An efficient BINAM-copper(II) catalyzed Ullmann-type synthesis of diaryl ethers

Article abstract of DOI:10.1016/j.tetlet.2007.11.203

A wide range of diaryl ethers are synthesized from the corresponding aryl iodides and phenols through Ullmann type coupling reactions in the presence of a catalytic amount of easily available BINAM-Cu(OTf)₂ complex under mild reaction conditions. Less reactive aryl bromides have also been shown to react with phenols under identical reaction conditions to give good yields of the diaryl ethers without increasing the reaction temperature and time.

Full text of DOI:10.1016/j.tetlet.2007.11.203

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1057–1061
An efficient BINAM–copper(II) catalyzed Ullmann-type
synthesis of diaryl ethers
Ajay B. Naidu, O. R. Raghunath, D. J. C. Prasad, G. Sekar *
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600 036, India
Received 20 October 2007; revised 17 November 2007; accepted 30 November 2007
Available online 4 December 2007
Abstract
A wide range of diaryl ethers are synthesized from the corresponding aryl iodides and phenols through Ullmann type coupling reac-
tions in the presence of a catalytic amount of easily available BINAM–Cu(OTf)2 complex under mild reaction conditions. Less reactive
aryl bromides have also been shown to react with phenols under identical reaction conditions to give good yields of the diaryl ethers
without increasing the reaction temperature and time.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Copper catalyst; Coupling reaction; Diaryl ether; Diamine ligands; Ullmann coupling
Diaryl ethers constitute a very important class of
organic compounds playing a significant role in a number
of chemical and pharmaceutical industries.1 A number of
them have been shown to possess significant biological
activity2 and the diaryl ether structural unit is prevalent
in numerous weed-killing chemicals.3 Palladium catalyzed
diaryl ether formation from the corresponding aryl halide
and phenol or its sodium salt used to be the method of
choice.4 However, the high costs of palladium salts, high
oxophillicity associated with phosphine ligands, and
tedious multistep processes involved in the synthesis of
these ligands have rendered Pd unpopular, particularly
for large scale reactions.5
Use of stoichiometric copper as demonstrated by Ull-
mann in 19046 itself, requires drastic conditions. In fact,
only in the last few years have the considerable efforts
taken to improve the efficiency of this reaction started to
bear fruit with the use of copper salts with several ligands
such as 1-naphthoic acid,7 1,10-phenanthroline,8 neocupro-
ine,9 triphenylphosphine,10 2,2,6,6-tetramethylheptane-3,5-
dione,11 tripod ligands,12 diimine ligands,13 b-keto ester,14
tetraethyl orthosilicate (as solvent),15 silica supported
Cu(II),16 and aryl boronic acid.17
It is thought that these ligands increase the efficiency of
the Ullmann reaction by increasing the solubility of the
copper salts by preventing their aggregation. However, this
advance in the field of Ullmann coupling is not sufficient as
most of the reactions still require long reaction times (more
than 24 h), high reaction temperatures (120–220 °C) and in
some cases, high catalytic loading (even super stoichio-
metric amounts of ligands are needed). Therefore a mild,
economic, and efficient catalytic system is still desirable
for this process.
NHMe
NHMe
NH2
NH2
NHBn
NHBn
1
2
3
We have developed efficient methodologies for the selec-
tive oxidation of alcohols to the corresponding carbonyl
compounds and carboxylic acids using Cu catalysts.18 As
a part of our ongoing research toward copper catalyzed
*
Corresponding author. Tel.: +91 44 2257 4229; fax: +91 44 2257 4202.
E-mail address: gsekar@iitm.ac.in (G. Sekar).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.203

