Synthesis of 3-carbamoyl-1,2,4-oxadiazoles

Article abstract of DOI:10.1023/A:1021348401329

A convenient method for the synthesis of 3-carbamoyl-1,2,4-oxadiazoles from carbamoylamidoximes and chlorides or anhydrides of haloacetic acids was developed. The reactions of 3-carbamoyl-5-trichloromethyl-1,2,4-oxadiazoles with amines and N,N-dimethylhydrazine were studied.

Full text of DOI:10.1023/A:1021348401329

Russian Chemical Bulletin, International Edition, Vol. 51, No. 10, pp. 1857—1861, October, 2002
1857
Synthesis of 3ꢀcarbamoylꢀ1,2,4ꢀoxadiazoles
ꢀ
V. N. Yarovenko, S. A. Kosarev, I. V. Zavarzin, and M. M. Krayushkin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: yarov@ioc.ac.ru
A convenient method for the synthesis of 3ꢀcarbamoylꢀ1,2,4ꢀoxadiazoles from carbamoylꢀ
amidoximes and chlorides or anhydrides of haloacetic acids was developed. The reactions of
3ꢀcarbamoylꢀ5ꢀtrichloromethylꢀ1,2,4ꢀoxadiazoles with amines and N,Nꢀdimethylhydrazine
were studied.
Key words: amidoximes, 1,2,4ꢀoxadiazoles, acid chlorides, trifluoroacetic anhydride.
1,2,4ꢀOxadiazole derivatives manifest a wide spectrum
of biological activity.1 The synthesis of 3ꢀcarbamoylꢀ
1,2,4ꢀoxadiazoles, which are of interest as herbicides,2,3
has attracted considerable attention in the recent time.
However, the available methods for the synthesis of these
heterocycles are multistep, based on the use of unavailꢀ
able compounds, and have several other disadvantages.1—3
In this work we studied the reactions of presently availꢀ
able carbamoylamidoximes4 with chloroacetyl chlorides
to develop a simple method for the synthesis of 3ꢀcarboꢀ
moylꢀ1,2,4ꢀoxadiazoles.
products were formed along with target oxadiazoles and
hampered to isolate the latter. The drastic conditions of
the reaction are likely related to the deactivation of the
amidoxime fragment by the electronꢀwithdrawing carꢀ
bamoyl group. It could be expected that the introduction
of strong electronꢀwithdrawing substituents into acid chloꢀ
ride or acid anhydride would favor heterocyclization enꢀ
hancing the electrophilicity of the carbon atom of the
C=O group.5
Indeed, the reaction of carbamoylamidoximes 1а,c—f
with trifluoroacetic anhydride affords successively
5ꢀtrifluoromethylꢀ1,2,4ꢀoxadiazoleꢀ3ꢀcarbamides 3a—e
(Scheme 2).
The reactions of carbamoylamidoximes 1a,b with
monochloroacetyl chloride were primarily studied
(Scheme 1).
Scheme 2
Scheme 1
R = Ph (1a, 3a); pꢀClC6H4 (1c, 3b); pꢀMeOC6H4 (1d, 3c);
pꢀO2NC6H4 (1e, 3d); pꢀH2NSO2C6H4 (1f, 3e)
R = Ph (a), Bn (b)
The solvent and temperature effects on heterocycliꢀ
zation were studied. It turned out that 1,2,4ꢀoxadiazoles
were not formed on boiling of the corresponding amidoxiꢀ
mes with chloroacetyl chloride in ethyl acetate or butyl
acetate. Oxadiazoles 2a,b were isolated in satisfactory
yields only upon manyꢀhour boiling in amyl acetate. Oily
When carbamoylamidoximes 1 are treated with diꢀ
chloroꢀ and trichloroacetyl chlorides, the correspondꢀ
ing 1,2,4ꢀoxadiazoles 4 and 5 are smoothly formed
(Scheme 3).
The 5ꢀtrichloromethyl group in the series of 1,2,4ꢀoxaꢀ
diazoles is known6 to be substituted under the action of
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1708—1712, October, 2002.
1066ꢀ5285/02/5110ꢀ1857 $27.00 © 2002 Plenum Publishing Corporation

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Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Yarovenko et al.
Scheme 3
Scheme 4
6
a
—R
—Nu
—Ph
b
c
4: R = Ph (a); 4ꢀClC6H4 (b); 4ꢀMeOC6H4 (c); 4ꢀNO2C6H4 (d)
d
e
f
—Ph
g
Scheme 5
R = Ph (1a, 5a); 3,4ꢀCl2C6H3 (1g, 5b); 4ꢀClC6H4 (1c, 5c);
4ꢀNO2C6H4 (1e, 5d); 2,3ꢀMe2C6H3 (1h, 5e);
(1i, 5f);
(1f, 5g)
various nucleophiles. The reactions of oxadiazoles 5 with
amines also afford the corresponding amino derivatives 6
in high yields (Scheme 4).
