Nano-ranged calix[4]arene tetracarboxylic acid catalyzed expeditious protocol for spiro[dihydropyridine-oxindoles] synthesis

Article abstract of DOI:10.1016/j.tetlet.2016.08.037

Calix[4]arene tetracarboxylic acid has been successfully established as the nanoranged organocatalyst for the synthesis of spiro[dihydropyridine-oxindoles]. Here we report a sustainable protocol for the synthesis of spiro[dihydropyridine-oxindoles], an Mannich type multi-component reaction involving the ortho-H of activated as well as un-activated aniline derivatives. A library of new spiro derivatives have been synthesized in very high yields in eco-friendly solvent water in one-pot multicomponent fashion.

Full text of DOI:10.1016/j.tetlet.2016.08.037

Accepted Manuscript
Nano-ranged calix[4]arene tetracarboxylic acid catalyzed expeditious protocol
for spiro[dihydropyridine-oxindoles] synthesis
Piyali Sarkar, Chhanda Mukhopadhyay
PII:
S0040-4039(16)31036-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.037
TETL 48008
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 July 2016
10 August 2016
11 August 2016
Please cite this article as: Sarkar, P., Mukhopadhyay, C., Nano-ranged calix[4]arene tetracarboxylic acid catalyzed
expeditious protocol for spiro[dihydropyridine-oxindoles] synthesis, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.08.037
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Graphical Abstract
Nano-ranged calix[4]arene tetracarboxylic acid
catalyzed expeditious protocol for
Leave this area blank for abstract info.
spiro[dihydropyridine-oxindoles] synthesis
Piyali Sarkar and Chhanda Mukhopadhyay

1
Tetrahedron Letters
Nano-ranged calix[4]arene tetracarboxylic acid catalyzed expeditious protocol for
spiro[dihydropyridine-oxindoles] synthesis
Piyali Sarkar and Chhanda Mukhopadhyay 
Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata, 700009, India.
ARTICLE INFO
ABSTRACT
Article history: (Office Use Only)
Received
Calix[4]arene tetracarboxylic acid has been successfully established as the nanoranged
organocatalyst for the synthesis of spiro[dihydropyridine-oxindoles]. Here we report
a
Received in revised form
Accepted
Available online
sustainable protocol for the synthesis of spiro[dihydropyridine-oxindoles], an Mannich type
multi-component reaction involving the ortho-H of activated as well as un-activated aniline
derivatives. A library of new spiro derivatives have been synthesized in very high yields in eco-
friendly solvent water in one-pot multicomponent fashion.
Keywords:
2009 Elsevier Ltd. All rights reserved.
spiro[dihydropyridine-oxindoles]
calix[4]arene tetracarboxylic acid
water-medium
ortho-H involvement
nano-ranged organocatalyst
Nano-organocatalyst, being a metal-free approach, becomes
the area of global interest in the recent decade. Water dispersed
nanoranged organic particle synthesis is a great challenge as they
have high affinity towards coagulation in aqueous phase.
Gratifyingly, calixarenes provide the opportunity to be nano-
ranged catalyst as they disperse in nano-range in water and this
nano-range dispersion is sufficiently stable for long time.1
Calix[4]arene derivatives appears at 100-200 nm range in water
at room temperature (30 ºC). Hence we tried to survey their
catalytic ability for some important organic transformations.2
Recently, we have reported p-tert-butylcalix[4]arene-tetra-O-
acetate as an efficient nanoreactor for the synthesis of the cross
azo-compounds.1c Next, we focused to synthesise some
biologically important heterocyclic cores with the aid of the
calixarene derivatives in greener fashion.
catalysis and optical materials.3 The derivatives of spirooxindole
ring systems are highly effective as antimicrobial, antitumor
agents and as inhibitors of the human NKI receptor.4 Some
alkaloids like horsifiline and alstonisine (Figure 2) contain
spirooxindole system as their structural motif.5 On the other
hand, 1,4-dihydropyridine scaffolds are ubiquitous structural
motifs found in a multitude of pharmaceuticals, basically as
calcium channel blockers, such as, Nifedipine, Felodipine,
Nicardipine, Nimodipine etc. (Figure 2).6 In addition, this is the
common core structure of various biologically active compounds
having selective adenosine-A3 receptor antagonism, along with
radioprotective activity, anticonvulsant activity, sirtuin activation
and inhibition etc.7 Because of the intense utility of these two
cores, we were interested to prepare oxindole-dihydropyridine
fused spiro derivatives i.e., spiro[dihydropyridine-oxindoles].
With
our
continuous
effort,
we
synthesized
spiro[dihydropyridine-oxindoles]
derivatives
using 1,3-
cyclohexanediones, substituted aniline derivatives and N-
substituted isatins where the ortho- attack of the aniline system
occurs to form the spiro centre. From the literature survey, we
found very few report on the synthesis of this spiro core
involving the naphthalen-2-amine where the reactive α–positional
attack has taken place.5,8
O
O
O
O
COOH
COOH
COOH
COOH
C4A4
Figure 1: Calix[4]arene tetracarboxylic acid
Recently, the development of spiro compounds has emerged
as a field of strong attention owing to their attractive
Only one report has been published using p-substituted
anilines, N-substituted isatins and 1,3-cyclopentanedione.9 In this
case, 1,3-cyclopentanedione is a highly reactive system and they
used harsh condition, acetic acid as solvent and catalyst. So, there
conformational features, potential medicinal applications,
———
 Corresponding author. Tel.: +91-9433019610; e-mail: cmukhop@yahoo.co.in

