A convenient solvent-free and one-pot synthesis of 4-hydroxythiazolidine-2- thiones

Article abstract of DOI:10.1080/17415993.2014.907407

A highly efficient solvent-free and simple one-pot approach for the synthesis of 4-hydroxythiazolidine-2-thione is described. The reaction of primary amines and carbon disulfide in the presence of 2-chloroacetaldehyde afforded the title compounds in high yields.

Full text of DOI:10.1080/17415993.2014.907407

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A convenient solvent-free and one-pot
synthesis of 4-hydroxythiazolidine-2-
thiones
Farough Nasiria, Amin Zolalib & Mohammad Ahmadiazarb
a Department of Applied Chemistry, Faculty of Science, University
of Mohaghegh Ardabili, P.O. Box 56199–11367, Ardabil, Iran
b Department of Chemistry, Faculty of Science, University of
Kurdistan, Sanandaj, Iran
Published online: 15 Apr 2014.
To cite this article: Farough Nasiri, Amin Zolali & Mohammad Ahmadiazar (2014): A convenient
solvent-free and one-pot synthesis of 4-hydroxythiazolidine-2-thiones, Journal of Sulfur Chemistry,
DOI: 10.1080/17415993.2014.907407
To link to this article: http://dx.doi.org/10.1080/17415993.2014.907407
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Journal of Sulfur Chemistry, 2014
http://dx.doi.org/10.1080/17415993.2014.907407
A convenient solvent-free and one-pot synthesis of
4-hydroxythiazolidine-2-thiones
Farough Nasiria∗, Amin Zolalib and Mohammad Ahmadiazarb
aDepartment of Applied Chemistry, Faculty of Science, University of Mohaghegh Ardabili, P.O. Box 56199–
11367, Ardabil, Iran; bDepartment of Chemistry, Faculty of Science, University of Kurdistan, Sanandaj, Iran
(Received 24 July 2013; accepted 19 March 2014)
A highly efficient solvent-free and simple one-pot approach for the synthesis of 4-hydroxythiazolidine-
2-thione is described. The reaction of primary amines and carbon disulfide in the presence of
2-chloroacetaldehyde afforded the title compounds in high yields.
S
R
Solvent-free
r.t., 10 min
H
R
NH2
+
N
S
+
CS2
Cl
O
HO
(86–90%)
R: Substituted benzyl, Alkyl, 2-Hydroxyethyl
Keywords: 2-chloroacetaldehyde; primary amines; dithiocarbamate; carbon disulfide
1. Introduction
In recent years, carrying out reactions under solvent-free conditions has been developed. These
reactions occur under mild conditions which minimizes the generation of waste as well as the
use of dangerous organic solvents.[1,2] Due to the presence of sulfur atoms in many biologically
and pharmaceutically active molecules (for a list of the top selling sulfur-containing drugs in
2012 with structures, see: http://cbc.arizona.edu/njardarson/group/top-pharmaceuticals-poster.)
its introduction into organic compounds has received much attention in organic synthesis.[3–7]
Organic dithiocarbamates, found in a variety of biologically active molecules,[8,9] are impor-
tant compounds that have numerous biological and medicinal characteristics.[10–12] These
compounds are also of interest in industry, for example, they are used as vulcanization accelerators
in the rubber industry.[13] There are several reports about the synthesis of 4-hydroxythiazolidine-
2-thione derivatives with α-haloketones in the literature.[14–18] The reactions between amines
and amino acids with carbon disulfide in the presence of 2-chloroacetaldehyde have been also
reported.[19,20] However, these reactions occur in the presence of a base and usually require long
∗Corresponding author. Email: nasiri@uma.ac.ir
© 2014 Taylor & Francis

