Synthesis, Characterization, and Antibacterial Activity of Some Novel Substituted Imidazole Derivatives via One-pot Three-Component

Article abstract of DOI:10.1002/jhet.2261

A simple and highly efficient one-pot, three-component synthesis of novel substituted imidazole derivatives has been reported by the reaction of 3-(2-bromoacetyl)-2H-chromen-2-one, ammonium thiocyanate, and phenacyl aniline in the presence of acetic acid

Full text of DOI:10.1002/jhet.2261

Month 2014
Synthesis, Characterization, and Antibacterial Activity of Some Novel
Substituted Imidazole Derivatives via One-pot Three-Component
Raj Kumar Ramagiri, Murali Krishna Thupurani, and Rajeswar Rao Vedula *
a
b
a
a
Department of Chemistry, National Institute of Technology, Warangal, Andhra Pradesh 506004, India
b
Department of Biotechnology, Chaitanya Postgraduate College (Autonomous), Hanamkonda, Andhra Pradesh 206001, India
*
E-mail: rajeswarnitw@gmail.com
Received January 20, 2014
DOI 10.1002/jhet.2261
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A simple and highly efficient one-pot, three-component synthesis of novel substituted imidazole
derivatives has been reported by the reaction of 3-(2-bromoacetyl)-2H-chromen-2-one, ammonium
thiocyanate, and phenacyl aniline in the presence of acetic acid as a solvent under reflux condition with
good yields. The structures of newly synthesized compounds were characterized by their analytical and
spectral data. One of these compounds 4a showed good antibacterial activity against Escherichia coli
gram-negative strains.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
RESULTS AND DISCUSSIONS
Imidazole ring has been of great interest for organic
chemists because of their useful biological and pharmaco-
logical aspects and plays an important role in biochemical
processes [1]. Many of them show antitumor [2],
antibacterial [3], anti-inflammatory agents, fungicides,
herbicides [4], and plant growth regulators [5]. They act
as inhibitors of p38 MAP kinase[6], B-Raf kinase [7],
transforming growth factor b1 type 1 active in receptor-like
kinase [8], cyclooxygenase-2 [9], and biosynthesis of
interleukin-1 [10], and also substituted imidazoles are
extensively used as glucagon receptors [11] and CB1
cannabinoid receptor antagonists [12], modulators of
P-glycoprotein-mediated multi drug resistance [13].
Imidazoles as ionic liquid and imidazole related N-
heterocyclic carbenes are well-known green solvents.
On the other hand, coumarin and its derivatives are bio-
logically active such as antibacterial [14,15], antifungal
In this work, a new series of compounds were synthe-
sized. Scheme 1 illustrates the synthetic pathway used for
the preparation of target compounds. For this reaction,
we first synthesized monophenacyl aniline 3 from the
easily available starting materials, such as aryl amines 7
and phenacyl bromides 6 as shown in Scheme 2. The
one-pot three-component reaction of 3-(2-bromoacetyl)-
2H-chromen-2-one 1 with ammonium thiocyanate 2 and
phenacyl anilines 3 proceeded smoothly in acetic acid
solvent and without any catalyst to give the corresponding
imidazole derivatives in good yields. In the formation of
products, it is believed that the ammonium thiocyanate first
reacts with phenacyl anilines to give mercapto imidazole a
cyclized intermediate, and further, this intermediate reacts
with 3-(2-bromoacetyl)-2H-chromen-2-one to give imidaz-
ole derivatives having coumarin moiety by HBr elimina-
tions in one pot. The structures of newly synthesized
compounds were confirmed by their analytical and spectral
[
16,17], herbicidal [18], antitumoral [19], cytotoxic [20],
1
anti-HIVagents [21,22], and also anti-inflammatory
activity [23]. Because of the various biological activities
of coumarins and imidazoles, we became interested in
synthesizing the title compounds.
As a part of our ongoing efforts toward the development
of new procedure for the highly substituted heterocyclic
systems [24–26] through one-pot three-components, we
have found an efficient and environment-friendly
procedure for the synthesis of imidazole ring substituted
with coumarin.
data. The H NMR spectrum of 4a in DMSO showed
methylene protons as singlet at 4.62, imidazole proton as
singlet at 8.09, and C proton of coumarin 8.68 δ ppm. In
4
13
the C NMR spectrum of 4a, the methylene carbon
appeared at 43.6, and two carbonyl carbons resonate at
158.3 and 191.1 δ ppm, respectively. The mass spectrum
+
of 4a exhibited the [M + H] peak at m/z 507.
