Chemo-selective copper-catalyzed C-O coupling reactions of phenols with aryl/vinyl halides using enaminone as efficient ligand

Article abstract of DOI:10.1002/aoc.2886

The copper-catalyzed Ullmann C-O coupling reactions between phenols and aryl/vinyl halides have been efficiently performed by employing (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one, an easily available enaminone, as ligand. This new ligand is advantageous for its easy availability, broad applicability and good efficiency. Copyright 2012 John Wiley & Sons, Ltd. Copyright

Full text of DOI:10.1002/aoc.2886

Full Paper
Received: 1 April 2012
Revised: 22 April 2012
Accepted: 24 April 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.2886
Chemo-selective copper-catalyzed C-O
coupling reactions of phenols with aryl/vinyl
halides using enaminone as efficient ligand
Jie-Ping Wan*, Chunping Wang and Yunyun Liu
The copper-catalyzed Ullmann C-O coupling reactions between phenols and aryl/vinyl halides have been efficiently
performed by employing (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one, an easily available enaminone, as
ligand. This new ligand is advantageous for its easy availability, broad applicability and good efficiency. Copyright © 2012 John
Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: copper catalysis; C-O; coupling; enaminone; ligand; aryl ethers; vinyl ethers
for Ullmann-type C-N coupling reactions of azoles[29] and the
Introduction
interesting tandem C-S coupling/C-H functionalization reactions
of thiophenols.[30] In addition, we recently reported the copper-
The Ullmann and Goldberg types of coupling reactions have been
employed as fundamental methodologies in organic synthesis to
construct sp2-C-C, C-N, C-O and C-S bonds for long history.[1–3]
In particular, the discovery of the promoting effect of an organic
ligand to these coupling reactions has shed light a new perspec-
tive on copper-catalyzed coupling transformations for both research
and industrial application.[4–6] The realization of performing these
reactions under much milder conditions significantly expanded
the possibility of using low-cost copper catalysts for diversified
coupling protocols. During the past decade, copper-catalyzed C-X
coupling reactions have made dramatic progress owing to the
occurrence of many ligands of high diversity and function.[7,8]
Following public recognition on the value of ligands in these
coupling reactions, developing new and practical ligands of
low cost and general application scope has accordingly become
a central issue in copper-catalyzed coupling chemistry. In fact, a
large number of different ligands have been reported to be
capable of promoting Cu-catalyzed coupling process in recent
years. Examples such as diamines,[9] L-proline,[10] 1,3-diketon,[11]
b-keto ester,[12] 1,10-phenanthroline[13] and diimine[14] are now serving
in numerous synthetic processes involving coupling transforma-
tion. Simultaneously, sustained interest in ligand design and
application led to the discovery of many new ligand identities for
copper-catalyzed coupling reactions. For instance, BINAM,[15]
benzotriazole,[16] hydroxyl quinoline,[17] N-hydroxyimide,[18] 2-pyridinyl
b-ketones,[19] D-glucosamine,[20] 2-pyridin-2-yl-1 H–benzoimidazole[21]
and acylhydrazine-/acylhydrazone,[22] to name but a few, are recent
examples of newly discovered practical ligands.
catalyzed self-O-arylation of L and its derivatives for the synthesis
of useful biaryl ethers containing enaminone subunit.[31] Based
on our long-standing interest in research of copper-catalyzed
coupling chemistry,[6] we report herein the chemo-selective C-O
coupling reactions of phenols with both aryl and vinyl halides
promoted by L (Scheme 1).
Results and Discussion
As our previous work showed that using CuI as catalyst in reflux-
ing MeCN selectively mediates the self-O-arylation of L with aryl
halides, we envisioned that it would be possible to achieve
C-O coupling of aryl halides with conventional phenols by
modifying reaction conditions using L as ligand. We began to
explore potential efficient catalyst conditions on the model
reaction of phenol 2a and iodobenzene 1a. Firstly, we selected
DMSO as solvent to carry out this reaction at 110 ꢀC; we were
delighted to observe the formation of expected product 4a,
albeit in moderate yield (Table 1, entry 1). We were therefore en-
couraged to further screen other reaction parameters for better
results. Accordingly, base additive was varied, and it has been
found that the entry with K2CO3 was able to provide an equally
good result as Cs2CO3, while other tested sodium bases such as
Na2CO3 and NaHCO3, as well as organic bases NEt3 and DMAP,
were ineffective for the reaction (Table 1, entries 2–6). The solvent
was also further screened; reactions performed in DMF, dioxane
as well as PEG200 all gave poor results (Table 1, entries 7–9).
Among all the known versions of Ullmann C-X coupling trans-
formations, C-O coupling is one with rather fewer reports than
equivalent C-N or C-S coupling, probably because of the lower
nucleophilicity of O-nucleophile.[23–28] It is therefore highly desir-
able to develop new and efficient ligands capable of facilitating
C-O coupling reactions. During our endeavor in this area, we
have identified the enaminone derivative (E)-3-(dimethylamino)-
1-(2-hydroxyphenyl)prop-2-en-1-one (L) as an excellent ligand
*
Correspondence to: Jie-Ping Wan, College of Chemistry and Chemical Engineer-
ing, Jiangxi Normal University, Nanchang 330022, China. E-mail: wanjieping@
gmail.com
College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, China
Appl. Organometal. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.

