A novel one-pot synthesis of spiro[indoline-3,4′-pyrazolo[3,4-e][1,4] thiazepine] diones using recyclable bioglycerol-based sulfonic acid functionalized carbon catalyst

Article abstract of DOI:10.1016/j.tetlet.2012.04.122

A novel, simple, and efficient synthetic protocol has been developed for the synthesis of spiro[indoline-3,4′-pyrazolo[3,4-e][1,4]thiazepine] diones, by using bioglycerol-based sulfonic acid functionalized carbon as a recyclable catalyst, devoid of moistu

Full text of DOI:10.1016/j.tetlet.2012.04.122

Tetrahedron Letters 53 (2012) 3497–3501
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel one-pot synthesis of spiro[indoline-3,40-pyrazolo[3,4-e][1,4]thiazepine]
diones using recyclable bioglycerol-based sulfonic acid functionalized carbon
catalyst
K. Karnakar a, S. Narayana Murthy a, K. Ramesh a, K. Harsha Vardhan Reddy a, Y.V.D. Nageswar a,
,
⇑
U. Chandrakala b, B.L.A. Prabhavathi Devi b, R.B.N. Prasad b
a Natural product Chemistry, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500 007, India
b Centre for Lipid Research, Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel, simple, and efficient synthetic protocol has been developed for the synthesis of spiro[indoline-
3,40-pyrazolo[3,4-e][1,4]thiazepine] diones, by using bioglycerol-based sulfonic acid functionalized
carbon as a recyclable catalyst, devoid of moisture sensitive metal catalysts and corrosive acidic reagents.
This new protocol produces novel heptacyclic spirooxindole derivatives in good to excellent yields, with
operational simplicity and recycling of the catalyst in comparison to predictable pentacyclic compounds.
The catalyst can be prepared by a simple adoptable procedure from an inexpensive and readily available
bio-glycerol and found to be recoverable and reusable up to four cycles without any loss of activity.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 12 March 2012
Revised 26 April 2012
Accepted 27 April 2012
Available online 2 May 2012
Keywords:
Bioglycerol-based carbon catalyst
1,4-Thiazepine
Spirooxindole
Isatin
Amino pyrazole
2-Mercapto acetic acid
Drug design and development have been accomplished with
iterative manipulation of individual structures with the aid of fun-
damental chemical reactions. Multi-component reaction (MCR)
strategy is a significant approach utilized by researchers globally
to create combinatorial libraries of molecules containing different
pharmacophoric components, which are responsible for diverse
biological activities.1 Multi-component condensations differ from
multi-step processes and are efficient in the modern drug discov-
ery and development. In the past decade, there has been tremen-
dous development in three- and four-component reactions.2
Heterocycles containing 1,4-thiazepine fragment are a key moi-
ety in a large number of natural and synthetic bio-active molecules.
Among them, aryl- and heteroaryl-fused derivatives of thiazepine
represent an important group of compounds with interesting phar-
maceutical properties. Some of these compounds exhibited angio-
tensin-converting enzyme inhibition,3 leading to the development
of temocapril,4 a drug used for the treatment of hypertension.
Very recently, some thiazepinones have shown nanomolar affin-
ity for a specific domain of a tyrosine kinase enzyme, the Src SH2,
following structure-based rational drug design.5 Different alkyl
derivatives of 3,4-dihydro-5-oxo-1,4-benzothiazepine were also
described as calcium channel antagonists, HIV-1 enzyme integrase
and reverse transcriptase inhibitors, and antitumor agents.6 Numer-
ous heteroannulated bioisosteric analogs of this core fragment were
reported as potent inhibitors of Herpes simplex virus type 1 (HSV-1)
replication, compounds possessing H1 antihistamine activity,
dopamine D2 receptors, and selective antagonists of 5-HT1A and
vasoconstrictor agents.7 Compounds from different 1,4-benzothi-
azepine type structural classes, such as CGP37157 and diltiazem
have been reported to inhibit mNCE activity (Fig. 1).8 CGP37157 is
the most potent inhibitor for mNCE, with a reported IC50 of 0.4 lM.
