Copper promoted synthesis of diaryl ethers

Article abstract of DOI:10.1039/b401179a

An efficient protocol using copper based reagents for the coupling of aryl halides with phenols to generate diaryl ethers is described. A copper(I) complex, [Cu(CH₃CN)₄]ClO₄, or the readily available copper(II) source, CuCO₃·Cu(OH)₂· H₂O (in combination with potassium phosphate), can be used. Aryl halides and phenols with different steric and electronic demands have been used to assess the efficiency of the procedure. The latter source of copper gives better yields under all conditions.

Full text of DOI:10.1039/b401179a

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P A P E R
Copper promoted synthesis of diaryl ethersw
Rajshekhar Ghosh and Ashoka G. Samuelson*
Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore
560 012 India. E-mail: ashoka@ipc.iisc.ernet.in; Fax: þ91 80 3601552; Tel: þ91 80 2932663
Received (in Montpellier, France) 24th January 2004, Accepted 29th April 2004
First published as an Advance Article on the web 22nd September 2004
An efficient protocol using copper based reagents for the coupling of aryl halides with phenols to generate
diaryl ethers is described. A copper(I) complex, [Cu(CH3CN)4]ClO4, or the readily available copper(II)
source, CuCO3 ꢀ Cu(OH)2 ꢀ H2O (in combination with potassium phosphate), can be used. Aryl halides and
phenols with different steric and electronic demands have been used to assess the efficiency of the procedure.
The latter source of copper gives better yields under all conditions.
We report here the results from a study carried out with
Introduction
copper(I) complexes to couple a variety of electron-deficient or
electron-rich aryl bromides with phenols ranging from the
favorable electron-rich, to the difficult-to-couple electron-defi-
cient, phenols. The aim was to find the most convenient copper
reagent to carry out the Ullmann coupling. Malachite, the
common copper source containing CuCO3 ꢀ Cu(OH)2 ꢀ H2O,
also known as basic copper carbonate, is shown to give very
good to excellent yields under the conditions described here
(Scheme 1).
The preparation of diaryl ethers by coupling a phenol and aryl
halide is an important reaction due to the number of medicin-
ally important compounds such as combretastatin D-2 (anti-
fungal), riccardin (cytotoxin), piperazinomycin (antifungal)
and (ꢁ)-K-13 (ACE inhibitor) that contain the diaryl ether
moiety.1 These linkages are also present in commercially
relevant polyphenylene polymers. Of the methods used for
the preparation of diaryl ethers, the classic Ullmann method2
is the most important,3 but it is often limited by the need to
employ harsh reaction conditions and stoichiometric or greater
amounts of copper. A number of interesting and useful tech-
niques for diaryl ether formation have been reported in recent
years4–6 based on Pd and Cu, of which Pd based reagents have
shown greater promise.
Results and discussion
Based on our earlier success in mimicking Pd with Cu,14 our
initial studies involved the use of the stable tetrakis acetonitrile
complex of copper(I) perchlorate, [Cu(CH3CN)4]ClO4, in stoi-
chiometric amounts. The results are summarized in Table 1.
Reactions were carried out in refluxing toluene or THF. The
reactions attempted in THF as a solvent, under reflux condi-
tions, led to o1% product formation. But if the same reaction
mixture was heated at 115 1C in a sealed vial with 25% of the
catalyst, 86% yield was obtained (cf. entries 5 and 8).
The base used for carrying out the reaction appeared to be a
critical factor in the reaction. In the presence of KOtBu,
reasonable formation of the coupled product was achieved in
toluene, which otherwise proved to be a poor choice as a
solvent. Other bases such as K2CO3 or Na3PO4 led to zero
percent or very poor yields of the product (entries 2 and 3). The
hydrolysis reaction observed with the use of KOtBu (entry 7),
could be avoided by using K2CO3 to give high yields of the
coupled product (entries 8 and 9).
