemetic

5

N

NN N CH3

O

CH3

Emedastine

Antiallegric

6

N

NN

N

H

CH3

Irtemazole

Uricosuric

agent

7 N

NH

SO N

CH3

O CF3

Lansoprazole

Antiulcer

16

8

N

N

ClO

H

N F

O

Milenperone

Antipsycho

tic

9 N

NCl

Cl

O

NH

H3CCH3

OH

OH

OH Maribavir

Antiviral

10 N

NH

H3COSO N

CH3

CH3

OCH3

Omeprazole

Antiulcer

11 N

NH

OCH3

NNH

CH3

O

Pimobendan

Cardiotoni

c

12 N

NH

NH CO

OCH3H3C

Parbendazole

Antielmenti

c

13 N

NH

SO N

CH3

O OCH3

Rabeprazole

Antiulcer

17

SYNTHESIS OF BENZIMIDAZOLES:-

The reviews17-19 and articles20-22 covering the chemistry of both

imidazoles and benzimidazoles have been published earlier. Therefore,

only a brief account is given here.

Benzimidazoles may be synthesized from:

1. o-phenylenediamines

2. o-(N-acylamino and aroylamino)arylamines and nitroamines and

nitroarenes.

3. o-Nitroarylamines and o-dinitroarenes

4. o-substituted-N-benzlideneanilines

5. Amidines and

6. Other heterocyclic compounds.

1) From o-phenylenediamines:

o-phenylenediamines react 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:

o-phenylenediamine (VIII) when condensed with carboxylic

acids under a variety of conditions gave 2-

substitutedbenzimidazoles in good yields.

18

NH2

NH2+ HOOCH

(VIII) (IX)

N

NH

H

(III)

Scheme-1.1

Benzimidazoles were syntheized from o-phenylenediamines and

aliphatic acids.24-27 Phillips.28-31 developed a satisfactory method for

the preparation of 2-alkylbenzimidazoles (X, R=CH3).

⭪ EMBED ChemDraw.Document.6.0

NH2

NH2+ HOOC-R

(VIII) (XI)

N

NH

R

(X)

4N HCl

(R=CH3) Scheme-1.2

The role of hydrochloric acid37 is to activate carboxyl group by

addition of a proton to oxygen, forming carbonium ion. The

reaction mechanism involves carbonium ion intermediate.

R C OOH H

R COH

OH

H2N

H2N

R COH

OHH2N

H2N

N

NR

H-2H2O

-H

(R=CH3)

(X)

Scheme-1.3

19

This procedure however, fails to give any respectable yields of 2-

arylbenzimidazoles (XIII)37 with aromatic acids. Yields of 2-

arylbenzimidazoles were increased with o-phenylenediamines in a

sealed tube at 180-190oC. Polyphosphoric acid or polyphosphate42

esters were used as condensing agents for o-phenylenediamines and

aromatic acids for good yields.

NH2

NH2

+ HOOC-ArPPA or PPE

N

NAr

H

(VIII) (XII) (XIII)

Scheme-1.4

The procedures described above were utilized in recent years for

the preparation of benzimidazoles possessing thiazolyl, thiadiazolyl

substituents in 2nd - position.43-44 The other derivatives include 1-aryl-

5-amino45, 2-trifluoromethyl46, 2,6-bis(trifluoromethyl)-4-nitro47, 2-β-

mercaptoethyl48, 2-(1-aminoalkyl)49, 2-(p-iodobenzyl) and 2-(p-

iodostryl)50 are benzimidazole derivatives.

The reaction between o-diamine and an ester was first investigated

by Von Niemantowski51 who prepared (XVI) by condensing equimolar

amounts of XIIII and XV at 225oC in sealed tube for 3hrs.

NH2

NH2

(XIIII)

H3C.2HCl + H C

OOC2H5

(XV)

225oCN

N

H3C

H

CH3

(XVI)

Scheme -1.5

20

Landenburg52 first prepared XVI by refluxing XVII in glacial

acetic acid.

