Supported protic acid-catalyzed synthesis of 2,3-disubstituted thiazolidin-4-ones: Enhancement of the catalytic potential of protic acid by adsorption on solid supports

Article abstract of DOI:10.1039/c3gc41218k

The catalytic potential of various protic acids has been assessed for the one pot tandem condensation-cyclisation reaction involving an aldehyde, an amine, and thioglycolic acid to form 2,3-disubstituted thiazolidin-4-ones. The catalytic potential of the various protic acids that follows the order TfOH > HClO₄ > H₂SO₄ ～ p-TsOH > MsOH ～ HBF₄ > TFA ～ AcOH is improved significantly by adsorption on solid supports, in particular using silica gel (230-400 mesh size), with the resulting relative catalytic potential following the order HClO ₄-SiO₂ > TfOH-SiO₂ ? H₂SO ₄-SiO₂ > p-TsOH-SiO₂ > MsOH-SiO ₂ ～ HBF₄-SiO₂ > TFA-SiO₂ ～ HOAc-SiO₂. The better catalytic potential of HClO ₄-SiO₂ as compared to that of Tf-SiO₂, although TfOH is a stronger protic acid than HClO₄, can be rationalised through a transition state model depicting the interaction of the individual protic acid with SiO₂. The catalytic efficiency of HClO₄ adsorbed on various solid supports was in the order HClO₄-SiO ₂ ? HClO₄-K10 > HClO₄-KSF > HClO ₄-TiO₂ ～ HClO₄-Al₂O₃. The catalytic system HClO₄-SiO₂ is compatible with different variations of aldehydes (aryl/heteroaryl/alkyl/cycloalkyl) and the amines (aryl/heteroaryl/arylalkyl/alkyl/cycloalkyl) affording the desired 2,3-disubstituted thiazolidin-4-ones in 70-87% yields (43 examples). The electronic and the steric factors associated with the aldehydes and the amines provide a handle for selective thiazolidinone formation and were found to be dependent on the extent of imine formation. No significant amount of thiazolidinone formation took place during the reaction of the preformed amide (synthesised from the amine and thioglycolic acid) with benzaldehyde suggesting that the reaction proceeds through the initial reversible imine formation followed by cyclocondensation of the preformed imine with thioglycolic acid, the reversible imine formation being the determining step to control selectivity of thiazolidinone formation in competitive environments. The feasibility of a large scale reaction and catalyst recycling/reuse is demonstrated.

Full text of DOI:10.1039/c3gc41218k

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Journal Name
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DOI: 10.1039/C3GC41218K
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ARTICLE TYPE
Supported protic acid-catalyzed syntheis of 2,3-disubstituted thiazolidin-
4-ones: enhancement of the catalytic potential of protic acid by
adsorption on solid supports
Dinesh Kumar, Mukesh Sonawane, Brahmam Pujala, Varun K. Jain and Asit K. Chakraborti*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The catalytic potential of various protic acids has been asssessed for the one pot tandem condensation-
cyclisation reaction involving an aldehyde, an amine, and thioglycolic acid to form 2,3-disubstituted
thiazolidin-4-ones. The catalytic potential of the various protic acids that follows the order TfOH >
10 HClO4 > H2SO4 ~ p-TsOH > MsOH ~ HBF4 > TFA ~ AcOH is improved significantly by adsorption on
solid support, in particular using silica gel (230 – 400 mesh size), with the resultant relative catalytic
potential following the order HClO4-SiO2 > TfOH-SiO2 >>H2SO4-SiO2 > p-TsOH-SiO2 > MsOH-SiO2
~ HBF4-SiO2 > TFA-SiO2 ~ HOAc-SiO2. The better catalytic potential of HClO4-SiO2 compared to that
of Tf-SiO2, although TfOH is a stronger protic acid than HClO4, can be rationalised through a transition
15 state model depicting the interaction of the individual protic acid with SiO2. The catalytic efficiency of
HClO4 adsorbed on various solid supports was in the order HClO4-SiO2 >> HClO4-K10 > HClO4-KSF >
HClO4-TiO2 ~ HClO4-Al2O3. The catalytic system HClO4-SiO2 is compatible with different variations of
aldehydes (aryl/heteroaryl/alkyl/cycloalkyl) and the amines (aryl/heteroaryl/arylalkyl/alkyl/cycloalkyl)
affording the desired 2,3-disubstitutedthiazolidin-4-ones in 70-87% yields (43 examples). The electronic
20 and the steric factors associated with the aldehydes and the amines provide handle for selective
thiazolidinone formation and was found to be dependent on the extent of imine formation. No significant
amount of thiazolidinone formation took place during the reaction of the preformed amide (synthesised
from the amine and thioglycolic acid) with benzaldehyde suggesting that the reaction proceeds through
the initial reversible imine formation followed by cyclocondensation of the preformed imine with
25 thioglycolic acid, the reversible imine formation being the determining step to control selectivity of
thiazolidinone formation during competitive environments. The feasibility of a large scale reaction and
catalyst recycling/reuse is demonstrated.
involving the synthesis of imine and the treatment of the pre-
Introduction
formed imine with thioglycolic acid. The one pot tandem
condensation-cyclization reaction may proceed (i) via initial
50 imine formation followed by attack of the sulfur moiety of the
thioglycolic acid on the imine carbon followed by
intramolecular cyclization with the expulsion of water giving
rise to the cyclized product thizolidinone (Route A) or (ii) via
the initial condensation of the amine with thioglycolic acid to
55 form the amide followed by cyclo-condensation of the
aldehyde carbonyl group with the thiol and NH moieties of the
in situ formed amide giving rise to the cyclized product
thizolidinone through the expulsion of water (Route B)
(Scheme 1).
Functionlized thiazolidinones (FTZs) are one of the most
30 extensively investigated class of compounds because of their
broad range of pharmacological profile.1 The FTZs have been
reported as anti-bacterial,2 anti-viral/HIV3, anti-cancer,4 anti-
convulsant,5 anti-histaminic,6 anti-inflammatory (CCR4
antagonist7 and COX inhibitors8), and cardio-vascular agents.9
35 These have given the 4-thiazolidinone framework the status of
priviledged pharmacophore that makes the FTZs the highly
sought for compounds for medicinal chemists towards the
generation of new therapeutic leads. Besides these, the FTZs
are precursors for the synthesis of different pharmaceutically
40 important compounds/substances such as polymethine cyanine
dye,10 monofluoro β-lactams11 and pyrazolethiazole
derivatives.12 Consequently, there has been perpetual interest
for the development of new synthetic protocols for the
construction of the 4-thiazolidinone scaffold.13 These methods
45 employ either one-pot tandem reaction between an aldehyde,
an amine, and thioglycolic acid or a two step process
Route A:
O
OH
S
H
S
S
O
-H2O
-H2O
OH
R1 NH2
R1
O
+
O
R
H
R
N
R
NH
R1
R
N
R1
Route B:
O
O
O
S
R1
-H2O
R1
-H2O
OH R1 NH2
N
+
N
H
R
O
R
H
R
N
H
S
S
S
R1
H
H
O
OH
60
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DOI: 10.1039/C3GC41218K
Scheme 1. Mechanistic pathway of formation of thiazolidinones.
protic acid, reactions were performed using 10 mol % and 100
mol % (equimolar amount with respect to 1) of the protic acid
55 (Table 1). It was noticed that stoichiometric amounts of the
protic acids are required to afford 4 in significant yields and
the results were, in general, inferior in using catalytic amount
of the protic acids. Among the difference protic acids used,
The latter step (cyclocondensation) seems to be critical for
obtaining high yields of 4-thiazolidinones and if this could be
enhanced, one could rapidly obtain the thiazolidinones in high
yields. Therefore, variations have been made in the removal of
water during the cyclisation. Most commonly the reported
protocols involve water removal through azeotropic
distillation or the use of various dehydrating agents such as
molecular sieves, Na2SO4, orthoester etc. The various
10 methodlogies developed for the purpose involve the use of
metal Lewis acid catalysts,13i-j (ZnCl2, iron salts), solid acid
catalyst13d, and activated fly ash13h to provide improved
yields. Alternatively, the use of microwave,13d,h,l,m coupling
reagents,13k,n like DCC and HBTU have also been documented
15 for the synthesis of 2,3-disubstituted 4-thiazolidinones.
