12 chapter-v synthesis of novel n...
TRANSCRIPT
CHAPTER-V
SYNTHESIS OF NOVEL N-SUBSTITUTED 2-CHLORO-1H- BENZIMIDAZOLE
DERIVATIVES
Introduction:
As we have been discussed in chapter -1 to chapter-4, benzimidazoles are a class of heterocyclic,
aromatic chemical compounds which share a fundamental structural characteristics of six
membered ring of benzene fused to five membered imidazole.
N
N NH
N
NH2
Adenine
N
N NH
N
O
N
N NH
N
N
N N
N
O
H2NO
HN
N NH
HN
O
O
O Purine
GuanineCaffeine
Uric acid
Figure-1 Some of the most well known molecules having 6+5 heterocyclic structures with
benzimidazole moiety.
Benzimidazole ring displays an important heterocyclic pharmacophore and privileged scaffold in
drug discovery. This compound carrying different subst ituent's encompassing adiversified range
of biological activities include anticancer, antiviral, antibacterial, antifungal, antihistaminic,
antihypertensive etc. Benzimidazole derivatives emerged to be an effective anti microbial agent
in the year of 1964. Since then, explorations of the same have already been made in different
corner of horizon. The synthesis of novel benzimidazole derivatives remains a main focus of
medicinal research. Recent observations suggest that substituted benzimidazoles and heterocycle,
which are the structural isosters of nucleotides owing fused heterocyclic nuclei in their structures
that, allow them to interact easily with the biopolymers, posses potential activity with lower
toxicities in the chemotherapeutic approach inman. As an outgrowth of our investigation to
discover novel antimicrobial agent a new series of 2-substituted benzimidazole analogs were
synthesized and their antimicrobial activity was evaluated.
For developing pharmaceutically important role in medicinal Chemistry199 the wide variety of
heterocyclics that have been explored. Due to their wide variety of biological and
pharmacological applications benzimidazole and their derivatives are of great importance in
medicinal chemistry.199-200
The literature survey shows the utility of benzimidazoles for cancer, and cardiovascular
diseases201. The benzimidazole shows anticancer202, antiinflammatory203, antibacterial204,
antifungal205, antidiabetic206, and anti‐HIV activities.207 The importance of benzimidazoles are
posseses as antimicrobial and antioxidant agents.208-212 Antimicrobial broad spectrum209 has also
been reported for certain substituted benzimidazole derivatives.
Further study it was found that the N-alkylation on benzimidazole ring plays an important role in
their biological activity such as antimicrobial, antiparasitic and even antitumor agents (Figure-
2).213-217
N
N
Cl
Cl
O
HN
N
(A)
4-[5-Chloro-1-(4-chloro-benzyl)-1H-benzoimidazol-2-yl]-N-(2-diethylamino-ethyl)-benzamide
O
N
HN
NH
O
O
(6-Benzoyl-1H-benzoimidazol-2-yl)-carbamic acid methyl ester
O
ClCl
1-[2-(2,6-Dichloro-benzyloxy)-2-phenyl-ethyl]-1H-indene
(B)
(C)
O
NN
O
N
N
OH3CO
H
(D)
8-[3-(2-Furan-2-yl-benzoimidazol-1-yl)-propoxy]-7-methoxy-1,2,3,11a-tetrahydro-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5-one
Figure-2 Some N-alkylated benzimidazole derivatives having antimicrobial, antiparasitic and
antitumor activity.
Aside from their place in biomedical research, benzimidazoles also have a prominent place in
organocatalysis, organometallic218, 219 and materials chemistry220 for two reasons stemming from
their molecular architecture: the imidazole is a precursor to N-heterocyclic carbenes; and the
benzene ring provides a convenient scaffold to which additional functionality may be easily
added to modify the spatial and electronic characteristics of a benzimidazole derivative. This
combination of a reactive carbine center with a modifiable backbone is without a doubt one of
the reasons for the recent rise in study and use of benzimidazoles and their N-heterocyclic
carbene derivatives.
In this chapter we will be discussing the N-alkylation on benzimidazole ring with different
heterocyclic intermediate compounds. Emedastine, a derivative of benzimidazole, is known as an
antiallergic agent with histamine release-suppressing
Activity and H1 receptor antagonizing activity.221-224 In view of these findings, we have
attempted to synthesize antibacterial and antifungal agents with multiple pharmacological
activities by hybridizing benzimidazole derivatives.
Results & Discussion:
Synthesis of Starting Material:
o-phenylenediamine 1 was refluxed with urea in DMF for 12 hrs, followed by simple workup in
water gives known benzimidazolin-2-one 2 in 94% yield.218-219
The compound 3 was then prepared by reacting compound 2 with phosphoryl chloride in
presence of catalytic phenol at 1100C for 12 hrs, gave 2-chlorobenzimidazole in 90% yield is
reported.220 (Scheme-1)
NH2
NH2
H2N
O
H2N
DMF/K2CO3
Reflux NH
HN
ONH
N
ClPOCl3
1 2 3
Scheme-1
For further study 2-chlorobenzimidazole is used as a starting compound for different synthesis of
novel benzimidazole derivatives.
Once starting compound 3 was synthesized then we have carried out the N-alkylation by using
different intermediates of active pharmaceutical ingredients.
For coupling we have used very simple reaction condition, the reaction was carried out in water
and base like sodium carbonate at heating for 4 to 5 hrs. After completion of reaction, it was
cooled to room temperature and filtered yielded white product which was recrystallized with
alcohol gave pure product. The IR, NMR, Mass and elemental analysis of the compound were
confirmes the structures.