2
is an extreme need of a new protocol for the synthesis of
Table 1: Optimization of reaction conditions for the multicomponent
spiro[dihydropyridine-oxindoles] derivatives involving electron
withdrawing or donating group substituted anilines with different
coupling reactionsa
N
NH2
O
O
O
O
N
Me
Me
N
O
O
conditions
3 ml H2O
H
O
O
O
H
CH3
N
O
O
O
O
O
NH
N
H
O
CH3
2a
H
N
H
O
1a
H
3a
horsfiline
O
N
N
H
4a
Me
Entry
Catalyst
Temp. (ºC)
Time
(h)
Yieldb
(%)
Nimodipine
alstonisine
O
O
Cl
N
N
O
O
Cl
1
2
3
4
5
5
6
7
8
No catalyst
SMSNP-CA
PSNP-CA
Calix[4]arene
MC4A4c
C4A1
100
100
100
100
100
100
100
100
60
72
72
72
72
72
72
72
72
72
12
24
12
NF
20
16
NF
NF
26
43
73
NF
93
93
93
O
O
O
O
O
O
O
N
O
O
O
O
O
N
N
N
H
H
H
Nicardipine
Felodipine
Nifedipine
Figure 2: First two are alkaloids containing spirooxindole and rests are
highly recommended calcium channel blockers containing 1,4-
dihydropyridine system
C4A2
C4A3
C4A4
C4A4
C4A4
C4A4
9
10
11
80
80
100
1,3-diones. For this purpose, we wanted to involve the water
dispersed nano-ranged acid graphed calix[4]arene derivatives.
Delightfully, we reached our goal i.e., we successfully done the
Mannich type multi-component reaction with calix[4]arene
tetracarboxylic acid (C4A4) (Figure 1) as catalyst in water, with
aReaction conditions: mixture of 1.0 equiv. of each of dimedone (1
mmol), N-allylisatin (1 mmol) and p-toluidine (1 mmol) was heated
with stirring in presence of different catalysts (10 mol% for
heterogeneous catalysts and 5 mol% of calixarene catalysts) in 3 ml
of solvent. bIsolated yield. cThe monomer is used in 20 mol%
amount. NF= not found.
approximately full conversion in
multicomponent fashion.
a
chromatography-free
In the beginning, we tried to find out the way of dispersion of
the calixarene derivatives in water. To our delight, just 5 minute
ultra-sonication provided the nano ranged dispersion of C4A4 in
water. The particle size was confirmed by SEM experiment as
80-100 nm and furthermore, the size remained around 190 nm
after keeping the solution intact for 2-3 days (Figure 3). So,
calixarene derivatives possess the possibility to be a nano-
catalyst.
Again, as we increased the acid substitution from mono to
tetra, the yield increased gradually (Table 1, entries 5-9). We
achieved our goal using C4A4 (5 mol%) at 80 ºC in 12 h (Table
1, entry 9).
