Syntheses of 4,5-diaryl-1,2,3-thiadiazoles

Article abstract of DOI:10.1080/104265090884283

Reaction of thionyl chloride with semicarbazones of 1-(4- methylsulfonylphenyl)-2-(4-substituted pheny)lethanone gave 4-(4- methylsulfonylphenyl)-5-(4-substituted) pheny-1,2,3-thiadiazoles 5. Compounds 5-phenyl-4-(substitutedphenyl)-1,2,3-thiadiazoles 14 were similarly prepared. Chlorosulfonation of the latter followed by ammonia gave the desired compounds 5-(4-aminosulfonylphenyl)-4-(substituted) phenyl-1,2,3-thiadiazoles 6. Copyright Taylor & Francis Inc.

Full text of DOI:10.1080/104265090884283

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Syntheses of 4,5-Diaryl-1,2,3-
thiadiazoles
Lila Karimi a , Latifeh Navidpour a , Mohsen Amini a
& Abbas Shafiee a
a Deapartment of Chemistry, Tehran University of
Medical Sciences, Tehran, Iran
Version of record first published: 01 Feb 2007.
To cite this article: Lila Karimi , Latifeh Navidpour , Mohsen Amini & Abbas Shafiee
(2005): Syntheses of 4,5-Diaryl-1,2,3-thiadiazoles , Phosphorus, Sulfur, and Silicon and
the Related Elements, 180:7, 1593-1600
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Phosphorus, Sulfur, and Silicon, 180:1593–1600, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090884283
Syntheses of 4,5-Diaryl-1,2,3-thiadiazoles1
Lila Karimi
Latifeh Navidpour
Mohsen Amini
Abbas Shafiee
Deapartment of Chemistry, Tehran University of Medical Sciences,
Tehran, Iran
Reaction of thionyl chloride with semicarbazones of 1-(4-methylsulfonylphenyl)-2-
(4-substituted pheny)lethanone gave 4-(4-methylsulfonylphenyl)-5-(4-substituted)
pheny-1,2,3-thiadiazoles 5. Compounds 5-phenyl-4-(substitutedphenyl)-1,2,3-
thiadiazoles 14 were similarly prepared. Chlorosulfonation of the latter followed by
ammonia gave the desired compounds 5-(4-aminosulfonylphenyl)-4-(substituted)
phenyl-1,2,3-thiadiazoles 6.
Keywords 1,2,3-Thiadiazole; 4,5-diaryl-1,2,3-thiadiazole; sulfonamide
INTRODUCTION
Highly selective cyclooxygenase (COX-2) inhibitor currently provide ef-
fective treatment of inflammatory diseases such as rheumatoid arthri-
tis and osetoarthritis, with improved therapeutics and fewer side
effects.2 Recent studies have shown that selective COX-2 inhibitors
can induce apotosis in colon, stomach, prostate, and breast cancer
cell lines.3−6 Selective COX-2 inhibitors offer potential for the prophy-
lactic prevention of inflammatory neurodegerative disorders such as
Alzheimer’s disease.7
Diarylheterocycles (such as Celecoxibe, Refecoxib, and Valdecoxib)
constitute a major class of selective COX-2 inhibitor drugs that pos-
sess a central five-membered heterocycles ring. Diarylthiadiazoles, 4
(Figure 1) showed only moderate COX-2 inhibition activity.8 We now
report synthesis of a series of 1,2,3-thiadiazoles with a suitably dis-
posed sulfonamide or methylsulfonyl pharmacophore.
Received July 2, 2004; accepted July 2, 2004.
Address correspondence to Abbas Shafiee, Faculty of Pharmacy, Tehran University of
Medical Sciences, PO Box. 14155-6451, Tehran, Iran. E-mail: ashafiee@ams.ac.ir
1593

