One-pot synthesis of α-bromoesters and ketones from β-ketoesters and diketones using supported reagents system

Article abstract of DOI:10.1016/j.tetlet.2004.01.014

A simple and efficient method has been developed for the synthesis of α-bromoesters and ketones from β-ketoesters and diketones in one pot using a supported reagents system, CuBr₂/Al₂O ₃-Na₂CO₃/Al₂O₃, in which β-ketoester reacts first with CuBr₂/Al₂O₃ and the product, α-bromo-β-ketoester, reacts with Na ₂CO₃/Al₂O₃ to give the final product, α-bromoesters in good yields.

Full text of DOI:10.1016/j.tetlet.2004.01.014

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1873–1876
One-pot synthesis of a-bromoesters and ketones from b-ketoesters
and diketones using supported reagents system
Tadashi Aoyama,a,* Toshio Takidoa and Mitsuo Kodomarib
aDepartment of Materials and Applied Chemistry, College of Science and Technology, Nihon University, Kanda Surugadai,
Chiyoda-ku, Tokyo 101-8308, Japan
bDepartment of Applied Chemistry, Shibaura Institute of Technology, Shibaura, Minato-ku, Tokyo 108-8548, Japan
Received 12 November 2003; revised 27 December 2003; accepted 6 January 2004
Abstract—A simple and efficient method has been developed for the synthesis of a-bromoesters and ketones from b-ketoesters and
diketones in one pot using a supported reagents system, CuBr2/Al2O3–Na2CO3/Al2O3, in which b-ketoester reacts first with CuBr2/
Al2O3 and the product, a-bromo-b-ketoester, reacts with Na2CO3/Al2O3 to give the final product, a-bromoesters in good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
a-Haloesters and ketones are useful compounds in
organic synthesis. For instance, a-haloesters have been
employed as precursors of a-amino acid and esters,1
thiazolidine-2,4-diones,2 juvenile hormone,3 and vaso-
peptidase inhibitors.4 a-Haloketones are valuable com-
pounds, which are useful in the synthesis of a variety of
precursors. Herein we report a simple and efficient
bromination–deacylation reactions of b-ketoesters and
diketones using supported reagents system CuBr2/
Al2O3–Na2CO3/Al2O3 (Scheme 1).
O
O
6
heterocycles such as thiazoles,5 imidazoles and pyran-
R1
R1
R2
R2
2,5-diones,7 as well as in other synthetic applications
Br
9
including cross aldol condensations,8 enaminoketones
O
1
3
and Favorskii rearrangements.10 a-Haloesters are pre-
pared from substitution of corresponding alcohols,11
halogenation of cyclopropanes,12 addition of halogens
to alkenes.13 Mignani et al.14 reported the synthesis of
a-haloesters by halogenation–deacylation reactions of b-
ketoesters using sodium methoxide and N-halosuccin-
imide. This method is very efficient, but many pre- and
after-treatments are necessary to obtain the products.
We have developed halogenation–deacylation reactions
using a combination of supported reagents. Recently,
polymer or inorganic solid-supported reagents have
been widely used in organic synthesis. However, there
are few examples using a mixture of supported reagents
for synthetic purposes in one pot. One-pot synthesis has
attracted much interest in recent years because it pro-
vides a simple and efficient entry to compounds by
including two or more transformations in a single
operation to increase the complexity of a product
starting from commercially available, relatively simple
Na2CO3/Al2O3
CuBr2 /Al2O3
O
O
R1
Br
R2
2
Scheme 1. One-pot reaction system.
b-Ketoesters or b-diketones were added to the suspen-
sion of alumina-supported copper(II) bromide (CuBr2/
Al2O3)15 and alumina-supported sodium carbonate
(Na2CO3/Al2O3)16 in benzene, and then the mixture was
stirred at 50 °C to give the corresponding a-bromoesters
or ketones in good yields. For example, a mixture of
2-benzyl-3-oxobutyric acid ethyl ester (1a) (1 mmol),
CuBr2/Al2O3 (2.4 mmol) and Na2CO3/Al2O3 (4.5 mmol)
was stirred in benzene (10 mL) at 50 °C for 1.5 h, and
then the used supported reagents were removed by fil-
tration. The filtrate was evaporated to afford the prod-
uct, 2-bromo-3-phenylpropionic acid ethyl ester (3a), in
79% yield, and the purity was >98%. Toluene also can
be used as a solvent for this reaction. When hexane and
* Corresponding author. Tel.: +81-3-3259-0818; fax: +81-3-3259-0818;
e-mail: aoyama@chem.cst.nihon-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.014

