Isocyanide-based multicomponent reactions: Concise synthesis of spirocyclic oxindoles with molecular complexity by using a [1,5]-hydrogen shift as the key step

Article abstract of DOI:10.1002/chem.201402576

A concise multicomponent reaction of isocyanide, α-substituted allenoate, and methyleneindolinone has been disclosed. This protocol provides a fast and straightforward approach to synthesize unusual tricyclic oxindoles in an efficient and atom-economic manner. Mechanistically, the present cycloaddition may proceed through a cascade sequence involving double Michael addition, double cyclization, double [1,5]-hydrogen shift, and group migration. The introduction of a special alkyl group to the allenoate is believed to play a key role in the cascade reaction. This method also features a broad substrate scope, which is particularly useful for the delivery of a large number of compounds. Shift your perspective! An unprecedented cascade reaction, under mild conditions, involving a double Michael addition, double cyclization, and double [1,5]-hydrogen shift, followed by group migration is disclosed. This reaction offers a fast and straightforward approach to unusual polycyclic spirooxindoles (see scheme).

Full text of DOI:10.1002/chem.201402576

DOI: 10.1002/chem.201402576
Communication
&
Organic Synthesis
Isocyanide-Based Multicomponent Reactions: Concise Synthesis
of Spirocyclic Oxindoles with Molecular Complexity by Using a
[1,5]-Hydrogen Shift as the Key Step
Shikuan Su,[a] Chunju Li,[a] Xueshun Jia,*[a, b] and Jian Li*[a]
tions, concise combination of reactive isocyanide functional
groups with known reactions is of fundamental importance.[7]
Abstract: A concise multicomponent reaction of isocya-
nide, a-substituted allenoate, and methyleneindolinone
has been disclosed. This protocol provides a fast and
straightforward approach to synthesize unusual tricyclic
oxindoles in an efficient and atom-economic manner.
Mechanistically, the present cycloaddition may proceed
through a cascade sequence involving double Michael ad-
dition, double cyclization, double [1,5]-hydrogen shift, and
group migration. The introduction of a special alkyl group
to the allenoate is believed to play a key role in the cas-
cade reaction. This method also features a broad substrate
scope, which is particularly useful for the delivery of
a large number of compounds.
In 2011, we reported the first example of a multicomponent
reaction involving an isocyanide and allenoate.[8a] Since then,
we have spent much time in exploring the potential synthetic
utility of the isocyanide-based [2+2+1] three-component reac-
tions with allenoate, thus providing a quick access to the syn-
theses of functionalized carbocycles and natural-product-like
N-containing heterocycles.[8b,c] Mechanistically, the above-men-
tioned three-component reaction is closely related to famous
phosphine-catalyzed cycloaddition with allenoate (Scheme 1).
The history of phosphine-catalyzed [3+2] reactions can be
dated back to 1995 when Lu and co-workers disclosed their
pioneering work on the phosphine-catalyzed cycloaddition of
allenoates and alkenes.[9] So far, the chemistry of organophos-
phine catalysis has been well documented and has emerged
as a significant synthetic tool in organic synthesis.[10] As shown
in Scheme 1, both isocyanide or phosphine can act as good
nucleophiles to trigger the allenoate forming the reactive zwit-
terionic species, which is then trapped by electron-poor
double bonds to produce stable five-membered rings. The
main difference lies in the fact that isocyanide also participates
in the ring formation as C1 building blocks, whereas the phos-
phine catalyst finally eliminates from the cycloadduct.
