An efficient one-pot strategy for the synthesis of 4- methylene-2-thiazolidinethiones in water

Article abstract of DOI:10.1080/00397911.2020.1746972

A simple and efficient, one-pot strategy for the preparation of 4-methylene-2-thiazolidinethiones has been developed. This protocol involved condensation of primary amines with carbon disulfide in water to generate the dithiocarbamate salts in situ, which coupled with 2,3-dibromopropene, followed by intramolecular cyclization to the corresponding heterocycles in moderate to good yields.

Full text of DOI:10.1080/00397911.2020.1746972

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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An efficient one-pot strategy for the synthesis of 4-
methylene-2-thiazolidinethiones in water
Chang-Long Hou, Mei-Hong Wei, Li-Li Chen, Xiao-Ling Liu & Shou-Ri Sheng
To cite this article: Chang-Long Hou, Mei-Hong Wei, Li-Li Chen, Xiao-Ling Liu & Shou-Ri Sheng
(2020): An efficient one-pot strategy for the synthesis of 4- methylene-2-thiazolidinethiones in
water, Synthetic Communications, DOI: 10.1080/00397911.2020.1746972
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1746972
An efficient one-pot strategy for the synthesis of 4-
methylene-2-thiazolidinethiones in water
Chang-Long Hou, Mei-Hong Wei, Li-Li Chen, Xiao-Ling Liu, and Shou-Ri Sheng
Key Laboratory of Functional Small Organic Molecule, Ministry of Education, Jiangxi Normal University,
Nanchang, PR China
ABSTRACT
ARTICLE HISTORY
Received 17 September 2019
A simple and efficient, one-pot strategy for the preparation of 4-
methylene-2-thiazolidinethiones has been developed. This protocol
involved condensation of primary amines with carbon disulfide in
water to generate the dithiocarbamate salts in situ, which coupled
with 2,3-dibromopropene, followed by intramolecular cyclization to
the corresponding heterocycles in moderate to good yields.
KEYWORDS
Carbon disulfide; 2,3-
dibromopropene; 4-
methylene-2-thiazolidine-
thiones; one-pot procedure;
primary amines
GRAPHICAL ABSTRACT
Br
S
Br
S
K2CO3
R
N
S
CS2
R
+
R NH2
N
SK
H2O, r.t.
H
Introduction
Thiazolidine-2-thiones are a class of important five-membered heteroaromatic com-
pounds containing both S and N atoms attaching on the carbon of C¼S bond, which
are usually used as useful organic intermediates,[1–3] especially in pharmaceutical chem-
istry and asymmetric synthesis.[4–7] Due to these reasons, the synthesis of thiazolidine-
2-thiones with different substituents has become one of hot spots in organic synthesis
chemistry in recent decades. Thiazolidine-2-thione derivatives were usually prepared
from b-amino alcohols and carbon disulfide.[8–10] In addition, they could be synthesized
by the palladium catalyzed reactions of propargylamine derivatives with carbon disul-
fide,[11] and by the functionalized ion-exchange resins catalyzed cycloaddition of CS2
with aziridines or propargyl amines.[12] Recently, some multi-component and one-pot
approaches to the thiazolidine-2-thiones have been described.[13–16] Weng and cow-
orkers discovered a switchable copper-catalyzed cascade synthesis of 5-methylene-thia-
zolidine-2-thiones from N-(2-bromoallyl)amines and carbon disulfide.[17] Anitha and
Kumara Swamy constructed thiazolidine-2-thiones in good to excellent yields via the
base promoting the cyclization of epoxy-sulfonamides and carbon disulfide.[18]
Although some useful methods for the their preparation through the reaction of vicinal
CONTACT Li-Li Chen
chenlili@jxnu.edu.cn; Shou-Ri Sheng
shengsr@jxnu.edu.cn
College of Chemistry and
Chemical Engineering, Jiangxi Normal University, Nanchang 330022, PR China.
Supplemental data for this article can be accessed on the publisher's website
ß 2020 Taylor & Francis Group, LLC

