Synthesis and antimicrobial activity of pyrazolyl 1,3,4-oxadiazoles

Article abstract of DOI:10.1080/00397910902985531

The pyrazolyl oxadiazoles are synthesized from arylsulfonylacetic acid methyl ester and benzylsulfonylacetic acid methyl ester. Preliminary antimicrobial screening of the compounds showed that bis heterocycles with a chloro-substituted benzyl moiety exhibited high activity. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910902985531

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Synthesis and Antimicrobial Activity of
Pyrazolyl 1,3,4-Oxadiazoles
Venkatapuram Padmavathi a , Gali Sudhakar Reddy a , Guda
Dinneswara Reddy a & Thalari Payani a
a Department of Chemistry , Sri Venkateswara University , Tirupati,
India
Published online: 03 Feb 2010.
To cite this article: Venkatapuram Padmavathi , Gali Sudhakar Reddy , Guda Dinneswara Reddy &
Thalari Payani (2010) Synthesis and Antimicrobial Activity of Pyrazolyl 1,3,4-Oxadiazoles, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:4, 482-493, DOI: 10.1080/00397910902985531
To link to this article: http://dx.doi.org/10.1080/00397910902985531
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Synthetic Communications1, 40: 482–493, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902985531
SYNTHESIS AND ANTIMICROBIAL ACTIVITY
OF PYRAZOLYL 1,3,4-OXADIAZOLES
Venkatapuram Padmavathi, Gali Sudhakar Reddy,
Guda Dinneswara Reddy, and Thalari Payani
Department of Chemistry, Sri Venkateswara University, Tirupati, India
The pyrazolyl oxadiazoles are synthesized from arylsulfonylacetic acid methyl ester and
benzylsulfonylacetic acid methyl ester. Preliminary antimicrobial screening of the
compounds showed that bis heterocycles with a chloro-substituted benzyl moiety exhibited
high activity.
Keywords: Antimicrobial activity; 1,3-dipolar cycloaddition; 1,3,4-oxadiazoles; pyrazolines
INTRODUCTION
The development of simple, facile, and efficient methodologies for the synthesis
of five-membered heterocycles is one of the major challenges in the field of synthetic
organic chemistry. Among five-membered heterocycles, oxadiazoles and pyrazoles
represent a class of compounds of great importance. Symmetrical and unsymmetrical
1,3,4-oxadiazoles are biologically versatile compounds possessing anti-
inflammatory,[1] antifungal,[2–4] antiparasitic,[5] antimicrobial,[6,7] and antiviral activi-
ties.[8–10] The widespread use of 1,3,4-oxadiazoles as a scaffold in medicinal chemis-
try established this moiety as a member of the privileged structures class. In addition,
pyrazolines have gained importance because of their chemotherapeutic properties.
Celecoxib, a pyrazole derivative, is now widely used in the market as an anti-
inflammatory drug.[11] Different methods have been reported for the synthesis of
1,3,4-oxadiazoles involving cyclization of diacylhydrazines prepared from acyl
chlorides and hydrazine. Several cyclodehydrating agents such as Et2O ꢀ BF3,[12]
1,1,1,3,3,3-hexamethyldisilazane,[13] triflic anhydride,[14] phosphorus pentoxide,[15]
polyphosphoric acid,[16] thionyl chloride,[17,18] phosphorus oxychloride,[19] and sulfu-
ric acid[20] have been used. Similarly, 1,3-dipolar cycloaddition of 1,3-dipole onto an
alkene in a [3 þ 2] manner is a facile route for the synthesis of pyrazolines.[21,22]
Among the ylides, diazomethane and nitrile imines have been used extensively as
reactive intermediates. The present communication deals with the synthesis and
antimicrobial activity of hitherto unknown bis heterocycles having oxadiazole and
pyrazoline moieties by a simple, facile, and elegant synthetic methodology.
Received January 23, 2009.
Address correspondence to Venkatapuram Padmavathi, Department of Chemistry, Sri
Venkateswara University, Tirupati 517502, India. E-mail: vkpuram2001@yahoo.com
482

PYRAZOLYL 1,3,4-OXADIAZOLES
483
RESULTS AND DISCUSSION
To synthesize the desired bis heterocycles, the acid hydrazides of arylsulfony-
lacetic acid methyl ester (1) and arylmethanesulfonylacetic acid methyl ester (2)
are used as synthetic intermediates. The arylsulfonylacetic acid hydrazide (3) and
arylmethanesulfonylacetic acid hydrazide (4) are prepared by the condensation of
the previous compounds with hydrazine hydrate in the presence of pyridine. The
cyclocondensation of 3=4 with cinnamic acid 5 in the presence of phosphorus oxy-
chloride led to 2-(styryl)-5-(arylsulfonylmethyl)-1,3,4-oxadiazole (6) and 2-(styryl)-5-
(arylmethanesulfonylmethyl)-1,3,4-oxadiazole (7) (Scheme 1). The 1H NMR spectra
of 6a and 7a displayed a singlet at d 4.60, 4.76 for methylene protons flanked
between heterocyclic and sulfonyl moieties. Two doublets are observed at d 7.68,
7.42 in 6a and at d 7.55, 7.34 in 7a that are due to olefin protons, HA and HB.
