Improved microwave-mediated synthesis of 3-(3-aryl-1,2,4-oxadiazol-5-yl) propionic acids and their larvicidal and fungal growth inhibitory properties

Article abstract of DOI:10.1248/cpb.57.819

The synthesis of 3-(3-aryl-1,2,4-oxadiazol-5-yl)propionic acids from arylamidoximes and succinic anhydride under focused microwave irradiation conditions is described. The new synthetic method furnished the desired products in 2-3 min and good yields. Fur

Full text of DOI:10.1248/cpb.57.819

August 2009
Chem. Pharm. Bull. 57(8) 819—825 (2009)
819
Improved Microwave-Mediated Synthesis of 3-(3-Aryl-1,2,4-oxadiazol-5-
yl)propionic Acids and Their Larvicidal and Fungal Growth Inhibitory
Properties
Ricardo Antonio Wanderley NEVES FILHO,a Cecília Aguiar da SILVA,a
Clécia Sipriano Borges da SILVA,a Vanessa Passos BRUSTEIN,b
Daniela Maria do Amaral Ferraz NAVARRO, ,a Fábio André Brayner dos SANTOS,c,d
*
Luiz Carlos ALVES,c,d Marília Gabriela dos Santos CAVALCANTI,c,d Rajendra Mohan SRIVASTAVA, ,a and
Maria das Graças CARNEIRO-DA-CUNHA
*
b
a Departamento de Química Fundamental, Universidade Federal de Pernambuco; 50745–540 Recife, PE, Brazil:
c
b Departamento de Bioquímica, Universidade Federal de Pernambuco; 50670–901 Recife, PE, Brazil: Departamento de
Parasitologia, Centro de Pesquisas Aggeu Magalhães (CPqAM/FIOCRUZ); 50.670–420 Recife, PE, Brazil: and
d Laboratório de Imunopatologia Prof. Keizo Asami (LIKA) da Universidade Federal de Pernambuco; 50.670–420 Recife,
PE, Brazil. Received March 20, 2009; accepted May 7, 2009; published online May 14, 2009
The synthesis of 3-(3-aryl-1,2,4-oxadiazol-5-yl)propionic acids from arylamidoximes and succinic anhydride
under focused microwave irradiation conditions is described. The new synthetic method furnished the desired
products in 2—3 min and good yields. Furthermore, the previously complicated purification procedure has been
simplified in a manner which is quick, eco-friendly and cost-effective. Larvicidal bioassay and fungal growth in-
hibitory tests were performed using several 3-(3-aryl-1,2,4-oxadiazol-5-yl)propionic acids. These acids presented
strong larvicidal activity against L4 larvae of Aedes aegypti. The results suggest that larvicidal activity might be
correlated with the presence of electron-withdrawing substituents in the para position of the phenyl ring except
the fluorine atom. The alterations observed in the larvae spiracular valves of the siphon and anal papillae by
1,2,4-oxadiazoles in the larvicidal bioassay are responsible for larvae’s death. Furthermore, all acids inhibited
the fungal growth of five different types of fungi, viz., Fusarium solani, F. o xysporum, F. moniliforme, F. decemcel-
lulare and F. lateritium in a preliminary evaluation. Both of these activities are being disclosed for the first time
for 1,2,4-oxadiazole-5-yl ring linked at C-3 of propionic acid.