2
C.-L. HOU ET AL.
Br
S
Br
(2)
S
Base
N
CS2
+
S
Bn NH2
Bn
N
SK
Solvent, r.t.,
H
1a
3a
Scheme 1. Optimization of one-pot reaction conditions for 3a formation.
Table 1. Screening of reaction conditions in the synthesis of 3a.a
Entry
Molar ratio (1a/CS2/2)
Base (equiv.)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
1:1:1
1:2:1
1:3:1
1:3:1
1:3:1
None
None
None
None
None
None
None
None
None
THF
THF
THF
CH3CN
DMF
EtOH
THF
THF
THF
H2O
THF
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
52
58
60
50
61
56
64c
75
73
72
83
85
72
78
71
84
83
80
75
70
1:3:1
1:3:1.5
1.5:3:1
1.5:3:2
1.5:3:1
1.5:3:1
1.5:3:1
1.5:3:1
1.5:3:1
1.5:3:1
1.5:3:1
1.5:3:1
1.5:3:1
1.5:3:1
1.5:3:1
9
10
11
12
13
14
15
16
17
18
19
20
None
Et3N (2.5)
Et3N (2.5)
NaOH (2.5)
KOH (2.5)
K3PO4 (2.5)
K2CO3 (2.5)
K2CO3 (3.0)
K2CO3 (2.0)
K2CO3 (1.5)
K2CO3 (1.0)
aAll reactions were carried out at open atmosphere in the appropriate solvent (10 mL) using benzylamine (1a), CS2, and
2,3-dibromopropene (2) at room temperature. For entries of 11–20, reaction of 1a (1.5 mmol), CS2 (3.0 mmol), and
K2CO3 (2.5 mmol) at room temperature for 30 min; then 2 (1.0 mmol) was added and stirred for 60 min.
bIsolated yield after silica gel chromatography based on 2.
cIsolated yield after silica gel chromatography based on 1a.
amino alcohols, aziridines, allylamines, and propargylamines with carbon disulfide have
been reported, it is still worth studying to develop facile and practical synthetic strategy
to the functional thiazolidine-2-thione derivatives. Herein, we wish to report a simple,
efficient and one-pot procedure for the synthesis of 4-methylene-thiazolidine-2-thiones
by reaction of primary amines, carbon disulfide, and 2,3-dibromopropene in the pres-
ence of potassium carbonate, using water as the reaction medium, under mild and tran-
sition-metal-free conditions.
In order to find the most suitable reaction conditions for our purpose, benzylamine
(1a), carbon disulfide and 2,3-dibromopropene (2) were chosen as model substrates for
the preparation of 3-benzyl-4-methylene-thiazolidine-2-thione (3a), as shown in Scheme
1. Initially, the reaction of 1a (1.0 mmol), carbon disulfide (1.0 mmol), and 2 (1.0 mmol)
was performed in THF at room temperature for 2 h without any catalyst, affording the
desired product 3a in 52% yield (Table 1, entry 1). The effect of the solvents was then
examined, and several polar solvents were screened. As shown in Table 1, the reaction
proceeded well in the solvents, such as CH3CN, EtOH, and DMF (entries 4–6), but the
yields were not as good as that in THF. Besides, the molar ratios of the reactants were
varied, when a molar ratio was 1.5:3:1 (1a/CS2/2), the product was isolated in the

