Synthesis, characterization, and bioassay of a new class of pyrazolyl/isoxazolyl oxadiazoles

Article abstract of DOI:10.1007/s00706-018-2295-7

Abstract: This study aimed at describing a simple and facile synthesis of pyrazolyl/isoxazolyl 1,3,4-oxadiazole derivatives from the synthetic intermediates pyrazolyl/isoxazolyl carboxylates adopting conventional and ultrasound irradiation methods. In fact ultrasound-promoted synthesis led to the formation of title compounds in higher yields and in shorter reaction times when compared with conventional methods. All the compounds were characterized by IR, ¹H NMR, ¹³C NMR, and mass spectra. The synthesized compounds were evaluated for their antioxidant and anti-inflammatory activities. The bioassay results indicated that some title compounds were found to be more potent than standard drugs. Amongst all the tested compounds furanyl/pyridinyl linked pyrazolyl/isoxazolyl methoxyphenylsulfonylmethyloxadiazoles were identified as potential antioxidant and anti-inflammatory agents. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-018-2295-7

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-018-2295-7(0123456789(). -, vo Vl
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ORIGINAL PAPER
Synthesis, characterization, and bioassay of a new class of pyrazolyl/
isoxazolyl oxadiazoles
Yamini Gudi1 Madhu Sekhar Mangali1 Sravya Gundala2 Padmavathi Venkatapuram1 Padmaja Adivireddy1
•
•
•
•
Received: 13 July 2018 / Accepted: 14 September 2018
Ó Springer-Verlag GmbH Austria, part of Springer Nature 2018
Abstract
This study aimed at describing a simple and facile synthesis of pyrazolyl/isoxazolyl 1,3,4-oxadiazole derivatives from the
synthetic intermediates pyrazolyl/isoxazolyl carboxylates adopting conventional and ultrasound irradiation methods. In
fact ultrasound-promoted synthesis led to the formation of title compounds in higher yields and in shorter reaction times
when compared with conventional methods. All the compounds were characterized by IR, 1H NMR, 13C NMR, and mass
spectra. The synthesized compounds were evaluated for their antioxidant and anti-inflammatory activities. The bioassay
results indicated that some title compounds were found to be more potent than standard drugs. Amongst all the tested
compounds furanyl/pyridinyl linked pyrazolyl/isoxazolyl methoxyphenylsulfonylmethyloxadiazoles were identified as
potential antioxidant and anti-inflammatory agents.
Graphical abstract
Keywords Azole Á Cyclization Á Ultrasonication Á Antioxidant activity Á Anti-inflammatory activity Á Structure–activity
relationship
Introduction
biologically active pharmaceuticals vital for increasing the
quality of life (Fig. 1).
The five-membered heterocyclic compounds with one or
two nitrogen atoms particularly 1,3,4-oxadiazoles, pyra-
zoles, and isoxazoles represent an indispensable class of
heteroaromatic compounds, as they are part of many
Literature searches reveal that there are several methods
for synthesis of 2,5-disubstituted 1,3,4-oxadiazoles either
thermal/acid catalyzed cyclization of 1,2-diacylhydrazines
[1] or by oxidative cyclization of semicarbazone/hydrazone
in the presence of an oxidant [2] or by microwave irradi-
ation of hydrazide and carboxylic acid mixture [3] or
cyclization of acylthiosemicarbazides. 1,3,4-Oxadiazoles
and its derivatives have been attracting great attention due
to their wide range of biological properties including
antioxidant [4], analgesic [5], anti-inflammatory [6], anti-
cancer [7], antidiabetic [8], anticonvulsant [9], anti-HIV
[10], antihypertensive [11], antiobesity [12], antibacterial
& Padmaja Adivireddy
adivireddyp@yahoo.co.in
1
Department of Chemistry, Sri Venkateswara University,
Tirupati, Andhra Pradesh, India
2
Chemical Engineering Institute, Ural Federal University,
Yekaterinburg 620002, Russia
123

Y. Gudi et al.
Fig. 1 Drugs containing pyrazole, isoxazole, and oxadiazole motifs
[13], antifungal [14], antitubercular [15], and cytotoxic
[16] activities. Besides, many commercial drugs such as
zibotentan [17], ataluren [18], raltegravir [19], tiodazosin
[20], nesapidil [21], and furamizole [22] possess oxadia-
zole scaffold as major structural unit. They have also
attracted interest in medicinal chemistry as surrogates for
carboxylic acids, esters, and carboxamides [23]. On the
other hand, a number of bioactive natural products and
therapeutics are based on pyrazole and isoxazole motifs
viz., celecoxib, tepoxalin, rimonabant, valdecoxib,
leflunomide, and cloxacillin. In addition, pyrazoles and
isoxazoles exhibit antibacterial [24], antioxidant [25],
antidepressant [26], anticancer [27], antifungal [28], and
anti-inflammatory [29] activities.
be considered as a processing aid in terms of energy con-
servation, waste minimization, more convenient and easily
controlled compared to conventional heating. A large
number of organic reactions can be carried out in high
yields, shorter reaction time, and milder conditions under
ultrasound irradiation. The characteristic feature of ultra-
sonicator is that the mechanical energy in the form of high-
intensity, high-frequency sound waves is transferred to the
reaction mixture. This results in the generation and the
collapse of large number of minute bubbles throughout the
mixture. This effect, which is known as cavitation, is
responsible for the quick and thorough stirring of reaction
mixture [32–35]. It can enhance chemical reaction, mass
transfer. and offer potential for shorter reaction cycles which
are inaccessible by conventional methods. Inspired by the
remarkable biopotency of above mentioned heterocycles and
in continuation of our interest in the synthesis of a variety of
biologically active heterocycles [36–38], it is proposed to
synthesize the molecules having two different pharmacophore
units and to study their biological activity (Fig. 2).
With this background heteroaromatic compounds have
attracted researchers to synthesize these compounds by
employing new innovative methods and techniques and to
study their biological properties. Ultrasonic assisted
organic synthesis, a green synthetic approach is a powerful
technique to accelerate organic reactions [30, 31]. This can
123

Synthesis, characterization, and bioassay of a new class of pyrazolyl/isoxazolyl oxadiazoles
Fig. 2 Design strategy of the
target compounds
carbohydrazide (5), 5-(pyridin-4-yl)-1H-pyrazole-3-carbo-
Results and discussion
hydrazide (6), respectively. In the 1H NMR spectra of 4, 5,
and 6 the absence of triplet and quartet due to ethoxy
moiety and presence of two broad singlets at d = 9.69,
9.79, 9.71 ppm (NH) and at 4.42, 4.48, 4.37 ppm (NH2)
indicated the formation of acid hydrazide. The cyclocon-
densation of acid hydrazide 4, 5, and 6 with arylsulfonyl-
acetic acid in the presence of phosphorus oxychloride
Chemistry
The synthetic route to prepare a new class of pyrazolyl/
isoxazolyl 1,3,4-oxadiazoles was synthesized from the
synthetic intermediates pyrazolyl/isoxazolyl carboxylates
by exploiting ester functionality adopting conventional and
ultrasonication methodologies as illustrated in Schemes 1,
2 and Table 1. The reaction of ethyl 5-(furan-2-yl)-1H-
pyrazole-3-carboxylate (1), ethyl 5-(5-bromothiophen-2-
yl)-1H-pyrazole-3-carboxylate (2), and ethyl 5-(pyridin-4-
yl)-1H-pyrazole-3-carboxylate (3) with hydrazine hydrate
in methanol afforded 5-(furan-2-yl)-1H-pyrazole-3-carbo-
hydrazide (4), 5-(5-bromo-thiophen-2-yl)-1H-pyrazole-3-
produced
2-[5-(furan-2-yl)-1H-pyrazol-3-yl]-5-arylsul-
fonylmethyl-1,3,4-oxadiazole (7), 2-[5-(5-bromothiophen-
2-yl)-1H-pyrazol-3-yl]-5-arylsulfonyl-methyl-1,3,4-oxa-
diazole (8), and 2-[5-(pyridin-4-yl)-1H-pyrazol-3-yl]-5-
arylsulfonyl-methyl-1,3,4-oxadiazole (9), respectively. The
1H NMR spectra of 7a, 8a, and 9a displayed a sharp singlet
at 4.15, 4.23, 4.12 ppm (CH2) and a broad singlet at 11.74,
Scheme 1
123