However, most of the methods described above suffer from
the common limitations/disadvantages such as the use of
special apparatus (Dean and Stark assembly for azeotropic
distillation, microwave oven/reactor), use of stoichiometric
20 amount of hazardous and costly catalysts/condensing
agents/auxiliary reagents, inert and dry atmosphere, and often
require longer reaction times (17-20 h). Further, the reported
methods exemplify only limited substrate scope. Thus, a
convenient, versatile, rapid and high yielding synthetic
25 method is needed to fulfill the timely supply of the designed
molecules for biological evaluation14 and enrichment of
medicinal chemists’ tool box.15
5
the catalytic potential was in the order TfOH > HClO4
>
60 H2SO4 ~ p-TsOH > MsOH ~ HBF4 > TFA ~ AcOH which are
in conformity with the acidity order (pKa value) of the protic
acids with the best result obtained in case of TfOH (strongest
protic acid H0 = -14.1) followed by HClO4 (H0 = -10).17
Table 1. Reaction of 1, 2 and 3 to form 4 in the presence of different
65 protic acids and protic acids immobilized on silica (230-400 mess size).a
Entry
Protic acid
TfOH
pKab
-15
Mol %c
10
100
10
100
10
100
10
100
10
100
10
100
10
100
10
100
10
10
10
10
10
10
10
Yield (%)d
1
2
3
70 4
5
6
7
8
75 9
10
11
12
13
80 14
15
16
17
18
85 19
20
21
38
55
32
48
21
34
22
32
15
24
15
28
14
21
12
20
72
85
55
48
40
36
28
25
12e
tracef
HClO4 (aq 70%)-10
H2SO4
p-TsOH
MsOH
-3
-2.8
-2.6
HBF4 (aq 50 %) -0.4
TFA
-0.25
4.76
AcOH
TfOH-SiO2
HClO4-SiO2
H2SO4-SiO2
p-TsOH-SiO2
MsOH-SiO2
HBF4-SiO2
TFA-SiO2
AcOH-SiO2
none
Result and Discussions
In search for a more convenient and improved method of
30 synthesis for the title compounds, the multicomponent
reaction (MCR) strategy was considered instead of the
stepwise imine formation and condensation of the preformed
imine with thioglycolic acid as it would avoid purification
procedures for the step-by-step protocol16 and is a recognized
22
23
90 24
25
26
10
--
none
--
a 1 (0.106 g, 1 mmol) was treated with 2 (0.093 g, 1 mmol, 1 equiv) and 3
14
35 synthetic tool to medicinal chemists in a convergent mode
(1 0.092 g, 1 mmol, 1 equiv) in the presence of the catalyst in PhMe (5
and atom-economical fashion. Keeping the mechanistic
pathway in the mind, it was thought that a chemical species
with strong electrophilic activation potential would be an
ideal candidate for catalysis as each step of thiazolidinone
40 formation requires electrophilic activation. The use of protic
acids, the known classical electrophilic activation agents, is
the immediate choice and therefore we decided to exploit the
catalytic potential of different protic acids for thiazolidinone
synthesis (Scheme 2).
b
c
95 mL) under heating (oil bath temp 100 °C) for 5 h. Ref 17. The molar
equiv of the protic acid used with respect to 1. dIsolated yield of product.
eThe reaction was carried out in the absence of catalyst. fThe reaction was
carried out under neat condition in the absence of catalyst.
The activity of a reagent dispersed on solid surface is
100 improved due to an increase (to the extent of hundred folds) in
the effective surface area of the reagent. Supported reagents
offer other advantages such as good thermal and mechanical
stabilities, easy to handle, non-corrosive, free flowing nature,
ease of separation from the reaction mixture by filtration and
105 can be reused adding advantages in eliminating/minimising
extra processing steps and spent catalyst disposal.
O
NH2
CHO
N
Protic acid
HS
COOH
S
PhMe, 100 °C
1
The use of solid acids (heterogeneous catalysis)18 and
chemical processes on solid surfaces19 are gaining popularity
as environmentally friendly approaches in organic synthesis as
110 homogeneous catalysts are often destroyed during product
isolation and the "once through" catalyst utilization leads to
unacceptably high manufacturing costs. Based on these and
our own expertise in the area of heterogeneous catalysis,20 it
was planned to immobilize these protic acids on solid support
115 (silica gel; 230 – 400 mesh size) and perform the model
2
3
4
45
Scheme 2. Protic acid-catalysed MCR of 1, 2 and 3 to form 4.
The model reaction (Scheme 2) involving equimolar
mixture of benzaldehyde (1), aniline (2) and thioglycolic acid
(3) was carried out in PhMe (commercial grade without
50 further purification/drying) under heating at 100 °C (oil bath)
for 5 h in the presence of various organic and inorganic protic
acids to form the 2,3-diphenylthiazolidin-4-one 4. For each
2
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DOI: 10.1039/C3GC41218K
reaction (Scheme 2) using these solid supported protic acids
strong electron withdrawing F3C group in TfOH decreases the
electron density at the oxygen atom of the S=O groups and
reduces its coordinating ability with Si. Further, as HClO4 has
three oxygen atom available for coordination with Si
as the catalyst. Improved results were obtained in each case,
affording moderate to excellent yields (entries 17-24, table 1).
Out of the different protic acids immobilized on silica the
5
catalyst systems HClO4-SiO2 and TfOH-SiO2 (entries 17 and 60 compared to only two such oxygen atoms in TfOH a more
18, Table 1) afforded 4 in excellent yields (85% and 72%,
respectively). The other protic acids immobilized on silica
(230 – 400 mesh size) proved to be inferior with the overall
catalytic activity following the order HClO4-SiO2 > TfOH-
10 SiO2 >>H2SO4-SiO2 > p-TsOH-SiO2 > MsOH-SiO2 ~ HBF4-
SiO2 > TFA-SiO2 ~ HOAc-SiO2.
To make a clear distinction between the two heterogeneous
catalyst systems HClO4-SiO2 and TfOH-SiO2 a few more
experiments were designed. For this purpose, six reactions
15 were performed using different combination of the aldehyde
and the amine with varying electronic factor viz the reactions
involving (i) 4-methoxy benzaldehyde (5) and 2, (ii) 1 and 4-
nitro aniline (6), (iii) pyridine-2-carboxaldehyde (7) and 2, (v)
effective coordination with the Si of SiO2 is expected to occur
with HClO4.
O
X
Y
O
H
X
Y
O
O
O
OH
Si
OH
Si
OH
O
H
HO
O
O
Si
Si
O
O
O
X = Cl, S; Y = O, F3C
O
O
O
O
O
Figure 1. The role of SiO2 (solid support) in increasing the electrophilic
65
activation potentiality of HClO4 and TfOH.
As the immobilisation of the protic acid on silica (230-400
mesh) significantly improved its catalytic efficiency, the
effect of immobilization of HClO4 on other varities of silica
gel (mesh size 100-200 and 60-120; Entries 2 and 3, Table 3)
70 as well as other solid supports such as different types of
alumina (acidic, neutral, and basic; Entries 4-6, Table 3),
natural clays K-10 and KSF (Entries 7 and 8, Table 3) and
TiO2 was evaluated. However, the results were inferior
compared to those of HClO4 immobilized on silica gel (230-
75 400).
As often the supported material itself exhibit catalytic
activity for various organic reactions,21 the model reaction
(Scheme 2) was carried out in the presence of the individual
solid support such as various silica gel, alumina, clays (K10
80 and KSF), zeolites, and amberlite. However, poor yields were
obtained in each case indicating the role of HClO4 in
catalyzing the reaction.
1
and 2-aminopyrinde (8), and (vi) 1 and 2-amino
20 benzothiazole (9) (table 2). The results of these reactions
clearly established the superior catalytic power of HClO4-SiO2
compared to that of TfOH-SiO2, indicating the specific role of
the solid support (silica gel) in potentiating the catalytic
activity of the protic acid in view of the fact that TfOH (H0 = -
25 14.1) is a stronger protic acid than HClO4 (H0 = -10).
Table 2. The comparison of the catalytic power of HClO4-SiO2 and
TfOH-SiO2 during the thiazolidinone formation.a
Entry
Catalyst
Aldehyde
Amine
Time
(h)
Yield
(%)b
Table 3. The reaction of 1, 2 and 3 to form 4 in the presence of HClO4
immobilized on various solid supports.a
30
1
2
3
4
HClO4-SiO2
TfOH-SiO
HClO4-SiO2
TfOH-SiO2
R1 = OMe
R1 = OMe
R1 = H
R2 = H
5
5
5
5
74
51
70
50
85 Entry
1
2
3
4
90 5
6
7
8
9
95 10
11
12
13
14
Solid supported acid
Yield (%)b
R2 = H
HClO4-SiO2 (230 – 400)
HClO4-SiO2 (100 – 200)
HClO4-SiO2 (60 – 120)
HClO4-Al2O3 (acidic)
HClO4-Al2O3 (neutral)
HClO4-Al2O3 (basic)
HClO4-K10
85
68
52
48
45
32
71
55
48
20
22
30
15
10
10
47
38
28
41
42
40
45
36
38
36
R2 = NO2
R2 = NO2
R1 = H
35
5
6
HClO4-SiO2
TfOH-SiO2
R2 = H
R2 = H
5
5
75
55
HClO4-KSF
HClO4-TiO2
SiO2 (60 – 120)
SiO2 (100 – 200)
SiO2 (230 – 400)
Al2O3 (Acidic)
Al2O3 (Neutral)
Al2O3 (Basic)
K10
KSF
TiO2
Zeolite type Y
Zeolite K/L (SAR 6.8)
Zeolite ZSM 5 (SAR 6.8)
Zeolite K/L (for synthesis)
Zeolite Na/Fau
Zeolite NH4-Y
7
HClO4-SiO2
TfOH-SiO2
R1 = H
R1 = H
5
5
70
52
40 8
N
S
NH2
9
10
HClO4-SiO2
TfOH-SiO2
R1 = H
R1 = H
5
5
69
35
100 15
16
a
17
18
19
Aldehyde (1 mmol) was treated with amine (1 mmol) and thioglycolic
45 acid 3 (1 mmol) in presence of HClO4-SiO2 (10 mol%) in PhMe under
heating (oil bath temp 100 °C). bIsolated yield of product.
105 20
21
The role of the silica support in enhancing the catalytic
power of HClO4-SiO2 and TfOH-SiO2 is depicted in Figure 1.
The Si is coordinated to the oxygen atom of the Cl=O/S=O
50 group due to the high oxophilicity of Si to form six-membered
cyclic structure and increases the electrophilicity of the OH
proton of HClO4/TfOH. The inferior catalytic activity of
TfOH-SiO2 compared to that of HClO4-SiO2 may be
rationalised by the loosley bound six-membered cyclic
55 structure in TfOH-SiO2 compared to that in HClO4-SiO2 as the
22
23
24
110 25
Amberlite
a 1 (0.106 g, 1 mmol) was treated with 2 (0.093 g, 1 mmol, 1 equiv) and 3
(0.092 g, 1 mmol, 1 equiv) in the presence of different catalyst (10 mol%)
in PhMe (5 mL) under heating (oil bath temp 100 °C) for 5 h. b Isolated
yield of 4.
