A Straightforward and High-Yielding Synthesis of 1,2,4-Oxadiazoles from Chiral N-Protected α-Amino Acids and Amidoximes in Acetone-Water: An Eco-Friendly Approach

Article abstract of DOI:10.1155/2019/8589325

A straightforward and high-yielding methodology for the synthesis of a high structural diversity of 1,2,4-oxadiazoles from different chiral N-protected α-amino acids and amidoximes under microwave (MW) irradiation is described herein. This greener approac

Full text of DOI:10.1155/2019/8589325

Hindawi
Journal of Chemistry
Volume 2019, Article ID 8589325, 9 pages
https://doi.org/10.1155/2019/8589325
Research Article
A Straightforward and High-Yielding Synthesis of
1
,2,4-Oxadiazoles from Chiral N-Protected α-Amino Acids and
Amidoximes in Acetone-Water: An Eco-Friendly Approach
1
1
1
1
2
Andr e´ C. Sauer, Lucas Wolf, Nat a´ lia Quoos, Mariele B. Rodrigues, Ant oˆ nio L. Braga ,
1
1
Oscar E. D. Rodrigues, and Luciano Dornelles
1
Departamento de Qu ´ı mica, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
Departamento de Qu ´ı mica, Universidade Federal de Santa Catarina, P.O Box 476, 88040-900 Florian o´ polis,
SC, Brazil
2
Correspondence should be addressed to Luciano Dornelles; ldornel@gmail.com
Received 27 September 2018; Accepted 25 November 2018; Published 16 January 2019
Academic Editor: Xinyong Liu
Copyright © 2019 Andr e´ C. Sauer et al. *is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A straightforward and high-yielding methodology for the synthesis of a high structural diversity of 1,2,4-oxadiazoles from
different chiral N-protected α-amino acids and amidoximes under microwave (MW) irradiation is described herein. *is greener
approach gives the desired products using acetone/water as solvent in very short reaction times.
N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU)
1
. Introduction
[
25, 26], and N,N′-diisopropylcarbodiimide (DIC)/HOBt
Among the various classes of heterocyclic compounds, 1,2,4-
oxadiazoles are noteworthy due to their usefulness in several
applications, including industrial materials, products for
agriculture (such as insecticides), and pharmaceutical and
medicinal products, representing the largest applicability for
these compounds [1–5]. *e 1,2,4-oxadiazole nucleus is found
in various synthetic drugs displaying a broad biological
spectrum of activities, including anti-inflammatory [6, 7],
antifungal [8, 9], antibiotic [10, 11], antioxidant [12–14],
anticonvulsant [15, 16], and anticancer [17, 18] properties.
Accordingly, several approaches are described in the
literature for the preparation of this class of compounds.
Generally, the synthesis of 1,2,4-oxadiazoles involves cou-
pling of an amidoxime with an activated carboxyl group,
yielding an O-acyl amidoxime followed by its dehydrative
cyclization. *e cyclization of O-acyl amidoximes has been
carried out by the use of additives such as N,N′-dicyclo-
hexylcarbodiimide (DCC) [19, 20], N-[3-(dimethylamino)
propyl]-N′-ethylcarbodiimide (EDC) [21, 22], N,N′-car-
bonyldiimidazole (CDI) [23, 24], O-(benzotriazol-1-yl)-
[27, 28].
Despite the diverse number of processes allowing the
preparation of the desired 1,2,4-oxadiazoles, there are some
drawbacks such as the use of high temperature, long reaction
times, and the use of hazardous solvents such as DMF,
diglyme, and 1,4-dioxane [19–21, 23, 24, 27].
In recent years, the use of water as a solvent has gained
increasing attention in the field of organic synthesis. Water
has many advantages over conventional organic solvents,
mainly due to its low cost and its nontoxic, nonpolluting,
and nonflammable characteristics [29, 30]. On the con-
trary, the use of microwave mediating organic trans-
formations has arisen as a very useful and effective tool for
synthetic protocols due to the strict reaction control, high
reaction rates, and energy savings [31, 32]. *e use of water
as the solvent in microwave transformations has been
described. Several reports have shown that, at higher
temperature and pressure, water behaves as a pseu-
doorganic solvent, as the dielectric constant decreases
substantially and an ionic product increases the solvating

2
Journal of Chemistry
power towards organic molecules to be similar to that of
acetone or ethanol [33–35].
with water. *e solvent (EtOH) was removed under reduced
pressure, and the aqueous layer extracted 2 times DCM. *e
Searching for an alternative protocol for the synthesis of
organic layer was dried over MgSO and concentrated under
4
1
,2,4-oxadiazoles, we decided to perform the preparation of
vacuum. *e crude product was purified by recrystallization
using chloroform-heptane or column chromatography over
silica gel using a mixture of hexane/EtOAc as the eluent to
afford pure aryl amidoximes.
these compounds under microwave irradiation, which from
a “green” point of view associated with solvent-free con-
ditions represents an environmentally benign alternative in
organic synthesis [34, 36, 37].
As part of our growing interest in using α-amino acids as
chiral building blocks in organic synthesis [21, 38–45] and in
connection with the increasing importance of the synthesis
of small libraries of compounds with programmed variations
of substituents, we describe herein an assay, an inexpensive
synthetic route for the preparation of a set of chiral N-
protected α-amino acids-derived 1,2,4-oxadiazoles under
microwave irradiation, as depicted in Scheme 1.
