Microwave-assisted synthesis of some novel benzimidazole derivatives containing imine function and evaluation of their antimicrobial activity

Article abstract of DOI:10.1002/jhet.1593

4-Bromo-o-phenylenediamine and ethylimido-p-bromophenylacetate, 1, were subjected to microwave irradiation to synthesize benzimidazole derivative, compound 2. Ester derivative, 3, and hydrazide derivative, 4, of compound 2 were also synthesized, respectiv

Full text of DOI:10.1002/jhet.1593

982
Microwave-Assisted Synthesis of Some Novel Benzimidazole Derivatives
Containing Imine Function and Evaluation of Their Antimicrobial Activity
Vol 51
a
b
b
b
c
*
Bahittin Kahveci , Fatih Yılmaz, Emre Menteşe, Musa Özil, and Şengül Alpay Karaoğlu
aDepartment of Nutrition and Dietetics, Faculty of Health Sciences, Karadeniz Technical University, Trabzon, Turkey
bDepartment of Chemistry, Recep Tayyip Erdoğan University, Rize 53100, Turkey
cDepartment of Biology, Recep Tayyip Erdoğan University, Rize 53100, Turkey
*
E-mail: bahittin@yahoo.com
Received October 5, 2011
DOI 10.1002/jhet.1593
Published online 16 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
Br
NH+
2 Cl
-
N
Br
NH
NH
2
2
Br
+
OEt
N
H
2
Br
N
N
Br
O
NH
Br
N
Ar
5a-k
4-Bromo-o-phenylenediamine and ethylimido-p-bromophenylacetate, 1, were subjected to microwave
irradiation to synthesize benzimidazole derivative, compound 2. Ester derivative, 3, and hydrazide derivative,
4, of compound 2 were also synthesized, respectively. Finally, compound 4 was treated with 11 different
aromatic aldehydes to obtain benzimidazole derivatives containing imine function. All reactions were carried
out with microwave irradiation and conventional heating, and results were compared. Some of the newly
synthesized compounds showed moderate antimicrobial activity against some tested organisms.
J. Heterocycl Chem., 51, 982 (2014).
INTRODUCTION
carboxylic acid or an aromatic aldehyde as intermediate
[19,20]. Also, microwave technology has been used to
synthesize benzimidazole derivatives, and important
changes have been seen on yield and reaction time
[3,9,21]. In this report, a new synthetic method is proposed
for benzimidazole derivatives and benzimidazole contain-
ing imine function under microwave irradiation starting
from new intermediates. The structure of new compounds
was identified by IR, 1H-NMR, 13C-NMR, elemental
analysis, and mass spectroscopic techniques.
Benzimidazole has become a privileged structure and an
important pharmacophore in modern drug discovery [1–4].
Some benzimidazole derivatives with different biological ac-
tivities, such as anticancer [5,6], antihelmintic [7,8], antimi-
crobial [9–11], antifungal [12], antihistaminic [13,14], and
antitumor [15], have been revealed in literature. Also, some
drugs containing benzimidazole skeleton (Fig. 1), such as
thiabendazole, flubendazole (antihelmintic) [14], Imet 3393
(anticancer) [16], and Astemizole (antihistaminic) [16], are
present for medicinal use (Fig. 1). Moreover, benzimidazole
nucleolus is naturally found in the structure of vitamin B12
and shows similarities with adenine and guanine [17].
RESULTS AND DISCUSSION
Because of these reasons, benzimidazole derivatives
have been studied by numerous scientists, and so far some,
methods have been developed to synthesize these
compounds [18–20]. The most common method for this
process is using an o-phenylenediamine derivative and a
Chemistry.
Firstly, compound 1, ethylimido-p-
bromophenylacetate hydrochloride, was prepared according
to the Pinner method [22,23] (Scheme 1).
o-Phenylenediamine derivatives and aromatic aldehydes
or carboxylacids are mostly used for preparation of
© 2013 HeteroCorporation

July 2014
Synthesis of Benzimidazole Derivatives Containing Imine Function
983
O
Cl
H
CO
3
(CH
)
2
2
N
O
N
N
S
Cl
N
2
N
N
(CH
)
NH
2
(CH
)
3
2
N
H
N
H
F
COOH
Thiabendazole
Flubendazole
CH
3
Imet 3393
N
NH
N
N
F
O
CH
3
Astemizole
Figure 1. Some drugs containing benzimidazole skeleton.
benzimidazole compounds. For the synthesis of potential bio-
logical active benzimidazole compounds, secondly, a simple
method was developed using p-bromo-o-phenylenediamine
and ethylimido-p-bromophenylacetate, compound 1, with
microwave irradiation and classical method, and then com-
pound 2, 5(6)-bromo-2-(4-bromobenzyl)-1H-benzimidazol,
was obtained. Compound 3 was prepared with treatment of
compound 2 and ethyl bromoacetate in acetone. Then,
compound 3 was reacted with hydrazine monohydrate in
ethanol to synthesize compound 4. Compound 4 was treated
with 11 different aromatic aldehydes to obtain benzimidazoles
containing imine function, compounds 5a–k (Scheme 2).
