Complete regio- and stereoselective construction of highly substituted silyl enol ethers by three-component coupling

Article abstract of DOI:10.1002/anie.201003152

Three components for total control: Trisubstituted silyl enol ethers were prepared by three-component coupling of α-silyl α, β-unsaturated ketones, organocopper reagents, and organic halides with complete regio- and stereoselectivity (see scheme). The reaction proceeded through a 1,3 migration of the silyl group via cyclic silicate intermediates, which controlled the configuration of the silyl enol ethers.

Full text of DOI:10.1002/anie.201003152

Angewandte
Chemie
DOI: 10.1002/anie.201003152
Stereoselctive Synthesis
Complete Regio- and Stereoselective Construction of Highly
Substituted Silyl Enol Ethers by Three-Component Coupling**
Akira Tsubouchi,* Shouko Enatsu, Ryo Kanno, and Takeshi Takeda*
Silyl enol ethers are important building blocks in organic
synthesis.[1] The aldol reaction carried out using trisubstituted
silyl enol ethers generates a quaternary carbon center next to
the carbonyl group, and can potentially provide a powerful
method for the stereocontrolled construction of adjacent
stereogenic centers on acyclic carbon chains.[1b] It is difficult to
attain the complete regio- and stereoselective formation of
trisubstituted silyl enol ethers by silylation of thermodynami-
cally or kinetically favorable enolates generated by enoliza-
tion of ketones with bases. Another approach involves the
regioselective formation of enolates through the conjugate
addition of organocopper reagents to enones.[2] This synthetic
strategy is not applicable, however, to the preparation of silyl
enol ethers with a broad range of substitution patterns and
geometries. Thus, much difficulty has been encountered in
controlling the stereochemical integrity of trisubstituted silyl
enol ethers.
Scheme 1. Regio- and stereoselective preparation of silyl enol ethers by
three-component coupling. Cy=cyclohexyl, TMS=trimethylsilyl.
copper compounds 6, and 3) alkylation of 6 with organic
halides 4 (Scheme 2). The organocopper reagents 3 were
prepared by adding a solution of copper(I) tert-butoxide[5] in
THF to a solution of alkylcopper species[6] in THF formed
from the Grignard reagents and copper(I) iodide.
In the context of our studies aimed at the synthetic
application of the silyl migration from an sp2 carbon atom to
an oxygen atom,[3] we have recently focused on the copper(I)
tert-butoxide-promoted silyl migration to the oxygen atom of
an enolate group[4] to develop a new strategy for the
preparation of silyl enol ethers. It was found that alkenylcop-
per species bearing a silyl enol ether substructure were
stereoselectively generated by treatment of acylsilanes[4b] and
o-silylphenyl ketones[4c] with copper(I) tert-butoxide through
1,2- and 1,4-silyl migration, respectively. Also, their alkylation
with organic halides produced disubstituted silyl enol ethers
stereoselectively. Herein we report a strategy based on silyl
migration for the highly regio- and stereoselecive preparation
of trisubstituted silyl enol ethers 1. This strategy consists of a
three-component coupling of a-silyl a,b-unsaturated ketones
2, new organocopper reagents 3 [RCu·tBuOCu], and organic
halides 4 (Scheme 1).
Scheme 2. Reaction pathway. DMF=N,N-dimethylformamide,
THF=tetrahydrofuran.
The a-silyl a,b-unsaturated ketone 2a was treated with
the organocopper reagent 3a in THF. The copper(I) enolate
5a thus formed was treated with DMF at 508C and then with
methallyl chloride 4a and gave the silyl enol ether 1a in 85%
yield with complete Z selectivity (Table 1, entry 1). The
addition of DMF is crucial for the silyl migration;[7] when
the reaction was performed without DMF, 1a was obtained
only in 4% yield along with the formation of hydrolysis
product of the enolate 5a (the a-silylketone, in 75% yield).