Key words 1,2,4-oxadiazole; propionic acid; larvicide; Aedes aegypti; antifungal activity
Mosquitoes are vectors for a large number of diseases, in- normal circumstances. The literature has described the resist-
cluding filariasis (transmitted by Culex quinquefasciatus), ance of mosquitoes to temephos chemical compound.7) Thus,
malaria (transmitted by Anopheles gambiae) dengue fever the search for new larval insecticides has been the focus of a
and yellow fever (transmitted by Aedes aegypti). Dengue large number of publications addressing the use of essential
fever may be as significant as diseases such as malaria and oils8—12) and plant extracts.13—21)
tuberculosis, posing economic burdens on the communities
Fungi are non-photosynthetic organisms which grow by
and governments. This disease occurs in tropical and sub- forming a mass of entwined and branched filaments called
tropical areas due to the favorable environment these regions micelia.22) Many fungi cause diseases in plants leading to
offer for the development of the transmitter mosquito of the economical losses and health problems to the affected com-
arbovirus from the genus Flavivirus.1) Dengue virus infection munities. The infection promoted by plant pathogens such as
can cause the classic form of the disease, debilitating a species of Fusarium do not cause only reduction in food
worker for weeks, or the hemorrhagic form, which leads to quality, but also contamination with mycotoxins, which are
death in many cases. Annual epidemics of dengue fever have hazardous to animal and human health.23) In particular, fungi
been advancing in the Americas and to our knowledge there like Fusarium oxyporum, F. solani and F. moniliforme, be-
is no vaccine for this illness.2)
sides attacking plants’ roots also promote systemic infection
One way to decrease the incidence of this disease is in immunosuppressed patients.22) Furthermore, F. o xysporum
through the eradication of Aedes aegypti. Mosquito control is a soilborne fungus that causes damage to a wide variety of
involves integrated pest management programs that include crops and has also been reported as an opportunistic human
larvicides, surveillance, source reduction, control of adult pathogen.24) In 2001 the antifungal properties of two 1,2,4-
mosquitoes (adulticide), biological control and public aware- oxadiazoles have been described.25) Although, these com-
ness campaigns.3,4) These integrated management actions pounds inhibited mycelial growth of Trychophyton mentagro-
focus on diminishing vector and larvicides are an important phytes, no evaluation has been done against Fusarium
part of eliminating the mosquito in the larval stage. The use species.
of a larvicide disrupts the evolutionary cycle of the mosquito
There are no reports in the literature about the larvicidal
vector, thereby promoting the interruption of virus transmis- activity of 1,2,4-oxadiazole containing compounds, but one
sion. The most often employed larvicide for Aedes aegypti report cites the fungicidal property of 1,2,4-oxadiazoles.25)
are temephos and toxins of Bacillus thuringiensis israe- This is an important class of heterocycle with a large number
lensis.5,6) Resistance is the ability of an insect population to of biological activities. To date, four literature reviews have
tolerate a dose of insecticide that would cause death under addressed the synthesis and biological studies on these
∗ To whom correspondence should be addressed. e-mail: rms_indu@yahoo.com
© 2009 Pharmaceutical Society of Japan

820
Vol. 57, No. 8
Table 1. Conditions for the F.MW. Reaction of 1g and 2
Temperature
(°C)
Time
(min)
Yields
(%)b)
Entry
Stirring
1a)
2
120
120
140
140
140
140
140
150
2
3
3
3
2
2
3
1
On
On
On
On
On
Off
On
On
N.R.
21
74
25
76
3
4a)
5
6
66
Fig. 1. 1,2,4-Oxadiazoles Possessing Biological Properties
7c)
8
77
62d)
rings.26—29) Many molecules containing a 1,2,4-oxadiazole
a) Experiment conducted without addition of DMF. b) Isolated yields. c) Ex-
moiety exhibit interesting pharmacological properties, such periment conducted at 10 mmol scale. d) The reaction mixture becomes a little red
as analgesic,30) anti-inflammatory,31) anti-convulsant,32) anti-
and we observed decomposition by TLC.
