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Chapter - 4 Chemistry of Bis-benzimidazoles

133

4.1 Introduction

GREEN CHEMISTRY FOR CLEAN ENVIRONMENT

Heterocycles make up an exceedingly important class of compounds

due to their expansive range of applications. They are predominant among

all types of pharmaceuticals, agrochemicals and veterinary products. This

comes as no surprise, since the most potent natural compounds and the

alkaloids are heterocycles. Benzimidazoles are fundamental structural units

not only in the pharmaceutical industry but also in several other fields such

as agricultural, electronic, and polymer chemistry. Owing to the immense

importance and varied bioactivities exhibited by benzimidazoles, efforts

have been made from time to time to generate libraries of these compounds

and screened them for potential biological activities. That is why

heterocycles are so widely used. However, Nitrogen heterocycles in

particular exhibit diverse biological and pharmacological activities.

The benzimidazole has been considered as one of the most important

and privileged structure in medicinal chemistry, encompassing a plethora of

useful biological activities such as antimicrobial, anti cancer, anti HIV, etc.

The scope of green chemistry considers the environmental, health and safety

problems associated with modern chemical manufacturing processes and

legal instruments that have resulted, along with the needs for green

chemistry solutions. It also considers some of the underlined principles and

concepts that should underpin chemistry and chemical manufacturing in the


134

future. Biotechnology is a burgeoning area worldwide which is an important

part of green chemistry tool kit. It plays an important role in green chemistry

through the use of bio-techniques such as the design of new drugs, the use of

bio-catalytic reactions and the production of agrochemicals.

The environmentally friendly, waste-minimization, remediation

(clean-up) and restoration strategies can be based on physical, chemical or

biological approaches. Therefore, the examples of green chemistry that has

been developed and encompassed most of the all areas of chemistry

including organic, bio-chemistry, inorganic, polymer, toxicology,

environmental, physical, industrial etc. The principles of green chemistry

that can be applied broadly to the areas like synthesis, catalysis, reaction

conditions, extraction, separations, computational chemistry and process

modeling etc. including the preparation of the bio-pesticide by plant cell

cultivation.

Green chemistry is also applicable to all sectors of the chemical

industry ranging from pharmaceuticals and special oleochemicals to the high

volume manufacture of bulk chemicals and oleochemicals. The growing

public sentiment in support of our environment, the focus of the industry has

shifted to reduce or eliminate the use of organic solvents during

manufacturing and processing. This involves ‘closed loop system’ leading to

reduction or recycling, switching to solvent free processes or solvent

alternatives.1 The metathesis of natural oils and fats and their derivatives is a


135

clean catalytic reaction that can be considered as an example of green

chemistry. Using this reaction, oleochemical feed stocks can be converted

into valuable chemical products directly or requires few reaction steps. With

the development of catalysts that are active and highly selective under mild

reaction conditions, there are favorable perspectives for the application of

the metathesis reaction in the oleochemical industry.2

In a recent time, there has been much interest for the use of

microwave irradiation in synthesis due to substantial reduction in time as

well as eco-friendly. Apart from being environmentally friendly technique,

microwave irradiation has carved its importance in the field of

pharmaceutical chemistry for the synthesis of new potent drugs. There has

been an unlimited expansion and exploration of molecular diversity in the

synthesis of organic compounds by the application of combinatorial

methodology.3– 8

Combinatorial organic synthesis on polymer support integrated with

microwave irradiation technology has emerged as a powerful technique to

generate a large number of aromatic and heterocyclic compounds with the

variety of structural features having a high potential to act as lead molecules

in drug discovery.9–14 Combinatorial chemistry and high-throughput parallel

synthesis have emerged and explored a powerful technique for the

generation of structurally diverse drug like compounds.15–18 Microwave

assisted organic synthesis has received much attention in recent years


136

because of its faster chemistry and formation of cleaner products compared

with conventional heating.19 – 25 It is clear that the application of microwave

technology to rapid synthesis of biologically significant molecules on the

solid support would be of great value for library generation.26–29 This

technology has been recently been recognized as a tool for drug-discovery

program.30, 31

Chemistry is critical to drug discovery, especially at the lead

optimization phase, but methods for the synthesis of organic compounds

have remained essentially unchanged for decades. Since lead optimization

time is usually very long with a very high manpower requirement, new ways

to improve the efficiency, output and quality in this phase are always

needed. One feasible solution is microwave-assisted synthesis, which is

many ways superior to traditional heating. Chemical reactions are completed

in minutes and yields are generally higher than those achieved by traditional

means, chemistry unfeasible by conventional procedures might be

performed. Furthermore, in these methods heating is immediate and

volumetric, the temperature is accurately controlled so that reactions can be

more easily repeated.32, 33, 34 Several microwave assisted organic reactions

proceed at mild reaction conditions at much enhanced reaction rates relative

to thermal reactions.35– 41

Environmentally benign solid catalysts such as clays and zeolites,

instead of mineral acids, are also employed for acid catalyzed microwave


137

4.1.1 Applications of Phosphotungstic acid in organic synthesis.

assisted synthetic transformations, rendering them eco-friendly.42

Microwave irradiation has been used to effect organic reactions such as

pericyclic,43 cyclization,44 aromatic substitution,45 oxidation,46 alkylation,47

decarboxylation,48 radical reactions,49 condensation,50 peptide synthesis,51

etc. The Microwave irradiation for the synthesis of substituted

benzimidazoles in the presence of montmorillonite K-10 has been carried

out and their derivatives displayed a number of important biological

activities such as local anesthetic,52 antipyretic52 and antihistaminic53

hence possess a great chemotherapeutic potential.54

Phosphotungstic acid (PTA) is a heteropolyacid with the chemical

formula H3PW12O40. It is normally present as a hydrate. EPTA is the name

for ethanolic phosphotungstic acid, its alcohol solution used in biology. It

has the appearance of small, colorless-greyish or slightly yellow-green

crystals, with melting point 89 °C (24 H2O hydrate). It is odourless and

soluble in water (200 g/100 ml). It is non toxic especially, but a mild acidic

irritant. The compound is known by a variety of different names and

acronyms including-

Phosphotungstic acid (PTA), (PWA)

