Palladium-catalyzed selective anti-markovnikov oxidation of allylic esters

Article abstract of DOI:10.1002/anie.201301809

An aldol alternative: The palladium(II)-catalyzed anti-Markovnikov oxidation of allylic esters to aldehydes at room temperature provides a viable alternative to valuable cross aldol products. High regioselectivity towards the aldehyde product was achieved using the ester protecting group for the allylic alcohol. Rapid isomerization and the much higher rate of oxidation of the branched isomer result in the same product forming from both linear and branched allylic esters. Copyright

Full text of DOI:10.1002/anie.201301809

Angewandte
Chemie
DOI: 10.1002/anie.201301809
Synthetic Methods
Palladium-Catalyzed Selective Anti-Markovnikov Oxidation of Allylic
Esters**
Jia Jia Dong, Martꢀn FaÇanꢁs-Mastral, Paul L. Alsters, Wesley R. Browne,* and Ben L. Feringa*
The palladium(II)-catalyzed oxidation of alkenes to carbonyl
compounds, usually referred to as the Wacker or Wacker–
Tsuji reaction,[1,2] is arguably one of the best-known reactions
catalyzed by palladium. It is an important catalytic process
industrially, for the production of ethanal, and synthetically,
for the conversion of olefins to ketones.[3,4] The oxidation of
terminal alkenes typically proceeds with selective formation
of methylketones.[5] The anti-Markovnikov (AM) Wacker
oxidation of terminal olefins to aldehydes remains, however,
a major challenge.[6] Under certain conditions, AM selectivity
is obtained with styrenes,[7–10] Michael-type acceptor
alkenes[11] and certain olefins, such as 2-vinyl-furanosides,
bearing a directing functional group.[12] Indeed, high aldehyde
selectivity in the catalytic oxidation of phthalimide-protected
allylic amines was reported by our group to yield a key
intermediate in the preparation of b-amino acids.[13] On the
other hand, Sigman and co-workers have reported the
regioselective oxidation of protected allylic amines controlled
by various palladium catalysts to yield the corresponding
methyl ketones.[14]
by selective attack at the terminal carbon of an a-olefin would
be a highly valuable alternative. However, the selective anti-
Markovnikov oxidation of allylic alcohols into b-hydroxy
aldehydes has proven to be very difficult owing to formation
of the ketone products and competing olefin isomerization.[17]
Herein, we demonstrate the aldehyde-selective catalytic
oxidation of ester-protected allylic alcohols with as low as
0.5 mol% of [PdCl2(PhCN)2] and p-benzoquinone (BQ) as
oxidant in tBuOH under ambient conditions. Importantly, the
same anti-Markovnikov oxidation products were obtained
selectively from both branched and linear allylic esters
(Scheme 1), owing to rapid isomerization between allylic
esters under the reaction conditions (see below).
In 1986, PdII-catalyzed aldehyde selective oxidation of
styrene with O2 and CuCl in tBuOH at 308C was reported by
Feringa.[7] Later, Wenzel reported good selectivity (6:1) for
aldehyde formation from allyl acetate (56% combined yield
of aldehyde and ketone), in tBuOH with PdCl2/CH3CN/CuCl/
NaCl at 508C.[15] More recently, the aldehyde-selective
oxidation of styrenes was reported by Grubbs and co-workers
using the catalyst [PdCl2(CH3CN)2], p-benzoquinone as
oxidant, and tBuOH as solvent at 858C.[10] However, a more
general anti-Markovnikov alkene oxidation of non-aryl
alkenes under mild conditions remains a challenge, despite
the tremendous value in extending this reaction to other
substrate classes, in particular allylic alcohols and esters.
b-Hydroxy aldehydes are usually prepared by the cross-
aldol reaction between aldehydes or an aldehyde and
a ketone.[16] The direct catalytic formation of an aldehyde
Scheme 1. Synthesis of b-hydroxy aldehydes by cross aldol reactions
compared with PdII-catalyzed oxidation of allylic esters.
