CuI-catalyzed hydroxylation of aryl bromides under the assistance of 5-bromo-2-(1H-imidazol-2-yl)pyridine and related ligands

Article abstract of DOI:10.1016/j.tetlet.2011.08.059

A number of substituted 2-pyridin-2-yl-1H-benzoimidazoles and 2-(1H-imidazol-2-yl)pyridines were screened for promoting CuI-catalyzed hydroxylation of aryl bromides, which led to the discovery of the combination of CuI and 5-bromo-2-(1H-imidazol-2-yl)pyridine as an effective catalytic system for this transformation. Both electron-rich and electronic-deficient aryl bromides could be converted into the corresponding substituted phenols in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2011.08.059

Tetrahedron Letters 52 (2011) 5593–5595
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Tetrahedron Letters
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CuI-catalyzed hydroxylation of aryl bromides under the assistance
of 5-bromo-2-(1H-imidazol-2-yl)pyridine and related ligands
Jianhuan Jia a, Chenglin Jiang a, Xiaojing Zhang a, , Yongwen Jiang b, Dawei Ma b,
⇑
⇑
a Shenyang Pharmaceutical University, 103 Wenhua Lu, Shenyang 110016, China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of substituted 2-pyridin-2-yl-1H-benzoimidazoles and 2-(1H-imidazol-2-yl)pyridines were
screened for promoting CuI-catalyzed hydroxylation of aryl bromides, which led to the discovery of
the combination of CuI and 5-bromo-2-(1H-imidazol-2-yl)pyridine as an effective catalytic system for
this transformation. Both electron-rich and electronic-deficient aryl bromides could be converted into
the corresponding substituted phenols in good to excellent yields.
Received 20 May 2011
Revised 8 August 2011
Accepted 9 August 2011
Available online 16 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Recently, copper-catalyzed hydroxylation of aryl halides has
attracted considerable attention because of its potential usage
for practically synthesizing substituted phenols. This transforma-
tion was found highly dependent on the use of some special
ligands, which include dibenzoylmethane,1 N,N-dimethylenedi-
amine,1 1,10-phen,2 8-hydroxyquinoline,3 pyridine-2-aldoxime,4
8-hydroxyquinalidine,5 as well as lithium pipecolinate.6 Although
these catalytic systems are all effective for hydroxylation of aryl io-
dides, only some of them are applicable for hydroxylation of aryl
bromides. For example, Taillefer and co-workers reported that CuI/
N,N-dimethylenediamine could catalyze the hydroxylation of aryl
bromides, but halo-exchange with sodium iodide was required.1
You2 and Fu’s4 reaction conditions were only suitable for some ac-
tive aryl bromides. CuI/lithium pipecolinate6 and CuI/8-hydroxyqu-
inalidine5 systems could be used for a wide range of aryl bromides.
However, in these cases both catalytic loading and reaction temper-
ature were considerably high (using 10 mol % copper salts and
20 mol % ligands, at 130 °C). Additionally, only moderate yields were
obtained in CuI/lithium pipecolinate catalyzed reaction.6 Herein, we
describe that CuI/5-bromo-2-(1H-imidazol-2-yl)pyridine is a more
efficient combination for promoting the hydroxylation of aryl bro-
mides, which led the reaction to complete at 120 °C by using only
2 mol % catalyst.
recovered (entry 1). Similar results were observed in the cases of
two substituted 2-pyridin-2-yl-1H-benzoimidazoles L2 and L3
(entries 2 and 3). However, 2-(5-bromopyridin-2-yl)-1H-benzo[d]-
imidazole L4 gave the desired product with 85% yield (entry 4).
From the crude mixture of CuI/L4 catalyzed coupling reaction,
2-(5-hydroxypyridin-2-yl)-1H-benzo[d]-imidazole L5 was isolated,
indicating that this compound might be the active ligand for the
hydroxylation reaction. To confirm this assumption, L5 was syn-
thesized with 20% isolated yield (this compound was found unsta-
ble during isolation) by CuI-catalyzed hydroxylation of L4. We
were pleased that this ligand provided a better result for hydroxyl-
ation of 4-bromoanisole (entry 5). These results suggested that
introducing electron-donating groups to pyridine ring could in-
crease the efficiency of the ligands. Therefore, another hydroxyl
substituted ligand L6 and a methoxy substituted ligand L7 were
examined. They were all effective for this transformation, although
the yields were not as good as L4-promoted coupling reaction (en-
tries 6 and 7). Interestingly, L8, a methylation product of L7, was
found inactive (entry 8). This result demonstrated that the free
NH group in benzimidazole part is essential for offering effective
ligand. Additional evidence could be obtained by observation on
the 2-(5-bromopyridin-2-yl)benzo[d]oxazole L12 promoted reac-
tion (entry 12).
As demonstrated in Table 1, several substituted 2-pyridin-2-yl-
1H-benzoimidazoles and 2-(1H-imidazol-2-yl)pyridines were
selected for promoting CuI-catalyzed hydroxylation of 4-bromoani-
sole because some of them had been used for copper-catalyzed dia-
ryl ether formation.7,8 These ligands were prepared from the
corresponding diamines and nitriles according to the known proce-
dure.9 When 2-pyridin-2-yl-1H-benzoimidazole (L1) was used, no
coupling reaction took place at 120 °C and 4-bromoanisole was
We then moved our attention to 2-(1H-imidazol-2-yl)pyridines.
Like benzimidazole ligands, the unsubstituted compound L9
gave a moderate yield (entry 9), while the bromo and hydroxy-
substituted ligands L10 and L11 provided 2a with excellent yields
(entries 10 and 11).
After identifying the L4 and L10 as suitable ligands, we ex-
plored optimized reaction conditions by varying copper sources,
catalytic loading and bases. As summarized in Table 2, changing
copper salts to CuCl, CuBr or Cu2O generally reduced the yields
(entries 1–4). Switching the base from CsOH to less expensive
KOH gave 2a with 93% yield, although prolonging reaction time
⇑
Corresponding authors.
E-mail address: madw@mail.sioc.ac.cn (D. Ma).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.059