tumor,33) anti-kinetoplastid,34) HPTPb inhibitors,35) human
bII-tryptase inhibitors36) and selective avb3 receptor antago-
nists.37) 3-(3-Aryl-1,2,4-oxadiazol-5-yl)propionic acids have
exhibited pharmaceutical properties with no mutagenic activ-
ity, as determined by the Ames and SOS Chromotest.38) This
makes such compounds an interesting area for further pesti-
cide activity studies. Recently, these compounds have also
been used as building blocks for the synthesis of pep-
tidomimetics I,38) cannabinoid receptor 2 (CB2) agonist II,39)
and niacin receptor agonist III (Fig. 1).40)
The first synthesis of 3-(3-aryl-1,2,4-oxadiazol-5-yl)propi-
onic acids was achieved by the reaction of amidoximes and
succinic anhydride in refluxing toluene or 1,4-dioxane.41)
Later, these reagents were heated in a household microwave
oven under solvent-free conditions for 10 min42) with better
yields in comparison with the solution method. It is now well
established that focused microwave reactors are quite supe-
rior to the domestic ones due to their ability of focusing
Chart 1
energy on the sample producing a faster heating of the
reagents.43) The oven which we used in this work is equipped
with infrared and pressure sensors, which improves the relia- This experiment gave the acid in 21% yield. Encouraged
bility of the reaction. with this, the temperature was raised to 140 °C while main-
The aim of the present study was to improve the synthesis taining other conditions the same. Here, the result was satis-
of 3-(3-aryl-1,2,4-oxadiazol-5-yl)propionic acids by employ- factory and the yield was 74%. In fact, the same result can be
ing focused microwave irradiation (FMW) with a quick, eco- obtained in 2 min. It is noteworthy that unstirred reaction
friendly and low-cost method of purification and to deter- causes a decrease in yields (Table 1). On a 10 mmol scale,
mine their larvicidal and fungicidal properties. Therefore, the reaction works well and yields 77% of the pure acid.
this work will be a novel addition in the literature and should
be the subject of further research.
It is known that the microwave-induced reaction of a suit-
able arylamidoxime 1 with succinic anhydride 2 under sol-
vent free conditions furnished the desired 3-(3-aryl-1,2,4-
oxadiazol-5-yl)propionic acids 3a—i as the major products
Results and Discussion
Chemistry Initially, we tried to repeat the reaction of along with two minor substances 4a—i and 5a—i (Chart 1).
arylamidoximes and succinic anhydride to synthesize 3-(3- In fact, compounds 3a—i can be crystallized and recrystal-
aryl-1,2,4-oxadiazol-5-yl)propionic acids at 120 °C in a do- lized to remove 4a—i and 5a—i, but it is tedious and the
mestic microwave oven without any solvent. As reported in final yields of the desired acids are low as has been found
the literature, the above-cited acids were obtained in good earlier by our group. In order to get the best yield of these
yields in 10 min.42)
acids, we have chromatographed the crude mixture over sil-
Since these compounds are gaining more and more signifi- ica gel. This way the yield was excellent,41,42) but this proce-
cance, we decided to improve their microwave-accelerated dure is expensive and time-consuming. In this work we iso-
synthesis under solventless conditions. With this aim, we lated compounds 4a—i and 5a—i, respectively. The com-
performed a few experiments using a specific focused mi- bined yields of these heterocycles were very low (ca. 10%).
crowave oven. First, the reaction was carried out at 120 °C Their structures were verified using spectroscopic techniques
using an equimolar quantity of amidoxime 1g and succinic (IR and NMR spectra) including the elemental analyses.
anhydride 2 for 2 min under stirring. This experiment did not
In the present article we wish to emphasize that the syn-
produce any result. Next, we repeated the reaction under the thetic procedure has been scaled-up (from milligrams to a
same conditions as described but by adding 3 drops of couple of grams quantity for both focused and unfocused mi-
DMF/mmol of 1 and increasing the time from 2 to 3 mins. crowave techniques) with remarkable results. In addition, we

August 2009
821
have been able to eliminate the chromatographic purification (3d) had the similar value of LC50 (71.5 ppm) as that of 3b.
procedure, thus getting rid of the expensive adsorbants and The electron-withdrawing substituents-Cl (3f), -Br (3g) and
solvents. The new purification strategy involves the direct NO2 (3i) in the para position significantly decreased LC50
transformation of the carboxylic acids to their sodium salts, values. Substitution of the fluorine atom at para position in
which become water soluble followed by the cautious addi- the phenyl ring (3e) was an exception in LC50 behavior, be-
tion of an aqueous citric acid solution to precipitate the de- cause of its resonance with the aromatic ring, thus achieving
sired acids. These acids are sufficiently pure and further crys- the highest value among electron-withdrawing groups. We
tallization becomes quite easy and the yields are high (Table observed a relationship between LC50 values and substituent
2).
