12 CHAPTER-V SYNTHESIS OF NOVEL N …shodhganga.inflibnet.ac.in/bitstream/10603/44637/12/12_chapter-v.pdf · SYNTHESIS OF NOVEL N-SUBSTITUTED 2-CHLORO-1H- BENZIMIDAZOLE DERIVATIVES

CHAPTER-V

SYNTHESIS OF NOVEL N-SUBSTITUTED 2-CHLORO-1H- BENZIMIDAZOLE

DERIVATIVES

Introduction:

As we have been discussed in chapter -1 to chapter-4, benzimidazoles are a class of heterocyclic,

aromatic chemical compounds which share a fundamental structural characteristics of six

membered ring of benzene fused to five membered imidazole.

N

N NH

N

NH2

Adenine

N

N NH

N

O

N

N NH

N

N

N N

N

O

H2NO

HN

N NH

HN

O

O

O Purine

GuanineCaffeine

Uric acid

Figure-1 Some of the most well known molecules having 6+5 heterocyclic structures with

benzimidazole moiety.

Benzimidazole ring displays an important heterocyclic pharmacophore and privileged scaffold in

drug discovery. This compound carrying different subst ituent's encompassing adiversified range

of biological activities include anticancer, antiviral, antibacterial, antifungal, antihistaminic,

antihypertensive etc. Benzimidazole derivatives emerged to be an effective anti microbial agent

in the year of 1964. Since then, explorations of the same have already been made in different

corner of horizon. The synthesis of novel benzimidazole derivatives remains a main focus of

medicinal research. Recent observations suggest that substituted benzimidazoles and heterocycle,

which are the structural isosters of nucleotides owing fused heterocyclic nuclei in their structures

that, allow them to interact easily with the biopolymers, posses potential activity with lower

toxicities in the chemotherapeutic approach inman. As an outgrowth of our investigation to

discover novel antimicrobial agent a new series of 2-substituted benzimidazole analogs were

synthesized and their antimicrobial activity was evaluated.

For developing pharmaceutically important role in medicinal Chemistry199 the wide variety of

heterocyclics that have been explored. Due to their wide variety of biological and

pharmacological applications benzimidazole and their derivatives are of great importance in

medicinal chemistry.199-200

The literature survey shows the utility of benzimidazoles for cancer, and cardiovascular

diseases201. The benzimidazole shows anticancer202, antiinflammatory203, antibacterial204,

antifungal205, antidiabetic206, and anti‐HIV activities.207 The importance of benzimidazoles are

posseses as antimicrobial and antioxidant agents.208-212 Antimicrobial broad spectrum209 has also

been reported for certain substituted benzimidazole derivatives.

Further study it was found that the N-alkylation on benzimidazole ring plays an important role in

their biological activity such as antimicrobial, antiparasitic and even antitumor agents (Figure-

2).213-217

N

N

Cl

Cl

O

HN

N

(A)

4-[5-Chloro-1-(4-chloro-benzyl)-1H-benzoimidazol-2-yl]-N-(2-diethylamino-ethyl)-benzamide

O

N

HN

NH

O

O

(6-Benzoyl-1H-benzoimidazol-2-yl)-carbamic acid methyl ester

O

ClCl

1-[2-(2,6-Dichloro-benzyloxy)-2-phenyl-ethyl]-1H-indene

(B)

(C)

O

NN

O

N

N

OH3CO

H

(D)

8-[3-(2-Furan-2-yl-benzoimidazol-1-yl)-propoxy]-7-methoxy-1,2,3,11a-tetrahydro-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5-one

Figure-2 Some N-alkylated benzimidazole derivatives having antimicrobial, antiparasitic and

antitumor activity.

Aside from their place in biomedical research, benzimidazoles also have a prominent place in

organocatalysis, organometallic218, 219 and materials chemistry220 for two reasons stemming from

their molecular architecture: the imidazole is a precursor to N-heterocyclic carbenes; and the

benzene ring provides a convenient scaffold to which additional functionality may be easily

added to modify the spatial and electronic characteristics of a benzimidazole derivative. This

combination of a reactive carbine center with a modifiable backbone is without a doubt one of

the reasons for the recent rise in study and use of benzimidazoles and their N-heterocyclic

carbene derivatives.

In this chapter we will be discussing the N-alkylation on benzimidazole ring with different

heterocyclic intermediate compounds. Emedastine, a derivative of benzimidazole, is known as an

antiallergic agent with histamine release-suppressing

Activity and H1 receptor antagonizing activity.221-224 In view of these findings, we have

attempted to synthesize antibacterial and antifungal agents with multiple pharmacological

activities by hybridizing benzimidazole derivatives.

Results & Discussion:

Synthesis of Starting Material:

o-phenylenediamine 1 was refluxed with urea in DMF for 12 hrs, followed by simple workup in

water gives known benzimidazolin-2-one 2 in 94% yield.218-219

The compound 3 was then prepared by reacting compound 2 with phosphoryl chloride in

presence of catalytic phenol at 1100C for 12 hrs, gave 2-chlorobenzimidazole in 90% yield is

reported.220 (Scheme-1)

NH2

NH2

H2N

O

H2N

DMF/K2CO3

Reflux NH

HN

ONH

N

ClPOCl3

1 2 3

Scheme-1

For further study 2-chlorobenzimidazole is used as a starting compound for different synthesis of

novel benzimidazole derivatives.

Once starting compound 3 was synthesized then we have carried out the N-alkylation by using

different intermediates of active pharmaceutical ingredients.

