Direct synthesis of α-keto esters from ethylbenzenes using 48% aqueous HBr by aerobic visible light photooxidation

Article abstract of DOI:10.1055/s-0030-1260585

We report that ethylbenzenes can be directly oxidized to the corresponding -keto esters with molecular oxygen in the presence of 48% aqueous HBr under visible light irradiation. This synthetic procedure is the first example for direct preparation of the corresponding α-keto esters from ethylbenzenes. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260585

LETTER
1381
Direct Synthesis of a-Keto Esters from Ethylbenzenes Using 48% Aqueous
HBr by Aerobic Visible Light Photooxidation
D
N
irec
t
Synthesis
o
o
f
a
-KetoEste
r
rsfrom
i
Ethylbe
h
nzene
s
iro Tada, Kazunori Ban, Tomoya Nobuta, Shin-ichi Hirashima, Tsuyoshi Miura, Akichika Itoh*
Gifu Pharmaceutical University 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
Fax +81(58)2308105; E-mail: itoha@gifu-pu.ac.jp
Received 7 February 2011
oxygen. In the course of our further study for extension of
the application, we have recently found that ethylben-
zenes were directly transformed to the corresponding a-
Abstract: We report that ethylbenzenes can be directly oxidized to
the corresponding a-keto esters with molecular oxygen in the pres-
ence of 48% aqueous HBr under visible light irradiation. This syn-
thetic procedure is the first example for direct preparation of the bromoacetophenones with molecular oxygen in the pres-
corresponding a-keto esters from ethylbenzenes.
ence of 48% aq HBr under visible light irradiation from a
1
4
fluorescent lamp. In this reaction, ethanol was generated
in situ by hydrolysis of ethyl acetate. This suggested to us
that successive combination of oxidation, bromination,
and alcoholysis will make it possible to synthesize the a-
keto esters from ethylbenzenes directly (Scheme 1). We
report here a direct aerobic photooxidative synthesis of a-
keto esters from ethylbenzenes.
Key words: photooxidation, HBr, aerobic, ethylbenzene, a-keto
ester
Oxidative functionalization using molecular oxygen un-
der metal-free conditions has advantages in terms of high
atom efficiency and environmentally benign process.1
Particularly, the selective and direct conversion of hydro-
carbons into synthetically useful compounds is an impor-
tant research theme in modern organic synthesis.
O
2
, hν
O
bromine source
ArEt
OR
Ar
a-Keto esters are important and versatile intermediates in
organic synthesis because they can be readily converted
into a variety of valuable compounds, such as furan deriv-
O
oxidation
alcoholysis
2
3
atives, and bioactive compounds. Due to the importance
of these a-keto esters, various synthetic methods have
4
–12
O
been reported.
O
Br
Br
bromination
Generally, the synthesis of the a-keto ester involves sub-
Ar
4
Ar
stitution of a-dicarbonyl compounds, oxidation of alky-
Br
5
6
7
nyl ethers, terminal alkyne, a-hydroxy esters, arylacetic
Scheme 1
8
9
esters, and dicarbonylation of aryl halide. In 1959, Co-
rey’s group reported the direct synthesis of a-keto esters
1
0
To develop this reaction, we first optimized conditions for
the conversion of ethylbenzene 1a into a-keto ester 2a
(Table 1). We found that 48% aq HBr was the best bro-
mine source and produced 2a in highest yield (entries 1–
from a-bromoacetophenone using selenium dioxide,
and recently, Zhang et al. have reported the one-pot syn-
1
1
thesis of a-keto esters from acetophenones. Further-
more, Tomioka’s group have also reported impressive
results on the photo-induced alcoholysis of a,a,a-trihalo-
1
2). Among the solvents examined, ethyl acetate appears
1
2
to be the most suitable solvent, and ethanol is not an effec-
tive solvent (entries 12–16). Under the optimized condi-
tion (entry 12), the yield of 2a was not very high, because
a-bromo ketone (11%), a,a-dibromo ketone (2%), and a-
keto acid (10%) were obtained as by-products. It suggests
that bromination is the slow step, and a decrease in the
amount of 48% aq HBr to two equivalents resulted in low-
acetophenone to a-keto esters. Although these ap-
proaches provide efficient access to a-keto esters, they
require higher oxidized starting materials than ethylben-
zenes.
Previously, we have reported that methyl groups at the ar-
omatic nucleus are oxidized directly to the corresponding
carboxylic acids and aromatic methyl carboxylates in the
presence of a catalytic amount of bromine source under an
15
er yield (entry 17). A lower yield of 2a was also ob-
served when Hg or Xe lamps were used instead of a
fluorescent lamp (entries 19 and 20). The fact that 2a was
not obtained without the addition of 48% aq HBr, molec-
ular oxygen, or irradiation shows the necessity of all fac-
tors for this reaction (entries 21–23).
13
oxygen atmosphere and irradiation of UV or VIS. These
effective oxidation reactions are of relevance to ‘green
chemistry’ ideals due to non-use of heavy metals and ex-
pensive reagents, waste reduction, and use of molecular
Table 2 shows the scope and limitation of the direct syn-
SYNLETT 2011, No. 10, pp 1381–1384
Advanced online publication: 26.05.2011
DOI: 10.1055/s-0030-1260585; Art ID: U01411ST
x
x
.x
x
.2
0
1
1
thesis of a-keto esters 2 from various ethylbenzenes 1 un-
16
der the optimal reaction conditions mentioned above. In
©
Georg Thieme Verlag Stuttgart · New York

