Aroylethenesulfonylacetic acid methyl ester - A synthon for novel sulfone linked bis heterocycles

Article abstract of DOI:10.1248/cpb.56.815

Novel sulfone linked bis heterocycles containing two different heterocyclic rings viz., pyrazoline in combination with thiadiazole, oxadiazole and triazole were synthesized and studied their antimicrobial activity.

Full text of DOI:10.1248/cpb.56.815

June 2008
Chem. Pharm. Bull. 56(6) 815—820 (2008)
815
Aroylethenesulfonylacetic Acid Methyl Ester—A Synthon for Novel
Sulfone Linked Bis Heterocycles
Venkatapuram PADMAVATHI,* Annaji Venkata NAGENDRA MOHAN, Konda MAHESH, and
Adivireddy PADMAJA
Department of Chemistry, Sri Venkateswara University; Tirupati–517 502, India.
Received February 5, 2008; accepted March 22, 2008; published online March 27, 2008
Novel sulfone linked bis heterocycles containing two different heterocyclic rings viz., pyrazoline in combina-
tion with thiadiazole, oxadiazole and triazole were synthesized and studied their antimicrobial activity.
Key words bis heterocycle; thiadiazole; oxadiazole; triazole; antimicrobial activity
Amongst different heterocyclic systems five membered is assigned to the one adjacent to CꢀO group. However, the
heterocycles represent a class of compounds of biological 1H-NMR spectrum of 6a displayed a singlet at 3.72 ppm for
significance. In fact, azoles occupy a unique place in the methoxy protons of carbomethoxy group, another singlet at
realm of natural and synthetic organic chemistry. These com- 4.39 ppm for SO2–CH2, a multiplet at 4.62—4.65 for H-5
pounds have intrinsic biological activities and constitute the and a doublet at 3.53 ppm for H-4. In order to get the desired
structural feature of many bioactive compounds. 1,3,4-Oxa- bis heterocycles, the olefinic moiety in 4 is used to develop
diazoles exhibit a broad spectrum of biological activities pyrazoline ring by 1,3-dipolar cycloaddition of diazo-
such as anti human immunodeficiency virus (HIV), antibac- methane. In 1,2-disubstituted ethylenes bearing two vicinal
terial and antifungal.1,2) Besides, triazoles possess antifungal electron withdrawing substituents a regioisomeric mixture of
activity and reduce toxicity when compared with the imida- cycloadducts are expected. However, the reaction of 1-aryl-2-
zole antifungals.3—8) Flucanazole and itraconazole are most aroylethylenes with diazomethane and its derivatives pro-
frequently used antifungal drugs. 1,3,4-Thiadiazoles are as- duced exclusively 3-aroyl-4-aryl-2-pyrazolines.15) Similarly,
sociated with diverse biological activities probably due to the cycloaddition of diazomethane to 1-aroyl-2-styrylsul-
toxophoric –NꢀC–S group.9—12) In fact, the advent of sulfur fonylethenes gave 3-aroyl-4-styrylsulfonyl-2-pyrazolines.16)
drugs and the discovery of mesoionic compounds greatly ac- The treatment of 4 with diazomethane in the presence of
celerated the rate of progress in the field of thiadiazoles. 5- Et3N at ꢁ20 °C for 48 h gave a solid which is identified
Unsubstituted 1,3,4-thiadiazoles are used as intermediates in as (3-aroyl-4,5-dihydro-1H-pyrazole-4-sulfonyl)-acetic acid
the synthesis of therapeutically potent antibiotic cefazolin.13) methyl ester (7). The addition of diazomethane to 4 may pro-
In addition, pyrazolines have gained importance due to their duce regioisomers. However, we have isolated only one pure
various chemotherapeutic properties. Celecoxib, a pyrazole regioisomer. A small amount of the other isomer if any,
1
derivative is now widely used in the market as an anti-inflam- formed could not be isolated by this process. The H-NMR
matory drug.14) Hence, it is considered worthwhile to pre- spectrum of 7a shows an AMX splitting pattern for the pyra-
pare molecules having pyrazoline and oxadiazole/thiadiazole/ zoline ring protons thus exhibiting three double doublets at
triazole rings.
5.07 (HA), 4.53 (HM) and 3.94 ppm (HX) respectively, in addi-
Chemistry The general synthetic pathway discussed tion to the signals due to methylene and methoxy protons.
hereafter is depicted in Charts 1 and 2. The synthetic inter- The 13C-NMR spectrum of 7a displayed a signal at
mediate aroylethenesulfonylacetic acid (3) is prepared by the 185.6 ppm due to carbonyl carbon, a characteristic signal for
condensation of 1-aroyl-2-chloroethene (1) with mercap- carbonyl carbon adjacent to an imine carbon. The articula-
toacetic acid in the presence of sodium hydroxide in tion of oxadiazole, thiadiazole and triazole rings is made by
methanol followed by oxidation with hydrogen peroxide in the use of ester moiety. The compound 7 on reaction with hy-
acetic acid. The 1H-NMR spectrum of 3a showed a singlet at drazine hydrate gave the corresponding acid hydrazide 8. The
4.38 ppm for methylene protons and two doublets at 7.66,
7.96 ppm for olefinic protons. The downfield shift is assigned
to the one adjacent to SO2 group. The methyl ester of 3 (4) is
prepared by treating 3 with methanol in conc. H2SO4. When
aroylethenesulfonylacetic acid methyl ester 4 is made to react
with hydrazine hydrate instead of the expected acid hy-
drazide, a mixture of products are obtained. The two are sep-
arated by column chromatography and identified as 1,1-
dioxo-6-phenacyl-[1,4,5]thiadiazinan-3-one (5) and (3-aryl-
4,5-dihydro-1H-pyrazole-5-sulfonyl)-acetic acid methyl ester
1
(6) by spectral parameters. The H-NMR spectrum of 5a
showed a singlet, a doublet and a multiplet at 4.28, 3.50 and
4.57—4.59 ppm for H-2, CO–CH2 and H-6 respectively. Two
broad singlets are observed at 2.82 and 8.50 ppm due to NH
Chart 1
which disappeared on deuteration. The downfield absorption
∗ To whom correspondence should be addressed. e-mail: vkpuram2001@yahoo.com
© 2008 Pharmaceutical Society of Japan

816
Vol. 56, No. 6
Chart 2
Table 1. The in Vitro Antibacterial Activity of 10—12
Zone of inhibition (mm)
Concentration
Compound
Gram-positive bacteria
Gram-negative bacteria
E. coli K. pneumoniae
(mg)
S. aureus
B. subtilis
10a
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
20
27
15
17
25
30
12
15
11
14
14
17
28
33
21
26
32
35
35
39
22
25
18
19
22
25
11
13
12
16
14
18
31
35
22
27
34
28
38
41
17
20
16
20
19
22
14
17
11
14
10
12
22
26
20
23
23
25
40
44
19
22
19
21
23
28
13
16
11
13
11
13
21
25
21
24
26
27
42
45
10b
10c
11a
11b
11c
12a
12b
12c
Chloramphenicol
1H-NMR spectrum of 8a displayed broad signals in the re- tons. The potassium dithiocarbazate of acid hydrazide (9) is
gions 10.49 and 5.15 ppm for NH and NH2 which disap- prepared from 8 on treatment with carbon disulfide in the
peared on deuteration in addition to signals due to other pro- presence of potassium hydroxide under ultrasonic conditions.

