Non-catalytic thermal multicomponent assembling of isatin, cyclic CH-acids and malononitrile: An efficient approach to spirooxindole scaffold

Article abstract of DOI:10.1016/j.mencom.2012.05.010

Thermal non-catalytic reaction of isatin, cyclic CH-acids and malononitrile in water or alcohols affords substituted spirooxindoles in 90-97% yields.

Full text of DOI:10.1016/j.mencom.2012.05.010

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 143–144
Non-catalytic thermal multicomponent assembling
of isatin, cyclic CH-acids and malononitrile:
an efficient approach to spirooxindole scaffold
a
a
a
Michail N. Elinson,* Alexey I. Ilovaisky, Valentina M. Merkulova,
b
a
Tatiana A. Zaimovskaya and Gennady I. Nikishin
a
b
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: + 7 499 135 5328; e-mail elinson@ioc.ac.ru
A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
DOI: 10.1016/j.mencom.2012.05.010
Thermal non-catalytic reaction of isatin, cyclic CH-acids and malononitrile in water or alcohols affords substituted spirooxindoles in
0–97% yields.
9
In recent years the concept of ‘privileged medicinal structures or
Table 1 One-pot transformation of isatin 1, N,N'-dimethylbarbituric
acid 2a and malononitrile into 7'-amino-1',3'-dimethyl-2,2',4'-trioxo-1,1',
1
,†
scaffolds’ has emerged as one of the guiding principles of drug
discovery process. These privileged scaffolds commonly consist
of rigid hetero ring system that assigns well-defined orientation of
2
,2',3',4'-hexahydrospiro[indole-3,5'-pyrano[2,3-d]pyrimidine]-6'-carbo-
a
nitrile 3a.
2
Yield of 3a (%)b
appended functionalities for target recognition. The indole scaf-
Entry
Solvent
T/°C
fold represents an important structural subunit for the discovery
1
2
3
4
6
H O
60
80
64
78
97
81
90
85
91
95
3
2
of new drug candidates. Isatin (1H-indole-2,3-dione) and its deriva-
H O
2
4
tives have also sufficient application in medicinal chemistry.
MeOH
EtOH
PrOH
The heterocyclic spirooxindole scaffold is widely distributed
5–7
in a number of pharmaceuticals and natural products and is
regarded as an attractive synthetic target.8
a
b
1 (5 mmol), 2a (5 mmol), malononitrile (5 mmol), 10 min. Isolated yield.
The general approach to formation of spirooxindoles utilizes
catalytic multicomponent procedures with using large amounts
Recently we have developed catalytic ‘on water’Knoevenagel
condensation of isatins with malononitrile. In the present study,
9–14
18
(
20–100%) of diverse catalysts.
The procedure is also known
However, prolonged reaction
15–17
in the electrocatalytic variant.
we wish to report our results on assembling of isatin, cyclic CH-
acids and malononitrile into substituted spirooxindoles under non-
catalytic conditions (Scheme 1, Table 1).
When the reaction of isatin 1, N,N'-dimethylbarbituric acid
2a and malononitrile was performed under basic conditions,18
spirooxindole 3a was obtained in 55% yield (NMR data) along
time, moderate yields and complexity of isolation or necessity to
use sufficient quantities of catalyst are the main drawbacks of the
known methods. Thus, the search for advanced procedures for
the synthesis of spirooxindoles such as fast and convenient non-
catalytic MCR methodology seems topical.
O
HN
CN
CN
Heating, 10 min
H2O/ ROH
O
O
+
+
CN
NH
O
1
2a–g
R = Me, Et, Pr
O
NH2
3
a–g
O
O
O
Me
Me
Me
OH
OH
O
N
Me
N
N
O
O
O
N
O
O
O
N
H
N
Me
Me
O
O
O
Me
Ph
2
a
2b
2c
HN
2d
2e
2f
2g
HN
HN
O
HN
HN
HN
HN
O
O
O
O
O
O
O
O
O
O
O
Me
Me
Me
N
CN
NH2
O
O
CN Me
NH2
CN
NH2
N
CN
NH2
N
CN
NH Me
CN
NH2
CN
NH2
O
N
O
O
O
N
O
N
O
O
O
2
Me
Me
H
Ph
3
a, 95%
3b, 94%
3c, 97%
3d, 91%
Scheme 1
3e, 92%
3f, 90%
3g, 91%
†
The term ‘privileged scaffolds or structures’ was originally introduced by Merck researchers in their work on benzodiazepins (see ref. 1).
2012 Mendeleev Communications. All rights reserved.
©
– 143 –

Mendeleev Commun., 2012, 22, 143–144
Heating
of even single malononitrile anion is theoretically sufficient for the
CH2(CN)2
CH(CN)2
NC
total conversion of equimolar quantities of isatins, cyclic CH-acids
and malononitrile into the corresponding spirooxindoles 3a–g.
In conclusion, the simple non-catalytic system can produce,
under neutral conditions, a fast (10 min) and selective multicom-
ponent transformation of isatin, cyclic CH-acids and malono-
nitrile into spirooxindoles 3a–g in 90–97% yields. This novel
thermalchainprocessopensfastandefficientwaytospirooxindole
derivatives – the promising compounds for the different bio-
medical applications. The procedure utilizes simple equipment;
it is easily carried out and is valuable from the viewpoint of
environmentally benign diversity-oriented large-scale processes.
CN
O–
O
CH(CN)2
O
O
–
OH–
NH
NH
N
1
Me
O
N
O
NC
CN
O
O
Me
NC
NC
2
a
OH–
NH
O
4
This work was supported by the Russian Foundation for
Basic Research (project no. 12-03-00135-a).
NH
Me
O
N
O
Me
O
N
N
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2012.05.010.
O
O
Me
N
NC
NC
NC
N
Me
CH2(CN)2
O
O
O
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NH
NH
The beginning of new reaction cycle
Scheme 2
1
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9
0 min.
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9
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solution with elimination of hydroxide anion and formation of the
Knoevenagel adduct 4.21 The subsequent hydroxide-promoted
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2
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4
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General procedure. A mixture of isatin 1 (5 mmol, 0.74 g), cyclic CH-
2
acid 2 (5 mmol), malononitrile (5 mmol, 0.33 g) and n-propanol (3 ml)
was stirred under reflux for 10 min. Then the reaction mixture was cooled
and filtered to isolate the solid product 3, which was twice rinsed with
ethanol (2×5 ml), and dried under reduced pressure.
For characteristics of compounds 3a–g, see Online Supplementary
Materials.
Received: 26th October 2011; Com. 11/3823
–
144 –