Copper(II) and 1,1′-trimethylene-2,2′-biimidazole-promoted arylation of acetylacetone with aryl iodides

Article abstract of DOI:10.1002/cjoc.201190083

A new and efficient way was developed to carry out the reaction of acetylacetone with aryl iodides under the assistance of Cu(II) and 1,1′-trimethylene-2,2′-biimidazole at 100°C. 3-Aryl-2,4-pentanediones were obtained in excellent yields. Copyright

Full text of DOI:10.1002/cjoc.201190083

FULL PAPER
Copper(II) and 1,1'-Trimethylene-2,2'-biimidazole-promoted
Arylation of Acetylacetone with Aryl Iodides
*
Liu, Jianli(刘建立)
Zeng, Runsheng (曾润生)
Zhou, Chunmei(周春梅)
Zou, Jianping(邹建平)
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and
Materials Science, Suzhou University, Suzhou, Jiangsu 215123, China
A new and efficient way was developed to carry out the reaction of acetylacetone with aryl iodides under the as-
sistance of Cu(II) and 1,1'-trimethylene-2,2'-biimidazole at 100 ℃. 3-Aryl-2,4-pentanediones were obtained in ex-
cellent yields.
Keywords Cu(II)-promoted arylation reaction, 1,1'-trimethylene-2,2'-biimidazole, 3-aryl-2,4-pentanedione
Kwong et al.27 found that in the presence of a catalytic
amount of 2-picolinic acid and CuI, the coupling of aryl
iodides and diethyl malonate was carried out smoothly
even at room temperature. However, copper(II)-pro-
moted arylation of acetylacetone with aryl iodides was
seldom reported. In 2006, we28 studied the
2,2'-biimidazole, Cu(II)-catalyzed coupling reaction of
aryl iodides and phenols. As the catalytic system was
applied to the arylation of acetylacetone, the desired
products were not obtained, thus helped us to focus on a
new catalytic system which had a higher activity than
that. To our surprise, copper(II) and 1,1'-trimethylene-
2,2'-biimidazole (6)-promoted arylation of acetylacetone
with aryl iodides could be carried out at 100 ℃ in ex-
cellent yields (Eq. 1).
Introduction
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,1-7 which are very important building blocks
for synthesizing various heterocycles, amino alcohols
and amino acids.8-11 Among the methods available for
the α-aryl carbonyl compounds, a great deal of recent
attention has focused on the development of palla-
dium-catalyzed arylation methodology.12-15 Some excit-
ing achievements have already appeared in the field. For
instance, the coupling of diethyl malonate or ethyl
cyanoacetate with aryl chloride could be carried out at
70 ℃ using certain phosphines as ligand.14 However,
high costs and toxicity of Pd reagents and the relative
ligands limit their application in industrial employment.
The arylation of activated methylene compounds medi-
ated by copper(I) salts is a well-established process。
Dating back to the development of the Hurtley reaction
in 1929,16 the reaction usually requires a stoichiometric
amount of copper salt unless the halides are activated by
an o-carboxylate group.17-22 In 1993, Miura et al.23 re-
ported CuI-catalyzed arylation of acetylacetone with
aryl iodides at 120 ℃. In recent years, research efforts
in several laboratories have delivered a series of mild
Ullmann type methodologies based on employing some
specific ligands. For examples, in 2002, Buchwald and
co-workers24 reported CuI-catalyzed methods for aryl-
ation of diethyl malonate using suitable additives such
as 2-phenylphenol. In 2005, Ma’s group25 and Jiang’s26
group discovered that L-proline was another type of
effective ligands for CuI-catalyzed coupling reactions of
aryl halides and activated methylene compounds.25,26
Experimental
In general, 1H NMR (at 400 MHz) and 13C NMR (at
100 MHz) spectra were recorded on Varian Inova-400
spectrometer with TMS as an internal standard and
CDCl3 as solvent. HRMS was recorded on a Micromass
OA-TOF instrument. For preparative column chroma-
*
E-mail: zengrunsheng@suda.edu.cn; Tel.: 0086-512-65880089
Received November 3, 2009; revised March 29, 2010; accepted September 30, 2010.
Project supported by the National Natural Science Foundation of China (No. 20772088).
Chin. J. Chem. 2011, 29, 309— 313
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309