Y. Gudi et al.
Scheme 2
11.93, 11.82 ppm (NH), respectively. Besides, a singlet
due to C4–H of pyrazole ring appeared at downfield region
and merged with aromatic protons. The signals due to NH
disappeared on deuteration.
3-yl]-1,3,4-oxadiazole-2-carboxylate (15) (Scheme 3). The
1H NMR spectra of 13, 14, and 15 showed a triplet at 1.34,
1.28, 1.33 ppm (CH3) and a quartet at 4.27, 4.31, 4.34 ppm
(OCH2) in addition to the signals of aromatic protons. A
broad singlet was also observed at 11.98, 11.80, 11.91 ppm
(NH), which disappeared on deuteration.
On the other hand, the treatment of compounds 4, 5, and
6 with ethyl 2-chloro-2-oxoacetate in tetrahydrofuran led to
the formation of ethyl 2-[2-[5-(furan-2-yl)-1H-pyrazole-3-
carbonyl]hydrazinyl]-2-oxoacetate (10), ethyl 2-[2-[5-(5-
bromothiophen-2-yl)-1H-pyrazole-3-carbonyl]hydrazinyl]-
2-oxoacetate (11), and ethyl 2-[2-[5-(pyridin-4-yl)-
1H-pyrazole-3-carbonyl]hydrazinyl]-2-oxoacetate (12),
respectively. The 1H NMR spectra of 10, 11, and 12
exhibited a triplet at 1.21, 1.24, 1.26 ppm and a quartet at
4.22, 4.26, 4.18 ppm due to methyl and methylene protons
of ester group and a singlet due to C4–H of pyrazole
appeared at much downfield region and merged with aro-
matic protons. Moreover, three broad singlets observed at
11.86, 11.82, 11.94; 9.80, 9.91, 9.78, and 9.98, 10.08,
9.84 ppm accounted for NH of pyrazole, CONH, and
NHCOCOOEt, respectively. The signals of highly acidic
protons disappeared when D2O was added. Furthermore,
the cyclocondensation of compounds 10, 11, and 12 with
POCl3 resulted in ethyl 5-[5-(furan-2-yl)-1H-pyrazol-3-yl]-
1,3,4-oxadiazole-2-carboxylate (13), ethyl 5-[5-(5-bro-
mothiophen-2-yl)-1H-pyrazol-3-yl]-1,3,4-oxadiazole-2-
carboxylate (14), and ethyl 5-[5-(pyridin-4-yl)-1H-pyrazol-
Adopting similar methodology the condensation of ethyl
5-(furan-2-yl)isoxazole-3-carboxylate (16), ethyl 5-(5-bro-
mothiophen-2-yl)isoxazole-3-carboxylate (17), and ethyl
5-(pyridin-4-yl)isoxazole-3-carboxylate (18) with hydra-
zine hydrate in methanol provided 5-(furan-2-yl)isoxazole-
3-carbohydrazide (19), 5-(5-bromothiophen-2-yl)isoxa-
zole-3-carbohydrazide (20), and 5-(pyridin-4-yl)isoxazole-
3-carbohydrazide (21), respectively. The absence of signals
1
due to ester group in H NMR spectra of 19, 20, and 21
confirmed the formation of acid hydazide. Two broad
singlets were also observed at 9.98, 10.02, 9.91 ppm, and
4.54, 4.62, 4.58 ppm due to NH and NH2, respectively,
which disappeared on deuteration.
Moreover,
2-[5-(furan-2-yl)-isoxazol-3-yl]-5-arylsul-
fonylmethyl-1,3,4-oxadiazole (22), 2-[5-(5-bromothio-
phen-2-yl)-isoxazol-3-yl]-5-arylsulfonylmethyl-1,3,4-oxa-
diazole (23), and 2-[5-(pyridin-4-yl)-isoxazol-3-yl]-5-aryl-
sulfonylmethyl-1,3,4-oxadiazole (24) were obtained by
cyclocondensation of acid hydrazide 19, 20, and 21 with
1
arylsulfonyl acetic acid in the presence of POCl3. The H
123

Synthesis, characterization, and bioassay of a new class of pyrazolyl/isoxazolyl oxadiazoles
(furan-2-yl)isoxazol-3-yl]-1,3,4-oxadiazole-2-carboxylate
Table 1 Synthesis of pyrazolyl/isoxazolyl 1,3,4-oxadiazole deriva-
tives 7–15 and 22–30 under conventional and ultrasonication methods
(28), ethyl 5-[5-(5-bromothiophen-2-yl)isoxazol-3-yl]-
1,3,4-oxadiazole-2-carboxylate (29), and ethyl 5-[5-(pyr-
idin-4-yl)isoxazol-3-yl]-1,3,4-oxadiazole-2-carboxylate
(30) were synthesized by the cyclocondensation of diacyl
hydrazide 25, 26, and 27 in the presence of POCl3. The 1H
NMR spectra of 28, 29, and 30 showed a triplet and a
quartet at 1.39, 1.32, 1.35 ppm and 4.35, 4.25, 4.39 ppm
due to CH3 and OCH2 groups apart from signals due to C4–
H of isoxazole and other aromatic protons. It was observed
that target compounds were obtained in shorter reaction
times and in higher yields under ultrasonication than in
conventional method. The structures of all the target
compounds were further ascertained by IR, 13C NMR,
mass, and microanalyses.
Product Time/h
Time/min
Yield/%
Conventional Ultrasound Conventional Ultrasound
7a
6.5
6
38
30
40
43
46
50
35
31
37
48
40
45
90
80
95
21
33
28
23
27
35
24
26
30
25
36
40
90
85
75
74
72
69
66
63
68
65
60
68
70
73
67
61
72
64
62
66
63
68
72
68
62
71
73
64
69
58
71
69
67
91
94
92
89
85
90
86
82
87
89
93
84
82
90
94
83
95
86
80
94
89
86
88
92
83
91
79
90
87
85
7b
7c
7.5
8
8a
8b
8c
7.5
9
9a
7
9b
9c
6.5
8.5
10
13
16
22
22
24
4.5
6
10
11
Antioxidant activity
12
13
The observed data on the antioxidant activity of the test
compounds and the standard drug are shown in Tables 2, 3
and 4 and Fig. 3. The results revealed that compounds 7b,
9b, 22b, and 24b showed greater radical scavenging
activity in all the three methods when compared with the
standard drug ascorbic acid. The compounds 7a, 8a, 8b, 9a,
22a, 23a, 23b, 24a exhibited good activity, whereas 10, 11,
12, 25, 26, 27, 28, 30 displayed moderate activity. On the
other hand, the compounds 7c, 13, 14, 15, 22c, 29 exhibited
low activity. However, the other compounds showed no
activity. The structure–activity relationship indicated that
isoxazole derivatives exhibited higher radical scavenging
activity than pyrazole derivatives. Moreover, it was
observed that electron donating substituents on the phenyl
ring increases the activity. This may be due to mesomeric
effect of methoxy group and inductive effect of methyl
substituent. It was also noticed that with increasing electron
donating effect the antioxidant activity increases. In fact,
methoxy-substituted compounds displayed higher activity
than methyl-substituted ones. Besides the compounds
having chloro and bromo substituents exhibited least
activity which indicated that with increasing electron
withdrawing effect the activity decreases. On the other
hand, the compounds 10, 11, 12, 25, 26, and 27 exhibited
higher activity than compounds 13, 14, 15, 28, 29, and 30.
This may be due to the increasing number of chromophoric
groups. In general, pyrazole in combination with furan/
pyridine and isoxazole in combination with furan/pyridine
displayed excellent activity than the thiophene-linked
compounds. The free radical scavenging activity of the
compounds 7b, 9b, 22b, and 24b was measured at different
concentrations and monitored the change in absorbance at
10, 20, and 30 min in DPPH method (Table 5). It was
perceived that at these 10-min intervals the values are very
close and the results exemplified that the antioxidant
14
15
22a
22b
22c
23a
23b
23c
24a
24b
24c
25
5.5
5
6.5
7
5
6
5.5
12
10
14
20
22
24
26
27
28
29
30
NMR spectra of 22a, 23a, 24a displayed a singlet
at 4.18, 4.21, and 4.22 ppm (CH2), respectively. In addi-
tion, a singlet due to C4–H of isoxazole appeared at
downfield region and merged with aromatic protons.
However, the resultant acid hydrazide 19, 20, and 21 was
treated with ethyl 2-chloro-2-oxoacetate followed by THF
gave ethyl 2-[2-[5-(furan-2-yl)isoxazole-3-carbonyl]hy-
drazinyl]-2-oxoacetate (25), ethyl 2-[2-[5-(5-bromothio-
phen-2-yl)isoxazole-3-carbonyl]hydrazinyl]-2-oxoacetate
(26), and ethyl 2-[2-[5-(pyridin-4-yl)isoxazole-3-car-
bonyl]hydrazinyl]-2-oxoacetate (27). The 1H NMR spectra of
25, 26, and 27 presented a triplet at 1.24, 1.26, 1.20 ppm
(CH3), a quartet at 4.19, 4.24, 4.17 ppm (OCH2), and two
broad singlets at 9.96, 9.94, 9.89 ppm (CONH) and 10.29,
10.05, 10.07 ppm (NHCOCOOEt). The signals due to NH
disappeared on deuteration. The cyclized products ethyl 5-[5-
123

Y. Gudi et al.
Scheme 3
activity is independent of time. The IC50 value of the
standard drug ascorbic acid in DPPH method was found to
be 17.03 lg/cm,3 whereas IC50 values of compounds 7b,
9b, 22b, and 24b were found to be 16.69, 16.88, 16.16, and
16.41 lg/cm3, respectively. It was also observed that rad-
ical scavenging activity increases with increase in con-
centration in all the three methods.
revealed that isoxazolyl oxadiazoles exhibited greater
activity than pyrazolyl oxadiazoles. In general, it was
observed that electron donating methyl and methoxy sub-
stituents on the phenyl ring enhance the anti-inflammatory
activity.
Conclusion
Statistical analysis
In summary, a series of new heteroaryl pyrazolyl/isoxa-
zolyl 1,3,4-oxadiazole derivatives were designed and syn-
thesized in good yields and in shorter reaction times
adopting a green approach—ultrasound irradiation. The
entire series of the compounds were characterized by IR,
NMR, and mass spectral parameters. The title compounds
were evaluated for their antioxidant and anti-inflammatory
activities. The activity results showed that the methoxy
substituted 1,3,4-oxadiazoles is a promising template for
antioxidant and anti-inflammatory activities. It was also
observed that the furanyl/pyridinyl pyrazolyl/isoxazolyl
1,3,4-oxadiazole displayed promising antioxidant and anti-
inflammatory activities than the thiophenyl/pyrazolyl/
isoxazolyl 1,3,4-oxadiazoles. Moreover, compounds hav-
ing electron donating groups on the phenyl ring enhances
the activity, when compared with the electron withdrawing
groups. As a result of this study, compounds 7b, 9b, 22b,
and 24b were identified as lead compounds for both
activities and may be used for further studies.
All experiments are performed in triplicate (n = 3), and an
ANOVA test (Microsoft Excel) is used to compare the mean
values across compounds and concentrations. The results
represented mean standard deviation (SD) of three repli-
cated determinations. The descriptive analysis is supported
by the statistical analysis. The following inferences are
supported through ANOVA analysis. Since the p value of
rows (compounds) is less than 0.05 (a) cannot reject the null
hypothesis, and so we conclude (with 95% confidence) that
there is significant difference in radical scavenging activity
exhibited by the compounds for different concentrations.
Since the p value of columns (concentrations) is less than
0.05 (a) cannot reject the null hypothesis, and so we conclude
(with 95% confidence) that there is significant difference in
radical scavenging activity displayed across the compounds.
Besides, the p value (interactions) is less than 0.05, indicat-
ing that there are significant differences in the interaction
between compounds and concentrations.
Anti-inflammatory activity
Experimental
The results (Table 6) indicated that the compounds 7b, 9b,
22b, and 24b showed significant anti-inflammatory activ-
ity. However, 22b displayed anti-inflammatory activity
equal to the standard drug phenylbutazone. The structure–
activity relationship of the synthesized compounds
All the chemicals were purchased from commercial sour-
ces and used without further purification. Ultrasonication
was performed in a Bandelin Sonorex RK 102H ultrasonic
bath operating at frequency of 35 kHz. Melting points were
determined in open capillaries on a Mel-Temp apparatus.
123