2
.2.2. General Procedure for the Synthesis of Chiral N-Protected
Amino Acid-Derived 1–5. *e L-amino acid (10.0 g) was
dissolved in H O (300 mL), and Na CO (2.0 equiv) and
2
2
3
NaHCO (1.0 equiv) were added at room temperature, with
3
stirring, to give a clear solution. Acetone (4.0 vol.) was
added, and the slightly turbid solution was cooled in an ice
°
water bath to 15–20 C. *en, ethyl chloroformate (1.5 equiv)
was added slowly, with stirring, and the reaction mixture
allowed to warm, to r.t. After stirring for an additional 3 h,
the organic layer was concentrated under vacuum. To the
aqueous phase was slowly added aqueous HCl, to give a pH
of 2. *e resulting mixture was extracted into EtOAc
2
. Experimental
2.1. General Information. All commercially available re-
agents and solvents were used without further purification
unless otherwise stated. *e experiments were performed in
MW Discover CEM using mode of operation with simul-
(
150 mL), and this was washed with H O (100 mL) and then
2
concentrated in vacuum to give the N-protected amino acid,
1
13
an oil.
taneous cooling. H NMR and C NMR spectra were
1
13
recorded at 200 ( H at 200.13 MHz and C at 50.32 MHz) or
1
13
4
00 MHz ( H at 400.13 MHz and C at 100.62 MHz), using a
2
.2.3. General Procedure for the Synthesis of 1,2,4-Oxadiazoles
Bruker Avance III HD-400 MHz or a Bruker Avance DPX-
(
1–5a–e) from Chiral N-Protected α-Amino Acids and Ami-
2
00 MHz spectrometers. Spectra were recorded in CDCl3
doximes under Microwave Irradiation. In a sealed tube in a
microwave reactor, 0.8 mmol of L-N-protected amino acid
solutions. Chemical shifts (δ) are reported in parts per
million, referenced to TMS. Samples were diluted in 1 :1 (v/
v) acetonitrile: water mixture, containing 0.1% of formic
acid. Analyses were performed by infusion mode in an
ACQUITY UPLC system from Waters Corp. (Milford, MA,
USA) equipped with sampler manager and quadrupole time-
of-flight (Q-Tof) MS detector. *e Q-Tof Xevo G2 mass
spectrometer was equipped with an electrospray ionization
source (ESI). Detections were performed in positive ion
(
1–5) and DCC (0.96 mmol, 0.199 g) were dissolved in ac-
etone (1.0 mL) and the mixture was magnetically stirred for
approximately 40 minutes to form the reactive intermediate.
*
en, 0.8 mmol of aryl amidoxime (a–e) was added, and the
mixture was homogenized. *e acetone was removed in
route evaporator without heating, and H O (1.0 mL) was
2
added to the mixture, which was subjected to microwave
°
irradiation at 100 W power, temperature of 115 C, during
+
mode (ESI ) and resolution mode. Optimized MS condi-
1
5 min. Soon after, the reaction crude was dissolved in ethyl
tions were capillary voltage 2.50 kV, cone voltage 15 V,
extractor cone 3.30 V, desolvation gas 300 L/h, cone gas 10 L/
acetate and washed with water. *e organic phase was dried
over magnesium sulfate, and the solvent was removed under
vacuum. *e residue was purified by column chromatog-
raphy on silica gel (hexane-ethyl acetate, 7 : 3) to afford pure
°
h, desolvation temperature 300 C, and source temperature
°
1
50 C. *e acquisition mass range was monitored from 50 to
000 Da. System control and data acquisition were per-
1
1
products (1–5a–e). Detailed experimental procedures, H
and 13C NMR spectra for all compounds, are available in the
supporting information, ESI (available here).
formed using MassLynx V 4.1 software. Column chroma-
tography was performed using Merck Silica Gel
230–400 mesh). *in-layer chromatography (TLC) was
(
performed using Merck Silica Gel GF254 (0.25 mm thick-
ness). For visualization, TLC plates were placed under ul-
traviolet light (254 nm) and then soaked in acidic vanillin,
followed by heating. *e product yields included in all tables
refer to isolated yields.
(
1) Ethyl((S)-1-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl)carbamate
2
0
°
(
1a). White solid; mp: 73-74 C; yield: 76%; [α] � −18 (c 0.2,
D
1
CH Cl ), lit. [19] −64 (c 0.5, CH Cl )]; H NMR (CDCl ,
2
2
2
2
3
4
00 MHz): δ � 8.06 (d, J � 8.1 Hz, 2H), 7.50–7.40 (m, 3H),
5
.58 (br s, 1H), 5.21 (br s, 1H), 4.16 (q, J � 7.0 Hz, 2H), 1.64
13
(
d, J � 7.1 Hz, 3H), and 1.25 (t, J � 7.0 Hz, 3H); C NMR
(
CDCl , 100 MHz): δ �179.78, 168.26, 155.63, 131.19,
2
2
.2. Synthesis of Compounds a–e, 1–5, and 1–5 (a–e)
3
1
28.75, 127.44, 126.54, 61.41, 44.61, 19.91, and 14.43; GCMS
+
.2.1. General Procedure for Preparation of Arylamidoximes
a–e. To a stirred solution of appropriate nitrile (a–e)
(t 11.700 min), MS (EI) m/z 261 [M ].
R
(
50 mmol) in EtOH (100 mL) was added hydroxylamine
(2) Ethyl((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)
carbamate (1b). Yellow solid; mp: 93-94 C; yield: 89%;
°
hydrochloride (2.2 equiv) and then Et N (2.3 equiv). *is
3
2
0
solution was stirred under reflux for 18 h and then diluted
[α] � −32 (c 0.2, CH Cl ), lit. [19] −67 (c 0.6, CH Cl )];
D
2
2
2
2

Journal of Chemistry
3
Ar
O
Ar
Microwave
irradiation
N
H
N
NH2
H
N
OEt
N
OEt
HO
+
O
N
O
OH
R
O
R
Scheme 1: Synthesis of 1,2,4-oxadiazoles.
1
H NMR (CDCl , 400 MHz): δ ꢀ 7.98 (d, J ꢀ 8.6 Hz, 2H),
(7) Ethyl((S)-2-phenyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl)
3
°
7
.43 (d, J ꢀ 8.6 Hz, 2H,), 5.59 (br s, 1H), 5.21 (br s, 1H),
.15 (q, J ꢀ 7.0 Hz, 2H), 1.64 (d, J ꢀ 7.2 Hz, 3H), and 1.25
carbamate (2b). Yellow solid; mp: 100–101 C; yield: 82%;
2
0
1
4
[α] ꢀ +37 (c 0.2, CH Cl ), lit. [19] −38 (c 0.55, CH Cl )]; H
D
2
2
2
2
1
3
(
t, J ꢀ 7.0 Hz, 3H); C NMR (CDCl , 100 MHz) δ ꢀ 180.03,
NMR (CDCl , 400 MHz): δ ꢀ 7.99 (d, J ꢀ 8.6 Hz, 2H), 7.44 (d,
3
3
1
1
67.45, 155.67, 137.40, 129.11, 128.74, 124.98, 61.47, 44.54,
J ꢀ 8.6 Hz, 2H), 7.32–7.20 (m, 3H), 7.12 (d, J ꢀ 6.4 Hz, 2H),
9.86, and 14.45; GCMS (t 12.550 min), MS (EI) m/z 295
5.61–5.31 (m, 2H), 4.14 (q, J ꢀ 7.1 Hz, 2H), 3.40–3.22 (m,
R
+
13
[M ].