The coupling constant value JAB ¼ 15.7 in 6a and 15.1 Hz in 7a indicates that they
possess E-configuration. Apart from these, 7a showed a singlet at d 5.05 for benzylic
protons. The olefin moiety present in 6 and 7 is used to build the pyrazoline ring by
1,3-dipolar cycloaddition of diazomethane. Thus, treatment of 6=7 with diazo-
methane at ꢁ20 to 15ꢂC for 48 h in the presence of Et3N resulted in
5-(arylsulfonylmethyl)-2-(40,50-dihydro-40-phenyl-10H-pyrazol-30-yl)-1,3,4-oxadiazole
(8) and 5-(arylmethanesulfonylmethyl)-2-(40,50-dihydro-40-phenyl-10H-pyrazol-30-
1
yl)-1,3,4-oxadiazole (9), respectively. The H NMR spectra of 8a and 9a displayed
three double doublets at d 4.64, 4.60 (HA); 4.04, 4.01 (HM); and 3.72, 3.66 (HX),
respectively. The coupling constant values JAX ¼ 4.2, 4.6; JMX ¼ 8.7, 8.6; and
JAM ¼ 12.0, 12.6 indicate that HA, HM are cis; HA, HX are trans, and HM, HX are
Scheme 1. (a) R ¼ H, R1 ¼ H; (b) R ¼ H, R1 ¼ Cl; (c) R ¼ Me, R1 ¼ H; (d) R ¼ Cl, R1 ¼ H; and (e) R ¼ Cl,
R1 ¼ Cl; n ¼ 0 (1,3,6,8); n ¼ 1 (2,4,7,9).

484
V. PADMAVATHI ET AL.
geminal. Besides, 8a and 9a showed a singlet at d 4.37 and 4.34 for methylene protons
present between sulfonyl and the oxadiazole ring. However, 9a displayed an
additional singlet at d 5.02 for benzylic protons. The structures of 6–9 are further
established by 13C NMR spectra.
Antimicrobial Testing
The compounds 8 and 9 were tested for in vitro antimicrobial activity against the
Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis, the Gram-negative
bacteria Klebsiella pneumoniae and Proteus vulgaris, and fungi Fusarium solani,
Curvularia lunata, and Aspergillus niger. The primary screen was carried out by the agar
disc-diffusion method[23] using nutrient agar medium. The minimum inhibitory concen-
tration for the most active compounds 9b, 9d, and 9e against the same microorganisms
used in the preliminary screening was carried out using the microdilution susceptibility
method.[24] Chloramphenicol and ketoconazole were used as control drugs.
Biological Results
The results of preliminary antibacterial testing for the compounds 8 and 9
are shown in Table 1. The results revealed that 5-(benzylsulfonylmethyl)-2-[40,
Table 1. In vitro antibacterial activity of 8 and 9
Zone of inhibition (mm)
Gram-positive bacteria
Gram-negative bacteria
Concentration
(mg=disc)
Staphylococcus
aureus
Bacillus
subtilis
Klebsiella
pneumoniae
Proteus
vulgaris
Compound
8a
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
15
18
20
25
12
15
20
24
22
27
17
22
28
32
16
18
27
30
32
36
35
41
15
17
23
27
11
13
22
25
23
26
19
25
29
35
14
17
30
33
34
37
38
44
14
16
19
21
16
18
14
18
16
19
14
19
26
28
15
18
25
29
31
35
37
42
12
15
16
19
14
17
18
21
15
20
15
18
26
30
16
18
24
27
29
33
42
45
8b
8c
8d
8e
9a
9b
9c
9d
9e
Chloramphenicol

PYRAZOLYL 1,3,4-OXADIAZOLES
485
50-dihydro-40-(p-chlorophenyl)-10H-pyrazol-30-yl]-1,3,4-oxadiazole (9b) and 5-(p-
chlorobenzylsulfonylmethyl)-2-[40,50-dihydro-40-(p-chlorophenyl)-10H-pyrazol-30-yl]-
1,3,4-oxadiazole (9e) exhibited pronounced activity on both Gram (þve) (32–36 mm)
and Gram (ꢁve) (28–32 mm) bacteria. The compounds 8b, 8d, 8e, 9a, and 9d showed
moderate to high activity toward Gram (þve) bacteria (22–27 mm) and moderate
activity toward Gram (ꢁve) bacteria (18–21 mm). On the other hand, 8a, 8c, and
9c displayed the least activity against both bacteria.
All the test compounds inhibited the spore germination of tested fungi
Aspergillus niger, Fusarium solani, and Curvularia lunata. Results of the investigation
presented in Table 2 revealed that all the compounds except 8a and 8c showed
relatively more inhibitory effect on Fusarium solani and Curvularia lunata than on
Aspergillus niger. Further, the compounds 5-benzylsulfonylmethyl-2-[40,50-dihydro-
40-(p-chlorophenyl)-10H-pyrazol-30-yl]-1,3,4-oxadiazole (9b), 5-(p-chlorobenzylsulfo-
nylmethyl)-2-(40,50-dihydro-40-phenyl-10H-pyrazol-30-yl)-1,3,4-oxadiazole (9d), and
5-(p-chlorobenzylsulfonylmethyl)-2-[40,50-dihydro-40-(p-chlorophenyl)-10H-pyrazol-30-
yl]-1,3,4-oxadiazole (9e) displayed greater activity.
