Convenient synthesis of triphenylphosphanylidene spiro[cyclopentane-1, 3′-indolines] and spiro[cyclopent[2]ene-1,3′-indolines] via three-component reactions

Article abstract of DOI:10.1021/ol5008394

Three-component reactions of triphenylphosphine, but-2-ynedioate, and isatylidene malononitrile (ethyl cyanoacetate) in dimethoxyethane resulted in triphenylphosphanylidene spiro[cyclopentane-1,3′-indolines] in satisfactory yields. Furthermore, similar th

Full text of DOI:10.1021/ol5008394

Letter
pubs.acs.org/OrgLett
Convenient Synthesis of Triphenylphosphanylidene
Spiro[cyclopentane-1,3′-indolines] and Spiro[cyclopent[2]ene-1,3′-
indolines] via Three-Component Reactions
Ying Han, Yin-Jian Sheng, and Chao-Guo Yan*
College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China
S
* Supporting Information
ABSTRACT: Three-component reactions of triphenyl-
phosphine, but-2-ynedioate, and isatylidene malononitrile
(ethyl cyanoacetate) in dimethoxyethane resulted in triphenyl-
phosphanylidene spiro[cyclopentane-1,3′-indolines] in satis-
factory yields. Furthermore, similar three-component reactions
of triphenylphosphine, hex-2-en-4-ynedioate, and isatylidene
malononitrile (ethyl cyanoacetate) afforded functionalized spiro[cyclopent[2]ene-1,3′-indolines] in good yields.
In a preliminary reaction, the reaction of DMAD and
isatylidene malononitrile with 20 mol % of triphenylphosphine
as the catalyst was used as standard substrates to optimize the
reaction conditions. The reaction can be accomplished quickly
at room temperature to afford a triphenylphosphanylidene
spiro[cyclopentane-1,3′-indoline]. The triphenylphosphanyli-
dene group could not be eliminated by carriying out the
reaction for a longer time or at the elevated temperature. Thus,
a stoichiometry reaction was further investigated. When
equivomolecular triphosphine was introduced in the reaction
at room temperature, a violent reaction was observed, which
resulted in the expected spiro[cyclopentane-1,3′-indoline] with
significantly more byproducts. It is better to add triphenyl-
phosphine to the mixture of dimethyl acetylenedicarboxylate
and isatylidene malononitrile in DME at 0 °C. Then, the
reaction mixture was carried out at room temperature for about
2 h. Under these simple conditions, the functionalized
triphenylphosphanylidene spiro[cyclopentane-1,3′-indoline]
1a was obtained in 86% yield. Various isatylidene malononi-
triles were used in the reaction, and the corresponding
spiro[cyclopentane-1,3′-indoline] 1b−1f were produced in
satisfactory yields (Table 1, entries 2−6). The substituents on
the oxindole moiety showed marginal effect on the reactions.
Under similar reaction conditions, the three-component
reaction containing ethyl isatylidene cyanoacetate also afforded
the corresponding spiro compounds 1g−1i in good yields. The
structures of the obtained spiro[cyclopentane-1,3′-indolines]
ver the past decade, nucleophilic phosphine catalyzed
Oreactions have attracted much research effort and have
emerged as highly efficient synthetic tools for diverse
carbocycles and heterocycles.1,2 In these phosphine catalyzed
reactions, in situ generated phosphorus ylides from the addition
of triphenylphosphine to electron-deficient alkenes or alkynes
are key reactive 1,3-dipoles, which can be captured by suitable
substrates to undergo a wide variety of cyclizations and
annulations to give versatile carbocyclic and heterocyclic
systems. Among these transformations, the electron-deficient
alkynoates3,4 and allenonates5,6 are the most common
substrates. In recent years, Morrita−Baylis−Hillman (MBH)
acetates and carbonates have also been widely used as
complementary and versatile substrates in phosphine catalyzed
reactions.7,8 Particularly, there have been increasing interest in
the applications of phosphine catalyzed cyclization reactions for
the construction of biologically active spiro-cyclopentane-
oxindole and spiro-cyclohexane-oxindole systems.9,10 Rammch-
ary and co-workers described phosphine catalyzed Tomiat
Zipper cyclization of methyleneoxindoles with but-3-yn-2-one
for the synthesis of spiro[cyclopentane-1,3′oxindoles].11
Marinetti and coworkers successfully developed phosphine
catalyzed [3 + 2] and [4 + 2] cyclizations between allenoates
and isatin-derived olefins to efficiently access spiranic
oxindoles.12 Several phosphine catalyzed diastereo- and
enatioselective syntheses of spiro-cyclopentene-oxindoles via
annulations of isatin-derived electron-deficient alkenes with
MBH adducts have also been disclosed.13 Against this
background and with the aim of expanding our previous
studies on providing multicomponent reactions for the
convenient synthesis of spirooxindoles,14,15 herein we wish to
report the facile construction of triphenylphosphanylidene
substituted spiro[cyclopentane-1,3′-indolines] and spiro[cyclo-
pent[2]ene-1,3′-indolines] from three-component reactions of
triphenylphosphine, electron-deficient alkynes, and isatylidene
derivatives.
1
1a−1i were fully characterized by IR, HRMS, H, and 13C
NMR spectra and were confirmed by X-ray determination of
single crystal structures of compounds 1b (Figure 1) and 1d. It
should be pointed out that several diastereoisomers can exist in
each sample of product due to two or three diastereoisomeric
carbon centers existing in the newly formed cyclopentyl ring of
spiro[cyclopentane-1,3′-indolines] 1a−1i. It can be seen that
