Palladium-catalyzed saegusa-ito oxidation: Synthesis of α,β-Unsaturated carbonyl compounds from trimethylsilyl enol ethers

Article abstract of DOI:10.1021/jo302465v

Palladium-catalyzed Saegusa-Ito oxidation of trimethylsilyl enol ethers is possible using Oxone as a stoichiometric oxidant and sodium hydrogen phosphate as a buffer. Cyclic and acyclic enones as well as α,β-unsaturated aldehydes are obtained in good to excellent yields.

Full text of DOI:10.1021/jo302465v

Note
pubs.acs.org/joc
Palladium-Catalyzed Saegusa−Ito Oxidation: Synthesis of α,β-
Unsaturated Carbonyl Compounds from Trimethylsilyl Enol Ethers
Yingdong Lu, Pierre Long Nguyen, Nicolas Levaray, and Helene Lebel*
́
́
̀
́ ́
Department of Chemistry and Centre in Green Chemistry and Catalysis (CGCC), Universite de Montreal, Pavillon Roger Gaudry,
́
́ ́
2900 Boul. Edouard-Montpetit, Montreal, Quebec, Canada, H3T 1J4
S
* Supporting Information
ABSTRACT: Palladium-catalyzed Saegusa−Ito oxidation of trimethylsilyl enol ethers is possible
using Oxone as a stoichiometric oxidant and sodium hydrogen phosphate as a buffer. Cyclic and
acyclic enones as well as α,β-unsaturated aldehydes are obtained in good to excellent yields.
here is significant interest in the synthesis of α,β-
unsaturated carbonyl derivatives because of their
perform the oxidation of silyl enol ethers to produce enones,
namely the complex 2-iodoxybenzoic acid•4-methoxypyridine-
N-oxide (IBX•MPO)33 and aza-adamantane-derived oxoam-
monium salts (TBS-enol ethers must be used in the latter
case).34 Many of these alternative catalytic procedures are
performed in DMSO, which is not always a suitable solvent for
hydrophobic organic molecules.34 Furthermore, it was recently
reported that oxygen gas solubility in DMSO is very low
compared to other typical solvents.35 It appears that a general
method using a cheap, readily available stoichiometric oxidant
in another solvent other than DMSO remains unreported.
Herein, we wish to report the use of readily available Oxone as
a stoichiometric oxidant for converting trimethylsilyl enol
ethers into α,β-unsaturated ketones and aldehydes in the
presence of a catalytic amount of palladium(II) acetate in
acetonitrile.
We first studied the oxidation of cyclohexanone trimethylsilyl
enol ether (1a) to cyclohexenone (2a) using 20 mol % of
palladium(II) acetate and a stoichiometric amount of Oxone,
under various reaction conditions (Table 1). We first noticed
that the yield improved when the reaction was run under an
oxygen atmosphere, compared to ambient air (entries 1−2). In
the absence of any base however, only low yields of the desired
product were observed even in the presence of 3 equiv of
Oxone (entries 1−2). We noticed that the major side product
of the reaction was cyclohexanone, which resulted from the
hydrolysis of the starting trimethylsilyl enol ether. Similar
hydrolysis products have been previously observed even with
more stable triisopropylsilyl enol ethers in a different catalytic
system and were prevented by using inorganic bases.29 Thus,
T
importance as building blocks in organic synthesis1−6 and as
key components of biologically active compounds.7 As a result,
numerous protocols have been developed for the preparation of
α,β-unsaturated carbonyl derivatives.8−10 Among them, the α,β-
dehydrogenation of saturated carbonyl compounds is a
powerful tool for the synthesis of such unsaturated com-
pounds.11−15 Various procedures using catalytic amounts of
palladium salts and cheap green oxidants have recently
appeared in the literature.16−18 Although significant progress
has been achieved, the direct oxidative formation of enones still
suffers from a lack of regiochemical control when performed
with unsymmetrical ketones. Conversely regiospecific enone
synthesis is possible when using an enol intermediate, such as
in the Saegusa−Ito oxidation.19 The palladium-mediated
oxidation of silyl enol ethers to form the corresponding α,β-
unsaturated carbonyl products is a widely used reaction in total
synthesis.20−27 The major drawback of the standard Saegusa−
Ito oxidation procedure is that often a superstoichiometric
amount of palladium(II) acetate is necessary to obtain a
satisfactory yield. Alternative procedures employing catalytic
amounts of a palladium(II) complex have appeared in the
literature. In their original communication, Saegusa and Ito
disclosed the use of 50 mol % of palladium(II) acetate in the
presence of benzoquinone.19 A few years later, Larock and co-
workers reported the use of 10 mol % of palladium(II) acetate
in DMSO under an oxygen atmosphere.28 Alternatively, the
conversion of TIPS-enol ethers with 5 mol % of palladium(II)
