Synthesis of new 2-hydrazono-4oxo-5-thiazolidineacetic acids and their alkylamides

Article abstract of DOI:10.1135/cccc19970124

The direct two step synthesis of three new 2-hydrazono-4-oxo-5-thiazolidineacetic acids from thiosemicarbazide, the appropriate ketones (acetophenone, cyclopentanone, cyclohexanone) and maleic anhydride is described. The prepared acids were transformed, v

Full text of DOI:10.1135/cccc19970124

124
Sigmundova, Meciarova:
SYNTHESIS OF NEW 2-HYDRAZONO-4-OXO-5-THIAZOLIDINEACETIC
ACIDS AND THEIR ALKYLAMIDES
1
2
Ivica SIGMUNDOVA and Maria MECIAROVA
Department of Organic Chemistry, Comenius University, 842 15 Bratislava, Slovak Republic;
e-mail: 1 sigmundova@fns.uniba.sk, 2 organika@fns.uniba.sk
Received July 1996
Accepted September 28, 1996
The direct two step synthesis of three new 2-hydrazono-4-oxo-5-thiazolidineacetic acids from thio-
semicarbazide, the appropriate ketones (acetophenone, cyclopentanone, cyclohexanone) and maleic
anhydride is described. The prepared acids were transformed, via their mixed anhydrides with ethyl
carbonate, into their alkylamides in a one-pot procedure.
Key words: 2-Hydrazono-4-oxo-5-thiazolidine; Effect on chlorophyll production.
Several 2-hydrazono- and 2-aza-4-oxo-5-thiazolidineacetic acids possess the antiviral
properties1–3. The fungicidal properties of the compounds with similar structure were
described also4. It is of interest that no attention has been paid to the investigation of
the biological activity of their amides.
The main goal of this work was to prepare new 2-hydrazono-4-oxo-5-thiazolidine-
acetic acids and their amides and to investigate their biological activity5.
Synthesis of 2-hydrazono-4-oxo-5-thiazolidineacetic acids1,6 2a–2c from the corre-
sponding thiosemicarbazones 1 (refs7–10) was performed by a two step procedure de-
picted in Scheme 1. Thiosemicarbazones 1a–1c, which were isolated in 80–90% yields,
were allowed to react with maleic anhydride in chloroform. After several hours heating
at reflux temperature and usual work-up reasonable yields (50–90%) of the acids 2a–2c
as good crystallizing solids were achieved. The conversion of 2-hydrazono-4-oxo-5-
thiazolidineacetic acids 2 into their alkylamides 3 was performed as described in
Scheme 1. The characteristic data of the compounds 3 are given in Table I.
The biological activity of the prepared compounds was briefly evaluated by their
effect on the chlorophyll production. No special effect of their addition on the chloro-
phyll production has been found. Their biological activity is under screening.
EXPERIMENTAL
1H NMR spectra (δ, ppm; J, Hz) were recorded in (CD3)2SO on a Tesla BS 487 apparatus (80 MHz)
with tetramethylsilane as internal standard. The effect of compounds 2a–2c and 3a–3o on chlorophyll
synthesis in stationary-cultivated Chlorella vulgaris algae (7 days, 16 h light/8 h dark period) was
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

Short Communication
125
TABLE I
Characteristic data of compounds 2 and 3
Calculated/Found
M.p., °C
Yield, %
Formula
M.w.
