Copper-catalyzed Ullmann coupling under ligand- and additive- free conditions. Part 1: O-Arylation of phenols with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2008.01.062

O-Arylation of a wide variety of substituted phenols and aliphatic alcohols with aryl halides catalyzed by copper iodide under mild ligand and additive free conditions (ⁿBu₄NBr, DMF, K₃PO₄, reflux, 22 h) is accomplished in good to excellent product yields (up to 95%).

Full text of DOI:10.1016/j.tetlet.2008.01.062

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2018–2022
Copper-catalyzed Ullmann coupling under ligand- and additive-
free conditions. Part 1: O-Arylation of phenols with aryl halides
Joyce Wei Wei Chang a, Sheena Chee a, , Shiya Mak a, , Pongchart Buranaprasertsuk a,b
Warinthorn Chavasiri b, Philip Wai Hong Chan a,*
,
a Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
b Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
Received 26 October 2007; revised 25 December 2007; accepted 10 January 2008
Available online 15 January 2008
Abstract
O-Arylation of a wide variety of substituted phenols and aliphatic alcohols with aryl halides catalyzed by copper iodide under mild
ligand and additive free conditions (nBu4NBr, DMF, K3PO4, reflux, 22 h) is accomplished in good to excellent product yields (up to
95%).
Ó 2008 Elsevier Ltd. All rights reserved.
The biaryl ether linkage is a common motif found in
many natural products and pharmaceutically active com-
pounds.1 Biaryl ethers also have wide applications in the
fine chemicals and polymer industries, and are useful
come some of the above-mentioned limitations, it remains
a challenge to develop analogous O-arylation of phenols
which does not require a ligand or additive with aryl
halides as the starting materials, which would be desirable
from an economical perspective. In this context and in view
of recent work in our group showing that the copper
iodide-catalyzed N-arylation of a variety of nitrogen het-
erocycles with an equimolar amount of aryl halide in the
presence of nBu4NBr as phase transfer catalyst and NaOH
as base could be accomplished in good to excellent yields,
we wondered whether the same catalytic system could be
applied to O-arylation of phenols.12 Herein, we report
the copper iodide-catalyzed O-arylation of a wide variety
of phenols with equimolar amounts of aryl halides under
ligand and additive free conditions that proceeded in yields
up to 95%, being comparable to those reported using
ligand and additive promoted strategies (Scheme 1). In
the following Letter, we also report the extension of this
strategy for the S-arylation of arylthiols.13
ligands in metal-catalyzed organic transformations.2
A
traditional method for installing this functionality is the
copper-catalyzed Ullmann coupling of phenols with aryl
halides.3,4 However, such strategies have often required
the use of high reaction temperatures, stoichiometric
amounts of the copper catalyst that make scale-up unfea-
sible and ecologically unfriendly, the use of toxic and
air-sensitive aryl coupling reagents that can be difficult
to access, and excess phenol starting materials to achieve
low to moderate product yields.4a,5,6 In view of these
limitations, strategies to construct the O-aryl functionality
have been actively pursued. A recent notable achievement
has been the Cu-catalyzed O-arylation of phenols with aryl
halides in the presence of a variety of P-, N-, and O-based
ligands or additives.7–11 While these procedures have over-
In preliminary studies with the CuI/NaOH system, the
O-arylation of phenol 1a with iodobenzene 2a was found
to give no reaction. Rationalizing that 1a could be resistant
to deprotonation, we conducted optimization studies with
*
Corresponding author. Tel.: +65 6316 8760; fax: +65 6791 1961.
E-mail address: waihong@ntu.edu.sg (P. W. H. Chan).
Equal contributions to this work.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.062

