Oxidation of Methyl Trimethylsilyl Ketene Acetals to α-Hydroxyesters with Urea Hydrogen Peroxide Catalyzed by Methyltrioxorhenium

Article abstract of DOI:10.1021/jo000212e

In the presence of catalytic amounts of MTO, methyltrioxorhenium, methyl trimethylsilyl ketene acetals are oxidized with urea hydrogen peroxide to afford α-hydroxy and α-siloxy esters. On treatment with potassium fluoride, the α-hydroxy esters are obtained in high yields.

Full text of DOI:10.1021/jo000212e

5528
J . Org. Chem. 2000, 65, 5528-5530
Oxid a tion of Meth yl Tr im eth ylsilyl Keten e Aceta ls to
r-Hyd r oxyester s w ith Ur ea Hyd r ogen P er oxid e Ca ta lyzed by
Meth yltr ioxor h en iu m
Sasˇa Stankovic´ and J ames H. Espenson*
Ames Laboratory and Department of Chemistry, Iowa State University, Ames, Iowa 50011
espenson@ameslab.gov
Received February 15, 2000
In the presence of catalytic amounts of MTO, methyltrioxorhenium, methyl trimethylsilyl ketene
acetals are oxidized with urea hydrogen peroxide to afford R-hydroxy and R-siloxy esters. On
treatment with potassium fluoride, the R-hydroxy esters are obtained in high yields.
In tr od u ction
active forms of the catalyst are the monoperoxo and
diperoxo complexes formed in reversible equilibria, eq 1.
Lead(IV) carboxylates,1 hypervalent iodine,2 m-chloro-
perbenzoic acid (m-CPBA),3 and dimethyldioxirane (DM-
DO)4 can be used to oxidize esters via their ketene acetals
to R-hydroxy carbonyl compounds. Catalytic reagents are
MnII(salen) complexes with various oxidants5 and cobalt6
or nickel(II)7 complexes with oxygen. Few reports of
hydrogen peroxide as the oxidant have appeared,8 pre-
sumably owing to the hydrolytic instability of ketene
acetals. The R-hydroxy esters are synthetic intermediates
of widespread use through the independent manipulation
of the hydroxy and ester groups. For example, they are
used in the preparation of esters and acids functionalized
at the 2-position, like 2-oxo esters and acids.9 R-Hydroxy
esters are also used in the synthesis of certain natural
products.10 We are unaware of any major application that
relies on the presence of the two functional groups; the
uses are those of the independent alcohol and ester
groups.
Water-labile silyl enol ethers form R-hydroxy ketones
with aqueous hydrogen peroxide and the MTO catalyst
in acetonitrile.16 We sought to extend this methodology
to ketene acetals, which are even more hydrolytically
sensitive owing to the presence of an additional alkoxy
functionality,17,18 because peroxide is such a convenient
laboratory reagent. For our study, we selected methyl-
trimethylsilyl ketene acetals. Herein, we report the
effectiveness of an optimized procedure that relies upon
the anhydrous material urea-hydrogen peroxide, UHP,
and quite importantly, the presence of pyridine.
Methyltrioxorhenium (CH3ReO3, abbreviated as MTO)
is a well-established catalyst for the reactions of hydrogen
peroxide,1,11 including the epoxidation of alkenes.12-15 The
Exp er im en ta l Section
Rea gen ts. The ketene acetals were prepared from the
parent esters and trimethylsilyl chloride using a published
procedure.19 The esters were purchased and used as such
except for methyl 2-phenylpropanoate, which was obtained
from 2-phenylpropanoic acid (10 g, 67 mmol) upon refluxing
for 7 days in methanol (50 mL in the presence of catalytic
amount of p-toluenesulfonic acid (0.6 g, 3.3 mmol). After
completion, the reaction mixture was dissolved in ether,
washed with saturated sodium bicarbonate solution, and dried
over anhydrous sodium sulfate. Solvent evaporation followed
by distillation afforded 8.64 g of methyl 2-phenylpropanoate.
Oxid a tion of Keten e Aceta ls. The ketene acetal (2.5
mmol) was introduced dropwise over 5 min into a cooled
mixture (0 °C) of UHP (0.35 g, 3.75 mmol), pyridine (0.05 g,
0.625 mmol), and MTO (0.031 g, 0.125 mmol) in 99:1 aceto-
nitrile/acetic acid (5 mL). After being stirred for an additional
5 min at room temperature, the reaction mixture was treated
with a minimal amount of saturated sodium bicarbonate
solution to neutralize acetic acid and destroy the catalyst. The
mixture was then dissolved in dichloromethane and the
organic layer separated and dried. After filtration and solvent
(1) Rubottom, G. M.; Gruber, J . M.; Marrero, R.; J uve, H. D.; Kim,
C. W. J . Org. Chem. 1983, 48, 4940.
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511.
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32, 1295.
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1993, 1579.
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1991, 281.
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Tetrahedron Lett. 1996, 6531.
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Wiley: New York, 1999.
(10) Hanessian, S. Total Synthesis of Natural Products. The Chiron
Approach; Pergamon Press: New York, 1983; Chapter 2.
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180.
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Angew. Chem., Int. Ed. Engl. 1993, 32, 1157.
(14) Al-Ajlouni, A.; Espenson, J . H. J . Am. Chem. Soc. 1995, 117,
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3976.
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4130.
(17) Kresge, J . A.; Straub, T. J . Am. Chem. Soc. 1983, 105, 3957.
(18) Kresge, J . A.; Leibovitch, M. J . Am. Chem. Soc. 1993, 114, 3099.
(19) Ainsworth, C.; Chen, F.; Kuo, Y. J . Organomet. Chem. 1971,
46, 59.
10.1021/jo000212e CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/10/2000