We have also found that the reaction of dimethylꢀ
hydrazine with compounds 5 involves reductive condenꢀ
sation to form hydrazones 7. Product 7a is also formed in
the reaction of dichloride 4а with dimethylhydrazine
(Scheme 5).
R = Ph (7a); 3,4ꢀCl2C6H3 (7b); 4ꢀClC6H4 (7c); 4ꢀNO2C6H4 (7d);
2,3ꢀMe2C6H3 (7e); (7f)
UVꢀ254 plates using an EtOAc—hexane (1 : 1 vol/vol) mixture
as the eluent. Before use, amyl acetate was dried above MgSO4
and distilled.
Thus, we proposed the convenient method for the
synthesis of carbamoylꢀ1,2,4ꢀoxadiazoles from available
compounds.
Synthesis of 3ꢀcarbamoylꢀ1,2,4ꢀoxadiazoles by the reaction
of carbamoylamidoximes with acid chlorides (general procedure).
Anhydrous Na2CO3 (1 mmol) and the corresponding acid chloꢀ
ride (Cl3–nHnCOCl) (2 mmol) or (CF3CO)2O (for the synthesis
of oxadiazoles 3) (2 mmol) were added to a solution of amiꢀ
doxime4 (1 mmol) in amyl acetate (5 mL). The mixture was
boiled with a reflux condenser equipped with a calcium chloride
tube (TLC monitoring). The solution cooled to ∼20 °C was
washed with water (3×30 mL), the organic layer was dried above
MgSO4, the solvent was evaporated in a vacuum of a rotary
evaporator, and the residue was recrystallized. Compounds 2a,b,
3a—e, 4a—d, and 5a—g were obtained by this method.
NꢀPhenylꢀ5ꢀchloromethylꢀ1,2,4ꢀoxadiazolylꢀ3ꢀcarboxamide
(2а) was obtained from amidoxime 1а and ClCH2COCl by reꢀ
fluxing for 7 h in 60% yield (0.14 g), m.p. 89—91 °С (from
Experimental
IR spectra were obtained on a Specord IRꢀ80 spectrophoꢀ
tometer in pellets with KBr. 1H NMR spectra were recorded on
a Bruker WMꢀ250 instrument (250 MHz) in (CD3)2SO. Mass
spectra (EI) were recorded on Varian MAT CHꢀ6 and Kratos
MSꢀ30 instruments with the direct injection of a sample into an
ion source, an ionizing voltage of 70 eV, and an emission current
of 0.1 mA. Melting points (were not corrected) were determined
on a Boetius heating stage. All reaction mixtures were analyzed
and purity of isolated products was monitored by TLC on Silufol

Synthesis of 3ꢀcarbamoylꢀ1,2,4ꢀoxadiazoles
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
1859
toluene). Found (%): С, 50.85; H, 3.53; Cl, 14.83; N, 17.49.
C10H8ClN3O2. Calculated (%): С, 50.63; H, 3.39; Cl, 14.75;
Nꢀ(4ꢀChlorophenyl)ꢀ5ꢀdichloromethylꢀ1,2,4ꢀoxadiazolylꢀ3ꢀ
carboxamide (4b) was synthesized from amidoxime 1c and
Cl2CHCOCl by refluxing for 3.5 h in 62% yield (0.13 g), m.p.
159—162 °С (from toluene). Found (%): С, 39.12; H, 1.90;
N, 17.68. 1H NMR, δ: 5.20 (s, 2 Н, СH2Cl); 7.20 (t, 1 Н, Harom
,
J = 7.3 Hz); 7.35 (m, 2 H, Harom); 7.75 (d, 2 H, Harom, J =
8.0 Hz); 10.85 (s, 1 Н, NH). MS, m/z: 237, 239 [M]+.
NꢀBenzylꢀ5ꢀchloromethylꢀ1,2,4ꢀoxadiazolylꢀ3ꢀcarboxamide
(2b) was synthesized from amidoxime 1b and ClCH2COCl, the
duration of refluxing was 7 h, 67% yield (0.16 g), m.p. 73—75 °С
(from toluene). Found (%): С, 52.43; H, 3.75; Cl, 14.15;
N, 16.70. C11H10ClN3O2. Calculated (%): С, 52.49; H, 3.98;
Cl, 14.12; N, 16.69. 1H NMR, δ: 4.40 (m, 2 H, СH2Ph); 5.15 (s,
2 H, СH2Cl); 7.20—7.40 (m, 5 H, Harom); 9.50 (s, 1 Н, NH).
MS, m/z: 251, 253 [M]+.