This journal is © The Royal Society of Chemistry [year]
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60 a1 (1 mmol) was treated with 2 (1 mmol, 1 equiv) and 3 (1 mmol, 1 equiv)
in the presence of different amount of HClO4-SiO2 in various solvent (5
mL) under heating at different temperature (oil bath temp) for the
indicated time period. bThe molar equiv of HClO4-SiO2 used with respect
To derive the optimal reaction parameters such as the
amount of the catalyst required, reaction time and
temperature, the influence of the solvent for the HClO4-SiO2-
catalysed thiazolidinone formation, the model reaction
(Scheme 2) was performed under different variation of these
parameters (Table 4). The use of 2.5 mol% of HClO4-SiO2
afforded 4 in 82% yields (entry 3, table 4). The optimum
reaction temperature was found to be 100 ºC as an increase of
the reaction temperature to 120 ºC did not show any
c
e
to 1. The isolated yield of 4. dOil bath temp 100 °C. A 60% yield of 4
f
65 was obtained for the overnight reaction. A 65% yield of 4 was obtained
5
for the overnight reaction.
The general applicability of the newly developed protocol
is demonstrated through the reaction of various
aryl/heteroaryl/alkyl aldehydes reacted elegently with
10 significant increase in yield of 4 (entry 11, table 4) which, 70 aryl/heteroaryl/alkylaryl/alkyl anilines and thioglycolic acid
however, decreased to 67 and 45 % in lowering the reaction
temperatures to 70 and 50 ºC, respectively (entries 9 and 8,
table 4). No significant amount of 4 was formed in carrying
out the reactions at rt (Entry 7, Table 4).
The influence of the reaction medium was evaluated for the
model reaction (Scheme 2) in hydrocarbon, halogenated
hydrocarbon, ethereal, protic polar and aprotic polar solvents
and PEG-200 (table 4) in the presence of catalytic amount of
HClO4-SiO2. The best results were obtained in PhMe (82 %,
to form the corresponding 1,3-disubstituted-4-thiazolidinone
in excellent yields (table 5). The reactions proceeded well
with
substituted
aromatic,
heteroaromatic,
and
aliphatic/alicyclic aldehydes, as well as different variation of
75 the amines (e.g., substituted aromatic, heteroaromatic,
aryl/heteroaryl alkyl, cycloalkyl, and alkyl amines) affording
the respective thiazolidinone in very good to excellent (70-
88%) yields.
15
The thiazolidinone formation is influenced by the electronic
20 entry 17, table 4) and 1,4-dioxane (85 %, entry 19, table 4). 80 factor associated with the aldehyde and the amine. Aromatic
However based on Pfizer solvent selection guideline,22 the use
aldehydes bearing electron donating substituenst (entries 3, 8,
of PhMe (usable solvent) was preferred instead of dioxane
(undesirable solvent) for further reactions. The desired result
with PhMe (non-polar solvent), encouraged to use some other
and 30) took longer times due to the lesser electrophic
property of the aldehyde group. The reaction of aromatic
aldehyde with electron withdrawing group (more electrophilic
25 non polar solvent with polarity index similar to PhMe but with 85 aldehyde) requires shorter tiem (entry 4). The requirement of
better green index such as n-heptane and cyclohexane,
however inferior results were obtained even after overnight
reaction (entries 25 and 26, table 4).
longer reaction time for heteroaromatic (entries 33-35),
alicylclic (entry 36), aliphatic (entry 37) aldehydes is due to
the lesser electrophilicity of the corresponding aldehyde
carbonyl. On the other hand, the reactions took lesser time for
90 electron rich aromatic amines (entries 12 and 20) and those
bearing electron withdrawing substituents required longer
time (entries 13-15). The heteroaromatic amines (39-41) took
longer reaction time due to their inferior nucleophilicity
compared to 1 but the aryl/heteroaryl alkyl (entries 21-28 and
95 31) and alkyl amine (entry 43) required lesser rection period
due to the better nucleophilicity of the correspnding amine
group. In case of the cycloalkyl amine (entry 42) the steric
factor contributes to the necessity of longer reaction time. In
order to assess the effect of the steric factor of the carbonyl
100 substrates, a few representative cyclic and acyclic aryl alkyl
Table 4. The HClO4-SiO2-catalysed reaction of 1 with 2 and 3 to form 4
30 under various conditions.a
Entry
Cat amtb
(mol%)
Solvent
Time
(h)
Temp
(°C)
Yield
(%)c
1
2
35 3
4
5
6
7
40 8
9
10
11
12
45 13
14
15
17
18
50 19
20
21
22
23
0.5
1
2.5
5
7.5
10
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
Dioxane
THF
DMF
EtOH
TFE
Water
n-Heptane
Cyclohexane
PEG 200
Neat
5
5
5
5
5
5
5
5
5
5
5
0.5
1
2
3
4
5
4
4
4
4
4
4
4
4
4
4
100
100
100
100
100
100
30 (rt)
50
70
100
120
100
100
100
100
100
100
30
55
82
83
82
82
12
45
67
82
82
40
53
62
70
82
82
83
10
20
45
20
40
50e
54f
45
30
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
ketones were used instead of the aldehyde (Scheme 3).
O
NH2
O
HClO4-SiO2 (2.5 mol%)
PhMe, 100 °C, 5 h
N
+
+
HS
COOH
S
63 %
NH2
NH2
O
O
H
N
HClO4-SiO2 (2.5 mol%)
PhMe, 100 °C, 5 h
SH
SH
+
+
+
+
HS
HS
COOH
COOH
O
5
5
100
61 %
H
N
refluxd
100
HClO4-SiO2 (2.5 mol%)
PhMe, 100 °C, 5 h
O
refluxd
refluxd
100
66 %
NH2
H
N
O
HClO4-SiO2 (2.5 mol%)
PhMe, 100 °C, 5 h
SH
55 24
25
26
27
28
+
+
HS
COOH
Ph
Me
O
refluxd
refluxd
100
63 %
5
Scheme 3. The reaction of aniline 2 and 3 with different ketones.
100
Although the reaction of cyclohexanone afforded the
105 desired thiazolidinone in good yield, no significant amount of
thiazolidinone formatioon took place with cyclopentanone,
cycloheptanone, and acetophenone. In each of these cases the
amide/anilide formed by condensation of 2 and 3 is obatined
4
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DOI: 10.1039/C3GC41218K
as the sole product (61-66% yields).
The feasibility of synthesis of the bis-thiazolidinone from
the reaction of a diamine was investigated and o/m/p-
phenylenediamines and ethylene diamine were separately
treated with two molar equiv of each of 1 and 3 (Scheme 4).
The reaction of o-phenylene diamine did not produce any
thiazolidinone and resulted in the formation of the
5
corrseponding
2-substituted
and
1,2-disubstituted
benzimidazoles.20k,22 The recation with p-phenylenediamine
10 and ethylenediamine gave the desired bis-thiazolidinone
derivatives in 62% yield. However, the reaction of m-
phenylenediamine produced the mono-thiazodiline derivative
wherein the senod amino moiety is converted to the imine of
1.
15
Scheme 4. The reaction of diamines with 1 and 3.
20
Table 5. The HClO4-SiO2-catalysed reaction of various aldehydes with different amines and
thiogluycolic acid to form 2,3-disubstituted-4-thiazolidinones.a
Entry
Aldehyde
Amine
Time (h) Yield (%)b
NH2
CHO
R4
R1
R2
R3
R1
R3
R2
25 1
2
3
4
5
30 6
7
8
9
10
35 11
12
13
14
15
40 16
17
18
19
20
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = H
4
4
5
3
4
4
4
5
4
4
4
3
6
6
5
5
4
4
4
4
85
81
74
88
80
80
81
76
78
78
78
87
71
70
75
77
80
82
81
81
R1 = R2 = R3 = H; R3 = Me
R1 = R2 = R3 = H; R3 = OMe
R1 = R2 = R3 = H; R3 = NO2
R1 = R2 = R3 = H; R3 = F
R1 = R2 = R3 = H; R3 = Cl
R1 = R2 = R3 = H; R3 = Br
R1 = R2 = R3 = H; R3 = OCH2Ph
R1 = R4 = H; R2 = OMe; R3 = OH
R1 = R4 = H; R2 = R3 = OMe
R1 = R3 = R4 = Me; R2 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = H
R1 = R2 = R3 = H
R1 = R2 = R3 = H
R1 = R2 = R3 = H
R1 = R2 = R3 = H
R1 = R2 = R3 = H
R1 = R2 = R3 = H
R1 = R2 = R3 = H
R1 = R2 = R3 = H
R1 = R2 = R3 = H
R1 = R3 = H; R2 = OMe
R1 = R3 = H; R2 = NO2
R1 = R3 = H; R2 = CN
R1 = R3 = H; R2 = CF3
R1 = R3 = H; R2 = CO2Et
R1 = R3 = H; R2 = F
R1 = R3 = H; R2 = Cl
R1 = R3 = H; R2 = Br
R1 = R2 = R3 = OMe
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R2
R1
NH2
R3
45
21
22
23
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R4 = H; R2 = R3 = OMe
R1 = R2 = R3 = H
4
4
4
4
4
4
4
4
4
5
84
75
80
82
82
78
75
75
77
76
R1 = Cl; R2 = R3 = H
R1 = R3 = H; R2 = Cl
R1 = R2 = H; R3 = Cl
R1 = F; R2 = R3 = H
R1 = R3 = H; R2 = F
R1 = R2 = H; R3 = F
R1 = Me; R2 = R3 = H
R1 = R2 = H; R3 = 4-OMe
R1 = R2 = R3 = H
24
50 25
26
27
29
28
55 30
NH2
O
31
R1 = R2 = R3 = R4 = H
4
82
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NH2
32
3
80
33
34
5
6
5
5
75
76
75
76
CHO
S
CHO
CHO
O
35
5 36
37
38
6
4
72
71
R1 = R2 = R3 = R4 = H
39
40
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
5
6
70
70
10 41
R1 = R2 = R3 = R4 = H
6
71
NH2
42
43
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
5
4
72
81
aThe aldehyde (2.5 mmol) was treated with the amine (2.5 mmol, 1 equiv) and thioglycolic acid (2.5
mmol, 1 equiv) in the presence of HClO4-SiO2 (2.5 mol%) in PhMe (5 mL) at 100°C (oil bath) for
15 the stipulated time. bIsolated yield of the thiazolidinone.