Tungstophosphoric acid (TPA)

12-phosphotungstic acid

12-tungstophosphoric acid

dodecatungstophosphoric acid


138

In the above the "12" or "dodeca" reflects the fact that the anion

contains 12 tungsten atoms. Some early workers who did not know the

structure, e.g. Wu 55 called it phospho-24-tungstic acid as they formulated it

as 3H2O.P2O5.24WO3.59H2O, (P2W24O80H6).29H2O, which correctly

identifies the atomic ratios of P, W and O. This formula was still quoted in

papers as late as 1970.56

Heteropolyacids are green catalysts that function in a variety of

reaction fields and are efficient bifunctional catalysts, safety, quantity of

waste and separability.57 Among the Keggin-type heteropolyacids are more

active and possess stronger Bronsted acidity than the usual mineral acids

such as H2SO4, HCl, HNO358

and conventional solid acids such as SiO2-

Al2O3, H3PO4-SiO2, zeolites including HX, HY, H-ZSM-5, Amberlyst-15

and Nafion-H.59 Among heteropoly acids, phosphotungstic acids are the

most widely used catalysts 60, 61 owing to their high acid strength, thermal

stabilities and low reducibilities. Some of the applications of

phosphotungstic acid in organic synthesis are discussed as follows.

Mallik et al., have synthesized a series of eco-friendly solid acid

catalyst by supporting phosphotungstic acid onto hydrous zirconia by an

incipient wetness impregnation method in order to contribute towards clean

technology. Their catalytic activities were evaluated for oxybromination

reaction of phenol by varying different reaction parameters. The

electrophilic substitution of bromine generated in situ from KBr as a

bromine source and hydrogen peroxide as an oxidant. The 15 wt.% of

phosphotungstic acid supported on hydrous zirconia shows highest surface

area acid sites and gives about 93% conversion with 81% para-selectivity.62


139

OH

ZPTA, AcOH

Br

OH OH

Br

Phenol Parabromophenol orthobromophenol

Di-bromophenolKBr, 30% H2O2+ +

Devassy et al., have carried out the alkylation of resorcinol with tert-

butanol using zirconia supported phosphotungstic acid (PTA) as catalyst in

liquid phase conditions. Among the different PTA loaded catalysts, the 15%

PTA/ZrO2 calcined at 750 oC was found to be the most active and yielding

4-tert-butyl resorcinol and 4,6-di-tert-butyl resorcinol as major products

under optimized reaction conditions.63

Rajagopal et al., have carried out the regioselective monobromination

of aromatic substrates with N-bromosuccinimide in excellent isolated yields

(84-98%) using phosphotungstic acid supported on zirconia as a novel

heterogeneous catalyst. Remarkably, the new catalyst system described

brought about the side-chain bromination of aromatics to afford

bromomethyl arenes in excellent yields (86-98%) without the need for a

radical initiator. Recovery and recyclability of the catalyst have been well

established.64

OH

OH

OH

O

OH

OH

OH

OH

O

OH

OH

OH

Resorcinol

resorcinol mono tert - butyl ether

OH

4- tert - butyl resorcinol

4,6-di- tert - butyl resorcinol

4, tert - butyl resorcinol mono tert-butyl ether


140

The synthesis of 3,4-dihydropyrimidin-2(1H)-ones was carried out by

one pot condensation of aryl aldehydes, urea derivatives and β-diketones

using sulfated zirconia or phosphotungstic acid as catalysts.65

Phosphotungstic acid was also used as an environmentally benign

solid acid catalyst for synthesis of aryl-1,4,dibenzo[α.β]xanthenes by

condensation of β-napthol and arylaldehydes. It was observed that 100 mg

of phosphotungstic acid is quite efficient for the condensation of β-napthol

and aryl aldehydes to produce the corresponding xanthenes under solvent

free condition and microwave irradiation.66

Phosphotungstic acid (PTA) was found to be a promising solid acid

catalyst as an alternative to the conventional stoichiometric reagents for the

rearrangement of benzyl phenyl ether giving 2-benzyl phenol as a major

Ar- H NBr

O

O

PTZ/ MethanolAr- Br NH

O

O

+68 oC

+

Ar -CHO

OHPWA

MW

O

Ar

+

, 60s

H

O

CH3

OR1

O O

NH2NH

2

X

NH

NH

CH3

X

O

OR

+

R

Where X = O/S

R1

Sulfated Zirconia / PWA

MW, 60 -120 s


141

O PhOH

Ph

OH OH

Ph

OH

Ph

Ph

OH

PhPh+ + + +

PTA hydrate

Solvent/ Solvent -free

product and 4-benzyl phenol and dibenzylated phenols as side products.66

Catalyst was recovered from the reaction mixture and reused again without

loss of activity.

Tungstophosphoric acid catalyzed rapid and good yielding reactions

of α, β-unsaturated aldehydes with arenethiols to give the corresponding

4-thioaryl-1,2,3,4-tetrahydro-1-benzothiopyrans (thiochromans) under

solvent-free and room temperature conditions.67

Sivaprasad et al., have developed a simple and efficient method for

the synthesis of quinaldines and lepidines by one-pot reaction of anilines

with crotonaldehyde or methyl vinyl ketone using phosphotungstic acid, a

Keggins-type heteropolyacid, under both thermal and microwave irradiation

conditions.68

Rocha et al., have developed direct transformations of α-pinene

oxide to either campholenic aldehyde, trans-carveol, trans-sobrerol or pinol

RCHO ArSH

S R

SAr

+

H3PW12O42 (0.01 mmol)

