Microwave-assisted copper-catalyzed hydroxylation of aryl halides in water

Article abstract of DOI:10.1039/c3ra44613a

A simple and efficient protocol for microwave-assisted copper-catalyzed hydroxylation of aryl halides is developed. A variety of phenols can be obtained in moderate to excellent yields of up to 95%. Its application is performed to synthesize 2,3-dihydroxy-1,4-naphthoquinone, which displays significant anti-proliferation effect.

Full text of DOI:10.1039/c3ra44613a

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Microwave-assisted copper-catalyzed hydroxylation of
aryl halides in water†
Cite this: RSC Adv., 2013, 3, 22837
a
a
b
b
b
*
Fang Ke, Xiaole Chen, Zhengkai Li, Haifeng Xiang and Xiangge Zhou
Received 5th August 2013
Accepted 16th September 2013
DOI: 10.1039/c3ra44613a
www.rsc.org/advances
Table 1 Optimization of hydroxylation of iodobenzenea
A simple and efficient protocol for microwave-assisted copper-cata-
lyzed hydroxylation of aryl halides is developed. A variety of phenols
can be obtained in moderate to excellent yields of up to 95%. Its
application is performed to synthesize 2,3-dihydroxy-1,4-naph-
thoquinone, which displays significant anti-proliferation effect.
Phenols are important building blocks for constructing phar-
maceuticals, polymers and natural compounds, and can serve
as versatile synthetic intermediates in preparing oxygenated
heterocycles.1 Also, they might be traditionally installed in the
early stages of synthesis, potentially leading to regiocontrol
issues in further arene functionalisation, or to instability towards
oxidation.2 The classical hydroxylation methods to prepare
phenols are usually carried out under harsh reaction conditions.3
For example, the reactions of non-activated substrates to form
phenols are typically proceeded under high temperature around
Entry
Cu source
Ligand
Base
T/ꢀC
t/min
Yieldb (%)
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
L1
L2
L3
L4
L5
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
—
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
K2CO3
Na2CO3
Cs2CO3
KOH
KOH
KOH
120
120
120
120
120
120
120
120
120
120
120
120
120
110
130
120
120
120
120
120
120
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
20
40
50
40
40
40
70
61
78
63
43
34
50
46
83
87
72
66
85
80
87
69
92
90
Trace
20
30
200–350 C,4 which would be incompatible with sensitive func-
ꢀ
tionality. The milder catalytic methods through a two-step
coupling procedure was then developed by Hartwig and co-
workers.5 Aer that, several groups have developed efficient
palladium-catalyzed hydroxylation processes of aryl halides with
hydroxide derivatives.6 Considering the cost and environmental
factor, the development of copper or iron catalytic system 10
enabling the direct hydroxylation of aryl halides has become an
important goal. Recently, an iron-catalyzed method has been
CuI
Cu(OAc)2
CuSO4
Cu2O
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
—
11
12
13
14
15
16
17
18
19
20
21c
reported for conversion of aryl halides to phenols in water at
180 C.7 We and others also reported efficient copper-catalyzed
ꢀ
synthesis of phenols from aryl halides under mild conditions.8
On the other hand, microwave (MW)-assisted synthetic
method has been reported in many cases to be able to speed up
KOH
KOH
KOH
KOH
CuCl2
CuCl2
L3
KOH
aCollege of Pharmacy, Fujian Medical University, Fuzhou 350004, China
a
Unless otherwise noted, the reactions were carried out using
iodobenzene (1.0 mmol), Cu source (10 mol%), ligand (10 mol%),
base (2.0 mmol) and (n-Bu)4NBr (10 mol%) in water (3 mL) under
bInstitute of Homogeneous Catalysis, College of Chemistry, Sichuan University,
Chengdu 610064, China. E-mail: zhouxiangge@scu.edu.cn; Fax: +86-28-85412026;
Tel: +86-28-85412026
b
microwave 200 W. Determined by GC with 1,4-dichlrobenzene as
internal standard. c Without addition of (n-Bu)4NBr.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra44613a
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Table 2 Microwave-assisted hydroxylation of aryl halides catalyzed by CuCl2/L3
in watera
Table 2 (Contd. )
Entry
20
Aryl halide
Product
Yieldb (%)
Entry
Aryl halide
Product
Yieldb (%)
79
82
92 (X ¼ I)
79 (X ¼ Br)
52 (X ¼ Cl)
84 (X ¼ I)
75 (X ¼ Br)
1
2
3
4
21
83 (X ¼ I)
22
75 (X ¼ Br)
78 (X ¼ I)
63 (X ¼ Br)
23
83
78
95 (X ¼ I)
83 (X ¼ Br)
24
5
88
86 (X ¼ I)
a
6
Reactions were carried out using aryl halide (1.0 mmol), CuCl2 (10 mol
78 (X ¼ Br)
%), L3 (10 mol%), KOH (2.0 mmol) and (n-Bu)4NBr (10 mol%) in water (3
b
mL) at 120 ꢀC for 40 min under 200 W. Isolated yield aer column
