A convenient synthesis of thiazolidin-2-ones from thiazolidine-2-thiones: Antibiotic activity and revisiting the mechanism

Article abstract of DOI:10.1080/10426507.2010.525770

Various substituted thiazolidin-2-ones were synthesized from the corresponding thiazolidine-2-thiones with bromoethanol in ethanol with sodium ethoxide as a base. The optimal reaction conditions and mechanism were reinvestigated in detail. The bioassay indicated that (S)-4-isobutyl and (S)-4-benzylthiazolidin-2-ones show certain inhibitive activities against Candida albicans and Escherichia coli. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Full text of DOI:10.1080/10426507.2010.525770

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A Convenient Synthesis of Thiazolidin-2-
ones from Thiazolidine-2-thiones:
Antibiotic Activity and Revisiting the
Mechanism
Xiaobing Deng a , Ning Chen a , Zhixin Wang a , Xinyao Li a , Hongyan
Hu b & Jiaxi Xu a
a State Key Laboratory of Chemical Resource Engineering,
Department of Organic Chemistry, Faculty of Science, Beijing
University of Chemical Technology, Beijing, P. R. China
b Department of Laboratory Medicine, The General Hospital of
Chinese People's Armed Police Forces, Beijing, P. R. China
Published online: 04 Aug 2011.
To cite this article: Xiaobing Deng , Ning Chen , Zhixin Wang , Xinyao Li , Hongyan Hu & Jiaxi Xu
(2011): A Convenient Synthesis of Thiazolidin-2-ones from Thiazolidine-2-thiones: Antibiotic Activity
and Revisiting the Mechanism, Phosphorus, Sulfur, and Silicon and the Related Elements, 186:7,
1563-1571
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Phosphorus, Sulfur, and Silicon, 186:1563–1571, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.525770
A CONVENIENT SYNTHESIS OF THIAZOLIDIN-2-ONES
FROM THIAZOLIDINE-2-THIONES: ANTIBIOTIC ACTIVITY
AND REVISITING THE MECHANISM
Xiaobing Deng,1 Ning Chen,1 Zhixin Wang,1 Xinyao Li,1
Hongyan Hu,2 and Jiaxi Xu1
1State Key Laboratory of Chemical Resource Engineering, Department of Organic
Chemistry, Faculty of Science, Beijing University of Chemical Technology,
Beijing, P. R. China
2Department of Laboratory Medicine, The General Hospital of Chinese People’s
Armed Police Forces, Beijing, P. R. China
GRAPHICAL ABSTRACT
O
S
OH
EtONa, EtOH, 60 oC
Br
R
R
N
S
N
S
R1
R1
R3
R2
R3
R2
Abstract Various substituted thiazolidin-2-ones were synthesized from the corresponding
thiazolidine-2-thiones with bromoethanol in ethanol with sodium ethoxide as a base. The
optimal reaction conditions and mechanism were reinvestigated in detail. The bioassay indi-
cated that (S)-4-isobutyl and (S)-4-benzylthiazolidin-2-ones show certain inhibitive activities
against Candida albicans and Escherichia coli.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Bromoethanol; mechanism; sodium ethoxide; thiazolidin-2-one; thiazolidine-2-
thione
INTRODUCTION
Thiazolidin-2-ones (1) are important compounds in both pharmaceutical and synthetic
organic chemistry. They have been widely used as building blocks in the synthesis of
valuable natural products,1 pesticides,2 and other compounds with anti-HIV3 and anticancer
activities.4 It is well known that the derivatives of thiazolidine-2-thione (2),5 oxazolidine-2-
thione (3),6 and oxazolidin-2-one (4)7 have been extensively applied as chiral auxiliaries in
Received 26 August 2010; accepted 19 September 2010.
