Simple and clean synthesis of ketones from internal olefins using PdCl 2/N,N-dimethylacetamide catalyst system

Article abstract of DOI:10.1016/j.tetlet.2013.01.049

A simple catalytic system consisting of PdCl₂ and N,N-dimethylacetamide enabled clean and selective synthesis of ketones from internal olefins using molecular oxygen. Various functionalized internal olefins were directly and regioselectively oxidized; C atoms of CC bonds far from substituted moieties were preferably oxidized.

Full text of DOI:10.1016/j.tetlet.2013.01.049

Tetrahedron Letters 54 (2013) 1596–1598
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Simple and clean synthesis of ketones from internal olefins using
PdCl2/N,N-dimethylacetamide catalyst system
Takato Mitsudome a, Syuhei Yoshida a, Yamato Tsubomoto a, Tomoo Mizugaki a, Koichiro Jitsukawa a,
Kiyotomi Kaneda a,b,
⇑
a Department of Materials Engineering Science, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan
b Research Center for Solar Energy Chemistry, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple catalytic system consisting of PdCl2 and N,N-dimethylacetamide enabled clean and selective
synthesis of ketones from internal olefins using molecular oxygen. Various functionalized internal olefins
were directly and regioselectively oxidized; C atoms of C@C bonds far from substituted moieties were
preferably oxidized.
Received 12 December 2012
Revised 8 January 2013
Accepted 11 January 2013
Available online 17 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Regioselective oxidation
Internal olefin
N,N-Dimethylacetamide
Palladium
Carbonyl groups are important moieties for the construction of
carbon-skeletons and synthetic intermediates.1 Oxygenation of ole-
fins is one of the most straightforward routes to synthesize car-
bonyl compounds. For example, Wacker–Tsuji oxidation is known
as a powerful method for converting terminal olefins into the corre-
sponding methyl ketones and is generally catalyzed by palladium
salts combined with copper salts under aerobic conditions.2–6 De-
spite high efficiency, conventional Wacker–Tsuji oxidation has lim-
ited substrate scope for only terminal olefins and does not show
high activity for internal olefins.7–9 Thus, oxygenation of internal
olefins to ketones is usually conducted via hydration followed by
the oxidation of alcohols (Fig. 1, Eq. 2),10 or hydroboration followed
by oxidation (Fig. 1, Eq. 3).11 These synthetic routes for the forma-
tion of ketones require multiple steps, resulting in the production
of large amounts of waste. Therefore, the development of clean
and highly efficient synthetic methods of ketones from internal ole-
fins is desired.
Recently, we found that the combination of PdCl2 and N,N-
dimethylacetamide (DMA) as the solvent functioned as a clean
and efficient catalyst system for Cu-free Wacker-type oxidation
of terminal olefins, and the in situ generated Pd0 species was di-
rectly reoxidized to PdII species by molecular oxygen.12 Moreover,
this simple catalytic system was successfully applied to direct
oxidation of internal olefins to the corresponding ketones (Fig. 1,
Eq. 1).13 This finding will open up new routes for direct synthesis
of various ketones. If the oxidation of internal olefins occurs regio-
selectively, a more powerful synthetic method could be realized.
Herein, we report a simple and clean method for selective synthe-
sis of ketones from internal olefins. The PdCl2/DMA system pro-
moted highly regioselective oxidation of internal olefins having
functional groups with O2 as a green oxidant.14 The oxygen atoms
were introduced to the C atoms of C@C bonds far from functional
groups (Scheme 1).
Initially, oxidation of (Z)-2-nonenyl acetate was carried out in
the presence of PdCl2 and water in DMA solvent under 6 atm
of O2. Interestingly, (Z)-2-nonenyl acetate was regioselectively
oxidized to 1-acetoxy-3-nonanone in 83% yield with over 99%
selectivity, and trace amounts of the regioisomer 1-acetoxy-2-
nonanone were formed (Table 1, entry 1). The excellent regioselec-
tivity is a sharp contrast to the result obtained from the oxidation
of internal olefins without the acetoxyl group; the use of (E)-2-
nonene afforded non-selective formation of both 2-nonanone and
3-nonanone (production ratio of 2-/3-nonanone = 56/44) (entry 6).
To gain more insight into the acetate-oriented high regioselectiv-
ity, various nonenyl acetates were tested in the PdCl2/DMA catalytic
system (Table 1, entries 1–5). The oxidation of nonenyl acetates
proceeded efficiently and the oxygen atoms were incorporated into
the original olefinic position of the starting materials. This showed
that the migration of C@C bonds in the starting materials did not
occur. The highest regioselectivity was obtained in the case of (Z)-
2-nonenyl acetate and the regioselectivity gradually decreased with
increasingthe number of methylene carbon (m) between C@C bonds
and the acetoxyl moiety. In all the test substrates with the acetoxyl
⇑
Corresponding author.
E-mail address: kaneda@cheng.es.osaka-u.ac.jp (K. Kaneda).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.049