Spectral analyses of newly synthesized compounds are
suitable with the proposed structures (Fig. 2). IR spectra
of each compound gave a C═N band at about 1620 cmꢀ1
and C═O bands at about 1730, 1650, and 1690 cmꢀ1 for
compounds 3, 4, and 5a–k, respectively. Compound 2
showed an NH signal at 3159, and no NH signal was seen
for compound 3. Also, new C═O and C-O band forma-
tions proved the alkylation reaction of compound 2. Com-
pound 4 had new C═O and NH and NH2 bands at 1659
and 3298–3100 cmꢀ1. Compounds 5a–k had no NH2 band
because of imine formation, and new C═O bands were
shown at 12.51 ppm for compound 2 and 11.49–11.86 ppm
for compounds 5a–k. When 1H-NMR spectra of compounds
3, 4, and 5a–k were compared, it was seen that some of the
protons of these compounds have two sets of signals at
different ppm. This is because of the compounds, which
have arylene-hydrazide structure, that exist as E/Z geometri-
cal isomer from C═N double bond and cis/trans amide con-
former at the CO-NH single bond. According to the literature
[24–28], compounds that have C═N double bond prefers E
geometrical isomer in DMSO-d6, and Z isomers can be
preferred in less polar solvents. N-CH2 and N-H signals were
observed in two sets of signals because of cis/trans
conformer. The ratio in each case was calculated by using
1H-NMR data. E/Z and cis/trans geometrical isomer of
compounds 5a–k (Scheme 3) and selected 1H-NMR spectrum
are given in and Fig. 3.
In addition, all compounds have suitable molecular ions
according to the literature [29] that originated from 79Br
(50.7%) and 81Br (49.3%).
Antimicrobial activity. Compounds 2, 3, 4, 5c, 5e, and
5h showed antimicrobial activity against some tested
organisms, and results are given in Table 2.
Conclusion. An efficient method for the synthesis of
benzimidazole derivatives containing imine function
using the microwave technology has been described. All
reactions were carried out with conventional heating in
order to compare. All compounds are new and identified
by spectral data.
between 1702 and 1677 cmꢀ1
.
1H-NMR spectra of each compound gave compatible
signals with the structures. N-H, NH2, and O-H signals
were controlled by changing with D2O addition to
DMSO-d6 solution of compounds. An N-H signal was
Scheme 1. Synthetic pathway for compound 1.
Br
NH.HCI
C
H OH
5
HCI(g)
Br
CH CN
2
2
+
+
CH
OC H
2 5
2
Journal of Heterocyclic Chemistry
DOI DOI 10.1002/jhet

984
B. Kahveci, F. Yılmaz, E. Menteşe, M. Özil, and Ş. A. Karaoğlu
Vol 51
Scheme 2. Conditions: a) BrCH2COOEt, K2CO3, Acetone; b) NH2NH2ꢁH2O, EtOH; c) AcOH, EtOH, aromatic aldehyde.
N
N
N
N
a)
b)
N
N
H
Br
Br
Br
O
O
NH
Br
OEt
Br
Br
NH
2
2
3
4
c)
N
N
Br
O
NH
Br
N
5a-k
Ar
H5C2O
..
NH+2
Cl-
R
NH2
H3C
O
R
NH2
NH2+CI-
Br
NH2
Br
NH2
OC2H5
..
N
OC2H5
N
R
Cl-
H3N+
H
-NH4Cl
R
N
..
Br
NH2
Br
NH2
N
R
-C2H5OH
N+
R
Br
N
H
H
Br
H
-
..
..
OC H
:
2
5
R: CH2
Br
Figure 2. Proposed mechanism for synthesis of compound 2.
Journal of Heterocyclic Chemistry
DOI DOI 10.1002/jhet

July 2014
Synthesis of Benzimidazole Derivatives Containing Imine Function
985
Scheme 3. E/Z geometrical isomer and cis/trans amid conformer of
compound 5a–k.
Synthesis of 5(6)-bromo-2-(4-bromobenzyl)-1H-benzimi-
dazole (2)
Conventional method.
