Highly efficient synthesis of phenols by copper-catalyzed hydroxylation of aryl iodides, bromides, and chlorides

Article abstract of DOI:10.1021/ol2016737

8-Hydroxyquinolin-N-oxide was found to be a very efficient ligand for the copper-catalyzed hydroxylation of aryl iodides, aryl bromides, or aryl chlorides under mild reaction conditions. This methodology provides a direct transformation of aryl halides to phenols and to alkyl aryl ethers. The inexpensive catalytic system showed great functional group tolerance and excellent selectivity.

Full text of DOI:10.1021/ol2016737

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4340–4343
Highly Efficient Synthesis of Phenols by
Copper-Catalyzed Hydroxylation of Aryl
Iodides, Bromides, and Chlorides
Kai Yang,†,§ Zheng Li, Zhaoyang Wang,§ Zhiyi Yao,‡ and Sheng Jiang*,†
Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health,
CAS, Guangzhou, 510530, P. R. China, Shanghai Institute of Technology, Shanghai,
210032, P. R. China, School of Chemistry and Environment, South China Normal
University, Guangzhou 510006, P. R. China, and The Methodist Hospital Research
Institute, Houston, Texas 77030, United States
jiang_sheng@gibh.ac.cn
Received June 22, 2011
ABSTRACT
8-Hydroxyquinolin-N-oxide was found to be a very efficient ligand for the copper-catalyzed hydroxylation of aryl iodides, aryl bromides, or aryl
chlorides under mild reaction conditions. This methodology provides a direct transformation of aryl halides to phenols and to alkyl aryl ethers. The
inexpensive catalytic system showed great functional group tolerance and excellent selectivity.
Phenols are very useful intermediates for constructing
pharmaceutical molecules, polymers, and natural com-
pounds.1 Traditional nonoxidative preparation of phenols
includes nucleophilic substitution of activated aryl halides,
copper-catalyzed transformation of diazoarenes, benzyne
protocols, and aromatic boronic acids all of which were
limited by harsh reaction conditions and the availability of
starting materials.2 While several iridium- or palladium-
catalyzed conversions of different aryl halides to phenols
have been reported in recent years,3,4 which involved the
use of rare and expensive metallic catalysts, and sophisti-
cated supporting ligands, only a few examples of the
copper-catalyzed hydroxylation of aryl iodides and elec-
tron-deficient aryl bromides were reported.5,6 Significant
limitations tothis processwere that aryl chlorides as well as
electron-rich aryl bromides did not react. To reduce costs,
† Guangzhou Institute of Biomedicine and Health.
‡ Shanghai Institute of Technology.
§ South China Normal University.
The Methodist Hospital Research Institute.
(1) (a) Rappoport, Z. The Chemistry of Phenols; Wiley-VCH:
Weinheim, 2003. (b) Tyman, J. H. P. Synthetic and Natural Phenols;
Elsevier: New York, 1996.
(2) For recent reviews on synthesis of phenols, see: (a) Hanson, P.;
Jones, J. R.; Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem. Soc.,
Perkin Trans. 2 2002, 1135. (b) Hoarau, C.; Pettus, T. R. R. Synlett 2003,
127.
(3) Iridium-catalyzed formation of phenols: Maleczka, R. E.; Shi, F.;
Holmes, D.; Smith, M. R., III. J. Am. Chem. Soc. 2003, 125, 7792.
(4) Palladium-catalyzed formation of phenols: (a) Anderson, K. W.;
Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128,
10694. (b) Willis, M. C. Angew. Chem., Int. Ed. 2007, 46, 3402. (c) Chen,
G.; Chan, A. S. C.; Kwong, F. Y. Tetrahedron Lett. 2007, 48, 473.
(d) Gallon, B. J.; Kojima, R. W.; Kaner, R. B.; Diaconescu, P. L. Angew.
(5) Copper-catalyzed formation of phenols: (a) Tilli, A.; Xia, N.;
Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 8725–8728.
(b) Zhao, D.; Wu, N.; Zhang, S.; Xi, P.; Su, X.; Lan, J.; You, J. Angew.
Chem., Int. Ed. 2009, 48, 8729–8732. (c) Xu, H.-J.; Liang, Y.-F.; Cai,
Z.-Y.; Qi, H.-X.; Yang, C.-Y.; Feng, Y.-S. J. Org. Chem. 2011, 76,
2296–2300. (d) Maurer, S.; Liu, W.; Zhang, X.; Jiang, Y.; Ma, D. Synlett
2010, 976. (e) Yang, D.; Fu, H. Chem.;Eur. J. 2010, 16, 2366. (f) Jing, L.;
Wei, J.; Zhou, L.; Huang, Z.; Li, Z.; Zhou, X. Chem. Commun. 2010, 4767.
(6) Formation of phenols from arylboronic acids: Xu, J.; Wang, X.;
Shao, C.; Su, D.; Cheng, G.; Hu, Y. Org. Lett. 2010, 9, 1964–1967.
€
Chem., Int. Ed. 2007, 46, 7251. (e) Schulz, T.; Torborg, C.; Schaffner, B.;
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Huang, J.; Zapf, A.; Kadyrov, R.; Borner, A.; Beller, M. Angew. Chem.,
Int. Ed. 2009, 48, 918. (f) Sergeev, A. G.; Schulz, T.; Torborg, C.;
Spannenberg, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2009,
48, 7595.
r
10.1021/ol2016737
Published on Web 07/25/2011
2011 American Chemical Society

