Multicomponent reaction to construct spirocyclic oxindoles with a Michael (triple Michael)/cyclization cascade sequence as the key step

Article abstract of DOI:10.1002/chem.201104071

Multicomponent cycloadditions with readily available isocyanides, allenoates, and isatylidene malononitriles are disclosed. This reaction, which does not require the aid of any catalyst, allows the efficient syntheses of spirocyclic oxindoles with excellent regioselectivity. Reactions with ethyl 2,3-butadienoate and various structurally diverse α- and γ-substituted allenoates are also fully explored. Remarkably, we have shown that the usual three-component process can be further developed into an unprecedented four-component cycloaddition in the presence of water, which provides a new strategy to access highly unusual tricyclic oxindoles. From a synthetic point of view, this protocol is very interesting considering the high level of complexity reached in one step. The mechanism is thought to proceed by a triple Michael/cyclization process by using allenoate as a three carbon atom component (3 C). Furthermore, multicomponent reaction with γ-substituted allenoate also results in a very interesting conversion. In such cases, the unusual cleavage of the "C=C" double bond of isatylidene malononitrile and one of the "C=C" double bonds of allenoate is always observed. Multiply your chemistry! Multicomponent reactions with readily available isocyanides, allenoates, and isatylidene malononitriles are disclosed. This protocol provides a synthetic route to an exocyclic double bond containing a spirocyclic ring in an efficient manner with excellent regioselectivity (see scheme). Copyright

Full text of DOI:10.1002/chem.201104071

FULL PAPER
DOI: 10.1002/chem.201104071
Multicomponent Reaction to Construct Spirocyclic Oxindoles with a Michael
(Triple Michael)/Cyclization Cascade Sequence as the Key Step
Jian Li,*[a] Ning Wang,[a] Chunju Li,[a] and Xueshun Jia*[a, b]
Abstract: Multicomponent cycloaddi-
tions with readily available isocyanides,
allenoates, and isatylidene malononi-
triles are disclosed. This reaction,
which does not require the aid of any
catalyst, allows the efficient syntheses
of spirocyclic oxindoles with excellent
regioselectivity. Reactions with ethyl
2,3-butadienoate and various structur-
ally diverse a- and g-substituted al-
lenoates are also fully explored. Re-
markably, we have shown that the
usual three-component process can be
further developed into an unprecedent-
ed four-component cycloaddition in the
presence of water, which provides
a new strategy to access highly unusual
tricyclic oxindoles. From a synthetic
point of view, this protocol is very in-
teresting considering the high level of
complexity reached in one step. The
mechanism is thought to proceed by
a triple Michael/cyclization process by
using allenoate as a three carbon atom
component (3C). Furthermore, multi-
component reaction with g-substituted
allenoate also results in a very interest-
ing conversion. In such cases, the un-
usual cleavage of the “C=C” double
bond of isatylidene malononitrile and
one of the “C=C” double bonds of al-
lenoate is always observed.
Keywords: allenoates · isocyanides ·
Michael addition · multicomponent
reactions · spiro compounds
Introduction
from cultures of Pennicillium paraherquei, has displayed
potent antiparasitic activity and antinematodal properties.[4]
Horsfiline[5] and spirotryprostatin A[6] have also proved to
be attractive to organic chemists. Owing to their increased
structural complexity and significant biological activities, the
past decades have witnessed a rapid progress in the efficient
and selecitve construction of these spirocyclic oxindole skel-
etons. Among these methods, the palladium-catalyzed pro-
cesses,[7] Lewis acid promoted annulations,[8] organocata-
lyzed reactions,[9] and other novel routes[10] represent signifi-
cant efforts to synthesize these natural product analogues,
thus dramatically facilitating biological evaluation. In spite
of these considerable advances, new strategies to effciently
construct these core structures in a chemo-, regio-, and ste-
reocontrolled manner are still in high demand.
Spirocyclic oxindole is a privileged synthetic motif that con-
stitutes a large family of natural products and clinical phar-
maceuticals.[1] These compounds have been shown to exhibit
a broad range of biological activities, including insecticidal,
antitumor, anthelmintic, and antibacterial properties.[2] For
example, the most notable paraherquamide A,[3] isolated
In recent years, the development of new methods that
provide synthetic efficiency has been an important goal of
synthetic chemistry.[11] In this light, multicomponent reac-
tions (MCRs) can serve as good candidates as they embody
many features of ideal synthesis, such as atom- and step-
economy, convergence, and structural diversity.[12] Thus,
MCRs have attracted enormous attention and become
a powerful tool in organic synthesis. Among the MCRs,
those with isocyanides (IMCRs) are particularly interesting
due to the exceptional reactivity of isocyanide.[13] From a syn-
thetic point of view, isocyanide-based multicomponent reac-
tions often benefit from the diversity of bond-forming pro-
cesses available, inherent atom economy, and the excellent
chemo-, regio-, and stereoselectivity often observed.[14] In
particular, IMCRs usually allow the efficient generation of
complex and diverse druglike small molecules, which are su-
perior to traditional methods.
[a] Dr. J. Li, N. Wang, Dr. C. Li, Prof. Dr. X. Jia
Department of Chemistry, Shanghai University
99 Shangda Road, Shanghai, 200444 (P.R. China)
Fax : (+86)21-66132408
E-mail: lijian@shu.edu.cn
xsjia@mail.shu.edu.cn
[b] Prof. Dr. X. Jia
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou, 730000 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201104071.
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9645