As valuable C1 synthons, isocyanides have proven themselves
to be irreplaceable building blocks in organic synthesis.[1] The
past decades have witnessed a rapid increase in various
carbon–carbon and carbon–heteroatom bond-forming reac-
tions involving isocyanides.[2,3] Remarkably, the exceptional di-
valent carbon atoms of isocyanides[4] makes them particularly
versatile components in multicomponent reactions (MCRs).[5] It
is therefore not surprising that the isocyanide-based multicom-
ponent reactions (IMCRs) have enjoyed considerable attention
from the synthetic community because of good atom- and
step-economy, convergence, and increased structural complex-
ity.[6] Moreover, IMCRs hold great promise for the fast and effi-
cient generation of complex and diverse druglike small mole-
cules, which would be superior to traditional methods. Since
most of the MCRs were found on the basis of bimolecular reac-
Notably, in 2003 Kwon and co-workers found that when
alkyl-substituted allenoate was used, a novel phosphine-cata-
lyzed [4+2] other than [3+2] annulation would take place to
generate tetrahydropyridines (Scheme 1).[11] This strategy was
further expanded to the syntheses of other six-membered
rings and employed as a key step in the total synthesis of
many natural products.[12] The key step in the [4+2] cycloaddi-
tion is believed to be the [1,3]-hydrogen shift process, which
has been verified by computational analysis.[13] Accordingly, in-
spired by the great success of phosphine-catalyzed cycloaddi-
tions and our continuous interest in multicomponent reactions
based on isocyanide and allenoate, we reasoned that introduc-
tion of a substituent at the a-position of allenoates might pro-
vide a new mechanism and exciting experimental results. As
a continuation of our ongoing research,[8] herein we report
that cascade multicomponent reactions of isocyanide, a-substi-
tuted allenoate, and methyleneindolinone can efficiently pro-
vide functionalized polycyclic compounds in a highly efficient
manner under mild reaction conditions with broad substrate
generality.
[a] S. Su, C. Li, Prof. Dr. X. Jia, Prof. Dr. J. Li
Department of Chemistry, Innovative Drug Research Center
Shanghai University, 99 Shangda Road
Shanghai, 200444 (P. R. China)
Fax: (+86)21-66132408
E-mail: xsjia@shu.edu.cn
lijian@mail.shu.edu.cn
[b] Prof. Dr. X. Jia
Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai Institute of Organic Chemistry
Chinese Academy of Science, 345 Lingling Road
Shanghai, 200032 (P. R China)
Spirocyclic oxindole is a significant synthetic motif that con-
stitutes a large family of natural products and clinical pharma-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402576.
Chem. Eur. J. 2014, 20, 1 – 6
1
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
the most suitable solvent for the reaction, although
xylene generally gave comparable results; solvents
such as mesitylene, THF, and DMF only resulted in
either a trace amount or none of the desired product.
Reflux conditions were also required because the re-
action yield decreased dramatically when the reac-
tion was conducted under a lower temperature (e.g.,
80 or 1008C). Encouraged by this experimental result,
we then explored the feasibility of allenoates bearing
different substitution patterns. To our delight, broad
generality was observed with various substituted alle-
noates 2 and several characteristics of this multicom-
ponent cycloaddition reaction were noteworthy. As
shown in Table 1, allenoates 2 with substituted
benzyl (Table 1, entries 2–8) and ꢀCH2CO2R (en-
tries 10–11) groups at the 2-position all worked well
to yield the cycloadduct 4.[17] On the contrary, no cor-
responding cycloadduct 4 was observed when alle-
noate with only a methyl group substituted (entry 9)
was used. These results indicated that the presence
Scheme 1. Representative phosphine-catalyzed cycloadditions and isocyanide-based
multicomponent reactions in the presence of allenoate and electron-deficient species.
ceuticals.[14] These compounds have demonstrated a broad
range of biological activities, including insecticidal, antitumor,
anthelmintic, and antibacterial properties.[15] In this regard, we
selected the methyleneindolinones as the electron-poor al-
kenes to establish the basic methodology for the proposed
three-component cycloaddition. As shown in Table 1, simply
heating a solution of isopropyl isocyanide (1a), substituted
ethyl 2,3-butadienoate 2a, and methyleneindolinone 3a in tol-
uene under reflux directly provided the cycloadduct 4a in
50% yield (Table 1, entry 1). The structure of compound 4a
was unambiguously confirmed by single-crystal X-ray analy-
sis.[16] Subsequent solvent screening revealed that the solvent
had a significant influence on the reaction yield: toluene was
of a conjugation stablizing group, such as an aryl or ester
group, in the R1 substituent was necessary for the whole con-
version. In addition, varying the aryl group in the R1 substitu-
ent also demonstrated that the present reaction proceeded
best when allenoates
2 containing electron-withdrawing
groups (e.g., hal, nitro; entries 2–6) were utilized, whereas the
electron-rich groups gave lower yields (entries 7–8). It was also
important to point out that the present protocol represented
an unprecedented and valuable multicomponent example
with excellent synthetic efficiency. Whereas allenoate was
often used as a C2 and C3 component in previous transforma-
tions, the allenoate bearing an alkyl group acted as C4 build-
ing block to form two fused rings, which was very rare.[18]
Table 1. Three-component cascade cycloaddition of isocyanide 1a,
a-substituted allenoate 2, and methyleneindolinone 3a.[a]
Table 2. Three-component cycloaddition reaction of isocyanide 1, a-sub-
stituted allenoate 2 f, and methyleneindolinone 3a.[a]
Entry
R1
Product
4a
Yield [%][b]
1
2
3
4
5
6
7
8
9
C6H5
50
41
62
54
64
71
18
24
n.r.