To a well stirred solution of 4-
O
O
bromo-o-phenylenediamine (0.01 mol) in methanol (25 mL),
compound 1 (0.012 mol) was added and stirred at room
temperature overnight. After the reaction was completed
(monitored by TLC, ethyl acetate : hexane 3:1), the product was
precipitated by the addition of water, and it was filtrated, dried,
and recrystallized by ethanol–water (1:1) or acetone–water (1:1).
Microwave method. 4-Bromo-o-phenylenediamine (0.01 mol)
and compound 1 (0.012 mol) in methanol (10 mL) were taken in a
closed vessel. Then, it was irritated in microwave at 60ꢃC for
10min (hold time) at 300 W maximum power. After the reaction
was completed (monitored as stated above), the mixture was
cooled to room temperature and taken in a beaker. The product
was precipitated by the addition of water, and the purification
methods mentioned above were applied.
Yield: 67 (for conventional method) and 78% (for microwave
method); mp 176ꢃC; IR (KBr): 1620 (C═N), 3057 (Ar-CH),
3159 (N-H) cmꢀ1; 1H-NMR (DMSO-d6, 200MHz): d 4.16 (2H, s,
CH2), 7.69–7.25 (7H, m, Ar-H), 12.51 (1H, br, N-H); 13C-NMR
(DMSO-d6, 50 MHz): 34.83, 114.39, 120.38, 124.98, 131.78,
132.06, 132.28, 137.28, 155.22; MS: m/z 369/367/365 (M + H).
Anal. Calcd for C14H10Br2N2: C, 45.94; H, 2.75; N, 7.65. Found:
C, 45.97; H, 2.74; N, 7.66.
N
R2
H
N
R1
N
R1
N
H
H
H
R2
trans, E
trans, Z
O
H
O
H
N
H
N
R2
H
R1
N
R1
N
R2
cis, E
cis, Z
EXPERIMENTAL
All the chemicals were supplied from Merck (Darmstadt,
Germany), Aldrich, and Fluka (Buchs SG, Switzerland). Melting
points were determined on capillary tubes on a Büchi oil heated melt-
ing point apparatus (Essen,Germany) and uncorrected. 1H-NMR and
13C-NMR spectra were performed on Varian-Mercury 200 and
400 MHz spectrophotometer (Varian, Darmstadt, Germany) in
DMSO-d6 using TMS as internal standard. The IR spectra were
Synthesis of ethyl [5(6)-bromo-2-4(bromobenzyl)-1H-
benzimidazole-1-yl]acetate (3)
Conventional method.
To a solution of compound 2
(0.01 mol) in acetone (30 mL), dry K2CO3 (0.25 mol) was added
and stirred for 20–25 min. Then, ethyl bromoacetate
(0.012 mol) was added to a solution and stirred overnight.
After the reaction was completed (monitored by TLC, ethyl
acetate : hexane 3:1), the product was precipitated by the
addition of water and was filtrated, dried, and recrystallized
by ethanol to afford the desired product.
Microwave method. A solution of compound 2 (0.01 mol) in
acetone (10 mL) was taken in a closed vessel, and dry K2CO3
(0.025 mol) was added. The mixture was irritated in microwave at
90ꢃC for 5 min (hold time) with pressure control. Then, the mixture
was cooled to room temperature, and ethyl bromoacetate
(0.012 mol) was added. Again, it was irritated in microwave at
90ꢃC for 10 min (hold time) at 300 W maximum power. After the
reaction was completed (monitored as stated above), the mixture
was cooled and taken in a beaker, and the product was precipitated
by addition of water. The purification methods mentioned above
were applied to yield the pure product.
recorded on
a Perkin-Elmer 100 FTIR spectrophotometer
(California,USA) as KBr pellets. The elemental compositions were
determined on a Carlo Erba 1106 CHN analyzer (Heraeus, Hanau,
Germany); the experimental values were in agreement (ꢂ0.4%) with
the calculated ones. Mass spectra were recorded on Thermo Scientific
Quantum Access max LC/MS spectrophotometer (Thermo-scientific,
Florida, USA). A monomode CEM Discover microwave (Linfort,
Germany) was used to carry out microwave reactions in 30 mL
microwave process vials with temperature control by infrared detec-
tion temperature sensor. All reactions were monitored by TLC using
precoated aluminum sheets (silica gel 60F 2.54, 0.2 mm thickness).