Address correspondence to Jiaxi Xu, State Key Laboratory of Chemical Resource Engineering, Department
of Organic Chemistry, Faculty of Science, Beijing University of Chemical Technology, 15 Northern 3rd Ring
Road East, Beijing 100029, P. R. China. E-mail: jxxu@mail.buct.edu.cn
1563

1564
X. DENG ET AL.
O
S
S
O
HN
S
O
HN
O
HN
HN
S
1
2
3
4
Figure 1 Thiazolidin-2-one (1), thiazolidine-2-thione (2), oxazolidine-2-thione (3), and oxazolidin-2-one (4).
numerous asymmetric syntheses (Figure 1). As their analogs, the derivatives of thiazolidin-
2-one (2) will have broad applications in the field as well.
Several synthetic methods for thiazolidin-2-one and substituted thiazolidin-
2-ones have been developed. Thiazolidin-2-ones have been synthesized via the
ring-closing procedure of vicinal aminomercaptans with phosgene or triphosgene,8
1,1ꢁ-carbonyldiimidazole,9 urea,10 or carbon monoxide11 under the catalysis of Se11a,b or
S11c and ethyl carbonochloridate under the catalysis of hydrotalcites.12 Desulfurization
(the S/O-exchange) of thiazolidine-2-thiones is an alternative method for synthesizing the
corresponding thiazolidin-2-ones via reactions with oxiranes13 or hydrogen peroxide.14
Other synthetic methods, including the ring-closing of aminoethanol or haloethylamine
with carbonyl sulfide,15 the O/S-exchange of oxazolidine-2-thione or oxazolidin-2-ones16
and the cyclization of iodoalkyl thiocyanates,17 were also reported in the literature.
Most of the reported preparative methods require harsh conditions (high temper-
ature or pressure) or toxic reagents such as selenium or phosgene. Furthermore, for
the ring-closing method, most vicinal aminomercaptans are not commercially available.
Thiazolidine-2-thiones 2 can be prepared conveniently from commercially available amino
alcohols and carbon disulfide in the presence of sodium hydroxide. Recently, Weng and
coworkers converted thiazolidine-2-thione itself to thiazolidin-2-one with chloroethanol
under basic conditions and noted that thiazolidin-2-one shows some antibacterial activity.18
To search for new antibiotic agents, we hoped to prepare substituted thiazolidin-2-ones
from easily synthesized thiazolidine-2-thiones via the S/O-exchange with haloethanols as
reagents for bioassay. We herein present the synthesis of various thiazolidin-2-ones with
further investigation into the reaction conditions and mechanism (Scheme 1).
S
O
NaOEt
R
R
OH
N
S
N
S
+
Br
EtOH, 60 oC
R1
R1
R3
R3
R2
R2
1
2
Scheme 1 Synthesis of thiazolidin-2-ones from thiazolidine-2-thiones.
RESULTS AND DISCUSSION
First, we synthesized a series of thiazolidine-2-thiones and planned to convert them to
the corresponding thiazolidin-2-ones according to the reported procedure: thiazolidine-2-
thione, bromoethanol, and sodium ethoxide (1:1.4:1 in molar ratio) in ethanol were stirred
◦
at 60 C for 4 h.18 After finishing several examples, we found that thiazolidine-2-thione

SYNTHESIS OF THIAZOLIDIN-2-ONES
1565
Table 1 Optimizing reaction conditions for synthesis of thiazolidin-2-ones
Thiazolidine-2-
thione
R/R1/
R2/R3
Reaction
Conditionsa
Yield
(%)
Entry
Product(s)
1
2
3
4
2a
2b
2c
2c
H/H/H/H
H/Me/H/H
H/Ph/H/H
H/Ph/H/H
60 ◦C, 4 h, EtONa
60 ◦C, 4 h, EtONa
60 ◦C, 4 h, EtONa
60 ◦C, 4 h, EtONa
ClCH2CH2OH
1a
1b
1c
1c
40
45
75
70
5
6
7
8
9
10
11
12
13
14
15
2d
2e
2c
2e
2e
2e
2e
2e
2c
2e
2l
H/iPr/H/H
H/iBu/H/H
H/Ph/H/H
H/iBu/H/H
H/iBu/H/H
H/iBu/H/H
H/iBu/H/H
H/iBu/H/H
H/Ph/H/H
H/iBu/H/H
Bn/Bn/H/H
60 ◦C, 4 h, EtONa
60 ◦C, 4 h, EtONa
60 ◦C, 1 h, EtONa
60 ◦C, 1 h, EtONa
80 ◦C, 1 h, EtONa
60 ◦C, 1 h, 3 eq. EtONa
60 ◦C, 4 h, NaOH
60 ◦C, 4 h, K2CO3
RT, 1 h, EtONa
1d
1e
1c & 5c
1e & 5e
1e
1e
1e
1e
85
73
81 (1:7)
81 (1:5)
67
70
38
23
80
5c
5e
RT, 1 h, EtONa
60 ◦C, 4 h, EtONa
82
—
No reaction
aWith BrCH2CH2OH.
