Regio- and stereoselective synthesis of novel dispiropyrrolidine: Bisoxindole derivatives via multicomponent reactions

Article abstract of DOI:10.1021/cc900195t

A convenient and efficient method for the synthesis of novel dispiropyrrolidine bisoxindole derivatives by 1,3-dipolar cycloaddition reaction of azomethine ylides has been developed. The synthesis was achieved by using a one-pot multicomponent procedure. The features of this procedure were characterized by the following: mild reaction conditions, high yields, high regio- and stereoselectivity, one-pot procedure, and operational simplicity.

Full text of DOI:10.1021/cc900195t

2
92
J. Comb. Chem. 2010, 12, 292–294
Regio- and Stereoselective Synthesis of Novel Dispiropyrrolidine
Bisoxindole Derivatives via Multicomponent Reactions
Hai Liu, Guolan Dou, and Daqing Shi*
Key Laboratory of Organic Synthesis of Jiangsu ProVince, College of Chemistry, Chemical Engineering
and Materials Science, Soochow UniVersity, Suzhou 215123, P. R. China
ReceiVed December 25, 2009
A convenient and efficient method for the synthesis of novel dispiropyrrolidine bisoxindole derivatives by
1
,3-dipolar cycloaddition reaction of azomethine ylides has been developed. The synthesis was achieved by
using a one-pot multicomponent procedure. The features of this procedure were characterized by the following:
mild reaction conditions, high yields, high regio- and stereoselectivity, one-pot procedure, and operational
simplicity.
Introduction
The use of multicomponent reactions (MCRs) is a valuable
3-ylidine-malononitrile derivatives preformed by reaction of
isatins with malononitrile.
1
approach to synthesize novel compounds. The MCRs
strategy offers significant advantages over conventional
linear-type synthesis, in that three or more simple and flexible
molecules are brought together to rapidly introduce structural
Results and Discussion
Azomethine ylides can be generated by a number of
methods, including the convenient decarboxylation route as
1
4
2
-4
described in the synthesis of substituted pyrrolidines. In
this method, an aldehyde and a secondary amino acid are
condensed to generate the reactive azomethine ylides, which
complexity and diversity.
Due to the range of readily
available starting materials, the simplicity of one-pot pro-
cedure, as well as the associated atom economy, MCRs has
been extensively employed in the synthesis of heterocyclic
compounds.
15a
15b
when using simple amino acids like sarcosine or proline
1
5
produce cycloaddition products in good yield. Here we
have chosen sarcosine, isatin and 2-(2-oxoindolin-3-ylidine)-
malononitrile for our studies. The reaction of sarcosine with
isatin in boiling methanol leads to the formation of an
azomethin ylide which readily undergoes 1,3-dipolar cy-
cloaddition reaction with 2-(2-oxoindolin-3-ylidene)- mal-
ononitrile (generated in situ from isatin and malononitrile
in boiling methanol without using any catalyst) to give a
single cycloadduct, in a one-pot pseudo-four-component
process (Scheme 1). This reaction afforded a series of novel
dispiroheterocycles 4 containing the two oxindole rings
system by a regio and stereo controlled cycloaddition of the
azomethine ylide to the exocyclic bond of 2-(2-oxoindolin-
3-ylidene)malononitrile in all cases.
The 1,3-dipolar cycloaddition reaction of 1,3-dipoles with
5
a
olefinic or acetylenic dipolarophiles, discovered by Huisgen
5
b
and developed by Woodward and Hoffman and Houk et
al, has became an important and general method for the
6
construction of five-membered heterocyclic rings. Further-
more, the reaction has been shown to be regio- and
7
,8
stereoselective.
Highly substituted pyrrolidines have gained much promi-
nence because they make up the central skeleton of many
9
natural products. Spirooxindole ring systems are the central
skeleton for numerous alkaloids and pharmacologically
important compounds. Some spiropyrrolidines are potential
10
antileukemic and anticovulsant agents and possess antiviral
The choice of an appropriate reaction medium is of crucial
importance for successful synthesis. Initially, the pseudo-
four-component reaction of isatin 1a, malononitrile 2, and
sarcosine 3, as a simple model substrate, was investigated
to establish the feasibility of the strategy and optimize the
reaction conditions. Different solvents, such as methanol,
ethanol, and acetonitrile, as well as ionic liquid [bmim]Br,
were screened. As can be seen from Table 1, methanol is
the solvent of choice for the reaction, and the desired product
is obtained in excellent yields (entry 1).
Encouraged by this success, we extended this reaction of
isatins 1a-f with malononitrile 2 and sarcosine 3 under
similar conditions, and corresponding dispiropyrrolidine
bisoxindole derivatives 4a-f were synthesized in high yield
(Table 2). We have shown that pseudo-four-component
1
1
and local anesthetic activities. Spiropyrrolidinyloxindole
ring systems are also found in a number of alkaloids like
12
horsifiline, spirotryprostatine A and B, elacomine, etc. The
derivatives of spirooxindole find very wide biological ap-
plications as antimicrobial, antitumoral, antibiotic agents and
1
3
inhibitors of human NK-1 receptor etc. As a part of our
own interest in cycloaddition reactions, we report herein the
facile synthesis of novel dispiropyrrolidine bisoxindole
derivatives via the one-pot, multicomponent condensation
of azomethine ylides (generated in situ from sarcosine and
isatin) with the Knoevenagel adduct 2-oxo-(3H)-indole-
*
To whom correspondence should be addressed. E-mail: dqshi@
suda.edu.cn.
1
0.1021/cc900195t  2010 American Chemical Society
Published on Web 02/15/2010

