Chapter - 3
Chemistry of Coumarin benzimidazoles
3.1 Introduction
The benzimidazoles contain a phenyl ring fused to an imidazole ring.
Imidazole (1) nucleus was first discovered by Debus1 in the year 1859 by
reacting glyoxal and ammonia to indicate its source, he proposed the name
glyoxaline. The term imidazole which is due to Hantzsch2 implies a five
membered heterocyclic ring system containing imino group in addition to a
tertiary nitrogen atom, that are located at the positions 1 and 3 respectively.
Thus, the ring system in which benzene ring is fused to the 4,5-positions of
imidazole ring is designated as benzimidazole (2). The various positions on
the benzimidazole ring are numbered as shown below.
4
4
5
N3
5
2
6
N1
H
(1)
8
N3
9 N1
7
H
2
(2)
Benzimidazole possessing a free imino hydrogen and tertiary nitrogen
are tautomeric systems (3) and (4). The two possible tautomeric forms of the
benzimidazole are identical. Substitution of the imino hydrogen eliminates
the possibility for tautomerism and a definite assignment of the structure
becomes possible.
N
N
H
NH
H
N
(4)
(3)
73
H
Chapter - 3
Chemistry of Coumarin benzimidazoles
Benzimidazole derivatives are being explored in pharmaceutical
industries and substituted benzimidazole derivatives have also been found in
the diverse therapeutic applications such as in anti-ulcers, antihypertensives, anti-virals, anti-fungals, anti-cancers and anti-histaminics.3
On the other hand, such benzimidazole derivatives are condensed with other
heterocycles like pyrazole, thiadiazole, triazole, thiazole, coumarin and 2azetidinone
moieties
which
have
shown
diverse
pharmacological
activities.4–12
3.1.1 Aromaticity of benzimidazole
The imidazole molecule is planar and exhibits aromaticity associated
with six -electrons one from each carbon atom, one from the pyridine
nitrogen and two from the pyrrole nitrogen. Actually, a similar situation
exists in case of benzimidazole, which can be envisaged as two overlapping
sextets having 10 -electrons. Benzimidazole is amphoteric compound,
which is pseudo acidic in character. Its basic properties result from its ability
of the pyridine nitrogen to accept a proton. Thus, benzimidazole (pKb 5.5) is
a base considerably weaker than imidazole (pKb 6.95).
3.1.2 Spectroscopic studies of benzimidazole
Ultraviolet (UV)
The ultraviolet spectra of benzimidazole and its derivatives have been
studied in alkaline, neutral and acidic media. The bands observed in the case
of benzimidazole13 are given below.
74
Chapter - 3
Chemistry of Coumarin benzimidazoles
Solvent
λmax (logε) m μ
Ethanol
280 (3.89); 272 (3.91); 243 (3.80)
0.01 N HCl
274 (3.91); 268 (3.92), 235 (3.61)
0.01 N NaoH
277 (3.75); 271 (3.74), 240 (3.63)
The marked shifts in the position and intensity of the absorption
spectra are because of the difference in electron distribution between the
charged and uncharged ions.
Infrared (IR)
The infra red spectra of benzimidazole ring system has strong
absorption band around 1400–1650 cm-1 for –C=N– stretching. It is very
difficult to distinguish13,14 the C–H stretching vibrations occurring in the
range of 3300-3100 cm-1 from the broad –NH stretching frequencies around
3300–2800 cm-1.
Nuclear Magnetic Resonance (1H NMR)
The chemical shifts of benzimidazole have been manifested15,16 at
lower field δ 7.71 (C2–H), 7.67 (C4–H), 7.17 (C5–H), 7.24 (C6–H) and 7.32
ppm (C7–H) respectively. The overlapping signals ascribable to aromatic
proton, and –NH proton have been observed at δ 3.0–8.2 ppm, which are
disappeared on D2O addition. The chemical shift of C4–H and its deviation
is because of various substituents to the magnetic anisotropy of the
unsaturated nitrogen lone pair,17 which is removed when protonation occurs.
75
Chapter - 3
Chemistry of Coumarin benzimidazoles
13
C NMR Spectroscopy
The
13
C NMR chemical shifts that have been reported by Pugmire
and Grant18 for benzimidazole anion (5), benzimidazole (6) and
benzimidazole cation (7) are tabulated as follows.
Compound
Position
δ ppm
Benzimidazole anion
2
150.45
4,7
116.41
5,6
120.10
8,9
143.88
2
141.46
4,7
115.41
5,6
122.87
8,9
137.92
2
139.58
4,7
114.44
5,6
127.29
8,9
129.79
N
N
-
(5)
Benzimidazole
N
N
H
(6)
Benzimidazole cation
+
NH
N
H
(7)
Mass spectroscopy (MS)
The mass spectrum of benzimidazoles exhibit molecular ion as a base
peak.19 It also shows an odd electron ion (8) m/z 91 (C6H5N) by the loss of
hydrogen cyanide, which further looses acetylene to lead to another odd
76
Chapter - 3
Chemistry of Coumarin benzimidazoles
electron ion, m/z 65 (C4H3N) and not the second molecule of hydrogen
cyanide.20
+.
N
+.
NH
N
H
(8)
In the case of 2-methyl benzimidazole, molecular ion m/z 131 is
formed by the loss of hydrogen radical from the methyl group, with a
concomitant ring expansion to form the stable quinoxalinium cation.
+.
N
N
N
+
N
H
..
N
H +
-H +
N
H
+
N
-HCN
CH
- HCN
+
C6 H5
3.1.3 Current trends in the benzimidazole derivatives
Traditionally, benzimidazoles have been most commonly prepared
from the reaction of 1,2-diaminobenzene with carboxylic acids under harsh
dehydrating
reaction
conditions,
utilizing
strong
acids
such
as
polyphosphoric acid, hydrochloric acid, boric acid or p-toluene sulfonic
acid.21 However, the use of milder reagents, particularly Lewis acids,22
inorganic clays,23 or mineral acids,24 has improved both the yield and purity
of this reaction.25
On the other hand, the synthesis of benzimidazoles via the
condensation of 1,2-diaminobenzene with aldehydes requires an oxidative
77
Chapter - 3
Chemistry of Coumarin benzimidazoles
reagent to generate the benzimidazole nucleus. Various oxidative reagents,
such as nitrobenzene, benzoquinone, sodium metabisulfite, mercuric oxide,
lead tetraacetate, iodine, copper (II) acetate, indium perfluoro octane
sulfonates, ytterbium perfluoro octane sulfonates and even air, have been
employed for this purpose.26 Moreover, a variety of benzimidazoles can also
be produced via coupling of 1,2-diaminobenzenes with carboxylic acid
derivatives such as nitriles, imidates, orthoesters, anhydrides or lactones.27
3.2 Methods for the synthesis of benzimidazole derivatives
Synthesis of 2-alkyl or aryl benzimidazoles
o-Phenylenediamine (0.02 mol), the requisite acid (0.03 mol) and 20
mL of hydrochloric acid were boiled for 30-40 min under reflux.28 On
neutralization of filtered solution with ammonia, the corresponding 2-alkyl
or 2-aryl benzimidazole (9) is separated.
NH2
+ R-COOH
4N HCl
NH2
N
N
H
R
(9)
Where R = Formic, Acetic, Propionic, Glycolic, Lactic, Mandelic, Benzoic
etc.
N-Arylamidine hydrochlorides were transformed to benzimidazoles
(10) with sodium hyphochlorite and base in excellent yields.29 The N-chloro
amidine (11) was isolated as a discrete intermediate.
78
Chapter - 3
Chemistry of Coumarin benzimidazoles
_
+
NH2Cl
N
H
R
N
NaOCl
-
R
N
H
OH
(10)
-
NaOCl
N-Cl
N
H
OH
R
(11)
R = Ph
Amongst various derivatives of fatty acids described in literature30,31
for characterization of organic acids the 2-alkyl benzimidazoles of Seka and
Muller.,32 appeared most promising. These 2-alkyl benzimidazoles (12)
were prepared by heating a mixture of acid and o-phenylenediamine. The
resulting compounds have comparatively high melting point range of the
series was continuous and broad.
