Efficient approach to thiazolidinones via a one-pot three-component reaction involving 2-amino-1-phenylethanone hydrochloride, aldehyde and mercaptoacetic acid

Article abstract of DOI:10.1016/S1872-2067(16)62536-6

A highly efficient three-component reaction has been developed for the synthesis of thiazolidinones involving the reaction of 2-amino-1-phenylethanone hydrochloride with an aromatic aldehyde and mercaptoacetic acid in the presence of diisopropylethylamine in a single pot. Critically, this reaction exhibited excellent chemoselectivity, with the nitrogen atom of the 2-amino-1-phenylethanone component reacting selectively with the aromatic aldehyde to give the corresponding Schiff base. Nucleophilic attack at the carbon of the Schiff base by the sulfur atom of mercaptoacetic, followed by a cyclocondensation reaction between the nitrogen and the carboxylic acid moiety afforded the desired thiazolidinones, which were fully characterized by spectroscopic techniques.

Full text of DOI:10.1016/S1872-2067(16)62536-6

Chinese Journal of Catalysis 37 (2016) 1997–2002
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c h n j c
Article
Efficient approach to thiazolidinones via a one‐pot three‐component
reaction involving 2‐amino‐1‐phenylethanone hydrochloride,
aldehyde and mercaptoacetic acid
Asha Vasantrao Chatea, Akash Gitaram Tathea, Prajyot Jayadev Nagtilaka, Sunil M. Sangleb,
Charansingh H. Gilla,*
a Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad‐431004, M.S., India
b Rajaram College, Kolhapur‐416004, M.S., India
A R T I C L E I N F O
A B S T R A C T
Article history:
A highly efficient three‐component reaction has been developed for the synthesis of thiazolidinones
involving the reaction of 2‐amino‐1‐phenylethanone hydrochloride with an aromatic aldehyde and
mercaptoacetic acid in the presence of diisopropylethylamine in a single pot. Critically, this reaction
exhibited excellent chemoselectivity, with the nitrogen atom of the 2‐amino‐1‐phenylethanone
component reacting selectively with the aromatic aldehyde to give the corresponding Schiff base.
Nucleophilic attack at the carbon of the Schiff base by the sulfur atom of mercaptoacetic, followed by
a cyclocondensation reaction between the nitrogen and the carboxylic acid moiety afforded the
desired thiazolidinones, which were fully characterized by spectroscopic techniques.
© 2016, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Received 15 June 2016
Accepted 21 August 2016
Published 5 November 2016
Keywords:
Tandem reaction
Thiazolidinones
Heterocycles
N,N‐diisopropylethylamine
Cyclization
Published by Elsevier B.V. All rights reserved.
1. Introduction
development of new and efficient procedures for the genera‐
tion of heterocyclic compounds is therefore highly desired.
For more than a century, heterocyclic compounds have
ranked amongst the most important classes of organic com‐
pounds. Notably, compounds belonging to this class participate
in a wide range of important biochemical processes, as well as
being key components of our genetic code (e.g., DNA and RNA).
It has been reported that around half of the therapeutic agents
developed and commercialized to date consist of heterocyclic
compounds [1]. Biologically active molecules containing het‐
eroatoms such as nitrogen, sulfur and oxygen, have always
attracted considerable interest from chemist because of the
challenges associated with their syntheses and the potential
application of these compounds as therapeutic agents and tool
compounds in medicine and the pharmaceutical sciences. The
Diversity‐oriented synthesis has been successfully applied to
the synthesis of structurally diverse and complex collections of
biologically active pharmacophores. Among the many strate‐
gies utilized to date, the sequential linking of several different
components in one reaction vessel has been studied extensive‐
ly as an efficient method for the rapid construction of increas‐
ingly complex molecular architectures. Critically, this process
avoids the requirement for costly and environmentally un‐
friendly isolation and purification of intermediates [2–5]. Mul‐
ti‐component reactions (MCRs) of this type represent efficient
approaches for the synthesis of five‐membered heterocycles
containing sulfur, nitrogen and oxygen in one moiety, allowing
for the production of privileged scaffolds of considerable me‐
* Corresponding author. Tel: +91‐240‐2403311; Fax: +91‐240‐2400491; E‐mail: chgill16@gmail.com
DOI: 10.1016/S1872‐2067(16)62536‐6 | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 37, No. 11, November 2016

1998
Asha Vasantrao Chate et al. / Chinese Journal of Catalysis 37 (2016) 1997–2002
dicinal value.