Another advantage of this reaction is that various
Grignard reagents can be used in the preparation of organo-
copper reagents 3 and hence various substituents can be
conveniently introduced in the silyl enol ethers. Thus, the
reaction of the a-silyl a,b-unsaturated ketone 2a with various
organocopper reagents 3 and the allylic halides 4a and 4b
produced silyl enol ethers 1b–e stereoselectively (Table 1,
entries 2–5). The three-component coupling of 2a proceeded
also with benzyl chloride (4c), methyl iodide (4d), and
chlorodimethylphenylsilane (4e) as well as with the allylic
halides 4a and 4b and gave silyl enol ethers 1 f–h (Table 1,
entries 6–8).
The process involves the following steps: 1) the formation
of copper(I) enolates 5 by conjugate addition of the organo-
copper reagent 3 to the silyl ketones 2, 2) the 1,3-silyl
migration to the enolate oxygen atom to form the alkenyl-
[*] Dr. A. Tsubouchi, S. Enatsu, R. Kanno, Prof. Dr. T. Takeda
Department of Applied Chemistry, Graduate School of Engineering
Tokyo University of Agriculture and Technology
Koganei, Tokyo 184-8588 (Japan)
Fax: (+81)42-388-7034
E-mail: tubouchi@cc.tuat.ac.jp
This coupling is found to be general for a-silylvinyl
ketones 2; aliphatic primary and secondary ketones 2b and 2c
can also be employed to give the silyl enol ethers 1 with good
yields and perfect stereoselectivity (Table 2). The normally
difficult achievement of regio- and stereoselective formation
of 1l and 1n through thermodynamically or kinetically
takeda-t@cc.tuat.ac.jp
[**] This work was supported by Grant-in-Aid for Scientific Research (C;
no. 19550032) from the Ministry of Education, Culture, Sports,
Science, and Technology (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003152.
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Table 1: Formation of trisubstituted silyl enol ethers by three-component
Table 2: Preparation of trisubstituted silyl enol ethers 1 utilizing a-
silylvinyl ketones 2.[a]
coupling of phenyl a-silylvinyl ketone 2a, organocopper reagents 3, and
organic halides 4.[a]
Entry
1
Silyl enone
2
3/4
Product 1
Yield [%][b]
(Z:E)[c]
Entry Copper
Organic
halide 4
Product 1
Yield [%][b]
reagent 3
(Z:E)[c]
2b
3a/4a
71 (100:0)
85
(100:0)
1
3a
4a
75
(100:0)
2
3
2b
2b
3c/4a
3b/4c
70 (100:0)
66 (100:0)
2
3
4
3b
3c
3d
4a
4b
4a
81
(100:0)
65 (97:3)
4
2c
2a
2c
3e/4b
3 f/4c
3 f/4 f
80 (0:100)
88 (100:0)
91 (100:0)
79
(0:100)
5
6
3e
3a
4a
4c
5[d]
76
(100:0)
6[d]
85
(13:87)
7
8
3a
3a
4d
4e
[a] Reaction conditions: 1) the ketone 2 (0.6 mmol), the copper reagent 3
(0.72 mmol), 2 h, 08C (for 3a, 3c, and 3e), À60 to 08C (for 3b), or À78
to 08C (for 3 f); 2) 708C (for 3a–c and 3e) or 258C (for 3 f), 30 min;
3) the halide 4 (1.8 mmol), 708C (for 3a–c and 3e), or 258C (for 3 f), 4 h.
[b] Yield of the isolated product. [c] Determined by 1H NMR analysis.
[d] tert-Butyllithium was used for the preparation of 3 f.
64 (93:7)
[a] Reaction conditions: 1) the ketone 2a (0.6 mmol), the copper reagent
3 (0.72 mmol), 2 h, 08C (for 3a, 3c, and 3e) or À60 to 08C (for 3b and
3d); 2) 508C, 30 min; 3) the halide 4 (1.8 mmol), 508C, 4 h. [b] Yield of
the isolated product. [c] Determined by 1H NMR analysis.
Z-alkenylcopper species 6 (containing a silyl enol ether
substructure) stereoselectively. Subsequent alkylation of 6
with organic halides 4 with retention of the configuration of
the double bond gives 1. The formation of the stereoisomers
of 1d, 1g, and 1h would arise from the stereoisomerization of
the primarily formed silyl enol ethers.
controlled deprotonation of the corresponding a,a’-di-
branched ketones demonstrates the unique advantage of
this method. The configuration of the silyl enol ethers 1 were
confirmed by NOE or NOESY experiments.
