Silica chloride (SiO2-Cl) catalyzed one pot synthesis of 2,3-disubstituted-thiazolidin-4-one

Article abstract of DOI:10.1080/00397911.2020.1741641

In this paper, we report one-pot, three-component cyclo condensation of an aldehyde, an amine and thioglycolic acid to form 2,3-disubstituted-thiazolidin-4-one by using supported protic acid (Silica Chloride: SiO₂-Cl) catalyst. The catalyst SiO₂-Cl is compatible with a variety of aldehydes (aryl/heteroaryl) and the aromatic amines affording 2,3-disubstituted-thiazolidin-4-one analogs in 72–89% yields. Moreover, the supported catalyst was recycled several times without significant loss of catalytical activity.

Full text of DOI:10.1080/00397911.2020.1741641

Synthetic Communications
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Silica chloride (SiO2-Cl) catalyzed one pot synthesis
of 2,3-disubstituted-thiazolidin-4-one
Kunal M. Gokhale & Vikas N. Telvekar
To cite this article: Kunal M. Gokhale & Vikas N. Telvekar (2020): Silica chloride (SiO2-Cl)
catalyzed one pot synthesis of 2,3-disubstituted-thiazolidin-4-one, Synthetic Communications, DOI:
10.1080/00397911.2020.1741641
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https://doi.org/10.1080/00397911.2020.1741641
Silica chloride (SiO2-Cl) catalyzed one pot synthesis of
2,3-disubstituted-thiazolidin-4-one
Kunal M. Gokhale and Vikas N. Telvekar
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology,
Mumbai, India
ABSTRACT
ARTICLE HISTORY
Received 17 January 2020
In this paper, we report one-pot, three-component cyclo condensa-
tion of an aldehyde, an amine and thioglycolic acid to form 2,3-
disubstituted-thiazolidin-4-one by using supported protic acid (Silica
Chloride: SiO2-Cl) catalyst. The catalyst SiO2-Cl is compatible with a
variety of aldehydes (aryl/heteroaryl) and the aromatic amines afford-
ing 2,3-disubstituted-thiazolidin-4-one analogs in 72–89% yields.
Moreover, the supported catalyst was recycled several times without
significant loss of catalytical activity
KEYWORDS
Cyclocondensation; 2,3-
disubstituted-thiazolidin-4-
one; one-pot reaction;
recycle; supported SiO2-Cl
catalyst; three-component
GRAPHICAL ABSTRACT
O
NH2
O
SiO2-Cl
N
X
o
HS
COOH
PhMe, 100 C
S
R
H
X
R
One pot three-component
Cyclocondensation
Recyclable catalyst
operationally simple
X= electron donating/
electron withdrawing
groups
R= Aryl/
heteroaryl
Introduction
Chemically functionalized thiazolidinones are the most extensively studied class of com-
pounds with a wide range of biological activities.[1] 4-Thiazolidinones are considered as
privileged pharmacophores with vibrant activities like antibacterial, antiviral, anticancer,
anticonvulsant, anti-inflammatory.[2–6] Numerous reports highlighting 4-thiazoliodi-
nones as a precursor for the synthesis of different pharmaceutically important substan-
ces like monohalogenated b-lactam, a polymethine cyanine dye, and pyrazolothiazole
derivative are available.[7–9] Consequently, there has been continuous interest in the
development of new synthetic protocols for the construction of thiazolidin-4-one.
General methods employ reaction between aldehyde, amine and thioglycolic acid or a
two-step condensation involving imine synthesis and treatment of imine with thiogly-
colic acid. It was proposed that the reaction may proceed either via-imine formation
followed by an attack of sulfur atom of thioglycolic acid on imine carbon involving
CONTACT Vikas N. Telvekar
vikastelvekar@rediffmail.com
Department of Pharmaceutical Sciences and
Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai 400019, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
K. M. GOKHALE AND V. N. TELVEKAR
intermolecular cyclization and expulsion of water or via-initial condensation of the
amine and thioacid to form amide followed by condensation and cyclization with an
aldehyde. The drawback of these methods is they require an efficient water removable
system/dehydrating agent to forward the reaction.[10–13] Protocols in presence of Lewis
acid like anhydrous ZnCl2[14,15], solid acid catalyst, activated fly ash by using sealed ves-
sels were also available.[16–17] An alternative greener method making the use of the
microwave for the synthesis of thiazolidinone with improved yield was also reported.[18]
However, most of these methods suffer from disadvantages such as the use of special
apparatus/reactor, use of the stoichiometric amount of hazardous catalyst, auxiliary sub-
stances, condensing agents, harsh reaction conditions, the formation of toxic byproducts,
tedious workup procedures, an inert, anhydrous atmosphere and long reaction time.
In recent years, the use of the immobilized or supported acid catalyst in a chemical
reaction is receiving much attention due to ease of preparation, recyclability, high util-
ization efficiency, and less toxicity. Silica Chloride (SiO2-Cl) is one such good solid acid
catalyst in terms of convenience, easy preparation and insolubility in organic solvents. It
is also considered as an excellent in-situ proton generating agent known for accepting a
wide variety of nucleophiles.[19] Homogenous catalysts are often destroyed during isola-
tion of the product. Also, these “single-use” catalyst utilization leads to high manufac-
turing costs. SiO2-Cl decreases the production of toxic wastes, at the same time it can
act as lewis acid center on silica, this increases the selectivity with respect to desired
product formation.[20] SiO2-Cl also has high thermal and mechanical stability offering
substituted-3,4-dihydropyrimidinone synthesis, facile tosylation of alcohol, C–C bond
formation, pyrano or furanoquinoline synthesis.[20–23] Ring expansion chlorination of
1,3-dithiolane and 1,3-dithianes with SiO2-Cl as catalyst was also reported.[24] Most
interestingly, SiO2-Cl works better in water as solvent giving higher yields of 2,3-dihy-
droquinazoline-4(1H)-one compounds.[25] Synthesis of 3-hydroxy-1H-indazole in pres-
ence of SiO2-Cl and ultrasound is also high yielding.[26]
Thus, convenient, versatile, high yielding SiO2-Cl attracted us in the search for
improved methods for synthesis of title compounds. The multicomponent, one-pot
strategy was under consideration instead of stepwise imine formation, and condensation
of the preformed imine with thioglycolic acid as to avoid purification procedures.
Keeping mechanism in mind, SiO2-Cl having strong electrophilic activation potential
was considered as an ideal reagent for our novel, one-pot, multicomponent protocol for
the synthesis of 2,3-disubstituted-thaizolidin-4-one. We have used a wide variety of
aldehydes, amines with thioglycolic acid.
Result and discussion
The model reaction (Scheme 1) involving an equimolar mixture of benzaldehyde 1a,
aniline 2a and thioglycolic acid 3 was carried out in toluene at 100 ꢀC with and without
SiO2-Cl. It was noticed that in the presence of SiO2-Cl expected product 4a affords in
significant yield, whereas no product was obtained in the absence of SiO2-Cl.
Considering the basic fact that as the surface area available for the reaction increases reac-
tion rate also increases; the activity of reagent adsorbed on solid support will also get
improved due to an increase in the effective surface area of the reagent. In the literature, it

