Magnesium Halide-Catalyzed Synthesis of Oxaspiro[2.5]octenes from a Methylenecyclopropane and Acyl Cyanoalkenes

Article abstract of DOI:10.1002/ejoc.202100500

MgX₂-catalyzed annulation of methylenecyclopropanes with acyl cyanoalkenes was accomplished to give oxaspiro[2.5]octenes in excellent yields. The reaction proceeded through a rare intramolecular oxa-Michael addition of Mg enolate. The oxaspiro

Full text of DOI:10.1002/ejoc.202100500

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doi.org/10.1002/ejoc.202100500
Magnesium Halide-Catalyzed Synthesis of Oxaspiro[2.5]
octenes from a Methylenecyclopropane and Acyl
Cyanoalkenes
Itaru Suzuki,[a] Kazuki Ogura,[b] Jun-ya Shimazu,[b] and Ikuya Shibata*[a, b]
MgX2-catalyzed annulation of methylenecyclopropanes with
acyl cyanoalkenes was accomplished to give oxaspiro[2.5]
octenes in excellent yields. The reaction proceeded through a
rare intramolecular oxa-Michael addition of Mg enolate. The
oxaspiro ring was transformed into 4H-pyran at a higher
temperature in the presence of MgX2.
Methylenecyclopropanes (MCPs) are unique synthetic inter-
mediates in organic chemistry. They have a high ring strain and
are readily opened by many kinds of metal catalysts to provide
reactive ring-opening intermediates.[1] Some of them are
regarded as ‘donor–acceptor’ cyclopropanes (DACs) that de-
pend on substituents to stabilize the ring-opened intermediates
that react with unsaturated bonds to form a variety of either
carbo- or heterocycles.[2] Our group reported examples of the
Scheme 1. Our Developments of Annulation between MCPs and Cyanoal-
kenes.
rings with the DACs and activated alkenes catalyzed by in situ-
generated ate complexes composed of Bu2SnX2 and MgX2
(X=Cl, Br, I).[3] In the case of dicyanoalkenes,[3b] either spirohex-
anes or alkylidenecyclopentanes were obtained depending on
the reaction conditions (Scheme 1, equiv a). The spirohexanes
were diastereoselectively formed when alkoxycarbonyl cyanoal-
kenes were employed (Scheme 1, equiv b). During the course of
the project, we unexpectedly found that neither the corre-
sponding spirohexanes nor alkylidenecyclopentane were
formed, but oxaspiro[2.5]octenes were generated when acyl
cyanoalkenes were employed. Herein, we report the details of
the annulation of MCP 1 with acyl cyanoalkenes 2 catalyzed by
a magnesium halide.
Table 1. Optimization of Reaction Conditions.[a]
First, optimization of the reaction conditions for the
annulation of MCP 1 with benzoyl acrylonitrile 2a was carried
out (Table 1). Previously optimized conditions[3c] were applied
to the system to give oxaspiro[2.5]octene 3a as a mixture of
diastereomers with 4H-pyran 4 as a by-product (entry 1). The
major form of the product 3a was characterized by X-ray
crystallography (3amajor, CCDC: 2065611). The yield of the
[a] Prof. Dr. I. Suzuki, Prof. Dr. 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/
[b] K. Ogura, J.-y. Shimazu, Prof. Dr. I. Shibata
Department of Applied Chemistry, Graduate School of Engineering
Osaka University
[a] MCP 1 (0.75 mmol), Cyanoalkene 2 (0.5 mmol), catalyst (0.05 mmol), and
solvent (1 mL). [b] Yields and diastereomer ratios were determined by 1H
NMR using an internal standard.
2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
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oxaspiro ring 3a was improved by lowering the reaction
Other metal halides, such as MgI2 or LiBr[5] were less effective
than MgBr2 (entries 7 and 8). No products were given by a
Brønsted acid (entry 9).[6]
°
temperature to 40 C (entry 2). THF as the solvent worked well
to suppress the formation of 4H-pyran 4 and improved the
diastereoselectivity of 3a (entries 3 and 4). The reaction was not
catalyzed by Bu2SnBr2,[4] but MgBr2 gave the product in an
excellent yield with high diastereoselectivity (entries 5 and 6).
The optimized reaction conditions were applied to a variety
of acyl cyanoalkenes 2. The results are displayed separately in
Table 2 and Table 3. The minor form of the product was
identified by X-ray crystallography (3qminor, CCDC; 2065610).
Neither the electron donating nor withdrawing groups on the
Ph ring of the acyl moiety had a noteworthy effect on either the
yields or the selectivities of the annulation (Table 2, entries 1–
10). The benzoyl could be replaced with acetyl, isobutyryl, or
pivaloyl at high temperatures for a longer duration, although
the bulkier the group became, the less efficient the reaction
was (entries 11–13). The reactions listed in Table 3 were
Table 2. Scope of Acyl Cyanoalkenes 2.[a]
°
conducted at 60 C because most of the alkenes 2 had different
substituents on the C=C bond that did not dissolve well in THF
°
at 40 C. Various substituents on the benzene ring were applied
