An efficient and mild CuI/L-proline-catalyzed arylation of acetylacetone or ethyl cyanoacetate

Article abstract of DOI:10.1055/s-2005-918921

The coupling reaction of aryl iodides with acetylacetone or ethyl cyanoacetate under catalysis of CuI/L-proline works at relatively mild conditions to provide 3-aryl-2, 4-pentanediones and α-aryl cyanoacetates in moderate to good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918921

LETTER
2731
An Efficient and Mild CuI/L-Proline-Catalyzed Arylation of Acetylacetone or
Ethyl Cyanoacetate
C
uI/
L
-Proline-Cata
o
lyzedArylat
n
ion of
A
cety
g
lacetone wen Jiang,* Nan Wu, Haihong Wu, Mingyuan He
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University,
3663 North Zhongshan Road, Shanghai, 200062, P. R. of China
Fax +86(21)62233424; E-mail: ywjiang@chem.ecnu.edu.cn
Received 25 July 2005
halides with amines, N-heterocycles, sodium azide,
Abstract: The coupling reaction of aryl iodides with acetylacetone
sulfinic acid salts, phenols, and 1-alkynes.9 Cristau and
co-workers have also developed mild copper-catalyzed N-
or ethyl cyanoacetate under catalysis of CuI/L-proline works at
relatively mild conditions to provide 3-aryl-2, 4-pentanediones and
arylation and C-arylation by employing chelating Schiff
base Chxn–Py–Al as the ligand.10 Stimulated by their re-
sults, we recently found that L-proline could serve as a
promoter for CuI-catalyzed coupling reaction of aryl io-
dides with acetylacetone or ethyl cyanoacetate, giving
cross-coupling products in relatively mild conditions.
Herein we wish to detail our results.
a-aryl cyanoacetates in moderate to good yields.
Key words: cross coupling, arylation, aryl iodide, catalysis, addi-
tive
Reaction of aryl halides with carbon nucleophiles, such as
anions of active methylene compounds, is a useful tool for
the preparation of substituted aromatic compounds,1 such
as 3-aryl-2,4-pentanediones and a-aryl cyanoacetates,
which are very important building blocks for synthesizing
various heterocycles, amino alcohols and amino acids.2,3
Initially, we used the reaction of iodobenzene with acetyl-
acetone as a model to explore the suitable reaction condi-
tions. It was found that under the conditions of 10 mol%
CuI, 20 mol% L-proline, and 4 equivalents K2CO3 in
DMSO the reaction gave 3-phenyl-2,4-pentanedione in
76% yield at 90 °C (Equation 1, entry 1 in Table 1). In the
absence of L-proline, the reaction gave only 35% yield at
90 °C (entry 2), which indicated that the addition of L-pro-
line is necessary to ensure a good yield. When the solvent
was changed from DMSO to DMF, a low yield (17%) was
obtained. Other additives were tested; N,N-dimethylgly-
cine hydrochloride or N-methylglycine also worked but
gave relatively low yields (46% for N,N-dimethylglycine
hydrochloride, 53% for N-methylglycine).a
Among the many methods available for the a-aryl carbo-
nyl compounds, a great deal of recent attention has
focused on the development of palladium-catalyzed aryl-
ation methodology.4 Some exciting achievements have
already appeared in this field. For instance, the coupling
of diethyl malonate or ethyl cyanoacetate with aryl chlo-
ride could be carried out at 70 °C using certain phosphines
as the ligands.4c However, high costs and toxicity of Pd
reagents and the relative ligands limit their application in
industrial employment.
The arylation of activated methylene compounds mediat-
ed by copper salts is a well-established process,5 but the
reaction usually requires a stoichiometric amount of
copper salt unless the halides are activated by an o-car-
boxylate group.6 In 1993, Miura et al. reported a copper-
catalyzed arylation of malononitrile, ethyl cyanoacetate
and acetylacetone using aryl iodides.7 However, their sys-
tem required harsh condition (120 °C) and the substrate
scope was limited. In recent years, research efforts in sev-
eral laboratories have delivered a series of mild Ullmann-
type methodologies based on employing some specific
ligands. For examples, Buchwald and co-workers report-
ed copper-catalyzed methods for arylation of amides,
amines, N-heterocycles, hydrazides, phenols and a-aryl
malonates using suitable additives such as glycol and di-
ethylsalicyamide.8 Ma’s group discovered that L-proline
and other amino acids were another type of effective
ligands for copper-catalyzed coupling reactions of aryl
O
O
10 mol% CuI, 20 mol% L-proline
K2CO3, DMSO, 90 °C
O
O
+
I
1a
2a
Equation 1
In order to explore the reaction scope, a number of aryl
iodides with different substituents were tested and the re-
sults were summarized in Table 1. It was found that either
electron-rich or electron-deficient aryl iodides were suit-
able for this reaction, giving desired coupling products in
moderate to good yields. When 4-iodophenol was em-
ployed, the desired product was obtained only in 20%
yield. It was possible that the self-coupling of 4-iodophe-
nol made the reaction complex. The reaction of 3-iodoani-
sole gave a higher yield using Cs2CO3 as the base (entry
11 vs. entry 10). A few amount of benzyl methyl ketone
as by-product was observed in some cases. It was noticed
that the coupling of 1,3-cyclohexanedione with 4-iodoani-
sole gave a good result (entry 13) while it did not work in
Buchwald’s catalytic system.8f
SYNLETT 2005, No. 18, pp 2731–2734
0
3
.1
1
.2
0
0
5
Advanced online publication: 10.10.2005
DOI: 10.1055/s-2005-918921; Art ID: U24705ST
© Georg Thieme Verlag Stuttgart · New York

