Antiinflammatory property of 3-aryl-5-(n-propyl)-1,2,4-oxadiazoles and antimicrobial property of 3-aryl-5-(n-propyl)-4,5-dihydro-1,2,4-oxadiazoles: Their syntheses and spectroscopic studies

Article abstract of DOI:10.1016/S0968-0896(03)00035-X

The synthesis of six 3-aryl-5-(n-propyl)-4,5dihydro-1,2,4-oxadiazoles 3a-f has been achieved in a facile manner by the reaction of an appropriate arylamidoxime 1a-f with butyraldehyde 2. Oxidation of 3a-f individually using MnO₂ in CH₂Cl₂ or sodium hypochlorite in THF/H₂O furnished 1,2,4-oxadiazoles 4a-f in good to excellent yields. Compounds 4a-f were also evaluated against inflammation. Except 4e, all of them reduced inflammation, however, 4c presented better antiinflammatory activity. A preliminary antimicrobial activity tests of 3a-f showed that these compounds possess activity against some microorganisms. In fact, 3c and 3f have been found to be more effective against Staphylococcus aureus, Mycobacterium smegmatis, and Candida albicans.

Full text of DOI:10.1016/S0968-0896(03)00035-X

Bioorganic & Medicinal Chemistry 11 (2003) 1821–1827
Antiinflammatory Property of 3-Aryl-5-(n-propyl)-
1,2,4-oxadiazoles and Antimicrobial Property of 3-Aryl-5-
(n-propyl)-4,5-dihydro-1,2,4-oxadiazoles:Their Syntheses
and Spectroscopic Studiesy
Rajendra M. Srivastava,a,* Analice de Almeida Lima,a Osnir S. Viana,a
Marcelo J. da Costa Silva,a Maria T. J. A. Catanhob and Jose Otamar F. de Moraisc
a
´
Departamento de Quımica Fundamental, Universidade Federal de Pernambuco, Cidade Universitaria, 50.740-540 Recife, PE, Brazil
´
Departamento de Biofısica, Universidade Federal de Pernambuco, Cidade Universitaria, 50.670-420 Recife, PE, Brazil
b
´
´
Departamento de Antibioticos, Universidade Federal de Pernambuco, Cidade Universitaria, 50.690-901 Recife, PE, Brazil
c
´
´
Received 3June 2002; accepted 2 December 2002
Abstract—The synthesis of six 3-aryl-5-(n-propyl)-4,5dihydro-1,2,4-oxadiazoles 3a–f has been achieved in a facile manner by the
reaction of an appropriate arylamidoxime 1a–f with butyraldehyde 2. Oxidation of 3a–f individually using MnO2 in CH2Cl2 or
sodium hypochlorite in THF/H2O furnished 1,2,4-oxadiazoles 4a–f in good to excellent yields. Compounds 4a–f were also eval-
uated against inflammation. Except 4e, all of them reduced inflammation, however, 4c presented better antiinflammatory activity. A
preliminary antimicrobial activity tests of 3a–f showed that these compounds possess activity against some microorganisms. In fact,
3c and 3f have been found to be more effective against Staphylococcus aureus, Mycobacterium smegmatis, and Candida albicans.
# 2003Elsevier Science Ltd. All rights reserved.
It is now well known that cyclooxygenase (COX) is
involved in the biosynthesis of proinflammatory pros-
taglandins from arachidonic acid. After their produc-
tion, prostaglandins are released locally in tissues and
cause inflammation. There are two isoforms of COX
enzyme, cyclooxygenase-1 (COX-1) and cyclooxygenase-2
(COX-2).1 The former is constitutively expressed for car-
rying on physiological activities in the body, while COX-2
is induced locally by cytokines and mitogens etc. causing
overproduction of prostaglandins during the inflamma-
tory and colorectal tumor formation processes.2 In 1998, it
has been suggested that the overexpression of COX-2 and
the subsequent enhanced production of prostaglandins
might be responsible for the evolution of colon cancer.3
Therefore, the selective inhibitors of COX-2 are needed to
combat the inflammation and also to controle the evo-
lution of cancer in the colon and other parts of the body.
(NSAIDs), more particularly to the selective inhibitors
of COX-2, because the importance of this class of drugs
is almost impossible to overestimate. The following
paragraphs describe the reason for undertaking the
synthesis and pharmacological evaluations of the title
compounds.