June 2008
817
This on refluxion in acetic acid cyclized to 5ꢂ-(3-aroyl-4,5- pores mlꢁ1 at a mg mlꢁ1 concentration by the Vincent and
dihydro-1H-pyrazole-4-sulfonylmethyl)-[1ꢂ,3ꢂ,4ꢂ]thiadiazole- Vincent method.17)
2ꢂ-thiol (10). Acid catalysed hydrolysis of 9 resulted in
The results of the compounds of preliminary antimicrobial
5ꢂ-(3-aroyl-4,5-dihydro-1H-pyrazole-4-sulfonylmethyl)- testing are shown in Tables 1 and 2. The results revealed that
[1ꢂ,3ꢂ,4ꢂ]oxadiazole-2ꢂ-thiol (11). Further, the compound 9 the inhibitory activity against Gram-positive bacteria was
on treatment with hydrazine hydrate produced 4ꢂ-amino- higher than Gram-negative bacteria. The oxadiazole deriva-
5ꢂ-(3-aroyl-4,5-dihydro-1H-pyrazole-4-sulfonylmethyl)- tives 11a—c were displayed least activity. The compounds
1
[1ꢂ,2ꢂ,4ꢂ]triazole-3ꢂ-thiol (12) (Chart 2). The H-NMR spec- 10a, 10c, 12a and 12c showed excellent activity against
tra of 10—12 displayed a singlet in the region 10.24— Gram-positive bacteria (inhibitory zone ꢃ25 mm) and good
10.35 ppm for SH besides signals due to pyrazoline ring and activity against Gram-negative bacteria (inhibitory zone
methylene protons. In addition to these, 12a showed a broad ꢃ20 mm). All the test compounds showed moderate to high
singlet at 5.64 ppm for NH2 which disappeared on deutera- inhibitory effect towards tested fungi. The presence of chloro
tion. The structures of 5—7 and 10—12 are further con- substituent at position of the arylsulfonyl moiety enhances
firmed by 13C-NMR spectra.
the antimicrobial activity.
Antimicrobial Testing The compounds 10—12 were
The minimal inhibitory concentration (MIC) values were
tested for in vitro antimicrobial activity at two different con- determined as the lowest concentration that completely in-
centrations 100 and 200 mg per disc. The antibacterial activ- hibited visible growth of the microorganisms (Table 3). The
ity was screened against Staphylococcus aureus, Bacillus structure–antimicrobial activity relationship of the synthe-
subtilis (Gram-positive bacteria) and Escherichia coli, Kleb- sized compounds revealed that the compounds having pyra-
siella pneumoniae (Gram-negative bacteria) on nutrient agar zoline with oxadiazole exhibited least activity when com-
plates at 37 °C for 24 h using chloramphenicol as reference pared with compounds having pyrazoline with thiadiazole
drug. The compounds were also evaluated for their antifun- and triazole moieties. Among the substituents on the aryl
gal activity against Fusarium solani, Curvularia lunata and group, 4-chlorophenyl derivatives were the most activity. The
Aspergillus niger using ketoconazole as standard drug. Fungi maximum activity was observed with the compounds 10c,
cultures were grown on potato dextrose agar medium (PDA) 12a and 12c.
at 25 °C for 3 d. The spore suspension was adjusted to 106
Conclusion
A new class of sulfone linked bis heterocycles, 5ꢂ-
(3-aroyl-4,5-dihydro-1H-pyrazole-4-sulfonylmethyl)-
Table 2. The in Vitro Antifungal Activity of 10—12
[1ꢂ,3ꢂ,4ꢂ]thiadiazole-2ꢂ-thiol (10), 5ꢂ-(3-aroyl-4,5-dihydro-
Zone of inhibition (mm)
Concentration
1H-pyrazole-4-sulfonylmethyl)-[1ꢂ,3ꢂ,4ꢂ]oxadiazole-2ꢂ-thiol
(11) and 4ꢂ-amino-5ꢂ-(3-aroyl-4,5-dihydro-1H-pyrazole-4-
sulfonylmethyl)-[1ꢂ,2ꢂ,4ꢂ]triazole-3ꢂ-thiol (12) were devel-
oped by the regiospecific 1,3-dipolar cycloaddition of dia-
zomethane to aroylethenesulfonylacetic acid methyl ester (4)
followed by functionalization of ester moiety with appropri-
ate reagents. The antimibcrobial testing showed that the com-
pounds having pyrazoline with thiadiazole and triazole units
possess greater antibacterial activity.
Compound
(mg)
F. solani
C. lunata
A. niger
10a
10b
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
24
27
23
27
26
30
19
20
15
20
17
22
33
35
27
32
36
39
38
42
28
30
24
25
25
27
15
22
14
18
18
22
34
36
28
34
38
42
41
44
26
31
22
26
26
29
17
21
18
23
14
17
31
37
32
35
34
36
36
39
10c
11a
Experimental
11b
Melting points were determined in open capillaries on a Mel-Temp appa-
ratus and are uncorrected. The purity of the compounds was checked by
TLC (silica gel H, BDH, hexane–ethyl acetate, 3 : 1). The IR spectra were
recorded on a Thermo Nicolet IR 200 FT-IR spectrometer as KBr pellets and
11c
12a
1
the wave numbers were given in cmꢁ1. The H-NMR spectra were recorded
in CDCl3/DMSO-d6 on a Varian EM-360 spectrometer (300 MHz). The 13C-
NMR spectra were recorded in CDCl3/DMSO-d6 on a Varian VXR spec-
trometer operating at 75.5 MHz. All chemical shifts are reported in d (ppm)
using TMS as an internal standard. The microanalyses were performed on
Perkin-Elmer 240C elemental analyzer. The mass spectra were recorded on
Finnigan Mat 1210 B and Waters Micromass Quattro Micro API at 70 eV
with an emission current of 100 mA. The starting compound 1-aroyl-2-
12b
12c
Ketoconazole
Table 3. Minimal Inhibitory Concentration of 10c, 12a and 12c
Minimal inhibitory concentration (MIC), mg/ml
Compound
S. aureus
B. subtilis
E. coli
K. pneumoniae
F. solani
C. lunata
A. niger
10c
12a
12c
100
50
25
200
100
50
200
100
50
200
100
50
100
100
50
100
100
25
200
100
25
Chloramphenicol
Ketoconazole
6.25
—
6.25
—
6.25
—
12.5
—
—
12.5
—
6.25
—
6.25

818
Vol. 56, No. 6
chloroethene (1) was prepared according to literature procedure.18)
General Procedure of Synthesis of Aroylethenemercapto Acetic Acid
(2a—c) To a solution of sodium hydroxide (0.002 mol) in methanol
(10 ml), mercaptoacetic acid (0.001 mol) was added dropwise. To this, com-
pound 1 (0.001 mol) was added in portions and the reaction mixture was
stirred at 0 °C for 3—4 h. The contents were poured onto crushed ice and
neutralized with dil. HCl. The reaction mixture was extracted with ethyl ac-
etate. The solvent when removed under reduced pressure gave the compound
2.
