One-pot, three-component synthesis of novel spiro[3H-indole-3,2'- thiazolidine]-2,4'(1H)-diones in an ionic liquid as a reusable reaction media

Article abstract of DOI:10.1002/hlca.201200168

A facile one-pot, three-component protocol for the synthesis of novel spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-diones by condensing 1H-indole-2,3-diones, 4H-1,2,4-triazol-4-amine and 2-sulfanylpropanoic acid in [bmim]PF₆ (1-butyl-3-methyl-1H-imidazolium hexafluorophosphate) as a recyclable ionic-liquid solvent gave good to excellent yields in the absence of any catalyst (Scheme 1 and Table 2). The advantages of this protocol over conventional methods are the mild reaction conditions, the high product yields, a shorter reaction time, as well as the eco-friendly conditions. Copyright

Full text of DOI:10.1002/hlca.201200168

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Helvetica Chimica Acta – Vol. 96 (2013)
One-Pot, Three-Component Synthesis of Novel Spiro[3H-indole-3,2’-
thiazolidine]-2,4’(1H)-diones in an Ionic Liquid as a Reusable Reaction Media
by Renuka Jain*, Kanti Sharma, and Deepak Kumar
Department of Chemistry, University of Rajasthan, Jaipur 302 004, India
(phone: þ 91-141-2742048; e-mail: profrjain@rediffmail.com)
A facile one-pot, three-component protocol for the synthesis of novel spiro[3H-indole-3,2’-
thiazolidine]-2,4’(1H)-diones by condensing 1H-indole-2,3-diones, 4H-1,2,4-triazol-4-amine and 2-
sulfanylpropanoic acid in [bmim]PF6 (1-butyl-3-methyl-1H-imidazolium hexafluorophosphate) as a
recyclable ionic-liquid solvent gave good to excellent yields in the absence of any catalyst (Scheme 1 and
Table 2). The advantages of this protocol over conventional methods are the mild reaction conditions, the
high product yields, a shorter reaction time, as well as the eco-friendly conditions.
Introduction. – In recent years, the development of multicomponent reactions
(MCRs) has become a powerful protocol in organic synthesis and medicinal chemistry
[1]. They have been established as one of the efficient as well as powerful ways for the
synthesis of biologically active heterocycles [2]. Imines are excellent reaction
intermediates that can act as nucleophiles/electrophiles. Imine-based multicomponent
reactions allow the facile and selective construction of highly functionalized molecules
with diverse and complex structures as well as small and drug-like heterocyclic
compounds from readily available starting materials in a single synthetic operation [3].
Hence, such reactions provide a valuable synthetic tool for the synthesis of heterocycles
with biological value.
As a part of our continuing efforts on the development of new methodologies for
the synthesis of bioactive heterocycles by employing eco-friendly tools [4], considering
the significance of the ionic liquid and need to develop a rapid as well as facile synthetic
procedure for spiro[3H-indole-3,2’-thiazolidine]-2,4’(1H)-diones 4, we report herein
the synthesis of the latter in excellent yields by employing a convenient one-pot, three-
component cyclocondensation of 1H-indole-2,3-diones 1, 4H-1,2,4-triazol-4-amine (2)
and 2-sulfanylpropanoic acid (3) in [bmim]PF6 (1-butyl-3-methyl-1H-imidazolium
hexafluorophosphate), an ionic liquid, in the absence of any catalyst.
Results and Discussion. – To optimize the reaction conditions of the synthesis of
spiro[3H-indole-3,2’-thiazolidine]-2,4’(1H)-diones 4, we first investigated a two-step
synthesis as well as the one-pot, three-component reaction of 1H-indole-2,3-dione (1a),
4H-1,2,4-triazol-4-amine (2), and 2-sulfanylpropanoic acid (3) as a model reaction in
various solvents such as benzene, toluene, acetic acid, and ionic liquid to afford the
functionalized spiro[indole-thiazolidine]-dione 4a (Table 1; Scheme 1). Thus, the yield
of 4a increased remarkably in ionic liquid with the increase of the temperature up to
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Table 1. Optimization of the Reaction Conditions for the Synthesis of Compound 4a
Solvent
Temp. [8]
Time [h]
Yield [%]a)
[bmim]PF6
[bmim]PF6
[bmim]PF6
[bmim]PF6
[bmim]PF6
Benzene
r.t.
60
70
80
10
6
5
4
4
10
9
7
50
75
80
92
92
55
68
69
53
57
90
reflux
reflux
reflux
reflux
reflux
Toluene
AcOH
Tolueneb)
Toluenec)
5 þ 7
5 þ 7
a) Yields refer to pure isolated 4a. b) The intermediate Schiff base was isolated (two step). c) The
intermediate Schiff base was not isolated (two step).
808. The best result, i.e., an excellent yield in a shorter reaction time was obtained in
[bmim]PF6, as ionic liquid because of the hydrophobic nature of the latter, which
creates a micro-environment to drive the equilibrium by extruding H2O out of the ionic
liquid phase resulting in a higher conversion.
Subsequently, 5’-methyl-3’-(4H-1,2,4-triazol-4-yl)spiro[3H-indole-3,2’-thiazolidine]-
2,4’(1H)-diones 4a – 4j were synthesized in exellent yields (89 – 93%) by the reaction of
1H-indole-2,3-diones 1a – 1j, triazol-amine 2, and acid 3 in [bmim]PF6 under N2 at 80 ꢀ
28 in the absence of any further catalyst (Scheme 1 and Table 2).
Scheme 1. Ionic-Liquid-Mediated One-Pot, Three-Component Synthesis of Spiro[3H-indole-3,2’-thia-
zolidine]-2,4’(1H)-diones 4a – 4j. For R and X, see Table 2.
For comparison, the spiro[3H-indole-3,2’-thiazolidine]-2,4’(1H)-diones 4 were also
synthesized by conventional heating in dry toluene via the Schiff bases 1,3-dihydro-3-
[(4H-1,2,4-triazol-4-yl)imino]-2H-indol-2-ones 5 (cf. below, Scheme 2), which were
prepared by the reaction of 1a – 1j and 2 and then isolated. In the second step, the Schiff
bases were treated with 3 to give 4a – 4j in 51 – 56% yields. Alternatively, 4a – 4j were
synthesized in poor to moderate yields (53 – 61%) under the same conditions but
without isolating the Schiff bases, the latter being cyclized in situ with 3.
The mechanism for the described reaction, exemplified for 4a involves the initial in
situ generation of 1,3-dihydro-3-imino-2H-indole-2-one 5a by condensation of 1a and
2. This event is followed by the nucleophilic attack of the sulfanyl group of 3 at the