Yield: 95 (for conventional method) and 98% (for microwave
method); mp 194–195ꢃC; IR (KBr): 1217 (C-O), 1609 (C═N), 1734
(C═O), 2979 (C-H) cmꢀ1; 1H-NMR (DMSO-d6, 200 MHz): d 1.07
(3H, t, CH3, J= 7.2), 3.97 (2H, q, OCH2, J= 7.2), 4.22 (2H, s, CH2),
5.19 (2H, s, N-CH2), 7.79–7.19 (7H, m, Ar-H); 13C-NMR (DMSO-
d6, 50 MHz): 15.60, 35.74, 47.12, 60.33, 112.78, 114.23, 120.43,
123.67, 130.89, 131.17, 134.12, 137.32, 145.90, 157.69, 170.45;
MS: m/z 455/453/451 (M + H). Anal. Calcd for C18H16Br2N2O2: C,
47.82; H, 3.57; N, 6.20. Found: C, 47.80; H, 3.55; N, 6.24.
Synthesis of 2-[5(6)-bromo-2(4-bromobenzyl)-1H-benzimidazol-
1-yl]acetohydrazide (4)
Conventional method.
To a solution of compound 3
(0.01 mol) in dry ethanol (25 mL), hydrazine monohydrate
(0.025 mol) was added, and it was refluxed for 6 h (monitored
by TLC, ethyl acetate : hexane 3:1). After cooling the mixture
to room temperature, a white solid appeared. This crude
Figure 3. 1H-NMR spectrum of compound 5a.
Journal of Heterocyclic Chemistry
DOI DOI 10.1002/jhet

986
B. Kahveci, F. Yılmaz, E. Menteşe, M. Özil, and Ş. A. Karaoğlu
Vol 51
product was filtrated, dried, and recrystallized from ethanol to
yield the pure product.
7.18–7.82 (11H, m, Ar-H), 7.98 and 8.02 (1H, s, N═CH, E/Z
geometrical isomer, E/Z ratio 73/27), 11.71 (1H, br, N-H); 13C-
NMR (DMSO-d6, 50 MHz): 20.15, 35.95, 48.21, 112.10,
114.55, 118.31, 120.22, 124.07, 126.86, 129.16, 131.02,
133.56, 135.17, 138.54, 139.57, 141.11, 147.02, 154.94,
166.91; MS: m/z 543/541/539 (M + H). Anal. Calcd for
C24H20Br2N4O: C, 53.36; H, 3.73; N, 10.37. Found: C, 53.33;
H, 3.78; N, 10.34.
Microwave method. A solution of compound 3 (0.01 mol)
in dry ethanol (10 mL) and hydrazine monohydrate (0.025 mol)
were taken in a closed vessel. The mixture was irritated in
microwave at 130ꢃC for 10 min (hold time) at 300 W maximum
power. After the reaction was completed (monitored as stated
above), the mixture was cooled to room temperature and taken
in a beaker, and the white solid appeared. This crude product
was filtrated, and the purification methods mentioned above
were applied.
2-[5(6)-Bromo-2-(4-bromobenzyl)-1H-benzimidazol-1-yl]-N0-
[4-(florophenyl)[methylene]acetohydrazide (5c).
Yield: 64
(for conventional method) and 83% (for microwave method);
mp 260–261ꢃC; IR (KBr): 1614 (C═N), 1699 (C═O), 2945 (C-
Yield: 60 (for conventional method) and 80% (for microwave
H), 3011 (Ar-H), 3188 (N-H) cmꢀ1 1H-NMR (DMSO-d6,
;
method); mp 249–251ꢃC; IR (KBr): 1613 (C═N), 1659 (C═O),
3049 (Ar-CH), 3298 (NH, NH2) cmꢀ1 1H-NMR (DMSO-d6,
;
200 MHz): d 4.21 (2H, s, CH2), 5.50 and 5.02 (2H, s, N-CH2,
trans and cis amid conformer, cis/trans ratio 75/25), 7.22-7.80
(11H, m, Ar-H), 8.02 and 8.21 (1H, s, N═CH, E/Z geometrical
isomer, E/Z ratio 75/25), 11.83 (1H, br, N-H); 13C-NMR
(DMSO-d6, 50 MHz): 36.70, 48.93, 110.18, 112.50, 116.99,
120.95, 122.97, 126.96, 129.49, 132.42, 133.94, 134.99,
136.98, 141.05, 143.72, 146.74, 157.29, 168.81; MS: m/z 547/
545/543 (M + H). Anal. Calcd for C23H17Br2 FN4O: C, 50.76;
H, 3.15; N, 10.30. Found: C, 50.72; H, 3.17; N, 10.32.
200 MHz): d 4.21 (2H, s, CH2), 4.36 (2H, s, NH2), 4.82 (2H, s,
N-CH2), 7.72–7.23 (7H, m, Ar-H), 9.50 (1H, s, NH); 13C-NMR
(DMSO-d6, 50 MHz): 32.12, 44.58, 111.88, 119.66, 123.65,
126.52, 128.63, 130.06, 135.07, 138.85, 141.53, 156.26,
165.36; MS: m/z 441/439/437 (M + H). Anal. Calcd for
C16H14Br2N4O: C, 43.86; H, 3.22; N, 12.79. Found: C, 43.90;
H, 3.20; N, 12.77.