2-chlorobenzimidazole (3) and 3-(2-Chloro-ethyl)-2-methyl-pyrido[1,2-a]pyrimidine-4-one (4)
reacted to give 3-[2-(2-Chloro-benzimidazole-1-yl)-ethyl]-2-methyl-pyrido[1,2-a]pyrimidine-4-
one as a target molecule. (DG@42, Scheme-2) IR value 1730cm-1 carbonyl and 1326cm-1
confirms C-N functional groups in the product. 1H-NMR; δ 2.25 (s, 3H, CH3), 3.20-3.23 (t,
J=7.32Hz, 2H, CH2), 4.47-4.51 (t, J=7.2Hz, 2H, CH2), 7.14-7.17 (t, J=6.72Hz, 1H, ArH), 7.22-
7.26 (m, 3H, ArH), 7.43-7.45 (m, 1H, ArH), 7.57-7.59 (m, 1H, ArH), 7.65-7.73 (m, 2H, ArH);
3.20-3.23 triplet shows CH2 group in the structure as well as δ2.25 singlet with three protons
confirms methyl in the structure. EI-MS 339.1 with M+1 confirms formation of target molecule.
(IR, 1H-NMR & EI-MS are in Figures - 136, 137 & 138).
NH
N
ClNN
Cl
N
N
O
Cl
N
N
OWater, 75-800C
Base
3 4 DG-42
Scheme-2
The compound 3 was reacted with 3-(2-Chloro-ethyl)-2-methyl-6,7,8,9-tetrahydro-pyrodo[1,2-
a]pyrimidine-4-one (5) gives target compound, 3-[2-(2-Chloro-benzimidazole-1-yl)-ethyl]-2-
methyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidine-4-one. (DG@43, Scheme-3) IR value
1722cm-1 carbonyl and 1233cm-1 confirms C-N functional groups in the product. 1H-NMR; δ
1.84-1.90 (m, 4H, Aliphatic ring), 2.00 (s, 3H, CH3), 2.82-2.85 (t, J=6.64Hz, 2H, Aliphatic ring),
2.99-3.03 (t, J=7.32Hz, 2H, CH2), 3.39-3.96 (t, J=6.2Hz, 2H, Aliphatic ring), 4.38-4.42 (t,
J=7.2Hz, 2H, CH2), 7.22-7.28 (m, 2H, ArH), 7.40-7.43 (dd, J=5.64Hz, 1H, ArH), 7.65-7.67 (m,
1H, ArH); 1.84-1.90 multiplet signals shows aliphatic ring part, δ 2.99-3.03 triplet shows CH2
group in the structure as well as δ 2.00 singlet with three protons confirms methyl in the
structure. EI-MS 343.2 with M+1 confirms formation of target molecule. (IR, 1H-NMR & EI-MS
are in Figures - 139, 140 & 141).
NH
N
Cl NN
Cl
N
N
O
ClN
N
O
Water, 75-800C
DG-43
Base
3 5
Scheme-3
The compound 3 was reacted with 4-Chloro-2, 2-diphenyl-butyronitrile (6) gives target
compound 4-(2-Chloro-benzimidazole-1-yl)2,2-diphenyl-butyronitrile. (DG@44, Scheme-4) IR
frequency 2361cm-1 nitrile and 1271cm-1 confirms C-N functional groups in the product. 1H-
NMR; δ 2.76-2.80 (t, J=8.0Hz, 2H, CH2), 4.18-4.22 (t, J=8.2Hz, 2H, CH2), 7.05-7.08 (m, 1H,
ArH), 7.17-7.22 (m, 2H, ArH), 7.26-7.30 (m, 2H, ArH), 7.32-7.38 (m, 8H, ArH), 7.59-7.61 (m,
1H, ArH); 2.76-2.80 triplet and δ 4.18-4.22 triplet with two protons each shows aliphatic chain
part in the structure as well as EI-MS 372.2 with M+1 confirms formation of target molecule.
(IR, 1H-NMR & EI-MS are in Figures - 142, 143 & 144).
NH
N
ClBase
Cl
CN NN
ClCN
Water, 75-800C
DG-4463
Scheme-4
The compound 3 was reacted with 4-Chloro-1-(4-fluoro-phenyl)-butan-1-one gives (7) 4-(2-
Chloro-benzimidazole-yl)-1-(4-fluoro-phenyl)-butan-1-one as a coupled product. (DG@45,
Scheme-5) IR frequency 1701cm-1 carbonyl and 1135cm-1 confirms C-N functional groups in the
product. 1H-NMR; δ 2.18-2.25 (m, 2H, CH2), 3.13-3.16 (t, J=8Hz, 2H, CH2), 3.65-3.68 (t,
J=8Hz, 2H, CH2), 7.11-7.15 (m, 4H, ArH), 7.98-8.02 (m, 4H, ArH); 2.18-2.25 multiplet, 3.13-
3.16 triplet and δ3.65-3.68 triplet with two protons each shows aliphatic chain part in the
structure as well as EI-MS 317.2 with M+1 confirms formation of target molecule. (IR, 1H-NMR
& EI-MS are in Figures - 145, 146 & 147).