1,2,4-Oxadiazole derivatives possess interesting pharma-
cological properties.4,5 Two of our recent publications
cite references describing diversified biological activities
of 3,5-disubstituted 1,2,4-oxadiazoles.6,7 Some of the
oxadiazoles, synthesized by us, presented analgesic and
antiinflammatory properties.8,9 For example, N-[3-aryl-
1,2,4-oxadiazol-5-yl-methyl]phthalimides have been found
to be analgesic, and one of them viz., N-[3-phenyl-1,2,4-
oxadiazol-5-yl-methyl]phthalimide exhibited analgesic
activity far superior than aspirin.8 Since 3-aryl-5-
isopropyl-1,2,4-oxadiazoles showed antiinflammatory
properties,9 we thought to prepare the title compounds,
in order evaluate their response against inflammation and
compare their behavior with the known 3-aryl-5-iso-
propyl-1,2,4-oxadiazoles.9 This paper therefore describes
first the synthesis of 4,5-dihydro-1,2,4-oxadiazoles 3a–f
from 1a–f and 2 followed by their oxidation to 4a–f
(Scheme 1). Five compounds, viz., 4a–d,f have been
For the last several years, our research has been directed
to discover the nonsteroidal antiinflammatory drugs
yTaken in Part from the MS Thesis (1994) of Analice De Almeida
Lima, Universidade Federal De Pernambuco, Recife, PE, Brazil.
*Corresponding author. Tel.: +55-81-3271-8440; fax: +55-81-3271-
8442; e-mail: rmns@npd.ufpe.br
0968-0896/03/$ - see front matter # 2003Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0968-0896(03)00035-X

1822
R. M. Srivastava et al. / Bioorg. Med. Chem. 11 (2003) 1821–1827
Scheme 1.
found to possess antiinflammatory properties although
less than aspirin, but are comparable with 3-aryl-5-iso-
propyl-1,2,4-oxadiazoles reported earlier.9
and with sodium hypochlorite are shown in Schemes 2
and 3. The mechanism of oxidation of benzyl alcohol
with manganese dioxide has been studied by Gold-
man.10 He concluded that the rate-determining step in
the oxidation of benzyl alcohols with activated manga-
nese dioxide involves cleavage of the a-CH bond, and
that the assumed adsorption step is reversible. Similar
mechanism should be considered for the oxidation of
3a–f to 4a–f (Scheme 2).
Chemistry
The synthesis of 3-aryl-5-propyl-4,5-dihydro-1,2,4-oxa-
diazoles 3a–f has been achieved from arylamidoximes
1a–f and n-butyraldehyde 2 in the presence of a small
quantity of an acidic ion-exchange resin (Amberlite IRP-
64) as a catalyst. The structures of these products were
deduced from infrared and nuclear magnetic resonance
spectroscopy.
Initially, 4,5-dihydro-1,2,4-oxadiazole is adsorbed at the
surface of manganese didoxide (shown in 5a–f) followed
by the proton transfer from N-4 to one of the oxygen
atoms of MnO2 with the formation of a coordinated
bond between N-4 and Mn (6a–f). Abstraction of a
hydrogen radical from C-5 generates a diradical species
which loses Mn(OH)2 from 7a–f to give 4a–f.
The synthesis of 3-aryl-5-propyl-1,2,4-oxadiazoles 4a–f
was achieved from 3a–f in two different oxidative ways:
first, with manganese dioxide in methylene chloride and
second, with sodium hypochlorite in a mixture of tetra-
hydrofuran and water. After purification, the compounds
gave the expected NMR signals for 1,2,4-oxadiazoles. The
infrared spectra also tallied with their structures.
The literature records the oxidation of 4,5-dihydro-
1,2,4-oxadiazoles to 1,2,4-oxadiazoles using sodium
hypochlorite, but no mechanism of such oxidation has
been reported.11 Therefore, we suggest a probable
mechanism of transformation of 4,5-dihydro-1,24-oxa-
diazoles to oxadiazoles with sodium hypochlorite (Scheme
The mechanism of formation of 1,2,4-oxadiazoles from
4,5-dihydro-1,2,4-oxadiazoles with manganese dioxide
Scheme 2.

R. M. Srivastava et al. / Bioorg. Med. Chem. 11 (2003) 1821–1827
1823
Scheme 3.
3). The first step is the removal of proton from N-4 which
leads to the formation of 3-aryl-2-chloro-2,5-dihydro-
1,2,4-oxadiazoles 8a–f. Subsequent elimination of HCl by
the hydroxide ion from this intermediate furnishes 4a–f.
4d were ꢀ70% less effective. Compound 4c gave sig-
nificant results and is comparable with aspirin (Table 1).
Heterocycle 4e did not cause any inflammation reduc-
tion.
A comparative analysis of the antiinflammatory test results
of compounds 4a–d,f and aspirin is shown in Figure 1.
