Synthetic approaches towards the sulfonamide substituted-1,5- diarylimidazole-2-thiones as selective cyclooxygense-2 inhibitors

Article abstract of DOI:10.1002/jhet.1695

A new series of sulfonamide substituted 1,5-diarylimidazole, possessing C-2 alkylthio moiety, were synthesized for their cyclooxygense-2 (COX-2) inhibitory activity starting from condensation of N,N-dibenzylaminosulfonylphenacylamine hydrochloride (2) and corresponding isothiocyanate in the presence of Et ₃N, followed by alkylation in the basic medium. In concomitant with these intermediates, 2-arylamino-5-arylthiazole derivatives 5 were also produced. The ratio of these two products was variable with different isothiocyanates. Final debenzylation was achieved using concentrated sulfuric acid to give the title sulfonamides 8.

Full text of DOI:10.1002/jhet.1695

January 2014
Synthetic Approaches towards the Sulfonamide Substituted-1,5-
Diarylimidazole-2-thiones as Selective Cyclooxygense-2 inhibitors
71
a
a
b
b
b
1
*
Latifeh Navidpour, Mohsen Amini, Ramin Miri, Omidreza Firuzi, Marjan Tavakkoli, and Abbas Shafiee
1Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, Tehran
University of Medical Sciences, Tehran 14176, Iran
2Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, P.O. Box 3288-71345,
Shiraz, Iran
*
E-mail: ashafiee@ams.ac.ir
Received October 4, 2011
DOI 10.1002/jhet.1695
Published online 8 October 2013 in Wiley Online Library (wileyonlinelibrary.com).
R2NO2S
N
1. X
2.
NCS, Et3N
O
R2NO2S
CCH2NH2.HCl
N
H
+
Ar (R')
S
N
RI, KOH
N
R2NO2S
(R') Ar
SR
A new series of sulfonamide substituted 1,5-diarylimidazole, possessing C-2 alkylthio moiety, were synthesized
for their cyclooxygense-2 (COX-2) inhibitory activity starting from condensation of N,N-dibenzylaminosulfonyl-
phenacylamine hydrochloride (2) and corresponding isothiocyanate in the presence of Et3N, followed by alkylation
in the basic medium. In concomitant with these intermediates, 2-arylamino-5-arylthiazole derivatives 5 were also
produced. The ratio of these two products was variable with different isothiocyanates. Final debenzylation was
achieved using concentrated sulfuric acid to give the title sulfonamides 8.
J. Heterocyclic Chem., 51, 71 (2014).
INTRODUCTION
with aniline and carbon disulfide. Different derivatives of
imidazole-2-thiones have also been prepared by the reac-
tion of o-phenylenediamine with carbon disulfide [22] or
thiocarbonyldiimidazole [23].
Herein, as part of our ongoing program to design novel
selective COX-2 inhibitors [24–31], we describe the syn-
thesis of a novel class of 1,5-diarylimidazole-2-thiones,
which for some derivatives need some modifications in
standard procedures.
The selective cyclooxygense (COX)-2 inhibitors celecoxib
(1) [1] and etoricoxib (2) [2,3] have been clinically validated
as anti-inflammatory therapeutics for indications such as
rheumatoid arthritis with less gastrointestinal and renal
toxicity (Fig. 1) [4–7]. In addition to its role in rheumatoid
arthritis and osteoarthritis, COX-2 is also implicated in
colon cancer and Alzheimer disease [8–10].
Tricyclic compounds possessing 1,2-diaryl substitution on
a central heterocyclic, or carbocyclic system constitute a
major class of selective COX-2 inhibitors. Structure-activity
relationship studies have shown that a SO2Me or SO2NH2
substituent at the para-position of one of the aryl rings often
provides optimum COX-2 selectivity and inhibitory potency
[11]. Whereas small lipophilic substituent (Me, CF3) on the
central ring frequently enhances, or is often a requirement
for COX-2 selectivity [12], their modification to find a new
ligand with improved properties is desirable. Regioisomeric
imidazoles have been explored previously as replacements
of the central heterocyclic core.
Several methods are available for the synthesis of substituted
imidazole-2-thiones in the literature [13–23]. McCombie
et al. and others [13–16] have reported the synthesis of
polyphenyl substituted imidazole-2-thiones by reaction of
phenacylamine derivatives with arylisothiocyanates. Also,
Bhatt et al. and others [17–20] have prepared them by the
reaction of benzoin or 1,2-diarylethane-1,2-diones with thio-
urea derivatives. Moreover, Mehrotra et al. [21] have prepared
these compounds by the reaction of 1,2-diarylethan-1,2-dione
RESULTS AND DISCUSSION
The reactions used for the synthesis of title componds
8 are outlined in Scheme 1. In an attempt to prepare the
target 4-[2-alkylthio-1-aryl (or cyclohexyl)imidazol-5-yl]
benzenesulfonamides 8, according to the standard procedure
for the synthesis of 1,5-diphenylimidazole-2-thione [16], the
reaction of respective phenacylamine hydrochloride and
isothiocyanate in the presence of Et3N followed by alkyaltion
was investigated. Treatment of 1 with hexamethylenetetramine
yielded the intermediate hexamethylene salt of a-bromoketone,
which was hydrolyzed under acidic conditions to 2. The
addition of 2 to the appropriate aryl (or cyclohexyl) iso-
thiocyanate in the presence of Et3N, followed by alkylation
in basic media using equimolar amount of alkyl iodide,
afforded 7 in variable yield, as well as 5 (2-anilinothiazole
derivatives).
The yield of 7 was highly variable with different substituted
isothiocyanates (see Table 1). When the substituent at the para
position of the phenyl ring was H, F, or Me, the predominant
© 2013 HeteroCorporation

72
L. Navidpour, M. Amini, R. Miri, O. Firuzi, M. Tavakkoli, and A. Shafiee
Vol 51
H3CO2S
compound 5. The conclusion that 5 was the only product
and that formation of 7 was insignificant is in good agree-
ment with the aforementioned mechanism.
H3C
Cl
CF3
N
A clear distinction between these two products could
N
N
1
be made by means of IR and H NMR. The structure of
H3C
H2NO2S
2-arylaminothiazoles 5 was elucidated by both the pres-
ence of the strong N–H stretch at ca. 3357–3365 cm-1,
absence of C═O stretch at ca. 1700 cm-1 in the IR and
absence of a singlet for the S–CH3 or a doublet and triplet
1 (Celecoxib)
2 (Etoricoxib)
Figure 1. Representative examples of selective tricyclic COX-2 inhibitors.
1
for S–CH2CH3 protons in the H NMR.
For further identification of 2-arylaminothiazoles,
alkylation of 5 in the presence of excess amount of methyl
iodide and strong basic media was next investigated.
This alkylation reaction produced N-methyl derivative
product was 7 and the formation of 5 was insignificant. For
X═Cl or Br on the phenyl ring, 5 was the major product
and 7 was produced in low yield. In the case of the cyclohexyl
derivative, 5 was the only product.
1
6 showing a singlet at 3.58 in H NMR spectra, which is
in good agreement with the chemical shift of methyl
(3.53) in previously reported compound, 2-(N-methyl-N-
phenylamino)thiazole [32].
This reaction seems to be somewhat sensitive to a substituent
effect. This method of ring synthesis is based on the cycli-
zation of intermediate 3 formed from the reaction of 2 and
substituted isothiocyanates. The partial deprotonation of
NH adjacent to the phenyl ring using Et3N improves the
cyclization. The substituent effect is believed to represent a
combination of resonance and field effects. Para substituents
are more suited for resonance interactions. The reaction
center is electron-rich and its formation should therefore
be favored by substituents that can stabilize the developing
partial charge (see Fig. 2). The phenyl ring facilitates the
ionization via a stabilizing interaction with the electron-rich
nitrogen, which drives cyclization to an imidazole ring,
whereas the cyclohexyl group, which acts as an electron-
releasing group, destabilizes the partial charge and limits the
ring formation. Groups that contain an unshared pair of elec-
trons on the atom connected to the ring (Cl, Br and OMe),
because of the resonance form of 11, destabilize the
electron-rich nitrogen. Therefore, the intermediate 9 is
not formed. The fluoro group was found to stabilize of 9
in comparison with other halogen groups (Cl and Br). In
this case, the field (or inductive) component of the sub-
stituent effect is particularly important. Regarding Me
derivative, as this group has a low resonance effect, the
ionization and cyclization proceed to provide the title
compounds.
