Microwave assisted synthesis of selected diaryl ethers under Cu(I)-catalysis

Article abstract of DOI:10.1016/j.tetlet.2015.02.073

A practical synthesis of diaryl ethers has been achieved from cross coupling reaction between aryl halides and phenols under Cu(I)-catalysis and using ACHN as a ligand. The presence of catalysis and microwave-assistance benefitted the synthesis by increasing the yield of diaryl ethers with a reduction of reaction time.

Full text of DOI:10.1016/j.tetlet.2015.02.073

Accepted Manuscript
Microwave assisted synthesis of selected diaryl ethers under Cu(I)-catalysis
Lorena Navarro, M. Dolors Pujol
PII:
S0040-4039(15)00354-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.073
TETL 45943
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
11 November 2014
12 February 2015
16 February 2015
Please cite this article as: Navarro, L., Dolors Pujol, M., Microwave assisted synthesis of selected diaryl ethers under
Cu(I)-catalysis, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.02.073
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Tetrahedron Letters
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Microwave assisted synthesis of selected diaryl ethers under Cu(I)-catalysis
Lorena Navarro and M. Dolors Pujol*
Laboratori de Química Farmacèutica (Unitat Associada al CSIC). Facultat de Farmàcia. Universitat de Barcelona. Av. Diagonal 643. E-08028-Barcelona. e-
mail: mdpujol@ub.edu
ARTICLE INFO
ABSTRACT
Article history:
Received
A practical synthesis of diaryl ethers has been achieved from cross coupling reaction between
aryl halides and phenols under Cu (I)-catalysis and using ACHN as a ligand. The presence of
catalysis and microwave-assistance benefitted the synthesis by increasing the yield of diaryl
ethers with a reduction of reaction time.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Phenol
Aryl halides
Diaryl ethers
Cross coupling
Cuprous bromide
Microwave irradiation
Functionalized diaryl ethers are important scaffolds found in a
variety of biologically active natural products.1 Diaryl ethers
constitute an important class of organic intermediates for the
synthesis of compounds with significant industrial interest2 or
therapeutically activity.3 Drugs with anti-inflammatory and
analgesic properties such as Fenoprofen4 or antitumor agents
such as Sorafenib5 contain a diaryl ether subunit in their structure
(Figure 1).
Our lack of success prompted us to approach the target by
assaying a variety of alternative methods. We needed diaryl
ethers substituted in meta, whereas the majority of reports only
give examples of diaryl ethers from para-substituted aryl
halides.12 Though there are many methods for the preparation of
diaryl ethers, none are of general application.
Here we report the extension of our strategy for the O-
arylation of several aryl halides using new ligands such as ACHN
(1,1′-azobis(cyclohexane carbonitrile)), which besides a radical
initiator is capable to form complexes with Cu(I) stabilizing this
one. Azo-derivatives were not considered as ligands for the
Ullmann diaryl ether synthesis in the study of Opatz et al.13
CH3
COOH
O
O
Cl
O
CH3
N
O
H
N
F3C
N
N
H
H
Fenoprof en
Soraf enib
H3C
CH3
Figure 1. Structures of fenoprofen and sorafenib
N
H3C
CH3
HOOC
HOOC
COOH
COOH
N
N
Diaryl ethers have been synthesized by arylation of phenols
with aryl halides using different methodologies. The classical
Ullmann coupling reaction,6 involving stoichiometric amounts of
copper or copper salts, high reaction temperatures in polar
solvents, and long reaction times, has been gradually replaced by
new carbon-oxygen bond-forming chemical strategies.7 The drive
toward environmentally friendly processes has resulted in the
increasing use of catalytic amounts of transition metals in the
presence of ligands8 or avoiding catalysts altogether.9 The SNAr
reaction of electron–deficient aryl halides has received
considerable attention.10 In a recent study, we attempted to form
complex synthetic scaffolds requiring diaryl ethers as
intermediates using conditions reported in the literature.11
N
N
CH3 CH3
TMEDA
N
EDTA
DMAP
H3C CH3
N
N
N
N
C
N
C
N
CN NC
ACHN
H3C CH3
AIBN
Figure 2. Structures of tested ligands
In preliminary studies oriented to the preparation of 3-
phenoxyphenyl methyl sulfone from phenol and 3-bromophenyl
methyl sulfone, the use of Pd14 or Cu7 catalysts and strong
conditions did not afford the required diaryl ether (Table 1, entry
1). However, using the Pd/BINAP catalyst provided the
corresponding ether in 19% yield (Table 1, entry 2) when the 3-
bromomethyl phenyl sulfone (electron-withdrawing substituent)
was substituted by the 3-bromomethyl thiobenzene (electro-
donating substituent) as the starting aryl halide.
____________
*Corresponding authors,
E-mail addresses: mdpujol@ub.edu, lorenanavarro85@gmail.com