T. Mitsudome et al. / Tetrahedron Letters 54 (2013) 1596–1598
1597
Our novel method
Direct Wacker-type oxidation
O
PdCl2
R2
R2
(eq. 1)
+
R1
R2
R1
R1
DMA/H2O, O2
O
Conventional methods
Hydration/oxidation
O
OH
R2
R2
OH
H2O
R2
[O]
+
R1
+
R1
(eq. 2)
R2
R2
H+
R1
R1
R1
O
Hydroboration/oxidation
1) BH3
R2
O
OH
R2
R2
OH
[O]
+
R1
+
R1
R1
(eq. 3)
R2
R2
2) H2O2, NaOH
R1
R1
O
Figure 1. Synthesis of carbonyl compounds from internal olefins.
PdCl2
DMA, O2
R
FG
R
FG
H2O
+
Table 2
Wacker-type oxidation of various functionalized internal olefinsa
O
FG = OAc, OMe,
CN, OPh etc.
R
FG
FG
PdCl2
R
( )n
+ H2O
( )n
DMA, O2
O
Scheme 1. Regioselective oxidation of internal olefins in PdCl2/DMA catalyst
system.
Entry Substrate
Major product
Yieldb Sel.c
(%)
(%)
OAc
CN
O
O
1
83
>99
Table 1
OAc
Wacker-type oxidation of various nonenyl acetates and 2-nonenea
2
3
4
5
6
90
83
78
64
85
>99
93d
91d
74d
>99
H2n+1Cn
FG
( )m
CN
CN
O
CN
O
O
PdCl2
+ H2O
H2n+1Cn
FG
( )m
1
DMA, O2
+
OMe
O
OMe
OMe
H2n+1Cn
FG
( )m
OMe
OPh
O
O
2
Entry
Substrate
Yieldb (%)
Sel. of 1:2c
OPh
OAc
1
2
3
4
83
79
80
75
>99:<1
90:10
74:26
56:44
O
COOMe
7
76
>99
OAc
OAc
OAc
OAc
COOMe
a
Reaction conditions: substrate (1 mmol), PdCl2 (0.1 mmol), DMA (5 ml), H2O
(0.5 ml), O2 (6 atm), 10 h, 80 °C.
b
Yields of products were determined by GC analysis using an internal standard
5
6
80
85
52:48
44:56
technique.
Ratio based on 1H NMR spectroscopic analysis of crude.
Regioisomer was formed as the by-product.
c
a
d
Reaction conditions: substrate (1 mmol), PdCl2 (0.1 mmol), DMA (5 ml), H2O
(0.5 ml), O2 (6 atm), 10 h, 80 °C.
b
Yields of 1 + 2 were determined by GC analysis using an internal standard
technique.
c
Ratio based on 1H NMR spectroscopic analysis of crude.
benzyl
(2S)-2-[(10Z)-prop-10-en-10-yl)pyrrolidine-1-carboxylate
which is the key step for total synthesis of tropane alkaloids
(Scheme 2).16 The oxidation proceeded efficiently without racemi-
zation to afford benzyl (2S)-2-(20-oxopropyl)pyrrolidine-1-carbox-
ylate as the sole product in 90% yield (87% isolated yield).
group, the C atoms of C@C bonds far from the acetoxyl moiety were
preferably oxidized.15
The scope of olefins with functional groups in the PdCl2/DMA
catalytic system was investigated. The results are summarized in
Table 2. Various olefins with substituents such as acetoxyl, cyano,
methoxy, phenoxy, and ester groups were regioselectively oxidized
to the corresponding ketones in high yields. Neither olefin isomers
nor oxidized products derived from the isomeric olefins were
formed in all substrates tested. In particular, the use of olefins with
functional groups in the allylic position gave the b-functionalized
ketones with excellent yields (entries 1, 2, 4, 6, and 7). Further-
more, this catalytic system was applicable to the oxidation of
In conclusion, we found that the simple catalytic system con-
sisting of PdCl2 and N,N-dimethylacetamide enabled clean and reg-
ioselective synthesis of ketones from internal olefins using
molecular oxygen. Various functionalized internal olefins were di-
rectly and regioselectively oxidized; the C atoms of C@C bonds far
from substituted moieties were preferably oxidized. Furthermore,
the regioselectivity was found to increase with decreasing distance
between C@C bonds and the functional groups. In particular, ole-
fins with functional groups in the allylic position gave the b-func-
tionalized ketones with excellent regioselectivity.