The spirooxindole system is one of the prominent heterocycles
found in numerous natural and synthetic products, with useful
pharmaceutical activities.9 For example, spirotryprostatin A, a nat-
ural alkaloid isolated from the fermentation broth of Aspergillus
fumigatus, has been identified as a novel inhibitor of microtubule
assembly,10 and pteropodine and isopteropodine have been shown
to modulate the function of muscarinic serotonin receptors.11 They
have been shown to exhibit local anesthetic properties. The unique
structural array and the highly pronounced pharmacological activ-
ity displayed by the class of spirooxindoles have made them attrac-
tive synthetic targets (Fig. 1).
Thia-azaheterocycles gained prominence because of their exten-
sive biological and pharmacological activities.12 Several methods
have been reported for the preparation of spirooxindole derivatives
connecting the thioacid synthon.13 Recently Shi et al., reported
⇑
Corresponding author. Tel.: +91 40 27191654; fax: +91 40 27160512.
E-mail address: dryvdnageswar@gmail.com (Y.V.D. Nageswar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.122

3498
K. Karnakar et al. / Tetrahedron Letters 53 (2012) 3497–3501
O
H3C
OCH3
N
N
S
N
Cl
O
O2N
O
H3C
O
O
O
Cl
S
HN
O
N
H
N
OCH3
spirotryprostatin A
CGP37157
diltiazem
Figure 1. Biologically active benzothiazepines and spirooxindole.
R2
S
R1
N
HO3S
O
R3
O
O
SO3H
HO3S
OH
N
R1
R3
MeCN, 75-80 0C
NH2
O
HS
N
Ph
N
N
Ph
N
R2
O
N
H
R1 = H, CH3, OCH3, Br, Cl ; R3 = H, CH3
R2 = H, CH3, Ph, Benzyl, Allyl
Scheme 1. Synthesis of spiro[indoline-3,40-pyrazolo[3,4-e][1,4]thiazepine] dione.
novel heptacyclic spirooxindole derivatives by using p-TSA as a
catalyst.14
reaction is explored. The progress of the reaction was studied at
different reaction temperatures and it has been observed that 75–
80 °C is the optimum temperature for obtaining good yields.19 To
expand the scope of this method, a variety of substituted isatins
were used in this reaction process, resulting in a range of varied
spiro[indoline-3,40-pyrazolo[3,4-e][1,4]thiazepine] dione. Isatins
with both electron donating or electron withdrawing substituents
reacted very well, affording moderate to high yields of spiro[indo-
line-3,40-pyrazolo[3,4-e][1,4]thiazepine] diones and results are tab-
ulated in Table 1. The isatins containing the electron donating
groups such as methyl and methoxy at 5-position produced the
products in high yields (Table 1, entries 3, 4, 5, and 6). Yields were
moderate with halogen substituted isatins (Table 1, entries 7, 8, 9,
and 10). Reaction was also conducted with N-substituted isatins
(Table 1, entries 11–18).
The scope of this protocol was extended a step further, using 2-
mercaptopropanoic acid in place of the 2-mercaptoacetic acid
component, providing the desired spiro[indoline-3,40-pyrazolo
[3,4-e][1,4]thiazepine] diones in good yields (Table 1, entries 2, 4,
6, and 8).
The recyclability of the catalyst, was also demonstrated. The
reaction mixture was allowed to cool and the catalyst was recov-
ered by simple filtration, washed with ethyl acetate and acetone,
and dried under reduced pressure. The catalyst was reused for
the same reaction without further activation. The reaction pro-
ceeded smoothly even after three cycles, without any extension
of reaction time or marked loss in yield (Table 2).
