The reaction of amidoximes with carboxylic acids or their esters under high-pressure conditions

Article abstract of DOI:10.1007/s11172-019-2391-9

3,5-Disubstituted 1,2,4-oxadiazoles were synthesized by the reaction of amidoximes with carboxylic acids or their esters under high-pressure conditions (10 kbar). The reaction proceeds without the use of other reagents or catalysts. Both aliphatic and aro

Full text of DOI:10.1007/s11172-019-2391-9

Russian Chemical Bulletin, International Edition, Vol. 68, No. 2, pp. 347—350, February, 2019
347
The reaction of amidoximes with carboxylic acids
or their esters under high-pressure conditions*
S. V. Baikov,a G. A. Stashina,b E. I. Chernoburova,b V. B. Krylov,b I. V. Zavarzin,b and E. R. Kofanovc
aK. D. Ushinsky Yaroslavl State Pedagogical University,
108 ul. Respublikanskaya, 150000 Yaroslavl, Russian Federation
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninskii prosp., 119991 Moscow, Russian Federation.
E-mail: zavi@ioc.ac.ru
c
Yaroslavl State Technical University,
88 Moskovskii prosp., 150023 Yaroslavl, Russian Federation
3,5-Disubstituted 1,2,4-oxadiazoles were synthesized by the reaction of amidoximes with
carboxylic acids or their esters under high-pressure conditions (10 kbar). The reaction proceeds
without the use of other reagents or catalysts. Both aliphatic and aromatic carboxylic acids
undergo this reaction. The obtained 1,2,4-oxadiazoles possess high fungicidal activity.
Key words: amidoximes, carboxylic acids, esters, 1,2,4-oxadiazoles, high pressure, fungi-
cidal activity.
1,2,4-Oxadiazole moiety is a part of the Libexin,1
Oxolamine,2 and Ataluren3 drug molecules, as well as of
other substances being at different phases of clinical and
pre-clinical trials.4—6 In addition, their find application
in the development of liquid-crystalline and high-energy
materials.7,8 Of specific interest are 1,2,4-oxatriazoles
possessing fungicidal activity,9—12 in particular, those of
quinoline series.13
extended this approach to low-reactive carboxylic acids
and their esters. First, we studied the reaction of a model
benzamidoxime (1a) and acetic acid (Scheme 1, Table 1).
Scheme 1
Among main methods for their synthesis is the reaction
of amidoximes with carboxylic acid derivatives.14 In the
case of reactive acylating agents such as anhydrides and
acid halides, the reaction proceeds in two steps: O-acylation
of amidoxime and cyclization of the resulting ester; the
rate of the second (rate-limiting) step strongly depends on
the properties of the medium.15
The use of carboxylic acids requires special activation.
Carbonyldiimidazole (CDI),16,17 carbodiimides (DCC,
EDC, DIC),18—20 or alkyl chloroformates21 are applied
for this purpose. Carboxylic esters are also low-reactive;
therefore, they would react in the presence of strong bases
such as sodium hydride or alkoxides.22,23 Only a few ex-
amples of the synthesis of 3,5-disubstituted 1,2,4-oxadia-
zoles without the use of activating agents are known, when
the reaction was carried out under extremely severe condi-
tions.24,25
R = H (a), NO2 (b), OMe (c)
When the reaction was carried using the excess of
acetic acid as a solvent, the reaction mass underwent
crystallization due to a high pressure within the system
(see Table 1, Run 1). Crystallization was prevented by
heating to 140 C (see Table 1, Run 2), which caused
partial resinification and, as a consequence, a decrease in
the yield of the target product. Besides the expected com-
pound 2a, 3,5-diphenyl-1,2,4-oxadiazole (3a) was isolated,
the formation of which can be explained by dimerization
of benzamidoxime 1a.27
Earlier,26 we have reported on the synthesis of 3,5-di-
substituted 1,2,4-oxadiazoles from amidoximes and nitriles
under ultrahigh-pressure conditions. In this work, we
* Dedicated to Corresponding Member of the Russian Academy
of Sciences G. I. Nikishin on occasion of his 90th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0347—0350, February, 2019.
1066-5285/19/6802-0347 © 2019 Springer Science+Business Media, Inc.

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Russ. Chem. Bull., Int. Ed., Vol. 68, No. 2, February, 2019
Baikov et al.