hydroxide in the presence of 5 equiv of tert-butylhydroperoxide
was achieved by Corey and co-workers.29 The oxidation of allyl
enol carbonates was also reported to proceed using catalytic
amounts of Pd(OAc)2 and diphenylphosphinoethane.30−32
Alternative organic oxidants have also been disclosed to
Received: November 12, 2012
Published: December 20, 2012
© 2012 American Chemical Society
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Note
Table 1. Palladium-Catalyzed Saegusa−Ito Oxidation using
Oxone as Stoichiometric Oxidant
Table 2. Synthesis of α,β-Unsaturated Carbonyl Compounds
from Trimethylsilyl Enol Ethers Using Oxone as the
Stoichiometric Oxidant
Oxone
(equiv)
Yield
b
a
Entry
Base (equiv)
Conditions
(%)
1
3
3
3
3
3
1
1
1
1
1
1
1
1
1
1
1
1
−
−
ACN (0.1 M), air
ACN (0.1 M), O2
ACN (0.1 M), air
ACN (0.1 M), O2
33
49
56
81
74
92
66
2
3
K2HPO4 (1)
4
K2HPO4 (1)
5
Na2HPO4 (1) ACN (0.1 M), O2
Na2HPO4 (1) ACN (0.1 M), O2
Na2HPO4 (2) ACN (0.1 M), O2
Na2HPO4 (1) ACN (0.1 M), O2
6
7
c
8
49
9
MgO (1)
ACN (0.1 M), O2
ACN (0.1 M), O2
ACN (0.1 M), O2
ACN (0.1 M), O2
ACN (0.1 M), O2
83
74
10
32
22
86
36
9
10
11
12
13
14
15
16
17
NaHCO3 (1)
KOAc (1)
Na2CO3 (1)
K3PO4 (1)
Na2HPO4 (1) DMF (0.1 M), O2
Na2HPO4 (1) DCM (0.1 M), O2
Na2HPO4 (1) DMSO (0.1 M), O2
Na2HPO4 (1) toluene (0.1 M), O2
5
a
b
Reaction performed on a 0.50 mmol scale. Yields determined by
c
GC-MS. Using 10 mol % of Pd(OAc)2
we tested inorganic bases that could effectively buffer the
strongly acidic Oxone and prevent the undesired hydrolysis
reaction. Gratifyingly the yields were improved to 81% by
adding 1 equiv of dipotassium hydrogen phosphate (K2HPO4)
(entry 4). As was observed previously, running the reaction
under an oxygen atmosphere was beneficial, although the exact
role of oxygen in the process using Oxone remains to be
elucidated (entries 3−4). The rest of the investigations were
performed using an oxygen atmosphere. No hydrolyzed
product was observed with either dipotassium or disodium
hydrogen phosphate; however we noticed overoxidized
products in the crude reaction mixture, indicating that an
excess of the oxidant is unnecessary. To our delight, a 92% yield
of cyclohexenone was obtained by lowering the amount of
Oxone to 1 equiv and using disodium hydrogen phosphate
(Na2HPO4) (entry 6). Using an excess of Na2HPO4 afforded
the desired product with lower yields (entry 7). Unfortunately
it was not possible to lower the catalyst loading, as only a 49%
yield was observed when the reaction was carried out in the
presence of 10 mol % of palladium(II) acetate (entry 8). While
moderate yields were observed when using either magnesium
oxide or sodium bicarbonate (entries 9−10), other bases such
as KOAc, Na2CO3,36 and K3PO4 afforded low yields only
(entries 11−13). Overall no other base proved as good as
Na2HPO4. A good yield was obtained with DMF as a solvent,
while DCM, DMSO, and toluene all gave low yields (entries
14−17). Acetonitrile remained the most efficient solvent for the
reaction.
a
b
c
Reaction performed on a 0.50 mmol scale. Isolated yields. Oxone
d
was added in two portions. Reaction performed at 45 °C.
e
1
Determined by H NMR.
form more stable double bonds as with substrate 1c (entries 1−
2).37 Other cyclohexenones were also produced in good yields,
and the reaction was compatible with a cyclic acetal (entries 2−
5). Our reaction conditions could also be used to produce
cyclopentenone derivatives, as steroid-derived enone 2g (entry
6). Trimethylsilyl enol ether 1h was smoothly converted into
enone 2h, a key intermediate in the total synthesis of
pleuromutilin (entry 7).38
The optimal reaction conditions, using 20 mol % of
palladium(II) acetate, a stoichiometric amount of Oxone, and
Na2HPO4 in acetonitrile under an oxygen atmosphere, were
tested with various trimethysilyl enol ethers (Table 2).
Nonsymmetrical cyclic enones were produced in good yields:
only one regioisomer was observed, even when others could
The catalytic Saegusa−Ito reaction conditions are also
compatible with the synthesis of acyclic E-enone 2i from Z-
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The Journal of Organic Chemistry
Note
enol ether 1i (entry 8).39 Terminal alkenes could also be
synthesized when the reaction was performed at 45 °C in a
moderate yield (entry 9). The reaction conditions also allowed
the formation of a conjugated aldehyde in a good yield (entry
10).
In conclusion, we have developed new Saegusa−Ito reaction
conditions using Oxone as the stoichiometric oxidant. Both
cyclic and acyclic trimethylsilyl enol ethers could be effectively
converted to the corresponding enones under these reaction
conditions, providing a useful process for α,β-unsaturated
ketone synthesis.
