Oxidative coupling of o -phenylenediamine with arylmethylamines to synthesize aryl-substituted benzimidazoles under catalyst-free and solvent-free conditions

Article abstract of DOI:10.1080/00397911.2014.908310

GRAPHICAL ABSTRACT Solvent-free oxidative synthesis of benzimidazoles from arylmethylamines and o-phenylenediamine has been achieved under catalyst-free conditions. This reaction can use tert-butyl hydroperoxide (TBHP) as the oxidant, and a wide variety of derivatives were obtained in good yields. The reaction mechanism was proposed and this method provides a direct and practical approach for the preparation of substituted benzimidazoles.

Full text of DOI:10.1080/00397911.2014.908310

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Oxidative Coupling of o-
Phenylenediamine with
Arylmethylamines to Synthesize
Aryl-Substituted Benzimidazoles
Under Catalyst-Free and Solvent-Free
Conditions
Jiatao Yu a & Ming Lu a
a Chemical Engineering College , Nanjing University of Science and
Technology , Nanjing , China
Accepted author version posted online: 07 May 2014.Published
online: 01 Jul 2014.
To cite this article: Jiatao Yu & Ming Lu (2014) Oxidative Coupling of o-Phenylenediamine with
Arylmethylamines to Synthesize Aryl-Substituted Benzimidazoles Under Catalyst-Free and Solvent-
Free Conditions, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 44:17, 2520-2528, DOI: 10.1080/00397911.2014.908310
To link to this article: http://dx.doi.org/10.1080/00397911.2014.908310
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Synthetic Communications1, 44: 2520–2528, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.908310
OXIDATIVE COUPLING OF O-PHENYLENEDIAMINE
WITH ARYLMETHYLAMINES TO SYNTHESIZE
ARYL-SUBSTITUTED BENZIMIDAZOLES UNDER
CATALYST-FREE AND SOLVENT-FREE CONDITIONS
Jiatao Yu and Ming Lu
Chemical Engineering College, Nanjing University of Science and
Technology, Nanjing, China
GRAPHICAL ABSTRACT
Abstract Solvent-free oxidative synthesis of benzimidazoles from arylmethylamines and
o-phenylenediamine has been achieved under catalyst-free conditions. This reaction can
use tert-butyl hydroperoxide (TBHP) as the oxidant, and a wide variety of derivatives were
obtained in good yields. The reaction mechanism was proposed and this method provides
a direct and practical approach for the preparation of substituted benzimidazoles.
Keywords Benzimidazoles; catalyst-free; oxidation; solvent-free; TBHP
INTRODUCTION
Aryl-substituted benzimidazoles and their derivatives are important structural
motifs found in natural and synthetic compounds and exhibit significant pharmaco-
logical and biological activities, such as anticonvulsant, anticancer, antiulcer, antihy-
pertensive, antibacterial, and antihistaminic properties.[1–5] In addition, they are
important intermediates in organic reactions.[6] Consequently, great efforts have
been made to develop efficient methods for the preparation of benzimidazoles. There
are two general methods for the synthesis of benzimidazoles. One is the treatment of
o-phenylenediamine with carboxylic acids or their derivatives under harsh dehydrat-
ing conditions, such as strongly acidic and high-temperature conditions.[7–11] The
other is the conventional method involves a two-step procedure that includes the oxi-
dative cyclo-dehydrogenation of aniline Schiff bases, which are often generated in
situ from the condensation of o-phenylenediamine and aldehydes, followed by
Received January 22, 2014.
Address correspondence to Ming Lu, Chemical Engineering College, Nanjing University of Science
and Technology, Nanjing, China. E-mail: luming302@126.com
2520

