Synthesis of novel 2-(2-methylsulfonyl-1-methyl-1H-imidazol-5-yl)-5- (alkylsulfonyl)-1,3,4-thiadiazoles

Article abstract of DOI:10.1002/jhet.535

Starting from 5-hydroxymethyl-2-mercapto-1-methyl-1H-imidazole (1), a series of 2-(1-methyl-2-methylsulfonyl-1H-imidazol-5-yl)-5-alkylthio and 5-alkylsulfonyl-1,3,4-thiadiazole derivatives (9a-d and 10a-d) were prepared as potential antimicrobial agents.

Full text of DOI:10.1002/jhet.535

454
Synthesis of Novel 2-(2-Methylsulfonyl-1-methyl-1H-imidazol-5-
yl)-5-(alkylsulfonyl)-1,3,4-thiadiazoles
Vol 48
Azita Javidnia,a Tahmineh Akbarzadeh,a Loghman Firoozpour,b
Mehdi Khoobi,b Abbas Shafiee,a and Alireza Foroumadia,b
*
aDepartment of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research
Center, Tehran University of Medical Sciences, Tehran 14174, Iran
bDrug Design and Development Research Center, Tehran University of Medical Sciences,
Tehran, Iran
*E-mail: aforoumadi@yahoo.com
Received January 27, 2010
DOI 10.1002/jhet.535
Published online 18 November 2010 in Wiley Online Library (wileyonlinelibrary.com).
Starting from 5-hydroxymethyl-2-mercapto-1-methyl-1H-imidazole (1), a series of 2-(1-methyl-2-
methylsulfonyl-1H-imidazol-5-yl)-5-alkylthio and 5-alkylsulfonyl-1,3,4-thiadiazole derivatives (9a–d
and 10a–d) were prepared as potential antimicrobial agents. The structure of the obtained compounds
was confirmed by NMR, IR, Mass spectroscopy, and elemental analysis.
J. Heterocyclic Chem., 48, 454 (2011).
INTRODUCTION
RESULTS AND DISCUSSION
The treatment of microbial infections has become an
important and challenging problem because of the emer-
gence of multidrug-resistant organisms. During recent
years, there have been intense investigations of different
classes of thiadiazole compounds many of which are
known to possess interesting biological properties such
as antibacterial, antituberculosis, and anticonvulsant
activities [1–3]. Imidazole nucleus has a vital rule and
substituted imidazoles are known to possess several bio-
logical activities, and their antimicrobial properties have
been largely described [4–6]. As a part of an extensive
search for finding new antimicrobial agents, we have
recently reported several classes of broad-spectrum anti-
bacterial agents from 1,3,4-thiadiazole series [7–9]. Fur-
thermore, substituted 1,3,4-thiadiazol-2-sulfides, sulfox-
ides, and sulfones have parasiticidal and antifungal
properties [10,11]. Based on these findings, in continua-
tion of our research program on 1,3,4-thiadiazole deriva-
tives [12,13], herein we would like to report the synthe-
sis of novel 2-substituted-5-alkylthio and 5-alkylsul-
fonyl-1,3,4-thiadiazole derivatives (9a–d and 10a–d)
containing 1-methyl-2-methylsulfonylimidazole moiety
as possible drugs effecting microbial infections.
The synthetic pathway for the target compounds is
shown in Scheme 1. Reaction of 5-hydroxymethyl-2-
mercapto-1-methylimidazole (1) with methyl iodide
afforded 5-hydroxymethyl-2-methylthio-1-methylimida-
zole (2) [14]. Oxidation of alkylthio group with m-chlor-
operbenzoic acid gave compound 3 [15]. Oxidation of
hydroxyl group at 5 position of compound 3 with acti-
vated manganese (IV) oxide yielded the desired alde-
hyde 4 [16].
Reaction of compound 4 with thiosemicarbazide in
refluxing ethanol afforded thiosemicarbazone 5. Oxida-
tive cyclization of compound 5 with ammonium iron
(III) sulfate dodecahydrate afforded 5-(1-methyl-2-meth-
ylsulfonyl-1H-imidazol-5-yl)-1,3,4-thiadiazole-2-amine (6).