NꢀPhenylꢀ5ꢀtrifluoromethylꢀ1,2,4ꢀoxadiazolylꢀ3ꢀcarboxꢀ
amide (3a) was synthesized from amidoxime 1a and trifluoroꢀ
acetic anhydride, the duration of refluxing was 90 min, 62%
yield (0.18 g), m.p. 155—157 °С (from toluene). Found (%):
С, 46.57; H, 2.28; N, 16.45. C10H6F3N3O2. Calculated (%):
С, 46.69; H, 2.33; N, 16.34. 1Н NMR, δ: 7.20 (t, 1 H, Harom, J =
7.2 Hz); 7.40 (m, 2 H, Harom); 7.80 (d, 2 H, Harom, J = 8.1 Hz);
11.10 (s, 1 H, NH). MS, m/z: 257 [M]+.
Nꢀ(4ꢀChlorophenyl)ꢀ5ꢀtrifluoromethylꢀ1,2,4ꢀoxadiazolylꢀ3ꢀ
carboxamide (3b) was synthesized from amidoxime 1c and
trifluoroacetic anhydride by refluxing for 90 min in 52% yield
(0.15 g), m.p. 164—166 °С (from toluene). Found (%): С, 41.20;
H, 1.75; N, 14.35. C10H5ClF3N3O2. Calculated (%): С, 41.16;
H, 1.71; N, 14.41. 1Н NMR, δ: 7.85 (d, 2 H, Harom, J = 8.7 Hz);
8.35 (d, 2 H, Harom, J = 8.7 Hz); 10.55 (s, 1 H, NH). MS, m/z:
291, 293 [M]+.
Cl, 34.70; N, 13.75. C10H6Сl3N3O2. Calculated (%): С, 39.15;
1
H, 1.96; Cl, 34.75; N, 13.70. Н NMR, δ: 7.45 (d, 2 H, Harom
,
J = 8.7 Hz); 7.80 (d, 2 H, Harom, J = 8.7 Hz); 8.05 (s, 1 H,
CHCl2); 11.10 (s, 1 H, NH). MS, m/z (for 35Cl): 305 [M]+.
Nꢀ(4ꢀMethoxyphenyl)ꢀ5ꢀdichloromethylꢀ1,2,4ꢀoxadiazolylꢀ
3ꢀcarboxamide (4c) was synthesized from amidoxime 1d and
Cl2CHCOCl by refluxing for 3.5 h in 60% yield (0.18 g), m.p.
144—146 °С (from toluene). Found (%): С, 43.63; H, 2.90;
Cl, 23.53; N, 13.95. C11H9Сl2N3O3. Calculated (%): С, 43.71;
1
H, 2.98; Cl, 23.51; N, 13.91. Н NMR, δ: 3.75 (s, 3 H, OMe);
6.95 (d, 2 H, Harom, J = 8.8 Hz); 7.70 (d, 2 H, Harom, J =
8.8 Hz); 8.05 (s, 1 H, CHCl2); 10.85 (s, 1 H, NH). MS, m/z:
301, 303, 305 [M]+.
Nꢀ(4ꢀNitrophenyl)ꢀ5ꢀdichloromethylꢀ1,2,4ꢀoxadiazolylꢀ3ꢀ
carboxamide (4d) was synthesized from amidoxime 1e and
Cl2CHCOCl by refluxing for 3.5 h in 49% yield (0.11 g), m.p.
164—166 °С (from toluene). Found (%): С, 37.87; H, 1.86;
Cl, 22.38; N, 17.55. C10H6Cl2N4O4. Calculated (%): С, 37.85;
H, 1.89; Cl, 22.40; N, 17.67. 1Н NMR, δ: 8.05 (s, 1 H, CHCl2);
8.10 (d, 2 H, Harom, J = 8.9 Hz); 8.30 (d, 2 H, Harom, J =
8.9 Hz); 11.50 (s, 1 H, NH). MS, m/z: 316, 318, 320 [M]+.
NꢀPhenylꢀ5ꢀtrichloromethylꢀ1,2,4ꢀoxadiazolylꢀ3ꢀcarboxꢀ
amide (5а) was synthesized from amidoxime 1а and CCl3COCl
by refluxing for 90 min in 70% yield (0.24 g), m.p. 108—111 °С
(from toluene). Found (%): С, 39.25; H, 1.88; Cl, 34.60;
N, 13.83. С10H6Cl3N3O2. Calculated (%): С, 39.15; H, 1.97;
Cl, 34.75; N, 13.70. 1Н NMR, δ: 7.20 (t, 1 H, Harom, J =
7.3 Hz); 7.35 (m, 2 H, Harom); 7.80 (d, 2 H, Harom, J = 8.0 Hz);
11.10 (s, 1 H, NH). MS, m/z (for 35Cl): 305 [M]+.