Solvent-free, rt

10-15 min

Yield = 59 -76 %

NH2

O

N

+

R1

R1

R2R2

R3 R3

R4

R5

R4

R5

Phosphotungstic acid(aq)/ Sio2

100 oC, 2h or

Phosphotungstic acid(aq)/ toluene

MW, 10-15 min


142

O

O

OH

OH

OH

O+ + +

pinene oxide campholenic aldehyde trans- sobrerolltrans- carveol pinol

Phosphotungstic acid

OH

TsNH2

NHTs

+

Phosphotungstic acid

1,4-dioxane, 80 oC, 12h

88 % yield

using phosphotungstic acid as catalyst. The use of very low catalyst loading

(0.005-1 mol%) and the possibility of catalyst recovery and recycling

without neutralization are significant advantages of this simple,

environmentally benign and low cost method.69

Wang et al., have developed mild nucleophilic substitution reactions

of benzhydrylic, benzylic, allylic and simple aliphatic alcohols with

sulfonamides, benzamide and 4-nitroaniline in the presence of 12-

phosphotungstic acid as an efficient, eco-friendly, cheap and air and

moisture-tolerant catalyst for the construction of C-N bonds. The amine

derivatives were obtained in good yields (up to 88%). The reusable nature of

12-phosphotungstic acid makes this protocol more attractive.70

Giri et al., have synthesized benzimidazoles in very good yield from

o-phenylenediamine and aromatic aldehydes in the presence of

monoammonium salt of 12-tungstophosphoric acid [(NH4)H2PW12O40], an

efficient heterogeneous catalyst. This catalyst has the advantages of simple

workup procedure, water insolubility and good activity with high yield for

the synthesis of benzimidazole derivatives.71


143

NH2

NH2

RCHO

(NH4)H

2PW

12O

40

DCE, Reflux N

NH

R

R1

R2

R3

+

R1

R2

R3

R = -Ph; R1 = -H, - CH3, CF3

R2 = -H, - CH3; R3 = -H, NO2

O NH2

CH2Cl

2, RT

NH

OH

R

R+

1 mol% H3PW12O40

4.2 Methods for the synthesis of bis-benzimidazoles

Suresh Babu et al., have developed a regioselective cleavage of

epoxides with aromatic amines in the presence of tungstophosphoric acid as

a catalyst. The reaction proceeded rapidly and afforded the corresponding

β-amino alcohols in moderate to high yields.72

Bis-benzimidazoles (1) are synthesized by heating two moles of o-

phenylenediamine with one of each dibasic acids ranging from succinic

through sebacic acid.73 A reaction temperature of 125–135 oC and 4 N

hydrochloric acid as a catalyst gave yields ranging from 28– 63 %.

N

N

H

NH2

NH2

HOOC(CH2)nCOOH

N

N

H

(CH2)n

+

4 N HCl

(1)

Where n = Alkyl chain


144

Bis-benzimidazoles are the most important potent inhibitors of

rhinoviruses. These were prepared74 by heating a mixture of o-phenylene

diamine (0.1 mol), dicarboxalic acids (0.05 mol), and 40 ml 5 N HCl (0.2

mol) in an oil bath at 135 oC under N2 for approx 18 hr. Subsequently, the

reaction mixture was basified with concentrated NH4OH. The precipitate of

bis-benzimidazole (2) was collected, washed and crystallized from alcohol.

N

N

H

NH2

NH2

HOOCXCOOHN

N

H

X+

5 N HCl

2

(2)

Bis-benzimidazoles (3) are synthesized by heating two moles of o-

phenylenediamine with one mole of each dibasic acids ranging from oxalic

through sebacic acid.75 A reaction temperature of 200–250oC and

polyphosphoric acid as a catalyst gave yields ranging from 85–95 %.

N

N

H

NH2

NH2

HOOC(CH2)nCOOH

N

N

H

(CH2)n

+

Polyphosporic acid

2

(3)

Where n = 0 – 8.

A number of new bis-benzimidazoles (4) have been prepared

containing substituents on the both benzene rings.76 The chain linking of the

two benzimidazole units has been varied from simple alkene chains to

substituted alkane chains or aryl chains (benzene rings). It was found that

polyphosphoric acid is a useful medium for preparing bis-benzimidazoles.


145

N

N

H

NH2

NH2

HOOC(CH2)nCOOH

N

N

H

(CH2)n

+ Polyphosphoric

acid

2 R

R

R

(4)

Where n = 2 - 8.

The synthesis and evaluation of the novel head-to-head bis-

benzimidazole compound 2,2-bis-[4'-(3''-dimethylamino-1''-

propyloxy)phenyl-5,5-bi-1H-benzimidazole (5) is described.77 An X-ray

crystallographic study of a complex with the DNA dodecanucleotide

sequence d(CGCGAATTCGCC) shows the compound bound in the A/T

minor region of a B-DNA duplex and that the head-to-head bis-

benzimidazole motif hydrogen-bonds to the edges of all four consecutive

A:T base pairs. The compound showed potent growth inhibition with a mean

IC50 across an ovarian carcinoma cell line panel of 0.31μM, with no

significant cross-resistance in two aruired cisplatin-resistant cell line and a

low level of cross-resistance in the P-glycoprotein over expressing aquired

doxorubicin-resistant cell line. Studies with the hallow fiber assay and the

In-vivo tumor xenografts showed.


146

NH2

NH2

O2N NO

2

NH2

NH2

NH2

NH2

PhNO2 X CHO

X = -O-CH2-CH

2-CH

2-N

CH3

CH3

N

NH

NH

N

X

X

Raney Nickel, H2

Acetone

150 0C

(5)

The synthesis of extended dicationic bis-benzimidazoles (6) starting

from trans-1,2-bis(4-cyanophenyl) ethene and trans –1,2-bis(4-

cyanophenyl) cyclopropane is reported.78

LNC CN LOHC CHO

NH

N

L

A

N

NH

A

1 a L =

1 a L =

(I) (II)

(III)

3 a L =

3 b

L = 3 c

L =

A = -C=NH(NH2)

A = -C=NH(NH2)

A = -C=NH(NH-I-Pr)

(i)

(ii)

(6)

Reagents and conditions: i) DIBAL, CH2Cl2 ii) 3,4-

Diaminobenzamidine or 3,4- Diamino-n-Isopropylbenzamidine, 1, 4-

Benzoquinone, CH2Cl2-EtOH The new methodology79 for the synthesis of

symmetric bis-benzimidazoles carrying 2-aryl moieties including 2-[4-(3’-

aminopropoxy)phenyl] (7) and 2-[4-(3’-aminopropanamido)phenyl] (8)


147

4.3 Biologically active Bis-benzimidazoles

substituents, together with the synthesis of novel hybrid molecules

comprising bis-benzimidazoles in ester and amide combination with the N-

mustard chlorambusil.

