Synthesis of symmetrical diaryl ethers from arylboronic acids mediated by copper(II) acetate

Article abstract of DOI:10.1016/S0040-4039(03)01776-3

Copper promoted generation of phenols in situ through arylation of water and their subsequent arylation with arylboronic acids affords a wide range of symmetrical diaryl ethers in good to high yield. The reaction is rapid, mild, convenient and tolerant of a wide range of functionalities on the arylboronic acid.

Full text of DOI:10.1016/S0040-4039(03)01776-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7061–7063
Synthesis of symmetrical diaryl ethers from arylboronic acids
mediated by copper(II) acetate
A. D. Sagar,* R. H. Tale and R. N. Adude
School of Chemical Sciences, S. R. T. M. University, Nanded-431 606 Maharashtra, India
Received 13 March 2003; revised 7 July 2003; accepted 18 July 2003
Abstract—Copper promoted generation of phenols in situ through arylation of water and their subsequent arylation with
arylboronic acids affords a wide range of symmetrical diaryl ethers in good to high yield. The reaction is rapid, mild, convenient
and tolerant of a wide range of functionalities on the arylboronic acid.
©
2003 Elsevier Ltd. All rights reserved.
Many synthetic methods have been developed for the
synthesis of diaryl ethers which are important building
blocks for a large number of natural products and
while optimising the reaction conditions for the cross
coupling between 4-tert-butylphenol and phenylboronic
acid in methylene dichloride, the formation of phenol
and diphenyl ether as unwanted side products, in sig-
nificant amounts, was observed. This formation of
these side products was attributed to the competitive
arylation of water, released from the phenylboronic
acid and coupling of the phenol with the phenylboronic
acid. This was supported by the fact that the addition
1
pharmaceuticals. Despite recent improvements, the
2
Ullmann ether synthesis requires elevated temperatures
(
>100°C) in the presence of base and can lead to
3
inconsistent results for functionalised systems.
The chemistry of arylboronic acids continues to be a
growth area in synthetic methodology. Oxidative cleav-
age, usually with hydrogen peroxide, is a well known
reaction of arylboronic acids leading to the formation
of 4 A molecular sieves to the reaction mixture com-
,
pletely suppressed the formation of these side products.
We reasoned that, formation of the side product,
diphenyl ether, as observed by Evans et al. could be
exploited to synthesise symmetrical diaryl ethers from
arylboronic acids. We sought to develop this procedure
for the formation of symmetrical diaryl ethers and
4
of phenols. More useful in synthesis are CꢀO and CꢀN
5
,6
coupling reactions of arylboronic acids with phenols,
7
8
9
amines, N-hydroxyphthalimides, amides and imides,
1
0,11
and N-heterocycles,
to give the corresponding N- or
13,14
O-arylated products. Formation of unsymmetrical
report herein the success of this approach.
1
2
thioethers, from arylboronic acids and alkylthiols,
promoted by copper(II) acetate has also been described.
The initial conditions explored were those of Evans et
al. but without the 4 A molecular sieves. Phenylboronic
,
5
Evans et al. reported a useful boronic acid-phenol
acid (1 equiv.), Cu(OAc) (1 equiv.) and triethylamine
2
cross-coupling reaction mediated by copper(II) acetate
for the expedient synthesis of thyroxine. In this study,
(5 equiv.) were allowed to react in methylene dichloride
at room temperature for 18 h to give diphenyl ether in
5
0% yield with only traces of phenol. Attempts to
increase the yield of product by lengthening the reac-
tion time, up to 24 h, were unsuccessful.
Since, in this case, the water was being released from
the phenylboronic acid via triphenyl boroxine forma-
tion we thought that the presence of sufficient water in
the reaction medium would enhance the rate of the
reaction as well as the yield of product. Therefore, we
decided to carry out the reaction in a methylene dichlo-
ride–acetonitrile system assuming that acetonitrile con-
tains some water. Interestingly, diphenyl ether was
Scheme 1.
Keywords: arylation; arylboronic acids; copper; symmetrical diaryl
ethers.
*
Corresponding author. Fax: 0091-2462-229245; e-mail: adsagar2001
yahoo.co.in
@
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01776-3

7
062
A. D. Sagar et al. / Tetrahedron Letters 44 (2003) 7061–7063
a
Table 1. Effect of added water in the synthesis of diphenyl ether from phenyl boronic acid
Entry
Amount of water added (equiv.)
Time (h)
Yield of the product (%)
1
2
3
4
5
6
2
4
6
8
10
12
6
6
6
6
6
55
67
72
85
95
97
24
a
All the reactions were performed in methylene dichloride–anhydrous acetonitrile (1:9).
Scheme 2.
obtained in 95% yield within 6 h under these reaction
conditions as outlined in Scheme 1.
Table 2. Copper-catalyzed synthesis of symmetrical diaryl
ethers
It was assumed that the use of acetonitrile in the
reaction media as a source of water improved the yield
of the diphenyl ether. In support of this postulate, it
was found that the use of acetonitrile freshly distilled
from P O directly into the reaction flask, furnished a
2
5
similar yield of diphenyl ether as in the previous experi-
ments without acetonitrile. This finding confirmed the
need for water in the reaction media to enhance the rate
of the reaction as well as the yield of the product, and
ruled out the possibility that acetonitrile itself plays
some role in the reaction.
We next turned our attention to find the optimum
amount of water for the maximum yield of product. We
performed a series of experiments with phenylboronic
acid as a model substrate adding known amounts of
water to the methylene dichloride–anhydrous acetoni-
trile system. We found that the maximum yield of the
product was obtained with 10 equiv. of water (Table 1).
Further addition of water resulted in no significant
improvement in the yield despite the reaction being
continued for 24 h.
These studies revealed that the optimum conditions for
the reaction were 1 equiv. of phenylboronic acid, 1
equiv. of copper(II) acetate, 5 equiv. of triethylamine
and 10 equiv. of water in methylene dichloride–anhy-
drous acetonitrile at room temperature (Scheme 2).
We speculate that the water in the reaction medium
must be playing the dual roles of activating the boronic
1
5
acid and enhancing the rate of phenol formation.
Using conditions outlined in Scheme 2, a variety of
arylboronic acids were successfully converted into the
corresponding symmetrical diaryl ethers in good to high
yield (Table 2). The reactions proceed with both elec-
a
b
The yield refers to the pure isolated product. All the products were
1
characterised by spectral characteristics ( H NMR, IR, elemental
microanalyses) and by comparison with authentic samples.

A. D. Sagar et al. / Tetrahedron Letters 44 (2003) 7061–7063
7063
tron-rich and electron-deficient arylboronic acids and
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4
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We wish to thank the Department of Science and
Technology (DST) New Delhi, Govt. of India, for
financial support of this work.