The use of palladium catalysts for the combination of
phenols and aryl halides or sulfonates permits the reaction to
be carried out under relatively mild conditions but with the
limitation that only electron-deficient aryl bromides can be
used.7 The more general method of coupling a wide range of
electron-deficient, electronically neutral and electron-rich aryl
halides with a variety of phenols using palladium catalysts
suffers from the serious drawback that it requires the use of
electron-rich, sterically bulky aryl dialkylphosphines as li-
gands.8 There are a few reports where copper(I) has been
employed as a catalyst. In one case, the catalyst is [(CuOTf)2 ꢀ
C6H6], which is unstable in air. It also requires the presence of a
carboxylic acid to couple unactivated aryl halides and phenols
containing electron-withdrawing groups.9 Another report em-
10
ploying [Cu(CH3CN)4]PF6 is limited to coupling aryl bro-
mides with o-tertiary and secondary benzamides and
sulfonamides. The most recent reports are with 50 mol %
CuCl used along with 2,2,6,6-tetramethylheptane-3,5-dione
and cesium carbonate to give the coupled product in reason-
able yields11 and with 10 mol % CuI and cesium carbonate in
N-methylpyrrolidinone (NMP) at 195 1C under microwave
irradiation.12 There are a few studies that report the synthesis
of diaryl ethers by the coupling of aryl boronic acids and
phenols.13 There appears to be ample scope for developing a
general, inexpensive method for C–O coupling reactions.
The use of phenoxide appeared to be an essential feature if
only mild bases are used. The phenoxide was prepared by the
reaction of the phenol with sodium hydride in tetrahydrofuran
as the solvent. If the phenol was used in combination with
K2CO3 no yield was obtained (entry 11). In a separate reaction,
w Electronic supplementary information (ESI) available: complete
spectroscopic data for all the coupled diaryl ethers. See http://
www.rsc.org/suppdata/nj/b4/b401179a/
Scheme 1 Reactions conditions for synthesis of diaryl ether.
T h i s j o u r n a l i s & T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
1390
N e w J . C h e m . , 2 0 0 4 , 2 8 , 1 3 9 0 – 1 3 9 3

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Table 1 Reaction conditions for coupling 4-methylphenol and 4-bromobenzonitrile using [Cu(CH3CN)4)ClO4
Entry
Solvent
T/1C
Additional base
Catalyst/mol %
Time/h
Yield (%)
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
THF
THF
THF
THF
THF
THF
THF
THF
THF
110
115
115
115
58
115
115
115
115
115
115
115
115
KOtBu
K2CO3
Na3PO4
K2CO3
K2CO3
K2CO3
KOtBu
K2CO3
K2CO3
KOtBu
K2CO3
–
100
100
100
25
25
100
25
25
10
25
25
25
–
24
20
20
24
24
18
18
18
18
18
18
18
18
60
0
1
4
1
17a
0b
86a
93a
60a
0
9
10c
11c
12
13
69a
15
K2CO3
a
b
c
About 5–8% of amide formation was observed. Complete conversion to the amide was observed [eqn. (1)]. The phenol was not converted
to the sodium phenolate in these runs.
the phenoxide was used (2.2 equiv) in the absence of an
additional base, leading to about 69% of the required product
(entry 12).
involves oxidative addition in the rate-determining step. In the
case of the bromobenzene, the aryl halide is unactivated and
oxidative addition occurs efficiently. After the catalytic cycle
CuX is generated. Subsequent oxidative additions to the
copper(I) intermediate will occur only if the halide is removed
from the coordination sphere of copper (Scheme 2).
Since copper in the þ2 state can be reduced in situ by the
phenoxide to copper(I), we attempted a reaction with catalytic
amounts of CuCO3 ꢀ Cu(OH)2 ꢀ H2O, which is readily available.
In this case, some amount of the hydrolysis product identified
as the amide was obtained. It is well-documented that nitriles
can be easily converted to the amide in the presence of base and
water [eqn. (1)]:15
Thus, reactions carried out with THF as a solvent proceeded
efficiently with a combination of K2CO3 as a base and the
sodium phenolate. Contrary to what is known about Ullmann
coupling, the reaction proceeded in a catalytic fashion and was
hindered by the presence of stoichiometric amounts of cop-
per(I). Thus, when the quantity of [Cu(CH3CN)4]ClO4 was
reduced from 100 to 25 to 10 mol %, the yield of the product
increased in both solvents: toluene (entries 2 and 4) and THF
(entries 6, 8 and 9). However, the yield was significantly lower
(56%) when 5 mol % catalyst was used. So the optimized
conditions were identified as a combination of aryl bromide
and 1.2 equiv of sodium aryl oxide, with 10 mol % of
[Cu(CH3CN)4]ClO4, and 1.5 equiv of pulverized K2CO3, in a
sealed vial with THF as the solvent kept at 115 1C for 18 h.
