Water-mediated multicomponent reaction: A facile and efficient synthesis of multisubstituted thiazolidine-2-thiones

Article abstract of DOI:10.1055/s-0029-1219558

A facile, efficient, and green method for the synthesis of multisubstituted thiazolidine-2-thione derivatives via a three-component reaction of amine, carbon disulfide, and -bromoketone is described. By using water as the reaction medium, the reaction proceeds smoothly to give corresponding products in good to excellent yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219558

LETTER
973
Water-Mediated Multicomponent Reaction: A Facile and Efficient Synthesis
of Multisubstituted Thiazolidine-2-thiones
Synthesis of
M
h
ultisubstitut
i
T
hia
-
z
olidine
F
-2-thiones eng Gan, Jie-Ping Wan, Yuan-Jiang Pan, Cui-Rong Sun*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87951629; E-mail: suncuirong@zju.edu.cn
Received 1 December 2009
thiones involving aryl hydrazines, carbon disulfide, and
Abstract: A facile, efficient, and green method for the synthesis of
multisubstituted thiazolidine-2-thione derivatives via a three-com-
ponent reaction of amine, carbon disulfide, and a-bromoketone is
described. By using water as the reaction medium, the reaction pro-
organic halides has been reported by Li.10 In spite of their
sound utilities, these reported methods suffer from several
disadvantages such as harsh reaction conditions, difficult-
ceeds smoothly to give corresponding products in good to excellent to-obtain starting materials, unsatisfactory yields, pro-
yields.
longed reaction times, or poor substrate tolerance. There-
fore, searching for more facile and practical synthetic
routes to multisubstituted thiazolidine-2-thiones is still
highly desirable work.
Key words: green method, synthesis, thiazolidine-2-thione, MCR,
heterocyclic compounds
Developing organic reactions in water has become highly
popular in recent years due to its specific properties in me-
diating organic reactions and its friendliness to the envi-
ronment.11 Previously, we successfully used water as a
reaction medium to accomplish the synthesis of 1,2-disub-
stituted benzimidazoles and quinoxalines in excellent ef-
ficiency and selectivity.12 As our ongoing efforts in
exploring environmentally benign synthesis, herein we re-
port a novel, efficient, and green synthesis of multisubsti-
tuted thiazolidine-2-thiones in water by the three-
component reaction of amines, carbon disulfide, and a-
bromoketones.
With the advantages of atom-efficient transformation,
easily available starting materials, high product structural
diversity, multicomponent reactions (MCR)1 have attract-
ed great interest from chemical and medicinal communi-
ties. During the past decades, MCR have witnessed great
progress as a widely applicable synthetic strategy. How-
ever, developing novel MCR of broad tolerance and sim-
ple operation for small molecule synthesis is still one of
the main goals in this field.
Thiazolidine-2-thione is a five-membered heterocyclic
scaffold containing both S and N atoms attaching on the
carbon of C=S bond, which has been extensively studied
in the past decades.2 And the thiazolidine-2-thione moiety
have been reported to possess versatile functions. For ex-
ample, polyHPMA terminated with a thiazolidine-2-
thione functional group can be conjugated to a protein sur-
face via covalent amide bonding and form protein–
polyHPMA conjugates,3 copolymers adopting the thiazo-
lidine-2-thione as reactive groups in the side chains are
suitable for the synthesis of polymeric drugs and polymer-
modified biologically active compounds.4 What is more,
thiazolidine-2-thione and its derivatives have been dis-
covered as excellent ligands in coordination chemistry.5
Initially, the reaction of benzylamine (0.5 mmol), carbon
disulfide (0.5 mmol), and benzoyl bromomethane (0.5
mmol) was performed in THF at room temperature for
one hour without any catalyst, affording the desired thi-
azolidine-2-thione 3a in 36% yield (Table 1, entry 1). In
order to improve the reaction efficiency, we varied the
molar ratios of the reactants, when a ratio of 1.5:1:3 (1a/
2a/CS2) was used, the product was isolated in the highest
yield among the entries (Table 1, entry 1–3). To our de-
light, when water was used as the alternative medium of
THF, a similarly good result was obtained (Table 1, entry
4).
There are currently a number of synthetic methodologies
available for the synthesis of thiazolidine-2-thione unit.6
Humphlett7 developed a protocol for the synthesis of 4-
hydoxythiazolidine-2-thione by employing the reaction of
ammonium dithiocarbamate and a-halo aldehydes or ke-
tones. Recently, Endo8 and co-workers described a highly
efficient chemical fixation of carbon disulfide to aziridine
to form 1,3-thioxazolidine-2-thiones based on Foglia’s9
protocol. Later, a simple three-component synthesis of
To further improve the efficiency of this green synthetic
approach, various catalysts such as MgCl2, Et3N, K3PO4,
and K2CO3 have been applied to promote this transforma-
tion (Table 1, entries 5–10). The results revealed that the
presence of base catalyst was necessary to drive the pro-
cess to completion rapidly, and 0.5 mol equivalents
K2CO3 turned out to be the most suitable promoter for the
reaction. The reaction conditions were then finally estab-
lished as shown in entry 8 (Table 1).
4,5-disubstituted
3-amino-4-hydroxy-thiazolidine-2-
After the optimization, different amines and a-bromoke-
tones were probed for the scope of the reaction (Table 2).
By using water as the reaction medium at room tempera-
ture, the corresponding products were afforded in good to
excellent yields. Among the different aliphatic primary
SYNLETT 2010, No. 6, pp 0973–0975
x
x.
x
x.
2
0
1
0
Advanced online publication: 02.03.2010
DOI: 10.1055/s-0029-1219558; Art ID: W18409ST
© Georg Thieme Verlag Stuttgart · New York