Br OH OH CHO Br O CHO

NH2NH

2

NH2NH

2

NH

N

O BrNH

N

O X

N N NMe

+

DEAD, PPh3

THF, 61 %

4 HCl. 2 H2O

22

OxoneNaOHDMF / H2O

x

X = or

Where

(7)

NH2

OH

N(H)BOC

OH

N(H)BOC

HO

NH

N

NHBOC

NH

N

NH2N

H

N

NH

O

NMe2

NH

N

NH NMe2

BOC2O

NaOHH2O

DIoxane

90 %

MnO2

72 %

2i. TFA

ii. K2CO3

91 %

22

2

OxoneNaOH

H2ODMF/

84 %

i. Cl(CH2)2COCl, DMF 82 %

ii. Me2NH, MeOH, 11%

(8)

A comprehensive review of the chemistry of biologically active bis

benzimidazoles with complete literature coverage revealed that number of

novel head-to-head bis-benzimidazole derivatives that are structurally

related to the fluorochrome, which possess strong affinity for A:T sites in


148

the minor groove of duplex DNA. Initial studies revealed that, these

compounds exhibit potent antiproliferative activity against a range of

ovarian cell lines and to inhibit transcription in an In-vitro setting, reflecting

the reduced sensitivity of this cell line to the bis-benzimidazoles in

comparison to the breast cancer cell lines.

Mechanistic studies revealed that compounds do inhibit the catalytic

activity of these enzymes. Drug uptake studies showed that these

compounds correlated with a markedly reduced intracellular drug

accumulation, suggesting that the biologically active DNA minor groove-

binding molecules inhibit the enzyme-DNA binding step of the

topoisomerase reaction sequence. The apparent selectivities for the parasite

enzymes and the low levels of toxicity to mammalian cells for the

biologically active bis-benzimidazoles suggest that these compounds hold

promising and effective therapeutic agents in the treatment of a life-

threatening AIDS-related diseases.


149

The chemotherapeutic potential of head to tail bis-benzimidazoles (4)

was realized in early 1980’s when enviroxime (1) and enviradene (2)

underwent clinical trials for their anti-rhinovirus activity

The natural product of bis(benzoxazole), has potential for use against

cancer cell lines. Structurally similar following bis-benzimidazole

derivatives were also found to exhibit potent anticancer activity.

Following substituted bis-benzimidazoles shown anti-tumor activity

as novel DNA minor groove binders.

Where R= CH3.OCH3


150

4.4 Present work

Over the past two decades, chemistry community, in particular

chemical industries have made the extensive efforts to synthesize novel

compounds associated with the new catalysts. Much innovative chemistry

has been developed using such catalysts that are most effective, excellent

and more environmentally benign. Hence, these catalysts play an important

role in the functional group transformations and also in the eco-friendly

synthetic approach in the synthetic organic chemistry as well as in the green

chemistry also. Due to climatic pollutions, these catalysts are being explored

to solve the environmental problems which have made very much

stimulation in increasing the interest to use such catalysts towards the most

potent organic biomolecules. Thus, solid acid catalysts are being the

important avenues in the pharmaceutical and polymer industries.80

The development of such efficient and environmentally acceptable

synthetic protocols using solid acid catalysts can prove to be the milestones

in the synthetic libraries, since these catalysts are being reused and also most

important in the industrial scale. This is the most challenging research work

to develop new protocols using catalyst with high densities of strong acid

sites and which are able to operate at low temperatures.81,82 Therefore, the

application of heterogeneous catalyst has become useful tool in the field of

catalytic chemistry. Amongst the various heterogeneous catalysts,

heteropoly acids are the most attractive catalyst, because they are easy to


151

handle and easy to display for their remarkable low toxicity,

environmentally friendly, possess very high Bronsted acidity and constitute

a mobile ionic structure and absorb polar molecule forming a ‘pseudoliquid

phase.83,84

Due to both, the surface protons and the bulk protons of

heteropolyacids (HPAs) participation in their catalytic activity, having

significant enhancement the reaction rates. Thus, the organic reactions using

HPAs as catalyst are placed in the development of synthetic protocols for

the synthesis of antioxidants, pharmaceuticals, vitamins and biologically

active chemical substances.85 Therefore, the incorporation of the imidazole

moiety to the aromatic hydrocarbon is an important synthetic strategy in the

drug discovery86 using catalyst leading to the benzimidazole analogues of

biological importance. Such biomolecules have broadened the scope and

possessing privileged structure in the medicinal chemistry.87,88 Such

benzimidazole derivatives are being explored in the proton pump inhibitor

Omeprazole,89,90 anthelmentic Albendazole,91,92 anti-dopaminergic

Domperidone,93,94 and anti-psychotic Pimozide. 95,96

Considering the extensive applications of such benzimidazoles, the

compounds containing bis-benzimidazole structures also drawn much

attention due to their wide range of pharmacological activities.97 Therefore,

bis-benzimidazoles have been reported to be the most effective towards the

inhibition of in-vitro replication of polio virus,98 anti-tumor effect,99 and a


152

pathogen of major clinical importance in the treatment of AIDS patients, as

well as cytotoxic activity against tumor cell lines.100 Pibenzimol drug is a

bis-benzimidazole derivative which binds to adenine-thymine base pairs of

double-stranded DNA and which is used as a water soluble fluorescent stain

in chromosomal analysis101–103 and also for In-vivo anti-tumor activity

against leukemia.104

The application of clean catalytic technologies, especially those with

the use of heterogeneous catalysts, is becoming increasingly important for

the development of environmentally benign chemical processes. The drive

towards clean technology has encouraged the application of PTA catalyst. A

move away from the use of solvents in organic synthesis has led in some

cases to improved results and more benign synthetic procedures. Our

approach is to reduce the use of organic solvents, which are potentially

toxic, hazardous and favours towards the use of simple and mild conditions

with inherently lower cost.