Received: March 20, 2014
Published: April 18, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Table 1. Three-Component Reaction for
Spiro[cyclopentane-1,3′-indolines] 1a−1i
Scheme 1. Formation Mechanism of Spiro[cyclopentane-
1,3′-indolines]
a
b
entry
compd
E
R
R′
yield (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
CN
H
F
CH2C6H5
CH2C6H5
CH2C6H5
n-C4H9
86
86
88
81
83
86
65
62
61
CN
CN
Cl
H
F
CN
CN
n-C4H9
CN
Cl
F
n-C4H9
1g
1h
1i
CO2Et
CO2Et
CO2Et
CH2C6H5
n-C4H9
F
Cl
n-C4H9
produces triphenylphosphanylidene spiro[cyclopentyl-1,3′-in-
doline] 1 as the separated product.
a
Reaction conditions: DMAD (1.2 mmol), isatylidene malononitrile
(ethyl cyanoacetate, 1.0 mmol), PPh3 (1.0 mmol) in DME (10.0 mL),
0 °C−rt, 2 h. Isolated yields.
The scope and limitation of this three-component reaction
were explored by using other electron-deficient alkynes in the
reaction. Under similar reaction conditions, another widely
used electron-deficient alkyne, methyl propiolate, cannot yield
any separated product in the three-component reaction. It is
known that methyl propiolate can easily dimerize to give
dimethyl hex-2-en-4-ynedioate in the presence of DABCO.16
Thus, the three-component reactions containing dialkyl hex-2-
en-4-ynedioate, triphenylphosphine, and isatylidene malononi-
trile (ethyl cyanoacetate) were investigated. After workup, the
functionalized spiro[cyclopent[2]ene-1,3′-indolines] 2a−2k
were produced in good yields. The results are summarized in
Table 2. The structures of the spiro compounds 2a−2k were
established using spectroscopic methods. The single crystal
structure of 2g was also determined by the X-ray diffraction
method (Figure 2). The most unusual feature of the structure
of spiro[cyclopent[2]ene-1,3′-indolines] 2a−2k to that of
spiro[cyclopentane-1,3′-indolines] 1a−1i is the fact that the
triphenylphosphanylidene group did not connect to the
b
Figure 1. Molecular structure of spiro compound 1b.
there are no protons directly connected to the newly formed
cyclopentyl ring, which would result in very small differences of
the 1H NMR signs for the different diastereoisomers. In fact the
1H NMR spectra of spiro compounds 1a−1i clearly display one
set of absorption signs for the characterized groups in the
molecules. The molecular structures of 1b and 1d indicated
that the methoxy and phenyl groups of the oxindole moiety
exist in a cis-configuration in the newly formed cyclopentyl ring.
Thus, we can conclude that the prepared spiro compounds 1a−
1i all have this configuration and this three-component reaction
is a highly diastereoselective reaction.
In order to explain the formation mechanism of the
spiro[cyclopentane-1,3′-indolines] 1a−1i, a domino reaction
path is proposed in Scheme 1 based on the known 1,4-dipolar
addition reactions of triphenylphosphine with electron-deficient
alkynes.3,4,11 The first reaction is the formation of the 1,3-
dipolar intermediate (A) from the addition of triphenylphos-
phine to acetylenedicarboxylate. The second reaction is the
addition of the 1,3-dipole (A) to isatinylidene malononitrile
resulting in an adduct intermediate (B). Third, the intra-
molecular nucleophilic substitution of the carbanion to alkoxide
in the ester affords the cyclic intermediate (C). Then, a
carbonium (D) was formed by the 1,3-arrangement of the
triphenylphosphanyl cation in cyclic intermediate C. Finally,
the coupling of carbonium D with the methoxide in solution
Table 2. Synthesis of Spiro[cyclopent[2]ene-1,3′-indolines]
a
2a−2k from Three-Component Reaction
b
entry compd
E
R
R′
R″
CH3
yield (%)
1
2a
2b
2c
2d
2e
2f
CN
H
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
n-C4H9
80
75
80
77
77
67
65
68
65
64
66
2
CN
CH3
F
CH3
3
CN
CH3
4
CN
Cl
Cl
H
F
CH3
5
CN
CH3
6
CO2Et
CO2Et
CO2Et
CO2Et
CN
CH2C6H5
CH2C6H5
n-C4H9
CH3
7
2g
2h
2i
CH3
8
F
CH3
9
Cl
H
F
n-C4H9
CH3
10
11
2j
CH2C6H5
CH2C6H5
CH2CH3
CH2CH3
2k
CN
a
Reaction conditions: dialkyl hex-2-en-4-ynedioate (1.2 mmol),
isatylidene malononitrile (ethyl cyanoacetate, 1.0 mmol), PPh3 (1.0
b
mmol) in DME (10.0 mL), 0 °C−rt, 2 h. Isolated yields.
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Organic Letters
Letter
reaction in synthetic and medicinal chemistry might be quite
significant.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data for all new
compounds including crystallographic data (CIF). This materi-
al is available free of charge via the Internet at http://pubs.acs.
org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cgyan@yzu.edu.cn.
Figure 2. Molecular structure of spiro compound 2g.
Notes
The authors declare no competing financial interest.
cyclopentyl ring, while connecting to the open acetyl chain in
the molecule.
An adjusted reaction mechanism for the formation of
spiro[cyclopent[2]ene-1,3′-indolines] is proposed in Scheme
2 on the basis of reported reactions.17 At first, the addition of
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (Grant No. 21172189) and the
Priority Academic Program Development of Jiangsu Higher
Education Institutions. We also thank the Analysis and Test
Center of Yangzhou University for providing necessary
instruments for analysis.
Scheme 2. Formation Mechanism of Spiro[cyclopent[2]ene-
1,3′-indolines]
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The Acknowledgment was updated and reference 17 was added
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■
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