A novel one-pot solvent-free synthesis of 3-alkyl-2-thioxo-1,3- thiazolidine-4-ones

Article abstract of DOI:10.1080/17415993.2013.789518

An easy, highly efficient solvent-free and simple one-pot approach to the synthesis of 3-alkyl-2-thioxo-1,3-thiazolidine-4-ones is reported. The reaction of a primary amine and carbon disulfide in the presence of chloroacetyl chloride or 2-chloro-2-phenylacetyl chloride at room temperature afforded 3-alkyl-2-thioxo-1,3-thiazolidine-4-one derivatives in high yields.

Full text of DOI:10.1080/17415993.2013.789518

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A novel one-pot solvent-free synthesis
of 3-alkyl-2-thioxo-1,3-thiazolidine-4-
ones
Farough Nasiri a , Amin Zolali b & Zeinab Azimian b
a Department of Applied Chemistry , University of Mohaghegh
Ardabili , PO Box 56199-11367, Ardabil, Iran
b Department of Chemistry , Faculty of Science, University of
Kurdistan , Sanandaj, Iran
Published online: 29 Apr 2013.
To cite this article: Farough Nasiri , Amin Zolali & Zeinab Azimian (2013): A novel one-pot
solvent-free synthesis of 3-alkyl-2-thioxo-1,3-thiazolidine-4-ones, Journal of Sulfur Chemistry,
DOI:10.1080/17415993.2013.789518
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Journal of Sulfur Chemistry, 2013
http://dx.doi.org/10.1080/17415993.2013.789518
A novel one-pot solvent-free synthesis of
3-alkyl-2-thioxo-1,3-thiazolidine-4-ones
Farough Nasiria*, Amin Zolalib and Zeinab Azimianb
aDepartment of Applied Chemistry, University of Mohaghegh Ardabili, PO Box 56199-11367, Ardabil, Iran;
bDepartment of Chemistry, Faculty of Science, University of Kurdistan, Sanandaj, Iran
(Received 2 December 2012; final version received 21 March 2013)
An easy, highly efficient solvent-free and simple one-pot approach to the synthesis of 3-alkyl-2-thioxo-1,3-
thiazolidine-4-ones is reported. The reaction of a primary amine and carbon disulfide in the presence of
chloroacetyl chloride or 2-chloro-2-phenylacetyl chloride at room temperature afforded 3-alkyl-2-thioxo-
1,3-thiazolidine-4-one derivatives in high yields.
S
S
O
Solvent-free
R
S
R'
R-NH2
N
O
+
+
C
S
Cl
r.t., 7 min
R'
Cl
R: Alkyl,2-Methoxyethyl, substituted benzyl; R
': H, Phenyl
Keywords: solvent-free reaction; rhodanines; primary amines; carbon disulfide
1. Introduction
During the last few decades, a central aim in synthetic organic chemistry has been to provide
greener and more economically viable processes for the efficient synthesis of biologically active
compounds with potential application in the pharmaceutical or agrochemical industries. One
approach to this goal is to design reactions using solvent-free condition (1). It reduces the use
of environmentally unsound organic solvents and diminishes the formation of other wastes. The
reactions occur under mild conditions and usually need simple workup procedures using readily
available equipment. Multicomponent reactions (MCRs) (2) are important to provide important
routes for the synthesis of heterocyclic compounds.Although significant advances have been made
in the case of MCRs, there is still a high demand for new processes for the synthesis of heterocyclic
molecules. 4-Thiazolidinones are one of the most important groups of heterocyclic compounds
(3). Among these 4-thiazolidinones, the rhodanine (2-thioxo-4-thiazolidinone) derivatives have
been the subject of several studies in the past years. Rhodanine derivatives are used in analytical
chemistry (4) as a sensitive reagent for the determination of ions. The application of rodanines as a
*Corresponding author. Email: nasiri@uma.ac.ir
© 2013 Taylor & Francis

2
F. Nasiri et al.
corrosion inhibitor of mild steel in acidic solution is well known (5). Rhodanine-based molecules
have pharmacological activities that include anticancer (6), anticonvulsant (7), antibacterial, and
antiviral activity (8). These compounds can also inhibit numerous targets such as bacterial MurD
ligase (9), bacterial RNA polymerase (10), enoyl acyl carrier protein (ACP) reductase (11), histone
acetyltransferases (12), ADAMTS-5 (13), and cholesterol esterase (14).
