A facile and effective procedure for the synthesis of 4-thiazolidinone derivatives using Y(OTf)3 as catalyst

Article abstract of DOI:10.1080/17415993.2016.1161045

ABSTRACT: A one-pot three-component reaction for the synthesis of 4-thiazolidinone derivatives has been established by reacting readily available and inexpensive starting materials of amines, aldehydes and thioglycolic acid using Y(OTf)₃ (5 mol%) as catalyst in tetrahydrofuran. This method is very efficient due to low catalyst loading and mild reaction conditions and provides an efficient and promising synthetic strategy for the construction of the thiazolidinone skeleton.

Full text of DOI:10.1080/17415993.2016.1161045

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
A facile and effective procedure for the synthesis
of 4-thiazolidinone derivatives using Y(OTf)3 as
catalyst
Juan Luo, Zijun Zhong, Hongfu Ji, Jiayin Chen, Jun Zhao & Furen Zhang
To cite this article: Juan Luo, Zijun Zhong, Hongfu Ji, Jiayin Chen, Jun Zhao & Furen Zhang
(2016): A facile and effective procedure for the synthesis of 4-thiazolidinone derivatives using
Y(OTf)3 as catalyst, Journal of Sulfur Chemistry, DOI: 10.1080/17415993.2016.1161045
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Date: 30 March 2016, At: 22:37

JOURNAL OF SULFUR CHEMISTRY, 2016
http://dx.doi.org/10.1080/17415993.2016.1161045
A facile and effective procedure for the synthesis of
4-thiazolidinone derivatives using Y(OTf)3 as catalyst
Juan Luo, Zijun Zhong, Hongfu Ji, Jiayin Chen, Jun Zhao and Furen Zhang
Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, School of Chemistry and
Chemical Engineering, Shaoxing University, Shaoxing, People’s Republic of China
ABSTRACT
ARTICLE HISTORY
Received 28 December 2015
Accepted 28 February 2016
A one-pot three-component reaction for the synthesis of 4-
thiazolidinone derivatives has been established by reacting readily
available and inexpensive starting materials of amines, aldehydes
and thioglycolic acid using Y(OTf)3 (5 mol%) as catalyst in tetrahy-
drofuran. This method is very efficient due to low catalyst loading
and mild reaction conditions and provides an efficient and promising
synthetic strategy for the construction of the thiazolidinone skeleton.
KEYWORDS
Three-component reaction;
4-thiazolidinones;
thioglycolic acid;
1,3-oxathiolan-5-ones;
yttrium triflate
1. Introduction
4-Thiazolidinone derivatives are an important family of organic compounds because
they have broad range of biological and medicinal properties such as anticancer,[1–3]
anti-HIV,[4–6] antimalarial,[7] antihistaminic,[8] antibacterial,[9] anti-inflammatory[10]
and antiarrhythmic.[11] In view of the biological significance of 4-thiazolidinone deriva-
tives, the synthesis of such compounds has attracted considerable attention. Recently, many
synthetic methods for preparing 4-thiazolidinone derivatives have been reported.[12–28]
Each of these methods not only has its own advantages, but also suffers from one or more
disadvantages such as complex experimental and work-up procedures, the requirement of
special catalysts (such as protic acid,[26] molecular iodine in [bmim][BF4][29] and [bmim]
[PF6][22]) or special apparatus (such as microwave),[15,17,26] low yields and limited tol-
erance of functional groups. Therefore, the development of a facile approach to synthesize
these compounds with structural and bioactive diversity is highly desirable and valuable
for biological chemistry and drug discovery.
CONTACT Furen Zhang
frzhang@usx.edu.cn
Zhejiang Key Laboratory of Alternative Technologies for Fine
Chemicals Process, School of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, Zhejiang Province
312000, People’s Republic of China
© 2016 Informa UK Limited, trading as Taylor & Francis Group

2
J. LUO ET AL.
Lewis acid-catalyzed reactions are of great interest in view of their unique reactivities
and selectivities and mild reaction conditions used.[30,31] Owing to their unique cat-
alytic advantages, a wide variety of synthetic reactions catalyzed by Lewis acid have been
developed.[30,31] However, conventional Lewis acids such as AlCl3, TiCl4, etc., are mois-
ture sensitive and easily decomposed or deactivated in the presence of even a small amount
of water. Since the first report of water-compatible lanthanide triflates,[32] new type of
Lewis acids [33–35] has become literature-known catalysts for organic synthesis. Moreover,
in almost all cases, the triflates are still active in the coexistence of many Lewis bases con-
taining nitrogen, oxygen, phosphorus and sulfur atoms, and reuse of the triflates is possible
and metal triflate catalysts are clean and regarded as environmentally friendly catalysts.