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SYNTHETIC COMMUNICATIONSV
3
S
CHO
NH2
N
O
SiO2-Cl
Toluene, 100oC
HS
COOH
3
2a
1a
4a
Scheme 1. Synthesis of 2,3-diphenyl-thiazolidine-4-one 4a using silica chloride (SiO2-Cl).
Table 1. Effect of surface area of silica supported SiO2-Cl on synthesis of 2,3-
diphenyl-thiazolidine-4-one (4a)a.
Entry
Mesh size of silica gel supported with SiO2-Cl
Yieldb
1
2
3
4
230–400
100–120
60–120
SiO2
82
75
72
No yield
aReaction conditions: 1 mmol of benzaldehyde (1a), 1 mmol of aniline (2a), 1 mmol of thiogly-
colic acid (3) in presence of 1 mmol of SiO2-Cl immobilized on silica gel of different mesh
size heated in toluene (10 ml) at 100 ꢀC for 3 h.
bIsolated yield of 4a.
Table 2. Optimization of 2,3-diphenyl-thiazolidine-4-one (4a)a.
Entry
Amount of SiO2-Clb
Solvent
Time (h)
Temp (ꢀC)
Yieldc (%)
1
2
3
4
5
6
7
8
0.5
1.0
2.0
2.5
2.5
4.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Benzene
1,4-Dioxane
THF
3
3
3
2
3
3
4
3
3
3
3
3
3
3
100
100
100
100
100
100
100
80
110
100
100
Reflux
100
Reflux
30
50
62
63
82
84
84
75
82
79
80
14
23
42
9
10
11
12
13
14
DMF
Ethanol
aReaction conditions: 1 mmol of benzaldehyde (1a), 1 mmol of aniline (2a), 1 mmol of thioglycolic acid (3) in presence
of various solvents (10 ml) heated at different temperatures for the indicated time period.
bThe molar equivalents of SiO2-Cl used with respect to aldehyde 1.
cIsolated yield.
was reported that silica chloride (SiO2-Cl) was prepared by using silica gel and thionyl chlor-
ide.[27] For our experiment, we prepared varieties of silica gel with mesh size 230–400,
100–120, 60–120 by using the reported procedure. The model reaction to yield 4a was fur-
ther carried out using SiO2-Cl of different mesh size and results were incorporated in
Table 1. Silica gel with mesh size 230–400 was found suitable for our reaction (Table 1,
entry 1).
To derive the optimal reaction parameters such as the amount of SiO2-Cl required,
time, temperature, and influence of solvent for the synthesis of substituted thiazolidin-
4-one formation; the model reaction was performed using different variations of these
parameters and results are incorporated in Table 2. The use of 2.5 mol% of SiO2-Cl