As mentioned previously, we were interested in exploring the
generality and scope of this multicomponent reaction through a
combination of a range of 1,3-diketones, anilines and N-
substituted isatins. With our optimized conditions in hand, the
synthesis of spiro[dihydropyridine-oxindoles] can be readily
diversified and the results obtained are summarized in Table 2.
Various types of activating (having electron donating substituent)
and deactivating (having electron withdrawing substituent)
aniline systems were used and interestingly all of them produced
good to excellent outputs. Nitro-aniline derivatives provided the
desired products with a little lowering of yields but still in good
extent (77-80 %) (Table 2, 4a’-4d’).
Figure 3: SEM image and DLS data of C4A4
Table 2: scope of the reactiona
To optimize the reaction conditions, the equimolar (1 mmol of each)
mixture of the dimethyl-1,3-cyclohexanedione, p-toluidine and N-
allylisatin were chosen as the starting materials. As central to our
objective is the reactivity of the catalyst, we investigated the activity
of the heterogeneous catalyst, spherical mesoporous silica
nanoparticle supported carboxylic acid (SMSNP-CA, Figure 4a) and
porous silica nanoparticle supported carboxylic acid (PSNP-CA,
Figure 4b), but they failed to show mentionable reactivity. Then we
tried to emphasize the particular effect of the cavity and the acid
group on this reaction. Unfortunately, neither the simple
calix[4]arene nor the monomer, MC4A4 (Figure 4c), could perform
the desired reaction. So, the combination of both the cavity and the
acid substitution were absolutely necessary for the effectiveness of
this protocol.
R6
R5
N
NH2
O
1
O
O
O
R5
R1
R1
5 mol% C4A4
80 ºC, 12 h
stirring
H2O
R1
R1
O
N
R
O
R4
2R3
R6
R
N
2R3
2
3
R4
H
4
Entry R1
R2
R3
R4
R5
R6
Yieldb(%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
H
H
H
H
H
H
H
CH3 CH3 p-CH3
CH3 CH3
CH3 CH3
H
H
H
H
H
H
H
H
H
H
allyl
allyl
allyl
allyl
93
90
92
87
92
89
85
90
92
93
p-Cl
H
p-Cl
H
H
H
O
CH3
O
SMSNP
Si
S
COOH
CH3 CH3 p-CH3
benzyl
benzyl
benzyl
benzyl
allyl
O
O
PSNP
Si
S
COOH
O
O
H
H
H
H
H
H
H
H
H
H
p-Cl
O
(a) SMSNP-CA
(b) PSNP-CA
COOH
(c) MC4A4
m-OCH3
p-OCH3
m-OCH3
p-OCH3
Figure 4: silica nanoparticle supported carboxylic acid (a) SMSNP-CA &
(b) PSNP-CA, tricarboxylic acid and monomer of C4A4 (c) MC4A4
4j
allyl

