Syntheses of 2-alkylthio-(4,5-diaryl)imidazoles

Article abstract of DOI:10.1080/104265090884265

A series of 2-alkylthio-4,5-diarylimidazoles were synthesized in three steps. The reaction of ammonium thiocyanate with benzoylbenzoins 4 gave 4,5-diarylimidazole-2-thiones 5. Alkylation of compound 5 with alkyl iodide yielded 2-alkylthio-4,5-diarylimidaz

Full text of DOI:10.1080/104265090884265

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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Syntheses of 2-Alkylthio-(4,5-
Diaryl)imidazoles
Mona Salimi a , Mohsen Amini a & Abbas Shafiee a
a Department of Chemistry and Pharmaceutical
Sciences Research Center, Tehran University of
Medical Sciences, Tehran, Iran
Published online: 01 Feb 2007.
To cite this article: Mona Salimi , Mohsen Amini & Abbas Shafiee (2005) Syntheses of
2-Alkylthio-(4,5-Diaryl)imidazoles , Phosphorus, Sulfur, and Silicon and the Related
Elements, 180:7, 1587-1592, DOI: 10.1080/104265090884265
To link to this article: http://dx.doi.org/10.1080/104265090884265
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Phosphorus, Sulfur, and Silicon, 180:1587–1592, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090884265
Syntheses of 2-Alkylthio-(4,5-Diaryl)imidazoles1
Mona Salimi
Mohsen Amini
Abbas Shafiee
Department of Chemistry and Pharmaceutical Sciences Research
Center, Tehran University of Medical Sciences, Tehran, Iran
A series of 2-alkylthio-4,5-diarylimidazoles were synthesized in three steps. The re-
action of ammonium thiocyanate with benzoylbenzoins 4 gave 4,5-diarylimidazole-
2-thiones 5. Alkylation of compound 5 with alkyl iodide yielded 2-alkylthio-4,5-
diarylimidazoles 6. Chlorosulfonation of compound 6 followed by ammonia gave
the desired compounds 4-[2-alkylthio-4(5)-(4-substituted phenyl)imidazole-5(4)-
yl]benzensulfonamides 7.
Keywords 2-Alkylthioimidazole; 4,5-diarylimidazole; imidazole
INTRODUCTION
Extensive libraries of selective Cox-II inhibitors have been developed
by different laboratories in the last 10 years. Most of the compounds fit
into three categories: (1) acidic sulfonamide such as NS-398,2 (2) diaryl-
heterocycles such as rofecoxib and celecoxib3,4, and (3) modifications of
classical nonsteroidal anti-inflammatory drugs (NSAIDs) such as in-
domethacin derivatives.
Flumizole is one of the early known 4,5-diarylimidazoles showing an-
tiinflammatory activity.5 Work from a number of laboratories has shown
that certain diarylheterocycles have useful antiinflammatory activity.
2-Alkyl-4,5-diaryl-imidazoles, 2-(trifluoromethyl)-4,5-diarylimidazoles,
2,4,5-triarylimidazoles, and 2,3-bis(4-methoxyphenyl)indole have all
been reported to have antiinflammatory activity.6 Further studies have
suggested that proper effect could be easily conferred by incorporation of
a suitably disposed sulfonamide pharmacophore and alkylthio group.7,8
Received June 8, 2004; accepted July 2, 2004.
This work was supported by grants from the Research Council of Tehran University
of Medical Sciences.
Address correspondence to Abbas Shafiee, Faculty of Pharmacy, Tehran University
Medical Sciences, PO Box 14155-6451, Tehran, Iran. E-mail: ashafiee@ams.ac.ir
1587

