Synthesis and transformations of (imidazolylimino)thiazolidinones

Article abstract of DOI:10.1023/A:1023439706631

The reaction of ethyl 5-phenylthioureido-3H-imidazole-4-carboxylate with bromoacetic acid afforded (imidazolylimino)thiazolidinones, which were transformed into the corresponding 5-arylidene-4-thiazolidinones by the reactions with aldehydes. Under the conditions of the Knoevenagel reaction, the thiazolidine ring in derivatives of 4-(4-oxothiazolidin-2-ylidene-amino)-3H- imidazole-4-carboxamides was opened to form substituted guanidines.

Full text of DOI:10.1023/A:1023439706631

Russian Chemical Bulletin, International Edition, Vol. 52, No. 2, pp. 461—466, February, 2003
461
Synthesis and transformations of (imidazolylimino)thiazolidinones
ꢀ
O. S. El´tsov, V. S. Mokrushin, N. P. Bel´skaya, and N. M. Kozlova
Urals State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 74 5483. Eꢀmail: eltsov@htf.ustu.ru
The reaction of ethyl 5ꢀphenylthioureidoꢀ3Hꢀimidazoleꢀ4ꢀcarboxylate with bromoacetic
acid afforded (imidazolylimino)thiazolidinones, which were transformed into the correspondꢀ
ing 5ꢀarylideneꢀ4ꢀthiazolidinones by the reactions with aldehydes. Under the conditions of the
Knoevenagel reaction, the thiazolidine ring in derivatives of 4ꢀ(4ꢀoxothiazolidinꢀ2ꢀylideneꢀ
amino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamides was opened to form substituted guanidines.
Keyꢀwords: (imidazolylimino)thiazolidinone, aldehydes, αꢀhaloalkanoic acids and their
esters, imidazolylthiourea, imidazolylisothiourea, 5ꢀarylideneꢀ4ꢀthiazolidinones, guanidines.
3
As part of our continuing studies of the synthesis of
new heterocyclic compounds based on esters and amides
of 5ꢀphenylthioureidoimidazoleꢀ4ꢀcarboxylic acid, which
are derivatives of imidazolyliminothiazolines1 and
2ꢀ(imidazolylamino)benzothiazoles,2 we reported on
the preparation of previously unknown (imidazolylꢀ
imino)thiazolidinones and characteristic features of their
selected transformations.
The condensation of thiourea derivatives with αꢀhaloꢀ
alkanoic acids and their esters3 serves as a convenient
procedure for the construction of the thiazolidinone ring.
The presence of several reactive nucleophilic centers in
derivatives of 5ꢀthioureidoꢀ3Hꢀimidazoleꢀ4ꢀcarboxylic
acid 1a—g is favorable for the formation of different prodꢀ
ucts. Thus, cyclization can proceed at one of the nitrogen
atoms of the thioureido substituent (to form thiazolidines
2 and 2´) or at the nitrogen atom of the imidazole ring (to
form thiadiazepines 2″) in the case of unsubstituted comꢀ
pounds.
2J (C(4)—CH2) = 6.2—6.9 Hz and J (C(4)—CH3) =
2.4 Hz. In the case of alternative structure 2´, the
C(4)—CH3 spinꢀspin coupling constant would have a
much smaller value.4 Structure 2″ is also highly improbꢀ
able, because the 13C NMR spectra show neither couꢀ
pling between the C(6) atom and the proton at the C(2´)
atom of the imidazole ring nor coupling between the C(2)
atom of the assumed sevenꢀmembered ring and the proꢀ
ton of the NH group.
Then we compared the UV spectra of the heterocycles
prepared based on methylꢀ and phenylthioureas. The presꢀ
ence of absorption maxima in the UV spectra of comꢀ
pounds 2a and 2d at 222, 298 nm (2a) and 225, 301 nm
(2d) are indicative of the similarity of these compounds.
The spectra of heterocycles 2e and 2g are also characterꢀ
ized by very similar absorption maxima observed at 227,
303, 310 nm (2e) and at 230, 301, 310 nm (2g). The
chemical shifts in the 13C NMR spectra of these bicyclic
compounds differ by 0.1—1.7 ppm, which also confirms
the identity of their heterocyclic systems.
