InBr3-Catalyzed Coupling Reaction between Electron-Deficient Alkenyl Ethers with Silyl Enolates for Stereoselective Synthesis of 1,5-Dioxo-alk-2-enes

Article abstract of DOI:10.1002/ejoc.202001342

A coupling reaction of electron-deficient alkenyl ethers with silyl enolates catalyzed by InBr₃ was achieved. Various silyl enolates and 2-carbonylalkenyl ethers were applicable, giving the corresponding 1,5-dioxo-alk-2-enes with perfect stereoselectivity of the alkene moieties. The present coupling reaction proceeds via the 1,4-addition of silyl enolates to alkenyl ethers followed by elimination of silyl alkoxides, in which moderate-Lewis acidic InBr₃ performs both the activation of alkenyl ethers and the elimination of alkoxy groups regardless of the presence of various coordinative functional groups.

Full text of DOI:10.1002/ejoc.202001342

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: InBr3-Catalyzed Coupling Reaction between Electron-deficient
Alkenyl Ethers with Silyl Enolates for Stereoselective Synthesis of
1,5-Dioxo-alk-2-enes
Authors: Shuichi Nakao, Miki Saikai, Yoshihiro Nishimoto, and Makoto
Yasuda
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001342
Link to VoR: https://doi.org/10.1002/ejoc.202001342
01/2020

10.1002/ejoc.202001342
European Journal of Organic Chemistry
COMMUNICATION
InBr3-Catalyzed Coupling Reaction between Electron-deficient
Alkenyl Ethers with Silyl Enolates for Stereoselective Synthesis
of 1,5-Dioxo-alk-2-enes
Shuichi Nakao, Miki Saikai, Yoshihiro Nishimoto,* and Makoto Yasuda*
[a]
Shuichi Nakao, Miki Saikai, Dr. Yoshihiro Nishimoto, Prof. Dr. Makoto Yasuda,
Department of Applied Chemistry, Graduate School of Engineering
Osaka University
2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)
E-mail: nishimoto@chem.eng.osaka-u.ac.jp, yasuda@chem.eng.osaka-u.ac.jp
http://www.chem.eng.osaka-u.ac.jp/~yasuda-lab/e/
Supporting information for this article is given via a link at the end of the document.
Abstract: A coupling reaction of electron-deficient alkenyl ethers with
silyl enolates catalyzed by InBr3 was achieved. Various silyl enolates
and 2-carbonylalkenyl ethers were applicable, giving the
corresponding 1,5-dioxo-alk-2-enes with perfect stereoselectivity of
the alkene moieties. The present coupling reaction proceeds via the
1,4-addition of silyl enolates to alkenyl ethers followed by elimination
of silyl alkoxides, in which moderate-Lewis acidic InBr3 performs both
the activation of alkenyl ethers and the elimination of alkoxy groups
regardless of the presence of various coordinative functional groups.
enolates (Scheme 1D). Various alkenyl ethers substituted by only
one carbonyl group are applicable to this reaction. The availability
of useful silyl enolates is a notable advantage over previously
reported reactions. It is noteworthy that the corresponding alk-2-
ene-1,5-diones were produced with alkene moieties that have
perfect stereoselectivity.
Catalytic cross-coupling via the transformation of C-O bonds to C-
C bonds has been an important pursuit of organic chemists for the
past twenty years in attempts to replace organic halides with more
environmentally benign oxygen-based electrophiles such as
alcohol, arenol, and enol derivatives.[1,2] In particular, the coupling
between enol derivatives and enolate nucleophiles is one of the
most significant of these reactions, because the α-alkenyl
carbonyl compounds produced in this process are recognized as
valuable building blocks for pharmaceuticals, natural products,
and organic materials (Scheme 1A),[3] but robust C-O bonds make
this catalytic reaction a challenge.[4] Thus far, the report of GaBr3-
catalyzed coupling reactions of enol derivatives with ketene silyl
acetals that were established by our group remains the only
description of the availability of electron-rich enol derivatives
(Scheme 1B).[5] As far as electron-deficient enol derivatives are
concerned, the Michael addition/elimination reaction system
using 2-carbonylalkenyl ethers is the sole methodology (Scheme
1C).[6,7,8] A severely narrow scope of substrates, however,
restricts both the generality and the diversity of this reaction
system. In fact, either a polyhalogenated acyl group or two
electron-withdrawing groups on enol derivatives is necessary,
and enolate nucleophiles are limited to stabilized alkali metal
enolates such as those from 1,3-diketone and β-keto ester
derivatives,[6]
phosphoranylideneacetates[7],
and
2-
oxoethylpyridinium salts.[8] Therefore, a strategy that could
achieve more versatile reactions is highly desirable. In this study,
we overcame these limitations and developed an InBr3-catalyzed
coupling reaction between 2-carbonylalkenyl ethers and silyl
Scheme 1. Coupling reaction between enol derivatives and enolate
nucleophiles.
