An efficient one-pot three-component reaction for synthesis of spirooxindole derivatives in water media under catalyst-free condition

Article abstract of DOI:10.1002/hc.20723

An efficient, clean, and environmentally benign synthesis of spirooxindole derivatives by one-pot three-component reaction of isatins, malononitrile, and carbonyl compound in the absence of catalysis in water was described. A variety of spirooxindole deri

Full text of DOI:10.1002/hc.20723

Heteroatom Chemistry
Volume 22, Number 5, 2011
An Efficient One-Pot Three-Component
Reaction for Synthesis of Spirooxindole
Derivatives in Water Media under Catalyst-Free
Condition
Liqin Zhao, Bo Zhou, and Yiqun Li
Department of Chemistry, Jinan University, Guangzhou 510632, People’s Republic of China
Received 12 December 2010; revised 26 February 2011
inal applications in modulating the function of mus-
ABSTRACT: An efficient, clean, and environmentally
carinic serotonin receptors [4] (Fig. 1).
benign synthesis of spirooxindole derivatives by one-
A literature survey reveals several multicom-
pot three-component reaction of isatins, malononi-
ponent reactions (MCRs) procedures using InCl3
trile, and carbonyl compound in the absence of catal-
[5], triethylbenzylammonium chloride (TEBA) [6],
ysis in water was described. A variety of spirooxindole
tris(2–8 hydroxyethyl)amine [7], tetrabutylammo-
derivatives were obtained with excellent yields within
nium fluoride (TBAF) [8], L-Proline [9], and
short reaction time. This novel protocol has the ad-
ethylenediamine diacetate(EDDA) [10] as catalyst,
vantages of convenient operation, low cost, and envi-
as well as using electrocatalytic method [11] to pre-
ꢀ
C
ronmental benign.
2011 Wiley Periodicals, Inc. Het-
pare them. However, few attempts have been done
on reducing prolonged reaction time, toxic solvents,
and moderate yields of the product. Their studies
may be more reasonable if they had considered the
essence of facile and convenient MCR methodology.
The increasing attention during the last decades
for environmental protection has led both modern
academic and industrial groups to develop chemical
processes with maximum yield and minimum cost,
while using nontoxic reagents, solvents, and cata-
lysts or solvent-free condition. Water, when used as
a reaction media, could strongly enhance the rate
of many organic reactions due to its hydrophobic
effects [12]. Thus, there has been a growing recog-
nition that water is an attractive medium for many
organic reactions [13] and many MCRs in aqueous
medium have been reported [14].
eroatom Chem 22:673–677, 2011; View this article online
at wileyonlinelibrary.com. DOI 10.1002/hc.20723
INTRODUCTION
Spirooxindoles are well known to exhibit
a
wide range of biological properties [1], such
as coerulescine, the simplest spirooxindole found
in nature, displays a local anesthetic effect [2],
spirotryprostatin A, a natural alkaloid isolated from
the fermentation broth of Aspergillus fumigatus, has
been shown as a novel inhibitor of the mammalian
cell cycle [3], and polycyclic alkaloid pteropodine
and isopteropodine have a long history for its medic-
We aim to extend the method of aqueous
medium organic synthesis according to our inces-
sant research efforts with MCR chemistry [15]. It is
hoped that the above questions will be resolved with
our proposed approach. This paper reports an effi-
cient green approach for the syntheses of spirooxin-
dole derivatives via a one-pot three-component
Correspondence to: Yi-Qun Li; e-mail: tlyq@jnu.edu.cn.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant numbers: 21072077 and 20672046.
Contract grant sponsor: The Guangdong Natural Science Foun-
dation.
Contract
grant
numbers:
10151063201000051
and
8151063201000016.
c
ꢀ
2011 Wiley Periodicals, Inc.
673

674 Zhao, Zhou, and Li
Me
N
Me
H
Me
H
O
O
O
HN
N
N
HN
O
CO2Me
CO2Me
N
H
O
Isopteropodine
Coerulescine
Pteropodine
FIGURE 1 Representatives of bioactive spirocyclic oxindoles.
TABLE 1 Optimization of Reaction Temperature
ried out at 60◦C under water media in the absence
of any catalyst. It was found that the model reac-
tion proceeded very smoothly and gave the corre-
sponding product 4a in 89% yield (Table 1, entry 4).
Encouraged by this result, we further demonstrated
the reaction of various isatin 1 with malononitrile
2 and carbonyl compounds 3 (Scheme 1). These re-
sults agreed well with the findings of the model re-
action.
