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Evidence that the availability of an allylic hydrogen governs the
regioselectivity of the Wacker oxidation
Matthew J. Gaunt, Jinquan Yu and Jonathan B. Spencer*
University Chemical Laboratory, Lensfield Road, Cambridge, UK CB2 1EW. E-mail: jbs20@cam.ac.uk;
Fax: +44 1223 336913; Tel: +44 1223 331696
Received (in Cambridge, UK) 4th April 2001, Accepted 24th July 2001
First published as an Advance Article on the web 4th September 2001
The allylic hydrogen is found to have a dramatic effect on
the regioselectivity of the Wacker oxidation, leading to the
postulation that an agostic hydrogen or enyl (
s
+
p
) complex
helps to stabilise the key intermediate.
allylic hydrogen is responsible for the change in regioselectivity
the oxidation of the
b
-methyl (4-methoxy)styrene
1b
was
directly compared with that of the
b
-
tert
-butylstyrene
1c
. The
result clearly demonstrates that the removal of the allylic
hydrogen switches the regioselectivity back to the Markovnikov
product (Table 1).
Both the substitution of the methyl group and the
tert
-butyl
group onto styrene increases the steric effects on the terminal
carbon of the double bond; however, they have the opposite
effect on the regioselectivity. To further probe the steric effect
on the reaction, the phenyl group in styrene and
b
-methylstyr-
ene was substituted by an adamantyl group (Table 2). The
results show that despite the bulk of the adamantyl group, the
availability of the hydrogens on the methyl group still governs
the outcome of the reaction (Table 2).
5
This suggests that the
steric environment does not have an overriding influence on the
regioselectivity of the Wacker oxidation.
The Wacker oxidation is a versatile reaction that has found
broad application in synthetic chemistry for the functionalisa-
tion of alkenes.
1
The
s
-bonded (
b
-hydroxyalkyl)palladium
complex has been determined as the key intermediate in this
reaction.
2
However, the factors controlling the regiochemistry
of the hydroxypalladation step to form this intermediate remain
obscure. Although terminal alkenes nearly always give methyl
ketones, suggesting that hydroxypalladation takes place accord-
ing to Markovnikov’s principles, disubstituted alkenes give
products that do not always obey these rules.
3
A striking
example of this paradox is the dramatically different regio-
selectivity observed with styrene (Markovnikov) and that of
b
-
methylstyrene (apparent anti-Markovnikov).
4
In this study we
have identified that there are two key factors that control the
regioselectivity:
Table 2
Probing steric effects in the Wacker oxidation
a
electronic
effects
(Markovnikov)
and
the
availability of a hydrogen atom allylic to the double bond.
It is intriguing that the substitution of a methyl group on the
terminal carbon atom of styrene (Scheme 1) or 4-methoxystyr-
ene (Table 1) switches the regioselectivity from Markovnikov
to anti-Markovnikov. To test whether the availability of an
a
R=H
1
—
b
R=CH
3
1
2.2
a
Reaction conditions are the same as those in Table 1.
These results implicate the involvement of the allylic
hydrogens in the reaction mechanism. It has been demonstrated
that C–H can coordinate to a transition metal centre and form a
sigma agostic structure
7
(Scheme 2).
6
s
-Electrons can serve as
electron donors to an empty metal orbital, and the high lying
C–H
s
* orbital serves as a
p
-acceptor from a filled metal
orbital. When the palladium adds remote to the methyl group
the electronic effect from the carbocation next to the allylic
hydrogen could weaken the C–H bond and should therefore
make the C–H
s
* more accessible and hence a better
p
acceptor
for the palladium (Scheme 2).
7
The agostic intermediate
8
could
account for the formation of the anti-Markovnikov product.
Scheme 1
Reagents and conditions
: PdCl
2(0.1)
,DMF,H
2
O, CuCl, O
2
,
50 °C.