Oxidation of Methyl Trimethylsilyl Ketene Acetals
J . Org. Chem., Vol. 65, No. 18, 2000 5529
Ta ble 1. Ca ta lytic P r ep a r a tion of r-Hyd r oxy Ester s
Ta ble 2. Effect of P yr id in e on th e Oxid a tion of
(1-Meth oxyh ep ten yloxy)tr im eth ylsila n e
entry
additive
% yielda
1
2
4-methylpyridine
4-methoxypyridine
60
70
3b
4b
5b
6c
7c
8c
9
pyridine
4-methylpyridine
4-methoxypyridine
pyridine/2,6-dimethylpyridine
pyridine/2, 4, 6-trimethylpyridine
pyridine/4-methyl-2.6-di-tert-butylpyridine
4-methyl-2.6-dimethylpyridine
35
55
65
75
81
56
<10d
a
NMR yield based on the ratio of methyl ester peak intensities
of the of R-hydroxy esters and of R-siloxy esters versus the parent
b
ester. No acetic acid present. c 1:1 ratio with the concentration
d
of pyridine equal in all experiments. Determined by GC/MS.
Ketene acetals with two â-alkyl substituents, or >1
unsaturated substituent, underwent oxidation cleanly.
One conjugated substrate has a double bond (entry 6),
such that two possible modes of oxygen addition will yield
two products. The addition of oxygen at the ketene acetal
double bond predominates, yielding the nonconjugated
product. The rationale for this preference might be the
coordination of the rhenium catalyst to an oxygen atom
of the ketene acetal moiety.
The two substrates having only one â-substituent were
predominantly hydrolyzed. To improve the extent of
oxidation for these substrates, further optimization was
undertaken. Pyridine was replaced by the more basic
4-substituted pyridines; there was an improvement, but
it was insufficient. Exclusion of acetic acid had a small
deleterious effect (entries 4-6). The best results were
obtained with a reaction system containing both pyridine
and a bulky pyridine (Table 2, entries 6 and 7), although
a bulky pyridine itself fails (Table 2, entry 9).
a
NMR yield based on the ratio of methyl ester peak intensities
of the R-hydroxy and of R-siloxy esters versus the methyl peak
b
intensity of the parent ester. Isolated yield after desilylation, in
Discu ssion
parentheses. c A 70:30 mixture of isomers by NMR. A 60:40
d
mixture of isomers by NMR. e Product ratio 80:20 by NMR.
Th e Effect of Str u ctu r e. The oxidation of ketene
acetals, as in the case of enol ethers, presumably proceeds
via an unstable transient epoxide 2 that undergoes either
silyl migration or hydrolysis to afford the R-siloxy ester
3 or the R-hydroxy methyl ester 4.16 Subsequent hydroly-
sis of the R-siloxy ester is slow under the employed
conditions, and fluoride treatment was needed to effect
desilylation, eq 2.
f Combined yield of both products. A mixture of isomers 70:30
g
h
by NMR. A mixture of isomers 70:30 by NMR.
removal, the crude product was dissolved in a saturated
solution of potassium fluoride in methanol and stirred for 1
h. The solution was then dissolved in water and extracted with
dichloromethane. After drying over anhydrous sodium sulfate
and solvent removal, the product was purified by flash
chromatography on silica gel (pentane/acetone)
Resu lts
The experimental procedure developed for the oxida-
tion of silyl enol ethers with aqueous hydrogen peroxide
in acetonitrile in the presence of pyridine20 turned out
to be inadequate for the more hydrolytically labile ketene
acetals. Initial experiments with 1-methoxy-1-trimeth-
ylsiloxy-1-methylenecyclohexane, using the same proce-
dure, showed significant substrate hydrolysis (70%). We
found, however, upon replacing aqueous hydrogen per-
oxide with UHP, a convenient and inexpensive source of
anhydrous hydrogen peroxide, that hydrolysis decreased
to about 30%. Use of a lower temperature, 0 °C, and
dropwise addition of the substrate, afforded nearly
complete oxidation. We applied this procedure to a
number of different ketene acetals. The results are shown
in Table 1.
The outcome of the oxidation reactions appears to be
the result of a balance between the rates of protonation
of ketene acetals and oxygen transfer. The hydrolysis of
ketene acetals is known to proceed through rate-
determining irreversible protonation followed by hydroly-
sis of the resulting oxocarbocation to the parent carbox-
ylic ester:1,21,22
(21) Gold, V.; Waterman, D. C. A. J . Chem. Soc. B 1968, 839.
(22) Hershfield, R.; Yeager, M. J .; Schmir, G. L. J . Org. Chem. 1975,
40, 2940.
(20) Stankovic′, S.; Espenson, J . H. J . Org. Chem. 2000, 39, 1549.