it is highly desirable to use aryl chlorides directly coupled
with hydroxide salt under mild reaction conditions in this
process. In this paper, we describe an efficient and versatile
method for the copper-catalyzed hydroxylation of elec-
tron-rich aryl bromides, and aryl chlorides that overcomes
these problems, providing a considerably more practical
and useful method for the conversion of aryl halides to
phenols.
were tested, and DMSO/H2O (1/1) provided the best result
(Table 1, entries 5, 11À16). Coppersalts alsoinfluenced the
progress of the reaction, and CuI afforded the highest
yield. Thus, after screening the ligands, bases, solvents, and
catalysts, the optimal conditions were a combination of
10 mol % CuI, 40 mol % L5, and CsOH (3.0 equiv) in
DMSO/H2O (1/1) at 100 °C.
Based on several of our previously discovered new
ligands (Figure 1) for the Cu-catalyzed Ullmann CÀN
coupling reactions under a low catalyst loading (1% [Cu]
mol),7,8 we are interested to explore a direct transforma-
tion of aryl halides especially aryl chlorides to the corre-
sponding substituted phenolsusing these ligands, which, to
the best of our knowledge, has never been reported. Here-
in, we report that the direct hydroxylation of a broad range
of aryl halides especially aryl chlorides can be achieved in
aqueous media under the catalysis of 10% CuI and 40%
L5 ligand.
Table 1. Optimization of Cu-Catalyzed Hydroxylation of
p-Iodotoluenea
yield
entry
ligand
base
[Cu]
CuI
solvent (1/1)
(%)b
1
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
None
CsOH
CsOH
CsOH
CsOH
CsOH
KOH
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMF/H2O
28
32
26
46
93
54
86
75
85
64
14
15
20
57
47
82
0
2
CuI
CuI
CuI
CuI
CuI
CuBr
CuBr2
CuCl
Cu
3
4
5
6
7
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
8
9
10
11
12
13
14
15
16
17
CuI
CuI
CuI
CuI
CuI
CuI
CuI
THF/H2O
CH3CN/H2O
C2H5OH/H2O
1,4-dioxane/H2O
DMSO/tBuOH
DMSO/H2O
Figure 1. Structure of designed ligands.
We initially chose 4-methyl iodobenzene as the model
substrate to evaluate the catalytic activity of the designed
ligands at 100 °C (Table 1). Ligands (L1ÀL5) were tested
in the mixed DMSO/H2O (1:1) solvent system with 10 mol
% CuI as the catalyst and CsOH as the base (entries 1À5),
and L5 gave the highest yield (93%, entry 5), while no
product formation was observed without addition of
ligands under similar reaction conditions (entry 17). Using
L5 as the ligand and CsOH as the base, different solvent
systems such as THF/H2O (1/1), DMF/H2O (1/1),
CH3CN/H2O (1/1), C2H5OH/H2O (1/1), 1,4-dioxane/
H2O (1/1), DMSO/t-BuOH (1/1), and DMSO/H2O (1/1)
a 1a (1.0 mmol), 10 mol % [CuX], 40 mol % ligand, base (3.0 mmol),
solvent (2 mL), Ar, 100 °C, 18 h. b Isolated yield.
The optimized reaction conditions were then applied to
the conversion of a variety of aryl iodides, and the results
are summarized in Scheme 1. Both electron-rich (2aÀ2f)
and -deficient (2gÀ2l) aryl iodides provided the corre-
sponding phenols in excellent yields. In addition, the
reaction showed a great tolerance to a range of functional
groups including alkoxy, acetyl, nitro, carboxylic acid, and
amino moieties (2dÀ2k). Remarkably, sterically hindered
aryl iodide also afforded the coupling products in excellent
yields (2b and 2f). When chloro or fluoro substituted aryl
iodides were used, the coupling reaction took place selec-
tively at the iodo part, leaving the fluoride and chloride
substituents untouched (2mÀ2o).
(7) (a) Yang, K.; Qiu, Y.; Li, Z.; Wang, Z.; Jiang, S. J. Org. Chem.
2011, 76, 3151. (b) Qiu, Y.; Liu, Y.; Yang, K.; Hong, W.; Li, Z.; Wang,
Z.; Jiang, S. Org. Lett. 2011, 13, 3556.
(8) For recent contributions on Cu catalysis CÀO coupling reactions,
see: (a) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.;Eur. J. 2006,
12, 3636. (b) Chen, Y.; Chen, H. Org. Lett. 2006, 8, 5609. (c) Lv, X.; Bao,
W. J. Org. Chem. 2007, 72, 3863. (d) Zhao, Y.; Wang, Y.; Sun, H.; Li, L.;
Zhang, H. Chem. Commun. 2007, 3186. (e) Niu, J.; Zhou, H.; Li, Z.; Xu,
J.; Hu, S. J. Org. Chem. 2008, 73, 7814. (f) Zhang, J.; Zhang, Z.; Wang,
Y.; Zheng, X.; Wang, Z. Eur. J. Org. Chem. 2008, 5112. (g) Naidu, A. B.;
Raghunath, O. R.; Prasad, D. J. C.; Sekar, G. Tetrahedron Lett. 2008,
49, 1057. (h) Naidu, A. B.; Jaseer, E. A.; Sekar, G. J. Org. Chem. 2009,
74, 3675.
When o-diiodobenzene, p-diiodobenzene, and 4-iodo-
phenol were used, we observed the formation of the phenol
in high yields, which is similar to that reported by Taillefer
(2p from 1qÀ1s).5a While Taillefer’s group and You’s
groupindependently reportedthathydroxylation of 4-bro-
mo-iodobenzene using their catalytic systems produced
Org. Lett., Vol. 13, No. 16, 2011
4341