The reactions of thioureas 1a—c with bromoacetic
acid and the reactions of thioureas 1e,f with ethyl chloroꢀ
acetate afforded heterocycles 2a—c,e,f, respectively
(Scheme 1). To confirm the structures of the resulting
compounds, (imidazolylimino)thiazolidines 2d and 2g
were prepared by the reactions of 5ꢀmethylthioureido deꢀ
rivatives of imidazoleꢀ4ꢀcarboxylic acid 1d,g with bromoꢀ
acetic acid. The structures of the latter compounds were
The reactions of compounds 2a—c with aldehydes in
the presence of piperidine afforded 5ꢀsubstituted (imidꢀ
azolylimino)thiazolidinones 3a—d. Their structures are
1
confirmed by the facts that the H NMR spectra of these
compounds have signals for the protons of the inserted
aldehyde fragment, whereas the signal for the protons of
the CH2 group of the thiazolidinone ring is absent. In the
mass spectra of compounds 3a—d, m/z for the molecular
ion peaks correspond to the calculated values.
Unlike ester derivatives 2a—c, methylamide of
5ꢀ(4ꢀoxoꢀ3ꢀphenylthiazolidinꢀ2ꢀylideneamino)ꢀ3Hꢀ
imidazoleꢀ4ꢀcarboxylic acid (2e) reacted with bezaldehyde
in the presence of piperidine to give a product devoid of
1
confirmed by H and 13C NMR spectroscopy (Tables 1
and 2). In the 13C NMR spectra, the signals for the C(2)
atoms are observed as a triplet of quartets with similar
spinꢀspin coupling constants with the protons of the meꢀ
thylene (3J = 1.9—2.0 Hz) and methyl (3J = 1.7—1.8 Hz)
groups. In the 13C NMR spectra, the signals for the carꢀ
bonyl C(4) atom of the thiazolidine ring located at lower
field are also observed as a triplet of quartets with
1
the sulfur atom. The H NMR spectrum of the resulting
compound has no signals for the protons of the ylidene
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 440—445, February, 2003.
1066ꢀ5285/03/5202ꢀ461 $25.00 © 2003 Plenum Publishing Corporation

Table 1. Characteristics of the resulting compounds
Comꢀ
pound
Yield
(%)
M.p.
/°С
MS,
m/z [M]+
Found
Calculated
Molecular
formula
1H NMR, δ (J/Hz)
(%)
C
H
N
S
2а
2b
41
39
203—207
179—180
358
372
56.79 5.22
56.97 5.06
15.50
15.63
9.10
8.95
C17H18N4O3S
C18H20N4O3S
7.73 (s, 1 Н, СH, Im); 7.50—7.32 (m, 5 H, Ph);
4.26 (q, 2 Н, NСН2CH3, J = 7.0); 4.03 (s, 2 Н, CН2);
4.00 (q, 2 Н, OСН2CH3, J = 7.0); 1.32, 1.00 (both t,
3 H each, NCH2CH3, OCH2CH3, J = 7.0)
7.70 (s, 1 Н, СH, Im); 7.50—7.32 (m, 5 H, Ph); 4.17
(t, 2 Н, NСН2CH2CH3, J = 7.0); 4.03 (s, 2 Н, CН2);
3.99 (q, 2 Н, OСН2CH3, J = 7.0); 1.70 (m, 2 H,
NCH2CH2CH3); 1.00 (t, 3 H, OCH2CH3, J = 7.0);
0.84 (t, 3 H, NCH2CH2CH3, J = 7.3)
57.89 5.19