Sch
eme
-5
The
com
pou
nd 3 was reacted with 2-Chloromethyl-3, 4-dimethoxy-pyridine (8) after workup of the reaction
and crystallization gives 2-Chloro-1-(3, 4-dimethoxy-pyridine-2-ylmethyl)-1H-benzimidazole as
targeted compound. (DG@46, Scheme-6) IR frequency 1137cm-1 methoxy functional groups in
the product. 1H-NMR; δ 4.14 (s, 3H, OCH3), 4.32 (s, 3H, OCH3), 5.92 (s, 2H, CH2), 7.34-7.41
(m, 2H, ArH), 7.75-7.79 (m, 2H, ArH), 8.03-8.05 (d, J=8Hz, 1H, ArH), 9.54-9.56 (d, J=8Hz, 1H,
ArH). 4.14 singlet, 4.32 singlet with three protons each of methoxy and δ 5.92 singlet with two
protons shows aliphatic chain part in the structure as well as EI-MS 304.2 with M+1 confirms
formation of target molecule. (IR, 1H-NMR & EI-MS are in Figures - 148, 149 & 150).
NH
N
Cl
N
OCH3
OCH3Cl
NN
Cl
N
OCH3
OCH3
DG-4683
Water,
75-800C
Scheme-6
K2CO3
The Physical Characteristics data for compounds DG-42 to 46 is give in table-1.
2-chlorobenzimidazole (3) and Phenylchloroformate (9) was reacted in presence of pyridine
gives (2-Chloro-benzimidazole-1-carboxylic acid methyl ester (DG@47, Scheme-7) IR
O
O
NH
N
Cl
3
F
NN
Cl
F
Water,
75-800C
7 DG-45
Cl
Base
frequency 1752cm-1 carbonyl & 1221 cm-1 C-N functional groups in the product. 1H-NMR; δ
7.05-7.09 (m, 1H, ArH), 7.10-7.15 (m, 1H, ArH), 7.16-7.18 (m, 1H, ArH), 7.32-7.36 (m, 3H,
ArH), 7.44-7.48 (m, 2H, ArH), 7.74-7.76 (d, J=7.92Hz, 1H, ArH) at aromatic region with nine
protons in the structure as well as EI-MS 273.2 with M+1 confirms formation of target molecule.
(IR, 1H-NMR & EI-MS are in Figures - 151, 152 & 153).
NH
N
Cl
3 DG-479
OO
Cl
Pyridine NN
Cl
O
O
Scheme-7
2-chlorobenzimidazole (3) and o-tolyl chloride (10) was reacted in presence of pyridine gives (2-
Chloro-benzimidazole-1-yl)-o-tolyl-methanone (DG@48, Scheme-8) IR frequency 1722cm-1
carbonyl & 1330 cm-1 C-N functional groups in the product. 1H-NMR; δ 2.6 (s, 3H, CH3), 7.14-
7.17 (t, J=6.73Hz, 1H, ArH), 7.23-7.26 (m, 3H, ArH), 7.43-7.45 (m, 1H, ArH), 7.57-7.59 (m,
1H, ArH), 7.66-7.73 (m, 2H, ArH). δ 2.66 singlet shows methyl substituent in the structure as
well as EI-MS 271.2 with M+1 confirms formation of target molecule. (IR, 1H-NMR & EI-MS
are in Figures - 154, 155 & 156).
NH
N
Cl
3 10
Pyridine
Scheme-8
OCl
N
N
Cl
O
DG-48
For the series of the synthesis of the some more novel benzimidazole derivatives, we have used
2-chlorobenzimidazole and some intermediates. They were synthesized by using dry conditions
such as, dimethylformamide or acetone as a solvent and potassium carbonate as a base. The
reaction was carried out at 50-70°C for 3-5 hrs. After workup of the reaction mixture gives crude
product which was further purified by crystallization techniques. The series of compounds were
characterized by spectral characterization techniques like IR, 1H-NMR, mass and elemental
analysis.
2-chlorobenzimidazole (3) and 4-bromobenzyl bromide (11) was reacted in presence of acetone
and potassium carbonate as a base gives 1-(4-Bromo-benzyl)-2-chloro-1H-benzimidazole.
(DG@49, Scheme-9) IR spectra not able to give specific characterization peak of the molecule
but in case of 1H-NMR; δ 5.26 (s, 2H, CH2), 6.96-6.98 (d, 2H, ArH), 7.11-7.13 (dd, J=8Hz, 1H,
ArH), 7.14-7.23 (m, 2H, ArH), 7.36-7.41 (m, 2H, ArH), 7.63-7.65 (m, 1H, ArH). δ 5.26 singlet
with two protons shows aliphatic chain part and aromatic region in the structure as well as EI-
MS 322.2 with M+1 confirms formation of target molecule. (IR, 1H-NMR & EI-MS are in
Figures - 157, 158 & 159).
NH
N
Cl
3
Br
Br
NN
Cl
Br
K2CO3
Acetone, Reflux
DG-4911
Scheme-9
2-chlorobenzimidazole (3) and 4-nitrobenzoyl chloride (12) was reacted in presence of pyridine
gives (2-Chloro-benzimidazole-1-yl)-(4-nitro-phenyl)-methanone (DG@50, Scheme-10) IR
frequency 1722cm-1 carbonyl & 1273cm-1 C-N functional groups in the molecule. 1H-NMR; δ
7.32-7.34 (m, 1H, ArH), 7.36-7.42 (m, 1H, ArH), 7.44-7.46 (m, 1H, ArH), 7.73-7.75 (dd, J=8Hz,
1H, ArH), 7.95-7.98 (m, 1H, ArH), 7.95-7.98 (m, 1H, ArH), 8.38-8.41 (m, 2H, ArH) at aromatic
region with eight protons in the structure as well as EI-MS 302.2 with M+1 confirms formation
of target molecule. (IR, 1H-NMR & EI-MS are in Figures - 160, 161 & 162).