Diazotization of 6 using NaNO2 in hydrochloric acid in
the presence of copper powder gave 2-chloro-5-(1-methyl-
2-methylsulfonyl-1H-imidazol-5-yl)-1,3,4-thiadiazole (7).
Reaction of compound 7 with excess of thiourea gave
5-(1-methyl-2-methylsulfonyl-1H-imidazol-5-yl)-1,3,4-thia-
diazole-2-thiol (8). Alkylation of compound 8 with appro-
priate alkyl halide gave the corresponding alkylthio-1,3,4-
thiadiazoles 9a–d. Subsequent oxidation of the sulfides
9a–d with hydrogen peroxide in glacial acetic acid gave
C
V
2010 HeteroCorporation

March 2011
Synthesis of Novel 2-(2-Methylsulfonyl-1-methyl-1H-imidazol-5-yl)-
5-(alkylsulfonyl)-1,3,4-thiadiazoles
455
Scheme 1
alkylsulphonyl derivatives 10a–d. The structure of all
[17], these novel 2-substituted-5-alkylthio and 5-alkyl-
sulfonyl-1,3,4-thiadiazole derivatives (9a–d and 10a–d)
containing 1-methyl-2-methylsulfonylimidazole moiety
have possibility to possess some biological properties
such as antibacterial, antituberculosis, and antifungal
activities based on their structures.
1
compounds was identified according to their H-NMR, IR,
and Mass spectroscopy.
According to the observed antimicrobial properties of
alkylthio and alkylsulfonyl-1,3,4-thiadiazoles such as
antifungal [10] and anti-Helicobacter pylori activities
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

456
A. Javidnia, T. Akbarzadeh, L. Firoozpour, M. Khoobi, A. Shafiee, and A. Foroumadi
Vol 48
1
EXPERIMENTAL
idazole); H NMR (DMSO-d6): d 3.50 (s, 3H, CH3S), 4.11 (s,
3H, CH3N), 7.72 (s, 1H, H-C4-imidazole); ms: m/z 276 (Mþ,
36), 200 (14), 76 (50). Anal. Calcd. For C7H8N4O2S3: C,
30.42; H, 2.92; N, 20.27. Found: C, 30.60; H, 3.23; N, 20.29.
General procedure for the synthesis of 2-(1-methyl-2-
methylsulfonyl-1H-imidazol-5-yl)-5-alkylthio-1,3,4-thiadia-
zoles (9). To a stirred solution of compound 8 (1 mmol) in
methanol (5 mL), 1.0N solution of sodium hydroxide (1 mL)
was added, and the mixture was stirred for 5 min. After addi-
tion of excess amounts of alkyl halide (3 mmol), the mixture
was stirred overnight. Methanol was removed under reduced
pressure, water was added to the residue, and the product was
extracted with chloroform and crystallized from ethanol.
Melting points were determined on a Kofler hot-stage appa-
ratus and are uncorrected. The IR spectra were obtained using
a Nicolet FT-IR magna 550 spectrograph. The 1H-NMR was
obtained on a Bruker 80 MHz. Mass spectra were obtained on
a Finnigan MAT-TSQ 70 spectrometer at 70 eV. Elemental
analyses for compounds 9a–d and 10a–d were within 60.4%
of theoretical value for C, H and N.
1-Methyl-2-methylsulfonyl-1H-imidazol-5-carbaldehyde thio-
semicarbazone (5). To a stirring mixture of compound 4 (4.7
g, 25 mmol) and thiosemicarbazide (2.46 g, 27 mmol) in etha-
nol (20 mL), three drops of hydrochloric acid 37% was added,
and the mixture was refluxed for 2 h. After cooling, the pre-
cipitate was filtered, washed with methanol, and crystallized
from ethanol–water 50:50 to give 5 as pale yellow powder,
(yield ¼ 82%), mp 242–243ꢀC; IR (KBr): 1325, 1165 cmꢁ1
(SO2); 1H NMR (DMSO-d6): d 3.43 (s, 3H, CH3S), 4.01 (s,
3H, CH3N), 7.70 (bs, 2H, NH2), 8.01 (s, 1H, H-C4 imidazole),
8.41 (s, 1H, NH), 11.49 (s, 1H, CH); ms: m/z 261 (Mþ, 100),
244 (39), 202 (36), 186 (68), 182 (21), 122 (30). Anal. Calcd.