SYNTHESIS OF BENZIMIDAZOLES FROM ARYLMETHYLAMINES
2521
oxidation with stoichiometric oxidants.[12–18] However, this method has some draw-
backs such as requiring a stoichiometric amount of oxidant, generating environmen-
tally hazardous or toxic by-products, and using malodorous and unstable aldehydes.
Recently, oxidative reactions using oxygen as the ultimate oxidant have attracted
much more attention from the synthetic community.[19] The reason is that the practical
reactions use oxygen as an economical and green oxidant and produce water as the
only by-product. In this regard, several examples of the synthesis of benzimidazoles
via aerobic oxidations have been reported with catalytic amounts of TEMPO,[20]
Au=CeO2, Pd=MgO, Pd=C,[21] and activated carbon.[22] However, in most cases, the
relative reactions generally required expensive and rare noble metal catalysts, high
catalyst loadings, long reaction times, or dangerous solvents. Therefore, development
of new methods for the construction of benzimidazoles is highly desirable.
Sustainable development has been accepted as common knowledge in current
society. For the development of green organic chemistry reactions, solvent-free
medium is one of the most main targets.[23] In 2013, researchers reported a mild
and efficient method for oxidation of benzylalcohols to primary amides under
catalyst-free condition by using tert-butyl hydroperoxide (TBHP) as the oxidant.
This methodology was conducted under metal-free conditions.[24]
Encouraged by this reported literature, we tried to extend this method to the
synthesis of five-membered heterocyclic rings, such as benzimidazoles. Herein, we
report a simple but efficient method for the synthesis of benzimidazoles directly from
o-phenylenediamine and arylmethylamines under catalyst-free and solvent-free
conditions. This reaction can use TBHP as the oxidant and achieves a wide range
of substrates in good yields.
RESULTS AND DISCUSSION
Initially, the reaction of o-phenylenediamine with benzylamine was selected as
a model reaction. The desired product could be formed by the use of 4 equivalents
TBHP as oxidant and toluene as solvent at 100 ꢀC (Table 1, entry 1). Encouraged by
this result, we investigated the reaction conditions in detail, and the results are sum-
marized in Table 1. Solvent screening experiments demonstrated that the effect of
solvent was crucial; when organic solvent was used in the reaction, the yield of the
desired product resulted in poor yields. If the reaction was conducted under
solvent-free conditions, to our delight, the yield of the desired product 2-phenyl-1H-
benzimidazoles was improved significantly, leading to 73% yield (entries 1–4).
Subsequent reaction temperature screening revealed that when the temperature
was reduced, the yield of the product was decreased, and we found a temperature
of 100 ꢀC was beneficial (entries 4–7). After extensive screening of the loadings of
TBHP, we were delight to find that 4 equivalents was most effective for this reaction.
In the absence of TBHP, the yield of the desired product was only 7% after 12 h
(entries 4 and 8–11). Further optimization by screening the loading of benzylamine
revealed that 1.5 equivalents was the most appropriate proportion and gave
a satisfactory result (entries 4 and 12–15). Finally, the effect of the reaction time
was also tested, and it was suggested that the greatest yield was obtained in 6 h.
When prolonging the reaction time, the yield of the desired product showed a little
decrease (entries 14 and 16–18).

2522
J. YU AND M. LU
Table 1. Screening of the reaction conditionsa
Benzylamine
(equiv.)
TBHP
(equiv.)
Reaction
time (h)
Entry
Solvent
Temp. (ꢀC)
Yield (%)b
1
2
1
1
4
4
4
4
4
4
4
0
2
6
8
4
4
4
4
4
4
4
Toluene
EtOH
EtOAc
—
100
100
100
100
80
6
6
23
27
25
73
66
27
18
7
3
1
6
4
1
6
5
1
—
—
6
6
1
60
40
6
7
1
—
—
6
8
1
100
100
100
100
100
100
100
100
100
100
100
12
6
9
1
—
—
64
65
58
51
55
82
48
61
75
69
10
11
12
13
14
15
16
17
18
1
6
1
—
—
6
0.8
1.2
1.5
2
6
—
—
6
6
—
—
6
1.5
1.5
1.5
4
—
—
8
10
aReaction conditions: A mixture of o-phenylenediamine, benzylamine, and TBHP (70% in H2O) was
mixed in a three-necked flask, and then stirred rapidly for several hours. The reaction progress was mon-
itored by TLC.
bIsolated yield.
Under the optimized conditions, a variety of substituted arylmethylamines and
o-phenylenediamine were investigated to explore the scope and generality of the pro-
cess. As shown in Table 2, a range of benzylamines bearing electron-rich, -neutral,
and -deficient substituents at the para position of the benzylamine also proceeded
efficiently with good yields. However, when the same functional groups were in
the ortho position, the yields were less than their para-substituted counterparts, prob-
ably due to the increased steric hindrance (entries c and d). The presence of strong
electron-donating substituent on the benzylamine led to significant reduction in pro-
duct yield (entries 7–9). In contrast, benzylamine bearing electron-deficient substitu-
ent at the para-position gave greater yields (entry f). The reason may be that the
strong electron-withdrawing groups (NO2) enhanced the reaction rate due to the
increase in electrophilicity of the carbonyl carbon. 1-Naphthalenemethylamine was
tested in the reaction and the yield was also very good (entry k). However, when
3-phenyl-2-propylene amine was conducted in the reaction, the yield was less than
other aromatic amines (entry l). Moreover, heteroaromatic amines were also tested
in this reaction system, and the yields were moderate (entries m–o). In addition,
4-nitro-o-phenylenediamine and 4-chloro-o-phenylenediamine was also employed in
the reaction, we found that 4-chloro-o-phenylenediamine showed greater reactivities

