A simple and practical copper-catalyzed approach to substituted phenols from aryl halides by using water as the solvent

Article abstract of DOI:10.1002/chem.200903468

Water surprise! A simple and practical copper-catalyzed approach to substituted phenols by hydroxylation of aryl halides has been developed by using environmentally benign water as the solvent (see scheme). The method proceeds under mild conditions and is tolerant towards various functional groups in the substrates.

Full text of DOI:10.1002/chem.200903468

DOI: 10.1002/chem.200903468
A Simple and Practical Copper-Catalyzed Approach to Substituted Phenols
from Aryl Halides by Using Water as the Solvent
Daoshan Yang and Hua Fu*[a]
Phenols are important building blocks in numerous phar-
maceuticals, polymers, and natural products,[1] and their
preparation usually uses an oxidative strategy, for example,
the cumene–phenol process (Hock process), based on the
decomposition of cumene hydroperoxide with sulfuric acid
to give phenol and acetone, is the current method for
phenol synthesis used worldwide.[2] Unfortunately, the
method shows low efficiency (only 5% overall yield). Smith,
Maleczka, and co-workers have developed a novel approach
to non-ortho-substituted phenols involving a one-pot, iridi-
ronmentally friendly solvent in the world,[11] and the wide
applications of substituted phenols found in many fields
have stimulated research into the development of new strat-
egies for their synthesis in water. However, synthesis of or-
ganic molecules in water entails the additional challenges of
water tolerance for the catalyst/ligand systems and the asso-
ciated problems of substrate solubility and reactivity.[12]
Kormos and Leadbeater attempted the direct conversion of
aryl halides to phenols in water with microwave heating, un-
fortunately, high temperatures (200–3008C) were required,
and the resulting yields were very low.[13] In a continuation
of our endeavors to develop copper-catalyzed cross-coupling
reactions in organic solvents[14] and in neat aqueous
medium[15] we, herein, report a simple, practical and efficient
copper-catalyzed synthesis of substituted phenols from aryl
halides by using environmentally benign water as the solvent
under mild conditions.
First, 1-chloro-4-iodobenzene (1e) was chosen as the
model substrate to optimize the reaction conditions, includ-
ing catalysts, ligands, and bases under a nitrogen atmos-
phere. As shown in Table 1, tetrabutylammonium hydroxide
was used as the base and phase transfer catalyst (PTC) at
1108C with CuI (10 mol%) as the catalyst and pyridine-2-al-
doxime (PAO; 20 mol%) as the ligand (relative to the
amount of 1e) in water (Table 1, entry 1), and the reaction
provided 4-chlorophenol (2e) in 45% yield with the corre-
sponding symmetric ether appearing in 15% yield. Other
bases, namely, KOH and CsOH (Table 1, entries 2 and 3, re-
spectively), were tested by using tetrabutylammonium bro-
mide (TBAB; 20 mol%) as the PTC, and CsOH showed
better activity. Other copper salts were screened (Table 1,
entries 4–6), and Cu2O proved to be the best choice
(Table 1, entry 6). No target product was observed in the ab-
sence of ligand (Table 1, entry 7), and 2e was afforded in
32% yield without addition of PTC (Table 1, entry 8). Other
ligands were also investigated, and the ligand for copper cat-
alysis, pyridine-2-aldoxime (PAO), afforded the highest effi-
ciency (Table 1, entry 6 vs. entries 9–14).
À
um-catalyzed aromatic C H bond borylation/oxidation se-
quence under milder conditions.[3] Clearly, the direct hydrox-
ylation of readily available aryl halides is an appealing ap-
proach to substituted phenols.[4,5] In the past, the nonoxida-
tive preparation of this class of compounds involving nucleo-
philic aromatic substitution of activated aryl halides was
often performed under harsh reaction conditions.[6] Recently,
several research groups have developed efficient palladium-
catalyzed hydroxylation reactions of aryl halides with hy-
droxide salts under mild conditions,[5,7] even at room tem-
perature.[8] Considering the ready availability and low toxici-
ty of copper catalysts and their ligands,[9] the development
of a cheaper copper-catalyzed system enabling the direct hy-
droxylation of aryl halides has become an important goal.