General synthetic procedure for 2-[5(6)-bromo-2-(4-
bromobenzyl)-1H-benzimidazol-1-yl]-N0-[phenylmethylene]
acetohydrazide (5a–k)
2-[5(6)-Bromo-2-(4-bromobenzyl)-1H-benzimidazol-1-yl]-N0-
[4-(chlorophenyl)methylene]acetohydrazide (5d).
Yield: 69
(for conventional method) and 80% (for microwave method);
Conventional method.
To a solution of compound 4
mp 255–256ꢃC; IR (KBr): 1590 (C═N), 1699 (C═O), 2951
(0.01 mol) in dry ethanol (20 mL) (containing 0.5 mL glacial
acetic acid), corresponding aromatic aldehyde (0.01 mol) was
added, and the mixture was refluxed for 4–6 h (monitored by
TLC, ethyl acetate: hexane 3:1). After cooling the mixture to
room temperature, a white solid appeared. This crude product was
filtrated and washed with ethanol to obtain the desired product.
(C-H), 3091 (Ar-H), 3207 (N-H) cmꢀ1 1H-NMR (DMSO-d6,
;
200 MHz): d 4.21 (2H, s, CH2), 5.52 and 5.03 (2H, s, N-CH2,
trans and cis amid conformer, cis/trans ratio 75/25), 7.19–7.82
(11H, m, Ar-H), 8.02 and 8.21 (1H, s, N═CH, E/Z geometrical
isomer, E/Z ratio 70/30), 11.82 (1H, br, N-H); 13C-NMR
(DMSO-d6, 100 MHz): 32.69, 45.01, 113.90, 114.78, 120.22,
120.62, 124.78, 129.34, 131.65, 131.73, 133.45, 134.96,
136.35, 137.92, 141.74, 143.24, 155.40 (2C), 168.46; MS: m/z
563/561/559 (M + H). Anal. Calcd for C23H17Br2 ClN4O: C,
49.27; H, 3.06; N, 9.99. Found: C, 49.23; H, 3.10; N, 9.97.
2-[5(6)-Bromo-2-(4-bromobenzyl)-1H-benzimidazol-1-yl]-N0-
[(2,3-dihydroxyphenyl)methylene]acetohydrazide (5e). Yield:
54 (for conventional method) and 75% (for microwave method);
mp 271–272ꢃC; IR (KBr): 1275, 1282 (C-O), 1610 (C═N),
1697 (C═O), 2963 (C-H), 3043 (Ar-H), 3154 (N-H), 3420 (O-
Microwave method. A solution of compound 4 (0.01 mol)
in dry ethanol (10 mL) (containing 0.25 mL glacial acetic acid)
and corresponding aromatic aldehyde (0.01 mol) were taken in a
closed vessel. The mixture was irritated in microwave at
120–130ꢃC for 5–10 min at 300 W maximum power. After the
reaction was complete (monitored as stated above), the mixture
was cooled to room temperature and taken in a beaker, and a
white solid appeared. This crude product was filtrated, and the
purification methods mentioned above were applied.
1
H) cmꢀ1; H-NMR (DMSO-d6, 200 MHz): d 4.21 (2H, s, CH2),
2-[5(6)-Bromo-2-(4-bromobenzyl)-1H-benzimidazol-1-yl]-N0-
[phenylmethylene]acetohydrazide (5a).
Yield: 61 (for
5.06 and 5.47 (2H, s, N-CH2, trans and cis amid conformer, cis/
trans ratio 75/25), 7.20–7.84 (10H, m, Ar-H), 8.23 and 8.33
(1H, s, N═CH, E/Z geometrical isomer, E/Z ratio 73/27), 9.20
(1H, s, OH), 9.65 (1H, s, OH), 11.70 (1H, br, N-H); 13C-NMR
(DMSO-d6, 50 MHz): 33.94, 44.82, 113.17, 114.02, 116.96,
120.29, 120.91, 124.06, 124.97, 125.71, 131.61, 132.76,
136.15, 141.77, 145.92, 146.18, 147.07, 149.95, 157.41,
158.01, 168.90; MS: m/z 561/559/557 (M + H). Anal. Calcd for
C23H18Br2N4O3: C, 49.49; H, 3.25; N, 10.04. Found: C, 49.52;
H, 3.26; N, 10.04.
