Iron-catalyzed highly efficient aerobic oxidative synthesis of benzimidazoles direct from oximes in water

Article abstract of DOI:10.1007/s11164-015-2031-4

This article presents a general and efficient method for aerobic oxidative synthesis of benzimidazoles from oximes catalyzed by Fe(NO₃)₃·9H₂O under air in water. This practical method uses air as an economic and green oxidant, water as a green solvent, and tolerates a wide range of substrates that can afford the target benzimidazoles in moderate to good yields.

Full text of DOI:10.1007/s11164-015-2031-4

Res Chem Intermed
DOI 10.1007/s11164-015-2031-4
Iron-catalyzed highly efficient aerobic oxidative
synthesis of benzimidazoles direct from oximes in water
Jiatao Yu1
Ming Lu1
•
Received: 28 October 2014 / Accepted: 21 March 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract This article presents a general and efficient method for aerobic oxidative
synthesis of benzimidazoles from oximes catalyzed by Fe(NO3)3Á9H2O under air in
water. This practical method uses air as an economic and green oxidant, water as a
green solvent, and tolerates a wide range of substrates that can afford the target
benzimidazoles in moderate to good yields.
Keywords Aerobic oxidation Á Benzimidazoles Á Oximes Á Iron Á Air
Introduction
Benzimidazole and its derivatives are important building blocks for the construction
of pharmaceuticals, natural products, functional materials, and agrochemical
compounds. They exhibit significant pharmacological and biological activities such
as anticonvulsant, anticancer, antiulcer, antihypertensive, antibacterial, and antihis-
taminic properties [1–9]. Consequently, great effort has been made to develop
efficient methods for the preparation of benzimidazoles. In general, 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) [10–26]. The other is oxidative cyclo-dehydrogenation of aniline
Schiff’s bases, which are often generated in situ from the condensation of
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2031-4)
contains supplementary material, which is available to authorized users.
&
Jiatao Yu
yjt1989926@163.com
1
Chemical Engineering College, Nanjing University of Science and Technology,
Nanjing 210094, China
123