NH2

NH2

(XVII)

H3C+ C

HO R

O

(XI)

N

NH

RH3C

(XVI) (R=CH3)

Scheme -1.6

X was obtained by prolonged treatment of VIII with XVIII

whereas treatment for a short time yielded only XIX53 Wagner54

reported improved yields X from VIII and XVIII by using dilute HCl.

NHCOCH3

NHCOCH3

NH2

NH2+ (CH3CO)2O N

NH

CH3

(XIX) (VIII) (XVIII) (X)

Scheme -1.7

XX when reacted with XVII in benzene solution yields XVI if the

reaction is done without cooling and XXI when the reaction is

cooled.55

H3C NHCOCH3

NHCOCH3

CH3COCl +NH2

NH2

H3C

N

NH3CH

CH3

(XXI) (XX) (XVII) (XVI)

Scheme -1.8

21

Niementowski synthesized IV by heating XIV with the

corresponding amides.56 Bisbenzimidazoles (XXV) were synthesized by

heating o-diamines or their salts with aliphatic acid amides XXIV in

solvents like ethylene glycol and glycerol57 having high boiling points.

NH2

NH2

.2HCl + (CH2)n(CONH2)2N

NH

(CH2)XN

NH

Xn

(XIV) (XXIV) (XXV)

Scheme -1.9

b) By reaction with imino-ethers (Imidates):

o - phenylenediamine on reaction with imino ether in dil.acidic

medium led to the formation of benzimidazole in high yields. The

drawback in the Phillips procedure is that diamine competes for the

proton of the acid. E.g. XXVIII was synthesized in 95% yield by

reacting o-phenylenediamine hydrochloride (XXVI) with

trichloroacetimidate (XXVII) at room temperature.59-60

NH2

NH3Cl+ CHN

H3COCCl3

RT

N

NH

CCl3

(XXVI) (XXVII) (XXVIII)

Scheme -1.10

The scope of imidate procedure has been assessed by Acheson

and King.68

22

c) By reaction with carbonyl compounds:

Rao and Ratnam,69 and by Smith and Ho70 independently

reviewed the reaction between o-diamines and aldehydes as a method

to synthesize benzimidazoles. o-phenylenediamine when condensed

with aldehydes resulting various 2-substitutedbenzimidazoles in the

presence of oxidising agents such as cupric acetate (Weidenhagen

procedure),71 mercuric oxide (for 2-NHCOOMe),72 chloranil (for 2-

furyl),73 lead tetra acetate,74 manganese dioxide,75 Nickel peroxide76

and nitrobenzene.77

NH2

NH2+ OHC-Ar

N

NH

Ar

(VIII) (XII) (XIII)

Scheme -1.11

The reaction between o-arylenediamines with formaldehyde gives

rise to 1-methylbenzimidazoles,79-80 and this type of procedures has

been studied in detail.81

Depending on the nature of the aldehyde and the molar

proportions in the reaction, o-phenylenediamine when condensed with

aromatic aldehydes results in the formation monoanils and dianils in

some cases69. Products containing cyclic structures such as XIII, 1:1

product and XXXI, 1:2 product are formed in varying proportions in

acetic acid at room temparature.

23

NH2

NH2

N

NH2

CH Ar

N

N

CH Ar

CH Ar

N

NH

Ar

N

NCH2

Ar

Ar(VIII)

(XXIX)

(XXX)

(XIII)

(XXXI)

Scheme -1.12

The monoanils (XXIX) which are prepared separately are

converted to 2-substitutedbenzimidazoles by treating with

dehydrogenating agents.76-80

NH2

NH2+

NH2

N CH Ar

N

NH

Ar

(VIII) (XXII) (XXIX) (XIII)

OHC-Ar

Scheme -1.13

Both under acidic as well as thermal conditions.82-83, 85-87 dianils

(XXX) can also be cyclised to 1, 2-disubstitutedbenzimidazoles.