electronegativity properties: LC50 F 3eꢂLC50 Cl 3fꢂLC50 Br
The focused microwave (FMW) methodology followed by 3g. Halogenated compounds 3g (LC50ꢁ15.2 ppm) and 3f
a practical procedure of purification provides the access to 3- (LC50ꢁ28.1 ppm) may be considered highly active (LC50 val-
(3-aryl-1,2,4-oxadiazol-5-yl)propionic acids 3a—i with high ues ꢀ50 ppm) and these LC50 values are similar to the activ-
purity in shorter reaction time and better yields in compari- ity of essential oils obtained from the leaf, stem and inflores-
son with the ones published previously using household mi- cence of Piper marginatum (LC50ꢁ19.9—23.8 ppm)42) as
crowave oven or conventional heating (Table 2).
well as the leaf of Cryptomeria japonica D. DON (LC50ꢁ37.6
Larvicidal Bioassay According to Cheng et al.,44) essen- ppm).45) Moreover the best LC50 values for 1,2,4-oxadiazole
tial oils or plant extracts with LC50 values ꢀ100 ppm should are comparable to the larvicidal effect of b-asarone, natural
be considered active in larvicidal bioassays. All compounds botanical insecticide, which have exhibited an LC100 of
reported in the present work were tested against fourth instar 16 ppm.46,47)
Aedes aegypti larvae and exhibited larvicidal activity below
The quantitative structure–activity relationship (QSAR)
100 ppm (Table 3). 3-(3-Phenyl-1,2,4-oxadiazol-5-yl)propi- study of larvicidal activity of eight substituted benzoyl-
onic acid (3a) has been found to have the highest LC50 con- phenylbiurets against the Aedes aegypti larvae demonstrated
centration among the compounds studied. The introduction a presence of strong electron withdrawing and high
of a substituent group in the orto, meta or para positions of lipophilicity of the para-substituent on the phenyl ring was
the phenyl ring attached on C-3 of these 1,2,4-oxadiazoles required for high larvicidal effect of the biuret and urea com-
led to a decrease in LC50 values in Aedes aegypti larvicidal pounds.48) The relationship between mosquito repellent activ-
bioassays. The acids containing –CH3 (meta, 3c) achieved a ity and chemical structure of 31 amide analogues of N,N-di-
lower LC50 (63.8 ppm) value when compared to compounds ethyl-m-toluamide and N,N-diethylphenylacetamide investi-
containing the same substituent in the ortho (3b) gated by Katritzky et al.49) demonstrated that the most active
(LC50ꢁ70.9 ppm) and para (3d) (LC50ꢁ65.8 ppm) positions. compounds seem to be amides with one substituent (CH3 or
The MeO-substituent in the para position of the phenyl ring Cl) in the aromatic ring. The data presented in these articles
corroborate with the previous results. Our observations sug-
gest that larvicidal activity might be correlated with the pres-
ence of electron-withdrawing substituents in the para posi-
Table 2. Synthesis of 3-(3-Aryl-1,2,4-oxadiazol-5-yl)propionic Acids 3a—i
tion in the phenyl group.
Yield (%)
Method A
Yield (%)
Method B
Yield (%)
lit.42)
mp (°C)
lit.41,42)
Compound
mp (°C)
Some 1,2,4-oxadiazoles have exhibited insecticidal and
pesticide properties.50,51) These properties have been reported
for 1,3,4-oxadiazoles-containing compounds as well.52—55) In
order to demonstrate the importance of 1,2,4-oxadiazole ring
on the larvicidal property we have tested the isomer of com-
pound 3a, 3-(3-phenyl-1,3,4-oxadiazol-5-yl)propionic acid
6. This compound displayed no larvicidal effect even at
100 ppm. Thus, this lack of activity might be related with the
no presence of 1,2,4-oxadizole ring.
3a
3b
3c
3d
3e
3f
3g
3h
3i
73
60
74
76
78
89
77
82
84
68.0
57.0
71.0
68.0
72.0
84.0
68.0
71.0
76.0
73.3
25.0
76.4
67.7
—
119—120
101—102
100—101
144—145
146—147
153—154
157
119—120
102
101—102
145
—
83.1
76.5
—
153—154
157—158
138—139
—
138—139
134—135
—
Furthermore, these parameters were involved in explaining
the relationship between larvicidal activity and chemical
structure. All bioassay results discussed here can play an im-
portant role in larvicidal activity against Aedes aegypti.