Nꢀ(3,4ꢀDichlorophenyl)ꢀ5ꢀtrichloromethylꢀ1,2,4ꢀoxadiꢀ
azolylꢀ3ꢀcarboxamide (5b) was synthesized from amidoxime 1g
and CCl3COCl by refluxing for 90 min in 65% yield (0.24 g),
m.p. 163—165 °С (from toluene). Found (%): С, 31.90; H, 1.00;
Cl, 47.30; N, 11.23. С10H4Cl5N3O2. Calculated (%): С, 31.96;
H, 1.07; Cl, 47.27; N, 11.19. 1Н NMR, δ: 7.65 (m, 1 H, Harom);
7.75 (m, 1 H, Harom); 8.10 (s, 1 H, Harom); 11.25 (s, 1 H, NH).
MS, m/z (for 35Cl): 373 [M]+.
Nꢀ(4ꢀMethoxyphenyl)ꢀ5ꢀtrifluoromethylꢀ1,2,4ꢀoxadiazolylꢀ
3ꢀcarboxamide (3c) was synthesized from amidoxime 1d and
trifluoroacetic anhydride by refluxing for 60 min in 78% yield
(0.11 g), m.p. 168—171 °С (from toluene). Found (%): С, 46.17;
H, 2.78; N, 14.45. C11H8F3N3O3. Calculated (%): С, 46.00;
1
H, 2.81; N, 14.63. Н NMR, δ: 3.80 (s, 3 H, OMe); 6.55 (dd,
2 H, Harom); 7.70 (dd, 2 H, Harom); 10.95 (s, 1 H, NH). MS,
m/z: 287 [M]+.
Nꢀ(4ꢀNitrophenyl)ꢀ5ꢀtrifluoromethylꢀ1,2,4ꢀoxadiazolylꢀ3ꢀ
carboxamide (3d) was synthesized from amidoxime 1e and
trifluoroacetic anhydride by refluxing for 90 min in 47% yield
(0.14 g), m.p. 142—144 °С (from toluene). Found (%): С, 39.87;
H, 1.69; N, 18.45. C10H5F3N4O4. Calculated (%): С, 39.74;
H, 1.66; N, 18.54. 1Н NMR, δ: 8.05 (d, 2 H, Harom, J = 9.0 Hz);
8.30 (d, 2 H, Harom, J = 9.0 Hz); 11.55 (s, 1 H, NH). MS,
m/z: 302 [M]+.
Nꢀ(4ꢀChlorophenyl)ꢀ5ꢀtrichloromethylꢀ1,2,4ꢀoxadiazolylꢀ3ꢀ
carboxamide (5с) was synthesized from amidoxime 1c and
CCl3COCl by refluxing for 90 min in 70% yield (0.24 g), m.p.
253—255 °С (from toluene). Found (%): С, 35.39; H, 1.49;
Nꢀ(4ꢀAminosulfonylphenyl)ꢀ5ꢀtrifluoromethylꢀ1,2,4ꢀoxadiꢀ
azolylꢀ3ꢀcarboxamide (3e) was synthesized from amidoxime 1f
and trifluoroacetic anhydride by refluxing for 90 min in 30%
yield (0.04 g), m.p. 203—205 °С (from toluene). Found (%):
С, 35.83; H, 2.16; N, 16.45. C10H7F3N4O4S. Calculated (%):
Cl, 41.32; N, 12.78. С10H5Cl4N3O2. Calculated (%): С, 35.19;
1
H, 1.47; Cl, 41.64; N, 12.32. Н NMR, δ: 7.85 (d, 2 H, Harom
,
J = 8.7 Hz); 7.35 (d, 2 H, Harom, J = 8.7 Hz); 11.25 (s, 1 H,
NH). MS, m/z (for 35Cl): 339 [M]+.
Nꢀ(4ꢀNitrophenyl)ꢀ5ꢀtrichloromethylꢀ1,2,4ꢀoxadiazolylꢀ3ꢀ
carboxamide (5d) was synthesized from amidoxime 1e and
CCl3COCl by refluxing for 90 min in 68% yield (0.24 g), m.p.
