Synthesis of Benzimidazoles via Iron-Catalyzed Aerobic Oxidation Reaction of Imine Derivatives with o-Phenylenediamine

Article abstract of DOI:10.1080/00397911.2015.1062987

A simple and efficient protocol for preparing benzimidazoles via Fe(NO₃)₃.9H₂O-catalyzed aerobic oxidation reaction of imine derivatives with o-phenylenediamine. This process uses air as an economical and green oxidant, tolerates a wide range of substrates, and affords the targeted benzimidazoles in moderate to excellent yields.

Full text of DOI:10.1080/00397911.2015.1062987

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Synthesis of Benzimidazoles via Iron-Catalyzed Aerobic
Oxidation Reaction of Imine Derivatives with o-
Phenylenediamine
Jiatao Yua & Ming Lua
a Nanjing University of Science and Technology, Chemical Engineering College, Nanjing,
China
Accepted author version posted online: 15 Jul 2015.
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To cite this article: Jiatao Yu & Ming Lu (2015): Synthesis of Benzimidazoles via Iron-Catalyzed Aerobic Oxidation Reaction of
Imine Derivatives with o-Phenylenediamine, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1062987
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Synthesis of Benzimidazoles via Iron-Catalyzed Aerobic Oxidation Reaction of
Imine Derivatives with o-Phenylenediamine
Jiatao Yu1, Ming Lu1
1Nanjing University of Science and Technology, Chemical Engineering College, Nanjing,
China
Corresponding Author to Jiatao Yu, E-mail: yjt1989926@163.com
Abstract
A simple and efficient protocol for preparing benzimidazoles via Fe(NO3)3·9H2O
catalyzed aerobic oxidation reaction of imine derivatives with o-phenylenediamine. This
procress uses air as the economic and green oxidant, tolerates a wide range of substrates,
and affords the targeted benzimidazoles in moderate to excellent yields.
INTRODUCTION
Synthesis of privileged benzimidazoles through an economical and environmental
friendly method is always desirable because benzimidazole moieties are of paramount
interest in medicinal chemistry due to their significant pharmacological and biological
activities such as anticonvulsant, anticancer, antiulcer, antihypertensive, antibacterial, and
antihistaminic properties. Moreover, benzimidazole and its derivatives are important
building blocks for the construction of pharmaceuticals, natural products, functional
materials, and agrochemical compounds.[1-5] Over the past few decades, there are two
1

main methods for the synthesis of benzimidazoles. One method involves the
condensation reactions of o-phenylenediamine with carboxylic acids or their derivatives
(nitriles, imidates, orthoesters).[6-10] Another method involves the oxidative
cyclo-dehydrogenation of aniline Schiff’s base, which is often generated in situ from the
condensation of o-phenylenediamines and aldehydes.[11-17] Although the reaction was
efficiently carried out by the above methods, these methods suffer from one or more
disadvantages, such as strong acidic conditions, high temperature conditions,
stoichiometric or excess amounts of strong oxidant, high cost of the catalyst, and generate
the environmentally hazardous/toxic by-products. In recent years, there have been a
number of simple and straightforward methods on the synthesis of benzimidazoles
through the coupling of aldehydes with o-phenylenediamine, such as using a nanoporous
aluminosilicate catalyst,[18] using simple air oxidation without catalyst,[19] and using
ammonium chloride as the catalyst.[20]
Despite the condensation of o-phenylenediamine with aldehydes is the most widely used,
the method of oxidative condensation of o-phenylenediamine and imines seems very
attractive, compared to aldehydes, imines are usually less toxic, more stable and easier to
handle.
Recently, the aerobic oxidative reactions have attracted increasing attention, which are
comparatively green, preferable, and practical processes, due to the use of pure oxygen or
2