1
382
N. Tada et al.
LETTER
Table 1 Study of Reaction Conditions
tert-butylbenzoylformate (2k) and propyl 3-tert-butyl-
benzoylformate (2l) were obtained in modest and moder-
ate yields, respectively.
O
O2, hν (fluorescent lamp)
bromine source (equiv)
OEt
ArEt
Ar
solvent (5 mL), 20 h
O
a
Table 2 Direct Synthesis of a-Keto Esters
1a Ar = p-ClC6H4
2
O2, hν (fluorescent lamp)
48% aq HBr (2.5 equiv)
O
Entry
Bromine source (equiv)
LiBr (2.5)
Solvent
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
Yield (%)a
OEt
ArEt
EtOAc (5 mL), 20 h
Ar
1
1
2
3
4
5
6
7
8
9
0
O
2
NaBr (2.5)
0
Entry Product
Yield (%)a
KBr (2.5)
0
1
2
3
4
5
2b R = OMe 0b
MgBr ·OEt (2.5)
0
2c R = Ph
2d R = H
2a R = Cl
2e R = Br
2f R = CN
2g R = NO2
54
62
64
59
55
2
2
O
AlBr (2.5)
4
OEt
3
CoBr (2.5)
0
O
2
6
7
R
b
0
CuBr (2.5)
0
2
O
ZnBr (2.5)
0
2
8
9
OEt
2h
2i
44
27
0b
CBr (2.5)
8
4
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
0
Br (2.5)
42
50
64
0
2
O
O
1
30% HBr in AcOH (2.5)
48% aq HBr (2.5)
48% aq HBr (2.5)
48% aq HBr (2.5)
48% aq HBr (2.5)
48% aq HBr (2.5)
48% aq HBr (2.0)
48% aq HBr (3.0)
48% aq HBr (2.5)
48% aq HBr (2.5)
–
S
N
OEt
2
O
3
EtOCOEt
1
1
1
0
OEt
2j
4
EtOCO-i-Pr 10
O
5
(EtO) CO
2
2
O
6
EtOH
0
1c
t-Bu
OMe
2k
2l
14
52
7
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
48
59
47
16
0
O
8
O
2d
t-Bu
OPr
9b
0c
O
a
Isolated yields.
1
b
Starting materials were recovered in 62% (entry 1), 46% (entry 7),
2d
and 86% (entry 10) yields, respectively.
48% aq HBr (2.5)
48% aq HBr (2.5)
0
c
MeOAc was used instead of EtOAc.
PrOAc was used instead of EtOAc.
d
3e
0
a 1
b
H NMR yields.
Reaction irradiated with 400 W Hg lamp.
Reaction irradiated with 500 W Xe lamp.
Reaction carried out under argon.
To examine the reaction mechanism, we studied the time
course of this reaction with 1a as a test substrate
c
d
e
(
Figure 1). In the course of reaction, ethyl acetate was
Reaction carried out in the dark.
gradually hydrolyzed to acetic acid and ethanol, and after
hydrolysis of ethyl acetate, a component of ethanol re-
maining was further oxidized to acetic acid at a late stage
of the reaction.
general, both electron-rich and electron-deficient ethyl-
benzenes gave the corresponding a-keto esters in good
yields except for highly electron-rich and electron-defi-
cient substrates, 4-ethyl anisole (1b) and 1-ethyl-4-
nitrobenzene (1g), respectively (entries 1–7). This reac-
tion is also applicable to the substrates, which possess
naphthalene and thiophene rings, albeit in modest yields
In this reaction, both 2-bromo-1-(4-chlorophenyl)ethan-
one (3a) (26%) and 2,2-dibromo-1-(4-chlorophenyl)ethan-
one (4a) (45%) were detected after seven hours under
optimal conditions (Table 2, entry 4). To determine the in-
termediates of this reaction, 4a and 2,2,2-tribromo-1-(4-
chlorophenyl)ethanone (5a), which are presumed as inter-
mediates,12 were subjected to the reaction conditions
(entries 8 and 9). However, 2-ethylpyridine (1j) is a poor
substrate, presumably due to the basic nitrogen of pyri-
dine ring, which reacted with HBr. Somehow, methyl 3-
(
Scheme 2). The reaction with 4a in the presence of etha-
Synlett 2011, No. 10, 1381–1384 © Thieme Stuttgart · New York