The minimum inhibitory concentration (MIC) values were determined as the
lowest concentration that completely inhibited visible growth of the microorganisms
(Table 3). The structure–antimicrobial activity relationship of the synthesized
compounds revealed that the compounds having an aryl moiety exhibited the least
activity when compared with compounds having a benzyl group. Besides, the
Table 2. In vitro antifungal activity of 8 and 9
Zone of inhibition (mm)
Compound
Concentration (mg=mL)
Fusarium solani
Curvularia lunata
Aspergillus niger
8a
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
17
21
24
27
15
18
22
25
28
31
20
25
28
33
22
26
27
32
31
37
38
42
19
23
23
25
15
19
20
24
25
27
20
23
28
32
18
23
26
30
34
39
41
44
16
19
17
20
14
17
19
22
20
23
17
21
22
26
18
21
22
28
28
32
36
39
8b
8c
8d
8e
9a
9b
9c
9d
9e
Ketoconazole

486
V. PADMAVATHI ET AL.
Table 3. Minimum inhibitory concentration (MIC, mg=mL) of 9b, 9d, and 9e
Compound
S. aureus B. subtilis K. pneumoniae P. vulgaris F. solani C. lunata A. niger
9b
9d
50
50
100
100
25
100
100
50
100
200
50
100
100
100
—
100
100
50
100
100
50
9e
Chloramphenicol
Ketoconazole
25
6.25
—
6.25
—
6.25
—
12.5
—
—
6.25
—
6.25
12.5
compounds with a chloro substituent at the 4-position of the aryl ring were the most
active. The maximum activity was observed with compounds 9b, 9d, and 9e (Table 3).
CONCLUSIONS
A new class of bis heterocycles, pyrazolyl oxadiazoles, are prepared from aryl-
sulfonylacetic acid methyl ester and benzylsulfonylacetic acid methyl ester with a
simple, facile, and well-versed methodology. The compounds having benzyl groups
showed greater antimicrobial activity. Further, the presence of a chloro substituent
enhances the activity.
EXPERIMENTAL
Melting points were determined in open capillaries on a Mel-Temp apparatus
and are uncorrected. The purity of the compounds was checked by thin-layer chro-
matography (TLC; silica gel H, BDH, ethyl acetate=hexane, 1:3). The infrared (IR)
spectra were recorded on a Thermo Nicolet IR 200 Fourier transfrom (FT)–IR spec-
trometer as KBr pellets, and the wave numbers were given in centimetersꢁ1. The 1H
NMR spectra were recorded in CDCl3= dimethylsulfoxide (DMSO-d6) on a Varian
EM-360 spectrometer (300 MHz). The 13C NMR spectra were recorded in CDCl3=
DMSO-d6 on a Varian VXR spectrometer operating at 75.5 MHz. All chemical
shifts are reported in d (ppm) using tetramethylsilane (TMS) as an internal
standard. The microanalyses were performed on a Perkin-Elmer 240C elemental
analyzer. The starting compounds arylsulfonylacetic acid methyl ester (1), aryl-
methanesulfonylacetic acid methyl ester (2), arylsulfonylacetic acid hydrazide (3),
and arylmethanesulfonylacetic acid hydrazide (4) were prepared by the literature
procedure.[25–27]
General Procedure of Synthesis of 2-(Styryl)-5-
(arylsulfonylmethyl)-1,3,4-oxadiazole (6a–e)
POCl3 (4 mL) was added to compounds 3 (5 mmol) and 5 (5 mmol) and heated
under reflux for 5–6 h. The excess POCl3 was removed under reduced pressure, and
the residue was poured onto crushed ice. The resulting precipitate was filtered,
washed with saturated sodium bicarbonate solution and then with water, dried,
and recrystallized from ethanol to get 6.

PYRAZOLYL 1,3,4-OXADIAZOLES
487
Selected Data
2-(Styryl)-5-(phenylsulfonylmethyl)-1,3,4-oxadiazole (6a). Yellow solid;
1
yield 1.06 g (65%); mp 91–93ꢂC; H NMR (DMSO-d6) d (ppm): 4.60 (s, 2H, SO2-
CH2), 7.42 (d, 1H, HB, J ¼ 15.7 Hz), 7.68 (d, 1H, HA, J ¼ 15.7 Hz), 7.15–7.48 (m,
10H, Ar-H); 13C NMR (DMSO-d6) d (ppm): 53.4 (CH2), 137.8 (CN-CH), 143.8
(Ar-CH), 157.5 (C-5), 165.8 (C-2), 126.8, 127.2, 128.3, 128.6, 129.2, 130.4, 132.2,
133.6 (aromatic carbons); IR (KBr, cmꢁ1): 1569 (C N), 1536 (C C), 1345, 1144
(SO2): Anal. calcd. for C17H14N2O3S (326.37): C, 62.56; H, 4.32; N 8.58. Found:
C, 62.44; H, 4.35; N, 8.64.