Therefore, in the case of some derivatives in the presence
of Et3N cyclization seems to be incomplete (conversion of
3g–n to 4g–n). Cyclization of the remaining intermediate
3 in strong basic media (provided in the alkylation step)
led to the thiazole ring, because complete deprotonation of
NH in basic media resulted in intermediate 12 (see Fig. 3).
In the subsequent step, the intermediate 13 was formed, then
the sulfur anion attacked as the more powerful nucleophile
to produce a thiazole ring.
Το confirm the aforementioned explanation, a-aminoketone
hydrochloride 2 was stirred with phenyl isothiocyanate
(in the absence of Et3N) to give the acyclic intermediate
3 and was then refluxed in strong basic media to give
To synthesize 7g–n derivatives, the modification of
previously standard procedure [16] was necessary. 1,5-
Disubstituted-1,3-dihyroimidazole-2-thione has previ-
ously been prepared by Doney and Atland by refluxing
the acyclic intermediate in AcOH [33]. For incomplete
conversion of the intermediate to the imidazole product,
refluxing of a mixture of the acyclic intermediate and
imidazole product in AcOH improved the yield of
cyclization to 1,5-diaryl-1,3-dihydroimidazole-2-thione.
Thus, it is possible to synthesize all the derivatives in
moderate to high yields. Final debenzylation was achieved
using concentrated sulfuric acid to give the target
sulfonamide 8.
Finally, novel sulfonamide substituted 2-alkylthio-1,
5-diaryl (or 1-cyclohexyl-5-phenyl)imidazoles when
substituent at the para position of phenyl ring was H, F,
or Me that were synthesized according to the standard
procedure, by the condensation of N,N-dibenzylaminosul-
fonylphenacylamine hydrochloride (2) and corresponding
isothiocyanate in the presence of Et3N, followed by
alkylation in the basic medium in acceptable yield.
Whereas, for para-Cl and Br substituted phenyl and 5-
cyclohexyl derivatives, it was necessary to do some
modifications in the latter procedure before alkylation
by refluxing the mixture in acetic acid to afford the 2-
thioalkyl-1,5-diaryl(or 1-cyclohexyl-5-aryl)imidazoles in
reasonable yield.
The effect of alkylthio substituents on central five-membered
imidazole ring on COX-2 selectivity and potency was
determined (Table 2) [34,35].
The compound, 4-[1-(4-bromophenyl)-2-methylthioimi-
dazol-5-yl]benzenesulfonamide (8i), was the most potent
and selective COX-2 inhibitor (COX-1 IC50 =44.1mM;
COX-2 IC50 =14.2mM; SI = 3.1) relative to the reference drug
celecoxib (COX-1 IC50 =10.6mM; COX-2 IC50 =0.544mM;
SI = 19.4).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2014
Synthetic Approaches towards the 1,5-Diarylimidazole-2-thiones
73
Scheme 1. Reagents and conditions: (a) HMTA, CH3CN, rt, 2 h; (b) HCl/EtOH (1:2), rt, overnight; (c) Ar-N═C═S, Et3N, EtOH, reflux, overnight; (d)
RI, KOH, EtOH, reflux, 3 h; (e) AcOH, reflux, 3 h; (f) H2SO4 concentrated, rt, 45 min; (g) CH3I, KOH, EtOH, reflux, 5 h.
O
O
a,b
c
Bn2NO2S
CCH2Br
Bn2NO2S
CCH2NH2.HCl
1
2
Bn2NO2S
S
O
NH
+
Bn2NO2S
CCH2NHCNH Ar (R')
N
(R') Ar
S
3
e
4
d
d
Bn2NO2S
N
N
Ar (R')
S
H
N
N
Bn2NO2S
(R') Ar
5
SR
7
g
f
H2NO2S
N
Ar (R')
N
S
CH3
N
N
Bn2NO2S
(R') Ar
SR
6
8
X: H, F, Cl, Br, OMe, Me
R: Me, Et
X
Ar:
R': cyclohexyl
(USA). Mass spectra were obtained with a Finnigan Mat TSQ-70
spectrometer (Germany). Elemental microanalyses (Perkin-Elmer,
Beaconsfield, UK) were within Æ 0.4% of the theoretical values for
EXPERIMENTAL
Melting points were determined with a Reichert-Jung hot-stage
microscope (Austria) and are uncorrected. 1H NMR (400 MHz)
spectra were recorded on a Varian Unity plus 400 spectrometer
(Switzerland) using CDCl3 and DMSO-d6 as solvent. Chemical shifts
(d) are reported in ppm relative to TMS as internal standard. Infrared
spectra were acquired on a Nicolet Magna 550-FT spectrometer
C, H, and N.
N,N-Dibenzylaminosulfonylphenacylamine hydrochloride
(2).
To a stirred solution of N,N-dibenzyl-4-(2-bromoacetyl)
benzenesulfonamide 1 (12 g, 26 mmoles) dissolved in acetonitrile
(75 mL), hexamethylenetetramine (3.69 g, 26 mmoles) was added.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

74
L. Navidpour, M. Amini, R. Miri, O. Firuzi, M. Tavakkoli, and A. Shafiee
Vol 51
Table 1
Physical data for 7.
N
N
NR1
Bn2NO2S
SR2
Bn2NO2S
S
N
R1
5
7
Compound
R1
R2
Mp (ꢀC)
Yield (%)
Formula
Procedure A
Procedure B
7 (5)
7
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
Phenyl
Phenyl
4-CH3-phenyl
4-CH3-phenyl
4-F-phenyl
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
193–195
157–159
181–183
161–163
185–187
145–147
151–153
171–173
165–167
162–164
163–165
146–148
150–152
139–141
77 (trace)
82 (trace)
75 (trace)
71 (trace)
72 (trace)
80 (trace)
27 (47)
23 (60)
13 (55)
14 (51)
–
–
–
–
–
C30H27N3O2S2
C31H29N3O2S2
C31H29N3O2S2
C32H31N3O2S2
C30H26FN3O2S2
C31H28FN3O2S2
C30H26ClN3O2S2
C31H28ClN3O2S2
C30H26BrN3O2S2
C31H28BrN3O2S2
C31H29N3O3S2
C32H31N3O3S2
C30H33N3O2S2
C31H35N3O2S2
4-F-phenyl
–
4-Cl-phenyl
4-Cl-phenyl
4-Br-phenyl
4-Br-phenyl
4-OCH3-phenyl
4-OCH3-phenyl
Cyclohexyl
71
60
63
59
53
50
20
26
6 (trace)
7 (trace)
Trace (25)
Trace (28)
Cyclohexyl
Et
d+
:N
Et
Et
- Ar(R')
O
H
N
H
N
O
H
N
d
H
N
Et3N
Ar(R')
S
S
Bn2NO2S
Bn2NO2S
3
9
Et
d+
:N
Et
d+
:N
Et
Et
Et
Et
O
H
O
H
N
H
H
N
N
N
d-
d-
S
S
Bn2NO2S
X:
Bn2NO2S
X
10
11
Figure 2. Partial deprotonation of NH in the intermediate by Et3N.
from a small amount of suspended solid and the filtrate was
cooled to 10 ꢀC. The crystalline product was removed by
filtration, washed with a small portion of ice-water and dried
to give 2 (3.6 g, 32%); IR (KBr): 3442 (NH), 1693 (CO),
1342, 1160 cm-1 (SO2); 1H NMR (CDCl3): d 8.52 (bs, 3H),
8.21 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.26–7.20
(m, 6H), 7.09 (m, 4H), 4.68 (s, 2H), 4.35 ppm (s, 4H); ms: m/z
394 (M+, 7), 379 (7), 365 (100), 337 (30), 301 (45), 288 (36),
274 (5), 196 (22), 194 (18), 91 (10). Anal. Calcd. for
C22H23ClN2O3S: C, 61.31; H, 5.38; N, 6.50. Found: C, 61.15,
H, 5.25; N, 6.66.