All the synthesized compounds were tested for their
antibacterial activity against Bacillus subtilis, Bacillus
cereus, Proteus vulgaris, Escherichia coli, Staphylococcus
©
2014 HeteroCorporation

R. K. Ramagiri, M. K. Thupurani, and R. R. Vedula
Vol 000
Scheme 1. One-pot three-component synthesis of imidazoles derivatives.
Scheme 2. Synthesis of phenacylaniline.
aureus, and Pseudomonas aeruginosa. The result revealed
that all compounds possess antibacterial activity (Table 1
and Fig. 1). Among the compounds tested, 4a 3-(2-(1,4-bis
possess chlorine atoms substituted to aromatic ring;
however, these compounds exhibited minimum biological
activity. By the literature survey, it has been confirmed that
the number of chlorine atoms and their positions are the
major factor that influence their biological activity.
(4-chlorophenyl)-1H-imidazol-2-ylthio)acetyl)-2H-chromen-
2-one noticed significant antibacterial activity compared with
other compounds. Whereas 4c had also exhibited good
antibacterial activity on all listed microbial stains. The results
were showed in inhibition zone diameter (millimeters). The
highest inhibition zone (11) was noticed against Escherichia
coli by compound 4a. Compound 4a exhibited immense po-
tency against gram-negative strains rather than gram-positive
strains (Fig. 2). This might be because of structural and
composition variation of cell wall of both strains. However,
compound 4j had showed least activity.
Among the test organisms, Bacillus cereus, Bacillus
subtilis, Staphylococcus aureus, and Pseudomonas
aeruginosa exhibited resistance toward the compound 4j,
and remaining species showed least susceptibility. This
might be because of high resistance of the organisms.
The descending order of antibacterial activity of the
compounds listed is as follows:
4
a > 4c > 4d > 4e > 4b > 4f > 4h > 4i > 4g > 4j
The literature review on biological activity of newly syn-
thesized compounds revealed that carbon–chlorine (C–Cl)
bonds influence the biological activity. Based on our studies,
it has been understood that the highest activity of compound
CONCLUSIONS
In summary, we have developed an efficient, one-pot
three-component reaction for the synthesis of some novel
substituted imidazole derivatives in good yields. The
4
a might be because of two chlorine atoms substituted to
aromatic ring at para positions. Other derivatives also
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis, Characterization, and Antibacterial Activity of Some Novel Substituted
Imidazole Derivatives via One-pot Three-Component
Table 1
Antibacterial activity of compounds 4a–j.
Zone of inhibition (mm)
Gram-positive
Gram-negative
Staphylococcus
aureus
Pseudomonas
aeruginosa
Compound
Bacillus subtilis
Bacillus cereus
Proteus vulgaris
Escherichia coli
4
4
4
4
4
4
4
4
4
4
a*
b*
c*
d*
e*
f*
g*
h*
i*
09
04
07
05
06
02
—
03
04
—
14
10
05
05
02
04
04
—
02
02
—
16
07
03
08
04
05
—
02
04
—
02
14
11
04
07
06
04
04
05
04
05
04
13
09
03
06
03
02
05
—
02
03
—
15
08
—
05
02
—
—
—
02
—
—
12
j*
≠
Gentamycin sulfate
*
Concentration of the test compounds (4a–4j) is 100 μg.
≠
Concentration of the standard gentamycin sulfate is 10 μg.
antibacterial activities of the synthesized compounds were
evaluated. Among these compounds, 4a and 4c showed
good antibacterial activity and emerged as potential
molecules for further development.
EXPERIMENTAL
All the reagents and solvents were pure and purchased from
commercial sources and were used without further purification
unless otherwise stated. 3-(2-Bromoacetyl)-2H-chromen-2-ones
were prepared by the literature procedure [27]. Melting points
were determined in open capillaries with a “Cintex” melting point
apparatus (Mumbai, India) and were uncorrected. CHN analysis
was carried out by Carlo Erba EA 1108 automatic elemental
analyzer. The purity of the compounds was checked by TLC
plates (E. Merck Mumbai, India) with chloroform as eluent, and
the spots were viewed in UV or iodine chamber. IR spectra were
recorded on a thermo Nicolet Nexus 670 Q8 instrument (KBr
Figure 1. Percentage of microbial growth inhibition by compound 4a.
[Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
1
pellets). H NMR spectra were recorded on a Bruker WM-400
spectrometer in δ ppm using TMS as the standard. EI-MS were
determined on a Perkin Elmer spectrometer (SCIEX API-2000,
ESI) at 12.5 eV.