J.-P. Wan et al.
Table 2. Biaryl ether synthesis using different aryl halides and
phenolsa
X
O
Ar
Cu powder/L
R
Ar OH
R
K2CO3/DMSO
120°C
2
4
1
Entry
Ar
R
X
Product
Yield (%)b
1
Ph
H
H
H
H
H
H
I
4a
4b
4c
78
65
70
63
55
49
60
70
80
85
93
72
51
53
56
60
2
4-MeC6H4
3-MeC6H4
4-BrC6H4
I
3
I
4
I
I
4d
4e
4f
Scheme 1. Selective synthesis of different ethers in the presence of L.
5
2-MeOC6H4
2-ClC6H4
6
I
Following these results, different copper catalysts were used for
investigating the effect of copper source on this transformation.
Among those conventional copper catalysts employed in our stud-
ies, copper powder was found to have a superior effect to CuI as
catalyst, while other copper catalysts were disfavored (Table 1,
entries 10–13). Finally, the variation in temperature indicated that
120 ꢀC is appropriate for obtaining good results (Table 1, entries
14–16). Therefore, the conditions employed in entry 15 were
selected as the optimal protocol for further research because the best
yield was obtained for this entry without observable side reaction.
For the first stage of application scope investigation, we
employed iodobenzene and its derivatives as starting material
to react with different phenols. As shown in Table 2, a broad
range of functional groups with different properties were found
to be acceptable with this protocol. The biaryl ethers were
7
Quinoline-8-yl
H
I
4 g
4d
4 h
4i
8
Ph
4-Br
I
9
3-MeC6H4
Pyridine-3-yl
3-MeC6H4
Naphth-2-yl
Ph
4-Me
4-Me
4-NO2
4-MeOOC
H
I
10
11
12
13
14
15
16
I
I
4j
I
4 k
4a
4 l
Br
Br
Br
Br
Ph
4-Cl
Ph
4-Ac
4 m
4n
Ph
Naphth-2-yl
aReaction conditions: 1 mmol phenol 2, 1 mmol aryl halide 1, 10 mol%
Cu powder and 20 mol% L, 2 mmol K2CO3 in 1.5 ml DMSO, 120 ꢀC for
aryl iodides and 130 ꢀC for aryl bromides, 24 h.
bIsolated yield.
produced in fair to excellent yield. Generally, product yields were
mainly determined by electronic and steric hindrance effects. For
example, phenols bearing ortho substitution usually gave lower
yields (Table 2, entries 5 and 6). The electron-withdrawing groups
in iodobenzene, on the other hand, facilitated this transformation
and led to high yields of corresponding biaryl ethers (Table 2,
entries 11 and 12). Finally, the O-arylation reactions using aryl
bromides have been investigated. These transformations turned
out to be practical until heated to 130 ꢀC and lower yields of
products were provided than those reactions of aryl iodides
(Table 2, entries 13–16). The electron-withdrawing group in the
para position of bromobenzene also led to higher product yield
(Table 2, entries 14 and 15).
To further expand the application scope of L-promoted,
copper-catalyzed C-O coupling reactions, we attempted to
change the halide agents to vinyl bromides 5. Initially, the catalyst
conditions screened out in Table 1 were employed; however, a
poor result was provided by the reaction of phenol with (E)-
(2-bromovinyl)benzene. The conditions were then further
modified by using CuI as catalyst at 130 ꢀC. Product 6a was
afforded in fair yield (Table 3, entry 1). Under the modified
conditions, the reactions of different phenols and vinyl
bromides were studied, and it was found that different vinyl
ethers could be practically synthesized in this catalyst system;
these products were furnished in generally moderate to good
yield (Table 3).
Table 1. Optimization on the conditions of C═O coupling reactiona
OH
O
4a
I
copper cat.
L
2a
1a
Base
Entry
Solvent
Catalyst
T (ꢀC)
Yield (%)b
1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Cs2CO3
K2CO3
Na2CO3
NaHCO3
NEt3
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuO
Cu2O
CuSO4
Cu
110
110
110
110
110
110
110
110
110
110
110
110
110
120
130
90
61
63
2
3
28
4
25
5
Trace
Trace
32
6
DMAP
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
7
8
Dioxane
PEG200
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Trace
Trace
Trace
41
9
10
11
12c
13d
14
15
16
Trace
68
Cu
78
Cu
79
Cu
28
aGeneral conditions: 1mmol 1a and 1 mmol 2a in 1.5 ml solvent, 10 mol
% copper catalyst, 20 mol%L and 2 equiv. mol. base, stirred for 24 h.
bIsolated yield.
cCuSO4.6H2O was used.
dCommercial copper powder was directly used.
Following the generally accepted mechanism on ligand-assisted
Ullmann C-heteroatom reactions, this enaminone-assisted, CuI-
catalyzed reaction was proposed to proceed following the
mechanism given in Scheme 2. First, enaminone ligand L chelated
copper catalyst (CuI, for example) to form organocopper complex
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Copyright © 2012 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2012)