5530 J . Org. Chem., Vol. 65, No. 18, 2000
Stankovic and Espenson
substituents in positions 2 and 6, used alone, do not show
a stabilizing effect.
It is known that MTO is deactivated by conversion to
perrhenic acid.26 An obvious role for pyridine is therefore
to act as a buffer by neutralizing the perrhenic acid
formed by the decomposition of the catalyst. This leaves
pyridinium cations as well as acetic acid as the principal
acidic species responsible for the protonation of ketene
acetals. Acetic acid favors this reaction because it buffers
the pyridine/pyridinium system. Relevant pKa values of
pyridinium ions in aqueous solutions are:28,29 Py, 5.25;
4-MePyH+, 6.02; 4-MeOPyH+, 6.47; 2,6-Me2PyH+, 6.75;
and 2,4,6-Me3PyH+, 7.43. This leaves sufficient pyridine
for the beneficial effect of its coordination, while not
making the system too basic that MTO and its peroxides
are rapidly destroyed. Pyridinium cations, being less
acidic than HOAc, will be poorer reagents for substrate
hydrolysis.
It has been shown that the rate of protonation of simple
enol ethers depends on the extent of substitution at the
â-carbon.23 The more substituted enol ethers are less
prone to protonation. Ground-state stabilization has been
invoked to rationalize this trend. The same trend might
be operable in the case of ketene acetals. Nevertheless,
more substituted ketene acetals are, like olefins, expected
to react faster with the peroxo adducts due to the
increased electron density in the ketene acetal double
bond. The presence of unsaturated substituents in the
â-position should decrease the rates of both processes.
Apparently the effect is more pronounced on the rate of
protonation leading to oxidation in preference to hydroly-
sis, even with only one â-substituent. Our attempts to
effect the oxidation of ketene acetals derived from 5- and
6-membered cyclic lactones failed, yielding only the
parent lactones. This is not surprising since their pro-
pensity for protonation has been well documented. For
example, with m-CPBA they undergo exclusive protona-
tion rather than oxidation.3
The best results were obtained with the most basic
bulky pyridines used in conjunction with pyridine. The
steric bulk around the pyridine nitrogen presumably also
plays a role as the most sterically protected 4-methyl-
2,6-di-tert-butylpyridine gives results slightly better than
pyridine itself, even though it is less basic than pyri-
dine.30-32 This simple explanation, however, does not
suffice: 2,6-dimethylpyridine by itself performs worse
even though it is more basic than pyridine itself. A
possible explanation might be that even though the bulky
pyridine can effectively neutralize the perrhenic acid it
is unable to coordinate to MTO and the peroxo adducts
A and B.
Th e Role of P yr id in e. Pyridine, when introduced to
the reaction system, can prevent the hydrolysis of ep-
oxides formed during the epoxidation of olefins with
hydrogen peroxide catalyzed by MTO. This significantly
improved the effectiveness of the catalyst and broadened
its applicability.24,25 Pyridine plays at least two roles in
the MTO-peroxide system,25 as a Lewis base to coordinate
to MTO, thereby accelerating the rate of peroxorhenium
formation, and as a Brønsted base. It lowers the acidity
of the medium, helping to lessen the rate at which acid-
sensitive reagents (here, ketene acetals) and products
(epoxides) are lost. Pyridine coordinates to MTO, strongly
accelerating the rate of the peroxide binding steps, eq
1.25 This shortens the time that the peroxorhenium
catalyst must last before deactivation.26 The reaction time
is particularly important in this heterogeneous system,
because without pyridine the reaction between UHP and
MTO is very sluggish. A low concentration of pyridine
proved inadequate,24 even worse than its omission, lead-
ing only to the base-catalyzed decomposition of cata-
lyst.26,27 For the same reason, pyridines with bulky
It is known that B coordinates one molecule of water13
and therefore represents a Brønsted acid; its pKa is 3.8.13
Similar binding of water molecules, also be possible for
1
monoperoxo adduct, could not be detected by H NMR.26
The role of sterically unhindered pyridines hence might
be to neutralize the acidity of the peroxo adducts by
displacing the coordinated water molecules. However, no
direct evidence supports that, and it has been established
that pyridine binds only to MTO, not to A and B.25
Ack n ow led gm en t. This research was supported by
the U. S. Department of Energy, Office of Basic Energy
Sciences, Division of Chemical Sciences under contract
W-7405-Eng-82.
Su p p or tin g In for m a tion Ava ila ble: NMR data for ob-
tained compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O000212E
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Chemical Rubber Handbook: New York, 1988.
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(30) Brown, H. C.; Kanner, B. J . J . Am. Chem. Soc. 1966, 88, 986.
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(32) Hopkins, H. P.; J ahangirdar, D. V.; Moulik, P. S.; Aue, D. H.;
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