NH2
N
+ R-COOH
N
H
NH2
R
(12)
Where R = Fatty acid chain
The thermal decomposition of the amidrazoneylid gives 85% yield of
2-phenyl benzimidazole (13).33
Ph
N Ph
+
N N-NMe3
172 oC
N
R
N
H
(13)
79
Chapter - 3
Chemistry of Coumarin benzimidazoles
Synthesis of 2-benzimidazolyl quinoxaline
Mamedov et al., have developed highly efficient and versatile method
for the synthesis of 2-benzimidazolylquinoxaline (14) on the basis of novel
ring contraction of 3-aroyl- and 3-alkanoylquinoxalin-2-ones with 1,2arylenediamines.34
O
Ph
N
NH2
Ph
N
H
O
-2H2O
NH2
N
N
AcOH
+
N
H
N
(14)
Synthesis of 1,2,4-triazino[4,5-a]benzimidazol-1-ones
Jakub Styskala et al., have prepared some of 1,2,4-triazino[4,5a]benzimidazol-1-one derivatives (15 & 16) using coupling reactions of
diazonium salts with 1,1-bis(1-ethoxycarbonyl-benzimidazol-2-yl)methane
to obtain unstable hydrazones, which readily undergo cyclization.35
H
N
N
COOC2H5
N
N
ClCOOEt
N
H
N
N
N
COOC2H5
Arene diazonium salt
Arene diazonium salt
H
N
N
Al. HCl
N
N
N
N
H
N
H
COOC2H5
N
N
COOC2H5
N
H
N
Ar
N
Ar
Al. HCl
H
N
N
Al. HCl
N
N
N
N
N
O
N
COOC2H5
N
N
N
Ar
O
N
Ar
(16)
(15)
80
Chapter - 3
Chemistry of Coumarin benzimidazoles
Synthesis of 2-aryl-3-(1H-benzimidazol-2-yl)-5,7-dimethoxyquinolines
Dzvinchuk et al., have developed three component cyclocondensation
of
p-(dimethylamino)benzaldehyde
with
3,5-dimethoxyaniline
and
2-phenacyl-1H-benzimidazoles which gave 2-aryl-3-(1H-benzimidazol-2yl)-5,7-dimethoxyquinolines (17). The Hanztsch type reaction occurs in
refluxing
acetic
acid
and
is
accompanied
by
aromatization
of
1,4-dihydroquinolines formed through loss of N,N-dimethylaniline.36
Me2N
OMe
NMe2
MeO
H
N
+
O
N
CHO
AcOH
H
N
120 oC, 2h
N
OMe +
Ar
H2N
H
OMe
N
H
Ar
(17)
Synthesis of anilino benzimidazoles
Takahashi and Kano have studied 1,3-dipolar additions with
imidazole N-oxides. In this, phenyl isocyanate and phenyl isothiocyanate
react with 1-methyl benzimidazole-3-oxide to yield the corresponding
anilino-benzimidazoles (18) with the loss of carbon dioxide or carbonoxy
sulphide.37
O+
N
N
+
N
O
O
X
N
N
Ar
CH3
CH3
N
N
H CH3
N
CH3
(18)
X = O, S
81
N
H
Ar
Chapter - 3
Chemistry of Coumarin benzimidazoles
Synthesis of 6-hydroxy-(1,3,4)thiadiazolo(2,3-b)benzimidazoles
Saxena and Soni have studied reactions of 2-aminothiadiazoles with
carbonyl compounds. These authors have reported the synthesis of 6hydroxy-(1,3,4)thiadiazolo(2,3-b)benzimidazoles (19) by the condensation
of p-benzoquinone with 2-aminothiadiazoles as follows.38
O
N
N
..
N
N
+
OH
+
S
H2N
R
N
R
S
N
+ H
N
O
N
R
OH
N
S
N
R
(19)
S
OH
N
R = H, alkyl, aryl
Synthesis of 3-Alkyl-thiazolo [3,2-a] benzimidazole
Christian Roussel et al., showed that 3-Alkyl-thiazolo [3,2-a]
benzimidazole derivatives (20) are obtained in high yields via the
corresponding 4-alkyl-N-3-(2-aminophenyl)-thiazoline-2-thiones which are
easily prepared from 1,2-diaminobenzene, CS2 and halogenoketones.39
R1
N
HN
+
O
R2
S
N
H
S
R2
R1 = CH3, R2 = H
82
N
R1
(20)
Chapter - 3
Chemistry of Coumarin benzimidazoles
Synthesis of 2-(2-benzimidazolyl) chromones
Reddy et al., synthesized 2-(2-benzimidazolyl) chromones by
refluxing o-hydroxy acetophenones with diethyl oxalate containing sodium
methoxide gives methyl chromone-2-carboxylate as an intermediate. Then
treating it with o-phenylenediamine in polyphosphoric acid gives the desired
product (21).4
R2
R2
R1
OH
CH3
R1
O
(COOC2H5)2
NaOCH3
R
COOCH3
R
O
O
PPA
OPD
R2
R1
N
O
N
H
R
O
(21)
R = H, CH3, R1 = H, OCH3, NHCOCH3, R2 = H, CH3
Synthesis of oleobenzimidazoles
Recently, Hosamani et al., has synthesized a series of 2-alkyl
substituted oleobenzimidazoles (22) using ethylene glycol as a solvent. The
reaction parameters such as temperature, density and yield have been
studied to understand whether ethylene glycol is an efficient solvent and can
have a positive effect on the synthesis of oleobenzimidazoles with good
yields.40
83
Chapter - 3
R
Chemistry of Coumarin benzimidazoles
+
NH3Cl
+
+
HCOOR'
NH3Cl
Ethylene glycol
R
, 150 - 200 0C
N
R'
N
H
(22)
Where, R =
a) -H, b) -Br, c) -NO2
R' = (a' ) -(CH2)7-CHOH-CHOH-(CH2)5-CH2OH
(b' ) -(CH2)7-CH=CH-(CH2)5-CH2OH
(c' ) -(CH2)7-CH=CH-(CH2)7-CH3
(d' ) -(CH2)8-CH=CH2
3.3 Biologically active benzimidazole derivatives
Amongst the heterocycles, benzimidazole acquires a special place in
view of its relation with vitamins and amino acids. Fischer41 in the year
1889 reported the bacteriostatic and fungicidal properties of the parent
benzimidazole. Benzimidazole is known to exhibit a wide range of
biological activities in the form of its innumerable derivatives.
Anti-microbial agents
The search for compounds with anti-bacterial activity has gained
increasing importance in recent times, due to growing worldwide concern
over the alarming increase in the rate of infection by antibiotic-resistant
microorganisms.42 Owing to the current importance of developing novel
anti-microbials and the varied bioactivities exhibited by benzimidazoles,
several researchers have investigated the anti-microbial activities of
benzimidazole derivatives.
2-Mercapto benzimidazole derivatives are known to possess varied
biological activities.43 Recently, an efficient and rapid synthesis of novel
benzimidazole azetidin-2-ones (23) has been established 44 and anti-bacterial
screening revealed that all newly synthesized azetidin-2-ones (23) exhibited
84
Chapter - 3
Chemistry of Coumarin benzimidazoles
potent anti-bacterial activity against Bacillus subtilis, Staphylococcus aureus
and Escherichia coli.
In general, compounds (23a), (23i) and (23j)
exhibited more
pronounced anti-bacterial activity than compounds (23b-h), with better
activity against both Gram-positive and Gram-negative bacteria. Among all
the compounds investigated, (23i) and (23j) exhibited the greatest antibacterial activity against Gram-negative E. coli as compared to the antibiotic streptomycin.
N
SCH2C
N
H
NH
O
R
N
O
Cl
(23)
(a) 4-NO2,(b) 3,4,5 (OMe)3, (c) 2-OH, (d) 3-OH, (e) 4-OH
(f) 2-OMe,(g) 4-OMe, (h) 2-Cl, (i) 3-Cl, (j) 4-Cl
Benzimidazole benzyl ethers (24) have exhibited good anti-bacterial
activity against S. aureus and anti-fungal activity against Candida albicans
and
Candida
krusei.
