Some regularities of the synthesis of ethyl 3-aryl-1,2,4-oxadiazole-5-carboxylates

Article abstract of DOI:10.1134/S1070428014110232

Features of amidoximes reactions with ethyl chlorooxalate in a wide range of solvents at the use of a number of bases were investigated. An efficient preparation method for ethyl 3-aryl-1,2,4-oxadiazole-5-carboxylates in acetonitrile in the presence of triethylamine was developed.

Full text of DOI:10.1134/S1070428014110232

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 11, pp. 1683–1686. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.A. Voronova, S.V. Baikov, G.G. Krasovskaya, A.V. Kolobov, E.R. Kofanov, 2014, published in Zhurnal Organicheskoi Khimii,
2014, Vol. 50, No. 11, pp. 1694–1697.
Some Regularities of the Synthesis
of Ethyl 3-Aryl-1,2,4-oxadiazole-5-carboxylates
A. A. Voronova, S. V. Baikov, G. G. Krasovskaya,
A. V. Kolobov, and E. R. Kofanov
Yaroslavl State Technical University, Moskovskii pr. 88, Yaroslavl, 150023 Russia
e-mail: kofanover@ystu.ru
Received March 28, 2014
Abstract—Features of amidoximes reactions with ethyl chlorooxalate in a wide range of solvents at the use of
a number of bases were investigated. An efficient preparation method for ethyl 3-aryl-1,2,4-oxadiazole-5-
carboxylates in acetonitrile in the presence of triethylamine was developed.
DOI: 10.1134/S1070428014110232
Among the numerous specimens of 3,5-
disubstituted 1,2,4-oxadiazoles are the 1,2,4-oxadia-
zoles containing functional groups as substituents [1].
Thus alkyl 1,2,4-oxadiazole-5-carboxylates are precur-
sors in the synthesis of many practically important
structures, for instance, exhibiting pesticidal [2, 3], anti-
thrombotic [4] properties. They underlie the synthesis
of efficient inhibitors of kinase-3 glycogensynthese
(GSK-3) [5], sirtuins of types I and II (SIRT1, SIRT2)
[6], and hydrolase of fatty acids amides [7], and also of a
series of reverse agonists of benzodiazepine receptors [8].
chlorooxalate (II) in weakly polar solvents [1, 9]. This
method is characterized by a long reaction time, and
the yields of the target products vary in a wide range.
On the other hand, we formerly have demonstrated that
the polarity and pH of the environment essentially
affect the formation of the 1,2,4-oxadiazole ring [10].
Aiming at the modification of the existing method
we investigated the reactions of amidoximes and ethyl
chlorooxalate in a wide set of solvents either posses-
sing strong polarity or capable of specific solvation.
The results obtained in reaction carried out in pyridine
are comprehensively described in [11]. In this paper
the data are presented on the features of the reaction
Commonly ethyl 3-aryl-1,2,4-oxadiazole-5-carbo-
xylates III are obtained from amidoximes I and ethyl
Scheme.
N
O
N
O
O
+
Me
N
N
AcOH
OR
IIIa, 90%
VI, 10%
N
O
Cl
OEt
O
O
N
i-PrOH
O
N
OH
OR
II
IIIb
Et3N
NH2
O
Ia
DMSO
EtOH
NH2
O
IV
N
N
V
1683

VORONOVA et al.
1684
Table 1. Synthesis conditions and the yield of ester IIIа
(molar ratio (Iа)–(II)–base 1 : 1.3 : 1.5, 3 h)
In ethanol the main reaction product was compound
V, in 2-propanol it was isopropyl ester IIIb (see the
scheme). Its formation evidently results from transes-
terification catalyzed with Et3N.
Solvent
Base
Temperature, °C Yield, %
DMF
Et3N
Et3N
Py
100
80
42
38
39
88
78
75
63
63
50
75
63
81
50
In acetic acid at 100°С alongside the target ester
IIIa formed 5-methyl-3-phenyl-1,2,4-oxadiazole (VI).
t-BuOH
t-BuOH
t-BuOH
MeCN
80
1
The products ratio according to Н NMR data was
NaHCO3
Et3N
Py
80
9 : 1. The decrease in the temperature to 80°С did not
affect the products ratio. At the use of sodium acetate
instead of Et3N the reaction products were obtained in
the same ratio. The formation of 1,2,4-oxadiazole (VI)
may be ascribed to the reaction between the amid-
oxime and a mixed anhydride obtained by the reaction
of ethyl chlorooxalate with acetic acid or its salt.