974
S.-F. Gan et al.
LETTER
Table 2 One-Pot Synthesis of Multisubstituted Thiazolidine-2-
Table 1 Synthesis of 3-Benzyl-4-hydroxy-4-phenylthiazolidine-2-
thione (3a) under Different Conditionsa
thione Derivatives in Watera
S
N
O
O
S
R2
S
H2O, r.t.
K2CO3
Br
S
R1NH2
+
Br
+
NH2
CS2
R2
+ CS2
N
+
HO
HO
R1
r.t., 1 h
1
2
3
1a
3a
2a
Entry
1
1
R1
R2
Ph
Product Yield (%)b
Entry
Molar ratio
1a/2a/CS2
Catalyst
(equiv)
Solvent
Yield
(%)b
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
1d
1d
1d
1d
1d
1d
1d
1e
1b
Bn
Bn
Bn
Bn
Bn
Bn
Bu
Bu
Bu
Bu
Bu
3a
3b
3c
3d
3e
3f
94
90
92
86
88
86
85
80
80
70
65
64
60
63
70
76
60
76
80
82
81
80
76
75
30
59
2
4-ClC6H4
4-BrC6H4
4-O2NC6H4
4-MeC6H4
4-MeOC6H4
Ph
1
2
1:1:1
none
THF
THF
THF
H2O
H2O
H2O
H2O
H2O
H2O
H2O
36
39
77
75
72
92
93
94
91
76
3
1:1:2
none
4
3
1.5:1:3
1.5:1:3
1.5:1:3
1.5:1:3
1.5:1:3
1.5:1:3
1.5:1:3
1.5:1:3
none
5
4
none
6
5
MgCl2 (0.5)
Et3N (0.5)
K3PO4 (0.5)
K2CO3 (0.5)
K2CO3 (0.3)
K2CO3 (0.1)
7
3g
3h
3i
6
8
4-ClC6H4
4-BrC6H4
4-O2NC6H4
4-MeC6H4
Ph
7
9
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3j
9
3k
3l
10
allyl
allyl
allyl
allyl
allyl
allyl
Pr
a All reactions were carried out at open atmosphere.
b Isolated yield based on 2a.
4-ClC6H4
4-BrC6H4
4-O2NC6H4
4-MeC6H4
4-MeOC6H4
Ph
3m
3n
3o
3p
3q
3r
3s
amines including benzylamine, n-propylamine, n-butyl-
amine, allylamine, no significant impact on the yield was
observed. However, a low yield (30%) was observed
when aromatic amine (Table 2, entry 25) was utilized in
the same reaction, this phenomenon probably resulted
from the decrease of nucleophilicity of the nitrogen at-
om.10 In addition, as shown in Table 2, this water-mediat-
ed MCR was also tolerant to different substituents on the
arene unit, both electron-donating and electron-withdraw-
ing ones, of the a-bromoketones.
Pr
4-ClC6H4
4-BrC6H4
4-O2NC6H4
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
4-ClC6H4
Et
Pr
3t
Besides, a similar reaction using aliphatic a-bromoketone
was also investigated, and corresponding product 3z from
the reaction using 1-bromo-2-butanone was obtained in
modest yield (Table 2, entry 26).
Pr
3u
3v
3w
3x
3y
3z
Pr
Pr
The structures of all products were characterized by IR,
1H NMR, 13C NMR, ESI-MS, and HRMS analysis, and
the structure of 3a was additionally confirmed by the X-
ray single-crystal diffraction (Figure 1).13
Pr
Ph
Bu
On the basis of the experimental results and the litera-
ture,10 a possible mechanism for the formation of multi-
substituted thiazolidine-2-thione derivatives is presented