4
K. M. GOKHALE AND V. N. TELVEKAR
afforded 4a in 82% yield (Table 2, entry 5). The influence of the solvent was also eval-
uated for the model reaction. The reaction was performed using hydrocarbon, halogen-
ated hydrocarbon, ethereal, protic polar and aprotic polar solvents in the presence of
SiO2-Cl. The best results were obtained in toluene (82%, Table 2, entry 5), benzene
(79%, Table 2, entry 10) and 1,4-dioxane (80%, Table 2, entry 11). Based on Pfizer solv-
ent selection guidelines,[28] toluene was preferred over benzene and 1,4-dioxane for fur-
ther reaction. The use of azeotropic distillation using the Dean–Stark apparatus was also
evaluated, and it was found that removal of the calculated amount of water using the
Dean–Stark apparatus is utmost necessary as the reaction carried out without using
azeotropic distillation assembly failed to offer a significant yield of 4a.
The optimum reaction temperature was found to be 100 ꢀC as an increase in tem-
perature to 110 ꢀC did not offer a high yield of 4a (Table 2, entry 9). The yield
decreases to 75% when the reaction was performed at 80 ꢀC (Table 2, entry 8).
The optimized reaction conditions were used to synthesize varieties of 2,3-disubsti-
tuted-thaizolidin-4-one derivatives and the results are summarized in Table 3.
It was observed that SiO2-Cl is an excellent catalyst in synthesizing substituted thaizo-
lidin-4-one. The formation of thaizolidinone was influenced by the electronic nature of
the substituent on aromatic aldehyde and the amine. Almost all electron-withdrawing
and donating substituted aromatic aldehydes and aromatic amines are suitable for this
reaction and converted into the desired product in satisfactory yields (4a–4h). For this
reaction, heteroaromatic substituted aldehydes are good substrates and gave a good yield
of the corresponding disubstituted thiazolidinone (4i–4k).
Recyclability is one of the ideal characteristics of the heterogeneous catalyst; therefore,
the recyclability of the catalyst was tested using benzaldehyde, aniline and thioglycolic
acid as substrate. After completion of the reaction, the mixture was filtered and the
catalyst was separated and washed with EtOAc (3 ꢁ 20 ml). The recovered catalyst was
dried and activated by heating at 80 ꢀC for 24 h. and used for the next reaction. It was
observed that SiO2-Cl was active even after 5 recycles (Fig. 1).
Conclusion
A convenient protocol for the synthesis of 2,3-disubstituted-thiazolidin-4-one analogs
has been developed under one-pot, three-component SiO2-Cl catalyzed cyclo condensa-
tion involving a variety of aldehydes, amines, and thioglycolic acid. In conclusion, we
have shown the potential of SiO2-Cl for synthesizing thiazolidine-4-one with good to
excellent yields. The new catalytic method offers distinct advantages such as one-pot,
three-component synthesis with broad substrate scope, high yield, less reaction time,
ease of product isolation, and ease of catalyst preparation, recovery, reusability without
loss of catalytic potential.
Experimental
General procedure for preparation of silica chloride
10 g of silica gel (Mesh size 230–400) placed in 250 ml round bottom flask was refluxed
with thionyl chloride (40 ml) for 2 h[27]. The reaction was quenched by the addition of