Benzoylethenemercapto Acetic Acid (2a): White solid, yield 71%, mp
34—36 °C; IR (KBr) cmꢁ1: 3200 (OH), 1725 (CꢀO), 1585 (CꢀC). 1H-
NMR (CDCl3) d: 3.74 (s, 2H, CH2), 7.68 (d, 1H, HB, Jꢀ13.7 Hz), 7.93 (d,
1H, HA, Jꢀ13.7 Hz), 7.46—7.84 (m, 5H, Ar-H), 9.91 (br s, 1H, OH); 13C-
NMR (CDCl3) d: 53.4 (CH2), 137.8 (COCH), 143.8 (CHS), 171.9 (COOH),
184.1 (ArCO), 128.7, 131.1, 132.6, 135.5.
4-Methylbenzoylethenemercaptoacetic Acid (2b): White solid, yield 76%,
mp 45—47 °C; IR (KBr) cmꢁ1: 3214 (OH), 1722 (CꢀO), 1581 (CꢀC). 1H-
NMR (CDCl3) d: 2.27 (s, 3H, Ar-CH3), 3.70 (s, 2H, CH2), 7.71 (d, 1H, HB,
Jꢀ13.9 Hz), 7.95 (d, 1H, HA, Jꢀ13.9 Hz), 7.38—7.82 (m, 4H, Ar-H), 10.1
(br s, 1H, OH); 13C-NMR (CDCl3) d: 23.2 (Ar-CH3), 53.8 (CH2), 137.2
(COCH), 143.3 (CHS), 170.5 (COOH), 183.5 (ArCO), 127.6, 130.4, 133.1,
139.5.
4-Chlorobenzoylethenesulfonylacetic Acid Methyl Ester (4c): White crys-
tals, yield 87%, mp 124—126 °C; IR (KBr) cmꢁ1: 1752 (CO2Me), 1669
1
(CꢀO), 1568 (CꢀC), 1149, 1325 (SO2). H-NMR (CDCl3) d: 3.75 (s, 3H,
OCH3), 4.38 (s, 2H, CH2), 7.69 (d, 1H, HB, Jꢀ14.2 Hz), 7.94 (d, 1H, HA,
Jꢀ14.2 Hz), 7.48—7.72 (m, 4H, Ar-H); 13C-NMR (CDCl3) d: 53.8 (OCH3),
58.9 (CH2), 138.9 (COCH), 147.3 (CHSO2), 168.6 (CO2CH3), 181.6
(ArCO), 128.9, 131.4, 135.8, 137.4. Anal. Calcd for C12H11ClO5S: C, 47.61;
H, 3.66; Found: C, 47.55; H, 3.69.
General Procedure of Synthesis of 1,1-Dioxo-6-phenacyl-[1,4,5]thiadi-
azinan-3-one (5a—c) and (3-Aryl-4,5-dihydro-1H-pyrazole-5-sulfonyl)-
acetic Acid Methyl Ester (6a—c) A mixture of 4 (0.0025 mol), hydrazine
hydrate (0.005 mol) and methanol (15 ml) was refluxed for 8—10 h and
cooled. The solid separated was filtered and dried. It was purified by column
chromatography (hexane–ethyl acetate, 3 : 1).
1,1-Dioxo-6-phenacyl-[1,4,5]thiadiazinan-3-one (5a): White crystals,
yield 26%, mp 102—104 °C; IR (KBr) cmꢁ1: 3284 (NH), 1682 (CꢀO),
1652 (NHCO), 1132, 1334 (SO2). 1H-NMR (DMSO-d6) d: 2.82 (br s, 1H,
NH), 3.50 (d, 2H, COCH2), 4.28 (s, 2H, H-2), 4.57—4.59 (m, 1H, H-6),
7.38—7.84 (m, 5H, Ar-H), 8.50 (s, 1H, CONH); 13C-NMR (DMSO-d6) d:
36.2 (CH2), 59.4 (C-2), 72.8 (C-6), 172.6 (CONH), 198.6 (ArCO), 127.7,
130.2, 133.1, 136.5; MS: m/zꢀ268 (Mꢄ ). Anal. Calcd for C11H12N2O4S: C,
·
49.24; H, 4.51; N, 10.44; Found: C, 49.20; H, 4.55; N, 10.55.
1,1-Dioxo-6-(4-methylphenacyl)-[1,4,5]thiadiazinan-3-one (5b): White
4-Chlorobenzoylethenemercaptoacetic Acid (2c): White solid, yield 74%,
mp 67—69 °C; IR (KBr) cmꢁ1: 3218 (OH), 1714 (CꢀO), 1574 (CꢀC). 1H-
NMR (CDCl3) d: 3.79 (s, 2H, CH2), 7.74 (d, 1H, HB, Jꢀ13.5 Hz), 7.98 (d,
1H, HA, Jꢀ13.5 Hz), 7.54—7.89 (m, 4H, Ar-H), 9.82 (br s, 1H, OH); 13C-
NMR (CDCl3) d: 54.1 (CH2), 138.1 (COCH), 144.2 (CHS), 171.4 (COOH),
184.2 (ArCO), 128.4, 130.6, 132.4, 141.5.
General Procedure of Synthesis of Aroylethenesulfonylacetic Acid
(3a—c) The compound 2 (0.001 mol) was subjected to oxidation with 30%
hydrogen peroxide (2 ml) in glacial acetic acid (6.5 ml). The contents were
stirred at 0 °C for 4 h and kept aside for 36 h. The reaction mixture was
poured onto crushed ice. The solid separated was filtered, dried and recrys-
tallized from water.
Benzoylethenesulfonylacetic Acid (3a): White solid, 88% yield, mp 132—
134 °C; IR (KBr) cmꢁ1: 3221 (OH), 1727 (CꢀO), 1584 (CꢀC), 1130, 1326
(SO2). 1H-NMR (CDCl3) d: 4.38 (s, 2H, CH2), 7.66 (d, 1H, HB, Jꢀ14.2 Hz),
7.96 (d, 1H, HA, Jꢀ14.2 Hz), 7.56—7.88 (m, 5H, Ar-H), 9.68 (br s, 1H,
OH); 13C-NMR (CDCl3) d: 56.8 (CH2), 138.7 (COCH), 141.8 (CHSO2),
172.8 (COOH), 182.4 (ArCO), 128.4, 129.4, 132.6, 134.4.
crystals, yield 16%, mp 97—99 °C; IR (KBr) cmꢁ1: 3286 (NH), 1678
1
(CꢀO), 1654 (NHCO), 1130, 1332 (SO2). H-NMR (DMSO-d6) d: 2.25 (s,
3H, Ar-CH3), 2.78 (br s, 1H, NH), 3.48 (d, 2H, COCH2), 4.27 (s, 2H, H-2),
4.54—4.57 (m, 1H, H-6), 7.36—7.85 (m, 4H, Ar-H), 8.47 (s, 1H, CONH);
13C-NMR (DMSO-d6) d: 23.6 (Ar-CH3), 35.8 (CH2), 59.1 (C-2), 71.9 (C-6),
169.3 (CONH), 198.3 (CꢀO), 128.4, 130.5, 134.2, 136.8. Anal. Calcd for
C12H14N2O4S: C, 51.05; H, 5.00; N, 9.92; Found: C, 51.16; H, 5.06; N, 9.99.
