Ambient temperature synthesis of spiro[indoline-3,2′-thiazolidinones] by a DBSA-catalyzed sequential reaction in water

Article abstract of DOI:10.1016/j.tetlet.2016.02.079

An energy-efficient eco-friendly methodology for the synthesis of a series of pharmacologically important spiro[indoline-3,2′-thiazolidinones] has been developed by the reaction of primary amines with various isatin derivatives and thioglycolic acid in the presence of p-dodecylbenzenesulfonic acid (DBSA) as an efficient Br?nsted acid surfactant combined catalyst in aqueous medium at 25 °C. This synthetic protocol demonstrates several advantages such as operational simplicity, energy-efficiency, good to excellent isolated yields, and the use of a preferred green solvent system for the preparation of desired products.

Full text of DOI:10.1016/j.tetlet.2016.02.079

Accepted Manuscript
Ambient temperature synthesis of spiro[indoline-3,2’-thiazolidinones] by a
DBSA-catalyzed sequential reaction in water
Amreeta Preetam, Mahendra Nath
PII:
S0040-4039(16)30188-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.079
TETL 47354
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
13 January 2016
17 February 2016
19 February 2016
Please cite this article as: Preetam, A., Nath, M., Ambient temperature synthesis of spiro[indoline-3,2’-
thiazolidinones] by a DBSA-catalyzed sequential reaction in water, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.02.079
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Graphical Abstract
Ambient temperature synthesis of
spiro[indoline-3,2’-thiazolidinones] by a
DBSA-catalyzed sequential reaction in water
Leave this area blank for abstract info.
Amreeta Preetam and Mahendra Nath*

Tetrahedron Letters
journal homepage: www.els evier.com
Ambient temperature synthesis of spiro[indoline-3,2’-thiazolidinones] by a
DBSA-catalyzed sequential reaction in water
Amreeta Preetama and Mahendra Natha,∗
a
Department of Chemistry, University of Delhi, Delhi-110007, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
An energy-efficient eco-friendly methodology for the synthesis of
a
series of
pharmacologically important spiro[indoline-3,2’-thiazolidinones] has been developed by the
reaction of primary amines with various isatin derivatives and thioglycolic acid in the presence
of p-dodecylbenzenesulfonic acid (DBSA) as an efficient Brønsted acid surfactant combined
catalyst in aqueous medium at 25 °C. This synthetic protocol demonstrates several advantages
such as operational simplicity, energy-efficiency, good to excellent isolated yields and the use
of a preferred green solvent system for the preparation of desired products.
Received in revised form
Accepted
Available online
Keywords:
Brønsted acid catalyst
p-Dodecylbenzenesulfonic acid
Eco-friendly synthesis
Isatin derivatives
.
Spiro[indoline-3,2’-thiazolidinones]
4-Thiazolidinone and indole scaffolds are the core
In recent years, multi-component reactions
units of many sulfur and nitrogen heterocycles of biological (MCR’s) are increasingly popular as versatile synthetic
significance.1 They have also been used as synthetic alternatives to the multistep syntheses for obtaining
building blocks to construct diverse biodynamic agents via structurally diverse molecular frameworks with high
the conjugation with other bioactive pharmacophores.2 In efficiency.13 They can be attractive synthetic tools to access
addition, spiro[indole-thiazolidinones] are important the molecular complexity and suited for generating libraries
structural motif present in various pharmacologically of diverse organic compounds. Thorough literature survey
relevant naturally occurring molecules3 and exhibit certain revealed that these reactions can be efficiently accelerated in
promising biological profiles such as antibacterial,4 aqueous medium by using surfactant combined catalysts,14
antifungal,5 anticancer,6 antihistaminic,7 antileukemic8 and thereby constituting eco-friendly protocols. Among the
anti-convulsant9 agents. Furthermore, these molecules were various surfactants,
found to be a potent and selective inhibitors of a protein, has emerged as an efficient Bronsted-acid catalyst for
p-dodecylbenzenesulfonic acid (DBSA)
10
tyrosinase phosphatase B in Mycobacterium tuberculosis
.
carrying out
a
number of water-sensitive organic
By considering the biological significance of spiro[indole- transformations in aqueous media.15 In view of growing
thiazolidinones], a number of methods have been developed interest to develop one-pot multi-component reaction
for their preparation by reacting amines with isatins and protocols and in continuation of our efforts to synthesize
mercaptoacetic acid under different conditions using either structurally diverse molecular scaffolds by using greener
one-pot strategy or two-step process involving isatin-3- methodologies,16 we wish to report herein a DBSA-
imine as a key intermediate.11,12 However, most of the catalyzed sequential strategy for the synthesis of a series of
reported synthetic procedures suffer from many spiro[indoline-3,2’-thiazolidinone] derivatives in aqueous
disadvantages such as high reaction temperature, longer medium at ambient temperature.
reaction times, use of flammable organic solvents,
expensive catalysts, harsh reaction conditions, tedious
workup and lower yields of the desired products. reacting aniline (1a) with 5-chloroindolin-2,3-dione (2a
Initially, a trial experiment was carried out by
)
Additionally, some of these methods also require and thioglycolic acid as model substrates in the molar ratio
dehydrating agents or carcinogenic hydrocarbons for the of 1:2:3, respectively in the presence of 10 mol% DBSA as
azeotropic removal of water formed during the reaction or an acidic catalyst in aqueous media at room temperature for
special apparatus such as microwave and ultra-sonicator to 24 hours. Surprisingly, a mixture of three compounds was
improve the yields of target spiro-indole derivatives. obtained which after chromatographic separation provided
Therefore, the development of an environmentally benign,
convenient and economical synthetic strategy for the phenylspiro[indoline-3,2
synthesis of pharmaceutically important spiro[indole- 2-mercapto- -phenylacetamide (
thiazolidinones] is highly desired. isolated yields, respectively (Scheme-1).
(
Z
)-5-chloro-3-(phenylimino)-indolin-2-one (
-thiazolidine]-2,4 -dione (4a) and
) in 5%, 15% and 75%
3), 5-chloro-3'-
'
'
N
5
———
∗ Corresponding author. fax: +91 11 27666605; e-mail: mnath@chemistry.du.ac.in