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5
Table 3. SiO2-Cl catalyzed synthesis of 2,3-disubstituted-thiazolidin-4-one analoguesa.
S
CHO
NH2
R1
COOH
N
SiO2-Cl
O
Toluene, 100 o
C
SH
R1
R2
4a-4k
3
1a-1k
2a-2k
R2
S
N
S
N
S
O2N
Cl
N
O
O
O
4a; 82%
4b; 86%
4c; 89%
S
S
N
S
N
H3CO
H3C
N
O
O
O
4d; 75%
4e; 78%
4f; 83%
Cl
S
N
S
N
S
N
O
O
O
O
4g; 73%
O2N
4h; 84%
H3CO
4i; 73%
S
N
S
N
S
O
N
O
4j; 77%
4k; 73%
aReaction conditions: 1 mmol of aromatic aldehyde, 1 mmol of aromatic amine, 1 mmol of thioglycolic
acid and SiO2-Cl (2.5 mol%) stirred in 10 ml of toluene at 100 ꢀC for 3 h.
bIsolated yield.

6
K. M. GOKHALE AND V. N. TELVEKAR
83
82
81
80
79
% Yield
78
77
76
75
74
1
2
3
4
5
Recycle turns
Figure 1. Recycle study of SiO2-Cl.
toluene (50 ml) and unreacted thionyl chloride was removed by vacuum distillation. The
resulting grayish-white powder was flame dried and stored in sealed glass vial without
loss of activity.
General procedure for the synthesis of 2,3-disubstituted-thiazolidin-4-one (4a–4k)
To a magnetically stirred mixture of aromatic aldehyde 1a–1k (1 equiv.), aromatic
amine 2a–2k (1 equiv.) and thioglycolic acid 3 (1 equiv.) in toluene (10 ml) 2.5 mol %
of SiO2-Cl was added. The reaction mixture was heated at 100 ꢀC using Dean–Stark
apparatus. The reaction was continued till water ceased to separate and the progress of
the reaction was monitored by TLC. After the completion of the reaction, the reaction
mixture was filtered to separate the catalyst. The filtrate was evaporated under reduced
pressure to get the crude product. The crude product thus obtained was washed with
sodium bicarbonate, sodium bisulfite solution, water and finally dried to get the
pure product.
General procedure for recyclability of catalyst
The catalyst which was separated from the reaction mixture was washed with ethyl acet-
ate and dried under the reduced pressure to evaporate traces of solvent. It was further
activated by heating at 80 ꢀC for 24 h. and used for the next reaction.
2,3-diphenyl-thiazolidin-4 one (4a):[10,29] White solid; mp 130–131 ꢀC (lit.
1
131–132 ꢀC), H NMR (400 MHz, CDCl3) d (ppm): 7.21–7.01 (m, J ¼ 5.84 Hz, 10H),
6.05 (s, 1H), 3.91–3.86 (d, J ¼ 15.8 Hz, 1H), 3.78–3.74 (d, J ¼ 15.8 Hz, 1H); 13C NMR
(400 MHz, CDCl3) d (ppm): 171.08, 139.55, 137.54, 129.12, 128.93, 129.91, 127.08,
126.96, 125. 63, 65.62, 33.51.
The supporting material contains the spectral characterization data. This material can
be found via the “Supplementary Content” section of this article’s webpage.
Acknowledgment
1
Authors would like to thank SAIF, Panjab University for recording H and 13C NMR.

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