air as the economic and green oxidant, much more easily disposable catalysts, and milder
reaction conditions, along with generating water as the by-product. In our previous work,
we have developed aerobic oxidative synthesis of benzimidazoles direct from aromatic
alcohols or amines with o-phenylenediamine under the corresponding oxidation
conditions.[21-23] So based on our previous work, herein, we report a general and efficient
procedure for aerobic oxidative synthesis of benzimidazoles from imines and
o-phenylenediamine catalyzed by Fe(NO3)3·9H2O. (Scheme 1)
RESULTS AND DISCUSSION
In our initial studies, the reaction of o-phenylenediamine with N-benzylidenebenzylamine
was chosen as a model to optimize the reaction conditions. The results are shown in Table
1. No product could be obtained when equal amounts of o-phenylenediamine and
N-benzylidenebenzylamine were treated in acetonitrile (MeCN) at 80oC in the absence of
catalyst (Table 1, entry 1). Fortunately, the desired product 2-phenylbenzimidazole was
obtained in 85% yield by using 5 mol% Fe(NO3)3·9H2O as a catalyst (entry 2). Other iron
catalyst, such as FeCl3 and Fe2(SO4)3, also worked for this reaction (entries 3-4).
However, lower yields were resulted when other metal salts were conducted in this
reaction, including Cu(OAc)2, CuCl2, Cu(NO3)2, CuI, and CoCl2 (entries 5-9). Among
which, Fe(NO3)3·9H2O exhibited the highest activity. In addition, we also investigated the
amount of o-phenylenediamine in the reaction. It was found that the use of 1.5 equivalent
gave the best results (entries 10-12). Further optimization by screening the loading of
3

Fe(NO3)3·9H2O indicated that 5 mol% was the most suitable proportion (entries 13-14).
Solvent screening demonstrated that MeCN is the best one compared with all the others
(entries 15-17). Reducing the reaction temperature from 80oC to room temperature led to
great decrease in the yield (entries 18, 19). Finally, the reaction was equally efficient
when proceeding in O2 atmosphere, but less product could be detected in the atmosphere
of N2 (entries 20, 21).
With the optimized reaction conditions, we proceeded to explore the substrate scope of
this transformation. As the reaction conditions are mild, we expected that various
functional groups would be tolerated. To our delight, we could indeed show that
homo-coupled imine with either electron-donating or electron-withdrawing groups on the
benzene ring smoothly generated the corresponding products in moderate to good yields
under the optimized reaction conditions. Clearly, the reaction conditions were compatible
with fluoro, chloro, and bromo substituent groups, giving the desire product in high
yields (Table 2, entries 2-4). When the N-benzylidenebenzylamines bear
electron-withdrawing substituents, the yield of the ortho-position was slightly lower than
the para position (entries 3, 5). That may be, in part, due to steric hindrance.
N-(2-furanylmethylene)-2-furanyl methanamine as a representative of heterocyclic
homo-coupled imine used in this transformation. To our surprise, it showed high
reactivity to give the corresponding product in good yield (entry 7). In addition,
4

4-chloro-o-phenylenediamine, and 4-nitro-o-phenylenediamine were also employed in
the reaction, giving the corresponding products in moderate yields (entries 8-9). Besides,
N-(amylmethylene)-octylamine could successfully be convered to 2-amylbenzimidazole
in a yield of 65% (entry 10).
To investigate the scope and limitation of this catalytic system, a series of hetero-coupled
imines could also be applied to synthesize benzimidazoles through the reactions of
o-phenylenediamine and imines. Initially, we investigated the aerobic oxidation reaction
of a series of N-benzylidene amines with o-phenylenediamine to form
2-phenylbenzimidazole. The results show that either N-benzylidene aromatic amines or
N-benzylidene aliphatic amines smoothly generated the corresponding products in
moderate to good yields under the optimized reaction conditions. Among them,
N-benzylideneaniline gave the highest yield (Table 3, entries 1a-1c). The reason may be
that aromatic ring easily removed in the reaction condition than aliphatic chain. With
these results in hand, we expected that various functional groups would be tolerated. As
expected, N-benzylideneaniline bearing electron-donating or electron-withdrawing
substituents on the aromatic ring under the reaction conditions, giving the corresponding
products in moderate yields. It seemed that N-benzylideneaniline bearing
electron-withdrawing substituents at the para-position gave higher yields of products
than did those bearing electron-donating substituents (entries 2-8). The reason may be
that the strong electron-withdrawing groups (NO2) enhanced the reaction rate.
5

N-heteroaryl anilines such as N-(2-furanylmethylene)-aniline,
N-(5-methyl-2-furanylmethylene)-aniline, and N-(2-pyridinylmethylene)-aniline, were
used in the reaction, and the yields were satisfactory (entries 14-16). In addition,
4-chloro-o-phenylenediamine and 4-nitro-o-phenylenediamine were also employed in the
reaction, the results revealed that the electron-donating group enhanced the reaction,
meanwhile electron-withdrawing substituent slowed the reaction (entries 17-18). To
demonstrate the scope and efficiency of the present method, this catalytic system was
then extended for the synthesis of 2-alkylbenzimidazole. We found the
N-(amylmethylene)-aniline could be converted to 2-amylbenzimidazole in a yield of 59%
(entry 19).
CONCLUSION
In summary, we have described an efficient protocol for preparing benzimidazoles via
Fe(NO3)3·9H2O catalyzed aerobic oxidation reaction of imine derivatives
with o-phenylenediamine. This procress uses air as the economic and green oxidant,
tolerates a wide range of substrates, and affords the targeted benzimidazoles in moderate
to excellent yields.
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
6

