Iron-catalyzed one-pot synthesis of benzimidazoles from 2-nitroanilines and benzylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2013.10.045

The iron-catalyzed heterocyclizations from 2-nitroanilines and benzylic alcohols to form benzimidazoles using hydrogen transfer reaction were investigated in this study. In the presence of dppf in toluene at 150 °C, various benzimidazoles were obtained in moderate to good yields within 24 h. The reaction was proposed to proceed via a cascade of alcohol oxidation, nitro reduction, condensation, and dehydrogenation.

Full text of DOI:10.1016/j.tetlet.2013.10.045

Accepted Manuscript
Iron-catalyzed one-pot synthesis of benzimidazoles from 2-nitroanilines and
benzylic alcohols
Gang Li, Jin Wang, Baokun Yuan, Dongfeng Zhang, Ziyun Lin, Peng Li,
Haihong Huang
PII:
S0040-4039(13)01780-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.10.045
TETL 43683
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
7 June 2013
27 September 2013
10 October 2013
Please cite this article as: Li, G., Wang, J., Yuan, B., Zhang, D., Lin, Z., Li, P., Huang, H., Iron-catalyzed one-pot
synthesis of benzimidazoles from 2-nitroanilines and benzylic alcohols, Tetrahedron Letters (2013), doi: http://
dx.doi.org/10.1016/j.tetlet.2013.10.045
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Iron-catalyzed one-pot synthesis of benzimidazoles
from 2-nitroanilines and benzylic alcohols
Gang Li, Jin Wang, Baokun Yuan, Dongfeng Zhang, Ziyun Lin, Peng Li, Haihong Huang*
State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key
Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia
Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing
100050, P. R. China
We herein report a new efficient method for the synthesis of benzimidazoles with hydrogen
transfer procedure. This method involves alcohol oxidation, nitro reduction, condensation and
dehydrogenation in a cascade.
*Corresponding author. Tel.: +86 10 63165244; fax: +86 10 63165244; e-mail: joyce@imm.ac.cn

Iron-catalyzed one-pot synthesis of benzimidazoles
from 2-nitroanilines and benzylic alcohols
Gang Li, Jin Wang, Baokun Yuan, Dongfeng Zhang, Ziyun Lin, Peng Li, Haihong Huang*
State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key
Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia
Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing
100050, P. R. China
Abstract: The iron-catalyzed heterocyclizations from 2-nitroanilines and benzylic alcohols to
form benzimidazoles using hydrogen transfer reaction were investigated in this study. In the
presence of dppf in toluene at 150oC, various benzimidazoles were obtained in moderate to good
yields within 24 h. The reaction was proposed to proceed via a cascade of alcohol oxidation, nitro
reduction, condensation and dehydrogenation.
Key words: benzimidazole, hydrogen transfer, dppf, one-pot synthesis.
Benzimidazoles are present as useful building blocks for the development of molecules that
are important in medicinal chemistry. This moiety is frequently used as an important
pharmacophore in drug discovery. Substituted benzimidazoles have been extensively studied for
their antiviral, antifungal, antiulcer, antihypertensive, antihistaminic and anticancer activities.1
Thus, various synthetic methods have been developed to construct substituted benzimidazoles,
with the most common method being the heterocyclization of o-diaminoarenes with carboxylic
acids or their derivatives under acidic conditions and several other conditions.2
Recently the benzimidazole formation from o-diaminobenzene and benzylic alcohol under
oxidative conditions, using hydrogen transfer reaction has been developed.3 Inspired by this highly
atom economic method, we pay more attention to the application and mechanism of hydrogen
transfer reaction. Hydrogen transfer reaction was widely used for the oxidation of a range of
organic substrates. In particular, the oxidation of alcohols to carbonyl compounds by hydrogen
transfer to a suitable acceptor represents a useful alternative to other oxidation reactions.4 More

