A novel multicomponent method for the synthesis of 2-thioxo-1,3- thiazolidin-4-ones

Article abstract of DOI:10.1055/s-0029-1217548

An easy, highly efficient and simple one-pot approach to the synthesis of 2-thioxo-1,3-thiazolidin-4-ones is reported. The reaction of a primary amine and carbon disulfide in the presence of fumaryl chloride in water afforded the title compounds in good y

Full text of DOI:10.1055/s-0029-1217548

2146
LETTER
A Novel Multicomponent Method for the Synthesis of
2-Thioxo-1,3-thiazolidin-4-ones
S
ynthesisof 2-Thi
b
oxo-1,3-thiaz
d
olidine-4-on
o
es lali Alizadeh,* Nasrin Zohreh
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran 18716, Iran
Fax +98(21)88006544; E-mail: abdol_alizad@yahoo.com; E-mail: aalizadeh@modares.ac.ir
Received 9 April 2009
ptotic Bcl-2 proteins,13 and 6 was evaluated as an inhibitor
Abstract: An easy, highly efficient and simple one-pot approach to
the synthesis of 2-thioxo-1,3-thiazolidin-4-ones is reported. The
reaction of a primary amine and carbon disulfide in the presence of
fumaryl chloride in water afforded the title compounds in good
yield.
of translation initiation (Figure 2).14
As part of our ongoing project devoted to the synthesis of
heterocycles, especially those containing two hetero-
atoms,15 we report herein a novel, one-pot, three-compo-
nent synthesis of 2-thioxothiazolidin-4-one in water.
Key words: thiazolidine, rhodanine, carbon disulfide, fumaryl
chloride, multicomponent reaction
S
S
HN
O
S
N
S
H
During the past decade, combinatorial chemistry has pro-
vided access to chemical libraries based on privileged
structures,1 with heterocyclic structures receiving special
attention as they belong to a class of compounds with
proven utility in medicinal chemistry.2 There are numer-
ous biologically active molecules with five-membered
rings containing two heteroatoms. Thiazolidine (1) and its
derivatives are important scaffolds known to be important
in several biologically active compounds.3 Thiazolidine-
2-thione (2) and thiazolidin-4-ones (3) are important sub-
structures found in numerous natural products and phar-
maceuticals (Figure 1).4
HO2C
Br
R
O
RO
6
5
Figure 2
Recently, we have become interested in the application of
fumarylchloride in multicomponent reactions.16 Thus, as
shown in Scheme 1, we investigated its reaction with
zwitterions derived from primary amines 7 and carbon
disulfide in water.17 The reaction, which is complete after
12 hours at room temperature, produces the 2-(3-alkyl-4-
oxo-2-thioxo-1,3-thiazolan-5-yl)acetic acid derivatives 8
in 75–85% yields (Table 1).
HN
S
1
thiazolidine
The structures of 2-(3-alkyl-4-oxo-2-thioxo-1,3-thiaz-
olan-5-yl)acetic acid derivatives were elucidated from
their elemental analysis, mass, IR and highfield H and
S
S
1
HN
O
S
13C NMR spectra as described for 8a. The mass spectrum
of 8a displayed the molecular ion peak (m/z = 281) and,
importantly, an ion peak (m/z = 237) indicating CO2 loss
and thus the presence of a CO2H group. In the IR spec-
trum, the O–H stretching absorption band of the acid ap-
peared between 3451–2625 cm–1, with peaks at 1718 and
1671 cm–1 due to the two carbonyl groups, and absorp-
tions at 1343 and 1186 cm–1 indicating the presence of a
C=S moiety.
HN
S
HN
O
S
2
3
4
thiazolidine-2-thione
thiazolidine-4-one
2-thioxothiazolidine-4-one
Figure 1
Compounds containing the 2-thioxothiazolidin-4-one ring
