Versatile three component procedure for combinatorial synthesis of biologically relevant scaffold spiro[indole-thiazolidinones] under aqueous conditions

Article abstract of DOI:10.1039/c0gc00863j

A straightforward aqueous-mediated ultrasound-promoted novel protocol is developed for the quantitative synthesis of medicinally important spiro[indole-thiazolidinone] libraries by the tandem reaction of readily available reagents using cetyltrimethylammo

Full text of DOI:10.1039/c0gc00863j

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PAPER
Versatile three component procedure for combinatorial synthesis of
biologically relevant scaffold spiro[indole-thiazolidinones] under aqueous
conditions†
Anshu Dandia,*a Ruby Singh,a Sumit Bhaskarana and Shriniwas D. Samantb
Received 30th November 2010, Accepted 11th April 2011
DOI: 10.1039/c0gc00863j
A straightforward aqueous-mediated ultrasound-promoted novel protocol is developed for the
quantitative synthesis of medicinally important spiro[indole-thiazolidinone] libraries by the
tandem reaction of readily available reagents using cetyltrimethylammonium bromide as a phase
transfer catalyst. The present method is more convenient and efficient as compared to multistep
conventional processes and it obviates the azeotropical removal of water and use of carcinogenic
solvents and dehydrating agents. Other features of this method are operational simplicity and
increased safety for high speed synthesis and minimal environment impact.
Introduction
Diversity-orientated synthesis (DOS) continues to be an area of
importance at the interface of the fields of organic synthesis and
chemical biology.1,2 Thiazolidinone, an important “privileged
scaffold,” is a very attractive target for combinatorial library
synthesis because of their structure activity relationship3 and is
an important class of N and S containing heterocycles which
are widely used as key building blocks in the field of drugs and
pharmaceutical agents.4 Further, the presence of the N–C–S
linkage in the thiazolidines is also responsible for nematocidal
activity,5 e.g. Omizole.
Indole nucleus appears in numerous medicinally active com-
pounds and natural products of biological significance.6 The
spirooxindole system is the core structure of many pharmaco-
logical agents and natural alkaloids.7 For example, spirotrypro-
statin A (1), a natural product isolated from the fermentation
Fig. 1 Representatives of spirooxindole-containing compounds.
broth of Aspergillus fumigatus, has been identified as a novel
inhibitor of microtubule assembly8 and pteropodine (2) and
isopteropodine (3) have been shown to modulate the function of
spirobrassinin10 (4) Fig. 1). The diversity of their biological func-
muscarinic and serotonin receptors9 (Fig. 1).
tions such as anti-inflammatory, antimicrobial, antileukemic
In addition, the spiro[indole-thiazolidine] system is a struc-
and anticonvulsant activities has stimulated efforts in the
tural motif present in many pharmacologically important
expedient development of their synthesis.11
synthetic and naturally occurring compounds (as typified by
With the emergence of high-throughout pharmaceutical
screening, there are increasing demands for the rapid genera-
tion of libraries of heterocyclic compounds. Multi-component
reactions12 are an excellent strategy to prepare libraries of high
molecular diversity because of their convergent nature, superior
atom economy and straight forward experimental procedure.
A literature survey shows that most of the reported methods
for the synthesis of thiazolidinone involve the use of high
boiling carcinogenic hydrocarbons with continuous azeotropic
aDepartment of Chemistry, University of Rajasthan, Jaipur, 302 004,
India
bInstitute of Chemical Technology, Mumbai, 400 019, India.
E-mail: dranshudandia@yahoo.co.in
† Electronic supplementary information (ESI) available: Experimen-
tal procedures, characterization data and twenty 1HNMR, twelve
13CNMR and nine mass spectra of representative compounds. See DOI:
10.1039/c0gc00863j
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removal of water13 or requiring desiccants like anhydrous
ZnCl2,14 sodium sulphate15 or molecular sieves16 and the use of
stoichiometric amount of DCC17 and Hu¨nig base18 in solution-
phase reactions.
can be carried out in higher yields, shorter reaction times or
milder conditions under ultrasound irradiation.33 Further, the
combination of phase transfer catalyst, water and ultrasound
irradiation has already been reputed in literature.34 Hence
encouraged by this we have tried to explore the combination of
ultrasound irradiations and phase transfer catalyst in aqueous
medium for the synthesis of spiro[indole-thiazolidinones].
First, to study the role of alternative green solvent, we tested
the reaction of indole-2, 3-dione (1), 4-amino antipyrine (2)
and 2-mercaptopropionic acid (3) as a simple model substrate
in aqueous medium in the presence of various additives under
sonication and the results are shown in Table 1. To our delight,
we got very encouraging results while earlier conventional
methods involve the azeotropic removal of water or use of
dehydrating agents.
In line with our interest on spiro indoles, extensive
work has been carried out in our lab on the spiro[indole-
thiazolidinone]19,20 system. Recently we have reported20 a non-
conventional microwave-assisted three-component, regioselec-
tive one-pot cyclocondensation method for the synthesis of a
series of novel spiro[indole-thiazolidinones] using montmoril-
lonite KSF as an inorganic solid support in an open vessel in a
modified domestic microwave. Although this method has its own
merits in comparison to a conventional two-step procedure but
these microwave assisted reactions still require use of solvent
for adsorption and desorption and also not suitable for large
scale preparation with reproducibility. Hence there is a scope for
further development of an efficient, high yielding green protocol
using water as green solvent.
With an increasing environmental consciousness in chemical
research and industry, the challenge for a sustainable environ-
ment calls for clean procedures.21 To remove organic solvents
from a chemical process, many old reactions have been revised
and carried out in water.22 It is presumed that water facilitates
the organic reaction in non-polar media by significant factors23
like a hydrophobic effect, enhanced hydrogen bonding in the
transition state and cohesive energy density. On the other hand
ultrasonic-assisted organic synthesis as a powerful technique is
being used more and more to accelerate organic reactions.24 This
technique is more convenient taking green chemistry concepts
into account.