1588
M. Salimi et al.
We now report synthesis of
a
series of 2-alkylthio-4,5-
diarylimidazoles as possible Cox-II inhibitors.
RESLUTS AND DISCUSSION
It has been shown that 2-benzylthio-4(5)-phenylimidazole could be pre-
pared by the reaction of S-benzylthiourea with phenacylbromide.9 This
reaction was extended to the preparation of 1-substituted-2-alkylthio-
4-phenylimidazoles by preparation of N-substituted-S-alkylthio ureas
with phenacylbromide.10 The reaction of S-ethylthiourea 1 with α-
bromoketone 2 (see Scheme 1) did not give the expected imidazole
5. Instead, the compound 2 was debrominated and deoxybenzoin 3
was isolated. Also, the reaction between compound 2 and ammo-
nium acetate and potassium thiocyanate did not give the desired
compounds.11
SCHEME 1 A possible route for synthesis of compounds.
Finally, the reaction of benzoyl acyloins 4 with ammonium thio-
cyanate in amyl alcohol at 150–200◦C gave the 4,5-diarylimidazole-2-
thiones 5 in good yield.12
Alkylation of compound 5 with alkyl iodide in the presence of sodium
hydroxide, sodium carbonate, and sodium alkoxide in methanol gave S
and N-dialkylated compounds, and the desired compounds 6 were not
obtained. However, alkylation could be accomplished in the presence of
triethylamine.
The reaction of compound 6 with chlorosulfonic acid at ice-bath
temperature followed by ammonia gave the desired compounds 7
(Scheme 2).
EXPERIMENTAL
Melting points were determined on a Kofler hot-stage apparatus and
are uncorrected. The IR spectra were obtained using a Nicolet FT-IR

Alkylthioimidazoles
1589
SCHEME 2 Synthesis of 4-[2-alkylthio-4(5)-(4-substituted phenyl) imidazole-
5(4)-yl] benzene sulfonamide (7)
Magna 550 spectrographs; the 1HNMR were obtained on a 400 Varian
Unity plus spectrometer. Mass spectra were obtained on a Finnigan
MAT TSQ 70 spectrometer at 70 eV. Column chromatography was car-
ried out using silica gel (230–400 mesh).
Preparation of 4,5-Diarylimidazole-2-thiones 5
General Procedure
A mixture of compound 4 (1 mmol)13 and ammonium thiocyanate
(1 mmol) in amyl alcohol or butyl alcohol was refluxed for 5 h. The
product was crystallized on cooling the reaction mixture. The unre-
acted benzoin was removed from the product by washing with ether and
the ammonium thiocyanate by water. The white-to-light yellow solids
were separated and crystallized from methanol. The yield was 80–
90%.
Selected data for 4(5)-(4-fluorophenyl)-5(4)-phenylimidazole-2-thione
1
5a,white solid, m.p. 277–280◦C, yield = 90%. H NMR (DMSO-d6): δ
7.1–7.3 (m, aromatic), IR (KBr) (νmax, cm−1): 1234, 1506, 3047; MS, m/z
(%): 270(M+, 43), 220 (23), 203 (100), 138 (57), 121 (35); Anal. Calcd.
for C15H11FN2S: C, 66.67; H, 4.07; N, 10.37. Found: C, 66.35; H, 4.35;
N, 10.54.
Compounds 5b–d were prepared similar to literature (see Table I).

1590
M. Salimi et al.
TABLE I Data for Compounds 5a–d
Calcd.
H
Found
H
Comp
no.
Yield
(%)
X
m.p. ◦
C
Formula
C
N
C
N
5a
5b
5c
5d
F
Cl
Me
OMe
90
89
80
80
277–280 C15H11FN2S 66.67 4.07 10.37 66.35 4.35 10.54
294–296 C15H11ClN2S 62.83 3.84 9.77 62.62 3.57 9.52
153–155
C16H14N2S
72.18 5.26 10.53 72.01 5.09 10.21
156–159 C16H14N2OS 68.08 4.96 9.93 68.23 5.12 10.10
Preparation of 2-Alkylthio-4,5-diarylimidazoles 6
General Procedure
A mixture of compound 5 (1 mmol) in methanol, alkyl iodide (4 mmol),
and excess amounts of triethylamine (up to pH = 10) was stirred at
room temperature for 24 h. Methanol was removed under reduced
pressure and the residue was purified by column chromatography us-
ing chloroform-ethyl acetate (5:1) and crystallized from chloroform-
petroleum ether. The yield was (16–63%) with methyl iodide and (24–
81%) with ethyl iodide.
Selected data for 2-ethylthio-4(5)-(4-fluorophenyl)-5(4)-phenylimida-
1
zole 6a white solid, m.p. 198–199◦C, yield = 81%. H NMR (CDCl3): δ
1.3 (t, 3H), 3.1 (q, 2H), 6.9 (m, 2H), 7.3 (m, 7H); MS, m/z (%): 298 (M+,
42), 297 (100), 279 (28), 264 (39), 246 (18), 229 (19); Anal. Calcd. for
C17H15FN2S: C, 68.46; H, 5.03; N, 9.39. Found: C, 68.21; H, 4.90; N,
9.12.
Compounds 6b–g were prepared using a similar procedure (see
Table II).
TABLE II Data for Compounds 6a–g
Calcd.
H
Found
H
Comp
no.
Yield
R
X
(%) m.p. ◦C
Formula
C
N
C
N
6a
6b
6c
6d
6e
6f
Et
Me
Et Cl
Me Cl
Et Me
Me Me
F
F
81 198–199 C17H15FN2S 68.46 5.03 9.39 68.21 4.90 9.12
63 242–245
80 215–218
C
C
16H13FN2S 67.60 4.58 9.86 67.34 4.30 9.55
17H15ClN2S 64.86 4.77 8.90 64.98 4.94 8.71
60 270–273 C16H13ClN2S 63.89 4.33 9.32 63.95 4.50 9.52
76 109–111 C18H18N2S
59 102–105 17H16N2S
73.47 6.12 9.52 73.21 5.90 9.32
72.86 5.71 10.00 72.60 5.45 9.69
C
6g
Et OMe 24 112–115 C18H18N2OS 69.68 5.81 9.03 69.43 5.55 9.23