For coupling we have used very simple reaction condition, the reaction was carried out in water

and base like sodium carbonate at heating for 4 to 5 hrs. After completion of reaction, it was

cooled to room temperature and filtered yielded white product which was recrystallized with

alcohol gave pure product. The IR, NMR, Mass and elemental analysis of the compound were

confirmes the structures.

2-chlorobenzimidazole (3) and 3-(2-Chloro-ethyl)-2-methyl-pyrido[1,2-a]pyrimidine-4-one (4)

reacted to give 3-[2-(2-Chloro-benzimidazole-1-yl)-ethyl]-2-methyl-pyrido[1,2-a]pyrimidine-4-

one as a target molecule. (DG@42, Scheme-2) IR value 1730cm-1 carbonyl and 1326cm-1

confirms C-N functional groups in the product. 1H-NMR; δ 2.25 (s, 3H, CH3), 3.20-3.23 (t,

J=7.32Hz, 2H, CH2), 4.47-4.51 (t, J=7.2Hz, 2H, CH2), 7.14-7.17 (t, J=6.72Hz, 1H, ArH), 7.22-

7.26 (m, 3H, ArH), 7.43-7.45 (m, 1H, ArH), 7.57-7.59 (m, 1H, ArH), 7.65-7.73 (m, 2H, ArH);

3.20-3.23 triplet shows CH2 group in the structure as well as δ2.25 singlet with three protons

confirms methyl in the structure. EI-MS 339.1 with M+1 confirms formation of target molecule.

(IR, 1H-NMR & EI-MS are in Figures - 136, 137 & 138).

NH

N

ClNN

Cl

N

N

O

Cl

N

N

OWater, 75-800C

Base

3 4 DG-42

Scheme-2

The compound 3 was reacted with 3-(2-Chloro-ethyl)-2-methyl-6,7,8,9-tetrahydro-pyrodo[1,2-

a]pyrimidine-4-one (5) gives target compound, 3-[2-(2-Chloro-benzimidazole-1-yl)-ethyl]-2-

methyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidine-4-one. (DG@43, Scheme-3) IR value

1722cm-1 carbonyl and 1233cm-1 confirms C-N functional groups in the product. 1H-NMR; δ

1.84-1.90 (m, 4H, Aliphatic ring), 2.00 (s, 3H, CH3), 2.82-2.85 (t, J=6.64Hz, 2H, Aliphatic ring),

2.99-3.03 (t, J=7.32Hz, 2H, CH2), 3.39-3.96 (t, J=6.2Hz, 2H, Aliphatic ring), 4.38-4.42 (t,

J=7.2Hz, 2H, CH2), 7.22-7.28 (m, 2H, ArH), 7.40-7.43 (dd, J=5.64Hz, 1H, ArH), 7.65-7.67 (m,

1H, ArH); 1.84-1.90 multiplet signals shows aliphatic ring part, δ 2.99-3.03 triplet shows CH2

group in the structure as well as δ 2.00 singlet with three protons confirms methyl in the

structure. EI-MS 343.2 with M+1 confirms formation of target molecule. (IR, 1H-NMR & EI-MS

are in Figures - 139, 140 & 141).

NH

N

Cl NN

Cl

N

N

O

ClN

N

O

Water, 75-800C

DG-43

Base

3 5

Scheme-3

The compound 3 was reacted with 4-Chloro-2, 2-diphenyl-butyronitrile (6) gives target

compound 4-(2-Chloro-benzimidazole-1-yl)2,2-diphenyl-butyronitrile. (DG@44, Scheme-4) IR

frequency 2361cm-1 nitrile and 1271cm-1 confirms C-N functional groups in the product. 1H-

NMR; δ 2.76-2.80 (t, J=8.0Hz, 2H, CH2), 4.18-4.22 (t, J=8.2Hz, 2H, CH2), 7.05-7.08 (m, 1H,

ArH), 7.17-7.22 (m, 2H, ArH), 7.26-7.30 (m, 2H, ArH), 7.32-7.38 (m, 8H, ArH), 7.59-7.61 (m,

1H, ArH); 2.76-2.80 triplet and δ 4.18-4.22 triplet with two protons each shows aliphatic chain

part in the structure as well as EI-MS 372.2 with M+1 confirms formation of target molecule.


NH

N

ClBase

Cl

CN NN

ClCN

Water, 75-800C

DG-4463

Scheme-4

The compound 3 was reacted with 4-Chloro-1-(4-fluoro-phenyl)-butan-1-one gives (7) 4-(2-

Chloro-benzimidazole-yl)-1-(4-fluoro-phenyl)-butan-1-one as a coupled product. (DG@45,

Scheme-5) IR frequency 1701cm-1 carbonyl and 1135cm-1 confirms C-N functional groups in the

product. 1H-NMR; δ 2.18-2.25 (m, 2H, CH2), 3.13-3.16 (t, J=8Hz, 2H, CH2), 3.65-3.68 (t,

J=8Hz, 2H, CH2), 7.11-7.15 (m, 4H, ArH), 7.98-8.02 (m, 4H, ArH); 2.18-2.25 multiplet, 3.13-

3.16 triplet and δ3.65-3.68 triplet with two protons each shows aliphatic chain part in the

structure as well as EI-MS 317.2 with M+1 confirms formation of target molecule. (IR, 1H-NMR

& EI-MS are in Figures - 145, 146 & 147).