Synthesis, characterization, and bioassay of a new class of pyrazolyl/isoxazolyl oxadiazoles
Table 2 The in vitro
Compound
Concentration/lg cm-3
IC50/lmol cm-3
antioxidant activity of
compounds 7–15 and 22–30 in
DPPH method
25
Mean SD
50
Mean SD
75
Mean SD
100
Mean SD
Mean SD
7a
69.28 0.19
74.87 0.24
48.76 0.10
63.96 0.31
65.09 0.16
–
73.85 0.13
78.03 1.26
52.15 0.30
68.38 0.34
69.67 0.23
–
76.06 0.21
79.15 0.23
56.30 0.31
71.06 0.28
71.91 0.27
–
78.56 0.15
82.34 0.10
59.33 1.24
74.26 0.24
75.68 1.31
–
18.04 0.15
16.69 0.24
25.63 0.30
19.54 0.31
19.20 0.28
–
7b
7c
8a
8b
8c
9a
68.94 0.30
74.04 0.23
–
72.13 0.27
77.25 0.32
–
74.41 0.26
77.86 0.32
–
78.35 0.34
81.06 0.26
–
18.13 0.19
16.88 0.24
–
9b
9c
10
58.81 1.23
56.95 0.27
57.25 0.32
53.26 0.29
44.37 1.72
52.93 0.32
72.08 0.24
77.31 0.23
49.09 0.26
66.38 0.30
67.61 1.41
–
64.67 1.81
60.84 0.24
62.88 0.18
56.74 0.19
49.53 0.30
55.70 0.25
76.11 1.51
79.23 0.13
53.11 0.21
71.21 0.20
70.94 0.30
–
68.81 0.30
64.71 0.30
67.17 1.71
61.28 0.28
53.35 0.19
59.12 0.27
77.30 1.37
82.72 0.14
57.61 1.80
73.82 0.24
74.19 0.3.6
–
69.14 0.23
66.28 0.26
68.96 0.31
62.65 0.12
57.92 0.32
61.05 1.90
80.67 0.20
85.21 0.12
60.17 0.30
76.34 0.28
77.10 1.91
–
21.25 0.12
21.94 0.25
21.83 0.30
23.46 0.29
50.47 0.31
23.61 1.84
17.34 0.31
16.16 0.17
25.46 0.29
18.83 0.24
18.48 1.87
–
11
12
13
14
15
22a
22b
22c
23a
23b
23c
24a
24b
24c
25
71.73 0.31
76.16 0.32
–
75.08 0.18
78.94 1.36
–
76.81 0.31
81.54 0.21
–
79.12 0.34
84.05 0.31
–
17.42 0.24
16.41 0.19
–
62.07 0.23
57.03 0.29
61.54 0.30
55.70 1.41
45.63 0.18
55.61 0.26
73.37 0.31
–
66.30 0.35
61.04 0.27
64.14 0.32
59.62 0.30
50.71 0.27
57.59 0.30
76.86 0.24
–
70.08 1.52
65.93 0.32
69.40 0.29
62.33 0.31
54.92 0.26
62.21 0.12
78.79 0.34
–
72.40 0.21
67.74 0.34
70.19 0.17
66.10 0.19
58.89 0.25
63.97 0.21
80.78 0.32
–
20.13 0.30
21.91 0.27
20.31 0.22
22.44 0.23
49.29 0.26
22.47 0.21
17.03 0.19
–
26
27
28
29
30
Ascorbic acid
Blank
(–) no activity, ( ) standard deviation
The IR spectra were recorded on a Thermo Nicolet IR 200
FT-IR spectrometer as KBr pellets and the wave numbers
were given in cm-1. The 1H NMR spectra were recorded in
DMSO-d6 on a Bruker-400 spectrometer (400 MHz). The
13C NMR spectra were recorded in DMSO-d6 on a Bruker
spectrometer operating at 100 MHz. All chemical shifts are
reported in d (ppm) using TMS as an internal standard. The
high-resolution mass spectra were recorded on micromass
Q-TOF micromass spectrometer using electrospray ion-
ization. The microanalyses were performed on a Perkin–
Elmer 240C elemental analyzer. The progress of the
reaction was monitored by TLC using silica gel plates
(silica gel 60 F254 0.25 mm) and components were visu-
alized by observation under UV light (254 and 365 nm).
The antioxidant activity was carried out using Shimadzu
UV-2450 spectrophotometer. The starting compounds ethyl
5-(heteroaryl)-1H-pyrazole-3-carboxylates 1–3, 5-(hetero-
aryl)-1H-pyrazole-3-carbohydrazides
4–6,
ethyl
5-(heteroaryl)isoxazole-3-carboxylates 16–18, and 5-(het-
eroaryl)-1H-isoxazole-3-carbohydrazides 19–21 were pre-
pared as per the literature precedents [39].
123

Y. Gudi et al.
Table 3 The in vitro
antioxidant activity of
compounds 7–15 and 22–30 in
H2O2 method
Compound
Concentration/lg cm-3
IC50/lmol cm-3
25
Mean SD
50
Mean SD
75
Mean SD
100
Mean SD
Mean SD
7a
72.32 1.21
77.08 0.71
49.56 0.66
65.22 0.79
66.96 0.44
–
75.69 0.45
79.17 0.57
54.50 0.61
69.66 0.26
70.97 0.29
–
77.85 0.55
81.25 0.24
56.53 0.69
71.67 0.31
73.45 0.43
–
79.73 0.63
83.79 0.87
59.42 0.21
74.18 0.92
75.79 0.71
–
17.28 0.83
16.21 0.32
25.22 1.01
19.16 1.23
18.66 0.41
–
7b
7c
8a
8b
8c
9a
70.49 0.68
76.91 1.14
–
74.17 0.25
79.84 0.68
–
76.52 1.27
80.79 0.75
–
77.91 1.14
83.35 0.74
–
17.73 0.73
16.25 0.60
–
9b
9c
10
60.27 0.78
57.30 0.40
59.62 0.48
53.47 0.84
46.83 0.51
52.10 0.31
74.37 0.42
78.23 0.68
50.71 0.54
67.24 0.80
69.15 0.92
–
65.15 0.29
61.91 0.26
64.02 0.42
58.74 0.22
51.64 1.90
56.46 0.32
77.25 0.98
82.73 0.39
55.31 0.21
71.74 0.86
72.53 1.06
–
66.72 0.32
63.85 0.49
65.27 0.37
59.18 0.52
53.73 0.24
58.04 0.30
79.16 0.37
83.94 0.42
57.60 0.57
73.50 0.95
74.01 0.31
–
70.83 0.60
66.14 0.23
69.51 0.56
62.17 2.5
57.47 1.07
61.70 0.92
82.43 0.64
85.07 0.33
60.16 0.69
76.57 0.74
77.80 0.65
–
20.74 0.41
21.81 0.51
20.96 0.66
23.37 1.03
48.41 0.43
23.99 0.30
16.80 0.59
15.97 0.28
24.64 0.72
18.59 0.31
18.07 0.46
–
11
12
13
14
15
22a
22b
22c
23a
23b
23c
24a
24b
24c
25
73.56 1.08
77.74 0.40
–
76.31 0.72
81.36 0.24
–
78.53 0.30
83.08 0.51
–
80.27 0.24
84.22 0.99
–
16.99 0.48
16.07 0.67
–
63.78 0.67
58.42 0.55
62.93 0.47
56.65 0.77
47.20 1.24
54.83 0.35
75.17 0.76
–
68.77 1.34
62.46 0.30
66.38 0.19
59.07 1.36
52.82 1.07
58.13 0.24
78.23 0.35
–
69.71 0.38
64.52 0.26
68.10 0.26
61.60 0.56
54.41 0.43
60.76 1.03
80.28 0.42
–
73.67 0.36
67.88 0.47
71.46 0.42
66.62 0.32
58.15 0.61
64.55 0.29
82.34 1.32
–
19.59 0.81
21.39 0.46
19.86 0.37
22.06 0.59
47.33 0.20
22.79 1.25
16.62 0.27
–
26
27
28
29
30
Ascorbic acid
Blank
(–) no activity, ( ) standard deviation
round bottomed flask fitted with reflux condenser and
refluxed on a water bath for 4–6 h. It was cooled and the
solid separated was filtered, dried, and recrystallized from
methanol.
General procedures for the synthesis of 5-(furan-
2-yl)-1H-pyrazole-3-carbohydrazide (4), 5-(5-
bromothiophen-2-yl)-1H-pyrazole-3-
carbohydrazide (5), and 5-(pyridin-4-yl)-1H-
pyrazole-3-carbohydrazide (6)
Ultrasonication method
Conventional method
Compound 1, 2, or 3 (1.0 mmol), hydrazine hydrate
(2.0 mmol), and 4 cm3 methanol were subjected to ultra-
sound irradiation for 42–55 min. The progress of the
reaction was monitored by TLC. After completion of the
reaction, the contents were cooled and poured onto crushed
ice. The solid separated was filtered on a Buchner funnel,
A solution of ethyl 5-(furan-2-yl)-1H-pyrazole-3-carboxy-
late (1), ethyl 5-(5-bromothiophen-2-yl)-1H-pyrazole-3-
carboxylate (2), or ethyl 5-(pyridin-4-yl)-1H-pyrazole-3-
carboxylate (3) (1.0 mmol) and hydrazine hydrate
(2.0 mmol) in 3 cm3 methanol were taken in a 100-cm3
123