In
general
the
dichlorophenyl
substituted
benzimidazoles (24e), (24f) and (24h) showed the best anti-bacterial (MIC
3.12 μg/mL) and anti-fungal (MIC 12.5 μg/mL) activity.45
R
N
N
O
R = (a) 4-H,(b) 4-F, (c) 4-Cl, (d) 4-Br, (e) 2,4-d-iCl
(f) 2,6-di-Cl, (g) 2,-di-Cl, (h) 3,4-di-Cl
(24)
85
Chapter - 3
Chemistry of Coumarin benzimidazoles
In addition, 5-fluoro benzimidazole carboxamide derivatives46 (25)
and benzimidazole isoxazolines47 (26) have been reported to show
anti-bacterial and anti-fungal activities.
F
N
H
N
OR2
N
H
R1
O
R1 = N -methylpiperazine, 3-methylpiperidine,
4-methylpiperidine, morpholine
R2 = H, n-propyl, cyclopropyl
(25)
N
N O
R
N
H
(26)
R = H, 4-OMe, 4-Cl, 4-NO2, 4-NMe2, 3,4,5, -tri-OMe, 3,4-di-OMe
Laixing Hu et al., have synthesized a series of bis-benzimidazole
diamidine compounds containing different central linkers and evaluated for
in-vitro anti-bacterial activities, including drug-resistant bacterial strains.
Seven compounds have shown potent anti-bacterial activities. The
anti-MRSA and anti-VRE activities of compound (27h) were found to be
more potent than that of the lead compound (27a) and vancomycin.48
NH
NH
N
H
N
N
L
N
H
N
H
N
H
(27)
L = a) CH2CH2, b)CH=CH (trans), c)
C
C d)
e) CH20, f) SO2NH g) CH2
h) O, i) S, j)NH, k) NMe, l) NPh, m)
O
Ansari and C. Lal have synthesized a series of 2-substituted-1-[{(5substituted
alkyl/aryl)-1,3,4-oxadiazol-2-yl}methyl]-1H-benzimidazoles
(28). All the synthesized compounds were screened for their anti-microbial
86
Chapter - 3
Chemistry of Coumarin benzimidazoles
activities. All the derivatives showed good activity towards Gram-positive
bacteria and negligible activity towards Gram-negative bacteria. Some of the
synthesized compounds showed moderate activity against tested fungi.49
N
R
N
N N
CH2
O
R1
(28)
R = H, Me
R1 = -CH3, -C2H5,-CH2Cl, -CH2CH2Cl, -C6H5, 2-ClC6H4, 4-ClC6H4
2-OHC6H4, 4-OHC6H4, 2-OCH3C6H4, 4-OCH3C6H4
The same author have synthesized a series of 3-chloro-1-{5-[(2methyl-1H-benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-yl}-4-(substituted)
phenylazetidin-2-one (29). The synthesized compounds were screened for
their anti-bacterial activity against Bacillus subtilis (Gram-positive)
and Escherichia coli (Gram-negative) and anti-fungal activity against
Candida albicans, Aspergillus flavus and Aspergillus niger fungal strains.
The compounds having o-chloro, o-methyl, p-methoxy, o-hydroxy
and p-amino group in phenyl ring showed good anti-bacterial activity. Antifungal results indicated that some of the derivatives possessed a broad
spectrum of activity against tested fungi. However, none of the derivatives
showed a better spectrum of activity than the reference drug.50
N
N
CH3
N N
Ar = - C6H5, - 4Br-C6H4, 2- ClC6H4, 4- ClC6H4
N
CH2
2- OHC6H4, 4- OHC6H4, 2- OCH3C6H4, 4- OCH3C6H4
Ar
S
O
Cl
(29)
87
Chapter - 3
Chemistry of Coumarin benzimidazoles
Shweta Sharma et al., have synthesized a series of novel 2-substituted
benzimidazoles (30) from long-chain alkenoic acids. The newly synthesized
compounds were screened in-vitro against an assortment of two
Gram-positive bacteria Staphylococcus aureus, Bacillus subtilis and two
Gram-negative bacteria Escherichia coli, Salmonella typhimurium and also
screened for anti-fungal activity against Aspergillus niger, Candida
albicans, Penicillium sp., Trichoderma viridae, Helminthosporum oryzae
strains. The chloro substituted derivatives have shown maximum antibacterial and anti-fungal activities.51
R1
N
R1 = H, NO2, Cl,
R
N
H
R = alkenoic acid
(30)
Rondla Rohini et al., have synthesized a series of mono,
bis-2-o-arylidene amino phenyl benzimidazoles (31) and corresponding
mono, bis-6-aryl benzimidazo[1,2-c] quinazolines (32). The target
benzimidazo[1,2-c]quinazoline
compounds
were
obtained
by
the
condensation of 2-(o-aminophenyl)benzimidazole with mono and di
carbonyl compounds, followed by oxidative cyclization of the resulting
mono and bis-2-o-arylidene amino phenyl benzimidazoles. The antimicrobial activities of all the benzimidazoles against various bacteria and
fungi were evaluated. Among the compounds tested, (32d-e) exhibited good
anti-bacterial and anti-fungal activities while (31b-c) also showed notable
88
Chapter - 3
Chemistry of Coumarin benzimidazoles
anti-microbial activity with reference to standard drugs Ampicillin and
Ketoconazole respectively.52
N
N
N
N
N
N
Ar
N
N
N
Ar
(32)
(31)
Ar = a) C6H5, b) 2-pyridyl, c)2-thienyl, d) 2-furyl, e) 2-pyrrolyl
Ar = a) 1,2 phenyl b) 1,3 phenyl, c) 1,4 phenyl, d) 2,6 pyridyl, e) 2,5 thienyl
Recently, our research group has synthesized a new series of novel 5(nitro/bromo)-styryl-2-benzimidazoles (33a, 33b) by simple and efficient
synthetic protocol by condensation of 5-(nitro/bromo)-o-phenylenediamine
with trans-cinnamic acids in ethylene glycol. The synthesized compounds
were screened for in-vitro anti-bacterial activity against Staphylococcus
aureus, Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae
bacterial strains and anti-fungal activity against Candida albicans and
Asperigillus fumigatus fungal strains. Some of the compounds have shown
excellent anti-bacterial and anti-fungal activities against the microbes.53,54
N
H
N
N N
N
H
N
R
N
H
R1
H
(33b)
(33a)
R = -NO2, -Br
R1 = H, 3,4 (OCH3), 4-CH3, 3,4-(CH2)O2, 2,4-Cl, 3-OH
89
S
HN
O
Chapter - 3
Chemistry of Coumarin benzimidazoles
Anthelmintic agents
Anthelmintic resistance is almost cosmopolitan in distribution and it
has been reported in almost all species of domestic animals and even in
some parasites of human beings. All of the major groups of anthelmintics
have encountered variable degrees of resistance from different species of
gastrointestinal nematodes.55 Bearing in mind previous benzimidazole
anthelmintics (e.g., albendazole, mebendazole), the search for new
anthelmintic drugs is being actively pursued. Synthetic benzimidazole
piperazine derivatives exhibited 50% anthelmintic activity in mice infected
with
Syphacia
obvelata.56
Furthermore,
piperazine
5(6)-substituted-(1H-benzimidazol-2-ylthio)acetic
acids
derivatives
(34-36)57
of
and
benzimidazolyl crotonic acid anilide (37) have shown good anthelmintic
activity.58
R2
Ph
N
Ph
N
N
O
N
O
N
N
R
S
R1
S
N
H
N
H
(35)
(34)
R1 =-H, -Me, -Cl, -NO2; R2 = -Cl, -Me
R = -H, -Me
R
N
R
N
N
H
N
N
H
S
N
O
N
H O
Me
Me
NH
N
S
Cl
O
R = -H, -Me
(37)
(36)
90
Chapter - 3
Chemistry of Coumarin benzimidazoles
Chassaing et al., have developed highly water-soluble prodrugs
(38a-g) of anthelmintic benzimidazole carbamates (39a-g). These prodrugs
combine high aqueous solubility and stability with high liability in the
presence of alkaline phosphatases. The veterinary utility of (38a) was shown
by a pharmacodynamic and pharmacokinetic study performed in swine.
Comparable anthelmintic efficacy was observed with prodrug (38a) or the
parent fenbendazole (39a). The pharmacokinetic results showed that (39a) is
better absorbed when derived from (36a) than when applied as such.59
O
N
R
N
ONa
N
H
O
O
N
R
N
H
P O
N
H
O
ONa
(38)
(39)
R = a) PhS, b) PhSO, c) n-Prs, d) PhCO, e) 4F-PhCO, f) 4F-PhSO3, g) n-Bu
Anti-inflammatory, Analgesic and Anti-ulcer agents.
