Synthesis of 2-thioxo-1,3-thiazolidin-4-one derivatives

Article abstract of DOI:10.1007/s11172-007-0254-2

A series of new 2-thioxo-1,3-thiazolidin-4-one derivatives containing arylidene, arylazo, and aminomethylene fragments in position 5 of the rhodanine cycle was synthesized.

Full text of DOI:10.1007/s11172-007-0254-2

Russian Chemical Bulletin, International Edition, Vol. 56, No. 8, pp. 1624—1630, August, 2007
1624
Synthesis of 2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ4ꢀone derivatives*
V. N. Yarovenko,aꢀ A. S. Nikitina,b I. V. Zavarzin,a M. M. Krayushkin,a and L. V. Kovalenkob
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 137 6939. Eꢀmail: yarov@mail.ioc.ac.ru
bD. I. Mendeleev Russian University of Chemistry and Technology,
9 Miusskaya pl.,125047 Moscow, Russian Federation.
Fax: +7 (495) 978 6132. Eꢀmail: lvkcpf@muctr.edu.ru
A series of new 2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ4ꢀone derivatives containing arylidene, arylazo,
and aminomethylene fragments in position 5 of the rhodanine cycle was synthesized.
Key words: thiohydrazides of oxamic acids, thiorhodanines, 2ꢀthioxothiazolidinꢀ4ꢀones,
azorhodanines.
Scheme 1
The Knoevenagel condensation, acylation, and azoꢀ
coupling reactions at the active methylene group of
rhodanines afford 5ꢀsubstituted derivatives manifesting a
wide range of pharmacological properties, in particular,
possessing anticancer properties.1,2
We have previously3 synthesized new derivatives of
2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ4ꢀones 1 by the reaction of
thiohydrazides of oxamic acids with trithiocarbonylꢀ
diglycolic acid in the presence of dicyclohexylcarboꢀ
diimide or carbonyldiimidazole.
In the present work, we studied the reactivity of the
active methylene group in position 5 of rhodanines 1 and
synthesized their 5ꢀarylideneꢀ, 5ꢀarylazoꢀ, and 5ꢀaminoꢀ
methylꢀsubstituted derivatives.
The influence of the catalyst and solvent on the reꢀ
action of rhodanines 1 with aldehydes was studied.
The reactions of 2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ4ꢀones 1a—d
with aromatic and heterocyclic aldehydes in methanol
in the presence of ethylenediammonium diacetate at
ambient temperature afford 5ꢀarylideneꢀ2ꢀthioxoꢀ1,3ꢀ
thiazolidinꢀ4ꢀones 2a—i in 85—95% yields (Scheme 1).
The use of sodium acetate in acetic acid or acetic anꢀ
hydride gives lower yields of products 2a—i (45—65%),
whereas the latter are not formed at all when the reꢀ
action is carried out in ethanol in the presence of pipꢀ
eridine.
1: R = Ph (a), pꢀClC6H4 (b), pꢀMeC6H4 (c),
(d)
2
a
R
Ph
R´
Ph
b
Ph
d
c
e
pꢀClC6H4
pꢀClC6H4
pꢀMeC6H4
Ph
Ph
f
pꢀMeC6H4
The treatment of 2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ4ꢀones
1a—d with triethyl orthoformate in acetic anhydride gave
5ꢀethoxymethylenerhodanines 3a—d in 60—75% yields.
They are convenient synthons for the synthesis of azoꢀ
methines. The reactions of compounds 3a—d with secꢀ
h
g
Ph
i
Ph
* Dedicated to Academician V. A. Tartakovsky on the occasion
of his 75th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1564—1569, August, 2007.
1066ꢀ5285/07/5608ꢀ1624 © 2007 Springer Science+Business Media, Inc.

2ꢀThioxoꢀ1,3ꢀthiazolidinꢀ4ꢀone derivatives
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
1625
ondary amines afford 5ꢀaminomethylenerhodanines 4a—h
in 70—80% yields (Scheme 2).
We failed to synthesize 5ꢀbromorhodanine according
to the described procedure4 (in acetic acid at 80—90 °C).
Resinification of the product occurs at the isolation stage.
We showed that the process occurred successfully in diꢀ
oxane at ambient temperature. Since bromination prodꢀ
uct 7a is unstable and decomposes in air, the reaction
mixture was treated with aniline or haloanilines without
isolating this bromide, and 5ꢀarylaminorhodanines 8a—c
are formed (Scheme 4).
Scheme 2
Scheme 4
3: R = Ph (a), pꢀClC6H4 (b), pꢀMeC6H4 (c),
4: R = Ph (a, b), pꢀClC6H4 (c, d),
(d)
pꢀMeC6H4 (e, f),
(g, h)
8: R = H (a), 3ꢀF (b), 3,5ꢀCl2 (c)
The thioamide group was modified into the amide
group with the formation of the corresponding amides
9a—d using the treatment of rhodanines 1a—d with hydroꢀ
gen peroxide in acetonitrile at ambient temperature
(Scheme 5).
X = O (a, c, e, g), CH2 (b, d, f, h)
Phenylhydrazones 5a—d were synthesized by the reꢀ
action of rhodanines 1a—d with phenyldiazonium salt in
70—75% yields, and this reaction with benzoyl chloride
afforded 5ꢀbenzoylthiazolidinꢀ4ꢀones 6a—d in 70—80%
yields (Scheme 3).