144—146 °С (from toluene). Found (%): С, 34.17; H, 1.36;
1
С, 35.72; H, 2.09; N, 16.66. Н NMR, δ: 8.05 (t, 2 H, Harom);
8.30 (t, 2 H, Harom); 11.55 (s, 1 H, NH). MS, m/z: 336 [M]+.
NꢀPhenylꢀ5ꢀdichloromethylꢀ1,2,4ꢀoxadiazolylꢀ3ꢀcarboxꢀ
amide (4a) was synthesized from amidoxime 1а and Cl2CHCOCl
by refluxing for 5 h in 53% yield (0.14 g), m.p. 111—113 °С
(from chloroform). Found (%): С, 44.19; H, 2.69; Cl, 26.14;
N, 15.40. C10H7Cl2N3O2. Calculated (%): С, 44.12; H, 2.57;
Cl, 26.10; N, 15.44. 1Н NMR, δ: 7.20 (t, 1 H, Harom, J =
7.3 Hz); 7.40 (m, 2 H, Harom); 7.75 (d, 2 H, Harom, J = 8.0 Hz);
8.00 (s, 1 H, CHCl2); 10.90 (s, 1 H, NH). MS, m/z: 271,
273, 275 [M]+.
Cl, 30.61; N, 16.18. С10H5Cl3N4O4. Calculated (%): С, 34.14;
1
H, 1.42; Cl, 30.30; N, 15.93. Н NMR, δ: 7.85 (d, 2 H, Harom
,
J = 9.0 Hz); 8.25 (d, 2 H, Harom, J = 9.0 Hz); 11.25 (s, 1 H,
NH). MS, m/z (for 35Cl): 350 [M]+.
Nꢀ(2,3ꢀDimethylphenyl)ꢀ5ꢀtrichloromethylꢀ1,2,4ꢀoxadiꢀ
azolylꢀ3ꢀcarboxamide (5e) was synthesized from amidoxime 1h
and CCl3COCl by refluxing for 90 min in 58% yield (0.19 g),
m.p. 184—186 °С (from toluene). Found (%): С, 43.15; H, 3.10;

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Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Yarovenko et al.
Cl, 31.83; N, 12.50. С12H10Cl3N3O2. Calculated (%): С, 43.08;
H, 3.01; Cl, 31.79; N, 12.56. Н NMR, δ: 2.05 (s, 3 H, Me);
2.30 (s, 3 H, Me); 3.60 (m, 4 H, СH2); 7.10 (m, 3 H, Harom);
10.00 (s, 1 H, NH). MS, m/z: 300 [M]+.
1
2.50 (s, 3 H, Me); 7.00 (m, 2 H, Harom); 7.35 (d, 1 H, Harom);
Nꢀ(2,3ꢀDimethylphenyl)ꢀ5ꢀmorpholinoꢀ1,2,4ꢀoxadiazolylꢀ3ꢀ
carboxamide (6e) was synthesized from oxadiazole 5e and
morpholine, the reaction duration was 3 h, and the yield was
0.11 g (56%), m.p. 200—202 °С. Found (%): С, 57.10; H, 5.15;
N, 20.29. C15H18N4O3. Calculated (%): С, 59.59; H, 6.00;
N, 18.53. 1Н NMR, δ: 2.10 (s, 3 H, Me); 2.30 (s, 3 H, Me); 3.60
(m, 4 H, СH2); 3.75 (m, 4 H, СH2); 7.10 (m, 3 H, Harom); 10.05
(s, 1 H, NH). MS, m/z: 302 [M]+.
NꢀPhenylꢀ5ꢀguanidinoꢀ1,2,4ꢀoxadiazolylꢀ3ꢀcarboxamide (6f)
was synthesized from oxadiazole 5а and guanidine, isolated from
guanidine nitrate (0.5 g, 5 mmol) in MeOH (5 mL) by the
treatment with KOH (0.3 g, 5 mmol) in MeOH (5 mL), and
filtered off from КNO3. The duration of the reaction was 24 h,
and the yield was 0.8 g (90%), m.p. 218—222 °С. Found (%):
С, 48.69; H, 4.10; N, 34.20. C10H10N6O2. Calculated (%):
С, 48.78; H, 4.07; N, 34.13. MS, m/z: 246 [M]+.
10.25 (s, 1 H, NH). MS, m/z (for 35Cl): 333 [M]+.
