Tetrazoles: LV. Perparation of 2-anilino-5-aryl(hetaryl)-1,3,4-oxadiazoles from 5-substituted tetrazoles under microwave activation

Article abstract of DOI:10.1134/S1070428009080211

In reaction of 5-aryl(hetaryl)tetrazoles with phenyl isocyanate under the conditions of microwave activation the corresponding 2-anilino-5-aryl(hetaryl)- 1,3,4-oxadiazoles formed in high yields. The application of the microwave activation fourfold reduced

Full text of DOI:10.1134/S1070428009080211

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 8, pp. 1241−1244. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © Yu.A. Efimova, G.G. Karabanovich, T.V. Artamonova, G.I. Koldobskii, 2009, published in Zhurnal Organicheskoi Khimii,
2009, Vol. 45, No. 8, pp. 1249−1251.
Tetrazoles: LV.
Perparation of 2-Anilino-5-aryl(hetaryl)-1,3,4-oxadiazoles
from 5-Substituted Tetrazoles under Microwave Activation
Yu.A. Efimova, G. G. Karabanovich, T.V .Artamonova, and G. I. Koldobskii
St. Petersburg State Technological Institute, St. Petersburg,190013 Russia
e-mail: koldobsk@lti-gti.spb.ru
Received December 20, 2008
Abstract—In reaction of 5-aryl(hetaryl)tetrazoles with phenyl isocyanate under the conditions of microwave
activation the corresponding 2-anilino-5-aryl(hetaryl)-1,3,4-oxadiazoles formed in high yields. The application of
the microwave activation fourfold reduced the reaction time.
DOI: 10.1134/S1070428009080211
In extension of research on the preparation methods
and chemical properties of tetrazoles and on the applica-
tion of these compounds to organic synthesis we investig-
ated the reaction of 5-aryl(hetaryl)tetrazoles with phenyl
isocyanate under the conditions of microwave activation
(MWA).
2,5-Disubstituted-1,3,4-oxadiazoles are extensively
used in the sybthesis of versatile pharmaceuticals [2–4].
A special place in this series belongs to 2-arylamino-
5-aryl-1,3,4-oxadiazoles that can be prepared by several
procedures where the main method is the cyclization of
1,4-disubstituted thiosemicarbazides in the presence of
reagents like tosyl chloride in pyridine [5] or dicyclo-
hexylcarbodiimide [6]. The disadvantage of this method
consists in the multistage synthesis of the initial 1,4-di-
substituted thiosemicarbazides.
Based on the data obtained in the study of the chemical
properties of tetrazoles under MWA conditions [1, 13,
14] it was presumable that the rate of the reaction of
5-substituted tetrazoles with the phenyl isocyanate would
significantly grow under the microwave irradiation.
Actually, the reaction of 5-aryl(hetaryl)tetrazoles with the
phenyl isocyanate under MWA conditions provided in
a good yield the corresponding 2-anilino-5-aryl(hetaryl)-
1,3,4-oxadiazoles, and compared to nonactivated process
the reaction time was 4 times shorter (see the table).
At the same time 2-arylamino-5-aryl-1,3,4-oxadiazoles
can be obtained in a good yield in the reaction of 5-phenyl-
tetrazole with aromatic isocyanates [7]. Huisgen et al.
suggested the mechanism of this reaction that was proved
in [8–11] (see the scheme).
The investigation of the transformation mechanism
under heating of acyltetrazoles and also 2,5-disubstituted
tetrazoles [12] is an important stage in the development
of concepts on the structure and reactivity of 1,3-dipoles
and on the involvement of these intermediates into
reactions of 1,5-electrocyclization and 1,3-dipolar cyclo-
addition.
The course of the reaction between the 5-substituted
tetrazoles and the phenyl isocyanate is considerably
affected by the nature of the used solvent. Thus in the
series of solvents under study (DMF, DMSO, nitro-
benzene) the latter proved to be the most efficient.
Finally, one more important trend calls for attention
established in the study of the reactions between the
5-substituted tetrazoles and the phenyl isocyanate. For
instance, at heating of 5-(4-pyridyl)tetrazole with the
phenyl isocyanate in nitrobenzene at 150°C for 8 h no
reaction occurred. Under the same conditions and at the
Therefore the new wide opportunities were
demonstrated of tetrazoles application to the synthesis
of heterocyclic substrates whose preparation by another
way was experimentally complicated.
* For Communication LIV, see [1].
1241

