Nano-CuO-catalyzed ullmann coupling of phenols with aryl halides under ligand-free conditions

Article abstract of DOI:10.1002/ejoc.200800637

Nano copper oxide has been found to be a highly efficient and reusable catalyst for the C-O cross-coupling of phenols with aryl halides under ligand-free conditions. With DMSO as solvent, Cs₂CO₃ and KOH are suitable bases for the cross-coupling reactions with phenyl iodides and bromides, respectively. Diaryl ethers with different substituted groups can be synthesized in moderate-to-good yields. The catalyst can be recycled at least five times without obvious loss in catalytic activity. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800637

FULL PAPER
DOI: 10.1002/ejoc.200800637
Nano-CuO-Catalyzed Ullmann Coupling of Phenols with Aryl Halides under
Ligand-Free Conditions
Jintang Zhang,[a] Zuhui Zhang,[a] Ye Wang,[a] Xiaoqi Zheng,*[a] and Zhiyong Wang*[a]
Keywords: Nanostructures / Copper / Ligand-free conditions / Heterogeneous catalysis / Arylation / Catalyst recycling
Nano copper oxide has been found to be a highly efficient
and reusable catalyst for the C–O cross-coupling of phenols
with aryl halides under ligand-free conditions. With DMSO
as solvent, Cs2CO3 and KOH are suitable bases for the cross-
coupling reactions with phenyl iodides and bromides,
respectively. Diaryl ethers with different substituted groups
can be synthesized in moderate-to-good yields. The catalyst
can be recycled at least five times without obvious loss in
catalytic activity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Diaryl ethers are important structural motifs in numer-
ous natural biologically active compounds, for example,
K13, perrottetin and vancomycin,[1] as well as in many
polymers such as poly(aryl ethers) (Figure 1). Copper-cata-
lyzed Ullmann coupling of aryl halides with phenols repre-
sents the most popular choice for the synthesis of diaryl
ethers on laboratory and industrial scales.[2] However, the
utility of classical Ullmann coupling has been greatly
limited by its harsh reaction conditions, for example, high
temperatures (ca. 200 °C), the stoichiometric use of copper
compounds and the low conversion of unactivated aryl ha-
lides.[3] Much effort has been devoted to developing more
convenient methods of Ullmann-type O-arylation, mainly
focusing on ligands,[4] bases,[5] copper species,[6] alternatives
to aryl halides[7] and new experimental techniques.[6b,8]
However, almost all of these methods involve ligands or
well-defined catalysts/reagents, which may increase the cost
and limit the scope of applications. Therefore, mild, simple
and low-cost methods are still highly desirable.
On the other hand, nanomaterials with high surface
areas as well as reactive morphologies have been widely
studied. Very recently, the employment of nanocrystalline
metal oxides as catalysts in organic synthesis has attracted
much attention.[9,10] Nanomaterial-catalyzed reactions are
generally characterized by easy product purification, ef-
ficient recycling of the catalyst and minimization of metal Figure 1. Examples of the diaryl ether structure in natural products
and synthetic polymers.
[a] Hefei National Laboratory for Physical Science at Microscale,
Joint Laboratory of Green Synthetic Chemistry and Depart-
ment of Chemistry, University of Science and Technology of
China,
Hefei, Anhui, 230026, People’s Republic of China
Fax: +86-551-3603185
traces in the products. Herein we report a nano-CuO-cata-
lyzed Ullmann cross-coupling of phenols with aryl halides
under ligand-free conditions.
E-mail: zwang3@ustc.edu.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
5112
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Ullmann Coupling of Phenols with Aryl Halides
Results and Discussion
Initially, the coupling of 4-methoxyphenol with iodo-
benzene was chosen as a model reaction to study the effect
of different copper species, bases, solvents, ratios of reac-
tants, concentrations and temperature. A mixture of 4-
methoxyphenol (1.0 mmol), iodobenzene (1.1 mmol) and
10 mol-% of catalyst were heated in the presence of base
(Cs2CO3, 1.5 mmol) in DMSO (1 mL) at 110 °C under ni-
trogen. For the sake of experimental efficiency, most reac-
tions were quenched after 8 h. First of all, catalysts of dif-
ferent copper salts were tested in this model reaction. Com-
mercially available copper sources catalyze this reaction to
afford the corresponding product in low yields of 22–28%
(Table 1, Entries 1–3). No product was detected in the ab-
sence of copper as a catalyst (Table 1, Entry 4). Inspired by
the fact that copper oxide also catalyzed the reaction, we
prepared nanocrystalline copper oxide by a procedure sim-
ilar to that described previously.[11] The nanoparticles were
characterized by XRD and HRTEM analyses, and the
average size of the copper oxide particles was about 28.5 nm
(Figure 2).