2H), and 1.24 (t, J ꢀ 7.1 Hz, 3H); C NMR (CDCl ,
3
1
00 MHz) δ ꢀ 178.84, 166.44, 155.69, 137.46, 134.90, 129.21,
(
3) Ethyl((S)-1-(3-p-tolyl-1,2,4-oxadiazol-5-yl)ethyl)carbamate
129.13, 128.79, 128.73, 127.37, 124.98, 61.56, 49.76, 39.76,
and 14.43.
2
0
°
(
1c). White solid; mp: 103–105 C; yield: 83%; [α] ꢀ –24 (c
D
1
0
4
2
2
3
1
1
.2, CH Cl ), lit. [19] –13 (c 0.6, CH Cl )]; H NMR (CDCl ,
2 2 2 2 3
00 MHz): δ ꢀ 7.94 (d, J ꢀ 8.3 Hz, 2H), 7.25 (d, J ꢀ 8.0 Hz,
H), 5.69 (br s, 1H), 5.21 (br s, 1H), 4.15 (q, J ꢀ 7.0 Hz, 2H,),
.39 (s, 3H), 1.63 (d, J ꢀ 7.0 Hz, 3H), and 1.25 (t, J ꢀ 7.0 Hz,
(8) Ethyl((S)-1-(3-p-tolyl-1,2,4-oxadiazol-5-yl)-2-phenylethyl)
°
carbamate (2c). White solid; mp: 95–97 C; yield: 89%.
2
0
1
[α] ꢀ −21 (c 0.2, CH Cl ), lit. [19] −32 (c 0.65, CH Cl )]; H
D
2
2
2
2
1
3
H); C NMR (CDCl , 100 MHz) δ ꢀ 179.60, 168.23, 155.69,
NMR (CDCl , 400 MHz): δ ꢀ 7.97 (d, J ꢀ 8.1 Hz, 2H),
3
3
41.53, 129.46, 127.36, 123.68, 61.39, 44.57, 21.44, 19.89, and
4.44; GCMS (t 12.292 min), MS (EI) m/z 275 [M ].
7.32–7.21 (m, 5H), 7.15 (d, J ꢀ 6.4 Hz, 2H), 5.70 (d, J ꢀ 8.3 Hz,
1H), 5.46 (br s, 1H), 4.14 (q, J ꢀ 7.1 Hz, 2H), 3.40–3.24 (m,
+
R
1
3
2
H), 2.41 (s, 3H), and 1.24 (t, J ꢀ 7.1 Hz, 3H); C NMR
(
4) Ethyl((S)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)
(CDCl , 100 MHz) δ ꢀ 178.46, 168.23, 155.82, 141.61, 135.16,
3
°
ethyl)carbamate (1d). White solid; mp: 121–122 C; yield:
129.53, 129.28, 128.68, 127.44, 127.28, 123.70, 61.48, 49.80,
39.75, 21.51, and 14.47.
2
0
8
9%; [α] ꢀ −21 (c 0.2, CH Cl ), lit. [19] −34 (c 0.5,
D
2
2
1
CH Cl )]; H NMR (CDCl , 400 MHz): δ ꢀ 7.98 (d,
2
2
3
J ꢀ 8.8 Hz, 2H), 6.95 (d, J ꢀ 8.8 Hz, 2H), 5.67 (br s, 1H), 5.18
(9) Ethyl((S)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-2-
°
(
br s, 1H), 4.14 (q, J ꢀ 7.2 Hz, 2H), 3.83 (s, 3H), 1.62 (d,
phenylethyl)carbamate (2d). White solid; mp: 92–94 C; yield:
13
20
J ꢀ 7.0 Hz, 3H), and 1.24 (t, J ꢀ 7.2 Hz, 3H). C NMR (CDCl ,
92%; [α] ꢀ −14 (c 0.2, CH Cl ), lit. [19] −60 (c 0.7,
3
D
2
2
1
1
1
1
00 MHz) δ ꢀ 179.47, 167.92, 161.96, 155.67, 129.04, 118.94,
CH Cl )]; H NMR (CDCl , 400 MHz): δ ꢀ 8.00 (d,
2
2
3
14.19, 61.36, 55.27, 44.55, 19.89, and 14.44. GCMS (t
J ꢀ 8.8 Hz, 2H), 7.32–7.10 (m, 5H), 6.98 (d, J ꢀ 8.8 Hz, 2H),
R
+
3.025 min), MS (EI) m/z 291 [M ].
5.44 (br s, 2H), 4.14 (q, J ꢀ 7.0 Hz, 2H), 3.86 (s, 3H),
1
3
3
.38–3.24 (m, 2H), and 1.24 (t, J ꢀ 7.0 Hz, 3H); C NMR
(
5) Ethyl((S)-1-(3-(4-nitrophenyl)-1,2,4-oxadiazol-5-yl)ethyl)
(CDCl , 100 MHz) δ ꢀ 178.21, 167.92, 162.03, 155.68, 135.01,
3
°
carbamate (1e). Yellow solid; m.p.: 105–106 C; yield: 76%;
129.26, 129.11, 128.68, 127.30, 118.93, 114.23, 61.49, 55.32,
49.73, 39.86, and 14.43.
2
0
1
[
α] ꢀ −18 (c 0.2, CH Cl ), lit. [19] −38 (c 0.7, CH Cl )]; H
D
2
2
2
2
NMR (CDCl , 400 MHz): δ ꢀ 8.28 (d, J ꢀ 8.8 Hz, 2H), 8.21 (d,
3
J ꢀ 9.0 Hz, 2H), 5.56 (br s, 1H), 5.21 (br s, 1H), 4.15 (q,
(10) Ethyl((S)-1-(3-(4-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-
°
J ꢀ 7.2 Hz, 2H), 1.66 (d, J ꢀ 7.0 Hz, 3H), and 1.24 (t,
phenylethyl)carbamate (2e). Yellow solid; mp: 103–105 C;
1
3
20
J ꢀ 7.2 Hz, 3H); C NMR (CDCl , 100 MHz) δ ꢀ 180.80,
yield: 71%; [α] ꢀ −76 (c 0.2, CH Cl ), lit. [19] −2 (c 0.5,
3
D
2
2
1
1
4
66.74, 157.74, 155.62, 149.52, 132.39, 128.37, 123.93, 61.50,
4.66, 19.63, and 14.38.