J. W. W. Chang et al. / Tetrahedron Letters 49 (2008) 2018–2022
2019
R1
R2
CuI (10 mol %)
R1
R2
O
+
OH
X
nBu4NBr, K3PO4
DMF, reflux, 22 h
1
1
3
R1, R2 = H, alkyl, halide
X = I, Br
Scheme 1.
Table 1
Optimization of the reaction conditionsa
1a–e and aryl iodides 2a–h. As shown in Table 2, O-aryl-
ation of 1a with aryl iodides bearing either electron-with-
drawing or electron-donating substituents was shown to
give the corresponding products in excellent yields of
80–95% (entries 1–5). Similarly, the coupling of phenols
and aryl iodides containing various electron-withdrawing
and electron-donating substrate combinations was found
to proceed in good to excellent yields, comparable to those
obtained for the analogous ligand or additive promoted
reactions (entries 7–14).15 The present procedure was also
shown to work well for the O-arylation of phenols and aryl
iodides in which either or both starting materials contained
a sterically demanding ortho-substituent such as a methyl
group, with good to excellent product yields being obtained
(entries 15–22). Only when both ortho-positions of the
phenol were substituted with a sterically bulky methyl
group as in 1e was there a pronounced effect on the product
yield observed. In these latter reactions, the aryl ethers 3t–v
were isolated in moderate yields of 40–41% along with
unreacted aryl iodide starting material in yields up to
20% (entries 23–25).
CuI (10 mol %)
O
+
OH
I
nBu4NBr, K3PO4
solvent, reflux, 22 h
1a
2a
3a
Yieldb (%)
Entry
Solvent
1c
2c,d
3
4
5
6e
7f
a
PhMe
PhMe
PhMe
DMSO
DMF
DMF
DMF
62
51
82
72
95
65
42
Unless otherwise stated, all reactions were run for 22 h at reflux with
CuI/nBu4NBr/1a/2a/K3PO4 ratio of 1:1:10:10:20 in the solvent.
b
Isolated yield.
c
Reaction carried out with 5 mol % CuI and nBu4NBr.
K2CO3 used in place of K3PO4.
Reaction carried out with C6H5Br 2b in place of 2a.
Reaction carried out at 90 °C.
d
e
f
the same starting materials as the model substrates (Table
1). After screening a series of bases, 2 equiv of K3PO4
was determined to be the most effective base and gave
diphenyl ether 3a in 62% yield (entry 1). While replacing
K3PO4 with K2CO3 afforded 3a in a slightly lower yield
of 51% (entry 2), the use of other inorganic bases such as
NaOAc, Al2O3, and MgO, on the other hand, gave no reac-
tion. Increasing the catalyst loading from 5 to 10 mol %
was found to give an improved product yield of 82% (entry
3). Finally, on turning our attention to examining solvent
effects, we were pleased to find that DMF as a solvent gave
the best result, furnishing 3a in 95% yield (entry 5).14 In
contrast, the analogous O-arylation of 1a with bromo-
benzene 2b was shown to proceed in a lower product yield
of 65% (entry 6). Similarly, a low product yield of 42% was
obtained on conducting the reaction at 90 °C (entry 7). The
presence of a trace amount of water intrinsically present in
The application of our catalytic system for the O-aryl-
ation of aliphatic alcohols was also examined and found
to be somewhat intriguing (Table 3). As anticipated, our
preliminary studies showed that the reaction of butanol
4f with 2d and 10 mol % CuI, 10 mol % nBu4NBr and
K3PO4 (2 equiv) in DMF at reflux for 22 h gave 1-
butoxy-4-chlorobenzene 5a in 60% yield (entry 1).
However, when the same conditions were applied to the
reactions of 4g with either aryl iodide 2d or 2e, the corres-
ponding O-arylated products were obtained in low yields of
25% and 26%, respectively. On the other hand, by employ-
ing the conditions found suitable for the N-arylation of
nitrogen heteroarenes by replacing K3PO4 and DMF with
NaOH and toluene, respectively, these latter reactions were
shown to proceed to give 5b and 5c in good yields (entries 2
and 3). In addition, when the present O-arylation method
was applied to 4h, which contains both an amino and an
alcohol functionality, the chemoselective outcome was
found to be dependent on the solvent employed. With
1 equiv of 2a as the aryl iodide coupling partner, the reac-
tion of 4h in the presence of 10 mol % of CuI, 10 mol % of
nBu4NBr, K3PO4 (2 equiv) in DMF as solvent at reflux for
22 h proceeded to afford the N-arylated and N,O-diaryl-
ated products 5d and 5e in yields of 50% and 15%, respec-
tively (entry 4). Conversely, repetition of the same reaction
with toluene as the solvent gave a switch in selectivity with
5e obtained as the major product in 55% yield and the
n
the commercially available inorganic bases and Bu4NBr
phase transfer catalyst was also shown to be essential for
the O-arylation reaction. Under our conditions, no reac-
n
tion occurred in the absence of Bu4NBr or when using
K3PO4 dried to a constant weight under reduced pressure
at 200 °C prior to use. This was consistent with our earlier
findings for the analogous N-arylation reactions of nitro-
gen heteroarenes.12
To define the scope of the CuI-catalyzed O-arylation
reaction, we applied this process to a variety of phenols