Sch

eme

-5

The

com

pou

nd 3 was reacted with 2-Chloromethyl-3, 4-dimethoxy-pyridine (8) after workup of the reaction

and crystallization gives 2-Chloro-1-(3, 4-dimethoxy-pyridine-2-ylmethyl)-1H-benzimidazole as

targeted compound. (DG@46, Scheme-6) IR frequency 1137cm-1 methoxy functional groups in

the product. 1H-NMR; δ 4.14 (s, 3H, OCH3), 4.32 (s, 3H, OCH3), 5.92 (s, 2H, CH2), 7.34-7.41

(m, 2H, ArH), 7.75-7.79 (m, 2H, ArH), 8.03-8.05 (d, J=8Hz, 1H, ArH), 9.54-9.56 (d, J=8Hz, 1H,

ArH). 4.14 singlet, 4.32 singlet with three protons each of methoxy and δ 5.92 singlet with two

protons shows aliphatic chain part in the structure as well as EI-MS 304.2 with M+1 confirms

formation of target molecule. (IR, 1H-NMR & EI-MS are in Figures - 148, 149 & 150).

NH

N

Cl

N

OCH3

OCH3Cl

NN

Cl

N

OCH3

OCH3

DG-4683

Water,

75-800C

Scheme-6

K2CO3

The Physical Characteristics data for compounds DG-42 to 46 is give in table-1.

2-chlorobenzimidazole (3) and Phenylchloroformate (9) was reacted in presence of pyridine

gives (2-Chloro-benzimidazole-1-carboxylic acid methyl ester (DG@47, Scheme-7) IR

O

O

NH

N

Cl

3

F

NN

Cl

F

Water,

75-800C

7 DG-45

Cl

Base

frequency 1752cm-1 carbonyl & 1221 cm-1 C-N functional groups in the product. 1H-NMR; δ

7.05-7.09 (m, 1H, ArH), 7.10-7.15 (m, 1H, ArH), 7.16-7.18 (m, 1H, ArH), 7.32-7.36 (m, 3H,

ArH), 7.44-7.48 (m, 2H, ArH), 7.74-7.76 (d, J=7.92Hz, 1H, ArH) at aromatic region with nine

protons in the structure as well as EI-MS 273.2 with M+1 confirms formation of target molecule.


NH

N

Cl

3 DG-479

OO

Cl

Pyridine NN

Cl

O

O

Scheme-7

2-chlorobenzimidazole (3) and o-tolyl chloride (10) was reacted in presence of pyridine gives (2-

Chloro-benzimidazole-1-yl)-o-tolyl-methanone (DG@48, Scheme-8) IR frequency 1722cm-1

carbonyl & 1330 cm-1 C-N functional groups in the product. 1H-NMR; δ 2.6 (s, 3H, CH3), 7.14-

7.17 (t, J=6.73Hz, 1H, ArH), 7.23-7.26 (m, 3H, ArH), 7.43-7.45 (m, 1H, ArH), 7.57-7.59 (m,

1H, ArH), 7.66-7.73 (m, 2H, ArH). δ 2.66 singlet shows methyl substituent in the structure as

well as EI-MS 271.2 with M+1 confirms formation of target molecule. (IR, 1H-NMR & EI-MS

are in Figures - 154, 155 & 156).

NH

N

Cl

3 10

Pyridine

Scheme-8

OCl

N

N

Cl

O

DG-48

For the series of the synthesis of the some more novel benzimidazole derivatives, we have used

2-chlorobenzimidazole and some intermediates. They were synthesized by using dry conditions

such as, dimethylformamide or acetone as a solvent and potassium carbonate as a base. The

reaction was carried out at 50-70°C for 3-5 hrs. After workup of the reaction mixture gives crude

product which was further purified by crystallization techniques. The series of compounds were

characterized by spectral characterization techniques like IR, 1H-NMR, mass and elemental

analysis.

2-chlorobenzimidazole (3) and 4-bromobenzyl bromide (11) was reacted in presence of acetone

and potassium carbonate as a base gives 1-(4-Bromo-benzyl)-2-chloro-1H-benzimidazole.

(DG@49, Scheme-9) IR spectra not able to give specific characterization peak of the molecule

but in case of 1H-NMR; δ 5.26 (s, 2H, CH2), 6.96-6.98 (d, 2H, ArH), 7.11-7.13 (dd, J=8Hz, 1H,

ArH), 7.14-7.23 (m, 2H, ArH), 7.36-7.41 (m, 2H, ArH), 7.63-7.65 (m, 1H, ArH). δ 5.26 singlet

with two protons shows aliphatic chain part and aromatic region in the structure as well as EI-

MS 322.2 with M+1 confirms formation of target molecule. (IR, 1H-NMR & EI-MS are in

Figures - 157, 158 & 159).

NH

N

Cl

3

Br

Br

NN

Cl

Br

K2CO3

Acetone, Reflux

DG-4911

Scheme-9

2-chlorobenzimidazole (3) and 4-nitrobenzoyl chloride (12) was reacted in presence of pyridine

gives (2-Chloro-benzimidazole-1-yl)-(4-nitro-phenyl)-methanone (DG@50, Scheme-10) IR

frequency 1722cm-1 carbonyl & 1273cm-1 C-N functional groups in the molecule. 1H-NMR; δ

7.32-7.34 (m, 1H, ArH), 7.36-7.42 (m, 1H, ArH), 7.44-7.46 (m, 1H, ArH), 7.73-7.75 (dd, J=8Hz,

1H, ArH), 7.95-7.98 (m, 1H, ArH), 7.95-7.98 (m, 1H, ArH), 8.38-8.41 (m, 2H, ArH) at aromatic

region with eight protons in the structure as well as EI-MS 302.2 with M+1 confirms formation

of target molecule. (IR, 1H-NMR & EI-MS are in Figures - 160, 161 & 162).