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SYNTHETIC COMMUNICATIONSV
3
Br
S
Br
K2CO3
R
N
S
CS2
+
R NH2
H2O, r.t.
Scheme 2. Preparation of 3-substituted-4-methylene-thiazolidine-2-thiones.
Table 2. One-pot synthesis of 4-methylene-thiazolidine-2-thiones 3.a
Entry
R
Products (3)
Yield (%)b
1
2
3
4
5
6
7
8
C6H4CH2
n-C4H9
C6H5
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
–
82
75
72
92
89
81
70
62
66
73
–
4-CH3OC6H4
2-CH3OC6H4
2-CH3C6H4
4-BrC6H4
4-ClC6H4
3-ClC6H4
3-NO2C6H4
4-NO2C6H4
4-CNC6H4
4-CF3C6H4
2-ClC6H4
2-BrC6H4
9
10
11
12
13
14
15
–
–
–
–
–
–
–
–
aReaction conditions: primary amines (1.5 mmol), CS2 (3.0 mmol), K2CO3 (2.5 mmol), H2O (10 mL), rt, 30–45 min; then
2,3-dibromopropene (2) (1.0 mmol), rt, 60–90 min.
bIsolated yield based on 2.
highest yield among the entries (Table 1, entry 8). To our delight, when water was used
as the alternative medium of THF, a similar good result was obtained (Table 1, entry
10). To further improve the efficiency of this synthetic approach, various bases, such as
triethylamine, sodium hydroxide, potassium hydroxide, tripotassium phosphate, and
potassium carbonate have been used to promote this transformation (Table 1, entries
11–16). The results indicated that the presence of base was conducive to the rapid com-
pletion of the process. Then, the reaction conditions were further optimized with potas-
sium carbonate as a base, and it was found that 2.5 equivalent potassium carbonate was
the most suitable reaction promoter, as shown in entry 16 (Table 1).
Next, under the optimal conditions, the scope and limitation of this one-pot reaction
were explored using a wide range of aliphatic and aromatic amines (Scheme 2), and the
results are listed in Table 2.
In general, as observed in Table 2, aliphatic primary amines such as benzylamine and
n-butylamine worked well to give the desired products 3a and 3b in 82 and 75% yields,
respectively (Table 2, entries 1 and 2). Furthermore, electron-rich aromatic amines are
more readily to form the corresponding heterocyclic compounds. For example, aromatic
amines with various electron-donating groups (Table 2, entries 4–6) in the para or ortho
position could generate the products in good to excellent yields of 81–92%. In addition,
when halogen groups were placed in the para or meta position of benzene ring, a long
reaction time was needed, but the corresponding products (3f, 3g, and 3h) could still
be obtained in a reasonable yield range of 62–70% (Table 2, entries 7–9).

4
C.-L. HOU ET AL.
Br
H
N
Br
H
N
Br
CS2
SK
S
R NH2
R
R
K2CO3
S
S
1
4
5
S
Br
Br
K2CO3
R
N
S
N
S
N
S
R
R
SH
SK
6
3
Scheme 3. Proposed reaction mechanism.
When strong electron-withdrawing groups such as NO2, CN, and CF3 in the para
position of benzene ring, the corresponding products could not be obtained under these
conditions even after the reaction time is extended or at a higher temperature (Table 2,
entries 11–13). However, 3-nitroaniline could be converted into corresponding product
3j in 73% yield (Table 2, entry 10). On the other hand, it was worth noting here that
aromatic amines bearing halide substituents in the ortho position, have no reaction
observed (Table 2, entries 14 and 15), which may be due to the electron induction effect
and steric hindrance effect of the halogens, preventing conversion of the amines to their
corresponding dithiocarbamate salts.
On the basis of the experimental results and the literature,[19] a plausible mechanism
for the formation of 4-methylene-thiazolidine-2-thiones is described in Scheme 3. The
initial step of the reaction is the nucleophilic attack of amine 1 on carbon disulfide,
which is activated by potassium carbonate, to afford the key intermediate dithiocarba-
mate salt 4, and then reacts with 2,3-dibromopropene to form S-allyl dithiocarbamate 5.
The final product 3 was obtained by intramolecular cyclization of intermediate 6.
In summary, we have described a novel, efficient, one-pot process for the synthesis of
4-methylene-thiazolidine-2-thiones in moderate to good yields from primary amines,
carbon disulfide, and 2,3-dibromopropene, through the condensation, S-allylation and
heterocyclization reaction in water successively.
Experimental
The reaction progress was detected by thin layer chromatography (TLC) on GF254 silica
gel analytical aluminum plates, and the products were visualized by UV spectrophotom-
eter. Column chromatography was performed on silica gel 60 (250–400 mesh). Melting
1
points were measured with a Beijing-Taike X-4 apparatus without corrected. H NMR
and 13C NMR spectra were recorded in deuterated CDCl3 or DMSO-d6 on an Avance-
Bruker 400 MHz NMR spectrometer (Bruker Optics Inc, Billerica, MA), operating at
400 and 100 MHz, respectively. FTIR analyses were performed with a Perkin-Elmer SP
One FTIR spectrophotometer (PerkinElmer, Inc., Waltham, MA). Microanalyses were