There are several reports about the synthesis of 2-thioxo-1,3-thiazolidine-4-one derivatives
in the literature (15). However, most of the reported methods for the synthesis of these com-
pounds require multiple-steps, toxic and harmful organic solvents, and also usually require a
catalyst to facilitate the reaction. For example, one route for the synthesis of 5c is reaction of
N-isopropyldithiocarbamate with α-bromophenylacetic acid in the presence of a base, but this
route is time-consuming and the yield of the reaction was only 30% (15e). Recently, a three-
component reaction between primary amines and carbon disulfide in the presence of fumaryl
chloride has been reported to produce 2-(3-alkyl-4-oxo-2-thioxo-1,3-thiazolidine-5-yl)acetic acid
derivatives (16). Herein, we report an efficient one-pot solvent-free route for synthesis of 3-alkyl-
2-thioxo-1,3-thiazolidine-4-one derivatives in high yields by the reaction of primary amines and
carbon disulfide in the presence of chloroacetyl chloride or 2-chloro-2-phenylacetyl chloride.
2. Results and discussion
The reaction between primary amines and carbon disulfide in the presence of chloroacetyl chloride
or 2-chloro-2-phenylacetyl chloride proceeds smoothly at room temperature and is completed
within 7 min (Scheme 1).
The structures of compounds 5c and 5e were deduced by the spectroscopic analysis and com-
parison of their physical data with those reported in the literature (15b, 15e). The structures of
other products were deduced from their IR, 1H-NMR, 13C-NMR and mass spectroscopic data. The
mass spectrum of 5a showed the molecular ion peak at m/z = 267. In the IR spectrum of 5a, the
1
=
=
C O stretching absorption appeared at 1730 and the C S group vibrated at 1324. The H-NMR
spectrum of 5a showed two singlets at δ = 3.33 and 5.26 ppm which were related to methoxy and
S
O
S
C
S
R
Solvent free
r, t, 7 min
S
N
R'
RNH2
+
+
Cl
Cl
R'
O
3
4
5 (80–87%)
R
R'
5
5a
5b
5c
5d
5e
5f
Ph
H
Ph
Ph
Ph
Ph
Ph
2-Methoxyethyl
i-Pr
i-Pr
n-Bu
Bn
2-Chlorobenzyl
2-Methoxybenzyl
5g
Scheme 1. Solvent-free synthesis of 3-alkyl-2-thioxo-1,3-thiazolidine-4-one derivatives 5
(see Section 4).

Journal of Sulfur Chemistry
3
S
-
+
R
S
-
S
N
H
Cl
-
RNH3Cl
+ 4
+
R NH2
5
CS2
RNH
S
+
RNH3
R'
O
3
6
7
Scheme 2. Proposed mechanism for the formation of 3-alkyl-2-thioxo-1,3-thiazolidine-4-one
derivatives 5a–5g.
methine protons and two multiplets at δ = 3.66–3.70 and 4.26–4.30 for two methylene protons.
Five aromatic protons appear as a multiplet at δ = 7.04–7.37 ppm. The 13C-NMR spectrum of 5a
showed 10 distinct signals in agreement with the proposed structure.
Although we have not established the mechanism of this reaction experimentally, a possible
pathway is shown in Scheme 2. The reaction presumably proceeds through an initial addition
of the amine 1 to carbon disulfide to afford alkylammonium dithiocarbamate salt 6 (17) which
then reacts with 2-chloro-2-phenylacetyl chloride concomitant with the loss of alkylammonium
chloride salt to produce the intermediate 7, which undergoes intramolecular cyclization to generate
compound 5 in high yield.
The reaction was also examined with aromatic amines under the same reaction conditions
without success.
3. Conclusions
In conclusion, we have described a convenient solvent-free route for the synthesis of 3-alkyl-2-
thioxo-1,3-thiazolidine-4-one derivatives of potential synthetic and pharmacological interest in
high yield using simple and inexpensive starting materials. The simplicity and environmentally
benign nature of the present procedure makes it an interesting route to produce functionalized
rhodanine derivatives.
4. Experimental section
Melting points were measured with an Electrothermal 9100 apparatus. Elemental analyses C, H,
and N were performed using a Heraeus CHN-O-Rapid analyzer. IR spectra were measured with a
Shimadzu IR-460 spectrometer. NMR spectra were recorded with a Bruker DRX-250 AVANCE
instrument (300.1 and 250.1 MHz for 1H and 75.5 and 62.9 MHz for 13C) with CDCl3 as solvent.
Mass spectra were recorded with an Agilent-5975 C inert XL MSD mass spectrometer operating
at an ionization potential of 70 eV. Amines, acetyl chlorides, and carbon disulfide were obtained
from Merck and were used without further purification.