The mixture was stirred at room temperature for 2 h. The
product (hexamethylene salt of a-bromoketone) was then
collected on a suction filter and washed with cold acetonitrile.
To a solution of concentrated hydrochloric acid (18 mL) in
ethanol (37 mL) at room temperature, the adduct was added,
and the resulting mixture was stirred overnight. After cooling
to 10 ꢀC, the separated solids were collected on a suction filter
and washed with fresh ethanol. To remove the ammonium
chloride present, the partially dried filter cake was dissolved at
70 ꢀC in water (50 mL), which contained concentrated
hydrochloric acid (2.5 mL), the hot solution was filtered free
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2014
Synthetic Approaches towards the 1,5-Diarylimidazole-2-thiones
75
O
H
N
H
N
O
H
KOH
N
N
Ar(R')
Ar(R')
S
S
Bn2NO2S
Bn2NO2S
3
12
O
H
N
N
Ar(R')
S
Bn2NO2S
13
Figure 3. Deprotonation of NH in the intermediate by KOH.
Table 2
Cyclooxygenase inhibition activities of 8.
Compound
R1
R2
IC50 (mM)
Selectivity index
(COX-1/COX-2)
COX-1a
COX-2a
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
Celecoxib
Phenyl
Phenyl
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
–
>100
>100
>100
>100
–
–
–
–
2.2
–
–
–
3.1
2.4
2.8
–
4-CH3-phenyl
4-CH3-phenyl
4-F-phenyl
4-F-phenyl
4-Cl-phenyl
4-Cl-phenyl
4-Br-phenyl
4-Br-phenyl
4-OCH3-phenyl
4-OCH3-phenyl
Cyclohexyl
Cyclohexyl
–
19.7 Æ 4.2
19.3 Æ 4.8
61.1 Æ 38.8
>100
>20b
>20b
27.9 Æ 8.4
99.8 Æ 64.6
>20b
>20b
>50b
32.4 Æ 13.8
14.2 Æ7.9
29.0 Æ 12.3
22.4 Æ 11.0
12.8 Æ 5.1
–
>100
0.544 Æ 0.332
44.1 Æ 11.9
68.8 Æ 9.8
62.9 Æ 11.3
>20b
–
–
–
19.4
>100
10.6 Æ 1.0
COX, cyclooxygense. Values represent the mean Æ SD of 3–5 different experiments. bBecause of lower solubility, these compounds were tested at the
a
maximum concentration of 20 or 50 mM.
N,N-Dibenzyl-4-(2-phenylaminothiazol-5-yl)benzenesulfonamide
(5a). Triethylamine (0.21 mL, 2.28 mmoles) was added dropwise
to a stirred suspension of N,N-dibenzylaminosulfonylphenacylamine
hydrochloride 2 (1.0 g, 2.28 mmoles) and phenylisothiocyanate
(308 mg, 2.28 mmoles) in ethanol (10 mL). The mixture was
stirred for a week and the precipitate was filtered. Then, the
precipitate was dissolved in KOH/EtOH (0.3 g/10 mL) and the
solution was heated under reflux for 2 h. Purification by
flash chromatography, eluting with CH3Cl/MeOH (98:2), and
crystallization from ethanol gave 5a (100 mg, 8%), mp: 199–
J = 8.4Hz, 2H), 7.45–7.28 (m, 4H), 7.26–7.14 (m, 6H), 7.15–6.95
(m, 4H), 4.35ppm (s, 4H); ms: m/z 512 (M+, 22), 511 (63), 315
(14), 267 (10), 251 (52), 196 (61), 164 (12), 106 (18), 91 (100),
77 (20). Anal. Calcd for C29H25N3O2S2: C, 68.07; H, 4.92; N,
8.21. Found: C, 68.19, H, 5.10; N, 8.02.
General procedure for the reaction of N,N-
dibenzylphenacylamine hydrochloride with aryl (cycloalkyl)
isothiocyanate
General procedure A.
To a stirred suspension of N,N-
dibenzylaminosulfonylphenacylamine hydrochloride 2 (0.33 g,
0.76 mmole) and respective phenylisothiocyanate (0.76 mmole) in
ethanol (10 mL), triethylamine (0.07 mL, 0.76 mmole) was added
1
201 ꢀC; IR (KBr): 3352 (NH), 1330, 1152 cm-1 (SO2); H NMR
(CDCl3): d 7.84 (d, J = 8.4 Hz, 2H), 7.72–7.62 (m, 2H), 7.61 (d,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

76
L. Navidpour, M. Amini, R. Miri, O. Firuzi, M. Tavakkoli, and A. Shafiee
Vol 51
dropwise and the mixture was refluxed overnight. After cooling, to
the mixture, potassium hydroxide (0.04 g, 0.76 mmol) dissolved in
water (0.6 mL) and alkyl iodide (2 mmoles) was added next, and
the solution was refluxed for 2 h. Then, again alkyl iodide
(0.76 mmol) was added, and the mixture was heated for
further 1 h. Purification by flash chromatography, eluting with
CH3Cl/MeOH (98:2), and crystallization from ethanol gave 5 and 7.
7.37 (s, 1H), 7.33–6.98 (m, 14H), 4.32 (s, 4H), 3.58 ppm
(s, 3H); ms: m/z 605 (M+, 6), 603 (6), 589 (92), 587 (92), 501
(27), 394 (32), 392 (32), 329 (58), 327 (58), 312 (20), 236
(18), 196 (44), 186 (18), 184 (18), 104 (12), 91 (100). Anal.
Calcd for C30H26BrN3O2S2: C, 59.60; H, 4.33; N, 6.95. Found:
C, 59.42; H, 4.12; N, 6.82.
N,N-Dibenzyl-4-(methylthio-1-phenylimidazol-5-yl)
benzenesulfonamide (7a). Following the general procedure A, 7a
General procedure B.
To a stirred suspension of N,N-
was obtained (310 mg, 77%), mp: 193–195 ꢀC; IR (KBr): 1333,
dibenzylaminosulfonylphenacylamine hydrochloride 2 (0.33 g,
0.76 mmole) and respective phenylisothiocyanate (0.76mmole) in
ethanol (10 mL) was added dropwise triethylamine (0.07mL,
0.76 mmole), and the mixture was refluxed overnight. The
volatiles were evaporated, and the residue was dissolved in acetic
acid (5 mL) and the solution was refluxed for 2 h. After
cooling, the acetic acid was evaporated and to the residue in
ethanol (10 mL), potassium hydroxide (0.04 g, 0.76 mmole)
dissolved in water (0.6 mL) and alkyl iodide (2 mmoles) was
added. The solution was heated under reflux for 2 h, then again
alkyl iodide (0.76 mmole) was added and the solution was
refluxed for further 1 h. Purification by flash chromatography,
eluting with CH3Cl/MeOH (98:2), and crystallization from
1
1152 cm-1 (SO2); H NMR (CDCl3): d 7.65 (d, J = 8.4 Hz, 2H),
7.52–7.46 (m, 2H), 7.42 (s, 1H), 7.28–6.75 (m, 15H), 4.29 (s, 4H),
2.63 ppm (s, 3H); ms: m/z 525 (M+, 100), 491 (8), 433 (3), 330
(4), 263 (5), 192 (5), 91 (15). Anal. Calcd for C30H27N3O2S2: C,
68.54; H, 5.18; N, 7.99. Found: C, 68.45; H, 5.02; N, 8.12.