Synthesis, characterization, and bioassay of a new class of pyrazolyl/isoxazolyl oxadiazoles
Table 4 The in vitro
Compound
Concentration/lg cm-3
IC50/lmol cm-3
antioxidant activity of
compounds 7–15 and 22–30 in
NO method
25
Mean SD
50
Mean SD
75
Mean SD
100
Mean SD
Mean SD
7a
75.71 0.26
79.53 0.47
55.31 0.05
70.20 0.40
71.28 0.48
–
78.53 1.06
81.78 0.19
60.71 0.03
73.18 0.24
75.55 0.72
–
80.93 0.80
84.86 0.92
61.160.01
82.28 0.65
86.20 0.42
63.60 0.28
77.30 0.99
78.05 0.24
–
16.51 0.46
15.71 0.37
22.59 0.26
17.80 0.67
17.53 0.30
–
7b
7c
8a
75.07 0.51
76.16 1.08
–
8b
8c
9a
74.23 0.20
78.85 0.41
–
76.69 1.07
81.20 0.95
–
79.47 1.24
83.38 0.66
–
80.93 0.61
84.66 0.35
–
16.83 0.43
15.85 0.29
–
9b
9c
10
65.87 0.57
62.20 0.95
64.59 0.31
58.62 0.41
52.12 0.37
57.19 0.59
77.60 0.58
81.65 0.29
56.83 0.26
72.14 0.42
73.57 0.48
–
70.62 0.39
67.49 0.21
69.89 0.86
63.50 0.35
56.60 0.52
62.67 1.36
80.15 0.31
83.10 0.32
61.18 0.49
75.25 0.37
76.31 0.71
–
71.68 0.42
68.63 0.68
70.90 0.54
64.92 0.74
58.85 0.23
62.24 0.77
82.11 0.92
85.69 0.60
62.71 0.23
77.27 0.55
78.62 0.63
–
73.35 0.33
70.32 0.69
71.63 0.74
66.57 0.18
60.26 0.29
65.30 0.32
84.32 0.26
88.51 0.41
64.49 0.51
79.81 0.34
80.79 0.27
–
18.97 0.28
20.09 0.72
19.35 0.31
21.32 1.12
23.98 0.34
21.85 0.56
16.10 0.46
15.30 0.78
21.99 0.40
17.32 0.45
16.99 0.57
–
11
12
13
14
15
22a
22b
22c
23a
23b
23c
24a
24b
24c
25
76.42 0.69
80.87 0.56
–
79.04 0.31
82.63 0.43
–
80.76 0.92
85.03 0.66
–
83.52 0.35
87.43 0.54
–
16.35 0.29
15.45 0.25
–
68.59 0.34
63.14 0.91
67.75 0.27
60.97 0.41
53.79 0.68
59.41 1.21
78.36 1.23
–
72.33 0.83
68.21 0.60
71.40 0.15
66.78 0.32
58.05 1.01
64.94 0.66
80.18 1.14
–
73.53 1.26
69.52 0.35
72.94 0.17
67.80 1.27
59.29 0.75
66.31 0.87
82.23 0.83
–
76.85 0.95
71.26 0.43
74.17 0.46
68.09 0.73
61.55 0.60
67.81 0.25
84.89 0.67
–
18.22 0.70
19.79 1.03
18.45 0.43
20.50 0.44
23.23 0.22
21.04 0.61
15.95 0.79
–
26
27
28
29
30
Ascorbic acid
Blank
(–) no activity, ( ) standard deviation
washed with cold water, dried, and recrystallized from
methanol to get 4, 5, 6.
residue was poured onto crushed ice. The resulting pre-
cipitate was filtered, washed with saturated sodium bicar-
bonate solution, and then with water, dried, and purified by
column chromatography (silica gel 60–120 mesh) using
ethyl acetate-hexane (1:3) as eluent.
General procedures for the synthesis
of compounds 7a–7c, 8a–8c, and 9a–9c
Conventional method
Ultrasonication method
A solution of 4, 5, or 6 (1.0 mmol), arylsulfonylacetic acid
(1.0 mmol), and 3 cm3 POCl3 was taken in a 100-cm3
round-bottom flask fitted with reflux condenser carrying a
calcium chloride guard-tube and refluxed for 6–9 h. The
excess POCl3 was removed under reduced pressure and the
A mixture of 4, 5, or 6 (1.0 mmol), arylsulfonylacetic acid
(1.0 mmol), and 3 cm3 phosphorus oxychloride was sub-
jected to ultrasound irradiation at a frequency of 35 kHz
for 30–50 min at 45 °C. After completion of the reaction,
the excess phosphorus oxychloride was removed under
123

Y. Gudi et al.
Fig. 3 The in vitro antioxidant activity of 7b, 9b, 22b, and 24b in all the three methods
145.2, 156.2, 156.4, 162.9, 164.2 ppm; IR (KBr):
ꢀ
Table 5 Antioxidant activity of the compounds 7b, 9b, 22b, and 24b
at 10 min time intervals by DPPH scavenging method
m = 1128, 1329 (SO2), 1556 (C=N), 1610 (C=C), 3256
(NH) cm-1; HRMS: m/z = 409.3710 ([M?Na]?).
Compound
10 min
20 min
30 min
2-[5-(5-Bromothiophen-2-yl)-1H-pyrazol-3-yl]-5-[(4-chloro-
7b
77.32
75.80
74.65
79.27
77.46
76.04
74.83
79.38
77.53
76.21
74.97
79.52
phenyl)sulfonylmethyl]-1,3,4-oxadiazole (7c, C16H11ClN4-
9b
1
O4S) White solid (0.35 g, 92%); m.p.: 193–195 °C; H
22b
24b
NMR (DMSO-d6): d = 4.04 (s, 2H, CH2), 6.91–8.01 (m,
8H, Ar–H), 11.96 (bs, 1H, pyrazole-NH) ppm; 13C NMR
(DMSO-d6): d = 60.2 (CH2), 105.3, 108.2, 114.1, 128.2,
128.8, 133.1, 133.4, 138.1, 141.7, 146.5, 156.5, 160.2,
ꢀ
162.3 ppm; IR (KBr): m = 1122, 1325 (SO2), 1560 (C=N),
reduced pressure and the residue was poured onto crushed
ice. The separated solid was collected by filtration. It was
washed with saturated sodium bicarbonate solution fol-
lowed by water, dried, and purified by column chro-
matography (silica gel 60–120 mesh) using ethyl acetate-
hexane (1:3) as eluent.
1612 (C=C), 3227 (NH) cm-1; HRMS: m/z = 413.7886
([M?Na]?).
2-[5-(5-Bromothiophen-2-yl)-1H-pyrazol-3-yl]-5-(tosyl-
methyl)-1,3,4-oxadiazole (8a, C17H13BrN4O3S2)
White
1
solid (0.41 g, 89%); m.p.: 234–236 °C; H NMR (DMSO-
d6): d = 2.51 (s, 3H, Ar–CH3), 4.23 (s, 2H, CH2), 6.52–
2-[5-(Furan-2-yl)-1H-pyrazol-3-yl]-5-(tosylmethyl)-1,3,4-oxa-
7.95 (m, 7H, Ar–H), 11.93 (bs, 1H, pyrazole-NH) ppm; 13
C
diazole (7a, C17H14N4O4S)
White solid (0.33 g, 91%);
NMR (DMSO-d6): d = 21.6 (Ar–CH3), 59.5 (CH2), 103.8,
113.5, 126.3, 128.7, 131.8, 132.5, 132.9, 135.7, 138.1,
1
m.p.: 176–178 °C; H NMR (DMSO-d6): d = 2.55 (s, 3H,
Ar–CH3), 4.15 (s, 2H, CH2), 6.69–8.07 (m, 8H, Ar–H),
11.74 (bs, 1H, pyrazole-NH) ppm; 13C NMR (DMSO-d6):
d = 21.4 (Ar–CH3), 59.1 (CH2), 104.2, 107.8, 114.3, 126.8,
131.2, 132.3, 134.3, 138.4, 141.5, 145.7, 156.8, 160.6,
ꢀ
143.7, 145.9, 160.9, 161.8 ppm; IR (KBr): m = 1134, 1337
(SO2), 1587 (C=N), 1619 (C=C), 3263 (NH) cm-1; HRMS:
m/z = 488.3289 ([M?Na]?).
2-[5-(5-Bromothiophen-2-yl)-1H-pyrazol-3-yl]-5-[(4-
methoxyphenyl)sulfonylmethyl]-1,3,4-oxadiazole (8b, C17-
ꢀ
162.5 ppm; IR (KBr): m = 1145, 1334 (SO2), 1565 (C=N),
1600 (C=C), 3242 (NH) cm-1; HRMS: m/z = 393.3736
([M?Na]?).
H13BrN4O4S2)
White solid (0.40 g, 85%); m.p.: 261–
263 °C; 1H NMR (DMSO-d6): d = 3.89 (s, 3H, Ar–OCH3),
4.18 (s, 2H, CH2), 6.47–7.93 (m, 7H, Ar–H), 11.87 (bs, 1H,
pyrazole-NH) ppm; 13C NMR (DMSO-d6): d = 55.8 (Ar–
OCH3), 60.9 (CH2), 105.5, 113.8, 118.1, 128.0, 130.4,
132.3, 133.1, 133.8, 143.2, 145.3, 159.7, 161.4, 164.7 ppm;
2-[5-(Furan-2-yl)-1H-pyrazol-3-yl]-5-[(4-methoxyphenyl)sul-
fonylmethyl]-1,3,4-oxadiazole (7b, C17H14N4O5S)
White
1
solid (0.36 g, 94%); m.p.: 187–189 °C; H NMR (DMSO-
d6): d = 3.95 (s, 3H, Ar–OCH3), 4.21 (s, 2H, CH2), 6.71–
7.86 (m, 8H, Ar–H), 11.79 (bs, 1H, pyrazole-NH) ppm; 13
C
ꢀ
IR (KBr): m = 1136, 1331 (SO2), 1584 (C=N), 1626 (C=C),
NMR (DMSO-d6): d = 55.2 (Ar–OCH3), 59.6 (CH2),
104.9, 108.0, 114.7, 118.5, 130.1, 132.9, 133.6, 141.1,
3210 (NH) cm-1; HRMS: m/z = 504.3296 ([M?Na]?).
123