58.05 5.41
14.90
15.04
8.79
8.61
2c
2d
44
35
243—244
149—150
386
296
56.11 4.54
55.95 4.70
14.33
14.50
8.46
8.30
C18H18N4O4S
C12H16N4O3S
7.64 (s, 1 Н, СH, Im); 7.47—7.33 (m, 5 H, Ph);
5.08 (s, 2 Н, NCН2COCH3); 4.04 (s, 2 Н, CН2); 3.97
(q, 2 Н, OСН2CH3, J = 7.3); 2.14 (s, 3 H,
NCН2COCH3); 0.97 (t, 3 H, OCH2CH3, J = 7.3)
7.77 (s, 1 Н, СH, Im); 4.28, 4.26 (both q, 2 H each,
NСН2CH3, OСН2CH3, J = 7.0); 3.87 (s, 2 Н, CН2);
3.21 (s, 3 Н, NCН3); 1.36, 1.34 (both t, 3 H each,
NCH2CH3, OCH2CH3, J = 7.0)
48.81 5.25
48.65 5.41
18.70
18.92
11.00
10.81
2e
2f
74
88
44
55
>300
>300
315
391
253
446
53.49 4.00
53.32 4.16
22.10
22.21
9.99
10.17
C14H13N5O2S
C20H17N5O2S
C9H11N5O2S
C24H22N4O3S
12.79 (br.s, 1 Н, NH, Im); 7.72—7.40 (m, 5 H, Ar,
NHCH3); 7.65 (s, 1 Н, СH, Im); 7.10—7.08 (m, 1 H,
Ar); 4.15 (s, 2 Н, CН2); 2.37 (d, 3 H, NHCH3, J = 4.9)
12.93, 9.07 (both br.s, 1 H each, 2 NH); 7.70 (s, 1 Н, СH,
Im); 7.58—7.42 (m, 5 H, Ph); 6.95—6.53 (АА´ВВ´, 4 H,
Ar, J = 8.2); 4.11 (s, 2 Н, CН2); 2.24 (s, 3 H, CH3)
12.80 (br.s, 1 Н, NH, Im); 7.73 (br.s, 1 H, NHCH3);
7.52 (s, 1 Н, СH, Im); 3.89 (s, 2 Н, CН2); 3.23 (s, 3 H,
NCH3); 2.89 (d, 3 H, NHCH3, J = 4.6)
7.83 (s, 1 Н, СH, Im); 7.72 (s, 1 Н, СH); 7.65—7.41
(m, 10 H, Ar); 4.30 (q, 2 Н, NСН2CH3, J = 7.3);
4.02 (q, 2 Н, OСН2CH3, J = 6.7); 1.35 (t, 3 H,
NCH2CH3, J = 7.3); 0.97 (t, 3 H, OCH2CH3, J = 6.7)
7.82 (s, 1 Н, СH, Im); 7.72 (s, 1 Н, СH); 7.66—7.42
(m, 10 H, Ar); 4.21 (t, 2 Н, NСН2CH2CH3, J = 6.7);
4.02 (q, 2 Н, OСН2CH3, J = 7.0); 1.73 (m, 2 H,
NCH2CH2CH3); 0.96 (t, 3 H, NCH2CH2CH3, J = 6.7);
0.87 (t, 3 H, OСН2CH3, J = 7.0)
61.21 4.28
61.37 4.38
17.74
17.89
8.29
8.19
2g
3a
292—293
232—233
42.84 4.17
42.69 4.35
27.50
27.67
12.82
12.65
64.72 4.80
64.56 4.97
12.39
12.55
7.01
7.18
3b
3c
51
43
217—218
212—213
460
478
65.33 5.44
65.19 5.26
12.02
12.17
6.79
6.96
C25H24N4O3S
62.58 4.68
62.74 4.85
11.90
11.71
6.88
6.70
C25H23FN4O3S
7.82 (s, 1 Н, СH, Im); 7.72—7.66 (m, 3 H, Ar); 7.55—7.40
(m, 5 H, Ar, CH); 7.33—7.26 (m, 2 H, Ar); 4.21 (t, 2 Н,
NСН2CH2CH3, J = 7.0); 3.98 (q, 2 Н, OСН2CH3, J = 7.0);
1.67 (m, 2 H, NCH2CH2CH3); 0.96 (t, 3 H,
NCH2CH2CH3, J = 7.0); 0.87 (t, 3 H, OСН2CH3, J = 7.3)

3d
3e*
3f
57
40
31
214—215
245—247
203—204
466
504
426
59.33 4.59
59.20 4.76
11.91
12.01
13.85
13.74
C23H22N4O3S2
C26H24N4O5S
C21H22N4O4S
7.96 (s, 1 Н, СH, Im); 7.86—7.21 (m, 9 H, Ar, CH,
thienyl); 4.21 (t, 2 Н, NСН2CH2CH3, J = 7.0);
4.02 (q, 2 Н, OСН2CH3, J = 7.0); 1.74 (m, 2 H,
NCH2CH2CH3); 0.96 (t, 3 H, NCH2CH2CH3, J = 7.0);
0.87 (t, 3 H, OСН2CH3, J = 7.3)
7.75, 7.69 (both s, 1 H each, СH, Im, СН); 7.64—7.06