3
for the enaminoketone formation. Then two consecutive
4k
4l
H
H
H
H
H
H
H
H
H
CH3 CH3
CH3 CH3 m-CH3
CH3 CH3 p-Br
CH3 CH3 m-CH3
p-Br
H
H
H
H
H
H
H
H
H
allyl
allyl
88
84
90
86
92
89
91
87
82
condensations occur, one, the active methylene carbon of the
enaminoketone and secondly, the ortho-carbon of the aniline
group, with isatin to provide our desired product (Scheme 1). The
enaminoketone could be separated from the reaction mixture
after 2h. This enaminoketone further produces the desired
product under the same reaction condition. So, the mechanistic
pathway obviously involves enaminoketone formation.
4m
4n
4o
4p
4q
4r
benzyl
benzyl
benzyl
benzyl
allyl
H
H
H
H
H
H
H
H
H
H
m-CH3
p-Br
m-CH3
p-Br
p-CH3,
m-CH3
allyl
allyl
4s
The structure of the compound 4 was confirmed by a single
crystal X-ray analysis of compound 4f and 4e’ (crystallized from
DMSO) (Figure 5).
4t
4u
H
H
CH3 CH3 o-CH3
H
H
allyl
benzyl
90
83
H
H
p-CH3,
m-CH3
4v
4w
H
H
CH3 CH3 p-CH3
H
H
butyl
butyl
89
82
H
H
p-CH3,
m-CH3
p-Cl
p-CH3
p-CH3
4x
4y
4z
H
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Cl
Cl
Br
H
butyl
benzyl
allyl
benzyl
benzyl
allyl
86
94
93
80
79
79
77
91
89
78
80
80
77
85
4a’
4b’
4c’
4d’
4e’
4f’
4g’
4h’
4i’
4j’
4k’
CH3 CH3 m-NO2
m-NO2
H
H
CH3 CH3 m-NO2
CH3 CH3 p-NO2
CH3 CH3 p-CH3
CH3 CH3 p-CH3
CH3 CH3 p-CH3
CH3 CH3 p-CH3
CH3 CH3 p-CH3
CH3 CH3 p-CH3
allyl
phenyl
methyl
allyl
(a)
(b)
H
H
H
H
allyl
Figure 5: X-ray single crystal structure of (a) 4f (CCDC 1477349) and (b)
4e’ (CCDC 1477350).
benzyl
benzyl
allyl
Table 3: DLS data of the recovered catalyst
Ph
H
p-CH3
aReaction conditions: mixture of 1.0 equiv. of each of 1,3-dione (1
mmol), isatin (1 mmol) and amine (1 mmol) was heated at 80 ºC
with stirring in presence of 5 mol% C4A4 in 3 ml water. Isolated
No. of run
Initial
DLS data
Size of the
partiles (nm)
~105
b
yield.
R1
R1
R
2R3
R4
1
2
3
~110
~110
O
O
HN
O
O
OH
HO
O
O
O
OH
O
O
O
OR5
N
HO
R6
R4
R4
H
O
O
N
O
O
O
O
OH
HO
O
OH
O
O
H
O
OH
O
OH
HO
O
N
O
O
H
O
O
R5
O
OH
N
HO
O
R6
HO
~115-120
O
O
R6
R5
N
O
O
R4
R4
O
O
OH
O
N
H
4
5
~120
~135
O
O
O
NH2
HO
O
4
O
OH
O
HO
O
Scheme 1: Suggested mechanism for the C4A4 catalyzed synthesis of
spiro[dihydropyridine-oxindoles] derivative
In our previous report,1c we showed that the calix[4]arene
moiety provides stability towards the aniline group. It is the main
driving force of the mechanism from the same point of view. The
hydrophilic lower rim part provides the favorable environment