Mode of Action The stage L4 mosquito larvae of the
Aedes aegypti were exposed to 3-(3-aryl-1,2,4-oxadiazol-5-
yl)propionic acids in the larvicide bioassays where consider-
able change in their movements has been observed followed
by paralysis between 5 and 8 h after being placed in the test
solution. Similarly, Chaithong et al.56) found excitation, rest-
lessness, tremors and convulsions, followed by paralysis dur-
ing the first 2 h of exposure to ethanol extracts from three
species of Piper [P. logum (fruit), P. ribesoides (wood) and P.
sarmentosum (whole plant)] in CL99 concentrations. The
number of dead and dying larvae increased significantly from
2 to 7 h after starting the bioassays, but death to all larvae
only occurred after 24 h of exposure. The authors report that
Table 3. Larvicidal Activity of 1,2,4-Oxadiazoles 3a—i and 1,3,4-Oxadia-
zole 6
Concentration
Compound
LC50 (ppm)
S.D.
range
3a
3b
3c
3d
3e
3f
3g
3h
3i
98.6
70.9
63.8
65.8
81.2
28.1
15.2
71.5
50.5
N.A.a)
2.9
2.5
2.9
3.2
1.3
1.9
0.8
1.5
2.4
—
70—130
50—90
50—90
57—73
70—95
22—36
13—25
65—76
47—60
ꢂ100
6
a) Non-active compound.

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Vol. 57, No. 8
Fig. 2. (A, C) Aedes aegypti Larvae after 8 h of Exposure to Control 2 and (B, D) Aedes aegypti Larvae after 8 h of Exposure to 3g
Observe larvae organs: breathing siphon (BS), spiracular valves (SV), anal papillae (AP), and saddle (S).
the symptoms that preceded larval death is correlated to the larvae following treatment with potential larval insecticides.
toxic effect that reaches the neuromuscular system of the lar- Preliminary Antifungal Assay All synthesized com-
vae. The authors also report that scanning electron mi- pounds 3a—i presented fungal growth inhibition for at least
croscopy (SEM) revealed that only the anal papillae under- one of the tested species. Nevertheless, compounds 3h, 3i, 3f
went morphological changes in the larvae treated with the and 3e inhibited the growth of five microorganisms during
plant extracts.
72 h (Fig. 3). Compound 3h was the most effective against F.
The Piper ethanol extracts treatment caused external de- decemcellulare and F. lateritium exhibiting 52.8ꢃ3.3% and
struction, with extensive damage and a shrunken cuticle of 45.8ꢃ1.6% inhibition, respectively. Product 3f presented the
the anal papillae, organ responsible for regulation of elec- best inhibitory effect against F. solani and F. decemcellulare,
trolyte levels in larva body.
displaying respectively 59.7ꢃ2.2% and 66.0ꢃ0.0% of inhi-
SEM of the L4 stage Ae. aegypti larvae exposed to dis- bition. For F. moniliforme, growth inhibition was observed at
tilled water (Control 1), co-solvent water solution (Control 2) 48 h time for all the tested compounds. Compound 3a was
and co-solvent water solution of 3-(3-p-bromophenyl-1,2,4- the most effective one against F. moniliforme exhibiting
oxadiazol-5-yl)-propionic acid 3g (treatment) revealed mor- 52.8ꢃ2.8% of inhibition. Although all 1,2,4-oxadiazoles
phological changes in the anal papillae and the spiracular 3a—i inhibited the growth of F. moniliforme for 48 h while
valves of the siphon. Scanning electron micrographs on the 3a was the only one capable to keep this inhibitory effect for
body of the larvae exposed to Controls 1 and 2 revealed no 72 h (52.8ꢃ2.8%). This observation contradicts the expected
morphological changes in the breathing siphon, saddle, anal results as antimicrobials usually show a greater killing effect
papillae, and thorax or abdomen segment.
