A facile synthesis of novel spiro-[indole-pyrazolinyl-thiazolidine]-2,4′-dione

Article abstract of DOI:10.1081/SCC-120015810

A reaction of appropriate indol-2,3-diones with 4-aminoantipyrine has resulted in the formation of hitherto unknown 3-(2,3-dimethyl-5-oxol-phenyl-3-pyrazolin-4-yl-imino)-indol-2- ones in quantitative yields which upon cyclocondensation with mercaptoacetic acid afforded a series of new spiro heterocycles 3'-(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl) spiro[3H-indol-3,2'-thiazolidine]-2,4'-diones.

Full text of DOI:10.1081/SCC-120015810

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A Facile Synthesis of Novel Spiro- [Indole-pyrazolinyl-
thiazolidine]-2,4′-dione
Subhash C. Jain a , Juhi Sinha a , Sunita Bhagat a , W. Errington b & Carl E. Olsen c
a Department of Chemistry, University of Delhi, Delhi, India
b Department of Chemistry, University of Warwick, Coventry, UK
c Chemistry Department, Royal Veterinary and Agricultural University, Frederiksberg C,
Copenhagen, Denmark
Version of record first published: 16 Aug 2006.
To cite this article: Subhash C. Jain , Juhi Sinha , Sunita Bhagat , W. Errington & Carl E. Olsen (2003): A Facile Synthesis
of Novel Spiro- [Indole-pyrazolinyl-thiazolidine]-2,4′-dione, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:4, 563-577
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 4, pp. 563–577, 2003
A Facile Synthesis of Novel Spiro-
[Indole-pyrazolinyl-thiazolidine]-2,40-dione
1,
1
Juhi Sinha, Sunita Bhagat,
1
*
Subhash C.Jain,
2
W.Errington, and Carl E.Olsen
3
1Department of Chemistry, University of Delhi,
Delhi, India
2Department of Chemistry, University of Warwick,
Coventry, UK
3Chemistry Department, Royal Veterinary and
Agricultural University, Frederiksberg C,
Copenhagen, Denmark
ABSTRACT
A reaction of appropriate indol-2,3-diones with 4-aminoantipyrine has
resulted in the formation of hitherto unknown 3-(2,3-dimethyl-5-oxo-
1-phenyl-3-pyrazolin-4-yl-imino)-indol-2-ones in quantitative yields
which upon cyclocondensation with mercaptoacetic acid afforded
a series of new spiro heterocycles 30-(2,3-dimethyl-5-oxo-1-phenyl-3-
pyrazolin-4-yl) spiro[3H-indol-3,20-thiazolidine]-2,40-diones.
*Correspondence: Subhash C. Jain, Department of Chemistry, University of
Delhi, Delhi 110 007, India; Fax: þ91-11-7667206; E-mail: jainsc48@hotmail.
com.
563
DOI: 10.1081/SCC-120015810
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564
Jain et al.
As a part of our continuing interest on the synthesis of new spiro
heterocycles of medicinal interest by molecular modification,[1–3] we now
wish to report a facile and elegant synthesis of novel spiro heterocycles
such as 30-(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl) spiro[3H-indol-
3,20-thiazolidine]-2,40-diones (5a–l) via hitherto unknown Schiff’s bases,
3-(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl-imino)-indol-2-ones (3a–l)
in 80–95% yield (Sch. 1). The Schiff’s bases were synthesized by the
reaction of indol-2,3-dione (1a–l) with 4-amino-2,3-dimethyl-1-phenyl-
3-pyrazolin-5-one (2), which on cyclocondensation with mercaptoacetic
acid afforded the desired spiro compounds. All synthetic compounds
1
have been fully characterized on the basis of their spectral data (IR, H
and 13C NMR and Mass). The structure of the spiro compound 5a has
also been confirmed by its X-ray crystallographic studies.
The chemistry of spiro indoles continues to draw the attention of
synthetic organic chemists due to their vast physiochemical properties
and varied biological activities.[4–7] Of these spiro[indol-thiazolidines]
has attracted our attention because of their antiinflammatory, fungistatic,
bacteriostatic, and anticonvulsant activities.[8,9] Thiazolidines themselves
are of potential pharmaceutical importance.[10–12] If spiro[indol-thiazol-
idine] nucleus is coupled to otherbiologically active heteorcycles, the
resulting system is expected to show an increased spectrum of biological
activities. 4-Amino antipyrine is of current interest for its analgesic and
antipyretic activities[13,14] and is main constituent of common drugs viz.
novalgin and neopyrin. It also contains the structural features (–NH2
group) which could be used to couple it with C-3 carbonyl group
of indol-2,3-dione. Moreover no report has been cited earlier on
spiro-indolines containing thiazolidines and pyrazoline moieties. Even
Schiff’s bases of indol-2,3-dione with 4-aminoantipyrine have not been
studied so far, for any kind of biological activities. Besides this, fluori-
nated analogues of above Schiff’s bases and spiro compounds could be of
interest as incorporation of fluorine often leads to changes in electronic
environment and increases the drug persistence by increasing the
solubility in lipoid material and fat deposits in the body.[15]
In view of above observations, we have synthesized new Schiff’s
bases (3a–l) by the reaction of appropriate indol-2,3-diones (1a–l) with
4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one (2) and subjected each
of these resulting imines (3a–l) to cyclocondensation reaction with
mercaptoacetic acid in order to obtain a novel spiro system containing
three biodynamic heterocyclic moieties viz. indole, thiazolidine and
pyrazoline, incorporating fluorine at different places in the molecule.
The reaction of indol-2,3-dione (1a) with 4-amino-2,3-dimethyl-1-
phenyl-3-pyrazolin-5-one (2) (1:1) in absolute ethanol at room tempera-