Scheme 5
Scheme 3
9: R = Ph (a), pꢀClC6H4 (b), pꢀMeC6H4 (c),
(d)
The structures of the synthesized compounds were
1
confirmed by the H, 13C NMR and mass spectral data.
1
The H NMR spectra of rhodanines 1a—d contain no
chemical shift of the proton of secondary amine near the
thiocarbonyl group because of screening of the latter,
whereas in the spectra of compounds 9a—d the signal
from this proton appears at 12 ppm.
5, 6: R = Ph (a), pꢀClC6H4 (b), pꢀMeC6H4 (c),
(d)

1626
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
Yarovenko et al.
The reaction mixtures were analyzed and purity of the isolated
products was monitored by TLC (EtOAc—hexane (1 : 1) mixꢀ
ture as eluent) on Merck 60 F254 plates.
2ꢀThioxoꢀ1,3ꢀthiazolidinꢀ4ꢀones 1a—d were synthesized acꢀ
cording to an earlier described procedure.3
The characteristics of the primarily synthesized compounds
are given in Tables 1 and 2.
2ꢀ[(5ꢀBenzylideneꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀ
yl)amino]ꢀ2ꢀthioxoꢀNꢀphenylacetamide (2a). Rhodanine 1a
Experimental
1
H and 13C NMR spectra were recorded on a Bruker ACꢀ300
instrument (working frequency 300 MHz) in DMSOꢀd6. Mass
spectra were recorded on a Kratos instrument with direct injecꢀ
tion of a sample into the ion source with an ionization energy of
70 eV and a controlling voltage of 1.75 kV. Melting points were
measured on a Boetius heating stage and were not corrected.
Table 1. Characteristics of synthesized compounds 2a—i, 3a—d, 4a—h, 5a—d, 6a—d, 8a—c, and 9a—d
Product
Yield (%)
M.p/°C
Found
Calculated
Molecular
formula
(%)
C
H
N
S
Cl
—
2a
2b
2c
2d
2e
2f
95
85
93
85
89
85
93
86
75
75
65
62
70
80
72
79
70
77
75
80
70
158—159
173—174
168—169
154—155
168—169
149—150
181—182
178—179
165—166
115—116
133—134
125—126
146—147
173—174
166—167
189—190
171—172
163—164
158—159
192—193
174—175
54.12
54.17
44.23
44.23
49.82
49.90
40.98
41.06
53.13
53.19
43.96
44.04
49.88
49.96
42.21
42.31
50.25
50.35
45.76
45.78
41.84
41.76
45.33
45.41
43.11
43.22
47.04
47.09
50.22
50.31
43.38
43.43
46.30
46.38
46.56
46.64
49.52
49.59
44.34
44.42
46.85
46.92
3.28
3.32
2.32
2.38
2.79
2.85
1.93
2.00
3.52
3.50
2.60
2.66
3.79
3.85
2.98
2.91
2.41
2.37
3.57
3.51
3.01
2.91
3.80
3.83
4.04
4.10
3.95
3.91
4.46
4.51
3.41
3.51
3.89
3.93
4.14
4.19
4.62
4.60
4.31
4.27
4.72
4.60
10.52
10.48
12.90
12.81
8.17
24.08
23.93
22.14
22.02
22.17
22.10
20.51
20.42
22.39
22.30
20.71
20.61
25.36
25.32
23.72
23.61
19.16
19.09
26.18
26.23
23.93
24.01
24.20
24.23
27.08
27.03
23.55
23.61
23.66
23.70
21.72
21.67
21.81
21.70
21.93
21.88
22.03
22.00
24.92
24.87
25.02
24.96
C18H13N3O2S3
C16H10N4O5S3
C18H12ClN3O2S3
C16H9ClN4O5S3
C19H15N3O3S3
C17H12N4O6S3
C21H19N3O4S4
C19H16N4O7S4
C21H12ClN3O4S3
C14H13N3O3S3
C14H12ClN3O3S3
C15H15N3O4S3
C17H19N3O5S4
C16H16N4O3S3
C17H18N4O2S3
C16H15ClN4O3S3
C17H17ClN4O2S3
C17H18N4O4S3
C18H20N4O3S3
C19H22N4O5S4
C20H24N4O4S4
—
8.17
8.21
7.56
7.63
—
8.21
11.95
11.85
9.78
9.71
12.06
12.13
8.31
—
—
—
2g
2h
2i
8.23
10.36
10.43