Dispiropyrrolidine Bisoxindole Derivatives
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 293
Scheme 1. Pseudo-Four-Component Reaction of Isatin, Malononitrile, and Sarcosine
Table 1. Synthesis Results of 4a under Different Reactions
Conditions
Table 3. Synthesis of Dispiropyrrolidine Bisoxindole 6 via
Three-Component Reaction
entry
temp/°C
solvent
time/h
yield/%
entry
R1
R2
R3
R4
products
time/h
yield/%
1
2
3
4
reflux
reflux
reflux
80
methanol
ethanol
acetonitrile
[bmim]Br
4
5
4
82
76
77
76
1
2
3
4
5
6
7
8
H
H
H
H
Br
Br
Br
Br
H
H
H
H
H
H
H
H
H
CH
F
Cl
H
CH
F
CH
H
H
H
H
H
H
H
3
6a
6b
6c
6d
6e
6f
3
4.5
5
2
2
3
2
2
91
85
90
89
91
90
92
91
3
10
3
Table 2. Synthesis of Dispiropyrrolidine Bisoxindole 4 via
Pseudo-Four-Component Reaction
6g
6h
Cl
entry
R1
R2
products
time/h
yield/%
spectrometer in KBr pellet. H NMR and 13C NMR spectra
1
1
2
3
4
5
6
H
H
CH
F
Cl
Br
H
CH
H
H
H
4a
4b
4c
4d
4e
4f
4
3
4
4
4
4
82
93
83
83
88
91
3
6 4
were obtained from a solution in DMSO-d with Me Si as
3
internal standard using Varian Invoa-400 MHz or Invoa-300
MHz spectrometer. HRMS analyses were carried out using
TOF-MS or TOF LC/MS 6220 instrument.
H
General Procedure for the Synthesis of 4. A dry 50 mL
flask was charged with isatin 1 (1 mmol), malononitrile 2
reaction makes possible the synthesis of libraries under
similar circumstances.
As expected, when the three-component reaction of 2-(2-
oxoindolin-3-ylidene)-malononitrile 5, isatin 1, and sarcosine
(0.5 mmol), sarcosine 3 (0.5 mmol), and methanol (10 mL).
The reaction mixture was stirred at refluxing temperature
for 3-4 h. After completion of the reaction, the solvent was
removed under vacuum. The solid was recrystallizated from
DMF and ethanol, and then dried at 80 °C for 4 h under
vacuum to give 4.
3
were carried out, the dispiropyrrolidine bisoxindole containing
two different indole rings 6 was obtained in good yield under
the same reaction conditions (Scheme 2 and Table 3).
Control of the relative stereochemistry at the spiro center
was observed. The regio- and stereochemical outcome of the
cycloaddition was determined by single crystal X-ray analysis
of the cycloadduct (4a) (Figure 1). The X-ray structure of
the product 4a reflects that the cycloaddition proceeds via
1
-Methyl-4,4-dicyano-2,3-bis(spiro-3′-indolino)-2,3,4,5-
tetrahydropyrrole 4a: mp 245-246 °C; IR (KBr) 3346,
219, 2958, 2285, 2257, 1722, 1621, 1598, 1471, 1390, 1320,
3
7
-1
1
57 cm ; H NMR (DMSO-d
), 4.19 (s, 2H, CH ), 6.62 (d, J ) 7.6 Hz, 1H, ArH), 6.74
d, J ) 7.6 Hz, 1H, ArH), 6.97 (t, J ) 7.6 Hz, 1H, ArH), 7.06
t, J ) 7.6 Hz, 1H, ArH), 7.16-7.20 (m, 1H, ArH), 7.26-7.30
m, 2H, ArH), 7.59 (d, J ) 7.6 Hz, 1H, ArH), 10.75 (s, 1H,
6 H
, 400 MHz) δ 2.07 (s, 3H,
CH
3
2
1
6
endotransition state (Scheme 3).
(
(
(
In conclusion, a convenient and efficient synthesis of novel
dispiropyrrilidine bisoxindole derivatives has been accom-
plished by 1,3-dipolar cycloaddition methodology. Advan-
tages of this method include the availability of starting
materials, mild reaction conditions employed, high yields,
as well as the complete regio- and stereoselectivity observed.
13
NH), 11.07 (s, 1H, NH); C NMR (DMSO-d
34.6, 39.5, 61.3, 63.1, 77.0, 110.8, 110.9, 115.4, 116.3,
20.3, 122.2, 122.8, 123.2, 126.8, 127.6, 131.5, 131.8, 143.6,
6
, 100 MHz)
δ
C
1
1
3
15 5 2
43.9, 173.1, 176.0; HRMS (m/z) calcd for C21H N O
69.1226, found 369.1224.
Experimental Section
General Procedure for the Synthesis of 6. A dry 50 mL
Melting points were determined in open capillaries and
uncorrected. IR spectra were recorded on a Varian F-1000
flask was charged with 2-(2-oxoindolin-3-ylidene)malono-
nitrile 5 (0.5 mmol), isatin 1 (0.5 mmol), sarcosine 3 (0.5
Scheme 2. Three-Component Reaction of 2-(2-Oxoindolin-3-ylidene)malononitrile, Isatin, and Sarcosine

2
94 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
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2
1
spiro-3′′-indolino)-2,3,4,5-tetrahydropyrrole 6a: mp 228-
30 °C; IR (KBr) 3332, 3088, 2988, 2943, 2861, 2245,
732, 1694, 1610, 1494, 1473, 1380, 1199, 1098, 760
-
1
1
cm ; H NMR (DMSO-d
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6
, 300 MHz) δ
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7
(
(
22 17 5 2
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(
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(
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CC900195T