NH
N
Cl
3 DG-5012
Cl Pyridine NN
Cl O
NO2
O
NO2
Scheme-10
2-chlorobenzimidazole (3) and n-hexylchloroformate (13) was reacted in presence of pyridine
gives (2-Chloro-benzimidazole-1-carboxylic acid hexyl ester (DG@51, Scheme-11) IR
frequency 1752cm-1 carbonyl & 1221 cm-1 C-N functional groups in the product. 1H-NMR;
δ7.03-7.13 (m, 3H, ArH), 7.72-7.74 (d, J=7.76Hz, 1H, ArH), δ1.21-1.23 triplet, 1.27-1.33
multiplet, 1.38-1.45 multiplet, 1.75-1.82 multiplet, 4.38-4.42 triplet shows aliphatic chain part in
the structure as well as EI-MS 281.2 with M+1 confirms formation of target molecule. (IR, 1H-
NMR & EI-MS are in Figures - 163, 164 & 165).
3 DG-5113
PyridineNHN
Cl
Cl
O
O
NN
Cl
OC6H13
O
Scheme-11
2-chlorobenzimidazole (3) and (2-Chloro-ethyl)-diisopropyl-amine (14) was reacted in presence
of DMF and potassium carbonate as a base gives [2-(2-Chloro-3H-indol-3-yl)-ethyl]-
diisopropyl-amine. (DG@52, Scheme-12) In this molecule also IR spectra not able to give
specific characterization peak but 1136 cm-1 shows C-N functional group. In case of proton
NMR δ 0.96-0.98 (d, J=6.56Hz, 12H, diisopropyl), 2.75-2.79 (t, J=7.36Hz, 2H, CH2), 3.00-3.05
(m, 2H, CH2), 4.10-4.14(t, J=7.2Hz, 2H, CH2), 7.23-7.32 (m, 3H, ArH), 7.66-7.69 (m, 1H, ArH)
δ0.96-0.98 with twelve protons, as well as δ 2.75-2.79, 3.00-3.05 & 4.10-4.14 shows aliphatic
chain part. EI-MS: 280.2 with M+1 confirm formation of target molecule. (IR, 1H-NMR & EI-
MS are in Figures - 166, 167 & 168).
ClN
NH
N
Cl
NN
Cl
N
3
K2CO3
DMF
DG-5214
Scheme-12
2-chlorobenzimidazole (3) and 4-bromobutyronitrile (15) was reacted in presence of DMF and
potassium carbonate as a base gives 4-(2-Chloro-benzimidazole-1-yl)-butyronitrile. (DG@53,
Scheme-13) IR frequency, 2329cm-1 nitrile functional groups in the structure. 2.18-2.24
multiplet, 2.37-2.41 triplet and δ 4.33-4.37 triplet with two protons shows aliphatic chain part in
the structure as well as EI-MS 220.0 with M+1 confirms formation of target molecule. (IR, 1H-
NMR & EI-MS are in Figures -169, 170 & 171).
NH
N
Cl BrN NN
Cl
NK2CO3
DMF,750C
3 15 DG-53
Scheme-13
2-chlorobenzimidazole (3) and 4-bromoethylbutyrate (12) was reacted in presence of DMF and
potassium carbonate as a base gives 2-Chloro-benzimidazole-1-yl)-pentoinoc acid ethyl ester.
(DG@54, Scheme-16) IR frequency 1752cm-1 carbonyl & 1221 cm-1 C-N functional groups in
the product. Proton NMR at δ 7.26-7.32 (m, 2H, ArH), 7.35-7.38 (m, 1H, ArH), 7.68-7.71 (m,
1H, ArH) & 1.23 multiplet, 2.11-2.16 singlet, 2.35-2.39 triplet, 4.11-4.17 multiplet, 4.26-4.30
triplet shows aliphatic chain part in the structure as well as EI-MS 281.2 with M+1 confirms
formation of target molecule. (IR, 1H-NMR & EI-MS are in Figures - 172, 173 & 174).
Br O
O NN
Cl
O
O
DMF,750C
K2CO3
NH
N
Cl
3 16 DG-54
Scheme-14
2-chlorobenzimidazole (3) and methylchloroacetete (17) was reacted in presence of DMF and
potassium carbonate as a base gives (2-Chloro-benzimidazole-1-yl)-acetic acid methyl ester.
(DG@55, Scheme-15) IR frequency 1752cm-1 carbonyl & 1298 cm-1 C-N functional groups in
the compound. Proton NMR at δ 3.67 singlet with three protons of methoxy shows aliphatic
chain part in the structure as well as EI-MS 225.2 with M+1 confirms formation of target
molecule. (IR, 1H-NMR & EI-MS are in Figures - 175, 176 & 177).
NH
N
Cl ClO
O
NN
Cl
O
O
K2CO3
DMF,750C
3 17 DG-55
Scheme-15
The physical and spectral characterization data of the compounds DG@42 to 55 is presented in
Tables-1 & 2 respectively.
Table - 1: Physical Characteristics data for compounds DG@42 to 55.
Sr.
No.
Compound
No.
Molecular
Formula
M.P.