4 (rhodanine) and its derivatives have shown a wide range
of pharmacological activities, which include antimicrobi-
al,5 antiviral,6 and anticonvulsant7 activity. Additionally,
rhodanine-based molecules have been popular as small
molecule inhibitors of numerous targets such as HCV
NS3 protease,8 aldose reductase,9 b-lactamase,10 and his-
tidine decarboxylase,11 and have been used as antidiabetic
agents.12 For example, 5 is an antagonist against anti-apo-
The 13H NMR spectrum of 8a, contains three double dou-
blets at d = 3.04 (J = 18.0, 9.0 Hz), 3.60 (J = 18.0, 3.5 Hz)
and 4.45 ppm (J = 8.9, 3.5 Hz), which are related to the di-
astereotopic hydrogens of CH2CO2H and the SCH, re-
spectively. The spectrum also contains two doublets at
d = 5.15 and 5.24 ppm (J = 14.2 Hz) arising from the two
diastereotopic hydrogens of CH2Ph, and the acidic hydro-
gen, which appears as a broad signal between d = 6.50 and
8.00 ppm. The 1H decoupled 13C NMR spectrum showed
ten distinct signals, in agreement with the proposed struc-
SYNLETT 2009, No. 13, pp 2146–2148
Advanced online publication: 10.07.2009
DOI: 10.1055/s-0029-1217548; Art ID: D09209ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Thioxo-1,3-thiazolidine-4-ones
2147
ture, with the resonance due to C=S, appearing at d =
200.05 ppm.
Table 1 The Reaction of Primary Amine 7, Carbon Disulfide, and
Fumaryl Chloride at Room Temperature
S
Although we have not established the mechanism experi-
mentally, a possible pathway is proposed in Scheme 1.
The reaction presumably proceeds through initial addition
of amine 7 to the carbon disulfide to afford zwitterion 9,17
which then attacks the conjugated double bond to produce
intermediate 10.18 Probably, the thiocarbamate 10 under-
goes intramolecular cyclization followed by loss of an
HCl molecule to convert it into the thiazolidine 11 (it is
important to note that five-membered-ring formation is
kinetically more favorable than six-membered-ring for-
mation).19 Finally, hydrolysis of intermediate 11 leads to
the corresponding 2-thioxo-1,3-thiazolidin-4-ones 8 in
75–85% yield.20
O
S
•
H2O
R
Cl
S
R
NH2
+
+
N
Cl
r.t., 12 h
S
O
CO2H
O
7
8
Entry Primary amine 7 Product 8
Yield (%)
85
S
NH2
a
N
S
S
S
CO2H
CO2H
CO2H
O
S
S
Cl
NH2
b
82
80
75
87
80
75
77
75
N
Cl
S
•
S
ClOC
COCl
O
+
NH2
R
R
RH2N
S
S
7
9
c
N
NH2
S
S
O
H2O
N
S
– HCl
R
S
N
S
8
H
Cl
Me
d
Me NH2
N
S
COCl
O
O
COCl
11
CO2H
CO2H
10
O
S
Scheme 1 Proposed mechanism for the formation of 2-thioxo-1,3-
thiazolidin-4-one derivatives
e
f
NH2
N
S
In summary, in this communication we report a novel and
concise method for the synthesis of 2-thioxo-1,3-thiazoli-
din-4-ones of potential synthetic and pharmacological in-
terest in good yields using simple and inexpensive starting
materials. The one-pot reaction is performed under neutral
conditions and the carboxylic acid group on the 5-position
is capable of further functionalization. The simplicity of
the present procedure makes it an interesting alternative to
more complex multistep approaches.
O
S
NH2
N
S
CO2H
O
S
g
h
i
N
S
NH2
NH2
CO2H
O
S
References and Notes
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N
S
CO2H
O
S
NH2
NH2
N
S
CO2H
O
S
N
S
j
78
CO2H
O
(7) Captan, G.; Ulusoy, N.; Ergenc, N.; Ekinic, A. C.; Vidin, A.
Farmaco 1996, 51, 729; Chem. Abstr. 1996, 126, 157436q.
Synlett 2009, No. 13, 2146–2148 © Thieme Stuttgart · New York