NH

N

Cl

3 DG-5012

Cl Pyridine NN

Cl O

NO2

O

NO2

Scheme-10

2-chlorobenzimidazole (3) and n-hexylchloroformate (13) was reacted in presence of pyridine

gives (2-Chloro-benzimidazole-1-carboxylic acid hexyl ester (DG@51, Scheme-11) IR

frequency 1752cm-1 carbonyl & 1221 cm-1 C-N functional groups in the product. 1H-NMR;

δ7.03-7.13 (m, 3H, ArH), 7.72-7.74 (d, J=7.76Hz, 1H, ArH), δ1.21-1.23 triplet, 1.27-1.33

multiplet, 1.38-1.45 multiplet, 1.75-1.82 multiplet, 4.38-4.42 triplet shows aliphatic chain part in

the structure as well as EI-MS 281.2 with M+1 confirms formation of target molecule. (IR, 1H-

NMR & EI-MS are in Figures - 163, 164 & 165).

3 DG-5113

PyridineNHN

Cl

Cl

O

O

NN

Cl

OC6H13

O

Scheme-11

2-chlorobenzimidazole (3) and (2-Chloro-ethyl)-diisopropyl-amine (14) was reacted in presence

of DMF and potassium carbonate as a base gives [2-(2-Chloro-3H-indol-3-yl)-ethyl]-

diisopropyl-amine. (DG@52, Scheme-12) In this molecule also IR spectra not able to give

specific characterization peak but 1136 cm-1 shows C-N functional group. In case of proton

NMR δ 0.96-0.98 (d, J=6.56Hz, 12H, diisopropyl), 2.75-2.79 (t, J=7.36Hz, 2H, CH2), 3.00-3.05

(m, 2H, CH2), 4.10-4.14(t, J=7.2Hz, 2H, CH2), 7.23-7.32 (m, 3H, ArH), 7.66-7.69 (m, 1H, ArH)

δ0.96-0.98 with twelve protons, as well as δ 2.75-2.79, 3.00-3.05 & 4.10-4.14 shows aliphatic

chain part. EI-MS: 280.2 with M+1 confirm formation of target molecule. (IR, 1H-NMR & EI-

MS are in Figures - 166, 167 & 168).

ClN

NH

N

Cl

NN

Cl

N

3

K2CO3

DMF

DG-5214

Scheme-12

2-chlorobenzimidazole (3) and 4-bromobutyronitrile (15) was reacted in presence of DMF and

potassium carbonate as a base gives 4-(2-Chloro-benzimidazole-1-yl)-butyronitrile. (DG@53,

Scheme-13) IR frequency, 2329cm-1 nitrile functional groups in the structure. 2.18-2.24

multiplet, 2.37-2.41 triplet and δ 4.33-4.37 triplet with two protons shows aliphatic chain part in

the structure as well as EI-MS 220.0 with M+1 confirms formation of target molecule. (IR, 1H-

NMR & EI-MS are in Figures -169, 170 & 171).

NH

N

Cl BrN NN

Cl

NK2CO3

DMF,750C

3 15 DG-53

Scheme-13

2-chlorobenzimidazole (3) and 4-bromoethylbutyrate (12) was reacted in presence of DMF and

potassium carbonate as a base gives 2-Chloro-benzimidazole-1-yl)-pentoinoc acid ethyl ester.

(DG@54, Scheme-16) IR frequency 1752cm-1 carbonyl & 1221 cm-1 C-N functional groups in

the product. Proton NMR at δ 7.26-7.32 (m, 2H, ArH), 7.35-7.38 (m, 1H, ArH), 7.68-7.71 (m,

1H, ArH) & 1.23 multiplet, 2.11-2.16 singlet, 2.35-2.39 triplet, 4.11-4.17 multiplet, 4.26-4.30

triplet shows aliphatic chain part in the structure as well as EI-MS 281.2 with M+1 confirms

formation of target molecule. (IR, 1H-NMR & EI-MS are in Figures - 172, 173 & 174).

Br O

O NN

Cl

O

O

DMF,750C

K2CO3

NH

N

Cl

3 16 DG-54

Scheme-14

2-chlorobenzimidazole (3) and methylchloroacetete (17) was reacted in presence of DMF and

potassium carbonate as a base gives (2-Chloro-benzimidazole-1-yl)-acetic acid methyl ester.

(DG@55, Scheme-15) IR frequency 1752cm-1 carbonyl & 1298 cm-1 C-N functional groups in

the compound. Proton NMR at δ 3.67 singlet with three protons of methoxy shows aliphatic

chain part in the structure as well as EI-MS 225.2 with M+1 confirms formation of target

molecule. (IR, 1H-NMR & EI-MS are in Figures - 175, 176 & 177).

NH

N

Cl ClO

O

NN

Cl

O

O

K2CO3

DMF,750C

3 17 DG-55

Scheme-15

The physical and spectral characterization data of the compounds DG@42 to 55 is presented in

Tables-1 & 2 respectively.

Table - 1: Physical Characteristics data for compounds DG@42 to 55.

Sr.

No.

Compound

No.

Molecular

Formula

M.P.