Entry
Temperature (◦C)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
20
40
50
60
70
80
90
90
60
60
20
20
20
20
84
80
86
89
85
84
86
Furthermore, the reactions were carried out at
different temperatures ranging from 20 to 90◦C. It is
clear that the yield was increased with the increasing
temperature, and the optimal temperature was 60◦C
(Table 1, entry 6). Higher temperatures could not,
obviously, improve the yield.
In addition, a series of syntheses of various
isatins 1 with malononitrile 2 and carbonyl com-
pounds 3 were carried out under optimal temper-
ature conditions. In all cases, excellent yields with
good selectivity were obtained (Table 2).
Reaction condition: isatin 1 (1.0 mmol), malononitrile 2 (1.0 mmol),
and carbonyl compound 3 (1.0 mmol) in H2O (5.0 mL).
aIsolated yields.
reaction of isatins, malononitrile, and carbonyl com-
pounds in the absence of any catalyst in water
(Scheme 1). To the author’s knowledge, there is lit-
tle information in literature about the synthesis of
spirooxindole derivatives in water medium under the
catalyst-free conditions.
As can be seen from Table 2, isatins with either
electron-donating or electron-withdrawing groups
on the aromatic ring underwent smoothly and gave
the products in good yields (Table 2).
RESULTS AND DISCUSSION
The model reaction of isatin, malononitrile, and 5,5-
dimethylcyclohexane-1,3-dione (dimedone) was car-
TABLE 2 Synthesis of Spirooxindole Derivatives in Water Medium
Entry
Isatin (1)
Carbonyl Compound (3)
Product (4)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1a
1b
1c
1a
1a
1a
1b
3a
3a
3a
3a
3b
3b
3b
3b
3c
3c
3c
3d
3d
3d
3e
3f
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
20
20
60
120
15
20
89
94
90
82
88
95
90
82
84
95
92
92
95
85
75
83
80
88
30
120
120
110
60
120
110
120
30
9
10
11
12
13
14
15
16
17
18
30
30
30
3g
3g
Reaction condition: isatin 1 (1.0 mmol), malononitrile 2 (1.0 mmol), and carbonyl compound 3 (1.0 mmol) in H2O (5.0 mL) at 60◦C◦
aIsolated yields.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Spirooxindole Derivatives in Water Media 675
R
NH
O
O
O
CN
CN
H2O
NC
+
O
R
+
60oC
N
H2N
O
H
2
1
3
4
Isatin 1
O
O
O
O
Me
Br
O
O
O
O
N
N
N
N
H
Br
H
H
H
1b
1a
1c
1d
Carbonyl compound 3
O
O
S
O
OH
O
O
HN
NH
HN
NH
N
O
N
O
O
O
OC2H5
O
O
O
O
O
Ph
3c
3a
3g
3e
3f
3b
3d
Product 4
R'
R'
H2N
NC
H2N
NC
O
O
O
O
O
O
R
N
N
NH2
R
O
R
CN
N
N
O
N
O
H
H
H
R=H, Br, Me
R'=H, Me
R=H, Br, Me
R=H, Br, Me
4l–4n
4a–4h
4i–4k
X
C2H5O
O
NH
HN
O
O
O
NH2
CN
NH2
CN
R
O
N
H
O
N
H
R=H, Br
X=O, S
4q–4r
4o–4p
SCHEME 1
CONCLUSION
aqueous medium organic synthesis will continue in
our next study.
In summary, a practical and efficient procedure for
the synthesis of spirooxindole derivatives was inves-
tigated via the one-pot three-component reaction
at 60◦C under water media in the absence of any
catalyst. This procedure offers several advantages
including higher yields, mild reaction conditions,
shorter reaction time, convenient procedure, and
environmental friendliness. Further research on
EXPERIMENTAL
Melting points are measured on an Electrothemal X6
microscopy digital melting point apparatus (Beijing
Tech Instrument Co. Ltd., Beijing, China) and are
uncorrected. Infrared (IR) spectra were recorded on
Heteroatom Chemistry DOI 10.1002/hc

676 Zhao, Zhou, and Li
a Nicolet 6700 FT-IR (Thermo Electron Corporation,
USA) spectrometer in KBr pellets. H NMR spectra
(KBr) ν: 3323, 3208, 2202, 1739, 1672, 1608,
1473, 1361, 1221, 1113, 1087, 976, 922, 868, 764,
578 cm−1. 1H NMR (DMSO-d6, 300 MHz) δ: 6.81
(d, J = 7.9 Hz, 1H, ArH), 7.38 (d, J = 7.9 Hz, 1H,
1
were recorded in DMSO-d6 on a Bruker Avance 300
(300 MHz; Swiss Bruker Corporation, Switzerland)
instrument with the TMS at δ0.00 ppm as an internal
standard. Chemicals used are of commercial grade,
without further purification.