These conditions were then tested for the coupling of other
substrates in a systematic fashion. Note that it is possible to
avoid the sealed tube reaction by carrying out the reaction in
diglyme at 115 1C.
In the absence of the catalyst, only 15% product is obtained,
showing that copper is essential to promote the reaction
(Table 1, entry 13). Activated aryl bromides gave excellent
yields of the coupled product with a variety of phenols (Table
2). However, rather poor yields were obtained with unactivated
aryl bromides such as bromobenzene. In these cases, surpris-
ingly, an increase in the copper concentration to 25 mol %
gave better results. In the case of unactivated aryl bromides,
the coupled product was obtained in good yield except in the
case of 4-chlorophenol and 4-methoxyphenol.
ð1Þ
A strong base is required for this reaction to take place. The
water required for this reaction could probably be from the
catalyst, which contains one molecule of water. However,
hydrolysis could be suppressed with K3PO4 as the base instead
of K2CO3. Hence K3PO4 was retained as the reagent of choice
in subsequent reactions. Where hydrolysis reduced the yield in
reactions promoted by [Cu(CH3CN)4]ClO4, as in entry 4 of
Table 2, the use of K3PO4 was found to be beneficial.
The catalytic transformation was attempted with different
phenols having electron-donating and -withdrawing substitu-
ents such as 4-methylphenol, phenol, 4-methoxyphenol and
4-chlorophenol. Excellent yields were obtained for the 4-bro-
mobenzonitrile and good yields for the bromobenzene reac-
tions with CuCO3 ꢀ Cu(OH)2 ꢀ H2O as the copper catalyst.
4-Bromoacetophenone also performed satisfactorily. However,
4-bromobenzaldehyde gave a mixture of the desired diaryl
The different efficiencies with which 4-bromobenzonitrile
and bromobenzene are converted suggest that the mechanism
Table 2 Results with catalytic [Cu(CH3CN)4]ClO4 under optimized conditionsa
Entry
Aryl halide
Phenol
Catalyst/mol %
Yield (%)
1
2
3
4
5
6
7
8
4-Bromobenzonitrile
4-Bromobenzonitrile
4-Bromobenzonitrile
4-Bromobenzonitrile
Bromobenzene
Bromobenzene
Bromobenzene
Bromobenzene
Bromobenzene
Bromobenzene
Bromobenzene
Bromobenzene
Bromobenzene
4-Methylphenol
Phenol
10
10
10
10
–
10
25
10
25
10
25
10
25
89
96
92
83
7
73
84
40
83
51
29
16
20
4-Methoxyphenol
4-Chlorophenol
4-Methylphenol
4-Methylphenol
4-Methylphenol
Phenol
9
Phenol
10
11
12
13
4-Methoxyphenol
4-Methoxyphenol
4-Chlorophenol
4-Chlorophenol
a
Reaction was carried out for 18
h in a sealed vial with 1.0 ml of THF as solvent with indicated mol % of [Cu(CH3CN)4]ClO4, 1.5 equiv K2CO3,
1.2 equiv sodium salt of the phenoxide and 1 equiv of the aryl bromide.
N e w J . C h e m . , 2 0 0 4 , 2 8 , 1 3 9 0 – 1 3 9 3
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Scheme 2 Mechanism of diaryl ether formation.
ether along with 40-bromo-2-hydroxybenzophenone, a result of
Friedel–Crafts reaction followed by benzylic alcohol oxidation;
this is being investigated further. The results obtained are
shown in Table 3.