Compound
% C
% H
% N
% S
2aa
246–247 C13H13N3O3S
89 291.3
181–184 C11H15N3O3S
70 269.3
210–212 C10H13N3O3S
48 255.3
204–207 C15H18N4O2S
19 318.4
163–165 C16H20N4O2S
20 332.4
227–229 C16H20N4O2S
42 332.4
168–173 C17H22N4O2S
47 363.4
194–196 C20H20N4O2S
380.5
183–185 C13H20N4O2S
25 296.4
164–167 C14H22N4O2S
310.4
210–214 C14H22N4O2S
32 310.4
165–167 C15H24N4O2S
22 324.4
170–175 C18H22N4O2S
49 358.5
188–190 C12H18N4O2S
16 282.4
209–211 C13H20N4O2S
11 296.4
53.61
53.16
4.50
4.56
14.43
14.22
10.98
10.65
2b
2c
3a
3b
3c
3d
3e
3f
49.06
49.40
5.61
5.68
15.60
15.95
11.91
12.26
47.05
46.95
5.13
5.05
16.46
16.42
12.56
12.75
56.58
56.50
5.70
5.70
17.60
17.48
10.07
10.14
57.81
56.72
6.06
6.16
16.85
17.06
9.65
9.62
57.81
57.49
6.06
6.08
16.85
16.77
9.65
9.38
58.94
59.24
6.40
6.63
16.17
16.22
9.26
9.06
63.14
62.91
5.30
5.40
14.73
14.76
8.43
8.37
5
52.68
52.60
6.80
6.77
18.90
18.88
10.82
10.84
3g
3h
3i
54.17
54.35
7.14
7.13
18.05
18.10
10.33
10.20
8
54.17
54.52
7.14
7.15
18.05
17.91
10.33
10.57
55.53
55.41
7.46
7.37
17.27
17.15
9.88
10.30
3j
60.31
60.32
6.19
6.08
15.63
16.09
8.94
9.14
3k
3l
51.04
51.26
6.42
6.51
19.84
19.64
11.36
11.19
52.68
52.40
6.80
6.80
18.90
18.78
10.82
10.56
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126
Sigmundová, Meciarová:
TABLE I
(Continued)
Calculated/Found
M.p., °C
Yield, %
Formula
M.w.
Compound
% C
% H
% N
% S
3m
3n
3o
234–237
41
C
13H20N4O2S
296.4
52.68
52.56
6.80
6.84
18.90
18.91
10.82
10.56
164–167 C14H22N4O2S
13 310.5
194–198 C17H20N4O2S
32 344.4
54.15
54.27
7.17
7.32
18.04
17.94
10.33
10.36
59.28
58.89
5.85
5.75
16.27
16.17
9.31
9.22
a
Ref.1 gives m.p. 248–249 °C, yield 80%.
O
1
1
S
H
N
R
R
+
C
N
NH
C
NH
O
C
N
N
O
2
2
2
R
R
S
O
1a-1c
CH COOH
2
2a-2c
2
1
R
R
1, 2
1. ClCOOC H , (C H ) N
2
5
2 5 3
3
CH
3
C H
6 5
a
b
c
2. R NH
2
-(CH ) -
2 5
-(CH ) -
2 4
1
H
N
R
C
N
N
O
2
2
1
3
R
R
R
R
3
O
C
S
3
CH
CH
CH
CH
CH
C H
6
C H
6
C H
6
C H
6
CH CH
2 3
(CH ) CH
2 2
CH(CH )
3 2
(CH ) CH
2 3
a
b
c
d
e
f
3
3
3
3
3
5
R
NH
CH
2
5
5
5
5
3
3a-3o
3
C H
6
CH C H
6 5
2
-(CH ) -
2 5
CH CH
2 3
-(CH ) -
2 5
(CH ) CH
2 2
g
h
3
-(CH ) -
2 5
CH(CH )
3 2
-(CH ) -
2 5
(CH ) CH
2 3
i
j
3
-(CH ) -
2 5
CH C H
6 5
2
-(CH ) -
2 4
-(CH ) -
2 4
CH CH
2 3
(CH ) CH
2 2
k
l
3
m
-(CH ) -
2 4
CH(CH )
3 2
-(CH ) -
2 4
(CH ) CH
2 3
n
o
3
-(CH ) -
2 4
CH C H
6 5
2
SCHEME 1
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127
TABLE II
1H NMR parameters of compounds 2 and 3
Compound
1H NMR spectrum
2a
2b
2c
3a
3b
2.39 s, 3 H (CH3); 2.84 d, 2 H, J = 3.4 (CH2); 4.37 dd, 1 H, J = 9.5, 4.0 (CH);
7.44–7.91 m, 5 H (arom); 12.10 s, 1 H (COOH)