were uncorrected. All known compounds were identified by appropriate technique such
as 1H 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). All the products are the known
compounds. The spectras were in supporting information.
TYPICAL PROCEDURE FOR OXIDATIVE SYNTHESIS OF
BENZIMIDAZOLES
A mixture of 1.5 mmol o-phenylenediamine, and 1 mmol imine, 5mol% Fe(NO3)3·9H2O,
and 5ml MeCN were mixed in a 10 ml three-necked flask, equipped with a condenser and
a thermometer, and then stirred rapidiy open to air at 80 oC for 12 hours. The reaction
progress was monitored by TLC. After completion of the reaction, the residue was
directly purified by column chromatograph on a silica gel using hexane/ethyl acetate (7:3)
as eluent to afford the pure product.
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10

Table 1. Reaction Optimization.[a]
Entry
Diamine Catalyst [mol%]
(equiv.)
Solvent
MeCN
T [oC]
Gas
Yield
[%][b]
Trace
85
1
1
-
80
80
80
80
80
80
80
80
80
80
80
80
80
80
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
2
1
Fe(NO3)3·9H2O (5) MeCN
3
1
FeCl3 (5)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
81
4
1
Fe2(SO4)3 (5)
Cu(OAc)2 (5)
CuCl2 (5)
78
5
1
56
6
1
59
7
1
Cu(NO3)2 (5)
CuI (5)
62
8
1
71
9
1
CoCl2 (5)
48
10
11
12
13
14
1.2
1.5
0.8
1.5
1.5
Fe(NO3)3·9H2O (5) MeCN
Fe(NO3)3·9H2O (5) MeCN
Fe(NO3)3·9H2O (5) MeCN
Fe(NO3)3·9H2O (1) MeCN
88
93
74
76
Fe(NO3)3·9H2O
(10)
MeCN
92
11

15
16
17
18
19
20
21
1.5
1.5
1.5
1.5
1.5
1.5
1.5
Fe(NO3)3·9H2O (5) EtOH
Fe(NO3)3·9H2O (5) DMSO
80
80
Air
Air
Air
Air
Air
O2
87
62
Fe(NO3)3·9H2O (5) Toluene 80
80
Fe(NO3)3·9H2O (5) MeCN
Fe(NO3)3·9H2O (5) MeCN
Fe(NO3)3·9H2O (5) MeCN
Fe(NO3)3·9H2O (5) MeCN
50
RT
80
80
55
Trace
93
N2
10
[a] Reaction conditions: A mixture of diamine and N-benzylidenebenzylamine, catalyst, 5
ml solvent were mixed in a 10 ml three-necked flask, and then stirred rapidiy for 10 hours.
The reaction progress was monitored by TLC.
[b] Isolated yield.
12

Table 2. Synthesis of 2-substituted benzimidazoles from Homo-coupled imines and
diamines.[a]
Entr Diamine
Imine
Product
Yield
(%)[b]
93
y
1
2
90
3
4
5
6
95
95
82
85
7
80
13

8
73
79
9
10
65
[a] Reaction conditions: 1.5 mmol o-phenylenediamine and 1 mmol imine, 5 mol%
Fe(NO3)3·9H2O, and 5 ml MeCN were mixed in a 10 ml three-necked flask, and then
stirred rapidiy in the open air for 12 hours. The reaction progress was monitored by
TLC.
[b] Isolated yield.
14

Table 3. Synthesis of 2-substituted benzimidazoles from Hetero-coupled imines and
diamines.[a]
Entr
y
Diamine
Imine
Product
Yield[b
] (%)
1 a
88
83
79
b
c
2
3
4
87
89
89
15

5
6
82
75
7
79
8
9
91
75
81
10
11
78
16

12
13
86
77
14
15
84
83
16
17
79
65
18
19
73
59
17

[a] Reaction conditions: 1.5 mmol o-phenylenediamine and 1 mmol imine, 5 mol%
Fe(NO3)3·9H2O, 5 ml MeCN were mixed in a 10 ml three-necked flask, and then
stirred rapidiy in the open air for 12 hours. The reaction progress was monitored by
TLC.
[b] Isolated yield.
18

Scheme 1. Methods for the preparing the benzimidazoles.
19