Table 1. Three-component [2+2+1] cycloaddition of isocyanide 1, al-
lenoate 2, and isatylidene malononitrile 3.[a]
More recently, we have focused our attention on multi-
component cycloaddition reactions involving isocyanides
and allenoates to synthesize functionalized carbocycles and
heterocycles.[15] In these atom-economic transformations, the
exceptional synthetic efficiency of IMCRs has been fully
demonstrated, which in turn prompts us to carry out further
investigation in this field. During the above-mentioned ex-
periments, we have also found that the in situ formation of
a zwitterionic intermediate plays a key role, which provides
an opportunity for the design of new IMCRs (Scheme 1).
Herein, as a continuation of our ongoing research toward
the syntheses of spirocyclic oxindole derivatives, we wish to
report the multicomponent cycloaddition of allenoates, iso-
cyanides, and isatylidene malononitriles.
1
R2
R3
PG[b]
4
Yield
[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1c
1c
1c
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
3-ClBn
H
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Bn
Bn
Me
Bn
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
80
71
85
79
65
86
74
83
52
65
70
76
68
60
5-fluoro
5-chloro
5-bromo
5-nitro
6-bromo
7-bromo
5,7-dimethyl
H
5-nitro
H
5-fluoro
5-chloro
5-chloro
Scheme 1. Mechanism for the design of new IMCRs based on the in situ
formed zwitterionic species.
Results and Discussion
To establish a basic methodology for the proposed three-
component cycloaddition reaction, we initially studied the
reaction of benzyl isocyanide (1a), ethyl 2,3-butadienoate
(2a), and 2-(1-benzyl-2-oxoindolin-3-ylidene)malononitrile
(3a). Gratifyingly, cycloaddition adduct 4a was isolated in
80% yield after heating the mixture for 24 h at 1008C with
toluene as the solvent (Table 1, entry 1). Encouraged by this
experimental result, we then explored the substrate scope.
As shown in Table 1, broad generality was observed with
various substituted isatylidene malononitriles 3: both elec-
tron-withdrawing (Table 1, entries 2–7) and -donating sub-
stituents (Table 1, entry 8) on the aryl ring were well tolerat-
ed. Experiments with different protecting groups at the ni-
trogen atom of the isatins were also conducted (Table 1, en-
tries 9 and 10). A feasibility investigation of substituted al-
lenoates 2 was also carried out, resulting in the formation of
compounds 4 in satisfactory yields (Table 1, entries 11–14).
It should be noted that all compounds 4 were characterized
by 1H NMR, 13C NMR, and HRMS spectra.[16] Moreover,
the structure of compound 4l was unambiguously confirmed
by single-crystal X-ray analysis.[17] This procedure provides
a synthetic route to exocyclic double-bond-containing spiro-
cycles in an efficient and atom-economical manner. Re-
markably, the present strategy showed excellent regioselec-
tivity and only the external double bond of the allenoate
was utilized to form the five-membered ring.
[a] Reaction conditions: isocyanide 1 (0.5 mmol), allenoate 2 (0.6 mmol),
isatylidene malononitrile 3 (0.5 mmol), toluene (5 mL), 1008C (Bn=
benzyl, Hex=hexyl, Hal=halide). [b] PG=protecting group. [c] Yields
of product after purigication by silica gel chromatography.
cies can serve as efficient tools to synthesize five-membered
carbocycles and heterocycles. In such cases, the allenoates
were always used as a two carbon atom component (2C) to
form the rings, whereas their participation as three carbon
atom components (3C) has not yet been observed.[18] Ac-
cording to our hypothesis, if both C=C double bonds of the