As a consequence of our interest to develop new selec-
tive environmentally friendly methodologies for the prepara-
tion of pharmaceutically important scaffolds,25 a high speed,
ultrasound-promoted, one-pot and multicomponent synthetic
route utilizing readily available reagents has been developed
in our laboratory, and is described in the present article, to
produce a library of spiro [indole-thiazolidinone] derivatives in
water using the surfactant CTAB (cetyltrimethyl ammonium
bromide) for the first time. Moreover, to the best of our
knowledge, synthesis of spiro[indole-thiazolidinones] involving
the cyclocondensation reaction of heterocyclic or aryl amines
with a-mercaptocarboxylic acids in water has also not been
demonstrated so far.
If the spiroindole nucleus is coupled to other biologi-
cally active heterocycles, the resulting system is expected to
show an increased spectrum of biological activities.26 Keeping
this in mind, we have synthesized a library of spiro[indole-
thiazolidinones]-2,4¢-diones by incorporating various poten-
tial pharmaceutically important heterocyclic moieties, e.g.,
dimethyl-2-phenyl-pyrazol-3-one,27 triazole,28 benzimidazole,29
benzothiazole,30 indazole31 by extending the title reaction to
various corresponding heterocyclic amines.
It was found that the presence of CTAB in water is the
best choice of reaction conditions out of various other
PTCs like sodium dodecyle sulfate (SDS) and cetyltrimethyl
ammonium chloride (CTAC) (entry 2, 3), because CTAB
acts as an emulsifying agent, forming colloidal dispersion
systems with organic substrates and makes the mixture more
even, which contributes to promoting these reactions.35 The
desired crystalline, pure (TLC) 3¢-(2,3-dihydro-1,5-dimethyl-3-
oxo-2-phenyl-1H-pyrazol-4-yl)-5¢-methyl-spiro[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4a) was obtained in quantitative
◦
yield under ultrasound irradiation at 80 C in 2 h using a low
intensity ultrasonic laboratory (LIU) cleaning bath (entry 4) and
in 50 min using a high intensity ultrasonic probe system (HIU)
(entry 10). The major advantage of ultrasound irradiation in the
present heterogeneous system is mainly a consequence of the
mechanical effects of cavitation36 involving the efficient mixing
of reactants which increases the rate and yield of the reaction
with easier work-up. We have also examined this reaction in
the absence and presence of several other additives including
acids such as LiCl, ZnCl2, AlCl3, p-TSA and biocatalysts such
as L-proline, which were found to push the reaction forward
but with rather unsatisfactory outcomes as compared to the
employed surfactants. It was found that when the reaction was
carried out without any additives, this resulted in poor yield
(entry 1). When reaction is carried out in boiling water (entry
9) using conventional heating, in the absence of sonication,
a lower yield was found and this method also suffers from
drawbacks such as tedious work-up and lower yield. Hence,
there is a combined effect of ultrasound and PTC to promote
the present reaction.
To optimize the reaction temperature using low cost and
easily available LIU, the reactions were carried out at different
temperatures, ranging from room temperature to 80 ◦C. We
found that the yield of product was improved and the reaction
time was shortened as the temperature was increased to 80 ◦C.
Therefore, the most suitable reaction temperature is 80 ◦C.
We also evaluated the amount of surfactant required for this
transformation. It was found that when increasing the amount
of the CTAB from 5, 10 and 20 mol%, the yields increased from
85 to 89 and 94%, respectively. Using a lower amount of catalyst
resulted in lower yields and a higher amount of catalyst did not
affect the reaction time or yields.
Results and discussion
In recent years many surfactants have been used as phase
transfer catalyst in a number of organic reactions having unique
capabilities to dissolve both organic and aqueous solution to
enhance the reaction rate.32 A large number of organic reactions
To further improve the procedure, the model reaction was
also carried out using high intensity ultrasound probe system
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Table 1 Model reaction: conditions and yields
Entry
Reaction conditions
Additive
T/◦C
Time (h/min)
Yield (%)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
LIU/water
LIU/water
LIU/water
LIU/water
LIU/water
LIU/water
LIU/water
LIU/water
Reflux/water
HIU/water
—
SDS
80
80
80
80
40
50
60
70
97
45
3 h
3 h
3 h
2 h
4 h
3 h
3 h
2 h
4 h
*50 min.
25
65
74
94
82
85
86
89
51
96
CTAC
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
LIU = Low intensity ultrasonic laboratory cleaning bath; HIU = High intensity ultrasonic probe system. CTAB (20 mol%) = 0.218 g; * Irradiation
time with 4 s pulse mode and interval of 5 min after every 15 min
(HIU) for comparative studies (entry 10) and it was found that
comparable yields in a shorter reaction time with reproducible
results was achieved using a sonicator as compared to LIU
ultrasonic bath.37 It is well established that LIU from an
ultrasonic cleaner has considerably less power and the energy
of the ultrasound is not uniformly available from the ultrasonic
bath when compared to HIU from a direct immersion horn.38
This can lead to reproducibility problems due to the lower power
involved for LIU.39 Hence, other compounds listed in Table 2
were synthesized under HIU irradiation.
analyses and comparisons with authentic samples prepared
conventionally. Although pure crystalline product (TLC) was
obtained under sonication, for analytical purposes the product
was further recrystallized from ethanol. The spiro compounds
(where R = CH3) contain two chiral centers, hence exists they in
two diastereomeric forms, which was confirmed by appearance
of two sets of signals in 1H NMR.