Structure activity relationship (SAR) studies of the 5,6-dialkoxy-2thiobenzimidazole derivatives (40) have revealed that compounds (40a-k)
possess pronounced anti-inflammatory properties.60 Using the carrageenan
model, the most significant anti-inflammatory effects were observed for
compounds (40a), (40d), (40h), (40i), and (40j). While using the bentonite
model, the maximum activities were observed for compounds (40e) and
91
Chapter - 3
Chemistry of Coumarin benzimidazoles
(40h). These results indicated that benzimidazoles are promising leads for
the development of new anti-inflammatory agents.
EtO
N
SMe
R = a) Ph, b) 4-MeC6H5, c) 4-MeOC6H4, d) 4-FC6H4, e) 4Cl-C6H4, f) 3-ClC6H4,
g) 2-pyridyl,h) 3-pyridyl, i) 4-pyridyl, j) 2-thienyl, k) 2-furyl
N
EtO
O
R
(40)
Pyrimido benzimidazole (41)61 and dioxino benzimidazothiazol-9ones (42)62 exhibited anti-inflammatory and analgesic activity, as evaluated
by carrageenan-induced rat paw edema and phenyl quinone-induced
writhing tests. In addition, N-benzoyl and N-tosyl benzimidazole
compounds (43) showed significant anti-inflammatory activity, as indicated
by ear swelling induced by xylene in mice, and their ulcer indices were all
lower than those of aspirin.63 Furthermore, N-morpholino methyl
benzimidazole (44) and its derivatives have been recently reported to show
significant anti-inflammatory activity.64
S
O2N
H
N
N
Me
N
R2
N
N
H
O
R2 = CCl3, CH2Ph, CH2Ph
R1
(41)
O
R1 = -Ts, COPh;
(42)
N
N
NO2
N
S
R
N
O
N
O
R = 4-FC6H4, 2-furyl, 3-pyridyl
(44)
(43)
92
Chapter - 3
Chemistry of Coumarin benzimidazoles
Despite of the success of several commercial benzimidazole proton
pump inhibitors for the treatment of ulcer disease, work is still in progress to
discover new benzimidazole-derived anti-ulcer drugs. Cinitapride (45) and
related benzimidazole derivatives (46) have been prepared and studied for
their
anti-ulcerative
activity.65
In
dihydropyrimido[1,6-a]benzimidazoles
addition,
(47)
1,3-disubstituted
and
3-substituted
3,43,4-
dihydropyrimido[1,6-a]benzimidazol-1(2H)-thiones (48) exhibited good
gastric antisecretory activity (> 50% inhibition).66
N-Pr
O2N
O
O
H2N
N
N
H
NH
N
OEt
OEt
N
H
N
(46)
(45)
N
N
N
R2
N
N
R2
HN
N
S
R1
R1
R1 = H, Cl, OMe
R2 = H, Cl, Me
R1 = Me, Et, CH2Ph
R2 = H, Cl
(48)
(47)
Philip Jesudason et al., synthesized a series of N-Mannich bases of
benzimidazole derivatives and the compounds were screened for analgesic
and
anti-inflammatory
activity.
1-((Diethylamino)-methyl)-2-styryl
benzimidazole (49) at 40 mg/kg was found to be equipotent to paracetamol.
1-((Piperidin-1-yl) methyl)-2-styryl-benzimidazole at 40 mg/kg was found
to be more potent than Diclofenac.67
93
Chapter - 3
Chemistry of Coumarin benzimidazoles
N
R1 = H, CH3,CH=CH-C6H5
R1
N
R2 =N(CH3)2, N(C2H5)2, N(C6H5)2,
R2
N
,
N
O
(49)
Cytotoxic and Anti-tumor agents
In cancer chemotherapy there is currently much interest in the design
of small molecules that bind to DNA with sequence selectivity and non
covalent interactions. A possible lead for this new class of compounds is
Hoechst 33258 28, which recognizes A/T sequences in human DNA and is
also an effective inhibitor of mammalian DNA topoisomerase.
Andrzejewska et al., have synthesized a series of several halogenated
benzimidazoles
substituted
in
position
2
with
trifluoromethyl,
pentafluoroethyl and 2-thioethylaminodimethyl group. Anti-protozoal and
anti-cancer activity of a series of newly synthesized and previously obtained
compounds was studied. All tested bezimidazoles showed remarkable antiprotozoal activity against Giardia intestinalis, Entamoeba histolytica and
Trichomonas vaginalis. Of the studied collection of halogenated
benzimidazoles
the
most
reliable
anti-cancer
was
5,6-dichloro-2-
pentafluoroethyl compound (50), particularly against breast and prostate
cancer cell lines.68
Cl
N
C2H5
Cl
N
H
(50)
94
Chapter - 3
Chemistry of Coumarin benzimidazoles
Thimmegowda et al., have synthesized a novel series of trisubstituted
benzimidazole and its precursors and the compounds were evaluated for
inhibition against MDA-MB-231 breast cancer cell proliferation. The results
revealed that the compound N-(4-cyano-3-(trifluoromethyl) phenyl)-4fluoro-3-nitrobenzamide (51) was found to be the potent inhibitor.69
CF3
O
Cl
NC
N
N
H
Cl
N
(51)
F
Gellis et al., have synthesized a new benzimidazole-4,7-diones
substituted at 2-position via a microwave-assisted reaction using 2-chloro
methyl-1,5,6-trimethyl-1H-benzimidazole-4,7-dione as a key intermediate
compound. Their cytotoxicity has been evaluated on colon, breast and lung
cancer cell lines. The compound 2,2’-Bis(chloromethyl)-1,1’-dimethyl-5,5’bi(1H-benzimidazole)-4,4’,7,7’-tetraone
(52) was shown to possess
excellent cytotoxicity comparable to that of mitomycin C.70
CH3
O
N
Cl
O
N
N
O
Cl
N
O
CH3
(52)
Penning et al., have developed a series of cyclic amine-containing
benzimidazole carboxamide PARP inhibitors with a methyl-substituted
quaternary center at the point of attachment to the benzimidazole ring
system. These compounds exhibited excellent PARP enzyme potency as
well as single-digit nanomolar cellular potency.
95
Chapter - 3
Chemistry of Coumarin benzimidazoles
These efforts led to the identification of 2-(R)-2-methylpyrrolidin-2yl]-1H-benzimidazole-4-carboxamide (53), currently in human phase I
clinical trials. Compound (53) displayed excellent potency against both the
PARP-1 and PARP-2 enzymes with a Ki of 5 nM and in C41 whole cell
assay with an EC50 of 2 nM. In addition, (53) is aqueous soluble, orally
bioavailable across multiple species, and demonstrated good in-vivo efficacy
in a B16F10 subcutaneous murine melanoma model in combination with
temozolomide (TMZ) and in an MX-1 breast cancer xenograft model in
combination with either carboplatin or cyclophosphamide.71
CONH2
H
N
N
H
N
H
(53)
The benzimidazole-6,9-dione (54) has been found to be 300 times
more cytotoxic towards the human skin fibroblast cell line in the MTT assay
than the clinically used bioreductive drug, mitomycin C. Attaching methyl
substituents onto the quinone moiety increased reductive potential and
decreased cytotoxicity and selectivity towards hypoxia.72 In addition, the
alkyl-linked bisbenzimidazole73 (55) and thiazolyl benzimidazole-4,7diones74 (56) exhibited cytotoxic activity against tumor cell lines.
O
H 3C
N
N
N
H 3C
O
(54)
()n
MeO
N
H
OH OH
C
C
H
H
(55)
O
N
N
H
R1
OMe
O
N
S
N
N
(56)
R1 = NH2, OMe;
R2 = NH2, OEt, OH
n = 1, 2, 3
96
COR2
Chapter - 3
Chemistry of Coumarin benzimidazoles
Anti-tubercular agents
Tuberculosis (TB), a contagious infection caused by Mycobacterium
tuberculosis (MTB), still remains the leading cause of the worldwide death
among the infectious disease.75 The WHO has estimated that every year
about eight million new cases of tuberculosis occur, and up to three million
individuals die due to this disease (one person dies every 10 s).76 It is also
estimated that between 2002 and 2020, approximately a billion people will
be newly infected, more than 150 million people will get sick and 36 million
will die because of TB.