over time. As experimental errors are not expected to have
When the larvae were submitted to the 1,2,4-oxadiazoles occurred (the applied procedure was repeated and was simi-
3a—i at concentrations capable of killing 50% or 100% of lar for all compounds), one possible explanation is that F.
the larvae, there were alterations in the spiracular valves of moniliforme became resistant to compounds 3b to 3i and the
the siphon (Figs. 2B, D) and a loss of anal papillae (Fig. 2B).
first 48 h corresponded to microbial growth lag phase. For
The larvae use a breathing siphon to obtain oxygen and fungus F. lateritium the greatest inhibition (43.0ꢃ1.6%) was
must periodically come to the surface to do so. The tracheal found for acid 3e.
system is correlated with breathing siphon and morphologi-
Interestingly, 3i was not the most active of the series,
cal alterations in the spiracular valves of the siphon may be though it contains the NO2 group. Nitro compounds are well
responsible for the flooding of the tracheal system when the known for its well related toxicity in live organisms.59) Many
larvae submerge, thereby causing death. According to Corbet fungicides assign their inhibitory effect to the presence of
et al.,57) physical flooding of the tracheal system in mosquito this group.60) Our results provide an evidence that the toxicity
larvae can be promoted by oils and others surface films as of compounds 3a—i is not due to the presence of NO2 moi-
larvicidal.
ety. Therefore, these compounds can be used against these
The loss of anal papillae also leads the larva to collapse fungi without adverse effect provoked by the nitro group.
due to the lack of one of the major sites of salt regulation in
this species.58,59) No other paper published thus far has deter- Conclusion
mined morphological alterations using scanning electron mi-
In summary, we have succeeded in scaling-up the mi-
croscopy on the spiracular valves of the siphon in mosquito crowave-induced synthesis of a series of nine 3-(3-aryl-1,2,4-

August 2009
823
Fig. 3. Fungal Growth Inhibition from Compounds 3a—i
following the procedure reported earlier.61)
Synthesis. Experimental Procedure Method A:
oxadiazol-5-yl)propionic acids. A new synthetic method fol-
lowed by an eco-friendly purification strategy allows us to
get the target compounds in good yields after simple work-
up. All compounds presented strong larvicidal activity
against L4 larvae of Aedes aegypti. The death of larvae may
be provoked by alterations in spiracular valves of the breath
siphon and loss of anal papillae as revealed by SEM studies.
Finally the 1,2,4-oxadiazole-based propionic acids 3a—i in-
hibited the fungal growth of five different species of Fusar-
ium.
A
suitable ami-
doxime 1a—i (1.0 mmol) was allowed to react with succinic anhydride 2
(1.2 mmol) in a 10 ml sealed vessel followed by microwave irradiation in a
CEM-Discover microwave reactor.62,63) The crude product was dissolved in
ethyl acetate (20 ml) and then a concentrated solution of NaHCO3 (50 ml)
was added, the mixture was stirred in a 100 ml round botton flask overnight.
The aqueous layer was separated and then a concentrated solution of citric
acid was added until total precipitation of the desired compounds 3a—i. The
obtained product was dissolved in chloroform, dried over anhydrous Na2SO4
and re-crystallized in above mentioned solvent to afford pure compounds
3a—i.
Method B: A suitable amidoxime 1a—i (22.0 mmol) was allowed to react
with succinic anhydride 2 (22.2 mmol) for 10 min under solvent free condi-
tions in a domestic microwave oven.41,42) The crude product was dissolved in
ethyl acetate (30 ml), then a concentrated aqueous solution of NaHCO3
(35 ml) was added to it, and the mixture was stirred overnight. The aqueous
layer was separated followed by the addition of concentrated aqueous citric
acid solution until total precipitation of the desired compound 3a—i oc-
curred. The precipitate was dissolved in chloroform, dried over anhydrous
Na2SO4 and re-crystallized from above mentioned solvent to afford pure
compounds 3a—i.