5594
J. Jia et al. / Tetrahedron Letters 52 (2011) 5593–5595
Table 1
Table 3
Ligand screening for CuI-catalyzed hydroxylation of 4-bromoanisolea
CuI/L10 catalyzed hydroxylation of aryl bromidesa
X
X
10 mol % CuI, 20 mol % ligand
L10
MeO
Br
2 mol % CuI, 4 mol %
Br
MeO
OH
OH
CsOH, t-BuOH-DMSO-H2O
CsOH (or KOH)
120 oC, 24 h
t-BuOH-DMSO-H2O, 120 o
C
2
1a
2a
1
Cl
Cl
Cl
N
F
N
Entry
X
Temp (°C)
Yieldb (%)
N
Cl
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4-Me
120
120
120
120
120
120
120
80
93 (83)
82 (82)
84 (79)
83 (77)
83 (73)
90 (80)
80 (73)
83 (82)
68 (65)
85 (80)
86 (84)
91 (80)
83 (83)
87 (80)
86 (83)
65 (58)
80 (83)
83 (87)
N
H
N
N
H
L3
N
H
N
N
4-OHc
3-OMe
2-OMe
3-CH2OH
2,4-Dimethyl
H
L1
L2
HO
N
N
N
Br
OH
N
H
N
H
N
H
N
N
N
4-NO2
4-Acd
80
L5
L6
L4
4-F
4-Cl
120
120
100
100
100
120
120
120
100
N
N
N
4-CO2Hd,e
3-CO2Hd,e
2-CO2Hd,e
4-Ph
OMe
OMe
N
N
N
H
N
H
L7
N
N
Me
L8
L9
4-OH, 3-CHO
4-CO2Mef
4-CNf
N
N
N
Br
OH
Br
N
H
N
H
N
N
O
N
a
Reaction conditions: aryl bromide (1.0 mmol), CuI (0.02 mmol), L10 (0.04 mmol),
CsOH (3 mmol), t-BuOH (1 mL), DMSO (1 mL), H2O (0.1 mL), 36 h.
L10
L12
L11
b
Isolated yield (yield in brackets is for KOH mediated reaction).
Reaction time was 48 h.
DMSO/H2O (1 mL/1 mL) was used as solvent.
4 mmol base was used.
Entry
Ligand
Yieldb (%)
Entry
Ligand
Yieldb (%)
c
d
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
ꢀ0
ꢀ0
ꢀ0
85
90
77
7
8
9
10
11
12
L7
L8
L9
54
ꢀ0
40
90
93
ꢀ0
e
f
Product was 4-hydroxybenzoic acid.
L10
L11
L12
a
Reaction conditions: 4-bromoanisole (1.0 mmol), CuI (0.1 mmol), ligand
36 h even if only 2 mol % CuI was utilized (entries 6 and 7). Further
reducing the catalytic loading gave a poor result (entry 8). Addi-
tionally, it was found that there was no influence on hydroxylation
reaction while reducing the amount of bases to 3 equiv (entries 9
and 10).
(0.2 mmol), Cs2CO3 (4.0 mmol), t-BuOH (1 mL), DMSO (1 mL), H2O (0.1 mL), 120 °C,
24 h.
b
Isolated yield.
Using 2 mol % catalyst loading, two other ligands were checked.
The benzimidazole ligand L4 gave a relatively low yield (entry 11),
while 8-hydroxyquinalidine offered only 7% yield (entry 12). These
results suggested that L10 is the best ligand for this transforma-
tion. Noteworthy is that the 1:2 ratio for CuI and ligand is impor-
tant for this reaction because using 2 mol % CuI and 2 mol % L10
only gave 57% yield (entry 13).
Table 2
Condition screening for copper-catalyzed hydroxylation of 4-bromoanisolea
[Cu], L10
MeO
Br
MeO
OH
base, t-BuOH-DMSO-H2O
120 oC, 24-48 h
1a
2a
Entry
Cat.
mol % of cat.
Base
Time (h)
Yieldb (%)
The established optimized conditions were then tested with dif-
ferent aryl bromides, and the results are summarized in Table 3.
