Synthesis of phenol, aromatic ether, and benzofuran derivatives by copper-catalyzed hydroxylation of aryl halides

Article abstract of DOI:10.1002/anie.200903923

A smooth operator: The copper-catalyzed synthesis of phenols from aryl halides was carried out under relatively mild reaction conditions. Alkyl aryl ethers and benzofurans could also be prepared smoothly by one-pot domino protocols based on hydroxylation of aryl iodides (see scheme).

Full text of DOI:10.1002/anie.200903923

Angewandte
Chemie
DOI: 10.1002/anie.200903923
Hydroxylation
Synthesis of Phenol, Aromatic Ether, and Benzofuran Derivatives by
Copper-Catalyzed Hydroxylation of Aryl Halides**
Dongbing Zhao, Ningjie Wu, Shuai Zhang, Peihua Xi, Xiaoyu Su, Jingbo Lan, and
Jingsong You*
Phenols are not only important building blocks for construct-
ing pharmaceuticals, polymers, and natural compounds, but
also serve as versatile synthetic intermediates in preparing
oxygenated heterocycles.[1] The classical non-oxidative prep-
arative routes of these compounds include transformation of
diazoarenes in the presence of a copper complex as well as
nucleophilic substitution of activated aryl halides and ben-
zyne. However, these methods generally suffer from limita-
tions with regard to substrate generality, the availability of
starting materials, and sometimes the harsh reaction condi-
tions.[2] A milder method of the preparation of non-ortho-
model substrate in the presence of copper(I) iodide (Table 1).
As KOH was used as the nucleophile, initial reaction screen-
ing led to disappointing results in the absence of a ligand
(Table 1, entry 1). We subsequently screened a variety of
ligands, solvents, and bases. 1,10-Phenanthroline proved to be
an excellent ligand (Table 1, entries 2–6), and the mixed
DMSO/H2O (1:1) solvent system was clearly the best choice
(Table 1, entries 6–10). When the base was altered to
potassium carbonate, cesium carbonate, or potassium phos-
phinate, only poor yields were obtained (Table 1, entries 11–
13). In addition, other sources of the copper salt were inferior
to CuI (compare Table 1, entry 6 to entries 14–17). Although
not yet investigated in detail, the hydroxylation of
p-iodotoluene could occur in 38% yield even with a
substantially low CuI loading of 0.1 mol% (Table 1, entry 20).
With the optimized conditions now determined, a variety
of substituted aryl halides were examined and the results are
summarized in Table 2. Gratifyingly, various phenol deriva-
tives were obtained with both non-activated and activated
À
substituted phenols has been achieved in two steps: C H
activation/borylation and oxidation in the presence of iridium
phosphine complexes.[3]
In contrast to well-established palladium- or copper-
catalyzed formation of aryl ethers,[4,5] the direct hydroxylation
of aryl halides has proved to be challenge in coupling
chemistry. Recently, several palladium-catalyzed processes
have allowed the cross-coupling of aryl halides with hydrox-
ide salts to proceed under relatively mild reaction condi-
tions.[6,7] Although the economic attractiveness of copper has
led to remarkable progress in the development of copper-
catalyzed coupling reactions,[8] the copper-mediated hydrox-
ylation of aryl halides with hydroxide salts (e.g., KOH and
NaOH) as nucleophiles to directly form phenols under mild
conditions is less developed.[9] Drawing from recent experi-
ences in the field of copper-catalyzed cross-coupling reac-
tions,[10] we herein disclose that aryl halides can directly
couple with potassium hydroxide under mild reaction con-
ditions, namely in the presence of CuI and 1,10-phenanthro-
line (phen)—which is inexpensive and commercially avail-
able. The process constitutes a practical, general, and efficient
method for the synthesis of phenols.