conventional method) and 82% (for microwave method); mp
268–269ꢃC; IR (KBr): 1620 (C═N), 3057 (Ar-CH), 3159 (N-H)
cmꢀ1 1H-NMR (DMSO-d6, 400 MHz): d 4.20 (2H, s, CH2),
;
5.02 and 5.49 (2H, s, N-CH2, trans and cis amid conformer, cis/
trans ratio 78/22), 7.20–7.80 (12H, m, Ar-H), 8.22 and 8.02
(1H, s, N═CH, E/Z geometrical isomer, E/Z ratio 70/30), 11.72
(1H, br, N-H); 13C-NMR (DMSO-d6, 100 MHz): 32.95, 45.21,
114.11, 114.98, 120.43, 120.84, 124.99, 127.86, 129.46,
130.72, 131.86, 134.70, 136.55, 138.15, 141.96, 144.80,
155.58, 168.56; MS: m/z 529/527/525 (M + H). Anal. Calcd for
C23H18Br2N4O: C, 52.50; H, 3.45; N, 10.65. Found: C, 52.53;
H, 3.47; N, 10.61 (Table 1).
2-[5(6)-Bromo-2-(4-bromobenzyl)-1H-benzimidazol-1-yl]-N0-
[(3, 4-dihydroxyphenyl)methylene]acetohydrazide (5f). Yield:
63 (for conventional method) and 80% (for microwave method);
mp 289–290ꢃC; IR (KBr): 1281 (C-O), 1621 (C═N), 1678
(C═O), 2932 (C-H), 3062 (Ar-H), 3164 (N-H), 3535 (O-H)
2-[5(6)-Bromo-2-(4-bromobenzyl)-1H-benzimidazol-1-yl]-N0-
[4-(methylphenyl)[methylene]acetohydrazide (5b).
Yield: 54
(for conventional method) and 79% (for microwave method);
cmꢀ1 1H-NMR (DMSO-d6, 200 MHz): d 4.19 (2H, s, CH2),
;
mp 271–272ꢃC; IR (KBr): 1610 (C═N), 1699 (C═O), 3021
5.00 and 5.47 (2H, s, N-CH2, trans and cis amid conformer, cis/
trans ratio 75/25), 6.46–7.85 (10H, m, Ar-H), 7.85 and 8.00
(1H, s, N═CH, E/Z geometrical isomer, E/Z ratio 71/29), 9.20
(1H, s, OH), 9.53 (1H, s, OH), 11.54 (1H, br, N-H); 13C-NMR
(Ar-H), 3193 (N-H) cmꢀ1 1H-NMR (DMSO-d6, 200 MHz):
;
d 2.34 (3H, s, CH3), 4.20 (2H, s, CH2), 5.02 and 5.48 (2H, s,
N-CH2, trans and cis amid conformer, cis/trans ratio 75/25),
Journal of Heterocyclic Chemistry
DOI DOI 10.1002/jhet

July 2014
Synthesis of Benzimidazole Derivatives Containing Imine Function
987
Table 1
Reaction conditions of compound 5a–k.
5a-k
Thermal
Microwave irradiation
Product
Ar
Time (h)
5
Yield (%)
61
Temperature (ꢃC)
120
Time (min)
10
Yield (%)
82
5a
5b
5.5
54
125
8
79
5c
5d
5e
4.5
4.5
4
64
69
54
125
130
120
7
5
7
83
80
75
5f
4.5
63
120
8
80
5g
5h
5.5
6
61
53
130
130
6
8
80
78
(Continued)
Journal of Heterocyclic Chemistry
DOI DOI 10.1002/jhet

988
B. Kahveci, F. Yılmaz, E. Menteşe, M. Özil, and Ş. A. Karaoğlu
Vol 51
Table 1
(Continued)
Product
Ar
Time (h)
6
Yield (%)
65
Temperature (ꢃC)
130
Time (min)
9
Yield (%)
5i
78
5j
6
5
57
62
130
125
7
68
73
5k
10
(DMSO-d6, 50 MHz): 31.92, 45.59, 111.79, 115.94, 121.29,
124.16, 125.97, 127.91, 130.69, 132.75, 139.92, 142.01,
143.93, 145.27, 148.36, 150.49, 154.41, 156.17, 167.83; MS:
m/z 561/559/557 (M + H). Anal. Calcd for C23H18Br2N4O3:
C, 49.49; H, 3.25; N, 10.04. Found: C, 49.53; H, 3.27; N,
10.01.