Conclusion
After optimization of the conditions, to delineate this ap-
proach, particularly in regard to library construction, this
methodology was evaluated by using different isatins, amines
and a-mercaptocarboxylic acids (Scheme 1). Seven substituted
isatins (1), six heterocyclic amines (2a–f)/twelve substituted
anilines (2g) and two a-mercaptocarboxylic acids (3) were
chosen for the library validation. Corresponding spiro[indole-
thiazolidinones] 4 were synthesized in good yields.
The present green methodology for “on water” mediated three-
component and CTAB catalyzed synthesis of spiro[indole-
thiazolidinones] under sonication, is a simple, convenient and
environmentally friendly method and would be applicable for
the library synthesis of spiro-ring systems in good yield without
using any dehydrating agents and solvents with easy purification.
We expect this method to find extensive application in the field
of combinatorial chemistry, diversity-oriented synthesis, large
scale preparation and drug discovery.
3. Experimental section
Melting points were determined on a Toshniwal apparatus. The
purity of compounds was checked on thin layers of silica gel in
various non-aqueous solvent systems, e.g. benzene : ethylacetate
(9 : 1), benzene : dichloromethane (8 : 2). IR spectra (KBr) were
1
recorded on a Magna FT IR–550 spectrophotometer and H
NMR and 13C NMR spectra were recorded on Bruker DRX-
300 using CDCl3 at 300.13 and 75.47 Hz, respectively. TMS was
used as internal reference. DART Mass spectra of representa-
tive compounds were recorded on YOKUDELNA_ES+_2000
spectrometer and EIMS were recorded on Kratos Mass spec-
trometer. The ultrasound-assisted reactions were carried out
in and ultrasonic bath (Bandelin Sonorex) operating at 230 V
generating 33 KHz output frequency. The location at which the
Scheme 1 Synthesis of spiro[indole- 3, 2¢- thiazolidinone]-2,4-diones
(4a–4uu).
All synthesized spiro compounds 4(a-uu) are stable solids
whose structures were established by spectral and elemental
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Table 2 Synthetic results of 4a–uu catalyzed by CTAB in water
2-mercaptopropionic acid (3.5 mmol) and cetyltrimethylammo-
nium bromide (0.218 g, 20 mol%) in water (10 ml) were taken in a
conical flask, which was immersed in water bath of an ultrasonic
cleaner. The flask was positioned 0.5 cm above the bottom of the
bath at 80 ◦C. After completion of reaction (monitored by TLC),
the reaction mixture was cooled to room temperature, and then
the product was filtered and washed with water to afford the
pure product 4a. (TLC)
Entry
X
R
Het/Ar
Yield (%)
4a
H
CH3
CH3
H
CH3
H
CH3
CH3
H
2a
92
93
95
90
94
98
98
90
90
95
90
93
93
88
84
92
89
96
93
91
93
90
89
92
90
90
90
90
89
90
89
87
85
89
91
95
85
72
80
80
90
97
95
98
92
96
93
4b
5-Br
5-Br
5-F
2a
4c
2a
4d
2a
4e
5-F
2a
4f
5-CH3
5-Cl
H
5-CH3
5-Cl
H
5,7-diCH3
5,7-diCH3
5-Cl
5-Cl
H
5-CH3
H
2a
4g
2a
(ii) Reaction under HIU irradiation using sonicator: A mixture
of indole-2,3-dione (3 mmol), 4-amino antipyrine (3 mmol), 2-
mercaptopropionic acid (3.5 mmol) and cetyltrimethylammo-
nium bromide (0.218 g, 20 mol%) in water (10 ml) were taken
in a flask. The flask was attached to a 12 mm tip diameter
probe and the reaction mixture was sonicated for the specified
period at 50% power of the processor at 4 s pulse mode. At the
end of the reaction period, TLC was checked and the flask was
detached from the probe and the content was transferred into a
beaker. The formed product was filtered and washed with water
to afford the pure crystalline product). Mp 320 ◦C. IR (KBr)
4h
2a
4i
4j
H
2a
CH3
CH3
CH3
H
CH3
H
H
H
H
H
H
CH3
H
H
CH3
H
CH3
H
H
CH3
CH3
H
2b
4k
4l
2b
2b
4m
4n
2b
2c
4o
2c
4p
2c
4q
2c
4r
2d
4s
H
2e
4t
5-Cl
5-Br
5,7-diCH3
5-CH3
H
H
H
H
H
H
5-CH3
5,7-diCH3
5,7-diCH3
5-Cl
H
H
H
2e
1
(nmax/cm-1) 3350, 2940, 2880, 1750, 1700, 1650. H NMR (300
4u
2e
4v
2e
MHz, DMSO-d6) dH (ppm) diastereomeric ratio (3 : 1) 1.52/1.79
(d, 3H, CH3), 2.12 (s, 3H, CH3), 3.01 (s, 3H, N-CH3), 4.52/4.31
(q, lH, CH), 6.75–7.62 (m, 9H, Ar-H), 10.82/10.45 (s, 1H, NH).
DART Mass 421.14 [M+1]. Anal. calc. for C22H20N4O3S; C,
62.84; H, 4.79; N, 13.32. Found C, 62.75; H, 4.85; N, 13.38.