General procedure for 4a–j.
To a stirred solution of
monophenacyl anilines 3(0.001mol) and an excess of ammonium
thiocyanate 2(1.14 g, 0.015mol) in acetic acid (10 mL) was added
3
-(2-bromoacetyl)-2H-chromen-2-one 1(0.001 mol) then refluxed
for 10 h. After completion of the reaction, the reaction mixture
was cooled; the solid separated was filtered and recrystallized
from ethanol.
3-(2-(1,4-Bis(4-chlorophenyl)-1H-imidazol-2-ylthio)acetyl)-2H-
chromen-2-one (4a).
value: 0.75; yield: 92%; IR (KBr) cm : 1752 (ketone C═O), 1727
Color: light yellow; mp: 283–285°C; Rf
À1
1
(lactone C═O), 1636 (C═N), 1564 (C═C); H NMR (400 MHz,
Figure 2. Zone of inhibition noticed against Escherichia coli by
compound 4a. [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
DMSO-d ): δ 4.62 (2H, s, methylene), 7.33 (2H, d, J=8.4Hz,
ArH), 7.43–7.59 (6H, m, ArH), 7.71 (2H, d, J= 8.4 Hz, ArH),
7.76–7.81 (1H, m, ArH), 7.95–7.98 (1H, m, ArH), 8.09 (1H, s,
6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. K. Ramagiri, M. K. Thupurani, and R. R. Vedula
Vol 000
13
imidazole), 8.68 (1H, s, C-4 of coumarin) ppm; C NMR (DMSO-
124.6,125.1, 127.5, 127.7, 128.7, 129.4, 130.9, 133.7, 134.7,
d6): δ 43.26, 116.14, 118.03, 119.94, 123.16, 125.91, 127.17,
134.9, 139, 140.6, 148.4, 154.5, 158.3 ppm. Anal. Calcd for
1
28.47, 129.37, 130.85, 131.85, 133.17, 134.81, 135.15, 139.81,
26 3 5
C H16ClN O S: C, 60.29; H, 3.11; N, 8.11%. Found: C, 60.21;
H, 3.18; N, 8.19%.
+
140.77, 148.11, 154.54, 158.36; ESI-MS m/z(%):507 [M + H] .
Anal. Calcd for C26
Found: C, 61.59; H, 3.24; N, 5.58%.
-(2-(1-(4-Chlorophenyl)-4-phenyl-1H-imidazol-2-ylthio)acetyl)-
H-chromen-2-one (4b). Color: yellow; mp: 188–190°C; R
value: 0.74; yield: 87%; IR (KBr) cm : 1712 (lactone C═O),
H
16Cl
2
N
2
O
3
S: C, 61.55; H, 3.18; N, 5.52%.
3-(2-(4-(4-Bromophenyl)-1-(4-chlorophenyl)-1H-imidazol-2-
ylthio)acetyl)-2H-benzo[h]chromen-2-one (4g).
Color: light
3
yellow; mp: 280–282°C; R value: 0.73 yield: 88%, IR (KBr)
f
À1
2
f
cm :1736 (lactone C═O), 1691 (ketone C═O), 1625 (C═N),
1599 (C═C); H NMR (400 MHz, DMSO-d
À1
1
6
): δ 4.65 (2H, s,
1
1
638 (ketone C═O), 1605 (C═N), 1557 (C═C); H NMR
methylene), 7.17–7.25 (5H, m, ArH), 7.48–7.57 (6H, m, ArH),
7.64–7.71 (1H, m, ArH), 7.76–7.80 (1H, m, ArH), 8.06–8.37
(2H, m, ArH, imidazol), 8.39 (1H, s, C-4 of coumarin)
(
(
400MHz, DMSO-d ): δ 4.61 (2H, s, methylene), 7.19–7.27
3H, m, ArH), 7.45–7.58 (6H, m, ArH), 7.69–7.78 (2H, m, ArH),
6
13
7
.95–7.7.98 (2H, m, ArH), 8.02 (1H, s, imidazole), 8.69 (1H, s,
6
ppm, C NMR (DMSO-d ): δ 30.7, 35.7, 95, 111.9, 116.2,
13
C-4 of coumarin) ppm; C NMR (DMSO-d
6
): δ 44.1, 116.6,
18.5, 120.5, 125.5, 126.8, 127.2, 127.8, 129.8, 131.4, 135.3,
39.4, 139.9, 141.1, 148.8, 155, 158.8, 191. Anal. Calcd for
17ClN S: C, 66.03; H, 3.62; N, 5.92%. Found: C, 66.18;
H, 3.72; N, 5.83%.