CH Cl )]; H NMR (CDCl , 400 MHz): δ ꢀ 8.32 (d,
2
2
3
J ꢀ 9.0 Hz, 2H), 8.24 (d, J ꢀ 8.8 Hz, 2H), 7.35–7.20 (m, 3H),
7
.14 (d, J ꢀ 6.4 Hz, 2H), 5.44 (br s, 1H), 5.36 (br s, 1H), 4.15
(
6) Ethyl((S)-2-phenyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl)
(q, J ꢀ 7.0 Hz, 2H), 3.41–3.28 (m, 2H), and 1.25 (t, J ꢀ 7.0 Hz,
1
3
°
carbamate (2a). White solid; mp: 96–98 C; yield: 84%;
3H); C NMR (CDCl , 100 MHz) δ ꢀ 179.59, 166.76, 155.52,
3
2
0
1
[
α] ꢀ −20 (c 0.2, CH Cl ), lit. [19] +2 (c 0.6, CH Cl )]; H
149.66, 134.77, 132.35, 129.13, 128.75, 128.43, 127.44, 123.95,
61.59, 49.94, 39.81, and 14.34.
D
2
2
2
2
NMR (CDCl , 400 MHz): δ ꢀ 8.08 (d, J ꢀ 7.6 Hz, 2H),
3
7
2
.55–7.40 (m, 3H), 7.33–7.22 (m, 3H), 7.14 (d, J ꢀ 6.6 Hz,
H), 5.64 (d, J ꢀ 7.1 Hz, 1H), 5.47 (br s, 1H), 4.14 (q,
(11) Ethyl((S)-3-methyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)butyl)
2
0
J ꢀ 7.1 Hz, 2H), 3.42–3.26 (m, 2H), and 1.24 (t, J ꢀ 7.1 Hz,
carbamate (3a). Oil; yield: 81%; [α] ꢀ −30 (c 0.2, CH Cl ),
D
2
2
1
3
1
3
1
1
H); C NMR (CDCl , 100 MHz): δ ꢀ178.64, 168.24,
lit. [19] −46 (c 0.65, CH Cl )]; H NMR (CDCl , 400 MHz):
3
2
2
3
55.80, 135.07, 131.29, 129.26, 128.82, 128.71, 127.50, 127.32,
26.50, 61.52, 49.80, 39.76, and 14.47.
δ ꢀ 8.05 (d, J ꢀ 7.8 Hz, 2H), 7.50–7.40 (m, 3H), 5.70 (br s,
1H), 5.19 (br s, 1H), 4.14 (q, J ꢀ 7.1 Hz, 2H), 1.85–1.70 (m,

4
3
Journal of Chemistry
H), 1.22 (t, J � 7.1 Hz, 3H), and 0.95 (d, J � 6.2 Hz, 6H); 13C
(17) Ethyl((R)-2-(benzylthio)-1-(3-(4-chlorophenyl)-1,2,4-
oxadiazol-5-yl)ethyl) carbamate (4b). White solid; mp:
NMR (CDCl , 100 MHz) δ � 179.84, 168.21, 156.00, 131.15,
3
2
0
°
1
28.72, 127.44, 126.58, 61.36, 47.13, 42.92, 24.57, 22.49,
94–96 C; yield: 55%; [α] � −48 (c 0.2, CH Cl ), lit. [19] −29
D
2
2
1
2
1.76, and 14.42.
(c 0.6, CH Cl )]; H NMR (CDCl , 400 MHz): δ � 8.01 (d,
2
2
3
J � 8.0 Hz, 2H), 7.45 (d, J � 8.0 Hz, 2H), 7.34–7.23 (m, 5H),
(
12) Ethyl((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-3-
5.75 (br s, 1H), 5.33 (br s, 1H), 4.18 (q, J � 7.0 Hz, 2H), 3.69
2
0
methylbutyl)carbamate (3b). Oil; yield: 80%; [α] � −28
(s, 2H), 3.03 (d, J � 5.6 Hz, 2H), and 1.28 (t, J � 7.0 Hz, 3H);
D
1
13
(
(
c 0.2, CH Cl ), lit. [19] −41 (c 0.6, CH Cl )]; H NMR
C NMR (CDCl , 100 MHz): δ �178.19, 167.58, 155.69,
2
2
2
2
3
CDCl , 400 MHz): δ � 7.96 (d, J � 8.8 Hz, 2H), 7.39 (d,
137.52, 137.20, 129.15, 128.88, 128.81, 128.63, 127.35, 124.93,
3
J � 8.3 Hz, 2H), 5.65 (d, J � 8.8 Hz, 1H), 5.17 (br s, 1H), 4.13
61.69, 48.41, 36.54, and 34.76, 14.46. HRMS-ESI(+) m/z
+
(
q, J � 7.2 Hz, 2H), 1.80–1.65 (m, 3H), 1.22 (t, J � 7.2 Hz,
calculated for C H ClN O S [(M + Na) ]: 440.0812; found:
2
0
20
3 3
1
3
3
1
1
1
H), and 0.95 (d, J � 6.4 Hz, 6H); C NMR (CDCl ,
440.0812.
3
00 MHz) δ � 180.04, 167.40, 155.96, 137.30, 129.04,
28.73, 125.06, 61.41, 47.10, 42.86, 24.57, 22.50, 21.73, and
4.42.