Initial attempts at AM oxidation of ester-protected allylic
alcohols, under conditions used earlier by our group for the
AM oxidation of phthalimide-protected allylic amines,[13]
primarily provided the Markovnikov product (Supporting
Information, Table S1,). A broad screening of reaction
conditions (see the Supporting Information), indicated that
tBuOH and the stoichiometric oxidant p-benzoquinone
offered the highest AM selectivity. The methyl ketone was
the main product obtained in the oxidation of unprotected
allylic alcohol with [PdCl2(CH3CN)2] and p-benzoquinone in
acetone/tBuOH (Table 1, entry 1). Protection of oct-1-en-3-ol
with 2-methoxyethoxymethyl and benzyl groups did not
realize an improvement in regioselectivity (Table 1, entries 2
and 4). Furthermore, the trimethylsilyl-protected allyl alcohol
was found to be unstable, with deprotection observed under
the reaction conditions (Table 1, entry 3).
[*] J. J. Dong, Dr. M. FaÇanꢀs-Mastral, Dr. W. R. Browne,
Prof. Dr. B. L. Feringa
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
E-mail: w.r.browne@rug.nl
b.l.feringa@rug.nl
Dr. P. L. Alsters
DSM Innovative Synthesis
PO Box 18, 6160 MD Geleen (The Netherlands)
In sharp contrast, a wide range of allylic esters were found
to give good aldehyde selectivity under the present reaction
conditions (Table 1, entries 5–12).[18] Aryl ester protected but-
3-en-2-ol provided a > 5:1 ratio of aldehyde to ketone
(Table 1, entries 5, 6, 7, and 10). 2-Furoyl protected but-3-
[**] The authors acknowledge the Netherlands Organization for Scien-
tific Research (NWO-VIDI (700.57.428, W.R.B.), Catchbio (J.J.D.,
M.F.M., B.L.F.), NRSC-C (B.L.F.), and ERC (279549, W.R.B.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301809.
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Table 1: Effects of protecting groups on the oxidation of allylic alcohols.[a]
pentane (Table S6), with acetone giving the highest selectiv-
ities (Table S3, entry 5b). The use of high substrate concen-
trations (0.5m), together with the fact that water does not
need to be added to the reaction indicates, tentatively, that the
tBuOH solvent is the source of the oxygen in the aldehyde
and ketone products.
A range of palladium complexes were tested for anti-
Markovnikov selectivity under optimized reaction conditions
(Table S2). The complex [PdCl2(PhCN)2] showed higher
selectivity in the oxidation of 2B into the corresponding
aldehyde 2A (Table S2) and shorter reaction times in general
compared with, for example, [PdCl2(CH3CN)2].[19]
A key challenge in the palladium-catalyzed oxidation of
alkenes is the often high catalyst loadings employed.[1,3] In the
present system, as little as 0.5–2.5 mol% catalyst is sufficient,
providing excellent aldehyde selectivity (A/M ratios were
7:1–20:1) when substrate concentrations of 0.1–0.5m in
tBuOH/acetone are used (Table 2). Allylic alcohols protected
with a 2-furoyl group (1–8B) were tested under the optimized
reaction conditions: [PdCl2(PhCN)2] (0.5–2.5 mol%), p-ben-
zoquinone (1 equiv) and tBuOH/acetone (24:1 v/v) at room
temperature (Table 2).
Entry
R1
R2
A/M/(L+K)[b]
1[c]
2
C5H11
C5H11
C5H11
H
MEM
TMS
11:89:0
15:85:0
–
3[d]
4
5
Me
Me
20:80:0
79:14:7
6
7
Me
Me
79.5:11.5:9
75:13.5:11.5
8
9
Me
Me
83:11:6
85:10:5
Table 2: PdII-catalyzed oxidation of branched allylic esters.[a]
10
Me
74.5:13.5:12
11
12
C5H11
C5H11
87:6:7
86:7:7
Entry
R
B
Conv.