Figure 2. HRTEM images of (a) fresh nano-CuO particles and (b)
nano-CuO particles after the fifth catalytic cycle.
and co-workers in the construction of C–S and C–N
bonds,[10a,10c] and Kantam et al. in the efficient arylation of
heterocycles with activated chloro- and fluoroarenes.[10b]
This encouraged us to optimize the reaction conditions fur-
ther (Table 1). The catalyst loading and the concentration
were also investigated in the model reaction (see the Sup-
porting Information) and a 10 mol-% of loading was found
to be the best choice. Common solvents, such as DMSO,
DMF, dioxane, toluene and NMP, were tested (see the Sup-
porting Information): DMSO gave the highest yield. Fol-
lowing these results, different bases, such as KOH, K2CO3
and K3PO4, were screened. The results indicated that
Cs2CO3 can be replaced by K2CO3 or KOH (Table 1, En-
tries 7 and 8), but when K2CO3 or KOH was used, diphenyl
ether was observed as a byproduct as a result of the com-
petitive arylation of water with iodobenzene.[12] When the
amount of base (Cs2CO3) was increased from 1.5 to
2.0 mmol and the amount of iodobenzene increased to
1.5 equiv., the yield was enhanced to 62% (Table 1, En-
try 10). Temperature also had a large effect on the reaction.
Below 100 °C the reaction produced the desired products in
low yields (Table 1, Entry 11), but when the reaction was
performed above 110 °C, there was no obvious improve-
ment in yield.
Table 1. Coupling of 4-methoxyphenol with iodobenzene under dif-
ferent conditions.
After a systematic investigation, we identified the opti-
mum conditions: nano-CuO as catalyst (10 mol-%), Cs2CO3
as base (2.0 equiv.) and DMSO as solvent at 110 °C with
nitrogen protection (Table 1, Entry 10). Also, the isolated
yield was increased to 83% when the reaction time was in-
creased to 18 h under these conditions (Table 1, Entry 10).
With these optimized reaction conditions in hand, we
employed a variety of substrates in an attempt to synthesize
different diaryl ethers, as shown in Table 2. The experimen-
tal results indicated that substituents on the phenol ring or
on the phenyl ring of the phenyl halides influenced the reac-
tion greatly. For example, substitution of a methyl group at
the ortho position of phenol incurs a reduction in yield from
84 to 73% (Table 2, Entries 1 and 2). With an increase in
the substituent bulk from methyl to ethyl, the correspond-
ing reaction yield decreased further to 54% (Table 2, En-
try 3). Moreover, no reaction occurred under these condi-
[a] Method A: ratio of phenol (1 mmol in 1  solution)/iodo-
benzene/base/nano-CuO = 1.0:1.1:1.5:0.1. Method B: ratio of phe-
nol (1 mmol in 1  solution)/iodobenzene/base/nano-CuO
=
1.0:1.1:1.5:0. Method C: ratio of phenol (1 mmol in 1  solution)/
iodobenzene/base/nano-CuO = 1.0:1.5:2.0:0.1. [b] Isolated yield. [c]
The reaction was carried out according to Method C for 24 h. [d]
n.d. = not detected. [e] In air. [f] The reaction time was lengthened
to 18 h. [g] The reaction mixture was stirred at 90 °C for 23 h.
The reaction yield was dramatically increased to 44% tions when the ortho position of phenol was occupied by a
when nanoparticles of copper oxide were used as the cata- tert-butyl group. Although a para-methyl group showed a
lyst (Table 1, Entry 5). The high catalytic efficiency of nano small positive effect (Table 2, Entry 5), a tert-butyl group
copper oxide has also been reported by Punniyamurthy hindered the reaction completely under these conditions,
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J.-T. Zhang, Z.-H. Zhang, Y. Wang, X.-Q. Zheng, Z.-Y. Wang
To further extend the scope of the reaction, phenyl bro-
FULL PAPER
even when it was at the para position. This indicated that
steric hindrance of the substituent on the phenol disfavours mides were examined (Table 2, Entry 10, and Table 3 En-
this reaction. As for electronic effects, electron-donating tries 1–5). Generally, the reactivity of phenyl bromides is
groups on the phenol ring had little effect on the reaction inferior to that of phenyl iodides. When an electron-with-
(Table 2, Entry 6). In contrast, electron-withdrawing groups drawing group such as a cyano group was installed on the
on the phenol ring affected the reaction remarkably: no re- phenyl ring of phenyl bromide, the corresponding coupling
action occurred with a chloro substituent at the para posi- reaction proceeded smoothly to afford the coupling product
tion. As expected, an electron-withdrawing substituent on in good yield under the same conditions as those used with
the phenyl ring of the phenyl halide favours this coupling the phenyl iodides (Table 2, Entry 10). However, other
(Table 2, Entries 7 and 8), whereas para-methoxy substitu- phenyl bromides did not react under the same conditions.
tion led to the failure of the reaction. When iodobenzene Interestingly, when Cs2CO3 was replaced with KOH, phenyl
was replaced by iodonaphthalene, the corresponding coup- bromides could be employed as the reaction substrates.[13]
ling reaction proceeded smoothly to give the aryl ether The corresponding coupling reactions were carried out to
product in good yield (Table 2, Entry 9).