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SYNTHETIC COMMUNICATIONSV
5
performed with a Carlo Erba 1106 Elemental Analyzer. The other reagents and solvents
were purchased from commercial suppliers and were used as received without further
purification.
General procedure for the preparation of 4-methylene-2-thiazolidinethione
A mixture of K2CO3 (2.5 mmol), amine (1.5 mmol), and CS2 (3.0 mmol) in H2O
(10.0 mL) was stirred at room temperature until the reaction was completed (deter-
mined by TLC). After 30–45 min, 2,3-dibromopropene (1.0 mmol) was added and the
reaction continued for another 60–90 min under vigorous smagnetic stirring at room
temperature. After completion, the organic matter was extracted with diethyl ether
(2 ꢀ 10 mL). The combined organic phase was washed with water, dried over anhydrous
sodium sulfate. The solvent was removed under reduced pressure to give the crude
product, which was purified by flash column chromatography (silica gel, petroleum
ether–EtOAc) to afford the target compound.
1
Characterization data of all target compounds, copies of H NMR and 13C NMR
spectra of all compounds. This material can be found via the “Supplementary Content”.
Funding
We are grateful to the National Natural Science Foundation of China [No. 21762022], the
Research Program of Jiangxi Province Department of Education [No. GJJ160289, GJJ11380], the
Opening Foundation of National Research Center for Carbohydrate Synthesis [No. GJDTZX-KF-
201414], and the Opening Foundation of Key Laboratory of Functional Small Organic Molecule
of Ministry of Education [No. KLFS-KF-201411] for the financial support.
References
[1] Rufino, A. R.; Biaggio, F. C. Synthesis of a Novel Prostaglandin Containing Heteroatoms
in the Ring Cyclopentane. Tetrahedron Lett. 2001, 42, 8559–8561. DOI: 10.1016/S0040-
4039(01)01861-5.
[2] Biaggio, F. C.; Rufino, A. R.; Silveira, M. C. F. Synthesis of Novel Heterocyclic
Prostaglandin Analogues. Lett. Org. Chem. 2007, 4, 1–3. DOI: 10.2174/
157017807780037388.
[3] Wang, J.; Liu, H.-B.; Wang, W.; Kim, I.; Ha, C.-S. A Thiazoline-Containing Cobalt (II)
Complex Based Colorimetric Fluorescent Probe: “Turn-on” Detection of Fluoride. Dalton
Trans. 2009, 104, 10422–10425. DOI: 10.1039/b918887h.
[4] Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J. Asymmetric Synthesis of Active
Pharmaceutical Ingredients. Chem. Rev. 2006, 106, 2734–2793. DOI: 10.1021/cr040700c.
ꢀ
ꢀ
ꢀ
[5] Baiget, J.; Cosp, A.; Galvez, E.; Gomez-Pinal, L.; Romea, P.; Urpı, F. On the Influence of
Chiral Auxiliaries in the Stereoselective Cross-Coupling Reactions of Titanium Enolates
and Acetals. Tetrahedron 2008, 64, 5637–5633. DOI: 10.1016/j.tet.2008.04.044.
[6] Hwu, J. R.; Hsu, Y. C. Stereospecific Benzyne-Induced Olefination from b-Amino
Alcohols and Its Application to Thetotal Synthesis of (–)-1-deoxy-D-Fructose. Chem. Eur.
J. 2011, 17, 4727–4731. DOI: 10.1002/chin.201133038.
[7] Tungen, J. E.; Aursnes, M.; Hansen, T. V. Stereoselective Synthesis of Maresin 1.
Tetrahedron Lett. 2015, 56, 1843–1846. DOI: 10.1016/j.tetlet.2015.02.080.
[8] Delaunay, D.; Toupet, L.; Le Corre, M. Reactivity of b-Amino Alcohols with Carbon
Disulfide. Study on the Synthesis of 2-Oxazolidinethiones and 2-Thiazolidinethiones.
J. Org. Chem. 1995, 60, 6604–6607. DOI: 10.1002/chin.199609139.