N,N-Dibenzyl-4-(ethylthio-1-phenylimidazol-5-yl)
benzenesulfonamide (7b). Following the general procedure A,
7b was obtained (340 mg, 82%), mp: 157–159 ꢀC; IR (KBr):
1
1339, 1156 cm-1 (SO2); H NMR (CDCl3): d 7.64 (d, J=8.4Hz,
2H), 7.50–7.44 (m, 2H), 7.42 (s, 1H), 7.28–6.75 (m, 15H), 4.29
(s, 4H), 3.18 (q, J= 7.2 Hz, 3H), 1.37 ppm (t, J = 7.2 Hz, 3H); ms:
m/z 540 (M+, 76), 539 (100), 511 (25), 435 (16), 430 (68), 357
(10), 344 (12), 316 (20), 279 (28), 251 (38), 191 (58), 170 (55),
105 (78), 91 (65). Anal. Calcd for C31H29N3O2S2: C, 68.99; H,
ethanol gave the title compound 7.
N,N-Dibenzyl-4-[2-(4-chlorophenylamino)thiazol-5-yl]
benzenesulfonamide (5c). Following the general procedure A, 5c
5.42; N, 7.79. Found: C, 68.88; H, 5.24; N, 7.62.
was obtained (250 mg, 60%), mp: 183–185 ꢀC; IR (KBr): 3358
N,N-Dibenzyl-4-[1-(4-methylphenyl)-2-methylthioimidazol-5-yl]
(NH), 1334, 1154 cm-1 (SO2); 1H NMR (CDCl3):
d
7.86
benzenesulfonamide (7c). Following the general procedure A, 7c
(d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.8 Hz,
2H), 7.38 (d, J = 8.8 Hz, 2H), 7.33 (s, 1H), 7.26–7.15 (m, 6H),
7.12–6.98 (m, 4H), 4.35 ppm (s, 4H). Anal. Calcd for
C29H24ClN3O2S2: C, 63.78; H, 4.43; N, 7.69. Found: C, 63.90;
H, 4.29; N, 7.54.
N,N-Dibenzyl-4-[2-(4-bromophenylamino)thiazol-5-yl]
was obtained (310 mg, 75%), mp: 181–183 ꢀC; IR (KBr): 1336,
1
1154 cm-1 (SO2); H NMR (CDCl3): d 7.66 (d, J=8.4Hz, 2H),
7.35 (d, J = 8.4 Hz, 2H), 7.35–6.90 (m, 15H), 4.30 (s, 4H), 2.62
(s, 3H), 2.43 ppm (s, 3H); ms: m/z 539 (M+, 100), 506 (8), 491
(5), 237 (10), 194 (9), 169 (7), 104 (9), 91 (18). Anal. Calcd for
C31H29N3O2S2: C, 68.99; H, 5.42; N, 7.79. Found: C, 68.82;
benzenesulfonamide (5d). Following the general procedure A, 5d
was obtained (250 mg, 55%), mp: 164–166 ꢀC; IR (KBr): 3357 (NH),
1334, 1155 cm-1 (SO2); uv: l max 227, 254, 347 nm; 1 H NMR
(CDCl3): d 7.84 (d, J= 8.4 Hz, 2H), 7.61 (d, J= 8.4 Hz, 2H), 7.49
(d, J= 8.4 Hz, 2H), 7.44 (d, J= 8.4 Hz, 2H), 7.32 (s, 1H), 7.26–7.14
(m, 6H), 7.12–6.96 (m, 4H), 4.35 ppm (s, 4H); ms: m/z 591
(M+, 5), 589 (5), 576 (25), 574 (25), 380 (29), 378 (29), 331
(10), 329 (10), 315 (28), 313 (28), 196 (85), 173 (18), 171
(18), 117 (22), 106 (27), 104 (26), 91 (100), 64 (34). Anal.
Calcd for C29H24BrN3O2S2: C, 58.98; H, 4.10; N, 7.12. Found:
H, 5.55; N, 7.95.
N,N-Dibenzyl-4-[2-ethylthio-1-(4-methylphenyl)imidazol-5-yl]
benzene sulfonamide (7d). Following the general procedure A,
7d was obtained (300 mg, 71%), mp: 161–163 ꢀC; IR (KBr):
1333, 1152cm-1 (SO2); H NMR (CDCl3): d 7.54 (d, J = 8.4 Hz,
1
2H), 7.35 (d, J = 8.4 Hz, 2H), 7.35–6.85 (m, 15H), 4.29 (s, 4H),
3.16 (q, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.36 ppm (t, J = 7.2 Hz, 3H);
ms: m/z 553 (M+, 100), 525 (15), 430 (33), 329 (8), 265 (12), 191
914), 170 (17), 119 (32), 91 (87). Anal. Calcd for C32H31N3O2S2:
C, 69.41; H, 5.64; N, 7.59. Found: C, 69.22; H, 5.48; N, 7.74.
N,N-Dibenzyl-4-[1-(4-fluorophenyl)-2-methylthioimidazol-5-yl]
C, 58.84, H, 4.26, N, 7.02.
N,N - Dibenzyl - 4 - [2 - cyclohexylaminothiazol-5-yl]
benzene sulfonamide (7e). Following the general procedure A,
7e was obtained (300 mg, 72%), mp: 185–187 ꢀC; IR (KBr): 1333,
benzenesulfonamide (5g). Following the general procedure A, 5g
was obtained (110 mg, 28%), mp: 158–160 ꢀC; IR (KBr): 3365
(NH), 1337, 1156 cm-1 (SO2); 1H NMR (CDCl3): d 7.80
(d, J= 8.4 Hz, 2H), 7.54 (d, J= 8.4 Hz, 2H), 7.35–7.02 (m, 10H),
6.98 (s, 1H), 4.33 (s, 4H), 3.75 (m, 1H), 2.25–1.10 ppm (m, 10H);
ms: m/z 517 (M+, 8), 501 (94), 483 (10), 418 (11), 327 (10), 289
(17), 241 (22), 224 (80), 196 (87), 174 (43), 159 (62), 103 (48), 91
(100), 55 (64). Anal. Calcd for C29H31N3O2S2: C, 67.28; H, 6.04;
1152 cm-1 (SO2); H NMR (CDCl3): d 7.66 (d, J = 8.4 Hz, 2H),
1
7.33 (d, J= 8.4 Hz, 2H), 7.41–6.85 (m, 15H), 4.30 (s, 4H),
2.64 ppm (s, 3H); ms: m/z 543 (M+, 100), 509 (10), 516 (12), 347
(16), 283 (28), 221 (15), 209 (16), 183 (10), 156 (8), 109 (11), 91
(48). Anal. Calcd for C30H26FN3O2S2: C, 66.28; H, 4.82; N, 7.73.
Found: C, 66.12; H, 4.68; N, 7.61.