(m, 9 H, Ar); 5.13, 5.08 (both s, 2 Н, NCН2COCH3);
4.04, 3.85 (both s, 3 Н, OCH3); 3.95 (q, 2 Н, OСН2CH3,
J = 7.0); 2.16, 2.14 (both s, 3 H, NCН2COCH3);
0.94 (t, 3 H, OCH2CH3, J = 7.0)
7.67 (s, 1 Н, СH, Im); 7.49—7.35 (m, 5 H, Ph); 6.85 (t,
1 H, CН3CH2CH, J = 6.6); 5.10 (s, 2 Н, NCН2COCH3);
3.93 (q, 2 Н, OСН2CH3, J = 7.3); 2.32 (m, 2 H,
CН3CH2CH); 2.15 (s, 3 Н, NCН2COCH3); 1.17 (t, 3 H,
CH3CH2CH, J = 6.7); 0.93 (t, 3 H, OCH2CH3, J = 7.3)
12.51 (br.s, 1 Н, NH, Im); 10.78, 8.63 (both br.s, 1 H each,
2 NH); 7.39 (s, 1 Н, СН, Im); 7.34—7.12 (m, 5 Н, Ph);
3.44—3.15 (m, 4 Н, СН2); 2.88 (d, 3 Н, NHСН3, J = 4.6);
1.60—1.51 (m, 6 Н, СН2)
12.10 (br.s, 1 Н, NH, Im); 8.90 (br.s, 2 H, 2 NH); 8.63
(br.s, 1 Н, NHCH3); 7.32—7.01 (m, 6 Н, СH, Im, Ph);
3.63, 3.41 (both m, 2 H each, NCH2СН2OH, NCH2СН2OH);
2.64 (d, 3 Н, NHСН3, J = 4.7)
61.78 4.61
61.89 4.79
10.96
11.11
6.48
6.35
59.39 4.99
59.15 5.16
13.28
13.15
7.40
7.51
4a
4b
4c
60
52
30
182—184
181—183
230—231
326
302
404
62.39 6.90
62.56 6.79
25.61
25.75
—
—
—
C17H22N6O
C14H18N6O2
C22H24N6O2
55.49 6.19
55.62 6.00
27.63
27.80
65.19 6.10
65.32 5.98
20.89
20.78
12.74 (br.s, 1 Н, NH, Im); 11.03, 10.57 (both br.s,
1 H each, 2 NH); 7.51 (s, 1 Н, СН, Im); 7.48—7.18 (m, 6 Н,
Ar); 7.11 (d, 2 Н, Ar, J = 8.2); 7.03—6.96 (br.s, 1 Н, Ar);
3.67—3.54 (m, 4 Н, СН2); 6.34—3.27 (s, 4 Н, СН2);
2.30 (s, 3 Н, СН3)
4d
5a
42
88
222—223
209—210
424
303
70.59 5.55
70.73 5.70
19.62
19.80
—
C25H24N6O2
C14H17N5OS
12.47, 10.63 (both br.s, 1 H each, 2 NH); 7.42—7.22 (m, 12 Н,
Ar, NH, CH, Im); 7.06—6.83 (m, 5 Н, Ar); 4.67 (d, 2 Н,
NHСН2, J = 5.8); 2.22 (s, 3 Н, CH3)
12.24, 11.76 (both br.s, 1 H each, 2 NH); 8.85 (br.s, 1 Н,
NHCH3); 7.49 (s, 1 H, CH, Im); 7.41—7.26 (m, 5 H, Ph);
3.03 (d, 3 Н, NHCH3, J = 4.1); 2.96 (q, 2 Н, SCH2CH3,
J = 7.6); 1.36 (t, 3 H, SCH2CH3, J = 7.6)
55.28 5.50
55.43 5.65
23.28
23.08
10.77
10.57
5b
82
55
207—208
250—252
379
63.21 5.72
63.30 5.58
18.28
18.45
8.59
8.45
C20H21N5OS
12.93, 12.07, 10.23 (all br.s, 1 H each, 3 NH); 7.58 (s, 1 H,
CH, Im); 7.45—7.20 (m, 7 H, Ph, Ar); 7.10 (d, 2 Н, Ar,
J = 8.2); 3.14 (q, 2 Н, SCH2CH3, J = 7.3); 2.30 (s, 3 H,
CH3); 1.32 (t, 3 H, SCH2CH3, J = 7.3)
12.09 (br.s, 1 Н, ОH); 8.11 (s, 1 Н, СH, Im); 7.56—7.34
(m, 5 H, Ph); 4.32 (q, 2 Н, NСН2CH3, J = 7.0); 3.86
(s, 2 Н, CН2); 1.44 (t, 3 H, NCH2CH3 J = 7.0)
7.49—7.24 (m, 5 H, Ph); 4.24 (s, 2 H, CH2)
6
7
330
193
54.80 4.15
54.55 4.24
17.21
16.97
9.80
9.69
C15H14N4O3S
C9H7NO2S
42 (55) 141—142
60.26 3.80
55.96 3.65
7.48
7.25
16.25
16.59
* A mixture of the cis and trans isomers.

