Multi-component supramolecular synthesis of spirooxindoles catalyzed byβ -cyclodextrin in water

Article abstract of DOI:10.1139/V09-137

A neutral and efficient one-pot three-component aqueous-phase synthesis is developed for various spirooxindole derivatives from isatin, malononitrile, and 1,3-dicarbonyl compounds in high yields by supramolecular catalysis involving β-cyclodextrin. The β-

Full text of DOI:10.1139/V09-137

1704
Multi-component supramolecular synthesis of
spirooxindoles catalyzed by b-cyclodextrin in
water
Regati Sridhar, Boga Srinivas, Bandaru Madhav, Vutukuri Prakash Reddy,
Yadavalli Venkata Durga Nageswar, and Kakulapati Rama Rao
Abstract: A neutral and efficient one-pot three-component aqueous-phase synthesis is developed for various spirooxindole
derivatives from isatin, malononitrile, and 1,3-dicarbonyl compounds in high yields by supramolecular catalysis involving
b-cyclodextrin. The b-cyclodextrin can be recovered and reused a number of times without any loss of activity.
Key words: spirooxindole, isatin, dimedone, 4-hydroxy coumarin, barbituric acid, biomimetic synthesis, b-cyclodextrin,
water.
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Resume : On a mis au point une synthese monotope neutre et efficace, a trois composants et en milieu neutre qui permet
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d’obtenir avec des rendements eleves des derives spirooxindoles de l’isatine a partir du malononitrile et de composes 1,3-
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dicarbonyles et faisant appel a une supracatalyse impliquant la b-cyclodextrine. La b-cyclodextrine peut etre recuperee et
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reutilisee un certain nombre de fois sans aucune perte d’activite.
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Mots-cles : spirooxindole, isatine, dimedone, 4-hydroxycoumarine, acide barbiturique, synthese biomimetique, b-cyclodex-
trine, eau.
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[Traduit par la Redaction]
nate the necessity for vigorously drying solvents and sub-
strates, but also because of the unique reactivity and
selectivity often observed in aqueous reactions. However,
the synthesis of spirooxindoles described so far by the three-
component reaction of isatin, malononitrile or methyl cya-
noacetate, and 1,3-dicarbonyl compounds have limited scope
because of the use of transition-metal catalysts, microwave
irradiation, surfactants, acidic or basic conditions, and haz-
ardous solvents.5 As a consequence, the development of en-
vironmentally benign practical synthetic routes under neutral
conditions using a recyclable catalyst in water for accessing
these spirooxindole derivatives still remains a major goal.
These aqueous reactions can be made more sophisticated
if they can be performed under supramolecular catalysis,
such as b-cyclodextrin, overcoming many of the drawbacks
observed in the previous methodologies. Cyclodextrins
(CDs) are cyclic oligosaccharides possessing hydrophobic
cavities which bind substrates and catalyze chemical reac-
tions with high selectivity. They catalyze reactions by supra-
molecular catalysis involving reversible formation of host-
guest complexes by non-covalent bonding as seen in en-
zymes.
Introduction
The spirooxindole is an important structure present in a
number of natural bioactive compounds, such as coerules-
cine, elacomine, horsfiline, welwitindolinone A, spirotry-
prostatin A, alstonisine, and surugatoxin.1 They display
potent cytotoxic activity and are also known as h5-HT6 se-
rotonin receptors, estrogen-receptor modulators, antiprolifer-
ative agents, and oxytocin antagonists.2 In view of their
significance, various methodologies have been developed
for the construction of spirooxindole frameworks.2 However,
our interest in the synthesis of heterocyclic compounds in-
volving supramolecular chemistry3 and the growing focus
on environment-friendly processes prompted us to revisit
the synthesis of spiroxindoles.
It is highly desirable to develop a chemical system that
can mimic the action of enzymes and effect organic reac-
tions in water with excellent efficiency and selectivity.