J. Yu, M. Lu
o-phenylenediamines and aldehydes [27–34]. Although the reaction was efficiently
carried out by the above methods, these methods suffer from one or more
disadvantages, for example, the former requires strong acidic conditions and high
temperature conditions; the latter method requires stoichiometric or excess amounts
of a strong oxidant, a high-cost catalyst, and odorous and unstable aldehydes, and
generates environmentally hazardous/toxic by-products. Moreover, these methods
are always conducted in organic solvents. Thus, it is of significant importance to
develop a mild, convenient, and efficient method that can avoid the use of organic
solvents for the synthesis of benzimidazoles.
Oximes have been widely used in medicine, industry, and analytical chemistry, and
they are widely used as intermediates in the synthesis of commodity products, fine
chemicals, medicines, and biologically active compounds [35–43]. Moreover, oximes
are valuable synthetic tools, which can be either reduced to amines or oxidized to
nitrile oxides [44, 45], and they can also be dehydrated to nitriles or undergo an acid-
catalyzed Beckmann rearrangement to obtain amides [46–50]. However, their
application in the catalytic oxidative synthesis of heterocycles is rare.
Recently, cross-coupling reactions and C-H activation reactions have been well
documented for the synthesis of benzimidazoles under many reaction conditions, such
as PhI/mCPBA and Cu(OTf)2 [51–53]. In recent years, aerobic oxidative reactions,
which are comparatively green, preferable, and practical, have attracted increasing
attention because they use pure oxygen or air as the terminal oxidant in view of the
concepts of green chemistry and atom economy, are much more easily disposable
catalysts, and have milder reaction conditions, along with generating water as the by-
product. In our previous work, we developed aerobic oxidative synthesis of
benzimidazoles from aromatic alcohols and o-phenylenediamine was achieved by
using CuCl, bpy, and TEMPO under solvent-free conditions [54]. In addition, we also
developed aerobic oxidative synthesis of benzimidazoles from aromatic amines and o-
phenylenediamine catalyzed by the Fe(NO3)3Á9H2O/TEMPO system under solvent-
free conditions or used TBHP as an oxidant under solvent-free and catalyst-free
conditions [55, 56]. Thus, based on our previous work, herein we report a general and
efficient procedure for aerobic oxidative synthesis of benzimidazoles from oximes
and o-phenylenediamine catalyzed by Fe(NO3)3Á9H2O using H2O as the solvent.
Results and discussion
We began our investigation by examining the reaction activity using 4-chloroben-
zaldoxime and o-phenylenediamine as the model substrates (Table 1). In the absence
of a catalyst, the reaction could not progress (entry 1). When 5 mol% Fe(NO3)3Á9H2O
was added to this reaction, the desired product 2-(4-chlorophenyl)-benzimidazole was
obtained with a yield of 47 % (entry 2). Screening the amounts of Fe(NO3)3Á9H2O
showed that 10 mol% was better than others, giving the highest yield (entries 3–5).
After conducting the reaction under different amounts of o-phenylenediamine, we
found that the amount of o-phenylenediamine was very important for the reaction, and
three equivalents was the most suitable (entries 6–9). Various metal catalysts were
then screened, showing varying activities in the reaction (FeCl3, 69 %; Fe2(SO4)3,
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Iron-catalyzed highly efficient aerobic oxidative synthesis…
Table 1 Optimization of reaction conditions
Entry
Diamine (equiv.)
Catalyst (mol%)
Solvent
T (°C)
Gas
Yield (%)a
1
1
1
1
1
1
2
3
4
0.5
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
–
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
EtOH
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
100
60
RT
100
100
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
O2
Trace
47
2
Fe(NO3)3Á9H2O (5)
Fe(NO3)3Á9H2O (2.5)
Fe(NO3)3Á9H2O (10)
Fe(NO3)3Á9H2O (20)
Fe(NO3)3Á9H2O (10)
Fe(NO3)3Á9H2O (10)
Fe(NO3)3Á9H2O (10)
Fe(NO3)3Á9H2O (10)
FeCl3 (10)
3
35
4
54
5
54
6
62
7
71
8
71
9
28
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
69
Fe2(SO4)3 (10)
50
CuCl2 (10)
58
Cu(OAc)2 (10)
54
CuI (10)
39
CoCl2 (10)
35
Fe(NO3)3Á9H2O (10)
Fe(NO3)3Á9H2O (10)
Fe(NO3)3Á9H2O (10)
Fe(NO3)3Á9H2O (10)
Fe(NO3)3Á9H2O (10)
Fe(NO3)3Á9H2O (10)
Fe(NO3)3Á9H2O (10)
Fe(NO3)3Á9H2O (10)
Fe(NO3)3Á9H2O (10)
78
DMSO
MeCN
H2O
68
73
81
H2O
90
H2O
59
H2O
Trace
90
H2O
H2O
N2
Trace
Reaction conditions: a mixture of diamine and p-chlorobenzaldoxime catalyst were mixed in 5 ml sol-
vent, and then stirred rapidly for 24 h. The reaction progress was monitored by TLC
a
Isolated yield
50 %; CuCl2, 58 %; Cu(OAc)2, 54 %; CuI, 39 %; CoCl2, 35 %), but often in lower
yields (entries 10–15). Solvent screening showed that H2O seemed a little better than
others (entries 7, 16–19), and as an environmental consideration, we chose H2O as
solvent. Further optimization by screening the reaction temperature, the results
showed that 100 °C was optimal for this reaction (entries 19–22). Finally, we tested
the influence of the gas, and we found that the reaction could not progress under N2
atmosphere (entry 24), and O2 is significant for the reaction. Further, when using O2
in the reaction, the yield was equal to using air (entries 20, 23). As an economic
consideration, we chose air as the oxidant (Scheme 1).
123