4-bromo-1-phenol,5 we found hydroxylation of 4-bromo-
1-iodobenzene using our catalytic system yielded phenol in
71% yield, which is totally different from those reported.
We assumed that the initial monohydroxylation of 4-bro-
mo-1-iodobenzene formed p-bromophenolate, which may
be in favor of a radical mechanism by stabilizing the
resulting phenolate radical anion (OC6H4•À). Then this
radical intermediate could readily form phenol.
Scheme 2. Copper-Catalyzed Conversion of Aryl Bromides to
Phenols
Scheme 1. Copper-Catalyzed Conversion of Aryl Iodides to
Phenols
Scheme 3. Copper-Catalyzed Conversion of Aryl Chlorides to
Phenolsa
We then extended the CuI/L5 system to the hydroxyla-
tion of aryl bromides, and the results are shown in Scheme
2. All the examined aryl bromides coupled with CsOH in
excellent yields at 110 °C. High yields were obtained for
those aryl bromides with an electron-withdrawing group,
regardless of the position of the substitution (4hÀ4l). In
addition, bromobenzene, β-bromonaphthalene, 4-fluoro-
1-bromobenzene, and electron-rich aryl bromides, such as
4-methoxy bromobenzene, 3-methoxybromobenzene, and
4-methyl bromobenzene, had been highly challenging
substrates for copper-catalyzed hydroxylation with hydro-
xide salts.5 The CuI/L5 system was found to effectively
catalyze the hydroxylation of these substrates inhigh yields
at 110 °C (4aÀ4g and 4mÀ4p).
a 150 °C.
4342
Org. Lett., Vol. 13, No. 16, 2011