(18) Ethyl((R)-2-(benzylthio)-1-(3-p-tolyl-1,2,4-oxadiazol-5-
°
yl)ethyl)carbamate (4c). White solid; mp: 63–65 C; yield:
2
0
6
0%; [α] � −65 (c 0.2, CH Cl ), lit. [19] −34 (c 0.5,
D
2
2
1
(
13) Ethyl((S)-3-methyl-1-(3-p-tolyl-1,2,4-oxadiazol-5-yl)bu-
CH Cl )]; H NMR (CDCl , 400 MHz): δ � 7.98 (d,
2
2
3
2
0
tyl)carbamate (3c). Oil; yield: 80%; [α] � −27 (c 0.2,
J � 8.1 Hz, 2H), 7.35–7.19 (m, 7H), 5.76 (br s, 1H), 5.35 (br s,
D
1
CH Cl ), lit. [19] −39 (c 0.7, CH Cl )]; H NMR (CDCl ,
1H), 4.19 (q, J � 7.2 Hz, 2H), 3.69 (s, 2H), 3.03 (d, J � 5.6 Hz,
2
2
2
2
3
13
4
2
2
0
00 MHz): δ � 7.95 (d, J � 8.3 Hz, 2H), 7.26 (d, J � 8.1 Hz,
H), 5.50 (br s, 1H), 5.19 (br s, 1H), 4.16 (q, J � 6.8 Hz, 2H),
.39 (s, 3H), 1.80–1.60 (m, 3H), 1.25 (t, J � 6.8 Hz, 3H), and
2H), 2.42 (s, 3H), and 1.29 (t, J � 7.2 Hz, 3H); C NMR
(CDCl , 100 MHz): δ �177.73, 168.40, 155.76, 141.69,
3
137.26, 129.53, 128.92, 128.62, 127.45, 127.31, 123.58, 61.66,
13
.98 (d, J � 6.2 Hz, 6H); C NMR (CDCl , 100 MHz)
48.35, 36.49, 34.82, 21.51, and 14.47. HRMS-ESI(+) m/z
3
+
δ � 179.58, 168.24, 155.91, 141.49, 129.45, 127.39, 123.75,
calculated for C H N O S [(M + Na) ]: 420.1358; found:
2
1
23 3 3
6
1.40, 47.12, 43.10, 24.60, 22.51, 21.82, 21.45, and 14.43.
420.1345.
(
14) Ethyl((S)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-
(19) Ethyl((R)-2-(benzylthio)-1-(3-(4-methoxyphenyl)-1,2,4-
2
0
3
-methylbutyl)carbamate (3d). Oil; yield: 88%; [α] � −30
oxadiazol-5-yl)ethyl) carbamate (4d). White solid; mp:
D
1
20
°
(
(
c 0.2, CH Cl ), lit. [19] −42 (c 0.6, CH Cl )]; H NMR
107–109 C; yield: 70%; [α] � −10 (c 0.2, CH Cl ), lit. [19]
2
2
2
2
D
2
2
1
CDCl , 400 MHz): δ � 7.95 (d, J � 8.3 Hz, 2H), 6.91 (d,
−22 (c 0.7, CH Cl )]; H NMR (CDCl , 400 MHz): δ � 8.01
3
2
2
3
J � 8.1 Hz, 2H), 5.76 (br s, 1H), 5.14 (br s, 1H), 4.11 (q,
(d, J � 8.8 Hz, 2H), 7.34–7.22 (m, 5H), 6.98 (d, J � 9.0 Hz,
2H), 5.76 (br s, 1H), 5.33 (br s, 1H), 4.17 (q, J � 7.2 Hz, 2H),
3.85 (s, 3H), 3.68 (s, 2H), 3.02 (d, J � 5.6 Hz, 2H), and 1.27
J � 6.8 Hz, 2H), 3.78 (s, 3H), 1.80–1.65 (m, 3H), 1.19 (t,
1
3
J � 6.8 Hz, 3H), and 0.93 (d, J � 6.2 Hz, 6H); C NMR
1
3
(
1
2
CDCl , 100 MHz) δ � 179.47, 167.88, 161.94, 155.88,
(t, J � 7.2 Hz, 3H); C NMR (CDCl , 100 MHz): δ �177.59,
3
3
29.00, 119.08, 114.14, 61.26, 55.17, 47.14, 42.92, 24.56,
2.43, 21.73, and 14.36.
168.07, 162.07, 155.75, 137.27, 129.13, 128.91, 128.61,
127.30, 118.83, 114.26, 61.63, 55.33, 48.32, 36.47, 34.80, and
1
4.47. HRMS-ESI(+) m/z calculated for C H N O S
21 23 3 4
+
(
15) Ethyl((S)-3-methyl-1-(3-(4-nitrophenyl)-1,2,4-oxadiazol-
[(M + Na) ]: 436.1307; found: 436.1283.
2
0
5
-yl)butyl)carbamate (3e). Oil; yield: 75%; [α] � −57 (c 0.2,
D
1
CH Cl ), lit. [19] −32 (c 0.5, CH Cl )]; H NMR (CDCl ,
(20) Ethyl((R)-2-(benzylthio)-1-(3-(4-nitrophenyl)-1,2,4-oxa-
2
2
2
2
3
2
0
4
00 MHz): δ � 8.28 (d, J � 8.8 Hz, 2H), 8.22 (d, J � 9.0 Hz,
diazol-5-yl)ethyl)carbamate (4e). Oil; yield: 63%; [α] � −14
D
1
2
H), 5.51 (d, J � 8.3 Hz, 1H), 5.19 (br s, 1H), 4.14 (q,
(c 0.2, CH Cl ), lit. [19] −14 (c 0.4, CH Cl )]; H NMR
2
2
2
2
J � 7.2 Hz, 2H), 1.85–1.69 (m, 3H), 1.23 (t, J � 7.2 Hz, 3H),
(CDCl , 400 MHz): δ � 8.29 (d, J � 8.8 Hz, 2H), 8.23 (d,
3
13
and 0.98 (d, J � 6.2 Hz, 6H); C NMR (CDCl , 100 MHz)
J � 8.6 Hz, 2H), 7.35–7.20 (m, 5H), 5.76 (d, J � 7.1 Hz, 1H),
5.33 (br s, 1H), 4.17 (q, J � 7.2 Hz, 2H), 3.72 (s, 2H), 3.06 (d,
3
δ � 180.77, 166.70, 155.92, 149.44, 132.44, 128.39, 123.95,
1
3
6
1.52, 47.19, 42.78, 24.61, 22.49, 21.71, and 14.40.
J � 6.4 Hz, 2H), and 1.27 (t, J � 7.2 Hz, 3H); C NMR
(
CDCl , 100 MHz) δ � 178.95, 166.85, 155.68, 149.59, 137.15,
3
(
16) Ethyl((R)-2-(benzylthio)-1-(3-phenyl-1,2,4-oxadiazol-5-
132.24, 128.84, 128.64, 128.45, 127.37, 123.99, 61.75, 48.49,
°
yl)ethyl)carbamate (4a). White solid; mp: 91–93 C; yield:
36.60, 34.67, and 14.43. HRMS-ESI(+) m/z calculated for
2
0
+
6
0%; [α] � −12 (c 0.2, CH Cl ), lit. [19] −25 (c 0.6,
C H N O S [(M + Na) ]: 451.1052; found: 451.1033.
