A simple and efficient synthesis of some novel thiazolidine-4-one derivatives

Article abstract of DOI:10.1002/jhet.458

Reaction of 4-phenylthiosemicarbazide with dialkyl acetylenedicarboxylate in CH₂Cl₂ at 0°C lead to construction of alkyl 3-amino-2-phenyliminothiazolidine-4-one-5-ylidene acetate in a few minutes and good yields. Alternatively, the u

Full text of DOI:10.1002/jhet.458

November 2010
A Simple and Efficient Synthesis of Some Novel
Thiazolidine-4-one Derivatives
1439
Khalil Porshamsian,a* Naser Montazeri,a Kurosh Rad-Moghadam,b
and Safa Ali-Asgaric
aChemistry Department, Islamic Azad University, Tonekabon 46841-61167, Iran
bChemistry Department, University of Guilan, Rasht 41335-19141, Iran
cChemistry Department, Islamic Azad University, Shahrood, Iran
*E-mail: Kshams49@gmail.com
Received November 19, 2009
DOI 10.1002/jhet.458
Published online 24 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
Reaction of 4-phenylthiosemicarbazide with dialkyl acetylenedicarboxylate in CH2Cl2 at 0ꢀC lead to
construction of alkyl 3-amino-2-phenyliminothiazolidine-4-one-5-ylidene acetate in a few minutes and
good yields. Alternatively, the use of thiosemicarbazide has given the corresponding 3-amino-2-imino-
thiazolidine-4-one-5-ylidene acetate, while application of di-t-butylacetylenedicarboxylate in these reac-
tions has not entailed with cyclization.
J. Heterocyclic Chem., 47, 1439 (2010).
INTRODUCTION
CH2Cl2 media at room temperature and needs no more
care on controlling the temperature or using special techni-
ques of activation. Only the thiazolidine products were
formed and separated from the reaction mixture. An
attracting feature of this reaction is the synthesis of a multi-
functionalized complex heterocycle from simple starting
materials.
Thiazolidine-4-ones are important building blocks in va-
riety of pharmaceutical agents and biologically active prod-
ucts [1]. Several substituted thiazolidinones have been
found to possess hypnotic, anesthetic, sedative, anticonvul-
sant, and microbiological activities [2–4]. Some thiazoline
derivatives show interesting anti-HIV or anticancer activ-
ities and can inhibit cell division [5–10]. Because of the
various physiological activities of thiazolidinones, many
thiazolidinone derivatives have been prepared and several
new methods for the preparation of substituted thiazoli-
dine-4-one have been recently reported [11,12]. Despite
the synthetic importance of these methods, they commonly
suffer from the need to elevated temperatures and also
from long reaction times. Therefore, it is reasonable that
development of mild and efficient methods for their syn-
thesis still is more desired. In this context, we present here
a mild and expedient method for synthesis of 2-iminothia-
zolidine-4-one-5-ylidene acetate derivatives in fairly good
yields.
Thus, 4-Phenylthiosemicarbazide (1a) and dimethyl ace-
tylenedicarboxylate undergo a smooth reaction in dry
CH2Cl2 at 0ꢀC to produce methyl 3-amino-2 phenylimino-
thiazolidine-4-one-5-ylidene acetate (3a) in 94% yield
(Scheme 1). In a similar manner, thiazolidine-4-ones (3c,d)
were formed on reaction between thiosemicarbazide and
the corresponding acetylenic ester in excellent yields
(Scheme 1). Surprisingly, di-tert-butyl acetylenedicarboxy-
late showed up a different behavior as instead of cyclocon-
densation with thiosemicarbazide their reaction lead to
addition of the two components and solely formation of
thiosemicarbazone derivatives (Scheme 2).
Structures of all the compounds were deduced from
1
their IR, H NMR, 13C NMR, and mass spectral data as
well as elemental analyses. The mass spectra of these
compounds displayed molecular ion peaks at the appro-
priate m/z values. The 1H NMR spectrum of 3a, for
example, in CDCl3 showed three singlet peaks arising
from resonances of methoxy d 3.48, amino d 4.89, and
olefinic protons d 7.00, along with multiplets at d 7.03–
7.42 ppm for the aromatic protons. The 13C NMR
RESULTS AND DISCUSSION
As is shown in Scheme 1, the synthesis of 2-imino-thia-
zolidine-4-one-5-ylidene acetate was simply effected by a
two component reaction between thiosemicarbazide and an
acetylenic ester. The reaction proceeds smoothly without
using any catalyst by mixing the two reactants in dry
C
V
2010 HeteroCorporation