2148
A. Alizadeh, N. Zohreh
LETTER
(8) Sing, W. T.; Lee, C. L.; Yeo, S. L.; Lim, S. P.; Sim, M. M.
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and the reaction mixture was allowed to stir for 12 h. The
reaction was extracted with CH2Cl2 (2 × 8 mL), and the
solvent was dried and evaporated. The residue was purified
by column chromatography (n-hexane–EtOAc, 4:1) to
obtain product 8a as a yellow wax (0.24 g, 85%). IR (KBr):
3451–2625 (OH), 1718 (CO2H), 1671 (CO), 1343 and 1186
(C=S) cm–1. 1H NMR (500.1 MHz, CDCl3): d = 3.04 (1 H,
dd, 2JH,H = 18.0 Hz, 3JH,H = 9.0 Hz, CHCH2), 3.60 (1 H, dd,
2JH,H = 18.0 Hz, 3JH,H = 3.5 Hz, CHCH2), 4.45 (1 H, dd,
3JH,H = 8.9 Hz, 3JH,H = 3.5 Hz, CHCH2), 5.15 (1 H, d,
3JH,H = 14.2 Hz, CH2Ph), 5.24 (1 H, d, 3JH,H = 14.2 Hz,
CH2Ph), 7.30 (2 H, t, 3JH,H = 7.2 Hz, 2 × CH of Ph), 6.51–
7.37 (1 H, br, OH), 7.40 (1 H, t, 3JH,H = 7.7 Hz, CH of Ph),
7.45 (2 H, d, 3JH,H = 7.1 Hz, 2 × CH of Ph). 13C NMR (125.7
MHz, CDCl3): d = 36.33 (CHCH2), 45.46 (CHCH2), 47.83
(CH2Ph), 128.16 (CH of Ph), 128.59 (2 × CH of Ph), 128.86
(2 × CH of Ph), 134.60 (Cipso-CH2), 174.06 (NCO), 175.39
(CO2H), 200.05 (C=S). MS: m/z (%) = 281 (58) [M+], 265
(11), 237 (17), 148 (68), 91 (100), 77 (9), 65 (27), 55 (10).
Anal. Calcd for C12H11NO3S2 (281.34): C, 51.23; H, 3.94; N,
4.98. Found: C, 51.29; H, 3.97; N, 4.95. Compound 8f:
Yield: 0.19 g (80%). Yellow wax. IR (KBr): 3350–2610
(OH), 1719 (CO2H), 1679 (CO), 1348 and 1125 (C=S) cm–1.
1H NMR (500.1 MHz, CDCl3): d = 0.94 (3 H, t, 3JH,H = 7.4
Hz, NCH2CH2CH3), 1.63–1.70 (2 H, m, NCH2CH2CH3),
3.02 (1 H, dd, 2JH,H = 18.2 Hz, 3JH,H = 9.2 Hz, CHCH2), 3.28
(1 H, dd, 2JH,H = 18.0 Hz, 3JH,H = 3.4 Hz, CHCH2), 3.95 (2 H,
t, 3JH,H = 7.5 Hz, NCH2CH2CH3), 4.42 (1 H, dd, 3JH,H = 8.8
Hz, 3JH,H = 3.6 Hz, CHCH2), 6.01–7.21 (1 H, br, OH).
13C NMR (125.7 MHz, CDCl3): d = 11.14 (NCH2CH2CH3),
20.08 (NCH2CH2CH3), 36.63 (CHCH2), 45.54 (CHCH2),
46.33 (NCH2CH2CH3), 173.91 (NCO), 175.59 (CO2H),
200.57 (C=S). MS: m/z (%) = 233 (100) [M+], 215 (18),
200(10), 187 (31), 174 (22), 146 (15), 100 (61), 86 (32), 43
(30). Anal. Calcd for C8H11NO3S2 (233.30): C, 41.19; H,
4.75; N, 6.00. Found: C, 41.23; H, 4.77; N, 6.05. Compound
8i: Yield: 0.17 g (75%). Yellow wax. IR (KBr): 3445–3060
(OH), 1717 (CO2H), 1677 (CO), 1333 and 1200 (C=S)
cm–1. 1H NMR (500.1 MHz, CDCl3): d = 3.04 (1 H, dd,
2JH,H = 17.6 Hz, 3JH,H = 8.7 Hz, CHCH2), 3.29 (1 H, dd,
2JH,H = 17.6 Hz, 3JH,H = 3.5 Hz, CHCH2), 4.45 (1 H, dd,
3JH,H = 8.6 Hz, 3JH,H = 3.4 Hz, CHCH2), 4.60–4.63 (2 H, m,
CH2N), 5.23–5.30 (2 H, m, CH=CH2), 5.77–5.80 (1 H, m,
CH=CH2), 6.35–7.28 (1 H, br, OH). 13C NMR (125.7 MHz,
CDCl3): d = 36.50 (CHCH2), 45.59 (CHCH2), 46.65 (NCH2),
119.58 (CH=CH2), 129.33 (CH=CH2), 173.93 (NCO),
175.10 (CO2H), 199.88 (C=S). MS: m/z (%) = 231 (39)
[M+], 216 (44), 197 (27), 187 (51), 149 (45), 98 (57), 86 (39),
71 (61), 58 (78), 55 (100), 42 (73). Anal. Calcd for
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mmol) and H2O (3 mL as solvent), was added CS2 (0.15 g, 2
mmol). Then, fumaryl chloride (0.15 g, 1 mmol) was added
C8H9NO3S2 (231.28): C, 41.55; H, 3.92; N, 6.06. Found: C,
41.56; H, 3.95; N, 6.07.
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