1594
L. Karimi et al.
FIGURE 1 Structure of COX-2 inhibitors and 4,5-diaryl-1,2,3-thiazoles.
RESULTS AND DISCUSSION
Synthesis of thiadiazoles have been reported via several pathways. Re-
action of aryl isothiocyanates with diazomethane gave the arylthiazole
ring.9 Diazotizing of α-amino ketones followed by ammonium hydrogen
sulfide10 or thionyl chloride with hydrazone gave 1,2,3-thiadiazole.11
In the present work, reaction between semicarbazone of ketones and
thionyl chloride that has been reported12 was extended for the prepa-
ration of 4,5-diaryl thiadiazole. The synthetic reactions used for the
synthesis of 5-(4-substituted phenyl)-4-(4-methylsulfonylphenyl)-1,2,3-
thiadiazole 5 and sulfonamide derivatives 6 are outlined in Schemes 1
and 2, respectively. Friedel-Crafts acylation of thioanisole 8 with sub-
stituted phenylacetyl choride 7 afforded 1-(4-methylthiophenyl)-2-(4-
substitutedphenyl)ethanone 9. Oxidation of compound 9 with oxone
at room temperature resulted in the Baeyer-Villiger rearrangement
and the corresponding ester of 9 instead of the expected compound 10
was isolated. However, Reaction of the ketone 10 with semicarbazide
hydrochloride in methanol-water yielded the corresponding semicar-
bazione 11. Reaction of the latter with thionyl chloride gave the desired
compounds 5 in moderate to good yield (69–80%) (Scheme 1).

Diarylthiadiazoles
1595
SCHEME 1
Thiadiazoles 14 was prepared in a similar manner (Scheme 2).
Chlorosulfonation of 14 at ice-bath temperature followed by aqueous
ammonia gave the desired compounds 6. The structures of all com-
pounds were confirmed by IR, 1H-NMR, and Mass spectra.
EXPERIMENTAL
Melting points were determined on a Kofler hot-stage apparatus and
are uncorrected. The IR spectra were obtained using a Nicolet FT-IR
Magna 550 spectrographs; the 1HNMR were obtained on a 400 Varian
Unity plus spectrometer. Mass spectra were obtained on a Finnigan

1596
L. Karimi et al.
SCHEME 2
MAT TSQ 70 spectrometer at 70 eV. Column chromatography was car-
ried out using silica gel (230–400 mesh).
Preparation of 1-[4-methylthiophenyl]-2-(4-substituted
Phenyl)ethanone 9
General Procedure
To a stirring mixture of aluminum chloride (0.9 mol) in methylen
chloride (100 mL) at ice-bath temperature phenyl acetyl chloride (0.06
mole) was added. After 30 min thioanisole (0.06 mole) was slowely added