Despite the importance of these reported protocols many suffer
from drawbacks such as use of expensive reagents, harsh reaction
conditions, prolonged reaction times, cumbersome product
isolation procedures, and low yields as well as more than stoichi-
ometric amount of catalyst. Hence, to explore a mild, efficient
and environmentally benign recyclable synthetic protocol for the
spiro[indoline-3,40-pyrazolo[3,4-e][1,4]thiazepine] diones is highly
desirable.
In recent years, carbon-based solid acid catalysts15 have gained
prominence, due to their significant advantages over the homoge-
neous catalytic systems such as increased activity, selectivity, long-
er catalyst life, negligible equipment corrosion, ease of product
separation, and reusability. Prabhavathi et al., reported sulfonic
acid-functionalized polycyclic aromatic carbon catalyst from bio-
glycerol (biodiesel by-product) and also from the glycerol-pitch
(waste from fat splitting industry) by the in situ partial carboniza-
tion and sulfonation in a single pot16 and studied carbon-based bio-
glycerol solid acid catalyst applications.17 In continuation of interest
in the development of novel heterocyclic compounds18 and exploring
the possible applications for the carbon-based bio-glycerol solid acid
catalyst, herein, we report a facile and efficient one-pot synthesis of
spiro[indoline-3,40-pyrazolo[3,4-e][1,4]thiazepine] diones for the
first time (Scheme 1), catalyzed by the inexpensive, highly stable, ro-
bust, and recyclable bio-glycerol based solid acid, which can be easily
produced from the naturally available bio-glycerol.
Initially, a model reaction was conducted by reacting isatin
(1.0 mmol), 5-amino-3-methylpyrazole (1.0 mmol), and 2-mer-
capto acetic acid (1.0 mmol) in polyethylene glycol (PEG-400) at a
temperature of 100–110 °C, but the reaction did not yield the de-
sired product, and starting materials were recovered back. However,
the same reaction was studied using bioglycerol-based carbon acid
as a catalyst, at room temperature, affording the desired spiro[indo-
line-3,40-pyrazolo[3,4-e][1,4]thiazepine]-dione in a moderate yield
(47%). Based on this interesting result, further optimization of this
The recyclability of the bioglycerol-based carbon catalyst was
examined by using isatin (1.0 mmol), 5-amino-3-methyl-1-phe-
nyl-pyrazole (1.0 mmol), and 2-mercaptoaceticacid (1.0 mmol) in
MeCN (10 mL), as a model reaction. We proposed a plausible
mechanism for the synthesis of spiro[indoline-3,40-pyrazolo[3,
4-e][1,4]thiazepine] diones in Scheme 2. At first, isatin forms
Baylis–Hillman type adduct (A) by the nucleophilic addition with
5-amino-3-methyl-1-phenyl-pyrazole. This is a key intermediate,
which on further dehydration produces the intermediate (B),
which on further Michael addition with thioacid followed by dehy-
dration forms the desired product (C).
In conclusion, we have demonstrated a mild and highly efficient
The bioglycerol based sulfonic acid carbon reagent is not commercially available
but prepared by following the reported procedure cited in the Ref. 16.
protocol for the synthesis of spiro[indoline-3,40-pyrazolo[3,

K. Karnakar et al. / Tetrahedron Letters 53 (2012) 3497–3501
3499
Table 1
Synthesis of spiro[indoline-3,40-pyrazolo[3,4-e][1,4]thiazepine] diones derivativesa
