Selective one-pot access to symmetrical or unsymmetrical diaryl ethers by copper-catalyzed double arylation of a simple oxygen source

Article abstract of DOI:10.1002/chem.201001373

Great CO-mbination: A novel method is reported for the controlled one-pot synthesis of various symmetrical or unsymmetrical diaryl ethers by double arylation of a simple inorganic oxygen source (see scheme). This versatile and highly selective process is based on the use of a cheap and low toxicity copper catalytic system.

Full text of DOI:10.1002/chem.201001373

COMMUNICATION
DOI: 10.1002/chem.201001373
Selective One-Pot Access to Symmetrical or Unsymmetrical Diaryl Ethers by
Copper-Catalyzed Double Arylation of a Simple Oxygen Source
Anis Tlili, Florian Monnier,* and Marc Taillefer*[a]
Table 1. Conditions for the selective synthesis of diphenyl ether 1.[a]
The preferential reaction of a chemical reagent with one
of two or more different functional groups is one of the
most important challenges in contemporary chemistry.[1] An
example of chemoselectivity is illustrated here in the synthe-
Entry
Solvent (2 mL)
MOH
(3 equiv)
Base
(n equiv)
1
1’
sis of symmetrical or unsymmetrical diaryl ethers, which
constitute a wide family of active compounds in natural
products and polymer science.[2] Their syntheses usually re-
quire the presence of copper[3] or palladium[4] catalytic sys-
tems that enable the coupling of aryl halides with phenols.
Only two examples have been described in which aryl hal-
ides are not coupled to oxygen via a phenol but via an inor-
ganic oxygen source (K3PO4/H2O or KOH) to afford diaryl
ethers. These methods, which suffer from drawback as a
result of the synthesis of only symmetric ethers, use palladi-
um catalytic systems.[5,6] We report herein a novel method
that affords selective one-pot access to symmetrical or un-
symmetrical diaryl ethers by Cu-catalyzed double arylation
of an oxygen source (hydroxide salts or water) by aryl hal-
ides.
G
R
[%][b]
[%][b]
1
2
3
4
5
6
7
8
DMSO/H2O (1/1)
DMSO/H2O (1/1)
DMSO/H2O (1/1)
DMSO
KOH
CsOH
CsOH
CsOH
CsOH
CsOH
–
–
–
–
–
–
–
0
0
75
95
0
0
10
0
0
0
0
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (4)
K2CO3 (4)
K3PO4 (3)
K3PO4 (3)
K3PO4 (3)
98
95
70
100
90
60
96[c]
0
EtOH
EtOH/H2O (1/1)
EtOH/H2O (1/1)
EtOH/H2O (1/1)
EtOH/H2O (1/1)
EtOH
9
10
11
0[d]
0
H2O
0
[a] Performed with 10 mol% of CuI, 50 mol% of 2,2,6,6-tetramethyl-3,5-
heptanedione L1, 3 equiv of MOH and/or n equiv of base. [b] GC yield
determined with 1,3-dimethoxybenzene as standard. [c] 10 mol% of CuI,
30 mol% of L1 and 3 equiv of K3PO4. [d] Formation of PhOEt (97%).
We recently observed that symmetrical diphenyl ether 1
occurred as a secondary product during the copper-catalyzed
synthesis of phenol 1’ from iodobenzene and hydroxide
salts.[7] This surprising development encouraged us to care-
fully adjust reaction parameters for the selective generation
of 1 by a double arylation of a simple oxygen source by PhI.
A systematic study was undertaken using PhI as the model
substrate and 2,2,6,6-tetramethyl-3,5-heptanedione as ligand
(L1). As expected, the former was selectively converted to 1’
(Table 1, entries 1 and 2) in the presence of KOH or CsOH
in a mixture of DMSO/water (1/1). However, we were
pleased to find that, in the presence of Cs2CO3 as an addi-
tional base, the synthesis of diphenyl ether 1 became fully
selective (Table 1, entry 3). The same reaction performed in
the presence of one solvent (DMSO or EtOH) also pro-
duced a high yield of 1 although the selectivity was lower in
the case of ethanol (Table 1, entries 4 and 5, respectively).
Finally, the addition of water as a co-solvent with ethanol al-
lowed us to observe the quantitative formation of
1
(Table 1, entry 6). Due to regulatory considerations[8] and
the obvious environmental benefits of using EtOH/H2O as
solvent, we optimized this system and first discovered that
the original MOH was not necessary to achieve high selec-
tivity (Table 1, entry 7).
[a] A. Tlili, Dr. F. Monnier, Dr. M. Taillefer
CNRS, UMR 5253
We also observed that K3PO4, a base of greater interest to
industry,[9] could successfully produce 1 (Table 1, entry 9).
Other ligands such as b-diketones (L2, L3), DMEDA L4, or
phenanthroline L5 were also tested, but in all cases, selectivi-
ty was disappointing.[10]
Institut Charles Gerhardt Montpellier
ENSCM, 8, rue de l’Ecole Normale
34296 Montpellier Cedex 5 (France)
Fax : (+33)467-144-319
E-mail: marc.taillefer@enscm.fr
florian.monnier@enscm.fr
We then investigated the breadth of application of this
new method by evaluating a series of aryl iodides under one
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001373.
Chem. Eur. J. 2010, 16, 12299 – 12302
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12299