1,1-Dioxo-6-(4-chlorophenacyl)-[1,4,5]thiadiazinan-3-one (5c): White
crystals, yield 24%, mp 135—137 °C; IR (KBr) cmꢁ1: 3286 (NH), 1684
(CꢀO), 1656 (NHCO), 1136, 1338 (SO2). 1H-NMR (DMSO-d6) d: 2.82
(br s, 1H, NH), 3.53 (d, 2H, COCH2), 4.31 (s, 2H, H-2), 4.55—4.58 (m, 1H,
H-6), 7.44—7.91 (m, 4H, Ar-H), 8.44 (s, 1H, CONH); 13C-NMR (DMSO-
d6) d: 37.1 (CH2), 58.5 (C-2), 72.6 (C-6), 171.8 (CONH), 197.8 (CꢀO),
128.2, 131.4, 133.7, 135.9. Anal. Calcd for C11H11ClN2O4S: C, 43.64; H,
3.66; N, 9.25; Found: C, 43.72; H, 3.59; N, 9.32.
(3-Phenyl-4,5-dihydro-1H-pyrazole-5-sulfonyl)-acetic Acid Methyl Ester
(6a): Yellow solid, yield 62%, mp 142—144 °C; IR (KBr) cmꢁ1: 3290 (NH),
1742 (CꢀO), 1558 (CꢀN), 1125, 1336 (SO2). 1H-NMR (CDCl3) d: 3.53 (d,
2H, H-4), 3.72 (s, 3H, OCH3), 4.39 (s, 2H, SO2CH2), 4.62—4.65 (m, 1H, H-
5), 7.20—7.69 (m, 5H, Ar-H), 10.22 (br s, 1H, NH); 13C-NMR (CDCl3) d:
32.8 (C-4), 47.5 (SO2CH2), 52.2 (OCH3), 67.2 (C-5), 152.2 (C-3), 161.8
4-Methylbenzoylethenesulfonylacetic Acid (3b): White solid, yield 85%,
mp 125—127 °C; IR (KBr) cmꢁ1: 3224 (OH), 1714 (CꢀO), 1568 (CꢀC),
1
1132, 1314 (SO2). H-NMR (CDCl3) d: 2.24 (s, 3H, Ar-CH3), 4.40 (s, 2H,
CH2), 7.63 (d, 1H, HB, Jꢀ14.4 Hz), 7.92 (d, 1H, HA, Jꢀ14.4 Hz), 7.42—
7.80 (m, 4H, Ar-H), 9.92 (br s, 1H, OH); 13C-NMR (CDCl3) d: 24.2 (Ar-
CH3), 57.2 (CH2), 137.6 (COCH), 142.3 (CHSO2), 172.3 (COOH), 181.3
(ArCO), 128.2, 129.2, 131.9, 135.4.
(CꢀO), 129.5, 130.4, 131.5, 133.2; MS: m/zꢀ282 (Mꢄ ). Anal. Calcd for
·
C12H14N2O4S: C, 51.05; H, 5.00; N, 9.92; Found: C, 51.02; H, 5.06; N, 9.86.
(3-(4-Methylphenyl)-4,5-dihydro-1H-pyrazole-5-sulfonyl)-acetic Acid
Methyl Ester (6b): Yellow solid, yield 69%, mp 158—160 °C; IR (KBr)
4-Chlorobenzoylethenesulfonylacetic Acid (3c): White solid, yield 87%,
1
cmꢁ1: 3288 (NH), 1748 (CꢀO), 1552 (CꢀN), 1122, 1343 (SO2). H-NMR
mp 151—153 °C; IR (KBr) cmꢁ1: 3218 (OH), 1724 (CꢀO), 1564 (CꢀC),
1
(CDCl3) d: 2.32 (s, 3H, Ar-CH3), 3.49 (d, 2H, H-4), 3.70 (s, 3H, OCH3),
4.34 (s, 2H, SO2CH2), 4.60—4.64 (m, 1H, H-5), 7.19—7.74 (m, 4H, Ar-H),
10.18 (br s, 1H, NH); 13C-NMR (CDCl3) d: 23.3 (Ar-CH3), 32.6 (C-4), 46.3
(SO2CH2), 51.8 (OCH3), 67.1 (C-5), 151.9 (C-3), 162.5 (CꢀO), 129.2,
130.8, 131.5, 132.6. Anal. Calcd for C13H16N2O4S: C, 52.69; H, 5.44; N,
9.45; Found: C, 52.74; H, 5.51; N, 9.51.
1138, 1336 (SO2). H-NMR (CDCl3) d: 4.42 (s, 2H, CH2), 7.69 (d, 1H, HB,
Jꢀ14.6 Hz), 7.98 (d, 1H, HA, Jꢀ14.6 Hz), 7.52—7.87 (m, 4H, Ar-H), 9.96
(br s, 1H, OH); 13C-NMR (CDCl3) d: 56.5 (CH2), 138.1 (COCH), 142.6
(CHSO2), 173.2 (COOH), 179.6 (ArCO), 128.1, 129.6, 132.3, 134.2.
General Procedure of Synthesis of Aroylethenesulfonylacetic Acid
Methyl Ester (4a—c) A solution of compound 3 (0.001 mol) in methanol
(10 ml) and sulfuric acid (2 ml) was refluxed for 5—7 h. The contents were
cooled and poured onto crushed ice. The solid separated was filtered, dried
and recrystallized from methanol.
(3-(4-Chlorophenyl)-4,5-dihydro-1H-pyrazole-5-sulfonyl)-acetic Acid
Methyl Ester (6c): Yellow solid, yield 65%, mp 149—151 °C; IR (KBr)
1
cmꢁ1: 3310 (NH), 1755 (CꢀO), 1554 (CꢀN), 1140, 1335 (SO2). H-NMR
(CDCl3) d: 3.57 (d, 2H, H-4), 3.75 (s, 3H, OCH3), 4.38 (s, 2H, SO2CH2),
4.65—4.68 (m, 1H, H-5), 7.25—7.78 (m, 4H, Ar-H), 10.25 (br s, 1H, NH);
13C-NMR (CDCl3) d: 32.9 (C-4), 47.9 (SO2CH2), 52.7 (OCH3), 67.5 (C-5),
151.9 (C-3), 162.1 (CꢀO), 129.2, 130.3, 131.6, 132.3. Anal. Calcd for
C12H13ClN2O4S: C, 45.50; H, 4.14; N, 8.84; Found: C, 45.59; H, 4.20; N,
8.89.
General Procedure of Synthesis of (3-Aroyl-4,5-dihydro-1H-pyrazole-
4-sulfonyl)-acetic Acid Methyl Ester (7a—c) To a cooled solution of 4
(0.005 mol) in dichloromethane (20 ml), an ethereal solution of diazo-
methane (40 ml, 0.4 M) and triethylamine (0.12 g) were added. The reaction
mixture was kept at ꢁ20 to ꢁ15 °C for 40—48 h. The solvent was removed
under reduced pressure. The resultant solid was purified by column chro-
matography (hexane–ethyl acetate, 4 : 1).