464
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 2, February, 2003
El´tsov et al.
Scheme 1
1, 2
a
b
c
d
e
f
g
4
a
b
c
d
R1
R2
R3
Ph
Et
OEt OEt
Ph
Pr
Ph
CH2Ac
OEt
Me
Et
OEt
Ph
H
NHMe
Ph
H
Me
H
R3
R5
R6
NHMe
—
OEt
NHTolꢀp
NHTolꢀp
H
(CH2)2OH
—
—
—
H
Bn
—
NHTolꢀp NHMe
—
R
5 + R6 (CH2)5
(CH2)2O(CH2)2
3
a
b
c
d
e
f
5
R3
a
b
R2
R4
Et
Ph
Pr
Pr
Pr
CH2Ac
C6H4OMeꢀm
CH2Ac
Et
Ph C6H4Fꢀp 2ꢀthienyl
NHMe
NHTolꢀp
Reagents and conditions: i. BrCH2CO2H, EtOH, NaOAc (for 1a—d); ClCH2CO2Et, DMF, Et3N (for 1e—g). ii. R4CHO, EtOH,
piperidine (for 2a—c). iii. EtI, Et3N, DMF (for 1e,f). iv. H2N(CH2)2OH or H2NBn. v. HNR5R6, DMF (for 2e,f).
fragment. However, multiplets of the CH2 groups of pipꢀ
eridine are observed at δ 3.44—3.15 and 1.60—1.51. We
proposed that piperidine interacted with the C(2) atom of
the thiazolidine ring, which was accompanied by the
ring opening and elimination of the sulfurꢀcontainꢀ
ing fragment. Actually, the reactions of thiazolidines
2e,f with amines also gave rise to guanidine derivaꢀ
tives 4a—d.
Scheme 2

Transformations of (imidazolylimino)thiazolidinones Russ.Chem.Bull., Int.Ed., Vol. 52, No. 2, February, 2003
Table 2. Data from 13C NMR spectroscopy* of compounds 2a,d,e,g
465
Compound
δ (J/Hz)
3
2a
171.6 (t, С(4), 2J = 6.3); 159.7 (t, С(6´), J = 4.4); 157.3 (t, С(2), 3J = 1.7); 150.0 (d, С(5´), 3J = 11.3);
138.7 (dt, С(2´), J = 210.5, J = 4.8); 135.5 (m, С(6)); 128.6 (dd, С(7), С(11), 1J = 162.6, J = 8.4);
1
3
2
128.4 (ddd, С(8), С(10), 1J = 162.9, 2J = 6.2, 3J = 1.7); 128.1 (ddd, С(9), 1J = 161.6, 2J = 8.0, 3J = 1.0);
110.9 (dt, С(4´), 3J = 3.2, 3J = 2.4); 59.4 (tq, С(9´), 1J = 147.7, J = 4.5); 41.8 (tqd, С(16´), J = 142.2,
2
1
2J = 4.5, 3J = 1.3); 33.1 (t, С(5), J = 147.1); 16.4 (qt, С(10´), J = 127.7, J = 3.3); 13.9 (qt, С(12´),
1
1
2
1J = 126.8, 2J = 2.6)
3
2d
2e
2g
171.9 (tq, С(4), 2J = 6.2, J = 2.4); 159.8 (t, С(6´), 3J = 2.7); 156.8 (qt, С(2), 3J = 1.9, 3J = 1.7);
150.1 (d, С(5´), J = 11.3); 138.7 (dt, С(2´), J = 210.6, 3J = 4.8); 111.3 (dt, С(4´), J = 3.2, J = 2.4);
3
1
3
3
59.6 (tq, С(9´), 1J = 147.7, J = 4.4); 41.9 (tqd, С(11´), 1J = 141.8, 2J = 4.6, J = 1.3); 33.0 (t, С(5),
2
3
1J = 146.8); 29.1 (q, С(6), J = 141.5); 16.4 (qt, С(10´), J = 127.6, J = 3.4); 13.9 (qt, С(12´), 1J = 126.7, J = 2.6)
1
1
2
2
171.2 (t, С(4), J = 6.2); 159.5 (m, C(6´)); 157.3 (t, С(2), J = 1.7); 143.6 (dd, С(5´), 3J = 7.8, J = 7.9);
2
3
3
1
2
1
2
135.8 (m, C(6)); 134.4 (dd, С(2´), J = 210.7, J = 1.6); 129.9 (dd, С(7), С(11), J = 163.8, J = 8.1);
128.8 (ddd, С(8), С(10), 1J = 162.5, J = 7.8); 128.1 (ddd, С(9), 1J = 167.4, 2J = 7.0); 115.9 (m, С(4´));