To our knowledge, we have here described the first
copper-catalyzed symmetrical diaryl ether synthesis by
double arylation of a simple oxygen source (water), whereas
the other known procedures employ expensive palladium-
based systems.[5,6] Although symmetrical diaryl ethers are
very interesting substrates, unsymmetrical examples are of
even greater interest. These were examined next.
We first tried to couple together two different aryl iodides
but the previously used conditions (with EtOH/H2O as sol-
vents) lead to mixtures. However, with DMSO as solvent
(conditions as in Table 1, entry 4), we were pleased to
obtain various unsymmetrical diaryl ethers 11–16 selectively
in good yields. These were synthesized from aromatic io-
dides substituted by electron-withdrawing or electron-donat-
ing groups and introduced in equimolecular amounts
(Table 3, entries 1–6). Under similar conditions, many un-
symmetrical diaryl ethers such as 11–23 were obtained in
good to excellent yields (Table 3, entries 7–18) by cross-cou-
pling of various aryl iodides, with either aryl bromides or
even less reactive aryl chlorides, substituted by electron-
withdrawing or -donating groups.
set of optimized conditions (specifically, Table 1, entry 9).
Good to excellent yields of symmetrical diaryl ethers 1–9
were obtained with water as the oxygen source (Table 2),
with both electron-donating and electron-withdrawing sub-
stituents on the aryl ring. The system was also efficient in
the presence of 2-bromopyridine, which led to the corre-
sponding diaryl ether 10.
Table 2. Cu-catalyzed selective synthesis of symmetrical diaryl ethers
1.[a,b]
In many cases, by-products are mainly unreacted aryl hal-
ides (see Table 3, column 3) and symmetrical diaryl ethers
formed from the more reactive aryl iodides (R1C6H4I, see
Table 3, column 2). It is worth noting that when R1C6H4I is
introduced in excess (1.8 equiv) over the less reactive
R2C6H4X (1 equiv), excellent yields of unsymmetrical ethers
are almost always obtained, as illustrated in some selected
cases (Table 3, entries 1, 7, 13).
The catalytic system presented here is also known to pro-
[11]
ꢀ
ꢀ
mote C O or C N bond formation from aryl halides, as
we showed for example with the Cu-catalyzed arylation of
ammonia.[12] The potential range of applications of this
method is thus very large. As an example, the combination
of diaryl ether synthesis and amination methods affords
simple access to one of the most popular monomers with a
flexible linkage, namely 4,4’-oxydianiline (Scheme 1). This
useful building block and cross-linking agent for polymers,[13]
was easily obtained (70% isolated yield) by a chemoselec-
tive one-pot procedure. Many other combinations could be
envisioned with applications in both polymer chemistry and
the life sciences.
[a] Yield of isolated product. [b] Reactions conducted in H2O/EtOH
(2 mL) using ArI except otherwise noted. [c] 2-Bromopyridine was em-
ployed as aryl source.
As already observed in related palladium-catalyzed reac-
tions, the selectivity is significantly dependent on the nature
of the base.[5] Thus, while the PhOH (in equilibrium with
the phenoxide) formed using hydroxide salts (Table 1, en-
tries 1 and 2) does not react with PhI, it is trapped by the
latter in the presence of Cs2CO3 or K3PO4 as bases to pro-
duce 1. Therefore the phenol, the probable intermediate in
the reaction, is not observed under our conditions (Table 1,
entries 7, 9).
In summary, we have presented here an original and ver-
satile method that allows the one-pot synthesis of various
symmetrical or unsymmetrical diaryl ethers from aryl hal-
ides and very simple oxygen sources, namely H2O or hy-
droxide salts. This controlled and highly selective process,
very competitive to existing protocols based on palladium,
Scheme 1. One-pot access to monomers for polyamides.
12300
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Chem. Eur. J. 2010, 16, 12299 – 12302

Symmetrical or Unsymmetrical Diaryl Ethers
COMMUNICATION
Table 3. Cu-catalyzed selective synthesis of unsymmetrical diaryl ethers 11–23.[a]
Yield [%][b,c]
Entry R1
R2, X
Entry R1
R2, X
Yield [%][b,c]
82
1
2
H
H
p-CH3, I
72, 96[d]
71
10
11
p-CH3
p-CN, Br
p-NO2, I
H
p-NO2, Br
83
3
4
5
H
H
H
p-COCH3, I
p-Cl, I
65
85
78
12
13
14
H
p-CN, Cl
p-CH3, Cl
p-CN, Cl
72
H
40, 95[d]
75
p-CN, I
p-CH3
6
m,m’-(CH3)2 p-NO2, I
93
15
p-CN
p-CF3, Cl
61
7
8
9
H
p-CH3, Br
2-Py, Br
59, 97[d]
16
17
18
m,m’-(CH3)2 p-CN, Cl
73
80
77
p-CH3
92
p-CH3
p-CF3, Cl
p-CF3, Cl
m,m’-(CH3)2 p-CH3, Br
50
H
[a] Reactions conducted with 1 equiv of each aryl halide, 3 equiv of CsOH, 1 equiv of Cs2CO3 in 2 mL of DMSO. [b] Yield of isolated product. [c] For
R2C6H4X (column 3) by-products are mainly unreacted aryl halides (e.g., 20% of the p-CF3C6H4Cl remains at the end of the reaction for entry 17). For
R1C6H4I (column 2) by-products are mainly the corresponding symmetrical diaryl ethers (between 2 and 15% when R1 =H and only traces when R1
¼
H). [d] 1.8 equiv of R1C6H4I and 1 equiv R2C6H4X: yield based on R2C6H4X.
employs a copper catalyst system. Extensive applications are
expected very soon.[7a,14]
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Acknowledgements
The authors are grateful to ANR and CNRS for financial support and
ThermoFisher for technical facilities.
Keywords: arylation · catalysis · copper · diaryl ethers ·
selectivity
Chem. Eur. J. 2010, 16, 12299 – 12302
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12301

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Received: May 19, 2010
Published online: September 17, 2010
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Chem. Eur. J. 2010, 16, 12299 – 12302