The reusability of HClO4–SiO2 was investigated (Table 6).
Table 6. The catalyst recovery and reuse during the HClO4-SiO2-
catalysed thiazolidinone formation.a
The reaction of 1 (50 mmol) with 2 (50 mmol,1 equiv) and 3
(50 mmol,1 equiv) in the presence of HClO4–SiO2 (2.5 mol%)
in PhMe at 100 °C. After completion of the reaction (4 h), the
20 the reacation mixture was passed through a plug of cotton to
filter off the catalyst. The cotton plug retaining the catalyst
was washed with EtOAc (3 × 5 mL). The combined PhMe and
EtOAc extracts were concentrated under reduced pressure to
afford 4 (10.8 g, 85 %). The cotton plug retaining the catalyst
25 was subjected to reduced pressure to remove the trace amount
of the solvent whereupon the catalyst separated out from the
cotton plug. The recovered catalyst was activated by heating
under reduced pressure (10 mm Hg) at 80 °C for 24 h. The
reactions were repeated at 40 mmol, 30 mmol, 20 mmol and
30 10 mmol scales the in presence of the recovered HClO4-SiO2
(0.5 g, 0.25 g, 0.12 g and 0.05 g, respectively) to afford 4 in
8.63 g (85 %), 6.3 g (82 %), 3.9 g (78 %), and 1.9 g (75%),
respectively as white solid identical (spectral data) with an
authentic sample. The feasibility of a large scale reaction was
35 demonstrated with the 100 mmol scale reaction of 1, 2, and 3
in affording 4 in 86% yield after 6 h
Run
Scale
HClO4-SiO2
recovered
(g)
40
(mmol)b used
(g)
recovery
(%)
yield
(%)c
1st
50
40
30
20
10
2.5
2. 0
1.5
1.0
0.5
2.3
92
91
85
83
81
85
85
82
78
75
2nd
3rd
1.82
1.27
0.83
0.40
45 4th
5th
a1 was treated with 2 (1 equiv) and 3 (1 equiv) in the presence of HClO4-
b
SiO2 (2.5 mol %) in PhMe (5 mL per mmol of 1) at 100 °C for 4 h. The
molar equivalent of 1, 2, and 3 used for the reaction.cIsolated yield of 4.
50
Anticipating that the differential rate of the reaction for
substrates with varying electronic environment would offer
handle for the selective formation of the thiazolidinone during
inter-molecular competition, equimolar mixtures of (A) 1 and
4-methoxybenzaldehyde (6), (B) 1 and 4-nitrobenzaldehyde
55 (7), and (C) 1 and furan-2-carboxaldehyde (8) were treated
with equimolar amounts of 2 and 3. Selective thiazolidinone
formation corresponding to 1 took place in preference to 6 and
8. However, selective thiazolidinone formation corresponding
to 7 took place in preference to 1 (Scheme 5).
6
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F) Aniline Vs 4-methoxy aniline
O
O
OCH3
CHO
NH2
NH2
HClO4-SiO2
(2.5 mol%)
N
N
S
+
S
+
+
+
HS
COOH
PhMe, 100 °C
5 h
OCH3
16
1
2
3
4
22
Total yield 78 %; 12 : 88 (9 % & 69 %)
G) Aniline Vs 4-nitro aniline
O
O
NO2
CHO
NH2
NH2
HClO4-SiO2
(2.5 mol%)
N
N
S
+
S
+
+
+
HS
COOH
PhMe, 100 °C
5 h
NO2
17
1
2
3
4
23
Total yield 80 %; 90 : 10 (72 % & 8 %)
H) Aniline Vs 2-amino pyridine
O
O
CHO
NH2
NH2
HClO4-SiO2
(2.5 mol%)
N
N
N
N
S
+
S
+
+
+
HS
COOH
PhMe, 100 °C
5 h
1
18
3
4
2
24
Total yield 82 %; 100 : 00 (82 % & 0 %)
I) Aniline Vs Benzylamine
O
O
NH2
CHO
NH2
HClO4-SiO2
(2.5 mol%)
N
N
Scheme 5: Selectivity of thiazolidinone formation during intermolecular
S
+
S
+
+
+
HS
COOH
competion between different aldehydes with varying electronic effect.
PhMe, 100 °C
5 h
1
2
19
3
4
25
The influenec of the steric factor of the carbonyl substrate
Total yield 85 %; 32 : 68 (27 % & 58 %)
5
was realised during inter-molecular competition for the
reaction of equimolar mixtures of (D) 1 and acetophenone
(12) and (E) 1 and cyclohexanone (13) with equimolar
amounts of 2 and 3 wherein selective thiazolidinone formation
corresponding to 1 took place in preference to 12 and 13
J) Aniline Vs cyclohexylamine
O
O
CHO
NH2
NH2
HClO4-SiO2
(2.5 mol%)
N
N
S
+
S
+
+
+
HS
COOH
PhMe, 100 °C
5 h
1
2
20
3
4
26
Total yield 78 %; 60 : 40 (49 % & 31 %)
10 (Scheme 6).
30
Scheme 7. The influence of the electronic and steric effect of the amine
for selective thiazolidinone formation during intermolecular competition.
Scheme 6. Selectivity of thiazolidinone formation during intermolecular
competition between and aldehyde and a cyclic/acyclic ketone.
During intra-molecular competition involving an aliphatic
35 amine and an aromatic amine group selective formation of
thiazolidinone takes place with the aliphatic amine (Scheme
8).
To assess the electronic and steric effects of the amine in
15 controlling selectivity, equimolar mixtures of (F) 2 and 4-
methoxyaniline (16), (G) 2 and 4-nitroaniline (17), (H) 2 and
2-aminopyridine (18), (I) 2 and benzylamine (19), and (J) 2
and cyclohexylamine (20), (K) 2 and n-propyl amine (21), and
(L) 20 and 21were treated with equimolar amounts of 1 and 3
20 (Scheme 7). Selective thiazolidinone formation corresponding
to 16, 19, and 21 took place in preference to 2 whereas
selective thiazolidinone formation corresponding to 2 was
observed in preference to 17, 18, and 20. Selective
thiazolidine formation with 21 in preferenec to 20 further
25 reflected the steric control on selectivity. These results
indicate that the thiazolidinone formation is dependent on the
better electrophilic nature of the carbonyl carbon and better
nucleophilicity of the amine nitrogen suggesting that the
reaction proceeds through the imine formation pathway.
Scheme 8. Selectivity control for thiazolidinone formation during
intramolecular competition involving aromatic and aliphatic amine
groups.
40
Although, the above selectivity profile in the thiazolidinone
formation is in close agreement with the imine formation
pathway, further selectivity studies were performed towards
45 the endeavour to correlate the extent of thiazolidinone
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formation with the ease of imine formation under the
condition of step-wise addition (Set 1) and simultaneous
addition of the reactants (Set 2).
Thus an equimolar mixture of the aldehydes 1, 6, and 7 was
treated with one equivalent of the amine 2 in the presence of
HClO4-SiO2 (2.5 mol%) in PhMe at 100 °C for 4 h (an aliquot
5
1
amount of the reaction mixture on being subjected to H NMR
analysis revealed the presence of the respective imines in 28,
12, and 60% yields) followed by treatment with 2 (one molar
10 equivalent with respect to one of the aldehydes) (Set 1,
Scheme 9). This led to selective formation of the
thiazolidinone 10 over 4 (82:18). Similar selectivity (10:4 =
90:10) was observed when all of the reactants were addeed
together (Set 2, Scheme 8). The selectivity outcome for these
15 two sets of experiments supports the implication of imine
formation.
Total Yield: 75 %; 18 : 82 (14 % & 61 %)
O
O
N
N
S
S
+
Scheme 10. Selectivity of thiazolidinone formation during inter-
molecular competition involving different amines with varying
nucleophilicity for reaction with a common aldehyde.