Synthesis, characterization, and bioassay of a new class of pyrazolyl/isoxazolyl oxadiazoles
1578 (C=N), 1621 (C=C), 3254 (NH) cm-1; HRMS: m/
z = 508.7459 ([M?Na]?).
Table 6 The in vivo anti-inflammatory activity of compounds 7–15
and 22–30
Compound
Edema volume
ml ( SD)a
Edema
inhibition (%)c
2-[5-(Pyridin-4-yl)-1H-pyrazol-3-yl]-5-(tosylmethyl)-1,3,4-
oxadiazole (9a, C18H15N5O3S) White solid (0.32 g, 86%);
m.p.: 181–183 °C; H NMR (DMSO-d6): d = 2.58 (s, 3H,
Ar–CH3), 4.12 (s, 2H, CH2), 6.61–8.20 (m, 9H, Ar–H),
11.82 (bs, 1H, pyrazole-NH) ppm; 13C NMR (DMSO-d6):
d = 21.1 (Ar–CH3), 60.1 (CH2), 104.3, 125.7, 126.6, 131.5,
132.4, 134.8, 136.1, 138.3, 145.6, 147.5, 160.3, 161.2 ppm;
1
7a
0.30 (0.02)b
0.22 (0.01)b
0.47 (0.01)b
0.40 (0.01)b
0.38 (0.02)b
0.53 (0.02)b
0.33 (0.02)b
0.23 (0.01)b
0.57 (0.01)b
0.50 (0.01)b
0.61 (0.02)b
0.42 (0.01)b
0.43 (0.02)b
0.52 (0.02)b
0.45 (0.01)b
0.24 (0.01)b
0.19 (0.01)b
0.46 (0.01)b
0.37 (0.01)b
0.35 (0.02)b
0.55 (0.02)b
0.29 (0.02)b
0.21 (0.02)b
0.60 (0.01)b
0.42 (0.01)b
0.59 (0.02)b
0.39 (0.01)b
0.29 (0.01)b
0.51 (0.01)b
0.42 (0.01)b
0.19 (0.01)b
0.69 (0.02)
56
68*
31
42
44
23
52
67
17
28
11
39
37
24
34
65
72*
33
46
49
20
57
70*
13
39
14
43
57
26
39
72*
–
7b
7c
8a
8b
ꢀ
IR (KBr): m = 1140, 1320 (SO2), 1572 (C=N), 1617 (C=C),
8c
3236 (NH) cm-1; HRMS: m/z = 404.3991 ([M?Na]?).
9a
9b
2-[5-(Pyridin-4-yl)-1H-pyrazol-3-yl]-5-[(4-methoxyphenyl)-
9c
sulfonylmethyl]-1,3,4-oxadiazole (9b, C18H15N5O4S)
1
10
White solid (0.32 g, 82%); m.p.: 197–199 °C; H NMR
11
(DMSO-d6): d = 3.91 (s, 3H, Ar–OCH3), 4.26 (s, 2H,
CH2), 6.49–8.09 (m, 9H, Ar–H), 11.92 (bs, 1H, pyrazole-
NH) ppm; 13C NMR (DMSO-d6): d = 54.6 (Ar–OCH3),
59.3 (CH2), 104.7, 118.8, 125.9, 126.5, 131.9, 132.8, 136.8,
145.4, 147.3, 160.8, 161.5, 164.5 ppm; IR (KBr):
12
13
14
15
22a
ꢀ
m = 1138, 1324 (SO2), 1553 (C=N), 1630 (C=C), 3250
(NH) cm-1; HRMS: m/z = 420.3995 ([M?Na]?).
22b
22c
2-[5-(5-Bromothiophen-2-yl)-1H-pyrazol-3-yl]-5-[(4-
chlorophenyl)sulfonylmethyl]-1,3,4-oxadiazole (9c, C17H12-
ClN5O3S) Pale yellow solid (0.34 g, 87%); m.p.: 203–
205 °C; 1H NMR (DMSO-d6): d = 4.17 (s, 2H, CH2),
6.73–8.24 (m, 9H, Ar–H), 11.89 (bs, 1H, pyrazole-NH)
ppm; 13C NMR (DMSO-d6): d = 59.8 (CH2), 105.4, 125.2,
128.7, 129.5, 133.6, 134.7, 136.4, 138.5, 146.1, 147.8,
159.1, 162.4 ppm; IR (KBr): mꢀ = 1125, 1326 (SO2), 1564
(C=N), 1629 (C=C), 3223 (NH) cm-1; HRMS: m/
z = 424.8139 ([M?Na]?).
23a
23b
23c
24a
24b
24c
25
26
27
28
29
General procedures for the synthesis
of compounds 10–12
30
Phenylbutazone
Control
Conventional method
*Statistically significant (p \ 0.05, Mann–Whitney)
aEdema volume was measured 3 h after carrageenan injection and
expressed as mean standard deviation
bControl edema volume = 0.69 (0.02)
cAt 100 mg/kg (p.o.) percent edema inhibition was calculated by
comparing edema volume with that of the respective vehicle-treated
control animals
The compound 4, 5, or 6 (1.5 mmol) was dissolved in
20 cm3 dry tetrahydrofuran and ethyl 2-chloro-2-oxoac-
etate (1.8 mmol) was added dropwise. The mixture was
stirred at room temperature for 13–16 h (monitored by
TLC). Then, the reaction mixture was poured onto crushed
ice and extracted with dichloromethane. The solvent was
removed under reduced pressure and the resultant residue
was purified by recrystallization from acetone/methanol.
2-[5-(5-Bromothiophen-2-yl)-1H-pyrazol-3-yl]-5-[(4-
chlorophenyl)sulfonylmethyl]-1,3,4-oxadiazole (8c, C16H10-
BrClN4O3S2) Pale yellow solid (0.43 g, 90%); m.p.: 268–
270 °C; 1H NMR (DMSO-d6): d = 4.09 (s, 2H, CH2),
6.58–8.02 (m, 7H, Ar–H), 11.92 (bs, 1H, pyrazole-NH)
ppm; 13C NMR (DMSO-d6): d = 60.4 (CH2), 105.8, 113.3,
127.7, 128.4, 129.5, 132.2, 132.8, 133.5, 138.6, 143.5,
Ultrasonication method
To a solution of 4, 5, or 6 (1.5 mmol) in 20 cm3 THF, ethyl
2-chloro-2-oxoacetate (1.8 mmol) was added and kept
under ultrasonication for 28–42 min. The progress of the
ꢀ
145.8, 159.5, 162.6 ppm; IR (KBr): m = 1129, 1332 (SO2),
123