( 0C )
Yield
( % )
Elemental Analysis
Calculate Found
1. DG@42 C18H15ClN4O 175-178 80 C = 63.81
H = 4.46
N = 16.54
C =63.90
H = 4.41
N = 16.61
2 DG@43 C18H19ClN4O 168-171 74 C = 63.09
H = 5.59
N = 16.34
C = 63.15
H = 5.60
N = 16.28
3 DG@44 C23H18ClN3 140-143 76 C = 74.29
H = 4.88
N = 9.53
C = 74.35
H = 4.81
N = 9.60
4 DG@45 C17H14ClFN2O 111-114 68 C = 64.46
H = 4.45
N = 8.84
C = 64.50
H = 4.41
N = 8.91
5 DG@46 C15H14ClN3O2 172-174 81 C = 59.31
H = 4.65
N = 13.83
C = 59.42
H = 4.55
N = 13.91
6 DG@47 C14H9ClN2O2 138-141 62 C = 61.66
H = 3.33
N = 10.27
C = 61.72
H = 3.23
N = 10.38
7 DG@48 C15H11ClN2O 115-118 65 C = 66.55
H = 4.10
N = 10.35
C = 66.51
H = 4.16
N = 10.29
8 DG@49 C14H10BrClN2 119-121 88 C = 52.29
H = 3.13
N = 8.71
C = 52.36
H = 3.18
N = 8.65
9 DG@50 C14H8ClN3 O3 155-158 85 C = 55.74
H = 2.67
N = 13.93
C = 55.88
H = 2.61
N = 13.87
10 DG@51 C14H17ClN2O2 111-113 87 C = 59.89
H = 6.10
N = 9.98
C = 59.95
H = 6.10
N = 9.98
11 DG@52 C15H22ClN3 123-126 74 C = 64.39
H = 7.92
N = 15.02
C = 64.32
H = 7.99
N = 15.11
12 DG@53 C11H10ClN3 134-137 88 C = 60.14
H = 4.59
N = 19.13
C = 60.19
H = 4.52
N = 19.09
13 DG@54 C14H17ClN2O2 118-121 78 C = 59.89
H = 6.10
N = 9.98
C = 59.95
H = 6.06
N = 9.92
14 DG@55 C10H9ClN2O3 131-134 69 C = 53.47
H = 4.04
N = 12.47
C = 53.39
H = 4.11
N = 12.51
Table - 2: Spectral Characteristics for compounds DG@42 to DG@55.
DG@42 Structure
NN
Cl
N
N
O
3-[2-(2-Chloro-benzoimidazol-1-yl)-ethyl]-2-methyl-pyrido[1,2-a]pyrimidin-4-one
IR(KBr):
(Fig. 136)
3148, 2406, 2216, 1730, 1664, 1609, 1471, 1326, 1179, 1097
cm-1.
1H - NMR:
(CDCl3)
(Fig. 137)
δ2.25 (s, 3H, CH3), 3.20-3.23 (t, J=7.32Hz, 2H, CH2), 4.47-
4.51 (t, J=7.2Hz, 2H, CH2), 7.14-7.17 (t, J=6.72Hz, 1H,
ArH), 7.22-7.26 (m, 3H, ArH), 7.43-7.45 (m, 1H, ArH), 7.57-
7.59 (m, 1H, ArH), 7.65-7.73 (m, 2H, ArH)
EI-MS
(Fig. 138)
339.1 (M++1).
DG@43 Structure
NN
Cl
N
N
O
3-[2-(2-Chloro-benzoimidazol-1-yl)-ethyl]-2-methyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one
IR(KBr):
(Fig. 139)
2945, 2216, 1722, 1620, 1610, 1459, 1437, 1379, 1233, 1175,
1104, 1082 cm-1.
1H-NMR:
(CDCl3)
(Fig. 140)
δ 1.84-1.90 (m, 4H, Aliphatic ring), 2.00 (s, 3H, CH3), 2.82-
2.85 (t, J=6.64Hz, 2H, Aliphatic ring), 2.99-3.03 (t, J=7.32Hz,
2H, CH2), 3.39-3.96 (t, J=6.2Hz, 2H, Aliphatic ring), 4.38-
4.42 (t, J=7.2Hz, 2H, CH2), 7.22-7.28 (m, 2H, ArH), 7.40-
7.43 (dd, J=5.64Hz, 1H, ArH), 7.65-7.67 (m, 1H, ArH)
EI-MS
(Fig. 141)
343.2 (M++1).
DG@44 Structure
NN
ClCN
4-(2-Chloro-benzoimidazol-1-yl)-2,2-diphenyl-butyronitrile
IR(KBr):
(Fig. 142)
2940, 2361, 1469, 1400, 1271, 1137, 1020, cm-1
1H-NMR:
(CDCl3)
(Fig. 143)
δ 2.76-2.80 (t, J=8.0Hz, 2H, CH2), 4.18-4.22 (t, J=8.2Hz, 2H,
CH2), 7.05-7.08 (m, 1H, ArH), 7.17-7.22 (m, 2H, ArH), 7.26-
7.30 (m, 2H, ArH), 7.32-7.38 (m, 8H, ArH), 7.59-7.61 (m,
1H, ArH)
EI-MS
(Fig. 144)
372.2 (M++1).
DG@45 Structure
NN
ClF
4-(2-Chloro-benzoimidazol-1-yl)-1-(4-fluoro-phenyl)-butan-1-one
O
IR(KBr):
(Fig. 145)
2804, 2655, 1701, 1517, 1369, 1135, 1097, 1054 cm-1.
1H-NMR:
(CDCl3)
(Fig. 146)
δ2.18-2.25 (m, 2H, CH2), 3.13-3.16 (t, J=8Hz, 2H, CH2),
3.65-3.68 (t, J=8Hz, 2H, CH2), 7.11-7.15 (m, 4H, ArH), 7.98-
8.02 (m, 4H, ArH).
EI-MS
(Fig. 147)
317.2 (M++1).
DG@46 Structure
NN
Cl
N
OCH3
OCH3
2-Chloro-1-(3,4-dimethoxy-pyridin-2-ylmethyl)-1H-benzoimidazole
IR(KBr):
(Fig. 148)
2940, 2696, 2681, 2469, 1489, 1470, 1137 cm-1.