1
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10.1002/ejoc.202001342
European Journal of Organic Chemistry
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The electron-donating effect of an alkoxy group reduces
electrophilicity of enol derivatives. Therefore, reported reactions
require quite strong or two electron-withdrawing groups on enol
derivatives and high-nucleophilic enolate species. A simple and
promising strategy to solve this problem would be the
enhancement of electrophilicity of electron-withdrawing group by
Lewis acids. However, there is no report for Lewis acid-catalyzed
system because typical Lewis acids are deactivated by substrates
(2-carbonylalkenyl ethers and enolate nucleophiles), products,
and by-products due to their coordinating sites which interacts
with the strong Lewis acids. Our and other groups have revealed
that moderate-Lewis acidic indium and gallium salts have an
important property of fast ligand exchange to be not tightly
trapped by one substrate but to flexibly interact with various
coordinating sites in the reaction system.[5,9,10] Therefore, indium
and gallium catalysts have a possibility to achieve a desired
reaction course when a suitable reaction system is designed. In
Table 1, we started from investigation of indium and gallium salts
in the reaction of alkenyl ether 1a with ketene silyl acetal 2a.[11] To
our delight, indium halides exhibited the effective catalytic activity
(Entries 1-3). InBr3 was the best catalyst to give an excellent yield
of the desired product 3aa (Entry 2). Gallium halides possessed
slightly less activity than indium halides (Entries 4-6). The use of
In(OTf)3 and Ga(OTf)3 resulted in low yields (Entries 7 and 8).
Typical group 13 Lewis acids, BF3·OEt2 and AlCl3, hardly gave
3aa (Entries 9 and 10). Transition metal salts such as zinc,
scandium, iron, palladium, gold salts were less effective to give
sluggish results (Entries 11-17). The cationic InI2 catalyst
generated from InI3 and AgSbF6 was less effective in the present
coupling reaction (Entry 18).[12] The catalyst-free conditions
afforded no products (Entry 19).
(Scheme 2B). A fluoride anion[14] is known to mediate the addition
of silyl enolates to α,β-unsaturated carbonyl compounds, but
tetrabutylammonium fluoride was ineffective in this reaction
(Scheme 2C). The use of lithium enolate 4 also gave a poor result
(Scheme 2D).[15] Under Reformatsky-type reaction conditions,
product 5 was obtained neither at room temperature nor at 50 °C,
although an over-reaction of 5 with the zinc enolate proceeded at
50 °C to give undesired product 7 in 32% yield (Scheme 2E).[16]
A
comparison study revealed that, rather than strong Lewis acid
catalysts and highly nucleophilic enolates, moderate Lewis acidic
InBr3 and moderate nucleophilic silyl enolates efficiently achieved
the desired coupling reaction.
Table 1. Investigation of metal salt catalysts in coupling reaction of alkenyl ether
1a with ketene silyl acetal 2a[a]
Scheme 2. Comparison among InBr3-catalyzed reaction and typical methods
With the optimal conditions in hand (Entry 2, Table 1), we
explored the scope of alkenyl ethers 1 (Scheme 3). Various 2-
carbonylalkenyl ethers were applicable to this reaction system,
and the single stereoisomers for alkene moieties were selectively
furnished in all cases. Acetyl and benzoyl groups were tolerated
and the desired products 3ba and 3ca were obtained in 61 and
88% yields, respectively. The coupling reactions using 1- or 2-
alkylsubstituted alkenyl ethers occurred in moderate yields (3da,
3ea, and 3fa). Phenyl-substituted substrates reacted effectively
(3gj). The halogen-substituted alkenyl ethers were also suitable
substrates, affording the corresponding products 3ha and 3ia. In
a reaction using a 2,2-di(methoxycarbonyl)-substituted substrate,
GaBr3 instead of InBr3 worked as an efficient catalyst to afford a
[a] 1a (0.5 mmol), 2a (0.75 mmol), Catalyst (0.025 mmol), CH2Cl2 (1 mL), room
temperature, 4 h. [b] The yields of 3aa were measured by 1H NMR analysis of
the crude mixture. The isolated yield is shown in a parenthesis. [c] 24 h. [d] InI3
(5 mol%) and AgSbF6 (5 mol%) were used.