Water is a safe, inexpensive, and environment-friendly sol-
vent, which makes its use favorable in both academic labora-
tories and industry. The pioneering studies of organic
reactions in water by Breslow4 in the early 1980s triggered
a more widespread interest in the use of water as a medium
for organic synthesis, not only because these reactions elimi-
In continuation of our interest in the b-cyclodextrin cata-
lyzed biomimetic synthesis of heterocyclic compounds in
aqueous phase,3 we have explored the aqueous-phase syn-
thesis of spiooxindole derivatives by the three-component
reaction of isatin, malononitrile, and dimedone under neutral
conditions catalyzed by b-cyclodextrin (Scheme 1).
Received 5 April 2009. Accepted 5 August 2009. Published on
the NRC Research Press Web site at canjchem.nrc.ca on
13 November 2009.
R. Sridhar, B. Srinivas, B. Madhav, V.P. Reddy,
Y.V.D. Nageswar, and K.R. Rao.1 Organic Chemistry
Division-I, Indian Institute of Chemical Technology, Uppal
Road, Hyderabad 500-007, India.
Results and discussion
In general, the reactions were carried out by forming an in
situ b-CD complex of the isatin in water, followed by the
1Corresponding author (e-mail: kakulapatirama@gmail.com).
Can. J. Chem. 87: 1704–1707 (2009)
doi:10.1139/V09-137
Published by NRC Research Press

Sridhar et al.
1705
Scheme 1.
Table 1. b-CD-catalyzed multi-component synthesis of spirooxindoles
1–10.
Entry
1
2
3
4
5
6
7
8
R
H
4-Br
6-Br
5-CH3
5-NO2
H
H
H
H
6-Br
R1
H
H
H
H
H
CH3
CH2Ph
Ph
H
R2
CN
CN
CN
CN
CN
CN
CN
Time (h)
Yield (%)
5
5
5
5
6
4
4
4
6
5
90
89
85
88
84
91
90
89
85
87
CN
COOMe
COOMe
9
10
H
Scheme 2.
Table 2. b-CD-catalyzed multi-component synthesis of spir-
ooxindoles 11–16.
9–10, 85%–87%) under similar conditions. These reactions
proceeded efficiently under neutral conditions. No byprod-
uct formation was observed. b-Cyclodextrin can be easily
recovered and reused.
Further applications of this methodology involve the reac-
tions of 4-hydroxy coumarin and barbituric acid under the
above optimized conditions (Scheme 2) to produce spiroox-
indole derivatives (Table 2, entries 11–16) efficiently in
yields ranging from 84–88%.
Entry
11
12
13
14
R
H
4-Br
H
H
R1
H
R2
CN
CN
Time (h) Yield (%)
8
7
8
8
7
8
88
88
85
86
85
84
H
CH3 COOMe
CN
CH3 CN
COOMe
H
15
16
H
H
H
The complexation of isatin with b-CD was confirmed by
the isolation of the b-CD–isatin complex and the study of
1
addition of malononitrile and dimedone, and stirring at
60 8C. The corresponding spirooxindole compounds were
obtained in impressive yields (84%–91%) after 4–6 h by
simple filtration. This methodology is compatible with vari-
ous substituted isatins having different functionalities such
as bromo, methyl, nitro, phenyl, and benzyl groups (Table 1,
entries 1–8). It was found that methyl cyanoacetate also
underwent condensation with isatin and dimedone to give
the desired product in impressive yields (Table 1, entries
its H NMR spectrum, which shows an upfield shift of H3
1
and H5 of b-CD as observed by us earlier.3a The H NMR
spectra (D2O) of b-CD, the b-CD–isatin complex, and the
freeze-dried reaction mixture of the b-CD–isatin complex
after the addition of malononitrile and dimedone were
studied. It was observed from Fig. 1 that there was an up-
field shift of H3 (0.02 ppm) and H5 (0.02 ppm) protons of
cyclodextrin in the b-CD–isatin complex as compared to b-
CD, indicating the formation of an inclusion complex of isa-
Published by NRC Research Press

1706
Can. J. Chem. Vol. 87, 2009
1
Fig. 1. H NMR spectra of (a) b-CD; (b) b-CD–isatin complex; and
(c) reaction mixture after 2 h. The spectra were recorded in D2O at
25 8C.
may find widespread applications in organic and medicinal
chemistry.
