Highly efficient copper catalytic system for the O-arylation of phenol with iodoarene

Article abstract of DOI:10.1016/j.tetlet.2011.10.149

An efficient Cu-catalyzed O-arylation was carried out by involving phenols with iodoarenes to afford various substituted diarylether derivatives with tiny loading of Cu₂O and 1H-imidazole-4-carboxylic acid as catalytic system under mild conditions, which provided good to excellent yields with good tolerance of functional groups.

Full text of DOI:10.1016/j.tetlet.2011.10.149

Tetrahedron Letters 53 (2012) 71–75
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Tetrahedron Letters
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Highly efficient copper catalytic system for the O-arylation of phenol
with iodoarene
⇑
An-Yi Cheng, Jen-Chieh Hsieh
Department of Chemistry, Tamkang University, New Taipei City 25137, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient Cu-catalyzed O-arylation was carried out by involving phenols with iodoarenes to afford var-
ious substituted diarylether derivatives with tiny loading of Cu2O and 1H-imidazole-4-carboxylic acid as
catalytic system under mild conditions, which provided good to excellent yields with good tolerance of
functional groups.
Received 19 August 2011
Revised 10 October 2011
Accepted 27 October 2011
Available online 4 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cu2O
Ullmann coupling
1H-imidazole-4-carboxylic acid
Diaryl ether
O-arylation
Diaryl ether derivatives are very important compounds for or-
ganic synthesis because of their wide application in biology,1 poly-
mer science2 and the synthesis of natural products;3 most of them
are prepared by the transition-metal-catalyzed O-arylation of phe-
nol with aryl halide. Among the various protocols reported to date,
the copper catalyzed O-arylation is the most general pathway to
generate diaryl ethers. Copper catalyzed Ullmann reaction4 involv-
ing the coupling of phenols with aryl halides is a convenient meth-
od for large scale synthesis under aerobic conditions. However,
they were always performed with high catalyst loadings5 or
requirement of high temperatures6 which inhibited their applica-
tion for the construction of complex molecules.7,8 The most effec-
tive modification for this Ullmann-type O-arylation is generally
by ligand screening. Thus, many efficient ligands were introduced
to promote the coupling reaction, including amine,9 triol,10 1,10-
phenanthroline,11 bipyridine,11 amino acid12 and phosphoric acid
etc.13
amount of catalyst and mild conditions to generate a wide range
of diaryl ethers.
In a preliminary reaction, iodobenzene (1a) was treated with
phenol (2a) in the presence of 10 mol CuI, 20 mol % 2,20-bipyridine
(L1) and 2.0 equiv K3PO4 in DMF at 100 °C for 24 h; the correspond-
ing diphenylether was obtained only in a 5% NMR yield (Table 1,
entry 1). Almost all of the starting materials were maintained under
the above condition, thus made us try to find the suitable ligand out
in our first investigation.
During the study of the effect of ligands, we discovered that
when the 1,10-phenanthroline (L2) and 2,20-biimidazole (L3) were
employed as ligands, the desired product 3a was obtained in 8%
and 11% yields, respectively, (entries 2 and 3). L4 and L8 were
found to be functionless, only amino acid species (Table 1, entries
5–7) significantly enhanced yields of the product 3a. The best
choice of the ligand was L6 (entry 6), which provided higher yield
than others.
It was revealed by recent reports that the Ullmann-type O-ary-
lation could be carried out under mild conditions.14 However, the
loading of catalyst for most cases was still high,15 which repressed
the economic consideration of industry. Therefore, a better combi-
nation of copper source with ligand was necessary for improve-
ment of the performance of this coupling reaction. Herein, we
wish to publish an efficient method with the effective combination
of Cu2O with amino acid species as the catalytic system for O-ary-
lation of phenols with iodoarenes, which require only small
With a suitable ligand in hand, we further optimized the reac-
tion conditions and the results are listed in Table 2. It was found
that only polar solvent afforded desired product 3a (Table 2, entries
1–7), DMF and DMAc were better than others. The CH3CN provided
slightly lower yield; however, it was chosen because of the easy
removable property. The performance of this coupling reaction also
strongly depends on the base (entries 8–10); the Cs2CO3 exhibited
better improvement than K2CO3 and K3PO4 to give the correspond-
ing product 3a in a 79% yield. t-BuOK showed no reactivity for this
reaction. When different copper sources were employed, the reac-
tion was also affected (entries 11–15); among the various copper
sources employed as catalyst, the Cu2O was found to be the most
⇑
Corresponding author. Tel.: 886 2 26215656x2545; fax: 886 2 26209924.
E-mail address: jchsieh@mail.tku.edu.tw (J.-C. Hsieh).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.149

