Regio- and stereoselective preparation of (Z)-silyl enol ethers by three-component coupling using α,β-unsaturated acylsilanes as core building blocks

Article abstract of DOI:10.1016/j.tetlet.2012.12.089

Based on the conjugate addition-silyl migration-alkylation strategy, (Z)-silyl enol ethers possessing a stereocenter at the γ-position were prepared with complete regio- and stereoselectivity by three-component coupling of α,β-unsaturated acylsilanes, Grignard reagents (or cuprates)/copper(I) tert-butoxide, and organic halides.

Full text of DOI:10.1016/j.tetlet.2012.12.089

Tetrahedron Letters 54 (2013) 1264–1267
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regio- and stereoselective preparation of (Z)-silyl enol ethers
by three-component coupling using
a,b-unsaturated acylsilanes
as core building blocks
⇑
⇑
Akira Tsubouchi , Natsuki Sasaki, Shouko Enatsu, Takeshi Takeda
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Based on the conjugate addition–silyl migration–alkylation strategy, (Z)-silyl enol ethers possessing a
Received 12 November 2012
Revised 17 December 2012
Accepted 21 December 2012
Available online 2 January 2013
stereocenter at the c-position were prepared with complete regio- and stereoselectivity by three-compo-
nent coupling of
a
,b-unsaturated acylsilanes, Grignard reagents (or cuprates)/copper(I) tert-butoxide, and
Ó 2012 Elsevier Ltd. All rights reserved.
organic halides.
Keywords:
Copper(I) tert-butoxide
Conjugate addition
Silyl enol ethers
Silyl migration
Three-component coupling
Silyl enol ethers are important intermediates in organic synthe-
sis, being employed for a number of stereocontrolled synthetic pro-
cesses.1 Reflecting these trends, a variety of methods have been
developed for the regio- and stereoselective preparation of silyl
enol ethers. Most of conventional methods rely on selective forma-
tion of kinetic and thermodynamic enolates by deprotonation of
carbonyl compounds. It is difficult, however, to control the regio-
chemistry in enolization of unsymmetrical internal ketones having
similar substituents in steric and electronic effects.
of the resulting 1-siloxy-1-alkenylcopper species with organic ha-
lides. To extend this synthetic strategy to regio- and stereoselective
preparation of fully substituted silyl enol ethers, we designed a
1,3-silyl migration based three-component coupling by the use of
a
-silyl-
ganic halides.7 We envisioned that, if the above multi-component
process could be extended to ,b-unsaturated acylsilanes 1, the
process would furnish the ,b-disubstituted silyl enol ethers 2. This
a,b-unsaturated ketones, organocopper reagents, and or-
a
a
process involves three steps: (1) the conjugate addition of organo-
metallic reagents to 1,8 (2) the 1,2-silyl migration in the copper(I)
enolates 3 giving the alkenylcoppers 4, and (3) the coupling of 4
with organic halides 5 (Scheme 1). Here we describe the synthesis
As an alternative to the above process, the Brook rearrange-
ment2-based strategy for the preparation of silyl enol ethers has
been developed.3 This strategy consists of the following proces-
sess:4 (1) generation of
a
-silylalkoxide intermediates having a
of (Z)-a,b-disubstituted silyl enol ethers 2 having a c-stereocenter
leaving group at the b-position, (2) the 1,2-Csp3-to-O silyl migra-
tion, and (3) b-elimination to form the C–C double bond of silyl
enol ethers. Despite these studies, only limited methods have been
developed for the preparation of silyl enol ethers of acyclic internal
ketones in a regio- and stereoselective manner.3e,f,s
by three-component coupling of
a,b-unsaturated acylsilanes 1, the
R2M
/ t-BuOCu
O
R2 OCu
In the course of our studies5a,b,d–f,j on synthetic application of si-
R1
Si(i-Pr)3
R1
Si(i-Pr)3
lyl migration from sp2 carbon to oxygen atom,5 we have recently
1
3
reported a stereoselective preparation of
a,b-disubstituted silyl
R2 OSi(i-Pr)3
R2 OSi(i-Pr)3
R3X 5
enol ethers by the reaction of acylsilanes with copper(I) tert-butox-
ide and organic halides.6 This transformation involves 1,2-silyl
migration in copper(I) enolates of the acylsilanes and alkylation
R1
Cu
R1
R3
2
4
R
1 = Me (1a), Ph (1b), H (1c); R2 = Me, n-Pr, i-Pr, Bn, TMSCH2;
R3 = methallyl ( ), allyl ( ), cinnamyl ( ), phenyl (
)
5d
⇑
Corresponding authors. Tel./fax: +81 42 388 7034.
E-mail addresses: tubouchi@cc.tuat.ac.jp (A. Tsubouchi), takeda-t@cc.tuat.ac.jp
5a
5b
5c
(T. Takeda).
Scheme 1. Reaction pathway.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.089