Liu et al.
FULL PAPER
tography, silica gel H60 was used with the solvent sys-
tem displayed in the text.
General procedure
A mixture of 1 mmol of aryl halide, 2 mmol of ace-
tylacetone, 4 mmol of K2CO3, 0.1 mmol of copper(II)
salt, 0.2 mmol of 1,1'-trimethylene-2,2'-biimidazole and
1 mL of the solvent were heated at 100 ℃ for 6 h. Af-
ter the reaction was completed as monitored by TLC,
the cooled mixture was partitioned between ethyl ace-
tate and saturated NH4Cl. The organic layer was sepa-
rated, and the aqueous layer was extracted with ethyl
acetate. The combined organic layer was washed with
brine, dried over Na2SO4, and concentrated in vacuo.
The residual was loaded on a silica gel column and
eluted with ethyl acetate/petroleum ether (V/V＝1/20—
30) to afford the product.
Table 1 Reaction of acetylacetone with iodobenzene under the
catalysis of copper salts and 1,1'-trimethylene-2,2'-biimidazolea
Entry
Copper salt
Cu(OAc)2•H2O
CuSO4•5H2O
CuCl2•2H2O
CuI
Isolated yield / %
1
2
3
4
5
6
89
63
58
42
28
0b
Results and discussion
Effect of ligand and copper salt
CuCl2
In the first stage of the study, we tried to seek the
optimal ligand from compounds 3—8 (Scheme 1) for
the reaction of the model substrate acetylacetone with
iodobenzene with Cu(OAc)2•H2O as the catalyst. The
reactions promoted by ligand 7 gave low yields, al-
though 7 was often used as an excellent ligand for the
C—C coupling,25,26 ligands 3, 4, and 8 were also tested,
and products were achieved. When the ligands were all
replaced with 1,1'-trimethylene-2,2'-biimidazole (6),
surprisingly the reaction provided 89% yield of 3-aryl-2,
4-pentanediones. Finally, a control experiment without
any ligand was carried out, and low yield was obtained
under the similar condition. From the above descriptions,
ligand 6 was chosen for further investigation. Thus, the
reaction was carried out with different ratios of
1,1'-trimethylene-2,2'-biimidazole (6) and Cu(OAc)2•
H2O. It was found that the combination of 20 mol%
ligand and 10 mol% copper(II) was effective catalytic
system.
—
a
Reaction conditions: [Cu] (0.1 mmol), 1,1'-trimethylene-2,2'-
biimidazole (0.2 mmol), acetylacetone (2 mmol), iodobenzene (1
mmol), K2CO3 (4 mmol), DMSO (1 mL), 100 ℃. b No copper
salt and ligand.
As indicated in the Table 1, the yield of the reaction
which was promoted by the copper salt with crystal wa-
ter was much higher than that without water. It possibly
proved that water participated in the reaction.
Effect of base
To find the suitable base, the reaction of acetylace-
tone with iodobenzene with different base was carried
out at 100 ℃. Based on the results in Table 2, K2CO3
was found to be the suitable base.
Table 2 Reaction of acetylacetone with iodobenzene under the
different basea
Scheme 1
Entry
Base
Isolated yield/%
1
2
3
4
5
6
7
K2CO3
K2CO3
Cs2CO3
Na2CO3
K3PO4
NaOH
NEt3
89
66b
75c
35
41
Trace
Trace
a Reaction conditions: Cu(OAc)2•H2O (0.1 mmol), 1,1'-trimethyl-
ene-2,2'-biimidazole (0.2 mmol), acetylacetone (2 mmol), iodo-
benzene (1 mmol), base (4 mmol), DMSO (1 mL), 100 ℃. b 2
mmol of K2CO3. c 2 mmol of Cs2CO3.
In order to find the best copper salt, the reaction of
iodobenzene with acetylacetone was chosen as the
model reaction (Eq. 2). According to the results in Table
1, Cu(OAc)2•H2O was found to be the best copper salt.
Effect of solvent
In order to find the best solvent, the reaction of ace-
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Chin. J. Chem. 2011, 29, 309— 313