2732
Y. Jiang et al.
LETTER
Table 1 CuI/L-Proline-Catalyzed Coupling Reaction of Aryl Iodides with Diketonesa
Entry
1
Aryl iodide
Product
Temp (°C)/Time (h)
90/6
Yield (%)b
76
35c
73
56
70
75
86
I
O
O
2
90/6
I
O
O
3
90/14
90/20
90/24
90/12
90/10
O
O
O
I
O
4
MeO
I
O
MeO
O
5d
6
O
O
HOOC
EtOOC
I
HOOC
EtOOC
O
O
I
7
O
O
I
F3C
H3C
F3C
H3C
8
9
90/9
89
20
45
O
I
O
90/10
90/20
O
HO
I
HO
O
10
O
I
I
O
MeO
MeO
MeO
MeO
11e
12e
60/20
60/24
66f
79
O
O
I
O
O
O2N
O2N
13g
90/24
78
O
MeO
I
MeO
O
a Reaction conditions: 0.5 mmol aryl iodide, 1.5 mmol acetylacetone, 0.05 mmol CuI, 0.1 mmol L-proline, 2 mmol K2CO3, DMSO, 90 °C.
b Isolated yield.
c
L-Proline was not used.
d The amount of 2.5 mmol K2CO3 was used.
e Cs2CO3 was used as the base, and reaction was carried at 60 °C.
f Yield based on aryl iodide recovery.
g 1,3-Cyclohexanedione was used.
Synlett 2005, No. 18, 2731–2734 © Thieme Stuttgart · New York

