Novel anti-Markovnikov regioselectivity in the Wacker reaction of styrenes

Article abstract of DOI:10.1002/chem.200400644

The Wacker reaction is one of the longest known palladium-catalysed organic transformations, and in the vast majority of cases proceeds with Markovnikov regioselectivity. Palladium(II)-mediated oxidation of styrenes was examined and in the absence of reoxidants was found to proceed in an anti-Markovnikov sense, giving aldehydes. Studies on the mechanism of this unusual transformation were carried out, and indicate the possible involvement of a η⁴-palladium-styrene complex. With a heteropolyacid as the terminal oxidant, oxidation of styrene to give the anti-Markovnikov aldehyde as the major product was found to be catalytic.

Full text of DOI:10.1002/chem.200400644

FULL PAPER
DOI: 10.1002/chem.200400644
Novel Anti-Markovnikov Regioselectivityin the Wacker Reaction of
Styrenes
Joseph A. Wright,[a, b] Matthew J. Gaunt,[a] and Jonathan B. Spencer*[a]
Abstract: The Wacker reaction is one
of the longest known palladium-cata-
lysed organic transformations, and in
the vast majority of cases proceeds
with Markovnikov regioselectivity. Pal-
ladium(ii)-mediated oxidation of styr-
enes was examined and in the absence
of reoxidants was found to proceed in
an anti-Markovnikov sense, giving al-
dehydes. Studies on the mechanism of
this unusual transformation were car-
ried out, and indicate the possible in-
volvement of a h4-palladium–styrene
complex. With a heteropolyacid as the
terminal oxidant, oxidation of styrene
to give the anti-Markovnikov aldehyde
as the major product was found to be
catalytic.
Keywords: homogeneous catalysis ·
palladium · reaction mechanisms ·
styrenes · Wacker reaction
Introduction
obscure. In the majority of cases, the regioselectivity of hy-
droxypalladation follows Markovnikovꢀs principles. This has
been widely used in synthesis[3] to the extent that “terminal
alkenes may be viewed as masked methyl ketones”.[4] The
major source of anti-Markovnikov regioselectivity in the
Wacker reaction is the presence of chelating heteroatoms in
the substrate.[5] Pellissier and co-workers have shown that
this can lead to lowering of the transition state energy for
attack by water at the methylene carbon atom of the vinyl
group.[6] There are also a very small number of reports of
apparent anti-Markovnikov regioselectivity where no heter-
oatom is present in the substrate. Two related systems have
been reported by Feringa[7] and Wenzel,[8] both of which
make use of palladium–nitro complexes as catalysts. Feringa
suggests a reaction mechanism somewhat different to that of
the Wacker reaction (it does not involve the palladium(0)–
palladium(ii) couple), while the conditions used by Wenzel
are selective for aldehyde only with allyl acetate as the sub-
strate.
The oxidation of alkenes to carbonyl compounds catalysed
by palladium(ii) salts, usually referred to as the Wacker re-
action, is one of the longest standing palladium-catalysed or-
ganic transformations.[1] The mechanism of this oxidation
has been the subject of intense study, and a great amount
has been learned concerning the pathway of the reaction.[2]
The generally accepted mechanism for reaction in aqueous
media is summarised in Scheme 1. Co-ordination of the
alkene to palladium is followed by nucleophilic attack by
water on the double bond. The intermediate formed then
re-arranges via an enol to give a second b-hydroxypalladium
species, which then breaks down to the carbonyl product
and palladium(0).
The s-bonded (b-hydroxyalkyl)palladium complex has
been determined as a key intermediate in this reaction.
However, the factors controlling the regiochemistry of the
hydroxypalladation step for unsymmetrical alkenes remain
The importance of aldehydes as useful synthetic inter-
mediates in synthesis has led us to investigate ways in which
the regioselectivity in the Wacker oxidation of alkenes can
be controlled. Two of us have reported that the apparent
anti-Markovnikov ketone is the major product obtained
from the oxidation of a number of b-methyl styrenes.[9] In
this report, reversal in the regioselectivity of the stoichiomet-
ric palladium(ii)-mediated oxidation of styrenes is reported.
Catalysis of this reaction is demonstrated by using a hetero-
polyacid as the terminal oxidant. Evidence for the mecha-
nism of this unusual transformation is also discussed.[10]
[a] Dr. J. A. Wright, Dr. M. J. Gaunt, Dr. J. B. Spencer
University Chemical Laboratories
University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax. (+44)1223-336-362
E-mail: jbs20@cam.ac.uk
[b] Dr. J. A. Wright
Current address: Department of Chemistry, University of East
Anglia, Norwich, NR4 7TJ (UK)
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949

Scheme 1. General mechanism for the Wacker reaction.
Table 1. Reaction in the presence of palladium(0).[a]
Results and Discussion
Entry
Pd0 source
Ratio aldehyde:ketone
Anti-Markovnikov reactivity: Under standard catalytic con-
ditions, the Wacker reaction of 4-methoxystyrene proceeds
to a mixture of the two possible products. As expected, the
Markovnikov product (the methyl ketone 2a) was found to
predominate, and only a small amount of the aldehyde 3a
was observed (Scheme 2).[11] However, when the reaction
1
2
3
4
none (reference)
Pd black
[Pd2(dba)3]
[Pd(PPh3)4]
2.7:1.0
2.5:1.0
2.3:1.0
1.7:1.0
[a] Reaction conditions: 1 equiv styrene, 2 equiv PdCl2, 10% Pd0 source,
DMF/H2O (10:1), 30 min.