46
51
3-FC6H4
3-ClC6H4
4-BrC6H4
3-NO2C6H4
4-NO2C6H4
2-MeC6H4
4-MeC6H4
H
4b
4c
4d
4e
4 f
4g
4h
–
Entry
R
Product
Yield [%][b]
1
2
3
4
5
6
7[c]
8[c]
tert-butyl
n-butyl
Cyclohexyl
1,1,3,3-tetramethylbutyl
4-bromophenyl
4-methoxyphenyl
2,6-dimethylphenyl
2-chloro-6-methylphenyl
5a
5b
5c
5d
5e
5 f
67
81
50
60
62
74
27
19
5g
5h
10
11
CO2Me
CO2Et
4i
4j
[a] Reaction conditions: isocyanide 1 (0.5 mmol), allenoate 2 f (0.6 mmol),
methyleneindolinone 3a (0.5 mmol), toluene (5 mL), reflux, 36 h.
[b] Yields of product after silica gel chromatography. [c] The reaction time
was prolonged to 48 h.
[a] All reactions were carried out with isocyanide 1a (0.5 mmol), allenoate
2 (0.6 mmol), and methyleneindolinone 3a (0.5 mmol) in toluene (5 mL)
and heated under reflux. [b] Yields of product after silica gel chromatog-
raphy.
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
2
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
After having demonstrated a broad scope for substituted
allenoates, a series of aliphatic and aromatic isocyanides
1 were next tested to react with allenoate 2 f and methyl-
eneindolinone 3a. The experimental results are summar-
ized in Table 2. Notably, the structure of compound 5a was
unambiguously confirmed by single-crystal X-ray analy-
sis.[19] The reaction of n-butyl isocyanide 1c, for instance,
furnished the cycloadduct 5b in 81% yields (Table 2,
entry 2). Gratifyingly, less reactive 4-bromophenyl isocya-
nide underwent a similar transformation to yield product
5e in good yield (entry 5). Sterically demanding aromatic
isocyanides, such as 2,6-dimethylphenyl and 2-chloro-6-
methylphenyl isocyanides, were also found to be compati-
ble with this cascade cycloaddition protocol albeit with di-
minished yield and prolonged reaction time (entries 7–8).
To further explore the versatility of this multicomponent
cycloaddition strategy, we turned our attention to the pos-
sibility of substituted methyleneindolinones 3. As shown in
Table 3, various methyleindolinones 3 with different sub-
stituents all proceeded readily underwent the cascade ad-
dition. Substrate 3 with an aliphatic unit (R3 =Me) was also
examined (Table 3, entry 6).
Table 3. Three-component reaction of isocyanide 1a, a-substituted allenoate
2 f, and methyleneindolinone 3.[a]
Entry
R2
R3
Product
Yield [%][b]
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
2-ClC6H4
4-ClC6H4
2-MeC6H4
3-MeOC6H4
4-MeOC6H4
CH3
C6H5
C6H5
C6H5
C6H5
6a
6b
6c
6d
6e
6 f
6g
6h
6i
71
63
44
84
67
75
66
72
47
68
31
5-chloro
5-bromo
5-methoxy
6-bromo
4-bromo
10
11
6j
6k
C6H5
[a] Reaction conditions: isocyanide 1a (0.5 mmol), allenoate 2 f (0.6 mmol),
methyleneindolinone 3 (0.5 mmol), toluene (5 mL), reflux, 36 h. [b] Yields of
product after silica gel chromatography.