J. Yu, M. Lu
With the optimized reaction conditions in hand, the iron-catalyzed method was
then applied to various oximes and o-phenylenediamine derivatives to test the scope
and generality, as shown in Table 2. A variety of oximes reacted with o-
phenylenediamine smoothly to give the corresponding benzimidazoles in good to
excellent yields, regardless of whether oximes were in electron-donating or
electron-withdrawing groups on the benzene ring. Clearly, the electronic effects of
substituents on the benzene ring affected the reaction to some extent. For instance,
electron-donating substituents favored the transformation (entries 7, 9–10).
Meanwhile, electron-withdrawing substituents rejected the transformation (entry
6). The sterical hindrance of the substituted oximes also influenced the reaction. For
example, the more sterically hindered ortho-chlorobenzaldoxime which reacted with
o-phenylenediamine furnished the target product in lower yield than para-
chlorobenzaldoxime (entries 2, 4). When 1-naphthaldehyde oxime and cinnamalde-
hyde oxime were subjected to the standard conditions, good yields could be
successfully obtained (entries 11–12). Moreover, we also conducted heterocyclic
oximes under the employed reaction conditions. To our surprise, heterocyclic
oximes show high reactivity to give the corresponding benzimidazoles in good
yields (entries 13–15). In addition, 4-chloro-o-phenylenediamine and 4-nitro-o-
phenylenediamine were also employed in the reaction, and to our delight, it resulted
in good yields (entries 16–17). Having successfully achieved the synthesis of
benzimidazoles, this catalytic system was expanded to catalyze the synthesis of
benzoxazoles and benzothiazoles using o-aminophenol and o-aminothiophenol,
Scheme 1 Aerobic oxidative synthesis of benzimidazoles directly oximes and o-phenylenediamine
catalyzed by Fe(NO3)3Á9H2O using H2O as the solvent
123

Iron-catalyzed highly efficient aerobic oxidative synthesis…
Table 2 Synthesis of 2-substituted benzimidazoles from oximes and diamines
Reaction conditions: 3 mmol diamine, 1 mmol oxime, and 0.1 mmol Fe(NO3)3Á9H2O were mixed in 5 ml
H2O, and then stirred rapidity at 100 °C for 24 h. The reaction progress was monitored by TLC
a
Isolated yield
123

J. Yu, M. Lu
respectively, with benzaldoxime as the starting materials. We found that trace only
was obtained of 2-phenyl-benzoxazole (entry 18), but 2-phenyl-benzothiazole
resulted in a yield of 76 % (entry 19). Furthermore, 4-chlorobenzaldoxime and
4-nitrobenzaldoxime were used to react with o-aminothiophenol, and benzothia-
zoles were also converted in high yields (entries 20–21).
Preliminary mechanistic studies of the reaction were also conducted. Originally,
we speculated that the possible reaction pathway could be divided into two steps,
including the oximes oxidated to aldehydes, and the generated aldehydes reacted
with o-phenylenediamine to form benzimidazoles under the catalytic system. Thus,
we conducted the two kinds of reaction in this catalytic system. Unfortunately, the
oximes could not be oxidated to aldehydes, and aldehydes could not react with o-
phenylenediamine in the catalytic system, as shown in Scheme 2.
Subsequently, we speculated that o-phenylenediamine with oximes took place to
form imine, and the imine further reacted with another amine group of o-
phenylenediamine to form benzimidazoline, benzimidazole could obtained after
oxidation of benzimidazoline. First, we turn our attention to the reaction of aniline
and benzaldoxime to synthesize the cross imines as shown in Table 3. When aniline
and benzaldoxime was treated with Fe(NO3)3Á9H2O under air atmosphere at 100 °C
for 24 h, the desired imine was isolated in 88 % yield (entry 1). In addition, we
found that almost no desired product occurred in absence of Fe(NO3)3Á9H2O or
under N2 atmosphere (entries 2, 3). Therefore, this reaction was an aerobic oxidative
step which catalyzed by Fe(NO3)3Á9H2O, O2 in the air as the oxidant.
By these encouraging results, we focused on the cyclo-dehydrogenation of
2-phenylbenzimidazoline (2-phenylbenzimidazoline is unstable in air; therefore,
2-phenylbenzimidazoline is formed in situ from an equimolar amount of o-phenylene-
diamine and benzaldehyde in a mixed solution, EtOH:H2O = 1:1, at room temperature
after 2 h). Preliminary studies of the reaction were conducted, the result is shown in
Table 4. After optimizing the reaction condition, the yield of the desired product
2-phenyl-1H-benzimidazole reached 85 % only when Fe(NO3)3Á9H2O added to the
reaction under air atmosphere (entry 1). In the absence of Fe(NO3)3Á9H2O, the yield
decreased substantially (entry 2). Moreover, the reaction could not react under N2
atmosphere (entry 3). Therefore, Fe(NO3)3Á9H2O and O2 were essential for the reaction.
Based on these results, a plausible reaction pathway for the formation of
benzimidazole is shown in Scheme 3. First, the aerobic oxidative synthesis of
Scheme 2 The oxidation of oxime and the reaction of o-phenylenediamine and aldehyde
123