( 0C )

Yield

( % )

Elemental Analysis

Calculate Found

1. DG@42 C18H15ClN4O 175-178 80 C = 63.81

H = 4.46

N = 16.54

C =63.90

H = 4.41

N = 16.61

2 DG@43 C18H19ClN4O 168-171 74 C = 63.09

H = 5.59

N = 16.34

C = 63.15

H = 5.60

N = 16.28

3 DG@44 C23H18ClN3 140-143 76 C = 74.29

H = 4.88

N = 9.53

C = 74.35

H = 4.81

N = 9.60

4 DG@45 C17H14ClFN2O 111-114 68 C = 64.46

H = 4.45

N = 8.84

C = 64.50

H = 4.41

N = 8.91

5 DG@46 C15H14ClN3O2 172-174 81 C = 59.31

H = 4.65

N = 13.83

C = 59.42

H = 4.55

N = 13.91

6 DG@47 C14H9ClN2O2 138-141 62 C = 61.66

H = 3.33

N = 10.27

C = 61.72

H = 3.23

N = 10.38

7 DG@48 C15H11ClN2O 115-118 65 C = 66.55

H = 4.10

N = 10.35

C = 66.51

H = 4.16

N = 10.29

8 DG@49 C14H10BrClN2 119-121 88 C = 52.29

H = 3.13

N = 8.71

C = 52.36

H = 3.18

N = 8.65

9 DG@50 C14H8ClN3 O3 155-158 85 C = 55.74

H = 2.67

N = 13.93

C = 55.88

H = 2.61

N = 13.87

10 DG@51 C14H17ClN2O2 111-113 87 C = 59.89

H = 6.10

N = 9.98

C = 59.95

H = 6.10

N = 9.98

11 DG@52 C15H22ClN3 123-126 74 C = 64.39

H = 7.92

N = 15.02

C = 64.32

H = 7.99

N = 15.11

12 DG@53 C11H10ClN3 134-137 88 C = 60.14

H = 4.59

N = 19.13

C = 60.19

H = 4.52

N = 19.09

13 DG@54 C14H17ClN2O2 118-121 78 C = 59.89

H = 6.10

N = 9.98

C = 59.95

H = 6.06

N = 9.92

14 DG@55 C10H9ClN2O3 131-134 69 C = 53.47

H = 4.04

N = 12.47

C = 53.39

H = 4.11

N = 12.51

Table - 2: Spectral Characteristics for compounds DG@42 to DG@55.

DG@42 Structure

NN

Cl

N

N

O

3-[2-(2-Chloro-benzoimidazol-1-yl)-ethyl]-2-methyl-pyrido[1,2-a]pyrimidin-4-one

IR(KBr):

(Fig. 136)

3148, 2406, 2216, 1730, 1664, 1609, 1471, 1326, 1179, 1097

cm-1.

1H - NMR:

(CDCl3)

(Fig. 137)

δ2.25 (s, 3H, CH3), 3.20-3.23 (t, J=7.32Hz, 2H, CH2), 4.47-

4.51 (t, J=7.2Hz, 2H, CH2), 7.14-7.17 (t, J=6.72Hz, 1H,

ArH), 7.22-7.26 (m, 3H, ArH), 7.43-7.45 (m, 1H, ArH), 7.57-

7.59 (m, 1H, ArH), 7.65-7.73 (m, 2H, ArH)

EI-MS

(Fig. 138)

339.1 (M++1).

DG@43 Structure

NN

Cl

N

N

O

3-[2-(2-Chloro-benzoimidazol-1-yl)-ethyl]-2-methyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one

IR(KBr):

(Fig. 139)

2945, 2216, 1722, 1620, 1610, 1459, 1437, 1379, 1233, 1175,

1104, 1082 cm-1.

1H-NMR:

(CDCl3)

(Fig. 140)

δ 1.84-1.90 (m, 4H, Aliphatic ring), 2.00 (s, 3H, CH3), 2.82-

2.85 (t, J=6.64Hz, 2H, Aliphatic ring), 2.99-3.03 (t, J=7.32Hz,

2H, CH2), 3.39-3.96 (t, J=6.2Hz, 2H, Aliphatic ring), 4.38-

4.42 (t, J=7.2Hz, 2H, CH2), 7.22-7.28 (m, 2H, ArH), 7.40-

7.43 (dd, J=5.64Hz, 1H, ArH), 7.65-7.67 (m, 1H, ArH)

EI-MS

(Fig. 141)

343.2 (M++1).

DG@44 Structure

NN

ClCN

4-(2-Chloro-benzoimidazol-1-yl)-2,2-diphenyl-butyronitrile

IR(KBr):

(Fig. 142)

2940, 2361, 1469, 1400, 1271, 1137, 1020, cm-1

1H-NMR:

(CDCl3)

(Fig. 143)

δ 2.76-2.80 (t, J=8.0Hz, 2H, CH2), 4.18-4.22 (t, J=8.2Hz, 2H,

CH2), 7.05-7.08 (m, 1H, ArH), 7.17-7.22 (m, 2H, ArH), 7.26-

7.30 (m, 2H, ArH), 7.32-7.38 (m, 8H, ArH), 7.59-7.61 (m,

1H, ArH)

EI-MS

(Fig. 144)

372.2 (M++1).

DG@45 Structure

NN

ClF

4-(2-Chloro-benzoimidazol-1-yl)-1-(4-fluoro-phenyl)-butan-1-one

O

IR(KBr):

(Fig. 145)

2804, 2655, 1701, 1517, 1369, 1135, 1097, 1054 cm-1.

1H-NMR:

(CDCl3)

(Fig. 146)

δ2.18-2.25 (m, 2H, CH2), 3.13-3.16 (t, J=8Hz, 2H, CH2),

3.65-3.68 (t, J=8Hz, 2H, CH2), 7.11-7.15 (m, 4H, ArH), 7.98-

8.02 (m, 4H, ArH).