The mechanism of this cycloaddition reaction has not
been unequivocally established, but one reasonable possi-
bility is proposed in Scheme 2. The beginning of the reac-
tion involves the formation of reactive zwitterionic species,
which exist as a resonance-stabilized form A$B.[8a–c] The allylic
carbanion B then adds to the carbon–carbon double bond of
substrate 3 to produce intermediate C. Since the imine nitro-
gen atom in intermediate D can act as a base to abstract the
acidic proton, it is reasonable to deduce that the [1,5]-hydro-
gen shift[20] then takes place to form E via a six-membered ring
transition state.[13] This process
cial way by facilitating a sequenced [1,5]-hydrogen shift and
subsequent annulation.[22] To some extent, the role of the alkyl
substituent of allenoate 2 can also be considered as a directing
group, which is quite different from the reported examples.
To further establish the scope and limitation of this method,
electron-deficient alkenes 7 derived from oxindoles and alde-
also explains the fact that the
present multicomponent reac-
tion works well if the allenoate
bears an R1 group (aryl or car-
bonyl group) that can stabilize
the anion formed in intermedi-
ate E. Subsequently, the more
stable resonance form F under-
goes the second-time intramo-
lecular cyclization and [1,5]-hy-
drogen shift to yield intermedi-
ate H. Finally, the concerted
ethoxy group migration essen-
tially leads to the formation of
product 5.[21] From the proposed
mechanism we can see that the
installation of an alkyl group to
allenoate is crucial to the pres-
ent cascade reaction although
the alkyl group does not directly
provide the carbon component
for the ring formation. In fact,
this group participates in the
cascade reaction in a quite spe- Scheme 2. Proposed mechanism for the three-component reaction.
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
3
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
and efficient construction of the corresponding com-
pound library.
The formed cycloadducts 5 were also subjected to
further conversion to demonstrate the potential ap-
plications of this method. As shown in Scheme 4, the
ethoxy group can be easily replaced by other alkyl
groups under acidic conditions in the presence of ex-
cessive alcohols. This reaction performed well with
linear alcohols, but the alcohol with a side chain,
such as tert-butyl alcohol, failed to yield the expected
product 10. A very interesting product, 11, was also
obtained under acidic conditions without the addi-
tion of alcohol. In this case, the structures of com-
pound 11 a was unambiguously confirmed by single-
crystal X-ray analysis.[23] To our surprise, one of the
five-membered rings opened together with the cleav-
age of one carbon–carbon single bond.
In conclusion, we have described a concise multi-
component reaction of isocyanide, a-substituted alle-
noate, and methyleneindolinone. The cascade se-
quence seems to comprise of a double Michael addi-
tion, double cyclization, and double [1,5]-hydrogen
shift followed by group migration, thereby offering
a fast and straightforward approach to unusual spiro-
cyclic oxindoles. The present multicomponent strat-
egy is also featured by the high synthetic efficiency
since the substituted allenoate contributes four
carbon atoms (C4) for the ring formation. Another re-
markable characteristic of this methodology is that
each of the three components can be readily varied,
thus enabling the efficient preparation of a large
number of compounds. For this reason, further works
may include constructing a compound library and
conducting an investigation on the structure–activity
relationship (SAR). Extension of the present strategy
to other electron-poor systems is still in progress in
our lab.
Scheme 3. Multicomponent reaction with expanded electron-deficient alkenes 7.
Experimental Section
Typical procedure
Methyleneindolinone 3 (0.5 mmol) was added to a solu-
tion of isocyanide
1 (0.5 mmol) and allenoate 2
(0.6 mmol) in 5 mL toluene. The stirred mixture was
heated under reflux for several hours and the progress
was monitored by using TLC detection. After completion
of the present reaction, the reaction mixture was con-
centrated under vacuum. The residue was purified by
column chromatography on silica gel (silica: 200–300;
eluant: petroleum ether/ethyl acetate) to afford the de-
sired product.
Scheme 4. Further application of the cycloaddition product 5.
hydes were also examined (Scheme 3). All of the tested new
substrates 7 served as excellent substrates to react with isocya-
nide and substituted allenoate, producing the cycloadduct 8 in Acknowledgements
an efficient manner. Considering the readily variability of alde-
hyde, the increased new reactant dimension makes the pres-
ent reaction more flexible, which is very significant for the fast
We thank the National Natural Science Foundation of China
(No: 21272148, 21272147) and the Key Laboratory of Synthetic
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
4
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
Su, M. Y. Huang, B. Y. Song, C. J. Li, X. S. Jia, Chem. Commun. 2013, 49,
10694–10696.