For C7H11N5O2S2: C, 32.17; H, 4.24; N, 26.80. Found: C,
31.85; H, 4.23; N, 26.61.
2-(1-Methyl-2-methylsulfonyl-1H-imidazol-5-yl)-5-methylthio-
1,3,4-thiadiazole (9a). (yield ¼ 42%), mp 189–191ꢀC; IR
1
(KBr): 1372, 1132 cmꢁ1 (SO2); H NMR (CDCl3): d 2.85 (s,
3H, CH3S), 3.44 (s, 3H, CH3SO2), 4.33 (s, 3H, CH3N), 7.42
(s, 1H, H-C4 imidazole); ms: m/z 290 (Mþ, 100), 218 (42),
173 (78), 138 (72), 98 (43), 92 (85), 89 (82). Anal. Calcd. For
C8H10N4O2S3: C, 33.09; H, 3.47; N, 19.29. Found: C, 33.12;
H, 3.16; N, 19.00.
2-(1-Methyl-2-methylsulfonyl-1H-imidazol-5-yl)-5-ethylthio-
1,3,4-thiadiazole (9b). (yield ¼ 40%), mp 142–146ꢀC; IR
(KBr): 1326 and 1142 cmꢁ1 (SO2); 1H NMR (DMSO-d6): d
1.42 (t, 3H, CH3), 3.42 (q, 2H, CH2), 4.19 (s, 3H, CH3N),
7.78 (s, 1H, H-C4 imidazole); ms: m/z 304 (Mþ, 100), 271
(43), 217 (20), 203 (28), 171 (50), 126 (79), 84 (43). Anal.
Calcd. For C9H12N4O2S3: C, 35.51; H, 3.97; N, 18.40. Found:
C, 35.53; H, 3.98; N, 18.38.
5-(1-Methyl-2-methylsulfonyl-1H-imidazol-5-yl)-1,3,4-thia-
diazole-2-amine (6). To a mixture of compound 5 (5.20 g, 20
mmol) and ammonium iron sulfate dodecahydrate (24.1 g, 50
mmol), water (250 mL) was added and refluxed for 1 h. Then,
water (500 mL) and ammonium iron sulfate dodecahydrate
(48.2 g, 100 mmol) were added again, and the mixture was
refluxed for 3 h. The cold reaction mixture was filtered, and
the filtrate was concentrated under the vacuum and extracted
with ethyl acetate. Ethyl acetate was evaporated, and final
compound was crystallized from ethanol to give 6 as a white
powder, (yield ¼ 75%), mp 223–226ꢀC; IR (KBr): 1311, 1137
2-(1-Methyl-2-methylsulfonyl-1H-imidazol-5-yl)-5-(n-pro-
pylthio)-1,3,4-thiadiazole (9c). (yield
¼
81%), mp 130–
132ꢀC; IR (KBr):1367 and 1132 cmꢁ1 (SO2); 1H NMR
(CDCl3): d 1.08 (t, 3H, CH3), 1.6–2.3 (m, 2H, CH2), 3.28–
3.44 (m, 5H, CH3SO2, CH2S), 4.34 (s, 3H, CH3N), 7.41 (s.
1H, H-C4 imidazole); ms: m/z 318 (Mþ, 72), 277 (100), 204
(26), 201 (16), 173 (57), 139 (43), 974 (43), 80 (64), 70 (85).
Anal. Calcd. For C10H14N4O2S3: C, 37.72; H, 4.43; N, 17.59.
Found: C, 38.02; H, 4.64; N, 17.60.