A. Tsubouchi et al. / Tetrahedron Letters 54 (2013) 1264–1267
1265
Table 1
Reaction under various conditions
OSi(i-Pr)3
O
1) BuM, t-BuOCu
Si(i-Pr)3
2)
Cl
2a
5a
1a
Entry
1
Conditions
Yield (%)
31a
1) BuCu/t-BuOCu, THF, À30 to 25 °C, 2 h, then DMF was added, 50 °C, 30 min
2) 50 °C, 4 h
2
3
1) BuMgCl, THF, À78 °C, 30 min, t-BuOCu, DMF, 25 °C
74
71
2) 50 °C, 1.5 h
1) Bu2CuMgCl, THF, À78 °C, 30 min, then 25 °C, 30 min, t-BuOCu, DMSO, 25 °C
2) 50 °C, 1.5 h
a
Triisopropyl(3-methylheptanoyl)silane was produced in 35% yield as a by-product.
Table 2
Formation of silyl enol ethers by three-component couplinga
R2 OSi(i-Pr)3
2
3
O
5
1) R M; 2) t-BuOCu; 3) R Cl
R1
Si(i-Pr)3
R1
R3
1
2
Entry
1
Acylsilane
R2M
R3X
Product
Yield (%)
OSi(i-Pr)3
OSi(i-Pr)3
1a
MeMgCl
5a
46
58
2b
Ph
2b
1a
BnMgCl
5a
2c
TMS
OSi(i-Pr)3
OSi(i-Pr)3
3
1a
1a
1a
1a
(TMSCH2)2CuMgCl
Pr2CuMgBr
5a
5a
5a
5b
73
70d
50
74
2d
2e
4c
OSi(i-Pr)3
5
i-Pr2CuMgBr
BuMgCl
2f
OSi(i-Pr)3
6
2g
OSi(i-Pr)3
7
1a
Bu2CuLie
5c
37
2h
Ph
OSi(i-Pr)3
f
8
9
1a
1b
BuMgCl
BuMgCl
—
73d
62
2i
OSi(i-Pr)3
5a
Ph
2j
(continued on next page)