Experimental
General remarks
The tetrahydrofuran solvent for the reaction was dried under
sodium ketyl radical. 4-Bromobenzonitrile and potassium phos-
phate were obtained from Lancaster and bromobenzene and
malachite were obtained from BDH; phenol, 4-methylphenol, 4-
chlorophenol were obtained from S.D.Fine-Chem. Ltd.; 4-
methoxyphenol was obtained from Sisco Chem Pvt. Ltd.;
K2CO3 was obtained from Ranbaxy; sodium hydride (60% in
mineral oil) from Aldrich, USA, was analysed using standard
procedures prior to use and potassium t-butoxide (Aldrich,
Conclusion
An efficient method using low amounts of solvent and an
inexpensive, readily available reagent, CuCO3 ꢀ Cu(OH)2 ꢀ
H2O, has been devised for the coupling of various aryl bro-
mides with different phenols. The circumstances under which
copper, either copper(II) or copper(I) sources, acts as a catalyst
and the conditions under which it functions in a stoichiometric
fashion have been highlighted. The method eliminates the need
to make unstable copper(I) precursors for these reactions. The
reaction works effectively even for substrates like 4-bromoben-
zyl alcohol, which is an electron-rich halide. Moderate yields
are seen for its reaction with electron-deficient phenols like
4-chlorophenol. Aldehyde groups do not seem to be compa-
tible with these reaction conditions, for 4-bromobenzaldehyde
could not be used to get the coupled diaryl ether using this
procedure.
16
USA) was used as received. [Cu(CH3CN)4]ClO4 and 4-bro-
mobenzyl alcohol17 were prepared by literature procedures.
1H NMR spectra were recorded on a Bruker ACF 200 MHz
instrument and 13C NMR on a Bruker AMX 400; high resolu-
tion electrospray ionisation mass spectra (HRESMS) were
acquired on a Micromass Q-Tof micro. All the compounds
prepared were characterised by 1H NMR and proton decoupled
13C NMR spectra in CDCl3 as the solvent with tetramethylsi-
lane (TMS) as the internal reference (Details are available in the
1392
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Table 3 Results with CuCO3 ꢀ Cu(OH)2 ꢀ H2O (5 mol %) under opti-
cated Instruments Facility and Organic Chemistry Department
of Indian Institute of Science for 13C NMR spectra and
HRESMS, respectively.
mized conditionsa
Entry
Aryl halide
Phenol
Yield (%)
1
2
3
4
5
6
7
8
4-Bromobenzonitrile
4-Bromobenzonitrile
4-Bromobenzonitrile
4-Bromobenzonitrile
4-Bromobenzonitrile
4-Bromobenzonitrile
Bromobenzene
4-Methylphenol
4-Methoxyphenol
Phenol
4-Chlorophenol
2,4-Dimethylphenol
2,6-Dimethylphenol
4-Methylphenol
4-Methoxyphenol
Phenol
499
499
499
499
72
77
79
81
91
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a
Reaction was carried out for 18 h in a sealed vial with 0.8 ml of THF as solvent
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4
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Finely powdered K2CO3 (0.2 g, 1.45 mmol), 4-bromobenzoni-
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0.1 mmol), along with a magnetic stir bar, are loaded into a
vial capped with a septum and fitted with a side arm attached
to a double manifold. The aryl oxide is prepared in a two
necked round bottom flask under nitrogen from 4-methylphe-
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tetrahydrofuran stirred with sodium hydride (0.056 g, 1.2
mmol) until a clear solution of the sodium aryl oxide is formed.
The aryl oxide is then transferred to the vial through a syringe.
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nitrogen and sealed after evacuating. The sealed vial is then
immersed in an oil bath maintained at 115 1C and the contents
stirred for the required time. At the end of the reaction, the vial
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concentrated to 4 ml and analysed by GC.
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given above except that the solvent used is reduced to 0.8 ml of
tetrahydrofuran. At the end of the reaction, the vial is cooled,
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Acknowledgements
We thank CSIR, New Delhi and Indian Institute of Science
(IISc) for generous financial support. We also thank Sophisti-
N e w J . C h e m . , 2 0 0 4 , 2 8 , 1 3 9 0 – 1 3 9 3
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