Synthesis of novel five-membered nitrogen-containing heterocyclic compounds from derivatives of arylsulfonyl- and arylthioacetic and -propionic acids

Article abstract of DOI:10.1023/A:1013275515682

A series of novel substituted 1,3,4-oxa(thia)diazoles and triazoline-3-thiones has been synthesized from thiosemicarbazides and nitriles of arylthio-, arylsulfonylacetic and -propionic acids. A mechanism is proposed for the preparation of 2-amino-5-substi

Full text of DOI:10.1023/A:1013275515682

Chemistry of Heterocyclic Compounds, Vol. 37, No. 9, 2001
SYNTHESIS OF NOVEL FIVE-MEMBERED
NITROGEN-CONTAINING HETEROCYCLIC
COMPOUNDS FROM DERIVATIVES OF
ARYLSULFONYL- AND ARYLTHIOACETIC
AND -PROPIONIC ACIDS
S. M. Golovlyova, Yu. A. Moskvichev, E. M. Alov, D. B. Kobylinsky, and V. V. Ermolaeva
A series of novel substituted 1,3,4-oxa(thia)diazoles and triazoline-3-thiones has been synthesized from
thiosemicarbazides and nitriles of arylthio-, arylsulfonylacetic and -propionic acids. A mechanism is
proposed for the preparation of 2-amino-5-substituted 1,3,4-thiadiazoles from carboxylic acids in
polyphosphoric acid medium.
Keywords: oxadiazole, thiadiazole, thiosemicarbazide, triazoline-3-thione, PPA, cyclization
Amongst derivatives of 1,3,4-oxa(thia)diazoles and 1,2,4-triazoles there are substances which possess
anti-inflammatory, analgesic, antiviral, antibacterial, and other biological activity [1-5]. Based on these, a large
number of medicinal preparations, polymers, dyes, etc. have been obtained. Since there is limited information in
the literature regarding the methods of synthesis and the starting materials for compounds of this type [6] it was
of interest to develop novel, efficient routes for their preparation thus increasing the range and establishing
methods for their practical usage.
In this work we report the preparation of several novel substituted 1,3,4-oxa(thia)diazoles and triazoline-
3-thiones, starting from the previously synthesized arylsulfonyl-, arylthioacetic and -propionic acids and also
their derivatives which show clearly expressed biological activity [7, 8]. 1-Substituted and 1,4-disubstituted
thiosemicarbazides 1, 2 were prepared on this basis by two routes: the reaction of arylsulfonyl-, arylthioacetic
and -propionic acid hydrazides with potassium thiocyanate or with phenyl isothiocyanate [9] and the acylation
of thiosemicarbazide with arylthio-, arylsulfonylacetic and -propionic acid chlorides [10].
1,3,4-Oxadiazole derivatives 3 were prepared by the oxidative cyclization of 1-substituted and
1,4-disubstituted thiosemicarbazides 1 and 2 in the presence of sodium hydroxide and iodine in ethanol medium
at 90°C. The yields of the target compounds achieved were 60-70%. Some parameters for the products obtained
are given in Table 1.
S
N
N
I2 + NaOH
RCONHNHCNHR'
'
NHR
R
O
1a–d, 2a–d
3a–h
1a-d, 3a-d R' = H; 2a-d, 3e-h R' = C6H5; 3a,e R = 4-ClC6H4SO2CH2CH2;
3b,f R = BrC6H4SO2CH2; 3c,g R = 4-CH3C6H4SCH2CH2; 3d,h R = 4-BrC6H4SCH2
__________________________________________________________________________________________
Yaroslavl State Technical University, Yaroslavl 150023, Russia; e-mail: sver@future.ystu.yar.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1201-1206, September, 2001. Original
article submitted July 18, 2000; revision submitted March 11, 2001.
1102
0009-3122/01/3709-1102$25.00©2001 Plenum Publishing Corporation