4.1. General procedure for the preparation of 5a–5f (exemplified to 5a)
To a magnetically stirred solution of 0.23 g 2-methoxyethylamine (3 mmol) was added 0.15 g
CS2 (2 mmol) at room temperature. The reaction mixture was then stirred for 2 min. Then, 0.19 g
2-chloro-2-phenylacetyl chloride (1 mmol) was added to the reaction mixture and the reaction
mixture was allowed to stir for 5 min. After completion, the product was separated by column

4
F. Nasiri et al.
chromatography over silica gel (Merck 230–400 mesh) using n-hexane-EtOAc mixture as eluent
(8:1) to obtained product 5a.
4.1.1. 3-(2-Methoxyethyl)-5-phenyl-2-thioxothiazolidine-4-one (5a)
Yellow powder; yield 86%; m.p. 61–62◦C. IR (KBr) (υmax, cm−1): 1730, 1324, 1118. 1H-NMR
(250.1 MHz, CDCl3): δ 7.37–7.04 (m, 5H, Ar), 5.26 (s, H, CH-Ph), 4.30–4.26 (m, 2H, NCH2),
3.70–3.66 (m, 2H, NCH2CH2), 3.33 (s, 3H, OMe). 13C-NMR (62.9 MHz, CDCl3): δ 200.2 (C S),
=
=
175.1 (C O), 134.1 (C), 129.3 (2CH), 129.2 (CH), 128.3 (2CH), 68.0 (OCH2), 58.8 (CH-Ph),
54.3 (OMe), 43.7 (NCH2). MS (EI, 70 eV): m/z (%) = 267 (M+, 7), 234 (24), 121 (50), 91 (100),
77 (20). Anal. Calcd for C12H13NO2S2 (267.04), C, 53.91; H, 4.90; N, 5.24; Found: C, 53.01; H,
4.85; N, 5.20%.
4.1.2. 3-Isopropyl-2-thioxo-1,3-thiazolidine-4-one (5b)
1
Yellow oil; yield 82%. IR (KBr) (υmax, cm−1): 1730, 1314, 1253 cm−1. H-NMR (300.1 MHz,
CDCl3): δ 5.24 (sept, 1H, 3JHH = 7.2 Hz, NCH), 3.84 (s, 2H, CH2), 1.48 (d, 6H, 3JHH = 7.2 Hz,
13
=
=
2CH3). C-NMR (75.5 MHz, CDCl3): δ 202.1 (C S), 174.2 (C O), 50.4 (CH2), 31.5 (NCH),
18.2 (2CH3). MS (EI, 70 eV): m/z (%) = 175 (M+, 65), 118 (100), 57 (35), 43 (58). Anal. Calcd
for C6H9NOS2 (175.26), C, 41.12; H, 5.18; N, 7.99; Found: C, 40.15; H, 5.09; N, 8.04%.
4.1.3. 3-Isopropyl-5-phenyl-2-thioxo-1,3-thiazolidine-4-one (5c)
White powder; yield 80%; m.p. 123–125◦C (15e). IR (KBr) (υmax, cm−1): 1733, 1318, 1100 cm−1
.
1H-NMR (250.1 MHz, CDCl3): δ 7.38–7.26 (m, 5H,Ar), 5.28 (m, 1H, NCH), 5.07 (s, 1H, CH-Ph),
1.52–1.48 (m, 6H, 2CH3). 13C-NMR (62.9 MHz, CDCl3): δ 200.1 (C S), 175.2 (C O), 134.1
(C), 129.4 (2CH), 129.1 (CH), 128.2 (2CH), 52.6 (CH-Ph), 50.5 (CH), 18.3 and 18.2 (2CH3).
MS (EI, 70 eV): m/z (%) = 251 (M+, 99), 118 (100), 100 (74), 91 (48), 77 (15).
=
=
4.1.4. 3-Butyl-5-phenyl-2-thioxothiazolidine-4-one (5d)
1
Pale yellow powder; yield 87%; m.p. 58–59◦C. IR (KBr) (υmax, cm−1): 1735, 1325, 1189. H-
NMR (250.1 MHz, CDCl3): δ 7.35–7.26 (m, 5H, Ar), 5.23 (CH-Ph), 4.03 (t, 2H, 3JHH = 7.5 Hz,
3
NCH2), 1.68–1.59 (m, 2H, CH2), 1.43–1.26 (m, 2H, CH2), 0.94 (t, 2H, JHH = 7.0 Hz, CH3).