N,N-Dibenzyl-4-[2-ethylthio-1-(4-fluorophenyl)imidazol-5-yl]
benzene sulfonamide (7f). Following the general procedure A, 7f
N, 8.12. Found: C, 67.20; H, 6.18; N, 8.26.
was obtained (340 mg, 80%), mp: 145–147 ꢀC; IR (KBr): 1330,
N,N-Dibenzyl-4-[2-(4-bromophenyl)methylamino)thiazol-5-yl]
1
1149 cm-1 (SO2); H NMR (CDCl3): d 7.66 (d, J=8.4Hz, 2H),
benzenesulfonamide (6d). To a stirring solution of compound 5d
(100 mg, 0.16 mmole) in ethanol (5 mL) was added potassium
hydroxide (18 mg, 0.32 mmole) dissolved in water (0.3 mL) and
methyl iodide (0.2 mL) and the mixture was refluxed for 5 h. The
volatiles were evaporated. Purification by flash chromatography,
eluting with CH3Cl/MeOH (20:1), and crystallization from
ethanol gave 6d (56 mg, 55%), mp: 108–110 ꢀC; IR (KBr):
1345, 1150 cm-1 (SO2); UV: l max 227, 255, 348 nm; 1H NMR
(CDCl3): d 7.78 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H),
7.35 (d, J = 8.4 Hz, 2H), 7.35–6.85 (m, 15H), 4.30 (s, 4H), 3.16
(q, J = 7.2 Hz, 2H), 1.38 ppm (t, J = 7.2 Hz, 3H); ms: m/z 557
(M+, 68), 529 (12), 430 (17), 334 (6), 298 (10), 269 (14), 234
(12), 209 (20), 170 (22), 123 (35), 91 (100). Anal. Calcd for
C31H28FN3O2S2: C, 66.76; H, 5.06; N, 7.53. Found: C, 66.59;
H, 4.92; N, 7.69.
N,N-Dibenzyl-4-[1-(4-chlorophenyl)-2-methylthioimidazol-5-yl]
benzene sulfonamide (7g). Following the general procedure A
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2014
Synthetic Approaches towards the 1,5-Diarylimidazole-2-thiones
77
(120 mg, 27%) and B (305 mg, 71%) 7g was obtained, mp:
151–153 ꢀC; IR (KBr): 1333, 1151 cm-1 (SO2); 1H NMR
(CDCl3): d 7.67 (d, J= 8.6 Hz, 2H), 7.48–7.29 (m, 4H), 7.25–6.85
(m, 13H), 4.31 (s, 4H), 2.63 ppm (s, 3H); ms: m/z 561 (33),
559 (100), 528 (5), 526 (15), 467 (8), 364 (5), 324 (5), 221
(4), 191 (8), 155 (6), 125 (10), 91 (38). Anal. Calcd for
C30H26ClN3O2S2: C, 64.33; H, 4.68; N, 7.50. Found: C,
(m, 4H). Anal. Calcd for C30H33N3O2S2: C, 67.76; H, 6.26; N,
7.90. Found: C, 67.59; H, 6.39; N, 7.72.
N,N-Dibenzyl-4-[1-cyclohexyl-2-ethylthioimidazol-5-yl]
benzenesulfonamide (7n). Following the general procedure B, 7n
was obtained (110 mg, 26%), mp: 139–141 ꢀC; IR (KBr): 1337,
1
1154 cm-1 (SO2); H NMR (CDCl3): d 7.86 (d, J=8.4Hz, 2H),
7.39 (d, J=8.4Hz, 2H), 7.25–6.85 (m, 10H), 4.38 (s, 4H), 3.90 (m,
1H), 3.25 (q, J= 7.7 Hz, 2H), 2.20–1.55 (m, 6H), 1.52–1.05 ppm
(m, 6H); ms: m/z 545 (58), 514 (12), 463 (19), 428 (10), 372 (12),
285 (15), 268 (29), 235 (18), 202 (34), 196 (58), 170 (20), 148
(10), 97 (17), 91 (100), 55 (58). Anal. Calcd for C31H35N3O2S2: C,
64.45; H, 4.82; N, 7.35.
N,N-Dibenzyl-4-[1-(4-chlorophenyl)-2-ethylthioimidazol-5-yl]
benzene sulfonamide (7h). Following the general procedure A
(100 mg, 23%) and B (265 mg, 60%) 7h was obtained, mp:
171–173 ꢀC; IR (KBr): 1334, 1153 cm-1 (SO2); 1H NMR
(CDCl3): d 7.66 (d, J = 8.6 Hz, 2H), 7.55–6.85 (m, 17H), 4.31
(s, 4H), 3.18 (q, J = 7.2 Hz, 2H), 1.37 ppm (t, J = 7.2 Hz, 3H);
ms: m/z 574 (M+, 20), 572 (60), 557 (33), 555 (100), 539 (43),
511 (12), 506 (8), 295 (4), 91 (12). Anal. Calcd for
C31H28ClN3O2S2: C, 64.85; H, 4.92; N, 7.32. Found: C, 64.69;
68.22; H, 6.46; N, 7.70. Found: C, 68.01; H, 6.26; N, 7.88.
General procedure for the preparation of 4-[2-alkylthio-1-aryl
(or cyclohexyl)imidazol-5-yl]benzenesulfonamides (8a–n).
A
suspension of 7a–n (150 mg) in concentrated H2SO4 (3 mL)
was stirred at room temperature for 45 min. The mixture was
poured into ice. The resulting solid was filtered, washed with
water, and dried. Purification by flash chromatography, eluting
H, 4.99; N, 7.48.
N,N-Dibenzyl-4-[1-(4-bromophenyl)-2-methylthioimidazol-5-yl]
with CH3Cl/MeOH (85:15), gave the title compounds 8a–n.
4-(Methylthio-1-phenylimidazol-5-yl)benzenesulfonamide
benzene sulfonamide (7i). Following the general procedure A
(60 mg, 13%) and B (290 mg, 63%) 7i was obtained, mp:
165–167 ꢀC; IR (KBr): 1333, 1152cm-1 (SO2); 1H NMR
(CDCl3): d 7.67 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.39
(s, 1H), 7.24–7.18 (m, 6H), 7.15 (d, J = 8.4 Hz, 2H), 7.12 (d,
J = 8.4 Hz, 2H), 7.06–7.02 (m, 4H), 4.31 (s, 4H), 2.64ppm (s,
3H); ms: m/z 605 (M+, 8), 603 (8), 561 (44), 559 (44), 467 (5),
416 (7), 364 (10), 299 (18), 249 (9), 221 (20), 191 (28), 155 (22),
125 (38), 91 (100). Anal. Calcd for C30H26BrN3O2S2: C, 59.60;
(8a). Following the general procedure, 8a was obtained (50 mg,
51%), mp: 191–193 ꢀC; IR (KBr): 3358 (NH2), 1342, 1160 cm-1
(SO2); 1H NMR (DMSO-d6): d 7.63 (d, J = 8.4 Hz, 2H),
7.55–7.49 (m, 3H), 7.46 (s, 1H), 7.35–7.25 (m, 4H), 7.21
(d, J = 8.4 Hz, 2H), 2.53 ppm (s, 3H); ms: m/z 345 (M+, 34),
312 (22), 284 (8), 266 (10), 250 (22), 236 (38), 206 (38), 196
(33), 179 (25), 165 (20), 105 (21), 91 (100), 76 (40), 45 (42).
Anal. Calcd for C16H15N3O2S2: C, 55.63; H, 4.38; N, 12.16.
Found: C, 55.50; H, 4.49; N, 12.02.
H, 4.33; N, 6.95. Found: C, 59.75; H, 4.25; N, 6.82.
N,N-Dibenzyl-4-[1-(4-bromophenyl)-2-ethylthioimidazol-5-yl]
4-(Ethylthio-1-phenylimidazol-5-yl)benzenesulfonamide
(8b).