Antiinflammatory activity
For the last many years, there has been a great interest
to develop new non-steroidal antiinflammatory drugs
(NSAIDs) which could specifically inhibit cyclooxy-
genase-2 (COX-2), the enzyme responsible for the pro-
duction of prostaglandins and other mediators which
are directly associated with inflammation process. Some
selective inhibitors for COX-2 have already been
found,12À14 and the research in this direction continues
with a view to discover new drugs for inhibiting this
enzyme. The aim is to have drugs with better efficacy,
less toxicity and less side effects.
The acute toxicity test in mice produced an interesting
phenomenon. The animals demonstrated a sign of ner-
vous system excitation (piloerection, cardiac accelera-
tion, psychomotor agitation with repeated shivering),
and soon after a light sedation. These phenomenon were
exacerbated with the gradual increase in dose adminis-
tration. Meanwhile, no animal of any group died after
Table 1. Antiinflammatory test results of compounds 4a–d,f and
acetylsalicylic acid (Aspirin)a
5-Methyl-3-phenyl-1,2,4-oxadiazole was examined in 1972
for antiinflammatory properties, which showed similar
effect as that of phenylbutazone15 in terms of activity.
Later on, other oxadiazoles have been examined by us
for analgesic and/or antiinflammatory activities with
promising results.8,9 Since, 3-aryl-5-alkyl-1,2,4-oxadia-
zoles possess an aromatic ring at position 3and an
alkyl group at C-5, they become liposoluble. It is sup-
posed that such property should possibly lead to
anaesthetic or hypoanalgesic properties in living beings,
because this lipophylic property is essential for a drug
to cross the hematoencephalic barrier and to reach the
central nervous system, exercising its effects, such as,
sedation.
Compd
Average difference in paw
weights (g) (standard deviation)
Edema reduction (%)
ASA
4a
4b
4c
4d
0.06392Æ0.00449
0.08160Æ0.00609
0.08666Æ0.01096
0.07240Æ0.00427
0.08516Æ0.00874
0.08008Æ0.00827
35.17
17.24
12.17
26.57
9.73
4f
18.78
aCompound 4e did not show any antiinflammatory activity.
Results
Preliminary antiinflammatory and toxicity tests of 3-
aryl-5-propyl-1,2,4-oxadiazoles 4a–f
Preliminary antiinflammatory activity tests have been
performed for compounds 4a–f. All of them except
compound 4e exhibited antiinflammatory properties
when compared with acetylsalicylic acid. Oxadiazoles 4a
and 4f were 50% less effective than aspirin while 4b and
Figure 1. Comparative analyses of the antiinflammatory activity of
compounds 4a–d,f and acetyl salicylic acid (ASA).

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R. M. Srivastava et al. / Bioorg. Med. Chem. 11 (2003) 1821–1827
Table 2. Acute toxicity test results of compounds 4a–f
Preliminary antimicrobial evaluation of compounds 3a–f
Compd Dose (mg/kg) Number of dead/batch. after 72 h DL-50
It is common in countries with tropical climate and
precarious socio-economic conditions to have higher
incidence of diseases caused by microorganisms, espe-
cially bacteria and fungi. The climate in conjunction
with sub-normal life conditions in certain regions cause
the microorganisms to proliferate. The indiscriminate
use of antibiotics has been increasing resulting in the
resistance of many bacteria. For example, Staphylo-
coccus aureus is responsible for hospital infections in
many patients. For this reason, we became interested to
test 3-aryl-4,5-dihydro-1,2,4-oxadiazoles 3a–f against
bacteria and fungi. In fact, many heterocycles have been
found to be effective against these microorganisms, the
literature, however, doesn’t contain much information
about 4,5-dihydro-1,2,4-oxadiazoles. The closer exam-
ple is a 4,5-dihydro-1,3-oxazole connected to a isoxazole
ring through an ether bridge.17 This compound inhibits
rhinovirus.
4a
4b
4c
4d
4e
4f
125
250
500
1000
0/5
0/5
0/5
0/5
n.f.
n.f.
n.f.
n.f.
—
125
250
500
1000
0/5
0/5
0/5
0/5
125
250
500
1000
0/5
0/5
0/5
0/5
125
250
500
1000
0/5
0/5
0/5
0/5
125
250
500
1000
4/5
4/5
5/5
5/5
A preliminary antimicrobial activity tests of compounds
3a–f against Mycobacterium smegmatis, Staphylococcus
aureus, Bacillus subtilis, Escherichia coli, Enterobacter
aerogenes, Saccharomyces cerevisae and Candida albi-
cans, were carried out. However, only two of them, viz.,
3c and 3f gave interesting results as shown in Tables 3
and 4. Two different technicques, viz., the procedure of
dilution in agar,18 and the disc method,19 have been
used to evaluate the antimicrobial activity. The disc test
involved the culture medium of Mueller–Hinton20 with
d-glucose, 2 g/L, 13mm of disc diameter, and the con-
centration of the compounds were 1.2 mg/disc.