2. Experimental
Five‐membered rings containing three heteroatoms are a
privileged class of heterocyclic structures with proven utility in
medicinal chemistry. For example, 4‐thiazolidinones are im‐
portant synthetic intermediates, which can also be found in a
wide range of therapeutic agents with interesting pharmaco‐
logical activities. The 4‐thiazolidinone ring system is a versatile
structure that can be found in numerous drugs currently being
used in clinical practice to treat various diseases. Compounds
belonging to this structural class have also been reported to
exhibit a broad range of interesting biological properties, in‐
cluding hypoglycemic, antibacterial [6], anticancer [7–10], an‐
titubercular [11–13], antioxidant [14], anti‐inflammatory [15],
COX‐1 inhibitory [16], anti‐HIV [17–20] and antihistaminic [21]
activities. The chemical structures of several important thia‐
zolidinone‐containing compounds from the literature are
shown in Fig. 1.
2.1. Materials and methods
All of the chemicals used in this study were purchased from
commercial suppliers and used as supplied without further
purification. Melting points (M.P.) were determined in open
capillary tubes and reported as the uncorrected values. 1H NMR
spectra were recorded on a 400‐MHz Varian spectrometer
model Avance‐II (Bruker) using DMSO‐d6 as a solvent. Chemical
shifts (δ) were reported in ppm relative to TMS, which was
used as an internal reference standard, and the coupling con‐
stants (J) were expressed in hertz (Hz). Mass spectra were rec‐
orded on a Macro mass spectrometer (Waters) using elec‐
trospray ionization. The reactions were monitored by thin layer
chromatography (TLC) using silica‐coated plates (Merck).
Several methods have been reported in the literature for the
synthesis of 4‐thiazolidinones. The main synthetic routes to
1,3‐thiazolidin‐4‐ones involve the three‐component reaction of
an amine with a carbonyl group‐containing compound and a
mercaptocarboxylic acid. This classical approach can either be
conducted as a one‐pot three‐component condensation or a
two‐step process. Mechanistically, these reactions begin with
the formation of an imine, followed by the nucleophilic attack
of the nitrogen atom of the amine component on the carbonyl
carbon of the aldehyde or ketone. The resulting imine then
undergoes a nucleophilic attack from the sulfur nucleophile,
followed by an intramolecular cyclocondensation reaction to
give the desired product [22–24]. Numerous catalysts [25–31]
have been reported to accelerate the cyclocondensation step of
this reaction. Several solid phase [32], microwave [33] and
polymer supported [4,34–37] systems have also been devel‐
oped. MCRs [38] are well‐known procedures for the rapid con‐
struction of diverse chemical structures. Notably, MCRs allow
for the synthesis of complex molecules in a modular manner,
thereby allowing for the incorporation of one or more units in a
final product in a well‐defined and predictable order.
With the three‐component, one‐flask preparation of TZD al‐
ready reported, we report here a synthetic approach to these
heterocycles involving three‐component, one‐flask, sequential
1 + 2 + 3 atom construction of five‐membered ring novel
3‐(2‐oxo‐2‐phenylethyl)‐2‐phenylthiazolidin‐4‐one. With this
in mind, the aim of the current paper was to achieve the syn‐
thesis of a new series of thiazolidinones by the condensation of
novel amines, with aromatic aldehydes and thioglycolic acid via
a one‐pot, three‐component reaction using DIPEA as a base
according to a MCR protocol.