Experimental
General
Melting points were recorded on a Buchi R-535 appara-
tus and are uncorrected. IR spectra were recorded on a
PerkinElmer FT-IR 240-c spectrometer using KBr optics.
1H NMR spectra were recorded on Gemini-200/Avance-
300/Inova-400 spectrometer in DMSO or CDCl3 using
TMS as internal standard. Mass spectra were recorded on
an Agilent 1200 spectrometer. Starting materials were ob-
tained commercially from Sigma-Aldrich or Lancaster and
were used without purification.
General procedure for the synthesis of spirooxindole
b-CD (1 mmol) was dissolved in water (15 mL) by warm-
ing to 60 8C until a clear solution was formed. Then, isatin
(1 mmol) dissolved in methanol (0.5 mL) was added drop-
wise followed by malononitrile (1.2 mmol) and dimedone
(1 mmol), and the mixture was stirred at 60 8C until the re-
action was complete (as monitored by TLC) (Table 1). The
mixture was cooled to 40 8C and the solid was filtered off,
washed with water (10 mL), and recrystallized from EtOH
to yield colorless crystals. The filtrate of the reaction mix-
ture was cooled to 5 8C to recover b-CD.
tin with b-CD from the secondary side of cyclodextrin.6 In
the spectra of the reaction mixture of the b-CD–isatin com-
plex after the addition of malononitrile and dimedone after
2 h, an upfield shift of the CD H6 proton by 0.048 ppm
was also observed. This indicated that the reaction pro-
ceeded by complexation of malononitrile and dimedone
from the primary side of cyclodextrin (Fig. 1). This clearly
demonstrates that the isatin is ideally located for the conden-
sation with malononitrile and dimedone in the hydrophobic
environment of the b-cyclodextrin cavity.
Characterization data
2-Amino-5-oxo-7,7-dimethyl-spiro[(4H)-5,6,7,8-
tetrahydrochromene-4,3’-(3’H)-indol]-(1’H)-2’-one-3-
carbonitrile (1)
Colorless solid; mp 287–289 8C. IR (cm–1) : 3380, 3308,
3142, 2195, 1723, 1659, 1608, 1466, 1350, 1219, 1059, 908,
1
748. H NMR (DMSO-d6, 300 MHz) d: 10.41 (s, 1H, NH),
The catalytic activity of cyclodextrins for these reactions
is established by the fact that in the absence of cyclodextrin,
the reaction was observed to proceed in very poor yields
(20%) even after long reaction times (24 h). The complexa-
tion of isatin with b-CD increases the reactivity of the keto
group due to intermolecular hydrogen bonding with the CD-
hydroxyl groups7 facilitating the Knoevenagel condensation
with malononitrile to form an isatylidene malononitrile de-
rivative. It then undergoes the established sequence of reac-
tions such as Michael addition of dimedone followed by the
cycloaddition of hydroxyl group to the cyano moiety to form
the spiro compound.5 Here, b-CD not only forms the inclu-
sion complex with isatin but is also involved in the intermo-
lecular hydrogen bonding with the guest to promote the
condensation and cycloaddition of the hydroxyl group to the
cyano moiety.
In summary, we have developed a neutral aqueous-
phase synthesis of various spirooxindole derivatives by
the one-pot three-component reaction of the corresponding
isatin, activated methylene reagent, and 1,3-dicarbonyl
compounds under biomimetic conditions in the presence
of b-cyclodextrin. These cyclodextrin mediated water sol-
vent reactions are very useful from both economical and
environmental points of view. b-Cyclodextrin, apart from
being nontoxic, is also considered as metabolically safe.