An interaction between the
aromatic group of the sub-
strate and the palladium(ii)
centre was a second possible
cause of the unusual regiose-
lectivity. To examine this, vi-
nyladamantane 4 was synthes-
ised; it is
a
non-aromatic
system, which like styrene con-
tains no allylic hydrogen
Scheme 2. Stoichiometric versus catalytic reaction.
atoms. Oxidation under the
same conditions as before gave
was performed in the absence of the reoxidant a reversal of
the usual regioselectivity occurred. Thus, reaction of 1a with
two equivalents of PdCl2 gave the aldehyde 3a as the major
product.[12,13] The reaction did not proceed to completion,
and after approximately five hours conversion reached 53%
(longer reaction periods did not improve conversion). This
surprising reversal in regioselectivity suggested that it might
be possible to control the outcome of the reaction by adjust-
ing the reaction stoichiometry and conditions. To fully ex-
ploit this potentially useful transformation, we carried out a
detailed investigation into the reasons for this unusual regio-
selectivity.
only the methyl ketone 5, thus confirming that the aromatic
group was crucial for the regioselectivity observed
(Scheme 3).
Scheme 3. Wacker reaction of adamantyl substrate 4.
Due to the lack of a reoxidant for palladium(0), the col-
loidal metal or a zero-valent complex could influence the re-
action pathway. If this were the case, the addition of a palla-
dium(0) source would increase aldehyde production in the
early stages of the reaction. Three common palladium(0)
sources were therefore examined over a reaction time of
30 min (Table 1). None of the sources led to an increase in
the production of aldehyde. Indeed, the use of palladium(0)
tetrakis(triphenylphosphane) gave a marked reduction in al-
dehyde formation; this may be attributable to the presence
of triphenylphosphane in the reaction mixture, although this
was not examined further.
Along with PdCl2, Pd(OAc)2 is a widely used source of
palladium(ii). Significantly, using Pd(OAc)2 in place of PdCl2
gave exclusively the methyl ketone in good yield (72% iso-
lated). The significant influence of the counter-ion on the
pathway of the reaction strongly implicated the presence of
an unusual palladium-styrene complex in solution; the sta-
bility of this complex would be dependent upon other li-
gands present in the reaction mixture.[14]
Nature of the palladium–substrate complex: To probe the
existence of a palladium–styrene complex, evidence for the
formation of such an intermediate was sought. When PdCl2
950
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Chem. Eur. J. 2006, 12, 949 – 955

Anti-Markovnikov Regioselectivity in the Wacker Reaction
FULL PAPER
was stirred overnight in a dry solution of styrene in DMF
prior to the addition of water, a product ratio of 6.0:1.0 (al-
dehyde:ketone) was obtained after a reaction time of
30 min. In comparison, when PdCl2 and water were added
concurrently to a solution of the substrate in DMF, the ratio
of the products was 2.7:1.0 after the same period (Table 1).
This strongly indicated the formation of a type of palladi-
um–styrene complex not previously implicated in the
Wacker reaction.
identical within experimental error. No deuterium isotope
effect was observed, meaning that an agostic interaction
could not be corroborated.
To clarify the nature of the palladium–styrene complex,
we tested a series of ortho-substituted styrenes under the
optimised reaction conditions (Table 3). For styrene (1b),
Table 3. Effect of ortho substituents.
Complexes of palladium(ii), alkenes and DMF are
known,[15] but have been isolated only as amorphous solids.
X-ray quality crystals of the styrene–palladium(ii) complex
have been obtained from benzene.[16] The marked difference
expected in the co-ordination sphere of palladium in DMF
and benzene solutions means that the available structure for
the palladium–styrene complex has little bearing on the in-
termediates postulated in the current study.
Entry
Substrate
Ratio aldehyde:ketone
1
2
3
R1, R2 =H (1b)
10.5:1.0
1:0
1.6:1.0
R1 =H, R2=Me (1c)
R1, R2 =Me (1d)
Three possible interactions were envisaged between the
palladium and the aromatic ring; a face-on interaction with
the aromatic ring 6a (involving two palladium centres), an
h4 interaction 6b,[17] or an agostic interaction 6c (Scheme 4).
the anti-Markovnikov aldehyde was produced in a 10.5:1
ratio to the methyl ketone. Increasing the size of one of the
ortho substituents (H!Me) produced the aldehyde exclu-
sively (1c, Table 3, entry 2), whilst if methyl groups occupied
both ortho positions, the selectivity dropped to 1.6:1.0 in
favour of the aldehyde.
The results of these three reactions were markedly differ-
ent. Unsubstituted styrene 1b gives good selectivity for the
aldehyde, whereas for 2-methylstyrene 1c only the anti-Mar-
kovnikov product was formed. The reaction is thus more se-
lective when only one of the ortho positions is occupied by a
substituent. However, in the case of the disubstituted sty-
rene 1d (Table 3, entry 3), the aldehyde and ketone are
formed in almost equal amounts. The reaction of 2,4-dime-
thylstyrene (Table 4, entry 17) demonstrates that this is not
due to the presence of two methyl groups.
Scheme 4. Possible palladium–aryl interactions: 6a: face-on; 6b: h4-type;
6c: agostic (L=DMF, Cl, H2O).
We[9] and others[18] have shown that agostic interactions
can have a strong influence on the regiochemistry of palladi-
um-catalysed reactions. An agostic interaction of type 6c
could show a significant kinetic isotope effect in the reaction
of substrates bearing deuterium atoms in the ortho positions.
The ring-deuterated styrene 9 was readily synthesised from
the commercially available alcohol 7 (Scheme 5), and al-
lowed kinetic experiments to be undertaken (Table 2). The
results for the deuterated and non-deuterated substrate are
Table 4. Stoichiometric Wacker reaction of a range of styrenes under op-
timised conditions.[a]
Entry
Compound
R group
Ratio of
aldehyde:ketone
Yield
[%][b,c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
4-OMe
H
2-Me
2,6-di-Me
n/a
4-Me
4-Cl
4-CF3
4-tBu
3-Me
3-Cl
3-NO2
3,5-di-tBu
2-OMe
2-F
2-Br
2,4-di-Me
9.5:1.0
10.8:1.0
>25:1
1.6:1.0
13.1:1.0
7.1:1.0
>25:1
>25:1
8.7:1.0
5.0:1.0
>25:1
16.2:1.0
6.4:1.0
17.4:1.0
>25:1
>25:1
> 25:1
63
71
89
60
38
61
76[d]
69[d]
82
50
80
54[d]
–
Scheme 5. Synthesis of ring[D5]styrene 9.