[9] C. Zhang, X. Lu, J. Org. Chem. 1995, 60, 2906–2908.
Chemistry of Natural Substances, Shanghai Institute of Organic
Chemistry, Chinese Academy of Science, for financial support.
We also thank Dr. H. Deng and M. Shao (Laboratory for Micro-
structures, Shanghai University) for NMR spectroscopy and X-
ray measurements.
[10] For reviews, see: a) X. Lu, C. Zhang, Z. Xu, Acc. Chem. Res. 2001, 34,
535–544; b) B. J. Cowen, S. J. Miller, Chem. Soc. Rev. 2009, 38, 3102–
3116. for applications in total synthesis, see: c) Y. Du, X. Lu, J. Org.
Chem. 2003, 68, 6463–6465; d) J.-C. Wang, M. J. Krische, Angew. Chem.
2003, 115, 6035–6037; Angew. Chem. Int. Ed. 2003, 42, 5855–5857;
e) T. Q. Pham, S. G. Pyne, B. W. Skelton, A. H. White, J. Org. Chem. 2005,
70, 6369–6377; for asymmetric variants, see: f) J. E. Wilson, G. C. Fu,
Angew. Chem. 2006, 118, 1454–1457; Angew. Chem. Int. Ed. 2006, 45,
1426–1429; g) Y.-Q. Fang, E. N. Jacobsen, J. Am. Chem. Soc. 2008, 130,
5660–5661; h) B. J. Cowen, S. J. Miller, J. Am. Chem. Soc. 2007, 129,
10988–10989; i) H. Xiao, Z. Chai, C.-W. Zheng, Y.-Q. Yang, W. Liu, J.-K.
Zhang, G. Zhao, Angew. Chem. 2010, 122, 4569–4572; Angew. Chem.
Int. Ed. 2010, 49, 4467–4470.
[11] X.-F. Zhu, J. Lan, O. Kwon, J. Am. Chem. Soc. 2003, 125, 4716–4717.
[12] a) R. P. Wurz, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 12234–12235;
b) Y. S. Tran, O. Kwon, J. Am. Chem. Soc. 2007, 129, 12632–12633; c) S.
Castellano, H. D. G. Fiji, S. S. Kinderman, M. Watanabe, P. de Leon, F.
Tamanoi, O. Kwon, J. Am. Chem. Soc. 2007, 129, 5843–5845; d) T. Wang,
S. Ye, Org. Lett. 2010, 12, 4168–4171.
[13] a) Y. Qiao, K.-L. Han, Org. Biomol. Chem. 2012, 10, 7689–7706; b) L.
Zhao, M. Wen, Z.-X. Wang, Eur. J. Org. Chem. 2012, 3587–3597.
[14] For reviews, see: a) C. Marti, E. M. Carreira, Eur. J. Org. Chem. 2003,
2209–2219; b) R. M. Williams, R. J. Cox, Acc. Chem. Res. 2003, 36, 127–
139; c) C. V. Galliford, K. A. Scheidt, Angew. Chem. 2007, 119, 8902–
8912; Angew. Chem. Int. Ed. 2007, 46, 8748–8758; d) B. M. Trost, C.
Jiang, Synthesis 2006, 369–396; e) F. Zhou, Y.-L. Liu, J. Zhou, Adv. Synth.
Catal. 2010, 352, 1381–1407.
[15] a) T. J. Greshock, A. W. Grubbs, P. Jiao, D. T. Wicklow, J. B. Gloer, R. M. Wil-
liams, Angew. Chem. 2008, 120, 3629–3633; Angew. Chem. Int. Ed. 2008,
47, 3573–3577; b) H. Venkatesan, M. C. Davis, Y. Altas, ##. Snyder, D. C.
Liotta, J. Org. Chem. 2001, 66, 3653–3661; c) M. M.-C. Lo, C. S. Neu-
mann, S. Nagayama, E. O. Perlstein, S. L. Schreiber, J. Am. Chem. Soc.
2004, 126, 16077–16086; d) S. Kotha, A. C. Deb, K. Lahiri, E. Manivann-
an, Synthesis 2009, 165–193.