The IR spectra of oxadiazoles 3a-h show bands corresponding to the deformation (970 cm-1) and
stretching (1000 cm-1) vibrations of the C–O–C group. The intense doublet band in the region of 3450 cm-1 is
assigned to the stretching vibrations of the C=N group at 1650 cm-1.
Cyclodehydration of thiosemicarbazides 1 and 2 in alkaline medium brought about the synthesis of
5-substituted 1,2,4-triazoline-3-thiones 4.
H
N
N
_
S
N
N
+
OH
H
R
S
N
RCONHNHCNHR'
R
SNa
N
∆
1a–d, 2a–e
R'
4a–i
R'
4a–d R' = H; 4e–i R' = C6H5; 4a,e R = 4-ClC6H4SO2CH2CH2; 4b,f R = BrC6H4SO2CH2;
4c,g R = 4-CH3C6H4SCH2CH2; 4d,h R = 4-BrC6H4SCH2; 2e, 4i R = C6H5
The basic cyclization agent used was sodium ethylate in ethanol or an aqueous solution of sodium
hydroxide. It should also be mentioned that sodium hydroxide is more active cyclization agent for
thiosemicarbazides (the reaction time is shortened from 12 to 2 h) and this allows one to suggest an ionic
mechanism for the reaction.
With the aim of exploring the optimum conditions for the synthesis we have examined the effect of the
concentration of sodium hydroxide and of temperature on the yield of 1,2,4-triazoline-3-thione 4i. It was found
that the maximum yield (85-90%) was achieved at reaction temperature of 60°C and sodium hydroxide
concentration of 10%.
The characteristics of the synthesized compounds 3 and 4 are given in Table 1.
In the IR spectra of compounds 4a-i there are two absorption maxima at 1350-1340 and 1325-1320 cm-1,
typical of the vibrations of C=S group in 1,2,4-triazoline-3-thiones, an intense absorption band at
1525-1520 cm-1 for NH(C=S)NR group vibrations, and the absence of absorption bands for SH or CSH groups,
all of which indicate that the given compound has 1,2,4-triazoline-3-thione structure rather than the tautomeric
3-mercapto-1,2,4-triazole structure.
There are a large number of methods for the synthesis of 2-amino-5-substituted 1,3,4-thiadiazoles [6]
with different variations amongst them. The most usual is a two stage method consisting of acylation of
thiosemicarbazide using carboxylic acid chlorides and subsequent cyclization of the intermediate
acylthiosemicarbazides [9]. In the known methods various dehydrating agents are used to achieve this. The most
widely applicable of these reagents are sulfuric acid, phosphorus oxychloride, benzoyl chloride, and acetyl
chloride. Not all of these substances are readily available and convenient to use, moreover they often take part
in side reactions which significantly lower the yield of the products and complicate their separation.
We have for the first time attempted to prepare 2-amino-5-substituted 1,3,4-thiadiazoles 5 in a single
stage by the reaction of arylthio-, arylsulfonylacetic and -propionic acids or their nitriles with thiosemicarbazide
in polyphosphoric acid (PPA) medium.
PPA
+
H2NNHCSNHR'
H2NNHCSNHR'
RCOOH
RCN
N
N
'
R
NHR
S
PPA
+
5a–i
5a–d, i R' = H; 5e–h R' = C6H5; 5a,e R = 4-ClC6H4SO2CH2CH2; 5b,f R = BrC6H4SO2CH2;
5c,g R = 4-CH3C6H4SCH2CH2; 5d,h R = 4-BrC6H4SCH2; 5i R = C6H5CH2
1103