9
10
11
12
13
14
15
16
17
Table 2. Kinetic isotope studies.[a]
Entry
Reaction
time [h]
Conversion [%]
95
78
–
ring-H5
ring-D5
1
2
3
4
0.5
1.0
1.5
2.0
9.3
17.0
20.2
23.8
9.8
16.9
20.6
24.0
82
[a] Reaction conditions: 1 equiv substrate, 2 equiv PdCl2, degassed DMF/
water (10:1), RT, 5 h. [b] Determined by GC. [c] Measured versus an ap-
propriate standard, and based on recovered starting material. [d] Re-
action time: 18 h.
[a] Reaction conditions: 1 equiv substrate, 2 equiv PdCl2, 10% Pd0
source, DMF/H2O (10:1), 30 min.
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951

J. B. Spencer et al.
These results strongly implicate a side-on palladium–sty-
rene complex. In the case of a face-on complex (6a), alter-
ing the size of the ortho substituent would be expected to
have only a small effect on the reaction outcome. This is
clearly not the case, especially for substrate 1d. Of the two
side-on complexes postulated, 6c should be completely im-
possible for the disubstituted substrate 1d. If this were the
case, the formation of the aldehyde would be expected to be
largely suppressed. However, an approximately 1:1 mixture
of products was obtained. This is consistent with the inter-
mediate 6b, which would be weakened but not completely
inhibited for substrate 1d.
Mechanistic rational preferential formation of the alde-
hyde could be due to the generation of a more stabilised h3-
intermediate following attack of water on 6b. In contrast,
formation of the ketone requires reaction via a non-delocal-
ised s-bonded intermediate (Scheme 6). The generation of
the h3-intermediate from the h4-complex could result from
attack of water on the double bond either internally (from
palladium) or externally (from the solution); in either case
the h3-intermediate is formed.
Scope of reaction: To further probe the reaction, a more ex-
tended study of the range of styrenes amenable to the reac-
tion conditions was undertaken (Table 4). The anti-Markov-
nikov product was found to predominate for a large range
of commercially available styrenes, from electron-deficient
(e.g. 1h) to electron-rich (1a, 1n). The broad range of styr-
enes that undergo the reaction implies that it may have po-
tential for application in more complex systems.
Catalysis: To extend the synthetic utility of the transforma-
tion, we examined methods for carrying out the anti-Mar-
kovnikov transformation catalytically. A number of ap-
proaches have been adopted to achieve catalytic cycles with
palladium(ii) reactions, and so it was hoped that an appro-
priate reoxidant could be found. It has already been shown
that reoxidation using copper(ii) (generated in situ from
copper(i) and oxygen) was not effective (Scheme 2), giving
largely the ketone product. The sensitivity of the reaction
products to oxygen (in the presence of palladium(ii)) also
precluded this method. A number of other reoxidants used
in the Wacker reaction were examined (Table 5), making
Table 5. Reoxidation attempts.
Entry
Reoxidant
Ratio aldehyde:ketone
1
2
3
4
5
6
1,4-benzoquinone
tBuOOH
H2O2
FeCl3
MnO2
1.0:11.1
1.0:3.0
1.3:1.0
no reaction
ketone only
no reaction
NMO
use of 10 mol% PdCl2 as the catalyst, and either 1a or 1 f as
the substrate. The reoxidants gave variable results: some led
to catalysis of the Wacker reaction but gave undesired regio-
selectivity, whilst others gave no detectable catalysis. For ex-
ample, 1,4-benzoquinone was a good reoxidant but gave
almost exclusively the Markovnikov product.
All of the reoxidants above examined are small molecules,
and had the potential to alter the co-ordination sphere of
palladium. We therefore decided to examine a large, non-
co-ordinating reoxidant. Heteropolyacids (HPA) are large,
cage molecules; HPAs containing molybdenum and vanadi-
um have been used as catalytic reoxidants in the Wacker re-
action, with oxygen as the terminal oxidant.[19] We postulat-
ed that as the ions are large and non-co-ordinating, reoxida-
tion using an HPA could be successful. The heteropolyacid
H4[PMo11VO40] was synthesised[20] and used as an approxi-
mately stoichiometric reoxidant[21] (Scheme 8). Reaction
Scheme 6. Mechanistic proposal for the reversal of regioselectivity.
The h4 nature of the proposed reaction mechanism im-
plied that the styrene acts as a pseudo-diene under the reac-
tion conditions employed; dienes are known to react to
form h3-palladium intermediates following attack by nucleo-
philes. Naphthalene shows more alkene-like character than
benzene; it was therefore reasoned that 2-vinylnaphthalene
1e could show enhanced anti-Markovnikov behaviour
(Scheme 7). As predicted, the more diene-like nature of the
aromatic system led to an increase in the regioselectivity of
the reaction providing additional evidence for the involve-
ment of a diene-like h4-intermediate.
Scheme 7. Reaction of 2-vinylnaphthalene 1e.
Scheme 8. Reoxidation of 1b using HPA.
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Chem. Eur. J. 2006, 12, 949 – 955

Anti-Markovnikov Regioselectivity in the Wacker Reaction
FULL PAPER
distilled in vacuo to give the product as a colourless oil (1.33 g, 40%).
overnight successfully led to catalytic turnover: three-quar-
ters of the starting material was converted to products in the
presence of only 12 mol% PdCl2, representing approximate-
ly 6 turn-over cycles per palladium centre. The major prod-
uct was the anti-Markovnikov aldehyde; the reason for the
degradation of the ratio of products is not entirely clear. We
are currently examining the scope of this catalytic method.