4w
4x
2e
2e
4y
4z
2f
2g (Y = 4-F)
2g (Y = H)
2g (Y = 4-F)
2g (Y = 3-CF3)
2g (Y = 2-CF3)
2g (Y = 3-Cl)
2g (Y = H)
2g (Y = 2-Cl, 5-CF3)
2g (Y = 4-OCH3)
2g (Y = 4-Br)
2g (Y = 4-Cl)
2g (Y = 4-OH)
2g (Y = 4-Br)
2g (Y = 4-Cl)
2g (Y = 4-Cl)
2g (Y = 4-Cl)
2g (Y = H)
2g (Y = 3-CF3)
2g (Y = 2-Cl, 5-CF3)
2g (Y = 2-NO2, 4-Cl)
2g (Y = 2,6-diCl)
2g (Y = 2,6-diCl)
4aa
4bb
4cc
4dd
4ee
4ff
4gg
4hh
4ii
5-Bromo-3¢-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-
pyrazol-4-yl)-5¢-methyl-spiro[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4b)
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
Mp 339 ◦C. IR (KBr) (nmax/cm-1) 3355, 2943, 2886, 1748, 1703,
1655. 1H NMR (300 MHz, DMSO-d6) dH (ppm) diastereomeric
ratio (3 : 1) 1.53/1.80 (d, 3H, CH3), 2.10 (s, 3H, CH3), 3.02 (s,
3H, N-CH3), 4.56/4.36 (q, lH, CH), 6.76–7.61 (m, 8H, Ar-H),
10.85/10.44 (s, 1H, NH). 13C NMR (75.47 MHz, DMSO-d6)
dC (ppm) 176.67, 174.16, 161.79 (three C O), 153.88, 141.77,
134.60, 131.15, 129.10, 127.60, 126.99, 125.44, 124.58, 123.92,
123.29, 122.10, 110.15, 103.97 (aromatic & other carbons), 67.26
(spiro carbon), 40.58, 34.93 (CH & N–CH3), 17.12 (CH3), 10.12
(CH3). Anal. calc. for C22H19BrN4O3S; C, 52.91; H, 3.83; N,
11.22. Found C, 52.80; H, 3.86; N, 11.28.
4jj
4kk
4ll
H
5-Br
5-Br
5-NO2
5-CH3
H
5,7-diCH3
H
H
5-Cl
5-Cl
4mm
4nn
4oo
4pp
4qq
4rr
4ss
4tt
4uu
H
CH3
H
CH3
CTAB (20 mol%) = 0.218 g; Irradiation time 40–50 min with 4 s pulse
mode.
5-Bromo-3¢-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-
pyrazol-4-yl)-spiro[3H-indole-3,2¢-thiazolidine]-2,4¢(1H)-
dione (4c)
intensity of ultrasound is maximum was checked by Weissler
reaction.40 HIU irradiation was provided by the ultrasonic
processor probe system (Processor SONOPROS PR-1000MP,
OSCAR ULTRASONICS made) operating at 20 KHz, 750 W
with 6mm/12 mm tip diameter probes and provided with an
infrared sensor for temperature measurement. The synthesized
compounds were compared with the authentic samples, pre-
pared by the conventional method.
Mp 333 ◦C. IR (KBr) (nmax/cm-1) 3350, 2946, 2884, 1750, 1703,
1
1655. H NMR (300 MHz, DMSO-d6) dH (ppm) 2.50 (s, 3H,
CH3), 3.04 (s, 3H, N–CH3), 3.99 (d, 1H, CH), 4.17 (d, 1H, CH),
6.76–7.79 (m, 8H, Ar–H), 10.93 (s, 1H, NH). C22H17BrN4O3S;
C, 51.97; H, 3.53; N, 11.54. Found C, 51.89; H, 3.56; N, 11.59.
5-Fluoro-3¢-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-
pyrazol-4-yl)-5¢-methyl-spiro[3H-indole-3,2¢-thiazolidine]-
2,4¢(1H)-dione (4d)
Typical procedure for preparation of 3¢-(2,3-dihydro-1,5-
dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)-5¢-methyl-spiro[3H-
indole-3,2¢-thiazolidine]-2,4¢(1H)-dione (4a)
Mp 337 ◦C/>280 ◦C.13f IR (KBr) (nmax/cm-1) 3357, 2945, 2889,
1
(i) Reaction under LIU irradiation using ultrasound bath: A mix-
1752, 1701, 1652. H NMR (300 MHz, DMSO-d6) dH (ppm)
ture of indole-2,3-dione (3 mmol), 4-amino antipyrine (3 mmol),
diastereomeric ratio (3 : 1) 1.59/1.78 (d, 3H, CH3), 2.50 (s, 3H,
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CH3), 3.04 (s, 3H, N-CH3), 4.50/4.37 (q, lH, CH), 6.70–7.56 (m,
8H, Ar-H), 10.78/10.72 (s, 1H, NH).
carbons), 67.16 (spiro carbon), 34.83 (CH), 17.85 (CH3). EI MS
302 [M+]
5-Fluoro-3¢-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-
pyrazol-4-yl)-spiro[3H-indole-3,2¢-thiazolidine]-2,4¢(1H)-
dione (4e)
3¢-(1H-1,2,4-Triazol-5-yl)-5,7,5¢-trimethyl-spiro[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4l)
◦
◦
Mp 280 C/278 C.20a IR (KBr) (nmax/cm-1) 3362–3274, 2946,
Mp 340 ◦C/307 ◦C.19b
1
2887, 1735, 1700, 1605. H NMR (300 MHz, DMSO-d6) dH
(ppm) diastereomeric ratio (3 : 1) 1.57/1.74 (d, 3H, CH3), 2.12
(s, 3H, CH3), 2.50 (s, 3H, CH3), 4.49 (q, 1H, CH), 6.81–7.82 (m,
2H, Ar-H), 8.31 (s, 1H, CH), 10.68/10.63 (s, 1H, NH), 13.92 (s,
1H, NH).
