that contain 12 equiv of metal per mol of HPA or
stoichiometric palladium. Above that, the reaction has to
be carried out under an inert atmopshere. Hence, a practical
method for aldehyde selective oxidation of styrene and
structurally related olefins remains to be realized.1,2,6,13
The aldehyde products are important precursors to terminal
alcohols13 as well as essential ingredients in artificial flavors,
perfumery, and soaps.14,15 Herein, we report a new catalytic
system that delivers high aldehyde selectivity of up to
>99% with high catalytic efficiencies without the need for
an inert atmosphere.
Table 1. Styrene Oxidation Control Experimentsa
BQ/%
solvent
H2O/%
yield/%
selectivity/%b
115
115
0
t-BuOH
i-PrOH
t-BuOH
t-BuOH
110
110
110
0
83
40
5
98
74
100
95
115
38
a Reactions carried out in 0.125 M solution (0.1 mmol) with 2.5 mol %
catalyst loading at 85 °C. b Selectivity and yield determined by GC with
tridecane as internal standard.
During our development of a method for anti-
Markonikov olefin hydration, we elaborated upon a strat-
egy for the anti-Markonikov Wacker oxidation of olefins
(reaction in abstract).13 The use of t-BuOH to deliver high
aldehyde selectivities in Wacker oxidation has been well
established, albeit often in low yields.2,3,16,17 p-Benzoqui-
none (BQ) is widely used as a hydrogen acceptor and two-
electron oxidant in PdII-catalyzed reactions.18 By combin-
ing PdCl2(MeCN)2, BQ, and t-BuOH in the presence of
stoichiometric amounts of water, we found that both high
aldehyde selectivity and high yields could be obtained with
styrene as the substrate (Tables 1, 2). The reaction with
styrene is highly efficient: a TOF of 37 hꢀ1 with 98%
aldehyde selectivity could be obtained. Such a high TOF
and selectivity is unprecedented for undirected aldehyde
selective Wacker oxidations. Without BQ, no appreciable
turnovers were observed. When the reaction is carried out
in i-PrOH instead of t-BuOH, the selectivity fell to 74%
and the TOF was nearly halved (Table 1). Without adding
H2O, only a 38% yield could be obtained. We attribute this
nonzero aldehyde yield touse of nonanhydrous t-BuOH or
simply to atmospheric moisture. This is consistent with our
earlier report that if water is excluded with molecular
sieves, no aldehyde is observed.13 A lower catalyst loading
of 1 mol % may also be used to give the same TOF of
37 hꢀ1 albeit at a slightly lower selectivity (96%) and lower
maximum aldehyde yield (72%). The selectivity appears
to be inversely proportional to catalyst loading, which
is consistent with previous reports.6,16 Nevertheless,
high aldehyde selectivity can still be achieved at high
yields and catalyst turnovers, without the need for inert
atmosphere or expensive reagents. The catalytic system
is also tolerant of a variety of ring substituents such as
alkyl, trifluoromethyl, ester, and nitro groups as well
as halogens. Generally, the more electron deficient aro-
matic systems resulted in the highest yield of aldehydes.
Electron rich systems such as p-tert-butylstyrene were
less reactive under the reaction conditions, resulting in
poorer yields.
It was initially suspected that the conditions used for the
hydration of styrene could be directly applied to the
Wacker oxidation step by the removal of the reductants.
However, without further modification beyond the re-
moval of reductants, the product yield was much poorer,
which we attributed to product instability and CuCl2 usage
(vide infra). Using the original conditions for hydration
(10% [Pd], 20% CuCl2, 100% BQ, t-BuOH/i-PrOH 2:1,
0.0625 M, 3 h), only a 36% yield of aldehyde at 100%
selectivity could be obtained (cf. 85% anti-Markonikov
products in hydration).13 A kinetic study for the oxidation
of styrene was carried out, and it was observed that the
product yield starts decreasing significantly upon reaching
a maxima, likely due to aldehyde self-condensation (Figure 1).
As such, all styrene oxidation reactions must be stopped
once the product yield reaches its maximum to avoid
product degradation. It is critical to note that when chang-
ing the scale of the reaction from 0.1 mmol of styrene to
0.6 mmol of styrene, we saw a notable delay in the reaction,
leading to a shift in maximum yield from 45 to 60 min
(see Supporting Information).
The usage of CuCl2 was also found to be unnecessary in
the oxidation of styrene. In the presence of only 2.5 mol %
CuCl2, a 10% lower yield was obtained. This may be
attributed to the increase in acidity of the reaction caused
by CuCl2 which in turn results in product instability. The
Wacker oxidation is also known to have an inverse second-
order dependence on chloride concentration, which likely
contributes to decreased oxidation rates.19 Furthermore,
lower catalyst loadings of 2.5 mol % [Pd] could be used
instead of the 10% required for hydration. Upon further
reduction of the catalyst loading both anti-Markovnikov
selectivity and yield are eroded.
As opposed to Feringa’s Pd/Cu/t-BuOH system, for
which a cyclic L-Pd-NO2 intermediate was proposed
(L = MeCNꢀCuCl2ꢀMe3COH) to account for anti-
Markonikov selectivity,16 we postulate a tert-butyl vinyl
ether intermediate (B) instead togive high regioselectivity.2
From earlier mechanistic studies, it was found that, in the
presence of t-BuOH, the olefin (A) would undergo Pd-
catalyzed oxidation to generate B. Due to the bulkiness of
t-BuOH, the linear vinyl ether is preferred, which consti-
tutes the key factor for high anti-Markonikov selectivity.
During the Wacker process, acid is generated and, in the
(13) Dong, G.; Teo, P.; Wickens, Z. K.; Grubbs, R. H. Science 2011,
333, 1609.
(14) Mosciano, G. Perfum. Flavor. 1998, 23, 49.
(15) Chaintreau, A.; Joulain, D.; Marin, C.; Schmidt, C.-O.; Vey, M.
J. Agric. Food Chem. 2003, 51, 6398.
(16) Feringa, B. L. J. Chem. Soc., Chem. Commun. 1986, 909.
(17) Ogura, T.; Kamimura, R.; Shiga, A.; Hosokawa, T. Bull. Chem.
Soc. Jpn. 2005, 78, 1555.
(18) Yang, T.-K.; Shen, C.-Y. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L., Ed.; J. Wiley & Sons: New York, 2004.
(19) Keith, J. A.; Henry, P. M. Angew. Chem., Int. Ed. 2009, 48, 9038–
9049.
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Org. Lett., Vol. 14, No. 13, 2012