72
A.-Y. Cheng, J.-C. Hsieh / Tetrahedron Letters 53 (2012) 71–75
Table 1
Comparison of various ligands in the coupling reactiona
10 mol% CuI
I
OH
20 mol% L
O
2.0 eq. K3PO4
DMF, 100 oC, 24 h
+
1a
2a
3a
N
N
N
N
H
L1
L2
L3
HO
OH L4
N
N
N
N
H
N
N
HN
H
OH
OH
OH
OH
N
H
N
N
L5
L6
L7
L8
O
O
O
O
Entry
L
Yieldb (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
5
8
11
0
44
59
53
0
a
Reactions were carried out using 0.1 mmol iodobenzene (1a), 0.12 mmol phenol (2a) with 10 mol % CuI, 20 mol %
ligand and 2.0 equiv K3PO4 in 1.0 mL DMF for 24 h.
b
1H NMR yield based on internal standard mesitylene.
Table 2
Optimization of reaction conditionsa
x mol% [Cu]
y mol% L6
I
OH
O
2.0 eq. Base
+
Solvent, T oC, 24 h
1a
2a
3a
Entry
x
y
[Cu]
Solvent
base
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16c
17c
18c
19c
20c
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
10
5
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
Cu(OAc)2
Cu(OTf)2
CuSCN
Cu2O
Cu2O
Cu2O
DMF
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
t-BuOK
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
100
100
100
100
100
80
80
80
80
80
80
80
80
80
80
80
80
60
59
28
0
Dioxane
Benzene
Toluene
DMAc
0
59
23
52
0
DME
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
62
79
67
62
81
67
93
96
93
75
5
5
5
5
1
5
5
2
Cu2O
Cu2O
Cu2O
rt
80
93
a
b
c
Reactions were carried out using 0.1 mmol iodobenzene (1a), 0.12 mmol phenol (2a) with copper source, ligand and 2.0 equiv base in 1.0 mL solvent for 24 h (under air).
1H NMR yield based on internal standard mesitylene.
0.05 mL solvent.
effective copper source to increase the yield of 3a (entry 15). High-
er concentration (entries 16–20) was helpful for decreasing the
loading of catalyst to only 1.0 mol % Cu2O with 2.0 mol % ligand.
In addition, lower temperature significantly reduced the yield of
desired product or made the reaction inert (entries 18–19). No
desired product was obtained without employment of L6.
The Cu-catalyzed O-arylation was successfully extended to var-
ious substituted phenols (2) with iodobenzene (1a); the results are