In the present work it has been found possible to develop

environment friendly, rapid synthesis of heterocyclic molecules of

biological interest, we explored the possibility of synthesizing bis-

benzimidazole derivatives (Scheme-1A) which involves the reaction

between 4-methyl-o-phenylene diamine and dicarboxylic acid in presence

of phosphotungstic acid as a catalyst to facilitate the rapid synthesis of new

bioactive heterocycles as targeted chemotherapeutic agents. These

observations have encouraged us to synthesize some new products


153

containing the bis-benzimidazole moiety hoping to obtain new compounds

with potential biological activity (Scheme-1B and Scheme-1C).

In the present study, All the reactions involved are highly efficient to

give the desired compounds in high yield and high purity. As a part of our

on going research works in the synthesis of novel heterocyclic compounds

of biological interest.105–113 Efforts have been made from time to time to

generate libraries of these compounds and screened them for potential

biological activities. This adopted procedure is simple, rapid and eco-

friendly due to easy experimental procedures. The versatility of this

methodology can be extended to develop a stream-lined approach to other

drugs like heterocycles in solvent-free conditions. In the present study, we

performed the synthesis and biological evaluation of some libraries of bis-

benzimidazole compounds.

Scheme-1A.

NH2

NH2

CH3

COOH-(CH2)-COOH

PTA N

NH

(CH2)

CH3

N

NH

CH3

2 +

80-90 oC, 20 hrn

n

1A (a-l)

Scheme-1B.

NH2

NH2

HOOC-(CH2)m-COOH

N

NH

NH

N

(CH2)m

BrBr

Br

+2

20 Hours

PTA

1B (a-l)

80-90 co

Scheme-1C. NH

2

NH2

O2N

COOH-(CH2)-COOH

PTA N

NH

(CH2)

O2N

N

NH

NO2

2 +

80-90 oC, 20 hrn

1C (a-l)


154

a) Oxalic acid e) Adipic acid i) Sebacic acid

b) Malonic acid f) Pimelic acid j) Phthalic acid

c) Succinic acid g) Suberic acid k) Isophthalicacid

d) Glutaric acid h) Azealic acid l) Terephthalic acid

a)Oxalic acid

b) – CH2–

c) –(CH2)2–

d) –(CH2)3–

e) –(CH2)4–

f) – (CH2)5–

g) –(CH2)6–

h) –(CH2)7–

i) –(CH2)8–

j) Phthalic acid

k) Isophthalic acid

l) Terphthalic acid

In summary, we have developed an efficient, facile and

environmentally acceptable synthetic methodology for the synthesis of bis-

benzimidazole derivatives using phosphotungstic acid as a eco-friendly

catalyst. The attractive features of this procedure are the mild reaction

conditions, high conversions, ease of separation and recyclability of the

catalyst, inexpensive and environmentally friendly catalyst, excellent yields,

all of which make it a useful and attractive strategy for the preparation of

various bis-benzimidazole derivatives simply by changing different

substrates. We decided to investigate the efficacy of these derivatives.

In contrast to the above-mentioned transformations, structural

optimization, study of the mechanism of action and in- vivo efficacy of this

new class of potent bis-benzimidazole compounds and their therapeutic

applications were carried out.


155

4.5 Materials and Methods

4.6 Experimental procedure

The melting points of the Phenyl thiazolo benzimidazole products

were determined by open capillaries on a Buchi apparatus and are

uncorrected. The IR spectra were recorded on a Nicolet Impact-410 FT-IR

Spectrophotometer using KBr pellets. The 1H and 13C NMR spectras were

recorded on a 300MHz Bruker-Avanace NMR instrument in CDCl3 and the

chemical shifts were expressed in parts per million (ppm) with

tetramethylsilane (TMS) as an internal standard. Mass spectrometer with

ionization energy maintained at 70eV using on Shimadzu mass spectrometer.

The elemental analysis was carried out by using Heraus CHN rapid

analyzer. All the compounds gave C, H and N analysis within ± 0.4% of the

theoretical values. The homogeneity of the compounds was described by

TLC on aluminum silica gel 60 F254 (Merck) detected by U.V light (254 nm)

and iodine vapours.

A novel catalytic approaches for the synthesis of bis-benzimidazole

derivatives 1(a-l) using phosphotungstic acid via cyclo-condensation of 4-

methyl-o-phenylenediamine with various dicarboxylic acids.

Phosphotungstic acid has been demonstrated as an efficient catalyst for this

methodology to afford the products in excellent yield with high purity. In

the present experimental protocol, a mixture of 4-methyl-o-phenylene

diamine (20 mmol) and dicarboxylic acid (10 mmol) were refluxed on an oil


156

4.7 Results and discussion

bath using phosphotungstic acid (0.04g, 0.01mmol) as a catalyst at moderate

temperature 80-90 oC for 14–24 h in 10 mL of 1, 4 dioxane solvent.

The progress of the reaction was monitored by TLC on silica gel 60

F254 (Merck) detected by UV light (254 nm) and iodine vapors. After

completion of the reaction, it was cooled, and then poured into ice cold

water. The crude solid was filtered, dried and recrystallised. The structure

elucidation of newly synthesized compounds has been carried out by IR, 1H-

NMR, 13C-NMR, MS and elemental analysis.

In the present study, we are reporting the cyclo-condensation of

dibasic acids with 4-methyl-o-phenylenediamine in the presence of PTA

catalyst using 1,4-dioxane solvent to give the corresponding bis-

benzimidazoles with excellent yield and high purity (Scheme-1). Although,

this unique synthetic technique has been successfully applied in the

preparation of bromo bis-benzimidazole and nitro bis-benzimidazole

derivatives. Physical and analytical data of the newly synthesized

compounds are summarized in (Table-1). The results of our studies in this

direction pertaining to effect of catalyst concentration for the synthesis of

6,61-Dimethyl-1H,1'H- 2,2' bis-benzoimidazole (1a) were presented in

(Table- 2). In fact, PTA catalyzed synthesis of title compound (Ia) with

different solvents were described in (Table-3).