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Table 2. Ionic Liquid-Mediated Synthesis of Spiro[3H-indole-3,2’-thiazolidine]-2,4’(1H)-diones 4a – 4ja)
Product
R
X
Time [h]
Yield [%]b)
M.p. [8]
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
Ac
Me
Et2NCH2
Me2NCH2
Bn
H
4
5
5
4
6
5
5
4
5
4
92
93
93
91
92
89
90
92
92
91
163 – 165
116 – 118
136 – 138
226 – 228
239 – 241
176 – 178
167 – 169
209 – 211
147 – 149
223 – 225
5-Cl
5-F
H
H
H
H
H
5-Cl
H
Me
4j
piperidin-1-ylmethyl
a) Reaction conditions: 1H-indole-2,3-dione 1 (1.0 mmol), 4H-1,2,4-triazol-4-amine (2; 1.0 mmol), 2-
sulfanylpropanoic acid (3; 1.2 mmol), and [bmim]PF6 (5.0 ml), TLC monitoring. b) Yield after
purification.
imino-substituted C(3) to give intermediate 6a [5], which undergoes cyclocondensation
by lactam formation to yield 4a (Scheme 2).
Scheme 2. Mechanistic Pathway
The structures of the products 4a – 4j were characterized unambiguously by
analytical and spectroscopic studies. The IR spectrum of compound 4a showed
absorption bands at 1710 and 1690 cmꢁ1 due to C¼O groups of the thiazolidinone and
oxindole moiety, respectively. The broad peak at 3190 cmꢁ1 indicated the presence of an
NH group in 4a, while the intense peak at 1615 cmꢁ1 was typical for the presence of
C¼N moieties. An absorption band at 748 cmꢁ1 was attributed to a CꢁSꢁC linkage. Due
to the presence of two stereogenic centers (C(3) and C(5’)), the compounds 4a – 4j
exist in two diastereoisomeric forms, in a ratio of 3 :1 for 4a (by 1H-NMR), exhibiting
1
two sets of signals in the H-NMR spectra for HꢁC(5’), MeꢁC(5’) and the NH group