Keywords: allenoates
·
hydrogen shift
·
isocyanides
·
multicomponent reactions · spirocyclic oxindoles
[1] For recent examples, see: a) Y. Odabachian, S. Tong, Q. Wang, M.-X.
Wang, J. Zhu, Angew. Chem. 2013, 125, 11078–11082; Angew. Chem. Int.
Ed. 2013, 52, 10878–10882; b) T. Buyck, Q. Wang, J. Zhu, Angew. Chem.
2013, 125, 12946–12950; Angew. Chem. Int. Ed. 2013, 52, 12714–
12718; c) C.-H. Lei, D.-X. Wang, L. Zhao, J. Zhu, M.-X. Wang, J. Am. Chem.
Soc. 2013, 135, 4708–4711; d) A. Zajdlik, Z. Wang, J. L. Hickey, A. Aman,
A. D. Schimmer, A. K. Yudin, Angew. Chem. 2013, 125, 8569–8573;
Angew. Chem. Int. Ed. 2013, 52, 8411–8415; e) G. Qiu, Q. Ding, J. Wu,
Chem. Soc. Rev. 2013, 42, 5257–5269; f) T. Okitsu, K. Nagase, N. Nishio,
A. Wada, Org. Lett. 2012, 14, 708–711; g) T. Vlaar, P. Mampuys, M. Helli-
well, B. U. W. Maes, R. V. A. Orru, E. Ruijter, J. Org. Chem. 2013, 78, 6735–
6745.
[2] For palladium-catalyzed insertion of isocyanide, see: a) T. Vlaar, E. Ruijt-
er, B. U. W. Maes, R. V. A. Orru, Angew. Chem. 2013, 125, 7222–7236;
Angew. Chem. Int. Ed. 2013, 52, 7084–7097; b) M. Tobisu, S. Imoto, S.
Ito, N. Chatani, J. Org. Chem. 2010, 75, 4835–4840; c) G. V. Baelen, S.
´ ˇ
Kuijer, L. Rycek, S. Sergeyev, E. Janssen, F. J. J. de Kanter, B. U. W. Maes,
E. Ruijter, R. V. A. Orru, Chem. Eur. J. 2011, 17, 15039–15044; for other
metal-catalyzed insertion, see: d) M. Zhang, S. L. Buchwald, J. Org.
Chem. 1996, 61, 4498–4499; e) W. D. Jones, W. P. Kosar, J. Am. Chem.
Soc. 1986, 108, 5640–5641.
[3] For construction of heterocycles, see: indole: a) T. Nanjo, C. Tsukano, Y.
Takemoto, Org. Lett. 2012, 14, 4270–4273; for a review on syntheses of
indoles from isocyanides, see: b) J. Campo, M. Garcia-Valverde, S. Mar-
caccini, M. J. Rojo, T. Torroba, Org. Biomol. Chem. 2006, 4, 757–765; Ox-
azole: c) P. Janvier, M. Bois-Choussy, H. Bienaymꢁ, J. Zhu, Angew. Chem.
2003, 115, 835–838; Angew. Chem. Int. Ed. 2003, 42, 811–814; d) O. V.
Larionov, A. de Meijere, Angew. Chem. 2005, 117, 5809–5813; Angew.
Chem. Int. Ed. 2005, 44, 5664–5667; e) A. V. Lygin, O. V. Larionov, V. S.
Korotkov, A. de Meijere, Chem. Eur. J. 2009, 15, 227–236; Imidazole:
f) C. J. Helal, J. C. Lucas, Org. Lett. 2002, 4, 4133–4134; g) C. Kanazawa,
S. Kamijo, Y. Yamamoto, J. Am. Chem. Soc. 2006, 128, 10662–10663;
h) A. M. van Leusen, J. Wildeman, O. H. Oldenyiel, J. Org. Chem. 1977,
42, 1153–1159.
[16] CCDC-983301 (4a) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
[17] See the Supporting Information for details.
[18] It should be pointed out that a substituted allenoate also serves as
a C4 component in phosphine-catalyzed [4+2] cycloaddition by using
one carbon atom in the alkyl substituent for the ring formation, which
was different from the present multicomponent reaction.