N

N CH

Ar

CH

Ar

N

NCH2

Ar

Ar

(XXX) (XXXI)

Scheme -1.14

24

Rao and Co-Workers, 88 studied the isolation, of XXXII (1:3

product) in the condensation of o-phenylenediamine with simple o-

chloro and m-nitrobenzimidazoles in acetic acid at room temparature.

NH2

NH2+

N

NH

Ar +N

NCH2-Ar

ArN

NCH2-Ar

H

ArCH2-Ar

+

(VIII) (XXII) (XIII) (XXXI) (XXXII)

Scheme -1.15

The monoanils have been shown89 to exist in taotomeric form

with the corresponding dihydrobenzimidazole by NMR spectroscopy.

N

NH2

CH

Ar

N

NH

H

ArH

(XXIX) (XXXIII)

Scheme -1.16

These dihydro derivatives could not be isolated in a free state in

the reaction of o-phenylenediamine with aromatic aldehydes. They

were, however, isolated90 in pure form in the reactions of 2,3-

pyridinediamine with aromatic aldehydes. Furthermore, the

structures of the monoanils obtained from the reaction between 2,3-

pyridinediamines and aromatic aldehydes has also been established91

unequivocally by X-ray crystallographic methods.

25

ii) By reaction with ketones:

IT has been reported92-94 that O-phenylenediamine when

condensed with ketones gave 2, 2-disubstitutedbenzimidazoles (XVI)

which decompose under the influence of heat to a 2-

substitutedbenzimidazole and a hydrocarbon.

NH2

NH2+ CO

RR

(VIII) (XXXV)N

NH

H

R

R1

(XXXIV)

R1 > R N

NH

R R1-H+

(X) R = CH3

Scheme -1.17

d) By reaction with nitriles:

XIV when heated with Nitriles at 200oC gave X. This reaction has

been studied by Hollies and Wagner95 and they proposed the following

mechanism for the reaction.

NH2

NH2

.2HCl + RCNNH2

NH2

+ R-CH NH.Cl

NH

NH2

CNH

R N

NH

H

NH3Cl

R N

NH

R + NH4Cl

R=CH3

(XIV) (XXXVI) (VIII)

(X)

Scheme -1.18

Using this procedure 2- substituted benzimidazoles have been

synthesized.

26

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

nitroarenes:

The o-phyenylenediamine can be synthesized insitu from the

appropriate o-nitroarylamine by using a variety of reducing agents

such as Sn/AcOH,108 Na2S2O4,109 H2/PD/C,110 Raney Ni,111

SnCl2/HCl,112 Fe/AcOH,113 Zn dust/AcOH,32 Na2S114 (sod.sulphide)

etc.

N

NH2

R1COR2 aq. HCl or

Heat N

NR2

R1Reductant N

NO2

R1COR2

(XXXVIII)(III)(XXXVII) R1, R2 = H

Scheme -1.19

Thus, Bisbenzimidazoles115-116 and releated derivatives were

synthesized by the cyclisation of mono-aryl-o-phenylenediamine.

N

NPh

XN

NPh

N

N N

NPh Ph

PhPh

SN

N

Ph

Ph

O

ON

NPh

Ph

X = p- and m-phenylene,4,41-C6H4-C6H4 etc

(XXXiX)

(XL)

(XIL)

Scheme -1.20

27

3) From o-nitroarylamines and o-dinitroarenes:

Benzimidazoles are synthesized in a single step from an o-

nitroarylamine or an o-dinitroarene by using various reducing agents.

These procedures have got commercial importance since reasonable

yields were obtained. A secondary reaction occurs and converts the 2-

alkylbenzimidazole into 1, 2-dialkylbenzimidazoles,122 when o-

nitroanilines are used in thermolysis.