2
33.8 (t, С(5), 1J = 147.2); 24.8 (qd, С(9´), 1J = 140.7, 2J = 3.1)
171.8 (tq, С(4), J = 6.9, J = 2.4); 159.9 (m, C(6´)); 157.4 (qt, С(2), 3J = 2.0, 3J = 1.8); 144.1 (dd, С(5´),
2
3
3J = 8.4, 3J = 11.2); 134.1 (dd, С(2´), 1J = 209.6, J = 3.4); 115.9 (m, С(4´)); 33.2 (t, С(5), J = 146.9);
2
1
29.3 (q, С(6), 1J = 141.6); 25.5 (qd, С(9´), J = 137.8, J = 3.0)
1
2
* The assignment of the chemical shifts was made and the spinꢀspin coupling constants were determined with the use of the BB and
Gate techniques.
The thiazolidineꢀring opening and the formation of
guanidine structures were confirmed by the independent
synthesis of compounds 4b,d involving alkylation of
thioureas 1e,f with iodoethane to give isothioureas 5a,b
followed by the reactions of the latter compounds with
amines.
ideneꢀ4ꢀthiazolidinones exhibiting antimicrobial and
painꢀrelieving activities,5 and guanidine derivatives are of
interest as potentially biologically active compounds.6
Experimental
Interestingly, the treatment of compound 2a with pipꢀ
eridine in aqueous ethanol did not lead to the thiazolidineꢀ
ring opening. In the latter case, the ester group was hyꢀ
drolyzed to form the derivative of imidazolecarboxylic
acid 6 (Scheme 2). In our opinion, the difference in the
behavior of bicyclic compounds 2a—c and 2e,f in the
presence of amines is associated with the possibility of the
formation of imidazolium salts in the case of compounds
2e,f resulting in the redistribution of the electron density
in the molecule and destabilization of the thiazole ring.
Acid hydrolysis of imidazolylthiazolidines 2a and 2e
afforded 3ꢀphenylꢀ2,4ꢀthiazolidinedione (7) indepenꢀ
dently on the nature of the substituents at positions 1
and 5 of the imidazole ring.
1
The H and 13C NMR spectra were measured on a Bruker
WMꢀ250 instrument (250.13 and 100.00 МHz) in DMSOꢀd6
with Me4Si as the internal standard. The course of the reactions
and the purities of the resulting compounds were monitored by
TLC on Sorbfil UVꢀ254 plates in the 1 : 10 EtOH—CHCl3 sysꢀ
tem. The UV spectra were recorded on a Specordꢀ240 instruꢀ
ment. The concentration of the compounds in solutions in EtOH
was 1.0•10–5 mol L–1. The mass spectra were measured on a
Varian MAT 311A instrument; the accelerating voltage was 3 kV,
the energy of ionizing electrons was 70 eV. The melting points
were not corrected.
Compounds 1a—g were prepared according to procedures
described earlier.1,7,8 The characteristics of the compounds are
given in Tables 1 and 2.