[19] CCDC-983302 (5a) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
[20] a) W. v. E. Doering, E. J. Keliher, X. Zhao, J. Am. Chem. Soc. 2004, 126,
14206–14216; b) M. Alajarꢃn, B. Bonillo, P. Sꢄnchez-Andrada, ꢅ. Vidal, J.
Org. Chem. 2010, 75, 3737–3750; c) M. Alajarꢃn, B. Bonillo, M.-M. Ortꢃn,
P. Sꢄnchez-Andrada, ꢅ. Vidal, Org. Lett. 2006, 8, 5645–5648.
[21] In this process, a mechanism by step also cannot be ruled out.
[22] In the chemistry of isocyanide-based multicomponent reactions, the
most popular [1,n]-hydrogen shift normally occurs to afford more
stable aromatic rings, such as pyrrole and furan rings. This meant that
the reaction generally terminated when the [1,n]-hydrogen shift finish-
ed.[5,7] In this case, however, the [1,5]-hydrogen shift process is quite dif-
ferent from the traditional ones since the [1,5]-hydrogen shift serves as
the driving force for subsequent cascade transformation.
[4] This unique property is also shared with carbon monoxide and formally
divalent carbenes.
[5] a) Multicomponent Reactions (Eds.: J. Zhu, H. Bienaymꢁ, Eds.), Wiley-
VCH, Weinheim, Germany, 2005; b) H. Bienaymꢁ, C. Hulme, G. Oddon, P.
Schmitt, Chem. Eur. J. 2000, 6, 3321–3329; c) R. V. A. Orru, M. De Greef,
Synthesis 2003, 1471–1499; d) D. J. Ramꢂn, M. Yus, Angew. Chem. 2005,
117, 1628–1661; Angew. Chem. Int. Ed. 2005, 44, 1602–1634; e) A. Dçm-
ling, Chem. Rev. 2006, 106, 17–89; f) N. Isambert, R. Lavilla, Chem. Eur. J.
2008, 14, 8444–8454; g) J. D. Sunderhaus, S. F. Martin, Chem. Eur. J.
2009, 15, 1300–1308; h) B. B. Toure, D. G. Hall, Chem. Rev. 2009, 109,
4439–4486; i) E. Ruijter, R. Scheffelaar, R. V. A. Orru, Angew. Chem. 2011,
123, 6358–6371; Angew. Chem. Int. Ed. 2011, 50, 6234–6246.
[6] For atom economy: a) B. M. Trost, Science 1991, 254, 1471–1477; for
step economy: b) P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc.
Chem. Res. 2008, 41, 40–49; for redox economy: c) J. M. Richter, Y. Ishi-
hara, T. Masuda, B. W. Whitefield, T. Llamas, A. Pohjakallio, P. S. Baran, J.
Am. Chem. Soc. 2008, 130, 17938–17954.
[7] a) J. Zhu, Eur. J. Org. Chem. 2003, 1133–1144; to invent new multicom-
ponent reactions from known MCR reactions is another significant strat-
egy, see: b) B. Ganem, Acc. Chem. Res. 2009, 42, 463–472.
[8] a) J. Li, Y. J. Liu, C. J. Li, X. S. Jia, Chem. Eur. J. 2011, 17, 7409–7413; b) J.
Li, Y. J. Liu, C. J. Li, X. S. Jia, Adv. Synth. Catal. 2011, 353, 913–917; c) J.
Li, N. Wang, C. J. Li, X. S. Jia, Chem. Eur. J. 2012, 18, 9645–9650; d) J. Li,
N. Wang, C. J. Li, X. S. Jia, Org. Lett. 2012, 14, 4994–4997; e) J. Li, S. K.
[23] CCDC-983303 (11 a) 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.ac.uk/data_
request/cif.
Received: March 13, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Organic Synthesis
S. Su, C. Li, X. Jia,* J. Li*
&& – &&
Isocyanide-Based Multicomponent
Reactions: Concise Synthesis of
Spirocyclic Oxindoles with Molecular
Complexity by Using a [1,5]-Hydrogen
Shift as the Key Step
Shift your perspective! An unprece-
dented cascade reaction, under mild
conditions, involving a double Michael
addition, double cyclization, and double
[1,5]-hydrogen shift, followed by group
migration is disclosed. This reaction
offers a fast and straightforward ap-
proach to unusual polycyclic spiro-
oxindoles (see scheme).
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!