Aerobic oxidative synthesis of 2-arylbenzimidazoles, 2-arylbenzoxazoles, and 2-arylbenzothiazoles from arylmethanols or arylmethylamines catalyzed by Fe(III)/TEMPO under solvent-free conditions

Article abstract of DOI:10.1007/s13738-014-0537-0

A simple and efficient aerobic oxidative synthesis of 2-arylbenzimidazoles, 2-arylbenzoxazoles, and 2-arylbenzothiazoles from arylmethanols or arylmethylamines with o-phenylenediamine, o-aminophenol and o-aminothiophenol catalyzed by Fe₂(SO₄)₃/TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl) system under solvent-free conditions. This reaction uses air as an environmental and economic oxidant, tolerates a variety of functional groups on the aromatic ring of the benzylic partner, and affords the products in moderate yields.

Full text of DOI:10.1007/s13738-014-0537-0

J IRAN CHEM SOC (2015) 12:771–778
DOI 10.1007/s13738-014-0537-0
ORIGINAL PAPER
Aerobic oxidative synthesis of 2‑arylbenzimidazoles,
2‑arylbenzoxazoles, and 2‑arylbenzothiazoles from arylmethanols
or arylmethylamines catalyzed by Fe(III)/TEMPO
under solvent‑free conditions
Jiatao Yu · Mengnan Shen · Ming Lu
Received: 23 February 2014 / Accepted: 14 September 2014 / Published online: 21 September 2014
© Iranian Chemical Society 2014
Abstract A simple and efficient aerobic oxidative syn-
thesis of 2-arylbenzimidazoles, 2-arylbenzoxazoles, and
2-arylbenzothiazoles from arylmethanols or arylmethy-
lamines with o-phenylenediamine, o-aminophenol and
o-aminothiophenol catalyzed by Fe2(SO4)3/TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxyl) system under sol-
vent-free conditions. This reaction uses air as an environ-
mental and economic oxidant, tolerates a variety of func-
tional groups on the aromatic ring of the benzylic partner,
and affords the products in moderate yields.
16]. The excellent characteristics of benzimidazole derivatives
have promoted extensive studies for their synthesis. Typically,
there are two methods for the synthesis of benzimidazoles.
One is the coupling of o-phenylenediamine with carboxylic
acids or their derivatives (nitriles, imidates, and orthoesters)
under harsh dehydrating conditions, such as strong acidic
conditions, high temperature conditions [17–33]. The other is
oxidative cyclization of aniline Schiff bases promoted by oxi-
dants, in which benzimidazoles are often generated from the
condensation of o-phenylenediamine and aldehydes [34–41]
However, this method has some drawbacks such as requiring
a stoichiometric amount of oxidant, generating environmen-
tally hazardous/toxic by-products, and using malodorous and
unstable aldehydes. Besides, different methods for the direct
synthesis of benzimidazoles, benzoxazoles, and benzothia-
zoles and also recent published papers for the preparation of
benzimidazoles catalyzed by transition metal and biocatalyst
had also recently reported [42–47].
In recent years, the preparation of benzimidazoles have
been greatly improved, especially by employing the reaction
of o-phenylenediamine with the greener, cheaper, and more
available alcohols or amines, but drawbacks still remain, for
example, the former methods require complex and expen-
sive metal catalysts, a large excess of oxidants, which also
produces large amounts of undesired waste, and an inert
atmosphere [48–50] Many issues have yet to be satisfactorily
addressed. So, the development of new efficient and greener
methods for their synthesis is, therefore, highly desirable.
Recently, the aerobic oxidative reactions have attracted
increasing attention, which are comparatively green, pref-
erable, and practical processes, due to the use of pure oxy-
gen or air as the economic and green oxidant, much more
easily disposable catalysts, and milder reaction conditions,
along with generating water as the by-product. However,
most reactions still require special conditions, expensive
Keywords 2-arylbenzimidazoles · 2-arylbenzoxazoles ·
2-arylbenzothiazoles iron TEMPO
Introduction
Five-membered N-containing heteroaromatic compounds
are important structures found in natural and synthetic
compounds. Among them, benzimidazole and its deriva-
tives are crucial core structures which exhibit significant
pharmacological and biological activities, such as anticon-
vulsant, anticancer, antiulcer, antihypertensive, antibacte-
rial, and antihistaminic agents. [1–9].
They also have been applied in dyes, fluorescence, chemo-
sensing, and corrosion science [10–14] In addition, they are
very useful intermediates/subunits in organic reactions [15,
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-014-0537-0) contains supplementary
material, which is available to authorized users.
J. Yu · M. Shen · M. Lu (*)
School of Chemical Engineering, Nanjing University of Science
and Technology, Nanjing 210094, People’s Republic of China
e-mail: luming302@126.com
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J IRAN CHEM SOC (2015) 12:771–778
Table 1 Condition optimization for aerobic oxidation of o-phenylenediamine and benzyl alcohol
Entry Benzyl alcohol (equiv.) Metal salt (mol %) Catalyst (mol %) Oxidant Solvent Temp. (°C) Reaction time (h) Yielda (%)
1
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
1
Fe2(SO4)3 (0)
Fe2(SO4)3 (10)
Fe2(SO4)3 (0)
Fe2(SO4)3 (10)
FeCl3 (10)
–
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
H2O2
Oxone
O2
–
80
80
80
80
80
80
80
80
80
80
80
80
80
24
24
24
24
24
24
24
24
24
24
24
24
24
24
4
Trace
35
2
–
–
3
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
HOBT (10)
NHS (10)
–
21
4
–
62
5
–
42
6
Fe(NO3)3 (10)
CuCl (10)
–
37
7
–
46
8
CuI (10)
–
55
9
Cu(OAc)2 (10)
Fe2(SO4)3 (10)
Fe2(SO4)3 (10)
Fe2(SO4)3 (10)
Fe2(SO4)3 (10)
Fe2(SO4)3 (10)
Fe2(SO4)3 (10)
Fe2(SO4)3 (10)
Fe2(SO4)3 (10)
Fe2(SO4)3 (10)
Fe2(SO4)3 (10)
Fe2(SO4)3 (5)
Fe2(SO4)3 (2.5)
Fe2(SO4)3 (10)
Fe2(SO4)3 (10)
Fe2(SO4)3 (10)
Fe2(SO4)3 (10)
–
42
10
11
12
13
14
15
16
17
18
19
20
21
22b
23b
24
25
–
57
–
49
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (5)
TEMPO (2.5)
–
DCE
EtOAc
21
Trace
54
Dioxane 80
Toluene
80
110
130
110
110
110
110
50
59
–
–
–
–
–
–
–
–
–
–
24
24
24
24
24
24
24
24
24
24
83
83
72
69
1.2
1.2
1.2
1.2
1.2
1.2
75
43
Trace
Trace
83
–
110
110
110
TEMPO (10)
TEMPO (10)
N2
Trace
Reaction conditions a mixture of o-phenylenediamine and benzyl alcohol, Metal salt, TEMPO, was mixed in a 10 ml three-necked flask, and
then stirred rapidiy for several hours. The reaction progress was monitored by TLC
a
Isolated yield
b
The reaction was conducted under N2 condition
and rare noble metal catalysts, or dangerous pure oxygen as
the oxidant [51–54].
ring of the benzylic partner, and affords the products in
moderate yields.
Herein, we introduce a simple and efficient method for
directly aerobic oxidative synthesis of benzimidazoles, ben-
zoxazoles, and benzothiazoles from the arylmethylamines
or the arylmethanols with o-phenylenediamine, o-ami-
nophenol and o-aminothiophenol catalyzed by Fe2(SO4)3/
TEMPO under solvent-free using air as the oxidant. This
method tolerates various functional groups on the aromatic
Result and discussion
Initially, o-phenylenediamine and benzyl alcohol were
selected as a model substrate to optimize the reaction con-
ditions (Table 1). When the model reaction was carried
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J IRAN CHEM SOC (2015) 12:771–778
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Table 2 Synthesis of 2-substituted benzimidazoles from the arylmethanol and o-phenylenediamines
Entry
R1
R2
Reaction time (h)
Yield (%)a
1
H
C6H5
24
24
24
26
24
20
26
26
26
27
28
30
26
28
83
85
85
81
80
86
83
76
80
73
71
69
87
78
2
H
4-BrC6H4
4-ClC6H4
2-ClC6H4
2, 4-ClC6H3
4-NO2C6H4
4-MeOC6H4
4-Me2NC6H4
3,4,5-MeOC6H2
2-Furyl
3
H
4
H
5
H
6
H
7
H
8
H
9
H
10
11
12
13
14
H
H
5-methyl-2-furyl
Pyridin-2-yl
C6H5
H
Cl
4-NO2
C6H5
Reaction conditions a mixture of 5 mmol o-phenylenediamine and 6 mmol aromatic alcohol, 10 mol % Fe2(SO4)3, 10 mol % TEMPO were
mixed in a 10 ml three-necked flask, and then stirred rapidiy open to air at 110 °C for several hours. The reaction progress was monitored by
TLC
a
Isolated yield
out under solvent-free conditions, at 80 °C for 24 h, and
in the absence of Fe2(SO4)3 and TEMPO, traces only of
the desire product was obtained (entry 1). In the presence
of Fe2(SO4)3 alone (entry 2) or of TEMPO alone (entry
3), the yield of 2-phenylbenzimidazole was also very low.
We were pleased to find that the combination of Fe2(SO4)3
and TEMPO could greatly enhance the yield of the product
(entry 4). This indicated that both Fe2(SO4)3 and TEMPO
were essential in this reaction. Several other iron and cop-
per salts [FeCl3, Fe(NO3)3, CuCl, CuI, Cu(OAc)2] were
also examined (entries 5–9) and Fe2(SO4)3 was found to
be the best (entry 4). HOBT (N-hydroxybenzotrizole),
NHS (N-hydroxysuccinimide) were used as catalyst in
this reaction, and found that TEMPO was the best choice
(entries 4, 10, 11). Solvent screening showed that the reac-
tion under solvent-free conditions gave a higher yield than
using solvents (entries 4, 12–15), and the reaction may be
the substrates is easier to contact the O2 in the air than in
the solvent. Moreover, Fe2(SO4)3 has a poor solubility in
organic solvent. The yield was improved by increasing the
temperature from 80 °C (entry 4) to 110 °C (entry 16) but
remained the same upon further increase of the temperature
to 130 °C (entry 17). Thus, 110 °C was selected as the best
temperature. The use of 1.2 equivalent of benzyl alcohol
gave the best results (compare entry 16 with entries 18–19).
Further optimization showed that the optimum amount of
Fe2(SO4)3 and TEMPO was 10 mol % of each (compare
entry 16 with entries 20–21). Besides, hydrogen peroxide
and oxone were used instead of air as oxidant for this reac-
tion, the yields were trace (entries 22–23). Finally, we also
tested the influence of the gas, lower yield was obtained
when the reaction was conducted under N2, and we found
that the O2 is significant for the reaction. However, using
O2 in the reaction, the yield was equal to use air (entries
16, 24–25). As economic consideration, we chose air as the
oxidant. Therefore, the optimal reaction conditions for the
synthesis of benzimidazole consist of 10 mol % Fe2(SO4)3
and 10 mol % TEMPO as catalyst at 110 °C under solvent-
free conditions.
Encouraged by these results, the optimized conditions
were then applied to various benzyl (heterocyclic) alcohol
and o-phenylenediamine to extend the scope of the method.
As shown in Table 2, benzyl alcohols bearing electron-
donating substituents as well as electron-withdrawing sub-
stituents at the para-position gave similar yields of 2-arylb-
enzimidazole (83–86 %, entries 2, 3, 6, 7) as the parent
benzyl alcohol (83 %, entry 1). The yield was slightly lower
with the substituent in the ortho position (80–81 %, entries
4 and 5). That may be due, in part, to steric hindrance.
A lower yield was obtained in the case of the strongly
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J IRAN CHEM SOC (2015) 12:771–778
electron-donating para N, N-dimethylamino substituent
(76 %, entry 8). However, three electron-donating methoxy
groups, two in the ortho and one in the para-position, did
not cause a significant lowering of the yield (80 %, entry
9). Moreover, heteroarylmethanols were also tested in this
reaction system, and the yields were moderate (entries 10–
12). In addition, 4-chloro-o-phenylenediamine and 4-nitro-
o-phenylenediamine was also employed in the reaction, and
to our delight, it resulted in moderate yields (entry 13–14).
Having successfully achieved the aerobic oxidative syn-
thesis of benzimidazoles, the Fe2(SO4)3/TEMPO system
was expanded to catalyze the synthesis of benzoxazoles
and benzothiazoles using o-aminophenol and o-aminothio-
phenol with the arylmethanols, respectively. As summa-
rized in Table 3, o-aminophenol and o-aminothiophenol
were also converted to corresponding benzoxazoles and
benzothiazoles in high yields.
The similar method could also be applied to synthesize
benzimidazoles through the reactions of arylmethylamines
and o-phenylenediamine. We began our investigation using
o-phenylenediamine and benzyl amine as the model sub-
strate under solvent-free conditions at 110 °C for 24 h
(Table 4). As expected, the yield of the desired product was
very poor in the absence of Fe2(SO4)3 and TEMPO (entry
1). Then we use Fe2(SO4)3 or TEMPO alone, the results
were not satisfying (entries 2 and 3). However, when the
model reaction was catalyzed by Fe2(SO4)3 and TEMPO, to
our delight, the yield was the highest (entry 4). The loading
Table 3 Fe2(SO4)3/TEMPO catalyzed aerobic oxidative synthesis of
benzoxazoles and benzothiazoles
Entry
X
R
Reaction time (h)
Yield (%)a
1
2
3
4
5
6
O
O
O
S
Ph
26
24
28
30
28
26
85
88
85
76
79
81
4-ClC6H4
4-CH3OC6H4
Ph
S
4-ClC6H4
4-NO2C6H4
S
Reaction conditions a mixture of 5 mmol 2-aminophenol or 2-ami-
nothiophenol and 6 mmol aromatic alcohol, 10 mol % Fe2(SO4)3,
10 mol % TEMPO were mixed in a 10 ml three-necked flask, and
then stirred rapidiy open to air at 110 °C for several hours. The reac-
tion progress was monitored by TLC
a
Isolated yield
Table 4 Optimization of the reaction conditions
Entry
Benzyl amine (equiv.)
Fe2(SO4)3 (mol %)
TEMPO (mol %) Temp. (°C) Solvent
Reaction time (h)
Gas
Yield (%)a
1
0.8
0.8
0.8
0.8
1
–
–
110
110
110
110
110
110
110
80
–
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
O2
19
52
36
79
82
88
81
77
83
87
35
12
79
85
88
Trace
2
10
–
–
–
3
10
10
10
10
10
10
10
10
10
10
10
10
10
10
–
4
10
10
10
10
10
10
10
10
10
10
10
10
10
–
5
–
6
1.2
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
–
7
–
8
–
9
100
130
110
110
110
110
110
110
–
10
11
12
13
14
11
12
–
DCE
EtOAc
Dioxane
Toluene
–
–
N2
Reaction conditions a mixture of o-phenylenediamine and benzyl amine, Fe2(SO4)3, TEMPO, were mixed in a 10 ml three-necked flask, and
then stirred rapidiy for several hours. The reaction progress was monitored by TLC
a
Isolated yield
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J IRAN CHEM SOC (2015) 12:771–778
775
Table 5 Fe2(SO4)3/TEMPO catalyzed aerobic oxidation synthesis of 2-substituted benzimidazoles, benzoxazoles, and benzothiazoles from the
arylmethylamine and o-phenylenediamines, 2-aminophenol or 2-aminothiophenol under air
Entry
X
R1
R2
Reaction time (h)
Yield (%)a
1
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
O
H
C6H5
24
24
24
26
24
20
26
26
26
27
28
30
28
30
22
20
24
26
26
24
88
85
86
84
85
90
85
78
83
80
81
69
91
79
90
89
87
85
79
83
2
H
4-BrC6H4
4-ClC6H4
2-ClC6H4
2, 4-ClC6H3
4-NO2C6H4
4-MeOC6H4
4-Me2NC6H4
3,4,5-MeOC6H2
2-Furyl
3
H
4
H
5
H
6
H
7
H
8
H
9
H
10
11
12
13
14
15
16
17
18
19
20
H
H
5-methyl-2-furyl
Pyridin-2-yl
C6H5
H
Cl
4-NO2
H
C6H5
C6H5
O
H
4-ClC6H4
4-CH3OC6H4
C6H5
O
H
S
H
S
H
4-ClC6H4
4-NO2C6H4
S
H
Reaction conditions a mixture of 5 mmol o-phenylenediamine, 2-aminophenol or 2-aminothiophenol and 6 mmol aromatic amine, 10 mol %
Fe2(SO4)3, 10 mol % TEMPO were mixed in a 10 ml three-necked flask, and then stirred rapidiy open to air at 110 °C for several hours. The
reaction progress was monitored by TLC
a
Isolated yield
of benzyl amine screening indicated 1.2 equivalent was
the most suitable proportion (entries 4–7). Further condi-
tion screening by investigating the effects of reaction tem-
perature, showing that a temperature of 110 °C was optimal
(entries 6, 8–10). Furthermore, screening the effects of gas
and the results indicated that when the reaction was con-
ducted under N2, the desired product was trace. We found
that the O2 is significant for the reaction. Moreover, using
O2 in the reaction, the yield was equal to use air (entries
6, 11–12). As economic consideration, we chose air as the
oxidant.
To investigate the scope and limitation of this catalytic
system, we applied the optimized conditions to differ-
ent substrates (Table 5). First, o-phenylenediamine was
chose to react with a series of the benzyl amines bearing
electron-donating or electron-withdrawing substituents
under the optimized reaction conditions, giving the cor-
responding products in moderate yields. It seemed that
benzyl amines 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 that the strong electron-withdraw-
ing groups (NO2) enhanced the reaction rate. Heteroaryl
amines such as ortho-furyl methylamine were used in the
reaction, and the yields were satisfactory (entries 10–12).
In addition, 4-chloro-o-phenylenediamine and 4-nitro-
o-phenylenediamine was also employed in the reaction, the
results revealed that the electron-donating group enhanced
the reaction, meanwhile electron-withdrawing substituent
slowed the reaction (compare entry 1 with entries 13–14).
Under the same condition, the methodology was extended
to the synthesis of various benzoxazoles and benzothiazoles
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J IRAN CHEM SOC (2015) 12:771–778
Table 6 Fe2(SO4)3/TEMPO catalyzed aerobic oxidation of ben-
zylamine and aniline to imine under air
the reaction to occur. Only a trace amount of imine was
obtained when the reaction was conducted under N2 (com-
pare entries 1 and 2 with entries 5 and 6). Higher yields
were obtained when the reaction was catalyzed by Fe2(SO4)3
(entries 3 and 8) or TEMPO (entries 4 and 9). When the
reaction was catalyzed by both Fe2(SO4)3 and TEMPO, the
yield of imine was the highest (entries 5 and 10).
By the encouragement of these results, we speculated, in
the imine formation step, o-phenylenediamine with benzyl
alcohol or benzyl amine took place to form imine 3, and
then the imine further reacted with another amine group of
o-phenylenediamine resulting in the formation of benzimi-
dazoline 4. Secondly, the cyclo-dehydrogenation of benzi-
midazoline step, preliminary studies of the reaction were
conducted, the results are shown in Table 7. Benzimidazo-
line was treated with 10 mol % Fe2(SO4)3 and 10 mol %
TEMPO at 110 °C under solvent-free conditions for 12 h,
the desired 2-phenylbenzimidazole was isolated in 97 %
yield. When the reaction was carried out in the absence of
Fe2(SO4)3 or TEMPO, the yield decreased substantially.
Besides, the reaction could not proceeded under N2. There-
fore, Fe(NO3)3, TEMPO and Air were essential for the
reaction (Table 7).
Entry
X
Fe2(SO4)3 (mol %) TEMPO (mol %) Gas Yield (%)a
1
2
3
4
5
6
7
8
9
10
O
–
–
Air 29
N2 Trace
Air 53
Air 47
Air 89
Air 31
N2 Trace
Air 59
Air 51
Air 92
O
–
–
O
10
–
–
O
10
10
–
O
10
–
NH
NH
–
–
NH 10
NH
NH 10
–
–
10
10
Reaction conditions a mixture of 5 mmol aniline and 6 mmol benzy-
lalcohol or benzylamine, Fe2(SO4)3, TEMPO were mixed in a 10 ml
three-necked flask, and then stirred rapidiy open to air at 110 °C for
24 h
a
Isolated yield
Based on these results and the literature reports [51–55],
a proposed pathway for the synthesis of benzimidazoles is
shown in Scheme 1. In the benzimidazoline formation step,
the aerobic oxidative synthesis imine via the coupling of
o-phenylenediamine with benzyl alcohol or benzyl amine,
which then transformed to the intermediary benzimidazo-
line. In the aerobic oxidative cyclo-dehydrogenation step,
benzimidazoline was oxidized to the finally product ben-
zimidazole. The whole process is catalyzed by Fe2(SO4)3/
TEMPO.
Table 7 The cyclo-dehydrogenation of benzimidazoline to benzimi-
dazole
Entry Fe(NO3)3 (mol %) TEMPO (mol %) Oxidant Yield (%)a
1
2
3
4
10
–
–
Air
Air
Air
N2
39
78
97
23
10
10
10
Conclusion
10
10
In summary, we developed a simple, and efficient method
for the aerobic oxidative synthesis of 2-arylbenzimida-
zoles, 2-arylbenzoxazoles, and 2-arylbenzothiazoles from
arylmethanols or arylmethylamines with o-phenylenedi-
amine, o-aminophenol and o-aminothiophenol catalyzed by
Fe2(SO4)3/TEMPO system under solvent-free conditions at
100 °C. This practical reaction uses air as an economic and
green oxidant, tolerates a variety of functional groups on
the aromatic ring of the benzylic partner, and affords the
products in moderate yields.
Reaction conditions
Fe2(SO4)3, TEMPO were mixed in a 5 ml three-necked flask, and
then stirred rapidiy open to air at 110 °C for 12 h
a
mixture of 4 mmol benzimidazoline,
a
Isolated yield
from o-aminophenol and o-aminothiophenol with benzy-
lamines. The results are summarized in Table 5, benzo-
xazoles and benzothiazoles were resulted in good yields
(entries 15–20).
To understand this reaction further, we conducted a series
of examples to gain an insight into possible mechanisms by
which this reaction may be operating. Firstly, we turn our
attention to the reaction of benzyl alcohol or benzyl amine
and aniline to synthesize the imines as shown in Table 6.
First, we found that the presence of oxygen is required for
Experimental section
All starting materials were purchased from commercial
sources and used without further treatment. Melting
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J IRAN CHEM SOC (2015) 12:771–778
777
Scheme 1 A possible mechanism for Fe2(SO4)3/TEMPO aerobic catalytic oxidative synthesis of benzimidazoles from benzyl amine or benzyl
alcohol with o-phenylenediamine
points were determined on a Thomas Hoover capillary
apparatus and are uncorrected. All known compounds
were identified by appropriate technique such as 1H
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