N(CN)COOR

NO2

H2 / Raney NiN

NCOOR

NH2N

NH

NHCOOR

(XIIL) (XIIIL) (XIVL)

Scheme -1.21

In thermally uncatalysed cyclisation reactions benzimidazoles

were obtained from N-substituted-o-nitroaniline (XVL) derivatives.124

NHCH2Ar

NO2

Heat in sandN

NH

Ar

(XVL) (XIII)

Scheme -1.22

The acid catalysed cyclisation of XVIL to N-aminobenzimidazoles

(XVIIL) has been reported.125

28

N

NO2

HN aq. HCl / Heat

N

NNH

(XVIL) (XVIIL)

Scheme -1.23

4) From o-substituted N-benzimideneanilines:

Aromatic nitro compounds on reduction by triethylphosphite and

related reagents has been widely used as a simple, route to a variety

of nitrogen containing heterocycles.127 XVIIIL derivatives are

converted128 into 2-phenylbenzimidazoles by using triethylphosphite

and similar reducing reagents and the yields are slightly higher than

those obtained by the use of classical weidenhagen aldehyde method.

N

NO2

CH

Ph (EtO)3P/ t-BuC6H5

reflux N

NH

Ph

(XVIIIL) (XIII)

Scheme -1.24

Good yields of benzimidzoles were obtained by heating XVIIIL in

1, 2-dichlorobenzene129 or dimethylformamide130 .

N

NO2

CH

Ph

N

NH

Ph

(XVIIIL) (XIII)

Scheme -1.25

29

5) From amidines:

Generally, benzimidazoles are synthesized from o-

phenylenediamine and its derivatives. The reactions were carried out

under mild conditions using benzenesulphonyl chloride in pyridine or

in triethylamine resulting good yields. Consequently, it has been

shown that such products can be obtained from the parent amidines

by oxidation under basic conditions.132

HN R

NH

PhSO2Cl / Et3N or Pyridine

<10oC N

NH

R

(XIXL) (X) R=CH3

Scheme -1.26

6) From heterocyclic compounds:

Benzimidazole derivatives (LI) were extracted133 from reductive

cyclisation of o-benzoquinonedibenzimide (L) by triphenylphosphine.

NCOPh

NCOPh+ Ph3P

N

NCOPh

Ph + Ph3PO

(L) (LI)

Scheme -1.27

Thus, in the absence of a substituent, LII is converted into

benzimidazole in poor yield together with trace quantities of LIII; LIV

are converted in very good yield into LV and LIV by opening of the N-

30

N-bond and migration of the hydrogen from C3 to Ni to give 2-

alkylaminobenzonitriles.134

NNH

N

NH

+CN

NH2(LII) (III) (LIII)(27%)

(Trace)

NN

R

H

N

NR

(LV)(LIV)

hv

hv

(73-96 for R=alkyl, aralkyl, Ar)

N

NR

(LV)

hv CN

NH2

(LIII)

Scheme -1.28

Recent work for the synthesis of benzimidazoles derivatives:-

Singh et. al. reported136 that bisbenzimidazole derivaties were

obtained by coupling of aromatic orthodiamines with aromatic and

heterocyclic aldehydes by oxidation.

31

NH2

NH2H3C+ OHC-Ar Fe III-FeII

IOI

N

N

H3CAr

H

N

N

HOH2CAr

HPCC / CH2Cl2

N

N

OHCAr

HNH2

NH2Hr

(XVII) (XXII) (LIX)

(LX) (LXI)

(LXII) N

NH

N

NH

ArHr

(LXIII)

Lu et al reported137 the synthesis 2-substitutedbenzimidazoles

by using polyphosphoric acid as a catalyst from organic acids under

micro-wave irradiation.

NH2

NH2+ HOOC-Ar

PPA / MW

N

NAr

H

(VII) (XXII) (XXIII)

Scheme -1.29

Substituted benzimidazoles were synthesized by using

ytterbium triflate as a catalyst.139

NH2

NH2ROHC-Ar

Yb (OTf)3N

NAr

H

R

(XXIII) (XXII) (LIX) R=CH3

+

Scheme -1.30

Taylor et al. reported140 the synthesis of 2-substitutedbenzi-

midazoles in good yields directly in the presence of manganesedioxide

and molecular sieves in a one-pot method.