157

The IR spectrum of all the compounds 1(a-l) showed –NH stretching

band in the range of 3456-3424 cm-1 in all imidazole ring of bis-

benzimdazole derivatives. The characteristic –C=N stretching band around

1625-1620 cm-1 and –CH stretching band were observed around 2925-2920

cm-1.The 1H NMR spectra of all the compounds exhibited structure

revealing proton signals from δ 7.0-7.8 ppm(multiplet, aromatic protons), δ

7.2-7.5 ppm (s, 2H, -NH which is merged with aromatic protons and

disappeared on D2O addition), δ 2.1-2.6 ppm (multiplet, shielded methylene

protons), δ 2.20-2.40 (s, 3H, CH3), respectively. 13C NMR spectra of all the

compounds have shown signals around δ 130–160 ppm for imidazole

carbon, δ 18.0-20.90 ppm for methyl carbon, around δ 120.32-138.30 for

aromatic carbon atoms, and δ 12-45 ppm for saturated carbon atoms

including tertiary carbon atoms.

Further structural optimization, study of the mechanism of action and

In- vivo efficacy of this new class of potent BBI compounds and therapeutic

applications were evaluated. The X-ray analysis of the compound(s) is under

progress.

The IR, 1H NMR, 13C NMR and Mass spectra of some compounds

are enclosed as Spectrum No. 1-10.

This part of the research work entitled “Synthesis and investigation of

anticonvulsant and antidiabetic activities of newly synthesized bis-benzimidazole

derivatives” has been published in International Journal of Drug Formulation and

Research, 2010, 1 (iii), 240-262.


158

Table-1 Physical and analytical data of bis-benzimidazole derivatives 1(a-l)

a Products were characterized by IR, NMR, MS and elemental analysis.

b Isolated yields.

c Melting points are uncorrected.

Entry aProduct n

bYield(

%)

cm. p

(0C)

Mol. Formula/

Mol. Wt

Elem.Analysis (Cal./Found)

C H N

1 1a - 60.02 212-214 C16H14N4

262.31

73.26

73.24

5.38

5.36

21.36

21.38

2 1b 1

56.84 223-225 C17H16N4

276.34

73.89

73.90

5.84

5.82

20.27

20.25

3 1c

2

72.46 207-208 C18H18N4

290.36

74.46

74.44

6.25

6.22

19.30

19.32

4 1d

3

68.00 276-278 C19H20N4

304.39

74.96

74.94

6.62

6.60

18.41

18.38

5 1e 4

64.48 264-265 C20H22N4

318.42

75.44

75.42

6.96

6.97

17.60

17.62

6 1f 5

54.34 226-227 C21H24N4

332.4

75.87

75.85

7.28

7.26

16.85

16.83

7 1g

6

66.08 232-234 C22H26N4

346.2

76.27

76.25

7.56

7.54

16.17

16.14

8 1h

7

58.44 227-229 C23H28N4

360.5

76.63

76.62

7.83

7.82

15.54

15.56

9 1i

8 70.64 269-271 C24H30N4

374.2

76.97

76.98

8.07

8.09

14.96

14.94

10 1j COOH

COOH

69.03 231-233 C22H18N4

338.4

78.08

78.12

5.36

5.34

16.56

16.52

11 1k COOH

COOH

72.49 216-218 C22H18N4

338.4

78.08

78.10

5.36

5.32

16.56

16.54

12 1l HOOC COOH

74.20 288-290

C22H18N4

338.4

78.08

78.12

5.36

5.34

16.56

16.53

N

NH

(CH2)

CH3

N

NH

CH3

n


159

Table-2 PTA catalyzed synthesis of 6,6’-Dimethyl-1H,1'H- 2,2' bis- benzoimidazolea

(1a) with different solvents.

Entry Solvent Catalyst

(mmol%) Time (h) Yieldb (%)

1 Toluene 2 22 54.22

2 THF 2 21 48.34

3 Dioxane 2 14 60.02

4 Acetonitirle 2 18 56.02

5 Xylene 2 20 52.36

a Reaction condition: 4-methyl-o-phenylene diamine (20 mmol) and dicarboxylic acid

(10 mmol), phosphotungstic acid (0.01mmol) solvent(5 ml) at 80-90 0C ,

Table-3 Effect of catalyst concentration for the synthesis of

6,6’-Dimethyl-1H,1'H- 2,2' bis-benzoimidazolea (1a)

Entry Catalyst

concentration

(% mmol)

Time

(h)

Yield

(%)

1 1 12 67

2 2 14 70

3 5 15 68

4 10 13 72

a Reaction condition: 4-methyl-o-phenylene diamine (20 mmol) and dicarboxylic acid

(10 mmol), phosphotungstic acid (0.01mmol) at 80-90 0C by varying the amount of

catalyst under1,4 dioxane solvent.


160

NH

N

NH

NCH3H3C

NH

NH3C

CH2

NH

NCH3

(1a) 6,6'-Dimethyl-1H,1'H- 2,2' bis-benzoimidazole

Colorless solid, m.p;212-214

oC; IR (KBr): υ (cm-1) 3440 (-NH),

1620 (C=N), and 1510 (C=C); 1H NMR (300MHz, δ ppm, CDCl3); 2.40 (s,

6H, CH3), 6.47- 8.12 (m, 6H, Ar-H), 7.30 (br, s, 2H, -NH-benzimidazole)

which are D2O exchangeable; 13C NMR (75 MHz, δ ppm, CDCl3); 20.88,

115.3, 116.1, 123.6, 132.1, 134.8, 137.2, 141.6 ; MS: 262 [M+!]. Anal.

Calcd. For C16H14N4: C 73.26, H 5.38, N 21.36 %. Found: C 73.21, H

5.34,N 21.40 %.