Gratefully, both electron-rich and electron-deficient aryl bromides
could be converted to the corresponding substituted phenols in
good to excellent yields. In the case of 4-bromophenol, the hydrox-
ylation was sluggish, but prolonging the reaction time to 48 h
could give complete conversion (entry 2). Steric hindrance seemed
to have litter influence on this reaction, as evident from observa-
tions that 2-methoxyphenyl bromide and 2,4-dimethylphenyl bro-
mide gave hydroxylation products with 83% and 90% yields
(entries 4 and 6). For some activated substrates, the reaction could
complete even at relatively low temperatures (entries 8, 9, 12–14).
In these cases DMSO/H2O was found to be a better reaction media.
For bromobenzoic acids, 5 equiv of the base was needed to obtain
satisfactory yields (entries 12 and 13). Polyfunctionalized
5-bromosalicylaldehyde was also applicable for this transforma-
tion, affording 2,5-dihydroxy-benzaldehyde in 65% yield (entry
16). When methyl 4-bromobenzoate and 4-bromobenzonitrile
were used, 4-hydroxy benzoic acid was isolated as a single product
(entries 17 and 18), indicating that the ester and nitrile groups
could not survive under these conditions. Noteworthy is that in
all cases good results were still observed if KOH was used to
1
2
3
4
5
6
7
8
9
10
11
12
13
CuI
10
10
10
10
10
2
2
1
2
2
CsOH
CsOH
CsOH
CsOH
KOH
CsOH
KOH
CsOH
CsOH
KOH
24
24
24
24
36
36
36
48
36
36
36
36
36
90
42
49
71
93
90
83
60
90c
82c
77d
7e
CuCl
CuBr
Cu2O
CuI
CuI
CuI
CuI
CuI
CuI
CuI
2
2
2
CsOH
CsOH
CsOH
CuI
CuI
57f
a
Reaction conditions: 4-bromoanisole (1.0 mmol), cat./ligand = 1:2, base
(4.0 mmol), t-BuOH (1 mL), DMSO (1 mL), H2O (0.1 mL).
b
Isolated yield.
3.0 mmol of base was used.
L4 was used as the ligand.
8-Hydroxyquinalidine was used as the ligand.
c
d
e
f
2 mol % CuI and 2 mol % L10 were used.
was required (entry 5). Next, we attempted to reduce the catalytic
loading, and were pleased to find that the reaction completes after

J. Jia et al. / Tetrahedron Letters 52 (2011) 5593–5595
5595
replace CsOH. This advantage provides an alternative and more
References and notes
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din-2-yl-1H-benzoimidazoles and 2-(1H-imidazol-2-yl)pyridines
for promoting CuI-catalyzed hydroxylation of aryl bromides. It
was found that electronic nature at pyridine ring plays a crucial role
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Acknowledgments
The authors are grateful to the Ministry of Science and Technol-
ogy (Grant 2009ZX09501-00), Chinese Academy of Sciences and
National Natural Science Foundation of China (Grant 20632050 &
20921091) for their financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.059.