Table 1. Reaction of amidoximes with carboxylic acids (10 kbar, amidoxime : acid = 1 : 3)
Run
Starting
amidoxime
Acid
Solvent
T/C
t/h
Products
(yield (%))
1
2
3
4
5
6
7
8
1а
1а
1а
1а
1а
1а
1а
1а
1b
1c
1а
4
AcOH
AcOH
AcOH
AcOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
110
140
170
170
180
190
100
100
100
100
100
100
100
100
6
6
6
9
6
6
6
6
6
6
6
6
6
6
—
2a (39), 3a (11)
2a (5)
AcOH
AcOH
2a (10)
2a (35), 3a (9)
AcOH
AcOH
2a (44), 3a (15)
2a (52), 3a (18)
2a (51), 3a (18)
2b (54), 3b (20)
2c (61), 3c (17)
3a (70)
AcOH
AcOH
9
AcOH
THF
10
11
12
13
14
AcOH
THF
THF
CH2Cl2
CH2Cl2
CH2Cl2
PhC(O)OH
PhC(O)OH
4-O2NC6H4C(O)OH
3-F3CC6H4C(O)OH
5a (58)
4
4
5b (56)
5c (52)
Scheme 3
The replacement of a portion of acetic acid with di-
chloromethane as a solvent allowed us to decrease the
temperature to 70—100 C (see Table 1, Runs 3—7). At
70 C, the yield of the target product 2a did not exceed
10% even within 9 h; however, no dimer 3a was observed.
The most complete transformation of amidoxime 1a into
the target product 2a was achieved at 100 C, but dimer
3a was produced in slight amounts along with compound
2a. It should be noted that these compounds are easily
separated by crystallization from ethanol.
Next, we performed the reaction of substituted benz-
amidoximes 1b,c (see Scheme 1 and Table 1, Runs 9 and
10). Due to their poor solubilities in dichloromethane, the
reaction was carried out in THF. Higher yields of com-
pounds 2b,c are thought to be due to the fact that amid-
oximes containing electron-withdrawing substituents are
less prone to condensation to form dimers 3b,c.
Ar = Ph (a), 4-O2NC6H4 (b), 3-F3CC6H4 (c)
Besides acetic acid, the reaction of benzamidoxime 1a
with benzoic acid was studied (Scheme 2), which gave
compound 3a as a single product.
Scheme 4
Scheme 2
i. 10 kbar, 100 C, 6 h.
To finalize, we showed that 1,2,4-oxadiazoles could be
synthesized from amidoximes and carboxylic acids or their
esters under high-pressure conditions (10 kbar) without
the use of additional reagents and catalysts.
Similarly, the reaction of amidoxime 4 with carboxylic
acids affords smoothly 1,2,4-oxadiazoles 5a—c possess-
ing high fungicidal activity13 (Scheme 3; see Table 1,
Runs 12—14).
Benzamidoxime 1a was also studied for the reac-
tion with ethyl acetate acting as both a reagent and
a solvent (Scheme 4). The reaction was carried out at
100 C. The outcome was analogous to that in the case of
acetic acid.
Experimental
All experiments were carried out under high pressure on
a Barostat machine28 allowing one to perform reactions under
pressures up to 18 kbar (1800 MPa) and at temperatures up to

Reaction of amidoximes with carboxylic acids
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 2, February, 2019
349
350 C. The 1H and 13C NMR spectra for solutions of analyzed
compounds in DMSO-d6 were recorded on a Bruker DRX-500
instrument. Electron impact mass spectra were recorded on
a GC/MS Perkin—Elmer Clarus 500 instrument. High-resolu-
tion mass spectra (ESI) were obtained on a Bruker micrOTOF
II instrument. The measurements were performed in a positive-
ion mode (the capillary voltage was 4500 V), the m/z range was
from 50 to 300 Da, external and internal calibration (Electrospray
Calibrant Solution, Fluka). Solutions of samples were injected
via a syringe, the flow rate was 3 μL min–1, the nebulizer gas was
nitrogen (4 L min–1), and the interface temperature was 180 C.
The starting amidoximes 1a—c were synthesized from commer-
cially available nitriles (Sigma—Aldrich Co.) according to known
procedures.29 Amidoxime 4 was prepared as described in Ref. 13.