2
F. Nasiri et al.
reaction times. As a consequence, the 4-hydroxythiazolidine-2-thiones formed in these reactions
are not isolated and instead often undergo dehydration in high yields. Herein, we report an effi-
cient and convenient solvent-free synthesis of 4-hydroxythiazolidine-2-thione derivatives from
the reaction of primary amines and carbon disulfide in the presence of 2-chloroacetaldehyde.
2. Results and discussion
The solvent-free reaction between primary amines 1 and carbon disulfide in the presence
of 2-chloroacetaldehyde 2 affords 4-hydroxythiazolidine-2-thione derivatives 3 in high yields
(Scheme 1).
S
R
Solvent-free
r.t., 10 min
H
N
S
+
NH2
CS2
+
Cl
R
O
HO
2
3a–3f
1
R
Yield%
87
89
90
88
88
86
3
a
b
c
d
e
f
Benzyl
2-Chlorobenzyl
Ethyl
2-Hydroxyethyl
Phenethyl
Propyl
Scheme 1. Synthesis of 4-hydroxythiazolidine-2-thione derivatives 3a–3f (see Section 4).
1
The structures of 3a–3f were deduced from their elemental analysis, IR, H NMR, and 13C
NMR spectroscopy and mass spectrometric data. The 1H NMR spectrum of 3a (CDCl3) exhibited
a multiplet at 7.38–7.35 ppm identified as phenyl group. The methylene protons of benzyl group
appeared as an AX system (δA = 5.66 and δX = 4.52 ppm, JAX = 14.7 Hz). The methine proton
in 3a appeared as a broad doublet (δ = 5.49 ppm, J = 5.8 Hz) and the methylene protons of
the thiazolidine ring showed an AMX system (δA = 3.57 and δM = 3.16 ppm, JAM = 12.4 Hz,
JAX = 6.5 Hz, and JMX = 1.7 Hz). The OH group appeared as a broad peak at δ = 3.37 ppm.
The 1H decoupled 13C NMR spectrum of 3a showed eight distinct signals in agreement with the
proposed structure. The mass spectrum of 3a showed the molecular ion peak at the appropriate
m/z value.
Although the mechanism of the above reaction is unknown, a possible mechanism for this
reaction is proposed in Scheme 2. The reaction starts by the addition of amine to carbon
disulfide to form alkylammonium dithiocarbamate salt 4,[21–23] which subsequently attacks
the 2-chloroacetaldehyde to produce acyclic dithiocarbamate 5. This intermediate undergoes
intramolecular cyclization to generate compound 3 in high yield.
To provide additional confirmation of structure 3, the product 3a was dehydrated with a catalytic
amount of H3PO4 in MeCN (Scheme 3).
In the 1H NMR spectrum of 6 the OH peak was absent and the olefinic protons resonated as
two doublets at δ = 6.94 and δ = 6.57 ppm with a coupling constant of 6.0 Hz. The 13C NMR
spectrum of 6 also verifies the removal of the OH group and the newly formed olefinic carbons
appeared at δ = 111.1 and δ = 130.8 ppm (see Experimental section). We also examined the

Journal of Sulfur Chemistry
3
S
R
S
S
N
-
+
2
H
R NH2
3
CS2
+
RNH
S
RNH3
H
-
+
–
RNH3Cl
O
1
4
5
Scheme 2. Proposed mechanism for the formation of compound 3.
S
H3PO4/CH3CN
reflux, 2 h
N
3a
S
6 (90%)
Scheme 3. Dehydration reaction of compound 3a.
acetylation reaction of compound 3a using acetic anhydride at room temperature. In this case,
the dehydrated product 6 was the only product obtained. This result shows that acetic anhydride
dehydrate compounds 3 under very mild conditions even in comparison to H3PO4.
3. Conclusion
In conclusion, we have reported a convenient solvent-free route for the synthesis of 4-
hydroxythiazolidine-2-thione derivatives of potential synthetic interest in good yields using
simple and inexpensive starting materials. The 4-hydroxythiazolidine-2-thione derivatives can
be easily converted to the related dehydrated compounds. The simplicity and environmentally
friendly nature of the present procedure makes it an interesting method to produce functionalised
dithiocarbamates.
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 MHz for 1H and 75.5 MHz for 13C) with CDCl3 or DMSO-d6 as solvent. Mass
spectra were recorded with an Agilent-5975 C inert XL MSD mass spectrometer operating at an
ionisation potential of 70 eV. Amines, 2-chloroacetaldehyde, and carbon disulfide were obtained
from Merck and used without further purification.
4.1. General procedure for the preparation of 4-hydroxythiazolidine-2-thione derivatives
(3a–f)
To a magnetically stirred mixture of primary amine (2 mmol) and CS2 (2 mmol) was added
2-chloroacetaldehyde (2 mmol, 45% in water) and the reaction mixture was allowed to stir for
10 min. After completion, the reaction mixture was purified by column chromatography over

