Synthesis of new substituted thiazoles containing aminooxadiazole ring

Article abstract of DOI:10.1134/S1070427208030385

Synthesis of biheterocyclic thiazole-amonooxadiazoles, the potential biologically active compounds is developed. Regularities of transformations and physico-chemical characteristics of intermediates and final compounds are revealed.

Full text of DOI:10.1134/S1070427208030385

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2008, Vol. 81, No. 3, pp. 513−515. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © O.V. Platonova, S.B. Volkova, S.A. Malin, E.A. Veretennikov, B.M. Laskin, A.S. Malin, 2008, published in Khimicheskaya Promyshlen-
nost’, 2008, Vol. 85, No. 1, pp. 1−4.
TECHNOLOGY OF ORGANIC
AND INORGANIC CHEMISTRY
Synthesis of New Substituted Thiazoles
Containing Aminooxadiazole Ring
O. V. Platonova, S. B. Volkova, S. A. Malin, E. A. Veretennikov, B. M. Laskin, and A. S. Malin
Russian Scientific Center “Applied Chemistry,” St. Petersburg, Russia
Received February 12, 2007
Abstract—Synthesis of biheterocyclic thiazole–amonooxadiazoles, the potential biologically active compounds
is developed. Regularities of transformations and physico-chemical characteristics of intermediates and final
compounds are revealed.
DOI: 10.1134/S1070427208030385
The heterocycles of thiazole series are known to pos-
sess biological activity; some representatives of this class
compounds are well-known medicine preparations [1,
2]. Compounds containing simultaneously thiazole and
aminooxadiazole fragments merit special mentioning.
Synthesis of these potentially biologically active com-
pounds practically has not been described. We developed
Compounds IIa–IId are crystalline substances melting
in the temperature range from 56 to 65°С.
Note that at the synthesis of compounds IIa–IIc the
process duration increases for the series of substituents
а to c, probably in connection with steric properties of
these substituents. The process duration for compound
IId increases probably due to strong electromeric ef-
a few-step procedure for the synthesis of thiazole–ami- fect of conjugated system that includes phenyl group.
Introduction of triethylamine to the reaction zone allows
accelerate the process considerably and increase yield of
compound IId to 75%.
nooxadiazoles and studied conditions of the process and
its technological parameters.
Substituted thiazoles IIa–IId were prepared by reaction
of chloroacetoacetic esters prepared in correspondence
with the procedure in [3] with thioacetamide in alcohol
medium (like Hanch reaction [4, 5]) at 80–90°С, duration
period 7–12 h, yield up to 75–80%.
The process conditions for the synthesis of the thiazoles
and some of their characteristics are listed in Table 1.
Synthesis of corresponding hydrazines IIIa–IIId has
been poorly illuminated in literature. We prepared hydra-
513