2-[5(6)-Bromo-2-(4-bromobenzyl)-1H-benzimidazol-1-yl]-N0-
[(3-bromophenyl)methylene]acetohydrazide (5i). Yield: 65
(for conventional method) and 78% (for microwave method); mp
264–265ꢃC; IR (KBr): 1590, 1601 (C═N), 1702 (C═O), 2957
(C-H), 3015 (Ar-H), 3202 (N-H) cmꢀ1 1H-NMR (DMSO-d6,
;
200 MHz): d 4.22 (2H, s, CH2), 5.05 and 5.55 (2H, s, N-CH2,
trans and cis amid conformer, cis/trans ratio 79/21), 7.21–8.01
(11H, m, Ar-H), 8.06 and 8.15 (1H, s, N═CH, E/Z geometrical
isomer, E/Z ratio 79/21), 11.85 (1H, br, N-H); 13C-NMR (DMSO-
d6, 50MHz): 30.11, 48.81, 110.32, 111.14, 123.49, 124.19,
126.90, 127.15, 130.12, 132.91, 139.42, 142.90, 143.13, 149.27,
150.30, 150.71, 156.21, 156.74, 169.13; MS: m/z 603/605/607/
609 (M+ H). Anal. Calcd for C23H17Br3N4O: C, 45.65; H, 2.83;
N, 9.26. Found: C, 45.62; H, 2.81; N, 9.29.
2-[5(6)-Bromo-2-(4-bromobenzyl)-1H-benzimidazol-1-yl]-N0-
{[4-(dimetilamino)phenyl]methylene}acetohydrazide (5g). Yield:
61 (for conventional method) and 80% (for microwave
method); mp 289–290ꢃC; IR (KBr): 1551, 1603 (C═N), 1677
(C═O), 2904 (C-H), 3052 (Ar-H), 3178 (N-H); 1H-NMR
(DMSO-d6, 200 MHz): d 2.97 (6H, s, 2ꢄN-CH3), 4.20 (2H, s,
CH2), 4.99 and 5.44 (2H, s, N-CH2, trans and cis amid
conformer, cis/trans ratio 75/25), 6.74–7.56 (11H, m, Ar-H),
8.44 and 8.51 (1H, s, N═CH, E/Z geometrical isomer, E/Z ratio
70/30), 11.89 (1H, br, N-H); 13C-NMR (DMSO-d6, 50 MHz):
34.70, 39.57, 49.23, 110.98, 111.59, 117.59, 121.45, 122.91,
125.96, 132.13, 133.54, 136.91, 141.92, 143.42, 146.75,
157.29 (2C), 168.11; MS: m/z 572/570/568 (M + H). Anal.
Calcd for C25H23Br2N5O: C, 52.74; H, 4.07; N, 12.30.
Found: C, 52.71; H, 4.09; N, 12.32.
2-[5(6)-Bromo-2-(4-bromobenzyl)-1H-benzimidazol-1-yl]-N0-
[(2-hydroxy-5-bromophenyl)methylene]acetohydrazide (5j). Yield:
57 (for conventional method) and 68% (for microwave
method); mp 255–256; IR (KBr): 1275 (C-O), 1615 (C═N),
1695 (C═O), 2989 (C-H), 3031 (Ar-H), 3154 (N-H), 3480
(O-H) cmꢀ1 1H-NMR (DMSO-d6, 200 MHz): d 4.23 (2H, s,
;
CH2), 5.06 and 5.54 (2H, s, N-CH2, trans and cis amid
conformer, cis/trans ratio 69/31), 6.87–7.96 (10H, m, Ar-H),
8.28 and 8.33 (1H, s, N═CH, E/Z geometrical isomer, E/Z
ratio 73/27), 10.44 (1H, s, OH), 11.78 (1H, br, N-H); 13C-
NMR (DMSO-d6, 50 MHz): 35.12, 49.51, 109.12, 112.74,
125.94, 128.18, 129.90, 130.52, 131.19, 133.71, 137.69,
142.71, 145.86, 145.97, 150.13, 152.42, 157.01, 157.93,
170.11; MS m/z 620/622/624/626 (M + H). Anal. Calcd for
C23H17Br3N4O2: C, 44.48; H, 2.76; N, 9.02. Found: C,
44.46; H, 2.78; N, 9.05.
2-[5(6)-Bromo-2-(4-bromobenzyl)-1H-benzimidazol-1-yl]-N0-
[(3,4-dimethoxyphenyl)methylene]acetohydrazide (5h).