ArH), 7.48–7.54 (m, 3H, ArH), 7.74 (s, 2H, NH ),
2
7.79 (d, J = 7.9 Hz, 1H, ArH), 7.92 (d, J = 7.5 Hz,
1H, ArH).
2-Amino-5-oxo-7-thioxo-spiro[(3ꢁH)-indol-3ꢁ,4,4
(H)-5,6,7,8-tetrahydropyrano(2,3-d)pyramidine]-(1ꢁ
H)-2ꢁ-one-3-carbonitrile (4p, C15H9N5O3S) mp 240–
242◦C (lit. [10] 238–242◦C); IR (KBr) ν: 3508, 3427,
3308, 3160, 2202, 1693, 1656, 1569, 1470, 1400,
Typical Procedure for Preparation of
Spirooxindole Derivatives
A mixture of isatin 1 (1.0 mmol), malononitrile 2
(1.0 mmol), and carbonyl compound 3 (1.0 mmol) in
H2O (5.0 mL) was stirred at 60◦C for 15–120 min. The
reaction was monitored by thin layer chromatogra-
phy (TLC). Upon completion, the reaction mixture
was allowed to cool to room temperature. Then, the
precipitated product was filtered and washed with
water and the crude product was purified by cooled
ethanol to afford the pure product 4.
1
1343, 1185, 1133, 919, 868, 768, 580 cm−1. H NMR
(DMSO-d6, 300 MHz) δ: 6.79 (d, J = 7.1 Hz, 1H,
ArH), 6.90 (t, J = 7.1 Hz, 1H, ArH), 7.16 (t, J = 8.1
Hz, 2H, ArH), 7.42 (s, 2H, NH ), 10.54 (s, 1H, NH),
2
12.51 (s, 1H, NH).
Ethyl
2ꢁ-Amino-3ꢁ-cyano-6ꢁ-methyl-2-oxospiro
[indoline-3,4ꢁ-pyran]-5ꢁ-carboxylate (8q, C17H15N3O4)
mp 259–260◦C (lit. [13] 258–260◦C); IR (KBr)
ν: 3484, 3160, 2188, 1713, 1620, 1472, 1380,
1288, 1212, 1072 cm−1. 1H NMR (DMSO-d6, 300
2-Amino-7,7-dimethyl-2ꢁ,5-dioxo-5,6,7,8-tetrahy-
drospiro[chromene-4,3ꢁ-indoline]-3-carbonitrile (4a,
C19H17N3O3) mp > 300◦C (lit. [13] > 300◦C); IR
(KBr) ν: 3377, 3312, 3144, 2192, 1723, 1683, 1655,
MHz) δ: 0.76 (t, J = 7.1 Hz, 3H, CH ), 2.30
3
(s, 3H, CH ), 3.34 (s, 2H, NH ), 3.73–3.77 (m, 2H,
3
2
1
1472, 1349, 1223, 1055 cm−1. H NMR (DMSO-d6,
CH ), 6.76 (d, J = 7.6 Hz, 1H, ArH), 6.92 (t, J = 7.2
2
300 MHz) δ: 0.98 (s, 3H, CH ), 1.04 (s, 3H, CH ),
Hz, 1H, ArH), 7.08 (d, J = 7.2 Hz, 1H, ArH), 7.20
(t, J = 7.6 Hz, 1H, ArH), 10.39 (s, 1H, NH).
3
3
2.10 (d, J = 16.0 Hz, 1H, CH ), 2.18 (d, J = 16.0 Hz,
2
1H, CH ), 2.48 (d, J = 18.0 Hz, 1H, CH ), 2.54
2
2
(d, J = 18.0 Hz, 1H, CH ), 6.78 (d, J = 7.6 Hz, 1H,
2
REFERENCES
ArH), 6.88 (t, J = 7.2 Hz, 1H, ArH), 6.95 (d, J =
7.2 Hz, 1H, ArH), 7.13 (t, J = 7.6 Hz, 1H, ArH), 7.23
[1] (a) Galliford, C. V.; Scheidt, K. A. Angew Chem Int
Ed Engl 2007, 46, 8748–8758; (b) Williams, R. M.;
Cox, R. J. Acc Chem Res 2003, 36, 127–139; (c) Ding,
K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.;
Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski,
K.; Roller, P. P.; Wang, S. J Med Chem 2006, 49, 3432–
3435.
[2] Kornet, M. J.; Thio, A. P. J Med Chem 1976, 19, 892–
898.
[3] Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1996,
52, 12651–12666.
[4] Kang, T. H.; Matsumoto, K.; Murakami. Y.;
Takayama, H.; Kitajima, M.; Aimi, N.; Watanabe, H.
