Pd(OH)2/C-mediated selective oxidation of silyl enol ethers by tert-butylhydroperoxide, a useful method for the conversion of ketones to α,β-enones or β-Silyloxy-α,β-enones

Article abstract of DOI:10.1021/ol050284y

(Chemical Equation Presented) Pd(OH)₂-catalyzed oxidation of silyl enol ethers by t-BuOOH gives either β-silyloxy-α,β-enones or α,β-enones in good yields depending on the base used.

Full text of DOI:10.1021/ol050284y

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1415-1417
Pd(OH)2/C-Mediated Selective Oxidation
of Silyl Enol Ethers by
tert-Butylhydroperoxide, a Useful
Method for the Conversion of Ketones
to
r,â-Enones or â-Silyloxy-r,â-enones
Jin-Quan Yu,†,‡ Hai-Chen Wu,‡ and E. J. Corey*,§
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138, Department of Chemistry,
Brandeis UniVersity, Waltham, Massachusetts 02454-9110, and Department of
Chemistry, Cambridge UniVersity, Cambridge CB2 1EW, UK
corey@chemistry.harVard.edu
Received February 10, 2005
ABSTRACT
Pd(OH)2-catalyzed oxidation of silyl enol ethers by t-BuOOH gives either
the base used.
â
-silyloxy-
r
,
â
-enones or
r,
â
-enones in good yields depending on
Exploration of the oxidation of silyl enol ethers under a
variety of conditions has led to a number of synthetically
valuable transformations.1 The formal 1,4-dehydrosilation
reaction using either Pd(OAc)2/benzoquinone2 or iodoxy-
benzoic acid (IBX) leading to the formation of R,â-enones3
has proven to be especially useful in synthesis. Recently,
we described a novel allylic oxidation of olefins using
t-BuOOH in the presence of Pd(OAc)2, Pd/C, or Pd(OH)2,
which provides a catalytic method for the synthesis of either
R,â-enones or 1,4-enediones.4,5 We report herein the ap-
plication of this catalytic system with an added base to the
oxidation of triisopropylsilyl enol ethers of ketones to form
selectively either â-keto enol silyl ethers or R,â-enones
depending on the base used.
The triisopropylsilyl (TIPS) group was selected as the
protecting group for the enol ether substrates due to its
stability under the required reaction conditions. Cyclo-
hexanone triisopropylsilyl ether (1) was initially subjected
to our oxidation conditions using 5 equiv of t-BuOOH, 5%
mol 20% Pd(OH)2 on carbon (Pearlman’s catalyst; Aldrich
Co.), and 1 equiv of K2CO3 in methylene chloride at 4 °C.
† Brandeis University.
‡ Cambridge University.
§ Harvard University.
1
The reaction mixture was analyzed by H NMR after 48 h,
(1) See: (a) Stankovic, S.; Espenson, J. H. J. Org. Chem. 1998, 63, 4129.
(b) Adam, W.; Fell, R. T.; Saha-Moller, C. R.; Zhao, C. G. Tetrahedron:
Asymmetry 1998, 9, 397. (c) Adam, W.; Fell, R. T.; Stegmann, V. R.; Saha-
Moller, C. R. J. Am. Chem. Soc. 1998, 120, 708. (d) Ryter, K.; Livinghouse,
T. J. Am. Chem. Soc. 1998, 120, 2658. (e) Yamamoto, H.; Tsuda, M.;
Sakaguchi, S.; Ishii, Y. J. Org. Chem. 1997, 62, 7174.
(2) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(3) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T.
Angew. Chem., Int. Ed. 2002, 41, 996.
which showed a 2:1 ratio of the â-keto enol silyl ether from
(4) (a) Yu, J. Q.; Corey, E. J. Org. Lett. 2002, 4, 2727. (b) Yu, J. Q.;
Corey, E. J. J. Am. Chem. Soc. 2003, 125, 3232.
(5) Also, for a recent example of Rh(I)-catalyzed allylic oxidation by
t-BuOOH, see: Catino, A. J.; Forslund, R. E.; Doyle, M. P. J. Am. Chem.
Soc. 2004, 126, 13622.
10.1021/ol050284y CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/11/2005