Following the general procedure, 8b was obtained
benzene sulfonamide (7j). Following the general procedure A
(65 mg, 14%) and B (275 mg, 59%) 7j was obtained, mp:
162–164 ꢀC; IR (KBr): 1333, 1152 cm-1 (SO2); 1H NMR
(CDCl3): d 7.66 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H),
7.39 (s, 1H), 7.35–6.92 (m, 14H), 4.31 (s, 4H), 3.18
(q, J = 7.3 Hz, 2H), 1.36 ppm (t, J = 7.3 Hz, 3H); ms: m/z 619
(M+, 22), 617 (22), 591 (5), 589 (5), 535 (8), 430 (25), 357
(10), 248 (14), 191 (25), 185 (24), 183 (24), 170 (20), 104 (8),
91 (100). Anal. Calcd for C31H28BrN3O2S2: C, 60.19; H, 4.56;
(55 mg, 59%), mp: 205–207 ꢀC; IR (KBr): 3388 (NH2), 1342,
1159 cm-1 (SO2); 1H NMR (DMSO-d6): d 7.63 (d, J=8.4Hz,
2H), 7.55–7.48 (m, 3H), 7.46 (s, 1H), 7.32–7.25 (m, 4H), 7.21
(d, J=8.4Hz, 2H), 3.07 (q, J=7.2Hz, 2H), 1.27ppm (s, 3H); ms:
m/z 359 (M+, 7), 330 (15), 256 (9), 250 (16), 191 (10), 152 (12),
97 (29), 84 (26), 69 (30), 60 (48), 45 (100). Anal. Calcd for
C17H17N3O2S2: C, 56.80; H, 4.77; N, 11.69. Found: C, 56.69; H,
4.96; N, 11.55.
4-[1-(4-Methylphenyl)-2-methylthioimidazol-5-yl]
N, 6.79. Found: C, 60.02; H, 4.41; N, 6.95.
N,N-Dibenzyl-4-[1-(4-methoxyphenyl)-2-methylthioimidazol-5-yl]
benzenesulfonamide (8c). Following the general procedure, 8c
was obtained (60 mg, 62%), mp: 211–213 ꢀC; IR (KBr): 3283
(NH2), 1340, 1158 cm-1 (SO2); 1H NMR (DMSO-d6): d 7.64
(d, J= 8.4 Hz, 2H), 7.44 (s, 1H), 7.36–7.25 (m, 4H), 7.22
(d, J= 8.4 Hz, 2H), 7.18 (d, J = 8 Hz, 2H), 2.53 (s, 3H), 2.38 ppm
(s, 3H); ms: m/z 359 (M+, 25), 326 (5), 264 (8), 236 (32), 204
(10), 191 (8), 131 (8), 105 (100), 92 (25), 60 (22), 45 (38). Anal.
Calcd for C17H17N3O2S2: C, 56.80; H, 4.77; N, 11.69. Found: C,
benzene sulfonamide (7k).
Following the general procedure A
(25 mg, 6%) and B (225 mg, 53%) 7k was obtained, mp:
163–165 ꢀC; IR (KBr): 1336, 1154 cm-1 (SO2); 1H NMR
(CDCl3): d 7.65 (d, J = 8.5 Hz, 2H), 7.40 (s, 1H), 7.32–6.78
(m, 16H), 4.29 (s, 4H), 3.86 (s, 3H), 2.63 ppm (s, 3H); ms: m/z
555 (M+, 100), 539 (8), 415 (4), 360 (5), 295 (4), 91 (22).
Anal. Calcd for C31H29N3O3S2: C, 67.00; H, 5.26; N, 7.56.
Found: C, 67.15; H, 5.12; N, 7.39.
N,N-Dibenzyl-4-[2-ethylthio-1-(4-methoxyphenyl)imidazol-5-yl]
56.66; H, 4.88; N, 11.82.
4 - [2 - Ethylthio - 1 -(4 -methylphenyl)imidazol -5-yl]
benzene sulfonamide (7l).
Following the general procedure
benzenesulfonamide (8d). Following the general procedure, 8d
was obtained (65 mg, 64%), mp: 197–199 ꢀC; IR (KBr): 3264
(NH2), 1342, 1155 cm-1 (SO2); 1H NMR (DMSO-d6): d 7.64
(d, J = 8.4 Hz, 2H), 7.44 (s, 1H), 7.36–7.26 (d, J =8Hz, 2H), 7.22
(d, J= 8.4 Hz, 2H), 7.16 (d, J = 8 Hz, 2H), 3.06 (q, J= 7.2 Hz, 2H),
2.37 (s, 3H), 1.27 ppm (t, J= 7.2 Hz, 3H); ms: m/z 373 (M+, 38),
343 (23), 285 (8), 264 (19), 250 (58), 204 (15), 191 (8), 170 (9),
119 (100), 91 (42), 60 (25), 45 (29). Anal. Calcd for C18H19N3O2S2:
A (30 mg, 7%) and B (220 mg, 50%) 7l was obtained, mp:
146–148 ꢀC; IR (KBr): 1334, 1154 cm-1 (SO2); 1H NMR (CDCl3):
d 7.64 (d, J=8.5Hz, 2H), 7.40 (d, J= 8.5 Hz, 2H), 7.32–6.80
(m, 16H), 4.29 (s, 4H), 3.86 (s, 3H), 3.28 (q, J= 7.3 Hz, 2H),
1.37 ppm (s, 3H). Anal. Calcd for C32H31N3O3S2: C, 67.46; H,
5.48; N, 7.38. Found: C, 67.30; H, 5.32; N, 7.56.
N,N-Dibenzyl-4-[1-cyclohexyl-2-methylthioimidazol-5-yl]
benzene sulfonamide (7m). Following the general procedure B,
7m was obtained (80 mg, 20%), mp: 150–152 ꢀC; IR (KBr): 1330,
C, 57.88; H, 5.13; N, 11.25. Found: C, 57.77; H, 5.02; N, 11.39.
4-[1-(4-Fluorophenyl)-2-methylthioimidazol-5-yl]
1
1152cm-1 (SO2); H NMR (CDCl3): d 7.86 (d, J = 8.5 Hz, 2H),
benzenesulfonamide (8e). Following the general procedure, 8e was
7.39 (d, J = 8.5 Hz, 2H), 7.35–6.85 (m, 10H), 4.38 (s, 4H), 3.95
(m, 1H), 2.70 (s, 3H), 2.55–1.55 (m, 6H), 1.52–1.05ppm
obtained (55 mg, 54%), mp: 201–203 ꢀC; IR (KBr): 3300 (NH2), 1345,
1
1159 cm-1 (SO2); H NMR (DMSO-d6): d 7.66 (d, J= 8.4 Hz, 2H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

78
L. Navidpour, M. Amini, R. Miri, O. Firuzi, M. Tavakkoli, and A. Shafiee
Vol 51
7.45 (s, 1H), 7.43–7.26 (m, 6H), 7.23 (d, J= 8.4 Hz, 2H), 2.53 ppm (s,
3H); ms: m/z 363 (M+, 84), 330 (18), 299 (5), 268 (10), 250 (22),
236 (78), 209 (25), 183 (18), 148 (18), 136 (21), 109 (100), 91
(42), 60 (52). Anal. Calcd for C16H14FN3O2S2: C, 52.88; H,
3.88; N, 11.56. Found: C, 52.77; H, 3.96; N, 11.72.
4-[2-Ethylthio-1-(4-fluorophenyl)imidazol-5-yl]benzenesulfonamide
(NH2), 1341, 1158 cm-1 (SO2); 1H NMR (DMSO-d6): d 7.72
(d, J= 8.8 Hz, 2H), 7.45 (s, 1H), 7.34–7.28 (m, 4H), 7.13
(d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H), 2.56 ppm
(s, 3H); ms: m/z 375 (M+, 5), 327 (32), 306 (15), 258 (8), 214 (8),
163 (18), 149 (45), 123 (17), 109 (28), 71 (24), 60 (75), 45 (100).
Anal. Calcd for C17H17N3O3S2: C, 54.38; H, 4.56; N, 11.19.
Found: C, 54.49; H, 4.68; N, 11.28.
(8f). Following the general procedure, 8f was obtained (55 mg,
56%), mp: 179–181 ꢀC; IR (KBr): 3392 (NH2), 1336, 1158 cm-1
(SO2); 1H NMR (DMSO-d6): d 7.67 (d, J= 8.4Hz, 2H), 7.46
(s, 1H), 7.41–7.29 (m, 6H), 7.23 (d, J= 8.4 Hz, 2H), 3.07
(q, J = 7.6 Hz, 2H), 1.27 ppm (t, J = 7.6 Hz, 3H); ms: m/z 377
(M+, 28), 348 (26), 289 (5), 268 (14), 245 (20), 250 (42), 237
(10), 209 (13), 196 (12), 165 (31), 150 (18), 123 (83),108 (76),
95 (32), 45 (100). Anal. Calcd for C17H16FN3O2S2: C, 54.09;
H, 4.27; N, 11.13. Found: C, 54.22; H, 4.39; N, 11.02.
