Palladium-catalyzed oxidation of benzyl ketones to synthesis of α-acetoxy ketones using molecular oxygen

Article abstract of DOI:10.1246/cl.130694

An efficient procedure for the preparation of α-acetoxy ketone derivatives by palladium-catalyzed oxidation reactions employing molecular oxygen as the sole oxidant has been reported. A variety of benzyl ketones were used to investigate the scope of the r

Full text of DOI:10.1246/cl.130694

doi:10.1246/cl.130694
1388
Published on the web August 10, 2013
Palladium-catalyzed Oxidation of Benzyl Ketones to Synthesis
of ¡-Acetoxy Ketones Using Molecular Oxygen
Zheng-Wang Chen,* Dong-Nai Ye, Min Ye, and Liang-Xian Liu*
Department of Chemistry and Chemical Engineering, Gannan Normal University,
Ganzhou, Jiangxi 341000, P. R. China
(Received July 28, 2013; CL-130694; E-mail: chenzwang@gnnu.cn)
An efficient procedure for the preparation of ¡-acetoxy
Pd(OAc)2
O2 (8 atm)
O
O
ketone derivatives by palladium-catalyzed oxidation reactions
employing molecular oxygen as the sole oxidant has been
reported. A variety of benzyl ketones were used to investigate
the scope of the reactions.
R2
R1
R2
KI, HOAc
R1
OAc
2
1
Scheme 1. Palladium-catalyzed synthesis of ¡-acetoxy
ketones with O2 as the oxidant.
Oxidation reactions are central components of organic
chemistry. Over the past decades, transition-metal-catalyzed
oxidation reactions have been important tools for constructing
carbon-carbon and carbon-heteroatom bonds, and hence are the
focus of intense synthetic attention.1 Among them, palladium-
catalyzed oxidation reactions have emerged as one of the most
powerful roles in organic synthesis since the development of the
Wacker reaction in the late 1950s.2 However, a great amount of
oxidants such as PIDA, IBX, DDQ, BQ, Oxone, and other noble
metals have been needed for the oxidation process which are
problematic for the cost and environmental impact. Oxygen
is regarded as an ideal oxidant due to its inexpensive and
environmentally benign nature. Therefore, palladium-catalyzed
aerobic oxidation has been one of the hot topics in organic
synthetic chemistry.3
¡-Acetoxy ketones are important sources for ¡-hydroxy
ketones which are highly desirable building blocks for fine
chemistry and pharmaceuticals. Several approaches have been
developed for the preparation of ¡-acetoxy ketones, such as the
oxidation of terminal alkynes in the presence of hypervalent
iodine compounds,4 gold-catalyzed hydration of propargyl
acetates,5 iodobenzene-catalyzed oxidation of ¡-methylene
ketones,6 oxidative coupling reactions of carbonyl compounds
with carboxylic acids,7 lead tetraacetate oxidation of trimethyl-
silyl enol ethers or ketones,8 the oxidation of ketones with
manganese acetate,9 the [Cu(acac)2]-catalyzed insertion reaction
of ¡-diazo ketones,10 the anodic oxidation of enol acetates,11
and some other methods.12 However, some of them present
significant limitations, such as expensive raw materials and
oxidants, low yields, and environmental problems. Therefore,
the continuous development of new reactions with safe and
environmentally friendly systems remains challenging. Herein,
we report an efficient oxidation of benzyl ketones to ¡-acetoxy
ketones catalyzed by palladium with O2 as the sole oxidant
(Scheme 1).13
Table 1. Optimization of reaction conditionsa
O
O
cat., O2
HOAc, additive
OAc
2a
1a
Entry
Cat.
Additive
Yield/%b
1
2
3
4
5
n.r.c
n.p.d
n.p.
10
FeCl3
AgNO3
Cu(OAc)2
PdCl2
27
6
7
8
9
10
11
12e
13f
14g
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[Pd(dba)2]
[Pd(PPh3)4]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
46
30
45
85 (78)
trace
trace
23
trace
trace
I2
ZnCl2
KI
KI
KI
KI
KI
KI
aReactions were performed with 1a (1 mmol), pressure of O2
(8 atm), catalyst (5 mol %), and additive (1 equiv) in 2 mL of
b
acetic acid at 120 °C for 10 h. Determined by GC. Isolated
yield is in parentheses. cNo reaction. dNo product. e60 °C.
g
fReacted in pressure of O2 (1 atm). Reacted in pressure of O2
(12 atm).
found that palladium salts and copper salts could smoothly
promote the transformation and palladium acetate was the most
efficient catalyst (Table 1, Entries 4-6). Inspired by this finding,
different additives were then tried, and we were pleased to find
that KI could improve the isolated yield (Table 1, Entries 7-9).
Further investigation on other palladium catalysts in the new
conditions led to inefficient results (Table 1, Entries 10 and 11).
Lower temperature disfavored the reaction (Table 1, Entry 12).
The pressure of oxygen is essential to the transformation. For