1874
T. Aoyama et al. / Tetrahedron Letters 45 (2004) 1873–1876
Table 1. Reaction of 2-benzyl-3-oxobutyric acid ethyl ester (1a) with
various reagents system
Table 2. Preparation of 2-bromo-3-phenylpropionic acid alkyl esters
O
O
Bn
R1
Bn
R1
O
CuBr2 /Al2O3-Na2CO3/Al2O3
Benzene 50 oC 1.5h
O
O
O
CuBr2/Al2O3 - Na2CO3 /Al2O3
Benzene 50 oC 1.5h
Br
Ph
OEt
Ph
OEt
R2
O
1a-d
3a-d
Br
O
1a
b-Ketoester
Products
Yield (%)
3a
O
O
Bn
Bn
79
O
O
Reagents system
Yield (%)
Br
Br
Br
Br
Br
3a
1a
O
2a
3a
CuBr2–Na2CO3
11a
0
7a
O
O
Bn
Bn
Bn
Bn
Bn
11a
100b
0
75
24
79
73
CuBr2–Na2CO3/Al2O3
CuBr2/Al2O3–Na2CO3
CuBr2/Al2O3–Na2CO3/Al2O3
O
O
0
79b
3a
1a'
O
Ph
O
a Yield was determined by GLC.
b Isolated yield.
O
Bn
O
O
3b
1b
O
1,2-dichloroethane were used as a solvent, the yield was
low. As shown in Table 1, both granular CuBr2 and
Na2CO3 are inactive in benzene. In a similar reaction in
DMF, the a-bromoester was observed only 9% yield
along with green precipitate. The reaction using CuBr2/
Al2O3 and Na2CO3 affords only brominated products
2a, and the deacylation did not occur.
O
O
Bn
O
Ph
O
Ph
3c
1c
O
O
O
O
Bn
O
O
O
O
3d
1d
The reaction of a variety of b-ketoesters with CuBr2/
Al2O3 and Na2CO3/Al2O3 in benzene gave correspond-
ing a-bromoesters in good yield, except for 2-benzyl-3-
oxobutyric acid tert-butyl ester (1b) (see Table 2). In the
reaction with 1b, 3-bromo-4-phenyl-2-butanone (3k)
was produced as a main product along with 3b. This
unexpected product 3k was formed by decarboxylation
of the acid, which was yielded by the hydrolysis of
2-benzyl-2-bromo-3-oxobutyric acid tert-butyl ester
(2b). The reactions of benzyl ester (1c) and methoxyethyl
ester (1d) were completed to produce the corresponding
bromoesters in 1 h. In the case of 2-benzyl-3-oxo-3-phe-
nylpropionic acid ethyl ester (1a0), debenzoylation
occurred under similar conditions to afford desired
product 3a, and a small amount of the intermediate,
2-benzyl-2-bromo-3-oxo-3-phenylpropionic acid ethyl
ester (2a0), was also yielded.
2-acetyl-2-bromodecanoic acid ethyl ester (2h) with
Na2 CO3/Al2O3produced deacylated and debrominated
products, 3h and 1h, in 34% and 37% yields (Scheme 2).
The use of large amounts of CuBr2/Al2O3 and Na2CO3/
Al2O3 caused a low yield of a-bromoesters because of
adsorption of the products on the supported reagents.
a-Bromoketones were also obtained from the corre-
sponding b-diketones (1k–p) by using supported
reagents system CuBr2/Al2O3–Na2CO3/Al2O3 (see Table
4). These reactions proceeded with a smaller amount of
Na2CO3/Al2O3 and shorter reaction time than that of
b-ketoesters. 3-(1-Phenylethyl)-2,4-pentanedione (1l)
required a larger amount of Na2CO3/Al2O3 and longer
reaction time than that of the other b-diketones. When
using b-diketones having a long alkyl chain at a-posi-
tion, brominated intermediates were not debrominated
with Na2CO3/Al2O3. Therefore a-bromoketones were
obtained in excellent yields at 50 °C for 1 h.
A series of 2-substituted-3-oxobutyric acid ethyl esters
(1e–j) were converted to the corresponding a-bromo-
esters under similar conditions. The bromination was
not influenced with the steric hindrance of a substituent
at a-position in b-ketoesters, whereas the deacylation
was affected by the steric hindrance. For instance, 2-
acetyl-3-phenylbutyric acid ethyl ester (1f) required a
larger amount of Na2CO3/Al2O3 than that of 1a to give
the product 3f. Bromophenylacetic acid ethyl ester 3e
was produced in good yield only 1 h. In contrast, the
reactions of acetoacetic acid ethyl esters having long
alkyl groups (1g–j) at a-position give corresponding
a-bromoesters in moderate yields (see Table 3).
In addition, we tried to carry out three step reaction in
one pot. That is, an ester having acetylthio group at
a-position was prepared from b-ketoester using three
components of supported reagents in one pot. Com-
pound 1a was added to a suspension of CuBr2/Al2O3,
Na2CO3/Al2O3 and AcOSK/SiO2 in benzene, and the
mixture was stirred at 50 °C for 2 h to give 4a in 34%
yield (Scheme 3).
These compounds are brominated by CuBr2/Al2O3 first
to give the a-bromo-b-ketoesters, which then react with
Na2CO3/Al2O3 to form a mixture of deacylated and
debrominated products. For instance, the reaction of
In conclusion, we have developed a simple and efficient
procedure for synthesis a-bromoesters and ketones in