A/M
A
Yield [%][b]
1[c]
2[d]
3[d]
4[e]
H
1B
2B
3B
4B
full
full
full
full
11:1
7:1
20:1
20:1
1A
2A
3A
4A
78
71
79
73
[a] Reactions were performed with a substrate concentration of 0.025m
and the reaction mixtures were stirred at RT until completion was
indicated by TLC, unless otherwise stated. All reactions gave full
conversion, as determined by 1H NMR spectroscopy. [b] Selectivity
CH3
C2H5
C5H11
1
determined by H NMR spectroscopy. [c] Unidentified side products
5[e,f]
5B
95%
20:1
5A
45
observed. [d] Deprotection was observed under the reaction conditions.
A=anti-Markovnikov product, M=Markovnikov product, K=ketone
product from oxidation of linear ester, L=linear ester, MEM=b-
methoxyethoxymethyl ether, TMS=trimethylsilyl.
6[c]
7[e,f]
8[e,g]
6B
full
20:1
6A
71
Ph
Bn
7B
8B
full
95%
20:1
20:1
7A
8A
52
64
[a] Reactions were performed on 1 mmol of substrate, with a substrate
concentration of 0.5m, unless otherwise noted. Conversion and
selectivity were determined by 1H NMR spectroscopy. Reaction mixtures
were stirred at RT until completion, as determined by TLC analysis.
[b] Yield of isolated product. [c] [PdCl2(PhCN)2] (0.5 mol%). [d] [PdCl2-
(PhCN)2] (1 mol%). [e] [PdCl2(PhCN)2] (2.5 mol%). [f] Unless otherwise
stated, the major side product was the corresponding linear allylic ester
(see the Supporting Information). [g] 0.1m substrate concentration.
Bn=benzyl.
en-2-ol and oct-1-en-3-ol gave a > 7:1 ratio of aldehyde and
ketone (Table 1, entries 8 and 11). Similar aldehyde selectiv-
ity was obtained using the thiophene-2-carboxyl and acetyl
protecting groups (Table 1, entries 9 and 12). The 2-furoyl
protecting group provided high selectivity for the aldehyde
products and was focused upon in the optimization of reaction
conditions (Tables S3, S4, and S5).
Although the selectivity was not affected significantly
when water was present in near stoichiometric amounts, the
addition of excess water led to a reduction in selectivity
(Table S3). The solidification of tBuOH at ambient temper-
atures was found to be problematic and, although the use of
higher temperatures (Table S3) avoided this, the selectivity
was also reduced. The solidification of tBuOH could be
conveniently avoided by the addition of cosolvents, other than
water, such as acetone, dichloromethane, diethyl ether, and
Most aliphatic allylic esters underwent oxidation with
high selectivity for the formation of aldehydes in > 70% yield
(Table 2, entries 1–4). Ester-protected 4-methylhex-1-en-3-ol
(5B) also provided good selectivity, albeit in a yield of only
45% of aldehyde 5A, owing to the formation of the
corresponding linear allylic ester 5L (Table 2, entry 5 and
see below).
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In contrast, the benzyl methyl ether substituted allylic
ester provided high selectivity and yield of the aldehyde
product (Table 2, entry 6). The phenyl- and benzyl-substi-
tuted allylic esters provided the aldehyde in slightly lower
yield (52% and 64%; Table 2, entries 7 and 8, respectively);
again primarily owing to rearrangement, not ketone forma-
tion (see below).
When p-benzoquinone was omitted from the reaction
mixture, the linear allylic ester (for example, 2L) was the
main species present within several minutes (Scheme 2). This
(2K), which result from oxidation of the linear allylic ester,
indicates that k3 @ k4 and that the Curtin–Hammett princi-
ple[23] applies (Scheme 2).