example, 1 atm of oxygen gave low conversion even with a
prolonged time and higher pressure mainly produced the side
product of benzoic acid (Table 1, Entries 13 and 14). After some
attempts, we considered that the optimized reaction conditions
As a starting point for the development of transition-metal
methodology, we chose 1,2-diphenylethanone (1a) under 8 atm
of O2 in acetic acid as the model reaction to study the oxidation
conditions. As summarized in Table 1, the reaction did not
proceed without catalyst (Table 1, Entry 1). Several different
commonly used metal salts were tested as the catalyst to conduct
this reaction, iron salt and silver salt were inactive for the
transformation (Table 1, Entries 2 and 3). To our delight, we
Chem. Lett. 2013, 42, 1388-1390
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1389
Table 2. Palladium-catalyzed oxidation of benzyl ketones for
synthesis of ¡-acetoxy ketonesa
O
O
R2
R2
R1
R1
Pd(OAc)2
2
PdX2
1
O
OAc
X
O2 (8 atm)
KI, HOAc
O
R2
R1
R2
R1
OAc
HX
PdIIX
R1
I
2
1
O
PdIV
O
OAc
R2
O
O
O
R2
R1
B
OAc
OAc
A
O
KI + HOAc + O2
IOAc
2b 86%
KOAc + H2O +
2c 79%
O
OAc
O
Scheme 2. Possible oxidation mechanism.
O
OAc
2e 74%
Scheme 2. First, the PdII catalyst as the electrophilic reagent
undergoes electrophilic substitution at the benzyl position to
afford intermediate A.14 Next, the organopalladium intermediate
A is oxidized to a PdIV intermediate B by IOAc generated in situ
by reacting KI, HOAc with oxygen.13e Finally, elimination
results in the formation of ¡-acetoxy ketone product and PdII.
In summary, we have developed an environmentally benign
and expedient procedure for the synthesis of ¡-acetoxy ketones
by palladium catalysis with O2 as sole oxidant.15 The results
also indicated that the oxidation reaction tolerated a variety of
functional groups.16 Further synthetic applications and studies of
the mechanism of the oxidation reaction are in progress.
2d 78%
O
O
O
O
OAc
2f 71%
OAc
2g 60%
Cl
O
F
O
OAc
OAc
2i 70%
2h 69%
O
O
The authors thank the NSFC (Nos. 21202023 and
21162001), NSF of Jiangxi Province (No. 20114BAB213006)
for financial support.
OAc
2k 32%
OAc
2j 83%
Br
aThe reactions were carried out with 1 (1 mmol), pressure of O2
(8 atm), Pd(OAc)2 (5 mol %), and KI (1 equiv) in 2 mL of
acetic acid at 120 °C for 10 h.
References and Notes
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acid (2 mL) and Pd(OAc)2 (5 mol %) at 120 °C for 10 h (Table 1,
Entry 9).
2
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With the optimized conditions in hand (Table 1, Entry 9),
we next turned our attention to the scope of this palladium-
catalyzed oxidation reaction. As showed in Table 2, different
ketones with either electron-donating or electron-withdrawing
groups attached to the benzene rings were applicable for such an
oxidation reaction, the corresponding ¡-acetoxy ketone products
could be obtained in moderate to good yields. It seemed that
both the aromatic and the aliphatic groups attached to the
carbonyl group had no obvious impact on the transformation
(2b-2j). Substitution at the 2-position of the aromatic ring
slightly lowered the yields (2e-2g). It should be pointed out that
carbon-halogen bonds were well tolerated and the products
containing halogen were afforded smoothly. Especially the aryl
bromides and chlorides could be further functionalized (2i
and 2j). Phenyl ketone (1k) was also tried under the standard
conditions, however, poor yield was obtained, which proved that
the high activity of the benzyl position plays important role for
such a reaction (2k). This reaction was not applicable to allyl
ketones for the double bonds were also oxidized.
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15 Typical experimental procedure: the reactions were carried
out in a HF-15 autoclave. Benzyl ketone (1 mmol), KI
(1 mmol), Pd(OAc)2 (5 mol %), and acetic acid (2 mL) were
added into a 15-mL autoclave in sequence. O2 was pumped
into the autoclave with a cooling pump to reach the desired
pressure, then the autoclave was heated with an oil bath
under magnetic stirring at 110 °C for 10 h. After the reaction
was finished, the autoclave was allowed to cool to room
temperature and O2 was vented. Water (10 mL) was added
and the solution was extracted with ethyl acetate (3 © 8 mL),
the combined extract was dried with anhydrous MgSO4.
Solvent was removed, and the residue was separated by
column chromatography to give the pure sample.
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© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/