Iron-catalyzed highly efficient aerobic oxidative synthesis…
Table 3 Fe(NO3)3Á9H2O catalyzed aerobic oxidation of benzylamine and aniline to imine under air
Entry
Catalyst
Gas
Yielda (%)
1
2
3
Fe(NO3)3Á9H2O
–
Air
Air
N2
88
Trace
Trace
Fe(NO3)3Á9H2O
Reaction conditions: 3 mmol aniline, 1 mmol benzaldoxime, 0.1 mmol Fe(NO3)3Á9H2O were mixed in
5 ml H2O, and then stirred rapidiy at 100 °C for 24 h at corresponding conditions. The reaction progress
was monitored by TLC
a
Isolated yield
Table 4 The cyclo-dehydrogenation of benzimidazoline to benzimidazole
Entry
Catalyst
Gas
Yielda (%)
1
2
3
Fe(NO3)3Á9H2O
–
Air
Air
N2
85
29
Fe(NO3)3Á9H2O
Trace
Reaction conditions: to a solution of 1 mmol o-phenylenediamine and 1 mmol benzaldehyde, 2.5 ml
ethanol, 2.5 ml H2O, the solution was stirred at room temperature for 2 h. 0.1 mmol Fe(NO3)3Á9H2O was
then added and stirred rapidiy at 100 °C for 24 h at corresponding conditions. The reaction progress was
monitored by TLC
a
Isolated yield
Scheme 3 A plausible reaction pathway for the formation of benzimidazole by oxime and o-
phenylenediamine
123

J. Yu, M. Lu
benzimidazoline proceed via the coupling of o-phenylenediamine with oxime to
form imine, and then the imine further reacted with another amine group of
o-phenylenediamine to form benzimidazoline. Finally, in the cyclo-dehydrogena-
tion of benzimidazoline step, benzimidazoline was oxidated to form benzimidazole
catalyzed by Fe(NO3)3Á9H2O under air atmosphere.
Experimental section
All starting materials were purchased from commercial sources and used without
further treatment. Melting points were determined on a Thomas Hoover capillary
apparatus and were uncorrected. All known compounds were identified by an
1
appropriate technique, such as H NMR, and compared with previously reported
data. 1H NMR (500 MHz) was recorded on a Bruker 500 spectrometer with
tetramethylsilane (TMS) as an internal standard. Mass spectra were recorded on an
Agilent Technologies 6110 quadrupole LC/MS equipped with an electrospray
ionization (ESI) probe operating in positive ion mode. Analytical thin layer
chromatography (TLC) was performed on precoated silica gel 60 F254 plates.
Yields refer to the isolated yields of the products after purification by silica-gel
column chromatography (300 mesh). The spectra were in supporting information.
Typical procedure for oxidative synthesis of benzimidazoles
A mixture of 1 mmol oximes and 3 mmol diamines, 0.1 mmol Fe(NO3)3Á9H2O,
H2O (5 ml) were prepared in a 10-ml three-necked flask, and then stirred at 100 °C
for 24 h, and the reaction progress was monitored by TLC. After completion of the
reaction, the reaction mixture was cooled to room temperature, the solution was
directly evaporated to dryness and the residue was purified by chromatography
using hexane/ethyl acetate (7:3) as eluent.
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