(3S,10R,13S)-3-(tert-Butyldimethylsilyloxy)-10,13-dimethyl-
1,3,4,7,8,9,10,11,12,13-decahydro-2H-cyclopenta[a]phenanthren-
17(14H)-one (2g). The trimethylsilyl ether (0.50 mmol), Na2HPO4
(71.0 mg, 0.50 mmol), oxone (307 mg, 0.50 mmol), and Pd(OAc)2
(22.5 mg, 0.1 mmol) were weighed in a 4 dram vial, and then dry
acetonitrile (5 mL) was added. The mixture was then purged with
oxygen 3 times and stirred at 45 °C for 18 h under an oxygen
atmosphere. After filtration through Celite, the solvent was removed
by vacuum and the residue was purified by recrystallization in ethyl
acetate/pentane. White crystalline solid. 63% yield. Mp 99−101 °C.
(lit.: 110−112 °C (hexane)).47 All spectroscopic data were identical to
those previously reported.47
3a-Vinyl-2,3,3a,4,5,6-hexahydroinden-1-one (2h). Colorless
liquid. 78% yield. All physical and spectroscopic data were identical
to those previously reported.16
EXPERIMENTAL SECTION
■
(E)-Hept-2-en-4-one (2i). Colorless liquid. 74% yield. All physical
and spectroscopic data were identical to those previously reported.48
1-Phenylprop-2-en-1-one (2j). The trimethylsilyl ether (0.50
mmol), Na2HPO4 (71.0 mg, 0.50 mmol), oxone (307 mg, 0.50
mmol), and Pd(OAc)2 (22.5 mg, 0.1 mmol) were weighed in a 4 dram
vial, and then dry acetonitrile (5 mL) was added. The mixture was
then purged with oxygen 3 times and stirred at 45 °C for 18 h under
an oxygen atmosphere. After filtration through Celite, the solvent was
removed by vacuum and the residue was purified by silica gel
chromatography. Colorless liquid. 56% yield. All physical and
spectroscopic data were identical to those previously reported.49
E-Cinnamaldehyde (2k). Colorless liquid. 69% yield. Commercially
available product: all physical and spectroscopic data were identical to
those previously reported.
General Information. Unless otherwise noted, all the nonaqueous
reactions were performed under an oxygen-free atmosphere of argon
with rigid exclusion of moisture from reagents and glassware using
standard techniques for manipulating air-sensitive compounds.40 All
glassware was stored in the oven and/or was flame-dried prior to use
under an inert atmosphere of gas. All oxidation reactions were
performed under oxygen. Trimethylsilyl ethers were prepared using
literature procedures.41 Acetonitrile and other solvents were obtained
from a solvent filtration purification system. Analytical thin layer
chromatography (TLC) was performed using 0.25 mm silica gel 60-F
plates. Visualization of the developed chromatograms was performed
by UV absorbance, aqueous cerium molybdate, ethanolic phospho-
molybdic acid, iodine, or aqueous potassium permanganate. Flash
chromatography was performed using Silica Gel 60 (230−400 mesh)
with the indicated solvent system according to a standard technique.42
Melting points are uncorrected. Infrared spectra are reported in
ASSOCIATED CONTENT
■
1
reciprocal centimeters (cm−1). Chemical shifts for H NMR spectra
S
* Supporting Information
are recorded in parts per million (ppm) on the δ scale relative to an
internal standard of residual solvent (chloroform, δ 7.27 ppm). Data
are reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, qn = quintet, m = multiplet, and br =
broad), coupling constant in Hz, integration, and assignment.
Chemical shifts for 13C NMR spectra are recorded in parts per
million from tetramethylsilane using the central peak of deuterochloro-
form (77.23 ppm) as the internal standard. All spectra were obtained
with complete proton decoupling. Analytical gas chromatography
(GLC) was carried out on a gas chromatograph equipped with a split
mode capillary injector and a flame ionization detector. Unless
otherwise noted, injector and detector temperatures were 250 °C and
the carrier gas was hydrogen.
Typical Procedure for the Palladium-Catalyzed Saegusa−Ito
Oxidation Using Oxone as Stoichiometric Oxidant. The
trimethylsilyl ether (0.50 mmol), Na2HPO4 (71.0 mg, 0.50 mmol),
oxone (307 mg, 0.50 mmol), and Pd(OAc)2 (22.5 mg, 0.1 mmol) were
weighed in a 4 dram vial, and then dry acetonitrile (5 mL) was added.
The mixture was then purged with oxygen 3 times and stirred at room
temperature for 18 h under an oxygen atmosphere. After filtration
through Celite, the solvent was removed by vacuum and the residue
was purified by silica gel chromatography. Yields as well as physical
and spectroscopic data follow.
Characterization spectra (1H and 13C NMR) for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: helene.lebel@umontreal.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC), the Centre
in Green Chemistry and Catalysis (CGCC), the Canada
́ ́
Foundation for Innovation, and the Universite de Montreal.
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