8.37
7.06
7.15
—
8.25
3a
3b
3c
3d
4a
4b
4c
4d
4e
4f
11.43
11.38
10.45
10.43
10.57
10.51
8.87
8.82
8.76
—
—
—
—
8.81
13.71
13.78
13.78
13.73
12.65
12.73
12.70
12.77
12.78
12.77
12.83
12.77
10.89
10.96
10.93
10.99
8.00
7.95
8.04
7.98
—
—
—
—
4g
4h
(to be continued)

2ꢀThioxoꢀ1,3ꢀthiazolidinꢀ4ꢀone derivatives
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
1627
Table 1 (continued)
Product
Yield (%)
M.p/°C
Found
Calculated
Molecular
formula
(%)
C
H
N
S
Cl
—
5a
5b
5c
5d
6a
6b
6c
6d
75
70
73
70
73
70
79
72
68
72
70
93
93
89
85
217—218
221—222
203—204
212—213
130—131
126—127
110—111
138—139
227—228
205—206
241—242
164—165
177—178
156—157
197—198
49.14
49.16
45.38
45.48
48.53
48.62
46.05
46.15
52.03
52.16
48.05
48.09
51.22
51.30
48.35
48.46
50.73
50.79
48.56
48.63
43.31
43.38
42.43
42.52
38.20
38.29
42.21
42.25
41.88
41.93
3.15
3.11
2.69
2.63
3.39
3.42
3.67
3.70
3.15
3.18
2.69
2.65
3.39
3.34
3.67
3.62
3.51
3.46
3.12
3.09
2.57
2.51
2.91
2.87
2.33
2.29
3.25
3.21
3.77
3.74
16.85
16.97
15.56
15.69
15.72
15.86
13.43
13.45
10.11
10.18
9.34
23.15
23.18
21.38
21.32
21.59
21.53
24.59
24.51
23.15
23.05
21.38
21.33
21.59
21.51
24.59
24.53
23.90
23.87
22.88
22.85
20.41
20.37
30.89
30.86
27.81
27.76
28.17
28.24
23.96
24.03
C17H13N5O2S3
C17H12ClN5O2S3
C18H15N5O3S3
C20H19N5O4S4
C18H13N3O3S3
C18H12ClN3O3S3
C19H15N3O4S3
C21H19N3O5S4
C17H14N4O2S3
C17H13FN4O2S3
7.88
7.79
—
—
—
7.88
7.81
—
9.48
9.43
9.52
8.06
—
—
—
8.11
13.92
14.03
13.32
13.42
11.88
11.96
13.49
13.58
12.15
12.22
12.31
12.36
10.47
10.42
8b
8c
9a
9b
9c
9d
15.04
15.00
—
C17H12Cl2N4O2S3
C11H9N3O2S3
10.25
10.23
—
C11H8ClN3O2S3
C12H11N3O3S3
C14H15N3O5S3
—
Table 2. Spectral data for compounds 2a—i, 3a—d, 4a—h, 5a—d, 6a—d, 8a—c, and 9a—d
Product
1H NMR (300.13 MHz, DMSOꢀd6),
MS,
δ (J/Hz)
m/z
2a
7.10, 7.25 (both t, 1 H each, 2 СНarom, J = 7.3, J = 7.5); 7.40 (t, 2 Н, 2 СНarom, J = 7.2);
7.55 (t, 2 Н, 2 СНarom, J = 7.8); 7.75 (d, 2 Н, 2 СНarom, J = 7.8);
7.85 (d, 2 Н, 2 СНarom, J = 7.9); 8.05 (s, 1 Н, CНaliph); 11.05 (s, 1 Н, NH)
399
434
433
2b
2c
7.20 (t, 1 Н, СНarom, J = 7.3); 7.31 (d, 1 Н, СНarom, J = 3.6); 7.45 (t, 2 Н, 2 СНarom
J = 7.2); 7.65 (d, 1 Н, СНarom, J = 3.5); 7.90 (d, 2 Н, 2 СНarom, J = 7.4);
8.05 (s, 1 Н, СНaliph); 10.90 (s, 1 Н, NH)
,
7.20 (t, 1 Н, СНarom, J = 7.4); 7.35 (d, 2 Н, 2 СНarom, J = 8.7); 7.55 (t, 2 Н,
2 СНarom, J = 9.0); 7.75 (d, 2 Н, 2 СНarom, J = 7.8); 7.95 (d, 2 Н, 2 СНarom
,
J = 8.74); 8.10 (s, 1 Н, СНaliph); 10.90 (s, 1 Н, NH)
2d
2e
7.20 (d, 1 Н, СНarom, J = 3.6); 7.50 (d, 2 Н, 2 СНarom, J = 8.7); 7.75 (d, 1 Н, СНarom
J = 3.5); 7.95 (d, 2 Н, 2 СНarom, J = 8.7); 8.05 (s, 1 Н, СНaliph); 11.2 (s, 1 Н, NH)
3.75 (s, 3 H, OCH3); 6.95 (d, 2 Н, 2 СНarom, J = 8.9); 7.35 (t, 1 Н, СНarom, J = 7.8);
7.05 (d, 2 Н, 2 СНarom, J = 9.0); 7.75 (t, 2 Н, 2 СНarom, J = 9.0); 7.95 (d,
2 Н, 2 СНarom, J = 8.7); 8.10 (s, 1 Н, СНaliph); 10.70 (s, 1 Н, NH)
,
468
429
(to be continued)

1628
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
Yarovenko et al.