Benzoylethenesulfonylacetic Acid Methyl Ester (4a): White crystals,
yield, 85%, mp 94—96 °C; IR (KBr) cmꢁ1: 1746 (CO2Me), 1668 (CꢀO),
1
1579 (CꢀC), 1142, 1316 (SO2). H-NMR (CDCl3) d: 3.78 (s, 3H, OCH3),
4.36 (s, 2H, CH2), 7.65 (d, 1H, HB, Jꢀ13.9 Hz), 7.91 (d, 1H, HA,
Jꢀ13.9 Hz), 7.36—7.52 (m, 5H, Ar-H); 13C-NMR (CDCl3) d: 53.1 (OCH3),
59.6 (CH2), 138.4 (COCH), 145.6 (CHSO2), 168.1 (CO2CH3), 182.4
(ArCO), 130.5, 132.3, 137.5, 139.4. Anal. Calcd for C12H12O5S: C, 53.72; H,
4.51; Found: C, 53.78; H 4.49.
4-Methylbenzoylethenesulfonylacetic Acid Methyl Ester (4b): White
crystals, yield 89%, mp 101—103 °C; IR (KBr) cmꢁ1: 1748 (CO2Me), 1662
1
(CꢀO), 1574 (CꢀC), 1128, 1341 (SO2). H-NMR (CDCl3) d: 2.28 (s, 3H,
Ar-CH3), 3.72 (s, 3H, OCH3), 4.32 (s, 2H, CH2), 7.62 (d, 1H, HB,
Jꢀ13.7 Hz), 7.88 (d, 1H, HA, Jꢀ13.7 Hz), 7.32—7.54 (m, 4H, Ar-H); 13C-
NMR (CDCl3) d: 23.1 (Ar-CH3), 53.4 (OCH3), 58.1 (CH2), 138.1 (COCH),
146.1 (CHSO2), 167.4 (CO2CH3), 181.3 (ArCO), 129.4, 131.6, 136.3, 138.4.
Anal. Calcd for C13H14O5S: C, 55.31; H, 5.00; Found: C, 55.34; H 5.02.
(3-Benzoyl-4,5-dihydro-1H-pyrazole-4-sulfonyl)-acetic Acid Methyl
Ester (7a): Yellow solid, yield 75%, mp 136—138 °C; IR (KBr) cmꢁ1: 3348
(NH), 1746 (CꢀO), 1684 (ArCO), 1576 (CꢀN), 1125, 1328 (SO2). 1H-

June 2008
819
NMR (CDCl3) d: 3.76 (s, 3H, OCH3), 3.94 (dd, 1H, HX, JAXꢀ5.4 Hz,
cmꢁ1: 3324 (NH), 2558 (SH), 1568 (CꢀN), 1146, 1338 (SO2). 1H-NMR
MXꢀ10.3 Hz), 4.32 (s, 2H, SO2CH2), 4.53 (dd, 1H, HM, JMXꢀ10.3 Hz, (DMSO-d6) d: 3.95 (dd, 1H, HX, JAXꢀ5.4 Hz, JMXꢀ10.3 Hz), 4.31 (s, 2H,
J
J
AMꢀ12.6 Hz), 5.07 (dd, 1H, HA, JAXꢀ5.4 Hz, JAMꢀ12.6 Hz), 7.23—7.72 SO2CH2), 4.74 (dd, 1H, HM, JMXꢀ10.3 Hz, JAMꢀ12.4 Hz), 5.15 (dd, 1H, HA,
(m, 5H, Ar-H), 10.52 (br s, 1H, NH); 13C-NMR (CDCl3) d: 48.3 (SO2CH2),
JAXꢀ5.4 Hz, JAMꢀ12.4 Hz), 7.23—7.76 (m, 5H, Ar-H), 10.27 (s, 1H, SH),
52.4 (OCH3), 57.0 (C-5), 65.8 (C-4), 152.2 (C-3), 162.4 (CO2CH3), 185.6 10.46 (br s, 1H, NH); 13C-NMR (DMSO-d6) d: 51.8 (C-5), 57.0 (SO2CH2),
(ArCO), 128.7, 129.8, 131.5, 132.4. MS: m/zꢀ310 (Mꢄ ). Anal. Calcd for 65.8 (C-4), 152.2 (C-3), 163.4 (C-2ꢂ), 168.5 (C-5ꢂ), 186.8 (CꢀO), 127.9,
·
128.6, 129.5, 131.4; MS m/z: 368 (Mꢄ ). Anal. Calcd for C13H12N4O3S3: C,
·
C13H14N2O5S: C, 50.31; H, 4.55; N, 9.03; Found: C, 50.38; H, 4.50; N, 9.13.
(3-(4-Methylbenzoyl)-4,5-dihydro-1H-pyrazole-4-sulfonyl)-acetic Acid 42.38; H, 3.28; N, 15.21; Found: C, 42.42; H, 3.24; N, 15.29.
Methyl Ester (7b): Yellow solid, yield 71%, mp 155—157 °C; IR (KBr)
5ꢂ-(3-(4-Methylbenzoyl)-4,5-dihydro-1H-pyrazole-4-sulfonylmethyl)-
cmꢁ1: 3343 (NH), 1743 (CꢀO), 1678 (ArCO), 1569 (CꢀN), 1132, 1323 [1ꢂ,3ꢂ,4ꢂ]thiadiazole-2ꢂ-thiol (10b): Yellow solid, yield 76%, mp 222—
(SO2). 1H-NMR (CDCl3) d: 2.23 (s, 3H, Ar-CH3), 3.72 (s, 3H, OCH3), 3.87 224 °C; IR (KBr) cmꢁ1: 3328 (NH), 2555 (SH), 1564 (CꢀN), 1140, 1330
(dd, 1H, HX, JAXꢀ5.2 Hz, JMXꢀ10.1 Hz), 4.36 (s, 2H, SO2CH2), 4.56 (dd, (SO2). 1H-NMR (DMSO-d6) d: 2.28 (s, 3H, Ar-CH3), 3.94 (dd, 1H, HX,
1H, HM, JMXꢀ10.1 Hz, JAMꢀ12.1 Hz), 5.00 (dd, 1H, HA, JAXꢀ5.2 Hz,
AMꢀ12.1 Hz), 7.16—7.70 (m, 4H, Ar-H), 10.46 (br s, 1H, NH); 13C-NMR
(CDCl3) d: 24.5 (CH3), 47.9 (SO2CH2), 52.2 (OCH3), 56.7 (C-5), 66.2 (C-4),
J
AXꢀ5.2 Hz, JMXꢀ10.1 Hz), 4.39 (s, 2H, SO2CH2), 4.59 (dd, 1H, HM,
MXꢀ10.1 Hz, JAMꢀ12.2 Hz), 5.11 (dd, 1H, HA, JAXꢀ5.2 Hz, JAMꢀ12.2 Hz),
J
J
7.18—7.69 (m, 4H, Ar-H), 10.29 (s, 1H, SH), 10.52 (br s, 1H, NH); 13C-
153.2 (C-3), 161.9 (CO2CH3), 186.1 (ArCO), 127.8, 128.9, 129.4, 131.6. NMR (DMSO-d6) d: 24.6 (Ar-CH3), 51.1 (C-5), 56.4 (SO2CH2), 65.6 (C-4),
Anal. Calcd for C14H16N2O5S: C, 51.84; H, 4.97; N, 8.64; Found: C, 51.76; 151.7 (C-3), 166.9 (C-2ꢂ), 167.8 (C-5ꢂ), 186.4 (CꢀO), 127.6, 128.7, 129.4,
H, 4.94; N, 8.55.