1.59 s, 6 H (3 × CH2); 2.26 s, 4 H (2 × CH2); 2.87 d, 2 H, J = 3.4 (CH2); 4.23 dd, 1 H,
J = 9.5, 4.0 (CH); 12.10 s, 1 H (COOH)
1.73 m, 4 H (2 × CH2); 2.33 m, 4 H (2 × CH2) 2.92 d, 2 H, J = 3.4 (CH2); 4.25 dd,
1 H, J = 9.5, 4.0 (CH); 12.03 s, 1 H (COOH)
1.02 t, 3 H, J = 7.3 (CH3); 2.38 s, 3 H (CH3); 2.76–3.20 m, 4 H (2 × CH2); 4.18 dd,
1 H, J = 9.5, 4.0 (CH); 7.40–7.91 m, 6 H (arom, NH); 11.89 s, 1 H (NH)
0.85 t, 3 H, J = 7.2 (CH3); 1.37 m, 2 H (CH2); 2.39 s, 3 H (CH3); 2.70–3.19 m, 4 H
(2 × CH2); 4.32 dd, 1 H, J = 9.5, 4.0 (CH); 7.39–7.91 m, 6 H (arom, NH); 11.92 s,
1 H (NH)
3c
1.05 d, 6 H, J = 6.4 (2 × CH3); 2.38 s, 3 H (CH3); 2.85 d, 2 H, J = 4.0 (CH2); 3.73 m,
1 H (CH); 4.29 dd, 1 H, J = 9.5, 4.0 (CH); 7.39–7.96 m, 6 H (arom, NH); 11.89 s,
1 H (NH)
3d
3e
3f
0.87–1.37 m, 7 H (CH3, 2 × CH2); 2.38 s, 3 H (CH3); 2.66–3.12 m, 4 H (2 × CH2); 4.30 dd,
1 H, J = 9.5, 4.0 (CH); 7.40–8.10 m, 6 H (arom, NH); 11.73 s, 1 H (NH)
2.38 s, 3 H (CH3); 2.76–3.00 m, 4 H (2 × CH2); 4.30 dd, 1 H, J = 9.5, 4.0 (CH); 7.28 s,
5 H (arom); 7.40–7.93 m, 5 H (arom); 8.52 t, 1 H, J = 6.0 (NH); 11.7 s, 1 H (NH)
1.04 t, 3 H, J = 7.3 (CH3); 1.58 s, 6 H (3 × CH2); 2.49 s, 4 H (2 × CH2); 2.55–3.16 m,
4 H (2 × CH2); 4.19 dd, 1 H, J = 9.5, 4.0 (CH); 8.07 t, 1 H, J = 6.0 (NH); 11.63 s,
1 H (NH)
3g
3h
3i
0.87 t, 3 H, J = 7.2 (CH3); 1.27–1.45 m, 2 H (CH2); 1.58 s, 6 H (3 × CH2); 2.50 s, 4 H
(2 × CH2); 2.70–3.14 m, 4 H (2 × CH2); 4.21 dd, 1 H, J = 9.5, 4.0 (CH); 7.96 t, 1 H,
J = 6.0 (NH); 11.59 s, 1 H (NH)
1.05 d, 6 H, J = 6.4 (2 × CH3); 1.59 s, 6 H (3 × CH2); 2.25 s, 4 H (2 × CH2); 2.79 d,
2 H, J = 4.0 (CH2); 3.71–3.87 m, 1 H (CH); 4.20 dd, 1 H, J = 9.5, 4.0 (CH); 7.87 d,
1 H, J = 7.3 (NH); 11.52 s, 1 H (NH)
0.34–1.36 m, 7 H (CH3, 2 × CH2); 1.59 s, 6 H (3 × CH2); 2.25 s, 4 H (2 × CH2);
2.69–3.30 m, 4 H (2 × CH2); 4.20 dd, 1 H, J = 9.5, 4.0 (CH); 7.95 t, 1 H, J = 6.0 (NH);
11.58 s, 1 H (NH)
3j
1.59 s, 6 H (3 × CH2); 2.27 s, 4 H (2 × CH2); 2.92 d, 2 H, J = 4.0 (CH2); 4.20 dd, 1 H,
J = 9.5, 4.0 (CH); 7.28 s, 5 H (arom); 8.61 t, 1 H, J = 6.0 (NH); 11.67 s, 1 H (NH)
3k
1.02 t, 3 H, J = 7.2 (CH3); 1.71 m, 4 H (2 × CH2); 2.36 m, 4 H (2 × CH2); 2.68–3.16 m,
4 H (2 × CH2); 4.21 dd, 1 H, J = 9.5, 4.0 (CH); 8.10 t, 1 H, J = 6.0 (NH); 11.66 s,
1 H (NH)
3l
0.84 t, 3 H, J = 7.2 (CH3); 1.41 m, 2 H (2 × CH2); 2.37 m, 4 H (2 × CH2); 2.69–3.05 m,
4 H (2 × CH2); 4.22 dd, 1 H, J = 9.5, 4.0 (CH); 7.96 t, 1 H, J = 6.0 (NH); 11.65 s,
1 H (NH)
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

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Sigmundová, Meciarová:
TABLE II
(Continued)
Compound
3m
1H NMR spectrum