Alkylthioimidazoles
1591
TABLE III Data for Compounds 7a–j
Calcd.
H
Found
H
Comp
no.
Yield
R
X
(%) m.p. ◦
C
Formula
C
N
C
N
7a
7b
7c
7d
7e
7f
7g
7h
7i
Me H
Et
Me F
Et
Me Cl
Et Cl
Me Me
Et Me
12
12
>350 C16H15N3O2S2
>350 C17H17N3O2S2
55.65 4.35 12.17 55.53 4.28 12.06
56.82 4.73 11.70 56.70 4.57 11.59
H
20 236–239 C16H14FN3O2S2 52.89 3.86 11.57 52.58 3.68 11.36
20 232–236 C17H16FN3O2S2 54.11 4.24 11.14 54.09 4.17 11.03
19 135–138 C16H14ClN3O2S2 50.59 3.69 11.07 50.49 3.71 11.16
19 145–148 C17H16ClN3O2S2 51.84 4.07 10.67 51.73 4.19 10.37
16
16
F
oil-
oil-
oil-
oil-
C17H17N3O2S2
C18H19N3O2S2
56.82 4.37 11.70 56.68 4.57 11.90
57.90 5.09 11.26 57.88 5.13 11.57
54.40 4.53 11.20 54.78 4.36 11.58
55.53 4.88 10.80 55.61 4.92 11.02
Me OMe 10
Et OMe 10
C
17H17N3O3S2
7j
C18H19N3O3S2
Preparation of 4-[2-Alkylthio-4(5)-(4-substituted
Phenyl)imidazole-5(4)-yl]benzensulfonamide 7
General Procedure
To a magnetically stirred solution of compound 6 (1 mmol) was added
slowly chlorosulfonic acid (5 mmol) at ice-bath temperature. After 4–
5 h cold water was added and yellow solid obtained. After filtration,
the residue was dissolved in methanol and excess amounts of ammonia
added. The solution stirred for 24 h. Methanol was removed at reduced
pressure and the residue purified by preparative thin layer chromatog-
raphy with solvent system chloroform-methanol (5:1) and crystallized
from methanol-petroleum ether.
Selected data for 4-[2-methylthio-4(5)phenylimidazole-5(4)-yl]benze-
nesulfonamide 7a yellow solid, m.p. >350◦, yield = 12%. 1H NMR
(DMSO-d6): δ 2.5 (s, 3 H), 7.3 (m, 5H), 7.5 (d, 2 H), 7.6 (d, 2 H); MS,
m/z (%): 345 (M+, 7), 266 (14), 252 (100), 220 (20), 165 (32); Anal. Calcd.
for C16H15N3O2S2: C, 55.65; H, 4.35; N, 12.17. Found: C, 55.53; H, 4.28;
N, 12.06.
Compounds 7b–j were prepared using a similar procedure (see
Table III).
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