=
=
2-(p-Chlorostyryl)-5-(phenylsulfonylmethyl)-1,3,4-oxadiazole (6b). Yel-
1
low solid; yield 1.26 g (70%); mp 102–104ꢂC; H NMR (DMSO-d6) d (ppm): 4.57
(s, 2H, SO2-CH2), 7.38 (d, 1H, HB, J ¼ 15.3 Hz), 7.61 (d, 1H, HA, J ¼ 15.3 Hz),
7.26–7.52 (m, 9H, Ar-H); 13C NMR (DMSO-d6) d (ppm): 53.8 (CH2), 137.2 (CN-
CH), 143.3 (Ar-CH), 157.6 (C-5), 166.3 (C-2), 126.8, 127.6, 128.1, 128.7, 129.2,
129.6, 134.5, 136.8 (aromatic carbons); IR (KBr, cmꢁ1): 1573 (C N), 1541 (C C),
1333, 1137 (SO2). Anal. calcd. for C17H13ClN2O3S (360.81): C, 56.59; H, 3.63; N,
7.76. Found: C, 56.50; H, 3.65; N, 7.80.
=
=
2-(Styryl)-5-(p-methylphenylsulfonylmethyl)-1,3,4-oxadiazole (6c). Yel-
1
low solid; yield 1.07 g (63%); mp 96–98ꢂC; H NMR (DMSO-d6) d (ppm): 2.28 (s,
3H, Ar-CH3), 4.53 (s, 2H, SO2-CH2), 7.46 (d, 1H, HB, J ¼ 15.9 Hz), 7.59 (d, 1H,
HA, J ¼ 15.9 Hz), 7.20–7.51 (m, 9H, Ar-H); 13C NMR (DMSO-d6) d (ppm): 23.4
(Ar-CH3), 54.1 (CH2), 138.1 (CN-CH), 144.2 (Ar-CH), 156.4 (C-5), 165.5 (C-2),
125.4, 126.1, 127.3, 128.7, 129.8, 131.7, 134.2, 135.1 (aromatic carbons); IR (KBr,
cmꢁ1): 1570 (C N), 1537 (C C), 1338, 1131 (SO2). Anal. calcd. for C18H16N2O3S
(340.40): C, 63.51; H, 4.74; N, 8.23. Found: C, 63.42; H, 4.70; N, 8.26.
=
=
2-(Styryl)-5-(p-chlorophenylsulfonylmethyl)-1,3,4-oxadiazole (6d). Yel-
1
low crystals; yield 1.19 g (66%); mp 103–105ꢂC; H NMR (DMSO-d6) d (ppm):
4.59 (s, 2H, SO2-CH2), 7.41 (d, 1H, HB, J ¼ 15.5 Hz), 7.64 (d, 1H, HA, J ¼ 15.5 Hz),
7.28–7.72 (m, 9H, Ar-H); 13C NMR (DMSO-d6) d (ppm): 56.8 (CH2), 138.7 (CN-
CH), 141.8 (Ar-CH), 156.8 (C-5), 167.2 (C-2), 126.5, 128.9, 129.2, 129.6, 130.5,
133.7, 134.3, 136.5 (aromatic carbons); IR (KBr, cmꢁ1): 1572 (C N), 1532 (C C),
1335, 1135 (SO2); Anal. calcd. for C17H13ClN2O3S (360.81): C, 56. 59; H, 3.63; N,
7.76. Found: C, 56.49; H, 3.60; N, 7.78.
=
=
2-(p-Chlorostyryl)-5-(p-chlorophenylsulfonylmethyl)-1,3,4-oxadiazole
(6e). Yellow solid; yield 1.42 g (72%); mp 115–117ꢂC; 1H NMR (DMSO-d6) d
(ppm): 4.51 (s, 2H, SO2-CH2), 7.35 (d, 1H, HB, J ¼ 15.2 Hz), 7.57 (d, 1H, HA,
J ¼ 15.2 Hz), 7.32–7.87 (m, 8H, Ar-H); 13C NMR (DMSO-d6) d (ppm): 57.2
(CH2), 137.6 (CN-CH), 142.3 (Ar-CH), 157.3 (C-5), 168.4 (C-2), 125.5, 126.4,
127.8, 129.5, 131.3, 133.7, 134.5, 137.2 (aromatic carbons); IR (KBr, cmꢁ1): 1567
=
=
(C N), 1539 (C C), 1342, 1129 (SO2); Anal. Calcd. for C17H12Cl2N2O3S (395.26):
C, 51.66; H, 3.06; N, 7.09. Found: C, 51.76; H, 3.09; N, 7.05.

488
V. PADMAVATHI ET AL.
General Procedure of Synthesis of 2-styryl-5-
(arylmethanesulfonylmethyl)-1,3,4-oxadiazole (7a–e)
A mixture of 4 (5 mmol), 5 (5 mmol), and POCl3 (4 mL) was heated under
reflux for 5–6 h. The excess POCl3 was removed under reduced pressure, and the resi-
due was poured onto crushed ice. The resulting precipitate was filtered, washed with
saturated sodium bicarbonate solution followed by water, dried, and recrystallized
from ethanol to get 7.
Selected Data
2-(Styryl)-5-(benzylsulfonylmethyl)-1,3,4-oxadiazole (7a). Yellow solid;
yield 1.25 g (74%); mp 101–103ꢂC; 1H NMR (DMSO-d6) d (ppm): 4.76 (s, 2H,
SO2-CH2), 5.05 (s, 2H, Ar-CH2), 7.34 (d, 1H, HB, J ¼ 15.1 Hz), 7.55 (d, 1H, HA,
J ¼ 15.1 Hz), 7.20–7.57 (m, 10H, Ar-H); 13C NMR (DMSO-d6) d (ppm): 48.4
(SO2-CH2), 58.9 (Ar-CH2), 138.1 (CN-CH), 145.2 (Ar-CH), 157.4 (C-5), 165.2
(C-2), 127.6, 128.3, 128.9, 129.6, 131.5, 132.6, 133.4, 134.8 (aromatic carbons); IR
(KBr, cmꢁ1): 1571 (C N), 1533 (C C), 1333, 1141 (SO2). Anal. calcd. for
C18H16N2O3S (340.40): C, 63.51; H, 4.74; N, 8.23. Found: C, 63.58; H, 4.78; N, 8.27.
