Aerobic photooxidative synthesis of benzimidazoles from aromatic aldehydes and diamines using catalytic amounts of magnesium iodide

Article abstract of DOI:10.1016/j.tetlet.2014.10.001

This Letter proposes a safe, mild, and environmentally benign method for the synthesis of benzimidazoles from aromatic aldehydes and diamines by aerobic photooxidation using irradiation with visible light, a catalytic amount of magnesium iodide, which serves as both a Lewis acid and an oxidant, and molecular oxygen as the terminal oxidant.

Full text of DOI:10.1016/j.tetlet.2014.10.001

Accepted Manuscript
Aerobic photooxidative synthesis of benzimidazoles from aromatic aldehydes
and diamines using catalytic amounts of magnesium iodide
Yoshitomo Nagasawa, Yoko Matsusaki, Toshiyuki Hotta, Tomoya Nobuta,
Norihiro Tada, Tsuyoshi Miura, Akichika Itoh
PII:
S0040-4039(14)01672-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.001
TETL 45230
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 July 2014
25 September 2014
1 October 2014
Please cite this article as: Nagasawa, Y., Matsusaki, Y., Hotta, T., Nobuta, T., Tada, N., Miura, T., Itoh, A., Aerobic
photooxidative synthesis of benzimidazoles from aromatic aldehydes and diamines using catalytic amounts of
magnesium iodide, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.10.001
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Aerobic photooxidative synthesis of
benzimidazoles from aromatic aldehydes and
diamines using catalytic amounts of
magnesium iodide
Leave this area blank for abstract info.
Yoshitomo Nagasawa, Yoko Matsusaki, Toshiyuki Hotta, Tomoya Nobuta, Norihiro Tada, Tsuyoshi Miura,
Akichika Itoh*

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Aerobic photooxidative synthesis of benzimidazoles from aromatic aldehydes
and diamines using catalytic amounts of magnesium iodide
Yoshitomo Nagasawa,a Yoko Matsusaki,a Toshiyuki Hotta,a Tomoya Nobuta,a Norihiro Tada,a Tsuyoshi
Miura,b Akichika Itoh*a
a
Gifu Pharmaceutical University 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
b
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
This paper proposes a safe, mild, and environmentally benign method for the synthesis of
benzimidazoles from aromatic aldehydes and diamines by aerobic photooxidation using
irradiation with visible light, a catalytic amount of magnesium iodide, which serves as both a
Lewis acid and an oxidant, and molecular oxygen as the terminal oxidant.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Aerobic
Benzimidazole
Magnesium iodide
Photooxidation
Visible light
applied to synthesis of benzimidazoles from diamine and
aldehyde.14 To the best of our knowledge, however, synthesis of
benzimidazoles from aldehydes and diamines using catalytic
amounts of iodine sources and molecular oxygen as terminal
oxidant has not been reported to date.
Benzimidazoles are one of the significant organic chemical
structures in medicinal and industrial chemistry. In particular,
they are potential PPI drugs,1 hypotensive drugs,2 anti-HIV
drugs,3 and molecular target drugs.4 Thus, benzimidazoles are
considered to be promising in drug discovery. Therefore, the
development of efficient methods for the synthesis of
benzimidazoles is an important research area. Numerous methods
have been reported for the construction of benzimidazoles on the
basis of condensation reactions between aldehydes and diamines
followed by oxidation of the aminal intermediates.5 However,
these methods usually require the use of stoichiometric amounts
We have been developed various oxidation methods that
involve the use of catalytic amounts of iodine sources and
molecular oxygen, which has received considerable attention as
an ideal oxidant because it is photosynthesized by plants,
produces little waste, is inexpensive, and exhibits greater atom
efficiency than other oxidants when used as a terminal oxidant
under visible light irradiation.15 Furthermore, molecular iodine
has served various functions in organic synthesis, including those
of an oxidant and a Lewis acid.16 Thus, we propose a one-pot and
metal-free synthetic protocol for the preparation of
acetophenones from styrenes using molecular iodine, which
serves as an oxidant in the aerobic photooxidation step and a
Lewis acid in the deiodination step.17 Furthermore, one-pot
synthesis of bis-indolylmethane from benzyl alcohol and indoles
was also performed using a catalytic amount of iodine, which
catalyzes the aerobic photooxidation of benzyl alcohol and the
condensation step between an indole and benzaldehyde.18 From
the perspective of green chemistry, the reagent used in the
upstream reaction of a multistep synthesis should be recycled to
catalyze the downstream reaction.19
6
of oxidants such as PhI(OAc)2 and iodine7 or transition-metal
5
8
catalysts such as Co(OH)2 and Sc(OTf)2 using molecular
oxygen as terminal oxidant. Furthermore, metal free reaction
have been reported including sulfamic acid/air,9 KHF2/O2,10 and
air.11 However, these methods have some problems such as low
yield, glass corrosion, and high temperature.
The catalytic amounts of iodine-source-catalyzed C–H
oxidation with stoichiometric amounts of various oxidants has
attracted great interest because iodine sources tend to exhibit low
toxicity and are inexpensive compared with transition-metal
catalysts. For example, Ishihara et al.12 and others13 have reported
novel C–H oxidation reactions using a catalytic amount of
quaternary ammonium iodide with aq H2O2 or tert-butyl
hydroperoxide as terminal oxidants, which generate only water or
tert-butanol waste products. This mild C–H oxidation can
produce C–O bonds, C–N bonds, or both. Recently, combination
of tetrabutylammonium iodide and hydrogen peroxide was
Given this background, we hypothesized that the successive
iodine-catalyzed cyclization of aldehyde with diamine and the
subsequent oxidation of the aminal intermediate would enable the
synthesis of N-heteroaromatics (Scheme 1). Herein, we describe
an aerobic photooxidative synthesis of benzimidazoles from