in Scheme 1. The initial step in this reaction is the nucleo-
philic attack of amine 114 to carbon disulfide to afford the
key intermediate 4, which subsequently reacts with 2 to
form another intermediate 5, and intermediate 5 under-
goes an intramolecular cyclization to give the final prod-
uct 3.
a Reaction conditions: amine (0.75 mmol), CS2 (1.5 mmol), a-bro-
moketone (0.5 mmol), K2CO3 (0.25 mmol), r.t., 1 h.
b Isolated yield based on 2.
thiazolidine-2-thione derivatives starting from amines,
carbon disulfide, and a-bromoketones. This newly devel-
oped procedure offers several advantages such as broad
application scope, excellent yields, mild reaction condi-
tions, simple operation, and environmental friendliness.
The present study provided a useful supplement for the
synthesis of thiazolidine-2-thione heterocycles.
In conclusion, we have reported a highly efficient and
green protocol for one-pot synthesis of multisubstituted
Synlett 2010, No. 6, 973–975 © Thieme Stuttgart · New York

LETTER
Synthesis of Multisubstituted Thiazolidine-2-thiones
975
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Figure 1 Crystal structure of 3a
SK
CS2
S
R1NH2
R1HN
K2CO3
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1
4
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2
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R2
R1
S
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S
S
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N
C
S
HO
N
R1
H
5
3
Scheme 1 Proposed mechanism for the formation of multisubstitu-
ted thiazolidine-2-thione derivatives
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(13) Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 747685.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(14) General Procedure
To a solution of amines 1 (0.75 mmol) in H2O (3 mL), CS2
(1.5 mmol) and a-bromoketone 2 (0.5 mmol) were added.
Subsequently, K2CO3 (0.25 mmol) was located to the
mixture. After stirring the mixture at r.t. for 1 h, the mixture
was extracted with EtOAc (3 × 10 mL), and the combined
organic layers were dried overnight with anhyd Na2SO4.
After the organic solvent was removed, the residue was
subjected to silical gel chromatography PE–EtOAc (5:1) as
eluent to give pure products.
Acknowledgment
This work was supported by the Natural Science Foundation of
China (No. 20772109).
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Synlett 2010, No. 6, 973–975 © Thieme Stuttgart · New York