13
=
=
C-NMR (62.9 MHz, CDCl3): δ 200.0 (C S), 175.0 (C O), 133.9 (C), 129.3 (2CH), 129.2
(CH), 128.2 (2CH), 54.3 (CH-Ph), 44.8 (NCH2), 28.9 and 20.0 (2CH2), 13.7 (CH3). MS (EI,
70 eV): m/z (%)9 265 (M+, 32), 232 (63), 118 (62), 105 (52), 91 (100), 77 (31). Anal. Calcd for
C13H15NOS2 (265.39), C, 58.83; H, 5.70; N, 5.28; Found: C, 58.50; H, 5.64; N, 5.11%.
4.1.5. 3-Benzyl-2-thioxo-1,3-thiazolidine-4-one (5e)
White powder; yield 85%; m.p. 231–233◦C (15b). IR (KBr) (υmax, cm−1): 1732, 1330, 1190 cm−1
.
1H-NMR (250.1 MHz, CDCl3): δ 7.53–7.11 (m, 10H, 2Ar), 5.47–5.16 (m, 3H, NCH2, CH-Ph).
13
=
=
C-NMR (62.9 MHz, CDCl3): δ 200.0 (C S), 175.2 (C O), 134.8 (C), 133.8 (C), 129.4 (2CH),
129.3 (CH), 128.9 (2CH), 128.7 (2CH), 128.4 (2CH), 128.3 (CH), 54.4 (CH-Ph), 47.9 (CH2).
MS (EI, 70 eV): m/z (%) = 299 (M+, 56), 148 (41), 118 (73), 91 (100).

Journal of Sulfur Chemistry
5
4.1.6. 3-(2-Chlorobenzyl)-5-phenyl-2-thioxothiazolidine-4-one (5f)
White powder; yield 82%; m.p. 116–117◦C. IR (KBr) (υmax, cm−1): 1726, 1329, 1191. 1H-NMR
(250.1 MHz, CDCl3): δ 7.41–6.97 (m, 9H, 2Ar), 5.39–5.34 (m, 3H, NCH2, CH-Ph). 13C-NMR
=
=
(62.9 MHz, CDCl3): δ 199.4 (C S), 174.6 (C O), 133.4 (C), 133.0 (C), 131.7 (C), 129.8 (CH),
129.4 (2CH), 129.3 (CH), 128.9 (CH), 128.3 (2CH), 127.0 (CH), 126.9 (CH), 54.6 (CH-Ph), 45.6
(CH2). MS (EI, 70 eV): m/z (%) = 298 (M–Cl, 100), 148 (14), 106 (28), 77 (15). Anal. Calcd
for C16H12ClNOS2 (333.00), C, 57.56; H, 3.62; N, 4.20; Found: C, 57.11; H, 3.70; N, 4.12%.
4.1.7. 3-(2-Methoxybenzyl)-5-phenyl-2-thioxothizaolidine-4-one (5g)
White powder; yield 84%; m.p. 109–110◦C. IR (KBr) (υmax, cm−1): 1731, 1336, 1199. 1H-NMR
(250.1 MHz, CDCl3): δ 7.38–6.83 (m, 9H, 2Ar), 5.31–5.15 (m, 3H, NCH2, CH-Ph), 3.74 (s, 3H,
OMe). 13C-NMR (62.9 MHz, CDCl3): δ 199.7 (C S), 174.6 (C O), 157.1 (C), 133.9 (C), 129.3
(2CH), 129.1 (CH), 128.9 (C), 128.3 (2CH), 128.0 (CH), 122.2 (CH), 120.2 (CH), 110.4 (CH),
55.3 (CH-Ph), 54.4 (OMe), 43.9 (CH2). MS (EI, 70 eV): m/z (%) = 329 (M+, 4), 136 (26), 121
(85), 91 (100), 77 (24).Anal. Calcd for C17H15NO2S2 (329.05), C, 61.98; H, 4.59; N, 4.25; Found:
C, 62.56; H, 4.63; N, 4.32%.
=
=
References
(1) (a) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025–1074; (b) Martins, M.A.P.; Frizzo, C.P.; Moreira, D.N.; Buriol,
L.; Machado, P. Chem. Rev. 2009, 109, 4140–4182.
(2) (a) Ugi, I. Pure Appl. Chem. 2001, 73, 187–191; (b) Ramón, D.J.; Yus, M. Angew. Chem. Int. Ed. Engl. 2005,
44, 1602–1634; (c) Dömling, A. Chem. Rev. 2006, 106, 17–89; (d) Toure, B.B.; Hall, D.G. Chem. Rev. 2009, 109,
4439–4486.