2
Tetrahedron
aromatic aldehydes and aromatic diamines using a catalytic
amount of magnesium iodide as both a Lewis acid and an oxidant
(Scheme 2).
18e
MgI2
EtOAc
36
6
a
The reaction conditions: 1a (0.15 mmol) and 2a (1.0 equiv) in
solvent (3 mL) was stirred under argon atmosphere for 30 min.
Then it was added iodine source (0.05 equiv) in solvent (2 mL)
and was stirred and irradiated with a fluorescent lamp under O2
atmosphere for 6 h.
b 1H NMR yields. Numbers in parentheses are isolated yields.
c Reaction was conducted under air.
d Reaction was conducted in the dark.
e Reaction was conducted under argon.
First, we optimized the reaction conditions for the synthesis of
benzimidazole 3aa, as shown in Table 1. The reaction conditions
for the photooxidative cyclization were optimized with 1,2-
phenylenediamine (1a) and benzaldehyde (2a) in the presence of
a catalytic amount of an iodine source under an oxygen
Table 2 shows the scope and limitations of benzimidazole
synthesis from several aromatic diamines and aromatic
aldehydes. Most of the reactions of 1,2-phenylenediamines and
aromatic aldehydes resulted in good-to-high yields, irrespective
of whether an electron-withdrawing or an electron-donating
group was present (entries 1–16).21 4-nitro-1,2-phenylenediamine
(1f) afforded 3fa in moderate yield when 0.2 equivalents of I2
was used for 20 h because of the weak nucleophilicity of 1f
(entry 17). Unfortunately, aliphatic aldehyde, propanal, and
diamine, ethylene diamine, were poor substrates, probably
because the oxidation step is slow. Notably, this reaction also
produced 2-phenyl benzothiazole (3ga) in high yield when 2-
aminobenzenethiol (1g) was used (Scheme 3). This result
suggests that this aerobic reaction condition is suitable for the
synthesis of sulfur containing heterocycles.14 On the other hand,
we have already reported the aerobic photooxidation of benzyl
alcohols to benzaldehydes using molecular iodine.15g Thus, we
attempted the one-pot synthesis of benzimidazole from benzyl
alcohol and obtained 3aa in 93% yield (Scheme 4).
atmosphere and under irradiation by
a general-purpose
fluorescent lamp. In this reaction, EtOAc was the most effective
solvent, and MgI2 was the most suitable reagent, which afforded
3aa in 93% isolated yield with side-product 4aa in only 2% yield
(entries 1–14). Interestingly, this reaction also proceeded under
an air atmosphere instead of O2 (entry 15). Notably, magnesium
iodide, visible-light irradiation, and molecular oxygen are
necessary for this reaction because 3aa was not obtained or was
obtained in low yields in the absence of one or more of these
ingredients (entries 16–18).20
Entry
Iodine source
Solvent
Yield (%)b
3aa
(93)
(86)
84
4aa
2
Entry
1
R
R’
Product Yield (%)b
1
MgI2
MgI2
MgI2
MgI2
MgI2
MgI2
MgI2
MgI2
I2
EtOAc
MeCN
PhMe
H
H
93
91
80
68
97
79c
77
80
77
71
87
71
90
75
86
89
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a 3aa
2b 3ab
2c 3ac
2d 3ad
2e 3ae
2f 3af
2g 3ag
2h 3ah
2i 3ai
2j 3aj
2k 3ak
2l 3al
2a 3ba
2a 3ca
2a 3da
2a 3ea
2
trace
trace
4
2
H
3-Me
4-Me
4-tBu
4-Cl
3
3
H
4
MeOH
CHCl3
Hexane
DMF
72
4
H
5
70
3
5
H
6
40
trace
trace
0
6
H
4-OH
4-OMe
4-CF3
4-CN
7
9
7
H
8
THF
trace
86
8
H
9
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
2
9
H
10
11
12
13
14
15c
16
17d
CaI2
CI4
79
trace
7
10
11
12
13
14
15
16
H
1a 4-NO2
85
H
3-Me
1a
1a
1b
1c
1d
1e
LiI
33
8
H
3-OMe
NaI
NIS
MgI2
-
8
trace
25
3-Me
4-Me
4-Br
4-OMe
H
H
H
H
49
81
trace
0
0
MgI2
29
7