125
250
500
1000
0/5
0/5
0/5
0/5
n.f.
n.f.: Not found., DL-50: lethal dose for 50% of the animals.
48 h with the dose tested (125–1000 mg/kg of body
weight) except in the case of 4e, where more than 50%
of the animals died (see Table 2).
Experimental determination of antiinflammatory activity
All compounds were evaluated for their antiin-
flammatory activity following the procedure developed
by Levy.16 The inflammation was introduced by
administering (0.1%) carrageenin in aqueous saline
(0.9% NaCl) solution on the hind paws of the white
male Swiss albino mice of specie Mus muscullus having
approximate weight of 30.00 g each. After 30 min, the
synthesized compounds were administered intraper-
itoneally in one dose of 250 mg/kg of the animal’s
weight to one group of five animals. Simultaneously,
for positive and negative controls, acetyl salicylic acid
and vegetable oil were injected intraperitoneally. The
animals were sacrificed 4 h after the drug admini-
stration, and the antiinflammatory activity determined
by amputation of the hind paws of the region, which
were weighed and the difference was obtained from the
control groups.
Although, 3c and 3f are more efficient, 3c has presented
much better activity against Mycobacterium smegmatis,
and needs exploration in the future for acid-resistant
bacteria specially the ones which cause tuberculosis and
leprosy.
Conclusion
We have achieved the syntheses of six 3-aryl-5-(n-pro-
pyl)-4,5-dihydro-1,2,4-oxadiazoles 3a–f, five of which
3b–f are new. Oxidation of 3a–f either with manganese
dioxide or with sodium hypochlorite furnished 3-aryl-5-
(n-propyl)-1,2,4-oxadiazoles 4a–f. The mechanism of
oxidation of 3a–f to 4a–f by both methods has been
suggested by us. Oxadiazoles 4a–d,f have been found to
possess antiinflammatory activity. Also, 4,5-dihydro-
Table 3. Antimicrobial activity of 3-aryl-5-(n-propyl)-4,5-dihydro-1,2,4-oxadiazoles 3c–fa using the dilution susceptibility test technique
Microorganisms
Minimum inhibitory concentration (MIC) in mg/L or in ppm
3c
3d
3e
3f
Staphylococcus aureus
Bacillus subtilis
Escherichia coli
Enterobacter aerogenes
Candida albicans
>100ꢁ200
>200ꢁ300
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>100ꢁ200
>200ꢁ300
>400
>400
>200ꢁ300
>300ꢁ400
>200ꢁ300
aCompounds 3a and 3b did not show any reasonable antimicrobial activity.

R. M. Srivastava et al. / Bioorg. Med. Chem. 11 (2003) 1821–1827
1825
Table 4. Antimicrobial activity of 3-aryl-5-(n-propyl)-4,5-dihydro-
1,2,4-oxadiazoles 3b–f using diffusion test procedures
(C-3). Anal. calcd for C11H14N2O. C, 69.47; H, 7.37; N,
14.72. Found C, 69.29; H, 7.13; N, 14.48.
Microorganisms
Zone diam (nearest whole mm)
5-(n-Propyl)-3-(o-tolyl)-4,5-dihydro-1,2,4-oxadiazole (3b).
(59%, 65.8–66.4 ꢂC, Rf 0.70). UVlmax (EtOH), 274.4
and 226.4 nm. IR (KBr) 3201 (N–H), 1608 (Ar–H),
3a
3b
3c
3d
3e
3f
S. aureus
B. subtilis
E. coli
E. aerogenes
M. smegmatis
S. cerevisae
—
—
—
—
3
—
—
—
—
2
—
—
—
—
6
—
—
—
—
3
—
—
—
—
1
—
—
—
—
4
1
1588 (C¼N), 830 (N–O), 1105 cmÀ1 (C–O). H NMR
(CDCl3) d 1.02 (t, 3H, J=7.35 Hz, CH3), 1.44–1.62 (m,
2H, CH2), 1.68–1.90 (m, 2H, CH2), 2.55 (s, 3H, Ar–
CH3), 4.50 (b, 1H, N–H), 5.67 (m, 1H, C–H), 7.20–7.39
(m, 3H, H-30, H-40, H-50), 7.51 (dd, 1H, J=7.65 Hz,
J=2.70 Hz, H-60); 13C NMR (CDCl3) d 13.93 (C-8),
17.18 (C-7), 21.45 (C-9), 38.14 (C-6), 92.03 (C-5), 125.03
(C-10), 125.80 (C-50), 128.41 (C-60), 130.16 (C-30), 131.26
(C-40), 137.96 (C-20) 156.08 (C-3). Anal. calcd for
C12H16N2O. C, 70.57; H, 7.89; N, 13.71. Found C,
70.46; H, 7.67; N, 13.47.