Diarylthiadiazoles
1597
and stirred for 24 h. Cruched ice (100 g) was added and the mixture
extracted with methylen chloride (3 × 100 mL). Organic phase was
dried (sodium sulfate) and filtered. The solvent was evaporated under
reduced pressure and the residue was crystallized from hexane. The
yield was 50–80%.
Selected data for 2-(4-flurophenyl)-1-(4-methylthiophenyl)etha-
none 9a. White solid, m.p. 135–138◦C, yield = 75%. 1H NMR (CDCl3):
δ 2.50 (s, 3H, CH3), 4.19 (s, 2H, CH2), 6.97–7.30 (m, 6H), 7.80 (d, 2H,
J = 8.8 Hz); IR (KBr)(νmax, cm−1): 1676 (CO); MS, m/z (%): 260(M+, 52),
213 (13), 151 (38), 137 (23), 109 (100).
Compounds 9b–9d were prepared similarly (See Table I).
Using halobenzene instead of thioanisole compounds 12a–12c were
prepared similarly (see Table I).
Preparation of 1-(4-Methylsulfonyl)phenyl-2-(4-substituted
Phenyl)ethanone 10
General Procedure
To a magnetically stirred solution of compound 9 (8 mmol) in a mix-
ture of methanol (80 mL) and THF (80 mL) was added slowly oxone
(10.60 g, 16 mmol) in water (40 mL) at ice-bath temperature. After 4 h
the mixture was filtered and the volume was reduced to about 40 mL
under reduced pressure. The mixture was extracted with ethyl acetate
(3 × 50 mL). The organic phase was dried (sodium sulfate) and the
TABLE I Data for Compounds 9(a–c) and 12(a–c)
Calcd. (%)
Found (%)
Comp.
No.
Yield
(%)
X
m.p. ◦
C
Formula
C
H
C
H
9a
9b
9c
9d
9e
10a
10b
10c
10d
10e
12a
12b
12c
F
75
68
51
60
55
82
70
52
45
46
42
54
54
135–138
124–127
170–172
97–98
110–114
150–153
180–184
188–191
175–178
163–165
71–74
C15H13FOS
C15H13ClOS
69.21
65.09
56.08
74.34
70.56
61.63
58.35
51.00
65.67
66.64
78.49
72.89
61.11
5.03
4.73
4.08
5.92
5.92
4.48
4.24
3.71
5.14
5.59
5.18
4.83
4.05
69.37
65.19
56.32
73.99
70.11
61.19
58.60
51.09
65.98
66.02
78.41
72.51
60.89
4.93
4.46
4.26
5.50
5.98
4.73
4.39
3.79
4.88
5.40
4.96
4.61
3.86
Cl
Br
H
OCH3
F
Cl
Br
H
H
F
Cl
Br
C15H13BrOS
C15H141OS
C16H16O3S
C15H13FO2S
C15H13ClO3S
C
C
14H13ClO3S
15H14O3S
C16H16O3S
C14H11FO
95–98
95–98
C
14H11ClO
C14H11BrO

1598
L. Karimi et al.
solvent was removed under reduced pressure. The residue was crys-
tallized from chloroform: hexane (1:1). The yield was 45–82%.
Selected data for 2-(4-fluorophenyl-1-(4-methylsulfonylphenyl)-
ethanone 10a. White solid, m.p. 150–153◦C, yield = 82%. 1H NMR
(CDCl3): δ 3.11 (s, 3H, CH3), 4.20 (s, 2H, CH2), 7.19–7.32 (m, 4H, aro-
matic), 8.06 (d, 2H, J = 8.8 Hz), 8.19 (d, 2H, J = 8.8 Hz), IR (KBr)(νmax
,
cm−1): 1691 (CO), 1314, 1153 (SO2); MS, m/z (%): 292 (M+, 17), 212 (15),
183 (100), 138 (12).
Compound 10b to 10e were prepared similarly (see Table I).
Preparation of 1-(4-Methylsufonylphenyl)-2-(4-substituted
Phenyl)ethanone Semicarbazone 11
General Procedure
To a solution of compound 10 (6.5 mmol) in ethanol (50 mL) was
added (1.76 g) by sodium acetate (13 mmol) and (1.6 g) semicarbazide
hydrochloride (13 mmol) in water (15 mL) and the mixture refluxed for
24 h. The mixture was filtered and the volume was reduced to about
50 mL under reduced pressure. It was cooled and the precipitate was
filtered. The solids were recrystallized from ethanol-water to give com-
pound 11. The yield was 60–85%.
Selected data for 2-(4-flurophenyl)-1-(4-methylsulfonylphenyl)
ethanone semicarbazone 11a. White solid m.p. 122–125◦C, yield =
73%. 1H NMR (CDCl3): δ 3.11 (s, 3H, CH3), 5.36 (s, 2H, CH2), 7.15–7.28
(m, 2H), 7.38–7.48 (m, 2H), 8.01 (d, 2H, J = 8.8 Hz), 8.25 (d, 2H, J =
8.8 Hz).
Preparation of 5-(4-Substituted Phenyl)-4-(4-
methylsulfonylphenyl)-1,2,3-thiadiazole 5
General Procedure
To compound 11 (1 g) was added thionyl chlorid (5 mL) and stirred
at 0◦C for 3 h. CH2Cl2 (20 mL) was added and filtered on the aque-
ous saturated solution of sodium bicarbonate. The organic phase was
dried (sodium sulfate) and filtered and the solvet was removed under
reduced pressure. Purificaction was carried out by column chromatog-
raphy (silica gel) with the solvent system chloroform: ethylacetat (5:1)
and the desired compound was crystallized from chloroform-petroleum
ether.
Selected data for 5-(4-flurophenyl)-4-(4-methylsulfonylphenyl)-
1,2,3-thiadiazole 5a. White solid, m.p. 173–175◦C, yield = 71%. 1H