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Com-
pound
Empirical
formula
Calculated, %
mp, °С
Yield, %
С
H
S
С10H10ClN3O3S
C9H8BrN3O3S
C11H13N3OS
42.27
41.74
3.5
3.5
10.82
11.14
176-180
194-197
156-159
158-161
230-233
254-256
200-202
220-225
234-235
210-212
208-210
224-225
267-268
242-243
236-237
267-268
234-236
277-278
289-291
268-270
272-273
315-316
302-304
257-258
284-286
202-204
40
48
40
45
42
45
43
42
86
87
84
82
89
90
88
93
89
89
78
88
76
95
84
89
86
87
3a
3b
3c
3d
3e
3f
32.76
2.2
9.86
33.96
2.52
10.06
53.57
56.15
5.67
14.15
5.57
13.65
C9H8BrN3OS
C16H14ClN3O3S
C15H12BrN3O3S
C17H17N3OS
39.11
2.44
2.8
11.31
11.19
37.76
54.11
52.82
4.04
8.84
3.88
8.81
44.07
2.8
8.47
8.12
45.69
3.05
67.78
65.57
5.28
9.87
3g
3h
4a
4b
4c
4d
4e
4f
5.5
10.3
C15H12BrN3OS
C10H10ClN3O2S2
C9H8BrN3O2S2
C11H13N3S2
51.52
3.17
3.31
8.79
8.84
49.72
37.58
39.54
3.46
20.64
3.32
21.11
32.9
2.1
2.4
18.71
19.16
32.34
54.00
5.44
26.01
52.56
5.21
25.51
C9H8BrN3S2
35.02
35.76
2.24
2.65
20.82
21.19
C16H14ClN3O2S2
C15H12BrN3O2S2
C17H17N3S2
49.03
3.56
16.94
50.59
3.71
16.88
44.44
43.9
2.69
2.93
15.57
15.61
65.3
5.41
19.31
4g
4h
4i
62.35
5.23
19.58
C15H12BrN3S2
C14H11N3S
47.42
2.98
3.17
16.39
16.93
47.62
66.03
66.40
4.22
12.55
4.35
12.65
C10H10ClN3O2S2
C9H8BrN3O2S2
C11H13N3S2
37.84
3.47
3.32
20.99
21.11
5a
5b
5c
5d
5e
5f
39.54
32.83
32.34
2.03
18.97
2.4
19.16
53.07
5.08
5.21
25.23
25.51
52.56
C9H8BrN3S2
35.54
35.76
2.43
21.82
2.65
21.19
C16H14ClN3O2S2
C15H12BrN3O2S2
C17H17N3S2
50.87
3.56
3.71
17.7
50.59
16.88
42.9
43.9
2.67
16.39
2.93
15.61
60.26
5.47
5.23
19.78
19.58
5g
5h
5i
60.35
C15H12BrN3S2
C9H9N3S
47.73
47.62
2.81
17.44
3.17
16.93
56.78
4.23
4.71
16.33
16.75
56.54
PPA possesses good solvent properties and contains anhydride groups by means of which water in the
dehydration reaction is taken up. Moreover, its effective acidity is unchanged. In contrast to sulfuric acid, PPA
is not an oxidant, does not take part in an aromatic substitution reaction, and is less likely to initiate
rearrangements [11].
1104

The investigation of the effect of temperature and duration of reaction of carboxylic acids with
thiosemicarbazide on the yield of the target products permitted the determination of the optimum conditions for
the reaction. These were: temperature of 130-140°C, reaction time of 3-4 h, and molar ratio of reagents of 1:1.
The yields of the target products in this case reaches 40%.
It is likely that the following process occurs:
HN
C
NH
C
NHNH2
S
PPA
PPA
R'HN
C
RCOOH
H
R'HN
+
O
S
–H2O
R
PPA
–H2O
N
N
N N
OH
R'HN
R'HN
R
S
S
R
If nitriles are used as the starting compounds it is possible to increase the yield of the products 5a-i
significantly and the maximum yield (70-80%) is achieved at 100-110°C. It should also be mentioned that the
reaction takes place within a rather narrow temperature range. At temperature below 90°C the reaction does not
take place and, above the optimum, strong tarring of the desired compounds is observed.
In most cases the target compounds do not need extensive purification and are obtained quite pure after
first recrystallization from ethanol or DMF. The structure of the synthesized compounds has been identified
1
using IR and H NMR spectroscopy. Their purity was monitored by TLC and nonaqueous potentiometric
titration.
The absence of depression of melting point for samples prepared by the different methods points to their
identity. This is also confirmed by 1H NMR data and by TLC. The parameters for the compounds 5a-i are given
in Table 1.
The IR spectra of 2-amino-5-substituted 1,3,4-thiadiazoles 5 show absorption bands in the regions of
1520, 1490, 1385, 1235, 1040, and 865 cm-1 which are typical of the vibrations of 1,3,4-thiadiazole ring [12]
and also absorption bands at 1320-1300 cm-1 assigned to the stretching vibrations of the C–N bond in aromatic
amines.
EXPERIMENTAL
2-Amino- and 2-Phenylamino-5-substituted 1,3,4-Oxadiazoles (3a-h). Solution of NaOH (4 N, 5 ml)
was added with cooling and stirring to suspension of the corresponding thiosemicarbazide 1 or 2 (0.01 mol) in
ethanol (150 ml) and then treated dropwise with solution of iodine in aqueous KI solution (5%) at room
temperature until the reaction product retained the iodine color. The mixture obtained was heated to reflux and
solution of iodine was carefully added until a permanent coloration remained. The product was cooled to 20°C,
poured onto ice, and the precipitated product was filtered, washed with warm water, dried, and recrystallized
from aqueous acetone.
5-Substituted 1,2,4-Triazoline-3-thiones (4a-i). A. Mixture of thiosemicarbazide 1 or 2 (0.01 mol) and
sodium (0.03 mol) in absolute ethanol (30 ml) was refluxed with stirring for 12 h. The reaction mixture was
evaporated to dryness at reduced pressure and the residue was extracted with hot water (3 × 30 ml). The
aqueous extract was cooled to 5°C and acidified using acetic acid to pH 5.5. The precipitated product 4 was then
filtered, washed with water, and dried. Average yield 87%.
1105