In the past several years, our group has developed a series of multi-component reac-
tions that provide easy access to multi-functionalized heterocyclic structures of chemical
and biological interest.[36–40] In view of the prominent merits of lanthanide triflates and
biological and medical activities of heterocycles, we have great interest in the synthesis of
heterocycles using lanthanide triflates as catalysts. As a continuous effort, we report a facile
and efficient synthesis of 4-thiazolidinone derivatives catalyzed by yttrium triflate between
amines, aldehydes and thioglycolic acid under mild reaction conditions.
2. Results and discussion
In order to optimize the reaction conditions, we selected benzaldehyde (1a), aniline (2a)
and thioglycolic acid (3) as a model starting material to examine their behavior under dif-
ferent conditions (Scheme 1); different types and loadings of catalysts, a variety of solvents
(including tetrahydrofuran (THF), methanol, ethanol and toluene) and various reaction
temperatures were screened in the model reaction. The results are shown in Table 1. It is
noteworthy to mention that in the absence of a catalyst, no product was found even after
24 h (Table 1, Entry 1). Inorganic acid (H2SO4) and organic acid (AcOH, TfOH and TFA)
exhibit low activity and only give low yields (11–39%) of goal products (Table 1, Entries
2–5). However, metal triflate catalysts exhibited a remarkably high activity for the forma-
tion of 2,3-diphenylthiazolidin-4-one (4a) (Table 1, Entries 6–8). Yttrium triflate showed
a superior advantage and gave the best yield of 86% (Table 1, Entry 6). Then, the effect of
catalyst loading on the reaction was evaluated. The results showed decreasing the amount
of yttrium triflate from 10 to 5 mol% only led to a trace decrease in the yields from 86%
to 85% (Table 1, Entries 6, 9), but a further decrease to 3 mol% did reduce the yield sig-
nificantly (Table 1, Entries 6,10). However, no significant increase in the yield of product
4a was obtained as when the amount of yttrium triflate was increased from 10 to 20 mol%
(Table 1, Entries 6, 11). Therefore, yttrium triflate (5 mol%) was chosen as the catalyst for
all further reactions.
To further optimize reaction conditions, screening of solvents was carried out, and the
results are also presented in Table 1. It was observed that 2,3-diphenylthiazolidin-4-one
(4a) could be obtained using all the above solvents. When the reaction was carried out in
alcohol (MeOH or EtOH), the product was generated in good to excellent yields (Table 1,
Entries 12–13). Whereas when chloroform was used as solvent, only 70% yield product
was obtained (Table 1, Entry 14), and when toluene was used as solvent, only trace goal
product 4a was obtained (Table 1, Entry 15). Additionally, the addition of a small amount

JOURNAL OF SULFUR CHEMISTRY
3
Scheme 1. The optimization of the model reaction.
Table 1. Optimization of reaction conditions for synthesis of
2,3-diphenylthiazolidin-4-one 4a.a
Entry
Catalyst (mol%)
Solvent
T (°C)
Time(h)
Yield(%)b
1
2
3
4
5
6
7
8
–
THF
THF
THF
THF
THF
THF
THF
THF
THF
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
80
24
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
24
5
5
5
0
22
11
34
39
86
80
83
85
72
87
77
76
70
22
83
0
H2SO4 (10)
HOAc (10)
TfOH (10)
TFA (10)
Y(OTf)3 (10)
Yb(OTf)3 (10)
Sc(OTf)3 (10)
Y(OTf)3 (5)
Y(OTf)3 (3)
Y(OTf)3 (20)
Y(OTf)3 (10)
Y(OTf)3 (10)
Y(OTf)3 (10)
Y(OTf)3 (10)
Y(OTf)3 (10)
Y(OTf)3(10)
Y(OTf)3(10)
Y(OTf)3(10)
Y(OTf)3 (10)
9
10
11
12
13
14
15
16
17
18
19
20
THF
THF
MeOH
C2H5OH
CHCl3
PhMe
THF/H2Oc
THF
THF
THF
THF
Reflux
70
65
20
40
47
77
85
60
80d
aReaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), 3a (1.0 mmol), Catalyst (5 mol%) and
THF (3.0 mL).
bIsolated yields.
cVTHF/VH2O = 3.0 mL/0.5 mL.
dThe reaction was carried out in sealed tube.
of water did not reduce the yield of the goal product, obviously (Table 1, Entry 16). Subse-
quently, the same reaction was carried out in THF at temperatures ranging from 20°C to
80°C (Table 1, Entries 17–20), with an increment of 20°C. As shown in Table 1, the results
showed that reflux temperature (65°C) is enough to push the reaction successfully; thus,
the reflux temperature was chosen as the reaction temperature for all further reactions.