1058
A. B. Naidu et al. / Tetrahedron Letters 49 (2008) 1057–1061
Table 2
X
OH
BINAM-Cu(OTf)2
Cs2CO3
dioxane, 110 oC
Effect of Cu salts, solvents, and base
O
+
I
OH
O
BINAM (20 mol %)
Cu salt (20 mol %)
R
R'
R
R'
+
X = I or Br
Cs2CO3 ( 2 eq.)
solvent, 110 oC
Scheme 1.
Entry
Cu salt
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
a
Cu(OTf)2
CuI
CuBr
CuCl2
CuCl
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
THF
Toluene
MeCN
DMSO
Xylene
18
22
22
24
24
30
26
20
24
22
24
26
26
80
71
76
50
55
55
27b
59
40b
56
35
0c
organic transformations, herein, for the first time we report
an easily available 1,10-binaphthyl-2,20-diamine (BINAM)–
copper(II) complex catalyzed Ullmann coupling for the
formation of diaryl ethers through C–O bond formation
in dioxane under mild conditions (Scheme 1). This proce-
dure is very simple, mild, clean, and works efficiently with-
out any additives.
In preliminary studies, we used 20 mol % N,N0-
dimethyl-1,10-binaphthyl-2,20-diamine
1
(N,N0-dimethyl-
BINAM) ligand with 20 mol % of Cu(OTf)2 for the
coupling of iodobenzene with p-cresol in dioxane at
110 °C. Iodobenzene was fully consumed in 15 h and the
reaction provided a 68% isolated yield of the corresponding
diaryl ether (Table 1, entry 1).
When the ligand N,N0-dimethyl BINAM 1 was replaced
with BINAM 2, surprisingly the reaction provided an 80%
yield of the diaryl ether. However, replacing BINAM 2 by
ligand 3 reduced the yield to 69%. Next, the reaction was
carried out with different ratios of BINAM and Cu(OTf)2
and it was found that 20 mol % of ligand–copper combina-
tion was the most effective catalytic system.
The reaction was screened with several copper salts, sol-
vents, and bases to increase the efficiency of the coupling
reactions and the results are summarized in Table 2.
Although several copper salts catalyzed the reaction,
Cu(OTf)2 turned out to be the copper salt of choice in view
of reaction time and yield (Table 2, entry 1). Similarly,
dioxane was the best solvent among those examined.
Cs2CO3 as base gave the best yields of product in compar-
ison with bases such as Na2CO3 and K2CO3.
Dioxane
Dioxane
40d
Isolated yield.
b
c
Reaction was carried out in a pressure tube.
Na2CO3 was used as base instead of Cs2CO3.
K2CO3 was used as base instead of Cs2CO3.
d
Using the above mentioned optimized conditions, we
initiated our investigations into the scope of the
BINAM–Cu(OTf)2 catalyzed Ullmann type coupling and
the results are summarized in Table 3. Various aryl iodides
and phenols reacted to give the corresponding diaryl
ethers. We found that iodobenzene reacted with phenols
containing electron-releasing groups as well as electron-
withdrawing groups. Also, even in the presence of an ortho
substituted phenol (which is capable of providing scope for
steric bias) the reaction proceeded smoothly. However, the
yields were different with electron rich and electron defi-
cient phenols. Electron-releasing groups such as methyl
and methoxy phenol increased the yield of the diaryl ether
(entries 2 vs 1, 3 and 5), whereas an electron-withdrawing
group such as chloride in the phenolic moiety decreased
the yield of the product (entries 2 vs 7).
In the aryl iodide component, the presence of a methoxy
group at the para position decreased the yield of the cou-
pling reaction by about 5–10% (entries 8–11 vs 1, 2, 4
and 6). Similarly, the presence of an o-methoxy group in
iodobenzene further decreased the yield by 5% to give a
65% isolated yield of the diaryl ether (entry 12). The yield
in this coupling reaction was increased when the electron-
releasing methoxy group was present at the meta position
in iodobenzene. We achieved a 90% isolated yield of the
corresponding diaryl ether when we coupled m-methoxy-
iodobenzene with m-methoxyphenol (entry 15).
We were pleased to note that under our optimized reac-
tion conditions, aryl bromides also reacted with phenols to
provide the corresponding diaryl ethers. 1-Bromo-4-methyl-
benzene and 1-bromo-4-methoxybenzene reacted with
methyl-substituted phenols to give the corresponding diaryl
Table 1
Effect of the ratio of ligand and Cu(OTf)2
I
ligand
Cu(OTf)2
Cs2CO3 (2 eq.)
dioxane, 110 oC
OH
O
+
Entry
Ligand (mol %)
Cu(OTf)2 (mol %)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
a
1 (20)
2 (20)
3 (20)
2 (5)
2 (10)
2 (10)
2 (15)
20
20
20
20
20
10
15
15
18
18
25
20
24
24
68
80
69
40
65
51
66
Isolated yield.