7
82
72
85
63
79
85
chromatography.
8
the rates of reactions as well as improve yields and inuence
selectivities.9 The combination of microwave and metal catal-
ysis has become one of the ways in future “green” catalytic
protocols.10 Moreover, water has attracted much attention as a
reaction medium because of its low cost, availability, safety and
environmental-friendliness.11 In continuation of our endeavors
to develop environmentally friendly protocols,12 herein we
disclose hydroxylation of aryl halides catalyzed by readily
available CuCl2 with proline lithium in water under microwave
irradiation.
To optimize the reaction conditions, iodobenzene was rstly
chosen as the model substrate. Selected results from the
screening experiments are summarized in Table 1. Screening of
several ligands indicated the most tful one was proline lithium
L3 with 78% yield (Table 1, entries 1–5), which also exhibited
high efficacy in other copper catalyzed coupling reactions
involving aryl halides.13 Among the copper salts used, CuCl2 was
superior to others including CuI, CuSO4, Cu(OAc)2, and Cu2O
(Table 1, entries 6–9). Control experiments conrmed that
either of copper salt and ligand was essential for the reaction
(Table 1, entries 19 and 20). Test of different bases revealed
KOH to be better than others to gave the product in 87% yield
(Table 1, entries 10–13). The effects of reaction time and
temperature were also studied, 120 ꢀC and 40 min were optimal
reaction conditions. Meanwhile, phase transfer reagent seemed
to be benecial for the reaction, and only 30% yield was
obtained in the absence of it (Table 1, entry 21). Therefore, the
optimal reaction conditions for the microwave-assisted copper-
catalyzed hydroxylation were aryl halide (1.0 mmol), CuCl2
(10 mol%), ligand (10 mol%), (n-Bu)4NBr (10 mol%), and KOH
9
10
11
12
13
14
79
84
15
16
17
83
78
73
18
19
76
63
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(2.0 equiv.), at 120 ꢀC with water (3.0 mL) as the solvent for
40 min under 200 W microwave.
In summary, we have developed a simple, economical and
efficient microwave-assisted copper-catalyzed method for the
With the optimal reaction conditions established, a variety synthesis of phenols. Proline lithium was used as ligand during
of substituted aryl halides were examined and the results are the copper catalysis, and environmentally friendly water was
summarized in Table 2. In general, aryl iodides were more used as solvent. The microwave irradiation as an efficient
reactive than aryl bromides and aryl chlorides with higher source of energy lowered the environmental impact of the
yields, and diphenyl ethers were not detected in the reaction. transformation, allowing us to accomplish the hydroxylation in
Catalytic hydroxylation reactions of dihalogenated aryl halides a few minutes. By using this protocol, the hydroxylation of aryl
resulted in good chemoselectivity between aryl iodide, bromide iodides, bromides and even aryl chlorides proceeded well under
or chloride (Table 2, entries 10–12). Electron-withdrawing mild conditions. The method is of high tolerance towards
substituents seemed to be more benecial to the reaction, and various functional groups in the substrates, and the synthesis of
the highest yield (95%) was obtained by using 4-iodoni- these compounds will attract much attention in academic and
trobenzene (Table 2, entry 4). Functional groups such as methyl, industrial research. Further studies into the reaction mecha-
methoxy, nitro, hydroxy, ketone carboxyl acid, aldehyde, cyano nism, and its application in synthesis will be reported in due
and uoro groups were well-tolerated under the reaction course.
conditions (Table 2, entries 2–10). Moreover, sterically
This project was supported by Natural Science Foundation of
demanding such as ortho substituents did not hamper the China (no. 21072132 and 21272161) and Research Fund of
reaction and the corresponding products were obtained in good Fujian Medical University (2011BS006), Fujian Provincial
yields (Table 2, entries 13–17). Furthermore, the copper catalyst Foundation (2012J05150).
also exhibited efficiency in coupling reactions to obtain more
challenging phenols bearing heterocycles such as pyridine,
pyrimidine, and quinoline, thus allowing access to heterocyclic
Notes and references
phenolic derivatives in numerous appealing compounds (Table
2, entries 22–24).
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Furthermore, the obtained 2,3-dihydroxy-1,4-naphthoquinone
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