Table 1
Oxidation of
b
-substituted styrenes
a
R=H 1 —
b
R=CH
3
1 10
c
R = C(CH
3
)
3
2.2 1
a
Representative procedure for the Wacker oxidations of
1a–c
and
4a–b
.A
solution of palladium(
II
) chloride (44 mg, 0.25 mmol) and alkene (0.25
mmol) in
N,N
-dimethylformamide (1 ml) and water (1 ml) was stirred at 100
°C until completion shown by TLC. The cooled reaction mixture was
filtered, concentrated and purified by flash silica gel chromatography and
the product analysed by
1
H NMR. Stoichiometric conditions were adopted
due to the low reactivity of the sterically hindered alkenes. The oxidation of
1a
and
1b
under catalytic Wacker oxidation conditions [palladium(
II
)
chloride (35.4 mg, 0.2 mmol) and copper(
I
) chloride (198 mg, 2 mmol) in
N,N
-dimethylformamide (1 ml) and water (1 ml)] gave the same
regioselectivity as observed when the reactions were carried out under the
stoichiometric conditions shown in Table 1.
Scheme 2
It has also been shown that interaction between palladium(
II
)
and an alkene with allylic hydrogens can result in the formation
of a
p
-allylic complex.
8
In fact, these complexes have been
isolated in the Wacker reaction and found to be stable species
that do not react further.
9
In order to establish whether a
p
-
allylic species could be involved in the reaction mechanism
b
-
methylstyrene labelled at the methyl group with deuterium was
oxidised (Scheme 3). The deuterium is completely retained in
the products
13
and
14
which is not consistent with a
p
-allylic
1844
Chem. Commun.
, 2001, 1844–1845
DOI: 10.1039/b103066n
This journal is © The Royal Society of Chemistry 2001
To investigate if the balance between path A (Markovnikov)
and B (anti-Markovnikov) can be influenced by altering the
electronic properties of the aromatic ring, a series of analogues
of
b
-methylstyrene,
15a–f
,
were
oxidised
under
standard
Wacker conditions.
The results clearly show that as the electron density of the
aromatic system is increased, path A (Scheme 3) is enhanced,
which is consistent with the greater stabilisation of the
carbocation at the benzylic position (Table 3). The dramatic
influence on the regioselectivity of the oxidation by involve-
ment of the allylic hydrogens is clearly illustrated since path A
only becomes dominant when the aromatic ring is substituted
with three methoxy groups,
15f
.
This study provides evidence that the regioselectivity of the
Wacker oxidation can be greatly influenced by the availability
of an allylic hydrogen. The allylic hydrogen might participate in
the Wacker oxidation by being involved in either an agostic C–
H or enyl (
s
+
p
) complex. The involvement of these complexes
could account for preferential formation of the anti-Markovni-
kov product when the substrate bears an allylic hydrogen.
We thank The Wellcome Trust (M. J. G.), St. John’s College,
Cambridge (J.-Q. Y) and the Royal Society (J. B. S.) for
funding.
Scheme 3
intermediate since deuterium should either be lost from the
methyl position or partially transferred to the benzylic posi-
tion.
10
This also confirms that isomerisation to the terminal
alkene followed by oxidation, which would require the loss of a
deuterium atom from the methyl group, is not the mechanism
that can account for the preferential formation of the anti-
Markovnikov product. It has been shown previously that enyl
(
s
+
p
) intermediates are precursors for
p
-allylic complexes,
11
and therefore may be formed in the Wacker reaction. While the
p
-allylic complex
11
is probably too stable to react with water,
it is possible that an enyl (
s
+
p
) complex
12
with the proton still
attached to the palladium could be intramolecularly reproton-
ated allowing this intermediate to react with water (Scheme 3).
The labelling studies are therefore consistent with either a
mechanism involving the stabilisation of the anti-Markovnikov
intermediate occurring through an agostic C–H
8
or a
mechanism where the intermediate is stabilised by an enyl
(
s
+
p
) complex
12
that can be intramolecularly reprotonated.
Notes and references
1 J. Tsuji, in
Comprehensive Organic Synthesis
,Eds.B.M.TrostandI.
Fleming, Pergamon Press, New York, 1991,
Vol. 7
, pp. 449–467.
2 O. Hamed, C. Thompson and P. M. Henry,
J. Org. Chem.
, 1997,
62
,
7082; O. Hamed and P. M. Henry,
Organometallics
, 1997,
16
, 4903; K.
Zaw and P. M. Henry,
Organometallics
, 1992,
11
, 2008; B. Akermark,
B. C. Soderberg and S. S. Hall,
Organometallics
, 1987,
6
, 2608; J. E.