Yield:
53 (for conventional method) and 78% (for microwave method);
mp 285–286ꢃC; IR (KBr): 1238, 1269 (C-O), 1576, 1601 (C═N),
1
1690 (C═O), 2991 (C-H), 3003 (Ar-H), 3203 (N-H) cmꢀ1; H-
NMR (DMSO-d6, 200 MHz): d 3.82 (6H, br, 2ꢄOCH3), 4.36
(2H, s, CH2), 5.23 and 5.95 (2H, s, N-CH2, trans and cis amid
conformer, cis/trans ratio 75/25), 6.46–7.85 (10H, m, Ar-H), 7.90
and 8.10 (1H, s, N═CH, E/Z geometrical isomer, E/Z ratio
73/27), 9.20 (1H, s, OH), 9.53 (1H, s, OH), 11.54 (1H, br, N-H);
13C-NMR (DMSO-d6, 100 MHz): 29.23, 47.84, 55.94, 56.10,
112.02, 116.22, 117.27, 119.62, 121.49, 122.50, 126.99, 127.05,
130.08, 131.70, 131.94, 131.99, 133.40, 145.20, 145.37, 149.48,
151.30, 154.33, 166.02; MS: m/z 589/587/586 (M + H). Anal.
Calcd for C25H22Br2N4O3: C, 51.22; H, 3.78; N, 9.56. Found: C,
51.26; H, 3.81; N, 9.57.
2-[5(6)-Bromo-2-(4-bromobenzyl)-1H-benzimidazol-1-yl]-N0-
[(3-bromo-4-florophenyl)methylene]acetohydrazide (5k). Yield:
62 (for conventional method) and 73% (for microwave method);
mp 235–236ꢃC; IR (KBr): 1597, 1610 (C═N), 1792 (C═O), 2925
(C-H), 3062 (Ar-H), 3202 (N-H) cmꢀ1 1H-NMR (DMSO-d6,
;
200 MHz): d 4.20 (2H, s, CH2), 5.05 and 5.53 (2H, s, N-CH2,
trans and cis amid conformer, cis/trans ratio 73/27), 7.20–7.81
Journal of Heterocyclic Chemistry
DOI DOI 10.1002/jhet

July 2014
Synthesis of Benzimidazole Derivatives Containing Imine Function
989
Table 2
Antimicrobial activity of the compounds (mg/mL).
Microorganisms and minimal inhibition concentration
Comp. no.
Ec
Yp
Pa
Sa
Ef
Bc
Ms
Ca
Sc
2
3
4
5a
5b
5c
5d
5e
—
—
—
—
—
—
—
—
—
—
—
—
—
—
2
—
—
—
—
—
—
—
—
—
—
—
—
—
—
32
—
—
—
—
—
—
—
—
—
—
—
—
—
—
>128
31.3
—
—
—
—
—
—
250
—
—
—
—
—
—
2
31.3
—
—
—
—
—
—
500
—
—
—
—
—
—
2
31.3
—
—
—
—
—
—
250
—
—
31.3
125
250
—
—
—
—
—
—
—
62.5
500
500
—
—
>500
—
—
—
—
—
31.3
250
250
—
—
500
—
—
—
—
—
5f
5g
5h
5i
—
—
—
—
125
—
—
—
—
—
—
—
—
5j
5k
Amp.
Strep.
Flu.
—
<1
4
<8
<8
Ec, E. coli ATCC 25922; Yp, Y. pseudotuberculosis ATCC 911; Pa, P. aeruginosa ATCC 43288; Sa, S. aureus ATCC 25923; Ef, E. faecalis ATCC
29212; Bc, B. cereus 702 Roma; Ms, M. smegmatis ATCC607; Ca, C. albicans ATCC 60193; Sc, S. cerevisiae RSKK 251; Amp., ampicillin; Strep.,
Streptomycin; Flu., Fluconazole; —, no activity.
(10H, m, Ar-H), 8.00 and 8.20 (1H, s, N═CH, E/Z geometrical
isomer, E/Z ratio 75/25), 11.86 (1H, br, N-H); 13C-NMR (DMSO-
d6, 50 MHz): 32.73, 47.32, 111.13, 113.98, 126.44, 128.28,
129.41, 129.55, 129.78, 131.39, 132.39, 133.66, 139.10, 142.17,
147.45, 149.90, 151.03, 153.98, 157.01, 158.27, 168.14; MS:
m/z 621/623/625/627 (M + H). Anal. Calcd for C23H16
Br3FN4O: C, 44.33; H, 2.59; N, 8.99. Found: C, 44.29; H,
2.60; N, 9.03.
Acknowledgement. This work was supported by the Scientific
and Technological Research Council of Turkey (TUBITAK,
project no: 108T356)
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Journal of Heterocyclic Chemistry
DOI DOI 10.1002/jhet

990
B. Kahveci, F. Yılmaz, E. Menteşe, M. Özil, and Ş. A. Karaoğlu
Vol 51
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Journal of Heterocyclic Chemistry
DOI DOI 10.1002/jhet