1
(SO2), 3421, 3277 cmꢁ1 (NH2); H NMR (CDCl3, DMSO-d6):
d 3.4 (s, 3H, CH3S), 4.40 (s, 3H, CH3N), 6.92 (bs, 2H, NH2),
7.50 (s, 1H, H-C4 imidazole); ms: m/z 259 (Mþ, 100), 217
(15), 172 (27), 138 (21), 96 (15), 74 (21). Anal. Calcd. For
C7H9N5O2S2: C, 32.42; H, 3.50; N, 27.01. Found: C, 32.24; H,
3.19; N, 27.31.
2-(1-Methyl-2-methylsulfonyl-1H-imidazol-5-yl)-5-(ben-
zylthio)-1,3,4-thiadiazole (9d). (yield ¼ 70%), mp 159–
161ꢀC; IR (KBr): 1362 and 1142 cmꢁ1 (SO2); 1H NMR
(CDCl3): d 3.44 (s, 3H, CH3SO2), 4.32 (s, 3H, CH3N), 4.62 (s,
2H, CH2), 7.30–7.60 (m, 6H, H-C4 imidazole, 5H, aromatic);
ms: m/z 366 (Mþ, 72), 344 (15), 204 (15), 1481 (11), 90
(100), 64 (79). Anal. Calcd. For C14H14N4O2S3: C, 45.88; H,
3.85; N, 15.29. Found: C, 45.88; H, 4.22; N, 14.97.
General procedure for the synthesis of 2-(1-methyl-2-
methylsulfonyl-1H-imidazol-5-yl)-5-alkylsulfonyl-1,3,4-thia-
diazole (10). To a stirred solution of compound 9 (0.35
mmol) in glacial acetic acid (1 mL), excess amount of hydro-
gen peroxide 37% (1 mL) was added and refluxed for 2 h.
Evaporating of the solvent under reduced pressure gave com-
pound 10, which was crystallized from ethanol.
2-Chloro-5-(1-methyl-2-methylsulfonyl-1H-imidazol-5-yl)-
1,3,4-thiadiazole (7). Compound 6 (1.56 g, 6 mmol) and so-
dium nitrite (138 g, 20 mmol) were robbed for 10 min. This
mixture was added slowly to a mixture of hydrochloric acid
37% (4.48 mL) and water (1.92 mL) containing copper powder
(0.08 g) at 0ꢀC. The mixture was stirred in an ice-bath for 1 h
and then at room temperature for 2 h. The resulting mixture
was heated at 60ꢀC for 15 min. The product was extracted
with chloroform. The solvent was removed, and the residue
was crystallized from ethanol to give compound 7 (yield ¼
1
50%), mp 155–159ꢀC; IR (KBr): 1320, 1150 cmꢁ1 (SO2); H
NMR (DMSO-d6): d 3.53 (s, 3H, CH3SO2), 4.21 (s, 3H,
CH3N), 7.92 (s, 1H, H-C4 imidazole); ms: m/z 280 (Mþ þ 2,
15), 278 (Mþ, 42), 217 (36), 172 (58), 138 (51), 97 (58).
Anal. Calcd. For C7H7ClN4O2S2: C, 30.16; H, 2.53; N, 20.10.
Found: C, 29.98; H, 2.52; N, 20.10.
5-(1-Methyl-2-methylsulfonyl-1H-imidazol-5-yl)-1,3,4-thia-
diazole-2-thiol (8). Compound 7 (1.4 g, 5 mmol) and excess
of thiourea (1.52 g, 20 mmol) in ethanol (15 mL) was stirred
at room temperature for 3 days. The precipitate was filtered
and gave compound 8 which was crystallized from ethanol
(yield ¼ 64%), mp 227–230ꢀC; IR (KBr): 3093 cmꢁ1 (CH-im-
2-(1-Methyl-2-methylsulfonyl-1H-imidazol-5-yl)-5-(methylsul-
fonyl)-1,3,4-thiadiazole (10a). (yield ¼ 46%), mp 240–242ꢀC;
1
IR (KBr): 1326 and 1142 cmꢁ1 (SO2); H NMR (DMSO-d6):d
3.49 (s, 3H, CH3SO2), 3.62 (s, 3H, CH3SO2), 4.29 (s, 3H,
CH3N), 7.78 (s, 1H, H-C4 imidazole); ms: m/z 322 (Mþ, 21),
217 (21), 123 (21), 93 (29), 85 (50), 79 (59), 66 (100). Anal.