3¢-(2,3-Dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)-
5,5¢-dimethyl-spiro[3H-indole-3,2¢-thiazolidine]-2,4¢(1H)-
dione (4f)
◦
◦
Mp 326 C/325 C.19b IR (KBr) (nmax/cm-1) 3354, 2942, 2880,
5,7-Dimethyl-3¢-(1H-1,2,4-triazol-5-yl)-spiro[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4m)
1
1746, 1705, 1665. H NMR (300 MHz, DMSO-d6) dH (ppm)
diastereomeric ratio (3 : 1) 1.59/1.81 (d, 3H, CH3), 2.08–2.39
(s, 6H, CH3), 3.22 (s, 3H, N–CH3), 4.55/4.34 (q, lH, CH),
6.70–7.89 (m, 8H, Ar–H), 10.72/10.40 (s, 1H, NH).13C NMR
(75.47 MHz, DMSO-d6) dC (ppm) 176.81, 175.04, 167.11 (three
Mp 152 ◦C/152 ◦C.20a
5-Chloro-3¢-(1H-benzimidazol-2-yl)-5¢-methyl-spiro[3H-indole-
3,2¢-thiazolidine]-2,4¢(1H)-dione (4n)
C
O), 141.85, 136.57, 130.85, 129.12, 128.63, 128.35, 128.12,
128.05, 126.17, 124.86, 122.81, 122.76, 110.90 (aromatic & other
carbons), 68.34 (spiro carbon), 43.03, 30.91 (CH & N–CH3),
22.36 (CH3), 17.99 (CH3), 10.36 (CH3).
Mp 263 ◦C. IR (KBr) (nmax/cm-1). 3375–3247, 1723, 1693, 1605,
1532. 1H NMR (300 MHz, DMSO-d6) dH (ppm), 1.38 (d,
3H, CH3), 4.50/4.38 (q, 1H, CH), 6.94–7.18 (m, 7H, Ar–H),
10.90/10.80 (s, 1H, NH). DART Mass 385.31(M+1) Anal. calc.
for C18H13ClN4O2S; C, 56.18; H, 3.40; N, 14.56. Found C, 56.11;
H, 3.43; N, 14.61.
5-Chloro-3¢-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-
pyrazol-4-yl)-5¢-methyl-spiro[3H-indole-3,2¢-thiazolidine]-
2,4¢(1H)-dione (4g)
Mp 323 ◦C/323 ◦C.19b
5-Chloro-3¢-(1H-benzimidazol-2-yl)-spiro-[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4o)
3¢-(2,3-Dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)-
spiro[3H-indole-3,2¢ thiazolidine]-2,4¢(1H)-dione (4h)
Mp 265 ◦C. IR (KBr) (nmax/cm-1). 3370–3241, 1725, 1690, 1605,
1
1530. H NMR (300 MHz, DMSO-d6) dH (ppm), 3.38 (d, 1H,
Mp 307 ◦C/307 ◦C.19b
CH), 4.39 (d, 1H, CH), 6.72–7.78 (m, 7H, Ar-H), 10.12 (s, 1H,
NH), 12.89 (s, 1H, NH).13C NMR (75.47 MHz, DMSO-d6)
dC (ppm) 171.47, 167.69, (two C O), 150.95, 145.01, 139.25,
132.08, 130.26, 128.01, 127.27, 126.01, 123.88, 122.47, 118.01,
108.01 (aromatic carbons), 65.30 (spiro carbon), 29.84 (CH2).
Anal. calc. for C17H11ClN4O2S; C, 55.06; H, 2.99; N, 15.11.
Found C, 55.01; H, 97; N, 15.09.
5-Methyl-3¢-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-
pyrazol-4-yl)-spiro[3H-indole-3,2¢-thiazolidine]-2,4¢(1H)-
dione (4i)
Mp 309 ◦C/305 ◦C.19b
5-Chloro-3¢-(1H-1,2,4-triazol-5-yl)-5¢-methyl-spiro[3H-indole-
3,2¢-thiazolidine]-2,4¢(1H)-dione (4j)
3¢-(1H-Benzimidazol-2-yl)-spiro-[3H-indole-3,2¢-thiazolidine]-
2,4¢(1H)-dione (4p)
Mp 295 ◦C. IR (KBr) (nmax/cm-1) 3358–3269, 2945, 2894,
Mp 235 ◦C/232 ◦C.20a
1
1737, 1696, 1603. H NMR (300 MHz, DMSO-d6) dH (ppm)
diastereomeric ratio (3 : 1) 1.89 (d, 3H, CH3), 4.56/4.30 (q, 1H,
CH), 6.88–7.22 (m, 3H Ar–H), 7.79 (s, 1H, CH), 10.46 (s, lH,
NH), 13.71 (s, lH, NH). DART Mass 336.16 [M+1]. Anal. calc.
for C13H10ClN5O2S; C, 46.50; H,3.00; N, 20.86. Found C, 46.59;
H, 3.03; N, 20.90.
5-Methyl-3¢-(1H-benzimidazol-2-yl)-spiro-[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4q)
Mp 260 ◦C/258 ◦C.20a
3¢-(6-Chloro-1,3-benzothiazol-2-yl)-spiro-[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4r)
3¢-(1H-1,2,4-Triazol-5-yl)-5¢-methyl-spiro-[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4k)
Mp 160 ◦C/157 ◦C.19b
◦
◦
Mp 275 C/272 C.20a IR (KBr) (nmax/cm-1) 3360–3270, 2943,
1
2890, 1735, 1700, 1605. H NMR (300 MHz, DMSO-d6) dH
3¢-(1,3-Benzothiazol-2-yl)-spiro-[3H-indole-3,2¢-thiazolidine]-
2,4¢(1H)-dione (4s)
(ppm) diastereomeric ratio (3 : 1) 1.78 (d, 3H, CH3), 4.62/4.25
(q, 1H, CH), 6.89–7.52 (m, 4H, Ar-H), 7.77 (s, 1H, CH), 10.43
(s, 1H, NH), 13.70 (s, 1H, NH).13C NMR (75.47 MHz, DMSO-
d6) dC (ppm) 176.31, 174.05, (two C O), 153.66 140.68, 134.54,
131.06, 129.16, 127.54, 125.43, 111.75, 103.48 (aromatic & other
◦
1
Mp 168 C. IR (KBr) (nmax/cm-1) 3285, 1730, 1677. H NMR
(300 MHz, DMSO-d6) dH (ppm) 4.41 (d, 1H, CH), 4.86 (d, 1H,
CH), 6.97–7.65 (m, 8H, Ar-H), 10.95 (s, 1H, NH). DART Mass
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354.23 (M+1). Anal. calc. for C17H11N3O2S2; C, 57.77; H, 3.14;
N, 11.89. Found C, 57.70; H, 3.13; N,11.85.