1.05 d, 6 H, J = 6.4 (2 × CH3); 1.70 m, 4 H (2 × CH2); 2.36 m, 4 H (2 × CH2); 2.79 d,
2 H, J = 4.0 (CH2); 3.82 m, 1 H (CH); 4.21 dd, 1 H, J = 9.5, 4.0 (CH); 7.88 d, 1 H,
J = 7.3 (NH); 11.65 s, 1 H (NH)
3n
3o
0.87–1.71 m, 7 H (CH3, 2 × CH2); 2.36 m, 4 H (2 × CH2); 2.53–2.83 m, 4 H (2 × CH2);
4.22 dd, 1 H, J = 9.5, 4.0 (CH); 7.99 t, 1 H, J = 6.0 (NH); 11.66 s, 1 H (NH)
1.71 m, 4 H (2 × CH2); 2.48 m, 4 H (2 × CH2); 2.68–2.93 m, 4 H (2 × CH2); 4.20 dd, 1 H,
J = 9.5, 4.0 (CH); 7.28 s, 5 H (arom); 8.58 t, 1 H, J = 6.0 (NH); 11.62 s, 1 H (NH)
investigated according to the ref.5. Thiosemicarbazones 1a–1c were prepared according to general
procedures7–10 with minor modifications in their purification. Thiosemicarbazone 1a was recrystal-
lized from aqueous 50% (v/v) methanol. Thiosemicarbazones 1b and 1c were recrystallized from
aqueous 30% (v/v) ethanol.
2-Hydrazono-4-oxo-5-thiazolidineacetic Acids1,6 2. General Procedure
Maleic anhydride (0.15 mol, 14.7 g) was dissolved in chloroform (500 ml) and then added eqiumolar
amount of corresponding thiosemicarbazone 1. The reaction mixture was stirred under reflux for 4 h
and then left overnight at room temperature. Crystalline product was filtered off and crystallized
from aqueous 30% (v/v) ethanol. Yields, melting points and elemental analyses of compounds 2 are
1
given in Table I, their H NMR spectra in Table II.
2-Hydrazono-4-oxo-5-thiazolidineacetic Acids Alkylamides11 3. General Procedure
To a stirred solution containing 0.01 mol of corresponding acid 2a–2c, triethylamine (1.0 g, 0.01 mol)
and anhydrous dichloromethane (60 ml) was added dropwise ethyl chloroformate (1.1 g, 0.01 mol) in
dichloromethane (15 ml). The reaction mixture was stirred at 0 °C for 15 min, then corresponding
amide (0.01 mol) dissolved in dichloromethane (15 ml) was added and the mixture was stirred for
further 20 min at 0 °C. The reaction mixture was left for 4 h at room temperature, then refluxed for
2 h, cooled and washed with water (2 × 50 ml), saturated solution of sodium hydrogen carbonate
(2 × 50 ml) and water (2 × 50 ml). The organic phase was dried with anhydrous sodium sulfate, the
solvent was evaporated under reduced pressure and the crude product was crystallized from aqueous
1
30% (v/v) ethanol. The characteristic data for compounds 3 are given in Table I, their H NMR spec-
tra in Table II.
1
Our thanks are due to Dr E. Solcániová and her staff for H NMR measurements, Dr E. Greiplová
and her staff for the microanalyses and Dr K. Králová for investigation of the biological activity.
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