B.p. 60–618C/5 mbar (Lit. [24] 65–668C/10 mm Hg); Rf =0.720 (hexane/
1
diethyl ether (4:1)); H NMR (400.1 MHz, CDCl3, 258C): d=2.37 (s, 6H;
Me), 5.32 (dd, 2J(H,H)=2.0 Hz, 3J(H,H)=18.0 Hz, 1H; alkene CH2 cis
to ring), 5.59 (dd, 2J(H,H)=2.0 Hz, 3J(H,H)=11.6 Hz, 1H; alkene CH2
trans to ring), 6.75 (dd, 3J(H,H)=11.6, 18.0 Hz, 1H; alkene CH), 7.07–
7.11 ppm (m, 3H; aromatic H); 13C{1H} NMR (100.6 MHz CDCl3, 258C):
d=20.8 (Me), 119.3 (CH2), 126.7 (aromatic CH), 127.7 (aromatic CH),
135.1 (aromatic C), 135.7 (aromatic C), 137.7 ppm (alkene CH); IR
(film): n˜ =3064 , 2952, 2861, 1924, 1850, 1632, 1578, 1466, 1443, 1377,
1163, 1097, 993, 922, 767 cmꢀ1; EI-MS: m/z: 68.9, 117.1, 132.1 [M+]; HR-
MS found (calcd for C10H12): m/z: 132.0939 (132.0933); elemental analysis
calcd (%) for C10H12: C 90.85, H 9.15; found: C 90.98, H 8.89.
Conclusion
3,5-Di-tert-butylstyrene (1m): The method of Schlosser and co-workers[26]
was used. Potassium tert-butoxide (491 mg, 4.38 mmol) was dissolved in a
solution of butyllithium in hexane (1.6m, 2.8 mL, 4.48 mmol). 1,3-Di-tert-
butylbenzene (0.96 mL, 4.34 mmol) was added, and the dark brown solu-
tion stirred overnight. The reaction mixture was cooled to 08C, and a so-
lution of DMF (0.34 mL, 4.40 mmol) in dry THF (5 mL) was added. The
reaction mixture was stirred for 10 min before the addition of methyltri-
phenylphosphonium bromide (1.57 g, 4.39 mmol). The orange solution
was stirred at room temperature for seven hours, before being diluted
with water (20 mL) and extracted with hexane (3”10 mL). The organic
solution was washed with aqueous NaCl (20 mL), dried over MgSO4 and
filtered through a silica pad. The solvent was removed at reduced pres-
sure to give a mixture of the product and 1,3-di-tert-butylbenzene, which
could not be separated by distillation. 1H NMR (400.1 MHz, CDCl3,
258C): d=1.35 (s, 18H; tBu), 5.23 (dd, 2J(H,H)=0.4 Hz, 3J(H,H)=
10.8 Hz, 1H; alkene CH2 proton trans to ring), 5.75 (dd, 2J(H,H)=
0.4 Hz, 3J(H,H)=17.6 Hz, 1H; alkene CH2 proton cis to ring), 6.76 (dd,
3J(H,H)=11.2, 17.6 Hz, 1H; alkene CH), 7.28 (d, 4J(H,H)=1.2 Hz, 2H;
In summary, the regioselectivity of the Wacker reaction of
styrenes has been shown to be anti-Markovnikov under stoi-
chiometric conditions. A plausible mechanistic explanation
for this involves an h4-interaction between the palladium
and the substrate. A full range of styrenes (both electron-
rich and electron-poor) undergo anti-Markovnikov addition
under the conditions used. A catalytic version of this reac-
tion has been demonstrated, and is the currently the subject
of further study.
Experimental Section
General: Dry solvents were obtained from Fluka or were dried by stan-
dard methods[22] prior to use, and stored under nitrogen over 4 Š molecu-
lar sieves. Solvents were degassed by carrying out three freeze–pump–
degas cycles. All air- or moisture-sensitive reactions were carried out
under dry nitrogen using standard Schlenk techniques. Solvents were re-
moved by evaporation on a Büchi rotary evaporator, with vacuum pro-
vided either by a water-aspirator pump or by a controlled Teflon-mem-
brane pump. All products were dried at oil-pump vacuum for at least one
hour before spectroscopic characterization. TLC analysis was performed
by using Merck 60 PF254 0.2 mm glass-backed plates; visualization was
achieved by UV or using potassium permanganate or phosphomolybdic
acid dips as appropriate. Flash chromatography[23] was performed using
Merck 9385 Kieselgel 60 silica gel.
4
aromatic H), 7.36 ppm (t, J(H,H)=1.2 Hz, 1H; aromatic H).
2-Methoxystyrene (1n): The method of Suschitzky and co-workers[24] was
used. Methyltriphenylphosphonium bromide (8.94 g, 25.0 mmol) was sus-
pended in dry diethyl ether (100 mL) under nitrogen. A solution of butyl-
lithium in hexane (15% w/w, 16.5 mL, 25.5 mmol) was added dropwise,
and the solution stirred for 2.5h. A solution of 2-methoxybenzaldehyde
(4.69 g, 34.4 mmol) in dry diethyl ether (40 mL) was added dropwise to
the reaction mixture, giving a thick solution. This was heated to reflux
and stirred overnight, giving a colourless solution and a precipitate. The
solution was cooled and filtered, and the solvent removed at reduced
pressure. The residue was distilled at reduced pressure to give the prod-
uct as a colourless oil (1.35 g, 40%). B.p. 38–398C/0.05 mm Hg (Lit. [24]
38–408C/0.05 Torr); Rf =0.523 (hexane/diethyl ether (20:1)); 1H NMR
(400.1 MHz, CDCl3, 258C): d=3.87 (s, 3H; MeO), 5.30 (dd, 2J(H,H)=
1.6 Hz, 3J(H,H)=11.2 Hz, 1H; alkene CH2 proton trans to ring), 5.78
(dd, 2J(H,H)=1.6 Hz, 3J(H,H)=17.6 Hz, 1H; alkene CH2 proton cis to
ring), 6.90 (d, J(H,H)=8.4 Hz, 1H; aromatic H), 6.97 (t, J(H,H)=7.4 Hz,
NMR spectra were recorded in deuterochloroform (CDCl3) unless other-
wise stated. NMR spectra were recorded at 258C in 5 mm tubes, at
400.1 MHz (1H) or 100.6 MHz (13C) on a Bruker Avance 400. Chemical
shifts are quoted relative to the residual solvent peak (d=7.24 ppm for
1H and d=77.0 ppm for 13C); coupling constants (J) are given in Hertz
(Hz). Proton signal multiplicities are given as s (singlet), d (doublet), t
(triplet), q (quartet), p (pentet) and m (multiplet); br indicates a broad
signal. IR spectra were recorded on a Perkin-Elmer Spectrum One FT-
IR with ATR Universal Sampling Accessory as neat solids or liquids.