3
1
8
2
3
1
1,2,4-oxadiazoles 3a–e have shown to possess reason-
able microbial activity against Mycobacterium smegta-
tis, Monila sitophila, Candida albicans, and
Staphylococcus aureus.
5-(n-Propyl)-3-(m-tolyl)-4,5-dihydro-1,2,4-oxadiazole (3c).
(85%, 67.0–67.5 ꢂC, Rf 0.77). UVlmax (EtOH), 282.2
and 232.2 nm. IR (KBr) 3204 (N–H), 1606 (C¼N), 857
Experimental
1
Melting points were determined on an Electrothermal
digital melting point apparatus (model 9100) and are
uncorrected. Infrared spectra were recorded with a
Brucker model IFS66 FT-IR spectrophotometer using
potassium bromide pellets for solid samples and neat
material for liquid samples. NMR spectra were mea-
sured with a Varian Unity Plus instrument (300 MH2)
using CDCl3 as solvent, and Me4Si as an internal refer-
ence. Silica gel coated plates with fluorescent indicator
(PF254) were used for thin-layer chromatography (TLC),
and the spots were detected under ultraviolet light. The
solvent system for TLC plates was chloroform for com-
pounds 4a–f and chloroform–ethyl acetate (8:2) for 3a–f.
(N–O), 1106 (C–O). H NMR (CDCl3) d 0.94 (t, 3H,
J=7.35 Hz, CH3), 1.42–1.60 (m, 2H, CH2), 1.64–1.90
(m, 2H, CH2), 2.35 (s, 3H, Ar–CH3), 5.60 (dd, 1H,
J=4.95 Hz, J=9.00 Hz, C–H), 7.21–7.34 (m, 2H, H-40
and H-50) 7.42–7.60 (m, 2H, H-20 and H-60); 13C NMR
(CDCl3) d 13.87 (C-8), 17.09 (C-7), 21.21 (C-9), 38.10
(C-6), 92.80 (C-5), 123.47 (C-60), 125.47 (C-10), 126.97
(C-20), 128.51 (C-50), 131.49 (C-40), 138.42 (C-30) 156.10
(C-3). Anal. calcd for C12H16N2O C, 70.57, H, 7.89, N,
13.71. Found C, 70.59, H, 8.14, N, 13.73%.
5-(n-Propyl)-3-(p-tolyl)-4,5-dihydro-1,2,4-oxadiazole
(3d). (87%, 82 ꢂC, Rf 0.67). UVlmax (EtOH) 288.8 and
235.8 nm. IR (KBr) 3222 (N–H), 1599 (either Ar–H or
1
C¼N), 865 (N–O), 1106 (C–O). H NMR (CDCl3) d
General procedure
0.96 (t, 3H, J=7.35 Hz, CH3), 1.40–1.58 (m, 2H, CH2),
1.64–1.86 (m, 2H, CH2), 2.37 (s, 3H, Ar–CH3), 4.86 (b,
1H, N–H), 5.63(dd, 1H, J=4.80 Hz, J=9.30 Hz, H-5),
7.17 (d, 2H, J=8.25 Hz, H-30 and H-50), 7.55 (d, 2H,
J=8.25 Hz, H-20 and H-60); 13C NMR (CDCl3) d 14.16
(C-8), 17.440 (C-7), 21.73 (C-9), 38.35 (C-6), 93.02 (C-5),
122.93(C-1 ), 126.67 (C-20 and C-60), 129.64 (C-30 and
C-50), 141.45 (C-40), 156.26 (C-3). Anal. calcd for
C12H16N2O. C, 70.57; H, 7.89; N, 13.71. Found C,
70.59; H, 7.91; N, 13.71.
3-Aryl-5-(n-propyl)-4,5-dihydro-1,2,4-oxadiazoles 3a–f.
Initially, the preparation of 3a–f was carried out
according to the method reported earlier.21 The reaction
was performed with an appropriate arylamidoxime and
freshly distilled butyraldehyde at room temperature. It
took between 5 and 8 days for the reaction to complete.