Bäckvall, B. Akermark and S. O. Ljunggren,
J. Am. Chem. Soc.
, 1979,
101
, 2411.
3 B. L. Feringa,
J. Chem. Soc., Chem. Commun.
, 1986, 909; H. Ogawa, S.
Miyamoto, T. Mandai, S. Wakabayashi and J. Tsuji,
Tetrahedron Lett.
,
1988,
29
,
5181;
H.
Pellissier,
P.
Y.
Michellys
and
M.
Santelli,
Tetrahedron
, 1997,
53
, 7577.
4 E. Keinan, K. K. Seth and R. Lamed,
J. Am. Chem. Soc.
, 1986,
108
,
3474; J. Tsuji, in
Comprehensive Organic Synthesis
,Eds.B.M.Trost
and
Table 3
Probing electronic factors in the oxidation of
b
-methylstyrenes
I.
Fleming,
Pergamon
Press,
New
York,
1991,
Vol.
7,
pp
465–466.
5 The reaction was monitored by GC which determined that approx-
imately 1% of the terminal double bond was formed by double bond
shift during the reaction course. This eliminates the possibility that the
major pathway for the formation of the anti-Markovnikov product is
from oxidation of the terminal alkene (also see the deuterium labeling
studies with
b
-methylstyrene later in the text).
6 M. Brookhart and M. L. H. Green,
J. Organometal. Chem.
, 1983,
250
,
395.
7 R. H. Crabtree,
Angew. Chem., Int. Ed. Engl.
, 1993,
32
,799.
8 B. M. Trost and P. J. Metzner,
J. Am. Chem. Soc.
, 1980,
102
, 3572; H.
Grennberg, V. Simon and J. E. Bäckvall,
J. Chem. Soc., Chem.
Commun.
, 1994, 265; R. G. Brown, R. V. Chaudhari and J. M.
Davidson,
J. Chem. Soc., Dalton Trans.
, 1977, 176.
9 A. D. Ketley and J. Braatz,
J. Chem. Soc., Chem. Commun.
, 1968, 169;
F. Conti, M. Donati, G. F. Pregaglia and R. Ugo,
J. Organomet. Chem.
,
1971,
30
, 421.
10 When compound
4b
, labelled with deuterium at position 2, was
oxidised, 90% of the deuterium was found to be located at position 1 and
10% at 3. Although the presence of 10% deuterium at the position 3
suggests the involvement of a
p
-allylic complex as a minor pathway,
GC analysis of the reaction mixture showed the formation of small
amount (1%) of terminal alkene that if oxidised could give this result.
11 D. N. Lawson, J. A. Osborn and G. Wilkinson,
J. Chem. Soc. A
, 1966,
1733; P. A. Evans and J. D. Nelson,
J. Am. Chem. Soc.
, 1998,
120
,
5581.
a
X = 4-CF
3
1 > 19
b
X = 4-H 1 7.5
c
X = 4-CH
3
1 3.8
d
X = 2-OCH
3
1 2.7
b
X = 4-OCH
3
1 2.0
e
X = 2,4-OCH
3
1.2 1
f
X = 2,4,6-OCH
3
2.3 1
a
Representative procedure for the Wacker Oxidations of methylstyrenes
15a–f
. A flask containing a suspension of palladium(
II
) chloride (35.4 mg,
0.2 mmol) and copper(
I
) chloride (198 mg, 2 mmol) in
N,N
-dimethylforma-
mide (1 ml) and water (1 ml) was stirred under an oxygen atmosphere for
1 h. Alkene, 1b, (296 mg, 2 mmol) in
N,N
-dimethylformamide (0.5 ml) and
water (0.5 ml) was added and the reaction mixture was stirred at 50 °C for
24 h. The crude reaction mixture was applied directly to a pad of silica (ethyl
acetate–hexane; 1+4) and the concentrated filtrate was analysed by
1
H
NMR. Purification by flash silica gel chromatography afforded ketones
2b
and
3b
(in the ratio 1+2.0) as a pale yellow oil (195 mg, 59%).
b
It is
interesting to note that the temperature of the reaction (compare to the result
at 100 °C, Table 1) can affect the regioselectivity of the reaction. At higher
temperatures the ‘anti-Markovnikov’ product is further favoured.
Chem. Commun.
, 2001, 1844–1845
1845
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