Very recently, the efficient copper-catalyzed synthesis of
phenols from aryl halides was reported under milder condi-
tions (100–1308C), and research showed that a well-defined
ratio of water/organic solvent was the key factor for the suc-
cess of the method, however, water alone was inefficient.[10]
It is well known that water is the most economical and envi-
[a] D. Yang, Prof. Dr. H. Fu
Key Laboratory of Bioorganic Phosphorus Chemistry and
Chemical Biology (Ministry of Education)
Department of Chemistry, Tsinghua University
Beijing 100084 (China)
Fax : (+86)10-62781695
E-mail: fuhua@mail.tsinghua.edu.cn
The scope of copper-catalyzed hydroxylation of aryl hal-
ides was investigated under our optimized conditions (Cu2O
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903468.
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COMMUNICATION
Table 1. Copper-catalyzed hydroxylation of 1e to form 2e in water: opti-
mization of conditions.[a]
Scheme 1. A possible mechanism for the hydroxylation of 2-chlorobenzo-
ic acid (1q) and 2-(2’-bromophenyl)acetic acid (1s).
Entry Cat.
L
MOH
Yield (2e) [%][b] Yield (2e’) [%][b]
1[c]
2
3
4
5
CuI
CuI
CuI
A
A
A
A
A
A
–
A
B
C
D
E
F
nBu4NOH
KOH
45
61
66
75
60
82
0
32
trace
35
12
17
5
15
13
13
10
7
5
0
0
0
0
0
0
0
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
into the target product (2q) (Table 2, entry 19), and the
pathway can undergo formation of the intra-ester (VI) and
the hydrolysis sequence as shown in Scheme 1b.
Compounds 1v and 1w also provided the corresponding
products (2t and 2u) in moderate yields with minor prod-
ucts 2-aminophenol and 2-amino-5-methylphenol from hy-
drolysis of the amide (-NHCOPh) appearing (Table 2, en-
tries 22 and 23). However, unactivated 2-bromobenzen-
amine (1y) did not work under our standard conditions
(Scheme 2a), and the results above showed an ortho-sub-
CuBr
CuCl
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
6
7
8[c]
9
10
11
12
13
14
G
22
0
[a] Reaction conditions: 1e (1 mmol), MOH (3 mmol), catalyst
(0.05 mmol for Cu2O, 0.1 mmol for others), ligand (0.1 mmol), TBAB
(0.2 mmol), water (1 mL) under a nitrogen atmosphere. Reaction time
(48 h). [b] Yield of the isolated product. [c] In the absence of TBAB.
stituent effect[16] of the NHCOPh group in 1v during hy-
À
(5 mol%) as the catalyst, PAO (10 mol%) as the ligand,
TBAB (20 mol%) as the phase-transfer catalyst, CsOH
(3 equiv) as the base, and water as the solvent). As shown in
Table 2, most of the substrates examined provided good to
excellent yields at 100 or 1108C. For the aryl iodides, the
substrates containing electron-withdrawing groups showed
higher reactivity than ones containing electron-donating
groups (compare Table 2, entries 1–13). Aryl bromides con-
taining activated groups (such as carboxyl, nitro, and alde-
hyde) afforded high yields (Table 2, entries 14–16, 20 and
21). Interestingly, 2-chlorobenzoic acid (1q) and 2-chloro-
pyridine-3-carboxylic acid (1r) also exhibited higher activity
(Table 2, entries 17 and 18). In fact, aryl chlorides were
weak substrates in the previous copper-catalyzed Ullmann-
type couplings,[9] and the results showed an ortho-substituent
effect[16] of the carboxyl group during hydroxylation, as
shown in Scheme 1a. Coordination of 1q with Cu2O first
forms I in the presence of base (CsOH). Oxidative addition
of I provides the coordination complex II, and exchange of
OHÀ from CsOH with the ClÀ of II gives III. Reductive
elimination of III leads to IV, treatment of IV with CsOH
gives V with release of the copper catalyst, and acidification
of V affords the target product (2m). Unactivated 2-(2’-bro-
mophenyl)acetic acid (1s) almost quantitatively transformed
Scheme 2. a) Attempted reaction of compound 1y under our standard
conditions; b) Possible mechanism for the hydroxylation of N-(2-bromo-
phenyl)benzamide (1v).
droxylation as shown in Scheme 2b. Coordination of N-(2-
bromophenyl)benzamide (1v) with Cu2O and subsequent
oxidative addition forms VII, and treatment of VII with
CsOH gives VIII. Reductive elimination of VIII affords the
target product (2t) with release of the copper catalyst. How-
ever, N-(2-bromophenyl)acetamide (1x) afforded hydrolysis
product 2-aminophenol (2v) as the major product under our
standard conditions (Table 2, entry 24), which can provide a
new approach to substituted 2-aminophenol derivatives.
