Silica gel promoted environment-friendly synthesis of 2,3-disubstituted 4-thiazolidinones

Article abstract of DOI:10.1016/j.tetlet.2014.03.007

Three-component one pot silica gel promoted synthesis of 2,3-disubstituted 4-thiazolidinones is described. The method provides rapid and easy access to thiazolidinone compounds in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.03.007

Tetrahedron Letters 55 (2014) 2463–2466
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Silica gel promoted environment-friendly synthesis of
2,3-disubstituted 4-thiazolidinones
⇑
Manoj P. Thakare, Puneet Kumar, Naresh Kumar, Sushil K. Pandey
Jubilant Chemsys Limited, B-34, Sector-58, Noida 201301, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Three-component one pot silica gel promoted synthesis of 2,3-disubstituted 4-thiazolidinones is
Received 9 January 2014
Revised 27 February 2014
Accepted 1 March 2014
Available online 10 March 2014
described. The method provides rapid and easy access to thiazolidinone compounds in good to excellent
yields.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
4-Thiazolidinones
Silica gel
Environment friendly
Three component synthesis
Thiazolidinones are extensively investigated compounds in the
recent years and have fascinated organic and medicinal chemists.
Thiazolidinones have emerged as an important class of compound
because of their biological importance and have shown interesting
biological activity profiles such as antibacterial,1 anticancer,2 anti-
tubercular,3 antioxidant,4 anti-inflammatory,5 COX-1 inhibitor,6
anti HIV,7 and anti-histaminic8 agents. Figure 1 shows a few
important compounds having thiazolidinones moieties.
O
O
N
S
N
O
N
S
S
N
O
A
B
Several methods have been described in the literature for the
synthesis of thiazolidinones which include one pot three- compo-
nent condensation of amine, carbonyl compound, and thioglycolic
acid or two-step synthesis.9 The three-component condensation
involves loss of water in the final step which is critical to obtain
in high yields of thiazolidinones. Different desiccants have been
used to affect the dehydration such as molecular sieves,10 trimeth-
ylorthoformate,11 sodium sulfate,12 ZnCl2,13 and azeotropic distil-
lation with benzene or toluene.14 The most recently used
methods for the synthesis of thiazolidinones include DCC,15 Sac-
Histamin antagonist
Antiinflammatory
O
O
S
O
N
N
S
N
Cl
Cl
O
C
D
19
charomyces cerevisiae,16 HBTU,17 [bmim][PF6],18 Bi(SCH2COOH)3,
CO2Et
COX-1 inhibitor
Anti HIV-I
and silica chloride.20 However, the use of these reagents has some
limitations such as high temperature, longer reaction time, corro-
sive, expensive, hazardous reaction condition, and purification is-
sues due to the formation of by-products. Therefore, it is desired
to develop a new method which can eliminate these difficulties.
There is always a need for greener alternative to any reaction
where formation of by-products can be avoided by using reagents
Figure 1. Some biologically important thiazolidinone compounds.
which are non-reactive in the reaction medium and are easily sep-
arable from the product. Silica gel is one such green alternative as
it is insoluble in most organic solvents and no by-product is formed
when used in reactions. Silica gel has been used as a reagent or
promoter for the synthesis21–24 because it is easily available, non-
toxic, cheap, and can be separated easily from the product. While
⇑
Corresponding author. Tel.: +91 1204093340.
E-mail address: sushilkumar1975@gmail.com (S.K. Pandey).
http://dx.doi.org/10.1016/j.tetlet.2014.03.007
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2464
M. P. Thakare et al. / Tetrahedron Letters 55 (2014) 2463–2466
Table 1
working on the synthesis of thiazolidinones, we encountered some
difficulties that encouraged us to develop a new method to elimi-
nate these difficulties. In this Letter, we report silica gel as environ-
ment friendly and benign reagent for the synthesis of
thiazolidinones via three-component one pot condensation of
aldehyde, amine, and thioglycolic acid. Slightly acidic and mild
desiccant25 nature of silica gel is being utilized for this reaction.
To the best of our knowledge silica gel has not been used as pro-
moter for the synthesis of thiazolidinones. The reactions are quick
and no work-up procedure26 is involved which make it clean and