Y. Gudi et al.
reaction was monitored by TLC. After completion of the
reaction, the contents of the flask were poured onto crushed
ice and extracted with dichloromethane. Removal of the
solvent under vacuum gave a residue which was purified by
recrystallization from acetone/methanol.
completion of the reaction, the contents of the flask were
cooled to room temperature and poured onto crushed ice.
The separated solid was filtered, washed with saturated
sodium bicarbonate solution followed by water, and dried.
It was purified by column chromatography (silica gel
60–120 mesh) using ethyl acetate-hexane (1:3) as eluent.
Ethyl
2-[2-[5-(furan-2-yl)-1H-pyrazole-3-carbonyl]hy-
drazinyl]-2-oxoacetate (10, C12H12N4O5) White solid
(0.39 g, 89%); m.p.: 152–154 °C; H NMR (DMSO-d6):
Ultrasonication method
1
d = 1.21 (t, 3H, CH3, J = 7.2 Hz), 4.22 (q, 2H, OCH2,
J = 7.2 Hz), 7.04–7.68 (m, 4H, Ar–H), 9.80 (bs, 1H, NH),
9.98 (bs, 1H, NH), 11.86 (bs, 1H, pyrazole-NH) ppm; 13C
NMR (DMSO-d6): d = 14.3 (CH3), 61.1 (CH2), 106.4,
109.1, 115.3, 136.8, 143.5, 148.2, 155.7, 159.7 (NHCO),
The compound 10, 11, or 12 (1.5 mmol) and 5 cm3 POCl3
were subjected to ultrasound irradiation at a frequency of
35 kHz for 80–95 min at 40 °C. The progress of the
reaction was monitored by TLC. After completion of the
reaction, the contents of the flask were cooled to room
temperature and poured onto crushed ice. The separated
solid was filtered, washed with saturated sodium bicar-
bonate solution followed by water, and dried. It was puri-
fied by column chromatography (silica gel 60–120 mesh)
using ethyl acetate-hexane (1:3) as eluent.
ꢀ
164.3 (CO), 164.9 (CONH) ppm; IR (KBr): m = 1583
(C=N), 1618 (C=C), 1665 (CO–NH), 1732 (CO–O), 3244
(NH) cm-1; HRMS: m/z = 315.2415 ([M?Na]?).
Ethyl
2-[2-[5-(5-bromothiophen-2-yl)-1H-pyrazole-3-car-
bonyl]hydrazinyl]-2-oxoacetate (11, C12H11BrN4O4S)
1
White solid (0.54 g, 93%); m.p.: 189–191 °C; H NMR
Ethyl 5-[5-(furan-2-yl)-1H-pyrazol-3-yl]-1,3,4-oxadiazole-2-
carboxylate (13, C12H10N4O4) White solid (0.33 g, 82%);
(DMSO-d6): d = 1.24 (t, 3H, CH3, J = 7.1 Hz), 4.26 (q,
2H, OCH2, J = 7.1 Hz), 6.94–7.65 (m, 3H, Ar–H), 9.91
(bs, 1H, NH), 10.08 (bs, 1H, NH), 11.82 (bs, 1H, pyrazole-
NH) ppm; 13C NMR (DMSO-d6): d = 14.5 (CH3), 61.5
(CH2), 106.8, 115.1, 129.4, 131.8, 136.3, 143.9, 148.6,
158.9 (NHCO), 164.1 (CO), 164.5 (CONH) ppm; IR
1
m.p.: 141–142 °C; H NMR (DMSO-d6): d = 1.34 (t, 3H,
CH3, J = 6.8 Hz), 4.27 (q, 2H, OCH2, J = 6.8 Hz), 7.11–
8.01 (m, 4H, Ar–H), 11.98 (bs, 1H, pyrazole-NH) ppm; 13
C
NMR (DMSO-d6): d = 14.8 (CH3), 61.2 (CH2), 103.3,
108.8, 114.5, 131.7, 140.4, 144.9, 153.2, 159.0, 159.4
ꢀ
(KBr): m = 1580 (C=N), 1610 (C=C), 1649 (CO–NH),
ꢀ
(CO), 160.7 ppm; IR (KBr): m = 1579 (C=N), 1623 (C=C),
1738 (CO–O), 3271 (NH) cm-1; HRMS: m/z = 410.1989
([M?Na]?).
1725 (CO–O), 3238 (NH) cm-1; HRMS: m/z = 297.2269
([M?Na]?).
Ethyl
2-[2-[5-(pyridin-4-yl)-1H-pyrazole-3-carbonyl]hy-
White solid
Ethyl 5-[5-(5-bromothiophen-2-yl)-1H-pyrazol-3-yl]-1,3,4-
oxadiazole-2-carboxylate (14, C12H9BrN4O3S) White solid
(0.49 g, 90%); m.p.: 173–175 °C; H NMR (DMSO-d6):
d = 1.28 (q, 3H, CH3, J = 7.0 Hz), 4.31 (q, 2H, OCH2,
J = 7.0 Hz), 6.86–8.08 (m, 3H, Ar–H), 11.80 (bs, 1H,
pyrazole-NH) ppm; 13C NMR (DMSO-d6): d = 14.6
(CH3), 60.9 (CH2), 103.8, 114.2, 128.4, 131.3, 132.9,
142.6, 144.1, 158.7, 159.1 (CO), 160.5 ppm; IR (KBr):
drazinyl]-2-oxoacetate (12, C13H13N5O4)
1
(0.38 g, 84%); m.p.: 158–160 °C; H NMR (DMSO-d6):
d = 1.26 (t, 3H, CH3, J = 7.2 Hz), 4.18 (q, 2H, OCH2,
J = 7.2 Hz), 7.10–8.16 (m, 5H, Ar–H), 9.78 (bs, 1H, NH),
9.84 (bs, 1H, NH), 11.94 (bs, 1H, pyrazole-NH) ppm; 13C
NMR (DMSO-d6): d = 13.9 (CH3), 60.9 (CH2), 106.3,
129.5, 135.7, 136.1, 148.3, 148.7, 158.5 (NHCO), 164.5
1
ꢀ
(CO), 164.9 (CONH) ppm; IR (KBr): m = 1585 (C=N),
1615 (C=C), 1658 (CO–NH), 1716 (CO–O), 3210 (NH)
cm-1; HRMS: m/z = 326.2670 ([M?Na]?).
ꢀ
m = 1566 (C=N), 1614 (C=C), 1720 (CO–O), 3235 (NH)
cm-1; HRMS: m/z = 392.1839 ([M?Na]?).
Ethyl 5-[5-(pyridin-4-yl)-1H-pyrazol-3-yl]-1,3,4-oxadiazole-2-
carboxylate (15, C13H11N5O3) White solid (0.40 g, 94%);
m.p.: 155–157 °C; H NMR (DMSO-d6): d = 1.33 (t, 3H,
CH3, J = 6.9 Hz), 4.34 (q, 2H, OCH2, J = 6.9 Hz), 6.90–
8.27 (m, 5H, Ar–H), 11.91 (bs, 1H, pyrazole-NH) ppm; 13
C
General procedures for the synthesis
of compounds 13–15
1
Conventional method
NMR (DMSO-d6): d = 13.8 (CH3), 61.5 (CH2), 103.5,
123.5, 131.5, 135.9, 144.7, 146.9, 159.1, 159.7 (CO),
A mixture of 10, 11, or 12 (1.5 mmol) and 5 cm3 POCl3
was taken in a 100-cm3 round-bottomed flask fitted with
reflux condenser carrying a calcium chloride guard-tube
and refluxed for 22–24 h (monitored by TLC). After
ꢀ
160.3 ppm; IR (KBr): m = 1561 (C=N), 1628 (C=C), 1718
(CO–O), 3249 (NH) cm-1; HRMS: m/z = 308.2539
[M?Na]?.
123