2.2. General procedure for the synthesis of
3‐(2‐oxo‐2‐phenylethyl)‐2‐phenylthiazolidin‐4‐ones 4a–4m
To a solution of 2‐amino‐1‐phenylethanone hydrochloride
2a (1 mmol) in toluene (8 mL) was added benzaldehyde 1a (1
mmol) and the mixture was heated for 1 h in the presence of
DIPEA (3 mmol) to afford the corresponding Schiff base. The
reaction was then treated with mercaptoacetic acid 3 (3 mol),
and the resulting mixture was heated for 3–4 h to give the cor‐
responding substituted thiazolidinone 4a–4m. Upon comple‐
tion of the reaction, as determined by TLC analysis, the toluene
was removed under vacuum to give a viscous oil, which was
treated with a saturated aqueous NaHCO3 solution to remove
any unreacted mercaptoacetic acid. The product subsequently
crystallized and was washed with water before being dried
under vacuum at 40 °C and recrystallized from alcohol to give
the pure product.
2.3. Spectral data for representative compounds
3‐(2‐Oxo‐2‐phenylethyl)‐2‐phenylthiazolidin‐4‐one (4a). 1H
NMR (DMSO, 400 MHz): δ 3.66–3.93 (dd, overlapped, 2H,
methylene), 4.26 (s, 2H, CH2), 5.80 (t, 1H, methine), 7.02–7.14
(m, 4H, Ar–H), 7.27–7.57 (m, 5H, Ar–H); 13C NMR (100 MHz,
CDCl3): δ 193.1, 170.3, 140.1, 138.5, 128.8, 127.3, 126.3, 62.1,
49.8, 32.4. LC‐MS (ES+) m/z: 298.12 [M]+ & 296.3 [M–H]+. Ele‐
mental analysis Calcd. for C17H15NO2S: C, 68.66; H, 5.08; N, 4.71;
S, 10.78; Found: C, 68.86; H, 5.18; N, 4.61.
2‐(4‐Chlorophenyl)‐3‐(2‐oxo‐2‐phenylethyl)thiazolidin‐4‐
1
one (4b). H NMR (DMSO, 400 MHz): δ 3.75–4.06 (dd, over‐
lapped, 2H, methylene), 4.78 (s, 2H, CH2), 5.87 (t, 1H, methine),
7.18–7.28 (m, 4H, Ar–H), 7.47–7.86 (m, 5H, Ar–H); 13C NMR
(100 MHz, CDCl3): δ 193.6, 171.0, 144.7, 135.9, 132.8, 127.9,
63.5, 48.8, 33.5. LC‐MS (ES+) m/z: 332.04 [M+H]+ & 334.12
[M+2H]+. Elemental analysis Calcd. for C17H14ClNO2S: C, 61.53;
H, 4.25; N, 4.22; S, 9.66; Found: C, 61.59; H, 4.30; N, 4.12.
2‐(4‐Hydroxyphenyl)‐3‐(2‐oxo‐2‐phenylethyl)thiazolidin‐4‐
1
one (4c). H NMR (DMSO, 400 MHz): δ 3.32–3.72 (dd, over‐
lapped, 2H, methylene), 4.81 (s, 2H, CH2), 5.75 (t, 1H, methine),
6.86–6.95 (m, 4H, Ar–H), 7.12–7.71 (m, 5H, Ar–H), 10.06 (s, 1H,
Fig. 1. Some biologically important thiazolidinone compounds.

Asha Vasantrao Chate et al. / Chinese Journal of Catalysis 37 (2016) 1997–2002
1999
OH); 13C NMR (100 MHz, CDCl3): δ 192.6, 170.7, 155.4, 136.8,
130.6, 123.7, 115.2, 61.9, 47.1, 32.8. LC‐MS (ES+) m/z: 313.08
[M]+. Elemental analysis Calcd. for C17H15NO3S: C, 65.16; H,
4.82; N, 4.47; S, 10.23; Found: C, 65.22; H, 4.89; N, 4.40.
one (4l). 1H NMR (DMSO, 400 MHz): δ 2.50 (s, 3H, CH3),
3.76–3.92 (dd, overlapped, 2H, methylene), 4.92 (s, 2H, CH2),
5.75 (t, 1H, methine), 7.22–7.30 (dd, 2H, Ar–H), 7.74–8.10 (m,
5H, Ar–H); 13C NMR (100 MHz, CDCl3): δ 193.6, 170.9, 141.6,
137.8, 131.8, 127.6, 126.4, 59.9, 48.1, 32.1. LC‐MS (ES+) m/z:
318.15 [M+H]+. Elemental analysis Calcd. for C16H15NO2S2: C,
60.54; H, 4.76; N, 4.41; S, 20.20; Found: C, 60.60; H, 4.86; N,
4.31.
2‐(3‐Methoxyphenyl)‐3‐(2‐oxo‐2‐phenylethyl)thiazolidin‐4‐
1
one (4d). H NMR (DMSO, 400 MHz): δ 3.65–3.69 (dd, over‐
lapped, 2H, methylene), 3.79 (s, 3H, OCH3), 5.11 (s, 2H, CH2),
5.96 (t, 1H, methine), 6.85–7.09 (m, 3H, Ar–H), 7.17 (s, 1H,
Ar–H), 7.20–7.64 (m, 5H, Ar–H); 13C NMR (100 MHz, CDCl3): δ
193.6, 172.4, 159.0, 140.4, 134.8, 129.9, 127.3, 122.7, 120.8,
111.1, 63.4, 55.6, 48.4, 32.5. LC‐MS (ES+) m/z: 327.09 [M+H]+.
Elemental analysis Calcd. for C18H17NO3S: C, 66.03; H, 5.23; N,
4.28; S, 9.79; Found: C, 66.13; H, 5.300; N, 4.20.
3‐(2‐Oxo‐2‐phenylethyl)‐2‐(p‐tolyl)thiazolidin‐4‐one (4e).
1H NMR (DMSO, 400 MHz): δ 2.32 (s, 3H, CH3), 3.33–3.73 (dd,
overlapped, 2H, methylene), 4.85 (s, 2H, CH2), 5.75 (t, 1H, me‐
thine), 7.02–7.27 (m, 4H, Ar–H), 7.20–7.77 (m, 5H, Ar–H); 13C
NMR (100 MHz, CDCl3): δ 193.4, 170.9, 139.0, 135.8, 133.9,
127.9, 63.4, 48.4, 31.8, 22.7. LC‐MS (ES+) m/z: 312.10 [M+H]+.
Elemental analysis Calcd. for C18H17NO2S: C, 69.43; H, 5.50; N,
4.50; S, 10.30; Found: C, 69.49; H, 5.58; N, 4.42.
3‐(2‐Oxo‐2‐(p‐tolyl)ethyl)‐2‐phenylthiazolidin‐4‐one (4f).
1H NMR (DMSO, 400 MHz): δ 2.49 (s, 3H, CH3), 3.64–3.98 (dd,
overlapped, 2H, methylene), 4.27 (s, 2H, CH2), 5.82 (t, 1H, me‐
thine), 7.10–7.19 (m, 4H, Ar–H), 7.37–7.59 (m, 4H, Ar–H); 13C
NMR (100 MHz, CDCl3): δ 193.2, 171.4, 145.0, 142.2, 139.2,
133.1, 128.5, 127.0, 124.6, 63.5, 49.5, 32.8, 21.0. LC‐MS (ES+)
m/z: 312.12 ([M]+ & 310.31 [M–H]+. Elemental analysis Calcd.
for C18H17NO2S: C, 69.43; H, 5.50; N, 4.50; S, 10.30; Found: C,
69.53; H, 5.40; N, 4.30; S, 10.21.
2‐(4‐Chlorophenyl)‐3‐(2‐oxo‐2‐(p‐tolyl)ethyl)thiazolidin‐4‐
one (4h): 1H NMR (DMSO, 400 MHz): δ 2.50 (s, 3H, CH3),
3.75–3.98 (dd, overlapped, 2H, methylene), 4.85 (s, 2H, CH2),
5.79 (t, 1H, methine), 7.17–7.29 (m, 4H, Ar–H), 7.35–7.73 (m,
4H, Ar–H); 13C NMR (100 MHz, CDCl3): δ 193.3, 170.7, 142.7,
141.2, 131.9, 128.8, 126.9, 62.7, 49.4, 33.8, 21.8. LC‐MS (ES+)
m/z: 345.06 [M]+ & 347.31 ([M+2H]+. Elemental analysis Calcd.
for C18H16ClNO2S: C, 62.51; H, 4.66; N, 4.05; S, 9.27; Found: C,
62.59; H, 4.72; N, 4.00.
2‐(3‐Methoxyphenyl)‐3‐(2‐oxo‐2‐(p‐tolyl)ethyl)thiazolidin‐
4‐one (4i). 1H NMR (DMSO, 400 MHz): δ 2.49 (s, 3H, CH3),
3.72–3.78 (dd, overlapped, 2H, methylene), 3.92 (s, 3H, OCH3),
4.82 (s, 2H, CH2), 5.55 (t, 1H, methine), 6.59–6.89 (m, 3H,
Ar–H), 7.30 (s, 1H, Ar–H), 7.32–7.39 (m, 4H, Ar–H); 13C NMR
(100 MHz, CDCl3): δ 193.7, 170.7, 158.7, 141.3, 139.9, 131.9,
129.8, 127.9, 63.7, 55.4, 49.6, 33.1, 21.8. LC‐MS (ES+) m/z:
342.11 [M]+. Elemental analysis Calcd. for C19H19NO3S: C, 66.84;
H, 5.61; N, 4.10; S, 9.39; Found: C, 66.90; H, 5.70; N, 4.02.
3‐(2‐Oxo‐2‐phenylethyl)‐2‐(thiophen‐2‐yl)thiazolidin‐4‐one
(4j). 1H NMR (DMSO, 400 MHz): δ 2.56 (s, 3H, CH3), 3.79–3.96
(dd, overlapped, 2H, methylene), 4.84 (s, 2H, CH2), 6.16 (t, 1H,
methine), 6.94–6.96 (dd, 2H, Ar–H), 7.29–8.50 (m, 6H, Ar–H);
13C NMR (100 MHz, CDCl3): δ 193.4, 170.6, 139.5, 134.6, 133.7,
127.8, 126.6, 58.9, 49.5, 32.7. LC‐MS (ES+) m/z: 304.14 [M+H]+.
Elemental analysis Calcd. for C15H13NO2S2: C, 59.38; H, 4.32; N,
4.62; S, 21.14; Found: C, 59.48; H, 4.40; N, 4.52.
3. Results and discussion
Herein, we report a new convergent approach for the effi‐
cient and convenient synthesis of a novel series of thiazoli‐
dinone derivatives, which could be conveniently incorporated
into a wide range of different drug molecules. This type of con‐
vergent approach has several advantages over existing proce‐
dures, including using catalyst for accelerating cyclocondensa‐
tion N,N’‐dicyclohexylcarbodiimide (DCC), O‐(benzotriazol‐yl)‐
N,N,N’,N”‐tetramethyluronium hexafluoro phosphate (HBTU),
activated fly ash and the use of microwave heating. Although
several 2‐amino‐1‐phenylethanone hydrochlorides are known
in the literature, the reported syntheses of these compounds
generally require 2–3 h at room temperature and are formally
recognized as two‐step procedures [39,40]. To the best of our
knowledge, the 3‐(2‐oxo‐2‐phenylethyl)‐2‐phenylthiazolidin‐4‐
ones (4a–4m) reported in this study have not been reported
elsewhere in the literature to date.
Compounds 4a–4m were prepared from two slightly dif‐
ferent 2‐amino‐1‐phenylethanone hydrochloride salts, which
were themselves prepared from the corresponding phenacyl
chlorides according to a two‐step procedure. Thus, the De‐
lépine reaction [39] of the phenacyl chlorides with hexameth‐
ylenetetramine afforded the corresponding heximinium salts in
high yields (90%–92%), which were subsequently hydrolyzed
under acidic conditions to give the corresponding amines as the
hydrochloride salts (Scheme 1) [40]. These amine hydrochlo‐
ride salts were then treated with a series of benzaldehydes
(1a–1m) in the presence of N,N‐diisopropylethylamine
(DIPEA) to give the corresponding imines, which underwent a
cyclocondensation reaction with mercaptoacetic acid in toluene
at 110 °C to give the desired thiazolidinones 4a–4m (Scheme
2). Compound 4a was obtained in 48% yield when CH3CN was
Scheme 1. Synthesis of the substituted 2‐amino‐1‐phenylethanone
hydrochlorides 2a.
S
O
N
DIPEA
Toluene/3-4 h
R
R1
HS COOH
NH2HCl
R1
CHO
1a-1m
O
O
2a
3
R
R = H/CH3
4a-4m
Scheme 2. Synthesis of substituted 3‐(2‐oxo‐2‐phenylethyl)‐2‐phenyl‐
thiazolidin‐4‐one derivatives.
3‐(2‐Oxo‐2‐(p‐tolyl)ethyl)‐2‐(thiophen‐2‐yl)thiazolidin‐4‐

2000
Asha Vasantrao Chate et al. / Chinese Journal of Catalysis 37 (2016) 1997–2002
used as the solvent at 110 °C for 7 h (Table 1, entry 1). The
yield was improved when the reaction was performed at 110
°C for 8 h, and a moderate yield was obtained using triethyla‐
mine as a base. When the reaction time was extended to 10 h,
the yield increased to 68%. Pleasingly, the addition of DIPEA to
the reaction led to an increase in the yield of the desired prod‐
uct 4a to 75% after 3 h.
The crude products were purified by column chromatog‐
raphy over silica gel eluting with a 3:1 (v/v) mixture of petro‐
leum ether/ethyl acetate to give the pure compounds. We have
investigated these reactions in more detail. Solvent screening
indicated that toluene was still the best solvent for this reac‐
tion, and when the reaction time was extended to 4 h, the de‐
sired product was obtained in 85% yield (Table 2, entry 1).
However, lowering the DIPEA led to a decrease in yield,
whereas increasing the amount of DIPEA had the opposite ef‐
fect. We also found that when the reaction was carried out un‐
Table 1
Optimization of solvent study for the synthesis on thiazolidinone deriv‐
atives.
Entry
Solvent
CH3CN
PEG‐400
THF
Yield * (%)
1
2
3
4
5
48
52
46
85
35
Toluene
Dichloromethane
* Yields are after purification of the compounds.
der a controlled temperature, the result was improved. We
explored a variety of different solvents and reaction parame‐
ters until we obtained the desired thiazolidinones in suitably
high yields (Scheme 2, Table 1). Thiazolidinone 4a was pre‐
pared in 66% yield (56% considering both reactions) using a
stepwise sequence, and in 85% yield under tandem conditions
(Table 2, entries 1–12). We found that a tandem sequence was
Table 2
Synthesis of substituted novel 3‐(2‐oxo‐2‐phenylethyl)‐2‐phenylthiazolidin‐4‐one 4a–4m derivatives.
En‐
try
1
Time Yield * M.P. En‐
(h) (%) (°C) try
Time Yield * M.P.
Aldehyde
Amine
Product
Aldehyde
Amine
Product
(h)
3
(%) (°C)
79 168–
170
O
O
CHO
4
4
4
85 180–
182
8
.
.
NH HCl
NH2 HCl
2
H C
3
Cl
O
O
CHO
Cl
S
2
3
75 175–
177
9
3
4
82 184–
186
.
.
NH HCl
NH HCl
2
2
O
O
N
HO
H C
3
CH3
O
O
78 190– 10
192
83 174–
176
.
.
NH HCl
NH2 HCl
2
H C
3
O
O
O
S
4
5
3
4
79 265– 11
267
3
4
78 165–
167
.
.
NH2 HCl
NH2 HCl
O
O
N
S
O
S
81 240– 12
242
76 186–
188
.
.
NH2 HCl
NH HCl
2
O
O
N
S
H C
3
CH3
O
O
S
6
7
4
4
74 234– 13
236
5.5
65 170–
172
.
.
NH HCl
NH2 HCl
2
O
O
N
H C
3
CH3
O
78 189–
191
.
NH HCl
2
H C
3
* Isolated yields obtained using 2‐amino‐1‐phenylethanone hydrochloride (1.0 mmol), aldehyde (1.0 mmol), mercaptoacetic acid (3.0 mmol) and
DIPEA (3.0 mmol) in toluene at 110 °C.

Asha Vasantrao Chate et al. / Chinese Journal of Catalysis 37 (2016) 1997–2002
2001
Acknowledgments
OH
R
N
R
N
H
Cl
NH2
NH2HCl
H
O
O
O
R1
This work was supported by Special Assistance Programme
SAP, University Grants Commission, New Delhi, India, intended
to encourage the pursuit of excellence and teamwork in ad‐
vanced teaching and research to accelerate the realization of
international standards in specific fields, and also Sophisticated
Analytical Instrumentation Facility, Chandigarh, for providing
characterization facility for this work.
H
NH
R1
R
H
N
N
O
H
H2O
R
HO
R
N
N
R1
N
H
O
-H2O
O
R1
H
O
OH2
O
N
O
O
O
HS
S
N
OH
S
R
R
R
R1
N
R1
R1
References
O
Scheme 3. Plausible mechanism for the synthesis of 3‐(2‐oxo‐2‐phe‐
nylethyl)‐2‐phenylthiazolidin‐4‐one derivatives.
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more efficient than a stepwise conversion under thermal con‐
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reaction proceeds by the initial nucleophilic attack of the sulfur
atom of the mercaptoacetic acid to the carbon atom of the
imine group, followed by an intramolecular cyclization, result‐
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Under optimized conditions (Table 1, entry 4), we converted
a wide range of aromatic and heterocyclic aldehydes (1a–1m)
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crystallization and their structures were confirmed by 1H NMR,
13C NMR, mass spectrometry and elemental analyses.
A plausible mechanism for the formation of 3‐(2‐oxo‐2‐
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DIPEA is shown in Scheme 3. 2‐Amino‐1‐phenylethanone hy‐
drochloride would initially react with DIPEA to give the corre‐
sponding free amine, which would react with the activated
carbonyl group of the aldehyde (activated by the DIPEA·HCl
salt) to give the corresponding imine. Nucleophilic attack at the
imine carbon by the sulfur atom of mercaptoacetic acid, fol‐
lowed by the cyclocondensation of the nitrogen atom of the
imine into the carboxylic acid group would give the desired
3‐(2‐oxo‐2‐phenylethyl)‐2‐phenylthiazolidin‐4‐one.
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2002
Asha Vasantrao Chate et al. / Chinese Journal of Catalysis 37 (2016) 1997–2002
Graphical Abstract
Chin. J. Catal., 2016, 37: 1997–2002 doi: 10.1016/S1872‐2067(16)62536‐6
Efficient approach to thiazolidinones via a one‐pot three‐component reaction involving 2‐amino‐1‐phenylethanone
hydrochloride, aldehyde and mercaptoacetic acid
Asha Vasantrao Chate, Akash Gitaram Tathe, Prajyot Jayadev Nagtilak, Sunil M. Sangle, Charansingh H. Gill*
Dr. Babasaheb Ambedkar Marathwada University, India; Rajaram College, India
We report the design and synthesis of a novel series of the thiazolidinone derivatives 4a–4m under thermal conditions via the
three‐component reaction of 2‐amino‐1‐phenylethanone hydrochloride with an aldehyde and mercaptoacetic acid in the presence of
DIPEA using toluene as a solvent.
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