LETTER
Direct Synthesis of a-Keto Esters from Ethylbenzenes
1383
ate tribromoacetophenone 5 through phenacyl bromide 3
and dibromoacetophenone 4. Then, 5 is thought to under-
go the photo-induced alcoholysis and form alkyl benzoyl-
formate 2.12
hν
hν, O2
HBr
Br
Br2
Ar
OO
Br
HBr
HBr Br
O2
Ar
Ar
1
6
7
OOH
O
O
Br2 HBr
Br2 HBr
Br
Ar
Ar
Ar
8
9
3
H2O
Br2 HBr
O
O
O
Br
Br
Br
hν
ROH
OR
Ar
Ar
Ar
Figure 1 T1ime course for the direct synthesis of a-keto ester 2a (de-
Br
Br
O
4
5
2
termined by H NMR analysis)
Scheme 3 Plausible mechanism
nol under photoirradiation gave a-keto ester 2a and 3a in
2
6% and 22% yields, respectively (equation 1 in In conclusion, we have reported a novel direct oxidative
Scheme 2). This result probably suggests that 4a was con- transformation of ethylbenzenes to a-keto esters with mo-
verted into 5a and 3a, and that only 5a was converted into lecular oxygen in the presence of 48% aq HBr under flu-
a-keto ester 2a. In the presence of molecular oxygen, 4a orescent lamp irradiation. The success of this direct
was converted into 2a in 55% yield due to in situ regener- synthesis of a-keto esters from ethylbenzenes depends
ation of bromine (equation 2 in Scheme 2). Furthermore, upon ethanol generated in situ from ethyl acetates in the
2
a was obtained from 5a in good yield only in the pres- course of the reaction.
ence of ethanol under photoirradiation.
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O
argon
O
O
Br
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N. Tada et al.
LETTER
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1
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2
irradiated with four 22-W fluorescent lamps, which were set
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Synlett 2011, No. 10, 1381–1384 © Thieme Stuttgart · New York