=
=
2-(p-Chlorostyryl)-5-(benzylsulfonylmethyl)-1,3,4-oxadiazole (7b). Yel-
low solid; yield 1.34 g (72%); mp 105–107ꢂC; 1H NMR (DMSO-d6) d (ppm):
4.72 (s, 2H, SO2-CH2), 5.07 (s, 2H, Ar-CH2), 7.38 (d, 1H, HB, J ¼ 15.7 Hz), 7.59
(d, 1H, HA, J ¼ 15.7 Hz), 7.26–7.64 (m, 9H, Ar-H); 13C NMR (DMSO-d6) d
(ppm): 48.7 (SO2-CH2), 58.2 (Ar-CH2), 138.8 (CN-CH), 145.6 (Ar-CH), 157.8
(C-5), 164.6 (C-2), 127.9, 128.7, 129.7, 130.4, 131.8, 133.1, 134.3, 136.6 (aromatic
carbons); IR (KBr, cmꢁ1): 1575 (C N), 1546 (C C), 1339, 1136 (SO2). Anal.
calcd. for C18H15ClN2O3S (374.84): C, 57.68; H, 4.03; N, 7.47. Found: C, 57.60;
H, 4.01; N, 7.44.
=
=
2-(Styryl)-5-(p-methylbenzylsulfonylmethyl)-1,3,4-oxadiazole (7c). Yel-
low solid; yield 1.22 g (69%); mp 98–100ꢂC; 1H NMR (CDCl3þDMSO-d6) d
(ppm): 2.27 (s, 3H, Ar-CH3), 4.68 (s, 2H, SO2-CH2), 5.11 (s, 2H, Ar-CH2), 7.31
(d, 1H, HB, J ¼ 15.9 Hz), 7.57 (d, 1H, HA, J ¼ 15.9 Hz), 7.18–7.62 (m, 9H, Ar-H);
13C NMR (CDCl3þDMSO-d6) d (ppm): 23.1 (Ar-CH3), 49.3 (SO2-CH2), 57.9 (Ar-
CH2), 138.5 (CN-CH), 146.1 (Ar-CH), 157.2 (C-5), 164.7 (C-2), 125.5, 127.2,
129.5, 131.3, 132.4, 133.0, 133.3, 135.8 (aromatic carbons); IR (KBr, cmꢁ1): 1570
=
(C N), 1540 (C C), 1331, 1134 (SO2). Anal. calcd. for C19H18N2O3S (354.42): C,
=
64.39; H, 5.12; N, 7.90. Found: C, 64.47; H, 5.09; N, 7.93.
2-(Styryl)-5-(p-chlorobenzylsulfonylmethyl)-1,3,4-oxadiazole (7d). Yel-
1
low solid; yield 1.40 g (75%) mp 108–110ꢂC; H NMR (DMSO-d6) d (ppm): 4.75
(s, 2H, SO2-CH2), 5.02 (s, 2H, Ar-CH2), 7.36 (d, 1H, HB, J ¼ 15.2 Hz), 7.60 (d,
1H, HA, J ¼ 15.2 Hz), 7.36–7.78 (m, 9H, Ar-H); 13C NMR (DMSO-d6) d (ppm):
48.8 (SO2-CH2), 58.1 (Ar-CH2), 138.7 (CN-CH), 147.3 (Ar-CH), 157.9 (C-5),
164.5 (C-2), 125.4, 126.4, 128.1, 129.5, 130.7, 132.1, 135.7, 136.2 (aromatic
carbons); IR (KBr, cmꢁ1): 1578 (C N), 1543 (C C), 1338, 1146 (SO2). Anal.
calcd. for C18H15ClN2O3S (374.84): C, 57.68; H, 4.03; N, 7.47. Found: C, 57.75;
H, 4.07; N, 7.52.
=
=

PYRAZOLYL 1,3,4-OXADIAZOLES
489
2-(p-Chlorostyryl)-5-(p-chlorobenzylsulfonylmethyl)-1,3,4-oxadiazole
1
(7e). Yellow crystals; yield 1.59 g (78%); mp 112–114ꢂC; H NMR (DMSO-d6) d
(ppm): 4.70 (s, 2H, SO2-CH2), 5.09 (s, 2H, Ar-CH2), 7.33 (d, 1H, HB, J ¼ 15.4 Hz),
7.62 (d, 1H, HA, J ¼ 15.4 Hz), 7.32–7.80 (m, 8H, Ar-H); 13C NMR (DMSO-d6) d
(ppm): 51.0 (SO2-CH2), 58.4 (Ar-CH2), 139.1 (CN-CH), 146.7 (Ar-CH), 158.4
(C-5), 167.5 (C-2), 128.6, 129.2, 129.8, 130.2, 132.4, 133.1, 134.6, 137.9 (aromatic
carbons); IR (KBr, cmꢁ1): 1565 (C N), 1534 (C C), 1333, 1130 (SO2). Anal.
calcd. for C18H14Cl2N2O3S (409.29): C, 52.82; H, 3.45; N, 6.84. Found: C,
52.76; H, 3.47; N, 6.88.
=
=
General Procedure of Synthesis of 5-(arylsulfonylmethyl)-2-
(40,50-dihydro-40-phenyl-10H-pyrazol-30-yl)-1,3,4-oxadiazole (8a–e)
An ethereal solution of diazomethane (20 mL, 0.4 M) and triethylamine (0.06 g)
was added to a cooled solution of 6 (2.5 mmol) in DCM (10 mL). The reaction mix-
ture was kept at ꢁ 20 to ꢁ 15ꢂC for 40–48 h. The solvent was removed under reduced
pressure. The resultant solid was purified by column chromatography (hexane–ethyl
acetate, 4:1).