Helvetica Chimica Acta – Vol. 96 (2013)
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(when present). However, the signals of the aromatic H-atoms could not be resolved
because of their complex m pattern. This is exemplified by the 1H-NMR spectrum of 4a
with 2 d at d(H) 1.59 and 1.81 (J ¼ 6.9 and 7.2 Hz) due to MeꢁC(5’), 2 q at d(H) 4.37
and 4.16 due to HꢁC(5’), 2 s at d(H) 9.99 and 10.42 due to the NH group, and 2 s at
d(H) 8.24 and 8.31 due to the triazole moiety. In the 13C-NMR spectrum of 4a, the peak
at d(C) 62.7 indicated the presence of a spiro C-atom, the C¼O groups of the oxindole
and thiazolidinone moiety resonated at d(C) 168.0 and 177.5, respectively, C(5’) and
MeꢁC(5’) appeared at d(C) 42.3 and 18.0, respectively, and the signals at d(C) 148.0
and 149.1 were attributable to C(3) and C(5) of the triazole moiety. The mass spectrum
of 4a displayed a distinguished peak at m/z 301.3, which further supported the
formation of a spiro compound. The spiro[indole-thiazolidine]dione derivatives
prepared by the conventional method had the same analytical and spectral data.
We also studied the reactivity of the recycled ionic liquid for the production of 4a
(Table 3): After two recycles, the yield of 4a had decreased, yet the ionic liquid could
be reused with significant success. Therefore, the ionic-liquid-mediated synthesis is an
excellent approach for the synthesis of the title compounds and superior to the reaction
in conventional reaction media.
Table 3. Studies on the Recovery and Reuse of [bmim]PF6 for the Production of 4aa)
Recycle
Time [h]
Temperature [8]
Yield [%]b)
Recovered [bmim]PF6 [w/w-%]
Fresh
1
2
4
4
4
80
80
80
92
89
87
98
95
93
a) Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), and 3 (1.2 mmol); 5.0 ml of ionic liquid [bmim]PF6
was used for the first run. b) Yield of 4a after purification.
In conclusion, we demonstrated an efficient, facile, one-pot, three-component ionic-
liquid-mediated, mild and high-yielding methodology for the synthesis of novel
spiro[3H-indole-3,2’-thiazolidine]-2,4’(1H)-diones with shorter reaction time as com-
pared to the conventional heating method. The use of a ionic liquid led to a higher
performance with the advantage that the ionic liquid could be recycled and reused
without substantial loss of its activity. The significance of this approach consists of its
environmentally acceptable conditions by the reduced use of volatile organic solvents,
the simplicity of the process, excellent yields, mild conditions, and low costs.
The authors are grateful to UGC and CSIR, New Delhi, India for the financial assistance as well as
CDRI, Lucknow, India for spectral studies.
Experimental Part
General. Commercially available (Acros Organics) 4H-1,2,4-triazol-4-amine (2), 2-sulfanylpropa-
noic acid (3), and [bmim]PF6 (1-butyl-3-methyl-1H-imidazolium hexafluorophosphate) were used
without further purification. The 1H-indole-2,3-dione (1a) and its derivatives (starting material 1) were
prepared according to [6]. M.p.: Gallenkamp melting-point apparatus; in open glass capillaries;
1
uncorrected. IR Spectra: FT-IR-8400S-Shimadzu spectrometer; in KBr; ˜n in cmꢁ1. H- and 13C-NMR
Spectra: Jeol spectrometer; at 300 and 75 MHz, resp.; in (D6)DMSO/CDCl3; d in ppm rel. to Me4Si as