Synthesis, characterization, and bioassay of a new class of pyrazolyl/isoxazolyl oxadiazoles
After completion of the reaction, the excess phosphorus
General procedures for the synthesis of 5-(furan-
2-yl)isoxazole-3-carbohydrazide (19), 5-(5-
bromothiophen-2-yl)isoxazole-3-carbohydrazide
(20), and 5-(pyridin-4-yl)isoxazole-3-
carbohydrazide (21)
oxychloride was removed under reduced pressure and the
residue was poured onto crushed ice. The separated solid
was collected by filtration. It was washed with saturated
sodium bicarbonate solution followed by water, dried, and
purified by column chromatography (silica gel 60–120
mesh) using ethyl acetate-hexane (1:3) as eluent.
Conventional method
2-[5-(Furan-2-yl)isoxazol-3-yl]-5-(tosylmethyl)-1,3,4-oxadia-
The compound ethyl 5-(furan-2-yl)isoxazole-3-carboxylate
(16), ethyl 5-(5-bromothiophen-2-yl)isoxazole-3-carboxy-
late (17), or ethyl 5-(pyridin-4-yl)isoxazole-3-carboxylate
(18) (1.0 mmol) and hydrazine hydrate (2.0 mmol) in
3 cm3 methanol was taken in a 100 cm3 round-bottomed
flask fitted with reflux condenser and refluxed on a water
bath for 3–4 h. The contents were cooled and poured onto
crushed ice. The solid separated was filtered, dried, and
recrystallized from methanol.
zole (22a, C17H13N3O5S) White solid (0.30 g, 83%); m.p.:
1
180–182 °C; H NMR (DMSO-d6): d = 2.59 (s, 3H, Ar–
CH3), 4.18 (s, 2H, CH2), 6.92–8.06 (m, 8H, Ar–H) ppm;
13C NMR (DMSO-d6): d = 21.8 (Ar–CH3), 60.3 (CH2),
107.3, 109.6, 115.4, 127.2, 131.7, 134.1, 138.6, 144.0,
149.3, 153.2, 154.6, 160.7, 162.0 ppm; IR (KBr):
-1
ꢀ
m = 1138, 1336 (SO2), 1576 (C=N), 1617 (C=C) cm
;
HRMS: m/z = 394.3557 ([M?Na]?).
2-[5-(Furan-2-yl)isoxazol-3-yl]-5-[(4-methoxyphenyl)sul-
fonylmethyl]-1,3,4-oxadiazole (22b, C17H13N3O6S) White
solid (0.36 g, 95%); m.p.: 188–190 °C; H NMR (DMSO-
Ultrasonication method
1
d6): d = 3.98 (s, 3H, Ar–OCH3), 4.26 (s, 2H, CH2), 6.79–
7.94 (m, 8H, Ar–H) ppm; 13C NMR (DMSO-d6): d = 56.1
(Ar–OCH3), 61.8 (CH2), 107.7, 109.3, 115.0, 117.8, 128.1,
131.3, 144.9, 149.3, 153.6, 154.2, 160.9, 162.3, 165.1 ppm;
A mixture of 16, 17, or 18 (1.0 mmol), hydrazine hydrate
(2.0 mmol), and 4 cm3 methanol was taken and heated at
reflux conditions under ultrasound irradiation at a fre-
quency of 35 kHz for 38–50 min. The progress of the
reaction was monitored by TLC. After completion of the
reaction, the contents were cooled and poured onto crushed
ice. The solid separated was filtered on a Buchner funnel,
washed with cold water, dried, and recrystallized from
methanol.
ꢀ
IR (KBr): m = 1125, 1324 (SO2), 1572 (C=N), 1623 (C=C)
cm-1; HRMS: m/z = 410.3563 ([M?Na]?).
2-[5-(5-Bromothiophen-2-yl)isoxazol-3-yl]-5-[(4-
chlorophenyl)sulfonylmethyl]-1,3,4-oxadiazole (22c, C16-
H10ClN3O5S)
White solid (0.33 g, 86%); m.p.: 192–
194 °C; 1H NMR (DMSO-d6): d = 4.12 (s, 2H, CH2),
6.70–8.13 (m, 8H, Ar–H) ppm; 13C NMR (DMSO-d6):
d = 60.5 (CH2), 107.1, 109.1, 115.7, 126.3, 131.2, 134.8,
138.4, 144.3, 149.7, 153.8, 154.1, 160.1, 162.9 ppm; IR
(KBr): mꢀ = 1162, 1320 (SO2), 1567 (C=N), 1614 (C=C)
cm-1; HRMS: m/z = 414.7710 ([M?Na]?).
General procedures for the synthesis
of compounds 22a–22c, 23a–23c, and 24a–24c
Conventional method
A mixture of 19, 20, or 21 (1.0 mmol) arylsulfonylacetic
acid (1.0 mmol), and 3 cm3 POCl3 was taken in a 100-cm3
round-bottomed flask fitted with reflux condenser carrying
a calcium chloride guard-tube and refluxed for 4.5–7 h.
The excess phosphorus oxychloride was removed under
reduced pressure and the residue was poured onto crushed
ice. The resulting precipitate was filtered, neutralized with
saturated sodium bicarbonate solution and then with water,
dried, and further purified by column chromatography
(silica gel 60–120 mesh) using ethyl acetate-hexane (1:3)
as eluent.
2-[5-(5-Bromothiophen-2-yl)isoxazol-3-yl]-5-(tosylmethyl)-
1,3,4-oxadiazole (23a, C17H12BrN3O4S2)
White solid
1
(0.37 g, 80%); m.p.: 243–245 °C; H NMR (DMSO-d6):
d = 2.53 (s, 3H, Ar–CH3), 4.21 (s, 2H, CH2), 6.58–8.08 (m,
7H, Ar–H) ppm; 13C NMR (DMSO-d6): d = 21.3 (Ar–
CH3), 60.6 (CH2), 113.2, 126.9, 127.3, 130.8, 131.3, 134.5,
134.9, 138.8, 150.4, 153.1, 154.8, 161.3, 163.1 ppm; IR
ꢀ
(KBr): m = 1136, 1325 (SO2), 1573 (C=N), 1619 (C=C)
cm-1; HRMS: m/z = 489.3146 ([M?Na]?).
2-[5-(5-Bromothiophen-2-yl)isoxazol-3-yl]-5-[(4-
methoxyphenyl)sulfonylmethyl]-1,3,4-oxadiazole (23b, C17-
Ultrasonication method
H12BrN3O5S2)
White solid (0.45 g, 94%); m.p.: 265–
267 °C; 1H NMR (DMSO-d6): d = 3.92 (s, 3H, Ar-OCH3),
4.15 (s, 2H, CH2), 6.43–8.00 (m, 7H, Ar–H) ppm; 13C
NMR (DMSO-d6): d = 55.7 (Ar–OCH3), 59.2 (CH2),
113.6, 118.3, 127.0, 128.6, 130.1, 131.2, 134.4, 149.9,
To an equimolar (1.0 mmol) solution of 19, 20, or 21 and
arylsulfonylacetic acid, 4 cm3 POCl3 was added and sub-
jected to ultrasound irradiation for 21–35 min at 45 °C.
123

Y. Gudi et al.
153.4, 154.3, 160.4, 162.7, 164.8 ppm; IR (KBr):
-1
guard-tube and the mixture was stirred at laboratory tem-
perature for 10–14 h. After completion of the reaction, the
reaction mixture was poured onto crushed ice and extracted
with dichloromethane. The solvent was removed under
reduced pressure and the resultant residue was purified by
recrystallization from acetone/methanol.
ꢀ
m = 1143, 1319 (SO2), 1575 (C=N), 1612 (C=C) cm
;
HRMS: m/z = 505.3137 ([M?Na]?).
2-[5-(5-Bromothiophen-2-yl)isoxazol-3-yl]-5-[(4-
chlorophenyl)sulfonylmethyl]-1,3,4-oxadiazole (23c, C16H9-
White solid (0.43 g, 89%); m.p.: 270–
BrClN3O4S2)
272 °C; 1H NMR (DMSO-d6): d = 4.17 (s, 2H, CH2),
6.51–7.14 (m, 7H, Ar–H) ppm; 13C NMR (DMSO-d6):
d = 60.9 (CH2), 113.1, 126.5, 127.5, 130.7, 131.7, 134.1,
134.4, 138.9, 149.6, 153.7, 154.0, 160.8, 163.4 ppm; IR
Ultrasonication method
The compound 19, 20, or 21 (1.5 mmol) was dissolved in
25 cm3 THF. To this ethyl 2-chloro-2-oxoacetate
(4.0 mmol) was added and subjected to ultrasound irradi-
ation for 25–40 min. After completion of the reaction
(monitored by TLC), the contents of the flask were poured
onto crushed ice and extracted with dichloromethane. The
solvent was removed in vacuo. The resultant residue was
purified by recrystallization from acetone/methanol.
ꢀ
(KBr): m = 1162, 1320 (SO2), 1597 (C=N), 1614 (C=C)
cm-1; HRMS: m/z = 509.7294 ([M?Na]?).
2-[5-(Pyridin-4-yl)isoxazol-3-yl]-5-(tosylmethyl)-1,3,4-oxadi-
azole (24a, C18H14N4O4S)
White solid (0.32 g, 86%);
1
m.p.: 196–198 °C; H NMR (DMSO-d6): d = 2.57 (s, 3H,
Ar–CH3), 4.22 (s, 2H, CH2), 6.74–8.16 (m, 9H, Ar–H)
ppm; 13C NMR (DMSO-d6): d = 20.7 (Ar–CH3), 59.7
(CH2), 125.1, 126.5, 131.0, 134.7, 136.2, 138.3, 147.9,
Ethyl 2-[2-[5-(furan-2-yl)isoxazole-3-carbonyl]hydrazinyl]-2-
oxoacetate (25, C12H11N3O6) White solid (0.36 g, 83%);
149.5, 152.8, 154.9, 161.6, 163.6 ppm; IR (KBr):
-1
1
m.p.: 158–160 °C; H NMR (DMSO-d6): d = 1.24 (t, 3H,
ꢀ
m = 1132, 1328 (SO2), 1580 (C=N), 1622 (C=C) cm
;
CH3, J = 6.4 Hz), 4.20 (q, 2H, OCH2, J = 6.4 Hz), 7.29–
7.68 (m, 4H, Ar–H), 9.96 (bs, 1H, NH), 10.29 (bs, 1H, NH)
ppm; 13C NMR (DMSO-d6): d = 14.6 (CH3), 60.7 (CH2),
105.3, 109.6, 116.4, 143.2, 151.7, 155.1, 157.6, 159.9
(NHCO), 164.7 (CO), 165.1 (CONH) ppm; IR (KBr):
HRMS: m/z = 405.3827 ([M?Na]?).
2-[5-(Pyridin-4-yl)isoxazol-3-yl]-5-[(4-methoxyphenyl)sul-
fonylmethyl]-1,3,4-oxadiazole (24b, C18H14N4O5S) White
1
solid (0.35 g, 88%); m.p.: 203–205 °C; H NMR (DMSO-
d6): d = 3.95 (s, 3H, Ar–OCH3), 4.24 (s, 2H, CH2), 7.56–
8.21 (m, 9H, Ar–H) ppm; 13C NMR (DMSO-d6): d = 55.5
(Ar–OCH3), 60.1 (CH2), 118.1, 125.6, 128.4, 131.7, 136.5,
147.2, 150.0, 153.9, 154.7, 159.8, 162.8, 164.3 ppm; IR
(KBr): mꢀ = 1151, 1336 (SO2), 1572 (C=N), 1617 (C=C)
cm-1; HRMS: m/z = 421.3816 ([M?Na]?).
ꢀ
m = 1568 (C=N), 1625 (C=C), 1660 (CO–NH), 1726 (CO–
O), 3235 (NH) cm-1; HRMS: m/z = 316.2256 ([M?Na]?).
Ethyl
2-[2-[5-(5-bromothiophen-2-yl)isoxazole-3-car-
bonyl]hydrazinyl]-2-oxoacetate (26, C12H10BrN3O5S)
White solid (0.52 g, 91%); m.p.: 206–208 °C; H NMR
(DMSO-d6): d = 1.26 (t, 3H, CH3, J = 6.4 Hz), 4.24 (q,
2H, OCH2, J = 6.4 Hz), 7.01–7.71 (m, 3H, Ar–H), 9.94
(bs, 1H, NH), 10.05 (bs, 1H, NH) ppm; 13C NMR (DMSO-
d6): d = 14.8 (CH3), 61.3 (CH2), 105.7, 116.0, 129.8,
131.3, 136.8, 151.2, 157.4, 159.5 (NHCO), 164.2 (CO),
1
2-[5-(5-Bromothiophen-2-yl)isoxazol-3-yl]-5-[(4-chlorophen-
yl)sulfonylmethyl]-1,3,4-oxadiazole (24c, C17H11ClN4O4S)
1
White solid (0.37 g, 92%); m.p.: 210–212 °C; H NMR
(DMSO-d6): d = 4.20 (s, 2H, CH2), 6.84–8.30 (m, 9H, Ar–
H) ppm; 13C NMR (DMSO-d6): d = 59.9 (CH2), 125.3,
126.1, 131.0, 134.5, 136.9, 138.2, 147.7, 149.8, 153.5,
ꢀ
164.8 (CONH) ppm; IR (KBr): m = 1563 (C=N), 1620
(C=C), 1668 (CO–NH), 1720 (CO–O), 3257 (NH) cm-1
;
HRMS: m/z = 411.1830 ([M?Na]?).
ꢀ
154.4, 160.3, 162.5 ppm; IR (KBr): m = 1129, 1334 (SO2),
1570 (C=N), 1630 (C=C) cm-1; HRMS: m/z = 425.7996
([M?Na]?).
Ethyl 2-[2-[5-(pyridin-4-yl)isoxazole-3-carbonyl]hydrazinyl]-
2-oxoacetate (27, C13H12N4O5) White solid (0.36 g,
1
79%); m.p.: 163–165 °C; H NMR (DMSO-d6): d = 1.20
(t, 3H, CH3, J = 6.6 Hz), 4.17 (q, 2H, OCH2, J = 6.6 Hz),
7.15–8.20 (m, 5H, Ar–H), 9.89 (bs, 1H, NH), 10.07 (bs,
1H, NH) ppm; 13C NMR (DMSO-d6): d = 14.3 (CH3), 61.5
(CH2), 105.1, 120.7, 139.6, 142.1, 151.5, 159.0 (NHCO),
160.4, 164.9 (CO), 165.5 (CONH) ppm; IR (KBr):
General procedures for the synthesis
of compounds 25–27
Conventional method
To a solution of 19, 20, or 21 (1.5 mmol), 20 cm3 dry THF,
1.8 cm3 ethyl 2-chloro-2-oxoacetate were taken in a
100-cm3 round-bottomed flask carrying a calcium chloride
ꢀ
m = 1570 (C=N), 1622 (C=C), 1656 (CO–NH), 1729 (CO–
O), 3266 (NH) cm-1; HRMS: m/z = 327.2532 ([M?Na]?).
123