3
17d
4-NO2
1f
H
2a 3fa
57
O , (VIS)
h
2
O , (VIS)
h
2
I2
MgI2
2HI
a
The reaction conditions: 1 (0.15 mmol) and 2 (1.0 equiv) in
EtOAc (3 mL) was stirred under argon atmosphere for 30 min.
Then it was added MgI2 (0.05 equiv) in EtOAc (2 mL) and was
stirred and irradiated with fluorescent lamp under O2 atmosphere
for 6 h.
I
I
I
I
O
H
N
N
Ph
NH2
I2
HI
H
Ph
H
Ph
N
H
7
NH2
NH2
b Isolated yields.
1
6
N
c 1H NMR yield. The isolated product was 31.3 mg (3ae : 4ae : 1a
= 200 : 7 : 10).
Ph
N
H
d I2 (0.2 equiv) was used for 20 h.
3
I
I
O
H
N
H
6
+
7
N
Ph
Ph
Ph
H
Ph
N
NH2
8
+
3
H
N
I2
N
N
H
Ph
Ph
Ph
N
HI
Ph
4
Scheme 6. Plausible reaction mechanism
To clarify the reaction mechanism, several control
experiments were performed. When 1 equivalent of magnesium
iodide was used in the absence of both molecular oxygen and
visible light, 3aa was obtained in low yield (Scheme 5, equation
1). In contrast, when 1 equivalent of molecular iodine was used,
3aa was obtained in good yield (Scheme 5, equation 1). These
results suggest that molecular iodine works well as a Lewis acid
and that oxidation of aminal intermediate 7 proceeds in the
absence of photo irradiation. Notably, this reaction was not
suppressed in the presence of 1 equivalent of BHT, and 3aa was
obtained in good yield (Scheme 5, equation 2), which indicates
that the reaction probably does not proceed through a radical
pathway
In conclusion, in this study, we developed a method for the
environmentally benign synthesis of benzimidazoles with a
catalytic amount of an iodine source under photooxidative
conditions. Furthermore, benzothiazole was obtained in high
yield. The one-pot synthesis of benzimidazole from benzyl
alcohol was also successful. This method is interesting from the
viewpoint of green chemistry because it involves the use of
molecular oxygen and visible-light irradiation. Further
applications of this approach are under investigation in our
laboratory.
Acknowledgments
This work was supported by Grant-in-Aid for Young
Scientists (B)(No. 24790015) from the Japan Society for the
Promotion of Science (JSPS).
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yield without further optimization.
21. Typical procedure: A Typical example of the synthesis of
benzimidazole (Table 2, entry1). A solution of 1,2-
benzenediamine (1a, 0.15 mmol) and benzaldehyde (2a, 0.15
mmol) in dry EtOAc (3 mL) in a Pyrex test tube was stirred under
an argon atmosphere for 30 min. Then magnesium iodide (0.0075
mmol) in dry EtOAc (2 mL) was added, and stirred and irradiated
externally with a fluorescent lamp for 6 h with an O2 balloon. The
reaction mixture was concentrated under reduced pressure, and
purification of the crude product by PTLC (CHCl3 : MeOH= 98 :
2) provided benzimidazole (3aa) (Rf = 0.6, 27.1 mg, 93%).
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