Angewandte
Chemie
DOI: 10.1002/anie.201301611
Synthetic Methods
Highly Atom-Efficient Oxidation of Electron-Deficient Internal
Olefins to Ketones Using a Palladium Catalyst**
Takato Mitsudome, Syuhei Yoshida, Tomoo Mizugaki, Koichiro Jitsukawa, and
Kiyotomi Kaneda*
Ketones are ubiquitous in nature and important as diverse
synthetic intermediates in organic synthesis and industrial
chemistry.[1] Selective oxidation of olefins using molecular
oxygen (O2) as a “green” oxidant is a simple and attractive
method for the synthesis of ketone compounds.[2] There has
long been a special interest in the Wacker–Tsuji reaction as
a straightforward and 100% atom-efficient synthesis of
methyl ketones from terminal olefins using Pd catalysts
combined with Cu salts.[3] This classical reaction, however,
inevitably requires large amounts of Cu salts and the substrate
scope is limited to terminal olefins.[4] Thus, conventional
synthesis of ketones from internal olefins has been conducted
employing a strategy with a low atom efficiency, such as the
use of peroxide as an oxidant[5] or a multiple-step synthesis
through hydroboration followed by oxidation.[6]
To overcome this low atom efficiency, recent advance-
ments in the catalytic oxidation of internal olefins have been
achieved. We previously disclosed an O2-coupled Cu-free
Wacker-type oxidation system that consists of PdCl2 and N,N-
dimethylacetamide (DMA) solvent. This simple catalytic
system was successfully applied to the oxidation of not only
various terminal olefins,[7] but also internal ones to afford the
corresponding ketones.[8] Grubbs and co-workers improved
the substrate scope for the Pd-catalyzed oxidation of internal
olefins under ambient temperature in the presence of strong
acid HBF4 in a mixed solvent (DMA/MeCN/H2O) by adding
stoichiometric amounts of benzoquinone (BQ) or catalytic
amounts of BQ and Fe(pc) (pc = phthalocyanine) under
1 atm of O2.[9] Thus, the highly atom-efficient synthesis of
various ketones from olefins is still the subject of considerable
interest.
not yet been achieved.[10] The present catalytic method
represents a simple and 100% atom-efficient synthesis of
ketones from electron-deficient internal olefins using O2 as
the sole oxidant. The selectivities for the corresponding
ketone products were higher than 99% without any forma-
tion of olefin isomers or other oxidized products.
Initially, we carried out the oxidation of methyl trans-2-
octenoate (1) as an electron-deficient internal olefin using our
previously reported PdCl2-DMA catalyst system, which
consists of PdCl2 in DMA as solvent with H2O under O2
atmosphere (Table 1, entry 1). Unfortunately, the oxidation
hardly proceeded and a trace amount of the oxygenated
product methyl 3-oxooctanoate (3) was formed. The addition
of CuCl2 as a co-catalyst also failed to promote the oxidation
of 1 (Table 1, entry 2). Interestingly, when MeOH was added
to the PdCl2-DMA system, the oxidation occurred to afford 3
in low yield accompanied by the formation of methyl 3-
methoxy-2-octenoate (2) in high quantity (Table 1, entry 3).
In contrast, the conventional Wacker–Tsuji oxidation (PdCl2-
CuCl2-DMF) and Pd(OAc)2-HBF4-BQ catalyst systems did
not promote the oxidation in the presence or absence of
Table 1: Oxidation of 1 under various conditions.[a]
Ent. Catalyst Solvent Alcohol[b] Acid[c] Conv.
of
Yield of
1 [%][d] 2 [%][d] 3 [%][d]
1
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
DMA
DMA
DMA
DMF
DMF
–
–
–
–
–
–
<1
<1
80
0
<1
0
0
0
52
0
<1
0
<1
<1
28
0
<1
0
2[e]
3
–
MeOH
–
MeOH
–
Herein, we report a novel oxidation method of electron-
deficient internal olefins to the corresponding ketones.
Electron-deficient internal olefins are extremely unreactive
toward oxidation, and the development of highly efficient
catalytic oxidations of electron-deficient internal olefins has
4[e]
5[e]
6[f] Pd(OAc)2 DMA/
MeCN
HBF4
7[f] Pd(OAc)2 DMA/
MeCN
MeOH
HBF4
–
<1
<1
<1
[*] Dr. T. Mitsudome, S. Yoshida, Dr. T. Mizugaki, Prof. Dr. K. Jitsukawa,
Prof. Dr. K. Kaneda
8[g]
9
10
11
12
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
DMA
DMA
DMA
DMA
DMA
MeOH
MeOH TsOH
MeOH AcOH
MeOH
MeOH MsOH
66
82
69
64
66
65
0
2
3
3
<1
82
67
61
63
Department of Materials Engineering Science
Graduate School of Engineering Science, Osaka University
1-3 Machikaneyama, Toyonaka, Osaka 560-8531 (Japan)
E-mail: kaneda@cheng.es.osaka-u.ac.jp
TFA
Prof. Dr. K. Kaneda
Research Center for Solar Energy Chemistry, Osaka University
1-3 Machikaneyama, Toyonaka, Osaka 560-8531 (Japan)
[a] Reaction conditions: substrate (0.5 mmol), Pd catalyst (0.05 mmol),
solvent (4 mL), H2O (0.5 mL), O2 (6 atm), 808C, 3 h. [b] 1.5 mL.
[c] 0.2 mmol. [d] Determined by GC analysis using an internal standard.
[e] 0.5 mmol CuCl2 added as co-catalyst. [f] Substrate (1 mmol), DMA
(2.2 mL), MeCN (2.2 mL), H2O (0.63 mL), aq HBF4 (48%, 0.18 mL),
benzoquinone (1 mmol), RT, 16 h. [g] Without H2O. TFA=trifluoroacetic
acid, MsOH=methanesulfonic acid.
[**] This work was supported by JSPS KAKENHI (grant numbers
23686116, 23360357, 24246129, and 22360339).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 1 – 4
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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