High resolution mass spectra were recorded on Kratos 890 spectrometer.
GC analysis was performed on an HP 5890 series II machine, using an
HP-1 25 m column.
3
1H; aromatic H), 7.10 (dd, J(H,H)=11.2, 17.6 Hz, 1H; alkene CH), 7.27
(dt, J(H,H)=2.4, 7.8 Hz, 1H; aromatic H), 7.51 ppm (dd, J(H,H)=2.0,
8.4 Hz, 1H; aromatic H); 13C{1H} NMR (100.6 MHz, CDCl3, 258C): d=
55.4 (MeO), 110.8 (aromatic CH), 114.3 (CH2), 120.5 (aromatic CH),
126.5 (aromatic CH), 126.7 (aromatic C), 128.8 (aromatic CH), 131.6
(alkene CH), 156.7 ppm (aromatic C); IR (film): n˜ =3073, 3002, 2957,
2835, 1625, 1598, 1487, 1463, 1437, 1415, 1314, 1291, 1174, 1110, 1036,
997, 909 cmꢀ1; EI-MS: m/z: 68.9, 91.0, 134.1 [M+]; HR-MS found (calcd
for C9H10O): m/z: 134.0734 (134.0732); elemental analysis calcd (%) for
C9H10O: C 80.56, H 7.51; found: C 80.53, H 7.45.
Synthesis of substrates
2,6-Dimethylstyrene (1d): The method of Suschitzky and co-workers[24]
was used with modifications. Methyltriphenylphosphonium bromide
(8.93 g, 25.0 mmol) was suspended in dry diethyl ether (100 mL) under
nitrogen. Butyllithium in hexane (15% w/w, 16.5 mL, 25.5 mmol) was
added dropwise, resulting in a strongly yellow-coloured solution. The re-
action mixture was stirred for 1.5 h, after which time the entire solid had
dissolved. A solution of 2,6-dimethylbenzaldehdye (3.70 g, 27.6 mmol) in
dry diethyl ether (40 mL) was added dropwise to the ylide solution, re-
sulting in rapid formation of a precipitate. The solution was then heated
to reflux overnight. The cooled reaction solution was filtered, before
being washed with HCl (1m, 50 mL), aqueous NaHCO3 (50 mL) and
aqueous NaCl (50 mL). The organic solution was dried over MgSO4, fil-
tered, and the solvent was removed at reduced pressure. The residue was
Adamantane-1-carbaldehyde (10): The general procedure of Corey and
Suggs[27] was used, with reference to the methods of Okamoto and co-
workers,[28] Ramsden and Nongkunsarn[29] and Olah and co-workers.[30]
Pyridinium chlorochromate(vi) (6.47 g, 20.0 mmol) was suspended in dry
dichloromethane (40 mL) under nitrogen. Adamantan-1-ylmethanol
(3.32 g, 20.0 mmol) dissolved in dry dichloromethane (40 mL) was added.
The reaction mixture was stirred for 70 min, after which time it was dilut-
ed with dry diethyl ether (~400 mL) and vigorously stirred. The solution
was filtered through a Florisil pad, the residue being flushed with copious
diethyl ether. The solvent was removed at reduced pressure, giving the
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J. B. Spencer et al.
product as a white, odorous solid (2.93 g, 89%). Attempts to recrystallise
the product failed due to its high solubility in most solvents. Rf =0.402
(hexane-ether 4:1); 1H NMR (400.1 MHz, CDCl3, 258C): d=1.70 (d, J-
(H,H)=2.4 Hz 6H; CH2), 1.66–1.77 (m, 6H), 2.05 (br s, 3H), 9.30 ppm
(s, 1H; CHO); 13C{1H} NMR (100.6 MHz, CDCl3, 258C): d=27.3 (ali-
phatic CH), 35.8 (aliphatic CH2), 36.4 (aliphatic quaternary), 36.5 (ali-
phatic CH2), 206.0 ppm (CHO); IR (solid): n˜ =2901, 2848, 1722 (C=O),
1451, 1075, 987 cmꢀ1; HR-MS (ESI) found (calcd for C11H16O): m/z:
187.1101 (187.1099).
to ring), 6.75 ppm (dd, 3 J(H,H)=10.4, 17.6 Hz, 1H; alkene CH); 13C{1H}
NMR (100.6 MHz, CDCl3, 258C): d=113.8 (CH2) 125.8 (t, 1J(C,D)=
25.2 Hz; aromatic CD), 127.5 (t, 1J(C,D)=25.2 Hz; aromatic CD), 128.0
(t, 1J(C,D)=20.0 Hz; aromatic CD), 136.8 (alkene CH), 137.4 ppm (aro-
matic C); IR (film): n˜ =3089, 2982, 1629, 1425, 1325, 1154, 988, 906, 841,
780, 679 cmꢀ1; EI-MS: m/z: 109.1 [M+], 82.0, 68.9; HR-MS found (calcd
for C8H3D5): m/z: 109.0941 (109.0940); elemental analysis calcd (%) for
C8H3D5: C 88.01, “H” 7.74; found: C 88.00, “H” 7.44.
General procedure for stoichiometric Wacker reactions: The following
general procedure was adopted for the Wacker reactions, which were car-
ried out at either a 0.25-mmol or 0.50-mmol scale. The substrate and any
additives were dissolved in a mixture of degassed DMF (2 mLmmolꢀ1
substrate) and degassed water (0.2 mLmmolꢀ1 substrate). Once dissolu-
tion was complete, the palladium(ii) source (2.0 equiv) was added, and
the reaction mixture stirred at room temperature. The reaction solution
was then poured onto a short pad of silica (approximately 10 g), and
eluted with ether (30 mL). The crude mixture was then examined by gas
chromatography.