Table 2 (continued)
Product
1H NMR (300.13 MHz, DMSOꢀd6),
MS,
δ (J/Hz)
m/z
2f
3.75 (s, 3 H, OCH3); 7.00 (d, 2 Н, 2 СНarom, J = 8.9); 7.35 (d, 1 Н, СНarom, J = 3.7);
7.60 (d, 2 Н, 2 СНarom, J = 9.0); 7.85 (d, 1 Н, СНarom, J = 3.6); 8.00 (s, 1 Н, СНaliph);
11.10 (s, 1 Н, NH)
1.25 (t, 3 Н, СН3(aliph); J = 7.4); 1.35 (t, 3 Н, СН3(aliph); J = 7.1); 2.70 (q, 2 Н, СН2(aliph));
4.35 (q, 2 Н, СН2(aliph)); 7.0 (s, 1 Н, СНarom); 7.20 (t, 1 Н, СНarom, J = 7.8); 7.40 (t, 2 Н,
2 СНarom, J = 8.9); 7.70 (d, 2 Н, 2 СНarom, J = 8.9); 8.10 (s, 1 Н, СН aliph); 11.50 (s, 1 Н, NH)
1.25 (t, 3 Н, СН3(aliph); J = 7.4); 1.35 (t, 3 Н, СН3(aliph); J = 7.1); 2.70 (q, 2 Н, СН2(aliph));
4.35 (q, 2 Н, СН2(aliph)); 7.10 (s, 1 Н, СНarom); 7.35 (d, 1 Н, СНarom, J = 3.7); 7.85 (d, 1 Н,
СНarom, J = 3.6); 8.20 (s, 1 Н, СНaliph); 11.40 (s, 1 Н, NH)
464
505
540
2g
2h
2i
3a
7.20—7.95 (m, 9 Н, Ar); 8.20 (s, 1 Н, СНaliph); 11.40 (s, 1 Н, NH)
501
367
1.33 (t, 3 Н, СН3(aliph); J = 7.0); 4.45 (q, 2 Н, СН2(aliph)); 7.20 (t, 1 Н, СНarom, J = 7.0);
7.40 (t, 2 Н, 2 СНarom, J = 7.8); 7.85 (d, 2 Н, 2 СНarom, J = 8.1); 8.20 (s, 1 Н,
СНaliph); 10.90 (s, 1 Н, NH)
3b
3c
3d
4a
1.35 (t, 3 Н, СН3(aliph); J = 7.0); 4.40 (q, 2 Н, СН2(aliph)); 7.50 (d, 2 H, 2 СНarom, J = 8.7);
7.75 (both d, 1 H each, 2 СНarom, J = 7.8); 8.15 (s, 1 Н, СНaliph); 10.70 (s, 1 Н, NH)
1.33 (t, 3 Н, СН3(aliph); J = 7.1); 3.75 (s, 3 H, OCH3(aliph)); 4.45 (q, 2 Н, СН2(aliph)); 7.00 (d, 2 H,
2 СНarom, J = 8.9); 7.70 (d, 2 Н, 2 СНarom, J = 9.0); 8.10 (s, 1 Н, СНaliph); 10.80 (s, 1 Н, NH)
1.25 (t, 3 Н, СН3(aliph); J = 7.4); 1.35 (t, 6 Н, 2 СН3(aliph); J = 7.2); 2.70 (q, 2 Н, СН2(aliph));
4.35 (q, 4 Н, 2 СН2(aliph)); 7.00 (s, 1 Н, СНarom); 8.20 (s, 1 Н, СН aliph); 10.80 (s, 1 Н, NH)
3.25—3.40 (m, 4 Н, 2 СН2(aliph)); 3.60—3.75 (m, 4 Н, 2 СН2(aliph)); 7.20 (t, 1 H, СНarom, J = 7.6);
7.40 (t, 2 H, 2 СНarom, J = 7.6); 7.75 (d, 2 H, 2 СНarom, J = 7.7); 8.05 (s, 1 Н, СНaliph);
10.35 (s, 1 H, NH)
401
397
473
408
4b
1.50—1.70 (m, 4 Н, 3 СН2(aliph)); 3.60—3.75 (m, 4 Н, 2 СН2(aliph)); 7.20 (t, 1 H, СНarom, J = 7.6);
7.40 (t, 2 H, 2 СНarom, J = 7.6); 7.75 (d, 2 H, 2 СНarom, J = 7.9); 8.05 (s, 1 Н, СНaliph);
10.35 (s, 1 H, NH)
406
4c
4d
4e
3.20—3.40 (m, 4 Н, 2 СН2(aliph)); 3.60—3.75 (m, 4 Н, 2 СН2(aliph)); 7.45 (both d, 2 H, 2 СНarom
J = 8.7); 7.85 (d, 2 H, 2 СНarom, J = 8.7); 8.20 (s, 1 Н, СНaliph); 10.35 (s, 1 H, NH)
,
440
442
438
1.35—1.75 (m, 4 Н, 3 СН2(aliph)); 3.15—3.35 (m, 4 Н, 2 СН2(aliph)); 7.50 (d, 2 H, 2 СНarom
,
J = 8.7); 7.90 (d, 2 H, 2 СНarom, J = 8.7); 8.15 (s, 1 Н, СНaliph); 10.30 (s, 1 H, NH)
3.20—3.40 (m, 4 Н, 2 СН2(aliph)); 3.60—3.70 (m, 4 Н, 2 СНaliph); 3.75 (s, 3 H, OCH3(aliph));
6.95 (d, 2 H, 2 СНarom, J = 8.9); 7.70 (d, 2 H, 2 СНarom, J = 9.0); 8.15 (s, 1 Н,
СНaliph); 10.20 (s, 1 H, NH)
4f
1.30—1.70 (m, 4 Н, 3 СН2(aliph)); 3.15—3.35 (m, 4 Н, 2 СНaliph); 3.75 (s, 3 H, OCH3(aliph));