131.2; MS m/z: 382 (Mꢄ ). Anal. Calcd for C14H14N4O3S3: C, 43.96; H,
·
(3-(4-Chlorobenzoyl)-4,5-dihydro-1H-pyrazole-4-sulfonyl)-acetic Acid 3.69; N, 14.65; Found: C, 43.89; H, 3.74; N; 14.58.
Methyl Ester (7c): Yellow solid, yield 74%, mp 163—165 °C; IR (KBr)
5ꢂ-(3-(4-Chlorobenzoyl)-4,5-dihydro-1H-pyrazole-4-sulfonylmethyl)-
cmꢁ1: 3335 (NH), 1749 (CꢀO), 1686 (ArCO), 1582 (CN), 1120, 1332 [1ꢂ,3ꢂ,4ꢂ]thiadiazole-2ꢂ-thiol (10c): Yellow solid, yield 73%, mp 237—
(SO2). 1H-NMR (CDCl3) d: 3.78 (s, 3H, OCH3), 3.90 (dd, 1H, HX,
239 °C; IR (KBr) cmꢁ1: 3336 (NH), 2562 (SH), 1566 (CꢀN), 1148, 1342
J
J
AXꢀ5.6 Hz, JMXꢀ10.6 Hz), 4.34 (s, 2H, SO2CH2), 4.54 (dd, 1H, HM,
MXꢀ10.6 Hz, JAMꢀ12.9 Hz), 5.10 (dd, 1H, HA, JAXꢀ5.6 Hz, JAMꢀ12.9 Hz),
(SO2). 1H-NMR (DMSO-d6) d: 3.91 (dd, 1H, HX,
J
AXꢀ5.6 Hz,
MXꢀ10.6 Hz), 4.34 (s, 2H, SO2CH2), 4.55 (dd, 1H, HM, JMXꢀ10.6 Hz,
AMꢀ12.6 Hz), 5.17 (dd, 1H, HA, JAXꢀ5.6 Hz, JAMꢀ12.6 Hz), 7.25—7.69
J
J
7.23—7.76 (m, 4H, Ar-H), 10.55 (br s, 1H, NH); 13C-NMR (CDCl3) d: 48.7
(SO2CH2), 52.6 (OCH3), 57.0 (C-5), 65.7 (C-4), 152.3 (C-3), 162.8
(m, 4H, Ar-H), 10.24 (s, 1H, SH), 10.57 (br s, 1H, NH); 13C-NMR (DMSO-
(CO2CH3), 185.9 (ArCO), 128.7, 129.6, 131.9, 132.7. Anal. Calcd for d6) d: 52.3 (C-5), 57.6 (SO2CH2), 66.5 (C-4), 152.8 (C-3), 166.5 (C-2ꢂ),
C13H13ClN2O5S: C, 45.29; H, 3.80; N, 8.13; Found: C, 45.23; H, 3.84; N, 168.5 (C-5ꢂ), 187.6 (CꢀO), 128.5, 129.9, 131.6, 132.5; MS m/z: 402 (Mꢄ ).
·
8.20.
Anal. Calcd for C13H11ClN4O3S3: C, 38.75; H, 2.75; N, 13.91; Found: C,
General Procedure of Synthesis of (3-Aroyl-4,5-dihydro-1H-pyrazole- 38.70; H, 2.77; N, 13.98.
4-sulfonyl)-acetic Acid Hydrazide (8a—c) To a solution of 7 (0.001 mol)
General Procedure of Synthesis of 5ꢀ-(3-Aroyl-4,5-dihydro-1H-pyra-
in absolute ethanol (5 ml), hydrazine hydrate (0.0045 mol) and pyridine zole-4-sulfonylmethyl)-[1ꢀ,3ꢀ,4ꢀ]oxadiazole-2ꢀ-thiol (11a—c) The com-
(0.4 ml) was added and stirred for 4—5 h at room temperature. The resultant
solid was filtered, dried and recrystallized from ethanol.
pound 9 (0.001 mol) was dissolved in 6 ml of water and acidified with 1—
2 ml of conc. HCl. The regenerated solid was collected by filtration, dried
(3-Benzoyl-4,5-dihydro-1H-pyrazole-4-sulfonyl)-acetic Acid Hydrazide and purified by recrystallization from 2-propanol.
(8a): Yellow solid, yield 75%, mp 149—151 °C; IR (KBr) cmꢁ1: 3320 (NH),
3225 (NH2), 1662 (CꢀO), 1653 (ArCO), 1578 (CꢀN), 1135, 1320 (SO2).
1H-NMR (CDCl3) d: 3.89 (dd, 1H, HX, JAXꢀ5.3 Hz, JMXꢀ10.5 Hz), 4.30 (s,
2H, SO2CH2), 4.42 (dd, 1H, HM, JMXꢀ10.5 Hz, JAMꢀ12.5 Hz), 5.00 (dd, 1H,
5ꢂ-(3-Benzoyl-4,5-dihydro-1H-pyrazole-4-sulfonylmethyl)-[1ꢂ,3ꢂ,4ꢂ]oxa-
diazole-2ꢂ-thiol (11a): Yellow solid, yield 73%, mp 169—171 °C; IR (KBr)
cmꢁ1: 3340 (NH), 2560 (SH), 1565 (CꢀN), 1130, 1335 (SO2). 1H-NMR
(DMSO-d6) d: 3.88 (dd, 1H, HX, JAXꢀ5.5 Hz, JMXꢀ10.4 Hz), 4.37 (s, 2H,
HA, JAXꢀ5.3 Hz, JAMꢀ12.5 Hz), 5.15 (br s, 2H, NH2), 7.21—7.70 (m, 5H, SO2CH2), 4.69 (dd, 1H, HM, JMXꢀ10.4 Hz, JAMꢀ12.5 Hz), 5.19 (dd, 1H, HA,
Ar-H), 9.49 (br s, 1H, CONH), 10.49 (br s, 1H, NH); 13C-NMR (CDCl3) d:
48.8 (C-5), 57.4 (SO2CH2), 65.7 (C-4), 152.6 (C-3), 170.9 (CONH), 185.9
(ArCO), 128.1, 128.9, 130.6, 132.0.
JAXꢀ5.5 Hz, JAMꢀ12.5 Hz), 7.26—7.73 (m, 5H, Ar-H), 10.26 (s, 1H, SH),
10.49 (br s, 1H, NH); 13C-NMR (DMSO-d6) d: 51.7 (C-5), 57.4 (SO2CH2),
66.2 (C-4), 152.5 (C-3), 160.8 (C-2ꢂ), 168.6 (C-5ꢂ), 187.8 (CꢀO), 127.5,
(3-(4-Methylbenzoyl)-4,5-dihydro-1H-pyrazole-4-sulfonyl)-acetic Acid 128.6, 129.7, 131.8; MS m/z: 352 (Mꢄ ). Anal. Calcd for C13H12N4O4S2: C,
·
Hydrazide (8b): Yellow solid, yield 80%, mp 166—168 °C; IR (KBr) cmꢁ1
3316 (NH), 3223 (NH2), 1665 (CꢀO), 1655 (ArCO), 1575 (CꢀN), 1140,
:
44.31; H, 3.43; N, 15.90; Found: C, 44.37; H, 3.46; N, 15.82.