Under optimal conditions, reactions of different aldehydes and amines were per-
formed and afforded 2,3-diaryl-4-thiazolidinone derivatives with good to excellent yields
(Scheme 2, Table 2). As shown in Table 2, at the beginning, we made a search for the
aldehydes substrate scope using aniline and thioglycolic acid as model substrates (Table 2,
Entries 1–4). The results indicate that aromatic aldehydes bearing both electron-donating
and withdrawing functional groups, such as methyl, fluoro or chloro, were able to give the
corresponding compound 4 with good yields (72–85%) in six hours. To further expand the
scope of the reaction, different amines were used as substrates with aldehydes and thiogly-
colic acid. It is worth noting that amines bearing electron-donating groups such as methyl

4
J. LUO ET AL.
Scheme 2. The synthesis of 1,3-oxathiolan-5-one derivatives 4.
or methoxy can give the corresponding 2,3-diaryl-4-thiazolidinones with excellent yields
of 93–94% (Table 2, Entries 5–13). However, amines bearing electron-withdrawing func-
tional groups such as nitro or chloro could not display reactivity under standard conditions
even under prolonged reaction times (Table 2, Entries 14–16). To further examine the effi-
ciency and applicability of this three-component reaction, benzylamine was employed to
react with aromatic aldehydes and thioglycolic acid. To our delight, under the above opti-
mized conditions, these reactions proceeded smoothly to give 4-thiazolidinone derivatives
with excellent yields of 92–94% (Table 2, Entries 17–19). In comparison with the similar
reaction type reported previously, which was conducted either under special reaction con-
ditions or with limited aldehyde substrates, and thereby suffered from narrow substrate
scope, long reaction time and unsatisfactory conversion in some cases, this approach offers
a global and efficient shortcut to prepare 4-thiazolidinones containing a wider substrate
scope, higher catalytic efficiency of yttrium triflate, mild reaction conditions and higher
yields.
It is worth noting that aside from the expected products 4, several undesired products 5
were generated when using different substrates 1 (Scheme 3). When the reaction was per-
formed with aromatic aldehydes bearing strong electron-withdrawing functional groups,
such as 2-nitro, 3-nitro or 4-nitro, as substrates to react with amines, none of the expected
2,3-diaryl-4-thiazolidinones (4) was obtained, but the corresponding 1,3-oxathiolan-5-
one derivatives (5) were obtained with good yields (82–89%).[41] The aromatic amines
could not display reactivity under similar reaction conditions; we attributed such results to
the higher reactivity of nitrobenzaldehydes, in which the existence of a strong electron-
withdrawing group reduced the stability of C =N bond of Schiff base intermediates
obviously.
Additionally, aside from the products 4 and 5, several unexpected products 6 and
7 also were obtained when ethanol was used as solvent (Scheme 4). We found that
the products are not the expected cyclization products 4 and 5. Instead, we found that
ethoxy group was introduced in the final product with ethanol as the substrate. More-
over, ethanol could be introduced in different positions by different types of reactions.
When the reaction was performed with aromatic aldehydes bearing weak electron-
withdrawing functional groups, such as chloro, as substrates to react with amines, diethyl
2,2ꢀ-(((4-chlorophenyl)methylene)bis(sulfanediyl)) diacetate (6) was obtained with good
yield (86%). When the reaction was performed with aromatic aldehydes bearing strong
electron-withdrawing functional groups, such as nitro, as substrates to react with amines,
ethyl 2-((ethoxy(aryl)methyl)thio)acetate (7) were obtained with good yields (82–88%).
The results indicate that aromatic aldehydes bearing different electron-withdrawing func-
tional groups were able to affect the types of goal products. Moreover, thioglycolic acid still

JOURNAL OF SULFUR CHEMISTRY
5
Table 2. Synthesis of 4-thiazolidinone derivatives by Y(OTf)3 catalyst.a
Entry
1
Aldehyde
Amine
Product
Time (h) Yield(%)b
Ref.