LETTER
CuI/L-Proline-Catalyzed Arylation of Acetylacetone
2733
The ligand effect of L-proline on the coupling of aryl tive, a relatively low yield (57% for N,N-dimethylglycine
iodides with ethyl cyanoacetate was also confirmed. Un- hydrochloride, 65% for N-methylglycine) was obtained.
der the promotion of L-proline, the reaction of iodoben- Further investigations indicated that a variety of aryl io-
zene with ethyl cyanoacetate gave a higher yield at 90 °C dides, including those with fluoro, methoxy, carboxylate,
(Table 2, entry 1 vs. entry 2). When N,N-dimethylglycine and acetyl substituents, showed great ability to react with
hydrochloride or N-methylglycine was used as the addi- ethyl cyanoacetate in the presence of L-proline, providing
Table 2 CuI/L-Proline-Catalyzed Coupling Reaction of Aryl Iodides with Ethyl Cyanoacetatea
CN
10 mol% CuI, 20 mol% L-proline
Ar
ArI
NC
COOEt
+
K2CO3, DMSO, 90 °C
COOEt
3
1
Entry
1
Aryl iodide
Product
Temp (°C)/Time (h)
90/5
Yield (%)b
67
CN
I
COOEt
CN
2
3
4
90/5
47c
60
I
COOEt
90/11
90/10
CN
COOEt
CN
H3C
O
I
H3C
O
92
I
COOEt
CN
5
6
7
90/10
60/11
90/12
63
MeO
MeO
I
MeO
MeO
COOEt
CN
84d
78
I
COOEt
CN
I
COOEt
F3C
F3C
8
9
90/19
90/13
90/13
37
67
78
CH3
CH3
I
CN
COOEt
CN
F
F
I
COOEt
CN
10
H3C
H3C
H3C
H3C
I
I
COOEt
11
90/14
69
CN
COOEt
MeO
MeO
12
90/12
90/14
80
82
CN
COOEt
EtOOC
MeO
I
EtOOC
MeO
13e
CN
CN
I
a Reaction conditions: 0.5 mmol aryl iodide, 1.5 mmol ethyl cyanoacetate, 0.05 mmol CuI, 0.1 mmol L-proline, 2 mmol K2CO3, DMSO, 90 °C.
b Isolated yield.
c
L-Proline was not used.
d Cs2CO3 was used as the base, and reaction was carried at 60 °C.
e Malononitrile was used.
Synlett 2005, No. 18, 2731–2734 © Thieme Stuttgart · New York

2734
Y. Jiang et al.
LETTER
(2) For 3-aryl-2,4-pentanedione, see: (a) Hauser, C. R.;
the corresponding coupling products (Table 2). Similar to
the above-mentioned results, the use of Cs2CO3 as the
base led to a higher yield for the reaction of 4-iodoanisole
with ethyl cyanoacetate under milder conditions (entry 5
vs. entry 6). For the sterically hindered substrates, slightly
low yields were observed (entry 8 and entry 9). The
coupling of 4-iodoanisole with malononitrile also gave a
good result (entry 13).
Manyik, R. M. J. Org. Chem. 1953, 18, 588. (b) Wright, J.
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Villegas, M. D.; Galvez, J. A. J. Org. Chem. 1994, 59, 2497.
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In summary, we have found that CuI/L-proline-catalyzed
coupling reaction of aryl iodides with acetylacetone or
ethyl cyanoacetate could be carried out at relatively mild
conditions, which allows assembling 3-aryl-2,4-pen-
tanediones or a-aryl cyanoacetates that possess a variety
of functional groups in moderate to good yields. Further
work on the coupling of less active aryl bromides or the
replacement of the solvent by room temperature ionic
liquids is in progress.
Typical Experimental Procedure
A mixture of iodobenzene (0.5 mmol), acetylacetone (1.5 mmol),
K2CO3 (2.0 mmol), CuI (0.05 mmol), L-proline (0.1 mmol) in 2 mL
of DMSO was heated at 90 °C under nitrogen atmosphere for 6 h.
The cooled solution was poured into 1 N HCl, extracted with
EtOAc. The combined organic layers were washed with brine, dried
over Na2SO4, and concentrated. The residue was chromatographed
to afford 3-phenyl-2, 4-pentanedione.
Acknowledgment
(7) Okuro, K.; Furuune, M.; Miura, M.; Nomura, M. J. Org.
Chem. 1993, 58, 7606.
The authors are grateful to Science and Technology Commission of
Shanghai Municipality (grant No. 03DJ14005) for their financial
support.
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Synlett 2005, No. 18, 2731–2734 © Thieme Stuttgart · New York