5ꢂ-(3-(4-Methylbenzoyl)-4,5-dihydro-1H-pyrazole-4-sulfonylmethyl)-
1
1334 (SO2). H-NMR (CDCl3) d: 2.25 (s, 3H, Ar-CH3), 3.93 (dd, 1H, HX, [1ꢂ,3ꢂ,4ꢂ]oxadiazole-2ꢂ-thiol (11b): Yellow solid, yield 68%, mp 188—
J
J
AXꢀ5.1 Hz, JMXꢀ10.3 Hz), 4.33 (s, 2H, SO2CH2), 4.42 (dd, 1H, HM,
MXꢀ10.3 Hz, JAMꢀ12.3 Hz), 4.96 (dd, 1H, HA, JAXꢀ5.1 Hz, JAMꢀ12.3 Hz),
190 °C; IR (KBr) cmꢁ1: 3345 (NH), 2556 (SH), 1563 (CꢀN), 1138, 1337
(SO2). 1H-NMR (DMSO-d6) d: 2.25 (s, 3H, Ar-CH3), 3.86 (dd, 1H, HX,
5.12 (br s, 2H, NH2), 7.19—7.73 (m, 4H, Ar-H), 9.45 (br s, 1H, CONH),
10.51 (br s, 1H, NH); 13C-NMR (CDCl3) d: 24.2 (Ar-CH3), 48.4 (C-5), 57.1
(SO2CH2), 64.9 (C-4), 151.3 (C-3), 169.8 (CONH), 185.4 (ArCO), 127.3,
128.2, 130.2, 131.9.
J
J
AXꢀ5.2 Hz, JMXꢀ10.2 Hz), 4.41 (s, 2H, SO2CH2), 4.73 (dd, 1H, HM,
MXꢀ10.2 Hz, JAMꢀ12.3 Hz), 5.13 (dd, 1H, HA, JAXꢀ5.2 Hz, JAMꢀ12.3 Hz),
7.14—7.68 (dd, 4H, Ar-H), 10.28 (s, 1H, SH), 10.54 (br s, 1H, NH); 13C-
NMR (DMSO-d6) d: 25.2 (Ar-CH3), 51.3 (C-5), 56.7 (SO2CH2), 65.9 (C-4),
(3-(4-Chlorobenzoyl)-4,5-dihydro-1H-pyrazole-4-sulfonyl)-acetic Acid 151.2 (C-3), 160.1 (C-2ꢂ), 168.2 (C-5ꢂ), 188.2 (CꢀO), 127.8, 129.5, 132.4,
Hydrazide (8c): Yellow solid, yield 78%, mp 178—180 °C; IR (KBr) cmꢁ1
:
133.5; MS m/z: 366 (Mꢄ ). Anal. Calcd for C14H14N4O4S2: C, 45.89; H,
·
3322 (NH), 3228 (NH2), 1669 (CꢀO), 1658 (ArCO), 1580 (CꢀN), 1138, 3.85; N, 15.29; Found: C, 45.94; H, 3.87; N, 15.36.
1340 (SO2). 1H-NMR (CDCl3) d: 4.01 (dd, 1H, HX,
J
AXꢀ5.5 Hz,
5ꢂ-(3-(4-Chlorobenzoyl)-4,5-dihydro-1H-pyrazole-4-sulfonylmethyl)-
199 °C; IR (KBr) cmꢁ1: 3349 (NH), 2564 (SH), 1567 (CꢀN), 1127, 1342
J
MXꢀ10.8 Hz), 4.35 (s, 2H, SO2CH2), 4.49 (dd, 1H, HM, JMXꢀ10.8 Hz, [1ꢂ,3ꢂ,4ꢂ]oxadiazole-2ꢂ-thiol (11c): Yellow solid, yield 71%, mp 197—
J
AMꢀ12.7 Hz), 5.07 (dd, 1H, HA, JAXꢀ5.5 Hz, JAMꢀ12.7 Hz), 5.17 (br s, 2H,
NH2), 7.25—8.14 (m, 4H, Ar-H), 9.38 (br s, 1H, CONH), 10.54 (br s, 1H, (SO2). 1H-NMR (DMSO-d6) d: 3.90 (dd, 1H, HX, JAXꢀ5.6 Hz, JMXꢀ
NH); 13C-NMR (CDCl3) d: 49.2 (C-5), 57.7 (SO2CH2), 65.7 (C-4), 152.3 10.7 Hz), 4.46 (s, 2H, SO2CH2), 4.76 (dd, 1H, HM,
(C-3), 171.3 (CONH), 186.3 (ArCO), 128.6, 129.5, 130.4, 132.3.
JMXꢀ10.7 Hz,
JAMꢀ12.7 Hz), 5.12 (dd, 1H, HA, JAXꢀ5.6 Hz, JAMꢀ12.7 Hz), 7.28—7.73
General Procedure of Synthesis of Potassium (3-Aroyl-4,5-dihydro- (m, 4H, Ar-H), 10.32 (s, 1H, SH), 10.51 (br s, 1H, NH); 13C-NMR (DMSO-
1H-pyrazole-4-sulfonylacetyl)-hydrazine-Nꢀ-carbodithioate (9a—c) To d6) d: 52.1 (C-5), 57.6 (SO2CH2), 66.5 (C-4), 152.8 (C-3), 161.2 (C-2ꢂ),
168.8 (C-5ꢂ), 187.5 (CꢀO), 128.1, 129.4, 130.5, 132.9; MS m/z: 386 (Mꢄ ).
Anal. Calcd for C13H11ClN4O4S2: C, 40.36; H, 2.87; N, 14.48; Found: C,
40.39; H, 2.85; N, 14.40.
·
a mixture of potassium hydroxide (0.002 mol) and compound 8 (0.001 mol)
in absolute ethanol (5 ml), carbon disulfide (0.004 mol) was added and soni-
cated for 10—12 h. The separated solid was filtered and dried.