32

NH

NH2

CH3

+ Ar-CH2-OH

MnO2Sieves

18hrN

NCH3

Ar

(LXIV) (LXV) (LXVI)

Scheme -1.31

Perumal et al. reported141 the synthesis of 2-aryl-1-arylmethyl-

1H-1,3-benzimidazoles in the presence of montmorillonite k-10 from

o-phenylenediamine and aromatic aldehydes in the absence of solvent

under microwave conditions.

NH2

NH2

+ OHC-Ar

(VIII) (XXII)

K-10 Clay

MWI N

NAr

Ar

(XXXI)

Scheme -1.32

Salehi et. al. reported145 selective synthesis of 2-aryl-1-

arylmethyl-1H-1, 3 benzimidazoles in the presence of silica and

sulphuric acid in water or ethanol.

NH2

NH2+ Silica sulfuric acid

N

NAr

(XXII) (XXXI) R=CH3

OHC-Arwater

(VIII)

Ar

Scheme -1.33

SPECTRAL PROPERTIES OF BENZIMIDAZOLES:-

IR spectra of benzimidazole were studied in detail by Rabiger and

Morgan.147 Turchin148 studied in detail, NMR spectrum of the

benzimidazole in the acid solutions, which was found to give the

33

following chemical shift values (ppm) in CD3OH and TMS as internal

standard.

N

NH

H

12

34

56

7

4H, 7H 5H, 6H 2H

7.61 7.24 8.12

13C spectrum of the benzimidazoles149 was found to give the

following chemical shift values in CD3OH.

N

NH

H

12

34

56

7

2 7 5, 6 8, 9

141.46 115.41 122.87 137.92

The mass spectral fragmentation of the benzimidzoles was

observed by Bowie150 from which it appears that the fragmentation

pathways of benzimidazoles are similar to that of imidazole. The

spectrum of benzimidazole indicates a sequential loss of two

molecules of hydrogen cyanide from the molecular ion.

N

NH

HC

NH2

N

-H

-HCN

C6H5N

C6H5N

(m/e 91)

(m/e 92)

34

CHEMICAL PROPERTIES OF THE BENZIMIDAZOLES:-

1) Reactions with electrophillic reagents:-

i) Electrophilic aromatic substitution does not occur easily in the

imidazole ring of benzimidazoles. Benzimidazole on treatment with Cl2

gives 4, 5, 6-trichlorobenzimidazole.152

N

NH

I2 / NaOH

N

NH

I

(III) (LXVII)

N

NH

N

NH

I

(III) (LXVIII)

Cl2Cl

ClCl

Scheme -1.34

ii) Sulphonation of the benzimdazole can be carried out in Conc.

Sulphuric acid or in chlorosulphonic acid to yield benzimidazole-5-

sulfonic acid.153

N

NH

H2SO4 or

ClSO3H N

NH

HO3S(III) (LXIX)

Scheme -1.35

iii) Nitration of the benzimdzole in presence of nitrating mixture gives

a mixture of 5, 6 or 4, 6-dintrobenzimidazole.154

N

NH

H2SO4/ HNO3

N

NH

(III) NO2

O2N+

N

NH

O2N

O2N

(LXX) (LXXI)

Scheme -1.36

35

iv) Alkylation of benzimidazoles:-

a) Alkylation: alkylation of alkyl halides usually occurs by SE2

mechanism.

b) Alkylation by Mannich reaction :- alkylation of benzimidazole

by Mannich reaction156 procedure .

N

NH

(III)

CH2O / morpholine

CH3OH N

NCH2 N O

N

NH

(III)

PhCO(CH2)2NR2

Xylene N

N(CH2)2COPh

(LXXII)

(LXXIII)

Scheme -1.37

c) Alkylation by activated alkenes :- Benzimidazole derivatives

have been alkylated by activated alkenes in thermal conditions and

also in acid and base catalysed processes.