4
References and notes
Next, we were concerned about the recovery of the catalyst. As
the nano-ranged C4A4 was dispersed in water, it was not
separable from water by filtration. Hence after the reaction the
crude product was filtered and the C4A4 was then stayed at the
filtrate. Also the residue was washed with a little water which
was mixed with the filtrate. The presence of nano-ranged catalyst
in the filtrate was confirmed by the DLS measurement. The
mother liquor i.e., the filtrate was reused for further preparation
of 4a and in a test of six cycles; the catalyst could be reused at
list five times without significant loss of catalytic activity (Figure
6). After every cycle the particle size was measured by DlS study
and they are given in Table 3.
1.
(a) Sarkar, P.; Maiti, S.; Ghosh, K.; Sengupta (Bandyopadhyay),
S.; Butcher, R. J. and Mukhopadhyay, C. Tetrahedron Letters,
2014, 55, 996–1001; (b) Sarkar, P. and Mukhopadhyay, C.
Current Organocatalysis. 2016, 3, 205-215; (c) Sarkar, P. and
Mukhopadhyay, C. Green Chem. 2016, 18, 442–451.
Sarkar, P. and Mukhopadhyay, C. Green Chem. 2015, 17, 3452–
3465.
(a) Yao, M. L. and Deng, M. Z. J. Org. Chem. 2000, 65, 5034–
5036; (b) Kongsaeree, P.; Prabpai, S.; Sriubolmas, N.; Vongvein,
C. and Wiyakrutta, S. J. Nat. Prod. 2003, 66, 709–711; (c)
Pradhan, R.; Patra, M.; Behera, A. K.; Mishra, B. K. and Behera,
R. K. Tetrahedron. 2006, 62, 779–828; (d) Fantacci, S.; Angelis,
F. D.; Nazeeruddin, M. K. and Grätzel, M. J. Phys. Chem.
C. 2011, 115, 23126–23133.
2.
3.
100
80
60
40
20
0
4.
5.
(a) Okita, T. and Isobe, M. Tetrahedron. 1994, 50, 11143-11152;
(b) Kornet, M. J. and Thio, A. P. J. Med. Chem. 1979, 19, 892-
898; (c) Hilton, S. T.; Ho, T. C.; Pljevaljcic, G. And Jones, K.
Org. Lett. 2000, 2, 2639-2641; (d) Sannigrahi, M. Tetrahedron
1999, 55, 9007.
Rad-Moghadam, K. and Youseftabar-Miri, L. Synlett. 2010, 13,
1969–1973.
6.
7.
Wan, J. P. and Liu, Y. RSC Advances. 2012, 2, 9763–9777.
(a) Radadiya, A.; Khedkar, V.; Bavishi, A.; Vala, H.; Thakrar, S.;
Bhavsar, D.; Shah, A. and Coutinho, E. European Journal of
Medicinal Chemistry. 2014, 74, 375-387; (b) Ren, Y. J.; Wang, Z.
C.; Zhang, X.; Qiu, H. Y.; Wang, P. F.; Gong, H. B.; Jiang, A. Q.
and Zhu, H. L. RSC Adv. 2015, 5, 21445-21454; (c) Cui, Z.; Li,
X.; Li, L.; Zhang, B.; Gao, C.; Chen, Y.; Tan, C.; Liu, H.; Xie,
W.; Yang, T. and Jiang, Y. Bioorganic & Medicinal Chemistry.
2016, 24, 261–269.
Rad-Moghadam, K. and Youseftabar-Miri, L. Journal of Fluorine
Chemistry. 2012, 135, 213–219.
Sun, Y.; Sun, J. and Yan, C. G. Beilstein J. Org. Chem. 2013, 9,
8–14.
1
2
3
4
5
6
No. of cycles
Figure 6: Recyclability of the C4A4 for the synthesis of 4a
In conclusion, we have developed a very simple, facile and
green method for easy access to a wide range of new
functionalized spiro[dihydropyridine-oxindoles]. This system
synthesized here involves the ortho-H of various activated as
well as un-activated (i.e., with electron donating or withdrawing
substitutions) aniline derivatives. Here, the nano ranged
calix[4]arene tetracarboxylic acid is used as efficient recyclable
catalyst generating a high throughput yield of the products in
environmentally benign solvent water. Moreover, the newly
generated spiro[dihydropyridine-oxindoles] may provide
effective biological activity in future studies.
8.
9.
Supplementary Material
Electronic Supplementary Information (ESI) [CCDC 924313
and 924314] and Details of supplementary information
(experimental procedure, spectral data and crystallographic data
in CIF) are given in the Supplementary Section.
Acknowledgments
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One of the authors (PS) thanks the Council of Scientific &
Industrial Research, New Delhi for her fellowship (SRF). We
also are grateful to CAS-V, Department of Chemistry, University
of Calcutta for funding as a departmental project.

5
Highlights
1. Facile sustainable new methodology for spiro[dihydropyridine-oxindoles] synthesis
2. nano-ranged tetra-acid grafted calix[4]arene derivative as efficient recyclable catalyst
3. Involvement of the ortho-H of activated as well as un-activated anilines
4. 37 new compounds are synthesized