Nꢀ(Thiazolꢀ2ꢀyl)ꢀ5ꢀtrichloromethylꢀ1,2,4ꢀoxadiazolylꢀ3ꢀ
carboxamide (5f) was synthesized from amidoxime 1i and
CCl3COCl by refluxing for 2 h in 40% yield (0.13 g), m.p.
148—150 °С (from chloroform). Found (%): С, 26.76; H, 1.15;
Cl, 34.15; N, 17.95. C7H3Cl3N4O2S. Calculated (%): С, 26.88;
H, 0.96; Cl, 34.08; N, 17.92. 1Н NMR, δ: 3.40 (s, 1 H,
NH); 7.30 (m, 1 H, Hthiazole); 7.60 (m, 1 H, Hthiazole). MS,
m/z (for 35Cl): 312 [M]+.
Nꢀ(4ꢀAminosulfonylphenyl)ꢀ5ꢀtrichloromethylꢀ1,2,4ꢀoxadiꢀ
azolylꢀ3ꢀcarboxamide (5g) was synthesized from amidoxime 1f
and ClCH2COCl by refluxing for 2.5 h in 60% yield (0.27 g),
m.p. 205—207 °С (from toluene). Found (%): С, 31.32; H, 1.95;
Cl, 27.50; N, 14.39. C10H7Cl3N4O4S. Calculated (%): С, 31.21;
1
H, 1.82; Cl, 27.69; N, 14.56. Н NMR, δ: 7.30 (s, 2 H, NH2);
7.85 (m, 2 H, Harom); 7.95 (m, 2 H, Harom); 11.35 (s, 1 H, NH).
Nꢀ(4ꢀAminosulfonylphenyl)ꢀ5ꢀmorpholinoꢀ1,2,4ꢀoxadiazolylꢀ
3ꢀcarboxamide (6g) was synthesized from oxadiazole 5g and
morpholine during 24 h in 50% yield (0.5 g), m.p. 204—206 °С
(from EtOH). Found (%): С, 44.23; H, 4.35; N, 19.73.
C13Н15N5O5S. Calculated (%): С, 44.19; H, 4.25; N, 19.83.
1Н NMR, δ: 3.60 (m, 4 H, СH2); 3.75 (m, 4 H, СH2); 7.30 (s,
2 H, NH2); 7.80 (m, 2 H, Harom); 7.95 (m, 2 H, Harom); 10.85 (s,
1 H, NH). MS, m/z: 353 [M]+.
MS, m/z (for 35Cl): 384 [M]+.
Reactions of 3ꢀcarbamoylꢀ5ꢀtrichloromethylꢀ1,2,4ꢀoxadiꢀ
azoles with Nꢀnucleophiles (general procedure). Freshly distilled
amine (10 mmol) was added to a solution of 3ꢀcarbamoylꢀ5ꢀ
trichloromethylꢀ1,2,4ꢀoxadiazole 5 (3 mmol) in MeOH (10 mL).
Then (TLC monitoring) the solvent was distilled off on a rotary
evaporator. Water (30 mL) was poured on the oily residue obꢀ
tained after evaporation, and the mixture was left over 1 h. The
solid precipitate was filtered off, dried, and recrystallized from
ethanol. This procedure was used to produce compounds 6a—g
and 7a—f.
NꢀPhenylꢀ5ꢀmorpholinoꢀ1,2,4ꢀoxadiazolylꢀ3ꢀcarboxamide
(6а) was synthesized from oxadiazole 5а and morpholine, the
duration of the reaction was 3 h, and the yield was 0.4 g (34%),
m.p. 155—157 °С. Found (%): С, 57.10; H, 5.15; N, 20.29.
C13H14N4O3. Calculated (%): С, 56.93; H, 5.11; N, 20.44.
1Н NMR, δ: 3.65 (s, 4 H, СH2); 3.75 (s, 4 H, СH2); 7.15 (m,
1 H, Harom); 7.35 (m, 2 H, Harom); 7.65 (m, 2 H, Harom); 10.45
(s, 1 H, NH). MS, m/z: 274 [M]+.