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[Indole-pyrazolinyl-thiazolidine]-2,40-dione
565

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566
Jain et al.
ture yielded an orange colored solid. Molecular ion peak Mþ, at m/z 332
in EIMS, corresponding to the molecular formula C19H16N4O2, indicated
that the two moieties have coupled togetherwith the loss of a water
molecule. The IR spectrum showed characteristic absorption bands at
3470 (>NH), 1724 (lactam carbonyl), 1689 (pyrazolinyl carbonyl) and
1
1650 (C¼N) cmꢀ1. Also its H NMR spectrum displayed two singlets at
ꢀ 3.10 and ꢀ 2.11 each integrating for three protons of the two methyl
groups of the pyrazolin moiety. Further, multiplets at ꢀ 7.50–7.30 inte-
grating for five protons (H-2000, H-3000, H-4000, H-5000, H-6000), indicated the
presence of a phenyl group as expected in the pyrazolin. The multiplets at
ꢀ 7.25 (H-4), ꢀ 7.00 (H-5 and H-6) and 6.85 (H-7) showed the presence of
aromatic protons of the indole moiety. 13C NMR spectrum of 3a
displayed characteristic carbonyl carbon signals at ꢀ 176.5 (C-2) and
ꢀ 160.2 (C-500), in addition to a signal at ꢀ 149.2 showing the presence
of (C¼N) at C-3 in the molecule. The above spectral studies confirmed
the formation of desired Schiff’s base which was characterized as
3-(2,3dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)imino-indol-2-one (3a).
The cyclocondensation reaction was carried out between 3a and 4
under refluxing conditions using Dean-Stark apparatus. The compound
obtained was different from 3a hence labelled as 5a. The molecularmass
of 406 corresponding to the molecular formula C21H18O3N4S was indi-
cated by its FAB-MS. The IR spectrum showed presence of characteristic
absorption peaks at 3481 cmꢀ1 (>NH), 1720 (lactam carbonyl), 1710
(thiazolidine carbonyl) and 1685 (pyrazolinyl carbonyl) cmꢀ1 indicating
1
that cycloaddition has occurred. This got further confirmation by its H
1
and 13C NMR data. In the H NMR spectrum of 5a the protons of the
phenyl group in pyrazolin moiety appeared as multiplets at ꢀ 7.40 (H-2000,
H-3000, H-5000, H-60000) and at ꢀ 7.30 (H-4000). The aromatic protons of
indole nucleus appeared as multiplets at ꢀ 7.20 (H-4), 6.96 (H-5 and H-6)
and at 6.80 (H-7). A double doublet, integrating for two geminal protons
appeared at ꢀ 4.20 and 3.80 (J ¼ 11.8 Hz each). The two methyl
groups appeared at ꢀ 3.10 (ꢀNCH3) and ꢀ 2.10 (300-CH3). 13C NMR
spectra showed all expected characteristic peaks at ꢀ 177.0 (C-40), 171.8
(C-2), 161.8 (C-500), ꢀ 134.5–117.1 (aromatic carbons), ꢀ 110.1 (C-3,
spiro carbon) alongwith two methyl carbons at ꢀ 38.9 (ꢀNCH3) and ꢀ
11.4 (300-CH3).
On the basis of above spectral studies 5a was assigned structure
as 30-(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl) spiro[3H-indol-
3,20-thiazolidine]-2,40-dione which was finally confirmed by its X-ray
crystallographic studies (Fig. 1). The asymmetric unit contains two
organic molecules with very similar dimensions and a single water
molecule. Selected bond lengths and angles are listed in Table 1; they