NO2
4
10
35
3
)
HS
CO2H(
Set 1
1H NMR: 28 %
12 %
60 %
To further consolidate the proof of finding (correlation of
imine formation and thiazolidinone synthesis), the another
sets of reaction (Set 3 and Set 4) were designed using
N
N
N
+
+
O2N
MeO
1a
6a
Ph-NH2
7a
HClO4-SiO2 (2.5 mol %)
PhMe, 100 oC, 4 h
40 preformed imines. In Set 3 experiment, equimolar mixture of
the preformed imines 1a, 6a and 7a was heated in PhMe in the
presence of HClO4-SiO2 at 100 °C for 4 h (so as to permit
equilibration of the imines) followed by addition of one
qeuivalent of thioglycolic acid 3. This afforded the formation
45 of the thiazolidinones 10 and 4 with 90 : 10 selectivity
(Scheme 11). Under Set 4 experiment, equimolar mixture of
the preformed imines 1a, 6a and 7a was treated with one
equivalent of thioglycolic acid 3 in PhMe in the presence of
HClO4-SiO2 at 100 °C for 4 h resulting in the formation of the
50 corresponding thiazolidinones 4, 9, and 10 in 25, 22, and 26 %
yields respectively. The differential outcome in the selectivity
of formation of the thiazolidinones indicated that under Set 3
experimental condition the imines undergo equilibration23
with the respective parent amine and the aldehyde and the
2
(
)
CHO
CHO
CHO
+
+
O2N
MeO
1
6
7
Set 2
O
S
O
Ph-NH2
HS CO2H
HClO4-SiO2 (2.5 mol %)
PhMe, 100 oC, 4 h
N
N
S
+
NO2
Total Yield: 72 %; 90 :10 (65 % & 7 %)
10
4
Scheme 9. Selectivity of thiazolidinone formation during intermolecular
competition involving different aldehydes with varying electrophilicity
for reaction with a common amine.
20
A similar study was performed using three amines with
varying electronic effect [e.g., equimolar amounts of the
amines 2, 16 and 17 was treated with one equivalent of the 55 ultimate selectivity is governed by the electrophilicity of the
aldehyde 1 under the conditions of Set 1 and Set 2, Scheme aldehyde.
25 10]. Under Set 1, the amines were allowed to undergo imine
formation with 1 [1H NMR analysis revealed the formation of
the corresponding imines in 26, 74, and
0 % yields,
respectively] followed by treatment of the in situ formed
imines with 3 (one molar equiv of any one of the amines).
30 This led to the formation of the thiazolidinones 22 and 4 with
88:12 selectivity. Under Set 2 condition 22 and 4 were formed
with 85:15 selectivity.
8
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Total Yield: 77 %; 10 : 90 (8 % & 69 %)
Scheme 12. Selectivity of thiazolidinone formation during intermolecular
competition involving different preformed imines of three different
amines and a common aldehyde.
O
O
N
N
S
S
+
25
When the respective Set 3 and Set 4 experiments (Scheme
12) were performed in anhydrous PhMe the thiazolidinones 4,
22, and 23 were obtained non-selectively in 25, 22, and 24 %
yields under Set 3 and 26, 24, and 22% yields under Set 4
experiment, respectively.
NO2
4
10
CO2H(3)
Set 3
HS
HClO4-SiO2 (2.5 mol %)
PhMe, 100 oC, 4 h
30
Thus, from the above studies, it is concluded that the
thiazolidinone formation depends on the initial reversible
imine formation which in turn depend on the nature of
reacting aldehydes and amines. The resultant thiazolidinones
are obtained by cyclocondensation of the preformed imine
N
N
N
+
+
MeO
O2N
1a
6a
7a
HClO4-SiO2 (2.5 mol %)
PhMe, 100 oC, 4 h
HS
CO2H
35 with thioglycolic acid and the reversible imine formation step
is the determining fator in controlling selective thiazolodinone
formation in competitive environments. That the
thiazolidinone formation in fact proceeds through the initial
formation of the imine was substantiated by the fact that no
40 significant amount of formation of the thiazolidinone 4 was
observed when the preformed amide 5 was treated with 1 in
PhMe at 100 °C for 4 h in the presence of HClO4-SiO2 (2.5
mol%).
O
O
S
O
N
N
N
Set 4
S
S
+
+
NO2
OMe
9
10
4
25 %
22 %
26 %
Scheme 11. Selectivity of thiazolidinone formation during inter-
molecular competition involving different preformed imines of three
different aldehydes and a common amine.
5
To prove that the selectivity obtained under Set 3
experiment above is due to imine equilibration, the Set 3 and
Set 4 experiments of Scheme 11 were performed in anhydrous
PhMe. The thiazolidinones 4, 9, and 10 were obtained in 24,
25, and 25 % yields under Set 3 experiments and in 25, 22,
10 and 24 % yields under Set 4, respectively. Thus, the presence
of water in the commercial grade PhMe allowed imine
equilibration23 to take place.
Similar set of experiments were performed with the
equimolar mixture of the preformed imines 1a, 16a, and 17a
15 (Scheme 12). Under Set 3 experiment the thiazolidinones 4
and 22 were formed in 10:90 selectivity without any
significant formation of the thiazolidinone 23 derived from
17a (the imine of 4-nitroaniline). Non-selective formation of
the thiazolidinones 4, 22, and 23 took place in 26, 24, and 25
20 % yields, respectively, under Set 4 experimental condition.
Conclusions
45
Convenient synthesis of 2-aryl/heteroary/alkyl/cycloalkyl-
3-aryl/heteroaryl/arylalkyl/alkyl/cycloalkyl-4-thiazolidinone
has been developed under one-pot tandem multicomponent
condensation-cyclisation involving an aldehyde, an amine,
and thioglycolic acid catalysed by HClO4-SiO2. The efficiency
50 of various protic acids (required in stoichiometric quantities)
used as a promoter (electrophilic activation agent) for the
formation of 2,3-disubstituted-4-thiazolidinone follows the
order TfOH > HClO4 > H2SO4 ~ p-TsOH > MsOH ~ HBF4 >
TFA ~ AcOH in correlation with their relative acidic property
55 (pKa value). A dramatic enhancement on their catalytic
potential took place on immoblisation on solid support
(particularly on 230-400 mesh size silica gel) so that
substoichiometric amount (2.5 - 10 mol%) is essential for
significant conversion with an overall catalytic potential in the
60 order HClO4-SiO2 > TfOH-SiO2 >>H2SO4-SiO2 > p-TsOH-
SiO2 > MsOH-SiO2 ~ HBF4-SiO2 > TFA-SiO2 ~ HOAc-SiO2.
The reversal of the catalytic potential of HClO4-SiO2 and
TfOH-SiO2 on immobilisation on silica support is rationized
through specific interaction between the protic acid and silica
65 involving a six-membered cyclic structure as the effective
catalytic species. The catalytic potential of HClO4
immobilized on other solid support were also examined and
found to be inferior compared to HClO4-SiO2 and followed
the order HClO4-SiO2 >> HClO4-K10 > HClO4-KSF > HClO4-
70 TiO2 ~ HClO4-Al2O3. The developed protocol is versatile in
terms of the substarte scope with different structural variation
of the aldehydes and amines. The effect of electronic and
steric factors associated with aldehydes and amines were
found to offer handle in controlling selective formatuion of
75 thiazolidinone during inter- and intra-molecular competition
studies. A mechanistic insight revealed the progress of the
reaction through an initial reversible imine formation
followed by cyclocondensation of the in situ formed imine
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65 3.85-3.89 (d, J = 15.8 Hz, 1H); MS (APCI) m/z: 256.33 (M+H)+. The
remaining reactions were carried out following this general procedure. In
some cases, the purification was done using column/flash cromarography.
Typical procedure for the synthesis of bis-thiazolidinone:
with thioglycolic acid and the former step being the
determining factor to control selectivity. The new catalytic
procedure offers the following distinct advantages: (i) one pot
multicomponent synthesis of thiazolidinones with braod
To the magnetically stirred mixture of p-phenylenediamine (0.27 g, 2.5
5
substrate scope, (ii) no requirement of additional reagent, (iii) 70 mmol), 1 (0.53 g, 0.51 mL, 5 mmol, 2 equiv) and 3 (0.35 mL, 0.46 g, 5
mmol, 5 equiv) in PhMe (5 mL), was added HClO4-SiO2 (50 mg, 0.025
high yields, (iv) ease of product isolation/purification, (v)
mmol, 2.5 mol %) and the resultant mixture was heated at 100 °C (oil
easy to prepare/handle the catalyst, and (vi) catalyst reuse that
bath) for 6 h The reaction mixture was dried using rotary evaporator to
remove PhMe and the crude reaction mixture was subjected to column
fulfill the triple bottom line philosophy of green chemistry.28
75 chromatography to obtain analytically pure 3,3'-(1,4-phenylene)bis(2-
phenylthiazolidin-4-one) (0.66 g, 62 %) as yellow solid25; mp = 252-254
Acknowledgement
C; IR (KBr) νmax = 3456, 2994, 1770, 1770, 1374, 1246, 1056; 1H NMR
10 Financial support (Reserach Associateship to DK and Senior
Reserach Fellowship to BP) received from CSIR, New Delhi
is duly acknowledged.
(CDCl3, 400 MHz): δ = 7.23-7.31 (m, 6H), 7.18-7.22 (m, 4H), 7.11-7.12
(d, J = 2.36 Hz, 4H), 6.00 (s, 1H), 5.98 (s, 1H), 3.91-3.95 (d, J = 15.84 Hz
80 2H), 3.76-3.80 (dd, J = 15.9 Hz & 1.52 Hz, 2H); MS (APCI) m/z =
433.33 (M+H)+.
Representative experimental procedure for recovery and reuse of
HClO4-SiO2 during the synthesis of 2, 3-disubtsitued thiazolidin-4-
one: The mixture of 1 (5.3 g, 50 mmol), 2 (4.65 g, 50 mmol, 1 equiv), 3
85 (4.59 g, 50 mmol, 1 equiv), and HClO4-SiO2 (2.5 g, 1.25 mmol, 2.5 mol
%) in PhMe (100 mL) was stirred magnetically at 100 ºC (oil bath). After
completion of the reaction (6 h, TLC, eluent, n-hexane/ethyl acetate 4/1),
the reaction mixture was passed through a plug of cotton (to separate the
catalyst), and the cotton plug was washed with PhMe (2  10 mL). The
90 combined filtrates were concentrated under reduced pressure (2 mm Hg)
and the crude product was purified by crystallization (EtOH) to afford 4
(10.8 g, 85 %) as white solid.13n The cotton plug retaining the recovered
catalyst was placed in a round bottom flask (50 mL) and dried by under
rotary vacuum evaporation (2 mm Hg) when the catalyst separated out
95 from the cotton (2.3 g, 92%). The catalyst was activated on heating under
reduced pressure (10 mm Hg) at 80 °C for 24 h. The reaction was
repeated with 1, 2 and 3 at 40 mmol, 30 mmol, 20 mmol and 10 mmol
scales in the presence of the recovered HClO4-SiO2 (2.0 g, 1.5 g, 1.0 g
and 0.5 g, respectively) to afforded 4 in 8.69 g (85 %), 6.28 g (82 %),
100 3.98 g (78 %) and 1.91 g (75 %) yields, respectively.