(1b) 2,2'-Methane diylbis(6-methyl-1H-benzimidazole)

Brown solid, m.p; 223-

225 ºC; IR (KBr):

υ(cm-1) 3444 (-NH),

2920 (-CH), 1624 (C=N), and 1520 (C=C) ; 1H NMR (300MHz, δ ppm,

CDCl3); 2.38 (s, 6H, CH3), 3.75 (s, 2H, CH2), 6.42- 8.10 (m, 6H, Ar-H),

7.28 (br, s, 2H, -NH-benzimidazole) which are D2O exchangeable; 13C NMR

(75 MHz, δ ppm, CDCl3); 20.82, 31.3, 115.3, 116.1, 123.6, 132.1, 134.8,

137.2, 141.6 ; MS: 278 [M+]. Anal. Calcd. For C17H16N4: C 73.89, H 5.84, N

20.27 %. Found: C 73.84, H 5.78, N 20.22 %.


161

NH

NH3C

CH2

NH

NCH3

2

NH

NH3C

CH2

NH

NCH3

3

(1c) 2,2'-Ethane-1,2-diylbis(6-methyl-1H-benzimidazole)

Light pink solid,

m.p; 207-208 ºC; IR

(KBr): υ (cm-1)

3438 (-NH), 2920 (-CH), 1618 (C=N), and 1512 (C=C) ; 1H NMR

(300MHz, δ ppm, CDCl3); 2.36 (s, 6H, CH3), 2.88 (s, 4H, (CH2)2), 6.48-8.20

(m, 6H, Ar-H ), 7.40 (br, s, 2H, -NH-benzimidazole) which are D2O

exchangeable; 13C NMR (75 MHz, δ ppm, CDCl3); 20.94, 32.6, 115.3,

116.1, 123.6, 132.1, 134.8, 137.2, 141.6 ; MS: 292 [M+1]. Anal. Calcd. For

C18H18N4 : C 74.46, H 6.25, N 19.30 %. Found: C 74.44, H 6.18, N19.25 %.

(1d) 2,2'-Propane-1,3-diylbis(6-methyl-1H-benzimidazole)

Dark brown solid,

m.p; 276 -278 ºC;

IR (KBr): υ (cm-1)

3446 (-NH), 2920 (-CH), 1628 (C=N), and 1510 (C=C) ; 1H NMR

(300MHz, δ ppm, CDCl3); 1.95 (s, 2H, CH2), 2.38 (s, 6H, CH3), 2.55 (s, 4H,

(CH2)2), 6.60-8.26 (m, 6H, Ar-H ), 7.42 (br, s, 2H, -NH-benzimidazole)


30.4,33.9, 115.3, 116.1, 123.6, 132.1, 134.8, 137.2, 141.6 ; MS: 304 [M+].

Anal. Calcd. For C19H20N4: C 74.97, H 6.62, N 18.41 %. Found: C 74.93, H

6.56, N 18.34 %.


162

NH

NH3C

CH2

NH

NCH3

4

NH

NH3C

CH2

NH

NCH3

5

(1e) 2,2’-Butane- 1,4-diylbis(6-methyl-1H-benzimidazole)

Dark brown solid,

m.p; 264-265 ºC; IR

(KBr): υ (cm-1) 3442

(-NH), 2920 (-CH), 1618 (C=N), and 1534 (C=C) ; 1H NMR (300MHz, δ

ppm, CDCl3); 2.10 (s, 4H, (CH2)2), 2.34 (s, 6H, CH3), 2.45 (s, 4H, (CH2)2),

6.48-8.46 (m, 6H, Ar-H), 7.36 (br, s, 2H, -NH-benzimidazole) which are

D2O exchangeable; 13C NMR (75 MHz, δ ppm, CDCl3); 20.62,30.8,31.7,

115.3, 116.1, 123.6, 132.1, 134.8, 137.2, 141.6 ; MS: 318 [M+1]. Anal.

Calcd. For C20H22N4: C 75.44, H 6.96, N 17.60 %. Found: C 75.34, H 6.92,

N 17.64 %.

(1f ) 2,2'-Pentane-1,5-diylbis(6-methyl-1H-benzimidazole)

Grey solid, m.p;

226- 227 ºC; IR

(KBr): υ (cm-1)

3442 (-NH), 2920 (-CH), 1614 (C=N), and 1522 (C=C); 1H NMR (300MHz,

δ ppm, CDCl3); 1.28 (s, 2H, CH2), 1.64 (s, 4H, (CH2)2), 2.38 (s, 6H, CH3),

2.55 (s, 4H, (CH2)2), 6.48-8.46 (m, 6H, Ar-H), 7.28 (br, s, 2H, -NH-

benzimidazole) which are D2O exchangeable ; 13C NMR (75 MHz, δ ppm,

CDCl3); 20.88, 29.7, 30.8, 32.7, 115.3, 116.1, 123.6, 132.1, 134.8, 137.2,

1.6 ; MS: 332 [M+]. Anal. Calcd for C21H24N4: C 75.87, H 7.28, N 16.85 %.

Found: C 75.84, H 7.23, N 16.80 %.


163

NH

NH3C

CH2

NH

NCH3

6

NH

N

CH2

NH

N CH3

H3C

7

(1g) 2,2'-Hexane-1,6-diylbis(6-methyl-1H-benzimidazole)

Brown solid, m.p; 232-

234 ºC; IR (KBr): υ

(cm-1) 3440 (-NH),

2920 (-CH), 1628 (C=N), and 1524 (C=C); 1H NMR (300MHz, δ ppm,

CDCl3): 1.28 (s, 4H, (CH2)2), 1.64 (s, 4H, (CH2)2), 2.38 (s, 6H, CH3), 2.55

(s, 4H, (CH2)2), 6.44-8.40 (m, 6H, Ar-H), 7.32 (br, s, 2H, -NH-

benzimidazole) which are D2O exchangeable; 13C NMR (75 MHz, δ ppm,

CDCl3); 20.88, 29.7, 30.8, 32.7, 115.3, 116.1, 123.6, 132.1, 134.8, 137.2,

141.6 ; MS: 346 [M+]. Anal. Calcd. For C22H26N4: C 76.27, H 7.56, N 16.17

%. Found: C 76.24, H 7.37,N 16.08 %.