S. No.
Isatin
Pyrazolo amine
R3
H
Product
Time (h)
Yeildb (%)
O
NH
S
O
N
NH2
N
Ph
8918
8618
8718
8518
91
N
H
O
1
7
N
N
Ph
N
O
O
H
O
NH
N
N
N
N
N
NH2
NH2
NH2
NH2
NH2
NH2
NH2
S
N
N
H
O
2
3
CH3
7
CH3
Ph
N
N
N
O
Ph H
O
NH
H3C
H3C
H3CO
H3CO
Br
H3C
O
S
N
Ph
N
O
H
7
H
N
N
N
Ph
N
H
O
O
NH
H3C
O
O
N
Ph
S
O
N
H
4
CH3
7
CH3
N
Ph
N
H
O
NH
H3CO
H3CO
O
N
Ph
S
O
N
H
5
H
7
N
N
Ph
N
O
H
O
NH
O
N
Ph
S
N
H
O
6
CH3
7
88
CH3
N
N
Ph
N
O
H
O
NH
Br
N
O
N
N
N
Ph
S
7918
O
N
H
7
H
7.5
7.5
7
N
Ph
N
O
O
H
O
Br
NH
Br
N
N
Ph
S
N
H
O
8
CH3
78
CH3
N
Ph
N
H
O
O
O
Cl
NH
Cl
N
N
N
N
NH2
NH2
NH2
N
S
O
N
H
9
H
77
Ph
N
Ph
N
H
O
O
NH
Cl
Cl
N
O
O
N
Ph
S
7618
N
H
O
10
CH3
7
CH3
N
Ph
N
H
O
O
CH3
N
N
Ph
O
S
N
11
12
H
7
7
8718
CH3
N
N
N
N
O
Ph
H
O
CH3
N
N
NH2
N
Ph
O
O
N
8618
S
CH3
CH3
CH3
N
Ph
N
H
O
(continued on next page)

3500
K. Karnakar et al. / Tetrahedron Letters 53 (2012) 3497–3501
Table 1 (continued)
S. No.
Isatin
Pyrazolo amine
R3
H
Product
Time (h)
7.5
Yeildb (%)
O
Ph
N
N
NH2
NH2
NH2
N
O
N
N
O
S
S
13
14
79
Ph
Ph
N
N
N
N
O
Ph
H
O
Ph
N
N
N
Ph
O
O
CH3
7.5
77
CH3
Ph
N
N
H
O
O
Ph
O
N
N
N
N
N
Ph
O
N
N
S
S
15
16
H
8
8
73
72
N
N
N
N
H
O
O
Ph
O
N
NH2
NH2
N
Ph
O
CH3
CH3
N
Ph
N
H
O
O
Ph
N
N
Ph
O
O
N
Ph
S
17
H
7
7
82
79
N
N
Ph
N
H
O
O
Ph
N
N
NH2
N
Ph
O
N
Ph
O
S
18
CH3
CH3
N
N
Ph
N
H
O
a
Reaction conditions: Isatin (1.0 mmol), 5-amino-3-methylpyrazole (1.0 mmol), 2-thio aceticcacid (1.0 mmol) and bioglycerol-based carbon catalyst (10 wt% of isatin) at
75–80 °C.
b
Isolated yields.
Table 2
Recyclability of bioglycerol-based carbon catalyst
4-e][1,4]thiazepine] diones, by using novel recyclable bio-glycerol
based carbon catalyst in CH3CN as a reaction medium. This novel
protocol was used to prepare the new heptacyclic spirooxindole
derivatives in moderate to good yields. Environmental acceptabil-
ity, high yields, easy work-up, cleaner reaction profiles, and recy-
clability of bio-glycerol based carbon catalyst are the important
features of this protocol.
Cycles
Yield (%)
Catalyst recovered (%)
Native
90
87
84
82
94
91
88
85
1
2
3
O
S
O
Ph
O
O
H
N
N
NH2
N
O
OH
H2N
N
Ph
OH
O
O
N
- H2O
N
N
R1
N
R1
R1
(A)
Ph
Ph
N
Ph
N
N
N
H
O
HO
NH2
N
NH2
N
O
O
S
O
HS
S
O
OH
O
- H+
- H2O
N
R1
N
R1
N
R1
(B)
(C)
Scheme 2. The plausible mechanism for the synthesis of [3,4-e][1,4]thiazepine] dione.