Jyoti Pandey et al., have synthesized a series of imidazole based
compounds by reacting simple imidazoles with alkyl halides or alkyl halo
carboxylate in presence of tetra butyl ammonium bromide (TBAB). The
compounds bearing carbethoxy group undergo amidation with different
amines in the presence of DBU to give respective carboxamides. The
synthesized compounds were screened against Mycobacterium tuberculosis
where compound (57) exhibited very good in- vitro anti-tubercular activity
and may serve as a lead for further optimization.77
N
N
R2
R1 = R2 = H
R1 = R2 = Cl
(57)
R1
Aridoss et al., have synthesized 3-tetrahydropyridin-4-ol based
benzimidazole
and
screened
for
anti-tubercular
activity
against
Mycobacterium tuberculosis H37Rv. The compound (58) has shown good
activity compared to the standard Rifampicin drug.78
97
Chapter - 3
Chemistry of Coumarin benzimidazoles
OH
COOCH2CH3
N
O
N
N
(58)
Gill et al., have synthesized a series of 2- (3-fluoro-phenyl)-1-[1(substituted-phenyl)-1H-[1,2,3]-triazol-4-yl-methyl)-1H-benzo[d]imidazoles
(59). The synthesized compounds screened for anti-tubercular activity
against Mycobacterium tuberculosis H37Rv. They conclude that the fluoro
groups have enhanced anti-mycobacterial activity, more than 96% of
inhibition at 6.25 mg concentration while other compounds exhibited less
than 90% inhibition at the same concentration.79
F
N
N
R1 = - H, - F, - OMe, - Me
R3
N
N N
R2 = - F, - H
R3 = - F, - H, - Me, - OMe,- CF 3
R1
R2
(59)
Recently, Hosamani et al., has synthesized a new series of novel
5-(nitro/bromo)-styryl-2-benzimidazoles (60) and screened for in-vitro antitubercular activity against Mycobacterium tuberculosis H37 Rv, some of the
synthesized compounds showed good activity.53
N
H
R = -NO2, -Br
R
R1
N
H
R1 = H, 3,4 (OCH3), 4-CH3, 3,4-(CH2)O2, 2,4-Cl, 3-OH
H
(60)
98
Chapter - 3
Chemistry of Coumarin benzimidazoles
Anti-retroviral agents (Anti-HIV)
Human Immuno deficiency Virus (HIV) is the primary cause of
acquired immuno deficiency syndrome (AIDS). The replication of HIV-1 in
infected patients can be reduced considerably by HAART, a highly active
combination of drugs with multiple viral targets. Officially approved drugs
for anti-HIV treatment belong to the class of nucleoside/nucleotide and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs), to protease
inhibitors (PIs) and more recently to viral entry (Enfuvirtide) and integrase
inhibitors (Isentress). Despite the successes with such treatments, the
permanent use of anti-AIDS drugs induces drug-resistant viral variants and
the emergence of unwanted metabolic side effects.80
Monforte et al., synthesized several N1-substituted 1,3-dihydro-2Hbenzimidazol-2-ones (61 & 62) and evaluated as anti-HIV agents. Some of
them proved to be highly effective in inhibiting HIV-1 replication at
nanomolar concentration as potent non-nucleoside HIV-1 RT inhibitors
(NNRTIs) with low cytotoxicity. SAR studies highlighted that the nature of
the substituents at N1 and on the benzene ring of benzimidazolone moiety
significantly influenced the anti-HIV activity of this class of potent
anti-retroviral agents.81
Y
R
R2
Y
R
N
N
S
O
R'
N
COCH3
(61)
'
N
H
R = CH3, Cl, CF3
R' = H, F ; Y = CH2, SO2,
R2 = 2,6-difluorophenyl, 3,5-dimethylphenyl, 3,5-difluorophenyl
(62)
99
Chapter - 3
Chemistry of Coumarin benzimidazoles
Barreca et al., have synthesized a series of 1H, 3H thiazolo[3,4a]benzimidazole derivatives (63) (TBZs). Some of the synthesized
derivatives proved to be highly effective in inhibiting human immuno
deficiency virus type-1 (HIV-1) replication at nanomolar concentrations
with minimal toxicity, acting as reverse transcriptase (RT) inhibitors.
Computational studies were used in order to probe the binding of our ligands
to HIV-1-RT.82
F
F
N
S
N
(63)
Xu et al., have synthesized 4-Oxo-4H-quinolizine-3-carboxylic acid
derivatives bearing sulfamido, carboxylamido, benzimidazoles (64) and
compounds were screened for possible HIV integrase inhibitory activity.
They concluded that aryl diketoacid-containing compounds are the most
promising HIV IN inhibitors.83
OH
O
H
N
O
R
N
R = H, Cl, OCH3
N
(64)
Thiazolobenzimidazoles (65) proved to be highly potent inhibitors of
HIV-1-induced cytopathic effects. Structure-activity relationship studies
showed that the C-1 substituents in benzimidazole greatly influence the
interaction of the active compound with the receptor. Substitution on the
benzene-fused ring influences the inhibitory potency depending on the
nature and position of the substituents, the presence of a methyl group at C-3
is favorable to the pharmacological profile.84
100
Chapter - 3
Chemistry of Coumarin benzimidazoles
R 3R4
R1 = H, 5-Me, 6- Me, 8-Me
R2 = H, 7-Me
S
N
R3 = 2-F, 3-NO2; R4 = H, 6-F
R 1R2
N
(65)
Enzyme and Receptor Agonists/Antagonists
Several benzimidazole derivatives have been reported to act on
various enzymes and receptors. Some examples of benzimidazoles acting as
agonists or antagonists of various receptors and enzymes are listed in
Table - 1.
Table -1 Benzimidazole derivatives that act on enzymes/receptors
Compound
Cl
N
z
Cl
N
X
Enzymes/Receptors
Androgen receptor
Activity
Antagonist
References
85
Cholecystokinin B
receptor
Antagonist
86
Cyclin-dependent
kinase 1 (CDK1)
Inhibitory
87
Enkephalinase B
(DPP III)
Antagonist
88
Y
R
R = H, Me, Et
X = H, OH; Y = Me, Et, n-Pr
Z = Me, Et
O
HO
N
O
N
R
N
R = H, OH
HN
N
N
N
N
N
N
H
N
N
H
N
H
101
Chapter - 3
Chemistry of Coumarin benzimidazoles
HN
N
N
H
O
S
O
89
Kinesin spindle
protein (KSP)
Inhibitory
90
Coxsackie virus B3
(CVB3)
Inhibitory
91
Opioid receptor-like
1 (ORL1)
Antagonist
92
Polo-like kinase
(PLK)
Inhibitor
93
Histone deacetylase
inhibitors(HDAC)
Inhibitor
94
Serotoninergic 5HT1A or 5-HT7
receptor
Receptor
95
O
N
R2
N
H
N
Inhibitory
N
H
O
X
Tyrosine phosphatase
1B
R1
CF3
X = NH2, OH, OMe, NHMe, NMe2
R1 = Ph, 4CF3Ph
R2= SO2NH2, SO2Me, OMe, SMe
CONHR2
N
R1
N
H
R1 = 2-furyl, 2,(5- nitro)-furyl
)
R2 = 2-Flourophenyl,2-Chlorophenyl
Cl
N
Me
S
N
H
N
EtN
R
R = NHCO2Me. NHAc, NHSO2Me
N
N
O
S
NH2
O
OR
O
R = Benzyl, CH2CH2Ph, 2-3-Thienylmethyl
O
N
N
H
OH
N
N
N
N
O
N
102
Chapter - 3
Chemistry of Coumarin benzimidazoles
3.4 Present work
The well known synthetic routes to coumarins including the Perkin,
Raschig, Pechmann, Knoevenagel and Wittig reactions suffer from the
requirement for the use of drastic conditions (acidic or basic), multiple steps,
complicated synthetic operations and lengthy work-up procedures.