Selected Data
5-(Phenylsulfonylmethyl)-2-[40,50-dihydro-40-phenyl-10H-pyrazol-30-yl]-
1
1,3,4-oxadiazole (8a). Yellow solid; yield 0.77 g (84%); mp 127–129ꢂC; H NMR
(DMSO-d6) d (ppm): 3.72 (dd, 1H, HX, JAX ¼ 4.2 Hz, JMX ¼ 8.7 Hz), 4.04 (dd, 1H,
HM, JAM ¼ 12.0 Hz), 4.37 (s, 2H, SO2-CH2), 4.64 (dd, 1H, HA), 7.26–7.73 (m,
10H, Ar-H), 10.49 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 50.9 (SO2-CH2),
52.4 (C-50), 65.8 (C-40), 151.9 (C-30), 152.6 (C-5), 163.4 (C-2), 128.6, 129.2, 129.8,
130.2, 132.4, 133.1, 134.6, 134.9 (aromatic carbons); IR (KBr, cmꢁ1): 3345 (NH),
=
1563 (C N), 1337, 1138 (SO2). Anal. calcd. for C18H16N4O3S (368.41): C, 58.68;
H, 4.38; N, 15.21. Found: C, 58.60; H, 4.40; N, 15.27.
5-(Phenylsulfonylmethyl)-2-[40,50-dihydro-40-(p-chlorophenyl)-10H-pyrazol-
30-yl]-1,3,4-oxadiazole (8b). Yellow crystals; yield 0.80 g (80%); mp 132–134ꢂC;
1H NMR (DMSO-d6) d (ppm): 3.66 (dd, 1H, HX, JAX ¼ 4.6 Hz, JMX ¼ 10.1 Hz),
3.98 (dd, 1H, HM, JAM ¼ 12.5 Hz), 4.32 (s, 2H, SO2-CH2), 4.59 (dd, 1H, HA),
7.19–7.75 (m, 9H, Ar-H), 10.51 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 50.3
(SO2-CH2), 51.9 (C-50), 65.9 (C-40), 150.2 (C-30), 153.3 (C-5), 163.1 (C-2), 127.2,
128.8, 129.2, 130.8, 131.3, 132.2, 134.8, 135.5 (aromatic carbons); IR (KBr, cmꢁ1):
=
3340 (NH), 1565 (C N), 1335, 1130 (SO2). Anal. calcd. for C18H15
ClN4O3S (402.85): C, 53.67; H, 3.75; N, 13.91. Found: C, 53.74; H, 3.72; N, 13.99.
5-(p-Methylphenylsulfonylmethyl)-2-(40,50-dihydro-40-phenyl-10H-pyrazol-
1
30-yl)-1,3,4-oxadiazole (8c). Yellow solid; yield 0.81 g (85%); mp 139–141ꢂC; H
NMR (CDCl3þDMSO-d6) d (ppm): 2.25 (s, 3H, Ar-CH3), 3.62 (dd, 1H, HX,
JAX ¼ 5.1 Hz, JMX ¼ 9.8 Hz), 4.01 (dd, 1H, HM, JAM ¼ 12.3 Hz), 4.35 (s, 2H, SO2-
CH2), 4.62 (dd, 1H, HA), 7.15–7.64 (m, 9H, Ar-H), 10.54 (bs, 1H, NH); 13C
NMR (CDCl3þDMSO-d6) d (ppm): 22.9 (Ar-CH3), 50.7 (SO2-CH2), 52.6 (C-50),
65.6 (C-40), 151.5 (C-30), 153.9 (C-5), 161.6 (C-2), 127.9, 128.7, 129.7, 130.4, 131.8,

490
V. PADMAVATHI ET AL.
132.6, 133.5, 134.3 (aromatic carbons); IR (KBr, cmꢁ1): 3336 (NH), 1566 (C N),
1342, 1148 (SO2). Anal. calcd. for C19H18N4O3S (382.44): C, 59.67; H, 4.74; N,
14.65. Found: C, 59.75; H, 4.72; N, 14.71.
=
5-(p-Chlorophenylsulfonylmethyl)-2-(40,50-dihydro-40-phenyl-10H-pyrazol-
30-yl)-1,3,4-oxadiazole (8d). Yellow crystals; yield 0.82 g (82%); mp 147–149ꢂC;
1H NMR (DMSO-d6) d (ppm): 3.70 (dd, 1H, HX, JAX ¼ 5.5 Hz, JMX ¼ 10.3 Hz),
4.06 (dd, 1H, HM, JAM ¼ 12.5 Hz), 4.30 (s, 2H, SO2-CH2), 4.58 (dd, 1H, HA),
7.20–7.70 (m, 9H, Ar-H), 10.49 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm):
51.7 (SO2-CH2), 52.1 (C-50), 66.5 (C-40), 152.8 (C-30), 155.6 (C-5), 165.8 (C-2),
126.5, 127.1, 127.9, 129.2, 130.5, 132.5, 135.8, 136.3 (aromatic carbons); IR (KBr,
cmꢁ1): 3328 (NH), 1564 (C N), 1330, 1140 (SO2). Anal. calcd. for C18H15ClN4O3S
=
(402.85): C, 53.67; H, 3.75; N, 13.91. Found: C, 53.60; H, 3.79; N, 13.82.