2
Tetrahedron
After testing a series of more economical conditions the Pd
catalysts were substituted by cuprous salts and ( )-BINAP was
replaced by ACHN.
catalyst, the reaction did not take place (data not introduced in
the Tables). Other conditions were tested using EDTA, TMEDA
or DMAP as ligands, affording the desired diaryl ethers in lower
yield or resulting in no reaction taking place.
In continuation, several bases were studied and the weak base
Cs2CO3 proved great efficiency coinciding with previous
studies.17 (Table 2, entries 3 and 4). Under the tested conditions,
other bases such as Na3PO4, K2CO3 or Na2CO3 did not provide
the desired diaryl ethers. While as solvent, the DMF gave better
results than the toluene due to the better solubility of the starting
phenols (Table 2, entries 4, 5 and 6). Under these conditions, no
reaction occurred in the presence of AIBN as the ligand
(conventional radical initiator such as ACHN (Table 2, entry 1)),
but TMEDA was less effective than ACHN (Table 2, see entries
5 and 6). In this work, blank experiments have been carried out to
prove the stability of ACHN and AIBN under the conditions of
the reaction (see supplementary material).
Table 1 Comparison of different conditions in the cross-coupling
reaction
Entry
Conditions
Ph-O-C6H4-R
Yield
1
a
a
b
-
1
2
1
1
2
3
19%
23%
Table 3 Several examples of O-arylation of phenols
Entry
R
R‘
cond
Product
Yield
(%)
Ref
12c
1
2
H
H
H
a
55
61
4
5
c (1 h)
58%
pMeO
a**
18
c (90 min)
100%
Conditions a: Cs2CO3/( )-BINAP/Pd[(o-tolyl)3P]Cl2/toluene, 160 ºC, 4 days.
b: CuBr/Cs2CO3/ACHN/DMF, 160 ºC, 26 h. c: CuBr/Cs2CO3/ACHN/DMF,
microwave, 100 ºC (extern temperature).
3
4
pF
pCl
a
a
65
65
H
pCN
The lengthy reaction time when using thermal heating (Table
4 and 5) was reduced employing microwave
19
1, entries
irradiation.15 This protocol was clean, cheap and more
environmentally-friendly than the previous one.
5
6
mNO2
pCN
pCN
a
a
80
86
Table 2 Copper-catalyzed O-arylation of phenols
mMeO
conditions
R-C6H4-O-C6H4-NO2-p
p-NO2-C6H4-Br
R-C6H4-OH +
7
8
pCl
pCN
pCN
a**
a**
88
90
20-
21
Entry
Conditions
Product
Yield Ref
(%)
pMeO
22
23
24
1
2
3
4
5
6
7
a
-
31
15
b
9
pMe
pAc
pNO2
pNO2
c + Na2CO3
c + Cs2CO3
d + ACHN
d +TMEDA
e
-
a
87
91
3
88
99
49
100
10
a*
8
9
f
g (30 min)
g (90 min)
h
e
62
52
68
68
99
11
12
pF
pNO2
pNO2
a
90
10
11
12
4
See
prod.
15
a*
100 25
Conditions a: CuBr/Cs2CO3/AIBN/toluene, 120 ºC, 24 h. b:
CuBr/Cs2CO3/ACHN/toluene, 120 ºC, 48 h. c: CuI/ACHN/DMF, 120 ºC, 24
h. d: CuBr/Cs2CO3/DMF, 120 ºC, 26 h. e: CuBr/ Cs2CO3/ACHN/DMF,
microwave, 90 min, 100 ºC. f: DMF/ NaH. g: CuBr/Cs2CO3/arginine/DMF,
microwave, 100 ºC. h: CuBr/Cs2CO3/lysine/DMF, microwave, 100 ºC, 90
min.
Conditions a: CuBr/Cs2CO3/ACHN/DMF, microwave, 100 ºC (extern
temperature), 1 h 30 min. a* time of reaction 30 min. a** time of reaction 60
min.
Applying the SNAr classical reaction conditions to p-
fluorophenol and p-nitrobromobenzene with NaH and DMF gave
the target diaryl ether in 62% of yield (Table 2, entry 8). Under
Microwave heating proved to be effective and increased the
yields (Table 1, entries 4 and 5). Under these conditions, 1 was
obtained in 92% yield with 20 mmol scale. In the absence of a