The increasing demands of environmental legislation have been
prompting the chemical industry to minimize or, preferably, eliminate waste
production in chemical manufacture. Environmentally benign processes are
in high demand for primary prevention of pollution, and enviro economic
factors will become the driving force behind new products and processes.
In the present study, our ongoing work devoted towards the
development of rapid synthesis of new bioactive heterocycles as targeted
chemotherapeutic agents of environment friendly. The reaction sequence for
the synthesis of coumarin benzimidazoles is outlined in (Scheme-1) which
involves the reaction between coumarin acid and o-phenylene diamine in the
presence of hydrochloric acid. The mixture was heated for 3 hrs with
constant stirring, cooled to about 5 oC. It was neutralized with concentrated
ammonia, the product obtained is treated with various fluorine substituted
phenols and 2 mL of Conc H2SO4. The reaction mixture was refluxed for 6h
at 120-125 oC, kept aside at room temperature and poured in to crushed ice.
The solid product 3-[1-(2-Fluoro-phenyl)-1H-benzoimidazol-2-yl]-chromen2-one, that precipitated were filtered off and recrystallized from the suitable
solvent.
103
Chapter - 3
Chemistry of Coumarin benzimidazoles
All the reactions involved are highly efficient to give the desired
compounds in high yield and purity. 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. To explore the scope of synthetic accessibility,
our work is focused on broad spectrum pharmacological activities.
Analytical data of synthesized compounds are shown in (Table- 1).
Scheme-1.
R
O
R
NH2
N
(z)
OH
O
(z)
NH2
N
H
O
O
O
2 (a-d)
1
OH
R'
R
N
(z)
N
O
R= H,
In
R'
3(a-l)
4-CH3, 4-NO2, 4-Br
R' 2-F,
= 4-F
O
3-F, 4-F
summary,
we
have
developed
an
efficient
facile
and
environmentally acceptable synthetic methodology for the synthesis of new
bioactive heterocycles as targeted chemotherapeutic agents like coumarin
benzimidazole derivatives. The attractive features of this procedure are the
104
Chapter - 3
Chemistry of Coumarin benzimidazoles
mild reaction conditions, high conversions, ease of separation, inexpensive
and excellent yields, all of which make it a useful and attractive strategy for
the preparation of various coumarin benzimidazole derivatives simply by
changing different substrates. The versatility of this methodology is suitable
for library synthesis in drug discovery efforts. These observations have
encouraged us to synthesize some new products containing the fluorine
coumarin benzimidazole moiety hoping to obtain new compounds with
potential biological activity. In the present protocol, we performed the
synthesis and biological evaluation of some libraries of these compounds.
3.5 Materials and methods
Chemicals were purchased from Merck, Fluka and Aldrich Chemical
Companies. The melting points of the products were determined by open
capillary tubes and are uncorrected. The IR spectra were recorded on Nicolet
5700 FT-IR spectrophotometers using KBr pellets. Wave numbers are
expressed in cm-1. The 1H NMR and
13
C NMR spectra were recorded on
Bruker-Avance 300MHz spectrophotometer using DMSO-d6 as solvent and
TMS as internal standard reference, chemical shifts are expressed in parts
per million. The mass spectra were recorded on Shimadzu-2010A
spectrophotometer. The elemental analyses were recorded on Heraus CHN
rapid analyzer. Completion of the reaction was checked by TLC on silica gel
60 F254 (Merck) detected by UV light (254 nm) and iodine vapors.
105
Chapter - 3
Chemistry of Coumarin benzimidazoles
3.6 3.6
Experimental
Experimental
procedure
procedure
Method-1
The synthesis of title compounds was achieved by using selected 2hydroxybenzaldehyde (10 mmol), malonic acid (15 mmol), and KSF (1 g)
in water (3.3 mL) were heated to reflux for 24 h. After cooling to room
temperature, the water was removed by Buchner filtration and the solid was
heated in methanol (60 mL) for 5 min. The catalyst was removed by
Buchner filtration and washed with methanol (10 mL). The solvent was
distilled off, and the crude product was purified and crystallized from ethyl
acetate. In the case of compound the unreacted aldehyde was removed with
warm hexane.
Method-2
With the aim of obtaining a process with better yields and higher
efficiency, we employed the malonic acid instead of ethyl malonate. Thus,
reacting both in H2O at reflux for 24 h, coumarin-3-carboxylic acid was
obtained in excellent yield (92%) and selectivity (93%), under conditions
milder than those previously reported. To investigate the generality of this
process, various salicylic aldehydes were reacted under similar conditions,
allowing the easy synthesis of coumarin-3-carboxylic acids.
Method-3
The synthesis of target compounds was achieved by using
Salicylaldehyde (1.48g, 0.01 mol) on reaction with ethanol (12 mL) in the
106
Chapter - 3
Chemistry of Coumarin benzimidazoles
presence of piperidine (12 mL) which was further stirred well with addition
of diethyl malonate (0.01 mol) drop wise, yielded yellow colour solid.
Washed the product with ethanol, the resulting solid was filtered, dried and
recrystallized to obtain coumarin-3-carboxylic acid.
In a 250 mL three necked round bottom flask a solution containing
1.8g (0.03mol) coumarin acid and 1.08g (0.01mol) of o–phenylenediamine
dissolved in 20 mL of 1 N Hydrochloric acid. The mixture was heated for 3
hrs with constant stirring. The reaction mixture is cooled to about 5 oC. It
was neutralized with concentrated ammonia. The product 3-(1HBenzoimidazol-2-yl)-chromen-2-one was filtered and washed with water to
remove traces of hydrochloric acid, dried and re-crystallized from 10%
aqueous ethanol.
A mixture of 3-(1H-Benzoimidazol-2-yl)-chromen-2-one (1.96 g,
0.01 mole) with various fluorine substituted phenols (0.01 mole) and 2 mL
of Conc H2SO4. The reaction mixture was refluxed for 6h at 120-125 oC,
kept aside at room temperature and poured in to crushed ice. The solid
product 3-[1-(2-Fluoro-phenyl)-1H-benzoimidazol-2-yl]-chromen-2-one that
precipitated were filtered off and recrystallized from the suitable solvent.
3.7 Results and discussion
The structures of newly synthesized 3-[1-(2-Fluoro-phenyl)-1Hbenzoimidazol-2-yl]-chromen-2-one
3(a)
compound
libraries
confirmed by IR, 1H NMR, 13C NMR spectra and Mass spectrometry.
107
were
Chapter - 3
Chemistry of Coumarin benzimidazoles
The IR spectrum of all the compounds 3(a–l) the appearance of
signals at
2928 cm-1 (-CH stretching), 1706 cm-1 (-C=O stretching of
coumarin), 1628 cm-1 and 1386 cm-1 (C=N and C=C ring stretching), 1032
cm-1 (C-O-C stretching), respectively.
The 1H NMR spectra of all the compounds 3(a–l) exhibited structure
revealing proton signals at δ 7.19-7.54 (multiplet, 12 aromatic protons),
8.16 (singlet, -C=CH, C3-H ).
The
13
C NMR spectra of all the compounds 3(a-l) showed sharp
singlet signals at δ 122-150 ppm for imidazole carbon. The aromatic carbons
of various environments present in all the compounds appeared as signals in
the range of δ 110-140 ppm, and at δ 10-40 ppm for saturated carbon atoms
with CDCl3 solvent signals. The mass spectra of the same compounds
showed peak corresponding to their molecular ion. The X-ray analysis of the
compound(s) is under progress. The IR, 1H NMR,
13
C NMR and Mass
spectra of some compounds are enclosed as Spectrum No. 1-8.
(3a) 3-[1-(2-Fluoro-phenyl)-1H-benzoimidazol-2-yl]-chromen-2-one
Yield 64.20%; Colorless solid; m.p. 176–
N
178oC; IR (KBr, υ cm-1): 2924 (-CH
N
F
stretching),
O
1712
(-C=O
stretching
of
O
coumarin), 1620 and 1345 (C=N and C=C
ring stretching), 1052 (C-O-C stretching); 1H NMR (300MHz, CDCl3, δ
ppm): 7.06-7.74 (m, 12H, ArH), 8.01 (s, 1H, -C=CH, C3-H ), 13C NMR (75
108
Chapter - 3
Chemistry of Coumarin benzimidazoles
MHz, CDCl3, δ ppm): 115.4, 116.4,121.3, 122.6, 122.9, 123.7,
125.00,125.2, 126.6, 127.8, 128.1, 129.4, 129.6,137.9,140.6, 141.5,150.8,
154.6,162.0.MS: m/z 356. Anal. calcd. for C22H13 FN2O2: C, 74.15, H,
3.68,N,7.86 ;Found: C, 74.16, H, 3.70, N,7.85%.