Experimental
General Experimental Procedures All reagents were obtained from
commercial sources and used without further purification. Infrared spectra
were recorded on a Perkin-Elmer model 283 spectrometer in KBr discs. 1H-
NMR spectra were obtained with a Varian 300-MHz instrument using
tetramethylsilane (TMS) as an internal standard. 13C-NMR spectra were
recorded on a Varian 75-MHz spectrometer. Elemental analysis was per-
formed with a Carlo Erba instrument model E-1110. The microwave experi-
ments were conducted in a CEM-Discover microwave reactor or in a Sanyo
domestic microwave oven model EM-300B (220v/650W/2450 MHz).
The 3-(3-phenyl-1,3,4-oxadiazol-5-yl)-propionic acid 6 was synthesized
3-(3-Phenyl-1,2,4-oxadiazol-5-yl)-propionic Acid (3a): Colorless crystals
from chloroform, mp 119—120 °C (Method A: 73%; Method B: 68%); lit.42)

824
Vol. 57, No. 8
1
plate. Ethyleneglicol was used as negative control, and the plates were incu-
bated at 28 °C for 72 h. All experiments were performed in triplicate. Anti-
fungal activity was determined by the reduction of fungus growth diameter
(f) and the percentage of inhibition (I%) was calculated as follows:
mp 119—120 °C. (73.3%) IR and H-NMR spectra gave the same absorp-
tions as reported earlier.41)
3-(3-o-Tolyl-1,2,4-oxadiazol-5-yl)-propionic Acid (3b): Colorless crystals
from chloroform, mp 101—102 °C (Method A: 60%; Method B: 57%); lit.42)
mp 102 °C. (25.0%) IR and 1H-NMR spectra agreed with the proposed
structure.41)
φ of negative controlꢄφ of sample
I%ꢁ
ꢅ100
(1)
φ of negative control
3-(3-m-Tolyl-1,2,4-oxadiazol-5-yl)-propionic Acid (3c): Colorless crys-
tals from chloroform, mp 100—101 °C (Method A: 74%; Method B: 71%);
Acknowledgment The authors are grateful to the Brazilian National
Research Council (CNPq) and Pernambuco State’s Scientific and Research
Foundation (FACEPE, PRONEX 200-CNPq) for providing financial support,
to Prof. Nelson Lima for helpful discussions and Prof. Marcus M. Sá
(UFSC) for kindly providing the CEM microwave reactor (PRONEX2003-
CNPq/FAPESC). One of us (C.A.d. S.) is thankful to Institutional Program
of Scholarship for Scientific Initiation (PIBIC) for an undergraduate fellow-
ship.
lit.42) mp 101—102 °C. (76.4%) IR and H-NMR spectra gave the same ab-
1
sorptions as reported earlier.41)
3-(3-p-Tolyl-1,2,4-oxadiazol-5-yl)-propionic Acid (3d): Colorless crystals
from chloroform, mp 144—145 °C (Method A: 76%; Method B: 68.0%);
lit.41) mp 145 °C. (67.7%) IR and 1H-NMR spectra gave the same absorp-
tions as reported earlier.41)
3-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-propionic Acid (3e): Color-
less crystals from chloroform, mp 146—147 °C. (Method A: 78%; Method
B: 72.0%) IR (KBr) cmꢄ1: 2929, 1707. 1H-NMR (300 MHz, CDCl3) d: 3.00
(2H, t, Jꢁ7.2 Hz), 3.25 (2H, t, Jꢁ7.2 Hz), 7.52 (2H, m), 8.05 (2H, m). Anal.
Calcd for C11H9FN2O3: C, 55.93; N, 11.86; H, 3.84. Found: C, 55.80; N,
12.05; H, 3.66.
References and Notes
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3-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-propionic Acid (3f): Color-
less crystals from chloroform, mp 153—154 °C (Method A: 89%; Method
B: 84.0%); lit.41) mp 153—154 °C. (83.1%) IR and 1H-NMR spectra gave
the same absorptions as reported earlier.41)
3-[3-(4-Bromophenyl)-1,2,4-oxadiazol-5-yl]-propionic Acid (3g): Color-
less crystals from chloroform, mp 157 °C (Method A: 77%; Method B:
1
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1
B: 71.0%); lit.41) mp 138—139 °C. IR and H-NMR spectra gave the same
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