4-[1-(4-Chlorophenyl)-2-methylthioimidazol-5-yl]
benzenesulfonamide (8g). Following the general procedure, 8g
was obtained (50 mg, 49%), mp: 215–217 ꢀC; IR (KBr): 3312
(NH2), 1346, 1158 cm-1 (SO2); 1H NMR (DMSO-d6): d 7.67
(d, J=8.4Hz, 2H), 7.59 (d, J= 8.8 Hz, 2H), 7.45 (s, 1H), 7.36–7.26
(m, 4H), 7.23 (d, J= 8.4 Hz, 2H), 2.54 ppm (s, 3H); ms: m/z 379
(M+, 20), 347 (7), 313 (12), 293 (9), 264 (12), 250 (10), 236 (52),
197 (19), 167 (23), 149 (85), 127 (28), 91 (63), 57 (78), 45 (100).
Anal. Calcd for C16H14ClN3O2S2: C, 50.59; H, 3.71; N, 11.06.
Found: C, 50.52; H, 3.56; N, 11.22.
4- [1 -(4 - Chlorophenyl) - 2- ethylthioimidazol -5-yl]
benzenesulfonamide (8h). Following the general procedure, 8h
was obtained (55 mg, 53%), mp: 209–211 ꢀC; IR (KBr): 3427
(NH2), 1341, 1157 cm-1 (SO2); 1H NMR (DMSO-d6): d 7.67
(d, J=8.8Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.46 (s, 1H),
7.38–7.25 (m, 4H), 7.24 (d, J= 8.4Hz, 2H), 3.07 (q, J=7.2Hz,
2H), 1.27 ppm (t, J=7.2Hz, 3H); ms: m/z 395 (M+, 8), 393
(9), 366 (12), 364 (6), 293 (15), 250 (12), 214 (6), 167 (10), 153
(16), 149 (28), 139 (16), 127 (20), 91 (22), 60 (38), 45 (100).
Anal. Calcd for C17H16ClN3O2S2: C, 51.83; H, 4.09; N, 10.67.
Found: C, 51.70; H, 4.01; N, 10.79.
4-[2-Ethylthio -1 -(4 -methoxyphenyl)imidazol- 5-yl]
benzenesulfonamide (8l).
Following the general procedure, 8l
was obtained (68 mg, 55%), mp: 250–252 ꢀC; IR (KBr): 3280
(NH2), 1341, 1157 cm-1 (SO2); 1H NMR (DMSO-d6): d 7.71
(d, J= 8.4 Hz, 2H), 7.46 (s, 1H), 7.35–7.23 (m, 4H), 7.15
(d, J = 8.4 Hz, 2H), 6.98 (d, J= 8.4 Hz, 2H), 3.89 (s, 3H), 3.09
(q, J= 7.2 Hz, 2H), 1.28 ppm (t, J= 7.2 Hz, 3H); ms: m/z 389
(M+, 5), 327 (12), 308 (8), 274 (18), 203 (11), 142 (10), 140 (14),
115 (19), 105 (100), 77 (82), 50 (24). Anal. Calcd for
C18H19N3O3S2: C, 55.51; H, 4.92; N, 10.79. Found: C, 55.63; H,
4.99; N, 10.66.
4-[1-Cyclohexyl-2-methylthioimidazol-5-yl]benzenesulfonamide
(8m). Following the general procedure, 8m was obtained (40 mg,
40%), mp: 212–214 ꢀC; IR (KBr): 3312 (NH2), 1340, 1156 cm-1
(SO2); 1H NMR (DMSO-d6): d 7.94 (d, J= 8.1 Hz, 2H), 7.44
(d, J= 8.1Hz, 2H), 7.52 (bs, 2H), 7.02 (s, 1H), 4.01 (m, 1H), 2.65
(s, 3H), 2.45–2.10 (m, 4H), 1.92–1.75 (m, 4H), 1.25–1.15 ppm
(m, 2H); ms: m/z 351 (M+, 8), 319 (16), 297 (20), 283 (43), 250
(42), 188 (100), 157 (95), 91 (44), 55 (74). Anal. Calcd for
C16H21N3O2S2: C, 54.67; H, 6.02; N, 11.95. Found: C, 54.87; H,
6.15; N, 11.79.
4-[1-Cyclohexyl-2-ethylthioimidazol-5-yl]benzenesulfonamide
(8n).
Following the general procedure, 8n was obtained
(45 mg, 45%), mp: 198–200 ꢀC; IR (KBr): 3325 (NH2), 1342,
1158 cm-1 (SO2); 1H NMR (DMSO-d6): d 7.91 (d, J = 8 Hz,
2H), 7.45 (d, J = 8 Hz, 2H), 7.48 (bs, 2H), 7.0 (s, 1H), 3.98
(m, 1H), 3.18 (q, J= 7.2 Hz, 2H), 2.45–2.10 (m, 4H), 1.92–1.75
(m, 4H), 1.35 (t, J= 7.2 Hz, 3H), 1.25–1.15 ppm (m, 2H); ms: m/z
365 (M+, 24), 336 (10), 283 (39), 255 (28), 250 (44), 202 (24),
174 (11), 149 (38), 105 (39), 84 (30), 60(100), 45 (92). Anal.
Calcd for C17H23N3O2S2: C, 55.86; H, 6.34; N, 11.50. Found: C,
55.99; H, 6.45; N, 11.39.
4 -[1-(4-Bromophenyl) -2-methylthioimidazol-5-yl]
benzenesulfonamide (8i).
Following the general procedure, 8i
was obtained (60 mg, 57%), mp: 207–209 ꢀC; IR (KBr): 3344
(NH2), 1344, 1157 cm-1 (SO2); 1H NMR (DMSO-d6): d 7.72
(d, J=8.8Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.45 (s, 1H),
7.36–7.26 (m, 4H), 7.23 (d, J= 8.4 Hz, 2H), 2.54ppm (s, 3H); ms:
m/z 425 (M+, 40), 423 (40), 392 (9), 390 (9), 329 (12), 311 (12),
255 (7), 250 (22), 236 (100), 192 (23), 190 (23), 171 (95), 169
(95), 157 (19), 155 (19), 119 (18), 99 (26), 76 (22), 45 (18). Anal.
Calcd for C16H14BrN3O2S2: C, 45.29; H, 3.33; N, 9.90. Found: C,
45.38, H, 3.50; N, 10.02.
Acknowledgment. This research was supported by grants from
the research council of Tehran University of Medical Sciences
and Drug Design & Development Research Center.
REFERENCES AND NOTES
4- [1 - (4 - Bromophenyl) - 2 - ethylthioimidazol-5-yl]
benzenesulfonamide (8j).