green alternative to other reported procedures and is feasible for
parallel synthesis of a large number of compounds.
The model reaction was performed using benzaldehyde, benzyl-
amine, and thioglycolic acid keeping in mind that mild dehydrating
nature of silica gel may provide assistance in removal of water in
the final step of the condensation to afford thiazolidinone com-
pound. Benzylamine (1.0 mmol) was added to a stirred solution
of benzaldehyde (1.05 mmol) in THF (10 mL) at 0 °C and the mix-
ture was stirred for 5 min. Thioglycolic acid (2.0 mmol) was then
added to the above reaction and stirring was continued for another
5 min followed by addition of silica gel (0.5 g). The reaction was
stirred for 4 h where upon the solvent was removed under reduced
pressure and the slurry was purified by flash column chromatogra-
phy to afford the pure product in 52% yield (Scheme 1).
Effect of solvent on silica gel mediated thiazolidinone synthesis
Entry
Solvent
Yield (%)
1
2
3
4
5
THF
Et2O
52a
15b
48a
87a
84a
Acetonitrile
Dichloromethane
1,2-Dichloroethane
a
Yields are after purification of the compounds.
Imine was isolated in 48% yield.
b
Table 2
Synthesis of 4-thiazolidines using benzaldehyde, thioglycolic, and different amines
Entry
Amines
NH2
Time (h)
Product
Yielda (%)
O
S
N
1
7
78b
O
NH2
S
S
N
2
3
4
3
87b
93
NH2
O
N
After the initial success in THF, we screened various solvents
and the results are shown in Table 1. The reaction was sluggish
when diethyl ether was used as solvent and only 15% product for-
mation was observed although the intermediate imine could be
isolated. This suggests that diethyl ether is not a suitable solvent
for the conversion of Schiff base to the desired thiazolidinone. A
lower yield of the product (48%) was obtained when acetonitrile
was used as solvent. The reaction yields were the best when
dichloromethane or 1,2-dichloroethane was used as solvent. The
easy availability, low cost, and easy evaporation of dichlorometh-
ane added advantage and was the solvent of choice for further
reactions.
Encouraged by the result, we explored the scope and generality
of the reaction using different amines and aldehydes and observed
the corresponding products in good to excellent yields (Tables 2
and 3). First the scope of the reaction was tested by treating benz-
aldehyde, thioglycolic acid with various amines (Scheme 2) and the
results are presented in Table 2.
Aliphatic and aromatic amines reacted smoothly to afford the
products in excellent yields, while aniline (Table 2, entry 1) gave
78% yield, benzylamine (Table 2, entry 2) and 2-phenylethylamine
(Table 2, entry 3) afforded respective thiazolidinones in 87% and
93% yields. The furan-2-ylmethanamine (Table 2, entry 7) and (tet-
rahydrofuran-2-yl)methanamine (Table 2, entry 6) which are sen-
sitive to acidic condition afforded the product in 83% and 77%
yields respectively. Aliphatic amines like 3-methoxypropan-1-
amine and cyclobutylamine (Table 2, entries 4 and 5) also reacted
smoothly to afford the product in 78% and 93% yields respectively.
Substituted aromatic methanamines (Table 2, entries 8 and 9) re-
acted in a similar fashion to give the required products in excellent
yields. Pyridine amine such as 2-picolylamine (Table 2, entry 10)
afforded the product in 86% yield after flash column
chromatography.
O
O
O
O
O
O
NH2
S
S
S
S
S
N
N
N
N
N
4
5
6
7
8
4
6
3
6
4
78
93
77c
83
90
O
NH2
NH2
O
O
O
O
NH2
O
O
NH2
NH2
O
O
O
O
O
O
O
S
S
N
N
O
9
6
7
96
86
N
NH2
10
N
a
Isolated yields obtained using 1.0 mmol of amine, 1.05 mmol of aldehyde,
2.0 mmol of thioglycolic acid, and 0.5 g of silica gel (100–200 mesh) in dichloro-
methane at room temperature.
b
Ref. 15.
c
Mixture of diastereomers.
Furthermore to evaluate the scope of the reaction, different
aldehydes were reacted with 2-picolylamine and thioglycolic acid
under the same reaction condition (Scheme 3) and the results are
presented in Table 3. Aldehydes having electron withdrawing
groups (Table 3, entries 1–4) reacted smoothly in 3–6 h and the
products were obtained in excellent yields ranging from 83% to
93%. Electron donating group such as OMe present in the aldehyde
(Table 3, entry 5) afforded excellent yields of the product. Presence
H2N
Silica gel
OH
O
HS
+
+
N
O
O
THF, rt, 4 h
S
Scheme 1. Reagent and condition: benzaldehyde (1.05 equiv), benzylamine
(1.0 equiv), thioglycolic acid (2.0 equiv), THF, silica gel (0.5 g), rt, 4 h, 52% yield.