514
PLATONOVA et al.
Table 1. Process conditions for the synthesis of compounds
IIa−IId
IVа−IVd is considerably less basic as compared with
related unsubstituted aminooxazoles. The most probably
this is defined by the presence of conjugated system thia-
zole–aminooxadiazole, in the case of IVd in particular,
due to presence of phenyl group expanding conjugation.
Spectral characteristics of the synthesized compounds
are listed in Table 4.
Compd.
no.
Process
Process
Yield,
mp,
°
duration, h temperature, °
%
8
5
80 7
82 7
85 7
0
56
65
61
5
IIa
7
7
IIb
8.5
12.3 9
0
IIc
CONCLUSIONS
73 5
IId
A series of new potentially biologically active bihetero-
cyclic compounds containing thiazole and aminooxazole
rings is synthesized, optimal conditions of the synthesis
are studied and revealed.
Table 2. Conditions of synthesis of compounds IIIa−IIId
Compd. Process duration,
Process
temperature, °
77–83
Yield, mp,
no.
h
%
°
Structure of the obtained compounds is proved and they
are characterized by means of 1H NMR spectroscopy.
10
11
13
16
82 1
80 1
77 1
74 1
01
IIIa
IIIb
IIIc
IIId
80–85
05
14
58
EXPERIMENTAL
84–88
The 1Н NMR spectra are recorded on a е Bruker AM
500 spectrometer, internal reference TMS, solvent DMSO-
d6. Melting points are measured on a PTP unit.
90–95
Table 3. The process conditions for the synthesis of compounds
IVa-IVd
Synthesis of R-substituted ethyl esters of thia-
zolecarboxylic acids IIa–IId. Mixture of preliminary
prepared R-substituted chloroacetoacetic ester Ia–Id
(0.236 mol) and thioacetamide (0.236 mol) in 100 ml of
ethanol or isopropyl alcohol was refluxed on water bath
with stirring for 7–12 h. After cooling the reaction mixture
was diluted with 200 ml of dichloromethane. Precipitate
formed was removed by filtration and filtrate was washed
with 20% solution of sodium hydrocarbonate (100 ml) to
neutral reaction and then by solution (100 ml) of sodium
chloride. The layers were separated, and from organic
layer dicloromethane was distilled off after drying over
magnesium sulfate, and then compounds IIa–IId were
isolated in 85–90% yield.
Compd. Process
Process
Yield,
mp,
°
no.
IVa
IVb
IVc
IVd
duration, h temperature, °
%
0
6
8.5
9
28 8
31 7
35 7
40
235
224
243
30
7
3
10
68 2
zides IIIa−IIId by reaction of thiazoles IIa−IId with 3–5-
fold excess of 64% hydrazine hydrate in absolute ethnol
at 90–100°С, reaction duration was 10 to 20 h, yield is
as high as 95%. The compounds obtained are character-
ized by high melting point; they are well crystallizing
from water–alcohol solutions. Results of the synthesis of
compounds IIIа−IIId are shown in Table 2.
Spectral characteristics of compounds IIa–IId obtained
are listed in Table 4.
Synthesis of hydrazides of R-substituted thiazole-
carboxylic acids IIIa–IIId. To a solution of the obtained
by above procedure R-substituted ethyl ester of thiazole-
carboxylic acid IIa–IId (0.5 mol) in 125 ml of ethanol
or isopropyl alcohol was dozed at 20–30°С 100 ml
of 64% hydrazine hydrate (0.236 mol) and the raction
mixture obtained was refluxed with stirring for 10–20 h.
Then reaction mixture was concentrated in a vacuum
to 60–75%. The crystals dropped are soluble in water.
They were recryctallized from ethanol, and compounds
IIIa–IIId were obtained in 85–93% yield.
Aminooxadiazole derivatives IVa−IVd were obtained
in 65–80% yield by cyclization of the prepared hydrazides
[6, 7] with bromocyane in the presence of anhydrous
potassium carbonate at equimolar ratio of reagents in
ethanol medium at 20–40°С for 6–10h. IR spectra of the
obtained compound do not contain adsorption bands of
carbonyl and hydrazide groups while adsorption of ami-
nooxadiazole NH2 group appears in the spectra.
Structure, purity and nature of compounds IVа−IVd
were revealed using 1H NMR spectroscopy. The NMR
data obtained showed that amine fragment in compounds
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 81 No. 3 2008

SYNTHESIS OF NEW SUBSTITUTED THIAZOLES
515
Table 4. 1H NMR spectral data of compounds II–IV (solutions in DMSO–d6)
Compound
1H NMR spectra, , ppm
3); 2.47 s 3); 1.31 t
2.55 s
3); 4.27 q
2); 4.27 q
)
2
IIa
IIb
1.31 t
3); 1.37 t
0.91 t
2.4 s
3); 2.47 s
3); 1.32 t
3); 2.91 t
3); 2.55 s
3); 2.9 q
3); 1.6 m
2); 4.25 d
3), 4.28 d
)
2
2);
IIc
)
2
1.33 t
2);
IId
IIIa
IIIb
7.72–7.8 m
3); 2.38 s (
)
arom
2.32 s
1.39 t
3); 5.68 s
3); 3.35 d
NH, NH2)
2);
3); 2.39 s
5.68 s
NH, NH2)
2); 2.29 s
NH, NH2)
3); 7.62–7.7 m (5 arom);
5.81 s (3 , NH, NH2)
0.92 t
3); 1.61 m
3);
IIIc
3.35 t
2); 5.7 s
3); 5.4 s (3 ,
2.47 s (3 ,
IIId
IVa
IVb
2.37 s
1.36 t
3); 2.55 s
3); 2.38 s
7.32 s
3); 7.4 s
3); 2.98 d
NH2)
2); 2.29 s
NH2)
NH2)
2);
0.9 t
3); 1.64 m
3);
IVc
IVd
2.97 t
2); 7.6 s
2.46 s (3 ,
3); 7.62–7.72 m (5 arom); 7.33 7.6 s (2 , NH2)
REFERENCES
Spectral characteristics of compounds IIIa–IIId ob-
tained are listed in Table 4.
1. Plouvier, B and Bailly, C., et al., Heterocycles, 1991, vol. 32,
no. 4, pp. 693–701.
Synthesis of R-substituted thiazoloaminooxazoles
IVa–IVd. To a suspension of hydrazide IIIa–IIId
(0.07 mol) and sodium hydrocarbonate (0.07 mol) in water
(50 ml) at cooling by ice was dozed solution of brmocyane
(0.07 mol) in ethanol. The reaction mixture was kept at
20–25°С for 6–12 h. Then for few hours it was cooled
to 3–5°С and crystals dropped were filtered off, washed
with water for removing sodium bromide, and dried.
Compounds IVa-IVd were obtained in 65–80% yield.
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Spectral characteristics of compounds IVa–IVd ob-
pp. 88–95.
tained are listed in Table 4.
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