Notably, the organocopper reagent 3a was more effective
than methylcopper and lithium dimethylcuprate toward the
three-component coupling. The reaction of methylcopper, 2b,
and 4a gave 1i in 47% yield and the similar reaction using
lithium dimethylcuprate gave 1i in 31% yield. In contrast, the
use of copper reagent 3a significantly improved the yield of 1i
to 71% under similar reaction conditions (Table 2, entry 1).
In the preparation of the reagent 3, the Grignard reagents can
be replaced with alkyl lithium compounds without loss of
stereoselectivity and reactivity (Table 2, entries 5 and 6).
The stereoselectivity of the current reaction apparently
originates from the formation of cyclic silicate species 7
(Scheme 3). Among the two potential stereoisomers of
copper(I) enolates 5 and 8, which exist in equilibrium via
isomeric C-metalated enolates,[8] only the enolates 5 undergo
Application of the Brook-type rearrangement to the
preparation of silyl enol ethers have been investigated.[9]
Typical approaches consist of three steps: 1) generation of
a-silylalkoxide intermediates having a leaving group at the
b position, 2) the 1,2 migration of the silyl group from an sp3
carbon atom to an oxygen atom and 3) b elimination to form
the silyl migration via the silicates
7
to furnish the
Scheme 3. Plausible stereochemical pathways.
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À
[3] a) H. Taguchi, K. Ghoroku, M. Tadaki, A. Tsubouchi, T. Takeda,
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of 1-alkenyl Grignard reagents to acylsilanes, 1,2-silyl migra-
tion of the resulting a-silylallylic alkoxides, and reaction of
electrophiles at the g position of a-siloxyallylic anions to
afford silyl enol ethers.[9e,f] There have been, however, only
limited examples of the preparation of trisubstituted silyl enol
ethers. In contrast, the current reaction made it possible to
assemble the stereochemically pure silyl enol ethers having
three different substituents, each of which were originated
from a-silyl a,b-unsaturated ketones, organocopper reagents,
and organic halides.
In conclusion, we have developed a new method for the
highly regio- and stereoselective preparation of synthetically
useful trisubstituted silyl enol ethers by a silyl migration from
an sp2 carbon atom to the oxygen atom of the enolate group
through three-component coupling. The configuration of the
silyl enol ethers is defined by the cyclic silicates. Such a
strategy for controlling regio- and stereochemistry of the silyl
enol ethers has not been reported until now. Study of the
scope of this new method and synthetic application of the
triphenylsilyl enol ethers to stereoselective carbon–carbon
bond formations is currently underway.[10]
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Experimental Section
Typical procedure: Methylmagnesium bromide (0.93m in THF,
0.77 mL, 0.72 mmol) was added to a suspension of CuI (137 mg,
0.72 mmol) in THF (1.5 mL) at 08C under Ar and the mixture was
stirred for 30 min. To this solution was added a solution of tBuOCu
(0.72 mmol) in THF, prepared by the reaction of CuI (137 mg,
0.72 mmol) with tBuOLi (0.93m in THF, 0.77 mL, 0.72 mmol) in THF
(1.5 mL), through a stainless-steel canula at 08C. After stirring for
30 min, a (1.5 mL) solution of ketone 2a (234 mg, 0.60 mmol) in THF
was added at 08C and the mixture was stirred for 2 h. After addition
of DMF (6 mL), the mixture was heated to 508C for 30 min. A (3 mL)
solution of methallyl chloride (163 mg, 1.8 mmol) in DMF was added
and the mixture was stirred for 4 h. The reaction was quenched by
addition of 3.5% aqueous NH3 and the product was extracted with
diethyl ether. The extract was washed with H2O and dried over
K2CO3. The solvent was evaporated under reduced pressure and the
residue was subjected to PTLC on silica gel and developed twice
(n-hexane/EtOAc = 98:2). The silyl enol ether 1a (235 mg, 85%) was
obtained as a single isomer.
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Received: May 25, 2010
Revised: July 14, 2010
Published online: August 18, 2010
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Keywords: copper · Michael addition ·
multicomponent reactions · silyl enol ethers · silyl migration
.
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