Ethyl 3ꢀethylꢀ5ꢀ(4ꢀoxoꢀ3ꢀphenylthiazolidinꢀ2ꢀylideneamino)ꢀ
3Hꢀimidazoleꢀ4ꢀcarboxylate (2a), ethyl 5ꢀ(4ꢀoxoꢀ3ꢀphenylꢀ
thiazolidinꢀ2ꢀylideneamino)ꢀ3ꢀpropylꢀ3Hꢀimidazoleꢀ4ꢀcarboxyꢀ
The new imidazolyliminoꢀsubstituted 5ꢀarylideneꢀ4ꢀ
thiazolidinones, which are structurally similar to 5ꢀarylꢀ

466
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 2, February, 2003
El´tsov et al.
late (2b), ethyl 3ꢀ(2ꢀoxopropyl)ꢀ5ꢀ(4ꢀoxoꢀ3ꢀphenylthiazolidinꢀ
2ꢀylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxylate (2c), and ethyl
3ꢀethylꢀ5ꢀ(4ꢀoxoꢀ3ꢀmethylthiazolidinꢀ2ꢀylideneamino)ꢀ3Hꢀimidꢀ
azoleꢀ4ꢀcarboxylate (2d) (general procedure). Sodium acetate
(3.45 mmol) and bromoacetic acid (1.38 mmol) were added to a
solution of substituted thiourea 1a—d (0.69 mmol) in EtOH
(30 mL). The reaction mixture was refluxed for 2—3 h. Then
water (30 mL) was added and the reaction mixture was cooled.
The precipitate that formed was filtered off and purified by
recrystallization from EtOH.
mixture was refluxed for 6 h and then cooled. The precipitates of
compounds 4b and 4d that formed were filtered off and crystalꢀ
lized from EtOH.
Methylamide of 5ꢀ(Sꢀethylꢀ1ꢀphenylisothioureido)ꢀ3Hꢀimidꢀ
azoleꢀ4ꢀcarboxylic acid (5a) and pꢀtolylamide of 5ꢀ(Sꢀethylꢀ1ꢀ
phenylisothioureido)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxylic acid (5b) (genꢀ
eral procedure). Compound 1e,f (0.69 mmol) was dissolved in
DMF (2 mL), and then Et3N (0.76 mmol) and EtI (0.76 mmol)
were added. The reaction mixture was kept at room temperature
for 10 h and then H2O (30 mL) was added. The precipitate that
formed was filtered off, recrystallized from EtOH, filtered off,
and dried.
Synthesis of 3ꢀethylꢀ5ꢀ(4ꢀoxoꢀ3ꢀphenylthiazolidinꢀ2ꢀylideneꢀ
amino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxylic acid (6). A solution of comꢀ
pound 2a (0.70 mmol) in EtOH (1 mL) and piperidine
(7.00 mmol) was kept at 70—80 °C for 24 h. The resulting
solution was neutralized with concentrated HCl to pH 6—7,
H2O (15 mL) was added, and the reaction mixture was cooled.
The precipitate that formed was filtered off and purified by
recrystallization from aqueous EtOH.
Methylamide of 5ꢀ(4ꢀoxoꢀ3ꢀphenylthiazolidinꢀ2ꢀylideneꢀ
amino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxylic acid (2e), pꢀtolylamide of
5ꢀ(4ꢀoxoꢀ3ꢀphenylthiazolidinꢀ2ꢀylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀ
carboxylic acid (2f), and methylamide of 5ꢀ(4ꢀoxoꢀ3ꢀmethylꢀ
thiazolidinꢀ2ꢀylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxylic acid (2g)
(general procedure). Triethylamine (0.76 mmol) and ethyl
chloroacetate (0.76 mmol) were added to a solution of substiꢀ
tuted thiourea 1e—g (0.69 mmol) in DMF (2 mL). The reaction
mixture was kept at room temperature for 10 h and then H2O
(30 mL) was added. The precipitate that formed was filtered off,
refluxed in EtOH (20 mL), filtered without cooling, and dried.