(3b) 3-[1-(3-Fluoro-phenyl)-1H-benzoimidazol-2-yl]-chromen-2-one
Yield 56.8%; Light brown solid; m.p. 185–
N
187oC; IR (KBr, υ cm-1): 2924 (-CH
N
stretching), 1736
O
(-C=O stretching of
F
O
coumarin), 1602 and 1406 (C=N and C=C
ring stretching), 1062 (C-O-C stretching); 1H NMR (300MHz, CDCl3, δ
ppm): 7.08-7.74 (m, 12H, ArH), 7.99 (s, 1H, -C=CH, C3-H ), 13C NMR (75
MHz, CDCl3, δ ppm): 116.4, 118.4,120.3, 122.6, 122.9, 123.7,
125.00,125.2, 126.6, 127.8, 128.1, 129.4, 129.6,137.9,140.6, 141.5,150.8,
154.6,164.0. MS: m/z 356. Anal. calcd. for C22H13 FN2O2: C, 74.15, H,
3.68,N,7.86 ;Found: C, 74.16, H, 3.70, N,7.85%.
(3c) 3-[1-(4-Fluoro-phenyl)-1H-benzoimidazol-2-yl]-chromen-2-one
Yield 62.46%; Light cream colored solid; m.p.
N
188-191oC; IR (KBr, υ cm-1): 2934 (-CH
N
O
stretching), 1712 (-C=O stretching of coumarin),
O
F
1632 and 1384 (C=N and C=C ring stretching),
1034 (C-O-C stretching); 1H NMR (300MHz, CDCl3, δ ppm): 7.20-7.58
(m, 12H, ArH), 8.14 (s, 1H, -C=CH, C3-H ), 13C NMR (75 MHz, CDCl3, δ
109
Chapter - 3
Chemistry of Coumarin benzimidazoles
ppm): 118.6, 118.4,120.3, 122.8, 122.9, 123.7, 125.0,125.2, 126.6, 127.8,
128.1, 129.4, 129.6,137.9,140.6, 141.5,150.8, 154.6,164.2. MS: m/z 356.
Anal. calcd. for C22H13 FN2O2: C, 74.15, H, 3.68,N,7.86 ;Found: C, 74.16,
H, 3.70, N,7.85%.
(3d) 3-[1-(2-Fluoro-phenyl)-4-methyl-1H-benzoimidazol-2-yl]-chromen2-one
Yield 67.04%; Colorless solid; m.p. 194-195oC; IR
H C
3
(KBr, υ cm-1): 2926 (-CH stretching), 1708 (-C=O
N
N
O
O
F
stretching of coumarin), 1626 and 1388 (C=N and
C=C ring stretching), 1034 (C-O-C stretching); 1H
NMR (300MHz, CDCl3, δ ppm): 2.32 (s, 3H, -CH3), 7.22-7.56 (m, 11H,
ArH), 8.12 (s, 1H, -C=CH, C3-H ),
13
C NMR (75 MHz, CDCl3, δ ppm):
115.2, 116.8,121.3, 122.6, 122.9, 124.7, 125.00,125.2, 126.8, 127.8, 128.1,
129.4, 129.6,137.9,140.6, 141.5,150.8, 154.6,158.2,160.4. MS: m/z 370.
Anal. calcd. for C23H15 FN2O2: C, 74.59, H, 4.08,N,7.56 ;Found: C, 74.60,
H, 4.10, N,7.54%.
(3e) 3-[1-(3-Fluoro-phenyl)-4-methyl-1H-benzoimidazol-2-yl]-chromen2-one
Yield 64.46%; Yellowish solid; m.p. 166-168oC;
H3C
IR (KBr, υ cm-1): 2926 (-CH stretching), 1708 (-
N
N
C=O stretching of coumarin), 1626 and 1384
O
O
F
(C=N and C=C ring stretching), 1036 (C-O-C
stretching); 1H NMR (300MHz, CDCl3, δ ppm): 2.32 (s, 3H, -CH3), 7.197.54 (m, 11H, ArH), 8.12(s, 1H, -C=CH, C3-H ),
110
13
C NMR (75 MHz,
Chapter - 3
Chemistry of Coumarin benzimidazoles
CDCl3, δ ppm): 115.7, 116.4,121.3, 122.6, 122.9, 123.7, 125.00,125.2,
126.6, 127.8, 128.1, 129.4, 129.8,137.9,140.6, 141.5,150.8, 154.6, 158.4,
164.3. MS: m/z 370. Anal. calcd. for C22H13 FN2O2: C, 74.15, H,
3.68,N,7.86 ;Found: C, 74.16, H, 3.70, N,7.85%.
(3f) 3-[1-(4-Fluoro-phenyl)-4-methyl-1H-benzoimidazol-2-yl]-chromen2-one
Yield 54.32%; Colorless solid; m.p. 180-182oC; IR
H3C
(KBr, υ cm-1): 2932 (-CH stretching), 1710 (-C=O
N
N
stretching of coumarin), 1632 and 1388 (C=N and
O
O
F
C=C ring stretching),1034 (C-O-C stretching);
1
H
NMR (300MHz, CDCl3, δ ppm): 2.28 (s, 3H, -CH3), 7.20-7.56 (m, 11H,
ArH), 8.18 (s, 1H, -C=CH, C3-H ),
13
C NMR (75 MHz, CDCl3, δ ppm):
115.6, 116.4,121.8, 122.6, 122.9, 123.7, 125.00, 125.2, 126.6, 127.8, 128.1,
129.4, 129.6, 137.9,140.6, 141.5, 150.8, 154.6, 158.3, 162.2. MS: m/z 370.
Anal. calcd. or C22H13 FN2O2: C, 74.15, H, 3.68, N, 7.86 ; Found: C, 74.16,
H, 3.70, N,7.85%.
(3g) 3-[1-(2-Fluoro-phenyl)-4-nitro-1H-benzoimidazol-2-yl]-chromen-2one
Yield 66.08%; Dark brown solid; m.p. 189-192
O2N
o
C; IR (KBr, υ cm-1): 2926 (-CH stretching),
N
N
F
O
O
1708(-C=O stretching of coumarin), 1630 and
1386 (C=N and C=C ring stretching), 1034
(C-O-C stretching); 1H NMR (300MHz, CDCl3, δ ppm): 7.19-8.19 (m,
11H, ArH), 8.14 (s, 1H, -C=CH, C3-H ),
111
13
C NMR (75 MHz, CDCl3, δ
Chapter - 3
Chemistry of Coumarin benzimidazoles
ppm): 115.0, 116.4, 121.3, 122.6, 122.9, 123.0, 125.00, 125.2, 126.6, 127.8,
128.0, 129.4, 129.6, 137.9, 140.6, 141.5, 150.8, 152.3, 154.6, 158.2, 160.4.
MS: m/z 401. Anal. calcd. for C22H12 FN3O4: C, 65.84, H, 3.01,N, 10.47
;Found: C, 65.82, H, 3.02, N,10.46%.
(3h) 3-[1-(3-Fluoro-phenyl)-4-nitro-1H-benzoimidazol-2-yl]-chromen-2one
Yield 58.47%; Colorless solid; m.p. 174-176
O N
2
o
C; IR (KBr, υ cm-1): 2933 (-CH stretching),
N
N
O
1709 (-C=O stretching of coumarin), 1629 and
F
O
1387 (C=N and C=C ring stretching), 1034 (C-
O-C stretching);
1
H NMR (300MHz, CDCl3, δ ppm): 7.2--8.16 (m, 11H,
ArH), 8.12 (s, 1H, -C=CH, C3-H ),
13
C NMR (75 MHz, CDCl3, δ ppm):
115.6, 116.4,121.3, 122.6, 122.9, 123.7, 125.00,125.2, 126.6, 127.8, 128.4,
129.4, 129.6, 137.9, 140.6, 141.5, 150.8, 153.4, 154.6, 158.0, 162.6. MS:
m/z 370. Anal. calcd. for C22H13 FN2O2: C, 74.15, H, 3.68,N,7.86 ;Found: C,
74.16, H, 3.70, N,7.85%.