Representative experimental procedure for large scale (100 mmol)
synthesis of 2, 3-disubtsitued thiazolidin-4-one: The mixture of 1 (10.6
g, 100 mmol), 2 (9.30 g, 100 mmol, 1 equiv), 3 (9.18 g, 100 mmol, 1
equiv), and HClO4-SiO2 (5 g, 2.5 mmol, 2.5 mol %) in PhMe (250 mL)
105 was stirred magnetically at 100 ºC (oil bath). After the completion of the
reaction (6 h, TLC, eluent, n-hexane/ethyl acetate 4/1), the reaction
mixture was passed through a plug of cotton (to separate the catalyst), and
the cotton plug was washed with PhMe (2  25 mL). The combined
filtrates were evaporated and the crude product was purified by
110 crystallization (EtOH) to afford 4 (21.19 g, 86 %) as white solid.13n The
cotton plug retaining the recovered catalyst was placed in a round bottom
flask (50 mL) and dried by rotary vacuum evaporation when the catalyst
separated out from the cotton (2.37 g, 95 %).
Notes and references
aDepartment of Medicinal Chemistry, National Institute of
15 Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S.
Nagar 160 062, Punjab, India. E-mail: akchakraborti@niper.ac.in;
akchakraborti@rediffmail.com
† Electronic Supplementary Information (ESI) available: Typical
experimental procedure, spectral data of all compounds, scanned spectra
20 of unknown compounds. See DOI: 10.1039/b000000x/
‡General information: The glassware to be used in reactions was
thoroughly washed and dried in an oven and the experiments were carried
out with required precautions. Chemicals and all solvents were
commercially available (Aldrich Chemical, Merck AG, Fluka and S-D
25 Fine Chemicals) and used without further purification/drying unless
otherwise mentioned. 1H and 13C NMR spectra were recorded on a Bruker
Avance 400 MHz NMR spectrometer in CDCl3 with residual
undeuterated solvent (CDCl3 : 7.26/77.0) using TMS as an internal
standard. Chemical shifts () are given in ppm and J values are given in
30 Hz. 13C NMR spectra were fully decoupled and were referenced to the
middle peak of the solvent CDCl3 at 77.00 ppm. Splitting pattern were
designated as s, singlet; bs, broad singlet; d, doublet; dd, doublet of
doublet; t, triplet; m, multiplet. Mass spectra were recorded on a Thermo
Scientific, LTQ-XL (APCI mode] mass spectrometers. Infra-red (IR)
35 spectra were recorded on Perkin Elmer FT-IR spectrometer in the range
4000-600 cm-1 either as neat samples or using KBr for preparing pellets
for solid samples. Compounds were routinely checked for their purity on
the silica gel GF-254 and visualized under UV at wavelength 254 nm.
Melting points were measured with Gupta scientific melting point
40 apparatus and were uncorrected. Evaporation of solvents was performed
at reduced pressure, using a Bǘchi rotary evaporator.
Preparation of Perchloric acid Adsorbed on Silica-Gel (HClO4-SiO2):
The preparation of HClO4-SiO2 was carried out following minor
modification20J of the originally reported procedure.20a To a suspension of
45 silica gel (23.75 g, 230–400 mesh) in EtOAc (50 mL), was added HClO4
(1.25 g, 12.5 mmol, 1.78 mL of a 70% aq solution of HClO4) and the
mixture was stirred magnetically for 30 min at r.t. The EtOAc was
removed under reduced pressure (rotary evaporator) and the residue
heated at 100 °C for 72 h under vacuum to afford HClO4-SiO2 (0.5 mmol
50 g–1) as a free flowing powder.
Typical procedure for inter-molecular competition study:
115 Inter-molecular competition of benzaldehyde and 4-nitro
benzaldehyde for the reaction with aniline and thioglycolic acid in the
presence of HClO4-SiO2: To a magnetically stirred mixture of 1 (0.1 g 1
mmol), 7 (0.15 g, 1 mmol, 1 equiv), 2 (0.09 g, 1 mmol, 1 equiv) and 3
(0.09 g, 1mmol, 1 equiv) in PhMe (5 mL mL), was added HClO4-SiO2 (50
120 mg, 0.025 mmol, 2.5 mol %) and the resultant mixture was heated at 100
°C (oil bath temp.) for 5 h. The reaction mixture was dried using rotary
evaporator to remove PhMe and the crude reaction mixture was subjected
to column chromatography to get 4 and 10 in 78 and 7% yields,
respectively [4 : 10 selectivity = 8 : 92; Total yield 85 %].
125 Inter-molecular competition of benzaldehyde and cyclohexanone for
the reaction with aniline and thioglycolic acid in the presence of
HClO4-SiO2: To a magnetically stirred mixture of 1 (0.1 g 1 mmol), 13
(0.98 g, 1 mmol, 1 equiv), 2 (0.09 g, 1 mmol, 1 equiv) and 3 (0.09 g,
1mmol, 1 equiv) in PhMe (5 mL), was added HClO4-SiO2 (50 mg, 0.025
130 mmol, 2.5 mol %) and the resultant mixture was heated at 100 °C (oil
bath temp.) for 5 h. The reaction mixture was dried using rotary
evaporator to remove the PhMe and the crude reaction mixture was
subjected to column chromatography to get 4 and 15 in 42 and 33%
yields, respectively [4 : 15 selectivity = 56 : 44; Total yield 75 %].
General procedure for the synthesis of 2, 3-disubtsitued thiazolidin-4-
one using HClO4-SiO2 (Entry 1, Table 5): To the magnetically stirred
mixture of 1 (0.26 g, 2.5 mmol), 2 (0.23 g, 2.5 mmol, 1 equiv) and 3 (0.23
g, 2.5 mmol, 1 equiv) in PhMe (5 mL), was added HClO4-SiO2 (125 mg,
55 0.0625 mmol, 2.5 mol %) and the resultant mixture was heated at 100 °C
(oil bath). After completion of the reaction (4 h, TLC, eluent, n-
hexane/ethyl acetate 4/1), the reaction mixture was passed through a
cotton plug to remove the catalyt. The cotton plug was washed with PhMe
(3 × 1 mL). The combined filtarates were concentrated under reduced
60 pressure (2 mm Hg) and the crude product was purified by
recrystallisation (EtOH) to afford 4 (0.54 g, 85 %) as white solid13n; mp =
259-260 C; IR (KBr) νmax = 1676, 1592, 1491, 1452, 1380, 1274, 1217,
1
749, 689, 466 cm-1; H NMR (CDCl3, 400 MHz) δ = 7.22-7.36 (m, 7H),
7.13-7.17 (m, 3H), 6.09 (s, 1H), 3.97-4.02 (dd, J = 15.8 & 1.6 Hz, 1H),
10 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 11 of 13
Green Chemistry
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DOI: 10.1039/C3GC41218K
Inter-molecular competition of aniline and 4-methoxy aniline for the
Set 4: To the magnetically stirred mixture of 1a (0.18 g, 1 mmol), 6a
(0.21 g, 1 mmol, 1 equiv), 7a (0.23 g, 1 mmol, 1 equiv) and 3 (0.09 g, 1
mmol, 1 equiv) in PhMe (5 mL), was added HClO4-SiO2 (50 mg, 0.025
75 mmol, 2.5 mol %) and heated at 100 °C (oil bath) for 4 h. The reaction
mixture was dried using rotary evaporator to remove PhMe and the crude
reaction mixture was subjected to column chromatography to afford the 4,
9 and 10 in 25, 22 and 26 % yields, respectively [4 : 9 : 10 selectivity =
34 : 30 : 36; Total yield 75 %].
reaction with benzaldehyde and thioglycolic acid in the presence of
HClO4-SiO2: To a magnetically stirred mixture of 2 (0.09 g, 1 mmol, 1
equiv), 16 (0.12 g, 1 mmol, 1 equiv), 1 1 (0.1 g 1 mmol) and 3 (0.09 g,
5 1mmol, 1 equiv) in PhMe (5 mL), was added HClO4-SiO2 (50 mg, 0.025
mmol, 2.5 mol %) and the resultant mixture was heated at 100 °C (oil
bath ) for 5 h. The reaction mixture was dried using rotary evaporator to
remove the PhMe and the crude reaction mixture was subjected to column
chromatography to get 4 and 22 in 9 and 69 % yields, respectively [4 : 22
10 selectivity = 12 : 88; Total Yield 78 %]
80
Synthesis of 2-mercapto-N-phenylacetamide
Typical procedure for the selectivity study of the thiazolidinone
formation during intramolecular competition involving aromatic and
aliphatic amine groups (Scheme 8): To a magnetically stirred mixture
of 1 (0.26 g, 2.5 mmol), 24 (0.34 g, 2.5 mmol, 1 equiv) and 3 (0.23 g, 2.5
15 mmol, 1 equiv) in PhMe (5 mL), was added HClO4-SiO2 (50 mg, 0.025
mmol, 2.5 mol %) and the resultant mixture was heated at 100 °C (oil
bath) for 4 h. The reaction mixture was dried using rotary evaporator to
remove the PhMe and the crude reaction mixture was subjected to column
chromatography to analytically pure 25 (0.50 g, 52%) as white solid; mp
20 = 259-260 C; IR (KBr) νmax = 2992, 1764, 1686, 1374, 1243, 1049, 753
cm-1; 1H NMR (CDCl3, 400 MHz) δ = 8.46 (s, 1H), 7.88-7.90 (m, 2H),
7.44-7.48 (m, 3H), 7.34-7.40 (m, 3H), 7.21-7.24 (m, 3H), 7.14-7.17 (m,
4H), 5.34 (d, J = 1.4 Hz 1H), 3.85-3.92 (m, 1H), 3.80 (dd, J = 1.5 Hz &
15.04 Hz, 1H), 3.78 (d, J = 15.8 Hz, 1H), 2.86-2.96 (m, 2H), 2.67-2.73
25 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ = 171.2, 160.2, 150.6, 139.2,
136.2, 131.1, 129.5, 129.3, 129.1, 128.8, 127.2, 121.2, 64.1, 44.6, 32.9;
HRMS (ESI) m/z calcd for C24H22N2OSNa+ [M + Na+], 409.1345; found
to be 409.1341.