1598
T. Mitsudome et al. / Tetrahedron Letters 54 (2013) 1596–1598
O
PdCl2 (10 mol %)
N
90 % yield
(87% isolated yield)
>99 % sel.
N
DMA (3 mL), H2O (0.3 mL)
Ph
Ph
O
O
O
O
O2 (6 atm), 80 oC, 24 h
benzyl (2S)-2-[(1'Z)-prop-1'-en-
1'-yl)-pyrrolidine-1-carboxylate
benzyl (2S)-2-(2'-oxopropyl)-
pyrrolidine-1-carboxylate
Scheme 2. Regioselective oxidation of benzyl (2S)-2-[(10Z)-prop-10-en-10-yl)-pyrrolidine-1-carboxylate in PdCl2/DMA catalyst system.
4. Tackas, J. M.; Jiang, X. T. Curr. Org. Chem. 2003, 7, 369.
5. Tsuji, J. Palladium Reagents and Catalysts; Wiley: Chichester, 2004.
6. Jira, R. Angew. Chem., Int. Ed. 2009, 48, 9034.
Acknowledgment
This work was supported by JSPS KAKENHI Grant Numbers
23686116, 23360357, 24246129, 22360339.
7. Alper, H.; Januszkiewicz, K.; Smith, D. J. H. Tetrahedron Lett. 1985, 26, 2263.
8. Miller, D. G.; Wayner, D. D. M. J. Org. Chem. 1990, 55, 2924.
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10. Wiseman, P. An Introduction to Industrial Organic Chemistry; Applied Science:
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11. Smith, M. B.; March, J. March’s Advanced Organic Chemistry, 5th ed.; Wiley: New
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12. Mitsudome, T.; Umetani, T.; Nosaka, N.; Mori, K.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. Angew. Chem., Int. Ed. 2006, 45, 481.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.01.
049.
13. Mitsudome, T.; Mizumoto, K.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Angew.
Chem., Int. Ed. 2010, 49, 1238.
14. Catalytic oxidation using molecular oxygen; see (a) Bäckvall, J. E. Modern
Oxidation Methods; Wiley-VCH: Weinheim, 2004; (b) Stahl, S. S. Angew. Chem.,
Int. Ed. 2004, 43, 3400; (c) Mizuno, N. Modern Oxidation Methods; Wiley-VCH:
Weinheim, 2009; (d) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012,
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