6.95 (d, 2 H, 2 СНarom, J = 8.9); 7.70 (d, 2 H, 2 СНarom, J = 9.0); 8.15 (s, 1 Н, СНaliph);
10.20 (s, 1 H, NH)
1.25 (t, 3 Н, СН3(aliph); J = 7.4); 1.35 (t, 3 Н, СН3(aliph); J = 7.1); 2.70 (q, 2 Н, СН2(aliph));
3.20—3.40 (m, 4 Н, 2 СН2(aliph)); 3.60—3.80 (m, 4 Н, 2 СН2(aliph)); 4.35 (q, 2 Н, СН2(aliph));
7.00 (s, 1 Н, СНarom); 8.00 (s, 1 Н, СНaliph); 11.40 (s, 1 H, NH)
1.25 (t, 3 Н, СН3(aliph); J = 7.4); 1.35 (t, 3 Н, СН3(aliph); J = 7.1); 1.40—1.70 (m, 4 Н, 3 СН2(aliph));
2.70 (q, 2 Н, СН2(aliph)); 3.20—3.30 (m, 4 Н, 2 СН2(aliph)); 4.35 (q, 2 Н, СН2(aliph)); 7.10 (s, 1 Н,
СНarom); 8.00 (s, 1 Н, СНaliph); 11.40 (s, 1 H, NH)
6.90 (t, 1 Н, СНarom, J = 7.5); 7.15 (t, 2 Н, 2 СНarom, J = 7.5); 7.35 (t, 1 Н, СНarom, J = 7.6);
7.55 (t, 2 Н, 2 СНarom, J = 7.8); 7.75 (d, 2 Н, 2 СНarom, J = 7.8); 7.95 (d, 2 Н,
2 СНarom, J = 7.9); 11.10, 11.80 (s, 2 H, NH)
436
514
512
415
449
4g
4h
5a
5b
6.90 (t, 1 Н, СНarom, J = 7.6); 7.20 (t, 2 Н, 2 СНarom, J = 7.5); 7.45 (d, 2 Н,
2 СНarom, J = 8.7); 7.60 (d, 2 Н, 2 СНarom, J = 7.8); 7.80 (d, 2 Н, CНarom, J = 7.8);
7.95 (d, 2 Н, 2 СНarom, J = 8.7); 10.90, 11.60 (both s, 1 H each, NH)
5c
5d
3.75 (s, 3 H, OCH3(aliph)); 6.95—7.60 (m, 9 Н, Ar); 11.10, 11.7 (both s, 1 H each, NH)
1.25 (t, 3 Н, СН3(aliph), J = 7.4); 1.35 (t, 3 Н, СН3(aliph), J = 7.1); 2.7 (q, 2 Н, СН2(aliph));
4.35 (q, 2 Н, СН2(aliph)); 6.90 (t, 1 Н, СНarom, J = 7.7); 7.0 (s, 1 Н, СНarom); 7.20 (t, 2 Н,
2 СНarom, J = 7.7); 7.70 (d, 2 Н, 2 СНarom, J = 8.8); 11.50, 12.20 (both s, 1 H each, NH)
6.50 (s, 1 H, CHaliph); 7.15 (t, 1 Н, СНarom, J = 7.3); 7.35 (t, 2 Н, 2 СНarom, J = 7.5);
445
521
6a
415
7.55 (t, 1 Н, СНarom, J = 7.8); 7.75 (d, 2 Н, 2 СНarom, J = 7.8); 7.85 (t, 2 Н, 2 СНarom
J = 7.9); 8.00 (d, 2 Н, 2 СНarom, J = 7.8); 11.15 (s, 1 H, NH)
,
(to be continued)

2ꢀThioxoꢀ1,3ꢀthiazolidinꢀ4ꢀone derivatives
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
1629
Table 2 (continued)
Product
1H NMR (300.13 MHz, DMSOꢀd6),
δ (J/Hz)
MS,
m/z
6b
6c
6.30 (s, 1 H, CHaliph); 7.35 (t, 2 Н, 2 СНarom, J = 8.7); 7.40 (t, 1 Н, СНarom, J = 7.8);
7.60—7.75 (m, 4 Н, Ar); 7.95 (d, 2 Н, 2 СНarom, J = 8.7); 10.70 (s, 1 H, NH)
3.75 (s, 3 H, OCH3(aliph)); 6.30 (s, 1 H, CHaliph); 6.95 (d, 2 Н, 2 СНarom, J = 8.9);
7.40 (d, 2 Н, 2 СНarom, J = 9.0); 7.60 (t, 1 Н, СНarom, J = 7.8); 7.85 (t, 2 Н,
2 СНarom, J = 7.8); 8.00 (d, 2 Н, 2 СНarom, J = 9.0); 11.10 (s, 1 H, NH)
1.25 (t, 3 Н, СН3(aliph), J = 7.4); 1.35 (t, 3 Н, СН3(aliph), J = 7.1); 2.70 (q, 2 Н, СН2(aliph));
4.35 (q, 2 Н, СН2(aliph)); 6.60 (s, 1 H, CHaliph); 7.00 (s, 1 Н, СНarom); 7.60 (t, 1 Н, СНarom, J = 7.8);
7.75 (t, 2 Н, 2 СНarom, J = 8.9); 7.90 (d, 2 Н, 2 СНarom, J = 8.9); 11.9 (s, 1 H, NH)
6.55 (s, 1 Н, СНaliph); 7.20—7.65 (m, 10 Н, Ar); 11.15 (s, 1 H, NH)
6.45 (s, 1 Н, СНaliph); 7.10 (t, 1 Н, СНarom, J = 7.4); 7.40 (t, 2 Н, 2 СНarom, J = 7.3);