1-Ethenyladamantane (4): Methyltriphenylphosphonium iodide (2.37 g,
5.86 mmol) was dissolved in dry THF (20 mL) under nitrogen. The solu-
tion was cooled to 08C, before dropwise addition of a solution of lithium
bis(trimethylsilyl)amide in THF (1.0m, 6.4 mL, 6.4 mmol). The reaction
mixture was stirred at room temperature for 1 h, after which time the so-
lution was clear and yellow. The reaction mixture was cooled to ꢀ788C,
and a solution of 10 (795 mg, 5.30 mmol) in dry THF (8 mL) was added
dropwise. The reaction mixture was allowed to stir overnight, and was
then diluted with diethyl ether (50 mL) and hydrochloric acid (1m,
100 mL). The layers were separated, and the aqueous layer was extracted
with diethyl ether (2”50 mL). The combined organic layers were washed
with HCl (1m, 2”50 mL), aqueous NaHCO3 (2”50 mL), and aqueous
NaCl (2”50 mL). The organic solution was dried over MgSO4, filtered,
and the solvent was removed at reduced pressure. Chromatography on
silica gel (hexane/diethyl ether (99:1)) gave the product as a clear oil
(507 mg, 65%). Rf =0.800 (hexane/diethyl ether (50:1)); 1H NMR
(400.1 MHz, CDCl3, 258C): d=1.57 (d, J(H,H)=2.4 Hz, 6H; aliphatic
CH2), 1.63–1.75 (m, 6H; aliphatic CH2), 1.97 (br s, 3H; aliphatic CH),
4.82 (dd, 2J(H,H)=1.6 Hz, 3J(H,H)=10.4 Hz, 1H; alkene CH2 proton
trans to adamantyl), 4.84 (dd, 2J(H,H)=2.0 Hz, 3J(H,H)=16.8 Hz, 1H;
alkene CH2 proton cis to adamantyl), 5.69 ppm (dd, 3J(H,H)=10.4,
16.8 Hz, 1H; alkene CH); 13C{1H} NMR (100.6 MHz, CDCl3, 258C): d=
28.5 (aliphatic CH), 36.9 (aliphatic CH2), 37.8 (aliphatic quaternary), 41.9
(aliphatic CH2), 108.9 (alkene CH2), 150.1 ppm (alkene CH); EI-MS: m/
z: 68.9, 131.0, 162.1 [M+]; HR-MS found (calcd for C12H18): m/z:
162.1416 (162.1409); elemental analysis calcd (%) for C12H18: C 88.82, H
11.18; found: C 88.97, H 11.33.
(1-Bromoethyl)(D5)benzene (8): The method of Smith and Amin[31] was
used. 1-[(D5)Phenyl]ethanol (7; 5.143 g, 40.4 mmol) was placed in a side-
armed flask and flushed with dry nitrogen for 5 min. Acetyl bromide
(6.00 mL, 81.1 mmol) was added dropwise to the reaction mixture, which
was cooled with an ice bath as soon as the addition was begun.[32] The re-
action mixture was stirred for an additional 10 min at 08C, followed by
10 min at room temperature. The volatile fractions were removed at re-
duced pressure (100 mbar, water bath 508C), and the residue distilled,
giving a colourless oil (6.679 g, 87%). B.p. 72–748C/7 mbar; Rf =0.582
(hexane/diethyl ether (20:1)); 1H NMR (400.1 MHz, CDCl3, 258C): d=
2.08 (d, 3J(H,H)=7.0 Hz, 3H; CH3), 5.25 ppm (q, 3J(H,H)=7.0 Hz, 1H;
CH); 13C{1H} NMR (100.6 MHz, CDCl3, 258C): d=26.7 (CH3), 49.4
(CHBr), 126.3 (t, 1J(C,D)=24.1 Hz; aromatic CD), 127.7 (t, 1J(C,D)=
24.8 Hz; aromatic CD), 128.1 (t, 1J(C,D)=24.5 Hz; aromatic CD),
143.0 ppm (aromatic quaternary); IR (film): n bar=2974, 2921, 1442,
1377, 1186, 1158, 1079, 1039, 967, 954, 841, 825 , 735 cmꢀ1; EI-MS: m/z:
110.1, 68.9, 82.0, 189.0 [M+]; HR-MS found (calcd for C8H4BrD5, 79Br):
m/z: 189.0194 (189.0201); elemental analysis calcd (%) for C8H4BrD5: C
50.55, “H” 5.07; found: C 50.57, “H” 4.80.
Wacker reaction of 1-ethenyladamantane (4): The reaction was carried
out by
a modification of the general procedure. PdCl2 (183 mg,
1.03 mmol) was suspended in DMF (0.75 mL) and water (0.25 mL). 1-
Ethenyladamantane (4; 72.7 mg, 0.490 mmol) was dissolved in DMF
(0.25 mL) and THF (0.25 mL),[33] and was added to the PdCl2 suspension.
The reaction mixture was stirred overnight, before being poured onto a
silica column and eluted with hexane/diethyl ether (4:1). 1-(Adamantan-
1-yl)ethanone (5) was obtained as a white solid (47.1 mg, 59%). Rf =
0.204 (hexane/diethyl ether (9:1)); 1H NMR (400.1 MHz, CDCl3, 258C):
d=1.66 (d, 2J(H,H)=12.0 Hz, 3H; one of C4H2), 1.73 (d, 2J(H,H)=
12.0 Hz, 3H; one of C4H2), 1.78 (d, J(H,H)=2.4 Hz, 6H; C2H2), 2.02 (br
s, 3H), 2.07 ppm (s, 3H; Me); 13C{1H} NMR (100.6 MHz, CDCl3, 258C):
d=24.3 (Me), 28.0 (CH of adamantyl), 36.6 (CH2 of adamantyl),
38.3 ppm (CH2 of adamantyl), aldehyde carbon not observed: in agree-
ment with literature values.[34]
Reaction using palladium(ii) acetate: The general method for the Wacker
reactions was modified as follows. Reaction using palladium(ii) acetate
(229 mg, 1.02 mmol) and 4-methoxystyrene (66.8 mg, 0.498 mmol) under
argon was carried out over 90 h. The reaction mixture was added to a
silica column and eluted using hexane/ethyl acetate (4:1). The product
was obtained as a white solid (53.6 mg, 72%), which was identical by
NMR spectroscopy to commercial material. 1H NMR (400.1 MHz,
CDCl3, 258C) d=2.53 (s, 3H; H3CCO), 3.85 (s, 3H; MeO), 6.91 (d, 3J-
(H,H)=9.2 Hz, 2H; aromatic CH), 7.92 ppm (d, 3J(H,H)=9.2 Hz, 2H;
aromatic CH).