80
MeCN
80
MeCN
NaHCO3
Et3N
Py
80
1,4-dioxane
1,4-dioxane
100
100
100
56
1,4-dioxane NaHCO3
Me2CO
Me2CO
Me2CO
Et3N
Py
O
O
O
AcOH + B
AcO_+ ClC(O)COOEt
56
BH+
Me
COOEt
NaHCO3
56
The reaction in acetone, acetonitrile, DMF, and 1,4-
dioxane afforded a single product: the target ester IIIа.
Besides Et3N pyridine and sodium hydrogen carbonate
were also used as bases (Table 1).
occurring in acetic acid, acetone, acetonitrile, 1,4-
dioxane, ethanol, 2-propanol, and tert-butanol, DMF,
DMSO.
As the model reaction we have chosen that with
benzamidoxime (Iа) with ethyl chlorooxalate in the
presence of Et3N (see the scheme).
It is evident from the above findings that quite a
number of polar solvents and various bases are suitable
for the synthesis of ethyl 1,2,4-oxadiazole-5-
carboxylate. Since the most practically important
compounds are amides and hydrazides of 1,2,4-
oxadiazole-5-carboxylic acids, we have taken into
account in the choice of the best system its suitability
The main reaction product in DMSO in the
presence of Et3N was benzamide (IV). The target ester
IIIа was detected in trace quantity. The heating of
ester IIIа in DMSO in the presence of Et3N led to the
formation of unsubstituted 5-phenyl-1,2,4-oxadiazole
(V). Compound V is unstable in basic media (pKa of
Et3N+H in DMSO is 9.0 [12]) and decomposes
liberating benzonitrile [13] that further suffers
hydrolysis into the amide of benzoic acid (IV). In the
absence of a base the heating of ester IIIa in DMSO
did not result in decomposition.
for performing
a
one-pot synthesis of these
compounds. Therefore in the preparation of esters
IIIc–IIIj we used acetonitrile and Et3N (Table 2).
II,
OH
N
O
Et3N, Δ
N
OEt
R
MeCN
N
R
NH2
O
IIIc-IIIj
Table 2. Yields of oxadiazoles IIIc–IIIj (acetonitrile, 80°С,
amidoxime–ethyl chlorooxalate–Et3N 1 : 1.3 : 1.5, 3 h)
Thus as a result of the study of conditions of the
reaction between amidoximes and ethyl chlorooxalate
a method was developed of synthesis in a high yield of
various ethyl 3-aryl-1,2,4-oxadiazole-5-carboxylates.
Compound no.
R
Yield, %
IIIc
IIId
4-Py
4-MeC6H4
74
91
IIIe
IIIf
IIIg
IIIh
IIIi
IIIj
4-NO2C6H4
4-MeOC6H4
4-ClC6H4
86
90
91
94
73
85
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer
Perkin Elmer Spektrum RX-1 from mulls in mineral
4-BrC6H4
oil. Н and 13С NMR spectra were registered on a
1
4-MeOC6H4CH2
3,4-(MeO)2C6H3
spectrometer Bruker MSL (300 MHz) in DMSO-d6,
internal reference TMS. Mass spectra were measured
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

SOME REGULARITIES OF THE SYNTHESIS
1685
1
on an instrument GC/MS Perkin Elmer Clarus 500,
quadrupole mass detector, EI, 70 eV. Elemental
analysis was carried out on a Perkin Elmer 2400,
Series II analyzer.
(C=O), 1567 (C–CAr), 1193 (C–O). H NMR spec-
trum, δ, ppm: 1.38 t (3Н, СН3, J 7.0 Hz), 4.48 m (2Н,
СН2), 7.99 d (2Н, 2СН, J 5.9 Hz), 8.84 d (2Н, 2СН, J
5.9 Hz). Mass spectrum, m/z (Irel, %): 219 (65) [M]+,
191 (15), 174 (5), 146 (7), 120 (100), 104 (31), 92
(39), 90 (23), 78 (25). С10Н19N3O3. Mcalc 219.20.
The solvents and auxiliary substances were
prepared by procedures [14, 15].