Cyclization of 2t in the presence of PCl5 provided com-
pound 3a (Scheme 3), and the protocol gives a novel
method for the synthesis of 2-arylbenzoxazoles.
The hydroxylation reactions above could tolerate various
À
functional groups, including C Cl bonds (Table 2, entries 5
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D. Yang and H. Fu
Table 2. Copper-catalyzed synthesis of substituted phenols by hydroxylation of aryl halides with CsOH in water.[a]
Entry
1
1
T [8C]/t [h]
2
Yield [%][b]
95
Entry
13
1
T [8C]/t [h]
2
Yield [%][b]
92
110/36
100/24
2
3
110/48
110/48
78
61
14
15
100/48
100/48
96
81
4
5
110/48
110/48
87
82
16
17
100/48
110/48
84
66
6
7
8
110/48
110/48
110/48
71
18
19
20
110/48
110/36
110/48
63
98
87
91
86[c]
9
110/36
110/48
92
45
21
22
110/48
110/24
62
60
10
11
12
110/48
100/24
73
95
23
24
110/24
110/48
52
53[d]
[a] Reaction conditions: aryl halide (1 mmol), CsOH (3 mmol for entries 1–11 and 21–24; 5 mmol for entries 12–20), Cu2O (0.05 mmol), PAO
(0.1 mmol), TBAB (0.2 mmol), and water (1 mL) under a nitrogen atmosphere. [b] Yield of the isolated product. [c] 0.8 mmol of TBAB was used.
[d] Product 2v from hydrolysis of amide -NHCOCH3 in N-(2-hydroxyphenyl)acetamide.
À
and 6) and C F bond (Table 2, entry 7) in aryl iodides, nitro
groups (Table 2, entries 8, 9, and 16), an aldehyde (Table 2,
entry 21), carboxyl groups (Table 2, entries 12–20), hydroxyl
group (Table 2, entry 21), and amide groups (Table 2, en-
tries 22 and 23) in aryl halides.
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Copper-Catalyzed Approach to Substituted Phenols
COMMUNICATION
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Scheme 3. Cyclization of 2t to form compound 3a.
In summary, we have developed a simple and efficient
copper-catalyzed method for the synthesis of substituted
phenols. The protocol uses pyridine-2-aldoxime as the ligand
of the copper catalyst and environmentally friendly water as
the solvent. By using this protocol, the hydroxylation of aryl
halides proceeded well under mild conditions. The method
is of high tolerance towards various functional groups in the
substrates, and the synthesis of these compounds will attract
much attention in academic and industrial research because
of their wide applications in numerous pharmaceuticals,
polymers, and natural products.
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Experimental Section
General procedure for the synthesis of substituted phenols (2a–2v): A
10 mL Schlenk tube equipped with a magnetic stirring bar was charged
with Cu2O (0.05 mmol, 7 mg), CsOH (3 mmol or 5 mmol), PAO
(0.1 mmol, 12 mg), TBAB (0.2 mmol, 65 mg) (note: 0.8 mmol, 260 mg for
substrate 1h), and aryl halide, if a solid (1 mmol). The tube was evacuat-
ed twice and backfilled with nitrogen. Aryl halide, if a liquid (1 mmol)
and water (1 mL) were sequentially added by syringe at RT under a
stream of nitrogen and the tube was sealed and put into a preheated oil
bath at 100 or 1108C for 24–48 h under a positive pressure of nitrogen (it
is necessary to occasionally shake the tube during the reactions of sub-
strate 1h because it can sometimes stick to the vessel wall above the so-
lution). After the resulting solution was cooled to RT, HCl (1n, 2 mL)
was added to acidify the solution (pH 2–3) and the solution was extracted
with ethyl acetate (3ꢁ2 mL). The combined organic phases were concen-
trated, and the remaining residue was purified by column chromatogra-
phy on silica gel to provide the desired product.
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Acknowledgements
Financial support was provided by the National Natural Science Founda-
tion of China (grant nos. 20672065, 20972083), the Chinese 863 Project
(grant no. 2007AA02Z160), and the Key Subject Foundation from Bei-
jing Department of Education (XK100030514).
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Keywords: aryl halides · copper · hydroxylation · phenols ·
water chemistry
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Received: December 18, 2009
Please note: Minor changes have been made to this publication in
Chemistry–A European Journal Early View. The Editor.
Published online: January 27, 2010
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