When the reaction of an arylamidoxime with butyr-
aldehyde was done in the presence of Amberlite IRP-64
(–CO2H form) following the published methodology,
the reaction time was reduced from 5–8 days to 3days. 9
The details of each 4,5-dihidro-1,24-oxadiazole is given
below. The compounds were crystallized from chloro-
form–n-hexane or ethanol–water.
3-(p-Chlorophenyl)-5-(n-propyl)-4,5-dihydro-1,2,4-oxa-
diazole (3e). (85%, 113 ꢂC, Rf 0.70). UVlmax (EtOH)
298.2 and 238.8 nm. IR (KBr) 3215 (N–H), 1599
1
(C¼N), 870.5 (N–O), 1089 (C–O). H NMR (CDCl3) d
0.99 (t, 3H, J=7.35 Hz, CH3), 1.46–1.54 (m, 2H, CH2),
1.71–1.76 (m, 2H, CH2), 4.58 (b, 1H, N–H), 5.68 (4
lines, 1H, C–H), 7.39 (d, 2H, J=8.85 Hz, H-30 and H-
50), 7.63(d, 2H, J=8.85 Hz, H-20 and H-60). 13C NMR
(CDCl3) d 13.91 (C-8), 17.19 (C-7), 38.11 (C-6), 93.15
(C-5), 124.27 (C-10), 127.74 (C-20 and C-60), 129.03(C-3 0
and C-50), 136.83 (C-40), 155.18 (C-3). Anal. calcd for
C11H13N2OCl. C, 58.79; H, 5.83; N, 12.46. Found C,
59.00; H, 5.59; N, 12.03%.
5-(n-Propyl)-3-phenyl-4,5-dihydro-1,2,4-oxadiazole (3a).
(89%, 75.6–76.0 ꢂC, Rf 0.69, lit.22 mp 74.0 ꢂC). UVlmax
(EtOH), 291.2 and 228.2 nm. IR (KBr) 3202 (NH), 1598
(C¼N), 861(NO), 1131 cmÀ1 (C–O). H NMR (CDCl3)
1
d 0.98 (t, 3H, J=7.35 Hz, CH3), 1.43–1.56 (m, 2H,
CH2), 1.66–1.86 (m, 2H, CH2), 4.77 (b, 1H, NH), 5.67
(4 line signal, 1H, J=5.10 Hz, J=9.30 Hz, CH), 7.35–
7.48 (m, 3H, H-30, H-40 and H-50), 7.65–7.72 (m, 2H, H-
20 and H-60); 13C NMR (CDCl3) d 13.88 (C-8), 17,12 (C-
7), 38.10 (C-6), 92.89 (C-5), 125.63 (C-10), 126.39 (C-20
and C-60), 128.64 (C-30 and C-50), 130.74 (C-40), 155.99
3-(p-Anisyl)-5-(n-propyl)-4,5-dihydro-1,2,4-oxadiazole (3f).
(85%, 105–106 ꢂC, Rf 0.81). UVlmax (EtOH), 246.0

1826
R. M. Srivastava et al. / Bioorg. Med. Chem. 11 (2003) 1821–1827
and 282.0 nm. IR (KBr) 3240 (N–H), 1614 (C¼N), 831
(C¼C), 906 (N–O), 1201 cmÀ1 (C–O). 1H NMR
(CDCl3) d 1.07 (t, 3H, J=7.35 Hz, CH3), 1.92 (m, 2H,
CH2), 2.62 (s, 3H, Ar–CH3), 2.93(t, 2H, J=7.50 Hz,
CH2), 7.26–7.42 (m, 3H, Ar–H), 7.95–8.05 (dd, 1H
J=7.50 Hz, J=1.80 Hz, Ar–H); 13C NMR (CDCl3) d
13. 66 (C-8), 20.23 (C-7), 22.07 (C-9), 28.38 (C-6),
125.94 (C-50), 126.27 (C-10), 130.02 (C-30), 130.44 (C-60),
131.33 (C-40), 138.16 (C-20), 168.84 (C-3), 178.80 (C-5).
Anal. calcd for C12H14N2O.0.5H2O. C, 68.22; H, 7.15.
Found C, 68.11; H, 7.45.
1
(N–O), 1179 (C–O). H NMR (CDCl3) d 0.98 (t, 3H,
J=7.20 Hz, CH3), 1.42–1.57 (m, 2H, CH2), 1.65–1.90
(m, 2H, CH2), 3.83 (s, 3H, OCH3), 4.56 (b, 1H, N–H),
5.63(dd, 1H, J=4.95 Hz, J=9.45 Hz, H–5), 6.90 (d,
2H, J=9.00 Hz, H-20 and H-60) 7.62 (d, 2H, J=9.00 Hz,
H-30 and H-50); 13C NMR (CDCl3) d 13.90 (C-8), 17.21
(C-7), 38.07 (C-6), 55.33 (C-10), 92.58 (C-5), 114.06 (C-30
and C-50), 118.04 (C-10), 128.00 (C-20 and C-60), 155.71 (C-
3), 161.52 (C-40). Anal. calcd for C12H16N2O2. C, 65.43 ;
H, 7.32; N, 12.72. Found C, 65.80; H, 7.25; N, 12.74.