3¢-(1H-Indazol-5-yl)-spiro[3H-indole-3,2¢-thiazolidine]-
2,4¢(1H)-dione (4y)
Mp 283 ◦C/283 ◦C.13c IR (KBr) (nmax/cm-1) 3283, 1739, 1684.1H
NMR (300 MHz, DMSO-d6) dH (ppm) 3.87(d, 1H, CH), 4.42
(d, 1H, CH), 6.45–7.95 (m, 8H, Ar-H and CH), 10.68 (s, 1H,
NH), 13.01(s, 1H, NH). 13C NMR (75.47 MHz, DMSO-d6)
dC (ppm) 176.69, 172.47, (two C O), 160.36 (C N), 150.44,
144.01, 141.74, 136.11, 131.01, 129.19, 128.26, 128.13, 126.26,
124.86, 122.83, 110.98 (aromatic carbons), 70.39 (spiro carbon),
32.93 (CH2).
5-Chloro-3¢-(1,3-benzothiazol-2-yl)-spiro-[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4t)
◦
1
Mp 171 C. IR (KBr) (nmax/cm-1) 3289, 1735, 1677. H NMR
(300 MHz, DMSO-d6) dH (ppm) 4.47 (d, 1H, CH), 4.84 (d,
1H, CH), 6.89–7.75 (m, 7H, Ar-H), 10.59 (s, 1H, NH). 13C
NMR (75.47 MHz, DMSO-d6) dC (ppm) 175.50, 169.39 (two
C
O), 159.27 (C N), 144.64, 142.27, 137.76, 136.91, 132.81,
129.08, 128.13, 127.02, 123.77, 122.67, 122.30, 107.72 (aromatic
carbons), 65.19 (spiro carbon), 25.76 (CH2). Anal. calc. for
C17H10ClN3O2S2; C, 52.64; H, 2.60; N, 10.83. Found C, 52.70;
H, 2.62; N, 10.86.
3¢-(4-Fluorophenyl)-5¢-methyl-spiro[3H-indole-3,2¢-thiazolidine]-
2,4¢(1H)-dione (4z)
◦
◦
Mp 205 C/205 C.19d IR (KBr) (nmax/cm-1) 3285, 1730, 1683.
1H NMR (300 MHz, DMSO-d6) dH (ppm) diastereomeric ratio
(3 : 1) 1.59/1.77 (d, 3H, CH3), 4.59/4.39 (q, 1H, CH), 6.75/7.54
(m, 8H, Ar-H), 10.80 (s, 1H, NH).
5-Bromo-3¢-(1,3-benzothiazol-2-yl)-5¢-methyl-spiro-[3H-indole-
3,2¢-thiazolidine]-2,4¢(1H)-dione (4u)
◦
1
Mp 173 C. IR (KBr) (nmax/cm-1) 3289, 1732, 1682. H NMR
(300 MHz, DMSO-d6) dH (ppm) 1.78/1.58 (d, 3H, CH3),
4.81/4.68 (q, 1H, CH), 6.91–7.54 (m, 7H, Ar-H), 10.99 (s, 1H,
NH). 13C NMR (75.47 MHz, DMSO-d6) dC (ppm) 178.62,
171.07 (two C O), 160.74 (C N) 145.73, 140.04, 138.53,
137.79, 137.31, 130.74, 130.09, 128.19, 127.81, 124.40, 124.04,
108.72, 102.41 (aromatic carbons), 73.09 (spiro carbon), 32.81
(CH), 21.39 (CH3). Anal. calc. for C18H12BrN3O2S2; C, 48.44;
H,2.71; N, 9.41. Found C, 48.39; H, 2.70; N, 9.44.
3¢-Phenyl-spiro[3H-indole-3,2¢-thiazolidine]-2,4¢(1H)-dione
(4aa)
◦
◦
Mp 233 C/233 C.11e IR (KBr) (nmax/cm-1) 3281, 1732, 1680.
1H NMR (300 MHz, DMSO-d6) dH (ppm) 3.87(d, 1H, CH),
4.36 (d, 1H, CH), 6.73–7.50 (m, 9H, Ar-H), 8.21 (s, 1H, NH).
3¢-(4-Fluorophenyl)-spiro[3H-indole-3,2¢-thiazolidine]-2,4¢(1H)-
dione (4bb)
◦
◦
Mp 245 C/244 C.19d IR (KBr) (nmax/cm-1) 3286, 1728, 1683.
1H NMR (300 MHz, DMSO-d6) dH (ppm) 3.78 (d, 1H, CH),
4.39 (d, 1H, CH), 6.69–7.56 (m, 8H, Ar-H), 9.97 (s, 1H, NH).
5,7-Dimethyl-3¢-(1,3-benzothiazol-2-yl)-spiro-[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4v)
◦
1
Mp 170 C. IR (KBr) (nmax/cm-1) 3283, 1735, 1673. H NMR
(300 MHz, DMSO-d6) dH (ppm) 2.17 (s, 3H, CH3), 2.06 (s, 3H,
CH3), 4.03 (d, 1H, CH), 4.19 (d, 1H, CH), 6.75–7.65 (m, 6H, Ar-
H), 10.83 (s, 1H, NH). Anal. calc. for C19H15N3O2S2; C, 59.82;
H, 3.82; N, 11.02. Found C, 59.75; H, 3.80; N, 11.06.