recently, using hydrogen transfer reaction, a simple and efficient iron-catalyzed one-pot synthesis
of benzoxazole has been reported.5 We believe that the same concept can be applied to the
synthesis of benzimidazoles as the reaction mechanism may be similar to that of the benzoxazole
formation reaction. Herein we report the development of one-pot synthesis of iron-catalyzed
heterocyclization toward benzimidazoles starting from 2-nitroanilines and benzylic alcohols.
First we screened various iron salts, temperature and solvent that might promote the
heterocyclization (Table 1).The results indicated that dppf [1,1’-bis(diphenylphosphino)-ferrocene]
was the most effective, and its use resulted in the formation of 3a in 74% yield (entry 4).6 The
choice of solvents was also crucial for the reaction. The use of xylene resulted much lower yield
and PEG400 gave no reaction. Toluene and benzylic alcohol were proved to be good solvents for
this reaction(entry 4, 6). Benzylic alcohol was not easy to remove so we chose toluene as the
reaction solvent. The reaction temperature plays a key role in this reaction. The reaction yield
decreased to 30% when the temperature was decreased from 150oC to 130oC. The reaction could
also be carried out at normal atmospheric pressure under argon with moderate yield (entry 7).
Encouraged by this promising result, the scope of the method for benzimidazole synthesis
was then investigated. To our delight, the substituted benzylic alcohol substrates 1a-m smoothly
underwent heterocyclization to afford benzimidazoles 3a-m in good yields. However, when allyl
alcohol 1n and ethanol 1o were used as substrates to react with 2-nitroaniline 2a under the
optimized conditions respectively, the reactions did not occur (Table 2). It was noticed that the
benzylic alcohol substrates with electron-donating groups and halogen substituents, such as 1b, 1c,
1d, 1f, 1k, 1l and 1m gave higher yields, while substrates bearing electron-withdrawing groups
such as 1i and 1j gave lower yields. Moreover, the coupling of hetero benzylic alcohols such as 1g,
1h and 1i with 2a afforded 3g, 3h and 3i, respectively, in moderate yields. In addition,
phenylallylic alcohol 1e reacted with 2a to smoothly afford 3e in 71% yield.
To further explore the scope of the reaction, various 2-nitroanilines with electron-donating
and electron-withdrawing substituent were employed to react with 1a under the optimized
conditions (Table 3). The desired products were obtained in moderate to good yields and a series
of functional groups including fluoro, chloro, bromo, trifluoromethyl and methoxy were well
tolerated under the optimal reaction conditions (entries 1-7). It was noticed that the 2-nitroanilines
with single halogen substituent, such as 2a, 2b and 2c gave higher yields, while 2-nitroanilines

with multiple halogen substituents, such as 2d and 2e gave moderate yields. Compounds with
electron-donating group (2g) and strong electron-withdrawing group (2f) gave lower yields under
optimized conditions.
In order to clarify the proposed reaction mechanism, three reactions in Scheme 1 were run
and it was found that the reaction hardly occurred before the first hydrogen transfer reaction of 1a
to A and 2a to B. So the first hydrogen transfer reaction was the rate-determining step of this
transformation. After the important step, the reaction smoothly proceeded to the desired product
3a. We also monitored the reaction at 2h, 6h, 12h and 24h. We can only observe the desired
product 3a and starting materials at these time points, without C and D in Scheme 1. The result
told us that when intermediate A and B were generated, the following condensation and
dehydrogenation were very fast.
A plausible mechanism based on our experiments and previous articles is proposed in
Scheme 2.3,5,7 Firstly, the benzylic alcohol 1a is oxidized to the corresponding aldehyde A and in
the meantime 2a is reduced to B by hydrogen transfer. Then aldehyde A is then condensed with B
to form C. Intramolecular cyclization of C generates dihydrobenzimidazole D. At last,
dehydrogenation of D affords the desired product 3a by a second hydrogen-transfer process. The
nitro group acts as a hydrogen acceptor twice in the whole process. Oxidation of 1a where
aromatization could act as a driving force for loss of hydrogen is crucial for this reaction. Most of
the benzylic alcohol substrates with electron-donating groups are easier to be oxidized and this
could be the possible reason why benzylic alcohol substrates with electron-donating groups gave
higher yields.
In conclusion, we have described a simple and efficient method for an iron-catalyzed reaction
to prepare benzimidazoles from 2-nitroanilines and benzylic alcohols by hydrogen transfer
reaction. This method involves alcohol oxidation, nitro reduction, condensation and
dehydrogenation in a cascade. This useful method could potentially be complementary to the
existing methods for the synthesis of benzimidazoles.
Acknowledgements
The authors are grateful to Fundamental Scientific Research Fund of Institute of Materia Medica
(No. 2013CHX07) for financial support.