allylic oxidation and cyclohexanone (from simple hydroly-
sis). Presumably, the in situ-generated water caused the
hydrolysis of the silyl enol ether. It was found that the
combined use of a different base, Cs2CO3, and 1 atm of
molecular oxygen increased the rate of oxidation and
minimized hydrolysis to ketone. Under these optimized
conditions, a variety of the silyl enol ether substrates were
oxidized in good yields to give the corresponding â-keto enol
silyl ethers as shown in Table 1.
nonsymmetric substrates. Zubaidha recently communicated
another procedure for the direct etherification of cyclic
â-ketones with alcohols mediated by iodine.7 We believe that
this two-step-sequence converting simple ketones into â-keto
enol silyl ethers provides a valuable transformation for
organic synthesis since it starts from readily available ketones
and since it is regioselective. This method also allows ready
access to chiral â-keto enol silyl ethers by use of chiral
ketone precursors (see Table 1, entries 4 and 5).8,9
On the basis of the mechanistic investigations previously
reported,4 the likely reaction pathway is that outlined in
Scheme 1.
Table 1. Synthesis of â-Keto Enol Silyl Ethers
Scheme 1
In principle, the allylic peroxide intermediate could also
undergo elimination of the tert-butylperoxy and TIPS groups
to form an R,â-enone (Scheme 1). In fact, we find that the
oxidation of the â-keto enol silyl ether 1 in the presence of
a milder base (Na2HPO4) gives the corresponding R,â-enone
as the main product. The oxidation of a series of â-keto enol
silyl ethers in the presence of molecular oxygen at 24 °C
gave R,â-enones in good yields as shown in Table 2. It is
noteworthy that in the case of entry 6 of Table 2, the
(7) Bhosale, R. S.; Bhosale, S. V.; Bhosale, S. V.; Wang, T.; Zubaidha,
P. K. Tetrahedron Lett. 2004, 45, 7187.
(8) General Procedure for the Preparation of Silyl Enol Ethers.
Triisopropylsilyl triflate (1.84 g, 6.0 mmol) was added to a solution of the
ketone (5.0 mmol) and triethylamine (0.91 g, 9.0 mmol) in dichloromethane
(15 mL). The progress of the reaction was monitored by TLC, and when
the reaction was complete, the mixture was diluted with dichoromethane
and washed with cold sodium bicarbonate. After the organic layer was dried
over anhydrous sodium sulfate and concentrated on a rotovap, the residue
was taken up in dry ether and separated from the insoluble triethylammo-
nium triflate. The ether solution was then concentrated and chromatographed
on basic alumina (pH 9.0-9.5) using pure hexane as an eluent to give the
pure product.
(9) General Procedure for the Synthesis of â-Silyloxy-r,â-enones. A
25 mL round-bottom flask equipped with a stir bar was charged under air
with Pd(OH)2/C (20% Pd) (8.5 mg, 0.016 mmol), Cs2CO3 (104 mg, 0.32
mmol), CH2Cl2 (1 mL), and silyl enol ether (0.32 mmol). The mixture was
cooled to 4 °C with an ice bath, and tert-butylhydroperoxide (TBHP) (160
µL, 1.6 mmol) was added with vigorous stirring. The flask was purged
with pure oxygen gas and kept under an oxygen atmosphere with a balloon.
The mixture was stirred at 4 °C for the time indicated in Table 1 (reaction
complete as indicated by TLC analysis). The reaction mixture was then
filtered through a short pad of silica gel and washed with CH2Cl2. After
removal of the solvent by rota-evaporation at 24 °C, the crude product was
purified by flash column chromatography (ether-hexane, 1:1) to provide
the analytically pure sample as a clear oil.
â-Keto enol ethers have been widely used as key inter-
mediates in organic synthesis.6 The most common method
for the synthesis of â-keto enol ethers, O-alkylation of cyclic
â-diketone enolates, suffers from competition of O- vs
C-alkylation and from regiochemical issues in the case of
(6) See: (a) Zhang, Y.; Raines, A. J.; Flowers, R. A., II. Org. Lett. 2003,
5, 2363. (b) House, H. O.; Rasmusson, G. H. J. Org. Chem. 1963, 28, 27.
(c) Takahashi, K.; Tanaka, T.; Suzuki, T.; Hirama, M. Tetrahedron 1994,
50, 1327.
1416
Org. Lett., Vol. 7, No. 7, 2005

molecular oxygen or t-BuOO• is fast relative to cleavage of
the three-membered ring. Pd(OAc)2-catalyzed oxidation of
silyl enol ethers by benzoquinone has been previously
reported by Saegusa and proposed to involve an oxo-π-
allylpalladium complex as a key intermediate.2 In contrast,
the oxidation reaction described herein is clearly a radical
process as shown in Scheme 1.4 The present methodology
can also be applied to aromatization of dihydroaromatic
substrates as shown by the oxidation of 2 to the TIPS ether
of R-naphthol (Scheme 2).10
Table 2. Synthesis ïf R,â-Enones
Scheme 2
In summary, the Pd-mediated oxidation of silyl enol ethers
by t-BuOOH provides a simple and convenient method for
the preparation of â-keto enol silyl ethers and R,â-enones
from a range of ketonic starting materials.
Acknowledgment. We acknowledge the Royal Society
for a Research Fellowship, the Camille and Henry Dreyfus
Foundation for a New Faculty Award and Brandeis Univer-
sity for financial support (to J.Q.Y.).
Supporting Information Available: Experimental and
characterization data for starting materials and products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL050284Y
(10) General Procedure for the Synthesis of r,b-Enones. A 50 mL
round-bottom flask equipped with a stir bar was charged under air with
Pd(OH)2/C (20% Pd) (17 mg, 0.032 mmol), Na2HPO4 (9.0 mg, 0.064 mmol),
CH2Cl2 (2 mL), and silyl enol ether (0.64 mmol). The flask was purged
with pure oxygen gas and kept under an oxygen atmosphere with a balloon.
To this mixture was added tert-butylhydroperoxide (TBHP) (40 µL, 0.40
mmol) in four portions every 2 h with vigorous stirring. The mixture was
stirred at 24 °C for the time indicated in Table 2 (reaction complete by
TLC analysis). The reaction mixture was then filtered through a short pad
of silica gel and washed with CH2Cl2. After removal of the solvent by rota-
evaporation at 24 °C, the crude product was purified by flash column
chromatography (ether-hexane, 1: 1) to provide the analytically pure
sample as a clear oil.
a Triethylamine as base.
cyclopropane unit survived this radical oxidation process,
an indication that the reaction of the allylic radical with the
Org. Lett., Vol. 7, No. 7, 2005
1417