1H-NMR:
(CDCl3)
(Fig. 149)
δ4.14 (s, 3H, OCH3 ), 4.32 (s, 3H, OCH3), 5.92 (s, 2H, CH2),
7.34-7.41 (m, 2H, ArH), 7.75-7.79 (m, 2H, ArH), 8.03-8.05
(d, J=8 Hz, 1H, ArH), 9.54-9.56 (d, J=8 Hz, 1H, ArH)
EI-MS
(Fig. 150)
304.2 (M++1).
DG@47 Structure
NN
ClO
O
2-Chloro-benzoimidazole-1-carboxylic acid phenyl ester
IR(KBr):
(Fig. 151)
2986, 2619, 1752, 1433, 1298, 1298, 1174, 1068 cm-1.
1H-NMR:
(CDCl3)
(Fig. 152)
δ7.05-7.09 (m, 1H, ArH), 7.10-7.15 (m, 1H, ArH), 7.16-7.18
(m, 1H, ArH), 7.32-7.36 (m, 3H, ArH), 7.44-7.48 (m, 2H,
ArH), 7.74-7.76 (d, J=7.92Hz, 1H, ArH)
EI-MS
(Fig. 153)
273.2 (M++1).
DG@48 Structure
NN
ClO
(2-Chloro-benzoimidazol-1-yl)-o-tolyl-methanone
IR(KBr):
(Fig. 154)
3035, 2214, 1722, 1607, 1530, 1330, 1176, 991 cm-1.
1H-NMR:
(CDCl3)
(Fig. 155)
δ2.6 (s, 3H, CH3), 7.14-7.17 (t, J=6.73Hz, 1H, ArH), 7.23-
7.26 (m, 3H, ArH), 7.43-7.45 (m, 1H, ArH), 7.57-7.59 (m,
1H, ArH), 7.66-7.73 (m, 2H, ArH)
EI-MS
(Fig. 156)
271.2 (M++1).
DG@49 Structure
NN
Cl
Br
1-(4-Bromo-benzyl)-2-chloro-1H-benzoimidazole
IR(KBr):
(Fig. 157)
2940, 2361, 1650, 1558, 1469, 1339, 1271, 1137 cm-1.
1H-NMR:
(CDCl3)
(Fig. 158)
δ5.26 (s, 2H, CH2), 6.96-6.98 (d, 2H, ArH), 7.11-7.13 (dd,
J=8Hz, 1H, ArH), 7.14-7.23 (m, 2H, ArH), 7.36-7.41 (m, 2H,
ArH), 7.63-7.65 (m, 1H, ArH).
EI-MS
(Fig. 159)
322.2 (M++1).
DG@50 Structure
NN
ClO
NO2
(2-Chloro-benzoimidazol-1-yl)-(4-nitro-phenyl)-methanone
IR(KBr):
(Fig. 160)
2983, 2848, 1722, 1424, 1273, 1149, 1018cm-1.
1H-NMR:
(CDCl3)
(Fig. 161)
δ 7.32-7.34 (m, 1H, ArH), 7.36-7.42 (m, 1H, ArH), 7.44-7.46
(m, 1H, ArH), 7.73-7.75 (dd, J=8Hz, 1H, ArH), 7.95-7.98 (m,
1H, ArH), 7.95-7.98 (m, 1H, ArH), 8.38-8.41 (m, 2H, ArH)
EI-MS
(Fig. 162)
302.2 (M++1).
DG@51 Structure
NN
Cl
O
O
2-Chloro-benzoimidazole-1-carboxylic acid hexyl ester
IR(KBr):
(Fig. 163)
2986, 2619, 1752, 1433, 1221, 1174, 1068 cm-1.
1H-NMR:
(CDCl3)
(Fig. 164)
δ 1.21-1.23 (t, J=6.88Hz, 3H, CH3), 1.27-1.33 (m, 4H,
2xCH2), 1.38-1.45 (m, 2H, CH2), 1.75-1.82 (m, 2H, CH2),
4.38-4.42(t, J=6.8Hz, 2H, CH2), 7.03-7.13 (m, 3H, ArH),
7.72-7.74 (d, J=7.76Hz, 1H, ArH)
EI-MS
(Fig. 165)
281.2 (M++1).
DG@52 Structure
NN
Cl
N
[2-(2-Chloro-benzoimidazol-1-yl)-ethyl]-diisopropyl-amine
IR(KBr):
(Fig. 166)
2940, 2748, 2679, 1582, 1469, 1136, 1029cm-1.
1H-NMR:
(CDCl3)
(Fig. 167)
δ 0.96-0.98 (d, J=6.56Hz, 12H, diisopropyl), 2.75-2.79 (t,
J=7.36Hz, 2H, CH2), 3.00-3.05 (m, 2H, CH2), 4.10-4.14(t,
J=7.2Hz, 2H, CH2), 7.23-7.32 (m, 3H, ArH), 7.66-7.69 (m,
1H, ArH)
EI-MS
(Fig. 168)
280.2 (M++1).
DG@53 Structure
NN
Cl
N
4-(2-Chloro-benzoimidazol-1-yl)-butyronitrile
IR(KBr):
(Fig. 169)
2940, 2697, 2361, 2329, 1650, 1509, 1469, 1137, 1020 cm-1.
1H-NMR:
(CDCl3)
(Fig. 170)
δ 2.18-2.24 (m, 2H, CH2), 2.37-2.41 (t, J=7.12Hz, 2H, CH2),
4.33-4.37(t, J=6.84Hz, 2H, CH2), 7.21-7.37 (m, 3H, ArH),
7.68-7.71 (m, 1H, ArH)
EI-MS
(Fig. 171)
220.0 (M++1).