N

NH

CH

CN CH2

N

NCH2-CH2-CN

(III) (LXXIV)

Scheme -1.38

d) Activated alkynes:- 1-Vinylbenzimdiazole is formed by the

reaction of benzimidazole with acetylene in aqueous dioxane at 160

oC.158

36

N

NH

CH CH

aq.Dioxane N

NHC CH2

(III) (LXXV)

Scheme -1.39

Reactions with Nucleophilic reagents:-

a) Tschitsichibabin reaction:- The tschitsichibabin reaction is

extensively used for the preparation of 2-aminobenzimidazole

derivatives.

N

NR

NaNH2 / xylene

N

NR

NH2

(LV) (LXXVII)

Scheme - 1.40

b) Reaction with reactive intermediates:- Benzimidazole -2-

carboxamide (LXXVII) is prepared by the reaction of benzimidazole

(III) with a carboxylic acid in the presence of ammonium

thiosulphate.161

N

NH 10% H2SO4 / AgNO3 /

(NH4)2S2O8

RCO2H / H2O N

NH

CO

NH2

(III) (LXXVIII)

Scheme -1.41

c) Reaction with benzyne:- Benzimidazole (III) reacts as a

nucleophile with benzyne in conventional fashion to give 1-

phenylbenzimidazole (LXXIX) along with polymeric materials.162

37

N

NH

benzyne

N

NC6H5

+ Polymeric materials

(III) (LXXIX)

Scheme -1.42

Photochemical reactions:- Benzimidazole (III) on irradiation with UV

light transforms into a mixture of dehydroisomers, the two dimmers

are formed by homolyic substitution at the 4 and 5 positions of

benzimidazole by a 2-benzimidazolyl free radical.163

N

NH

(III)

EtOH

253.7 nm N

NHN

N

H

N

NH

NNH

+

(LXXX) (LXXXI)

Scheme -1.43

Oxidation:- Oxidation of benzimidazole (III) with lead dioxide gives

2,2’-biisobenzimidazolylidine (LXXXII). Alternatively, the compound

can also be prepared by a similar oxidation of 2, 2’-

biisobenzimidazole.164

N

NH

PbO2 / C6H6 / reflux

24 hrs N

N

N

NPbO2 / C6H6/reflux

24 hrs N

NH

N

NH

(III) (LXXXII) (LXXXIII)

Scheme -1.44

Reduction:- Benzimidazoles on reduction with H2 in the presence of

charcoal results in the formation of hexadehydrobenzimidazole

(LXXXIV).165

38

N

NH

H2 (100 atm) / Rh-C

aq. MeOH N

NH

(III) (LXXXIV)

Scheme -1.45

Present Work:- It is evident from the literature that benzimidazoles

are known to be biologically and pharmacologically important

molecules. Also, not much work seems to have done on the synthesis

of 1-substituted benzimidazole derivatives.

Chapter 2: The present chapter deals with the studies on preparation

of 2-Acetylbenzimidazole based on o-phenylenediamine. Condensation

of o-phenylenediamine with lactic acid under Phillips conditions to

give 2-(α-hydroxyethyl)benzimidazole, followed by oxidation studies

with various oxidizing agents such as K2Cr2O7, MnO2, H2O2 in AcOH,

CaOCl2, m-CPBA,10% HNO3, 50% HNO3, CAN has been described.

This chapter also discuss the studies on reactions of 2-(α-

hydroxyethyl)benzimidazole with acid chlorides such as benzoyl

chloride, benzenesulphonyl chloride and tosylation under various

conditions and subsequently alkylations reactions on 2-

acetylbenzimidazole and O-benzoylated products . This chapter also

describes the reactions of 2-(α-chloroethyl)benzimidazole with

anilines.

39

Chapter 3: A study of literature showed that derivatives of

thiadiazines, thiazolidinones and thiadiazol containing heterocyclic

compounds have potential biological activity. Keeping this in view, it

was considered worthwhile to study the synthesis of benzimidazole-2-

acetyl thiosemicarbazone derivatives and their further chemical

modifications.