D
2
2
21 23 3 4
1
CH Cl )]; H NMR (CDCl , 400 MHz): δ � 8.10 (d,
2
2
3
J � 8.3 Hz, 2H), 7.55–7.43 (m, 3H), 7.35–7.22 (m, 5H), 5.72
(21) Ethyl((S)-3-(methylthio)-1-(3-phenyl-1,2,4-oxadiazol-5-
°
(
br s, 1H), 5.36 (br s, 1H), 4.19 (q, J � 7.2 Hz, 2H), 3.70 (s,
yl)propyl)carbamate (5a). White solid; mp: 60–62 C; yield:
2
0
2
H), 3.05 (d, J � 5.9 Hz, 2H), and 1.29 (t, J � 7.2 Hz, 3H);
84%; [α] � −28 (c 0.2, CH Cl ), lit. [19] −34 (c 0.65,
D
2
2
1
3
1
C NMR (CDCl , 100 MHz): δ �177.92, 168.40, 155.75,
CH Cl )]; H NMR (CDCl , 400 MHz): δ � 8.02 (d,
3
2
2
3
1
1
37.23, 131.35, 128.92, 128.83, 128.65, 127.53, 127.34,
J � 7.8 Hz, 2H), 7.45–7.36 (m, 3H), 5.92 (br s, 1H), 5.27 (br s,
26.40, 61.69, 48.35, 36.51, 34.82, and 14.47. HRMS-ESI(+)
1H), 4.12 (q, J � 7.1 Hz, 2H), 2.58 (t, J � 7.2 Hz, 2H), 2.32–
+
13
m/z calculated for C H N O S [(M + Na) ]: 406.1201;
2.17 (m, 2H), 2.06 (s, 3H), and 1.21 (t, J � 7.1 Hz, 3H);
C
2
0
21
3
3
found: 406.1199.
NMR (CDCl , 100 MHz) δ � 178.87, 168.23, 155.99, 131.24,
3

Journal of Chemistry
5
1
1
28.76, 127.42, 126.43, 61.50, 47.91, 32.07, 29.74, 15.31, and
4.43.
temperature, reaction time, and solvents in order to de-
termine the optimal reaction conditions (Table 1).
As described in Table 1 (Entries 9–11), the use of
less polar solvents such as toluene, THF, and 1,4-dioxane
are clearly less suitable for microwave-assisted synthe-
sis, because their dielectric constants are substantially
lower [37, 46]. *e use of a small amount of ionic liquid
(
(
22) Ethyl((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-3-
methylthio)propyl) carbamate (5b). Oil; yield: 91%;
2
0
[
α] � −33 (c 0.2, CH Cl ), lit. [19] −44 (c 0.55, CH Cl )];
D
2
2
2
2
1
H NMR (CDCl , 400 MHz): δ � 7.92 (d, J � 8.6 Hz, 2H),
3
7
.37 (d, J � 8.6 Hz, 2H), 5.88 (d, J � 8.6 Hz, 1H), 5.24 (br s,
H), 4.11 (q, J � 7.2 Hz, 2H), 2.58 (t, J � 7.0 Hz, 2H),
.32–2.15 (m, 2H), 2.05 (s, 3H), and 1.19 (t, J � 7.2 Hz, 3H);
(BMIMBF ) as a “doping agent” for microwave heating of
4
1
2
the nonpolar solvents (THF, 1,4-dioxane, and toluene)
allowed heating above boiling points in sealed vessels
[37, 47–49], with the formation of the products in
moderate to good yields (Table 1, Entries 2, 4, and 8).
Since these less polar solvents poorly absorb MW irra-
diation due to their lower loss tangent, the use of ionic
liquid as a doping agent becomes essential to achieve high
1
3
C NMR (CDCl , 100 MHz) δ � 178.94, 167.24, 155.74,
3
1
1
37.18, 128.87, 128.53, 124.80, 61.35, 47.79, 32.88, 29.61,
5.13, and 14.22.
(
23) Ethyl((S)-1-(3-p-tolyl-1,2,4-oxadiazol-5-yl)-3-(methyl-
20
°
thio)propyl)carbamate (5c). Oil; yield: 88%; [α] � −29 (c 0.2,
temperature (160 C).
D
1
CH Cl ), lit. [19] −48 (c 0.65, CH Cl )]; H NMR (CDCl ,
*e best result was obtained using DCC which furnished
the desired product in the best yield. As observed in Table 1,
the best solvent for this reaction was the mixture acetone/
water, affording the respective compound (5b) in 91% yield
in 15 min (Table 1, Entry 13). Increasing the reaction
2
2
2
2
3
4
00 MHz): δ � 7.89 (d, J � 8.1 Hz, 2H), 7.20 (d, J � 7.8 Hz, 2H),
5
.97 (br s, 1H), 5.24 (br s, 1H), 4.12 (q, J � 7.0 Hz, 2H), 2.57 (t,
J � 7.0 Hz, 2H), 2.34 (s, 3H), 2.32–2.11 (m, 2H), 2.05 (s, 3H), and
1
3
1
.20 (t, J � 7.0 Hz, 3H); C NMR (CDCl , 100 MHz) δ � 178.72,
3
°
1
68.24, 156.04, 141.58, 129.49, 127.38, 123.65, 61.50, 47.93, 33.11,
9.78, 21.45, 15.32, and 14.46.
temperature from 115 to 160 C resulted in a decrease in yield
2
to 50% (Entry 6). *e influence of coupling agents was also
studied in order to determine the most efficient promoter for
this transformation. *us, a series of coupling agents in-
cluding CDI, DCC, DIC, and TBTU was used to afford the
1,2,4-oxadiazole.
(
24) Ethyl((S)-1-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-
°
3
-(methylthio)propyl) carbamate (5d). mp: 105–106 C; yield:
2
0
8
1%; [α] � −29 (c 0.2, CH Cl ), lit. [19] −47 (c 0.4,
D
2
2
1
CH Cl )];
H
NMR (CDCl , 400 MHz): δ � 7.96
*e extensive reduction in the reaction time in the
microwave-assisted conditions along with a very simple
work-up, better yield as well as the use of acetone/water as
solvent when compared with conventional heating [19],
makes more benign protocol to the environment in the
process synthesis of the compound (5b).