EFIMOVA et al.
1242
Scheme.
O
C
R1
R1
R2
NH
N
N
160°C
N
+ OCNR2
N
N
N
H
N
_
N
O
C
O_
C
N N
O
2
2
R1
C
+
N N
R1
C
+
N N
.
.
NH R
NH R
2
R1
NH R
_N2
.
microwave irradiation the corresponding 1,3,4-oxadiazole
formed in 2 h in 96% yield.
Although the data on the activation parameters of the
thermal transformation of N-acyl derivatives of 5-sub-
stituted tetrazole are now lacking, from the findings
obtained in the study of the thermolysis mechanism of
2,5-disubstituted tetrazoles [16, 17] it is possible to
presume that these reactions proceed with a high
activation energy. Evidently this circumstance is among
the principal reasons of the strong influence of the
microwave irradiation on the reactions of the 5-substituted
tetrazoles with the phenyl isocyanate.
Similar trends were formerly found in the study of
reactions of isomeric 5-pyridyltetrazoles with phenyl
isothiacyanate under MWA conditions [14].
These results are well consistent with to-day concepts
on the effect of the microwave irradiation on the course
of the chemical reactions [15].
According to common standpoint the microwave
radiation significantly affects the course of reactions with
high activation energies.
EXPERIMENTAL
Yields (%) of 2-anilino-5-aryl(hetaryl)-1,3,4-oxadiazoles Ia–Ij
obtained under heating (2 h, 150°C) and MWA(0.5 h, 150°C)
IR spectra were recorded on a spectrophotometer
Shimadzu FTIR-8400s from pellets with KBr. 1H NMR
spectra were registered on a spectrometer Bruker WM-
400 in DMSO-d6. Reactions under MWAconditions were
carried out in a reactor Milestone P/N 44072. Elemental
analyses were performed on an analyzer LECO
CHNS(O)-932. The purity and homogeneity of com-
pounds obtained were checked by TLC on Silufol plates,
eluent acetone–hexane, 1 : 2.
Compound no.
Heating
86
MWA
81
Ia
71
84
Ib
85
82
Ic
97
81
Id
85
73
Ie
84
92
If
Reactions of 5-aryl(hetaryl)tetrazoles with the phenyl
isocyanate were carried out by identical procedure both
at heating and under MWA conditions.
86
73
Ig
96
90
Ih
a
–
96b
Ii
2-Anilino-5-(4-dimethylaminophenyl)-1,3,4-
oxadiazole (Ia). A mixture of 0.5 g (2.6 mmol) of 5-(4-
dimethylaminophenyl)tetrazole and 0.35 g (2.9 mmol) of
phenyl isocyanate in 5 ml of nitrobenzene was stirred for
0.5 h in a microwave reactor at 150°C (70 W). The
reaction mixture was cooled to 20°C, diluted with 20 ml
of hexane, the separated precipitate was filtered off,
washed with hexane (2×20 ml), and dried in air. Yield
55
94
Ij
Reaction time: a 8 h, b 2 h.
R
NH
N N
МWА
150°C, 0.5 h
+ PhNCO
N
N
.
R
NH Ph
N
O
Iа_Ij
1
81%, mp 256–257°C (from acetonitrile) [5]. H NMR
spectrum, δ, ppm: 3.00 s (6H, NCH3), 6.81 d (2Harom),
6.97 t (1Harom), 7.34 t (2Harom), 7.56 d (2Harom), 7.69 d
(2Harom), 10.47 s (1H, NH).
R = 4-Me2NC6H4 (a), 4-MeOC6H4 (b), 4-MeC6H4 (c), Ph
(d), 4-ClC6H4 (e), 4-NO2C6H4 (f), 2-pyridyl (g), 3-pyridyl
(h), 4-pyridyl (i), 2-furyl (j).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 8 2009