7.65 (d, 2 Н, 2 СНarom, J = 7.9); 7.30 (d, 1 Н, СНarom, J = 7.9); 7.15—7.25 (m, 2 Н,
2 СНarom); 7.85 (d, 1 Н, СНarom, J = 7.8); 9.45, 10.00 (both s, 1 H each, NH)
6.40 (s, 1 Н, СНaliph); 7.10 (t, 1 Н, СНarom, J = 7.4); 7.40 (t, 2 Н, 2 СНarom, J = 7.3);
7.65 (d, 2 Н, 2 СНarom, J = 7.9); 7.85 (s, 2 Н, 2 СНarom); 8.00 (s, 1 Н, СНarom);
9.30, 10.05 (both s, 1 H each, NH)
449
445
6d
521
8a
8b
402
420
8c
471
9a
9b
9c
9d
4.50 (s, 2 H, CH2(aliph)); 7.20 (t, 1 H, СНarom, J = 7.6); 7.40 (t, 2 H, 2 СНarom, J = 7.6);
7.90 (d, 2 H, 2 СНarom, J = 7.6); 10.85, 12.05 (both s, 1 H each, NH)
295
329
325
401
4.40 (s, 2 H, CH2(aliph)); 7.50 (t, 2 H, 2 СНarom, J = 8.7); 7.90 (d, 2 H, 2 СНarom
J = 8.7); 10.40, 11.9 (both s, 1 H each, NH)
,
3.75 (s, 3 H, OCH3(aliph)); 4.50 (s, 2 H, CH2(aliph)); 6.95 (t, 2 H, 2 СНarom, J = 8.9);
7.70 (d, 2 H, 2 СНarom, J = 9.0); 11.60, 12.00 (both s, 1 H each, NH)
1.25 (t, 3 Н, СН3(aliph), J = 7.4); 1.35 (t, 3 Н, СН3(aliph), J = 7.1); 2.70 (q, 2 Н, СН2(aliph));
4.20 (s, 2 H, CH2(aliph)); 4.35 (q, 2 Н, СН2(aliph)); 7.10 (s, 1 Н, СНarom); 11.40, 12.1 (both s, 1 H each, NH)
(0.1 g, 0.32 mmol) in methanol (10 mL) was mixed with
ethylenediammonium diacetate (0.01 g, 0.0055 mmol) and benꢀ
zaldehyde (0.034 g, 0.32 mmol) at ambient temperature. The
reaction mixture was kept at room temperature for 20 min, and
then poured into water (30 mL). The precipitate was filtered off
and recrystallized from acetic acid (2 mL). Compounds 2b—i
were synthesized analogously.
2ꢀ{5ꢀ[(5ꢀNitroꢀ2ꢀfuryl)methylene]ꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀ
thiazolidinꢀ3ꢀyl}aminoꢀ2ꢀthioxoꢀNꢀphenylacetamide (2b) was synꢀ
thesized from rhodanine 1a.
2ꢀ[(5ꢀBenzilydeneꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀ
yl)amino]ꢀ2ꢀthioxoꢀNꢀ(4ꢀchlorophenyl)acetamide (2c) and
2ꢀ{5ꢀ[(5ꢀnitroꢀ2ꢀfuryl)methylene]ꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolꢀ
idinꢀ3ꢀyl}aminoꢀ2ꢀthioxoꢀNꢀ(4ꢀchlorophenyl)acetamide (2d) were
synthesized from rhodanine 1b.
rhodanine 1а (0.1 g, 0.32 mmol) and triethyl orthoformate
(0.048 g, 0.32 mmol) in acetic acid with sodium acetate was
refluxed for 3 h. Then the reaction mixture was poured into
water. The precipitate was filtered off and recrystallized from
acetic acid (1 mL). Compounds 3b—d were synthesized analoꢀ
gously.
2ꢀ(5ꢀEthoxymethyleneꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀ
yl)aminoꢀ2ꢀthioxoꢀNꢀ(4ꢀchlorophenyl)acetamide (3b) was syntheꢀ
sized from rhodanine 1b.
2ꢀ(5ꢀEthoxymethyleneꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀ
yl)aminoꢀ2ꢀthioxoꢀNꢀ(4ꢀmethoxyphenyl)acetamide (3c) was synꢀ
thesized from rhodanine 1c.
Ethyl 2ꢀ(5ꢀethoxymethyleneꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ
3ꢀyl)aminoꢀ5ꢀethylꢀ2ꢀthioxoacetylaminothiopheneꢀ3ꢀcarboxylate
(3d) was synthesized from rhodanine 1d.