4
F. Nasiri et al.
silica gel (Merck 230–400 mesh) using the n-hexane–EtOAc mixture as eluent (5:1) to obtain
product 3.
4.1.1. 3-Benzyl-4-hydroxythiazolidine-2-thione (3a)
White powder; yield 87%; mp 104 − 105◦C. IR (KBr) (υmax, cm−1): 3325, 1462, 1306, 1238,
1
1163. H NMR (300.1 MHz, CDCl3): δ 7.38–7.35 (m, 5H, Ar), 5.09 (AX system, δA = 5.66
and δX = 4.52 ppm, JAX = 14.7 Hz, 2H, NCH2), 5.48 (bd, 1H, J = 5.8 Hz, CH), 3.57 and 3.16
(AMX system, δA = 3.57 and δM = 3.16 ppm, JAM = 12.4 Hz, JAX = 6.4 Hz and JMX = 1.8 Hz,
2H, SCH2), 3.37 (bs, 1H, OH).13C NMR (75.5 MHz, CDCl3): δ 197.1 (C9S), 135.2 (C), 129.0
and 128.4 (4CH), 128.3 (C), 88.4 (OCH), 49.5 (NCH2), 36.1 (CH2). EI-MS (m/z): 225 (M+, 25),
207 (50), 148 (38), 91 (100). Anal. Calcd for C10H11NOS2 (225.32): C, 53.31; H, 4.92; N, 6.22;
Found: C, 52.67%; H, 4.89%; N, 6.10%.
4.1.2. 3-(2-Chlorobenzyl)-4-hydroxy thiazolidine-2-thione (3b)
White powder; yield 89%; mp 149 − 150◦C. IR (KBr) (υmax, cm−1): 3241, 1471, 1299, 1236,
1
1174. H NMR (300.1 MHz, CDCl3): δ 7.46–7.40 and 7.30–7.27 (2m, 5H, CH-Ph, CH), 5.20
(AX system, δA = 5.61 and δB = 4.79 ppm, JAX = 15.3 Hz, 2H, NCH2), 3.63 and 3.18 (AMX
system, δA = 3.63 and δM = 3.18 ppm, JAM = 12.4 Hz, JAX = 6.3 Hz, and JMX = 1.5 Hz, 2H,
SCH2), 3.33 (bd, 1H, J = 9.5 Hz, OH).13C NMR (75.5 MHz, CDCl3): δ 191.2 (C9 S), 133.7 and
132.9 (2C), 130.3, 129.8, 129.6, and 127.4 (4CH), 88.6 (CHOH), 47.1 (NCH2), 36.1 (CH2). EI-
MS (m/z): 260 (M+, 5), 224 (100), 206 (60), 125 (80), 89 (50). Anal. Calcd for C10H10 ClNOS2
(259.77): C, 46.24; H, 3.88; N, 5.39; Found: C, 46.10%; H, 3.80%; N, 5.29%.
4.1.3. 3-Ethyl-4-hydroxythiazolidine-2-thione (3c)
Brown oil; yield 90%. IR (KBr) (υmax, cm−1): 3380, 1474, 1363, 1264, 1117. 1H NMR
(300.1 MHz, CDCl3): δ 5.69 (m, 1H, CH),4.20 (bs, 1H, OH), 4.07 and 3.66 (2m, 2H, NCH2),
3.60 and 3.18 (2m, 2H, SCH2), 1.26 (t, 3JHH = 7.2 Hz, 3H, CH3).13C NMR (75.5 MHz, CDCl3):
δ 196.1 (C9 S), 89.3 (CHOH), 42.0 (NCH2), 36.3 (SCH2), 12.5 (CH3). EI-MS (m/z): 163 (M+,
90), 145 (32), 116 (44), 90 (100). Anal.Calcd for C5H9NOS2 (163.25): C, 36.79; H, 5.56; N, 8.58;
Found: C, 36.70%; H, 5.60%; N, 8.62%.
4.1.4. 4-Hydroxy-3-(2-hydroxyethyl) thiazolidine-2-thione (3d)
Brown oil; yield: 88%.IR (KBr) (υmax, cm−1): 3353, 1465, 1306, 1232, 1173. 1H NMR
(300.1 MHz, DMSO-d6): δ 4.97 (bs, 1H, OH), 3.95 (m, 1H, CH), 3.68–3.21 (m, 7H, 3CH2,
OH).13C NMR (75.5 MHz, DMSO-d6): δ 195.3 (C9 S), 90.0 (CHOH), 57.7 (OCH2), 48.3 (NCH2),
35.3 (SCH2). EI-MS (m/z):179 (M+, 25), 161 (100), 117 (98), 77 (30), 58 (70). Anal.Calcd for
C5H9NO2S2 (179.25): C, 33.50%; H, 5.06%; N, 7.81%; Found: C, 33.48%; H, 5.00%; N, 7.75%.
4.1.5. 4-Hydroxy-3-phenethylthiazolidine-2-thione (3e)
White powder; yield 88%; mp 116 − 117◦C. IR (KBr) (υmax, cm−1):3315, 1464, 1310, 1222,
1148. 1H NMR (300.1 MHz, CDCl3): δ 7.36–7.23 (m, 5H, CH-Ph), 5.17 (m, 1H, CH), 4.30 and
3.83–3.72 (2m, 3H, NCH2, OH), 3.45 and 3.05 (AMX system, δA = 3.45 and δM = 3.05 ppm,
JAM = 12.3 Hz, JAX = 6.5 Hz, and JMX = 2.0 Hz, 2H, SCH2), 3.10–2.99 (m, 2H, CH2Ph).13C