6
C.-L. HOU ET AL.
[9] Chen, N.; Jia, W.-Y.; Xu, J.-X. A Versatile Synthesis of Various Substituted Taurines from
Vicinal Amino Alcohols and Aziridines. Eur. J. Org. Chem. 2009, 2009, 5841–5846. DOI:
10.1002/ejoc.200900759.
[10] Lu, Z.; Yang, Y.-Q.; Xiong, W.-X. Preparation of 1,3-Thiazolidine-2-Thiones by Using
Potassium Ethylxanthate as a Carbon Disulfide Surrogate. Synlett. 2019, 30, 713–716.
DOI: 10.1055/s-0037-1612124.
[11] Shi, M.; Shen, Y.-M. Transition-Metal-Catalyzed Reactions of Propargylamine with
Carbon Dioxide and Carbon Disulfide. J. Org. Chem. 2002, 67, 16–21. DOI: 10.1021/
jo0014966.
[12] Liu, A. H.; He, L. N.; Peng, S. Y.; Pan, Z. D.; Wang, J. L.; Gao, J. Environmentally Benign
Chemical Fixation of CO2 Catalyzed by the Functionalized Ion-Exchange Resins. Sci.
China Chem. 2010, 53, 1578–1585. DOI: 10.1007/s11426-010-4028-6.
[13] Nasiri, F.; Zolali, A.; Ahmadiazar, M. A Convenient Solvent-Free and One-Pot Synthesis
of 4-Hydroxythiazolidine-2-Thiones. J. Sulfur. Chem. 2014, 35, 412–417. DOI: 10.1080/
17415993.2014.907407.
[14] Ziyaei-Halimehjani, A.; Marjani, K.; Ashouri, A. A One-Pot, Three-Component Synthesis
of Thiazolidine-2-Thiones. Tetrahedron Lett. 2012, 53, 3490–3492. DOI: 10.1016/j.tetlet.
2012.04.129.
[15] Safa, K. D.; Alyari, M. Synthesis of Thioalkyne-Substituted Thiazolidine-2-Thiones Using
Tris(Trimethylsilyl)Methyllithium and Carbon Disulfide. Synthesis 2014, 47, 256–262.
DOI: 10.1055/s-0034-1379253.
[16] Nechaev, A. A.; Peshkov, A. A.; Hecke, K. V.; Peshkov, V. A.; Van der Eycken, E. V.
Synthesis of Thiazolidine-2-Thiones through a One-Pot A-Coupling-Carbon Disulfide
Incorporation Process. Eur. J. Org. Chem. 2017, 2017, 1063–1069. DOI: 10.1002/ejoc.
201601103.
[17] Weng, H.-Q.; Yue, B.-J.; Xu, M.; Yang, Y.-K.; Jin, H.-W. Switchable Copper-Catalyzed
Cascade Synthesis of Thiazolidine-2-Thiones and Thiazole-2(3H)-Thiones. Synthesis 2015,
47, 2991–2996. DOI: 10.1055/s-0034-1380815.
[18] Anitha, M.; Kumara Swamy, K. C. Synthesis of Thiazolidine-Thiones, Imino-Thiazolidines
and Oxazolidines via the Base Promoted Cyclisation of Epoxy-Sulfonamides and
Heterocumulenes. Org. Biomol. Chem. 2018, 16, 402–413. DOI: 10.1039/C7OB02915B.
[19] Jacobine, A. M.; Posner, G. H. Three-Component, One-Flask Synthesis of Rhodanines
(Thiazolidinones). J. Org. Chem. 2011, 76, 8121–8125. DOI: 10.1021/jo201561t.