M. P. Thakare et al. / Tetrahedron Letters 55 (2014) 2463–2466
2465
O
Table 3
silica gel
N
Synthesis of 4-thiazolidine using 2-picolylamine, thioglycolic acid, and various
aldehydes
OH
N
NH2
HS
+
+
R' CHO
N
S
O
CH Cl , rt, 3-7 h
R'
2
2
Entry
Aldehydes
Time (h)
Product
Yielda (%)
Scheme 3. Reagents and conditions: aldehyde (1.05 equiv), 2-picolylamine
(1.0 equiv), thioglycolic acid (2.0 equiv), CH2Cl2, silica gel (0.5 g), rt, 3–7 h.
S
O
O
N
N
Cl
1
4
93
Cl
O
Br
Br
S
S
O
N
HO
O
Si
O
Si
O
Si
O
O
Si
O
Si
O
Si
O
O
2
3
4
5
5
6
6
4
91
83
86
92
N
O2N
Cl
H
HO
S
O
O
O
N
Cl
N
R'
NH2
+
R'
O
R
N
R
O
R'
A
NO2
HO
R
N
H
HS
OH
S
O
O
N
O
NC
NC
N
HO
O
O
S
O
O
N
H
O
N
O
H
HO
N
R'
R'
N
HO
S
-H2O
S
O
O
S
O
HO
R
N
R
B
HO
6
7
8
5
6
3
82
85
95
N
F
S
O
F
Scheme 4. Plausible mechanism of the reaction.
N
O
HO
N
HO
of the free hydroxyl group in the aldehydes (Table 3, entries 6 and
7) did not affect the yield to a larger extent and the products were
obtained in 82% and 85% yields respectively.
CHO
CHO
S
S
N
N
N
Similarly, more reactive aliphatic aldehydes (Table 3, entries 8
and 9) when reacted with 2-picolylamine and thioglycolic acid
afforded higher yields of the products in short reaction time.
Finally, to evaluate the significance of the method, reactions were
performed using different heterocyclic aldehydes (Table 3, entries
10–13). Thiophene-2-aldehyde and thiazole-2-aldehyde reacted
cleanly under the above reaction condition and the products were
obtained in 88% and 78% yields without any difficulty. Slightly low-
er yield of the product was obtained when pyrazolo[1,5-a]pyri-
dine-3-carbaldehyde was reacted with 2-picolylamine and the
product was obtained in 72% yield after flash column chromatogra-
phy purification. The substituted pyridine aldehyde such as 6-chlo-
ronicotinaldehyde reacted well to afford the product in 85% yield.
The reactions are clean and require a short column chromatogra-
phy purification to get the pure product which makes the proce-
dure useful to run parallel reactions for library synthesis.
We hypothesize that silica gel may activate the acid group there-
by generating an electron deficient carbon. This facilitates the intra-
molecular addition of amine to form intermediate B. Finally, the loss
of H2O from intermediate B affords thiazolidinones (Scheme 4).
In summary, an efficient synthesis of thiazolidinones derived
from diverse aldehydes, amines, and thioglycolic acid is reported.
This method avoids the use of toxic, expensive, hazardous chemicals,
and provides an easy and rapid access to pharmaceutically impor-
tant thiazolidinone derivatives. The method offers many advantages
over the reported methods such as shorter reaction time, cleaner
reaction profile, easy isolation, and excellent yield of the products.
O
9
4
4
5
7
7
96
88
78
72
85
N
S
O
CHO
CHO
S
S
N
10
11
12
13
N
S
S
N
S
O
N
N
N
CHO
S
O
N
N
N
N
N
N
S
O
O
N
Cl
N
N
Cl
N
a
Isolated yields obtained using amine (1.0 mmol), aldehyde (1.05 mmol), thio-
glycolic acid (2.0 mmol). and silica gel (0.5 g, 100–200 mesh) in dichloromethane at
room temperature.
O
R
silica gel
N
OH
O
Acknowledgment
HS
+
R
NH2
+
S
O
CH2Cl2, rt, 3-7 h
We are thankful to Jubilant Chemsys management for providing
financial support and analytical facilities for the execution of this
research work.
Scheme 2. Reagents and conditions: Benzaldehyde (1.05 equiv), amine (1.0 equiv),
thioglycolic acid (2.0 equiv), CH2Cl2, silica gel (0.5 g, 100–200 mesh), rt, 3–7 h.

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M. P. Thakare et al. / Tetrahedron Letters 55 (2014) 2463–2466
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26. General experimental procedure: To a solution of benzylamine (1.0 mmol) in
dichloromethane (10 mL) at 0 °C was added benzaldehyde (1.05 mmol) and the
mixture was stirred for 5 min. Thioglycolic acid (2.0 mmol) was then added to
the above reaction and stirring was continued for another 5 min at 0 °C
followed by addition of silica gel (0.5 g, 100–200 mesh). The reaction was
stirred for 4 h at room temperature when TLC showed complete conversion of
starting amine, the solvent was removed under reduced pressure and the
slurry so formed was purified by flash column chromatography over 12 g SNAP
cartridge by eluting with gradient of 10–20% ethyl acetate in hexane to afford
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