(3i) 3-[1-(4-Fluoro-phenyl)-4-nitro-1H-benzoimidazol-2-yl]-chromen-2one
O N
Yield 71.60%; Light yellowish solid; m.p. 1902
192oC; IR (KBr, υ cm-1): 2930 (-CH stretching),
N
N
1708 (-C=O stretching of coumarin), 1632 and
O
O
1388 (C=N and C=C ring stretching),1034(C-O-C
F
stretching); 1H NMR (300MHz, CDCl3, δ ppm): 7.19-8.22 (m, 11H, ArH),
8.12(s, 1H, -C=CH, C3-H ),
13
C NMR (75 MHz, CDCl3, δ ppm): 115.0,
112
Chapter - 3
Chemistry of Coumarin benzimidazoles
116.4, 121.3, 122.6, 122.4, 123.7, 125.00, 125.2, 126.6, 127.8, 128.1, 129.2,
129.6, 136.9, 140.6, 141.5, 150.8, 152.0, 154.6, 158.5, 160.2. MS: m/z 370.
Anal. calcd. for C22H13 FN2O2: C, 74.15, H, 3.68,N,7.86 ;Found: C, 74.16,
H, 3.70, N,7.85%.
(3j) 3-[(4-Bromo-1-(2-fluoro-phenyl)-1H-benzoimidazol-2-yl]-chromen2-one
Yield 65.03%; Cream colored solid; m.p. 164Br
166oC; IR (KBr, υ cm-1): 2932 (-CH stretching),
N
N
F
O
1708 (-C=O stretching of coumarin), 1626 and
O
1384 (C=N and C=C ring stretching),1034(C-O-C
stretching); 1H NMR (300MHz, CDCl3, δ ppm): 7.22-7.56 (m, 11H, ArH),
8.16 (s, 1H, -C=CH, C3-H ),
13
C NMR (75 MHz, CDCl3, δ ppm): 115.6,
116.7, 121.5, 122.6, 123.2, 123.7, 125.0, 125.2, 126.6, 127.8, 128.1, 129.4,
129.6, 137.9, 140.6, 141.5, 150.8, 152.0, 154.6, 138.4, 164.2. MS: m/z 435.
Anal. calcd. for C22H13BrFN2O2: C, 60.71, H, 2.79,N,6.43 ;Found: C, 60.73,
H, 2.80, N,6.42%.
(3k) 3-[(4-Bromo-1-(3-fluoro-phenyl)-1H-benzoimidazol-2-yl]chromen2-one
Br
Yield 64.49%; Colorless solid; m.p. 186-188oC;
IR (KBr, υ cm-1): 2933 (-CH stretching), 1710
N
N
(-C=O stretching of coumarin), 1630 and 1388
O
O
F
(C=N and C=C ring stretching), 1034(C-O-C
stretching); 1H NMR (300MHz, CDCl3, δ ppm): 7.20-7.56 (m, 12H, ArH),
113
Chapter - 3
Chemistry of Coumarin benzimidazoles
8.18 (s, 1H, -C=CH, C3-H ),
13
C NMR (75 MHz, CDCl3, δ ppm): 112.8,
116.4,121.3, 122.6, 122.8, 123.6, 125.9,126.0, 126.6, 127.8, 128.1, 129.4,
129.6, 138.9, 140.6, 141.5, 153.8, 154.6, 158.0, 160.4, 162.4. MS: m/z 435.
Anal. calcd. for C22H13BrFN2O2: C, 60.71, H, 2.79,N,6.43 ;Found: C, 60.73,
H, 2.80, N,6.42%.
(3l) 3-[(4-Bromo-1-(4-fluoro-phenyl)-1H-benzoimidazol-2-yl]-chromen2-one
Yield 63.20%; Light brown solid; m.p. 174-176oC;
Br
IR (KBr, υ cm-1):2930(-CH stretching), 1712 (-C=O
N
N
stretching of coumarin), 1632 and 1388 (C=N and
O
O
C=C ring stretching), 1036 (C-O-C stretching); 1H
F
NMR (300MHz, CDCl3, δ ppm): 7.22-7.52 (m, 12H, ArH), 8.14 (s, 1H, C=CH, C3-H ),
13
C NMR (75 MHz, CDCl3, δ ppm): 114.2, 116.4,121.3,
122.6, 122.8, 123.9, 125.4,125.2, 126.2, 127.8, 128.3, 129.4, 129.6, 137.9,
140.6, 141.5, 148.2, 152.2, 154.6, 158.7, 162.3. MS: m/z 435. Anal. calcd.
for C22H13BrFN2O2: C, 60.71, H, 2.79,N,6.43 ;Found: C, 60.73, H, 2.80,
N,6.42%.
114
Chemistry of Coumarin benzimidazoles
Table-1
Physical and analytical data of the Coumarin benzimidazole derivatives
N
(z)
N
F
O
a
Product
R
R1
3a
H
2F
H
3F
3c
H
4F
3d
4-CH3
2F
3e
4-CH3
3F
3f
4-CH3
4F
3g
4-NO2
2F
3h
4-NO2
3i
O
m. p (0C)
Mol. Formula/
Mol. Wt
64.20
176-178
56.88
b
Yield (%)
c
Elem.Analysis (Cal./Found)
C
H
N
C22H13 FN2O2
356
74.15
74.16
3.68
3.70
7.86
7.85
185-187
C22H13 FN2O2
356
74.15
74.16
3.68
3.70
7.86
7.85
188-191
C22H13 FN2O2
356
74.15
74.16
3.68
3.70
7.86
7.85
194-195
C23H15 FN2O2
370
74.59
74.60
4.08
4.10
7.56
7.54
166-168
C23H15 FN2O2
370
74.59
74.60
4.08
4.10
7.56
7.54
180-182
C23H15 FN2O2
370
74.59
74.60
4.08
4.10
7.56
7.54
66.08
189-192
C22H12 FN3O4
401
65.84
65.82
3.01
3.02
10.47
10.46
3F
54.47
174-176
C22H12 FN3O4
401
65.83
65.82
3.02
3.03
10.48
10.46
4-NO2
4F
71.60
190-192
C22H12 FN3O4
401
65.83
65.82
3.01
3.02
10.47
10.46
3j
4-Br
2F
164-166
C22H12 BrFN2O2
435
60.71
60.73
2.79
2.80
6.43
6.42
3k
4-Br
3F
64.49
186-188
C22H12 BrFN2O2
435
60.70
60.73
2.79
2.81
6.44
6.43
3l
4-Br
4F
63.20
174-176
C22H12 BrFN2O2
435
60.71
60.73
2.78
2.80
6.44
6.42
3b
62.46
67.04
64.46
54.32
65.03
a
Products were characterized by IR, NMR, MS and elemental analysis.
b
Isolated yields.
c
Melting points are uncorrected.
120
Chapter - 3
Chemistry of Coumarin benzimidazoles
N
(z)
N
F
O
O
Spectrum 1: IR Spectrum of compound (3b) (Code-COU-BZ)
N
(z)
N
F
O
O
Spectrum 2: 1H NMR (300MHz) Spectrum of compound (3b) in DMSO
121
Chapter - 3
Chemistry of Coumarin benzimidazoles
N
(z)
N
F
O
O
Spectrum 3: 13C NMR (75MHz) Spectrum of compound (3b)
N
(z)
N
F
O
O
Spectrum 4: Mass Spectra of compound (3b)
122
Chapter - 3
Chemistry of Coumarin benzimidazoles
CH3
N
(z)
N
O
F
O
Spectrum 5: IR Spectrum of compound (3d)
CH3
N
(z)
N
O
F
O
Spectrum 6: 1H NMR (300MHz) Spectrum of compound (3d) in DMSO
123
Chapter - 3
Chemistry of Coumarin benzimidazoles
CH3
N
(z)
N
O
F
O
Spectrum 7: 13C NMR (75MHz) Spectrum of compound (3d)
CH3
N
(z)
N
O
Spectrum 8: Mass Spectra of compound (3d)
124
O
F
Chapter - 3
Chemistry of Coumarin benzimidazoles
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