(3) (a) Brown, F.C. Chem. Rev. 1961, 61, 463–521; (b) Singh, S.P.; Parmar, S.S.; Raman, K.; Stenberg, V.I. Chem. Rev.
1981, 81, 175–203; (c) Kandeel, K.A. Arkivoc 2006, x, 1–6; (d) Verma, A.; Saraf, S.K. Eur. J. Med. Chem. 2008, 43,
897–905.
(4) (a) Pourreza, N.; Rastegarzadeh, S. Anal. Chim. Acta 2001, 437, 273–280; (b) Yuan, C.-G.; Liang, P.; Zhang, Y.-Y.
Microchim. Acta 2011, 175, 333–339.
(5) Solmaz, R.; Kardaþ, G.; Yazıcı, B.; Erbil, M. Prot. Met. 2007, 43, 476–482.
(6) Kaminskyy, D.V.; Lesyk, R.B. Biopolym. Cell 2010, 26 (N2), 136–145.
(7) Capan, G.; Ulusoy, N.; Ergenc, N.; Ekinic, A.C.; Vidin, A. Farmaco 1996, 51, 729–732.
(8) Foye, W.O.; Tovivich, P. J. Pharm. Sci. 1977, 66, 1607–1611.
(9) Tomašiæ, T.; Kovaè, A.; Simèiè, M.; Blanot, D.; Grdadolnik, S.G.; Gobec, S.; Kikelj, D.; Peterlin Mašiè, L. Eur. J.
Med. Chem. 2011, 46, 3964–3975.
(10) Mariner, K.R.; Trowbridge, R.; Agarwal, A.K.; Miller, K.; O’Neill, A.J.; Fishwick, C.W.; Chopra, I. Antimicrob.
Agent. Chemother. 2010, 54, 4506–4509.
(11) Kumar, G.; Parasuraman, P.; Sharma, S.K.; Banerjee, T.; Karmodiya, K.; Surolia, N.; Surolia, A. J. Med. Chem.
2007, 50, 2665–2675.
(12) Furdas, S.D.; Shekfeh, S.; Kannan, S.; Sippl, W.; Jung, M. Med. Chem. Commun. 2012, 3, 305–311.
(13) Gilbert,A.M.; Bursavich, M.G.; Lombardi, S.; Georgiadis, K.E.; Reifenberg, E.; Flannery, C.R.; Morris, E.A. Bioorg.
Med. Chem. Lett. 2007, 17, 1189–1192.
(14) Heng, S.; Tieu, W.; Hautmann, S.; Kuan, K.; Pedersen, D.S.; Pietsch, M.; Gütschow, M.; Abell, A.D. Bioorg. Med.
Chem. 2011, 19, 7453–7463.
(15) (a) Redemann, E.; Icke, R.N.;Alles, G.A. Coll. 1955, 3, 763; (b) Raval, B.K.; Trivedi, J.J. J. Indian Chem. Soc. 1962,
39, 53–55; (c) Abrahamson, S.; Westerdahl, A.; Isaksson, G.; SandstrBm, J. Acta Chim. Scand. 1967, 21, 442–456;
(d) Nagase, H. Chem. Pharm. Bull. 1974, 22, 505–513; (e) Rang, K.; Sandström, J.; Thell, L.;Yang, Q. Acta Chem.
Scand. B 1985, 39, 123–129; (f) Yavari, I.; Hajinasiri, R.; Sayyed-Alangi, S.Z.; Iravani, N. Monatsh Chem. 2008,
139, 1029–1031.
(16) Alizadeh, A.; Zohreh, N. Synlett. 2009, 13, 2146–2148.
(17) (a) Safaei-Ghomi, J.; Salimi, F.; Ramazani, A.; Zeinali Nasrabadi, F.; Ahmadi, Y. J. Sulfur Chem. 2012, 33, 87–92;
(b)Yavari, I.; Sirouspour, M.; Souri, S. Monatsh Chem. 2010, 141, 49–52; (c) Azizi, N.; Aryanasab, F.; Torkiyan, L.;
Ziyaei,A.; Saidi, M.R. J. Org. Chem. 2006, 71, 3634–3635; (d)Alizadeh,A.; Rostamnia, S.; Zohreh, N.; Hosseinpour,
R.A. Tetrahedron Lett. 2009, 50, 1533–1535; (e) Azizi, N.; Ebrahimi, F.; Aakbari, E.; Aryanasab, F.; Saidi, M.R.
Synlett. 2007, 2797–2800.