afford the coupling products in good yields (Table 3, En-
tries 1–5). Phenols with a bulky tert-butyl group or a bromo
substituent, which were difficult substrates when Cs2CO3
was used as the base, can also be used in the presence of
KOH to produce the coupling products in moderate yields
(Table 3, Entries 3–5). Moreover, even phenyl chloride
showed some reactivity when KOH was employed as the
base, and the corresponding aryl ether products were ob-
Table 2. Coupling of 4-methoxyphenol and iodobenzene with
Cs2CO3.[a]
Table 3. Coupling of phenols with bromobenzenes and chloroben-
zenes.[a]
[a] Reaction conditions: nano-CuO (0.05 mmol), aryl halide
(0.75 mmol), phenol (0.5 mmol), KOH (1 mmol), DMSO (0.5 mL),
110 °C, 18–20 h. [b] Isolated yield.
[a] Method C, 18–20 h. [b] Isolated yield.
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Eur. J. Org. Chem. 2008, 5112–5116

Ullmann Coupling of Phenols with Aryl Halides
and phenols were purchased from Sinopharm Chemical Reagent
Co., Ltd., except for 2-ethylphenol, 2-tert-butylphenol and 4-bro-
mobenzonitrile which were obtained from Alfa Aesar. Solid sub-
strates were purified by recrystallization, and liquid substrates were
purified by distillation under vacuum.
served (Table 3, Entries 6 and 7). In particular, a strongly
electron-withdrawing substituent at the para position of
phenyl chloride can increase the reaction yield efficiently
(Table 3, Entry 8). The ligand-free system employing much
cheaper phenyl bromides or phenyl chlorides and KOH is
attractive and may find applications in the future.
As nano-CuO is a heterogeneous catalyst, the recycl-
ability of the catalyst in this coupling reaction was exam-
ined. The coupling of 4-methoxyphenol with iodobenzene
was chosen as a model reaction. After each cycle, the cata-
lyst was recovered by simple centrifugation, washing with
deionized water and ethanol and then drying in vacuo. The
recovered nano-CuO was used directly in the next cycle.
The recycling results are listed in Table 4 and show that the
catalyst was still highly efficient after the fifth cycle. TEM
images showed that the shape and size of the copper oxide
nanoparticles has undergone almost no change even after
the fifth cycle.
Preparation of CuO Nanoparticles: Cu(NO3)2·3H2O (3.624 g,
15 mmol) was dissolved in distilled water (50 mL) in air with stir-
ring, and then the pH value of the solution was rapidly adjusted
to 10 with Na2CO3 solution (1 ). The resultant solution was then
aged together with the mother liquor at room temperature for 12 h.
The final product was collected by filtration, washed with deionized
water, dried at 60 °C for 24 h and then calcined at 350 °C for 24 h.
General Procedure for the Coupling of Phenols with Aryl Halides:
A magnetic stirring bar, nano-CuO (4.0 mg, 0.05 mmol), Cs2CO3
(326 mg, 1 mmol) and phenol (0.5 mmol) were added into an oven-
dried tube (5 mL) cooled under nitrogen. The tube was sealed with
a septum, followed by three cycles of evacuation and back-filling
with pure, dry nitrogen. Then DMSO (0.5 mL) and aryl halide
(0.75 mmol) were injected through a syringe. The tube was sealed
and heated to 110 °C under nitrogen and its content stirred at that
temperature until the phenol was consumed, as determined by
TLC. The reaction mixture was cooled to room temperature, di-
luted with water and extracted with ethyl acetate three times. The
combined organic extracts were dried with anhydrous Na2SO4 and
concentrated under reduced pressure. Then the crude mixture was
purified by column chromatography on silica gel to afford the prod-
uct with high purity. The product was characterized by IR, 1H and
13C NMR spectroscopy and HR mass spectrometry.
Table 4. Recycling of nano-CuO.[a]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental methods, details of optimization, characteriza-
tion data and copies of spectra.
[a] Method C, 18–24 h. [b] Isolated yield.
Acknowledgments
The authors are grateful to the Natural Science Foundation of
China (30572234) and for support from the Chinese Academy of
Sciences.
Conclusions
We have prepared air-stable nano-CuO and employed it
as an efficient catalyst in the Ullmann coupling reaction of
phenols with aryl halides. The reaction can be carried out
under mild conditions without any organic ligands or other
auxiliaries, affording the corresponding aryl ethers in mod-
erate-to-good yields. Cs2CO3 enabled the Ullmann-type O-
arylation of phenyl iodides to be performed cleanly, whereas
KOH activated this O-arylation when phenyl bromides or
chlorides were employed as the reaction substrates. More-
over, the catalyst can be reused at least five times without
obvious loss in catalytic activity. To the best of our knowl-
edge this is the first example of a nano copper oxide as an
efficient catalyst for C–O coupling under ligand-free condi-
tions. The employment of nanoparticles as heterogeneous
catalysts in other reactions is currently under study in our
laboratory.
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Received: June 28, 2008
Published Online: September 16, 2008
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Eur. J. Org. Chem. 2008, 5112–5116