allenoates participated in the ring formation, it would open
new pathways for the construction of more complicated
structures together with increased synthetic efficiency. To
our delight, direct evidence to support the above hypothesis
has been obtained in our successive experiments. When 2,6-
dimethylphenyl isocyanide (1c), a-methyl-substituted alle-
noate 2b and 2-(1-benzyl-5-chloro-2-oxoindolin-3-ylidene)-
malononitrile (3c) were heated in the presence of water, un-
precedented tricyclic product 5a was isolated in 31% yield.
In such a case, a prolonged reaction time (72 h) did not sig-
nificantly increase the yield (34%). The scope of this new
cycloaddition was subsequently investigated, focusing on the
reaction with structurally diverse a-substituted allenoate 2
(Table 2, entries 2–6). Despite the prolonged reaction time
and somewhat lower yields, all substituted allenoates includ-
ing sterically demanding ones were found to be compatible
Our previous efforts[15] and the above mentioned annula-
tion strategy have all demonstrated that the [2+2+1] cyclo-
addition of isocyanide, allenoate, and electron-deficient spe-
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Multicomponent Reaction to Construct Spirocyclic Oxindoles
FULL PAPER
Table 2. Unprecedented four-component cycloaddition reaction of isocy-
anide 1c, allenoate 2, isatylidene malononitrile 3, and water.[a]
R2
Product
Yield
[%][b]
1
2
Me
31
54
Me
Figure 1. X-ray structure of product 5d.
vergent and powerful method for the construction of a poly-
cyclic skeleton that cannot be otherwise accessed. During
our investigation, compounds 5’ were also isolated with
a poor yield in some cases (Scheme 2). The absolute config-
uration of 5’a was determined by X-ray crystallographic
analysis.[20] Judging from these experimental results, it was
apparent that the nucleophilic addition occurred on the
carbon atom bearing the two cyano groups to yield com-
pound 5’. Moreover, the exact structure of 5’ might help to
account for the mechanistic formation of unusual cycloaddi-
tion adduct 5.
3
4-NO2Bn
39
4
3-FBn
47
35
27
5[c]
3-ClBn
3-BrBn
6
Scheme 2. Unexpected isolation of 5’ with different regioselectivity.
[a] Reaction conditions: isocyanide 1c (0.5 mmol), allenoate
2
(0.6 mmol), isatylidene malononitriles (0.5 mmol), mixed solvent
3
(5 mL, H2O/toluene (v/v) 1:7), 1008C, 48 h. [b] Yields of product after
purification by silica gel chromatography. [c] In this case compound 4n
was also isolated.
The mechanism of the above four-component cycloaddi-
tion reaction has not been unequivocally established, but
one reasonable possibility is proposed in Scheme 3. The be-
ginning of the present procedure involves the formation of
zwitterionic species from isocyanide 1 and allenoate 2,
which exist in a resonance-stabilized form AQB.[15] The re-
active species are then trapped by the dual-activated
carbon–carbon double bond of substrate 3 to undergo the
second Michael addition process to afford C. The intermedi-
ate C may follow two possible reaction pathways, that is,
path a or b. Intramolecular cyclization of C followed by
with this cycloaddition protocol, giving the desired tricyclic
adducts 5. Notably, the structures of compounds 5b and 5d
(Figure 1) were unambiguously confirmed by single-crystal
X-ray analysis.[19] Most importantly, this four-component cy-
cloaddition represents the first example of the synthesis of
highly unusual tricyclic oxindoles by using allenoate as
a three carbon atom component (3C), which provides a con-
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9647