To a magnetically stirred mixture of 2 (0.09 g, 1 mmol, 1 equiv) and 3
(0.09 g, 1mmol, 1 equiv) in PhMee (5 mL), was added HClO4-SiO2 (50
mg, 0.025 mmol, 2.5 mol %) and the resultant mixture was heated at 100
85 °C (oil bath) for 4 h. The reaction mixture was dried using rotary
evaporator to remove the PhMe and the crude reaction mixture was
subjected to column chromatography to get analytically pure 5 (0.11 g, 65
%) as white solid27; mp = 106-107 C; 1H NMR (CDCl3, 400 MHz): δ =
8.53 (s, 1H, bd), 7.55-7.62 (m, 2H), 7.27-7.37 (m, 2H), 7.15 (t, J = 7.4
90 Hz, 1 H), 3.42 (t, J = 9.2 Hz, 2H), 2. 0 (t, J = 9.3 Hz, 1H); MS (APCI)
m/z = 168.12 (M+H)+.
1
(a) W. Cunico, C. R. B. Gomes and W. T. Jr. Vellasco, Mini-Rev.
Med. Chem., 2008, 5, 336; (b) A. Verma and S. K. Saraf, Eur. J.
Med. Chem., 2008, 43, 897.
95 2 (a) D. Patel, P. Kumari and N. Patel, Eur. J. Med. Chem., 2012, 48,
354; (b) X.-F. Liu, C.-J. Zheng, L.-P. Sun, X.-K. Liu and H.-R. Piao,
Eur. J. Med. Chem., 2011, 46, 3469; (c) N. Zidara, T. Tomašića, R.
Šinka, A. Kovača, D. Patinb, D. Blanotb, C. Contreras-Martel, A.
Dessenc, M. M. Premruf, A. Zegaa, S. Gobeca, L. P. Mašiča and D.
Kikelja, Eur. J. Med. Chem., 2011, 46, 5512.
Typical procedure for the selectivity study of the thiazolidinone 100
30 formation during inter-molecular competition involving different
amines with varying nucleophilicity for reaction with a common
aldehyde in the presence of HClO4-SiO2 (Scheme 10):
3
(a) J. L. Romine, D. R. St. Laurent, J. E. Leet, S. W. Martin, M. H.
Serrano-Wu, F. Yang, M. Gao, D. R. O’Boyle, J. A. Lemm, J.-H.
Sun, P. T. Nower, X. (Stella), Huang, M. S. Deshpande, N. A.
Meanwell and L. B. Snyder, ACS Med. Chem. Lett., 2011, 2, 224; (b)
J. Balzarini, B. Orzeszko-Krzesinska, J. K. Maurin and A. Orzeszko,
Eur. J. Med. Chem., 2009, 44, 303; (c) R. K. Rawal, S. B. Katti, N.
Kaushik-Basu, P. Arora and Z. Pan, Bioorg. Med. Chem. Lett., 2008,
18, 6110; (d) R. K. Rawal, R. Tripathi, S. B. Katti, C. Pannecouque
and E. De Clercq, Eur. J. Med. Chem., 2008, 43, 2800; (e) R. K.
Rawal, R. Tripathi, S. B. Katti, C. Pannecouque and E. De Clercq,
Bioorg. Med. Chem., 2007, 15, 3134; (f) R. K. Rawal, Y. S.
Prabhaskar, S. B. Katti and E. De Clercq, Bioorg. Med. Chem., 2005,
13, 6771; (g) A. Rao, J. Balzarini, A. Carbone, A. Chimirri, E. De
Clercq, A. M. Monforte, P. Monforte, C. Pannecouque and M.
Zappala, Antiviral Res., 2004, 63, 79.
Set 1: To the magnetically stirred mixture of 1 (0.1 g 1 mmol), 2 (0.09 g,
1 mmol), 16 (0.21 g, 1 mmol, 1 equiv), 17 (0.14 g, 1 mmol, 1 equiv) in 105
35 PhMe (5 mL), was added HClO4-SiO2 (50 mg, 0.025 mmol, 2.5 mol %)
and the resultant mixture was heated at 100 °C (oil bath) for 4 h. An
aliquot sample was withdrawn and subjected to 1H NMR. To this
reaction mixture, the 3 (0.09 g, 1 mmol, 1 equiv) was added and stirring
was continued for further 4 h. The reaction mixture was dried using rotary 110
40 evaporator to remove the PhMe and the crude reaction mixture was
subjected to column chromatography to afford 4 and 22 in 9 and 63 %
yields, respectively [4 : 22 selectivity = 9 : 63; Total yield 72 %].
Set 2: To the magnetically stirred mixture of 1 (0.1 g 1 mmol), 2 (0.09 g,
1 mmol), 16 (0.21 g, 1 mmol, 1 equiv), 17 (0.14 g, 1 mmol, 1 equiv) and 115
45 3 (0.09 g, 1mmol, 1 equiv) in PhMe (5 mL), was added HClO4-SiO2 (50
mg, 0.025 mmol, 2.5 mol %) and the resultant mixture was heated at 100
°C (oil bath) for 4 h. The reaction mixture was dried using rotary
evaporator to remove the PhMe and the crude reaction mixture was
subjected to column chromatography to afford 4 and 22 in 10 and 60 % 120
50 yields, respectively [4 : 22 selectivity = 15 : 85; Total yield 70 %].
Typical experimental procedure for the synthesis of imine26:
4
5
(a) S. Wang, Y. Zhao, G. Zhang, Y. Lv, N. Zhang and P. Gong, Eur.
J. Med. Chem., 2011, 46, 3509; (b) P. J. Edwards, Drug Discov
Today, 2008, 13, 1107; (c) R. Ottana, S. Carotti, R. Maccari, I.
Landini, G. Chiricosta, B. Caciagli, M. G. Vigorita and E. Mini, Bio.
Med. Chem. Lett., 2005, 15, 3930.
(a) N. Siddiqui, M. F. Arshad, S. A. Khan and W. Ahsan, J. Enzyme
Inhib. Med. Chem., 2010, 25, 485; (b) R. K. Rawal, S. B. Katti, N.
Kaushik-Basu, P. Arora and Z. Pan, Bioorg. Med. Chem. Lett., 2008,
18, 6110.
1 (0.53 g, 5 mmol) was treated with 12 (0.61 g, 5 mmol) in DCE (10 mL)
at rt for 1 h with magnetic stirring in the presence of Mg(ClO4)2 (5
mol%). The reaction mixture was diluted with DCE (10 mL), filtered 125 6 M. G. Vigorita, T. Previtera, M. Basile, G. Fenech, R. Costa de
55 through a bed of Na2SO4, and concentrated to afford the desired product
(0.97 g, 92 %) IR (KBr) νmax = 3480, 3361, 1676, 1625, 1595, 1330, 1106,
Pasquale, F. Occhiuto and C. Circosta, IL Farmaco, 1999, 54, 583.
S. Allen, B. Newhouse, A. S. Anderson, B. Fauber, A. Allen, D.
Chantry, C. Eberhardt, J. Odingo and L. E. Burgess, Bioorg. Med.
Chem. Lett., 2004, 14, 1619.
7
1
1025, 885 cm-1; H NMR (CDCl3, 400 MHz) δ = 8.48 (s, 1H), 7.87-7.90
(m, 2H), 7.44-7.48 (m, 3H), 7.22-7.25 (m, 3H), 6.92-6.95 (m, 2H), 3.56
(s, 3H); MS (APCI) m/z: 212.28 (M+H)+.
130 8 A. Zarghi, L. Najafnia, B. Daraee, O. G. Dadrass and M. Hedayati,
60 Inter-molecular competition of different imines with thioglycolic acid
for the synthesis of 2, 3-disubstituted thiazolidin-4-one in the
presence of HClO4-SiO2 in PhMe (Scheme 11) :
Bioorg. Med. Chem. Lett. 2007, 17, 5634.
T. Kato, T. Ozaki, K. Tamura, Y. Suzuki, M. Akima and N. Ohi, J.
Med. Chem., 1998, 41, 4309.