Synthesis, characterization, and bioassay of a new class of pyrazolyl/isoxazolyl oxadiazoles
8.34 (m, 5H, Ar–H) ppm; 13C NMR (DMSO-d6): d = 14.5
(CH3), 60.7 (CH2), 106.2, 125.2, 136.1, 147.5, 149.7,
General procedures for the synthesis
of compounds 28–30
ꢀ
154.2, 159.3 (CO), 160.1, 162.9 ppm; IR (KBr): m = 1559
(C=N), 1622 (C=C), 1716 (CO–O) cm-1; HRMS: m/
z = 309.2360 ([M?Na]?).
Conventional method
The compound 25, 26, or 27 (1.5 mmol) dissolved in 5 cm3
POCl3 was taken in a 100-cm3 round-bottom flask fitted
with reflux condenser carrying a calcium chloride guard-
tube and refluxed for 20–24 h. The progress of the reaction
was monitored by TLC. After completion of the reaction,
the contents of the flask were cooled to room temperature
and poured onto crushed ice. The resulting precipitate was
filtered, washed with saturated sodium bicarbonate solution
followed by water, and dried. It was purified by column
chromatography (silica gel 60–120 mesh) using ethyl
acetate-hexane (1:3) as eluent.
Antioxidant activity
The compounds 7–15 and 22–30 were tested for antioxi-
dant property by 2,2-diphenyl-1-picrylhydrazyl (DPPH),
hydrogen peroxide (H2O2), and nitric oxide (NO) methods
at four different concentrations 25, 50, 75, and 100 lg/cm3
using ascorbic acid as the standard drug [40].
Anti-inflammatory activity
The in vivo anti-inflammatory activity of the title com-
pounds 7–15 and 22–30 was studied using carrageenan-
induced hind paw edema test in male albino rats
(150–180 g) of Wistar strain at 100 mg/kg body weight
using phenylbutazone as the standard [41].
Ultrasonication method
To the compound 25, 26, or 27 (1.6 mmol) 5 cm3 POCl3
was added and kept under ultrasonication for 75–90 min at
40 °C. The progress of the reaction was monitored by TLC.
After completion of the reaction, the contents of the flask
were cooled to room temperature and poured onto crushed
ice. The resulting precipitate was filtered, washed with
saturated sodium bicarbonate solution followed by water
and dried. It was purified by column chromatography
(silica gel 60–120 mesh) using ethyl acetate-hexane (1:3)
as eluent.
Acknowledgements The author G. Yamini is thankful to the
University Grants Commission (UGC), New Delhi, for the sanction of
UGC-BSR fellowship. One of the authors, M. Madhu Sekhar is
grateful to UGC-New Delhi, India, for the sanction of SRF
fellowship.
References
Ethyl 5-[5-(furan-2-yl)isoxazol-3-yl]-1,3,4-oxadiazole-2-car-
1. Liras S, Allen MP, Segelstein BE (2000) Synth Commun 30:437
2. Gaonkar SL, Rai KML, Prabhuswamy B (2006) Eur J Med Chem
41:841
boxylate (28, C12H9N3O5)
White solid (0.39 g, 90%);
1
m.p.: 144–146 °C; H NMR (DMSO-d6): d = 1.39 (t, 3H,
CH3, J = 6.4 Hz), 4.35 (q, 2H, OCH2, J = 6.4 Hz), 6.92–
8.21 (m, 4H, Ar–H) ppm; 13C NMR (DMSO-d6): d = 14.7
(CH3), 61.8 (CH2), 106.8, 109.7, 115.4, 144.1, 149.2,
150.2, 153.3, 159.5 (CO), 159.9, 162.5 ppm; IR (KBr):
3. Khan KM, Ullah Z, Rani M, Perveen S, Haider SM, Choudhary
MI, Rahman A, Voelter W (2004) Lett Org Chem 1:50
4. (a) Mihailovic N, Markovic V, Matic IZ, Stanisavljevic NS,
Jovanovi ZS, Trifunovic SZ, Joksovic L (2017) RSC Adv 7:8550;
(b) Reddy GM, Muralikrishna A, Padmavathi V, Padmaja A,
Tilak TK, Rao CA (2013) Chem Pharm Bull 61:1291
5. Almasirad A, Mousavi Z, Tajik M, Assarzadeh M, Shafiee A
(2014) Daru J Pharm Sci 22:1
m = 1575 (C=N), 1625 (C=C), 1697 (CO–O) cm-1; HRMS:
ꢀ
m/z = 298.2091 ([M?Na]?).
6. Husain A, Ahmad A, Alam MM, Ajmal M, Ahuja P (2009) Eur J
Med Chem 44:3798
Ethyl 5-[5-(5-bromothiophen-2-yl)isoxazol-3-yl]-1,3,4-oxadi-
7. El-Din MMG, El-Gamal MI, Abdel-Maksoud MS, Yoo KH, Oh
CH (2015) Eur J Med Chem 90:45
8. Shingalapur RV, Hosamani KM, Keri RS, Hugar MH (2010) Eur
J Med Chem 45:1753
9. Chaudhary SK, Chaudhary M, Chaudhari A, Parmar SS (1978) J
Pharm Sci 67:1507
10. El-Emam AA, Al-Deeb OA, Al-Omar M, Lehmann J (2004)
Bioorg Med Chem 12:5107
azole-2-carboxylate (29, C12H8BrN3O4S)
White solid
1
(0.51 g, 87%); m.p.: 198–200 °C; H NMR (DMSO-d6):
d = 1.32 (t, 3H, CH3, J = 6.8 Hz), 4.25 (q, 2H, OCH2,
J = 6.8 Hz), 6.91–8.15 (m, 3H, Ar–H) ppm; 13C NMR
(DMSO-d6): d = 14.1 (CH3), 61.3 (CH2), 105.8, 113.0,
127.2, 130.5, 134.8, 149.0, 153.9, 159.5, 160.4 (CO),
ꢀ
163.0 ppm; IR (KBr): m = 1562 (C=N), 1618 (C=C), 1712
11. Dolman SJ, Gosselin F, O’Shea PD, Davies IW (2006) J Org
Chem 71:9548
(CO–O) cm-1; HRMS: m/z = 393.1677 ([M?Na]?).
12. Biftu T, Feng DD, Liang GB, Kuo H, Qian X, Naylor EM,
Colandrea VJ, Candelore MR, Cascieri MA, Colwell LF, Forrest
MJ, Hom GJ, MacIntyre DE, Stearns RA, Strader CD, Wyvratt
MJ, Fisher MH, Weber AE (2000) Bioorg Med Chem Lett
10:1431
Ethyl
5-[5-(pyridin-4-yl)isoxazol-3-yl]-1,3,4-oxadiazole-2-
carboxylate (30, C13H10N4O4) White solid (0.38 g, 85%);
m.p.: 156–158 °C; H NMR (DMSO-d6): d = 1.35 (t, 3H,
CH3, J = 7.0 Hz), 4.39 (q, 2H, OCH2, J = 7.0 Hz), 6.98–
1
123

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