microwave irradiation, the diaryl ether yield was high and
required a shorter reaction time and the lowest temperature
(Table 2, entry 7 and 12). Using CuBr, Cs2CO3 in DMF, other
ligands such arginine or lysine also proved to be effective but less
so than ACHN under the same conditions (Table 2, entry 9, 10
and 11).
In summary, a new, efficient and environmentally friendly
protocol for O-arylation has been developed using CuBr as a
catalyst and ACHN as a ligand under microwave irradiation,
which provided diaryl ethers in moderate to excellent yields. The
single process is clean and simple and different phenols and
substituted aryl halides were well tolerated in this cross-coupling
procedure. Our method offers competitive advantages such as
low amounts of catalyst and ligand, low temperatures and
reduced reaction times. Electron-withdrawing groups (e.g. -NO2,
-CN, -SO2CH3) in the aryl halides favored the coupling reaction,
while phenols with electron-donating substituents (e.g. -CH3, -O-
CH3) gave the diaryl ethers in lower yields.
To define the scope of this O-arylation procedure (conditions
e, see Table 2 entries 7 and 12), we applied these conditions to a
range of substituted phenols and aryl halides (see Table 3). Our
studies showed that the reaction of phenol with 4-
methoxybromobenzene and 0.2 mol% CuBr, Cs2CO3 (1 mol),
ACHN (0.2 mol%) in DMF at 130 ºC for 6 days gave the desired
ether in only 15% yield. Under conventional heating, longer
reaction times were required, ranging from hours to days, and
yields were low. From the same starting material on microwave
oven with an irradiation programmed at 100 W and a fixed
temperature at 100 ºC (extern temperature) the corresponding
ether was obtained in 61% yield after only 1 h (Table 3, entry 2).
To confirm these results, other additives were tested instead of
ACHN, such as EDTA or DMAP, which gave no reaction, or
TMEDA, which at 180 ºC for 5 days provided the corresponding
diaryl ether in 52% yield. The reaction of 4-fluorophenol (1
equiv) with 4-chlorobromobenzene (1 equiv) under the same
conditions (100 ºC for 30 min) under microwave assistance
(Table 3, entry 3) regioselectively afforded the 4-(4-
chlorophenoxy)fluorobenzene in 65% yield. This result shows
the greater reactivity of aryl bromide in comparison with aryl
chloride and aryl fluoride (Table 3, entry 3). Electron-deficient
phenols such as 3-nitrophenol (Table 3, entry 5) and 4-
fluorophenol (Table 3, entry 11) were successfully coupled with
electron-deficient aryl bromides. Notably, with our procedure, we
were able to obtain diaryl ethers from the reaction of
unsubstituted phenols with unsubstituted aryl bromide, albeit in
low yield (Table 3, entry 1). Electron-rich phenols underwent
arylation more efficiently (Table 3, entries 6, 8 and 9) than
unsubstituted phenols. The application of our conditions to 4-
acetylphenol and 4-bromonitrobenzene furnished 4-(4-
acetylphenoxy) nitrobenzene in 91% yield after only 30 min of
reaction (Table 3, entry 10). Under conventional heating, without
microwave irradiation, the same ether was obtained after 16 h at
170 ºC in 70% yield. In addition, when the microwave assisted
O-arylation procedure was applied to the reaction of 4-
nitrophenylbromide with 4-fluorophenol or 2-naphthol; the
corresponding O-diaryl ethers were obtained in 90% (Table 3,
entry 11) and 100% (Table 3, entry 12) respectively. In the case
of 2-naphthol, after heating at 160 ºC for 16 h without microwave
irradiation the target ether was obtained only in 30% yield (data
not introduced in the Tables). Under the same conditions, ligands
such as TMEDA or DMAP did not improve the yield (data not
introduced in the Table).
Acknowledgment
We thank the Ministry of Science and Innovation (MICINN,
Spain) for financial support (CTQ2011-29285-C02-01).
Supplementary Material
1
Copies of the H and 13C NMR spectra of all new compounds,
detailed experimental information and NMR spectra of the blank
experiments proving the stability of ACHN and AIBN under the
reaction conditions can be found, in the online version, at
http://dx.doi.org/
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Graphical Abstract
Microwave assisted synthesis of selected diaryl
ethers under Cu(I)-catalysis
Lorena Navarro and M. Dolors Pujol*
Leave this area blank for abstract info.