9
Set 3: To the magnetically stirred mixture of 1a (0.18 g, 1 mmol), 6a
(0.21 g, 1 mmol, 1 equiv), 7a (0.23 g, 1 mmol, 1 equiv) in PhMe (5 mL), 135
65 was added HClO4-SiO2 (50 mg, 0.025 mmol, 2.5 mol %) and heated at
100 °C (oil bath) for 4 h. To this reaction mixture, the 3 (0.09 g, 1 mmol,
1 equiv) was added and stirring was continued for further 4 h. The
reaction mixture was dried using rotary evaporator to remove the PhMe
10 R. M. A. El-Aal, Phosphorus, Sulfur, Silicon Relat. Ele., 2003, 178,
681.
11 T. Fuchigami, S. Narizuka and A. Konno, J. Org. Chem., 1992, 57,
3755.
12 Z. Turgut, C. Yolacan, F. Aydogan, E. Bagdatli and N. Ocal,
Molecules, 2007, 12, 2151.
and the crude reaction mixture was subjected to column chromatography 140 13 (a) D. Prasad, A. Preetam and M. Nath, RSC Advances, 2012, 2,
70 to afford the 4 and 10 in 8 and 69 % yields, respectively [4 : 10 selectivity
= 10 : 90; Total yield 75 %].
3133; (b) D. Gautam, P. Gautam and R. P. Chaudhary, Chin. Chem.
Lett., 2012, 23, 1221; (c) U. R. Pratap, D. V. Jawale, M. R. Bhosle
This journal is © The Royal Society of Chemistry [year]
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Page 12 of 13
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DOI: 10.1039/C3GC41218K
and R. A. Mane, Tetrahedron Lett., 2011, 52, 1689; (d) J. Meshram,
P. Ali and V. Tiwari, Green Chem. Lett., Rev. 2010, 3, 195; (e) D.
Lingampalle, D. Jawale, R. Waghmare and R. Mane, Synth.
Commun., 2010, 40, 2397; (f) A. K. Yadav, M. Kumar, T. Yadav and
R. Jain, Tetrahedron Lett., 2009, 50, 5031; (g) X. Zhang, X. Li, D.
Li, G. Qu, J. Wang, P. M. Loiseau and X. Fan, Bioorg.Med. Chem.
Lett., 2009, 19, 6280; (h) V. Kanagarajana, J. Thanusua and M.
Gopalakrishnana, Green Chem. Lett. Rev., 2009, 2, 161; (i) C. T.
Sadashivaa, J. N. N. S. Chandraa, C. V. Kavitha, A. Thimmegowda,
M. N. Subhashc and K. S. Rangappaa, Eur. J. Med. Chem., 2009, 44,
4848; (j) K. G. Desai and K. R. Desai, J. Sul. Chem., 2006, 27, 315;
(k) R. K. Rawal, T. Srivastava, W. Haq and S. B. Katti, J. Chem.
Res., 2004, 5, 368; (l) V. Gududuru, V. Nguyen, J. T. Dalton and D.
D. Miller, Synlett, 2004, 2357; (m) Fraga-Dubreuil and J. P.
Bazureau, Tetrahedron, 2003, 59, 6121; (n) T. Shrivastava, W. Haq
and S. B. Katti, Tetrahedron, 2002, 58, 7619; (o) E. Stephanie, A.
Justus, J. C. Hodges and M. W. Wilson, Biotech. Bioeng., 2000, 61,
17; (p) C. P. Holmes, J. P. Chinn, G. C. Look, E. M. Gorden and M.
A. Gallop, J. Org. Chem., 1995, 60, 7328; (q) J. Tierney, J.
Heterocycl. Chem. 1989, 26, 997; (r) A. R. Surrey, J. Am. Chem. Soc.
1947, 69, 2911.
25 A. R. Surrey, J. Am. Chem. Soc., 1949, 71, 3105
26 A. K. Chakraborti, S. Bhagat and S. Rudrawar, Tetrahedron, 2004,
45, 7641.
75 27 J. Brask, H. Wackerbarth, K. J. Jensen, J. Zhang, Ib Chorkendorff,
and J. Ulstrup, J. Am. Chem. Soc., 2003, 125, 94.
28 P. Tundo, P. Anastas, D. S. Black, J. Breen, T. Collins, S. Memoli, J.
5
10
15
20
25
30
35
Miyamoto, M. Polyakoff and W. Tumas, Pure Appl. Chem. 2000, 72,
1207.
80
85
90
14 J. Potosky, Drug Disc. Today 2005, 10, 115.
15 S. D. Roughley and A. M. Jordan, J. Med. Chem. 2011, 54, 3451.
16 (a) S. Raha Roy, P. S. Jadhavar, K. Seth, K. K. Sharma and A. K.
Chakraborti, Synthesis, 2011, 2261. For reviews: (b) A. Dömling,
Chem. Rev., 2006, 106, 17; (c) J. Zhu and H. Bienaymé,
Multicomponent Reactions, Wiley-VCH, Weinheim, 2005.
17 (a) G. A. Olah, G. K. Surya Prakash, Á. Molnár and J. Sommer,
Superacid Chemistry, John Wiley and Sons, 2nd edn, 2009; (b) D.
Evans,
pKa
and
pKb
table,
http://www2.lsdiv.harvard.edu/labs/evans/pdf/evans_pKa_table.pdf;
(c) J. P. Guthrie, Can. J. Chem., 1978, 56, 2342; (c)
http://en.wikipedia.org/wiki/Fluoroboric_acid
18 K. Wilson and J. H. Clark, Pure Appl. Chem., 2000, 72, 1313; (b) A.
Corma and H. Garcı´a, Chem. Rev., 2003, 103, 4307; (c) J. K.
Nørskov, T. Bligaard, J. Rossmeisl and C. H. Christensen, Nature
Chem., 2009, 1, 37.
19 G. Ertl, Angew. Chem. Int. Ed. 2008, 47, 3525; (b) The 2007 Nobel
Prize in Chemistry.
40 20 (a) A. K. Chakraborti and R. Gulhane, Chem. Commun., 2003, 1896;
(b) A. K. Chakraborti and R. Gulhane, Tetrahedron Lett., 2003, 44,
3521; (c) A. K. Chakraborti and R. Gulhane, Indian Patent, 248506;
Date: 20-07-2011. Appl. No. 266/DEL/2003; (d) A. K. Chakraborti,
S. V. Chankeshwara and B. Singh, Indian Patent, 2764/DEL/2007;
45
50
55
60
65
70
(e) A. K. Chakraborti, S. V. Chankeshwara, B. Singh and A. R. Patel,
J. Org. Chem. 2009, 74, 5967; (f) R. Kumar, D. Kumar and A. K.
Chakraborti, Synthesis 2007, 299; (g) G. L. Khatik, G. Sharma, R.
Kumar and A. K. Chakraborti, Tetrahedron 2007, 63, 1200; (h) S.
Rudrawar, R. C. Besra and A. K. Chakraborti, Synthesis 2006, 2767;
(i) A. K. Chakraborti and S. V. Chankeshwara, Org. Biomol. Chem.
2006, 4, 2769; (j) G. Sharma, R. Kumar and A. K. Chakraborti,
Tetrahedron Lett. 2008, 49, 4272; (k) D. Kumar, R. Kumar and A. K.
Chakraborti, Synthesis 2008, 1249; (l) S. Rudrawar, R. C. Besra, And
A. K. Chakraborti, Synthesis, 2006, 2767; (m) D. Kumar, A. R. Patel
and A. K. Chakraborti, Green Chem., 2012, 14, 2038. (n) D. Kumar,
D. N. Kommi, R. Chebolu, S. K. Garg, R. Kumar and A. K.
Chakraborti, RSC Adv. 2013, 3, 91.
21 (a) G. Sharma, R. Kumar and A. K. Chakraborti, J. Mol. Catal. A:
Chem., 2007, 263, 143; (b) S. V. Chankeshwara and A. K.
Chakraborti, J. Mol. Cat. A: Chem., 2006, 253, 198; (c) A. K.
Chakraborti, A. Kondaskar and S. Rudrawar, Tetrahedron, 2004, 60,
9085; (d) A. K. Chakraborti, S. Rudrawar and A. Kondaskar, Org.
Biomol. Chem., 2004, 2, 1277.
22 D. N. Kommi, P. S. Jadhavar, D. Kumar and A. K. Chakraborti,
Green Chem., 2013, 15, 798. (b) R. Chebolu, D. N. Kommi, D.
Kumar, N. Bollineni and A. K. Chakraborti, J. Org. Chem., 2012, 77,
10158.
23 K. Osowska and O. Š. Miljanić, Angew. Chem. Int. Ed., 2011, 50, 1.
24 K. Alfonsi, J. Colberg, P. J. Dunn, T. Fevig, S. Jenings, T. A.
Johnson, H. P. Klein, C. Knight, M. A. Nagy, D. A. Perry and M.
Stefaniak, Green Chem., 2008, 10, 31.
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Page 13 of 13
Green Chemistry
View Article Online
DOI: 10.1039/C3GC41218K
Supported protic acid-catalyzed synthesis of 2,3-disubstituted
thiazolidin-4-one: enhancement of the catalytic potential of
protic acid by adsorbtion on solid support
Dinesh Kumar, Mukesh Sonawane, Brahmam Pujala, Varun K. Jain and and Asit K.
Chakraborti*
Department of Medicinal Chemistry, National Institute of Pharamaceutical Education and
Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India.
E. mail: akchakraborti@niper.ac.in; akchakraborti@rediffmail.com
O
HClO4-SiO2 (2.5 mol%)
PhMe, 100 oC, 3-6 h
S
NH2
+
O
+
HS
COOH
R1
R
H
N
R
R1
Yield 70-85%
43 Examples
R = R1 = aryl, heteroaryl, alkyl, aryl alkyl, and cycloalkyl
Enhancement of the catalytic potential of protic acids on adsorption on solid support for a convenient one pot tandem
multi-component synthesis of versatile thiazolidinones.