EI-MS

(Fig. 147)

317.2 (M++1).

DG@46 Structure

NN

Cl

N

OCH3

OCH3

2-Chloro-1-(3,4-dimethoxy-pyridin-2-ylmethyl)-1H-benzoimidazole

IR(KBr):

(Fig. 148)

2940, 2696, 2681, 2469, 1489, 1470, 1137 cm-1.

1H-NMR:

(CDCl3)

(Fig. 149)

δ4.14 (s, 3H, OCH3 ), 4.32 (s, 3H, OCH3), 5.92 (s, 2H, CH2),

7.34-7.41 (m, 2H, ArH), 7.75-7.79 (m, 2H, ArH), 8.03-8.05

(d, J=8 Hz, 1H, ArH), 9.54-9.56 (d, J=8 Hz, 1H, ArH)

EI-MS

(Fig. 150)

304.2 (M++1).

DG@47 Structure

NN

ClO

O

2-Chloro-benzoimidazole-1-carboxylic acid phenyl ester

IR(KBr):

(Fig. 151)

2986, 2619, 1752, 1433, 1298, 1298, 1174, 1068 cm-1.

1H-NMR:

(CDCl3)

(Fig. 152)

δ7.05-7.09 (m, 1H, ArH), 7.10-7.15 (m, 1H, ArH), 7.16-7.18

(m, 1H, ArH), 7.32-7.36 (m, 3H, ArH), 7.44-7.48 (m, 2H,

ArH), 7.74-7.76 (d, J=7.92Hz, 1H, ArH)

EI-MS

(Fig. 153)

273.2 (M++1).

DG@48 Structure

NN

ClO

(2-Chloro-benzoimidazol-1-yl)-o-tolyl-methanone

IR(KBr):

(Fig. 154)

3035, 2214, 1722, 1607, 1530, 1330, 1176, 991 cm-1.

1H-NMR:

(CDCl3)

(Fig. 155)

δ2.6 (s, 3H, CH3), 7.14-7.17 (t, J=6.73Hz, 1H, ArH), 7.23-

7.26 (m, 3H, ArH), 7.43-7.45 (m, 1H, ArH), 7.57-7.59 (m,

1H, ArH), 7.66-7.73 (m, 2H, ArH)

EI-MS

(Fig. 156)

271.2 (M++1).

DG@49 Structure

NN

Cl

Br

1-(4-Bromo-benzyl)-2-chloro-1H-benzoimidazole

IR(KBr):

(Fig. 157)

2940, 2361, 1650, 1558, 1469, 1339, 1271, 1137 cm-1.

1H-NMR:

(CDCl3)

(Fig. 158)

δ5.26 (s, 2H, CH2), 6.96-6.98 (d, 2H, ArH), 7.11-7.13 (dd,

J=8Hz, 1H, ArH), 7.14-7.23 (m, 2H, ArH), 7.36-7.41 (m, 2H,

ArH), 7.63-7.65 (m, 1H, ArH).

EI-MS

(Fig. 159)

322.2 (M++1).

DG@50 Structure

NN

ClO

NO2

(2-Chloro-benzoimidazol-1-yl)-(4-nitro-phenyl)-methanone

IR(KBr):

(Fig. 160)

2983, 2848, 1722, 1424, 1273, 1149, 1018cm-1.

1H-NMR:

(CDCl3)

(Fig. 161)

δ 7.32-7.34 (m, 1H, ArH), 7.36-7.42 (m, 1H, ArH), 7.44-7.46

(m, 1H, ArH), 7.73-7.75 (dd, J=8Hz, 1H, ArH), 7.95-7.98 (m,

1H, ArH), 7.95-7.98 (m, 1H, ArH), 8.38-8.41 (m, 2H, ArH)

EI-MS

(Fig. 162)

302.2 (M++1).

DG@51 Structure

NN

Cl

O

O

2-Chloro-benzoimidazole-1-carboxylic acid hexyl ester

IR(KBr):

(Fig. 163)

2986, 2619, 1752, 1433, 1221, 1174, 1068 cm-1.

1H-NMR:

(CDCl3)

(Fig. 164)

δ 1.21-1.23 (t, J=6.88Hz, 3H, CH3), 1.27-1.33 (m, 4H,

2xCH2), 1.38-1.45 (m, 2H, CH2), 1.75-1.82 (m, 2H, CH2),

4.38-4.42(t, J=6.8Hz, 2H, CH2), 7.03-7.13 (m, 3H, ArH),

7.72-7.74 (d, J=7.76Hz, 1H, ArH)

EI-MS

(Fig. 165)

281.2 (M++1).

DG@52 Structure

NN

Cl

N

[2-(2-Chloro-benzoimidazol-1-yl)-ethyl]-diisopropyl-amine

IR(KBr):

(Fig. 166)

2940, 2748, 2679, 1582, 1469, 1136, 1029cm-1.

1H-NMR:

(CDCl3)

(Fig. 167)

δ 0.96-0.98 (d, J=6.56Hz, 12H, diisopropyl), 2.75-2.79 (t,

J=7.36Hz, 2H, CH2), 3.00-3.05 (m, 2H, CH2), 4.10-4.14(t,

J=7.2Hz, 2H, CH2), 7.23-7.32 (m, 3H, ArH), 7.66-7.69 (m,

1H, ArH)

EI-MS

(Fig. 168)

280.2 (M++1).

DG@53 Structure

NN

Cl

N

4-(2-Chloro-benzoimidazol-1-yl)-butyronitrile

IR(KBr):

(Fig. 169)

2940, 2697, 2361, 2329, 1650, 1509, 1469, 1137, 1020 cm-1.