Diarylthiadiazoles
1599
TABLE II Data for Compounds 5a–e, 6a–c, and 14a–c
Calcd. (%)
Found (%)
H N
Comp.
no.
Yield
(%)
X
m.p. ◦
C
Formula
C
H
N
C
5a
5b
5c
5d
5f
F
173–175 71 C15H11FN2O2S2 53.88 3.32 8.38 53.67 3.63 8.65
170–172 80 C15H11ClN2O2S2 51.35 3.16 7.98 50.99 3.01 7.73
Cl
Br
H
188–191 69
C15H11BrN2O2S2 45.57 2.80 7.09 45.61 2.89 7.40
153–154 71 C15H11N2O2S2
56.94 3.82 8.85 57.03 3.45 8.61
55.47 4.07 8.09 55.92 4.28 8.22
OCH3 123–126 75 C16H14N2O3S2
6a
F
157–161 37
C14H10FN3O2S2 50.14 3.01 12.53 49.86 3.09 12.18
6b
6c
14a
14b
14c
Cl
Br
F
Cl
Br
166–168 29 C14H10ClN3O2S2 47.78 2.87 11.94 47.42 2.55 11.65
145–147 46 C14H10BrN3O2S2 42.43 2.54 10.60 42.03 2.51 10.96
oil
oil
oil
62
60 C14H9ClN2S
33 14H9BrN2S
C
14H9FN2S2
65.61 3.54 10.93 65.47 3.79 10.61
61.65 3.32 10.27 61.96 3.49 10.30
53.01 2.86 8.83 53.26 2.53 8.56
C
NMR (CDCl3): δ 3.11 (s, 3H, CH3), 7.09–7.23 (m, 2H), 7.28–7.45 (m,
2H), 7.82 (d, 2H, J = 8.8 Hz), 7.99 (d, 2H, J = 8.8 Hz), IR (KBr)(νmax
,
cm−1): 1310, 1150 (SO2); MS, m/z (%): 334 (M+, 10), 306 (100), 274 (17),
243 (85).
Compounds 5b–5f were prepared similarly (Table II).
Preparation of 4-[4-(4-Substituted Phenyl)1,2,3-thiadiazole-
5-yl]benzen-sulfonamide 6
General Procedure
To a magnetically stirred solution of compound 14 (1 mmol) at ice-
bath temperature was slowly added to chlorosulfonic acid (5 mL). After
5 h crushed ice was added and the precipitate was filtered. It was dis-
solved in methanol and excess amounts of ammonia solution (25%) was
added. The solution was stirred for 24 h. The solvent was removed at
reduced pressure and the residue purified by preparative TLC with the
solvent system chloroform: ethyl acetate and crystallized from CHCl3-
peteroleum ether.
Selected data for 4-[4-(4-flurophenyl)-1,2,3-thiadiazole-5-yl]benze-
nsulfonamide 6a. White solid, m.p. 157–161◦C, yield = 37%. 1H NMR
(CDCl3/DMSO-d6): 7.15–7.58 (m, 2H), 7.22 (bs, 2H, NH2), 7.49 (d, 2H,
J = 8.8 Hz), 7.53–7.62 (m, 2H), 7.94–8.10 (m, 2H), IR (KBr)(νmax, cm−1):
3310 and 3380 (NH2); MS, m/z (%): 335 (18), 309 (100), 275 (35), 255
(73), 155 (22), 95 (15).

1600
L. Karimi et al.
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