Silicon-induced ene-type reaction in the thermal conversion of enolates to ss-silyl enones with molecular dioxygen

Article abstract of DOI:10.1021/ol800007v

Reaction of alkyl, acetoxy, and silyl enol ethers of 3-(organosilyl) cyclohexanone with molecular dioxygen in toluene at 110 °C produced the corresponding conjugated enones in yields up to 88% yield. The reaction of the same type failed on replacement of

Full text of DOI:10.1021/ol800007v

ORGANIC
LETTERS
2008
Vol. 10, No. 10
1913-1916
Silicon-Induced Ene-Type Reaction in
the Thermal Conversion of Enolates to
ꢀ-Silyl Enones with Molecular Dioxygen
Jih Ru Hwu,*,†,‡ Chien Hsien Chen,† Chuan-I Hsu,† Asish R. Das,†
Yen Cheng Li,§ and Lung Ching Lin§
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu, Taiwan 30013,
Republic of China, Department of Chemistry, National Central UniVersity, Jhongli,
Taoyuan, Taiwan 32001, Republic of China, and Department of Chemistry, National
Taiwan UniVersity, Taipei, Taiwan 10671, Republic of China
jrhwu@mx.nthu.edu.tw
Received January 30, 2008
ABSTRACT
Reaction of alkyl, acetoxy, and silyl enol ethers of 3-(organosilyl)cyclohexanone with molecular dioxygen in toluene at 110 °C produced the
corresponding conjugated enones in yields up to 88% yield. The reaction of the same type failed on replacement of the silyl group at the C-3
position with an isopropyl group. These results indicate the existence of an unprecedented silicon-induced ene-type reaction. Its reaction
mechanism, generality, limitations, and exceptions are discussed.
Electronic effects due to silicon can direct organic reactions
of various types:1 because a silyl group is present at an
appropriate position of the reactants, some reactions that do
not otherwise proceed become feasible; some reactions that
otherwise generate a mixture of products then yield an
exclusive product, and some reactions that otherwise afford
a desired product in a low yield then generate it efficiently.
Examples involving photochemical2–5 and electrochemical6–9
processes include photodecarbonylation of trimethylsilyl ꢀ,γ-
enals and formyl octalins,10,11 Norrish type-I cleavage of
ꢀ-trimethylsilyl cycloalkanones,12–14 electrochemical aldol
condensation,15 and electrochemical oxidation of enol ac-
etates to enones.16
(2) Brook, A. G. In The Chemistry of Organic Silicon Compounds;
Rappoport, Z., Apeloig, Y., Eds.; Wiley: New York, 1998; Vol. 2, Part 2,
Chapter 21.
(3) Steinmetz, M. G. Chem. ReV. 1995, 95, 1527–1588.
(4) Kako, M.; Nakadaira, Y. Coord. Chem. ReV. 1998, 176, 87–112.
(5) Tamai, T.; Hayamizu, T.; Mizuno, K. In Handbook of Photochemistry
and Photobiology; Nalwa, H. S., Eds.; American Scientific Publishers:
Stevenson Ranch, CA, 2003; Vol. 1, pp 125-156.
* To whom correspondence should be addressed. Fax: 886-35-721-594.
† National Tsing Hua University.
‡ National Central University.
(6) Fuchigami, T. In The Chemistry of Organic Silicon Compounds;
Rappoport, Z., Apeloig, Y., Eds.; Wiley: New York, 1998; Vol. 2, Part 2,
Chapter 20.
§ National Taiwan University.
(1) For recent reviews, see: (a) Chabaud, L.; James, P.; Landais, Y. Eur.
J. Org. Chem. 2004, 3173–3199. (b) Lambert, J. B.; Zhao, Y.; Emblidge,
R. W.; Salvador, L. A.; Liu, X.; So, J.-H.; Chelius, E. C. Acc. Chem. Res.
1999, 32, 183–190. (c) Bassindale, A. R.; Glynn, S. J.; Taylor, P. G. In
The Chemistry of Organic Silicon Compounds; Rappoport, Z., Apeloig, Y.,
Eds.; Wiley: New York, 1998; Vol. 2, Part 1, Chapter 7. (d) Fleming, I.;
Barbero, A.; Walter, D. Chem. ReV. 1997, 97, 2063–2192.
(7) Zhuikov, V. V. Russ. J. Electrochem. 2000, 36, 117–127.
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2001, 123, 5104–5105.
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(10) Hwu, J. R.; Furth, P. S. J. Am. Chem. Soc. 1989, 111, 8834–8841.
(11) Furth, P. S.; Hwu, J. R. J. Am. Chem. Soc. 1989, 111, 8842–8849.
10.1021/ol800007v CCC: $40.75
Published on Web 04/24/2008
2008 American Chemical Society