This straightforward, environmentally benign methodology
7.22 (br s, 2H, NH2), 7.11 (t, 1H, J = 10.0 Hz, ArH), 7.01–
6.73 (m, 3H, ArH), 2.56 (s, 2H, CH2), 2.23–2.03 (m, 2H,
CH2), 1.03 (s, 3H, CH3), 1.00 (s, 3H, CH3). EIMS m/z: 335
[M+]. Anal. calcd. for C19H17N3O3: C 68.05, H 5.11, N
12.53; found: C 68.24, H 5.22, N 12.61.
2-Amino-5-oxo-7,7-dimethyl-spiro[(4H)-5,6,7,8-
tetrahydrochromene-4,3’-(3’H)-4’-bromo-indol]-(1’H)-2’-
one-3-carbonitrile (2
Colorless solid; mp 312–315 8C. IR (cm–1): 3363, 3310,
3152, 2962, 2199, 1724, 1659, 1605, 1497, 1350, 1219,
1
1048, 928. H NMR (DMSO-d6, 300 MHz) d: 10.41 (s, 1H,
NH), 7.28 (br s, 2H, NH2), 7.14 (t, 1H, J = 7.6 Hz, ArH),
6.98 (d, 1H, J = 7.2 Hz, ArH), 6.78 (d, 1H, J = 7.6 Hz,
ArH), 2.56 (d, 2H, J = 7.6 Hz, CH2), 2.17 (d, 1H, J =
15.6 Hz, CH), 2.08 (d, 1H, J = 16.0 Hz, CH), 1.03 (s, 3H,
CH3), 1.00 (s, 3H, CH3). Anal. calcd. for C19H16BrN3O3: C
55.09, H 3.89, N 10.14; found: C 55.19, H 3.97, N 10.19.
Methyl 2-amino-5-oxo-7,7-dimethyl-spiro[(4H)-5,6,7,8-
tetrahydrochromene-4,3’-(3’H)-indol]-(1’H)-2’-one-3-
carboxylate (9)
Colorless solid; mp 255–256 8C. IR (cm–1): 3366, 3241,
3187, 2955, 1690, 1614, 1520, 1471, 1304, 1225, 1167,
1
1054, 928, 746. H NMR (CDCl3, 400 MHz) d: 10.22 (s,
1H, NH), 7.88 (br s, 2H, NH2), 7.05–7.11 (m, 1H, ArH),
Published by NRC Research Press

Sridhar et al.
1707
T.; Iitaka, Y. Tetrahedron Lett. 1981, 22 (35), 3417. doi:10.
1016/S0040-4039(01)81920-1.
6.90 (d, 1H, J = 6.0 Hz, ArH), 6.82 (t, 1H, J = 7.8 Hz,
ArH), 6.76 (d, 1H, J = 6.9 Hz, ArH), 3.32 (s, 3H, CH3),
2.66 (d, 1H, J = 17.4 Hz, CH), 2.55 (d, 1H, J = 17.4 Hz,
CH), 2.23 (d, 1H, J = 15.66 Hz, CH), 2.07 (d, 1H, J =
15.66 Hz, CH), 1.10 (s, 3H, CH3), 1.01 (s, 3H, CH3). EIMS
m/z: 368 [M+]. Anal. calcd. for C20H20N2O5: C 65.21, H
5.47, N 7.60; found: C 65.47, H 5.35, N 7.68.
(2) (a) Edmondson, S. E.; Danishefsky, S. J.; Sepp-Lorenzino, L.;
Rosen, N. J. Am. Chem. Soc. 1999, 121 (10), 2147. doi:10.
1021/ja983788i.; (b) Zaveri, N. T.; Jiang, F.; Olsen, C. M.;
Deschamps, J. R.; Parrish, D.; Polgar, W.; Toll, L. J. Med.
Chem. 2004, 47 (12), 2973. doi:10.1021/jm034249d. PMID:
15163178.; (c) Tokunaga, T.; Hume, W. E.; Umezome, T.;
Okazaki, K.; Ueki, Y.; Kumagai, K.; Hourai, S.; Nagamine,
J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R. J. Med.