Ethyl 3-(4-methylphenyl)-1,2,4-oxadiazole-5-car-
boxylate (IIId). Yield 91%, white powder, mp 61–62°С.
IR spectrum, ν, cm–1: 1751 (C=O), 1559 (C–CAr), 1183
Condensation of benzamidoxime (I) with ethyl
chlorooxalate (II) in diverse solvents. In 5 mL of
solvent was charged at stirring 0.2 g (1.6 mmol) of
amidoxime, 2.4 mmol of a base was added. The mixture
was cooled to 0–10°С and at maintaining this
temperature 0.2 mL (2 mmol) of ethyl chlorooxalate
was added. Then the reaction mixture was stirred at
room temperature for 30 min, further the mixture was
heated to the desired temperature and maintained at it
for 3 h. Afterwards it was cooled, diluted with cold
water, and extracted with chloroform (3 × 4 mL), the
extract was evaporated at a reduced pressure.
1
(C–O). H NMR spectrum, δ, ppm: 1.41 t (3Н, СН3, J
7.1 Hz), 2.41 s (3Н, СН3), 4.47 m (2Н, СН2), 7.37 d
(2Н, 2СН, J 8.1 Hz), 7.94 d (2Н, 2СН, J 8.1 Hz). Mass
spectrum, m/z (Irel, %): 232 (100) [M]+, 204 (10), 159
(10), 133 (100), 117 (20), 91 (30). Found, %: C 62.15;
H 5.11; N 11.37. С12Н12N2O3. Calculated, %: С 62.06;
H 5.21; N 12.06. M 232.24.
Ethyl 3-(4-nitrophenyl)-1,2,4-oxadiazole-5-car-
boxylate (IIIe). Yield 86%, light yellow powder, mp
113–114°С (118–120°C [17]). IR spectrum, ν, cm–1:
1745 (C=O), 1579 (C–CAr), 1528 (NO2), 1295 (C–O).
1H NMR spectrum, δ, ppm: 1.43 t (3Н, СН3, J 7.2 Hz),
4.50 m (2Н, СН2), 8.33 d (2Н, 2СН, J 8.9 Hz), 8.42 d
(2Н, 2СН, J 8.6 Hz). Mass spectrum, m/z (Irel, %): 263
(100) [M]+, 235 (20), 164 (45), 134 (40). С11Н9N3O5.
Mcalc 263.21.
Ethyl 3-aryl-1,2,4-oxadiazole-5-carboxylates (III).
In 5 mL of acetonitrile was dissolved at stirring 2
mmol of amidoxime and 3 mmol of triethylamine was
added. The mixture was cooled to 0–10°С and at
maintaining this temperature 2.2 mmol ethyl chloro-
oxalate was added. Then the reaction mixture was
stirred at room temperature for 30 min, boiled for 3 h,
cooled, poured into cold water, and worked up
according to the general procedure.
Ethyl 3-(4-methoxyphenyl)-1,2,4-oxadiazole-5-car-
boxylate (IIIf). Yield 90%, white powder, mp 63–64°С.
IR spectrum, ν, cm–1: 1752 (C=O), 1564 (C–CAr), 1179
(C–O), 1029 (OCH3). 1H NMR spectrum, δ, ppm: 1.39 t
(3Н, СН3, J 7.1 Hz), 3.86 s (3Н, СН3), 4.47 m (2Н,
СН2), 7.14 d (2Н, 2СН, J 8.9 Hz), 8.00 d (2Н, 2СН, J
8.6 Hz). Mass spectrum, m/z (Irel, %): 248 (100) [M]+,
220 (20), 203 (2), 175 (5), 149 (40), 133 (50), 106 (22).
Found, %: C 58.34; H 4.67; N 11.09. С12Н12N2O4.
Calculated, %: С 58.06; H 4.87; N 11.28. M 248.24.