This chapter deals with the synthesis of 1, 3, 4-thiadiazolines. 2-

Acetylbenzimidazole (4) on condensation with thiosemicarbazide gave

thiosemicarbazone (82). The latter on condensation with p-

chlorophenacyl bromide (83) gave 3-[1H-benzimidazol-2-yl)-

ethylideneamino]-4-(4-chlorophenyl)-3H-thiazol-2-one (84). 84 on

reaction with m-CPBA in chloroform at (-)10 oC for 6 hrs yielded [1-

(1H-benzimidazol-2-yl)ethylidene]-[5-(4-chlorophenyl)-1,1-dioxo-

1,2,5,6-tetrahydro-1λ6-{1,3,4}thiadiazin-2-yl]amine (85).

Chapter 4: The present chapter describes the alkylation studies on

benzimidazole chalcones and subsequent functional modifications of

resulting products into pyrazole and isoxazole derivatives. 2-

Acetylbenzimidazole (4) was prepared by oxidation of 2-(α-

hydroxyethyl) benzimidazole (3) in acetic dichromate conditions. 4 on

reaction with benzaldehyde in 5%NaOH solution at room temperature

for 3hrs resulted in the formation of known benzaldehyde chalcone

(97). Benzimidazole-2-chalcone (97) on reaction with ethyl

chloroacetate, in DMF containing K2CO3 and catalytic amount of

phase transfer catalyst TBAB, at room temperature for 1 hr resulted

40

in the formation of [2-(3-pheylacryloyl)benzimidazolyl] acetic acid ethyl

ester (103). Reaction of 103a with NaBH4 in methanol at room

temperature for 1 hr resulted in the formation of 1-[1-(2-

hydroxyethyl)-1H-benzimidazolyl]-3-phenyl propanol 105. 2-

Acetylbenzimidazole (4) on heating with dimethyl formamide diemthyl

acetal [CH(OMe)2NMe2] at 105oC for 1 hr resulted in the formation of

1-(1H-benzimidazolyl)-3-dimethylamino propenone (108). Reaction of

108 with hydrazine hydrate in methanol on refluxing for 1 hr resulted

in the formation of 2-(1H-pyrazolyl)-1H benzimidazole 110. The

isoxazole derivative of the benzimidazole was prepared by the reaction

of 108 with NH2OH.HCl in methanol under refluxing conditions for 3

hrs resulting in the formation of 2-isoxazolyl-1H-benzimidazole (113).

Chapter 5: It has been reported that pyrazolines possess analgesic,

anti-inflammatory and antimicrobial activities. Therefore, it has been

considered worthwhile to study the synthesis of pyrazoles hooked to

benzimidazole ring system. This chapter deals with the synthesis of

pyrazolyl derivatives of benzimidazole chalcone. 97 on reaction with

dimethyl sulphate (DMS) in the presence of K2CO3 and TBAB as PTC

in CH3CN at room temperature for 3 hrs yielded N-methyl-2-

acetylchalcone (129a, i.e., 129, R=CH3) which is also known in

literature. 129a (i.e., 129, R=CH3) on refluxing with hydrazine hydrate

in glacial acetic acid for 3 hrs resulted in the formation of 1-[3-(1-

methyl-benzimidazole-2-yl)-5-phenyl-4, 5-dihydro pyrazol-1-yl]

ethanone (130). 130 was condensed with different aromatic aldehydes

such as benzaldehyde (14), in 10% methanolic NaOH under reflux for

41

4 hrs resulting in 1-[3-(1-methyl-1H-benzimidazol-2-yl)-5-phenyl-4, 5-

dihydro-pyrazol-1-yl]-3-phenyl-propenone (132). 97 on reaction with

malononitrile in the presence of sodium ethoxide in ethanol for 3 hrs

at room temperature yielded a new product. This

product was assigned as 6-(1H-benzimidazol-2-yl)-2-ethoxy-4-phenyl

nicotinonitrile (136). 97 on reaction with melononitrile in the

presence of sodium methoxide in methanol for 3 hrs yielded a new

product 6-(1H-benzimidazol-2-yl)-3-methoxy-2-phneyl-isonicotinonitril

(137). 137 on reaction with hydrazine hydrate in the presence of BF3

in ethanol under reflux for 3 hrs yielded a product (138).