Nꢀ(4ꢀNitrophenyl)ꢀ5ꢀmorpholinoꢀ1,2,4ꢀoxadiazolylꢀ3ꢀ
carboxamide (6b) was synthesized from oxadiazole 5d and
morpholine, the reaction duration was 3 h, and the yield was
0.20 g (68%), m.p. 235—237 °С. Found (%): С, 48.87; H, 4.15;
N, 21.79. C13H13N5O5. Calculated (%): С, 48.91; H, 4.10;
N, 21.94. 1Н NMR, δ: 3.65 (m, 4 H, СH2); 3.75 (m, 4 H, СН2);
8.00 (d, 2 H, Harom, J = 8.9 Hz); 8.30 (d, 2 H, Harom, J =
8.9 Hz); 11.00 (s, 1 H, NH). MS, m/z: 319 [M]+.
Nꢀ(4ꢀNitrophenyl)ꢀ5ꢀpiperidinoꢀ1,2,4ꢀoxadiazolylꢀ3ꢀcarboxꢀ
amide (6c) was synthesized from oxadiazole 5d and piperidine,
the reaction duration was 3 h, and the yield was 0.18 g (65%),
m.p. 233—235 °С. Found (%): С, 52.95; H, 4.70; N, 22.19.
C14H15N5O4. Calculated (%): С, 52.99; H, 4.76; N, 22.07.
1Н NMR, δ: 1.65 (m, 6 H, СH2); 3.65 (m, 4 H, СН2); 8.00 (d,
2 H, Harom, J = 8.9 Hz); 8.25 (d, 2 H, Harom, J = 8.9 Hz); 11.00
(s, 1 H, NH). MS, m/z: 317 [M]+.
NꢀPhenylꢀ5ꢀ(2,2ꢀdimethylhydrazonomethyl)ꢀ1,2,4ꢀoxadiꢀ
azolylꢀ3ꢀcarboxamide (7а). А. Synthesis from oxadiazole 5a.
Product 7a was synthesized from oxadiazole 5а and 1,1ꢀdiꢀ
methylhydrazine (0.1 g, 1.6 mmol) during 12 h. The yield was
0.06 g (75%), m.p. 239—240 °С with decomposition (from
EtOH). Found (%): С, 55.38; H, 4.93; N, 27.15. C12H13N5O2.
1
Calculated (%): С, 55.59; H, 5.02; N, 27.03. Н NMR, δ: 3.65
(s, 6 H, Me); 7.25 (t, 1 H, Harom, J = 7.3 Hz); 7.35 (m, 2 H,
H
arom); 7.75 (d, 2 H, Harom, J = 8.0 Hz); 10.10 (s, 1 H, NH);
11.75 (s, 1 H, СH=). MS, m/z: 259 [M]+.
B. Synthesis from oxadiazole 4a. Hydrazone 7a was syntheꢀ
sized from oxadiazole 4a (50 mg, 0.2 mmol) and 1,1ꢀdimethylꢀ
hydrazine (0.2 g, 3 mmol) during 12 h in 50% yield (20 mg).
MS, m/z: 259 [M]+.
Nꢀ(3,4ꢀDichlorophenyl)ꢀ5ꢀ(2,2ꢀdimethylhydrazinomethyl)ꢀ
1,2,4ꢀoxadiazolylꢀ3ꢀcarboxamide (7b) was synthesized from
oxadiazole 5b (0.5 mmol) and 1,1ꢀdimethylhydrazine (0.15 g,
2.5 mmol). The reaction duration was 24 h, and the yield was
0.12 g (66%), m.p. 246—248 °С. Found (%): С, 43.67; H, 3.20;
Cl, 21.55; N, 21.70. C12H11Cl2N5O2. Calculated (%): С, 43.92;
1
H, 3.38; Cl, 21.61; N, 21.34. Н NMR, δ: 3.65 (s, 6 H, Me);
7.65 (m, 1 H, Harom); 7.75 (m, 1 H, Harom); 8.10 (s, 1 H, Harom);
10.25 (s, 1 H, NH); 11.70 (s, 1 H, СН=). MS, m/z: 327,
329, 331 [M]+.
Nꢀ(4ꢀChlorophenyl)ꢀ5ꢀ(2,2ꢀdimethylhydrazinomethyl)ꢀ1,2,4ꢀ
oxadiazolylꢀ3ꢀcarboxamide (7c) was synthesized from oxadiazole
5c (0.3 g, 0.9 mmol) and 1,1ꢀdimethylhydrazine (0.30 g, 5 mmol).
The duration of the reaction was 24 h, and the yield was 0.11 mg
(44%), m.p. 243—245 °С. Found (%): С, 49.14; H, 4.20;
Cl, 12.19; N, 23.70. C12H12ClN5O2. Calculated (%): С, 49.07;
Nꢀ(2,3ꢀDimethylphenyl)ꢀ5ꢀpiperidinoꢀ1,2,4ꢀoxadiazolylꢀ3ꢀ
carboxamide (6d) was synthesized from oxadiazole 5e and pipꢀ
eridine, the reaction duration was 3 h, and the yield was 0.12 g
(58%), m.p. 171—173 °С. Found (%): С, 63.94; H, 6.53;
N, 18.49. C16H20N4O2. Calculated (%): С, 63.98; H, 6.71;
1
H, 4.12; Cl, 12.07; N, 23.84. Н NMR, δ: 3.65 (s, 6 H, Me);
7.35 (d, 2 H, Harom, J = 8.7 Hz); 7.75 (d, 2 H, Harom, J =
8.7 Hz); 10.25 (s, 1 H, NH); 11.70 (s, 1 H, СН=). MS, m/z:
293, 295 [M]+.