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[Indole-pyrazolinyl-thiazolidine]-2,40-dione
567
Figure 1.
are all largely unexceptional. The integrity of the solid state is largely due
to intermolecular hydrogen bonding as indicated in Table 2.
EXPERIMENTAL
Melting points were determined in a capillary tube in sulphuric acid
bath and are uncorrected. Infrared spectra were recorded on Shimadzu
model IR-435 spectrophotometer using KBr discs. 1H NMR spectra
were recorded on Bruker AC (250 Mz and 300 MHz) in CDCl3 and
DMSO-d6. 13C NMR were recorded on Bruker AC (62.89 MHz and
79.47 MHz) in CDCl3 and DMSO-d6. Mass spectra were recorded on
Jeol-JMS-DX 303 mass spectrometer. Substituted indol-2,3-diones
(1b–l) were prepared by literature procedures starting from the
corresponding anilines.[16–18]
Crystals of 5a suitable for single crystal X-ray diffraction studies were
obtained as colorless blocks by recrystallization from a methanol–
chloroform mixed solvent system. Data were collected using a Siemens
SMART CCD area-detector diffractometer, fitted with an Oxford
Cryosystem Cryostream cooler.[19] Absorption corrections were applied
using SADABS.[20] The structure was solved by direct methods and refined
by full-matrix least-squares on F2 forall data using SHELXL 97. [21]
Crystal Data: C21H19N4O3.5S, M ¼ 415.46, monoclinic, a ¼ 19.4422
(10), b ¼ 9.9645 (6), c ¼ 20.4690 (12) A, ꢁ ¼ 90.027 (3)ꢁ, U ¼ 3965.5 (4) A3,

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568
Jain et al.
Table 1. Selected bond lengths [A] and
angles [ꢀ] for 5a.
S(11)-C(110)
S(11)-C(103)
S(21)-C(210)
S(21)-C(203)
N(13)-N(14)
N(23)-N(24)
C(110)-S(11)-C(103)
C(210)-S(21)-C(203)
1.809 (3)
1.849 (2)
1.808 (3)
1.832 (2)
1.393 (3)
1.412 (3)
91.72 (11)
92.52 (11)
ꢀ
Table 2. Hydrogen bonds for 5a [A and ].
D-H. . .A
d (D-H)
d (H...A)
d (D...A)
<(DHA)
O(1S)-H(1S). . .O(12)#1
O(1S)-H(2S). . .O(21)
N(11)-H(11K). . .O(23)#2
N(21)-H(21K). . .O(13)
0.88 (4)
0.86 (4)
0.88
2.04 (4)
2.02 (4)
1.98
2.916 (3)
2.869 (3)
2.790 (2)
2.742 (2)
171 (3)
170 (3)
151.6
0.88
1.87
172.7
Symmetry transformations used to generate equivalent atoms: #1 x, y þ 1, z;
#2 xÀ1/2, Ày þ 3/2, z À1/2.
T ¼ 180 (2) K, space group P21/n, Z ¼ 8, ꢂ (Mo–K) ¼ 0.197 mmꢀ1, 19461
reflections measured, 6931 unique (Rint ¼ 0.0475). The final values of R1
[I>2ꢃ (I)] and wR2 are ¼ 0.045 and 0.111 respectively.
Synthesis of 3-(2,3-Dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)-
imino-indol-2-one (3a)
A mixture of indol-2,3-dione (1a) (1.47 g, 10 mmol) and 4-amino-2,3-
dimethyl-1-phenyl-3-pyrazolin-5-one (2) (2.03 g, 10 mmol) in absolute
ethanol (50 mL) alongwith 2–3 drops of glacial acetic acid was stirred
at room temperature. An orange colored solid that separated out after
10 min of stirring was filtered, dried and recrystallized from ethanol to
give Schiff’s base 3a as orange crystals. Compounds 3b–l were also
synthesized in a similarmanneras above. The specatrl data of
compounds 3a–l is discussed in Table 3.

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[Indole-pyrazolinyl-thiazolidine]-2,40-dione
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[Indole-pyrazolinyl-thiazolidine]-2,40-dione
575

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Synthesis of 30-(2,3-Dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)
spiro[3H-indol-3,20-thiazolidine]-2,40-dione (5a)
A mixture of 3-indolylimine (3a) (0.83 g, 2.5 mmol) and mercapto-
acetic acid (4) (0.23 g, 2.6 mmol) was refluxed in dry toluene for 8 h,
with simultaneous removal of water azeotropically, using Dean-Stark
apparatus. Solution turned light yellow and a sticky yellow solid was
formed. The solvent was removed under reduced pressure and the residue
left was treated with saturated solution of sodium bicarbonate, to remove
the unreacted acid. The solid left was filtered, dried and crystallized from
methanol–chloroform mixture to obtain 5a as colorless crystals. (Found:
C, 62.12; H, 4.41; N, 13.82. C21H18O3N4S requires C, 62.06; H, 4.43;
N, 13.79%) Compounds 5b–l were also synthesized by following the
similar procedure as above and their spectral data is discussed in Table 4.
ACKNOWLEDGMENT
We thank Danish International Development Agency (DANIDA,
Denmark) for the financial support.
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Received in the UK August 16, 2001

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