27
4a
6
6
6
6
5
5
5
5
5
5
85
75
72
76
86
88
85
89
83
87
2
4b
4c
4d
4e
4f
27
27
27
27
27
22
22
27
15
3
4
5
6
7
4g
4h
4i
8
9
10
4j
11
12
4k
4l
5
5
92
93
–
–
13
14
15
4m
4n
4o
5
6
6
89
0
–
–
–
0
16
17
18
19
4p
4q
4r
6
4
4
4
0
93
94
92
–
27
27
19
4s
aReaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol), Y(OTf)3 (5 mol%) and THF (3.0 mL) at reflux.
bIsolated yields.
displayed high reactivity under standard conditions. We attributed the formation of com-
pounds 6 and 7 to the high reaction activity of ethanol, which prevented the cycloaddition
reaction. Note that this result is significant because there is no literature precedent for the
synthesis of ethyl 2-((ethoxy(aryl)methyl)thio)acetate derivatives (7).

6
J. LUO ET AL.
Scheme 3. The synthesis of 1,3-oxathiolan-5-one derivatives 5.
Scheme 4. The synthesis of undesired products 6 and 7.
3. Conclusion
In summary, we have reported a one-pot three-component reaction (benzaldehydes,
amines and thioglycolic acid) as an approach to the annulations of 2,3-diaryl-4-
thiazolidinones and 1,3-oxathiolan-5-ones. Particularly, valuable features of this method
included the structural diversity of products, mild reaction conditions and higher catalytic
efficiency of yttrium triflate, as well as short reaction times. Therefore, this work not only
provides plenty of novel 2,3-diaryl-4-thiazolidinone and 1,3-oxathiolan-5-one derivatives,
but also enriches the research contents of rare earth metals.
4. Experimental
4.1. General
All reagents were commercial products without further purification, unless otherwise
stated. Analytical thin layer chromatography (TLC) was performed using Merck silica gel
GF254 plates. Column chromatography was carried out with silica gel (Silica Gel 200–300
mesh, pH 6.0–7.0 for 10% suspension). Melting points were measured on an X-4 melting
point apparatus. 1HNMR spectra were recorded on a 400 MHz instrument (Bruker Avance
400 Spectrometer). Chemical shifts (δ) are given in ppm relative to TMS as the internal
reference, with coupling constants (J) in Hz. 13C NMR spectra were recorded at 100 MHz.
Chemical shifts were reported in ppm with the internal chloroform signal at 77.0 ppm as a
standard. Elemental analysis was carried out on EuroEA elemental analyzer.

JOURNAL OF SULFUR CHEMISTRY
7
4.2. General procedure for synthesis of 2,3-diaryl-4-thiazolidinones 4
In a 10-mL reaction vial, benzaldehyde (1.0 mmol), amine (1.0 mmol), thioglycolic acid
(1.0 mmol) and THF (3.0 mL) were mixed. The mixture was stirred in THF at reflux tem-
perature. Upon completion as shown by TLC monitoring, the reaction mixture was cooled
to room temperature and extracted with ethyl acetate (5.0 mL × 3). The combined organic
layer was dried over Na2SO4, and concentrated in vacuum. The resulting residue was
purified by column chromatography on silica gel with the eluent (ethyl acetate/petroleum
ether = 1:10–1:2) to give the pure products.
4.2.1. 2,3-Diphenylthiazolidin-4-one (4a) [27]
Yellow solid, mp 127–128°C; 1H NMR (400 MHz, CDCl3): δ = 7.23–7.34 (m, 9H, ArH),
7.10–7.13 (m, 1H, ArH), 6.01 (s, 1H, CH), 3.89 (d, 1H, J = 15.6 Hz, CH2), 3.78 (d, 1H,
J = 16.4 Hz, CH2) ppm.
4.2.2. 3-Phenyl-2-(p-tolyl)thiazolidin-4-one (4b) [27]
Yellow solid, mp 115–116°C; 1H NMR (400 MHz, CDCl3): δ = 7.23–7.27 (m, 2H, ArH),
7.14–7.21 (m, 5H, ArH), 7.08–7.10 (d, 2H, J = 7.6 Hz, ArH), 6.03 (s, 1H, CH), 4.00 (d, 1H,
J = 15.6 Hz, CH2), 3.94 (d, 1H, J = 16.0 Hz, CH2), 2.28 (s, 3H, CH3) ppm.