Scheme 1: Synthesis of 5-chlorospiro[indoline-3,2'-thiazolidine]-2,4'-dione (4a).
In order to improve the yield of desired product 4a, we smoothly and produced the corresponding spiro[indole-
thought to add the starting materials in a sequential manner. thiazolidinones] (4a-l) in good to excellent yields (Table-1).
Firstly, a reaction of aniline (1a, 1 mmol) and 5- In general, an aryl amine having electron-donating
chloroindolin-2,3-dione (2a, 2 mmol) was carried out for 18 substituent such as methoxy on the para-position of a phenyl
hours at ambient temperature in water containing 10 mol% ring reacted well with
DBSA to generate the corresponding Schiff base acid and produced the desired spiro-indole derivative (4i) in
intermediate ( ) which after the addition of thioglycolic acid 82% yield (Table entry ) whereas the reaction of less
(3 mmol) in the same flask afforded the desired product, 5- reactive -fluoroaniline containing electron withdrawing
chloro-3 -phenylspiro-[indoline-3,2 -thiazolidine]-2,4 -dione fluoro substituent on the phenyl ring with 2f and
4a) in 81% isolated yield (Scheme 1). thioglycolic acid was found to be sluggish and afforded the
desired product 4g in 75% yield (Table , entry ). In
N-phenylisatin (2f) and thioglycolic
3
1
9
p
'
'
'
(
1
7
contrast, the reactions of benzylamine with various isatins
and thioglycolic acid were proceeded in a faster rate and
afforded the desired products (4j-l) in higher yields (Table
Under the optimized conditions, the generality of
this synthetic protocol was investigated by the reaction of
various primary amines (1a-e) with a number of isatin
derivatives (2a-f) and thioglycolic acid in the presence of 10
mol% DBSA in water at 25 °C. All the reactions underwent
1
, entries 10-12).
Table 1: DBSA-catalyzed synthesis of spiro[indoline-3,2'-thiazolidine]-2,4'
-dione derivatives (4a-l)a at 25 °C.
Entry
Amines
Isatins
Products
Yield (%)b
1.
81
2.
78
3.
78
4.
5.
76
78