Ethyl 3-phenyl-1,2,4-oxadiazole-5-carboxylate
(IIIа). White powder, mp 51–52°С (54–55°C [16]). IR
spectrum, ν, cm–1: 1742 (C=O), 1561 (C–CAr), 1189
1
(C–O). H NMR spectrum, δ, ppm: 1.39 t (3H, СH3, J
7.1 Hz), 4.48 d.d (2H, СH2, J 7.1 Hz), 7.63 m (3H, 3СH),
8.07 m (2Н, 2СН). 13C NMR spectrum, δ, ppm: 14.2, 63.7,
125.7, 127.5, 129.8, 132.5, 154.1, 167.3, 168.9. Mass
spectrum, m/z (Irel, %): 218 (70) [M]+, 190 (10), 173 (3),
145 (5), 119 (100), 103 (33), 91 (30), 89 (6), 77 (27),
76 (13), 64 (14), 51 (19). С11Н10N2O3. Mcalc 218.21.
Ethyl 3-(4-chlorophenyl)-1,2,4-oxadiazole-5-carbo-
xylate (IIIg). Yield 91%, white powder, mp 69–70°С. IR
spectrum, ν, cm–1: 1747 (C=O), 1555 (C–CAr), 1181
(C–O), 745 (Cl). 1H NMR spectrum, δ, ppm: 1.41 t (3Н,
СН3, J 7.0 Hz), 4.48 m (2Н, СН2), 7.61 d (2Н, 2СН, J
8.4 Hz), 8.05 d (2Н, 2СН, J 8.4 Hz). Mass spectrum, m/z
(Irel, %): 252 (100) [M]+, 224 (9), 207 (7), 179 (12), 153
(100), 137 (20). Found, %: C 52.49; H 3.44; N 10.71.
С11Н9ClN2O3. Calculated, %: С 52.29; H 3.59; N
11.09. M 252.66.
Isopropyl 3-phenyl-1,2,4-oxadiazole-5-carbo-
1
xylate (IIIb). White powder, mp 51–52°С. H NMR
spectrum, δ, ppm: 1.42 t (6H, 2СН3, J 6.3 Hz), 5.26–
5.31 m (1H, СН), 7.55–7.59 m (3H, 3СН), 8.07 d (2H,
2СН, J 6.3 Hz). Mass spectrum, m/z (Irel, %): 232 (98)
[M]+, 190 (99), 173 (5), 145 (52), 130 (4), 119 (100),
103 (47), 91 (20), 77 (55), 76 (18), 64 (10), 51 (30).
Found, %: C 62.29; H 5.02; N 11.42. С12Н12N2O3.
Calculated, %: С 62.06; H 5.21; N 12.06. M 232.24
Ethyl 3-(4-bromophenyl)-1,2,4-oxadiazole-5-car-
boxylate (IIIh). Yield 94%, white powder, mp 84–85°С.
IR spectrum, ν, cm–1: 1753 (C=O), 1569 (C–CAr), 1188
Ethyl 3-(4-pyridyl)-1,2,4-oxadiazole-5-carbo-
xylate (IIIc). Yield 74%, light yellow powder, mp 93–
94°С (92–94°C [5]). IR spectrum, ν, cm–1: 1749
1
(C–O), 667 (Br). H NMR spectrum, δ, ppm: 1.35 t
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

VORONOVA et al.
1686
Rita, I.R., Heterocycl. Commun., 2005, vol. 11,
p. 29.
3. Santos-Filho, J.M., Leite, A.C.L., de Oliveira, B.G.,
Moreira, D.R.M., Lima, M.S., and Soares, M.B.P.,
Bioorg. Med. Chem., 2009, vol. 17, p. 6682.
(3Н, СН3, J 7.2 Hz), 4.44 m (2Н, СН2), 7.77 d (2H,
2СН, J 8.6 Hz), 7.96 d (2Н, 2СН, J 8.5 Hz). Mass
spectrum, m/z (Irel, %): 296 (100) [M]+, 269 (13), 250
(2), 196 (85), 182 (23), 168 (10), 154 (13). Found, %:
C 44.75; H 2.97; N 9.53. С11Н9BrN2O3. Calculated, %:
С 44.47; H 3.05; N 9.73. M 297.11.
4. Bethge, K., Pertz, H.H., and Rehse, K., Arch. Pharm.
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Ethyl 3-(4-methoxybenzyl)-1,2,4-oxadiazole-5-car-
boxylate (IIIi). Yield 73%, white powder, mp 55–56°С.
IR spectrum, ν, cm–1: 1757 (C=O), 1551 (C–CAr), 1185
(C–O), 1034 (OCH3). 1H NMR spectrum, δ, ppm: 1.39 t
(3Н, СН3, J 7.1 Hz), 3.86 s (2Н, СН2), 4.47 m (2Н, СН2),
7.14 d (2Н, 2СН, J 8.9 Hz), 8.00 d (2Н, 2СН, J 8.6 Hz).