Eur J Pharmacol 2002, 444, 39–45.
[5] Shanthi, G.; Subbulakshmi, G.; Perumal, P. T. Tetra-
hedron 2007, 63, 2057–2063.
[6] Zhu, S. L.; Ji, S. J.; Zhang, Y. Tetrahedron 2007, 63,
9365–9372.
[7] Shemchuk, L.; Chernykh, V.; Red’kin, R. Russ J Org
Chem 2008, 44, 1789–1794.
[8] Gao, S.; Tsai, C. H.; Tseng, C.; Yao, C. F. Tetrahedron
2008, 64, 9143–9149.
[9] Li, Y.; Chen, H.; Shi, C.; Shi, D.; Ji, S. J Comb Chem
2010, 12, 231–237.
[10] Hari, G. S.; Lee, Y. R. Synthesis 2010, 453–464.
[11] (a) Elinson, M. N.; Ilovaisky, A. I.; Merkulova, V.
M.; Demchuk, D. V.; Belyakov, P. A.; Ogibin, Y. N.;
Nikishin, G. I. Electrochim Acta 2008, 53, 8346–
8350; (b) Elinson, M.; Dorofeev, A.; Miloserdov, F.;
Nikishin, G. Mol Divers 2009, 13, 47–52.
(s, 2H, NH ).
2
2-Amino-5ꢁ-methyl-2ꢁ,5-dioxo-1ꢁ,2ꢁ,5,6,7,8-hexahy-
drospiro[chromene-4,3ꢁ-indole]-3-carbonitrile
(4g,
C18H15N3O3) mp 288◦C (lit. [11] 287◦C); IR (KBr)
ν: 3362, 3145, 2195, 1658, 1603, 1351, 1213, 1075,
1009 cm−1. 1H NMR (DMSO-d6, 300 MHz) δ: 1.90 (t,
J = 6.0 Hz, 2H, CH ), 2.19–2.21 (m, 5H, CH , CH ),
2
3
2.64 (t, J = 5.9 Hz, 2H, CH ), 6.65 (d, J = 27.8 Hz,
2
1H, ArH), 6.80 (s, 1H, ArH), 6.92 (d, J = 7.8 Hz, 1H,
ArH), 7.19 (s, 2H, NH ).
2
6ꢁ-Amino-3ꢁ-methyl-2-oxo-1ꢁ-phenyl-1ꢁH-spiro[in-
doline-3,4ꢁ-pyrano[2,3-c]pyrazole]-5ꢁ-carbonitrile (4i,
C21H15N5O2) mp 238–240◦C (lit. [13] 236–237◦C);
IR (KBr) ν: 3461, 3296, 3178, 2196, 1701, 1655,
1595, 1470, 1392, 1331, 1221, 1127, 1070 cm−1. H
1
NMR (DMSO-d6, 300 MHz) δ: 1.53 (s, 3H, CH ),
3
6.94 (d, J = 7.3 Hz, 1H, ArH), 7.02 (t, J = 7.3 Hz,
1H, ArH), 7.17 (d, J = 7.1 Hz, 1H, ArH), 7.27 (t,
J = 7.3 Hz, 1H, ArH), 7.35 (d, J = 7.3 Hz, 1H, ArH),
7.50 (t, J = 7.0 Hz, 2H, ArH), 7.57 (s, 2H, NH ), 7.78
2
(d, J = 7.3 Hz, 2H, ArH), 10.74 (s, 1H, NH).
2ꢁ-Amino-5-bromo-2,5ꢁ-dioxo-5ꢁH-spiro[indoline-
3,4ꢁ-pyrano[3,2-c]chromene]-3ꢁ-carbonitrile
(4m,
C20H10N3O4) mp > 300◦C (lit. [13] > 300◦C); IR
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Spirooxindole Derivatives in Water Media 677
[12] Rideout, D. C.; Breslow, R. J Am Chem Soc 1980, 102,
7816–7817.
[15] (a) Lian, X. Z.; Huang, Y.; Li, Y. Q.; Zheng, W. J.
Monatsh Chem 2008, 139, 129–131; (b) Chen, L.;
Huang, X. J.; Li, Y. Q.; Zhou, M. Y.; Zheng, W. J.
Monatsh Chem 2009, 140, 45–47; (c) Chen, L.; Li,
Y. Q.; Huang, X. J.; Zheng, W. J. Heteroatom Chem
2009, 20, 91–94.
[13] Li,
2035.
C.
J
Chem
Rev
1993,
93,
2023–
[14] Kumaravel, K.; Vasuki, G. Curr Org Chem 2009, 13,
1820–1841.
Heteroatom Chemistry DOI 10.1002/hc