With the optimized reaction conditions determined, we
extended the protocol to a broader range of protected amino
acids (1–5) as shown in Figure 1 and to a set of aryl ami-
doximes (a–e), in the presence of DCC, using microwave
irradiation (Table 2). *e 1,2,4-oxadiazoles were obtained in
moderate to good yields (62–92%).
2
2
3
(
d, J � 8.8 Hz, 2H), 6.93 (d, J � 8.8 Hz, 2H), 5.82 (br s, 1H),
5
.25 (br s, 1H), 4.13 (q, J � 7.2 Hz, 2H), 3.81 (s, 3H), 2.59
(
(
t, J � 7.0 Hz, 2H), 2.34–2.15 (m, 2H), 2.07 (s, 3H), and 1.22
1
3
t, J � 7.2 Hz, 3H); C NMR (CDCl , 100 MHz): δ �178.45,
3
1
4
67.95, 162.03, 155.85, 129.04, 118.92, 114.23, 61.49, 55.27,
7.98, 33.27, 29.77, 15.32, and 14.40.
(
25) Ethyl((S)-3-(methylthio)-1-(3-(4-nitrophenyl)-1,2,4-oxadia-
2
0
zol-5-yl)propyl)carbamate (5e). Oil; yield: 70%; [α] � −32 (c
D
1
0
.2, CH Cl ), lit. [19] −18 (c 0.45, CH Cl )]; H NMR
2
2
2
2
(
CDCl , 400 MHz): δ � 8.26 (d, J � 8.8 Hz, 2H), 8.19 (d,
3
J � 8.8 Hz, 2H), 5.87 (d, J � 8.6 Hz, 1H), 5.28 (br s, 1H), 4.11
An important point to note is the primary activation of
the carboxyl in the amino acid by DCC and the subsequent
aryl amidoxime addition in the reaction medium. *is se-
quence of reagents is an important factor, especially because
the amidoxime can also react with DCC, before the acti-
vation of the carboxyl in the amino acid residue, resulting in
undesired byproducts.
(
q, J � 7.0 Hz, 2H), 2.61 (t, J � 7.0 Hz, 2H), 2.37–2.20 (m, 2H),
1
3
2
1
1
.08 (s, 3H), and 1.21 (t, J � 7.0 Hz, 3H); C NMR (CDCl ,
3
00 MHz) δ � 179.88, 166.74, 155.86, 149.51, 132.31, 128.38,
23.94, 61.62, 48.01, 32.92, 29.79, 15.33, and 14.38.
3
. Results and Discussion
*
e process of formation of the intermediate I was
*
e synthetic approach to give the 1,2,4-oxadiazoles was
carried for approximately 40 minutes, at room temperature,
with the use of acetone as the solvent, which is also con-
sidered a solvent with green features [50]. *e solvent was
subsequently removed by evaporation under reduced
pressure, without heating. After this, water was added to the
formed intermediate I, and then, the reaction mixture was
subjected to microwave irradiation (Table 2).
performed, starting from the protected amino acids shown
in Figure 1.
*
e L-amino acids alanine (1), phenylalanine (2), leucine
(
3), S-benzyl-L-cysteine (4), and methionine (5) were
conveniently protected by treatment with ethyl chlor-
oformate in an aqueous sodium bicarbonate solution [46].
In order to determine the optimal reaction conditions
for the synthesis of 1,2,4-oxadiazole derivatives, we carried
out the reaction employing the protected amino acid me-
thionine (5) and aryl amidoxime (b) as a model substrate. In
this set of experiments, we studied the effect of the
*e electronic effect of the substituents at the aryl
amidoximes was studied. Amidoximes containing electron-
donating groups such as methyl and methoxy and electron-
withdrawing groups such as chloro and nitro were prepared
(Table 2, compounds 1–5c, d).

6
Journal of Chemistry
SCH Ph
2
O
O
CH3
COOH
O
O
CH CH O
N
H
CH CH O
N
H
COOH
3
2
3
2
CH(CH3)2
COOH
O
1
4
5
CH SCH
CH CH O
N
H
2
3
CH Ph
3
2
2
CH CH O
N
H
COOH
CH CH O
N
H
COOH
3
2
3
3
2
2
Figure 1: Chiral protected amino acids used for the synthesis of 1,2,4-oxadiazoles. “Figure 1 is reproduced from [45] (under the Creative
Commons Attribution License/public domain)”.
Table 1: Optimization of the reaction conditions for the synthesis of 1,2,4-oxadiazoles 5b by microwave irradiation.
Cl
O
Cl
H
N
OEt
DCC, solvent
HO
NH2
OH
N
+
temperature, time
N
H
N
MeS
O
OEt
N
O
5
b
MeS
O
5b
Yield (%)4
°
Entry
T ( C)
Solvent
Time (min)
1
2
3
4
5
6
7
8
9
160
160
160
160
160
160
115
115
115
115
115
115
115
115
80
—
10
10
10
10
10
10
15
15
15
15
15
10
15
20
15
15
15
20
37
35
61
86
52
50
78
76
25
50
56
79
91
76
42
52
77
80
61
1
Toluene
1
EtOH
THF
1
1
1,4-Dioxane
2
Acetone/H
2
O
1
THF
2
1,4-Dioxane
3
Toluene
3
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
THF
3
1,4-Dioxane
2
2
Acetone/H O
2
2
Acetone/H O
2
Acetone/H
2
O
1
THF
1
80
1,4-Dioxane
2
80
Acetone/H O
2
2
2
80
Acetone/H
Acetone/H
2
O
O
80
2
30
1
2
3
4
Mixture of 1.0 mL of solvent and 0.5 mL of BMIMBF
products.