Mass spectrum, m/z (Irel, %): 262 (100) [M]+, 234 (3), 217
(2), 189 (20), 174 (12), 162 (41), 161 (100), 147 (43),
134 (28), 121 (81), 107 (9), 91 (18), 78 (25), 77 (37),
63 (9). Found, %: C 59.83; H 5.31; N 10.48. С13Н14N2O4.
Calculated, %: С 59.54; H 5.38; N 10.68. M 262.27.
5. Koryakova, A.G., Ivanenkov, Ya.A., Ryzhova, E.A.,
Bulanova, E.A., Karapetian, R.N., Mikitas, O.V.,
Katrukha, E.A., Kazey, V.I., Okun, I., Kravchenko, D.V.,
Lavrovsky, Ya.V., Korzinov, O.M., and Ivachtchenko, A.I.,
Bioorg. Med. Chem. Lett., 2008, vol. 18, p. 3661.
6. Huhtiniemi, T., Suuronen, T., Rinne, V.M., Wittekindt, C.,
Lahtela-Kakkonen, M., Jarho, E., Wallen, E.A.A.,
Salminen, A., Poso, A., and Leppanen, J., J. Med.
Chem., 2008, vol. 51, p. 4377.
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Hwang, I., and Boger, D.L., J. Med. Chem., 2008, vol. 51,
p. 4392.
Ethyl 3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazole-
5-carboxylate (IIIj). Yield 85%, white powder, mp 94–
95°С. IR spectrum, ν, cm–1: 1755 (C=O), 1608 (C–CAr),
1183 (C–O), 1023 (OCH3). 1H NMR spectrum, δ, ppm:
1.42 t (3Н, СН3, J 7.1 Hz), 3.86 s (3Н, СН3), 3.87 s (3Н,
СН3), 4.48 m (2Н, СН2), 7.10 d (2Н, 2СН, J 8.2 Hz), 7.64
d (2Н, 2СН, J 8.2 Hz). Mass spectrum, m/z (Irel, %): 278
(100) [M]+, 250 (8), 233 (10), 205 (16), 179 (34), 163
(21). Found, %: C 56.34; H 4.97; N 9.86. С13Н14N2O5.
Calculated, %: С 56.11; H 5.07; N 10.07. M 278.27.
8. Street, L.J., Sternfeld, F., Jelley, R.A., Reeve, A.J.,
Carling, R.W., Moore, K.W., McKernan, R.M., Sohal, B.,
Cook, S., Pike, A., Dawson, G.R., Bromidge, F.A.,
Wafford, K.A., Seabrook, G.R., Thompson, S.A.,
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Benzamide (IV), mp 127–129°С (125–128°C [18]).
Mass spectrum, m/z (Irel, %): 121 (71) [M]+, 114 (3),
106 (7), 105 (100), 103 (4), 83 (3), 78 (10), 77 (90), 74
(11), 52 (8), 51 (45), 50 (23). С7Н7NO. Mcalc 121.14.
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Krasovskaya, G.G., Izv. Vuzov. Ser. Khim. i Khim.
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3-Phenyl-1,2,4-oxadiazole (V), mp 15–16°С (15°C
[19]). 1H NMR spectrum, δ, ppm: 7.63 m (3Н, 3СН), 8.31
m (2Н, 2СН), 9.10 s (1Н, СН). Mass spectrum, m/z (Irel,
%): 146 (100) [M]+, 119 (88), 103 (25), 91 (39), 89
(15), 77 (12), 63 (25), 51 (18). С8Н6N2O. Mcalc 146.15.
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5-Methyl-3-phenyl-1,2,4-oxadiazole (VI). White
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cm–1: 1573 (C–CAr). 1H NMR spectrum, δ, ppm: 2.65 s
(3H, СН3), 7.55–7.61 m (3H, 3СН), 8.01 d (2H, 2СН,
J 7.9 Hz). Mass spectrum, m/z (Irel, %): 160 (89) [M]+,
119 (100), 103 (11), 91 (86), 89 (12), 77 (23), 76 (18),
64 (43), 63 (29), 51 (25). С9Н8N2O. Mcalc 160.18.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014