X. Jia, J. Li et al.
Table 3. Highly unusual three-component reaction of isocyanide 1, g-sub-
stituted allenoate 2, and isatylidene malononitrile 3.[a]
R3
PG[b]
Product
Yield
[%][c]
1
5-fluoro
Me
76
2
3
4
5-chloro
4-bromo
5-fluoro
Me
Bn
Bn
65
58
78
Scheme 3. Proposed mechanism for the formation of 5 (PG=protecting
group).
[1,5]H shift will essentially lead to the formation of com-
pound 5’, which seems to be a less favorable process. On the
other hand, the intermediate C may experience the third
Michael addition and the nucleophilic attack of water[21] si-
multaneously to generate intermediate D.[22] Subsequent
proton transfer essentially leads to the formation of E,
which undergoes a further cyclization process to yield highly
unusual tricyclic oxindole 5.
To further demonstrate the versatility of the above multi-
component cycloaddition strategy, we sought to briefly in-
vestigate the cycloaddition reaction with g-substituted al-
lenoate 2. Surprisingly, only unprecedented cycloaddition
adducts 6 were isolated other than the expected usual spiro-
cyclic product. Importantly, the formation of product 6 obvi-
ously involved the cleavage of the “C=C” double bond of 3
and one of the “C=C” double bonds of 2. Although the
exact mechanism was not clear, the present reaction was
found to proceed readily with a series of substituted isatyli-
dene malononitriles 3 (Table 3, entries 1–10). In addition,
the structure of compound 6d was also confirmed by single-
crystal X-ray analysis.[23]
5
6
7
5-fluoro
5-chloro
5-fluoro
Me
Me
Bn
80
81
75
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Multicomponent Reaction to Construct Spirocyclic Oxindoles
Table 3. (Continued)
FULL PAPER
Conclusion
R3
PG[b]
Product
Yield
[%][c]
We have described a novel multicomponent reaction with
isocyanide, allenoate, and isatylidene malononitrile to gener-
ate functionalized spirocyclic oxindoles in an efficient fash-
ion. Excellent regioselectivity and stereoselectivity were ob-
served in this process. In addition, the scope and limitation
of the present strategy have been well established with a va-
riety of substituted allenoates and isatylidene malononitriles.
We also demonstrated that the behavior of allenoate has
been greatly changed in the presence of water, which led to
the discovery of a new four-component reaction. Most im-
portantly, this four-component reaction enabled the con-
struction of a highly unusual tricyclic oxindole system
through an efficient triple Michael/cyclization process. Fur-
thermore, a very interesting rearrangement with g-substitut-
ed allenoate was also briefly explored, in which the unusual
cleavage of the “C=C” double bond of isatylidene malononi-
trile and one of the “C=C” double bonds of allenoate was
observed. Since the multicomponent protocol provides
a new opportunity to synthesize natural-product-like spiro-
cyclic oxindole molecules, further work will include the
preparation of a series of analogues for an investigation into
the structure–activity relationship (SAR). Extension of the
present strategy to other systems is also in progress in our
laboratory.
8
5-chloro
Bn
65
9
7-bromo
Bn
54
10
5-methoxy
Bn
70
[a] Reaction conditions: isocyanide 1 (0.5 mmol), allenoate 2 (0.6 mmol),
isatylidene malononitrile (0.5 mmol), toluene (5 mL), 1008C, 18 h.
3
[b] PG=protecting group. [c] Isolated yield.
Experimental Section
During our investigation, much effort has been devoted to
obtaining the evidence for the reaction mechanism. A series
of control experiments including performing the possible cy-
cloaddition of g-methyl substituted allenoate 2 and 3 have
also been carried out to isolate a possible intermediate, but
no favorable findings were observed (Scheme 4). Studies on
the reaction mechanism are still underway in our lab and we
hope to give a reasonable explanation in the near future.
Typical procedure for the synthesis of 4: Isatylidene malononitrile isatin
3 (0.5 mmol) was added to a solution of isocyanide 1 (0.5 mmol) and al-
lenoate 2 (0.6 mmol) in toluene (5 mL) under a nitrogen atmosphere.
The stirred mixture was heated to 1008C for several hours and progress
was monitored by using TLC detection. After completion of the reaction,
the reaction mixture was concentrated under vacuum. The residue was
purified by column chromatography on silica gel (silica: 200–300; eluant:
petroleum ether/ethyl acetate) to afford the desired product 4.
Typical procedure for the preparation of tricyclic oxindole 5: Isatylidene
malononitrile isatin 3 (0.5 mmol) was added to a solution of isocyanide
1 (0.5 mmol) and allenoate 2 (0.6 mmol) in a mixed solvent (5 mL; tolu-
ene/H2O, v/v=7:1) under air. The stirred mixture was heated to 1008C
for several hours and progress was monitored by using TLC detection.
After completion of the reaction, the reaction mixture was concentrated
under vacuum. The residue was purified by column chromatography on
silica gel (silica: 200–300; eluant: petroleum ether/ethyl acetate) to afford
the desired product 5.
Typical procedure for the formation of product 6: Isatylidene malononi-
trile 3 (0.5 mmol) was added to a solution of isocyanide 1 (0.5 mmol) and
g-substituted allenoate 2 (0.6 mmol) in toluene (5 mL) under air. The
stirred mixture was heated to 1008C for several hours and progress was
monitored by using TLC detection. After completion of the reaction, the
reaction mixture was concentrated under vacuum. The residue was puri-
fied by column chromatography on silica gel (silica: 200–300; eluant: pe-
troleum ether/ethyl acetate) to afford the desired product 6.
Scheme 4. Control experiments.
Acknowledgements
We thank the National Natural Science Foundation of China (No:
21002061, 21142012, 20902057), the State Key Laboratory of Applied Or-
Chem. Eur. J. 2012, 18, 9645 – 9650
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9649

X. Jia, J. Li et al.
ganic Chemistry, Lanzhou University, and the Leading Academic Disci-
pline Project of Shanghai Municipal Education Commission (No: J50101)
for financial support. We also thank Dr. H. Deng and M. Shao (Labora-
tory for Microstructures, Shanghai University) for NMR and X-ray meas-
urements.
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[17] CCDC-856076 (4l) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
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data_request/cif.
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via www.ccdc.cam.ac.uk/data_request/cif.
[20] CCDC-867533 (5a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
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[22] In this process a stepwise mechanism also cannot be ruled out.
[23] CCDC-856075 (6d) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
Received: December 30, 2011
Revised: April 1, 2012
Published online: July 2, 2012
9650
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Chem. Eur. J. 2012, 18, 9645 – 9650