A. B. Naidu et al. / Tetrahedron Letters 49 (2008) 1057–1061
1059
Table 3
Coupling reaction of aryl halides with phenols in the presence of BINAM–Cu(OTf)2 catalyst
X
OH
BINAM (20 mol%)
O
Cu(OTf)2 (20 mol%)
+
Cs2CO3 (2 equiv.)
dioxane, 110 oC
R
R'
R
R'
Entry
1
Aryl halide
Phenol
Time (h)
18
Producta
Yieldb (%)
80
I
I
I
HO
O
2
3
18
19
70
75
HO
O
HO
O
MeO
MeO
4
16
84
I
HO
HO
HO
OMe
OMe
O
O
O
5
6
15
22
72
66
I
I
t
Bu
tBu
7
8
15
14
14
28
60
70
62
60
I
Cl
O
Cl
HO
HO
I
I
I
MeO
MeO
O
MeO
MeO
MeO
9
HO
O
10
HO
O
MeO
MeO
11
12
13
36
10
22
75
65
72
MeO
I
HO
HO
OMe
O
OMe
I
OMe
OMe
O
MeO
HO
MeO
I
O
(continued on next page)

1060
A. B. Naidu et al. / Tetrahedron Letters 49 (2008) 1057–1061
Table 3 (continued)
Entry
Aryl halide
Phenol
Time (h)
18
Producta
Yieldb (%)
80
HO
14
15
MeO
I
I
MeO
O
20
24
90
64
MeO
HO
HO
OMe
MeO
O
OMe
16
I
O
17
18
20
18
75
70
HO
I
O
I
O
HO
HO
OMe
OMe
19
20
22
20
62
60
Br
O
Br
Br
HO
HO
O
O
21
18
28
76
66
22
Br
MeO
O
MeO
HO
a
All the diaryl ethers gave satisfactory spectral data.
Isolated yield.19
b
ethers in good isolated yields. It is very important to men-
tion that in general, aryl bromides are less reactive than
aryl iodides and require much more drastic reaction condi-
tions for arylation. However in the presence of our
BINAM–Cu(OTf)2 catalyst even aryl bromides reacted
with phenols to give good yields of the expected diaryl
ethers without increasing the reaction temperature and
time.
methoxy at the ortho and para positions of phenol
decreased the yield of the coupling reaction whereas the
presence of a methoxy group at the meta position increased
the yield of the coupling reaction. Efforts to expand the
utility of our new catalytic system to other classes of
nucleophiles will be reported in due course.
In summary, we have developed an efficient, experimen-
tally simple, and economically attractive copper catalyzed
O-arylation of phenols with aryl iodides. Aryl bromides
can also be used for O-arylation of phenols under the same
reaction conditions without increasing the reaction temper-
ature. The presence of an electron-releasing group such as
Acknowledgments
We thank DST (SERC Fast Track Research Project
No.: SR/FTP/CS-19/2004) New Delhi for the financial
support. A.B.N. and D.J.C.P. thank UGC for their
fellowship.

A. B. Naidu et al. / Tetrahedron Letters 49 (2008) 1057–1061
14. Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863–3867.
1061
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