3¢-[3-(Trifluoromethyl)phenyl]-5¢-methyl-spiro[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4cc)
Mp 219 ◦C/218 ◦C.19d
5-Methyl-3¢-[2-(trifluoromethyl)]-5¢-methyl-spiro[3H-indole-
3,2¢-thiazolidine]-2,4¢(1H)-dione (4dd)
5-Methyl-3¢-(1,3-benzothiazol-2-yl)-spiro-[3H-indole-
3,2¢-thiazolidine]-2,4¢(1H)-dione (4w)
Mp 193 ◦C/190 ◦C.19c
◦
1
Mp 163 C. IR (KBr) (nmax/cm-1) 3280, 1729, 1679. H NMR
(300 MHz, DMSO-d6) dH (ppm) 2.24 (s, 3H, CH3), 3.87 (d,
1H, CH), 4.51 (d, 1H, CH), 7.06–7.66 (m, 7H, Ar-H), 8.30 (s,
1H, NH). 13C NMR (75.47 MHz, DMSO-d6) dC (ppm) 178.45,
169.99 (two C O), 160.60 (C N), 141.98, 140.71, 134.75,
132.25, 131.46, 130.64, 129.50, 129.01, 127.77, 128.40, 123.78,
122.23 (aromatic carbons), 66.05 (spiro carbon), 20.92 (CH2).
Anal. calc. for C18H13N3O2S2; C, 58.84; H, 3.57; N, 11.44. Found
C, 58.76; H, 3.55; N, 11.42.
5,7-Dimethyl-3¢-[3-chlorophenyl]-spiro[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4ee)
Mp 169 ◦C/168 ◦C.25d
5,7-Dimethyl-3¢-phenyl-spiro-[3H-indole-3,2¢-thiazolidine]-
2,4¢(1H)-dione (4ff)
Mp 224 ◦C/222 ◦C.19e Yield = 87%. IR (KBr) (nmax/cm-1) 3284,
1730, 1685. 1H NMR (300 MHz, DMSO-d6) dH (ppm) 2.21 (s,
3H, CH3), 2.25 (s, 3H, CH3), 3.70 (d, 1H, CH), 4.34 (d, 1H, CH),
6.71–7.54 (m, 7H, Ar-H), 9.99 (s, 1H, NH).
3¢-(1,3-Benzothiazol-2-yl)-5¢-methyl-spiro-[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4x)
5-Chloro-3¢-[5-(trifluoromethyl)2-chloro-phenyl]-5¢-methyl-
spiro[3H-indole-3,2¢-thiazolidine]-2,4¢(1H)-dione (4gg)
◦
1
Mp 165 C. IR (KBr) (nmax/cm-1) 3280, 1730, 1675. H NMR
(300 MHz, DMSO-d6) dH (ppm) diastereomeric ratio (3 : 1)
1.53/1.75 (d, 3H, CH3), 4.49 (q, 1H, CH), 6.80–7.63 (m, 8H, Ar-
H), 10.95 (s, 1H, NH). Anal. calc. for C18H13N3O2S2; C, 58.84;
H, 3.57; N, 11.44. Found C, 58.78; H, 3.55; N, 11.42.
◦
◦
Mp 146 C/146 C.13e IR (KBr) (nmax/cm-1) 3285, 1731, 1682.
1H NMR (300 MHz, DMSO-d6) dH (ppm) Diastereomeric ratio
(3 : 1) 1.60/1.77 (d, 3H, CH3), 4.57/4.26 (q, 1H, CH), 6.79/7.53
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(m, 6H, Ar-H), 10.83 (s, 1H, NH).13C NMR (75.47 MHz,
DMSO-d6) dC (ppm) 174.51, 173.15 (two C O), 150.95, 143.89,
141.44, 140.09, 138.48, 130.52, 129.73, 125.11, 123.83, 123.12,
122.31, 122.84, 108.77 (aromatic carbon), 63.72 (spiro carbon),
30.56 (CH), 18.36 (CH3).
Ar-H), 10.50 (s, 1H, NH). DART Mass 393.17 (M+1). Anal.
calc. for C19H15F3N2O2S; C, 58.16; H, 3.85; N, 7.14. Found C,
58.21; H, 3.86; N, 7.16.
3¢-(5-Trifluoromethyl-2-chlorophenyl)-spiro-[3H-indole-
3,2¢-thiazolidine]-2,4¢(1H)-dione (4rr)
3¢-[4-Methoxyphenyl]-5¢-methyl-spiro[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4hh)
◦
1
Mp 145 C. IR (KBr) (nmax/cm-1) 3280, 1735, 1685. H NMR
(300 MHz, DMSO-d6) dH (ppm) 3. 85 (d, 1H, CH), 4.18 (d,
1H, CH), 6.61– 7.67 (m, 7H, Ar-H), 11.30 (s, 1H, NH).13C
NMR (75.47 MHz, DMSO-d6) dC (ppm) 175.50, 171.07, (two
Mp 184 ◦C/183 ◦C.13e
3¢-[4-Bromophenyl]-5¢-methyl-spiro[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4ii)
C
O),143.43, 138.92, 136.47,132.51, 129.73, 129.64, 128.50,
128.50, 113.43, 113.43, 111.87, 101.37, 100.30 (aromatic & other
carbons), 73.09 (spiro carbon), 21.27 (CH2). Anal. calc. for
C17H10Cl3F3N2O2S; C, 51.20; H, 2.53; N, 7.02. Found C, 51.12;
H, 2.52; N, 7.04.
Mp 225 ◦C/222 ◦C.13e
3¢-(4-Chlorophenyl)-5¢-methyl-spiro[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4jj)
◦
◦
Mp 249 C/246 C.13e IR (KBr) (nmax/cm-1) 3280, 1733, 1685.
1H NMR (300 MHz,DMSO-d6) dH (ppm) Diastereomeric ratio
(3 : 1) 1.72/1.98 (d, 3H, CH3), 4.65/4.30 (q, 1H, CH), 6.72–7.51
(m, 8H, Ar-H), 8.48 (s, 1H, NH).