Ethyl 5ꢀ(5ꢀbenzylideneꢀ4ꢀoxoꢀ3ꢀphenylthiazolidinꢀ2ꢀylideneꢀ
amino)ꢀ3ꢀethylꢀ3Hꢀimidazoleꢀ4ꢀcarboxylate (3a), ethyl 5ꢀ(5ꢀbenꢀ
zylideneꢀ4ꢀoxoꢀ3ꢀphenylthiazolidinꢀ2ꢀylideneamino)ꢀ3ꢀpropylꢀ
3Hꢀimidazoleꢀ4ꢀcarboxylate (3b), ethyl 5ꢀ[5ꢀ(4ꢀfluorobenzylꢀ
idene)ꢀ4ꢀoxoꢀ3ꢀphenylthiazolidinꢀ2ꢀylideneamino]ꢀ3ꢀpropylꢀ3Hꢀ
imidazoleꢀ4ꢀcarboxylate (3c), ethyl 5ꢀ[4ꢀoxoꢀ5ꢀ(2ꢀthienylꢀ
methylene)ꢀ3ꢀphenylthiazolidinꢀ2ꢀylideneamino]ꢀ3ꢀpropylꢀ3Hꢀ
imidazoleꢀ4ꢀcarboxylate (3d), ethyl 5ꢀ[(5ꢀ(3ꢀmethoxybenzylꢀ
idene)ꢀ4ꢀoxoꢀ3ꢀphenylthiazolidinꢀ2ꢀylideneamino]ꢀ3ꢀ(2ꢀoxoꢀ
propyl)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxylate (3e), and ethyl 3ꢀ(2ꢀoxoꢀ
propyl)ꢀ5ꢀ[4ꢀoxoꢀ5ꢀpropylideneꢀ3ꢀphenylthiazolidinꢀ2ꢀylideneꢀ
amino]ꢀ3Hꢀimidazoleꢀ4ꢀcarboxylate (3f) (general procedure).
Compounds 2a—c (0.70 mmol) were dissolved in EtOH
(10—15 mL). Then aldehyde (0.77 mmol) and piperidine
(7.00 mmol) were added. The reaction mixture was refluxed for
4—5 h and cooled. The precipitates of product 3a—f that formed
were filtered of and recrystallized from EtOH.
Synthesis of 3ꢀphenylꢀ2,4ꢀthiazolidinedione (7). Compound
2a (or 2e) (0.70 mmol) was dissolved in concentrated HCl
(5 mL). The reaction mixture was kept at 70—80 °C for 0.5 h
and then cooled. The precipitate that formed was filtered off and
washed on a filter with water and EtOH.
This study was financially supported by the Russian
Foundation for Basic Research (Project Nos. 01ꢀ03ꢀ32609
and 01ꢀ03ꢀ96433) and the US Civilian Research and Deꢀ
velopment Foundation (CRDF, Grant RECꢀ005).
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Methylamide of 5ꢀ(piperidinoꢀNꢀphenylaminomethyleneꢀ
amino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxylic acid (4a), methylamide of
5ꢀ[(Nꢀ(2ꢀhydroxyethyl)ꢀN´ꢀphenylguanidino]ꢀ3Hꢀimidazoleꢀ4ꢀ
carboxylic acid (4b), pꢀtolylamide of 5ꢀ(morpholinoꢀNꢀphenylꢀ
aminomethyleneamino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxylic acid (4c), and
methylamide of 5ꢀ[(NꢀbenzylꢀN´ꢀphenylguanidino]ꢀ3Hꢀimidꢀ
azoleꢀ4ꢀcarboxylic acid (4d) (general procedure).
A. Dimethylformamide (2—3 mL) and amine (7.00 mmol)
were added to compound 2e,f (0.70 mmol). The reaction mixꢀ
ture was kept at 80 °C for 2—24 h and H2O (30 mL) was added.
Then 1 N HCl was added to pH 6—7, and the reaction mixture
was kept for ∼16 h. The precipitates of compound 4a—d
that formed were filtered off and purified by recrystallization
from EtOH.
6. K. Feichtinger, C. Zapf, H. L. Sings, and M. Goodman,
J. Org. Chem., 1998, 63, 3804.
7. A. H. Cook, A. C. Davis, Sir Ian Heilbron, and G. H.
Thomas, J. Chem. Soc., 1949, 1071.
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G. Stevens, Chem. Commun., 1997, 363.
B. Isothiourea 5a,b (0.70 mmol) was dissolved in EtOH
(5 mL) and then amine (7.00 mmol) was added. The reaction
Received March 18, 2002;
in revised form October 8, 2002