DG@54 Structure
NN
Cl
O
O
5-(2-Chloro-benzoimidazol-1-yl)-pentanoic acid ethyl ester
IR(KBr):
(Fig. 172)
2986, 1752, 1433, 1221, 1174, 1068, 1018 cm-1.
1H-NMR:
(CDCl3)
(Fig. 173)
δ 1.23-1.33 (m, 5H, CH2 & CH3), 2.11-2.16 (m, 2H, CH2),
2.35-2.39 (t, J=7.04Hz, 2H, CH2), 4.11-4.17 (m, 2H, CH2),
4.26-4.30 (t, J=7.2Hz, 2H, CH2), 7.26-7.32 (m, 2H, ArH),
7.35-7.38 (m, 1H, ArH),7.68-7.71 (m, 1H, ArH)
EI-MS
(Fig. 174)
281.2 (M++1).
DG@55 Structure
NN
Cl
O
O
(2-Chloro-benzoimidazol-1-yl)-acetic acid methyl ester
IR(KBr):
(Fig. 175)
2986, 2618, 1752, 1433, 1298, 1221, 1174, 1068, 1035 cm-1.
1H-NMR:
(CDCl3)
(Fig. 176)
δ 3.67 (s, 3H, CH3), 4.69 (s, 2H, CH2), 7.25-7.30 (m, 2H,
ArH), 7.43-7.47 (m, 1H, ArH), 8.06-8.08 (dd, J=8.36Hz, 1H,
ArH).
EI-MS
(Fig. 177)
225.2 (M++1).
Experimental section-
a) Synthesis of 3-[2-(2-Chloro-benzimidazole-1-yl)-ethyl]-2-methyl-pyrido[1,2-
a]pyrimidine-4-one (DG@42)
To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and potassium carbonate (39.47
mmoles) in water (25 ml) was added 3-(2-Chloro-ethyl)-2-methyl-pyrido[1,2-a]pyrimidine-4-one
(4, 39.47 mmoles) at RT. At 70-750C the reaction mixture was then heated for 3-4 hrs. &
monitored by TLC. By the completion of reaction, added 50 ml ethyl acetate stirred for 15 min.
layers were seperated. Ethyl acetate layer was washed with 25 ml water, dried over sodium
sulfate. After concentration of solvent under vacuum yielded 8.3g (74%) of the corresponding N-
substituted derivative.
b) Synthesis of 3-[2-(2-Chloro-benzimidazole-1-yl)-ethyl]-2-methyl-6, 7, 8, 9-tetrahydro-
pyrido[1,2-a]pyrimidine-4-one. (DG@43)
To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and potassium carbonate
(39.47mmoles) in water (25 ml) was added 3-(2-Chloro-ethyl)-2-methyl-6,7,8,9-tetrahydro-
pyrodo[1,2-a]pyrimidine-4-one (5, 39.47 mmoles) at RT. At 70-750C the reaction mixture was
then heated for 3-4 hrs. & monitored by TLC. By the completion of reaction, added 50 ml ethyl
acetate stirred for 15 min. layers were seperated. Ethyl acetate layer was washed with 25 ml
water, dried over sodium sulfate. After concentration of solvent under vacuum yielded 8.0g
(72%) of the corresponding N-substituted derivative.
c) Synthesis of 4-(2-Chloro-benzimidazole-1-yl) 2, 2-diphenyl-butyronitrile (DG@44)
To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and potassium carbonate (39.47
mmoles) in water (25 ml) was added 4-Chloro-2, 2-diphenyl-butyronitrile (6, 39.47 mmoles) at
RT. At 70-750C the reaction mixture was then heated for 3-4 hrs. & monitored by TLC. By the
completion of reaction, added 50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl
acetate layer was washed with 25 ml water, dried over sodium sulfate. After concentration of
solvent under vacuum yielded 9.3g (76%) of the corresponding N-substituted derivative.
d) Synthesis of 4-(2-Chloro-benzimidazole-yl)-1-(4-fluoro-phenyl)-butan-1-one 4-Chloro-2,
2-diphenyl-butyronitrile (DG@45)
To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and potassium carbonate
(39.47mmoles) in water (25 ml) was added 4-Chloro-1-(4-fluoro-phenyl)-butan-1-one gives (6,
39.47 mmoles) at RT. At 70-750C the reaction mixture was then heated for 3-4 hrs. & monitored
by TLC. By the completion of reaction, reaction mixture was extracted with ethyl acetate (2 x
25ml). The organic layer was washed with water (2 x 25ml), brine and dried over anhydrous
sodium sulfate and concentrated under vacuum to yielded 7.06g (68%) of the corresponding N-
substituted derivative.
e) Synthesis of 2-Chloro-1-(3,4-dimethoxy-pyridine-2-ylmethyl)-1H-benzimidazole
(DG@46)
To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and potassium carbonate (39.47
mmoles) in water (25 ml) was added 2-Chloromethyl-3,4-dimethoxy-pyridine (8, 39.47 mmoles)
at RT. At 70-750C the reaction mixture was then heated for 3-4 hrs. & monitored by TLC. By the
completion of reaction, added 50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl
acetate layer was washed with 25 ml water, dried over sodium sulfate. After concentration of
solvent under vacuum yielded 5.6 g (62%) of the corresponding N-substituted derivative.