(2a) itself and its 4-methyl derivative (2b) gave rise to the corresponding 2-thiazolidinones
in relatively low yields in comparison with other substituted thiazolidine-2-thiones, such
as (S)-4-pheny-thiazolidine-2-thione (2c), (S)-4-isopropyl-thiazolidine-2-thione (2d), and
(S)-4-isobutyl-2-thiazolidine-2-thione (2e) (Table 1, entries 1–5). The yield of product 1a
did not reach the reported value (80%). We had to reinvestigate the reaction conditions and
the mechanism of the formation of thiazolidin-2-ones.
We initially selected the reaction of (S)-4-phenylthiazolidine-2-thione (2c) as a model
reaction to optimize the reaction conditions, because both its starting material and product
show obvious absorption under ultraviolet (UV) light for convenient thin-layer chromatog-
raphy (TLC) analysis. When we traced the reaction process with TLC, we found that the
reaction might have already completed in 1 h because the possible product 1c (Rf = 0.54,
PE: EA = 3:2, v/v) was generated and 2c (Rf = 0.77, PE: EA = 3:2, v/v) disappeared.
Furthermore, a byproduct (5cꢁ, Rf = 0.36, PE: EA = 3:2, v/v) was also observed. There-
fore, we stopped the reaction after 1 h and separated the major product (81% yield) and
by-product (5cꢁ, 3% yield) on a silica gel column. However, the 1H-NMR spectrum of the
major product revealed that it was a mixture of two compounds (the products 1c and 5c in a
ratio of 1:7) that cannot be separated via column chromatography due to their close polarity
(Table 1, entry 7). Thus, we had to try another substrate 2e and hoped that its products
were separable on TLC. We conducted the reaction with 2e (Rf = 0.50, PE: EA = 4:1,
v/v) under the same conditions, and TLC analysis demonstrated that another new product
5e (Rf = 0.40, PE: EA = 4:1, v/v) as the major product was generated in the reaction at 1
h in addition to the desired product 1e (Rf = 0.33, PE: EA = 4:1, v/v; Table 1, entry 8).
Both 1e and the new product 5e were obtained after column chromatographic separation.
1H- and 13C-NMR spectra indicated that the new product 5e had a more CH2CH2 group
than substrate 2e. In addition, a new absorption peak appeared at 166.9 ppm in 13C-NMR
with the disappearance of the thiocarbonyl group. The infrared (IR) spectrum confirmed

1566
X. DENG ET AL.
Table 2 Typical absorption in spectra of compounds 1, 2, 5, and 5ꢁ
Entry
Compounds
13C-NMR (ppm)
IR (cm−1
)
1H-NMR (ppm)
1
2
3
4
5
6
7
1e
2e
5e
1c
2c
5c
5cꢁ
175.7 (C O)
200.5 (C S)
166.9 (C N)
175.2 (C O)
201.5 (C S)
169.0 (C N)
198.3 (C S)
1674 (C O)
1268 (C S)
1558 (C N)
1674 (C O)
1267(C S)
1556 (C N)
1261 (C S)
6.82 (NHC O)
8.42 (NHC S)
5.10 (OH)
6.21 (NHC O)
8.03 (NHC S)
4.44 (OH)
2.35 (OH)
that no carbonyl group formed, but there was a strong absorption at 1558 cm−1. This vali-
dated that there must be a C N bond in compound 5e. Thus, it should be the S-alkylation
product, (S)-2-hydroxyethylthio-4-isobutylthiazoline (5e), which was further verified by
high-resolution mass spectrometry (HRMS) and elemental analysis. Some typical spectral
data of compounds 1, 2, 5, and 5ꢁ are listed in Table 2.