We used typical methods to compare the InBr3-catalyzed
reaction (Scheme 2). As mentioned above, a catalytic amount of
InBr3 gave 3aa in an excellent yield in the reaction of 1a with 2a
[13]
(Scheme 2A). A typical Mukaiyama-type reaction with TiCl4
resulted in the recovery of 1a without the formation of 3aa
2
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10.1002/ejoc.202001342
European Journal of Organic Chemistry
COMMUNICATION
high yield of 3ja. The alkynyl group at the 2-position was
compatible in this coupling reaction (3kj). It is noted that an E/Z-
mixture of alkenyl ether 1l led to the exclusive yield of E-isomer
product 3la.[17]
Table 2. Scope of ketene silyl acetals 2 in the reaction with 1b[a]
Entry
2
3
Yield
[%]
1
81%
70%
2b
3bb
2
3
2c
2d
3bc
3bd
78%
4
5
46%[b,c]
2e
2f
3be
3bf
97%
(81:19)[b]
Scheme 3. Scope of alkenyl ethers 1 in the coupling of 2a. Standard conditions:
1 (0.5 mmol), 2a (0.5-0.75 mmol), InBr3 (0.025 mmol), CH2Cl2 (1 mL), 4 h.
Isolated yields are shown. [a] 0 °C, 2 h. [b] In(OTf)3 instead of InBr3. [c] InBr3
(10 mol%) was used. [d] Ketene silyl acetal 2j (R = Me) was used. [e] The NMR
yield is shown. [f] GaBr3 instead of InBr3 was used. 2 h.
3bf’
The scope of ketene silyl acetals 2 in the coupling reaction of
alkenyl ether 1b was investigated (Table 2). Disubstituted ketene
silyl acetals 2b, 2c and 2d afforded the corresponding α-alkenyl
esters in yields that ranged from moderate to high (Entries 1-3).
Butylketene silyl acetal 2e and unsubstituted ketene silyl acetal 2f
were applicable to afford products 3be (Entry 4) and 3bf (Entry 5)
in 49 and 97% yields, respectively, although the alkene moiety of
3bf was isomerized. The coupling with cyclic ketene silyl acetal
2g proceeded to give product 3bg in 52% yield (Entry 6). Silyl enol
ethers acted as efficient nucleophiles. The desired products 3bh
and 3bi were selectively obtained in the reactions using 2h and
2i, respectively (Entries 7 and 8).
6
52%
2g
3bg
7
8
54%[d]
56%[b]
2h
2i
3bh
3bi
[a] 1b (0.5 mmol), 2 (0.6 mmol), InBr3 (0.025 mmol), CH2Cl2 (1 mL), 0 °C, 2 h.
Isolated yields are shown. [b] The yield and the ratio of products determined by
1H NMR analysis in crude products is shown. [c] room temperature. [d] 6 h.
We monitored the reaction progress via 1H NMR spectroscopy
to gain insight into the mechanism (Scheme 4A). In the reaction
of alkenyl ether 1b with ketene silyl acetal 2j, the 1,4-addition of
2j to 1b readily proceeded at -60 °C to give silyl enol ether
intermediate 8. Then, an elimination of the MeO group took place
3
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10.1002/ejoc.202001342
European Journal of Organic Chemistry
COMMUNICATION
at -20 °C with the formation of coupling product 9.[18] Based on
these results, a plausible reaction mechanism is illustrated in
Scheme 4B(i). InBr3 activates alkenyl ether 1 via coordination of
the carbonyl group of 1 to the indium center. The 1,4-addition of
silyl enolate 2 to 1 activated by InBr3 gives indium enolate 12.