4.2.3. 2-(4-Fluorophenyl)-3-phenylthiazolidin-4-one (4c) [27]
Brown solid, mp 127–128°C; 1H NMR (400 MHz, CDCl3): δ = 7.24–7.28 (m, 4H, ArH),
7.12–7.20 (m, 3H, ArH), 6.95–7.00 (m, 2H, ArH), 6.08 (s, 1H, CH), 3.96 (dd, 1H, J = 15.6,
1.2 Hz, CH2), 3.88 (dd, 1H, J = 15.6, 0.8 Hz, CH2) ppm.
4.2.4. 2-(4-Chlorophenyl)-3-phenylthiazolidin-4-one (4d) [27]
Brown solid, mp 128–130°C; 1H NMR (400 MHz, CDCl3): δ = 7.09–7.48 (m, 9H, ArH),
6.08 (s, 1H, CH), 3.99 (dd, 1H, J = 15.6, 1.2 Hz, CH2), 3.89 (d, 1H, J = 15.6 Hz, CH2)
ppm.
4.2.5. 2-Phenyl-3-(p-tolyl)thiazolidin-4-one (4e) [27]
Yellow solid, mp 116–118°C; 1H NMR (400 MHz, CDCl3): δ = 7.33 (d, 2H, J = 8.0 Hz,
ArH), 7.23–7.27 (m, 3H, ArH), 7.19 (d, 2H, J = 8.4 Hz, ArH), 7.09 (d, 2H, J = 8.0 Hz,
ArH), 6.05 (s, 1H, CH), 3.99 (dd, 1H, J = 16.0, 1.2 Hz, CH2), 3.90 (d, 1H, J = 15.6 Hz,
CH2), 2.30 (s, 3H, CH3) ppm.
4.2.6. 2,3-Di-p-tolylthiazolidin-4-one (4f) [27]
Yellow solid, mp 129–130°C; 1H NMR (400 MHz, CDCl3): δ = 7.19 (d, 2H, J = 8.0 Hz,
ArH), 7.10 (d, 2H, J = 7.2 Hz, ArH), 6.98 (d, 2H, J = 8.0 Hz, ArH), 6.30 (d, 2H,
J = 8.4 Hz, ArH), 6.04 (s, 1H, CH), 3.99 (dd, 1H, J = 16.0, 1.2 Hz, CH2), 3.87 (d, 1H,
J = 15.6 Hz, CH2), 2.31 (s, 3H, CH3), 2.26 (s, 3H, CH3) ppm.
4.2.7. 2-(4-Methoxyphenyl)-3-(p-tolyl)thiazolidin-4-one (4g) [22]
Yellow solid, mp 145–146°C; 1H NMR (400 MHz, CDCl3): δ = 7.23 (d, 2H, J = 8.4 Hz,
ArH), 7.08 (d, 2H, J = 8.4 Hz, ArH), 7.00 (d, 2H, J = 8.4 Hz, ArH), 6.81 (d, 2H,
J = 8.4 Hz, ArH), 6.03 (s, 1H, CH), 3.98 (dd, 1H, J = 16.0, 1.2 Hz, CH2), 3.88 (d, 1H,
J = 15.6 Hz, CH2), 3.77 (s, 3H, OMe), 2.26 (s, 3H, CH3) ppm.

8
J. LUO ET AL.
4.2.8. 2-(4-Fluorophenyl)-3-(p-tolyl)thiazolidin-4-one (4h) [22]
1
Pale yellow solid, mp 172–174°C; H NMR (400 MHz, CDCl3): δ = 7.30–7.31 (m, 2H,
ArH), 7.09 (d, 2H, J = 8.0 Hz, ArH), 6.99 (d, 4H, J = 9.2 Hz, ArH), 6.05 (s, 1H, CH), 3.98
(dd, 1H, J = 16.0, 1.6 Hz, CH2), 3.89 (d, 1H, J = 15.6 Hz, CH2), 2.27 (s, 3H, CH3) ppm.