References and notes
1.
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N.; Moore, A. L.; Larson, R. A.; Cerruti, N. R.; Amberg, S. M.; Bolken, T. C.; Hruby, D. E. Bioorg. Med.
Chem. Lett. 2013, 23, 744; (c) Bauer, J.; Kinast, S.; Burger-Kentischer, A.; Finkelmeier, D.; Kleymann, G.;
Rayyan, W. A.; Schröppel, K.; Singh, A.; Jung, G.; Wiesmüller, K.-H.; Rupp, S.; Eickhoff, H. J. Med. Chem.
2011, 54, 6993; (d) Yan, Y.; Liu, Z.; Zhang, J.; Xu, R.; Hu, X.; Liu, G. Bioorg. Med. Chem. Lett. 2011, 21,
4189; (e) Wang, J. L.; Zhang, J.; Zhou, Z. M.; Li, Z. H.; Xue, W. Z.; Xu, D.; Hao, L. P.; Han, X. F.; Fei, F.;
Liu, T.; Liang, A. H. Eur. J. Med. Chem. 2012, 49, 183; (f) Demirayak, S.; Kayagil, I.; Yurttas, L. Eur. J.
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2. (a) Bommegowda, Y. K.; Lingaraju, G. S.; Thamas, S.; Vinay Kumar, K. S.; Pradeepa Kumara, C. S.;
Rangappa, K. S.; Sadashiva, M. P. Tetrahedron Lett. 2013, 54, 2693; (b) Nguyen, T. B.; Ermolenko, L.; Dean,
W. A.; Al-Mourabit, A. Org. Lett. 2012, 14, 5948; (c) Adharvana Chari, M.; Shobha, D.; Sasaki, T.
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4. (a) Samec, J. S. M.; Backvall, J.-E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev. 2006, 35, 237; (b) Gladiali,
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with 2-nitroaniline (0.36 mmol), benzyl alcohol (0.094 mL, 0.90 mmol) and dppf (0.018 mmol). The tube was
flushed with argon for 10 min. Then the degassed toluene (3 mL) was added. The tube was flushed with argon,
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Table 1
Iron-catalyzed heterocyclization of 2-nitroaniline (1 equiv) with benzylic alcohol (2.5 equiv) under
different reaction conditions
Entry
Catalystc
Solvent
Yieldd(%)
Temperature(℃)
1a
2a
dppf
dppf
90
toluene
toluene
trace
trace
30
110
130
150
150
150
150
150
150
150
150
150
150
150
3a
dppf
toluene
4a
dppf
toluene
74
5a
dppf
xylene
36
6a
dppf
benzyl alcohol
benzyl alcohol
PEG400
toluene
78
7b
dppf
50
8a
dppf
NRe
trace
trace
trace
trace
NR
NR
9a
FeSO4
Fe(NO3)3
FeCl2
FeCl3
ferrocene
-
10a
11a
12a
13a
14a
toluene
toluene
toluene
toluene
toluene
a Reaction was run in a sealed tube under argon, 24h.
b Reaction was run at normal atmospheric pressure under argon, 24h.
c Using 5% of the catalyst.
d Isolated yields.
e No reaction.

Table 2
Iron-catalyzed heterocyclization of 2-nitroaniline (1 equiv) with substituted benzylic alcohol
substrates (2.5 equiv) in the presence of dppf (0.05 equiv) in toluene at 150oC
Entry
Alcohol
1a
Product
3a
Yielda(%)
1
74
2
81
1b
1c
1d
3b
3c
3d
3
4
70
78
5
6
71
66
1e
3e
3f
1f
7
8
63
55
1g
3g

1h
1i
3h
3i
9
45
46
88
75
68
10
11
12
13
1j
3j
3k
3l
1k
1l
1m
3m
14
15
-
NRb
NR
1n
1o
-
a Reaction was run in a sealed tube under argon for 24 h, isolated yields.
b No reaction.

Table 3
Iron-catalyzed heterocyclization of 2-nitroanilines (1 equiv) with benzylic alcohol (2.5 equiv) in
the presence of dppf (0.05 equiv) in toluene at 150oC
Entry
Nitroaniline
Product
3n
Yielda(%)
1
73
2a
2b
2c
2d
2
3
4
70
73
62
3o
3p
3q
5
56
2e
2f
3r
3s
3t
6
7
53
40
2g
a Reaction was run in a sealed tube under argon for 24 h, isolated yields.

Scheme 1. Exploration of the mechanism

Scheme 2. Proposed mechanism for benzimidazole synthesis

Iron-catalyzed one-pot synthesis of benzimidazoles
from 2-nitroanilines and benzylic alcohols
Gang Li, Jin Wang, Baokun Yuan, Dongfeng Zhang, Ziyun Lin, Peng Li, Haihong Huang*
State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key
Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia
Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing
100050, P. R. China
We herein report a new efficient method for the synthesis of benzimidazoles with hydrogen
transfer procedure. This method involves alcohol oxidation, nitro reduction, condensation and
dehydrogenation in a cascade.
*Corresponding author. Tel.: +86 10 63165244; fax: +86 10 63165244; e-mail: joyce@imm.ac.cn