Then, silyl enol ether 13 is generated via the exchange of InBr3
with Me3Si groups. Finally, InBr3 mediates the elimination of the
R5O group (14) to give coupling product 15. The explanation
about the selective production of E-isomer 15 via the elimination
of Me3SiOR5 from the E/Z-mixture of intermediate 13 is shown in
Scheme 4B(ii).[19] The elimination of Me3SiOR5 from the Z-isomer
of 13 proceeds via the six-membered ring transition state TS A to
avoid the steric repulsion between the Br atom on the indium
center and the substituent CR1R2(COR3), giving the Z-isomer of
15. In the case of the E-isomer of 13, the elimination occurs via
acyclic transition state TS B to afford the Z-isomer of 15. As
catalysts, strong Lewis acids such as TiCl4 (Scheme 2B) and AlCl3
(Table 1, Entry 10) suffer from a detrimental interaction with either
silyl enolate 2 or product 9 so that the catalytic reaction hardly
proceeds (Scheme 4C-1). On the other hand, lithium enolates
could cause a 1,4-addition to 1 (Scheme 2D), but the alkoxy (R5O)
group could not released without the assistance of Lewis acids,
and an anionic polymerization of 1 would occur (Scheme 4C-2).[20]
It is noteworthy that moderate Lewis acidic InBr3 capably performs
both the activation of alkenyl ethers (10) and the elimination[21] of
the R5O group (14) in the presence of various coordinative
functional groups.
Scheme 4. (A) Monitoring reaction progress and silyl enol intermediate by 1H
NMR spectroscopy. (B) Plausible mechanism of the InBr3-catalyzed coupling of
2-carbonylalkenyl ethers with silyl enolates. (C) Problems of other reaction
systems.
The reductive transformation of alk-2-ene-1,5-diones, which
were endowed with alkene moieties that have perfect
stereoselectivity via the present reaction, was demonstrated
toward the construction of 1,5-hydroxyalk-2-ene structures that
are important in molecules with biological relevance (Scheme
4
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10.1002/ejoc.202001342
European Journal of Organic Chemistry
COMMUNICATION
5).[22] The InBr3-catalyzed coupling between alkenyl ether 1d and
ketene silyl acetal 2k gave alk-2-ene-1,5-dione 3dk with E-
selectivity. Then, the reduction of 3dk by LiAlH4 afforded 1,5-
hydroxyalk-2-ene 16 with the retention of the E-configuration. The
structure of 16 is included in berkleasmins that are eremophilane
sesquiterpenoids from a saprobic fungus, and these have
exhibited cytotoxic activity against cancer cell lines as well as
antimalarial activity.[23]
Zhang, Chem. Soc. Rev. 2015, 44, 7929. B. M. Trost, M. L. Crawley,
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Scheme 5. Application to the construction of 1,5-hydroxyalk-2-ene structure
included in berkleasmins. [a] The isolated yield is shown. The
diastereoselectivity determined by 1H NMR analysis in crude products is shown.
In conclusion, we established an InBr3-catalyzed coupling
reaction of 2-carbonylalkenyl ethers with silyl enolates to give the
corresponding alk-2-ene-1,5-diones that feature alkene moieties
with perfect stereoselectivity. The scope of the substrates is wide,
and various functional groups are compatible with this reaction
system. The observation of the silyl enolate intermediate by in situ
1H NMR study revealed that the present reaction proceeded via
1,4-addition of silyl enolates to alkenyl ethers and elimination of
silyl alkoxides. The reductive transformation of the synthesized
alk-2-ene-1,5-diones enabled ready access to valuable
compounds in organic synthesis such as 1,5-dihydroxyalk-2-enes.
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Acknowledgements
This work was supported by JSPS KAKENHI grant number
JP15H05848 in the Middle Molecular Strategy, and also by grant
numbers JP16K05719, JP18K19079, JP18H01977, and
JP19K05455. Thanks are due to the Analytical Instrumentation
Facility, Graduate School of Engineering, Osaka University.
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Keywords: Alkenylation • C-C coupling • Indium • Lewis acids •
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10.1002/ejoc.202001342
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
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InBr3 catalysis enable the coupling between 2-carbonylalkenyl ethers and silyl enolates to give alk-2-ene-1,5-diones featuring alkene
moieties with perfect stereoselectivity. Various types of 2-carbonylalkenyl ethers and silyl enolates are applicable to the present
reaction. InBr3 with moderate Lewis acidity plays an important role in both the activation of alkenyl ethers and in the elimination of
alkoxy groups regardless of the presence of various coordinative functional groups.
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