After the structure of 5e was identified, the mixed products in the reaction of
2c were ascertained to be a mixture of (S)-4-phenylthiazolidin-2-one (1c) and (S)-2-
hydroxyethylthio-4-phenylthiazoline (5c). We tried to purify 5c via recrystallization. The
mixture of 5c and 1c was dissolved in refluxing EtOH and a large amount of colorless
crystals was crystallized as the temperature decreased. However, only 1c was crystallized
according to its nuclear magnetic resonance (NMR) spectra. Moreover, after removing the
solvent of the filtrate, only a small amount of mixture remained. This demonstrated that
compound 5c was converted to the product 1c in refluxing ethanol. To further confirm
the conversion, pure 5e was refluxed in EtOH, affording 1e quantitatively after cooling.
Subsequently, we found that 5e can transform to 1e slowly in EtOH at r.t. (for 2 days) as
well.
The less steric thiazolidin-2-ones 1a and 1b were crystallized from diethyl ether
due to lower melting points. Some 2-(2-hydroxyethylthio)thiazolidines 5a and 5b did not
convert to the corresponding products 1a and 1b in refluxing ether because its boiling point
is obviously lower than that of ethanol, resulting in relatively lower yields. In the reported
procedure, 1a was purified by distillization at a high temperature, favorably transforming
5a to 1a. After prolonging the refluxing time and increasing the temperature of the reaction,
the yields of 1a and 1b were improved obviously.
It was reported that thiazolidine-2-thiones react with alkyl halides in the presence of
a base to produce the corresponding 2-alkylthiothiazolines.19 On the basis of the formation
mechanism of thiazolidin-2-ones from thiazolidine-2-thiones and oxirane,13a the conversion
mechanism from thiazolidine-2-thiones to thiazolidin-2-ones was proposed as follows18:
thiazolidine-2-thiones 2 were alkylated firstly on their S-atom with haloethanols to afford
2-(2-hydroxyethylthio)thiazolidines 5 in the presence of a base (NaOEt), which further
underwent an intramolecular 5-exo-trig ring-closing process to form zwitterionic interme-
diates 6, followed by a proton transfer to give rise to the spiro intermediates 7. Unstable
intermediates 7 readily underwent a ring-opening reaction to generate new alkylthioth-
iazolidine intermediates 8,20 which subsequently released a molecule of thirane via an
intramolecular nucleophilic substitution to afford thiazolidin-2-ones 1 (Scheme 2). In the
process, 2-(2-hydroxyethylthio)thiazolidines 5 were the key intermediates to determine
whether the reactions occurred or not. Subsequently, we explored whether intermediates 5

SYNTHESIS OF THIAZOLIDIN-2-ONES
1567
Br
OH
S
S
S
S
N
OH
OH
5-exo-trig
NaOEt
N
S
HN
R
S
S
N
S
- NaBr
R
R
6
R
5
2
S
O
O
S
O
S
H+ transfer
HN
HN
R
S
S
HN
R
S
-
R
7
8
1
Scheme 2 Mechanism for the generation of thiazolidin-2-ones.
could be afforded under mild conditions. The reaction of 2c with bromoethanol and NaOEt
was conducted at r.t. for 1 h. No 1c was formed and pure 5c was obtained in an 80%
yield via column chromatograph (entries 13–14, Table 1). In addition, by-product 5cꢁ was
1
obtained in a 3% yield. H-NMR and HRMS indicated that it was an isomer of 5c. We
hypothesized initially that it might be the spiro intermediate 7c. Nevertheless, there was an
absorption peak of the C S group at 198.3 ppm in the 13C-NMR spectrum, revealing that
it is the N-alkylated product of 2c: (S)-N-hydroxyethyl-4-phenylthiazolidine-2-thione (5cꢁ)
(Scheme 3). We obtained the intermediates 5 and verified the conversion from 5 to 1. To
further confirm the proposed mechanism, we used (S)-4,N-dibenzylthiazolidine-2-thione
(2l) as the starting material to conduct the reaction. However, no new product was observed
(Table 1, entry 15). This illustrated that if there was no H-atom on the N-atom, neither
intermediate 5 nor the corresponding thiazolidin-2-one 1 yielded. However, if there was no
substituent on the nitrogen atom, intermediate 5 was generated initially and then converted
to the corresponding 2-thiazolidinone 1. Our results provide the experimental evidence for
the proposed conversion mechanism from thiazolidine-2-thiones to thiazolidin-2-ones via
the reaction with haloethanols.
OH
S
S
S
NaOEt
RT, 1h
N
S
HO
OH
+
HN
Ph
S
N
S
+
Br
Ph
Ph
5c'
3%
2c
5c
80%
Scheme 3 S-Alkylation and N-alkylation of (S)-4-pheny-thiazolidine-2-thione (2c).
After understanding the reaction very well, further application was used for the
preparation of 5-substituted, 4,4-disubstituted, and 4,5-disubstituted thiazolidine-2-ones.
All of these reactions gave rise to the products in moderate to good yields (Table 3).

1568
X. DENG ET AL.
Table 3 Synthesis of thiazolidin-2-ones
S
O
NaOEt
OH
HN
R1
S
HN
R1
S
+
Br
EtOH
R3
R3
R2
R2
2
1
Entry Thiazolidine-2-thione 2
R1
R2
R3
Reaction Conditions Yield (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
H
H
H
H
H
(R)-Ph
H
H
H
H
H
H
H
H
)-Me
4 h, 80 ◦C
4 h, 80 ◦C
4 h, 60 ◦C
5 h, 60 ◦C
4 h, 60 ◦C
5 h, 60 ◦C
4 h, 60 ◦C
4 h, 60 ◦C
4 h, 60 ◦C
4 h, 60 ◦C
4 h, 60 ◦C
60
66
70
85
73
73
71
67
79
74
79
(S)-Me
(S)-Ph
(S)-iPr
(S)-iBu
(S)-Bn
H
H
H
Me
H
(
H
Me
(R)-Ph
H
10
11
2j
2k
CH2CH2CH2CH2
Biological Activities
The antibiotic activity of all synthetic compounds was assayed with ciprofloxacin
and amphotericin B as positive controls (see Supplemental Materials, Table S1).
CONCLUSION
In conclusion, we have achieved the synthesis of various substituted thiazolidine-2-
ones from corresponding thiazolidine-2-thiones and bromoethanol. The reaction process
and mechanism were reinvestigated and verified through meticulous works and careful spec-
tral analysis. The current procedure provides an efficient synthetic method of substituted
thiazolidin-2-ones. The bioassay indicated that (S)-4-isobutyl and (S)-4-benzylthiazolidin-
2-ones show certain inhibitive activities against Candida albicans and Escherichia coli.
EXPERIMENTAL
General
Melting points were obtained on a Yanaco MP-500 melting point apparatus and are
uncorrected. The 1H- and 13C-NMR spectra were recorded on a Varian Mercury 200, Varian
Mercury 300 Plus, or Bruker 400 spectrometer with tetramethylsilane (TMS) as an internal
standard in CDCl3 solution and the chemical shifts (δ) are reported in ppm. The IR spectra
were taken on a Nicolet 5700 Fourier transform infrared (FTIR) spectrometer. HRMS
data were determined using an Agilent LC/MSD TOF mass spectrometer. TLC separations
were performed on silica gel GF254 plates, and the plates were visualized with UV light.
Optical rotations were measured on a PE340C polarimeter with a thermally jacketed 10-
cm cell (concentration c expressed as g/100 mL). All of the thiazolidine-2-thiones were

SYNTHESIS OF THIAZOLIDIN-2-ONES
1569
synthesized according to our reported protocol.21 PE and EA are abbreviations for petroleum
ether (50–90 ◦C) and ethyl acetate, respectively.
General Procedure for the Preparation of Thiazolidin-2-Ones
Sodium (230 mg, 10 mmol) was added to anhydrous EtOH (10 mL) to generate the
sodium ethanolate, and then a thiazolidine-2-thione (10 mmol) and bromoethanol (1.75 g,
14 mmol) or chloroethanol (1.◦13 g, 14 mmol) was added to the solution. The resulting
solution was heated at 60–80 C in an oil bath for 3–5 h and then cooled to r.t. After
filtration of the inorganic salt (NaBr or NaCl) and removal of the solvent, the residue was
purified via column chromatography or recrystallization to obtain the desired products.
The characterization data for the compounds are given below together with additional
characterization data that may not have appeared in previous reports.
◦
Thiazolidin-2-one (1a). Colorless crystals, yield 70%; m.p. 50–52 C (ether).
Lit.11 m.p. 50–52 ◦C.
(S)-4-Methylthiazolidin-2-one (1b). Colorless crystals, yield 76%; lit.22 m.p.
44–44.5 ◦C (ether).
(S)-4-Phenylthiazolidin-2-one (1c). Colorless crystals, yield 75%; lit.14b m.p.
175–176 ◦C (PE-EA). m.p. 175–176 ◦C.
(S)-4-Isopropylthiazolidin-2-one (1d). Colorless crystals, yield 85%; m.p.
◦
89.5–92 C (hexane-ether). Rf = 0.32 (PE: EA = 3:1, v/v); [α]20 = +6.90 (c, 1.10,
D
Me2CO); IR (CHCl3) v (cm−1): 1664; 1H-NMR (300 MHz, CDCl3) δ: 6.72 (br s, 1H, NH),
3.64 (td, J = 8.2, 7.4, 6.8 Hz, 1H, CHN), 3.35 (dd, J = 10.9, 7.4 Hz, 1H in CH2S), 3.17
(dd, J = 10.9, 8.2 Hz, 1H in CH2S), 1.84 (dheptet, J = 6.8, 6.8 Hz, 1H, CH in iPr), 1.01
(d, J = 6.8 Hz, 3H, CH3), 0.97 (d, J = 6.8 Hz, 3H, CH3); 13C-NMR (75 MHz, CDCl3) δ:
175.8, 61.4, 32.6, 32.5, 18.8, 18.2. HRMS (electrospray ionization [ESI]): Anal. Calcd. for
C6H12NOS [M+H]+ m/z: 146.0636. Found: 146.0639.
(S)-4-Isobutylthiazolidin-2-one (1e). Colorless crystals, yield 73%; m.p. 61–64
◦C (PE). Rf = 0.33 (PE: EA = 4:1, v/v); [α]20 = +15.9 (c, 1.4, Me2CO); IR (CHCl3)
D
v (cm−1): 1674; H-NMR (300 MHz, CDCl3) δ: 6.82 (br s, 1H, NH), 4.04–3.87 (m, 1H,
1
CHN), 3.44 (dd, J = 10.8, 7.1 Hz, 1H in CH2S), 3.07 (dd, J = 10.8, 7.5 Hz, 1H in CH2S),
1.77–1.56 (m, 2H, CH & 1H in CH2), 1.51–1.31 (m, 1H in CH2), 0.95 (d, J = 6.4 Hz, 6H,
2CH3); 13C-NMR (75 MHz, CDCl3) δ: 175.7, 53.7, 43.9, 35.2, 25.0, 22.7, 22.1. HRMS
(ESI): Anal. Calcd. for C7H14NOS [M+H]+ m/z: 160.0790. Found 160.0790.
(S)-4-Benzylthiazolidin-2-one (1f). Colorless crystals, yield 73%; 3% yield at
lit.23 m.p. 72–74 ◦C (PE-EA).
(R)-4-Phenylthiazolidin-2-one (1g). Colorless crystals, yield 71%; m.p.
175.5–177.5 ◦C (EtOH). Lit.14b m.p. 175–176 ◦C.
( )-5-Methylthiazolidin-2-one (1h). Colorless crystals, yield 67%; m.p.
38–39.5 ◦C (ether), lit.24 m.p. 39 ◦C.
(R)-5-Phenylthiazolidin-2-one (1i). lit.8a: Colorless crystals, yield 79%; m.p.
132.5–134 ◦C (PE-EA). Rf = 0.43 (PE: EA = 3:2, v/v); [α]20 = +81.2 (c, 0.5, Me2CO);
D
IR (CH2Cl2) v (cm−1): 1673; 1H-NMR (300 MHz, CDCl3) δ: 7.39 (m, 5H, ArH), 6.79 (br
s, 1H, NH), 5.05 (dd, J = 8.1, 7.7 Hz, 1H, CHS), 3.92 (dd, J = 10.2, 7.7 Hz, 1H in CH2N),
3.66 (dd, J = 10.2, 8.1 Hz, 1H in CH2N); 13C-NMR (75 MHz, CDCl3) δ: 175.8, 138.6,
128.9, 128.4, 127.4, 51.1, 50.3.
4,4-Dimethylthiazolidin-2-one (1j). Colorless crystals, yield 74%; m.p.
101.5–103.5 ◦C (PE-ether). Rf = 0.38 (PE: EA = 2:1, v/v); IR (CH2Cl2) v (cm−1): 1676;

1570
X. DENG ET AL.
1H-NMR (200 MHz, CDCl3) δ: 6.96 (br s, 1H, NH), 3.20 (s, 2H, CH2S), 1.42 (s, 6H,
2CH3); 13C-NMR (50 MHz, CDCl3) δ: 174.3, 57.9, 42.1, 27.8. Anal. Calcd. for C5H9NOS:
C, 45.77; H, 6.91; N, 10.68. Found: C, 45.80; H, 6.83; N, 10.69.
cis-( )-7,9-Thiazabicyclo[4.3.0]nonane-8-one (1k). Colorless crystals, yield
74%; m.p. 71.5–72 ◦C (hexane). Lit.17 m.p. 51–52 ◦C.
General Procedure for the Preparation of Intermediates 3
Sodium (230 mg, 10 mmol) was added in anhydrous EtOH (10 mL) to generate
the sodium ethanolate in an ice-water bath, and then thiazolidine-2-thione (10 mmol) and
bromoethanol (1.75 g, 14 mmol) or chloroethanol (1.13 g, 14 mmol) were added to the
above solution. The resulting solution was reacted at r.t. for 2 h. After the filtration of
inorganic salt (NaBr or NaCl) and removal of the solvent, the residue was purified via
column chromatography.
(S)-2-(2-Hydroxyethylthio)-4-phenylthiazoline (5c). Colorless crystals, yield
80%, m.p. 46.5–47.5 ◦C (PE-EA), Rf = 0.54 (PE: EA = 3:2, v/v), [α]20D = +199.5 (c, 0.63,
Me2CO); IR (CH2Cl2) v (cm−1): 1556 (vC = N); 1H-NMR (300 MHz, CDCl3) δ: 7.40–7.28
(m, 5H, ArH), 5.45 (dd, J = 9.3, 8.2 Hz, 1H, CHN), 4.44 (br s, 1H, OH), 3.92 (br s, 2H,
CH2O), 3.80 (dd, J = 10.9, 8.2 Hz, 1H in CH2S), 3.35 (dd, J = 10.9, 9.3 Hz, 1H in CH2S),
3.31–3.20 (m, 2H, CH2S); 13C-NMR (50 MHz, CDCl3) δ: 169.0, 140.8, 128.7, 127.8,
126.3, 79.0, 63.1, 43.4, 36.0. HRMS (ESI), Anal. Calcd. for C11H14NOS2+ [M+H]+ m/z:
240.0511. Found: 240.0520.
(S)-2-(2-Hydroxyethylthio)-4-isobutylthiazoline (5e). Colorless oil, yield
82%. Rf = 0.40 (PE: EA = 4:1, v/v). [α]20 = −19.7 (c, 0.88, Me2CO); IR (CH2Cl2) v
D
(cm−1): 1558 (vC = N); 1H-NMR (300 MHz, CDCl3) δ: 5.10 (br s, 1H, OH), 4.52–4.34 (m,
1H, CHN), 4.03–3.84 (m, 2H, CH2O), 3.52 (dd, J = 10.7, 7.8 Hz, 1H in CH2S), 3.23 (dd,
J = 6.1, 4.1 Hz, 1H in CH2S), 3.20 (dd, J = 5.7, 3.9 Hz, 1H in CH2S), 3.09 (dd, J =
10.7, 8.3 Hz, 1H in CH2S), 1.76 (m, 2H, CH & 1H in CH2 at iBu), 1.39 (ddd, J = 7.0,
7.0, 7.0 Hz, 1H in CH2 at iBu), 0.98 (d, J = 6.7 Hz, 3H, CH3), 0.96 (d, J = 6.8 Hz, 3H,
CH3); 13C-NMR (50 MHz, CDCl3) δ: 166.9,+74.4, 63.6, 43.7, 41.2, 36.1, 25.9, 22.8, 22.4.
HRMS (ESI), Anal. Calcd. for C9H18NOS2 [M+H]+ m/z: 220.0824. Found: 220.0831.
Anal. Calcd. for C9H18NOS2: C, 49.28; H, 7.81; N, 6.39. Found: 49.56, H, 7.73, N, 6.68.
N-(2-Hydroxyethyl)-4-phenylthiazolidine-2-thione (5cꢀ). Colorless oil, yield
3%, Rf = 0.36 (PE: EA = 3:2, v/v). [α]20D = +12.4 (c, 0.45, Me2CO); IR (CH2Cl2) v (cm−1):
1491 (vC(S)-N), 1261 (vC = S); 1H-NMR (300 MHz, CDCl3) δ: 7.47–7.29 (m, 5H, ArH), 5.51
(dd, J = 8.8, 5.5 Hz, 1H, CHN), 4.40 (ddd, J = 14.2, 5.8, 4.0 Hz, 1H in CH2O), 3.93 (ddd,
J = 11.4, 7.4, 4.0, 1H in CH2S), 3.82 (dd, J = 11.2, 8.8 Hz, 1H), 3.72 (ddd, J = 11.4, 5.8,
4.1, 1H in CH2S), 3.198 (ddd, J = 14.2, 7.4, 4.1 Hz, 1H in CH2O), 3.196 (dd, J = 11.2,
5.5 Hz, 1H in CH2S). 2.37 (br s, 1H, OH); 13C-NMR (125 MHz, CDCl3) δ: 198.3, 138.0,
+
129.4, 129.2, 126.8, 72.8, 58.4, 49.5, 35.9. HRMS (ESI), Anal. Calcd. for C11H14NOS2
[M+H]+ m/z: 240.0511. Found: 240.0520.
General Procedure for the Measurement of Antibacterial Activity
A pure culture of C. albicans (ATCC-10231) and E. coli (ATCC 25922) was grown
overnight, and then diluted to a concentration of about 1 × 108 cfu/mL. The diluted
microbial suspension was spread by a sterile swab on a Kirby-Bauer plate. The 1.0-mg
sample was dissolved in chloroform and applied to the center of Whatman filter paper
discs approximately 6 mm in diameter. The discs were placed onto the surface of the

SYNTHESIS OF THIAZOLIDIN-2-ONES
1571
◦
inoculated agar plate. After 24 h in the incubator at 35 C, the diameter of the zone of
inhibition was measured. Supported by the National Natural Science Foundation of China
(Nos. 20972013 and 20772005), Beijing Natural Science Foundation (No. 2092022), and
the Scientific Research Foundation of Graduate School of Beijing University of Chemical
and Technology
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