Following the general procedure, 8j
[1] Pennig, T.; Talley, J. J.; Bertenshaw, S.; Carter, J.; Collins,
P.; Doctor, S.; Graneto, M.; Lee, L.; Malecha, J.; Miyashiro, J.; Rogers,
R.; Rogier, D.; Yu, S.; Anderson, G.; Burton, E.; Cogburn, J.; Gregory,
S.; Koboldt, C.; Perkins, W.; Siebert, K.; Veenhuizen, A.; Zhang, Y.; Isakson,
P. J Med Chem 1997, 40, 1347.
[2] Riendeau, D.; Percival, M. D.; Brideau, C.; Charleson,
S.; Dube, D.; Ethier, D.; Falguevret, J.-P.; Friesen, R. W.; Gordon,
R.; Greig, G.; Guay, I.; Manacini, J.; Quellet, M.; Wong, E.; Xu,
L.; Boyce, S.; Visco, D.; Girad, Y.; Prasit, P.; Zamboni, R.; Rodger,
J. W.; Gresser, M.; Ford-Hutchinson, A. W.; Young, R. N.; Chan,
C.-C. J Pharmacol Exp Ther 2001, 296, 558.
was obtained (55 mg, 52%), mp: 201–203 ꢀC; IR (KBr): 3325
(NH2), 1346, 1159 cm-1 (SO2); 1H NMR (DMSO-d6): d 7.71
(d, J= 8.4 Hz, 2H), 7.67 (d, J= 8 Hz, 2H), 7.46 (s, 1H), 7.355–7.25
(m, 4H), 7.23 (d, J= 8.4 Hz, 2H), 3.07 (q, J= 7.2 Hz, 2H),
1.27 ppm (t, J= 7.2 Hz, 3H); ms: m/z 439 (M+, 30), 437 (30), 410
(25), 408 (25), 359 (7), 329 (34), 255 (50), 250 (100), 205 (12),
191 (38), 185 (63), 183 (63), 157 (21), 155 (21), 147 (16), 120
(20), 89 (24), 76 (37), 65 (20), 63 (20). Anal. Calcd for
C17H16BrN3O2S2: C, 46.58; H, 3.68; N, 9.59. Found: C, 46.44; H,
3.59; N, 9.76.
[3] Davies, I. W.; Marcoux, J.-F.; Corley, E. G.; Journet, M.; Cai,
D.-W.; Palucki, M.; Wu, J.; Larsen, R. D.; Rossen, K.; Pye, P. J.; Dimichele,
L.; Dormer, P.; Reider, P. J. J Org Chem 2000, 65, 8415.
4-[1-(4-Methoxyphenyl)-2-methylthioimidazol-5-yl]
benzenesulfonamide (8k). Following the general procedure, 8k
was obtained (60 mg, 50%), mp: 256–258 ꢀC; IR (KBr): 3278
[4] Turini, M. E.; DuBois, R. N. Ann Rev Med 2002, 53, 35.
[5] Sakamoto, C.; Soen, S. Digestion 2010, 83, 108.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2014
Synthetic Approaches towards the 1,5-Diarylimidazole-2-thiones
79
[6] Bombardier, C.; Laine, L.; Reicin, A.; Shapiro, D.; Burgos-Vargas,
R.; Davies, B.; Day, R.; Ferraz, M. B.; Hawkey, C. J.; Hochberg, M. C.; Kvien,
T. K.; Schnitzer, T. J. N Engl J Med 2000, 343, 1520.
[7] Silverstein, F. E.; Faich, G.; Goldstein, J. L.; Simon, L. S.; Pincus,
T.; Whelton, A.; Makuch, A.; Eisen, G.; Agrawal, N. M.; Stenson,
W. F.; Burr, A. M.; Zhao, W. W.; Kent, J. D.; Verburg, J. B.; Geis,
G. S. JAMA 2000, 284, 1247.
[8] Katsumata, K.; Musiake, N.; Shibuya, K.; Nakajima, T.;
Watanabe, M.; Sasaki, M.; Sugiyama, Y. Oncology Lett 2011, 2, 509.
[9] Rizzo, M. T. Clinica Chim Acta 2011, 412, 671.
[10] Cakala, M.; Strosznajder, J. B. Neurol Neurochir Pol 2010, 44, 65.
[11] Talley, J. J Prog Med Chem 1999, 36, 201.
[12] Hood, W. F.; Gierse, J. K.; Isakson, P. C.; Kiefer, J. R.; Kurumbail,
R. G.; Siebert, K.; Monahan, J. B. Mol Pharmacol 2003, 63, 870.
[13] Brazier, S. A.; McCombie, H. J Chem Soc 1912, 101, 2352.
[14] McCombie, H.; Scarborough, H. A. J Chem Soc 1913,
103, 56.
[15] Lantos, I.; Gombatz, K.; McGuire, M.; Pridgen, L.; Remich,
J.; Shilcrat, S. J Org Chem 1988, 53, 4223.
[16] Korohoda, M. J.; Bojarska, A. B. J Prakt Chem 1991, 333, 355.
[17] Bhatt, V.; Iyer, B. H.; Guha, P. C. J Indian Inst Sci 1949, 31, 43.
[18] Broan, C. J.; Butler, A. R. J Chem Soc, Perkin Trans 2: Phys
Org Chem 1972–1999, 1991, 1501.
J. R.; Knafla, R. T.; Maye, P. V.; Nikolaides, N.; Oneyemi, F. Y.; Parkhurst,
G. J.; Pecore, S. E.; Reiter, M. J.; Scribner, L. S.; Testerman, T. L.; Thompson,
N. J.; Wagner, T. L.; Weeks, C. E.; Andre, J. D.; Lagain, D.; Bastard,
Y.; Lupu, M. J Med Chem 2005, 48, 3481.
[24] Daha, F. J.; Matloubi, H.; Tabatabai, S. A.; Shafii, B.; Shafiee,
A. J Heterocycl Chem 2005, 42, 33.
[25] Salimi, M.; Amini, M.; Shafiee, A. Phosphorus, Sulfur, and
Silicon 2005, 180, 1587.
[26] Karimi, L.; Navidpour, L.; Amini, M.; Shafiee, A. Phosphorus,
Sulfur, and Silicon 2005, 180, 1593.
[27] Navidpour, L.; Shafaroodi, H.; Abdi, K.; Amini, M.; Ghahre-
mani, M. H.; Dehpour, A. R.; Shafiee, A. Bioorg Med Chem 2006,
14, 2507.
[28] Navidpour, L.; Amini, M.; Shafaroodi, H.; Abdi, K.;
Ghahremani, M. H.; Dehpour, A. R.; Shafiee, A. Bioorg Med Chem
Lett 2006, 16, 4483.
[29] Eskandari, R.; Navidpour, L.; Amini, M.; Shafaroodi, H.;
Shafiee, A. J Heterocycl Chem 2007, 44, 449.
[30] Navidpour, L.; Shafaroodi, H.; Amini, M.; Dehpour, A. R.;
Shafiee, A. Bioorg Med Chem 2007, 15, 1976.
[31] Navidpour, L.; Amini, M.; Shafiee, A. J Heterocycl Chem
2007, 44, 1323.
[32] Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J Org Chem
2003, 68, 2861.
[33] Doney, J. J.; Atland, H. W. J Heterocycl Chem 1979, 16, 1057.
[34] Gierse, J. K.; Zhang, Y.; Hood, W. F.; Walker, M. C.; Trigg, J.
S.; Maziasz, T. J.; Koboldt, C. M.; Muhammad, J. L.; Zweifel, B. S.;
Masferrer, J. L.; Isakson, P. C.; Seibert, K. J Pharmacol Exp Ther 2005,
312, 1206.
[19] Purushothaman, E.; Pillai, V. N. R.; Indian J Chem, Sect B:
Org Chem Includ Med Chem 1990, 29, 18.
[20] Kidwai, M.; Kukreja, S.; Rastogi, S.; Singhal, K. Indian J
Chem, Sect B: Org Chem Includ Med Chem 2007, 46, 1549.
[21] Mehrotra, K. N.; Singh, G. Synthesis 1980, 12, 1001.
[22] Fischer, O. Chem Ber 1894, 27, 2776.
[23] Gerster, J. F.; Lindstrom, K. J.; Miller, R. L.; Tomai, M. A.;
Birmachu, W.; Bomersine, S. N.; Gibson, S. J.; Imbertson, L. M.; Jacobson,
[35] Brideau, C.; Kargman, S.; Liu, S.; Dallob, A. L.; Ehrich, E.
W.; Rodger, I. W.; Chan, C. C. Inflamm Res 1996, 45, 68.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet