Copper-catalyzed highly efficient aerobic oxidative synthesis of benzimidazoles, benzoxazoles and benzothiazoles from aromatic alcohols under solvent-free conditions in open air at room temperature

Article abstract of DOI:10.1002/aoc.3039

Solvent-free oxidative synthesis of benzimidazoles, benzoxazoles and benzothiazoles from aromatic alcohols and o-phenylenediamine, o-aminophenol and o-aminothiophenol has been achieved by using CuCl, 2,2′-bipyridine and TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl). The reaction proceeds via a dehydrogenation in open air at room temperature, and a wide variety of derivatives were obtained in good to excellent yields. The reaction mechanism was proposed and this method provides a mild and efficient access to substituted benzimidazoles, benzoxazoles and benzothiazoles. Copyright

Full text of DOI:10.1002/aoc.3039

Full Paper
Received: 20 May 2013
Revised: 20 June 2013
Accepted: 5 July 2013
Published online in Wiley Online Library: 10 September 2013
(wileyonlinelibrary.com) DOI 10.1002/aoc.3039
Copper-catalyzed highly efficient aerobic
oxidative synthesis of benzimidazoles,
benzoxazoles and benzothiazoles from
aromatic alcohols under solvent-free
conditions in open air at room temperature
Jiatao Yu, Jian Xu and Ming Lu*
Solvent-free oxidative synthesis of benzimidazoles, benzoxazoles and benzothiazoles from aromatic alcohols and
o-phenylenediamine, o-aminophenol and o-aminothiophenol has been achieved by using CuCl, 2,2′-bipyridine and TEMPO
(2,2,6,6-tetramethylpiperidine-1-oxyl). The reaction proceeds via a dehydrogenation in open air at room temperature, and a wide
variety of derivatives were obtained in good to excellent yields. The reaction mechanism was proposed and this method provides
a mild and efficient access to substituted benzimidazoles, benzoxazoles and benzothiazoles. Copyright © 2013 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: benzimidazoles; benzoxazoles; benzothiazoles; copper; aerobic oxidation
I
and industry, especially in aerobic oxidation. A recent Cu/TEMPO/
Introduction
Bpy (2,2′-bipyridine) aerobic catalytic oxidative system was particu-
Benzimidazoles and their derivatives, known as an important class
of N-containing heterocyclic compounds, have received consider-
able attention in recent years because they exhibit significant phar-
macological and biological activities. Substituted benzimidazole
derivatives have found application in diverse therapeutic areas
including anticonvulsant, antiulcer, antihypertensive and antihista-
larly effective for the aerobic oxidation of aromatic alcohols to
[20–23]
aldehydes,
but this catalytic system has not been successful
in the synthesis of five-membered heterocyclic rings, such as
benzimidazoles, benzoxazoles and benzothiazoles.
Herein we report a simple but efficient method for the synthesis
of benzimidazoles, benzoxazoles and benzothiazoles directly from
aromatic alcohols and o-phenylenediamine, o-aminophenol and
[1–5]
minic agents.
In addition, benzimidazoles are very important
[
6]
I
intermediates in organic reactions. The excellent characteristics
of benzimidazole derivatives have promoted extensive studies of
their synthesis. Typically, there are two methods for the synthesis
of benzimidazoles. One is the condensation of o-phenylenediamine
with carboxylic acids or their derivatives (nitriles, imidates,
orthoesters), but this method suffered from harsh dehydrating
o-aminothiophenol catalyzed by Cu/TEMPO/Bpy under ambient
conditions. This method can tolerate a wide range of substrates
and afford the corresponding products in high yields.
Results and Discussion
[
7–11]
conditions, such as strong acid and high temperature.
The
other method is oxidative cyclo-dehydrogenation of aniline Schiff
base, in which benzimidazoles are often generated from the
condensation of o-phenylenediamines and aldehydes, and various
Initially, o-phenylenediamine and benzyl alcohol were selected
as the model substrates to optimize the reaction conditions
(Table 1). When o-phenylenediamine and benzyl alcohol were
[12]
[13]
[14]
oxidative reagents such as Pb(OAc)
4
,
Na
2
S
2
O
5
,
(NH
4 2 2 8
) S O ,
treated with Bpy (5mol%)/CuCl (5mol%)/TEMPO (10 mol%) at
room temperature for 12 h, the desired 2-phenylbenzimidazole
was isolated in 95% yield (entry 1). In the absence of one of them,
the yield decreased substantially (entries 1–3); thus CuCl, TEMPO
and Bpy were essential for the reaction. Solvent screening showed
that the reaction under solvent-free conditions gave a higher yield
[15]
[16]
[17]
[18]
DDQ,
2
MnO ,
oxone,
2 2
and H O
have been reported.
However, this method has drawbacks such as a requirement for stoi-
chiometric amounts of reactive oxidants, low yield, harsh reaction
conditions and the generation of environmentally hazardous/toxic
by-products. Despite the condensation of o-phenylenediamine
with aldehydes or carboxylic acids being the most widely used
method, oxidative condensation of o-phenylenediamine and
alcohols is attractive, because aldehydes and carboxylic acids
are usually obtained from the oxidation of alcohols, which are
* Correspondence to: Ming Lu, College of Chemical Engineering, Nanjing
University of Science and Technology, Nanjing, Jiangsu, China. Email:
luming302@126.com
[
19]
relatively cheap and more stable.
I
Homogeneous Cu/TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl)
catalyst systems have exhibited broad utilities in both academe
College of Chemical Engineering, Nanjing University of Science and Technol-
ogy, Nanjing, Jiangsu, China
Appl. Organometal. Chem. 2013, 27, 606–610
Copyright © 2013 John Wiley & Sons, Ltd.

Aerobic oxidative synthesis of benzimidazoles, benzoxazoles and benzothiazoles
a
Table 1. Optimization of reaction conditions
b
Entry
Cu salt
CuCl
Ligand
Co-catalyst
Gas
Solvent
Reaction time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Bpy
none
none
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
TEMPO
TEMPO
none
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
None
None
None
MeCN
EtOH
EtOAc
MeOH
None
None
None
None
None
None
None
None
None
None
None
12
12
12
12
12
12
12
12
12
12
12
12
12
8
95
65
CuCl
CuCl
NR
76
CuCl
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
CuCl
86
CuCl
78
CuCl
83
Cu(OAc)
2
71
CuSO
CuCl
4
68
10
11
12
13
14
15
16
17
18
2
73
CuBr
CuI
2
77
76
CuBr
CuCl
CuCl
CuCl
CuCl
CuCl
81
75
10
14
12
12
87
95
N
2
Trace
95
O
2
a
Reaction conditions: A mixture of 1 mmol benzyl alcohol and 1.05mmol o-phenylenediamine, 5mol%CuCl, 5 mol% Bpy, 10 mol%TEMPO was placed
in a 10ml three-necked flask and stirred rapidly open to air at room temperature for several hours. The reaction progress was monitored by TLC.
b
Isolated yield.
than using commercial solvents (entries 4–7). A variety of Cu
catalysts were examined and CuCl was the best one, affording
the product in 95% yield (entries 1 and 8–13). The effect of the
reaction time was also tested, and it was suggested that the
highest yield was obtained in 12 h (entries 1 and 14–16). Finally,
Table 2. Synthesis of 2-substituted benzimidazoles from aromatic al-
cohols and o-phenylenediamines
a
we also tested the influence of the gas, and we found that O is
2
2
significant for the reaction. Furthermore, using O in the reaction,
the yield was equal to using air. For economic considerations, we
chose air as the oxidant (entries 16–18).
With optimized conditions in hand, we then turned our atten-
tion to the scope of the reaction, and the results are shown in
Table 2. First, a series of aromatic alcohols were reacted with
o-phenylenediamine under the optimized reaction conditions.
In most cases, o-phenylenediamine reacted with various benzyl
alcohols smoothly to give the corresponding products in good
to excellent yields. It seemed that benzyl alcohols bearing
electron-deficient aromatic rings at the para-position gave higher
yields of products than did those bearing electron-rich aromatic
rings (entries 2–9). The reason may be that the strong
b
Entry
R
1
R
2
Reaction time (h) Yield (%)
1
2
3
4
5
6
7
8
9
H
H
C
6
H
5
12
12
12
13
12
11
13
13
13
14
14
14
95
93
93
89
91
94
92
86
91
86
85
91
6 4
4-BrC H
H
4-ClC
2-ClC
6
H
H
4
H
6
4
H
2, 4-ClC
4-NO
4-MeOC
4-Me NC
6
H
3
H
2
C
6
H
4
H
6 4
H
H
2
6 4
H
electron-withdrawing groups (NO ) enhanced the reaction rate
2
H
3,4,5-MeOC
6 2
H
due to the increase in electrophilicity of the carbonyl carbon
1
1
1
0
1
2
H
2-Furyl
(entries 6–8). The steric hindrance of the substituted benzyl
H
5-Methyl-2-furyl
Ph
alcohols also influenced the reaction. For example, the more
sterically hindered ortho-chlorobenzyl alcohol, which reacted
with o-phenylenediamine, furnished the target product in
lower yield than para-chlorobenzyl alcohol (entries 3 and 4).
Heteroaryl alcohols such as ortho-furyl methanol were used in
the reaction, and the yields were satisfactory (entries 10 and 11).
In addition, 4-nitro-o-phenylenediamine was also employed in
the reaction, and to our delight it resulted in good yields (entry 12).
4-NO
2
a
Reaction conditions: a mixture of 1 mmol aromatic alcohol and
1.05 mmol o-phenylenediamine, 5 mol% CuCl, 5 mol% Bpy and
1
0 mol% TEMPO was placed in a 10 ml three-necked flask
and stirred rapidly open to air at room temperature for several
hours. The reaction progress was monitored by TLC.
b
Isolated yield.
Appl. Organometal. Chem. 2013, 27, 606–610
Copyright © 2013 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

J. Yu et al.
Having successfully achieved the aerobic oxidative synthesis of
benzimidazoles, the Cu /TEMPO/Bpy system was expanded to
Table 4. CuCl/Bpy/TEMPO aerobic alcohol oxidation in the presence
of o-phenylenediamine
I
a
catalyze the synthesis of benzoxazoles and benzothiazoles
using 2-aminophenol and 2-aminothiophenol with benzyl alco-
hols, respectively. As summarized in Table 3, 2-aminophenol
and 2-aminothiophenol were also converted to corresponding
benzoxazoles and benzothiazoles in high yields.
Preliminary mechanistic studies of the reaction were conducted
as shown in Tables 4 and 5.
In the first, the alcohol-to-aldehyde oxidation, when o-
phenylenediamine was not added to the reaction, benzyl alcohol
was rarely converted to the product benzaldehyde (Table 4, entry 1),
I
which is in great contrast to the reported efficient Cu /TEMPO-
[
21]
catalyzed aerobic alcohol oxidation. Conversely, when 0.1–1.05
equiv. o-phenylenediamine was added, a large amount of benzyl
alcohol was oxidized along with unreacted benzyl alcohol
decreased. These results implied that o-phenylenediamine would
have an important role in the CuCl/TEMPO/Bpy-catalyzed oxidized
alcohol step.
Entry
2 equiv.
Unreacted 1 (%)
3 (%)
6 (%)
1
2
3
4
5
6
0
>92
82
66
37
<1
0
<8
3
0
0.1
0.3
0.6
1
10
24
52
93
95
5
6
<1
0
Recently, Zhu and co-workers reported that the condensation of
o-phenylenediamine with aldehyde took place very quickly to form
Schiff base 4, and the Schiff base further reacted with another
1.05
a
Reaction conditions: a mixture of 1 mmol benzyl alcohol (1), 5mol%
CuCl, 5mol% Bpy, 10 mol% TEMPO and different loadings of o-
phenylenediamine (2) was placed in a 10 ml two-necked flask
and stirred rapidly open to air at room temperature for several
hours. The reaction progress was monitored by HPLC. Yields
calculated based on HPLC analysis.
[
24]
amine group of o-phenylenediamine to form benzimidazoline 5.
Hence, in the second step of the condensation, generated
benzaldehyde was reacted with o-phenylenediamine to form Schiff
base 4, which then transformed to intermediary benzimidazoline 5.
In the cyclo-dehydrogenation of benzimidazoline step, preliminary
studies of the reaction were conducted. First, the reaction was
carried out without any catalysts or in the presence of only
o-phenylenediamine, and the yield of 2-phenylbenzimidazole
was much lower (Table 5, entries 1 and 2). The yield increased
to 75% with only CuCl added to the reaction (entry 3). While
Table 5. The condensation of o-phenylenediamine with benzalde-
hyde to form benzimidazole
a
(
Bpy)CuCl/TEMPO was used in the system, the yield increased
obviously (entries 4 and 5). When CuCl, TEMPO, Bpy and
o-phenylenediamine were all added, the yield of product was
highest (entries 5, 7–9).
Entry
CuCl
TEMPO
Bpy
o-Phenylenediamine Yield (%)
(
mol%) (mol%) (mol%)
1
2
3
4
5
6
7
8
9
0
0
5
5
5
5
0
5
5
0
0
0
0
0
5
5
5
5
0
0
5
0
0
0
5
5
5
5
41
41
75
82
83
98
85
86
81
Table 3. CuI/Bpy/TEMPO-catalyzed aerobic oxidative synthesis of
benzoxazoles and benzothiazoles
a
0
0
10
10
10
10
0
10
Entry
X
R
Reaction time (h)
Yield (%)
a
Reaction conditions: a mixture of 1 mmol benzimidazoline
and 0.05 mmol o-phenylenediamine, 5 mol% CuCl, 5 mol% Bpy
and 10mol% TEMPO was placed in a 10 ml three-necked flask
and stirred rapidly open to air at room temperature for several
hours. The reaction progress was monitored by TLC.
1
2
3
4
5
6
O
O
O
S
Ph
12
11
13
13
12
12
89
90
87
93
91
89
6 4
4-ClC H
4-CH
3 6 4
OC H
b
Ph
Isolated yield.
S
6 4
4-ClC H
S
2 6 4
4-NO C H
a
Reaction conditions: a mixture of 1 mmol alcohol and 1.05 mmol
-aminophenol or 2-aminothiophenol, 5 mol% CuCl, 5 mol%
2
Based on these results and literature reports about the reaction of
I
[21–23]
Bpy and 10 mol% TEMPO was placed in a 10 ml three-necked
flask, and then stirred rapidly open to air at room temperature
for several hours. The reaction progress was monitored by TLC.
Cu/TEMPO/Bpy aerobic alcohol oxidation reaction,
a proposed
reaction pathway for the formation of benzimidazole is shown in
Scheme 1. First, the present aerobic oxidative synthesis of benzimid-
azole can readily proceed via CuCl/TEMPO/Bpy aerobic alcohol
b
Isolated yield.
wileyonlinelibrary.com/journal/aoc
Copyright © 2013 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2013, 27, 606–610

Aerobic oxidative synthesis of benzimidazoles, benzoxazoles and benzothiazoles
+
Cl-
N
R
1/2O2
TEMPOH
N
TEMPO
+
Cl-
N
NH
N
TEMPO
H
N
O
+
R
N
TEMPOH
H2O
H2N
N
Cu OH
H2N
+
Cl-
H2N
H2N
+
Cl-
N
N
Cu
H2N
R
N
OH
OH
N
Cu
H2N
+
Cl-
H2N
H2O
H2N
N
Cu
1
/2O , TEMPOH
H
N
R
TEMPO
O
TEMPOH
+
H
H2N
H2N
R
O
TEMPO
NH2
NH2
H
N
R
N
H
H2O
Scheme 1. A possible mechanism for CuCl/TEMPO/Bpy aerobic catalytic oxidative synthesis of benzimidazoles.
oxidation reaction in the presence of o-phenylenediamine. The
condensation of aldehyde and o-phenylenediamine was achieved
to form Schiff base, which then transformed to the intermediary
benzimidazoline. Finally, the CuCl/TEMPO/Bpy system in the pres-
ence of o-phenylenediamine catalyzed the cyclo-dehydrogenation
to afford the product benzimidazole.
Typical Procedure for Synthesis of Benzimidazoles,
Benzoxazoles or Benzothiazoles
A
mixture of 1 mmol benzyl alcohol and 1.05 mmol
o-phenylenediamine, o-aminophenol or o-aminothiophenol, 5 mol
CuCl, 5 mol% Bpy and 10mol% TEMPO was placed in a 10ml
%
three-necked flask and stirred in the open air at room temperature
for several hours. The reaction progress was monitored by TLC. The
reaction mixture was concentrated under vacuum and the residue
was directly purified by column chromatograph on silica gel using
hexane–ethyl acetate (7:3) as eluent to afford the pure product.
Conclusion
A green and mild CuCl/TEMPO/Bpy catalytic system was developed to
synthesize benzimidazoles, benzoxazoles and benzothiazoles directly
fromaromaticalcoholsando-phenylenediamine, o-aminophenoland
o-aminothiophenol under solvent-free conditions in open air at room
temperature, and yields were effective. This system has provided a
new method for the preparation of benzimidazoles, benzoxazoles
and benzothiazoles. The extension of this catalytic system for the
preparationof other useful heterocyclesisunderway inthelaboratory.
Supporting Information
Supporting information may be found in the online version of this
article.
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Appl. Organometal. Chem. 2013, 27, 606–610