(1h) 2,2'-Heptane-1,7-diylbis(6-methyl-1H-benzimidazole)

Dark brown solid ,

m.p; 227-229 ºC; IR

(KBr): υ (cm-1) 3434

(-NH), 2920 (-CH), 1624 (C=N), and 1512 (C=C); 1H NMR (300MHz, δ

ppm, CDCl3): 1.29 (s, 6H, (CH2)3), 1.62 (s, 4H, (CH2)2), 2.38 (s, 6H, CH3),

2.54 (s, 4H, (CH2)2), 6.44-8.40 (m, 6H, Ar-H), 7.22 (br, s, 2H, -NH-

benzimidazole) which are D2O exchangeable; 13C NMR (75 MHz, δ ppm,

CDCl3); 20.64, 29.9, 30.3, 30.8, 32.1, 115.3, 116.1, 123.6, 132.1, 134.8,

137.2, 141.6 ; MS: 360 [M+1]. Anal. Calcd. For C23H28N4: C 76.63, H 7.83,

N 15.54 %. Found: C 76.44, H 7.80, N 15.50 %.


164

NH

N

CH2

NH

N CH3

H3C

8

NH

NH3C

HN

N

CH3

(1i) 2,2'-Octane-1,8-diylbis(6-methyl-1H-benzimidazole)

Pink solid m.p; 269-271

ºC; IR (KBr): υ (cm-1)

3442 (-NH), 2920 (-

CH), 1618 (C=N), and 1524 (C=C); 1H NMR (300MHz, δ ppm, CDCl3):

1.29 (s, 8H, (CH2)4), 1.62 (s, 4H, (CH2)2), 2.38 (s, 6H, CH3), 2.52 (s, 4H,

(CH2)2), 6.34-8.42 (m, 6H, Ar-H), 7.34 (br, s, 2H, -NH-benzimidazole)


29.7, 30.3, 30.8, 32.1, 115.3, 116.1, 123.6, 132.1, 134.8, 137.2, 141.6; MS:

374 [M+1]. Anal. Calcd. For C24H30N4: C 76.97, H 8.07, N 14.96 %. Found:

C 76.92, H 8.03, N 14.89 %.

(1j) 2,2'-Benzene-1,2-diylbis(6-methyl-1H-benzimidazole)

Dark brown solid, m.p; 231-233 ºC; IR (KBr): υ

(cm-1 ) 3444 (-NH), 1622 (C=N), and 1522 (C=C);

1H NMR (300MHz, δ ppm, CDCl3): 2.34 (s, 6H,

CH3), 6.38-8.58 (m, 10H, Ar-H), 7.38 (br, s, 2H, -

NH- benzimidazole) which are D2O exchangeable; 13C NMR (75 MHz, δ

ppm, CDCl3); 20.64, 115.3, 116.1, 123.6, 127.5, 129.0, 132.1, 134.8, 135.0,

137.2, 141.6; MS: 338 [M+]. Anal. Calcd. For C22H18N4: C 78.08, H 5.36, N

16.56 %. Found: C 78.04, H 5.32, N 16.48 %.


165

NH

NH3C

HN

N

CH3

NH

NH3C

NH

NCH3

(1k) 2,2'-Benzene-1,3-diylbis(6-methyl-1H-benzimidazole)

Brown solid, m.p; 216-218 ºC; IR

(KBr): υ (cm-1) 3442 (-NH), 1618

(C=N), and 1520 (C=C); 1H NMR

(300MHz, δ ppm, CDCl3): 2.36 (s, 6H, CH3), 6.44-8.64 (m, 10H, Ar-H),

7.28 (s, 2H, -NH-benzimidazole) which are D2O exchangeable ; 13C NMR

(75 MHz, δ ppm, CDCl3); 20.9, 115.3, 116.1, 123.6, 125.5, 127.5, 129.0,

132.1, 134.8, 135.0, 137.0, 138.2, 141.6; MS: 338 [M+1]. Anal. Calcd. For

C22H18N4: C 78.08, H 5.36, N 16.56 %. Found: C 78.04, H 5.33, N 16.60 %.

(1l) 2,2'-Benzene-1,4-diylbis(6-methyl-1H-benzimidazole

Dark grey solid,

m.p; 288-290

ºC; IR (KBr): υ

(cm-1)3436 (-NH), 1618 (C=N), and 1532 (C=C); 1H NMR (300MHz, δ

ppm, CDCl3): 2.36 (s, 6H, CH3), 6.44-8.64 (m, 10H, Ar-H), 7.28 (s, 2H, -

NH-benzimidazole) which are D2O exchangeable ; 13C NMR (75 MHz, δ

ppm, CDCl3); 20.8, 115.3, 116.1, 123.6, 127.5, 132.1, 134.8, 136.5, 137.0,

141.6; MS: 338 [M+1]. Anal. Calcd. For C22H18N4: C 78.08, H 5.36, N

16.56 %. Found: C 78.02, H 5.31, N16.52 %.


166

Spectrum 1: IR Spectrum of compound (IA-a) (Code-BBI)

Spectrum 2: 1H NMR (300MHz) Spectrum of compound (IA-a) in

DMSO

NH

N

NH

NCH3H3C

NH

N

NH

NCH3H3C


167

Spectrum 3: 1H NMR (300MHz) Spectrum of compound (IA-a) D2O

Spectrum 4: 13C NMR (75MHz) Spectrum of compound (IA-a)

NH

N

NH

NCH3H3C

NH

N

NH

NCH3H3C


168

Spectrum 5: Mass Spectra of compound compound (IA-a)

NH

N

NH

NCH3H3C


169

Spectrum 6: IR Spectrum of compound (IA-b)

Spectrum 7: 1H NMR (300MHz) Spectrum of compound (IA-b)

NH

NH3C

CH2

NH

NCH3

NH

NH3C

CH2

NH

NCH3


170

Spectrum 8: 1H NMR (300MHz) Spectrum of compound (IA-b) D2O

Spectrum 9: 13C NMR (75MHz) Spectrum of compound (IA-b)

NH

NH3C

CH2

NH

NCH3

NH

NH3C

CH2

NH

NCH3


171

Spectrum 10: Mass Spectra of compound (IA-b)

NH

NH3C

CH2

NH

NCH3


172

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