The observation of isomerization predominantly to the
linear isomer under the reaction conditions encouraged us to
examine the possibility of using linear allylic esters as starting
material to obtain protected b-hydroxy aldehydes A. Indeed,
several examples of linear esters L (Table 3) demonstrated
Table 3: Oxidation of linear allylic esters.
Entry
R
L
Conv.[a,b]
A/M
A
Yield [%][b]
1[c]
2[d]
3[d]
CH3
C2H5
C5H11
2L
3L
4L
full
full
95%
7:1
16:1
15:1
2A
3A
4A
70
74
72
4[c]
5[e,f]
6L
8L
full
20:1
10:1
6A
8A
71
43
Bn
85%
[a] Reactions were performed on 1 mmol of substrate, with a substrate
concentration of 0.5m. Conversion and selectivity were determined by
1H NMR spectroscopy. Reaction mixtures were stirred at RT until
completion, as determined by TLC analysis. [b] Yield of isolated product.
[c] [PdCl2(PhCN)2] (2.5 mol%). [d] [PdCl2(PhCN)2] (1 mol%). [e] [PdCl2-
(PhCN)2] (10 mol%). [f] 0.1m substrate concentration.
Scheme 2. a) Isomerization equilibrium and oxidation of linear and
branched alkenes. The mechanism is consistent with b) the partial loss
of ee in the benzyl-protected substrate and the conversion of linear
allylic esters (such as 2L) into branched ester-protected b-hydroxy
aldehydes (Table 3).
that this alternative substrate class could be used, with
selectivities and yields essentially the same as those obtained
from the corresponding branched allylic esters (Table 3). An
exception was 2-furoyl protected 3-phenyl-prop-2-ene-ol 8L,
which showed lower conversion and yield, and which required
higher catalyst loadings than the corresponding branched
allylic ester 8B.
indicates that it is the thermodynamically most stable
regioisomer and that, under the reaction conditions, an
equilibrium (for example, between 2B and 2L) is established.
Such a rearrangement, catalyzed by palladium, has been
noted previously by Henry, Oehlschlager, and others.[20] In the
presence of p-benzoquinone, the rearrangement also oc-
curred, but was slower (ca. 30 min).[26,27] Using the (S)-
enantiomer of benzoate-protected pent-1-en-3-ol,[21] the anti-
Markovnikov product, which was obtained with 30% ee,
(Scheme 2b), showed partial retention of configuration. This
indicated that the rate of oxidation was of a similar order of
magnitude as the rate of isomerization to the corresponding
linear allylic ester (Scheme 2).
A
major advantage of the isomerization between
branched and linear allylic esters is that even substrate
mixtures provide only a single major product, that is, the
aldehyde, in this PdII-catalyzed oxidation (Scheme 3).
Scheme 3. Oxidation of a mixture of linear and branched allylic esters.
From a mechanistic perspective, the rearrangement could
suggest the involvement of (p-allyl)-palladium complexes.
However, in the presence of deuterated acetic acid, neither
The ester group at the allylic position of the alkenes was
found to be key to the anti-Markovnikov selectivity when
compared with other protecting groups (Table 1). This
protecting-group class was previously found to also be
important in the rearrangement of allylic esters with palla-
dium(II) complexes.[20] However, we have found that the
rearrangement can be blocked by the use of cyclic protecting
groups, for example with 4-vinyl-1,3-dioxolan-2-one, where
the oxidized nor the rearrangement products of an acetyl-
[22]
=
À
protected allylic ester contained the CD3C( O) moiety.
Importantly, despite the relatively rapid reversible rear-
rangement to the linear allylic ester, in the presence of
p-benzoquinone, all substrates examined gave the branched
aldehyde as the main product under optimized reaction
conditions. This, together with the low amounts of the ketone
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the corresponding aldehyde was obtained with high selectivity
along with only trace ketone formation and no observed
rearrangement (Scheme 4a). Furthermore, the reaction pro-
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ceeded at a much faster rate than with acyclic allylic esters,
possibly owing to the absence of the competing rearrange-
ment. In this case, competing decarboxylation[28] was also
observed, which leads to decreased yield. It is notable that, as
for isomerization, decarboxylation is much faster in the
absence of p-benzoquinone.