SYNTHESIS OF BENZIMIDAZOLES FROM ARYLMETHYLAMINES
2523
Table 2. Synthesis of 2-substituted benzimidazoles from aromatic amines and diaminesa
Entry
a
Diamine
Amine
Product
Time (h) Yield (%)b
6
6
6
82
85
84
b
c
d
7
79
e
f
7
5
80
86
g
h
i
8
8
8
77
76
79
j
8
9
80
k
83
(Continued )

2524
J. YU AND M. LU
Table 2. Continued
Entry
Diamine
Amine
Product
Time (h) Yield (%)b
l
12
42
m
10
10
10
10
65
71
68
73
n
o
p
q
5
84
r
s
12
12
25
34
aReaction conditions: A mixture of 1 mmol diamine, 1.5 mmol aromatic amine, and 4 mmol TBHP (70%
in H2O) was mixed in a three-necked flask, and then stirred rapidiy at 100 ꢀC for several hours. The reac-
tion progress was monitored by TLC.
bIsolated yield.
than o-phenylenediamine. However, 4-nitro-o-phenylenediamine showed lower
reactivities (entries 1, p and q). Furthermore, we also expanded the system to the
synthesis of 2-phenyl-benzoxazole and 2-phenyl-benzothiazole using o-aminophenol
and o-aminothiophenol respectively with benzylamine as the starting materials.
Unfortunately, the results were obtained in 25% and 34% yields, respectively (entries
r and s).
Preliminary mechanistic studies of the reaction were also conducted. First,
we turn our attention to the reaction of benzylamine and aniline to synthesize
the cross imines as shown in Scheme 1. When the reaction between benzylamine
and aniline was conducted using 4 equiv. TBHP at 100 ꢀC under solvent-free
conditions for 4 h, to our delight, we found that the imine was isolated in
91% yield.
Encouraged by this result, we speculated, in the imine formation step, o-phe-
nylenediamine with benzylamine took place to form imine 3, and then the imine

SYNTHESIS OF BENZIMIDAZOLES FROM ARYLMETHYLAMINES
2525
Scheme 1. Reaction of benzylamine and aniline to synthesize the cross imines.
further reacted with another amine group of o-phenylenediamine to form
benzimidazoline 4. In the cyclo-dehydrogenation of benzimidazoline step, as
shown in Scheme 2, we took the benzimidazoline with 2 equiv. TBHP at 100 ꢀC
under solvent-free conditions and we were delighted to find that 2-phenyl-
benzimidazole was resulted in 93% yield. Moreover, several metal salts [ZnCl2,
ZnBr2, FeCl3, and CuBr] were tested as an additional catalyst for the oxidative
coulping of benzylamine and o-phenylenediamine, but the yield of benzimidazole
was decreased.
Based on these results and the literature reports about the aerobic oxidation of
primary amines to imines,[25–27] a plausible reaction pathway for the formation of
benzimidazole is shown in Scheme 3. First, the oxidative synthesis of benzimidazo-
line proceeds via the coupling of o-phenylenediamine with benzylamine to form
imine, which then is transformed to the intermediary benzimidazoline. Finally, the
oxidative cyclo-dehydrogenation of benzimidazoline afforded the product benzimi-
dazole. The whole process was oxidized by TBHP.
In conclusion, we have developed a simple and efficient protocol for oxidat-
ive coupling of arylmethylamines and o-phenylenediamine using TBHP as the
oxidant under catalyst-free and solvent-free conditions at 100 ꢀC, and the desired
2-substituted benzimidazoles were obtained in good yields. This simple oxidant
system uses TBHP as the oxidant and tolerates a wide range of substrates in good
yields. This is a practical procedure for benzimidazole synthesis, which may find
a wide range of applications in green oxidation chemistry. The extension of this
catalytic system for the preparation of other heterocycles is under way in the
laboratory.
Scheme 2. Formation of benzimidazoline and oxidation to benzimidazole.

2526
J. YU AND M. LU
Scheme 3. Proposed reaction mechanism.
EXPERIMENTAL
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
1
by 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 chroma-
tography (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 chromato-
graphy (300 mesh). The spectras were in supporting information.
A mixture of 1.5 mmol aromatic amines, 1 mmol o-phenylenediamine, and
4 mmol TBHP were prepared in a 10-ml, three-necked flask, stirred at 100 ꢀC for
several hours, and the reaction progress was monitored by TLC. After completion
of the reaction, the reaction mixture was cooled to room temperature. The pure
product was isolated after a simple filtration. When necessary, the crude product
was purified by chromatography using hexane=ethyl acetate (7:3) as eluent.

SYNTHESIS OF BENZIMIDAZOLES FROM ARYLMETHYLAMINES
2527
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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