2ꢀ[(5ꢀBenzilydeneꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀ
yl)amino]ꢀ2ꢀthioxoꢀNꢀ(4ꢀmethoxyphenyl)acetamide (2e) and
2ꢀ{5ꢀ[(5ꢀnitroꢀ2ꢀfuryl)methylene]ꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolꢀ
idinꢀ3ꢀyl}aminoꢀ2ꢀthioxoꢀNꢀ(4ꢀmethoxyphenyl)acetamide (2f)
were synthesized from rhodanine 1c.
Ethyl 2ꢀ(5ꢀbenzilydeneꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ
3ꢀyl)aminoꢀ5ꢀethylꢀ2ꢀthioxoacetylaminothiopheneꢀ3ꢀcarboxyꢀ
late (2g) and ethyl 5ꢀethylꢀ2ꢀ[5ꢀ(5ꢀnitroꢀ2ꢀfuryl)methyleneꢀ
4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀyl]aminoꢀ2ꢀthioxoacetylꢀ
aminothiopheneꢀ3ꢀcarboxylate (2h) were synthesized from
rhodanine 1d.
2ꢀ(5ꢀMorpholinomethyleneꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ
3ꢀyl)aminoꢀ2ꢀthioxoꢀNꢀphenylacetamide (4a). A mixture of
5ꢀoxomethylenerhodanine 3a (0.05 g, 0.14 mmol) in ethanol
(2 mL) with morpholine (0.014 g, 0.16 mmol) was kept for 1 h at
ambient temperature. Then the reaction mixture was poured
into water. The precipitate was filtered off and recrystallized
from acetic acid. Compounds 4b—d were synthesized analoꢀ
gously.
2ꢀ(4ꢀOxoꢀ5ꢀpiperidinomethyleneꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀ
yl)aminoꢀ2ꢀthioxoꢀNꢀphenylacetamide (4b) was synthesized from
rhodanine 1а.
2ꢀ{4ꢀOxoꢀ5ꢀ[(2ꢀoxoꢀ4ꢀchloroꢀ2Нꢀchromenꢀ3ꢀyl)methylꢀ
ene]ꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀyl}aminoꢀ2ꢀthioxoꢀNꢀphenylꢀ
acetamide (2i) was synthesized from rhodanine 1а.
2ꢀ(5ꢀEthoxymethyleneꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ
3ꢀyl)aminoꢀ2ꢀthioxoꢀNꢀphenylacetamide (3a). A mixture of
2ꢀ(5ꢀMorpholinomethyleneꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ
3ꢀyl)aminoꢀ2ꢀthioxoꢀNꢀ(4ꢀchlorophenyl)acetamide (4c) and 2ꢀ(4ꢀ
oxoꢀ5ꢀpiperidinomethyleneꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀyl)aminoꢀ
2ꢀthioxoꢀNꢀ(4ꢀchlorophenyl)acetamide (4d) were synthesized
from rhodanine 1b.

1630
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
Yarovenko et al.
2ꢀ(5ꢀMorpholinomethyleneꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ
3ꢀyl)aminoꢀ2ꢀthioxoꢀNꢀ(4ꢀmethoxyphenyl)acetamide (4e) and
2ꢀ(4ꢀoxoꢀ5ꢀpiperidinomethyleneꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀ
yl)aminoꢀ2ꢀthioxoꢀNꢀ(4ꢀmethoxyphenyl)acetamide (4f) were synꢀ
thesized from rhodanine 1c.
Ethyl 5ꢀethylꢀ2ꢀ(5ꢀmorpholinomethyleneꢀ4ꢀoxoꢀ2ꢀthioxoꢀ
1,3ꢀthiazolidinꢀ3ꢀyl)aminoꢀ2ꢀthioxoacetylaminothiopheneꢀ3ꢀ
carboxylate (4g) and ethyl 5ꢀethylꢀ2ꢀ(4ꢀoxoꢀ5ꢀpiperidinomethylꢀ
eneꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀyl)aminoꢀ2ꢀthioxoacetylꢀ
aminothiopheneꢀ3ꢀcarboxylate (4h) were synthesized from
rhodanine 1d.
Ethyl 2ꢀ(5ꢀbenzoylꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀylꢀ
aminoꢀ2ꢀthioxoacetylaminoꢀ5ꢀethyl)thiopheneꢀ3ꢀcarboxylate (6d)
was synthesized from rhodanine 1d.
2ꢀ(5ꢀAnilinoꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀyl)aminoꢀ2ꢀ
thioxoꢀNꢀphenylacetamide (8a). Rhodanine 1a (0.1 g, 0.32 mmol)
was dissolved in dioxane (5 mL) and mixed with bromine
(0.056 g, 0.35 mmol). The reaction mixture was kept for 14 h.
Then aniline (0.03 g, 0.32 mmol) was added to the solution
at 10 °С, and the reaction mixture was stirred for 1 h. The
mixture was poured into water, and the precipitate was filtered
off. Compounds 8b,c were synthesized analogously.
