Rate enhancement in the Wacker oxidation of hydroxy-α,β-unsaturated esters: A fast neutral method for the preparation of masked β-ketoesters

Article abstract of DOI:10.1016/0040-4039(93)88033-F

Wacker oxidation of 6- or 7-hydroxyalkenoate esters is a mild one step means of generating both simple and highly functionalized protected β-ketoesters in high yield, under essentially neutral conditions.

Full text of DOI:10.1016/0040-4039(93)88033-F

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Vol.
Rate Enhancement in the Wacker Oxidation of
Esters: A Fast Neutral Method for the Preparation
of Masked
Simon X Auclair, Michelle Morris, Michael A.
of Chemistry and Biochemistry, University of Arkansas,
AR 72701
oxidation; intramolecular;
eaters;
Key Words
Abstract
Wacker oxidation of
highly
or
esters is a mild one step means of generating both simple and
in high yield, under essentially neutral conditions.
protected
The industrial oxidation of ethylene by palladium@) catalysts known as the Wacker oxidation
has been developed into an efficient method of oxidizing terminal alkenes to methyl ketones in the
organic laboratory.1 However, the oxidation of internal alkenes is a more difficult problem. The
oxidation of such alkenes is complicated by the question of regiochemistry. Additionally, oxidation of
internal alkenes using the standard
is dramatically slower than for terminal alkenes. The regiochemistry of these oxidations may be
controlled by electron withdrawing substituents, thus esters are specifically oxidized at
Oxidation of esters
chloride
chloride oxygen catalyst system
2
the however, the rate of this reaction is very slow.
proceeds at a faster rate at 500C in aqueous acetic acid employing sodium tetrachloropalladate
as the catalyst and t-butyl hydroperoxide or hydrogen peroxide as the Although
the reported yields were moderate, the substrates lacked additional functionality. Hosokawa has shown
that Wacker oxidation of vinyl ketones and acrylate esters in the presence of or gives the
analogous cyclic however, the oxidation of more substituted esters and ketones was very slow.
n=l
n
= l

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In connection with the synthesis of venturicidin5 we were interested in developing a mild method
under neutral conditions for the conversion of c&unsaturated esters to protected We
thought that oxidation of alkene to give protected by way of intramolecular
nucleophilic addition to generate alkyl palladium species would be significantly enhanced with respect
to the intermolecular variant. This concept has not previously been employed to overcome the
unreactive nature of internal alkenes. Under Hosokawa’s conditions, alkene was slowly oxidized to
give as one component (44%) of a complex mixture. However, using a mixture of
as the reoxidant, in the presence of gave the desired product in excellent yield
(89%). It was found that use of either less reoxidant, or omission of was detrimental to the yield of
In extending this result to other alkenes we have found the requirement for is not general.
We have extended this result to the oxidation of an interesting range of hydroxy-a&unsaturated
esters (Table Of note is the tremendous rate enhancement due to the presence of the hydroxyl
unit. Oxidation of methyl was run as a comparative standard. Under the optimum
conditions (either with or without oxidation of over a 14 day period gave a poor of
cyclic along with significant recovery of the substrate (50%). By contrast, the hydroxyalkenes
were cleanly consumed within 3 days. Formation of the semicyclic acetals was
much faster than that of the corresponding species (Entry 2 3, and 4 and 5 vs 6).
and
Oxidation of primary alcohols, or appears to be slightly less facile than that of secondary alcohols
(Entry 2 vs 4 and 5, and 3 vs 6). This result may be a consequence of the solution conformations of
these species. Of interest was the oxidation of arabinose derivative
species would be stereochemically labile, resulting in racemization of the
oxidation of resulted in less than 5% of epimerized species. Oxidation of
and in good yield. Of the two products which may result from
of lower energy than a-furanoside
the structure of was attained by conversion to
Under acidic conditions this
However,
gave a 3: 1 mixture of
is predicted7 to be
whilst enolether
is intermediate in stability. Confirmation of
upon treatment with catalytic TSA in dry
This clearly demonstrates the mild non-acidic nature of our oxidation conditions. Studies are presently
underway to explore the potential of this process in the elaboration of simple carbohydrates.8
In the presence of
provided complete oxidation of the substrate. Whereas, in the absence of
proceeded over a number of days often terminated prior to complete consumption of the alkene.
all of these oxidations proceeded at a slower rate, but eventually
those oxidations which

7741
Indeed, the presence of
has been correlated with a retardation of the rate of oxidation in similar
presumably through chloride complexation of the active catalyst. We suggest that this
complexation may also reduce the rate at which the active catalyst under goes irreversible destruction.
a-OMe
Table 1
Trisubstituted alkenes usually under go very slow Wacker oxidation, however, oxidation of
trisubstituted alkene is complete within 76hr to give as a inseparable mixture of
indicates the oxidation was performed in the presence of
diastereomers. Such highly substituted acetals are not as readily available employing other traditional
techniques. This result clearly shows the advantage of the intramolecular Wacker oxidation.
Alternatively, oxidation of and
and and the corresponding
in aqueous THF gave equilibrating mixtures of the hemiacetals
in lower yields (38% and 31% respectively). The lower
yields may be a result of the lower solubility of the catalyst system in aqueous THF.

1742
5
11
18
20
21
n = 1
It may be argued that chelation of the hydroxyl oxygen to the palladium and subsequent intra-
molecular delivery of the catalyst to the alkene is the cause of the rate enhancement observed for these
alkenes. However, oxygen ligands bind weakly to such palladium Rather, this result may be
=
a consequence of the high rate enhancements observed in intramolecular reactions.11 Nucleophilic
intramolecular reactions may result in high rate enhancements compared to the inter-molecular
variants. Our results indicate an effective molarity of the hydroxyl group of
This suggests that
addition to the palladium alkene x-complex is the rate limiting step not the formation of the x-complex.
In summary we have shown that the Wacker oxidation may be employed in the fast and clean
one step preparation of masked
under almost neutral reaction conditions. In addition we
have identified a key factor in the Wacker oxidation of internal alkenes which may be valuable in the
future utility of this reaction in a synthetic sense.
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(Received in USA 18 August 1992; accepted 16 September 1992)