to the conversion of aryl chlorides to phenols with CsOH.
As shown in Scheme 3, aryl chlorides bearing either
electron-donating or -withdrawing groups produced the
corresponding phenols in good to excellent yields (6aÀ6h).
Many functional groups, such as a nitro, methoxy, nitrile,
aldehyde, and carboxylic acid, were well tolerated under
the reaction conditions (6aÀ6h, 6f, and 6g). 2-Chloro-
naphthalene was also converted into the corresponding
naphthol under these conditions (6e). Additionally, steric
hindrance has no influence on the coupling reaction (6f vs
6g). All of these results demonstrated the high efficiency of
the CuBr/L5 catalyst system for the conversion of aryl
halides to phenols.
Table 2. One-Pot Synthesis of Alkyl Aryl Ethers from Aryl
Halidesa,b
To further extend the scope of this methodology, we
developed a method for the conversion of aryl halides to
alkyl aryl ethers in a one-pot fashion. Although You’s
group has reported copper-catalyzed formation of alkyl
aryl ethers by a one-pot phenoxide/alkylation protocol, his
method is limited to aryl iodides.5b As shown in Table 2,
using the present catalytic system a variety of alkyl aryl
ethers could be obtained from either aryl iodides or aryl
bromides in excellent yields (8aÀ8f). Thus, the procedure
provides a straightforward strategy for the catalytic synth-
esis of alkyl aryl ethers from the combination of both aryl
halides and alkyl halides. Interestingly, this ether forma-
tion process requires two electrophilic components instead
of one nucleophile and one electrophile.
In summary, a general, economical, and highly efficient
method for the copper-catalyzed conversion of all kinds of
aryl iodides, aryl bromides, and aryl chlorides to phenols
was developed. To the best of our knowledge, the present
catalytic systemforcopper-catalyzed hydroxylationof aryl
chlorides or electron-rich aryl bromides is unprecedented.
This inexpensive catalytic system showed great functional
group tolerance and high selectivity at moderate tempera-
tures. Furthermore, this protocol provides a one-pot pro-
cedure for the direct formation alkyl aryl ethers from aryl
halides and alkyl halides.
a Reaction conditions: ArX (1.0 mmol), CuI (0.10 mmol, 10 mol %),
L5 (0.4 mmol, 40 mol %), CsOH•H2O (504 mg, 3.0 mmol) and DMSO/
H2O (1:1, 2 mL) at 100 °C for 24À36 h under argon. After the reaction
mixture was cooled to ambient temperature, n-Bu4NI (0.1 mmol, 10 mol
%), CsOH•H2O (504 mg, 3.0 mmol), and RX (2.0 mmol) were added,
and the reaction system was then kept at 100 °C for 12 h. b Isolated yield.
Acknowledgment. This project was supported by the
National Natural Science Foundation (Nos. 20802078,
20972160, and 20772035), Shanghai University Distin-
guished Professor (Eastern scholars) Program (DF2009-02),
Pujiang Talent Plan Project (09PJ1409200), and National
Basic Research Program of China (2009CB940900) .
Due to their low cost and ready availability, aryl chlori-
des are more highly desirable for industrial applications.
Because of the low reactivity of aryl chlorides, the copper-
catalyzed hydroxylation of aryl chlorides was indeed a
challenge. We further extended the CuBr/L5 catalytic system
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
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