Arylation of Acetylacetone with Aryl Iodides
tylacetone with iodobenzene was carried out in several
kinds of normal solvent. According to the results in Ta-
ble 3, DMSO was found to be the suitable reaction sol-
vent.
Table 4 Reaction of acetylacetone with different aryl iodides
under the catalysis of Cu(OAc)2•H2O and 1,1'-trimethylene-2,2'-
biimidazolea
Entry
Aryl iodide
Product
Time/h Yieldb/%
Table 3 Reaction of acetylacetone with iodobenzene under the
common organic solventa
1
6
6
3
6
6
6
6
6
6
6
89
85
87
83
0
Entry
Solvent
DMSO
DMF
Isolated yield/%
1
2
3
4
5
89
Trace
THF
No reaction
21
2
3
Dioxane
Toluene
Trace
a Reaction conditions: Cu(OAc)2•H2O (0.1 mmol), 1,1'-trimethyl-
ene-2,2'-biimidazole (0.2 mmol), acetylacetone (2 mmol), iodo-
benzene (1 mmol), K2CO3 (4 mmol), solvent (1 mL), 100 ℃.
Synthesis
With optimized condition in hand, the reaction cata-
lyzed by Cu(OAc)2•H2O (10% mmol), 1,1'-trimethyl-
ene-2,2'-biimidazole (20% mmol) was tested with sev-
eral different aryl iodides, and the results are summa-
rized in Table 4.
The reaction was effective for a wide variety of aryl
iodides in excellent yields. However, the protocol is not
tolerant to the presence of a functional group at ortho-
position of the aryl iodide as substrates (Table 4, Entry
5). It was also found that this system was not applied to
the arylation of 1,3-diphenylpropane-1,3-dione,
1-phenyl-butane-1,3-dione, ethyl 3-oxobutanoate, di-
ethyl malonate and ethyl 2-cyanoacetate.
4
5
—
6
81
73
83
65
76
We turned our attention to insight into the mecha-
nism of the reaction (Scheme 2). The solubility of cop-
per acetate cooperated with 2,2'-biimidazole would be
increased. Acetylacetone existed as the enolized anion
in the conditon of base circumstance, and the acetoxyla-
tion of the methylene group seemed to proceed much
more easily when intermediate I reacted with the eno-
lized form of a 1,3-diketone to generate intermediate II.
The intermediate II enhanced the enolized anion
α-carbon nucleophilicity. The reaction of intermediate
II with iodobenzene was greatly influenced by the sub-
stituent group R1 and R2. Definitely the SNAr reaction
was suppressed when R2 was an aryl group and R1 was
an aryl group or an alkyl one due to the possible conju-
gation effect which stabilized the existed enolized anion.
Apart from what presented above, the SNAr reaction
was also suppressed when R2 was an aryl group and R1
was an EtO group as a result of the electronic effect.
7
8
9
3-Phenylpentate-2,4-dione (2a)28
Yield 89%,
white solid, m.p. 38—40 ℃; 1H NMR δ: 16.61 (s, 1H),
7.08—7.33 (m, 4H), 1.80 (s, 6H); 13C NMR δ: 191.1,
137.1, 131.7, 129.0, 127.7, 115.4, 24.4; HRMS calcd for
C11H11O2 176.0837, found 176.0838.
10
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www.cjc.wiley-vch.de
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Liu et al.
FULL PAPER
1
Yield 85%, white solid, m.p. 78—80 ℃; H NMR δ:
16.64 (s, 1H), 7.07 (d, J＝8.4 Hz, 2H), 6.91 (d, J＝8.5
Hz, 2H), 3.83 (s, 3H), 1.88 (s, 6H); 13C NMR δ: 191.4,
159.1, 138.4, 132.3, 129.2, 114.4, 55.4, 24.3; HRMS
calcd for C12H14O3 206.0943, found 206.0944.
Continued
Entry
11
Aryl iodide
Product
Time/h Yieldb/%
3-p-Tolylpentane-2,4-dione28 (2c)
Yield 87%,
6
6
6
82
80
65
white solid, m.p. 66—68 ℃; 1H NMR δ: 16.68 (s, 1H),
7.19 (d, J＝7.8 Hz, 2H), 714 (d, J＝7.7 Hz, 1H), 2.36 (s,
3H), 1.88 (s, 6H); 13C NMR δ: 189.9, 136.1, 132.8,