5-(p-Chlorophenylsulfonylmethyl)-2-[40,50-dihydro-40-(p-chlorophenyl)-
10H-pyrazol-30-yl]-1,3,4-oxadiazole (8e). Yellow crystals; yield 0.95 g (87%); mp
154–156ꢂC; 1H NMR (DMSO-d6) d (ppm): 3.74 (dd, 1H, HX, JAX ¼ 5.2 Hz,
JMX ¼ 10.0 Hz), 4.00 (dd, 1H, HM, JAM ¼ 12.1 Hz), 4.37 (s, 2H, SO2-CH2), 4.59
(dd, 1H, HA), 7.23–7.81 (m, 8H, Ar-H), 10.52 (bs, 1H, NH); 13C NMR (DMSO-
d6) d (ppm): 51.3 (SO2-CH2), 52.3 (C-50), 65.9 (C-40), 154.2 (C-30), 157.5 (C-5),
168.2 (C-2), 125.1, 125.7, 126.6, 127.4, 128.3, 131.7, 133.8, 138.4 (aromatic carbons);
IR (KBr, cmꢁ1): 3324 (NH), 1568 (C N), 1338, 1146 (SO2). Anal. calcd. for
=
C18H14Cl2N4O3S (437.30): C, 49.44; H, 3.23; N, 12.81. Found: C, 49.40; H, 3.20;
N, 12.74.
General Procedure of Synthesis of 5-(Arylmethanesulfonylmethyl)-2-
(40,50-dihydro-40-phenyl-10H-pyrazol-30-yl)-1,3,4-oxadiazole (9a–e)
An ethereal solution of diazomethane (20 mL, 0.4 M) and triethylamine (0.06 g)
were added to a cooled solution of 7 (2.5 mmol) in DCM (10 mL). The reaction mix-
ture was kept at ꢁ20 to ꢁ15ꢂC for 40–46 h. The solvent was removed under reduced
pressure. The resultant solid was purified by column chromatography (hexane–ethyl
acetate, 4:1).
Selected Data
5-(Benzylsulfonylmethyl)-2-[40,50-dihydro-40-phenyl-10H-pyrazol-30-yl]-1,3,4-
oxadiazole (9a). Yellow solid; yield 0.75 g (79%); mp 117–119ꢂC; 1H NMR
(DMSO-d6) d (ppm): 3.66 (dd, 1H, HX, JAX ¼ 4.6 Hz, JMX ¼ 8.6 Hz), 4.01 (dd, 1H,
HM, JAM ¼ 12.6 Hz), 4.34 (s, 2H, SO2-CH2), 4.60 (dd, 1H, HA), 5.02 (s, 2H,
Ar-CH2), 7.25–7.59 (m, 10H, Ar-H), 10.57 (bs, 1H, NH); 13C NMR (DMSO-d6) d
(ppm): 48.6 (SO2-CH2), 51.7 (C-50), 57.4 (Ar-CH2), 66.2 (C-40), 152.5 (C-30), 157.8
(C-5), 166.6 (C-2), 126.4, 126.9, 127.2, 129.3, 130.4, 131.3, 133.6, 134.2 (aromatic car-
bons); IR (KBr, cmꢁ1): 3330 (NH), 1582 (C N), 1336, 1126 (SO2). Anal. calcd. for
=
C19H18N4O3S (382.44): C, 59.67; H, 4.74; N, 14.65. Found: C, 59.62; H, 4.70; N,
14.72.

PYRAZOLYL 1,3,4-OXADIAZOLES
491
5-(Benzylsulfonylmethyl)-2-[40,50-dihydro-40-(p-chlorophenyl)-10H-pyrazol-
30-yl]-1,3,4-oxadiazole (9b). Yellow crystals; yield 0.83 g (80%); mp 146–148ꢂC; 1H
NMR (DMSO-d6) d (ppm): 3.75 (dd, 1H, HX, JAX ¼ 4.2 Hz, JMX ¼ 8.2 Hz), 4.03
(dd, 1H, HM, JAM ¼ 12.3 Hz), 4.41 (s, 2H, SO2-CH2), 4.68 (dd, 1H, HA), 5.07 (s,
2H, Ar-CH2), 7.28–7.73 (dd, 9H, Ar-H), 10.54 (bs, 1H, NH); 13C NMR (DMSO-d6)
d (ppm): 49.3 (SO2-CH2), 52.3 (C-50), 57.6 (Ar-CH2), 66.5 (C-40), 152.8 (C-30), 158.5
(C-5), 167.5 (C-2), 125.3, 127.1, 128.6, 129.5, 131.7, 133.9, 135.2, 137.5 (aromatic
carbons); IR (KBr, cmꢁ1): 3328 (NH), 1577 (C N), 1330, 1142 (SO2). Anal. calcd.
=
for C19H17ClN4O3S (416.88): C, 54.74; H, 4.11; N, 13.44. Found: C, 54.70; H, 4.13;
N, 13.50.