General Procedure of Synthesis of 5ꢀ-(3-Aroyl-4,5-dihydro-1H-pyra-
General Procedure of Synthesis of 4ꢀ-Amino-5ꢀ-(3-aroyl-4,5-dihydro-
zole-4-sulfonylmethyl)-[1ꢀ,3ꢀ,4ꢀ]thiadiazole-2ꢀ-thiol (10a—c) The com- 1H-pyrazole-4-sulfonylmethyl)-[1ꢀ,2ꢀ,4ꢀ]triazole-3ꢀ-thiol (12a—c) To a
pound 9 (0.001 mol) in acetic acid (4 ml) was refluxed for 20—24 h. It was solution of 9 (0.001 mol) in 6 ml of water, hydrazine hydrate (0.002 mol) was
cooled and poured onto crushed ice. The solid obtained was filtered, dried
and recrystallized from 2-propanol.
added and refluxed for 7—10 h. The contents of the flask were cooled, di-
luted with water and acidified with 2 ml of acetic acid. The separated solid
5ꢂ-(3-Benzoyl-4,5-dihydro-1H-pyrazole-4-sulfonylmethyl)-[1ꢂ,3ꢂ,4ꢂ]thia- was collected by filtration, dried and recrystallized from 2-propanol.
diazole-2ꢂ-thiol (10a): Yellow solid, yield 71%, mp 198—200 °C; IR (KBr) 4ꢂ-Amino-5ꢂ-(3-benzoyl-4,5-dihydro-1H-pyrazole-4-sulfonylmethyl)-

820
Vol. 56, No. 6
(400, 200, 100, …, 6.25 mg/ml). The microorganism suspensions were inoc-
ulated to the corresponding wells. The plates were incubated at 36 °C for 24
and 48 h for bacteria and fungi, respectively. The minimum inhibitory con-
centrations of the compounds were recorded as the lowest concentration of
each chemical compounds in the tubes with no turbidity (i.e. no growth) of
inoculated bacteria/fungi.
[1ꢂ,2ꢂ,4ꢂ]triazole-3ꢂ-thiol (12a): Yellow solid, yield 77%, mp 210—212 °C;
IR (KBr) cmꢁ1: 3325 (NH), 3242 (NH2), 2557 (SH), 1570 (CꢀN), 1137,
1334 (SO2). 1H-NMR (DMSO-d6) d: 4.07 (dd, 1H, HX, JAXꢀ5.5 Hz,
J
MXꢀ10.5 Hz), 4.36 (s, 2H, SO2CH2), 4.77 (dd, 1H, HM, JMXꢀ10.5 Hz,
AMꢀ12.7 Hz), 5.18 (dd, 1H, HA, JAXꢀ5.5 Hz, JAMꢀ12.7 Hz), 5.64 (br s, 2H,
J
NH2), 7.14—7.72 (m, 5H, Ar-H), 10.29 (s, 1H, SH), 10.44 (br s, 1H, NH);
13C-NMR (DMSO-d6) d: 50.7 (C-5), 56.8 (SO2CH2), 65.6 (C-4), 151.5 (C-
3), 153.4 (C-5ꢂ), 155.6 (C-3ꢂ), 188.8 (CꢀO), 128.3, 131.3, 132.4, 134.2; MS
Acknowledgements The Department of Science and Technology
(DST), New Delhi, India, is gratefully acknowledged for its financial sup-
port.
m/z: 366 (Mꢄ ). Anal. Calcd for C13H14N6O3S2: C, 42.61; H, 3.85; N, 22.94;
·
Found: C, 42.56; H, 3.80; N, 23.05.
4ꢂ-Amino-5ꢂ-(3-(4-Methylbenzoyl)-4,5-dihydro-1H-pyrazole-4-sulfonyl-
methyl)-[1ꢂ,2ꢂ,4ꢂ]triazole-3ꢂ-thiol (12b): Yellow solid, yield 71%, mp 202—
204 °C; IR (KBr) cmꢁ1: 3337 (NH), 3245 (NH2), 2548 (SH), 1573 (CꢀN),
1137, 1334 (SO2). H-NMR (DMSO-d6) d: 2.27 (s, 3H, Ar-CH3), 4.04 (dd,
1H, HX, JAXꢀ5.3 Hz, JMXꢀ10.3 Hz), 4.37 (s, 2H, SO2CH2), 4.68 (dd, 1H,
References
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(Bucharest), 47, 77—84 (1999).
1
HM,
JMXꢀ10.3 Hz, JAMꢀ12.5 Hz), 5.19 (dd, 1H, HA, JAXꢀ5.3 Hz,
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J
AMꢀ12.5 Hz), 5.61 (br s, 2H, NH2), 7.09—7.68 (m, 4H, Ar-H), 10.33 (s,
1H, SH), 10.49 (br s, 1H, NH); 13C-NMR (DMSO-d6) d: 23.5 (Ar-CH3),
50.3 (C-5), 55.4 (SO2CH2), 65.9 (C-4), 150.2 (C-3), 142.3 (C-3ꢂ), 153.1 (C-
5ꢂ), 187.6 (CꢀO), 129.6, 131.5, 132.7, 134.5; MS m/z: 380 (Mꢄ ). Anal.
Calcd for C14H16N6O3S2: C, 44.20; H, 4.24; N, 22.09; Found: C, 44.25; H,
4.28; N, 21.98.
4ꢂ-Amino-5ꢂ-(3-(4-chlorobenzoyl)-4,5-dihydro-1H-pyrazole-4-sulfonyl-
methyl)-[1ꢂ,2ꢂ,4ꢂ]triazole-3ꢂ-thiol (12c): Yellow solid, yield 74%, mp 246—
248 °C; IR (KBr) cmꢁ1: 3330 (NH), 3248 (NH2), 2559 (SH), 1569 (CꢀN),
·
1
1144, 1345 (SO2). H-NMR (DMSO-d6) d: 4.09 (dd, 1H, HX, JAXꢀ5.6 Hz,
J
J
MXꢀ10.8 Hz), 4.40 (s, 2H, SO2CH2), 4.78 (dd, 1H, HM, JMXꢀ10.8 Hz,
AMꢀ12.8 Hz), 5.25 (dd, 1H, HA, JAXꢀ5.6 Hz, JAMꢀ12.8 Hz), 5.67 (br s, 2H,
NH2), 7.28—7.82 (m, 4H, Ar-H), 10.35 (s, 1H, SH), 10.43 (br s, 1H, NH);
13C-NMR (DMSO-d6) d: 50.9 (C-5), 57.1 (SO2CH2), 65.8 (C-4), 151.9 (C-
3), 142.6 (C-3ꢂ), 153.4 (C-5ꢂ), 188.7 (CꢀO), 129.2, 131.7, 132.4, 133.6; MS
m/z: 400 (Mꢄ ). Anal. Calcd for C13H13ClN6O3S2: C, 38.95; H, 3.27; N,
·
20.96; Found: C, 38.96; H, 3.29; N, 20.89.
Antimicrobial Testing The compounds 10—12 were dissolved in
DMSO at different concentrations of 100, 200 and 800 mg/ml.
Antibacterial and Antifungal Assays Preliminary antimicrobial activi-
ties of 10—12 compounds were tested by Agar disc-diffusion method. Ster-
ile filter paper discs (6 mm diameter) moistened with the test compound so-
lution in acetone of specific concentration 100 mg and 200 mg/disc were
carefully placed on the agar culture plates that had been previously inocu-
lated separately with the microorganisms. The plates were incubated at
37 °C and the diameter of the growth inhibition zones were measured after
24 h in case of bacteria and after 48 h in case of fungi.
The MICs of the compounds assays were carried out using microdilution
susceptibility method. Chloramphenicol was used as reference antibacterial
agent. Ketroconazole was used as reference antifungal agent. The test com-
pounds, chloramphenicol and ketoconazole were dissolved in DMSO at con-
centration of 800 mg/ml. The two-fold dilution of the solution was prepared
18) Bhaskar Reddy D., Chandrasekhar Babu N., Padmavathi V., Sumathi
R. P., Synthesis, 1999, 491—494 (1999).