Table 1: Optimization of the hydroxylation of p-iodotoluene.[a]
Entry Ligand
Solvent (1:1)
Base
[Cu]
Yield [%][b]
1
2
3
4
5
6
7
8
–
DMSO/H2O
DMSO/H2O
DMSO/H2O
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
45
76
66
86
89
Hacac
l-Pro
TMEDA DMSO/H2O
DMEDA DMSO/H2O
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
DMSO/H2O
DMSO
H2O
DMF/H2O
1,4-dioxane/H2O KOH
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
96
<10
n.r.
n.r.
35
16
25
20
48
52
92
9
10
11
12
13
14
15
16
17
18[c]
19[d]
20[e]
It was determined during a preliminary survey of the
reaction conditions that we should use p-iodotoluene as the
K2CO3
Cs2CO3 CuI
K3PO4
KOH
KOH
KOH
KOH
KOH
KOH
KOH
CuI
CuSO4
Cu(OAc)2
CuCl
Cu(acac)2
CuI
[*] D. Zhao, N. Wu, S. Zhang, P. Xi, Dr. X. Su, Prof. Dr. J. Lan,
Prof. Dr. J. You
Key Laboratory of Green Chemistry and Technology of Ministry of
Education, College of Chemistry and State Key Laboratory of
Biotherapy, West China Medical School, Sichuan University
29 Wangjiang Road, Chengdu 610064 (China)
Fax: (+86)28-8541-2203
87
84
85
38
CuI
CuI
E-mail: jsyou@scu.edu.cn
[a] Reactions were carried out using CuI (10 mol%), base (3.0 equiv),
ligand (20 mol%), and p-iodotoluene (1 mmol) in a 1.25m solution at
1008C for 24 h. [b] Yield of isolated product. [c] Reaction was carried out
for 15 h. [d] CuI (5 mol%). [e] CuI (0.1 mol%). DMEDA=N,N’-dime-
thylethanediamine, DMF=N,N-dimethylformamide, DMSO=dimethyl
sulfoxide, Hacac=acetylacetone, l-Pro=l-proline, n.r. =no reaction,
TMEDA=N,N,N’,N’-tetramethylethanediamine.
[**] This work was supported by grants from the National Natural
Science Foundation of China (grant nos 20772086, 20872101, and
20702035). We also thank the Center of Testing and Analysis,
Sichuan University for NMR measurements.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903923.
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Table 2: Copper-catalyzed synthesis of phenols from aryl halides.[a]
binaphthyl (3s; Table 2, entry 19)
from 2,2’-dihydroxy-3,3’-diiodo-
1,1’-binaphthyl in one synthetic
step in 86% yield. As building
blocks, 2,2’,3,3’-tetrahydroxy-1,1’-
binaphthyls have already shown
promise in the area of supramolec-
ular chemistry. The previously
reported route toward these prod-
ucts employed a multi-steps pro-
cess involving borylation and oxi-
dation.[11]
Entry
1
X
I
Product
Yield [%][b]
96
Entry
11
X
I
Product
Yield [%][b]
84
3a
3b
3k
3l
2
3
I
I
94
85
12
13
I
I
I
87
75
82
This methodology has been
combined with the Williamson
ether synthesis leading to the for-
mation of alkyl aryl ethers in one-
pot from aryl iodides.[12] Aryl
iodides first formed phenoxides,
and subsequent treatment with
alkyl halides gave alkyl aryl
ethers, which was expedited by
tetrabutylammonium iodide as the
3c
3m
4
5
I
I
3d
3e
92
89
14
15
3n
3o
I
Br
95
86
6
7
I
I
3 f
97
94
16
17
Br 3p
Br 3q
92
76
phase-transfer
catalyst.[6a]
As
shown in Table 3, a variety of
alkyl aryl ethers could be obtained
in good yields. Thus, the procedure
offers an alternative route in the
synthesis of alkyl aryl ether from
aryl iodides and alkyl halides.