1H-NMR:

(CDCl3)

(Fig. 170)

δ 2.18-2.24 (m, 2H, CH2), 2.37-2.41 (t, J=7.12Hz, 2H, CH2),

4.33-4.37(t, J=6.84Hz, 2H, CH2), 7.21-7.37 (m, 3H, ArH),

7.68-7.71 (m, 1H, ArH)

EI-MS

(Fig. 171)

220.0 (M++1).

DG@54 Structure

NN

Cl

O

O

5-(2-Chloro-benzoimidazol-1-yl)-pentanoic acid ethyl ester

IR(KBr):

(Fig. 172)

2986, 1752, 1433, 1221, 1174, 1068, 1018 cm-1.

1H-NMR:

(CDCl3)

(Fig. 173)

δ 1.23-1.33 (m, 5H, CH2 & CH3), 2.11-2.16 (m, 2H, CH2),

2.35-2.39 (t, J=7.04Hz, 2H, CH2), 4.11-4.17 (m, 2H, CH2),

4.26-4.30 (t, J=7.2Hz, 2H, CH2), 7.26-7.32 (m, 2H, ArH),

7.35-7.38 (m, 1H, ArH),7.68-7.71 (m, 1H, ArH)

EI-MS

(Fig. 174)

281.2 (M++1).

DG@55 Structure

NN

Cl

O

O

(2-Chloro-benzoimidazol-1-yl)-acetic acid methyl ester

IR(KBr):

(Fig. 175)

2986, 2618, 1752, 1433, 1298, 1221, 1174, 1068, 1035 cm-1.

1H-NMR:

(CDCl3)

(Fig. 176)

δ 3.67 (s, 3H, CH3), 4.69 (s, 2H, CH2), 7.25-7.30 (m, 2H,

ArH), 7.43-7.47 (m, 1H, ArH), 8.06-8.08 (dd, J=8.36Hz, 1H,

ArH).

EI-MS

(Fig. 177)

225.2 (M++1).

Experimental section-

a) Synthesis of 3-[2-(2-Chloro-benzimidazole-1-yl)-ethyl]-2-methyl-pyrido[1,2-

a]pyrimidine-4-one (DG@42)

To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and potassium carbonate (39.47

mmoles) in water (25 ml) was added 3-(2-Chloro-ethyl)-2-methyl-pyrido[1,2-a]pyrimidine-4-one

(4, 39.47 mmoles) at RT. At 70-750C the reaction mixture was then heated for 3-4 hrs. &

monitored by TLC. By the completion of reaction, added 50 ml ethyl acetate stirred for 15 min.

layers were seperated. Ethyl acetate layer was washed with 25 ml water, dried over sodium

sulfate. After concentration of solvent under vacuum yielded 8.3g (74%) of the corresponding N-

substituted derivative.

b) Synthesis of 3-[2-(2-Chloro-benzimidazole-1-yl)-ethyl]-2-methyl-6, 7, 8, 9-tetrahydro-

pyrido[1,2-a]pyrimidine-4-one. (DG@43)

To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and potassium carbonate

(39.47mmoles) in water (25 ml) was added 3-(2-Chloro-ethyl)-2-methyl-6,7,8,9-tetrahydro-

pyrodo[1,2-a]pyrimidine-4-one (5, 39.47 mmoles) at RT. At 70-750C the reaction mixture was

then heated for 3-4 hrs. & monitored by TLC. By the completion of reaction, added 50 ml ethyl

acetate stirred for 15 min. layers were seperated. Ethyl acetate layer was washed with 25 ml

water, dried over sodium sulfate. After concentration of solvent under vacuum yielded 8.0g

(72%) of the corresponding N-substituted derivative.

c) Synthesis of 4-(2-Chloro-benzimidazole-1-yl) 2, 2-diphenyl-butyronitrile (DG@44)


mmoles) in water (25 ml) was added 4-Chloro-2, 2-diphenyl-butyronitrile (6, 39.47 mmoles) at

RT. At 70-750C the reaction mixture was then heated for 3-4 hrs. & monitored by TLC. By the

completion of reaction, added 50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl

acetate layer was washed with 25 ml water, dried over sodium sulfate. After concentration of

solvent under vacuum yielded 9.3g (76%) of the corresponding N-substituted derivative.

d) Synthesis of 4-(2-Chloro-benzimidazole-yl)-1-(4-fluoro-phenyl)-butan-1-one 4-Chloro-2,

2-diphenyl-butyronitrile (DG@45)

To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and potassium carbonate

(39.47mmoles) in water (25 ml) was added 4-Chloro-1-(4-fluoro-phenyl)-butan-1-one gives (6,

39.47 mmoles) at RT. At 70-750C the reaction mixture was then heated for 3-4 hrs. & monitored

by TLC. By the completion of reaction, reaction mixture was extracted with ethyl acetate (2 x

25ml). The organic layer was washed with water (2 x 25ml), brine and dried over anhydrous

sodium sulfate and concentrated under vacuum to yielded 7.06g (68%) of the corresponding N-

substituted derivative.

e) Synthesis of 2-Chloro-1-(3,4-dimethoxy-pyridine-2-ylmethyl)-1H-benzimidazole

(DG@46)


mmoles) in water (25 ml) was added 2-Chloromethyl-3,4-dimethoxy-pyridine (8, 39.47 mmoles)

at RT. At 70-750C the reaction mixture was then heated for 3-4 hrs. & monitored by TLC. By the



solvent under vacuum yielded 5.6 g (62%) of the corresponding N-substituted derivative.