5
O
O
N
6.
80
75
2f
O
O
N
7.
2f
8.
76
O
O
N
9.
82
87
88
86
2f
10.
11.
12.
aReagents and conditions: Amines 1a-e (1 mmol), isatin derivatives 2a-f (2.0 mmol), H2O (2.0 ml), DBSA (0.10 mmol), thioglycolic acid (3 mmol), 25 °C.
bIsolated yields after column chromatography.
1728, 1689 cm-1 due to the stretching of a NH and two C=O
bonds of cyclic amide rings, respectively. In the H NMR
A possible mechanistic pathway for the formation
1
of spiro[indoline-3,2’-thiazolidinones] (4a-l) is depicted in
figure . The reaction likely proceeds through the formation
of a protonated Schiff base ( ) after the reaction of amine
and isatin substrates in water in the presence of DBSA as a
Brønsted acid catalyst. In the next step, the intermediate (
spectrum of 4a, each methylene proton appeared as a
doublet at δ 4.03 and 4.15 ppm with the value 15.26 Hz
1
J
I
due to the geminal coupling between two hydrogens of S-
CH2-CO group. Besides the aromatic protons, a broad
singlet for NH proton was appeared at δ 10.90 ppm. The
presence of three characteristic carbon signals observed at δ
32.57, 176.20 and 171.90 ppm in 13C NMR spectrum of
compound 4a owing to S-CH2-CO and C=O groups,
respectively, confirmed the formation of spiro(indoline-
thiazolidinone) ring in the product. In addition, the mass
spectrum of compound 4a also supported the assigned
structure by showing a [M+H]+ ion peak at m/z 331.0295
for the molecular formula, C16H12ClN2O2S. Finally, the
structure of compound (4a) was confirmed by single crystal
I
)
reacts with thioglycolic acid to form intermediate (II) which
probably undergoes a proton shift from the electron
deficient sulfur to the carboxylic group followed by an
intramolecular cyclization to generate a gem-diol (III).
Further, proton transfer and release of a water molecule
afford the desired product (4).
All the newly synthesized compounds have been
1
characterized on the basis of IR, H NMR, 13C NMR and
mass spectral analysis. The IR spectrum of the 5-chloro-3
phenylspiro[indoline-3,2 -thiazolidine]-2,4 -dione 4a)
exhibited three characteristic absorption peaks at 3416,
'-
X-ray analysis (Figure 2
).17
'
'
(

6
Figure 1: Plausible reaction mechanism for the synthesis of spiro[indole-thiazolidinones].
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Figure 2: X-ray crystal structure of compound 4a.
,
,
In summary, an ambient temperature eco-friendly
,
,
synthetic strategy for the construction of
spiro[indole-thiazolidinones] has been accomplished by using
DBSA as Brønsted acid catalyst. This methodology
a variety of
,
a
demonstrates several key advantages including green reaction
conditions, use of aqueous media and good to excellent yields of
desired products.
,
,
9
Raghuvanshi, D. S.; Singh, K. N. J Heterocycl. Chem. 2009
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This work is supported by University of Delhi, India under the
scheme to strengthen R&D Doctoral Research Programme. We
are thankful to Central Instrumentation Facility, University of
Delhi, India for providing NMR and mass spectra and single
crystal X-ray data. Amreeta Preetam is grateful to CSIR, New
Delhi, India for providing Senior Research Fellowship.
,
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,
Supplementary data
,
, 1
Supplementary data associated with this article can be
found in the online version, at http://dx.doi.org/
,
,
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7
Highlights
An energy efficient synthesis of
•
diverse
spiro[indoline-3,2’-
thiazolidinones].
•
•
•
The present methodology avoids the
use of hazardous organic solvents.
The reactions are run in pure water
at ambient temperature.
The use of aqueous media makes the
process green and economical.