3g
8
I
3h
93
18
19
I
I
3r
70
86
Benzofuran-containing mole-
cules are frequently found in a
variety of biologically active com-
pounds.[13] Although these bioac-
tive properties have motivated the
development of efficient methods
for constructing the benzofuran
9
I
I
3i
3j
95
86
3s
10
framework,[14]
exploring
new
[a] Reactions were carried out using CuI (10 mol%), 1,10-phenanthroline (20 mol%), KOH (2.0–
6.0 mmol: for details see the Supporting Information), and aryl halide (1.0 mmol) in DMSO/H2O (1:1;
1.25m concentration) at 1008C for 24 h. [b] Yield of isolated product. MOM=methoxymethyl.
improved routes is still a very
active and prolific field of
research.[15] Herein, we utilize our
catalytic protocol to prepare a
aryl iodide derivatives. No matter if the aryl iodides were
electron-rich, electron-poor, or sterically bulky, all of them
afforded good to excellent yields (3a–n; Table 2, entries 1–
14). The high yields observed in the reaction of 4-chloro-
phenyl iodide or 4-bromophenyl iodide implied that there was
good chemoselectivity between aryl iodide, bromide, or
chloride (3h and 3i; Table 2, entries 8 and 9). Moreover,
high-yielding hydroxylation was possible with aryl bromides
bearing electron-withdrawing groups: although the reaction
has not yet been investigated in detail (3o–q; Table 2,
entries 15–17). It is important to stress that the reaction
conditions were compatible with the presence of functional
groups such as hydroxy, hydroxymethyl, ketone, aldehyde,
carboxyl acid, and nitro groups, which could all then be
subject to further synthetic transformations (3j–p; Table 2,
entries 10–16).
substituted benzofuran directly from 2-iodoaryl alkyne by a
sequential one-pot reaction. For example, 2-iodoaryl alkyne 5
underwent the domino reactions involving hydroxylation
coupling and subsequent intramolecular hydroalkoxylation to
provide the benzofuran 6 in good yield (Scheme 1).
In conclusion, we have developed a copper-catalyzed
hydroxylation that allows the direct transformation of aryl
halides into phenols in one step. The process is not only
simple and convenient in terms of the reaction conditions and
purification, but is also tolerant of a variety of functional
groups, thus constitutes a practical route to give phenols.
Although aryl bromides or iodides rather than chlorides are
required in this copper-catalyzed system, the scope, exper-
imental ease, and reliability of a system are often much more
important factors in terms of practical application.[16] We have
also demonstrated that alkyl halides can be converted into
alkyl aryl ethers by a one-pot phenoxide/alkylation protocol.
In addition, a benzofuran was prepared smoothly by treat-
The value of this methodology is evident from its
application to the synthesis of 2,2’,3,3’-tetrahydroxy-1,1’-
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Table 3: One-pot synthesis of alkyl aryl ethers from aryl iodides.[a]
[3] R. E. Maleczka, Jr., F. Shi, D. Holmes, M. R. Smith III, J. Am.
Chem. Soc. 2003, 125, 7792.
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[5] Selected examples for copper-catalyzed synthesis of diaryl ether:
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128, 15990.
Entry
1
R’X
Product
Yield [%][b]
89
4a
4b
2
3
CH3I
84
81
4c
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4
5
6
4d
4e
4 f
82
80
81
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[a] Reactions were carried out using CuI (10 mol%), KOH (3.0–
6.0 mmol: for details see the Supporting Information), ligand
(20 mol%), and aryl iodide (1 mmol) in a 1.25m DMSO/H2O (1:1) at
1008C for 24 h. After the reaction mixture was cooled to ambient
temperature, nBu4NI (0.1 mmol), KOH (0-3.0 mmol, for details see the
Supporting Information), and R’X (2.0 mmol) were added, and the
reaction system was then kept at 1008C for 12 h. [b] Yield of isolated
product. Bn=benzyl.
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Scheme 1. Synthesis of a benzofuran from 2-iodoaryl alkyne.
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mild reaction conditions. We believe that this simple proce-
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Received: July 17, 2009
Published online: September 22, 2009
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Keywords: aryl ethers · benzofurans · copper · hydroxylation ·
phenols
.
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