Continuing our research on silicon-induced, -directed, and
-promoted reactions, we sought to develop a synthetically
valuable reaction that is induced by silicon under thermal
conditions. Herein, we report our success in utilizing the
electronic effect of silicon to induce an ene-type reaction.
Our design in placing a silyl group at the C-3 position of
enol ethers or acetates proved to be an essential factor that
allowed these compounds to react with molecular dioxygen
in toluene upon heating to give the corresponding R,ꢀ-
unsaturated ketones in attractive yields up to 88% (see Table
1).
Scheme 1
.
Synthetic Applicability of R,ꢀ-Unsaturated ꢀ-Silyl
Ketones
Table 1. Oxidation of Silyl Enol Ethers of 3-(Organosilyl)Cy-
clohexanone to the Corresponding Conjugated Enones
substrate
R1
SiMe3
SiMe2(t-Bu) SiMe3
SiPh3
Ac
R2
time (h) yield(%) product
synthesized substrates 1-9 by a Michael addition of R3SiLi
(R ) Me or Ph) to 2-cyclohexen-1-one. The resultant
enolates were then treated with an appropriate organic
chloride in situ. Second, we dissolved 3-silylenol trimeth-
ylsilyl ether 1 in toluene (0.11 M) and heated the solution at
reflux (i.e., 110 °C) in the presence of O2 from air for 4.0 h.
Pure 3-silyl enone 12 was isolated in 61% yield from the
reaction mixture through chromatography. Replacing toluene
with other solvents having lower boiling points, including
benzene, p-dioxane, diethyl ether, and THF, furnished
product 12 in lower yields.
1
2
3
4
5
6
7
8
9
SiMe3
4.0
4.0
10
4.0
4.0
48
10
10
10
4.0
4.0
61
88
40
82
71
0
31
15
0
12
12
12
12
12
12
13
14
15
–
SiMe3
SiMe3
SiMe3
SiMe3
SiMe2Ph
SiMePh2
SiPh3
Me
PO(OPh)2
SiMe3
SiMe3
SiMe3
Ac
10
11
isopropyl
H
0
Ac
0
–
By replacing the SiMe3 group attached to the enol moiety
with a bulkier SiMe2(t-Bu) group (see Table 1), we improved
the efficiency of the transformation. Under the same condi-
tions, substrate 2 was converted to 12 in 88% yield. Reactions
of the same type also proceeded on replacement of the silyl
group with an acetoxy or methyl group in the enolates. For
example, we obtained 82% and 71% yields for 12 from enol
acetate 4 and methyl enol ether 5, respectively. This
transformation failed, however, on replacement of the
acetoxy group in 4 with a phosphoryl group (cf. 6).
Furthermore, replacement of the SiMe3 group at position
C-3 with a bulkier silyl group,24,25 including SiMe2Ph,
SiMePh2, and SiPh3, gave the corresponding 3-silyl-2-
cyclohexen-1-ones 13-15 in 31%, 15%, and 0% yields,
respectively. These results indicate that a smaller C-3 silyl
group in the substrate provided a greater yield; the SiMe3
group was the most effective one among various silyl groups
tested.
Oxygenation of olefins through an ene reaction typically
occurs through a photochemical pathway and requires a dye
as sensitizer.17 These reactions and their mechanisms have
been extensively investigated and applied in organic syn-
thesis.18 We undertook to broaden its applicability by
modifying the basic ene reaction for the preparation of R,ꢀ-
unsaturated ꢀ-silyl ketones. Some intriguing examples in the
literature that utilize these organosilicon compounds in
synthesis are illustrated in Scheme 1.19–23
To realize the possibility of an ene-type reaction between
a silicon-containing enolate with molecular dioxygen, we first
(12) Hwu, J. R.; Gilbert, B. A.; Lin, L. C.; Liaw, B. R. J. Chem. Soc.,
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Commun. 1996, 509–510.
As first control experiments, we applied the same oxy-
genation conditions to 3-(isopropyl)-1-cyclohexenyl acetate
(10) and the parent cyclohexenyl acetate (11). Although the
isopropyl group in 10 and the trimethylsilyl group in 4 might
(16) Lin, L. C.; Chueh, L. L.; Tsay, S.-C.; Hwu, J. R. Tetrahedron Lett.
1995, 36, 4093–4096.
(17) For a review and a book, see: (a) Stratakis, M.; Orfanopoulos, M.
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13944.
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1998; Vol. 2, Part 1, Chapter 8.
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1914
Org. Lett., Vol. 10, No. 10, 2008