K. Karnakar et al. / Tetrahedron Letters 53 (2012) 3497–3501
3501
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Acknowledgments
We thank the CSIR, New Delhi, India, for fellowships to K.K.,
S.N.M., K.H.V.R., U.C. and UGC for fellowship to K.R.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
122.
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amino-3-methylpyrazole (1.0 mmol) in MeCN (10 mL) containing bioglycerol-
based carbon catalyst (10 wt% of isatin), 2-thioacid (1.0 mmol) was added and
heated to reflux under nitrogen atmosphere at 75–80 °C, until the reaction was
complete as indicated by TLC. After completion of the reaction, the catalyst was
separated by filtration and washed with ethyl acetate/acetone for reuse. The
reaction mixture was concentrated to remove MeCN. After evaporation of the
solvent under reduced pressure, the crude residue was extracted with EtOAc
and the combined organic layers were washed with brine solution, dried over
anhydrous Na2SO4, evaporated to get the crude product, which was purified by
column chromatography (Silica gel-60), using hexane and EtOAc (80:20) as
eluent to give the title compound. 30-Methyl-10-phenyl-60,80-dihydrospiro
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IR (KBr) 3244, 3109, 2933, 1710, 1650, 1222, 1089 cmꢀ1 1H NMR (300 MHz,
;
CDCl3 + DMSO-d6, TMS) d = 10.72 (s, 1H), 9.76 (s, 1H), 7.47–7.54 (m, 4H), 7.40–
7.42 (m, 1H), 7.28 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 7.3 Hz, 1H), 6.91–7.03 (m, 2H),
4.70 (d, J = 14.9 Hz, 1H), 3.06 (d, J = 14.9 Hz, 1H), 1.53 (s, 3H) ppm. 13C NMR
(75 MHz, CDCl3 + DMSO-d6, TMS) d 177.7, 170.7, 146.6, 141.0, 137.9, 136.4,
129.3, 128.6, 127.8, 127.2, 124.7, 124.4, 122.1, 109.9, 105.3, 48.1, 29.8,
11.7 ppm. ESI-MS: 377 (M+H)+; C20H17N4O2S. 30,5-Dimethyl-10-phenyl-60,800-
dihydrospiro[indoline-3,40-pyrazolo[3,4-e][1,4]thiazepine]-2,70(10H)-dione (Table
1, entry 3): IR (KBr) 3244, 3109, 2933, 1710, 1650, 1222, 1089 cmꢀ1 1H NMR
;
(300 MHz, CDCl3 + DMSO-d6, TMS) d = 10.48 (s, 1H), 9.31 (s, 1H), 7.39–7.58 (m,
5H), 7.09 (d, J = 7.9 Hz, 1H), 7.01 (s, 1H), 6.88 (d, J = 7.9 Hz, 1H), 4.77 (d,
J = 14.9 Hz, 1H), 3.05 (d, J = 14.9 Hz, 1H), 2.28 (s, 3H), 1.58 (s, 3H) ppm. 13C NMR
(75 MHz, CDCl3 + DMSO-d6, TMS) d 177.8, 170.9, 146.8, 138.4, 137.7, 136.2,
131.5, 129.7, 128.7, 127.6, 127.3, 124.9, 124.8, 109.7, 105.3, 48.2, 29.8, 20.4,
11.8 ppm. ESI-MS: 391 (M+H)+; C21H19N4O2S.
12. a Reifschneider, W.; Bisabari-Ershadi, B.; Dripps, J. E.; Bonron, J. B. U.S. Patent
5,075,293, 1991; Chem. Abstr. 1991, 116, 129249f.; b Rovnyak, G. C.; Narayanan,
V. L.; Haugwitz, R. D. U.S. Patent 4,053,613, 1975; Chem. Abstr. 1978, 88,
22892.; (c) Ali, S.; Alam, M. Arch. Pharmacol Res. 1994, 17, 131–133.