Chem. 2001, 44 (26), 4641. doi:10.1021/jm0103763. PMID:
11741481.; (d) Gallagher, G., Jr.; Lavanchy, P. G.; Webster,
C. A.; Wilson, J. W.; Hieble, J. P.; DeMarinis, R. M. J. Med.
Chem. 1985, 28 (10), 1533. doi:10.1021/jm00148a028. PMID:
4045928.
(3) (a) Sridhar, R.; Srinivas, B.; Kumar, V. P.; Reddy, V. P.; Ku-
mar, A. V.; Rao, K. R. Adv. Synth. Catal. 2008, 350 (10),
1489. doi:10.1002/adsc.200800121.; (b) Narender, M.; Reddy,
M. S.; Kumar, V. P.; Reddy, V. P.; Nageswar, Y. V. D.; Rao,
K. R. J. Org. Chem. 2007, 72 (5), 1849. doi:10.1021/
jo062421q. PMID:17266376.; (c) Narender, M.; Reddy, M.
S.; Pavan Kumar, V.; Srinivas, B.; Sridhar, R.; Rama Rao, K.
Synthesis 2007, 22, 3469; doi:10.1055/s-2007-990849;.(d)
Narender, M.; Reddy, M. S.; Sridhar, R.; Nageswar, Y. V.
D.; Rama Rao, K. Tetrahedron Lett. 2005, 46 (35), 5953.
doi:10.1016/j.tetlet.2005.06.130.
2-Amino-5,7-dioxo-spiro[(3’H)-indol-3’,4,4(H)-5,6,7,8-
tetrahydropyrano(2,3-d)pyrimidine]-(1’H)-2’-one-3-
carbonitrile (11)
Colorless solid; mp 273–274 8C. IR (cm–1): 3448, 3280,
3142, 3033, 2204, 1697, 1643, 1511, 1443, 1396, 1242,
1
1114, 1003, 846, 663. H NMR (DMSO-d6, 300 MHz) d:
12.40 (br s, 1H, NH), 12.02 (br s, 1H, NH), 10.52 (br s,
1H, NH), 7.41 (br s, 2H, NH2), 7.17 (t, 2H, J = 8.0 Hz,
ArH), 6.91 (t, 1H, J = 7.6 Hz, ArH), 6.79 (d, 1H, J =
7.6 Hz, ArH). EIMS m/z: 323 [M+]. Anal. calcd. for
C15H9N5O4: C 55.73, H 2.81, N 21.66; found: C 55.40, H
2.89, N 21.68.
2-Amino-5-oxo-spiro[(3’H)-indol-3’,4-4(H)-
pyrano(3,2-c)chromen]-(1’H)-2’-one-3-carbonitrile (14)
Colorless solid; mp 290–292 8C. IR (cm–1): 3350, 3300,
3195, 2954, 2199, 1720, 1667, 1613, 1522, 1474, 1364,
1224, 1132, 1072, 972, 748. 1H NMR (DMSO-d6,
300 MHz) d: 10.64 (s, 1H, NH), 7.95 (d, 1H, J = 8.0 Hz,
ArH), 7.77 (t, 1H, J = 7.6 Hz, ArH), 7.67 (br s, 2H, NH2),
7.57 (t, 1H, J = 7.6 Hz, ArH), 7.50 (d, 1H, J = 8.4 Hz,
ArH), 7.22 (t, 2H, J = 7.6 Hz, ArH), 6.93 (t, 1H, J =
7.6 Hz, ArH), 6.85 (d, 1H, J = 8.0 Hz, ArH). EIMS m/z:
357 [M+]. Anal. calcd. for C20H11N3O4: C 67.23, H 3.10, N
11.76; found: C 67.49, H 3.02, N 11.86.
(4) (a) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102
(26), 7816. doi:10.1021/ja00546a048.; (b) Breslow, R. Acc.
Chem. Res. 1991, 24 (6), 159. doi:10.1021/ar00006a001.; (c)
Breslow, R. Acc. Chem. Res. 2004, 37 (7), 471. doi:10.1021/
ar040001m. PMID:15260509.