2ꢀ(4ꢀOxoꢀ2ꢀthioxoꢀ5ꢀphenylhydrazonoꢀ1,3ꢀthiazolidinꢀ3ꢀ
yl)aminoꢀ2ꢀthioxoꢀNꢀphenylacetamide (5a). Rhodanine 1a (0.1 g,
0.32 mmol) was dissolved in aqueous ethanol (1 : 1, v/v), and
the solution was cooled in an iceꢀcold bath down to 0 °C. Diꢀ
azonium salt was prepared from aniline (0.03 g, 0.32 mmol) and
sodium nitrite (0.028 g, 0.4 mmol) in aqueous hydrochloric acid
(3 mL) at 0 °C. A solution of rhodanine in aqueous alcohol was
mixed with the diazonium salt at 0 °С, and the mixture was
stirred for 2 h. The precipitate that formed was filtered off and
recrystallized from acetic acid. Compounds 5b—d were syntheꢀ
sized analogously.
2ꢀ(4ꢀOxoꢀ2ꢀthioxoꢀ5ꢀphenylhydrazonoꢀ1,3ꢀthiazolidinꢀ3ꢀ
yl)aminoꢀ2ꢀthioxoꢀNꢀ(4ꢀchlorophenyl)acetamide (5b) was syntheꢀ
sized from rhodanine 1b.
2ꢀ(4ꢀOxoꢀ2ꢀthioxoꢀ5ꢀphenylhydrazonoꢀ1,3ꢀthiazolidinꢀ3ꢀ
yl)aminoꢀ2ꢀthioxoꢀNꢀ(4ꢀmethoxyphenyl)acetamide (5c) was synꢀ
thesized from rhodanine 1c.
2ꢀ(5ꢀAnilinoꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀyl)aminoꢀ2ꢀ
thioxoꢀNꢀ(3ꢀfluorophenyl)acetamide (8b) were synthesized from
rhodanine 1a and 3ꢀfluoroaniline.
2ꢀ(5ꢀAnilinoꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀyl)aminoꢀ2ꢀ
thioxoꢀNꢀ(3,5ꢀdichlorophenyl)acetamide (8c) was synthesized
from rhodanine 1a and 3,5ꢀdichloroaniline.
Nꢀ(4ꢀOxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀyl)ꢀN´ꢀphenylethaneꢀ
diamide (9а). A solution of rhodanine 1a (0.05 g, 0.16 mmol) in
acetonitrile (5 mL) was mixed with three droplets of hydrogen
peroxide at ambient temperature. Then the reaction mixture
was poured into water. The precipitate was filtered off and reꢀ
crystallized from an ethanol—petroleum ether (1 : 1, v/v) mixꢀ
ture. Compounds 9b—d were synthesized analogously.
Nꢀ(4ꢀOxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀyl)ꢀN´ꢀ(4ꢀchloropheꢀ
nyl)ethanediamide (9b) was synthesized from rhodanine 1b.
Nꢀ(4ꢀMethoxyphenyl)ꢀN´ꢀ(4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ
3ꢀyl)ethanediamide (9с) was synthesized from rhodanine 1с.
Ethyl 5ꢀethylꢀ2ꢀ(4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀyl)aminoꢀ
glyoxylylaminothiopheneꢀ3ꢀcarboxylate (9d) was synthesized from
rhodanine 1d.
Ethyl 5ꢀethylꢀ2ꢀ(4ꢀoxoꢀ2ꢀthioxoꢀ5ꢀphenylhydrazonoꢀ1,3ꢀ
thiazolidinꢀ3ꢀyl)aminoꢀ2ꢀthioxoacetylaminothiopheneꢀ3ꢀcarboxyꢀ
late (5d) was synthesized from rhodanine 1d.
2ꢀ(5ꢀBenzoylꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀyl)aminoꢀ2ꢀ
thioxoꢀNꢀphenylacetamide (6a). A mixture of rhodanine 1a (0.1 g,
0.32 mmol) with benzoyl chloride (0.32 mmol) and sodium
hydroxide (0.01 g, 0.32 mmol) in anhydrous dioxane (5 mL) was
refluxed for 1.5 h. Then the reaction mixture was poured into
water. The precipitate was filtered off and recrystallized from an
ethanol—petroleum ether (1 : 1, v/v) mixture. Compounds 6b—d
were synthesized analogously.
2ꢀ(5ꢀBenzoylꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀyl)aminoꢀ2ꢀ
thioxoꢀNꢀ(4ꢀchlorophenyl)acetamide (6b) was synthesized from
rhodanine 1b.
2ꢀ(5ꢀBenzoylꢀ4ꢀoxoꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ3ꢀyl)aminoꢀ2ꢀ
thioxoꢀNꢀ(4ꢀmethoxyphenyl)acetamide (6c) was synthesized from
rhodanine 1c.
References
1. S. Bondoc, W. Khalifa, and A. A. Fadda, Eur. J. Med. Chem.,
2007, 42, 948.
2. R. Dayam, T. Sanchez, O. Clement, R. Shoemaker, S. Sei,
and N. Neamati, J. Med. Chem., 2005, 48, 111.
3. V. N. Yarovenko, A. S. Nikitina, I. V. Zavarzin, M. M.
Krayushkin, and L. V. Kovalenko, Synthesis, 2006, 8, 1246.
4. S. N. Baranov and R. O. Kochkanyan, Khim.ꢀFarm. Zh., 1970,
3, 25 [Pharm. Chem. J., 1970, 3 (Engl. Transl.)].
Received July 23, 2007