5-Ethyl-3-(m-tolyl)-1,2,4-oxadiazole (4c). (81%, color-
less liquid, Rf 0.62): UVlmax (EtOH), 242.0, 281.0 and
291.6 nm. IR (Nujol) 1593(C ¼N), 1572 (C¼C), 904 (N–
3-Aryl-5-propyl-1,2,4-oxadiazoles 4a–f
1
Two methods have been used for the oxidation of 4,5-
dihydro-1,2,4-oxadiazoles 3a–f to 4a–f. These are given
below.
O), 1281 cmÀ1 (C–O). H NMR (CDCl3) d 1.05 (t, 3H,
J=7.35 Hz, CH3), 1.82–1.98 (m, 2H, CH2), 2.41 (s, 3H,
Ar–CH3), 2.92 (t, 2H, J=7.50 Hz, CH2), 7.27–7.40 (m,
2H, H–40 and H-50), 7.85–7.92 (m, 2H, H-20 and H-60);
13C NMR (CDCl3) d 13. 59 (C-8), 20.20 (C-7), 21.27 (C-
9), 28.44 (C-6), 124.45 (C-60), 126.764 (C-10), 127.90 (C-
50), 128.69 (C-20), 131.79 (C-40), 138.56 (C-30), 168.30 (C-
3), 179.76 (C-5). Anal. calcd for C12H14N2O. C, 71.26; H,
6.98; N, 13.85. Found C, 71.19; H, 7.19; N, 13.44.
Procedure A. To a solution of 3-phenyl-5-propyl-4,5-
dihydro-1,2,4-oxadiazole 3a (2.63mmol) in 250 mL of
dichloromethane was added manganese dioxide (10
mmol) and the contents stirred for 2 h at room tem-
perature. TLC plate (chloroform–hexane, 4:1) revealved
the completion of the reaction. Filtration and solvent
evaporation yielded the desired compound 4a in almost
quantitative yield. Quick chromatography over silica gel
gave chromatographically pure product. Similarly,
other 4,5-dihydro-1,2,4-oxadiazoles 3b–f were trans-
formed to 1,2,4-oxadiazoles 4b–f. The details of each
compound are given below.
5-(n-Propyl)-3-(p-tolyl)-1,2,4-oxadiazole (4d). (95%, col-
orless oil, Rf 0.56): UVlmax (EtOH) 247.0, 279.0 and
288.0 nm. IR (Nujol) 1598 (C¼N), 1577 (C¼C), 913(N–
1
O), 1210 cmÀ1 (C–O). H NMR (CDCl3) d 1.06 (t, 3H,
J=7.5 Hz, CH3), 1.82–1.98 (m, 2H, CH2), 2.41 (s,3H,
Ar–CH3), 2.91 (t, 2H, J=7.5 Hz, CH2), 7.28 (d, 2H,
J=8.40 Hz, H-30 and H-50) 7.96 (d, 2H, J=8.40 Hz, H-
20 and H-60). 13C NMR (CDCl3) d 13.60 (C-8), 20.19 (C-
7), 21.51 (C-9), 28.44 (C-6), 124.07 (C-10), 127.26 (C-20
and C-60), 129.48 (C-30 and C-50), 141.31 (C-40) 168.19
(C-3), 179.67 (C-5). Anal. calcd for C12H14N2O. C,
71.26; H, 6.98; N, 13.85. Found C, 71.38; H, 7.26; N,
13.48.
Procedure B. An aqueous solution (5%) of sodium
hypochlorite (3.9 mL) was added to 3-phenyl-5-propyl-
4,5-dihydro-1,2,4-oxadiazole 3a (3.63 mmol) dissolved
in tetrahydrofuran (5–10 mL) and the contents were
stirred overnight at room temperature. Next morning,
an additional 1.5 mL solution of sodium hypochlorite
was added to the mixture and left stirring for a few
hours. The completion of the reaction was monitored by
TLC. Evaporation of tetrahydrofuran, neutralization of
the contents with a saturated solution of sodium bicar-
bonate followed by extraction with chloroform, drying
and solvent evaporation gave 4a in a somewhat com-
parable yield reported above in procedure A, although
this method provided somewhat lesser yield. A quick
chromatography over silica gel furnished pure oxadia-
zoles.