(5) (a) Gao, S.; Tsai, C. H.; Tseng, C.; Yao, C.-F. Tetrahedron
2008, 64 (38), 9143. doi:10.1016/j.tet.2008.06.061.; (b) Zhu,
S.-L.; Jia, S.-J.; Zhanga, Y. Tetrahedron 2007, 63 (38), 9365.
doi:10.1016/j.tet.2007.06.113.; (c) Joshi, K. C.; Dandia, A.;
Baweja, S.; Joshi, A. J. Heterocycl. Chem. 1989, 26 (4),
1097. doi:10.1002/jhet.5570260435.; (d) Joshi, K. C.; Jain,
R.; Nishith, S. J. Indian Chem. Soc. 1990, 67, 490; (e) Ab-
del-Latif, F. F.; Mashaly, M. M.; El-Gawish, E. H. J. Chem.
Res. Miniprint 1995, 5, 1220; (f) Dandia, A.; Singh, R.; Sar-
awgi, P.; Khaturia, S. Chin. J. Chem. 2006, 24 (7), 950.
doi:10.1002/cjoc.200690180.; (g) Shanthi, G.; Subbulakshmi,
G.; Perumal, P. T. Tetrahedron 2007, 63 (9), 2057. doi:10.
1016/j.tet.2006.12.042.
Supplementary data
Supplementary data for this article are available on the
journal Web site (canjchem.nrc.ca) or may be purchased
from the Depository of Unpublished Data, Document Deliv-
ery, CISTI, National Research Council Canada, Ottawa, ON
K1A 0R6, Canada. DUD 5305. For more information on ob-
taining material, refer to cisti-icist.nrc-cnrc.gc.ca/cms/
unpub_e.shtml.
(6) (a) Jia, S.-Y.; Hao, Y.-Q.; Li, L.-N.; Chen, K.; Wu, Y.; Liu,
J.; Wu, L.; Ding, Y.-H. Chem. Lett. 2005, 34 (9), 1248.
doi:10.1246/cl.2005.1248.; (b) Schneider, H. J.; Hacket, F.;
Ru¨diger, V.; Ikeda, H. Chem. Rev. 1998, 98 (5), 1755. doi:10.
1021/cr970019t. PMID:11848948.; (c) Demarco, P. V.; Thak-
kar, A. L. J. Chem. Soc. D, Chem. Commun. 1970, 2, 2;
doi:10.1039/C29700000002;.(d) Krishnaveni, N. S.; Surendra,
K.; Rao, K. R. Chem. Commun. (Camb.) 2005, (5): 669.
doi:10.1039/b411736k. PMID:15672172.; (e) Surendra, K.;
Krishnaveni, N. S.; Reddy, M. A.; Nageswar, Y. V. D.; Rao,
K. R. J. Org. Chem. 2003, 68 (5), 2058. doi:10.1021/
jo026751w. PMID:12608839.
Acknowledgement
We thank the Council for Scientific and Industrial Re-
search (CSIR), New Delhi, India, for fellowships to RS, BS,
BM, and VPR.
References
(1) (a) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127
(44), 15394. doi:10.1021/ja056171r. PMID:16262402.; (b)
Chang, M.-Y.; Pai, C.-L.; Kung, Y. H. Tetrahedron Lett.
2005, 46 (49), 8463. doi:10.1016/j.tetlet.2005.10.015.; (c) Hil-
ton, S. T.; Ho, T. C.; Pljevaljcic, G.; Jones, K. Org. Lett.
2000, 2 (17), 2639. doi:10.1021/ol0061642. PMID:10990416.;
(d) Kosuge, T.; Tsuji, K.; Hirai, K.; Yamaguchi, K.; Okamoto,
(7) Netto-Ferreira, J. C.; Ilharco, L. M.; Gracia, A. R.; Vieira Fer-
reira, L. F. Langmuir 2000, 16 (26), 10392. doi:10.1021/
la001041b.
Published by NRC Research Press