Copper-catalyzed O-arylation
Table 3. C═O coupling reaction between phenols and vinyl bromides
Experimental
O
Br
General Procedure for the Synthesis of Biaryl Ethers 4 and
Vinyl Ethers 6
CuI/L, K2CO3
DMSO, 130 o
Ar
Ar OH
R
R
C
2
5
6
To a 25ml round-bottom flask containing 1 mmol phenol 2 and
1 mmol aryl/vinyl halide, 20 mol% ligand L, 10mol% copper
powder or CuI and 1.5ml DMSO were added, and the mixture
was stirred at 120ꢀC (130 ꢀC for aryl/vinyl bromide) for 24 h. After
completion of the reaction, 5 ml water was added, and the mixture
was extracted with 3Â 8 ml ethyl acetate. The organic layer was
combined and dried overnight with anhydrous Na2SO4. The solvent
was removed in vacuo and the residue was subjected to silica-gel
chromatography to give analytically pure products. All aryl/vinyl
ethers reported herein are known compounds and were unambig-
uously characterized by comparing their 1 H, 13 C NMR and mass
spectrometric results with the literature (see supporting informa-
tion for characterization data as well as copies of NMR spectra).
Entry
Ar
R
Product
Yield (%)b
1
2
3
4
5
6
Ph
Ph
Ph
H
4-Cl
4-Br
H
6a
6b
6c
6d
6e
6f
55
58
47
48
42
51
4-MeC6H4
3-MeC6H4
4-MeC6H4
H
4-Cl
aReaction conditions: 1mmol phenol 2, 1mmol vinyl bromides 5, 10 mol
% CuI and 20mol%L, 2mmol Cs2CO3 in 1.5ml DMSO, 130 ꢀC, 24h.
bIsolated yield.
Acknowledgments
We are grateful for the financial support from NSFC of China (No.
21102059), NSF of Jiangxi Province (No. 20114BAB213005) and a
Sponsored Program for Cultivating Youths of Outstanding Ability
in Jiangxi Normal University.
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We have developed effective copper-catalyzed synthesis of vari-
ous aryl/vinyl ethers by using (E)-3-(dimethylamino)-1-(2-hydroxy
phenyl)prop-2-en-1-one as ligand. This newly developed catalyst
system was generally applicable for the C-O coupling of phenols
using both aryl and vinyl halides. Combined with the known
results in C-N and C-S coupling reactions using L as ligand, this
present work further confirmed the universal function of L in
copper-catalyzed coupling chemistry as ligand. In addition,
combined with the previous results on the O-arylation of this
hydroxyl functionalized enaminone itself, the results presented
in this paper suggested the versatile utility of this enaminone as
both ligand as well as reaction partner of C-O coupling reactions.
The present protocol is also useful for aryl and vinyl ethers
synthesis as a complementary route to known methods.
Appl. Organometal. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.
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