exert a similar steric effect,25 the smooth oxidation of 10
with molecular dioxygen occurred to a negligible extent, as
for the unsuccessful oxygenation of 11. The thermal oxida-
tion shown in Table 1 was therefore induced by a silicon
atom through its electronic effect. As second control experi-
ments, we irradiated toluene solutions of 1 and 4, separately,
with UV light (λ >300 nm) near 23 °C instead of 110 °C;
enone 12 was not detectably generated. We conclude
accordingly that 3-silyl-1-cyclohexenyl ethers or acetates (i.e.,
1 or 4) react with molecular dioxygen to produce the
corresponding enones through a thermal, rather than a
photochemical, process.
Scheme 2
.
Proposed Mechanism for the Conversion of Enol
Acetate 4 to 3-Silyl Enone 12
We considered whether the newly developed reaction
produces radical intermediates. Repeating the conversion 2
f 12 under conditions similar to those described above, we
added 4-methyl-2,6-di(tert-butyl)phen-1-ol (1.0 equiv) to the
reaction mixture. This phenol functions as an efficient
scavenger of peroxyl radical.26 After 4.0 h, we recovered
the starting material 2 in 17% yield and detected no enone
12 by GC-mass spectrometry. These results indicate that
peroxyl radical intermediates were likely generated in the
reactions shown in Table 1.
The enol acetate moiety is known to be stable27 and cannot
be oxidized to the corresponding enone with air at 110 °C
(see 10 and 11 in Table 1). Oxidation of enol ethers to the
corresponding enones can be accomplished; however, it
requires a catalyst Pd0/SiO2.28 On the other hand, a silyl
group at the allylic position acts as an activating group for
alkene toward oxidation.29 The effect of silyl groups can be
attributed to the orbital interaction between the π-orbital of
the carbon to carbon double bond and the C-Si σ bond.30
The allylsilane moiety can be oxidized with easy because
of the electron-donating ability of ꢀ-silyl group.31 Combining
this information and our experimental results, we propose a
plausible mechanism shown in Scheme 2, in which the
conversion 4 f 12 serves as a representative example.
“σ-π hyperconjugation.”1c This stabilization was absent
from the corresponding radical intermediate generated on
oxygenation of nonsilylated enol acetates 10 and 11.
After the energy barrier of the step 4 f 16a was overcome,
the resultant intermediate 16a could alter its conformation
to 16b. Although the former is thermodynamically more
stable than the latter, equilibrium exists between these two
conformational isomers. The isomer 16b allows an intramo-
lecular transfer of hydrogen to take place from a carbon atom
to an oxygen atom. Monodeoxygenation32 subsequently
occurs in the resultant peroxide 17 to afford hydroxy acetate
18; extrusion of acetic acid in situ then furnishes final product
12. The entire process has the same outcome as an ene-type
reaction. For a typical ene reaction involving molecular
dioxygen as an enophile,33 the reactive species is molecular
dioxygen in its first excited singlet state, O2 (1∆g), which
requires UV light and a dye as a sensitizer. In contrast, we
found that the reactions shown in Table 1 proceeded in the
dark; they thus conform to an “ene type” reaction.
Through computation with the CVFF force field, we
obtained the thermodynamically most stable conformation
of 4 by energy minimization. Addition of molecular dioxygen
to enol acetate 4 might occur at an elevated temperature from
the anti face of the activating SiMe3 group to give peroxyl
radical 16a. Because of the possible coplanarity exerted by
the radical orbital, the C-C bond, and the C-Si bond in
•
the moiety C-C-Si of 16a, the carboradical center can
Molecular dioxygen might abstract the hydrogen R to the
SiMe3 group in 4 to generate an allylic carboradical center
that becomes stabilized by the silyl group through an R
effect.34 Pioneering works reported by Nickon,35 Schenck,36
Foote,37 and co-workers indicate that the double bond in the
hydroperoxide product is invariably shifted to a position
adjacent to the original double bond in an ene reaction. A
become stabilized by a ꢀ silyl group, predominantly through
(26) Burton, G. W.; Doba, T.; Gabe, E. J.; Hughes, L.; Lee, F. L.; Prasad,
L.; Ingold, K. U. J. Am. Chem. Soc. 1985, 107, 7053–7065.
(27) Minami, I.; Takahashi, K.; Shimizu, I.; Kimura, T.; Tsuji, J.
Tetrahedron 1986, 42, 2971–2977.
(28) Baba, T.; Nakano, K.; Nishiyama, S.; Tsuruya, S.; Masai, M.
J. Chem. Soc., Chem. Commun. 1989, 1697–1699.
(29) Yoshida, J.; Nishiwaki, K. J. Chem. Soc., Dalton Trans. 1998, 2589–
2596.
(32) Shul’pin, G. B.; Su¨ss-Fink, G.; Lindsay-Smith, J. R. Tetrahedron
1999, 55, 5345–5358.
(30) For related reports, see: (a) Giordan, J. C. J. Am. Chem. Soc. 1983,
105, 6544–6546. (b) Bock, H.; Kaim, W. J. Am. Chem. Soc. 1980, 102,
4429–4438. (c) Brown, R. S.; Eaton, D. F.; Hosomi, A.; Traylor, T. G.;
Wright, J. M. J. Organomet. Chem. 1974, 66, 249–254. (d) Traylor, T. G.;
Hanstein, W.; Berwin, H. J.; Clinton, N. A.; Brown, R. S. J. Am. Chem.
Soc. 1971, 93, 5715–5725. (e) Hanstein, W.; Berwin, H. J.; Traylor, T. G.
J. Am. Chem. Soc. 1970, 92, 829–836.
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577.
(34) Doncaster, A. M.; Walsh, R. J. Chem. Soc., Faraday Trans. 1 1976,
72, 2908–2916.
(35) Nickon, A.; Bagli, J. F. J. Am. Chem. Soc. 1961, 83, 1498–1508.
(36) Gollnick, K.; Schenck, G. O. Pure Appl. Chem. 1964, 9, 507–525.
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Org. Lett., Vol. 10, No. 10, 2008
1915

