Bio-inspired copper catalysts for the formation of diaryl ethers

Article abstract of DOI:10.1016/j.tetlet.2008.01.036

Aryl bromides and phenols are coupled efficiently to the corresponding diaryl ethers in the presence of a practical Cu(I)/1-butylimidazole catalyst system. The convenient protocol is applied successfully to the synthesis of 16 different diaryl ethers in high yield and selectivity.

Full text of DOI:10.1016/j.tetlet.2008.01.036

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1851–1855
Bio-inspired copper catalysts for the formation of diaryl ethers
a
a
b
b
a,
*
´
Thomas Schareina , Alexander Zapf , Alain Cotte , Nikolaus Muller , Matthias Beller
¨
a Leibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock, Albert-Einstein-Str. 29A, 18059 Rostock, Germany
b Saltigo GmbH, Building Q 18-2, 51369 Leverkusen, Germany
Received 29 October 2007; revised 23 December 2007; accepted 8 January 2008
Available online 12 January 2008
Abstract
Aryl bromides and phenols are coupled efficiently to the corresponding diaryl ethers in the presence of a practical Cu(I)/1-butyl-
imidazole catalyst system. The convenient protocol is applied successfully to the synthesis of 16 different diaryl ethers in high yield
and selectivity.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Diaryl ether; Aryl bromide; Copper; N-Ligands; Imidazole
Diaryl ethers represent a common feature in natural
N
products, pharmaceuticals and agrochemicals as well as
in industrial polymers.1 Selected examples are shown in
O
NH
Figure 1. In addition, macrocyclic diarylethers are of spe-
cial interest for biologically active compounds, for exam-
ple, vancomycine, piperazinomycin, RA-I–IV, K13 and
others.2
OH
O
HO
O
In the past, the most general method for the synthesis of
diaryl ethers has been the copper-mediated Ullmann cou-
pling of aryl bromides/iodides and phenols with the draw-
back of harsh reaction conditions and the need of a
stoichiometric amount of metal.3 Due to these problems
significant efforts have been undertaken in the last decade
to develop more efficient and environmentally benign cata-
lytic coupling processes of phenols. The current status of
the methodology is described in detail by Frlan and
Kikelj,4 Beletskaya et al.,5 and by Kunz et al.6
O
O
2
1
Y
OArO
n
Y = SO2, C=O
The increased attention in this field over the past years
has led to the development of several catalyst systems,
which enable aryl ether formation under much milder
conditions compared to the classical Ullmann and Gold-
berg reactions.4,6,7 So far, mainly copper8 and palladium9
3
Fig. 1. Riccardine from liverwort (1), the herbicide difenoxuron (2),
poly(aryl ethers) (3) used for high-tech plastics.
complexes evolved as catalysts for this type of reaction.
While palladium catalysis has the common disadvantage
of high metal and ligand costs (and sometimes the air-sen-
sitivity of special phosphines), copper catalysis is generally
*
Corresponding author. Tel.: +49 (0) 381 12810; fax: +49 (0) 381 1281
5000.
E-mail address: Matthias.Beller@catalysis.de (M. Beller).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.036

