Diastereoselective Synthesis of Spiro[2.3]hexanes from Methylenecyclopropane and Cyanoalkenes Catalyzed by a Tin-Ate Complex

Article abstract of DOI:10.1002/ejoc.201900518

A diastereoselective synthesis of spiro[2.3]hexane catalyzed by Sn and Mg halides was developed from a combination of methylenecyclopropane and cyanoalkene bearing an ester group. The selectivity was affected by the size of the halogen in the catalyst and

Full text of DOI:10.1002/ejoc.201900518

A Journal of
Accepted Article
Title: Diastereoselective Synthesis of Spiro[2.3]hexanes from
Methylenecyclopropane and Cyanoalkenes Catalyzed by a Tin-
ate Complex
Authors: Itaru Suzuki, Jun-ya Shimazu, Shinji Tsunoi, and Ikuya
Shibata
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Diastereoselective Synthesis of Spiro[2.3]hexanes from
Methylenecyclopropane and Cyanoalkenes Catalyzed by a Tin-ate
Complex
Itaru Suzuki[a], Jun-ya Shimazu[a],[b], Shinji Tsunoi[a] and Ikuya Shibata*[a]
Abstract:
A
diastereoselective synthesis of spiro[2.3]hexane
catalyzed by Sn and Mg halides was developed from a combination
of methylenecyclopropane and cyanoalkene bearing an ester group.
The selectivity was affected by the size of the halogen in the catalyst
and by an electron deficiency in the alkene. Once synthesized only
with a Pd catalyst, the spirocarbocycle was easily transformed into
cyclopentene under transition metal-free conditions.
Scheme 1. Tin-ate complex catalysed synthesis of spirohexanes.
Introduction
Spiro[2.3]hexane, a bicyclocarbocycle with three- and four-
membered rings connected by one carbon center, has recently
shown a degree of bioactivity1 and is expected to be a
conformationally rigid cyclopropane analogue of GABAs.4g
Although demand for investigations into the potential of the
spiro ring are mounting, research into its physical or
pharmaceutical character is unexpectedly sluggish probably
because there continues to be few practical methods that can
be used to produce the ring system.2,3,4 Among them, a
thermal [2+2] annulation of methylenecyclopropane (MCP)
with alkenes2 has been accepted as a reliable synthetic
method since the first preparation of the spiro[2.3]hexane was
accomplished by Anderson in 1962.2g On the other hand, the
catalytic annulation of MCP with alkenes has been less
developed and only a transition metal catalyst has been
exploited.3 During the course of our research project on the
preparation of hetero- or carbocycles catalyzed by the tin-ate
complex made from Bu2SnX2 and Li or Mg halides,5 we found
that the MCP coupled with dicyanoalkenes gave the
spiro[2.3]hexane in a high yield.5a The spiro ring was preferred
when the reaction was carried out with Bu2SnCl2+MgCl2 as a
catalyst in CH2Cl2. Herein, we report the diastereoselective
annulation of MCP with cyanoalkenes substituted with ester
groups to give the spiro rings.
Results and Discussion
We initiated optimization of the reaction conditions with MCP
1 and cyanoalkene 2a. The results are shown in Table 1. The
spirocarbocycle 3a was given in a low yield when the
previously optimized conditions were applied (entry 1).5a The
yield was improved in 1,2-dichloroethane at 80 °C for 2 h,
though diastereoselectivity was not observed (entry 2).
Bu2SnCl2 did not catalyze the coupling but MgCl2 worked as a
catalyst for the coupling (entries 4 and 5). The heavier a
halogen atom of the catalyst was, the better the
diastereoselectivity was, though more of the undesired
cyclopentane 4a was produced, which was previously found to
be mainly formed by the Bu2SnBr2+MgI2 catalyst5a,6 and
difficult to separate from the reaction mixture (entry 6). Finally,
the Bu2SnBr2+MgCl2 system was chosen as optimal. Each
diastereomer structure was defined via X-ray crystallography
using cyanoalkene 2b (Scheme 2, CCDC: 1906464, 1820470).
Table 1. Optimization of the conditions with MCP 1 and cyanoalkene 2a.a
[a]
Dr. I. Suzuki, J.-Y. Shimazu, Prof. S. Tsunoi, Prof. I. Shibata*
Research Center for Environmental Preservation, Osaka University
2-4, Yamadaoka, Suita, Osaka 565-0871, Japan
E-mail: shibata@epc.osaka-u.ac.jp
http://www.chem.eng.osaka-u.ac.jp/shibataken/
J.-Y. Shimazu
[b]
Division of Applied Chemistry
Graduate School of Engineering, Osaka University
2-1, Yamadaoka, Suita, Osaka 565-0871, Japan
a Reaction conditions: 1 (0.75 mmol), 2a (0.50 mmol), catalyst (0.050 mmol) and
b
c
solvent (1 mL). 1H NMR yield. at 25 °C in CH2Cl2 for 24 h. DCE =
dichloroethane
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Scheme 2. Investigation on the scope of cyanoalkene 2a
.
The optimized conditions were then applied to investigate
the scope of the cyanoalkenes 2 (Scheme 2). The electron
donating groups on the phenyl ring diminished the yields
somewhat (2c and 2d), but the electron-withdrawing groups
tended to afford the corresponding products 3e-3k in high
yields (2e-2k). Other aromatic rings such as 1- or 2-naphthyl
and 2-furyl were applicable to this coupling that formed the
spiro rings (3l-3n), although the bulky ester moiety of the
cyanoalkene affected the yields (2o and 2p).
A plausible reaction mechanism is shown in Scheme 3. First,
the tin-ate complex bearing a nucleophilic Sn-X bond opens
MCP 1 to give vinylogous dienolate 5.7 Then, a conjugate γ-