mechanism involving an initial hydrogen abstraction followed
by radical recombination thereby explains how the smaller
silyl groups gave greater yields (cf. entries 1 and 7-9 of
Table 1).
C-10 quaternary center. Hydrogen transfer via a transition
structure with a five-membered ring in 28 would then be
followed by formation of a double bond to give R-silyl cross
dienone 26.
After understanding the intrinsic properties of this silicon-
induced ene-type reaction, we validated its applicability using
substrates with varied structural complexity; these included
a bridged bicyclic 19, 1,2-substituted enol acetate 21,
hindered organosilane 23, and polycyclic 25. All four such
enolate substrates with an SiMe3 group at the position C-3
listed in Scheme 3 were successfully oxidized to the
corresponding enones 20, 22, 24, and 26 in satisfactory yields
The two singlets at δ 6.02 and 7.13 ppm associated with
vinylic protons of cross dienone 26 in its 1H NMR spectrum
disclosed a clue about its structure. The peak at δ 7.13 ppm
is expected to indicate a ꢀ, not an R, proton of the
Hꢀ-CdC-CdO group. To realize the neighboring environ-
ment around the SiMe3 group, the ꢀ vinylic proton and the
C-19 angular methyl group, we irradiated them individually
and observed the possible NOE. Mutual enhancements
existed between the pair of SiMe3 protons (7.6%) and the
vinylic proton (7.7%) as well as the pair of vinylic proton
(5.1%) and angular methyl protons (3.9%). In contrast, no
enhancement was detected between the pair of SiMe3 protons
and angular methyl protons. These data clearly support our
assignment that the vinylic proton at δ 7.13 ppm is adjacent
to the C-19 angular methyl group and the SiMe3 group, but
these two groups are far apart. The SiMe3 group in dienone
26 must hence reside at the C-2, not the C-1, position.
Scheme 3
.
Oxidation of Various 3-Silyl Enol Acetates to the
Corresponding Conjugated Enones
In conclusion, according to a silicon-induced reaction of
ene type, the oxidation of 3-silyl-1-cyclohexenyl ethers or
acetates with molecular dioxygen at 110 °C produced the
corresponding ꢀ-silyl enones. Synthetically appealing yields
are obtained upon an appropriately chosen C-3 silyl group
and a cross substituent attached to the enol functionality.
Mechanistic experiments indicate that the electronic stabiliz-
ing effect of silicon (R or ꢀ effect) on a carboradical
intermediate likely plays a vital role in the induction of this
new ene-type reaction.
Acknowledgment. The National Science Council of
Republic of China supported this work. J.R.H. thanks the
Royal Society of Chemistry for providing a Journals Grant
for International Authors and Professor John Ogilvie for his
efforts to improve the quality of this manuscript.
Supporting Information Available: Synthetic procedures
and spectral data for compounds 2-14 and 19-26. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(51-63%) under the same conditions as the conversion 4
f 12. The Z configuration of 20 was assigned on the basis
of the nuclear Overhauser enhancement (NOE) between the
dCH (3.6%) and the bridgehead dCCH (4.0%).
In the conversion 25 f 26, the SiMe3 group resided
notably at the R, instead of the ꢀ, position in product 26.
This 1,2-silyl migration38–40 in intermediate 27 might reflect
severe steric hindrance around the C-1 SiMe3 group and the
OL800007V
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