TETRAZOLES: LV.
1243
ethanol) [6]. 1H NMR spectrum, δ, ppm: 7.02 t (1Harom.),
7.36 t (2Harom), 7.60 d (2Harom), 7.80 d (2Harom), 8.78 d
(2Harom), 10.85 s (1H, NH).
Oxadiazoles Ib–Ij were obtained similarly.
2-Anilino-5-(4-methoxyphenyl)-1,3,4-oxadiazole
(Ib). Yield 84%, mp 203°C (from ethanol) [9]. 1H NMR
spectrum, δ, ppm: 3.82 s (3H, OCH3), 6.99 t (1Harom),
7.11 d (2Harom), 7.34 t (2Harom), 7.60 d (2Harom), 7.83 d
(2Harom), 10.58 s (1H, NH).
2-Anilino-5-(2-furyl)-1,3,4-oxadiazole (Ij). Yield
94%, mp 204–205°C (from toluene). IR spectrum, ν,
cm–1: 3334, 3178, 3127, 3057, 2940, 2877, 1939, 1855,
1667, 1620, 1509, 1448, 1441, 1408, 1370, 1309, 1295,
1237, 1226, 1159, 1087, 1054, 1030, 1018, 1008, 988, 960,
901, 886, 881, 863, 841, 825, 797, 769, 749, 740, 720, 688,
627, 590, 501, 447. 1H NMR spectrum, δ, ppm: 6.75 s
(1Harom), 7.01 t (1Harom), 7.12 d (1Harom), 7.35 t (2Harom),
7.56 d (2Harom), 7.97 s (1Harom), 10.71 s (1H, NH). Found,
%: C 63.27; H 4.24; N 18.56. C12H9N3O2. Calculated,
%: C 63.44; H 3.96; N 18.50.
2-Anilino-5-(4-methylphenyl)-1,3,4-oxadiazole
(Ic). Yield 82%, mp 226–227°C (from acetonitrile). IR
spectrum, ν, cm–1: 3284, 3134, 3064, 2925, 2853, 2786,
1711, 1620, 1615, 1606, 1594, 1577, 1556, 1547, 1519,
1449, 1313, 1300, 1230, 1190, 1122, 1090, 1047, 1019,
957, 901, 859, 821, 789, 753, 726, 691, 569, 504. 1H NMR
spectrum, δ, ppm: 2.37 s (3H, CH3), 7.00 t (1Harom),
7.36 m (4Harom), 7.59 d 2Harom), 7.79 d (2Harom), 10.62 s
(1H, NH). Found, %: C 71.39; H 4.91; N 16.21.
C15H13N3O. Calculated, %: C 71.71; H 5.18; N 16.73.
The study was carried out under the financial support
of the Russian Foundation for Basic Research (grant
no. 08-03-00342a).
2-Anilino-5-phenyl-1,3,4-oxadiazole (Id). Yield
1
81%, mp 218°C (from ethanol) [7]. H NMR spectrum,
REFERENCES
δ, ppm: 7.00 t (1Harom), 7.34 t (2Harom), 7.61 m (5Harom),
7.89 d (2Harom), 10.67 s (1H, NH).
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2-Anilino-5-(4-chlorophenyl)-1,3,4-oxadiazole
(Ie). Yield 73%, mp 258–260°C (from ethanol) [9].
1H NMR spectrum, δ, ppm: 7.02 t (1Harom.), 7.35 t
(2Harom), 7.58–7.65 m (4Harom), 7.88 d (2Harom), 10.70 s
(1H, NH).
2-Anilino-5-(4-nitrophenyl)-1,3,4-oxadiazole (If).
Yield 92%, mp 269–270°C (from acetic acid) [18].
1H NMR spectrum, δ, ppm: 7.03 t (1Harom), 7.37 t
(2Harom), 7.61 d (2Harom), 8.11 d (2Harom), 8.39 d (2Harom),
10.83 s (1H, NH).
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vol. 24, p. 1233.
2-Anilino-5-(2-pyridyl)-1,3,4-oxadiazole (Ig).
Yield 73%, mp 230–231°C (from toluene). IR spectrum,
ν, cm–1: 3311, 3177, 3035, 2991,2935, 2873, 1664, 1585,
1561, 1546, 1502, 1456, 1437, 1384, 1312, 1251, 1233,
1150, 1094, 1060, 1033, 985, 893, 864, 791, 755, 741, 724,
10. Broggini, G., Molteni, G., and Zecchi, G., Heterocycles, 1988,
vol. 47, p. 541.
1
625, 500. H NMR spectrum, δ, ppm: 7.02 t (1Harom.),
7.37 t (2Harom), 7.60 m (3Harom), 8.00 m (2Harom), 8.71 d
(1Harom), 10.83 s (1H, NH). Found, %: C 65.45; H 4.17;
N 23.34. C13H10N4O. Calculated, %: C 65.54; H 4.20;
N 23.53.
11. Ostrovskii, V.A., Koldobskii, G.I., and Trifonov, R.E.,
Comprehensive Heterocycl. Chem. III, 2008, vol. 6, p. 257.
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vol. 64, p. 1698.
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Org. Khim., 2008, vol. 44, p. 1361.
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Koldobskii, G.I., Zh. Org. Khim., 2009, vol. 45, p. 644.
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Orbital Symmetry, Cambridge: Cambridge Univ., 1972.
2-Anilino-5-(3-pyridyl)-1,3,4-oxadiazole (Ih).
Yield 90%, mp 237–238°C (from ethanol) [6]. 1H NMR
spectrum, δ, ppm: 7.02 t (1Harom), 7.36 t (2Harom), 7.62 d
(3Harom), 8.24 d (1Harom), 8.73 d (1Harom), 9.05 s (1Harom),
10.83 C (1H, NH).
2-Anilino-5-(4-pyridyl)-1,3,4-oxadiazole (Ii).
Reaction time 2 h. Yield 96%, mp 216–218°C (from
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 8 2009