[12] a) M. Mori, Y. Watanabe, K. Kagechika, M. Shibasaki, Hetero-
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Finally, the AM selectivity observed for homoallylic
esters, which cannot undergo isomerization to the linear
allylic esters, was found to be surprisingly high under the
optimized reaction conditions for allylic esters (Scheme 4b).
In summary, we have developed the first highly selective
catalytic anti-Markovnikov oxidation of allylic esters, which
provides a facile route to the synthesis of protected b-hydroxy
aldehydes from terminal alkenes with high selectivity, high
yield, and, importantly, with low Pd catalyst loadings.
Furthermore, the aldehyde products can be obtained using
either the branched or linear protected allylic esters under the
same reaction conditions, which provides a new synthetic
approach for the preparation of b-hydroxy aldehydes from
linear allylic esters, or even mixtures of terminal and internal
alkenes. Future studies will focus on the catalytic use of
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p-benzoquinone using
a redox coupling with oxygen
approach,[24] as applied recently in the Pd-catalyzed oxidation
of internal alkenes.[25]
[18] Although the anti-Markovnikov oxidation products of the
branched allylic esters were the major products, other products,
including Markovnikov oxidation products, rearrangement to
the linear allylic esters, and the oxidation product of the linear
allylic ester were obtained (Table 2, entries 1–8).
[19] Several other palladium complexes, such as Pd(OAc)2, PdCl2-
(PPh3)2 provided no conversion (see also Table S2), whereas
PdCl2 primarily provided the linear allylic ester (L). Oxidants,
other than benzoquinone (Table S4), and other solvents
(Table S1 and S5) provided lower reactivity and selectivity.
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128, 15572 – 15573.
Experimental Section
General procedure for the catalytic oxidation of branched allylic
esters (Table 2): [PdCl2(PhCN)2] and p-benzoquinone were dissolved
in a mixture of tBuOH and acetone (24:1 v/v). The branched allylic
ester B (0.5m) was added to the mixture under N2 and stirred at room
temperature until the reaction was complete, as indicated by TLC
analysis. The combined organic layers were washed with brine, dried
over Na2SO4, and concentrated in vacuo. Purification by flash silica-
gel chromatography yielded the desired aldehyde A.
Received: March 3, 2013
Published online: && &&, &&&&
Keywords: allylic esters · anti-Markovnikov · benzoquinone ·
.
oxidation · palladium
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[22] The addition of acetic acid, although not affecting the selectivity
of the reaction, modestly increased the rate of reaction.
[23] J. I. Seeman, J. Chem. Educ. 1986, 63, 42 – 48.
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[27] The decrease in the isomerization rate in the presence of
p-benzoquinone is consistent with p-benzoquinone binding to
palladium as a ligand (see Ref. [26]), however, it can also be
interpreted as being due to the reduction in the concentration of
Pd0 species in solution, if such species would be responsible for
isomerization.
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Communications
Synthetic Methods
J. J. Dong, M. FaÇanꢁs-Mastral,
P. L. Alsters, W. R. Browne,*
B. L. Feringa*
&&&& — &&&&
Palladium-Catalyzed Selective Anti-
Markovnikov Oxidation of Allylic Esters
An aldol alternative: The palladium(II)-
catalyzed anti-Markovnikov oxidation of
allylic esters to aldehydes at room tem-
perature provides a viable alternative to
valuable cross aldol products. High
regioselectivity towards the aldehyde
product was achieved using the ester
protecting group for the allylic alcohol.
Rapid isomerization and the much higher
rate of oxidation of the branched isomer
result in the same product forming from
both linear and branched allylic esters.
6
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