Calcd. For C8H10N4O4S3: C, 29.80; H, 3.13; N, 17.38. Found:
C, 29.62; H, 3.00; N, 17.60.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
Synthesis of Novel 2-(2-Methylsulfonyl-1-methyl-1H-imidazol-5-yl)-
5-(alkylsulfonyl)-1,3,4-thiadiazoles
457
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2-(1-Methyl-2-methylsulfonyl-1H-imidazol-5-yl)-5-(ethylsul-
fonyl)-1,3,4-thiadiazole (10b). (yield ¼ 55%), mp 203–206ꢀC;
1
IR (KBr): 1337 and 1133 cmꢁ1 (SO2); H NMR (DMSO-d6):d
1.56 (t, 3H, CH3), 3.52 (s, 3H, CH3SO2), 3.68 (q, 2H,
CH2SO2), 4.45 (s, 3H, CH3N), 7.66 (s, 1H, H-C4 imidazole);
ms: m/z 336 (Mþ, 100), 218 (60), 173 (73), 139 (58), 123
(66), 98 (60), 80 (80), 58 (15). Anal. Calcd. For
C9H12N4O4S3: C, 32.13; H, 3.60; N, 16.65. Found: C, 32.45;
H, 3.39; N, 16.46.
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2-(1-Methyl-2-methylsulfonyl-1H-imidazol-5-yl)-5-(n-propyl-
sulfonyl)-1,3,4-thiadiazole (10c). (yield ¼ 60%), mp 189–
192ꢀC; IR (KBr): 1326 and 1142 cmꢁ1 (SO2); 1H NMR
(CDCl3): d 1.12 (t, 3H, CH3), 1.75–2.36 (m, 2H, CH2), 3.44
(s, 3H, CH3SO2), 3.71 (t. 2H, CH2SO2), 4.35 (s, 3H, CH3N),
7.40 (s, 1H, H-C4 imidazole); ms: m/z 350 (Mþ, 100), 336
(27), 145 (61), 91 (10), 62 (70). Anal. Calcd. For
C10H14N4O4S3: C, 34.27; H, 4.03; N, 15.99. Found: C, 34.24;
H, 4.04; N, 16.00.
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2782.
2-(1-Methyl-2-methylsulfonyl-1H-imidazol-5-yl)-5-(benzylsul-
fonyl)-1,3,4-thiadiazole (10d). (yield ¼ 50%), mp 197–199ꢀC;
[11] Foroumadi, A.; Rineh, A.; Emami, S.; Siavoshi, F.; Massar-
rat, S.; Safari, F.; Rajabalian, S.; Falahati, M.; Lotfali, E.; Shafiee, A.
Bioorg Med Chem Lett 2008, 18, 3315.
1
IR (KBr): 1337, 1147 cmꢁ1 (SO2); H NMR (CDCl3): d 3.45
(s, 3H, CH3SO2), 4.36 (s, 3H, CH3N), 4.83 (s, 2H, CH2), 7.3–
7.53 (m, 6H, H-C4 imidazole, 5H benzyl); ms: m/z 398 (Mþ,
10), 334 (26), 137 (16), 91 (100), 63 (99).). Anal. Calcd. For
C14H14N4O4S3: C, 42.20; H, 3.54; N, 14.06. Found: C, 42.42;
H, 3.54; N, 14.27.
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Acknowledgment. This work was supported by a grant from the
Research Council of Tehran University of Medical Sciences.
[15] Shafiee, A.; Akbarzadeh, T.; Foroumadi, A.; Hadizadeh, F.
J Heterocycl Chem 1998, 35, 141.
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Pharm Acta Helv 1998, 73, 75.
REFERENCES AND NOTES
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet