Polyethylene glycol mediated one-pot three-component synthesis of new 4-thiazolidinones

Article abstract of DOI:10.1002/hc.20766

An efficient one-pot three-component cyclocondensation of 4-(p-toulyl sulfonoxy) benzaldehyde, aryl amines, and mercaptoacetic acid in polyethylene glycol 400 (PEG-400) was conducted to obtain new 2,3-disubstituted-4- thiazolidinones. This route is econom

Full text of DOI:10.1002/hc.20766

Heteroatom Chemistry
Volume 23, Number 2, 2012
Polyethylene Glycol Mediated One-Pot
Three-Component Synthesis of New
4-Thiazolidinones
Manisha R. Bhosle, Jyotirling R. Mali, Aparna A. Mulay,
and Ramrao A. Mane
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad 431 004, India
Received 13 July 2011; revised 11 October 2011
nones with toluene sulfonoxy phenyl and aryl/heteryl
moieties.
Keeping the significance of 4-thiazolidinones
and sulfonoxy bioisosteres in mind, it was planned
to synthesize new 4-thiazolidinones with the above-
referred pharmacophoric systems by providing an
efficient/convenient synthetic protocol.
ABSTRACT: An efficient one-pot three-component
cyclocondensation of 4-(p-toulyl sulfonoxy) ben-
zaldehyde, aryl amines, and mercaptoacetic acid in
polyethylene glycol 400 (PEG-400) was conducted
to obtain new 2,3-disubstituted-4-thiazolidinones.
ꢀ
C
This route is economical and ecofriendly.
2011 Wi-
ley Periodicals, Inc. Heteroatom Chem 23:166–170, 2012;
View this article online at wileyonlinelibrary.com. DOI
10.1002/hc.20766
Several synthetic methods are reported to pre-
pare 4-thiazolidinones. The two widely used meth-
ods are cyclocondensation of thioureas with α-
halo acid derivatives [14] and cyclocondensation
of azomethines (Schiff bases) with mercaptoacetic
acid [15] or its derivatives. The first method
has been widely used to obtain 2-imino thiazo-
lidinones, whereas 2,3-disubstituted value-added
4-thiazolidinones have been synthesized by using the
second method. Attempts are also being made to ac-
celerate the rate of the cyclocondensation of Schiff’s
bases and mercaptoacetic acid and to conduct the
reactions using volatile aprotic organic solvents and
catalysts/dececants such as anhydrous ZnCl2[16],
sodium sulfate [17], KSF montmorillonite [18], N,Nꢁ-
dicyclohexylcarbodiimide [19], activated fly ash [20],
and ionic liquid, [bmim][PF6] [21]. Solvent-free syn-
thesis has also been reported for 4-thiazolidinones
[22].
INTRODUCTION
Thiazolidinone and its derivatives are an important
class of heterocyclic compounds. They have a wide
range of biological and pharmacological activities
[1], such as antiinflammatory [2], anti-HIV [3], anti-
cancer [4], antimalarial [5], antitubercular [6], anti-
convulsant [7], antibacterial [8], and antiarrythmic
[9]. Moreover, agents bearing sulfonyl moieties have
also been found to display diverse therapeutic activi-
ties, such as hypoglycemia [10], anticancer [11], and
antiinflammation [12].
The literature reveals that 4-thiazolidinones with
heteryl derivatives/moieties have shown potential
biodynamic activity [13]. It has also been observed
that there is scanty information on the thiazolidi-
However, these reported methods still have
one or more limitations such as requiring haz-
ardous solvents, expensive catalysts, prolonged heat-
ing or tedious workup procedures. In our group,
Lingampalle et al. [23], Mali et al. [15], and Pratap
Correspondence to: Ramrao A. Mane; e-mail: manera2011@
gmail.com.
c
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2011 Wiley Periodicals, Inc.
166

Polyethylene Glycol Mediated One-Pot Three-Component Synthesis of New 4-Thiazolidinones 167
et al. [24] have also tried to provide convenient syn-
In the initial optimization studies, the synthesis
of 4-thiazolidinones was conducted in two steps. In
first step, intermediate azomethine was prepared by
condensing 4-(p-toulylsulfonoxy) benzaldehyde (1)
and 4-chloroaniline (2a) in ethanol as a model re-
action. Subsequently, the azomethine was cyclocon-
densed in the second step with mercaptoacetic acid
in toluene/benzene/THF under reflux for more than
4 h and less than 50% yield of titled 4-[3-(chloro)-
4-oxothiazolidin-2-yl] phenyl-4-methyl benzene sul-
fonate (4a) was obtained. It was noticed that none of
the approaches was convenient to afford the desired
4-thiazolidinones with high yields.
thetic routes for value-added 4-thiazolidinones using
ionic liquid, heterogeneous catalysts such as silica
chloride, and biocatalyst baker’s yeast, respectively.
These routes have certain advantages along with few
limitations. To circumvent these difficulties and to
speed up the synthesis, we focused on developing an
alternate route for the synthesis of 4-thiazolidinones.
The use of environment-friendly catalysts and
solvents in organic and medicinal chemistry is an
area of considerable importance. From both an eco-
nomical and environmental point of view, the use
of nonvolatile solvents and green catalysts enhances
various value-added organic transformations [25].
In this connection, polyethylene glycols (PEGs)
have attracted much attention with organic chemists
as a result of their inexpensive, ecofriendly nature,
high thermal stability, biodegradability, and the abil-
ity to act as phase transfer catalysts [26]. PEGs are
widely used as a medium and catalysts for carry-
ing out various organic transformations [27] such as
Heck, asymmetric dihydroxylation, Baylis–Hillman,
Biginelli, Stille cross coupling, Wacker, and asym-
metric Aldol reactions.
Considering the synthetic utilities of PEG-400
as a green reaction catalyst and a safe medium, it
was therefore considered worthwhile to use PEG-
400 to carry out the cyclocondensation, leading to
the desired 4-thiazolidinones.
Using these results, an effort was made to
carry out the cyclocondensation in PEG-400
in two steps, leading to more knowledge about
4-thiazolidinones. In the first step, anisaldehyde
and 4-chloroaniline (2a) were condensed in PEG-400
at room temperature for 15 min and azomethine
with 92% yield was obtained. Then, the cyclo-
condensation of the azomethine was carried out
with mercaptoacetic acid in PEG-400 at 50◦ C
for 2 h. It was noticed that this gave 69% yield of the
3-(4-chlorophenyl)-2-(4-methoxyphenyl)thiazolidin-
4-one (a reported molecule) [28]. From the above
results, it was confirmed that PEG-400 promotes
the formation of the intermediate, azomethine, as
well as the subsequent cyclization of azomethine
and mercaptoacetic acid, leading to the desired
4-thiazolidinone.
Considering the above-mentioned significance
of PEGs and 4-thiazolidinones and in continua-
tion of our earlier endeavors [15,23,24] toward the
development of ecofriendly synthetic routes for 4-
thiazolidinones, it was thought worthwhile to de-
velop a facile, greener, and expeditious synthetic
route for new 2,3-disubstituted 4-thiazolidinones.
RESULTS AND DISCUSSION
In this article, we report the synthesis of
known and some new 4-thiazolidinones. The
one-pot three-component cyclocondensation of
4-(p-toulylsulfonoxy) benzaldehyde (1), aryl/heteryl
amines (2a–j), and mercaptoacetic acid (3) in
PEG-400 was performed to obtain the titled
4-thiazolidinones (4a–j) (Scheme 1).
Next, we synthesized 4-thiazolidinones in one
pot. The one-pot three-component cycloconden-
sation of anisaldehyde, 4-chloroaniline (2a), and
mercaptoacetic acid was carried out to obtain 4-
thiazolidinone at 50◦C. It was observed that the re-
action has smoothly produced 3-(4-chlorophenyl)-2-
(4-methoxyphenyl)thiazolidin-4-one with 78% yield.
S
O
O
N
R
O
NH2
O
R
PEG-400
50oC, 2 h
OH
O2S
O
SH
O2S
3
1
2a–j
4a–j
SCHEME 1 Synthesis of 4-[3-(substituted)-4-oxothiazolidin-2-yl]phenyl-4-methyl benzene sulfonates.
Heteroatom Chemistry DOI 10.1002/hc

168 Bhosle et al.
TABLE 1 Screening of Reaction Medium for the Synthesis
of Compound 4aa
TABLE 2 Synthesis of 4-[3-(Substituted)-4-oxothiazolidin-2-
yl]phenyl-4-methyl Benzene Sulfonatesa
Entry
PEG-400
Isolated Yields (%)
Yield Melting
Entry
R
Product (%)b Point ( ◦C)
1
2
3
4
5
6
7
8
9
0·2 mL
0·4 mL
76
79
80
84
89
87
86
61
59
1
2
3
4
5
6
7
8
9
p-Cl C6H4
C6H5
p-F C6H4
4a
4b
4c
4d
4e
4f
89 177–179
82 122–123
79 154–156
85 118–120
87 183–184
92 139–140
74 190–192
69 150–152
58 162–163
65 167–169
0·6 mL
0·8 mL
1·0 mL
p-CH3C6H4
1·2 mL
p-OCH3 C6H4
p-OCH2CH3 C6H4
p-NO2 C6H4
1·4 mL
Ionic liquid (1 mL)
Deep eutectic solvent (1 mL)
4g
4h
4i
2-Pyridinyl
5-p-Tolylthiazole
4-(4-Chlorophenyl)thiazole
aAll the reactions were carried out at 50◦C for 2 h.
10
4j
aReaction conditions: Aldehyde (2 mmol), amine (2 mmol), and mer-
captoacetic acid (2 mmol) in PEG-400 (1 mL) stirred for 2 h at 50◦C.
bIsolated yields.
To study the effect of the solvent on the model re-
action, the environmentally acceptable media such
as ionic liquid and deep eutectic solvents (choline
chloride:urea) were used. It was noticed that in these
media this cyclocondensation was accomplished af-
ter prolonged reaction time and gave moderate
yields of the product.
All the efforts confirmed that PEG-400 has the
potential to act as a safe medium and catalyst while
performing the one-pot cyclocondensation of alde-
hydes, amines, and mercaptoacetic acid, leading
to 4-thiazolidinones. Prompted by these observa-
tions, we used PEG-400 to conduct the one-pot cy-
clocondensation of 4-(p-toulylsulfonoxy) benzalde-
hyde (1), 4-chloroaniline (2a), and mercaptoacetic
acid (3) and obtained better yields of the desired
4-thiazolidinone (4a) within 2 h at 50◦C.
site free hydroxyl groups and ethereal oxygen link-
ages. These hydroxyl groups via hydrogen bonding
with carbonyl oxygen of aldehydes might increase
the electrophilic character of carbonyl carbon of
aldehyde, thereby accelerating the rate of addition
of amines on aldehydes, generating intermediate
azomethines. Ethereal oxygen linkages might be re-
sponsible for enhancing nucleophilicity of the mer-
capto group of mercaptoacetic acid, resulting in its
facile addition on the imino intermediates (azome-
thines), generated in situ. These factors might be re-
sponsible for acceleration of the cyclocondensation.
To optimize the quantity of PEG-400, various at-
tempts were made to use different amounts of PEG-
400, i.e., 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, and 1.4 mL for
2 mmol of the substrates (Table 1), and the best
results were achieved when 1 mL of PEG-400 was
employed for the model reaction (Table 1, entry 5).
The reaction was completed within 2 h, yielding 89%
of 4-thiazolidinone (4a). When we used PEG-400 in
an amount more than 1 mL for 2 mmol of the sub-
strate, there was no improvement in the yield of the
product.
CONCLUSION
In summary, the use of PEG-400 to promote the one-
pot cyclocondensation of aldehydes, amines, and
mercaptoacetic acid to obtain 4-thiazolidinones has
been well explored for the first time. The devel-
oped synthetic route is simple, ecofriendly, and high
yielding.
EXPERIMENTAL
For further optimization, PEG-400 was used in
combination with various solvents. However, the use
of solvents in combination with PEG-400 for the re-
action failed to improve the product yields and the
rate of the reaction. One milliliter of PEG-400 for
2 mmol of the substrates was found to promote the
reaction without need for any additional catalysts/
solvents. Using these optimized conditions, the other
4-thiazolidinenones (4a–j) were synthesized and re-
sults are presented in Table 2.
The chemicals used were of laboratory grade. Melt-
ing points of all the synthesized compounds were
determined in open capillary tubes and are uncor-
1
rected. H NMR spectra were recorded on a Var-
ian USA 400 MHz NMR spectrometer in CDCl3 us-
ing tetramethylsilane (TMS) as an internal standard
and chemical shift in δ (in ppm). Mass spectra were
recorded on a Sciex model API 3000 LCMS/MS in-
strument. The purity of each compound was checked
by thin layer chromatography (TLC) using silica-gel,
60F254 aluminum sheets as an adsorbent, and vi-
sualization was accomplished by iodine/ultraviolet
The success of PEG-400 could be due to the
following reasons: PEG-400 possesses two active
Heteroatom Chemistry DOI 10.1002/hc

Polyethylene Glycol Mediated One-Pot Three-Component Synthesis of New 4-Thiazolidinones 169
Compound 4h. 1H NMR (400 MHz, CHCl3,
δ ppm): 2.42 (d, 3H, J = 8.23 Hz), 3.77 (d, 1H,
J = 10.2 Hz), 3.94 (d, 1H, J = 10.2 Hz), 6.4 (s, 1H,
methine), 6.87 (d, 2H, J = 7.8 Hz), 7.24–7.36 (m, 4H),
7.61 (d, 2H, J = 7.2 Hz), 7.68 (d, 2H, J = 7.9 Hz),
8.02 (d, 1H, J = 7.8 Hz), and 8.18 (d, 1H, J = 7.8
Hz). MS (m/z): 427 (M+).
light. 4-(p-Toulylsulfonoxy) benzaldehyde (1) was
synthesized by using the procedure discussed in the
literature[29].
General Procedure for the Synthesis of
4-[3-(Substituted)-4-oxothiazolidin-2-yl]
phenyl-4-methyl Benzene Sulfonates(4a–j)
Compound 4i. 1H NMR (400 MHz, CDCl3,
δ ppm): 2.26 (s, 6H), 3.80 (d, 1H, J = 10.0 Hz), 4.04
(d, 1H, J = 10.0 Hz), 5.91 (s, 1H), 6.80 (s, 1H, me-
thine), 7.08 (d, 2H, J = 8.5 Hz), 7.22 (d, 2H, J = 8.5
Hz), 7.25 (m, 6H), and 7.61 (d, 2H, J = 7.9 Hz). MS
(m/z): 522 (M+).
A mixture of 4-(p-toulylsulfonoxy) benzaldehyde (1)
(2 mmol), aryl/heteryl amines (2a–j) (2 mmol), and
mercaptoacetic acid (3) (2–3 mmol) in PEG-400
(1 mL) was stirred at 50◦C. The progress of the re-
action was monitored by TLC using ethyl acetate:
hexane (3:7) as solvent. After 2 h of stirring, the re-
action mass was poured onto cold water, washed
with NaHCO3, and extracted with ethyl acetate
(2 × 50 mL). Ethyl acetate was removed under
reduced pressure, and the obtained crude prod-
ucts were crystallized from ethanol. The physical
characterization of compounds 4a–j is presented in
Table 2, and their synthesis route is shown in
Scheme 1.
Compound 4j. 1H NMR (400 MHz, CDCl3,
δ ppm): 2.35 (s, 3H), 3.77 (d, 1H, J = 10.1 Hz), 4.01
(d, 1H, J = 10.1 Hz), 5.74 (s, 1H,), 6.45 (s, 1H, me-
thine), 6.89 (d, 2H, J = 7.2 Hz), 7.14 (d, 2H, J =
7.9 Hz), 7.19 (m, 6H), and 7.60 (d, 2H, J = 7.9 Hz).
MS (m/z): 543 (M+).
ACKNOWLEDGMENT
Spectral Data of a Few Representative
Thiazolidin-4-ones
The authors are thankful to Professor D. B. Ingle for
his invaluable discussion and guidance.
Compound 1. 1H NMR (400 MHz, CDCl3,
δ ppm): 2.45 (s, 3H), 7.18 (d, 2H, J = 7.89 Hz), 7.33
(d, 2H, J = 7.89 Hz), 7.82(d, 2H, J = 7.88 Hz), 7.84
(d, 2H, J = 7.89 Hz), and 9.96 (s, 1H). MS (m/z): 276
(M+).
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