129.8, 128.5, 113.9, 23.1, 20.1; HRMS calcd for
C12H14O2 190.0994, found 190.0993.
12
13
3-m-Tolylpentane-2,4-dione (2d)
Yield 83%,
yellow solid, m.p. 36—38 ℃; 1H NMR δ: 16.68 (s, 1H),
7.27 (t, J＝7.5 Hz, 1H), 7.14 (d, J＝7.7 Hz, 1H), 6.97 (t,
J＝7.7 Hz, 2H), 2.37 (s, 3H), 1.89 (s, 6H); 13C NMR δ:
191.4, 138.8, 137.2, 132.2, 129.1, 128.6, 128.5, 110.2,
23.1, 20.1; HRMS calcd for C12H14O2 190.0994, found
190.0995.
3-(4-Chlorophenyl)pentane-2,4-dione27
(2f)
a Reaction conditions: Cu(OAc)2•H2O (0.1 mmol), 1,1'-trimethyl-
ene-2,2'-biimidazole (0.2 mmol), acetylacetone (2 mmol), aryl
aryl iodide (1 mmol), K2CO3 (4 mmol), DMSO (1 mL), 100 ℃.
b Isolated yield.
1
Yield 76%, yellow solid, m.p. 82—84 ℃; H NMR δ:
16.69 (s, 1H), 7.37 (d, J＝8.3 Hz, 2H), 7.12 (d, J＝8.2
Hz, 2H), 1.89 (s, 6H); 13C NMR δ: 190.2, 134.7, 132.9,
131.8, 128.4, 113.4, 23.5; HRMS calcd for C11H11ClO2
210.0448, found 210.0448.
Scheme 2
3-(3-Chlorophenyl)pentane-2,4-dione27
(2g)
1
Yield 81%, yellow solid, m.p. 52—54 ℃; H NMR δ:
16.69 (s, 1H), 7.37 (d, J＝8.3 Hz, 2H), 7.12 (d, J＝8.2
Hz, 2H), 1.89 (s, 6H); 13C NMR δ: 190.8, 138.7, 134.5,
131.1, 130.1, 114.1, 24.2; HRMS calcd for C11H11ClO2
210.0448, found 210.0448.
3-(4-Bromophenyl)pentane-2,4-dione29
(2h)
1
Yield 83%, yellow solid, m.p. 76—78 ℃; H NMR δ:
16.70 (s, 1H), 7.53 (d, J＝8.4 Hz, 2H), 7.06 (d, J＝8.4
Hz, 2H), 1.89 (s, 6H); 13C NMR δ: 189.8, 134.8, 131.8,
131.0, 120.7, 113.0, 23.2; HRMS calcd for C11H11BrO2
253.9942, found 253.9942.
3-(2-Fluorophenyl)pentane-2,4-dione (2i) Yield
1
65%, yellow oil; H NMR δ: 16.81 (s, 1H), 7.32—7.37
(m, 1H), 7.18 (d, J＝8.4 Hz, 2H), 7.12 (t, J＝8.7 Hz,
1H), 1.91 (s, 6H); 13C NMR δ: 190.8, 161.3, 158.8,
132.8 (d, J＝2.6 Hz), 129.6 (d, J＝8.0 Hz), 124.0 (d,
J＝3.8 Hz), 115.5 (d, J＝22.6 Hz), 107.7, 23.4; HRMS
calcd for C11H11FO2 190.0743, found 190.0745.
3-(4-Nitrophenyl)pentane-2,4-dione27 (2j) Yield
1
76%, yellow solid, m.p. 104—106 ℃; H NMR δ:
16.78 (s, 1H), 8.27 (d, J＝8.7 Hz, 2H), 7.39 (d, J＝8.7
Hz, 2H), 1.91 (s, 6H); 13C NMR δ: 190.9, 147.7, 144.5,
132.6, 124.5, 114.1, 24.7; HRMS calcd for C11H11NO4
221.0688, found 221.0688.
3-(4-Ethoxyphenyl)pentane-2,4-dione (2k) Yield
82%, white solid, m.p. 66—68 ℃; 1H NMR δ: 16.66 (s,
1H), 7.06 (d, J＝8.6 Hz, 2H), 6.90 (d, J＝8.6 Hz, 2H),
4.04 (q, J＝6.8 Hz, 2H), 1.91 (s, 6H), 1.45 (t, J＝7.0
Hz); 13C NMR δ: 191.7, 158.6, 132.5, 129.3, 115.0, 24.6,
15.3; HRMS calcd for C13H16O3 221.1099, found
221.1166.
3-(4-Fluorophenyl)pentane-2,4-dione (2l) Yield
1
3-(4-Methoxyphenyl)pentane-2,4-dione28
(2b)
80%, yellow oil; H NMR δ: 16.69 (s, 1H), 7.06—7.18
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Chin. J. Chem. 2011, 29, 309— 313

Arylation of Acetylacetone with Aryl Iodides
(m, 4H), 1.89 (s, 6H); 13C NMR δ: 191.3, 164.1, 160.8,
133.0, 132.9, 116.2, 115.9, 24.2; HRMS calcd for
C11H11FO2 190.0743, found 190.0745.
Chem. Soc. 2000, 122, 1360.
8
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In summary, a mild, simple and efficient way was
developed to carry out the Ullmann α-aryl carbonyl
compounds synthesis, which is applicable to a large va-
riety of substrates with different functional groups. This
simple and remarkably active catalytic system repre-
sents the first report of Ullmann-type C—C bond for-
mation using Cu(OAc)2•H2O, which potentially offers
an efficient protocol in accessing a variety of α-arylated
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