1852
T. Schareina et al. / Tetrahedron Letters 49 (2008) 1851–1855
considered to be less expensive. However, this statement is
only true for easily available copper pre-catalysts and
ligands. In this respect there is still a need for improved
and more general catalysts.
The preparation of bis(o-tolyl)ether from 2-bromotolu-
ene and 2-cresol served as a model reaction to study the
general influence of different bases, solvents, additives/
ligands, temperature and the copper pre-catalyst. Selected
experiments are shown in Table 1.14 As a starting point
for our investigations, reaction conditions were chosen sim-
ilar to those of the Cu/imidazole-catalyzed cyanation reac-
tion. However, a stoichiometric amount of base is added to
secure the deprotonation of the phenol for the C–O cou-
pling reaction. In initial experiments K2CO3 was used as
base. In contrast to the copper-catalyzed cyanation of aryl
bromides a reduced amount of 1-butylimidazole led to the
best results. Significantly higher or lower concentration of
this ligand decreased the yield of the desired bis(o-tolyl)-
ether (Table 1, entries 1–3).
Recently, we have developed new catalyst systems for
the cyanation of aryl halides based on palladium and
copper.10,11 The combination of copper(I)/1-alkylimid-
azoles showed unprecedented selectivity and substrate
range in that reaction. Inspired by nature, we assumed that
imidazoles might be good ligands to control the stability
and selectivity of copper catalysts.12 This idea resulted
from the fact that the most abundant metal-binding
amino acid in nature is histidine. In fact, in most metallo-
enzymes the actual binding site contains at least one, in
some cases up to three histidine units per metal atom.13
Consequently, we believed that this and similar systems
might be useful for other coupling reactions of aryl halides,
too. In this Letter, we report our results on the copper-
catalyzed diaryl ether formation from aryl bromides and
phenols.
Obviously, there is a balance between sufficient stabiliza-
tion of the catalyst metal and access to free coordination
sites. Other N-donor ligands, mostly imidazoles, and O-
donors were tested and showed no improved performance
(Table 1, entries 4–12). Amino acids, like proline15 and
Table 1
Copper-catalyzed reaction of 2-cresol with 2-bromotoluenea
Br
HO
O
Entry
Additivec (mol %)
Metalb
T (°C)
Basec (mol %)
Solvent
Conv.c (%)
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
a
1-Butylimidazole 200
1-Butylimidazole 50
1-Butylimidazole 20
1-Methylimidazole 50
1-Benzylimidazole 50
1,2-Dimethylimidazole 50
2-Methylimidazole 50
4-Methylimidazole 50
2,20-Bipyridine 50
Acetylacetone 25
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuBr
Cu2O
CuI (5)
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
140
120
120
120
120
120
120
120
120
120
120
K2CO3 130
K2CO3 130
K2CO3 130
K2CO3 130
K2CO3 130
K2CO3 130
K2CO3 130
K2CO3 130
K2CO3 130
K2CO3 130
K2CO3 130
K2CO3 130
Cs2CO3 130
K3PO4 130
K3PO4 130 (dry, Ar-box)
Na2CO3 130
NaOtBu 130
K2CO3 200
K2CO3 200
K2CO3 130
K2CO3 130
K2CO3 130
K2CO3 130
K3PO4 130
K2CO3 200
K2CO3 200
K2CO3 200
K2CO3 200
K2CO3 200
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
o-Xylene
NMP
59
83
27
82
81
43
5
5
36
0
64
8
81
51
85
5
47
75
20
75
69
31
0
0
22
0
8
0
70
46
74
4
1,2-Ethylenediamine 50
TMEDA 50
1-Butylimidazole 50
1-Butylimidazole 50
1-Butylimidazole 50
1-Butylimidazole 50
1-Butylimidazole 50
1-Butylimidazole 50
1-Butylimidazole 50
1-Butylimidazole 50
1-Butylimidazole 50
1-Butylimidazole 50
—
1-Methylimidazoled
1-Butylimidazole 50
1-Butylimidazole 50
1-Butylimidazole 50
1-Butylimidazole 50
1-Butylimidazole 50
2
0
89
100
67
33
71
5
30
95
80
61
76
45
81
91
56
30
63
3
26
87
72
56
67
38
NMP
1-Methylimidazole
Toluene
Toluene
Toluene
Toluene
Toluene
CuI (2.5)
General reaction conditions: 2 mmol 2-bromotoluene, 2.4 mmol 2-cresol, 2 mL solvent, 200 lL tetradecane as internal standard for GC, 16 h.
10 mol % Cu unless otherwise stated.
GC-conversion and yield.
b
c
d
Large excess (solvent).

T. Schareina et al. / Tetrahedron Letters 49 (2008) 1851–1855
1853
Table 2
Scope and limitations of the copper/1-alkylimidazole-catalyzed diarylether synthesisa
Entry
Aryl bromide
Hydroxybenzene
Product
T (°C)
Metal
CuCl
Conversionb (%)
Yieldb (%)
87
Br
HO
O
1
120
95
Br
HO
O
2
120
CuCl
78
54
OMe
OMe
Br
O
O
HO
HO
3
4
120
140
CuCl
CuI
>99
88
89
75
Br
Br
O
HO
HO
5
6
120
120
CuCl
CuCl
>99
>99
>99
>99
O2N
O2N
Br
N
O
N
Br
O
HO
7
8
120
120
CuCl
CuCl
>99
>99
93
85
H2N
H2N
Br
O
AcHN
Br
AcHN
O
O
9
120
CuCl
84
84
Br
Br
10
11
120
120
CuCl
CuCl
89
86
85
84
O
O
Br
Br
12
13
140
140
CuI
CuI
99
51
96
49
O
(continued on next page)