1440
K. Porshamsian, N. Montazeri, K. Rad-Moghadam, and S. Ali-Asgari
Vol 47
Scheme 1
MHz, respectively. Mass spectra were recorded on a Finnigan-
MAT 8430 mass spectrometer operating at an ionization poten-
tial of 70 eV. 4-Phenylthiosemicarbazide, thiosemicarbazide,
dimethyl acetylenedicarboxylate, and diethyl acetylenedicar-
boxylate were obtained from Fluka (Buchs, Switzerland) and
were used without further purification.
spectrum of 3a showed 10 signals in agreement with the
proposed structure. Partial assignments of these resonan-
1
ces are given in the experimental section. The H- and
13C NMR spectra of 3b–3d are very similar to those of
3a, except for the ester and aryl moieties, which exhibit
characteristic signals at appropriate chemical shift.
On the basis of well established chemistry of electro-
philic acetylenes [10], it is reasonable to assume that the
synthesis proceeds through initial conjugate addition of
the sulfur atom of 1 onto the acetylenic ester following
cyclocondensation of the thus formed 1:1 adduct [13,14]
to yield the products 3 (Scheme 3).
Typical procedure for the preparation of compounds
3. To a stirred solution of 1 (2 mmol) in 10 mL of dichloro-
methane was added dropwise a mixture of 2 (2 mmol) in 2
mL dichloromethane at 0ꢀC over 1 min. The reaction quickly
went to complete, as monitored by tlc on silica-gel 60 using
1:1 solution of ethyl acetate:petroleum ether, and the solid
product precipitate. After 5 min, the solid was filtered and
recrystallized from diethyl ether to afford the pure products.
Methyl 3-amino-2-phenylimino-4-oxo-1,3-thiazolan-5-ylide-
neacetate (3a). Pale yellow crystals; yield: 0.55g (99%), mp 161–
162ꢀC; IR (KBr): m ¼ 3306, 3145 (NH2), 1731, 1645
In the cases of using di-t-butyl acetylenedicarboxy-
late, the reactions are prevented from proceeding
through above mechanism due to steric hindrance of
bulky alkyl groups, so are unable to give the desired
thiazolidine products.
1
(C¼¼O), 1694 (C¼¼C), 1608 (C¼¼N) cmꢁ1; H NMR: d ¼
3.84 (3H, s, MeO), 4.89 (2H, s, NH2), 7.0 (1H, s, CH),
7.03–7.42 (5H, m, Ph) ppm; 13C NMR: d ¼ 166.6, 161.8
(C¼¼O), 149.6 (C¼¼N), 146.8 (C), 139.8 (C), 129.9
(2CH), 126.0 (CH), 121.5 (2CH), 117.3 (CH), 53.0
(CH3AO) ppm; ms: m/z (%) 277 (28, Mþ), 160 (8), 142
(1), 117 (23), 85 (86), 77 (100), 58 (63), 44 (24). Anal.
Calcd. for C12H11N3O3S (277.24): C, 51.19; H, 3.96; N,
In conclusion, we have made a contribution to the
synthesis of thiazolidine-4-one compounds [13,14] by
using the reaction between 4-phenylthiosemicarbazide or
thiosemicarbazide with a dialkyl acetylenedicarboxylate
to produce some novel thiazolidine-4-one derivatives.
The method carries the advantage that is not only the
reaction performed under neutral conditions but also the
substrates can react by mixing without any activation or
modification.
15.14%. Found: C, 51.33; H, 3.87; N, 15.05%.
Ethyl 3-amino-2-phenylimino-4-oxo-1,3-thiazolan-5-ylide-
neacetate (3b). Pale yellow powder; yield: 0.57 g (98%), mp
160–163ꢀC; IR (KBr): m ¼ 3299, 3146 (NH2), 1729, 1642
1
(C¼¼O), 1688 (C¼¼C), 1593 (C¼¼N) cmꢁ1; H NMR: d
EXPERIMENTAL
3
3
¼ 1.33 (3H, t, JHH ¼ 7.1, Me), 4.28 (2H, q, JHH
¼
Melting points were measured on an Electrothermal 9100
apparatus. Elemental analyses for C, H, and N were performed
using a Heraeus CHN–O-Rapid analyzer. IR spectra were
measured on a Shimadzu IR-460 spectrometer. 1H and 13C