Journal of Sulfur Chemistry
5
NMR (75.5 MHz, CDCl3): δ 196.4 (C9 S), 138.3 (C), 128.8 and 128.7 (4CH), 126.9 (CH), 90.4
(CHOH), 48.6 (NCH2), 36.3 (SCH2), 33.2 (CH2Ph). EI-MS (m/z): 239 (M+, 60), 117 (50), 104
(100), 91 (67), 77 (63). Anal.Calcd for C11H13NOS2 (239.35), C, 55.20; H, 5.47; N, 5.85; Found:
C, 55.30%; H, 5.40%; N, 5.90%.
4.1.6. 4-Hydroxy-3-propylthiazolidine-2-thione (3f)
Brown oil; yield: 86%.IR (KBr) (υmax, cm−1): 3305, 1455, 1306, 1225, 1100. 1H NMR
(300.1 MHz, CDCl3): δ 5.64 (dd, J1 = 6.4 Hz, J2 = 1.5 Hz, 1H, CH), 4.16–4.00 and 3.51 (2m,
3H, NCH2 and OH), 3.65 and 3.18 (AMX system, δA = 3.65 and δM = 3.18 ppm, JAM = 12.4 Hz,
JAX = 6.5 Hz, and JMX = 1.7 Hz, 2H, SCH2), 1.81–1.66 (m, 2H, CH3CH2), 0.96 (t, 3H, 3JHH
=
7.3 Hz, CH3).13C NMR (75.5 MHz, CDCl3): δ 196.4 (C9S), 89.7 (CH), 48.5 (NCH2), 36.4 (SCH2),
20.7 (CH2CH3), 11.3 (CH3). EI-MS (m/z): 177 (M+, 100), 118 (45), 100 (97), 91 (22).Anal.Calcd
for C6H11NOS2 (177.28): C, 40.65; H, 6.25; N, 7.90; Found: C, 40.60%; H, 6.30%; N, 7.84%.
4.2. Procedure for the preparation of 3-benzylthiazole-2(3H)-thione (6)
To a stirred solution of 3a (2 mmol) in 2 ml of CH3CN was added 0.1 ml of H3PO4. The mixture
was refluxed for 2 h. After completion, the solvent was removed under reduced pressure and the
residue was purified by column chromatography over silica gel (Merck 230–400 mesh) using
the n-hexane–EtOAc mixture as the eluent (5:1) to afford 6 as white crystals. Yield 90%; mp
99 − 100◦C. IR (KBr) (υmax, cm−1): 1370, 1306, 1205, 1135. 1H NMR (300.1 MHz, CDCl3): δ
7.40–7.33 (m, 5H, CH-Ar), 6.94 (d, 3JHH = 6.0 Hz, 1H, NCH 9CH), 6.57 (d, 3JHH = 6.0 Hz, 1H,
NCH9 CH), 5.38 (s, 2H, NCH2). 13C NMR (75.5 MHz, CDCl3): δ 188.3 (C 9 S), 134.9 (C), 130.8
(NCH 9CH), 129.1 (2CH), 128.5 (CH), 128.3 (2CH), 111.1 (NCH9 CH), 52.8 (CH2N). EI-MS
(m/z): 207 (M+, 73), 174 (25), 91 (100), 65 (50). Anal.Calcd for C10H9NS2 (207.31): C, 57.94;
H, 4.38; N, 6.76; Found: C, 57.85; H, 4.41; N, 6.80.
Acknowledgements
We are grateful to Dr Farzad Nikpour for his assistance.
Supplemental data
Supplemental data for this article can be accessed at http://dx.doi.org/10.1080/17415993.2014.907407.
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