3¢-(2-Nitro-4-chlorophenyl)-5¢-methyl-spiro-[3H-indole-
3,2¢-thiazolidine]-2,4¢(1H)-dione (4ss)
◦
1
Mp 195 C. IR (KBr) (nmax/cm-1) 3287, 1738, 1680. H NMR
(300 MHz, DMSO-d6) dH (ppm) diastereomeric ratio (3 : 1)
1.63/1.95 (d, 3H, CH3), 4.56 (q, 1H, CH), 6.73–7.50 (m, 7H,
Ar-H), 10.35/10.20 (s, 1H, NH). DART Mass 390 (M+1). Anal.
calc. for C17H12ClN3O4S; C, 52.38; H, 3.10; N, 10.78. Found C,
52.29; H, 3.08; N, 10.75.
3¢-(4-Hydroxyphenyl)-5¢-methyl-spiro[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4kk)
Mp 308 ◦C/306 ◦C.13e
5-Bromo-3¢-[4-bromophenyl]-5¢-methyl-spiro[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4ll)
5-Chloro-3¢-(2,6-dichlorophenyl)-spiro-[3H-indole-
3,2¢-thiazolidine]-2,4¢(1H)-dione (4tt)
Mp 269 ◦C/269 ◦C.13e
◦
1
Mp 189 C. IR (KBr) (nmax/cm-1) 3286, 1737, 1680. H NMR
(300 MHz, DMSO-d6) dH (ppm) 3.70 (d, 1H, CH), 4.41 (d, 1H,
CH), 6.80–7.65 (m, 6H, Ar-H), 10.95 (s, 1H, NH).13C NMR
(75.47 MHz, DMSO-d6) dC (ppm) 177.90, 170.92 (two C O),
145.54, 139.13, 138.40,130.00, 129.75, 128.55, 126.36, 125.12,
122.42, 109.70, 100.36 (aromatic carbons), 73.11 (spiro carbon),
26.57 (CH2). Anal. calc. for C16H9Cl3N2O2S; C, 48.08; H, 2.27;
N, 7.01. Found C, 48.14; H, 2.28; N, 7.03.
5-Bromo-3¢-[4-chlorophenyl]-5¢-methyl-spiro[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4mm)
◦
Mp 284 ◦C/282 C.13e IR (KBr) (nmax/cm-1) 3281,1731,1683.
1H NMR (300 MHz, DMSO-d6) dH (ppm) diastereomeric ratio
(3 : 1) 1.53/1.77 (d, 3H, CH3), 4.52/4.38 (q, 1H, CH), 6.70–7.76
(m, 7H, Ar-H), 10.95/10.61 (s, 1H, NH).
5-Nitro-3¢-(4-chlorophenyl)-5¢-methyl-spiro[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4nn)
5-Chloro-3¢-(2,6-dichlorophenyl)-5¢-methyl-spiro-[3H-indole-
3,2¢-thiazolidine]-2,4¢(1H)-dione (4uu)
Mp 280 ◦C/277 ◦C.13e
Mp 191 ◦C. 3284, 1737, 1681. 1H NMR (300 MHz,DMSO-d6)
dH (ppm) diastereomeric ratio (3 : 1) 1.71/1.97 (d, 3H, CH3),
4.61 (q, 1H, CH), 6.71–7.39 (m, 6H, Ar-H), 9.22/9.10 (s,
1H, NH).13C NMR (75.47 MHz, DMSO-d6) dC (ppm) 176.01,
170.52 (two C O), 144.14, 139.22, 135.28, 129.81, 129.75,
128.53, 127.11, 125.61, 121.74, 109.85 (aromatic carbons),
73.20 (spiro carbon),34.38 (CH), 20.55 (CH2). Anal. calc. for
C17H11Cl3N2O2S; C, 49.35; H, 2.68; N, 6.77. Found C, 49.30; H,
2.66; N, 6.78.
5-Methyl-3¢-(4-chlorophenyl)-5¢-methyl-spiro[3H-indole-3,2¢-
thiazolidine]-2,4¢(1H)-dione (4oo)
Mp 253 ◦C/252 ◦C.13e
3¢-Phenyl-5¢-methyl-spiro[3H-indole-3,2¢-thiazolidine]-2,4¢(1H)-
dione (4pp)
◦
◦
Mp 200 C/200 C.13e IR (KBr) (nmax/cm-1) 3279, 1735, 1683.
1H NMR (300 MHz, DMSO-d6) dH (ppm) diastereomeric ratio
(3 : 1) 1.71/1.97 (d, 3H, CH3), 4.59/4.25 (q, 1H, CH), 6.73–7.43
(m, 9H, Ar-H), 7.87/7.80 (s, 1H, NH).
Acknowledgements
5,7-Dimethyl-3¢-(3-(trifluoromethylphenyl)-spiro-[3H-indole-
3,2¢-thiazolidine]-2,4¢(1H)-dione (4qq)
Financial assistance from the C.S.I.R (01/2248/08/EMR-II)
(No. 13 (8424-A) 2010-Pool) and U.G.C. 540/16/CAS/2005
(SAP-I), New Delhi are gratefully acknowledged. We are also
thankful to the Central Drug Research Institute, Lucknow, for
the elemental and spectral analyses.
◦
1
Mp 228 C. IR (KBr) (nmax/cm-1) 3286, 1727, 1685. H NMR
(300 MHz, DMSO-d6) dH (ppm) 2.12 (s, 3H, CH3), 2.24 (s, 3H,
CH3), 3.85 (d, 1H, CH), 4.30 (d, 1H, CH), 6.83–7.59 (m, 6H,
1858 | Green Chem., 2011, 13, 1852–1859
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21 (a) F. Fringuelli, O. Piermatti and F. Pizzo, J. Chem. Educ., 2004, 81,
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