4
. 1.0 mL of acetone and 1.0 mL of water as solvent. 1.0 mL of solvent. Yields for isolated pure
In this way, the presence of strong electron-withdrawing
In terms of amino acids, the nature of the side chain
does not play a signižcant role in terms of conversion to
the desired heterocycle, since the results obtained with
lipophilic and sulfurated side chains were quite similar. An
exception was observed for the derivatives of S-benzyl-L-
cysteine (Table 2, compounds 4a–e) probably due to the
formation of by-products. Despite the small di¡erence in
the reactivity of the aryl amidoximes, all the 1,2,4-oxa-
diazoles were obtained in moderate to good yields for all
groups such as nitro (NO ) yield slightly lower products
2
compared with donating or soft electron-withdrawing
groups (Table 2, compounds 1–5e and 1–5a–d, re-
spectively). ›is result could be explained by the reduced
nucleophilicity in aryl amidoximes when this group is di-
rectly attached. Electron-donating and soft withdrawing
groups allowed the preparation of the respective 1,2,4-
oxadiazoles with similar eœciency.

Journal of Chemistry
7
Table 2: Synthesis of α-amino acid-derived 1,2,4-oxadiazoles under microwave irradiation.
O
H
N
Ar
NH2
O
H
N
OEt
a
Ar
N
HO
OEt
+
O
N
R
O
OH
NH2
R
O
1
–5
a–e
I
b
(
a) DCC, acetone, 40 min rt. The solvent was
removed in rotary evaporator without heating.
Ar
(
b) H O, MW, 100 W, 15 min, 115 °C.
2
N
H
N
N
OEt
O
R
–5 a–e
O
1
Compounds
Yield (%) 1,2
Ar
N
Ar:
Ph 1a = 76%
H
N
4-ClC H 1b = 89%
6
4
N
OEt
4-MeC H 1c = 83%
6 4
O
4
-MeOC H 1d = 89%
6 4
Me
O
4-NO C H 1e = 76%
2 6 4
Ar
N
Ar:
Ph 2a = 84%
4-ClC H 2b = 82%
N
N
H
N
6
4
OEt
4
4
-MeC H 2c = 89%
O
6 4
-MeOC H 2d = 92%
6
4
Bn
O
O
4-NO C H 2e = 71%
2 6 4
Ar
Ar:
Ph 3a = 81%
4-ClC H 3b = 80%
H
N
6
4
N
OEt
4
4
-MeC H 3c = 80%
6 4
O
-MeOC H 3d = 88%
6
4
iBu
4-NO C H 3e = 75%
2
6
4
Ar
Ar:
N
Ph 4a = 65%
H
N
4-ClC H 4b = 65%
6
4
N
OEt
4
4
-MeC H 4c = 62%
O
6 4
-MeOC H 4d = 70%
6
4
O
4-NO C H 4e = 63%
2 6 4
BnS
Ar
Ar:
Ph 5a = 84%
N
H
4-ClC H 5b = 91%
N
6
4
N
OEt
4
4
-MeC H 5c = 88%
O
6 4
-MeOC H 5d = 81%
6
4
MeS
O
4-NO C H 5e = 70%
2 6 4
1
Reactions performed in the presence of aryl amidoxime (a–e) (0.8 mmol), N-protected amino acid (1–5) (0.8 mmol), 1.2 equiv DCC, acetone and water as
2
°
solvent (1.0 mL), 115 C, 15 min, MW irradiation (power of 100 W). Yields for isolated pure products.

8
Journal of Chemistry
the amino acids studied, showing the versatility of the
methodology.
[6] M. Farooqui, R. Bora, and C. R. Patil, “Synthesis, analgesic and
anti-inflammatory activities of novel 3-(4-acetamido-benzyl)-
5-substituted-1,2,4-oxadiazoles,” European Journal of Me-
dicinal Chemistry, vol. 44, no. 2, pp. 794–799, 2009.
4
. Conclusions
[
7] M. Gobec, T. Toma ˇs i cˇ , T. Markovi cˇ , I. Mlinari ˇc -Ra ˇs ˇc an,
ˇ
M. S. Dolenc, and Z. Jakopin, “Antioxidant and anti-
In conclusion, we developed a straightforward, efficient,
and greener procedure for the high structural diversity
of 1,2,4-oxadiazoles under microwave irradiation using
acetone/water as the solvent in very short reaction times.
Moreover, the method using microwave irradiation and
water as the solvent is more efficient and greener, allowing
the synthesis of 1,2,4-oxadiazoles by carrying out all re-
actions with an easy work-up, in short reaction times and
better yields, when compared to conventional heating [19].
Although a limited number of substituents have been
presented, this method can be extended to other substrates,
since amino acids are inexpensive and easily available
starting materials. *e reaction conditions proved to be
compatible with the carbamate protective group.
inflammatory properties of 1,2,4-oxadiazole analogs of
resveratrol,” Chemico-Biological Interactions, vol. 240,
pp. 200–207, 2015.
[
8] I. Kumita and A. Niwa, “Synthesis of antifungal 5-anilino-1, 2,
4-oxadiazoles and 5-anilino-1, 2, 4-thiadiazoles, and their
inhibitory effects on fungal sterol biosynthesis,” Journal of
Pesticide Science, vol. 26, no. 1, pp. 60–66, 2001.
[9] J. N. Sangshetti and D. B. Shinde, “Synthesis of some novel 3-
(1-(1-substitutedpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-
substituted phenyl-1,2,4-oxadiazoles as antifungal agents,”
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[
[
Data Availability
1
13
*
e H NMR and C NMR spectral data used to support the
findings of this study are included within the supplementary
information file.
[
12] C. Zhao and Z.-Q. Liu, “Diaryl-1,2,4-oxadiazole antioxidants:
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8
49, 2013.
13] J. Brahmi, S. Ghannay, S. Bakari et al., “Unprecedented
stereoselective synthesis of 3-methylisoxazolidine-5-aryl-
[
*
e authors declare that they have no conflicts of interest.
1
,2,4-oxadiazoles via 1,3-dipolar cycloaddition and study of
Acknowledgments
their in vitro antioxidant activity,” Synthetic Communications,
vol. 46, no. 24, pp. 2037–2044, 2016.
*
e authors gratefully acknowledge CAPES (PPGQ-
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14] J. G. Leal, A. C. Sauer, J. C. P. Mayer et al., “Synthesis and
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4
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2
2002010012P7), CNPq (Produtividade em Pesquisa–Pq
015-307312/2015-1), and FAPERGS (Ed. PqG 001/2013–
009-2551/13-5) for financial support.
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Supplementary Materials
Figures S1–S50 : H NMR and 13C NMR spectra (com-
1
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“
Design, synthesis, pharmacological evaluation, and docking
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