addition of the enolate 5 to cyanoalkene 2 takes place to form
ketenimine 6. Next, an intramolecular conjugate addition
proceeds to provide the intermediate 7 followed by a further
ring closure to afford the spirocarbocycle 3. The side product
4 is generated if the ketenimine attacks the C-X bond of the
intermediate 6, which is likely to happen when X is Br or I.5a
Scheme 3. Plausible reaction mechanism.
One possibility for how the diastereoselectivity is
determined is proposed in Scheme 4. It could be elucidated by
a steric hindrance that may exist between the ketenimine
moiety and the C-X bond in the reaction of intermediate 6. In
the case of X=Cl, there is so little steric repulsion in the
intermediate 6right that the ketenimine moiety can rotate to
adopt both conformations 6left and 6right, which ends up
forming 3-syn and 3-anti, respectively. In the case of X=Br or I,
the conformation of the intermediate 6 is restricted to 6left by
an effective repulsion that preferentially forms the
diastereomer 3-syn. To our surprise, however, the
diastereoselectivity was inverted when electron-deficient
alkenes such as 2g, 2j, and 2l were employed under the
Bu2SnCl2-MgCl2 catalyst system (Table 3). The results implied
that the selectivity was controlled not only by the steric
hindrance but also by electronic factors. At this time, we are
unsure why the selectivity was changed so we are now
carrying out DFT calculations to clarify the precise
conformation model of the reaction with intermediate 6.
Table 2. Investigation on the scope of cyanoalkene 2a
Scheme 4. Plausible differentiation of the diastereomers
3
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Table 3. Inversion of the diastereoselectivity of 3.
Experimental Section
(Scheme 2) To a mixture of MgCl2 (0.050 mmol) and Bu2SnBr2 (0.050 mol)
in 1,2-dichloroethane (1 mL) was added MCP 1 (0.75 mmol) and
cyanoalkene 2 (0.50 mmol). The reaction mixture was heated at 80 °C for
2 h and quenched with brine (10 mL). The resulting mixture was extracted
with Et2O (3 x 10 mL) and the collected organic layer was dried over
MgSO4. After filtration, the organic solvent was evaporated in vacuo to give
crude product 3, which was analyzed by 1H NMR. The crude product was
purified by a silica gel column chromatography to give pure product 3.
Acknowledgements ((optional))
We thank the Instrumental Analysis Center, Faculty of
Engineering, Osaka University, for assistance with collecting the
spectral data.
Finally, the transformation of the spiro[2.3]hexane 3f
was carried out under heating conditions (Scheme 5).8 We
expected to have its methoxy carbonyl moiety removed by
means of Krapcho decarboxylation even though diethyl ester
groups were contained in the product.9 Actually, not only the
removal but also a rearrangement reaction10 took place to give
the cyclopentene ring 8, which probably followed the pathway
shown in Scheme 6. After the decarboxylation occurred, the
ring opening led to methylene cyclopentane 8’ followed by
isomerization of the double bond to form the product 8.11 This
is the first example of preparing the same cyclopentanoids
without the use of a precious transition-metal catalyst.12
Keywords: Methylenecyclopropane • Cyanoalkene • Tin • Ate
Complex • Spirohexane
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Conclusion
A diastereoselective coupling of MCP 1 and cyanoalkene 2
succeeded in the formation of spiro[2.3]hexane 3. The
selectivity depended on the size of the halogen derived from
the Bu2SnX2+MgX2 catalyst, which can be explained by
considering the steric hindrance in the reaction with
intermediate 6. The spiro[2.3]hexane 3 was converted into
cyclopentene 8 via decarbonylation and rearrangement.
Further elucidation of the reaction mechanism and a
transformation of spirocarbocycles 3 while maintaining their
skeleton is underway.
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Scheme 5. Further conversion of the spirohexane 3f by Krapcho
decarboxylation.
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H. Takahashi, S. Yasui, S. Tsunoi, I. Shibata, Eur. J. Org. Chem. 2013,
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40.
[6]
[7]
[8]
The cyclopentane 4a was actually formed selectively under the reaction
conditions with the Bu2SnI2-MgI2 catalyst in THF.
We have already observed a fast ring opening of the MCP 1 by the tin-
ate complex. See ref.5a.
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conditions. See ref.5a.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Key Topic: Tin-catalyzed Annulation
Itaru Suzuki, Jun-ya Shimazu, Shinji
Tsunoi and Ikuya Shibata*
Page No. – Page No.
Diastereoselective Synthesis of
Spiro[2.3]hexanes from
Methylenecyclopropane and
Cyanoalkenes Catalyzed by a Tin-ate
Complex
Spirohexanes were synthesized via thermal annulation of methylenecyclopropanes
with cyanoaokenes substituted with ester groups catalysed by a Sn and Mg ate
complex. The diastereoselectivity was affected by the halogen of the catalyst and
electron-withdrawing groups on the cyanoalkene. The transformation of the
spirohexane was carried out to afford a cyclopentanoid which has been prepared
only by a transition metal catalyst.
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