to the system and resulted in satisfactory yields (entries 1–9).
Other aromatic rings such as naphthyl, 2-pyrroyl, or 2-furyl were
introduced into the oxaspiro rings (entries 10–13).
A plausible reaction cycle is shown in Scheme 2. The MCP 1
is opened by MgX2 to form a vinylogous enolate, which then
adds to cyano alkene 2 via a γ-addition that gives int-A.[7] Next,
an intramolecular reversible oxa-Michael addition[8] occurs from
Mg enolate to the alkylidene malonate moiety of int-A to form
int-B with a dihydropyran ring. Finally, a ring closing between
Mg malonate and the alkyl halide moiety proceeds to give
oxaspiro[2.5]octene 3, which is followed by the regeneration of
MgX2. The cyclopropyl ring formation shifts the reversible oxa-
Michael addition pathway to another type where the dihydro-
pyran ring is obtained. By contrast, in our previous work
producing carbocycles,[3b–c] a similar reaction intermediate, int-
A, was generated and a typical Michael addition of either the
Mg enolate or keteneimine to the C=C bond or allyl halide
[a] MCP 1 (0.75 mmol), Cyanoalkene 2 (0.5 mmol), MgBr2 (0.05 mmol), and
THF (1 mL). [b] Yields were determined by 1H NMR using an internal
°
standard. [c] Temp. (60 C). [d] Time (1 day). [e] The major diastereomer was
identified by X-ray crystallography (CCDC: 2065611).
Table 3. Scope of Benzoyl Cyanoalkenes 2.[a]
[a] MCP 1 (0.75 mmol), Cyanoalkene 2 (0.5 mmol), catalyst (0.05 mmol), and
solvent (1 mL). [b] Yields were determined by 1H NMR using an internal
°
standard. [c] MgI2 (0.05 mmol), DCE (1 mL), at 40 C. [d] The minor
diastereomer was identified by X-ray crystallography (CCDC: 2065610).
Scheme 2. A Plausible Catalytic Cycle.
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this paper. These data are provided free of charge by the joint
Cambridge Crystallographic Data Centre and Fachinformations-
zentrum Karlsruhe Access Structures service www.ccdc.cam.a-
c.uk/structures.
Acknowledgements
This work was supported by JSPS KAKENHI grant number
19K15563 (Early-Career Scientists).
Conflict of Interest
Scheme 3. Transformation of Oxaspiro Ring 3a into 4H-Pyran 4.
The authors declare no conflict of interest.
Keywords: Annulation · Magnesium · Methylenecyclopropane ·
Oxa-Michael addition · Oxaspiro ring
proceeded. The unprecedented chemoselectivity might have
been shown because the reactive carbon site lacks sufficient
reactivity to create a more rigid 4 or 5-membered ring
compared with that of the 6-membered one, and the Mg
enolate that forms is a dominant reactive species. As far as we
could ascertain, there have been no reports of the O-addition of
an enolate into a Michael acceptor favored over the C-addition.
The O-addition would be achieved by an effective trap of the
oxa-Michael adduct int-B via subsequent cyclopropanation. A
DFT calculation to clearly establish the chemoselectivity or
diastereoselectivity is ongoing in our lab.[9]
Finally, a further transformation of the oxaspiro ring 3a was
examined. Unfortunately, hydrolysis of either the ester or the
cyano groups or the reduction of C=C bonds by H2 using a Pd/C
catalyst gave either a complicated mixture or a full recovery of
the oxaspiro[2.5] octene 3a, respectively. We realized that the
transformation created 4H-pyran 4 (Scheme 3). The isolated
oxaspiro ring 3a was treated with a catalytic loading of MgI2 at
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°
80 C to produce 4H-pyran 4 in a 71% yield. The yield was
improved via the use of a Bu2SnI2/MgI2 catalyst and resulted in
an 83% yield. The transformation failed to proceed without a
catalyst. These results led to a mechanism whereby the cyclo-
propyl ring of the spiro ring 3 is opened via MgI2 chelation
accompanying the generation of an oxonium cation. Then, the
intramolecular H-transfer proceeds to give the 4H-pyran 4.
In summary, we developed an annulation between MCP 1
and acyl cyanoalkenes 2 catalyzed by MgX2 to provide oxaspiro
[2.5]octene 3 in a high yield. The reaction contains a rare
intramolecular oxa-Michael addition of Mg enolate. The oxas-
piro ring 3 evolved into 4H-pyran 4 at elevated temperature via
the ring opening by MgX2 and intramolecular H-transfer.
Further investigation into the reaction mechanism and applica-
tion of the oxaspiro ring is in progress in our lab.
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Alder process beteween the MCP 1 and cyano alkenes 2 catalyzed by Mg
halides.
Manuscript received: April 23, 2021
Revised manuscript received: April 27, 2021
Accepted manuscript online: May 5, 2021
Deposition Numbers 2065611 (for 3amajor), and 2065610 (for
3qminor
)
contain the supplementary crystallographic data for
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