B. Suspension of thiosemicarbazide 1 or 2 (0.01 mol) in solution of sodium hydroxide (5%, 100 ml) was
refluxed for 2 h and then held at room temperature for 12 h. The precipitate was filtered off, suspended with
stirring in water (200 ml), and solution of HCl (5%) was added to pH 4.5-5.0. The precipitated product 4 formed
was filtered off, washed with water, dried, and recrystallized from ethanol. Average yield 85%.
2-Amino-5-substituted 1,3,4-Thiadiazoles (5a-i). A 100 ml round-bottomed flask was fitted with a
reflux condenser, thermometer, mechanical stirrer, and dropping funnel and polyphosphoric acid (25 ml) was
poured in. Thiosemicarbazide (0.01 mol) was added and the mixture obtained was heated on an oil bath at 50°C
under constant stirring. The flask was then charged with the corresponding acid or nitrile (0.01 mole) and the
product was held strictly at 100-110°C for 3 h. The reaction mixture was then poured into water, cooled to room
temperature, and aqueous ammonia (25%) was added to pH 9-10. The precipitate was filtered off and dried at
60°C. The obtained product 5 was recrystallized from mixture of DMF and ethanol (3:7).
REFERENCES
1.
2.
N. N. Mel'nikov, K. V. Novozhilov, R. S. Belan, and T. N. Pylova, Pesticide Handbook [in Russian],
Khimiya, Moscow (1985), pp. 95, 98.
J. S. Ward and E. Lilly, USSR Inventor's Certificate 725558, Byul. Izobr., No. 12, 255 (1980), Chem.
Abstr., 87, 210546c (1977).
3.
4.
K. D. Larionov, Chemotherapy of Malignant Tumors [in Russian], Moscow (1962).
V. S. Chernov, Cytostatic Substances in the Chemistry of Malignant Cytoplasms [in Russian], Moscow
(1964), pp. 62, 66, 180.
N. D. Platonova, in the book Aspects of the Chemistry of Malignant Tumors [in Russian], Moscow
(1960), p. 167.
5.
6.
7.
T. S. Gilchrist, The Chemistry of Heterocyclic Compounds, [Russian Translation], Mir, Moscow (1996).
T. T. Levkovskaya, Yu. I. Kryukova, Yu. A. Moskvichev, G. S. Mironov, G. G. Kryukova,
A. N. Mirskova, and M. G. Voronkov, Khim.-Farm. Zh., 431 (1984).
E. M. Alov, S. E. Novikov, A. V. Nikiforov, Yu. A. Moskvichev, G. G. Kryukova, T. M. Smirnova,
B. Ya. Berenev, and M. A. Nefedova, USSR Patent 1806134; Byul. Izobr., No. 12, 180 (1993).
V. I. Kelarev, V. A. Karakhanov, S. Sh. Gasanov, G. V. Morozova, and K. P. Kuatbekova, Zh. Org.
Khim., 29, 388 (1993).
8.
9.
10.
11.
Organikum [in Russian], Mir, Moscow (1992), Vol. 1, p. 487.
L. F. Fieser and M. Fieser, Reagents for Organic Synthesis [Russian translation], Mir, Moscow (1970),
Vol. 3.
12.
A. R. Katritzky (editor), Physical Methods in the Chemistry of Heterocyclic Compounds [Russian
translation], Mir, Moscow-Leningrad (1996).
1106