Pre-complexation of styrene and PdCl2: Styrene (52.1 mg, 0.50 mmol)
was dissolved in dry DMF (2.0 mL), and the solution freeze-pump de-
gassed three times. PdCl2 (177 mg, 1.00 mmol) was added, and the mix-
ture stirred overnight, giving a dark red-brown solution. Degassed water
(0.2 mL) was added, and the reaction stirred for 30 min. It was then
poured onto silica and eluted with diethyl ether (50 mL) prior to analysis
by gas chromatography.
Formation of 11-molybdo-1-vanadophophoric acid (9): The method of
Tsigdinos and Hallada[20] was used. Solutions of disodium hydrogen phos-
phate (7.15 g, 50.4 mmol) in water (100 mL) and sodium vanadate(v)
(6.13 g, 50.3 mmol) in boiling water (100 mL) were prepared, mixed and
allowed to cool to room temperature. Concentrated sulfuric acid
(5.0 mL) was added, giving a dark red solution. A solution of sodium mo-
lybdate decahydrate (133 g, 0.55 mol) in water (200 mL) was added, and
the mixture stirred vigorously. Concentrated sulfuric acid (85 mL) was
added cautiously, the reaction mixture cooled to room temperature and
diluted with diethyl ether (400 mL). Three layers were formed: an ether
layer, an aqueous layer, and a bottom layer of deep red liquid. The
bottom layer (the product etherate) was isolated, and the diethyl ether
evaporated by a stream of nitrogen. The resulting solid was redissolved
in water (50 mL), which was then concentrated until crystals were
formed. The product was obtained as red crystals (54.0 g).
1-Ethenyl(D5)benzene (9): Potassium tert-butoxide (11.25 g, 100.0 mmol)
was dissolved in dry THF (100 mL), (1-bromoethyl)(D5)benzene (8;
6.33 g, 33.3 mmol) was added, and the mixture stirred. The solution
became yellow and a precipitate formed. After 30 min, no starting mate-
rial was visible by TLC. The solution was filtered, diluted with diethyl
ether (100 mL), and washed with HCl (1m, 2”50 mL), aqueous NaHCO3
(2”50 mL) and aqueous NaCl (2”50 mL). The organic solution was
dried over MgSO4, filtered and the solvent distilled off by using a 200-
mm Vigreux column. The residue was then distilled at atmospheric pres-
sure, giving a colourless oil (2.360 g, 65%). B.p. 142–1448C; Rf =0.445
(hexane/diethyl ether (20:1)); 1H NMR (400.1 MHz, CDCl3, 258C): d=
5.26 (dd, 2J(H,H)=1.0 Hz, 3J(H,H)=10.4 Hz, 1H; alkene CH trans to
ring), 5.77 (dd, 2J(H,H)=1.2 Hz, 3J(H,H)=17.6 Hz, 1H; alkene CH cis
Catalysis using 11-molybdo-1-vanadophophoric acid: Styrene (98.0 mg,
0.941 mmol) was dissolved in degassed DMF (4.0 mL) and degassed
water (0.4 mL). The reoxidant 9 (2.02 g, 1.13 mmol) and PdCl2 (19.4 mg,
954
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Chem. Eur. J. 2006, 12, 949 – 955

Anti-Markovnikov Regioselectivity in the Wacker Reaction
FULL PAPER
0.109 mmol) were added, and the reaction mixture stirred overnight. It
was then poured onto silica and eluted using ether (50 mL). Gas chroma-
tographic analysis gave a ratio of aldehyde:ketone of 6.35:1.0, and a ratio
of products:starting material of 3.0:1.0.
[11] Unless otherwise started, product ratios were determined by gas
chromatography (see Experimental Section). Authentic samples of
products 3a and 3b, necessary for calibration of the gas chromatog-
raphy system, were produced by IBX oxidation of the corresponding
commercial alcohols. See: a) M. Frigerio, M. Santagostino, S. Spu-
tore, G. Palmisano, J. Org. Chem. 1995, 60, 7272–7727; b) M. Friger-
io, M. Santagostino, Tetrahedron Lett. 1994, 35, 8019–8022; c) M.
Frigerio, M. Santagostino, S. Sputore, J. Org. Chem. 1999, 64, 4537–
4538.
[12] The same reversal of regioselectivity was observed with lower load-
ing of PdCl2 (down to 10 mol% PdCl2). Conversion of the starting
material was obviously lowered.
[13] The reactions were carried out under a nitrogen atmosphere, in
freeze-pump degassed solvents. In the presence of oxygen, the alde-
hyde products were found to be rapidly degraded to the analogous
benzaldehydes. This reaction occurred even in the absence of palla-
dium(ii), but was markedly accelerated by the presence of the metal
salt.
[14] Of the other palladium(ii) salts examined, only [PdCl2(MeCN)2]
gave predominantly aldehyde; all others either failed to react at all
(e.g. PdI2) or gave predominantly methyl ketone (e.g. Pd(NO3)2).
The addition of external ligand sources, such as LiCl, also led to
preferential formation of ketones.
[15] a) M. Donati, D. Morelli, F. Conti, R. Ugo, Chim. Ind. 1968, 50,
231–235; b) F. Conti, M. Donati, G. F. Pregaglia, J. Organomet.
Chem. 1971, 30, 421–429.
[1] Discovery and early references: a) J. Smidt, W. Hafner, R. Jira, J.