3-(p-Chlorophenyl)-5-(n-Propyl)-1,2,4-oxadiazole (4e).
(86%, 56.8–57.1 ꢂC, Rf 0.54): UVlmax (EtOH) 247.6,
272.2 and 286.6 nm. IR (Nujol) 1592 (C¼N), 1570
(C¼C), 909 (N–O), 1119 cmÀ1 (C–O). 1H NMR
(CDCl3) d 1.06 (t, 3H, J=7.50 Hz, CH3), 1.84–1.98 (m,
2H, CH2), 2.92 (t, 2H, J=7.35 Hz, CH2), 7.45 (d, 2H,
J=8.70, H-30 and H-50), 8.02 (d, 2H, J=8.70 Hz, H-20
and H-60); 13C NMR (CDCl3) d 13.62 (C-8), 20.17 (C-
0
7), 28.43(C-6), 125.44 (C-1 ), 128.67 (C-20 and C-60),
129.12 (C-30 and C-50), 137.16 (C-40), 167.43(C-)3,
180.10 (C-5). Anal. calcd for C11H11N2OCl. C, 59.38;
H, 4.94; N, 12.58. Found C, 59.53; H, 4.89; N, 12.32.
3-(Phenyl)-5-(n-propyl)-1,2,4-oxadiazole (4a). (90%, col-
orless oil, Rf 0.50): UVlmax (EtOH) 241.0, 276.4 and
284.4 nm. IR (Nujol) 1596 (C¼N), 1572 (C¼C), 910 (N–
1
O), 1200 cmÀ1 (C–O). H NMR (CDCl3) d 1.05 (t, 3H,
3-(p-Anisyl)-5-(n-propyl)-1,2,4-oxadiazole (4f). (85%,
colorless liquid, Rf 0.63): UVlmax 237.0 and 261.0 nm.
IR (Nujol) 1594 (C¼N), 1568 (C¼C), 911 (N–O), 1119
J=7.5 Hz, CH3). 1.92 (m, 2H, CH2). 2.93(t, 2H,
J=7.35 Hz. CH2). 7.45–7.51 (m, 3H, Ar–H). 8.06–8.12
(m, 2H, Ar–H); 13C NMR (CDCl3) d 13.60 (C-8), 20.18
(C-7), 28.44 (C-6), 126.91 (C-10) 127.34 (C-20 and C-60),
128.77 (C-30 and C-50), 131.02 (C-40), 168.20 (C-3),
179.85 (C-5). Anal. calcd for C11H12N2O. C, 70.2; H,
6.32; N, 14.74. Found C, 69.89; H, 6.19; N, 14.66.
1
cmÀ1 (C–O). H NMR (CDCl3) d 1.05 (t, 3H, J=7.50
Hz, CH3), 1.83–1.96 (m, 2H, CH2), 2.90 (t, 2H, J=7.50
Hz, CH2), 3.85 (s, 3H, OCH3), 6.98 (d, 2H, J=9.00 Hz,
H-30 and H-50), 8.00 (d, 2H, J=9.00 Hz, H-20 and H-60);
13C NMR (CDCl3) d 13.88 (C-8), 20.46 (C-7), 28.71 (C-
6), 55.59 (C-10), 114.44 (C-30 and C-50), 119.67 (C-10),
129.21 (C-20 and C-60), 162.06 (C-40), 168.17 (C-3),
179.84 (C-5). Anal. calcd for C12H14N2O2. C, 66.05; H,
6.42; N, 12.84. Found C, 66.12; H, 6.24; N, 12.81.
5-(n-Propyl)-3-(o-tolyl)-1,2,4-oxadiazole (4b). (74%, col-
orless liquid, Rf 0,46): UVlmax (EtOH) 2.39, 276.4 and
284.4 nm IR Nujol 1605 (C¼C), 1592 (C¼N), 1571

R. M. Srivastava et al. / Bioorg. Med. Chem. 11 (2003) 1821–1827
1827
Acknowledgements
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The authors express their gratitude to the Brazilian
National Research Council (CNPq) for financial assis-
tance. Two of us (A. de A. Lima and O.S. Viana) are
grateful to CNPq for Research Fellowships. Some of
the chemicals and solvents used in this research were
acquired from the grants provided by the Research
Foundation of Pernambuco State (FACEPE) and Bra-
zilian and French Ministry of Education (CAPES-
COFECUB) for which we are thankful. Our thanks are
also due to Marilu L. de Oliveira and Natercia M. M.
Bezerra for their help in the laboratory.
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