f) Synthesis of (2-Chloro-benzimidazole-1-carboxylic acid methyl ester (DG@47)
To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and pyridine (39.47 mmoles) in DMF
(5 volume) was added Phenylchloroformate (14, 39.47 mmoles) was reacted in presence of gives
(13, 39.74 mmoles At 60-650C the reaction mixture was then heated for 3-4 hrs. & monitored by
TLC. By the completion of reaction, added 50 ml ethyl acetate stirred for 15 min. layers were
seperated. Ethyl acetate layer was washed with 25 ml water, dried over sodium sulfate. After
concentration of solvent under vacuum yielded 8.41g (85%) of the corresponding N-substituted
derivative.
g) Synthesis of (2-Chloro-benzimidazole-1-yl)-o-tolyl-methanone (DG@48)
To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and pyridine (39.47 mmoles) in DMF
(5 volume) was added and o-tolyl chloride (17, 39.47 mmoles). At 60-650C the reaction mixture
was then heated for 3-4 hrs. & monitored by TLC. By the completion of reaction, added 50 ml
ethyl acetate stirred for 15 min. layers were seperated. Ethyl acetate layer was washed with 25 ml
water, dried over sodium sulfate. After concentration of solvent under vacuum yielded 5.77g
(65%) of the corresponding N-substituted derivative.
h) Synthesis of 1-(4-Bromo-benzyl)-2-chloro-1H-benzimidazole (DG@49)
To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and potassium carbonate (39.47
mmoles) in acetone (5 volume) was added 4-bromobenzyl bromide (9, 39.47 mmoles). At 70-
750C the reaction mixture was then heated for 3-4 hrs. & monitored by TLC. By the completion
of reaction, added 50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl acetate
layer was washed with 25 ml water, dried over sodium sulfate. After concentration of solvent
under vacuum yielded 5.6 g (62%) of the corresponding N-substituted derivative.
i) Synthesis of (2-Chloro-benzimidazole-1-yl)-(4-nitro-phenyl)-methanone (DG@50)
To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and pyridine (39.47 mmoles) in DMF
(5 volume) was added 4-nitrobenzoyl chloride (15, 39.47 mmoles). At 70-750C the reaction
mixture was then heated for 3-4 hrs. & monitored by TLC. By the completion of reaction, added
50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl acetate layer was washed with
25 ml water, dried over sodium sulfate. After concentration of solvent under vacuum yielded
5.54g (62%) of the corresponding N-substituted derivative.
j) Synthesis of (2-Chloro-benzimidazole-1-carboxylic acid hexyl ester (DG@51)
To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and pyridine (39.47 mmoles) in DMF
(5 volume) was added and n-hexylchloroformate (16, 39.47 mmoles). At 65-700C the reaction
mixture was then heated for 3-4 hrs. & monitored by TLC. By the completion of reaction, added
50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl acetate layer was washed with
25 ml water, dried over sodium sulfate. After concentration of solvent under vacuum yielded
8.0g (87%) of the corresponding N-substituted derivative.
k) Synthesis of [2-(2-Chloro-3H-indol-3-yl)-ethyl]-diisopropyl-amine (DG@52)
To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and potassium carbonate (39.47
mmoles) in DMF (5 volume) was added 2-Chloro-ethyl)-diisopropyl-amine (10, 39.47 mmoles).
At 70-750C the reaction mixture was then heated for 3-4 hrs. & monitored by TLC. By the
completion of reaction, added 50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl
acetate layer was washed with 25 ml water, dried over sodium sulfate. After concentration of
solvent under vacuum yielded 6.79 g (74%) of the corresponding N-substituted derivative.
l) Synthesis of 4-(2-Chloro-benzimidazole-1-yl)-butyronitrile (DG@53)
To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and potassium carbonate (39.47
mmoles) in DMF (5 volume) was added 4-bromobutyronitrile (11, 39.47 mmoles) 39.47 mmoles
). At 70-750C the reaction mixture was then heated for 3-4 hrs. & monitored by TLC. By the
completion of reaction, added 50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl
acetate layer was washed with 25 ml water, dried over sodium sulfate. After concentration of
solvent under vacuum yielded 6.74g (88%) of the corresponding N-substituted derivative.
m) Synthesis of 2-Chloro-benzimidazole-1-yl)-pentoinoc acid ethyl ester (DG@54)
To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and potassium carbonate (39.47
mmoles) in DMF (5 volume) was added 4-bromoethylbutyrate (12, 39.47 mmoles). At 70-750C
the reaction mixture was then heated for 3-4 hrs. & monitored by TLC. By the completion of
reaction, added 50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl acetate layer
was washed with 25 ml water, dried over sodium sulfate. After concentration of solvent under
vacuum yielded 7.17g (78%) of the corresponding N-substituted derivative.
n) Synthesis of (2-Chloro-benzimidazole-1-yl)-acetic acid methyl ester (DG@55)
To a solution of 2-chlorobenzimidazole (3, 32.89 mmoles) and potassium carbonate (39.47
mmoles) in DMF (5 volume) was added methylchloroacetete (13, 39.74 mmoles). At 70-750C
the reaction mixture was then heated for 3-4 hrs. & monitored by TLC. By the completion of
reaction, added 50 ml ethyl acetate stirred for 15 min. layers were seperated. Ethyl acetate layer
was washed with 25 ml water, dried over sodium sulfate. After concentration of solvent under
vacuum yielded 5.0g (69%) of the corresponding N-substituted derivative.
Conclusion-
We have synthesized a series of N-alkylated derivatives using a known starting benzimidazole
and with good yields. Here we have used different intermediated for akylation and presented
novel derivatives. The structures of all the synthesized compounds were characterized by
spectroscopic data, and allowed these molecules for study of antibacterial and antifungal
activities Benzimidazole derivatives shows a very good anti bacterial activities which are
explained in chapter-6.