Reaction of amidoximes with carboxylic acids (general proce-
dure). A solution of amidoxime (2.2 mmol) and carboxylic acid
(6.6 mmol) in the corresponding solvent (see Table 1) was pre-
pared in a 1.5-mL Teflon tube and the tube was placed in
a high-pressure unit. The unit with plungers and sealings in-
serted thereto and a furnace place thereon was mounted in the
Barostat machine. The reaction mixture was kept under specified
conditions. The unit was cooled and the reaction mixture was
removed from the unit and diluted with dichloromethane until
a volume of 15 mL. The resulting solution was washed with an
aqueous solution of sodium bicarbonate (10 mL) and water
(10 mL), dried with sodium sulfate, and the solvent was removed
under reduced pressure. Further purification was performed by
column chromatography (SiO2, ethyl acetate—hexane, 1 : 4) or
recrystallization from ethanol.
Reaction of benzamidoxime (1a) with ethyl acetate. A solution
of benzamidoxime (1a) (0.3 g, 2.2 mmol) in ethyl acetate was
prepared in a 1.5-mL Teflon tube and the tube was placed in
a high-pressure unit. The unit with plungers and sealings in-
serted thereto and a furnace placed thereon was mounted in the
Barostat machine. The reaction mixture was kept for 6 h at 10 kbar
and 100 C. After the experiment has been completed, the unit
was cooled, the reaction mixture was removed from the unit, and
the excess of ethyl acetate was evaporated under reduced pressure.
Further purification was performed by column chromato-
graphy (SiO2, ethyl acetate—hexane, 1 : 4) or recrystallization
from ethanol.
MS (EI, 70 eV), m/z (Irel (%)): 190 [M+] (100), 149 (87), 134
(24), 133 (23), 119 (8), 106 (56), 103 (7), 91 (14), 90 (9), 78 (18),
76 (18), 63 (14), 50 (12).
3,5-Diphenyl-1,2,4-oxadiazole (3a). M.p. 109—110 C
(cf. Ref. 26: m.p. 109—110 C). 1H NMR (500 MHz, DMSO-d6),
: 7.63, 7.68, 7.75 (all t, 2 H each, H arom., J = 7.5 Hz); 8.11
(d, 2 H, H arom., J = 8.0 Hz); 8.20 (d, 2 H, H arom., J = 8.6 Hz).
13C NMR (125 MHz, DMSO-d6), : 123.4, 126.2, 127.1, 127.9,
129.3, 129.6, 131.6, 133.4, 168.3, 175.5. MS (EI, 70 eV), m/z
(Irel (%)): 222 [M+] (56), 119 (100), 111 (5), 105 (6), 96 (7),
91 (23), 77 (23), 64 (18), 51 (18).
3,5-Bis(4-nitrophenyl)-1,2,4-oxadiazole (3b). M.p. 235—236 C
(cf. Ref. 30: m.p. 233—235 C). 1H NMR (500 MHz, DMSO-d6),
: 8.29 (d, 2 H, H arom., J = 8.8 Hz); 8.38—8.51 (m, 4 H,
H arom.); 8.43 (d, 2 H, H arom., J = 9 Hz). 13C NMR (125 MHz,
DMSO-d6), : 124.5, 124.6, 128.3, 128.5, 129.5, 131.4, 149.3,
150.1, 167.2, 174.4. MS (EI, 70 eV), m/z (Irel (%)): 312 [M+] (24),
282 (4), 164 (20), 150 (7), 134 (15), 116 (9), 105 (12), 104 (13),
102 (11), 90 (7), 88 (14), 76 (38), 62 (14), 50 (20) 30 (100).
3,5-Bis(4-methoxyphenyl)-1,2,4-oxadiazole (3c). M.p.
126—127 C (cf. Ref. 31: m.p. 126—127 C). 1H NMR (500 MHz,
DMSO-d6), : 3.86, 3.88 (both s, 3 H each, CH3); 7.12, 8.01
(both d, 2 H each, H arom., J = 8.6 Hz); 7.18, 8.10 (both d, 2 H
each, H arom., J = 8.7 Hz). 13C NMR (125 MHz, DMSO-d6),
: 55.4, 55.6, 114.6, 114.9, 115.9, 118.6, 128.8, 129.9, 161.7, 163.0,
167.8, 175.0. MS (EI, 70 eV), m/z (Irel (%)): 282 [M+] (100),
149 (6), 134 (6), 133 (7), 119 (6), 106 (6), 92 (5), 76 (8), 63 (8), 50 (6).