-(2-(1-(4-Chlorophenyl)-4-(4-methoxyphenyl)-1H-imidazol-
121.8, 126.4, 128.6, 128.8, 129, 129.8, 130.2, 134.5, 138.7,
1
1
C
153.4, 158.3, 162.2 ppm. Anal. Cacld for C H BrClN O S:
30
18
2 3
C, 59.86; H, 3.01; N, 4.65%. Found: C, 59.81; H, 3.14; N, 4.61%.
26
H
2
O
3
3-(2-(4-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1H-imidazol-
2-ylthio)acetyl)-6,8-dibromo-2H-chromen-2-one (4h).
Color:
3
orange yellow; mp: 238–240°C; R
f
value: 0.65; yield: 90%; IR
À1
2
-ylthio)acetyl)-2H-chromen-2-one (4c). Color: light yellow;
(KBr) cm : 1720 (lactone C═O), 1683 (ketone C═O), 1605
À1
1
mp: 203–205°C; R value: 0.66; yield: 88%; IR (KBr) cm : 1727
(C═N), 1554 (C═C); H NMR (400MHz, DMSO-d ): δ 3.75
f
6
(
lactone C═O), 1715 (ketone C═O), 1607 (C═N), 1558 (C═C);
(3H, s, methoxy), 4.55 (2H, s, methylene), 7.03 (2H, d, J = 8.8 Hz,
ArH), 7.40 (2H, d, J = 8.8 Hz, ArH), 7.48 (2H, d, J = 8.8 Hz,
ArH), 7.64 (2H, d, J = 8.8 Hz, ArH), 8.05 (1H, s, imidazol), 8.22
(1H, d, J = 2 Hz ArH), 8.29 (1H, s, J = 1.6 Hz ArH), 8.56 (1H, s,
C-4 of coumarin) ppm. Anal. Calcd for C H Br ClN O S:
C, 49.08; H, 2.59; N, 4.24%. Found: C, 49.15; H, 2.64; N, 4.29%.
3-(2-(4-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-imidazol-
2-ylthio)acetyl)-6-chloro-2H-chromen-2-one (4i). Color: light
1
H NMR (400 MHz, DMSO-d
.61 (2H, s, methylene), 6.85 (2H, d, J = 8 Hz, ArH), 7.46–7.63
8H, m, ArH), 7.71–7.96 (1H, m, ArH), 7.96–7.98 (2H, m,
6
): δ 3.74 (3H, s, methoxy),
4
(
13
ArH, imidazol), 8.68 (1H, s, C-4 of coumarin) ppm; C NMR
DMSO-d ): δ 43.1, 56.1, 116.7, 118.5, 119.7, 120, 121.6,
23.2, 125, 126.2, 127.1, 129.3, 131.3, 132, 133.2, 135, 139.6,
27
17
2
2 4
(
6
1
1
5
3
40.6, 143.8, 146.2, 148.2, 158, 191.2 ppm; ESI-MS: m/z (%);
+
03 [M + H] . Anal. Calcd for C H ClN O S: C, 64.47; H,
yellow; mp: 253–255°C; R value: 0.68; yield: 91%; IR (KBr)
2
7
19
2
4
f
À1
.81; N, 5.57%. Found: C, 64.4; H, 3.88; N, 5.51%.
-(2-(4-(4-Bromophenyl)-1-(4-chlorophenyl)-1H-imidazol-2-
cm : 1717 (lactone C═O), 1687 (Ketone C═O), 1620 (C═N),
1558 (C═C); H NMR (400 MHz, DMSO-d
1
3
6
): δ 3.73 (3H, s,
ylthio)acetyl)-2H-chromen-2-one (4d).
Color: light yellow;
methoxy), 4.58 (2H, s, methylene), 7.03 (2H,t, J = 8.8 Hz, ArH),
7.41–7.53 (5H, m, ArH), 7.65–7.68 (2H, m, ArH),7.79–7.82 (3H,
m, ArH), 8.08–8.09 (3H, m, ArH, imidazole), 8.60 (1H, s, C-4
À1
mp: 232–234°C; R value: 0.74; yield: 89%; IR (KBr) cm
:
f
1
733 (lactone C═O), 1671 (ketone C═O), 1602 (C═N), 1557
1
(
C═C); H NMR (400 MHz, DMSO-d
6
): δ 4.62 (2H, s,
2 2 4
of coumarin). Anal. Calcd for C27H18Cl N O S: C, 60.34; H,
methylene), 7.45–7.59 (8H, m, s, ArH), 7.65 (2H, d, J = 8 Hz,
ArH), 7.76–7.81 (1H, m, ArH), 7.96 (1H, d, J = 8 Hz, ArH),
3.38; N, 5.21%. Found: C, 60.18; H, 4.10; N, 5.29%.
