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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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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.
Chapter - 4 Chemistry of 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.
Chapter - 4 Chemistry of Bis-benzimidazoles
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)
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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.
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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)
Chapter - 4 Chemistry of Bis-benzimidazoles
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.
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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).
Chapter - 4 Chemistry of Bis-benzimidazoles
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.
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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.
Chapter - 4 Chemistry of Bis-benzimidazoles
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 %.
Chapter - 4 Chemistry of Bis-benzimidazoles
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)
which are D2O exchangeable; 13C NMR (75 MHz, δ ppm, CDCl3); 20.12,
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 %.
Chapter - 4 Chemistry of Bis-benzimidazoles
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 %.
Chapter - 4 Chemistry of Bis-benzimidazoles
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 %.
Chapter - 4 Chemistry of Bis-benzimidazoles
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)
which are D2O exchangeable; 13C NMR (75 MHz, δ ppm, CDCl3); 20.68,
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 %.
Chapter - 4 Chemistry of Bis-benzimidazoles
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 %.
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
168
Spectrum 5: Mass Spectra of compound compound (IA-a)
NH
N
NH
NCH3H3C
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
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
Chapter - 4 Chemistry of Bis-benzimidazoles
171
Spectrum 10: Mass Spectra of compound (IA-b)
NH
NH3C
CH2
NH
NCH3
Chapter - 4 Chemistry of Bis-benzimidazoles
172
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