1266
A. Tsubouchi et al. / Tetrahedron Letters 54 (2013) 1264–1267
Table 2 (continued)
Entry
Acylsilane
R2M
R3X
Product
Yield (%)
46g
OSi(i-Pr)3
10
1c
Bu2CuLie
5a
H
2k
a
The reactions were performed under the conditions described in Table 1, entry 2 for the Grignard reagents and entry 3 for magnesium cuprates unless otherwise noted.
Reaction of the alkenylcopper 4 with 5a was carried out at 70 °C.
Reaction of the alkenylcopper 4 with 5a was carried out for 2.5 h.
b
c
d
e
f
Contaminated with a trace amount of E-isomer.
Conditions: 1) À78 °C, 30 min then 25 °C, 30 min, 2) DMF, 50 °C, 1 h, 3) 25 °C, 1 h.
The alkenylcopper 4 was protonated without the treatment with organic halide 5.
Contaminated with 1-(triisopropylsiloxy)-1-heptene. The yield was determined by NMR analysis.
g
Grignard reagents (or cuprates), and allylic and aryl halides 5 in a
regioselective manner.
was carried out in a similar manner in the presence of 5 mol % of
Pd(PPh3)4 (see Supplementary data).
The treatment of 1a with the organocopper reagent,
(BuCu/t-BuOCu),7 prepared by mixing of copper(I) tert-butoxide
and butylcopper in THF, followed by the addition of DMF and then
methallyl chloride (5a) gave the silyl enol ether 2a in 31% yield
(Table 1, entry 1). To improve the yield of 2a, we investigated a
series of organometallic compounds in the conjugate addition pro-
cess. When 1a was treated with butylmagnesium chloride in THF
prior to the successive addition of copper(I) tert-butoxide and 5a
in DMF, an efficient increase in the yield was observed (entry 2).
The magnesium cuprate Bu2CuMgCl can also be employed for this
reaction by the use of DMSO as a polar aprotic co-solvent (entry 3).
Encouraged by these results, we explored the use of other Grig-
nard reagents and allylic chlorides 5 (Table 2). The (Z)-silyl enol
The configuration of the disubstituted silyl enol ethers 2a, c–g, j,
and k was confirmed by NOE or NOESY experiments (see Supple-
mentary data). The stereochemistry of other silyl enol ethers 2b,
2h, and 2l was deduced from the above results.
The stereochemistry of 2 can be explained by the exclusive for-
mation of thermodynamically more stable (E)-enolates E-3 rather
than (Z)-enolates Z-3, which are destabilized by the steric repul-
sion between the triisopropylsilyl group and the secondary alkyl
substituent (R1R2CH) at the b-position (Scheme 3).12 The (E)-eno-
lates undergo 1,2-silyl migration with retention of the geometry
of double bond, followed by the alkylation of resulting alkenylcop-
pers to afford the (Z)-silyl enol ethers 2 stereoselectively.
In conclusion, regio- and stereoselective preparation of silyl
enol ethers of unsymmetrical internal ketones has been achieved
by the three-component coupling.13 It has also been demonstrated
ethers 2 possessing various substituents at the c-position were ob-
tained with complete regio- and stereoselectivity. These unconju-
gate 1,4-pentadienic silyl enol ethers 2 are difficult to prepare
that a,b-unsaturated acylsilanes are efficient linchpins in introduc-
from the corresponding b,
c
-unsaturated ketones.9 Although the
ing a stereocenter into the silyl enol ethers as well as construction
of the unconjugated dienol ether structure. Studies on the scope of
this reaction and synthetic application of the silyl enol ethers are
currently underway.
yields of 2h and 2k were less than 10% in the reactions using the
Grignard reagent, the use of the Gilman reagent resulted in a
substantial increase in the yields of 2 in these reactions (entries
7 and 10).
When the alkenylcopper species 4, generated from 1a and BuM-
gCl, was trapped with H2O, (Z)-b-monosubstituted silyl enol ether
2i was stereoselectively obtained (entry 8). Its stereochemistry was
confirmed by the coupling constant (5.9 Hz)10 between two vinyl
protons. It has been reported that (E)-silyl enol ethers were favor-
ably produced by the silylation of enolates generated by conjugate
addition of organometallic reagents to unsaturated enals.11
Therefore, the present reaction is a useful complementary to the
conventional method with respect to the stereochemistry.
Furthermore iodobenzene can be employed as an alkylating re-
agent in the three-component coupling (Scheme 2). The reaction
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Re-
search (C) (No. 23550118) from the Ministry of Education, Culture,
Sports, Science, and Technology (Japan).
Supplementary data
Supplementary data (experimental procedures and full charac-
terization of all compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2012.12.089.
References and notes
1) BuMgCl, THF
OSi(i-Pr)3
2) t-BuOCu / Pd(PPh3)4 (5 mol%),
O
DMF
1. Kobayashi, S.; Manabe, K.; Ishitani, H.; Matsuo, J.-I. Product Subclass 16: Silyl
Enol Ethers In Science of Synthesis: Houben-Weyl Methods of Molecular
Transformations; Fleming, I., Ed.; Thieme: Shuttgart, 2002; Vol. 4, pp 317–
369; (b) Schetter, B.; Mahrwald, R. Aldol Reactions. In Quaternary Stereocenters:
Challenges and Solutions for Organic Synthesis; Christoffers, J., Baro, A., Eds.;
Wiley-VCH: Weinheim, 2005; pp 51–82. Chapter 3.
Si(i-Pr)3
2l
60%
3)
I
1a
5d
Scheme 2. Palladium(0)-catalyzed cross-coupling.
2. For selected reviews for synthetic application of the Brook rearrangement, see:
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R2 OCu
Si(i-Pr)3
R2 Si(i-Pr)3
R1
OCu
R1
E-3
Z-3
Scheme 3. Stereochemistry of the copper enolates.

A. Tsubouchi et al. / Tetrahedron Letters 54 (2013) 1264–1267
1267
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13. Typical procedure:
A solution of the unsaturated acylsilane 1a (45 mg,
a
a
-silylallylic alkoxides, and reaction of electrophiles at
-siloxyallylic anions, see Refs. 3e and f.
c
-position of
0.20 mmol) in THF (0.85 mL) was added to butylmagnesium chloride (2.0 M
in THF, 0.12 mL, 0.24 mmol) at À78 °C under Ar. After stirring for 30 min, the
temperature was raised to 25 °C and then the mixture was stirred for
additional 30 min. To this mixture were successively added a solution of t-
BuOCu (0.48 mmol) in DMF, prepared by the reaction of CuI (91 mg,
0.48 mmol) and t-BuOLi (0.98 M in THF, 0.49 mL, 0.48 mmol) in DMF
(1.8 mL), and then a solution of methallyl chloride (5a) (54 mg, 0.60 mmol)
in DMF (1.0 mL) at 25 °C. The mixture was heated at 50 °C for 1.5 h and then
the reaction was quenched by addition of 3.5% aqueous NH3. The product was
extracted with diethyl ether and the extract was washed with H2O, and dried
over K2CO3. The solvent was evaporated under reduced pressure and the
residue was purified by PTLC (hexane) to give the silyl enol ether 2a (50 mg,
74%) as a single isomer.
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