3-(2-(4-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1H-imidazol-
2-ylthio)acetyl)-2H-benzo[h]chromen-2-one (4j). Color: yellow;
13
8
.10 (1H, s, imidazole), 8.68 (1H, s, C-4 of coumarin) ppm;
C
À1
NMR (DMSO-d ): δ 43.7, 116.1, 118, 120.4, 122.8, 125.1,
mp: 244–246°C; R value: 0.67; yield: 90%; IR (KBr) cm : 1749
6
f
1
1
26.5, 127.4, 129.4, 130.9, 131.5, 133.6, 134.8, 134.9, 138.6,
(lactone C═O), 1630 (Ketone C═O), 1616 (C═N), 1574 (C═C);
H NMR (400 MHz, DMSO-d ): δ 3.59 (3H, s, methoxy), 4.66
6
(2H, s, methylene), 6.96 (2H, d, J = 8.8 Hz, ArH), 7.43–7.45
(3H, m, ArH), 7.63–7.68 (4H, m, ArH), 7.76–7.78 (2H, m, ArH),
8.11–8.13 (1H, d, J = 8.8 Hz, ArH), 8.37–8.39 (1H, d, J = 8.8 Hz,
ArH), 8.60–8.62 (2H, m, ArH, imidazol), 9.2 (1H, s, C-4
1
40.9, 148.3, 154.5, 158.3, 190.8 ppm; ESI-MS: m/z (%); 552
+
[
M + H] . Anal. Calcd for C26
H
16BrClN
2
O
3
S: C, 56.59; H,
2
.92; N, 5.08%. Found: C, 56.51; H, 2.98; N, 5.18%.
-{2-[4-Biphenyl-4-yl-1-(4-chlorophenyl)-1H-imidazol-2-
3
ylsulfanyl]-acetyl}-chromen-2-one (4e).
64–266°C; R
Color: yellow; mp:
À1
2
f
value: 0.73; yield: 90%; IR (KBr) cm : 1702
2 4
of coumarin). Anal. Calcd for C31H21ClN O S: C, 67.33; H, 3.81;
(
(
lactone C═O), 1684 (ketone C═O), 1607 (C═N), 1557
N, 5.07%. Found: C, 67.24; H, 3.73; N, 5.18%.
1
C═C); H NMR (400 MHz, DMSO-d ): δ 4.65 (2H, s,
6
methylene), 7.34–7.60 (11H, m, ArH), 7.65–7.79 (5H, m, ArH),
.97–7.99 (1H, m, ArH), 8.13 (1H, s, imidazole), 8.70 (1H, s,
7
+
REFERENCES AND NOTES
C-4 of coumarin) ppm; ESI-MS: m/z (%); 549 [M + H] . Anal.
Calcd for C H ClN O S: C, 70.00; H, 3.86; N, 5.10%.
32
21
2
3
[1] Shalini, K.; Sharma, P. K.; K. N. Der Chemica Sinica 2010, 1, 36.
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Found: C, 69.55; H, 3.88; N, 5.13%.
[
3
-(2-(1-(4-Chlorophenyl)-4-(4-nitrophenyl)-1H-imidazol-2-
Hannick S. M.; Gherke L.; Credo, R. B.; Hui, Y. H.; Marsh, K.; Warner, R.;
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ylthio)acetyl)-2H-chromen-2-one (4f). Color: light yellow; mp:
48–250°C; R
lactone C═O), 1685 (ketone C═O), 1626(C═N), 1556(C═C);
H NMR (400 MHz, DMSO-d ) : δ 4.63 (2H, s, methylene),
.20–7.57 (8H, m, ArH), 7.69–7.81 (3H, m, ArH), 7.96–7.98 (1H,
m, ArH), 8.08 (1H, s, imidazole), 8.69 (1H, s, C-4 of coumarin)
6
ppm; C NMR (DMSO-d ): δ 43.9, 116.1, 117.9, 120.1, 122.7,
À1
2
f
value: 0.65; yield: 86%, IR (KBr) cm : 1719
[
3] Antolini, M.; Bozzoli, A.; Ghiron, C.; Kennedy, G.; Rossi, T.;
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1
6
[
7
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Synthesis, Characterization, and Antibacterial Activity of Some Novel Substituted
Imidazole Derivatives via One-pot Three-Component
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