4.2.9. 3-(4-Methoxyphenyl)-2-phenylthiazolidin-4-one (4i) [27]
Yellow solid, mp 60–62°C; 1H NMR (400 MHz, CDCl3): δ = 7.30 (s, 5H, ArH), 7.03 (d, 2H,
J = 9.2 Hz, ArH), 6.79 (d, 2H, J = 8.8 Hz, ArH), 5.99 (s, 1H, CH), 4.01 (dd, 1H, J = 15.6,
1.6 Hz, CH2), 3.73 (d, 1H, J = 15.6 Hz, CH2) ppm.
4.2.10. 2-(4-Chlorophenyl)-3-(4-methoxyphenyl)thiazolidin-4-one (4j) [15]
Yellow solid, mp 166–168°C; 1H NMR (400 MHz, CDCl3): δ = 7.40 (d, 2H, J = 8.4 Hz,
ArH), 7.33 (d, 2H, J = 8.8 Hz, ArH), 7.17 (d, 2H, J = 8.8 Hz, ArH), 6.84 (d, 2H,
J = 8.4 Hz, ArH), 6.40 (s, 1H, CH), 4.02 (dd, 1H, J = 15.2, 2.0 Hz, CH2), 3.86 (d, 1H,
J = 15.2 Hz, CH2), 3.68 (s, 3H, OMe) ppm.
4.2.11. 3-(2,4-Dimethylphenyl)-2-phenylthiazolidin-4-one (4k)
Yellow solid, mp 220–222°C; 1H NMR (400 MHz, CDCl3): δ = 7.48–7.52 (m, 3H, ArH),
7.35–7.42 (m, 3H, ArH), 6.99 (s, 1H, ArH), 6.63 (s, 1H, ArH), 5.64 (s, 1H, CH), 3.25 (d, 1H,
J = 12.0 Hz, CH2), 2.99 (d, 1H, J = 11.6 Hz, CH2), 2.27 (s, 3H, CH3), 2.22 (s, 3H, CH3)
ppm; 13C NMR (100 MHz, CDCl3): δ = 171.0, 143.5, 139.0, 135.6, 131.3, 128.7, 128.4,
127.5, 127.3, 126.3, 126.0, 121.0, 70.3, 32.8, 21.0, 19.8 ppm; Anal. Calcd for C17H17NOS:
C, 72.05; H, 6.05; N, 4.94. Found: C, 71.88; H, 5.87; N, 5.23.
4.2.12. 3-(2,4-Dimethylphenyl)-2-(p-tolyl)thiazolidin-4-one (4l)
Yellow solid, mp 166–168°C; 1H NMR (400 MHz, CDCl3): δ = 7.37 (d, 2H, J = 8.0 Hz,
ArH), 7.21 (d, 3H, J = 8.0 Hz, ArH), 6.98 (s, 1H, ArH), 6.65 (s, 1H, ArH), 5.62 (s, 1H,
CH), 3.25 (d, 1H, J = 12.0 Hz, CH2), 2.97 (dd, 1H, J = 12.0, 1.6 Hz, CH2), 2.38 (s, 3H,
CH3), 2.26 (s, 3H, CH3), 2.20 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): δ = 169.5,
143.4, 139.1, 135.7, 131.1, 128.6, 128.2, 127.4, 127.3, 126.2, 126.0, 121.1, 70.6, 32.3, 21.5,
21.2, 19.9 ppm; Anal. Calcd for C18H19NOS: C, 72.69; H, 6.44; N, 4.71. Found: C, 72.78;
H, 6.10; N, 5.02.
4.2.13. 2-(4-Chlorophenyl)-3-(2,4-dimethylphenyl)thiazolidin-4-one (4m)
Pale yellow solid, mp 228–230°C; 1H NMR (400 MHz, CDCl3): δ = 7.50 (s, 1H, ArH), 7.43
(d, 2H, J = 8.4 Hz, ArH), 7.36 (d, 2H, J = 8.4 Hz, ArH), 7.00 (s, 1H, ArH), 6.61 (s, 1H,
ArH), 5.57 (s, 1H, CH), 3.22 (d, 1H, J = 12.0 Hz, CH2), 2.99 (d, 1H, J = 12.0 Hz, CH2),
2.26 (s, 3H, CH3), 2.24 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): δ = 170.9, 143.2,
138.9, 135.5, 131.3, 128.5, 128.1, 127.3, 127.1, 126.5, 126.0, 121.1, 70.4, 32.1, 20.1, 19.9 ppm;
Anal. Calcd for C17H16ClNOS: C, 64.24; H, 5.07; N, 4.41. Found: C, 64.39; H, 4.88; N, 4.20.
4.2.14. 3-Benzyl-2-phenylthiazolidin-4-one (4q) [27]
White solid, mp 156–158°C; 1H NMR (400 MHz, CDCl3): δ = 7.20–7.40 (m, 8H, ArH),
7.07–7.13 (m, 2H, ArH), 5.36 (s, 1H, CH), 5.16 (d, 1H, J = 14.8 Hz, CH2), 3.90 (d, 1H,
J = 15.6 Hz, CH2), 3.76 (d, 1H, J = 15.6 Hz, CH2), 3.53 (d, 1H, J = 14.8 Hz, CH2) ppm.

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4.2.15. 3-Benzyl-2-(4-methoxy)thiazolidin-4-one (4r) [27]
Yellow solid, mp 144–146°C; 1H NMR (400 MHz, CDCl3): δ = 6.88–7.28 (m, 9H, ArH),
5.35 (s, 1H, CH), 5.11 (d, 1H, J = 14.8 Hz, CH2), 3.87 (d, 1H, J = 15.6 Hz, CH2), 3.81 (s,
3H, OMe), 3.74 (d, 1H, J = 15.6 Hz, CH2), 3.52 (d, 1H, J = 14.8 Hz, CH2) ppm.
4.2.16. 3-Benzyl-2-(4-chlorophenyl)thiazolidin-4-one (4s) [19]
1
White solid, mp 208–210°C; H NMR (400 MHz, CDCl3): δ = 7.37 (d, 2H, J = 8.4 Hz,
ArH), 7.31–7.32 (m, 3H, ArH), 7.17 (d, 2H, J = 8.4 Hz, ArH), 7.08–7.10 (m, 2H, ArH),
5.36 (s, 1H, CH), 5.16 (d, 1H, J = 14.8 Hz, CH2), 3.91 (d, 1H, J = 15.6 Hz, CH2), 3.78 (d,
1H, J = 15.6 Hz, CH2), 3.53 (d, 1H, J = 14.8 Hz, CH2) ppm.
4.3. General procedure for synthesis of 2,3-diaryl-4-thiazolidinones 5
In a 10-mL reaction vial, nitrobenzaldehyde (1.0 mmol), amine (1.0 mmol), thioglycolic
acid (1.0 mmol) and THF (3.0 mL) were mixed. The mixture was stirred at reflux temper-
ature. Upon completion as shown by TLC monitoring, the reaction mixture was cooled to
room temperature and extracted with ethyl acetate (5.0 mL × 3). The combined organic
layer was dried over Na2SO4, and concentrated in vacuum. The resulting residue was
purified by column chromatography on silica gel with the eluent (ethyl acetate/petroleum
ether = 1:10–1:6) to give the pure products.
4.3.1. 2-(2-Nitrophenyl)-1,3-oxathiolan-5-one (5a) [41]
Pale yellow solid, mp 64–66°C; 1H NMR (400 MHz, CDCl3): δ = 8.25 (d, 1H, J = 8.4 Hz,
ArH), 7.76 (t, 1H, J = 6.8 Hz, ArH), 7.69 (d, 1H, J = 7.2 Hz, ArH), 7.60 (t, 1H, J = 8.4 Hz,
ArH), 7.13 (s, 1H, CH), 3.77 (d, 1H, J = 16.8 Hz, CH2), 3.66 (d, 1H, J = 16.8 Hz, CH2)
ppm; Anal. Calcd for C9H7NO4S: C, 48.00; H, 3.13; N, 6.22. Found: C, 47.81; H, 2.76; N,
6.51.
4.3.2. 2-(3-Nitrophenyl)-1,3-oxathiolan-5-one (5b) [41]
Pale yellow solid, mp 70–72°C; 1H NMR (400 MHz, CDCl3): δ = 8.51 (d, 1H, J = 8.4 Hz,
ArH), 8.25 (d, 1H, J = 7.69 Hz, ArH), 7.77 (d, 1H, J = 8.0 Hz, ArH), 7.64 (t, 1H,
J = 8.0 Hz, ArH), 6.55 (s, 1H, CH), 3.93 (d, 1H, J = 16.4 Hz, CH2), 3.82 (d, 1H,
J = 16.4 Hz, CH2) ppm; Anal. Calcd for C9H7NO4S: C, 48.00; H, 3.13; N, 6.22. Found:
C, 48.15; H, 2.81; N, 6.00.
4.3.3. 2-(4-Nitrophenyl)-1,3-oxathiolan-5-one (5c) [41]
Pale yellow solid, mp 82–84°C; 1H NMR (400 MHz, CDCl3): δ = 7.30 (d, 2H, J = 8.8 Hz,
ArH), 7.65 (d, 2H, J = 8.8 Hz, ArH), 6.56 (s, 1H, CH), 3.92 (d, 1H, J = 16.8 Hz, CH2),
3.80 (d, 1H, J = 16.8 Hz, CH2) ppm; Anal. Calcd for C9H7NO4S: C, 48.00; H, 3.13; N,
6.22. Found: C, 48.31; H, 3.38; N, 6.31.
4.4. General procedure for synthesis of 2,3-diaryl-4-thiazolidinones 6 and 7
In a 10-mL reaction vial, aromatic aldehyde (1.0 mmol), amine (1.0 mmol), thioglycolic
acid (1.0 mmol) and EtOH (3.0 mL) were mixed. The mixture was stirred at 80°C. Upon

10
J. LUO ET AL.
completion as shown by TLC monitoring, the reaction mixture was cooled to room temper-
ature and extracted with ethyl acetate (5.0 mL × 3). The combined organic layer was dried
over Na2SO4, and concentrated in vacuum. The resulting residue was purified by column
chromatography on silica gel with the eluent (ethyl acetate/petroleum ether = 1:10–1:4)
to give the pure products.
4.4.1. Diethyl 2,2ꢀ-(((4-chlorophenyl)methylene)bis(sulfanediyl))diacetate (6) [42]
Brown oil; 1H NMR (400 MHz, CDCl3): δ = 7.41 (d, 2H, J = 8.4 Hz, ArH), 7.32 (d, 2H,
J = 8.4 Hz, ArH), 5.34 (s, 1H, CH), 4.12–4.18 (m, 4H, CH2), 3.42 (d, 2H, J = 15.2 Hz,
CH2), 3.16 (d, 2H, J = 14.8 Hz, CH2), 1.27 (t, 6H, J = 7.2 Hz, CH3) ppm.
4.4.2. Ethyl 2-((ethoxy(2-nitrophenyl)methyl)thio)acetate (7a)
Pale yellow oil; 1H NMR (400 MHz, CDCl3): δ = 7.96 (d, 1H, J = 8.0 Hz, ArH), 7.87 (d,
1H, J = 7.6 Hz, ArH), 7.63 (t, 1H, J = 7.6 Hz, ArH), 7.45 (t, 1H, J = 7.6 Hz, ArH), 6.42 (s,
1H, CH), 4.06–4.11 (m, 2H, CH2), 3.86–3.94 (m, 1H, CH2), 3.50–3.58 (m, 1H, CH2), 3.22
(d, 1H, J = 15.2 Hz, CH2), 3.10 (d, 1H, J = 15.2 Hz, CH2), 1.22–1.29 (m, 6H, CH3) ppm;
13C NMR (100 MHz, CDCl3): δ = 170.0, 146.6, 134.9, 133.1, 128.7, 128.1, 125.0, 80.2, 65.1,
61.5, 30.7, 14.8, 14.0 ppm; Anal. Calcd for C13H17NO5S: C, 52.16; H, 5.72; N, 4.68. Found:
C, 52.00; H, 5.43; N, 4.31.
4.4.3. Ethyl 2-((ethoxy(3-nitrophenyl)methyl)thio)acetate (7b)
Yellow oil; 1H NMR (400 MHz, CDCl3): δ = 8.36 (s, 1H, ArH), 8.16 (d, 1H, J = 8.4 Hz,
ArH), 7.82 (d, 1H, J = 7.6 Hz, ArH), 7.55 (t, 1H, J = 8.0 Hz, ArH), 5.77 (s, 1H, CH),
4.08–4.16 (m, 2H, CH2), 3.89–3.97 (m, 1H, CH2), 3.53–3.59 (m, 1H, CH2), 3.23 (d, 1H,
J = 15.2 Hz, CH2), 3.08 (d, 1H, J = 14.8 Hz, CH2), 1.31 (t, 3H, J = 7.2 Hz, CH3), 1.26 (t,
3H, J = 7.2 Hz, CH3) ppm; 13C NMR (100 MHz, CDCl3): δ = 170.0, 148.2, 141.7, 132.6,
129.2, 123.0, 121.6, 84.0, 65.0, 61.5, 30.3, 14.8, 14.1 ppm; Anal. Calcd for C13H17NO5S: C,
52.16; H, 5.72; N, 4.68. Found: C, 51.88; H, 5.39; N, 4.89.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was made possible by the financial support from the Natural Science Foundation of Zhe-
jiang Province [No. LY16B020007]; the Foundation of Education Department of Zhejiang Province
[No. Y201533906] and the Natural Science Foundation of China [No. 21172149].
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