T. Aoyama et al. / Tetrahedron Letters 45 (2004) 1873–1876
1875
Table 3. Preparation of a-bromo esters
O
O
CuBr2/Al2O3-Na2CO3/Al2O3
Benzene, 50 o
R
O
R
OEt
OEt
3e-j
C
Br
1e-j
Products
CuBr2/Al2O3 (mmol)
2.4
Na2CO3/Al2O3 (mmol)
3.75
Time (h)
1.0
Yield (%)
74
R
3e
Ph
3f
3g
3h
3i
2.4
4.5
4.5
4.5
7.5
7.5
7.5
7.5
2.5
1.5
82
66
46
59
Ph
Ph
22.0
6.0
6
Br
4
O
3j
4.5
7.5
2.0
46
EtO
2
O
O
O
O
AcS
OEt
34 %
OEt
OEt
6
6
O
Br
+
Bn
4a
Bn
1a
Br
Na2CO3/Al2O3
Benzene 50 oC 1.5h
3h
OEt
6
O
2h
O
OEt
37 %
AcSK/SiO2
CuBr2/Al2O3
1h
O
CuBr2/Al2O3
O
O
O
Br
Br
OEt
OEt
Scheme 2.
Bn
Bn
3a
Na2CO3/Al2O3
2a
one pot from readily available starting materials. These
experimental results demonstrate that two reagents
reacting with each other in homogeneous solution are
rendered mutually inactive by supporting them onto
separate inorganic supports, and two step reactions are
possible in one pot by using a couple of supported
reagents. Moreover, these a-bromoesters and ketones,
Scheme 3. One-pot three step reaction.
which have been produced by this method, would be
able to undergo further transformations in the same
vessel, because more reaction stages could be supplied
Table 4. Preparation of a-bromo ketones
O
O
R
O
R
CuBr2/Al2O3-Na2CO3/Al2O3
Benzene, 50 o
C
Br
1k-p
3k-p
Products
CuBr2/Al2O3 (mmol)
2.4
Na2CO3/Al2O3 (mmol)
3.0
Time (h)
1.0
Yield (%)
84
R
3k
Ph
3l
2.4
2.4
2.4
2.4
6.0
3.0
3.0
3.0
2.0
1.0
1.0
1.0
81
88
90
90
Ph
Ph
3m
3n
3o
6
Br
4
O
3p
2.4
3.0
1.0
77
EtO
2

1876
T. Aoyama et al. / Tetrahedron Letters 45 (2004) 1873–1876
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