5-(p-Methylbenzylsulfonylmethyl)-2-(40,50-dihydro-40-phenyl-10H-pyrazol-
1
30-yl)-1,3,4-oxadiazole (9c). Yellow solid; yield 0.82 g (83%); mp 133–135ꢂC; H
NMR (DMSO-d6) d (ppm): 2.25 (s, 3H, Ar-CH3), 3.70 (dd, 1H, HX, JAX ¼ 4.6 Hz,
JMX ¼ 8.7 Hz), 4.05 (dd, 1H, HM, JAM ¼ 12.7 Hz), 4.46 (s, 2H, SO2-CH2), 4.66 (dd,
1H, HA), 5.01 (s, 2H, Ar-CH2), 7.14–7.68 (m, 9H, Ar-H), 10.51 (bs, 1H, NH); 13C
NMR (DMSO-d6) d (ppm): 23.6 (Ar-CH3), 48.7 (SO2-CH2), 51.1 (C-50), 56.4 (Ar-
CH2), 65.6 (C-40), 151.7 (C-30), 156.9 (C-5), 167.8 (C-2), 127.9, 128.7, 129.7, 131.8,
132.6, 133.1, 134.3, 135.6 (aromatic carbons); IR (KBr, cmꢁ1): 3335 (NH), 1585
=
(C N), 1324, 1136 (SO2). Anal. calcd. for C20H20N4O3S (396.46): C, 60.59; H,
5.08; N, 14.13. Found: C, 60.65; H, 5.12; N, 14.17.
5-(p-Chlorobenzylsulfonylmethyl)-2-(40,50-dihydro-40-phenyl-10H-pyrazol-
30-yl)-1,3,4-oxadiazole (9d). Yellow crystals; yield 0.81 g (78%); mp 159–161ꢂC; 1H
NMR (CDCl3þDMSO-d6) d (ppm): 3.69 (dd, 1H, HX, JAX ¼ 4.8 Hz, JMX ¼ 8.5 Hz),
4.00 (dd, 1H, HM, JAM ¼ 12.2 Hz), 4.36 (s, 2H, SO2-CH2), 4.65 (dd, 1H, HA), 5.05 (s,
2H, Ar-CH2), 7.19–7.68 (m, 9H, Ar-H), 10.44 (bs, 1H, NH); 13C NMR
(CDCl3þDMSO-d6) d (ppm): 49.5 (SO2-CH2), 51.8 (C-50), 57.0 (Ar-CH2), 65.8
(C-40), 152.2 (C-30), 157.4 (C-5), 166.5 (C-2), 128.6, 129.2, 129.8, 130.2, 132.7,
133.1, 134.6, 136.4 (aromatic carbons); IR (KBr, cmꢁ1): 3327 (NH), 1579 (C N),
=
1333, 1145 (SO2). Anal. calcd. for C19H17ClN4O3S (416.88): C, 54.74; H, 4.11; N,
13.44. Found: C, 54.77; H, 4.07; N, 13.48.
5-(p-Chlorobenzylsulfonylmethyl)-2-[40,50-dihydro-40-(p-chlorophenyl)-
10H-pyrazol-30-yl]-1,3,4-oxadiazole (9e). Yellow solid; yield 0.95 g (85%); mp
166–168ꢂC; 1H NMR (DMSO-d6) d (ppm): 3.72 (dd, 1H, HX, JAX ¼ 4.3 Hz,
JMX ¼ 8.9 Hz), 4.03 (dd, 1H, HM, JAM ¼ 12.5 Hz), 4.37 (s, 2H, SO2-CH2), 4.68 (dd,
1H, HA), 5.10 (s, 2H, Ar-CH2), 7.24–7.72 (m, 8H, Ar-H), 10.49 (bs, 1H, NH); 13C
NMR (DMSO-d6) d (ppm): 49.1 (SO2-CH2), 51.4 (C-50), 56.8 (Ar-CH2), 65.5
(C-40), 152.7 (C-30), 158.2 (C-5), 167.0 (C-2), 124.9, 128.8, 129.3, 130.8, 131.1,
133.4, 134.6, 137.2 (aromatic carbons); IR (KBr, cmꢁ1): 3334 (NH), 1580 (C N),
=
1330, 1125 (SO2). Anal. calcd. for C19H16Cl2N4O3S (451.33): C, 50.56; H, 3.57; N,
12.41. Found: C, 50.60; H, 3.59, N, 12.37.
Antimicrobial Testing
The compounds 8 and 9 were dissolved in DMSO at concentrations of 100,
200, and 800 mg=mL.

492
V. PADMAVATHI ET AL.
Antibacterial and Antifungal Assays
Preliminary antimicrobial activities of these compounds were tested by the agar
disc-diffusion method. Sterile filter-paper discs (6 mm diameter) moistened with the
test compound solution in DMSO of specific concentrations of 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 37ꢂC, and
the diameter of the growth-inhibition zones were measured after 24 h in the case
of bacteria and after 48 h in the case of fungi.
The MICs of the compounds assays were carried out using the microdilution
susceptibility method. Chloramphenicol was used as the reference antibacterial
agent. Ketoconazole was used as the reference antifungal agent. The test com-
pounds, chloramphenicol and ketoconazole, were dissolved in DMSO at a concen-
tration of 800 mg=mL. Twofold dilutions of the solution were prepared (400, 200,
100, 50, 25, 12.5, 6.25 mg=mL). The microorganism suspensions were inoculated to
the corresponding wells. The plates were incubated at 36ꢂC for 24 and 48 h for bac-
teria and fungi, respectively. The MICs of the compounds were recorded as the low-
est concentration of each chemical compounds in the tubes with no turbidity (i.e., no
growth) of inoculated bacteria=fungi.
ACKNOWLEDGMENT
The authors are thankful to the Department of Science and Technology,
New Delhi, India, for the financial assistance as a major research project.
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