A.-Y. Cheng, J.-C. Hsieh / Tetrahedron Letters 53 (2012) 71–75
73
Table 3
Copper-catalyzed O-arylation of phenols with iodobenzenea
I
OH
O
Cu2O (1 mol%), L6 (2 mol%)
R2
+
Cs2CO3 (2.0 eq.), CH3CN
80 oC, 24h, under air
R2
1a
2
3
O
N
L6 :
HN
OH
Entry
1
2
3
Yieldb (%)
93
O
2a
3a
O
O
2b
OH
2
3
4
5
95
99
96
85
3b
2c
MeO
OH
3c
OMe
O
O
OH
2d
3d
OH
2e
2f
3e
O
O
Cl
OH
3f
Cl
F
6
7
79
81
F
F
OH
3g
2g
F
O
OH
3h
3i
8
9
2h
99
94
MeO
O
OMe
OH
2i
tBu
tBu
OH
O
N
10
76
3j
N
2j
a
Reactions were carried out using 0.5 mmol iodobenzene (1a), 0.6 mmol phenol (2) with 1 mol % Cu2O, 2 mol % L6 and 2.0 equiv
Cs2CO3 in 0.25 mL CH3CN for 24 h (under air).
b
Isolated yield after column chromatography.
listed in Table 3. An electron-donating group at the para-position of
phenols reacted with iodobenzene in the presence of 1 mol % Cu2O,
2 mol % L6 and Cs2CO3 (2 equiv) in acetonitrile to give the corre-
sponding diarylethers in excellent yields ( Table 3, entries 2–4).
Under the same reaction conditions, 2-naphthol and para elec-
tron-withdrawing groups also reacted well but gave slightly lower
yields (entries 5–7). The ortho-substitutes on the phenol did not
display effective steric effect to reduce the yields. Thus, the ortho
-substituted phenols 2h and 2i provided the corresponding prod-
ucts 3h and 3i in 99% and 94% yields, respectively, (entries 8–9).
The 8-hydroxyquinoline derivative performed well for this reac-
tion but only with a good yield of 76% probably due to the forma-
tion of a five-membered copper complex (entry 10).
ever, a strong electron-donating group at the para-position of iodo-
benzene significantly inhibited the coupling reaction due to the
sluggish oxidative addition of Cu complex to 1c (entry 2).
Para electron-withdrawing group provided very good yields ex-
cept 1f (entries 3–7). Meta-substituted iodoarenes also well reacted
to phenol and afforded the corresponding diarylethers 3o and 3p in
excellent yields (entries 8–9); however, a methyl group at the ortho
-position of iodoarene showed large hindrance to retard the oxida-
tive addition of Cu complex (entry 10) and gave only moderate
yield. 1-Naphthyliodide (1l) provided the corresponding product
3r in only a 32% yield (entry 11). 1,2-diiodobenzene (1m) reacted
with phenol to afford single product 3s in moderated yield 42%.
It is noteworthy that no double O-arylation adduct was observed
in this reaction (entry 12). Poly-fluoro substituted compound was
also well tolerated in this coupling reaction and the product 3t
was obtained in a 64% yield (entry 13). A lot of unreacted starting
materials were recovered in the cases with comparative lower
By using the same protocol, we were also able to carry out the
C–O coupling reaction of phenol with various substituted iodoare-
nes (Table 4). The 4-tolyliodide reacted smoothly with phenol to
give the corresponding product 3b in a 92% yield (entry 1), how-

74
A.-Y. Cheng, J.-C. Hsieh / Tetrahedron Letters 53 (2012) 71–75
Table 4
Copper-catalyzed O-arylation of phenols with iodoarenesa
Entry
1
2
3
Yieldb
(%)
1
2
3
2a
2a
2a
3b
3c
3f
92
64
90
I
1b
MeO
Cl
I
1c
1d
1e
I
O
F
I
4
5
6
2a
2a
2a
81
72
95
3k
F
O
F3C
I
1f
3l
F3C
O
NC
O
I
1g
3m
3n
NC
O
O
I
1h
7
8
2a
2a
94
92
O
I
I
3o
1i
O
3p
9
10
11
1j
2a
2a
2a
93
51
32
I
O
3q
1k
I
OPh
1l
3r
I
OPh
3s
12
13
2a
2a
42
64
1m
I
I
F
F
F
F
F
F
I
F
F
OPh
F
1n
3t
F
O
3u
14
15
1c
1j
2c
96
95
MeO
OMe
O
3v
2b
a
Reactions were carried out using 0.5 mmol iodoarene (1), 0.6 mmol phenol (2) with 1 mol % Cu2O, 2 mol % L6 and 2.0 equiv Cs2CO3
in 0.25 mL CH3CN for 24 h (under air).
b
Isolated yield after column chromatography.
yields even for double reaction time (entries 10–12), and no
byproducts were observed. The combinations of various iodoare-
nes with phenols also generated the desired products in excellent
yields (entries 14–15).
amount of catalyst under mild conditions, thus increased the pos-
sibility for the application to industry. Further studies to extend
the application of this catalytic system are currently underway.
In conclusion, we have developed an effective Cu2O/1H-imidaz-
ole-4-carboxylic acid catalytic condition for the O-arylation of
phenols with iodoarenes. This method efficiently provided diaryl
ether derivatives in moderate to excellent yields with good toler-
ance of various functional groups and only required very small
Acknowledgment
We thank the National Science Council of the Republic of China
(NSC-99-2113-M-032-003-MY2) for the financial support of this
research.

A.-Y. Cheng, J.-C. Hsieh / Tetrahedron Letters 53 (2012) 71–75
75
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