3-(2-Morpholinoquinolin-3-yl)-5-phenyl-1,2,4-oxadiazole
(5a). M.p. 210—212 C (cf. Ref. 13: m.p. 210—212 C). 1H NMR
(CDCl3), : 3.51—3.54 (m, 4 H, CH2NCH2); 3.87—3.91 (m, 4 H,
CH2OCH2); 7.36—7.51 (m, 4 H, H arom.); 7.68—7.93 (m, 3 H,
H arom.); 8.01—8.11 (m, 3 H, H arom.). 13C NMR (100 MHz,
DMSO-d6), : 50.3, 66.1, 113.8, 123.7, 124.0, 124.8, 127.0, 128.3,
129.0, 130.1, 131.8, 134.0, 142.2, 147.6, 157.5, 168.7, 175.3. HRMS,
found: m/z 359.1527 [M + H]+. Calculated for C21H18N4O2:
M + H = 359.1502.
3-(2-Morpholinoquinolin-3-yl)-5-(4-nitrophenyl)-1,2,4-oxa-
diazole (5b). M.p. 285—287 C (cf. Ref. 13: m.p. 285—287 C).
1H NMR (CDCl3), : 3.50—3.55 (m, 4 H, CH2NCH2); 3.88—3.93
(m, 4 H, CH2OCH2); 7.39—7.52 (m, 4 H, H arom.); 7.67—8.13
(m, 5 H, H arom.). 13C NMR (100 MHz, DMSO-d6), : 50.0, 66.2,
113.3, 123.9, 125.1, 125.3, 127.2, 129.0, 130.1, 132.0, 142.4, 147.5,
150.4, 151.0, 157.2, 168.8, 174.0. HRMS, found: m/z 404.1375
[M + H]+. Calculated for C21H17N5O4: M + H = 404.1353.
3-(2-Morpholinoquinolin-3-yl)-5-(3-trifluoromethylphenyl)-
1,2,4-oxadiazole (5c). M.p. 245—247 C (cf. Ref. 13: m.p.
245—247 C). 1H NMR (CDCl3), : 3.45—3.54 (m, 4 H,
CH2NCH2); 3.86—3.91 (m, 4 H, CH2OCH2); 7.41—7.53 (m, 4 H,
H arom.); 7.69—8.22 (m, 5 H, H arom.). HRMS, found: m/z
427.1307 [M + H]+. Calculated for C22H17F3N4O2: M + H =
= 427.1382.
5-Methyl-3-phenyl-1,2,4-oxadiazole (2a). M.p. 43—44 C
(cf. Ref. 26: m.p. 43—44 C). 1H NMR (500 MHz, DMSO-d6),
: 2.65 (s, 3 H, CH3); 7.55—7.61 (m, 3 H, H arom.); 8.01 (d, 2 H,
H arom., J = 7.9 Hz). 13C NMR (125 MHz, DMSO-d6), : 12.0,
126.4, 126.9, 129.2, 131.4, 167.6, 177.4. MS (EI, 70 eV), m/z
(Irel (%)): 160 [M+] (89), 119 (100), 103 (11), 91 (86), 89 (12),
77 (23), 76 (18), 64 (43), 63 (29), 51 (25).
5-Methyl-3-(4-nitrophenyl)-1,2,4-oxadiazole (2b). M.p.
142—143 C (cf. Ref. 26: m.p. 142—143 C). 1H NMR (500 MHz,
DMSO-d6), : 2.72 (s, 3 H, CH3); 8.23, 8.38 (both d, 2 H each,
H arom., J = 8.7 Hz). 13C NMR (125 MHz, DMSO-d6), : 12.1,
124.4, 128.3, 132.1, 149.1, 166.4, 178.3. MS (EI, 70 eV), m/z
(Irel (%)): 205 [M+] (100), 175 (36), 164 (79), 159 (8), 147 (10),
134 (48), 117 (15), 106 (39), 90 (19), 88 (48), 87 (8), 76 (19),
75 (17), 62 (21), 51 (16).
This work was financially supported by the Russian
Science Foundation (Project No. 14-23-00199).
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Received November 7, 2018;
in revised form December 11, 2018;
accepted December 25, 2018