1854
T. Schareina et al. / Tetrahedron Letters 49 (2008) 1851–1855
Table 2 (continued)
Entry
Aryl bromide
Hydroxybenzene
Product
T (°C)
Metal
CuCl
Conversionb (%)
Yieldb (%)
Br
O
O
14
120
100
95
N
N
Br
15
140
CuI
93
87
Br
O
16
120
120
CuCl
CuCl
>99
>99
N
N
O
HO
Br
17
79
78
MeO
MeO
a
General reaction conditions: 2 mmol aryl bromide, 2.4 mmol phenol, 10 mol % metal precursor, 4 mmol K2CO3, 1 mmol 1-butylimidazole, 2 mL
toluene, 200 lL tetradecane as internal standard for GC, 16 h.
b
GC-conversion and yield.
pipecolinic acid,16 which have been successfully used as
ligands in aryl halide aminations, were also tested in the
model reaction, but gave no diaryl ether coupling product.
Variation of bases revealed that Cs2CO3 also led to good
results (Table 1, entry 13), comparable to dry K3PO4,
which must be handled under strict exclusion of moisture
(Table 1, entries 14 and 15). Other typical bases such as
NaOtBu and Na2CO3 are not suited for the aryl ether cou-
pling under these conditions (Table 1, entries 16 and 17).
Increasing the amount of K2CO3 from 1.3 to 2 equiv
showed a slight positive effect on the yield (Table 1, entry
18). At higher temperature (140 °C instead of 120 °C) the
yield increased to 91% (Table 1, entry 19).
Other solvents like dioxane, o-xylene or NMP resulted
in lower yield of the product (up to 63%) (Table 1, entries
20–22). Even in polar NMP, which is known to stabilize
metals, the presence of 1-butylimidazole is essential (Table
1, entry 23). Notably, applying 1-alkylimidazoles (e.g., 1-
methylimidazole) in large excess as solvent for the reaction
resulted in low yield (Table 1, entry 24).
With the optimized results in hand, we set out to evalu-
ate the scope of our novel protocol for the coupling of aryl
bromides with various phenols (Table 2). Most electron-
poor and electron-rich aryl bromides react with 2-cresol
in good to excellent yield and selectivity. Only for the ste-
rically more hindered 2-bromo-m-xylene a higher tempera-
ture of 140 °C is required to obtain 75% of the product. In
general, there is no significant difference in reactivity
between electron-rich and electron-poor bromobenzenes.
For example, both 4-bromonitrobenzene and 4-bromoani-
line are coupled with 2-cresol in 99% and 93% yield, respec-
tively (Table 2, entries 5 and 7). At this point it is also
interesting to note that 4-bromoaniline showed no sign of
self-coupling, indicating an excellent selectivity of the cata-
lytic system towards the reaction at the oxygen atom.
Despite the basic conditions and the reaction tempera-
ture of 120 °C, the acetyl group of 4-bromoacetanilide is
not cleaved, resulting in a good yield of 85% of the product
(Table 2, entry 8). In addition to bromobenzenes, also 2-
bromopyridine gave the corresponding ether in excellent
yield (Table 2, entries 6, 14 and 16). Here, without copper
catalyst only ca. 10% of the desired product is formed at
this temperature. All other cresols and phenols themselves
react similarly well.
Experiments with different copper sources showed that
copper(I) chloride gave slightly better results than cop-
per(I) iodide, while copper(I) bromide and copper(I) oxide
are worse catalyst precursors (Table 1, entries 25–27). In
agreement with other known copper-catalyzed coupling
reactions lower concentrations of the active metal (Table
1, entries 28 and 29) are not sufficient for high conversion
and good yields.
By comparing the reaction of 2-bromo-m-xylene and 2-
cresol (Table 2, entry 4) with the reaction of 2-bromotolu-
ene and 2,6-dimethylphenol (Table 2, entry 13), in which
the same product is formed, it became clear that steric

T. Schareina et al. / Tetrahedron Letters 49 (2008) 1851–1855
1855
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hindrance is better tolerated on the side of the aryl bromide
than on the phenol substrate (75% vs 49% yield).
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In conclusion, we have shown that Cu(I)/1-alkylimidaz-
ole allows for a general diaryl ether synthesis from aryl bro-
mides and phenols. Good to excellent yields are obtained
with this bio-inspired catalyst system. Due to the low cost
of the metal and ligands and no expensive base or solvents
the reaction is very convenient and can be easily upscaled.
10. (a) Schareina, T.; Zapf, A.; Ma¨gerlein, W.; Muller, N.; Beller, M.
¨
Synlett 2007, 555–558; (b) Schareina, T.; Zapf, A.; Ma¨gerlein, W.;
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¨
Acknowledgements
11. (a) Schareina, T.; Zapf, A.; Ma¨gerlein, W.; Muller, N.; Beller, M.
¨
Tetrahedron Lett. 2007, 48, 1087–1090; (b) Schareina, T.; Zapf, A.;
Beller, M. Tetrahedron Lett. 2005, 46, 2585–2588; (c) Schareina, T.;
Zapf, A.; Beller, M. J. Organomet. Chem. 2004, 689, 4576–4583; (d)
Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 1388–1389;
(e) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem. 2003, 115,
1700–1703; Angew. Chem., Int. Ed. 2003, 42, 1661–1664; (f) Sun-
dermeier, M.; Mutyala, S.; Zapf, A.; Spannenberg, A.; Beller, M. J.
Organomet. Chem. 2003, 684, 50–55; (g) Sundermeier, M.; Zapf, A.;
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Financial support for this work from Lanxess (Saltigo
GmbH), the state of Mecklenburg-Vorpommern and the
BMBF as well as the DFG (Leibniz Price) are gratefully
acknowledged.
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