Sedlmeier, R. Sieber, Angew. Chem. 1959, 71, 176–182; b) J. Smidt,
W. Hafner, J. Jira, R. Sieber, J. Sedlmeier, J. Sable, Angew. Chem.
Int. Ed. Engl. 1962, 1, 80–88; c) W. Hafner, R. Jira, J. Sedlmeier, J.
Smidt, Chem. Ber. 1962, 95, 1575–1581. For a recent overview of
the reaction, see: d) J. Tsuji, Palladium Reagents and Catalysts. Ap-
plications in Organic Synthesis, Wiley, New York, 1995; e) P. M.
Henry, in Handbook of Organopalladium Chemistry for Organic
Synthesis, vol. 2 (Ed.: E.-I. Negishi), Wiley Interscience, New York,
2002, pp. 2119–2140.
[2] For an overview of the lead mechanistic studies on the Wacker reac-
tion to 1980, see: P. M. Henry, Palladium Catalyzed Oxidation of
Hydrocarbons, D. Riedel Pub. Co., Dordrecht (Netherlands), 1980.
For more recent advances, see: P. M. Henry, in Handbook of Orga-
nopalladium Chemistry for Organic Synthesis, vol. 2 (Ed.: E.-I. Ne-
gishi), Wiley Interscience, New York, 2002, pp. 2119–2140.
[3] For reviews see: a) J. Tsuji, Synthesis 1984, 369–384; b) J. Tsuji,
Palladium Reagents and Catalysts. Applications in Organic Synthesis,
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Chem. 2003, 7, 369–396.
[16] J. R. Holden , N. C. Baenziger, J. Am. Chem. Soc. 1955 77, 4987–
4990. The palladium(ii) chloride–ethene complex is also known:
N. C. Baenziger, J. N. Dempsey, J. Am. Chem. Soc. 1955, 77, 4984–
4987.
[4] J. Tsuji, I. Shimizu, K. Yamamoto, Tetrahedron Lett. 1976, 17, 2975–
2976.
[5] See for example: a) A. K. Bose, L. Krishnan, D. R. Wagle, M. S.
Manhas, Tetrahedron Lett. 1986, 27, 5955–5958; b) H. Pellissier, P.-
Y. Michellys, M. Santelli, Tetrahedron Lett. 1997, 38, 7577–7586;
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[17] An h4 complex of styrene and rhodium has recently been isolated:
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1602.
[18] M. Rubina, V. Gevorgyan, J. Am. Chem. Soc. 2001, 123 11107–
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[7] B. L. Feringa, J. Chem. Soc. Chem. Commun. 1986, 909–910.
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[9] M. J. Gaunt, J. Yu, J. B. Spencer, Chem. Commun. 2001, 1844–1845.
Keinan has reported anti-Markovnikov regioselectivity in the
Wacker oxidation of b-methylstyrenes, in this case due to the influ-
ence of heteroatoms: E. Keinan, K. K. Seth, R. Lamed, J. Am.
Chem. Soc. 1986, 108, 3474–3480.
[10] The mechanism of the Wacker reaction has been investigated
mainly with ethene and higher homologues. There have been a
small number of studies of the mechanism of the Wacker reaction of
styrenes. These have been mainly carried out in largely aqueous
media, see: a) L. M. Zakharova, M. N. Vargaftik, I. I. Moiseev, L. A.
Katsman, Izv. Akad. Nauk SSSR Ser. Khim. 1970, 700–702; Bull.
Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.) 1970, 19, 656–658;
b) L. M. Zakharova, M. N. Vargaftik, I. I. Moiseev, L. A. Katsman,
Kinet. Catal. 1969, 10, 901–903; Kinet. Catal. 1969, 10, 736–744;
c) L. M. Martynova, L. A. Katsman, Kinet. Catal. 1988, 29, 1489–
1491; Kinet. Catal. 1989, 30, 1298–1299; d) L. M. Martynova, L. A.
Katsman, Kinet. Catal. 1990, 31, 844–849; L. M. Martynova, L. A.
Katsman, Kinet. Catal. 1990, 31, 739–744; e) J. Vojtko, A. Kaszonyi,
[19] See for example: a) S. F. Davison, B. E. Mann, P. M. Maitlis, J.
Chem. Soc. Dalton Trans. 1984, 1223–1228; b) B. El Ali, J.-M. Brꢂ-
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[20] G. A. Tsigdinos, C. J. Hallada, Inorg. Chem. 1968, 7 437–441.
[21] The unknown quantity of water in the HPA makes exact stoichiome-
try difficult to assess.
[22] W. L. F. Armarego, D. D. Perrin, Purification of Laboratory Chemi-
cals, 4th ed., Butterworth-Heinemann, Oxford, 2000.
[23] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43 2923–2925.
[24] F. Hollywood, H. Suschitzky, R. Hull, Synthesis 1982, 662–665.
[25] A. H. Schmidt, G. Kircher, J. Zylla, S. Veit, J. Chem. Soc. Perkin
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[26] Q. Wang, H.-X. Wei, M. Schlosser, Eur. J. Org. Chem. 1999, 3263–
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[27] E. J. Corey, J. W. Suggs, Tetrahedron Lett. 1975, 17, 2647–2650.
[28] K. Takeuchi, I. Kitagawa, F. Akiyama, T. Shibata, M. Kato, K. Oka-
moto, Synthesis 1987, 612–615.
[29] P. Nongkunsarn, C. A. Ramsden, Tetrahedron 1997, 53 3805–3830.
[30] O. Farooq, M. Marcelli, G. K. S. Prakash, G. A. Olah, J. Am. Chem.
Soc. 1988, 110 864–867.
[31] P. J. Smith, M. Amin, Can. J. Chem. 1989, 67, 1457–1467.
[32] Cooling the neat alcohol in ice led to the liquid freezing.
[33] THF was used as the substrate was insoluble in neat DMF.
[34] V. V. Krishnamurthy, P. S. Iyer, G. A. Olah, J. Org. Chem. 1983, 48
3373–3378.
ˇ
´
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Received: June 25, 2004
Revised: March 16, 2005
Published online: September 6, 2005
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955