f) Synthesis of (2-Chloro-benzimidazole-1-carboxylic acid methyl ester (DG@47)

To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and pyridine (39.47 mmoles) in DMF

(5 volume) was added Phenylchloroformate (14, 39.47 mmoles) was reacted in presence of gives

(13, 39.74 mmoles At 60-650C the reaction mixture was then heated for 3-4 hrs. & monitored by

TLC. By the completion of reaction, added 50 ml ethyl acetate stirred for 15 min. layers were

seperated. Ethyl acetate layer was washed with 25 ml water, dried over sodium sulfate. After

concentration of solvent under vacuum yielded 8.41g (85%) of the corresponding N-substituted

derivative.

g) Synthesis of (2-Chloro-benzimidazole-1-yl)-o-tolyl-methanone (DG@48)


(5 volume) was added and o-tolyl chloride (17, 39.47 mmoles). At 60-650C the reaction mixture

was then heated for 3-4 hrs. & monitored by TLC. By the completion of reaction, added 50 ml

ethyl acetate stirred for 15 min. layers were seperated. Ethyl acetate layer was washed with 25 ml

water, dried over sodium sulfate. After concentration of solvent under vacuum yielded 5.77g

(65%) of the corresponding N-substituted derivative.

h) Synthesis of 1-(4-Bromo-benzyl)-2-chloro-1H-benzimidazole (DG@49)


mmoles) in acetone (5 volume) was added 4-bromobenzyl bromide (9, 39.47 mmoles). At 70-

750C the reaction mixture was then heated for 3-4 hrs. & monitored by TLC. By the completion

of reaction, added 50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl acetate

layer was washed with 25 ml water, dried over sodium sulfate. After concentration of solvent

under vacuum yielded 5.6 g (62%) of the corresponding N-substituted derivative.

i) Synthesis of (2-Chloro-benzimidazole-1-yl)-(4-nitro-phenyl)-methanone (DG@50)


(5 volume) was added 4-nitrobenzoyl chloride (15, 39.47 mmoles). At 70-750C the reaction

mixture was then heated for 3-4 hrs. & monitored by TLC. By the completion of reaction, added

50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl acetate layer was washed with

25 ml water, dried over sodium sulfate. After concentration of solvent under vacuum yielded

5.54g (62%) of the corresponding N-substituted derivative.

j) Synthesis of (2-Chloro-benzimidazole-1-carboxylic acid hexyl ester (DG@51)


(5 volume) was added and n-hexylchloroformate (16, 39.47 mmoles). At 65-700C the reaction

mixture was then heated for 3-4 hrs. & monitored by TLC. By the completion of reaction, added

50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl acetate layer was washed with

25 ml water, dried over sodium sulfate. After concentration of solvent under vacuum yielded

8.0g (87%) of the corresponding N-substituted derivative.

k) Synthesis of [2-(2-Chloro-3H-indol-3-yl)-ethyl]-diisopropyl-amine (DG@52)


mmoles) in DMF (5 volume) was added 2-Chloro-ethyl)-diisopropyl-amine (10, 39.47 mmoles).

At 70-750C the reaction mixture was then heated for 3-4 hrs. & monitored by TLC. By the



solvent under vacuum yielded 6.79 g (74%) of the corresponding N-substituted derivative.

l) Synthesis of 4-(2-Chloro-benzimidazole-1-yl)-butyronitrile (DG@53)


mmoles) in DMF (5 volume) was added 4-bromobutyronitrile (11, 39.47 mmoles) 39.47 mmoles

). At 70-750C the reaction mixture was then heated for 3-4 hrs. & monitored by TLC. By the



solvent under vacuum yielded 6.74g (88%) of the corresponding N-substituted derivative.

m) Synthesis of 2-Chloro-benzimidazole-1-yl)-pentoinoc acid ethyl ester (DG@54)


mmoles) in DMF (5 volume) was added 4-bromoethylbutyrate (12, 39.47 mmoles). At 70-750C

the reaction mixture was then heated for 3-4 hrs. & monitored by TLC. By the completion of

reaction, added 50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl acetate layer

was washed with 25 ml water, dried over sodium sulfate. After concentration of solvent under

vacuum yielded 7.17g (78%) of the corresponding N-substituted derivative.

n) Synthesis of (2-Chloro-benzimidazole-1-yl)-acetic acid methyl ester (DG@55)


mmoles) in DMF (5 volume) was added methylchloroacetete (13, 39.74 mmoles). At 70-750C

the reaction mixture was then heated for 3-4 hrs. & monitored by TLC. By the completion of

reaction, added 50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl acetate layer

was washed with 25 ml water, dried over sodium sulfate. After concentration of solvent under

vacuum yielded 5.0g (69%) of the corresponding N-substituted derivative.

Conclusion-

We have synthesized a series of N-alkylated derivatives using a known starting benzimidazole

and with good yields. Here we have used different intermediated for akylation and presented

novel derivatives. The structures of all the synthesized compounds were characterized by

spectroscopic data, and allowed these molecules for study of antibacterial and antifungal

activities Benzimidazole derivatives shows a very good anti bacterial activities which are

explained in chapter-6.

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12 CHAPTER-V SYNTHESIS OF NOVEL N …shodhganga.inflibnet.ac.in/bitstream/10603/44637/12/12_chapter-v.pdf · SYNTHESIS OF NOVEL N-SUBSTITUTED 2-CHLORO-1H- BENZIMIDAZOLE DERIVATIVES