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Helvetica Chimica Acta – Vol. 96 (2013)
internal standard, J in Hz. MS: Waters-Xevo-Q-TOF instrument, equipped with an ASAP (atomspheric
solids analysis probe). Elemental analyses (C, H, and N): Vario-EL-III analyzer.
Typical Experimental Procedure for the Synthesis of Compounds 4a – 4j (exemplified with 4a). A
soln. of 1H-indole-2,3-dione (1a; 1.0 mmol), 4H-1,2,4-triazol-4-amine (2; 1.0 mmol), 2-sulfanylpropanoic
acid (3; 1.2 mmol), and [bmim]PF6 (5.0 ml) stirred magnetically at 80 ꢀ 28 under N2 (monitoring by TLC
(petroleum ether/AcOEt 4 :1, visualization by I2 vapor)). After completion of reaction as evidenced by
TLC, the mixture was cooled to r.t., neutralized with 10% aq. NaHCO3 soln., and extracted with AcOEt
(3 ꢂ 10 ml). The solvent was evaporated, the pasty mass thus obtained extracted with Et2O (3 ꢂ 10 ml),
the extract dried (Na2SO4), the Et2O distilled off, and the residual product purified by crystallization
from EtOH: 4a (92%).
Recovery of the Ionic Liquid [bmim]PF6. After completion of the reaction, the reaction mixture was
poured into ice water (instead of cooling and washing with NaHCO3 soln. followed by extraction), and
the product was filtered off. The filtrate was extracted with AcOEt to recover unreacted reactants, and
the aq. layer was subjected to evaporation of H2O to get a viscous liquid which, on cooling, gave the ionic
liquid. The ionic-liquid was washed with H2O (3 ꢂ 10 ml) and kept for 2 h at 80 – 858 under reduced
pressure. This ionic liquid was used twice in recycling experiments (Table 3).
5’-Methyl-3’-(4H-1,2,4-triazol-4-yl)spiro[3H-indole-3,2’(1H)-thiazolidine]-2,4’(1H)-dione (4a). Yel-
lowish white solid. M.p. 163 – 1658. IR: 3190 (ꢁNH), 1710 (C¼O), 1690 (C¼O), 1615 (C¼N), 748
(CꢁSꢁC). 1H-NMR (diastereoisomer ratio 3 :1): 1.59, 1.81 (2 d, J ¼ 6.9 and 7.2, MeꢁC(5’)); 4.37, 4.16 (2 q,
J ¼ 6.9 and 7.2, HꢁC(5’)); 6.85 (d, J ¼ 7.5, 1 arom. H); 7.04 (t, J ¼ 7.5, 1 arom. H); 7.25 (t, J ¼ 7.8, 1 arom.
H); 7.35 (d, J ¼ 7.5, 1 arom. H); 8.24, 8.31 (2 s, CH triazole); 9.99, 10.42 (2br. s, NH, D2O exchangeable).
13C-NMR: 18.0; 42.3; 62.7; 110.6; 122.6; 125.3; 126.9; 130.6; 141.8; 148.0; 149.1; 168.0; 177.5. MS: 301.3.
Anal. calc. for C13H11N5O2S: C 51.78, H 3.65, N 23.23; found: C 51.89, H 3.58, N 23.31.
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Received March 31, 2012