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J. W. W. Chang et al. / Tetrahedron Letters 49 (2008) 2018–2022
Table 2
CuI-catalyzed O-arylation of phenols 1a–e with aryl iodides 2a–ha
Me
Me
R
OH
OH
I
R
I
R
1b, R = Me
1c, R = Cl
1d, R = H
1e, R = Me
2c, R = F
2h
2d, R = Cl
2e, R = Me
2f, R = NO2
2g, R = OMe
Entry
Substrates
Product
Yieldb (%)
1
2
3
4
5
1a + 2c
1a + 2d
1a + 2e
1a + 2f
1a + 2g
3b, R = F
3c, R = Cl
3d, R = Me
3e, R = NO2
3f, R = OMe
90
90
89
95
80
O
R
6
7
8
9
10
1b + 2a
1b + 2d
1b + 2e
1b + 2f
1b + 2g
3d, R = H
92
82
87
89
48
O
3h, R = Cl
3i, R = Me
3j, R = NO2
3k, R = OMe
Me
R
11
12
13
14
1c + 2d
1c + 2e
1c + 2f
1c + 2g
3m, R = Cl
3h, R = Me
3n, R = NO2
3o, R = OMe
80
81
80
62
O
Cl
R
15
16
17
18
19
20
21
1a + 2h
1b + 2h
1d + 2e
1c + 2h
1d + 2d
1d + 2f
1d + 2g
3g, R = H
3l, R = Me
74
81
75
52
80
77
60
Me
O
O
3p, R = Cl
R
3q, R = NO2
3r, R = OMe
Me
Me
Me
22
1d + 2h
3s
87
O
23
24
1e + 2d
1e + 2e
3t, R = Cl
3u, R = Me
40
41
Me
R
Me
Me
O
25
1e + 2h
3v
40
Me
a
All reactions were performed with CuI/nBu4NBr/1/2/K3PO4 molar ratio = 1:1:10:10:20 in DMF at reflux for 22 h.
Isolated yield.
b
O-arylated amine 5f isolated as the minor product in 20%
yield (entry 5).
In summary, we have developed a practical copper-
catalyzed procedure for the coupling of a wide variety of
phenols and aliphatic alcohols with aryl iodides that
proceeded in good to excellent yields. The present protocol
is applicable to a variety of phenols and aryl iodides
containing electron-withdrawing, electron-donating, and
sterically demanding substrate combinations under mild
conditions. Further investigation of the scope and applica-
tions of this reaction is currently underway and will be
reported in due course.

J. W. W. Chang et al. / Tetrahedron Letters 49 (2008) 2018–2022
2021
Table 3
CuI-catalyzed O-arylation of alcohols 4f–h with aryl iodides 2a and 2c–da
Entry
Alcohol
Aryl iodide
Product
Yieldb (%)
60
nPr
O
nPr OH
1
2d
4f
Cl
5a
O
O
2c
2d
2e
55
54
OH
Cl
5b
5c
4g
3c
Me
NHPh
4
50
OH
5d
5e
NH2
OH
NHPh
OPh
2a
15
55
4h
5d
NH2
OPh
20
5f
a
Unless otherwise stated, all reactions were performed with CuI/nBu4NBr/2/4/K3PO4 molar ratio = 1:1:10:10:20 in DMF at reflux for 22 h.
Isolated yield.
Reaction carried out with NaOH as base and PhMe as solvent.
Reaction carried out with PhMe as solvent.
b
c
d
3. (a) Ullmann, F.; Sponagel, P. Chem. Ber. 1905, 38, 2211–2212; (b)
Acknowledgment
Ullmann, F. Chem. Ber. 1904, 37, 853–854; (c) Ullmann, F. Chem.
Ber. 1903, 36, 2382; (d) Ullmann, F. Chem. Ber. 1901, 34, 2174–2185.
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5. Lindley, J. Tetrahedron 1984, 40, 1433–1456.
This work was supported by a College of Science Start-
Up Grant from Nanyang Technological University.
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