1
N, 18.65. Н NMR, δ: 1.65 (m, 6 H, СH2); 2.10 (s, 3 H, Me);

Synthesis of 3ꢀcarbamoylꢀ1,2,4ꢀoxadiazoles
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
1861
Nꢀ(4ꢀNitrophenyl)ꢀ5ꢀ(2,2ꢀdimethylhydrazinomethyl)ꢀ1,2,4ꢀ
oxadiazolylꢀ3ꢀcarboxamide (7d) was synthesized from oxadiazole
5d (0.14 g, 0.5 mmol) and 1,1ꢀdimethylhydrazine (0.15 g,
2.5 mmol) during 24 h in 67% yield (0.08 g), m.p. 216—218 °С.
Found (%): С, 47.67; H, 4.14; N, 27.70. C12H12N6O4. Calcuꢀ
lated (%): С, 47.37; H, 3.98; N, 27.62. 1Н NMR, δ: 3.65 (s, 6 H,
Me); 7.75 (d, 2 H, Harom, J = 9.0 Hz); 7.95 (d, 2 H, Harom, J =
9.0 Hz); 10.25 (s, 1 H, NH); 11.70 (s, 1 H, СН=). MS,
m/z: 304 [M]+.
Nꢀ(2,3ꢀDimethylphenyl)ꢀ5ꢀ(2,2ꢀdimethylhydrazinomethyl)ꢀ
1,2,4ꢀoxadiazolylꢀ3ꢀcarboxamide (7e) was synthesized from
oxadiazole 5e (0.3 g, 1 mmol) and 1,1ꢀdimethylhydrazine (0.30 g,
5 mmol) during 24 h in 42% yield (0.11 g), m.p. 252—254 °С.
Found (%): С, 58.67; H, 5.72; N, 24.70. C14H17N5O2. Calcuꢀ
lated (%): С, 58.53; H, 5.96; N, 24.38. 1Н NMR, δ: 2.10 (s, 3 H,
Me); 2.70 (s, 3 H, Me); 3.60 (s, 6 H, Me); 7.10 (m, 3 H, Harom);
9.80 (s, 1 H, NH); 11.70 (s, 1 H, СН=). MS, m/z: 287 [M]+.
Nꢀ(4ꢀAminosulfonylphenyl)ꢀ5ꢀ(2,2ꢀdimethylhydrazinoꢀ
methyl)ꢀ1,2,4ꢀoxadiazolylꢀ3ꢀcarboxamide (7f) was synthesized
from oxadiazole 5g (0.2 g, 5 mmol) and 1,1ꢀdimethylhydrꢀ
azine (1.5 g, 25 mmol) during 24 h in 59% yield (0.10 g),
m.p. 216—218 °С. Found (%): С, 42.67; H, 4.23; N, 24.70.
C12H14N6O4S. Calculated (%): С, 42.60; H, 4.17; N, 24.84.
1Н NMR, δ: 3.65 (s, 6 H, Me); 7.20 (s, 2 H, NH2); 7.75 (m, 2 H,
Harom); 7.95 (m, 2 H, Harom); 10.25 (s, 1 H, NH); 11.70 (s, 1 H,
СН=). MS, m/z: 338 [M]+.
References
1. Leallyn B. Clapp, Adv. Heterocycl. Chem., 1976, 20, 102.
2. Pat. ЕР0647635А1 С1СО7D 271/06 12.04.95.
3. Pat. DE43069662А1 СО7D 271/06 8.09.94.
4. V. N. Yarovenko, S. A. Kosarev, I. V. Zavarzin, and M. M.
Krayushkin, Izv. Akad. Nauk, Ser. Khim., 1998, 2002 [Russ.
Chem. Bull., 1998, 47, 1947 (Engl. Transl.)].
5. V. N. Yarovenko, V. K. Taralashvili, I. V. Zavarzin, and M. M.
Krayushkin, Tetrahedron, 1990, 46, 3941.
6. F. Eloy and R. Lenaers, Helv. Chim. Acta, 1966, 49, 1430.
Received October 29, 2001;
in revised form July 15, 2002