NMR spectra were recorded by a Bruker DRX-300 AVANCE
instrument with deuteriochloroform as solvent at 300 and 75
7.1, CH2O), 4.88 (2H, br s, NH2), 6.99 (1H, s, CH),
7.03–7.39 (5H, m, Ph) ppm; 13C NMR: d ¼ 166.2,
161.9 (2C¼¼O), 149.7 (C¼¼N), 146.9 (C), 139.5 (C),
129.9 (2CH), 126.0 (CH), 121.5 (2CH), 117.8 (CH),
62.3 (CH2O), 14.5 (CH3) ppm; ms: m/z (%) 291 (24,
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010 A Simple and Efficient Synthesis of Some Novel Thiazolidine-4-one Derivatives
1441
Scheme 3
1
Mþ), 264 (4), 142 (23), 135 (26), 107 (40), 85 (66), 77
(100), 57 (20), 44 (54). Anal. Calcd. for C13H13N3O3S
(291.28): C, 53.55; H, 4.46; N, 14.01%. Found: C,
51.78; H, 4.83; N, 14.39%.
C¼¼O), 1685 (C¼¼C), 1591 (C¼¼N) cmꢁ1; H NMR: d
3
3
¼ 1.32 (t, JHH ¼ 7.1, Me), 4.26 (q, JHH ¼ 7.1,
CH2O), 4.88 (br s, NH2),5.11(s, NH), 6.90 (s, CH)
ppm;13C NMR: d ¼ 166.2, 161.9 (2 C¼¼O), 149.7
(C¼¼N), 146.9 (C), 139.5 (C), 126.0 (CH), 62.5 (CH2O),
14.4 (CH3) ppm; ms: m/z (%) ¼ 215 (28, Mþ), 170
(14), 142 (36), 135 (26), 107 (40), 85 (100), 57 (20), 44
(54). Anal. Calcd. for C7H9N3O3S (215.21): C, 39.01;
H, 4.18; N, 19.53%. Found: C, 38.88; H, 4.13; N,
Di-t-butyl
succinal-2-ylidene-4-phenylthiosemicarbazone
(4a). Greenish white powder; yield: 0.74 g (95%), mp 152–
153ꢀC; IR (KBr): m ¼ 3286, 3271 (NH), 1721, 1685
1
(2 C¼¼O), 1598 (C¼¼N), 1584 (C¼¼S) cmꢁ1; H NMR:
d ¼ 1.50 (9H, s, 3CH3), 1.57 (9H, s, 3CH3), 3.44 (2H,
s, CH2), 7.25–7.70 (5H, m, Ph), 9.31 (1H, s, NH), 12.55
(1H, s, NH) ppm;13C NMR: d ¼ 176.7 (C¼¼S), 169.2,
161.2 (2C¼¼O), 138.0 (C¼¼N), 131.0 (C), 129.1 (2CH),
126.6 (C), 124.4 (2CH), 85.1 (C) 82.2 (C), 41.4 (CH2),
28.5 (3CH3), 28.30 (3CH3) ppm; ms: m/z (%) 393 (8,
Mþ), 292 (70), 264 (28), 236 (100), 190 (18), 151 (18),
136 (44), 57 (88). Anal. Calcd. for C19H27N3O4S
(393.12): C, 58.01; H, 6.87; N, 10.68%. Found: C,
20.11%.
Di-t-butyl succinal-2-ylidenethiosemicarbazone (4b). White
powder; yield: 0.54g (85%), mp 162–163ꢀC; IR (KBr): m ¼
3286, 3273 (NH), 1724, 1685 (2 C¼¼O), 1595 (C¼¼N),
1584 (C¼¼S) cmꢁ1; H NMR: d ¼ 1.52 (9H, s, 3CH3),
1
1.55 (9H, s, 3CH3), 3.48 (2H, s, CH2), 9.35 (2H, s, NH2),
12.50 (1H, s, NH) ppm;13C NMR: d ¼ 176.7 (C¼¼S),
169.2, 161.2 (2 C¼¼O), 138.0 (C¼¼N), 85.8 (C) 82.1 (C),
41.6 (CH2), 28.9 (3 CH3), 28.38 (3 CH3) ppm; ms: m/z
(%) 317 (18, Mþ), 216 (77), 200 (22), 156 (100), 99 (18).
Anal. Calcd. for C13H23N3O4S (317.12): C, 49.21; H,
7.25; N, 13.24%. Found: C, 49.37; H, 7.89; N, 14.01%.
58.37; H, 6.89; N, 11.01%.
Methyl3-amino-2-imino-4-oxo-1,3-thiazolan-5-ylideneacetate
(3c). Yellow crystals; yield: 0.36 g (89%), mp 181–182ꢀC; IR
(KBr): m ¼ 3302, 3147 (NH2), 1732, 1646 (2 C¼¼O),
1
1694 (C¼¼C), 1608 (C¼¼N) cmꢁ1; H NMR: d ¼ 3.86
(s, MeO), 4.85 (s, NH2), 5.2(s, NH), 7.01 (s, CH), ppm;
13C NMR: d ¼ 166.2, 162.8 (2 C¼¼O), 148.6 (C¼¼N),
146.1 (C), 139.8 (C), 126.3 (CH), 52.3 (MeO) ppm; ms:
m/z (%) 201 (38, Mþ), 170 (8), 142 (5), 126 (25), 85
(86), 56 (100), 44 (24). Anal. Calcd. for C6H7N3O3S
(201.3): C, 35.82; H, 3.48; N, 20.89%. Found: C, 35.34;
Acknowledgment. Financial support of this work by the
Research Council of Islamic Azad University, Tonekabon
Branch, is gratefully acknowledged.
REFERENCES AND NOTES
H, 3.27; N, 21.44%.
Ethyl3-amino-2-imino-4-oxo-1,3-thiazolan-5-ylideneacetate
(3d). Greenish yellow powder; yield: 0.39 g (91%), mp 170–
173 ꢀC; IR (KBr): m ¼ 3291, 3143 (NH2), 1727, 1643 (2
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