An efficient route for the synthesis of benzimidazoles via a hydrogen-transfer strategy between o-nitroanilines and alcohols

Article abstract of DOI:10.1016/j.tetlet.2016.09.018

[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) has been used as an efficient catalyst for the synthesis of 2-substituted benzimidazoles via a hydrogen-transfer strategy. Various 2-substituted benzimidazoles were synthesized in good to excellent yields (up to 97%). The reaction shows good functional group tolerance. And no additional additive, oxidant, or reductant was required for the reaction.

Full text of DOI:10.1016/j.tetlet.2016.09.018

Tetrahedron Letters 57 (2016) 4645–4649
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Tetrahedron Letters
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An efficient route for the synthesis of benzimidazoles via a hydrogen-
transfer strategy between o-nitroanilines and alcohols
Xiaotong Li a, Renhe Hu a, Yao Tong a, Qiang Pan a, Dazhuang Miao a, Shiqing Han a,b,
⇑
a College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, CAS, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
[1,10-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) has been used as an efficient catalyst for
the synthesis of 2-substituted benzimidazoles via a hydrogen-transfer strategy. Various 2-substituted
benzimidazoles were synthesized in good to excellent yields (up to 97%). The reaction shows good func-
tional group tolerance. And no additional additive, oxidant, or reductant was required for the reaction.
Ó 2016 Elsevier Ltd. All rights reserved.
Article history:
Received 21 August 2016
Revised 2 September 2016
Accepted 6 September 2016
Available online 8 September 2016
Keywords:
Benzimidazoles
o-Nitroanilines
Benzyl alcohols
Hydrogen-transfer strategy
Being important kind of benzazoles, benzimidazole derivatives
can be used as building blocks of pharmaceuticals and agrochem-
icals due to their high biological activities and low toxicity.1 What’s
more, benzimidazoles are vital intermediates in different organic
reactions.2 As a result, there are various efforts aiming at develop-
ing efficient and mild methods for the synthesis of benzimidazoles.
Traditional methods typically involve the coupling of o-phenylene-
diamines with carboxylic acids or the condensation of
o-phenylenediamines with aldehydes.3 However, these methods
are associated with several limitations such as usage of stoichiom-
etry of acid, base, or oxidant, generation of several side products, or
unsatisfactory yields.
Recently, numerous catalytic systems for direct C–N bond for-
mation using the hydrogen-transfer strategy (or borrowing hydro-
gen methodology) have been developed.4 The strategy is regarded
as one of the most efficient method for the synthesis of benzazole
compounds. And using alcohols as reducing partners has attracted
much attention because of their availability and low prices.5
Indeed, alcohols have been used in redox condensations with
o-nitrophenols,6 o-nitrobenzamides,7 and o-nitroanilines8 leading
to the corresponding products. As for catalysts, several transi-
tion-metal catalysts such as gold,6b dppf,8b palladium,8c or
ruthenium9 were successfully used in this kind of reaction. Blacker
et al. developed a ruthenium-catalyzed of alcohols into benzimida-
zoles using crotononitrile as a hydride acceptor (Scheme 1, Eq. a).4a
Huang group reported a dppf-catalyzed heterocyclizations from
o-nitroanilines and benzyl alcohols to form benzimidazoles
(Scheme 1, Eq. b).8b However, the yields of these approaches are
not satisfactory and most of the reactions give the corresponding
product in moderate yields. Hence, finding a more efficient
catalyst for this kind of reaction would be highly desirable.
Recently, the formation of benzimidazoles from o-nitroanilines
and benzylic alcohols using Fe/S catalyst has been reported and the
Previous reports:
Ru(PPh3)3(CO)H2
C5H10NH.HOAc
Xantphox
NH2
NH2
N
OH
OH
OH
a
crotononitrile
ref 4a
N
H
72%
NH2
NO2
dppf
Toluene
Argon
ref 8b
N
b
c
N
H
74%
NH2
NO2
N
FeCl3•6H2O
N
Na2S•nH2O
ref 5
H
90%
Our work:
NH2
N
OH
d
Pd(dppf)Cl2
N
H
NO2
⇑
Corresponding author. Tel.: +86 25 58139970; fax: +86 25 58139369.
E-mail address: hanshiqing@njtech.edu.cn (S. Han).
Scheme 1. Different routes for the synthesis of benzimidazoles.
http://dx.doi.org/10.1016/j.tetlet.2016.09.018
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

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X. Li et al. / Tetrahedron Letters 57 (2016) 4645–4649
Table 1
Reaction conditions optimizationa
Entry
Catalyst (mol %)
Temperature (°C)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Fe2O3 (5)
FeCl2 (5)
Pd(OAc)2 (5)
PdCl2 (5)
dppf (5)
Pd(dppf)Cl2 (5)
Pd(dppf)Cl2 (5)
Pd(dppf)Cl2 (5)
Pd(dppf)Cl2 (5)
Pd(dppf)Cl2 (5)
Pd(dppf)Cl2 (5)
Pd(dppf)Cl2 (5)
Pd(dppf)Cl2 (3)
Pd(dppf)Cl2 (5)
Pd(dppf)Cl2 (5)
150
150
150
150
150
150
160
170
160
160
160
160
160
160
160
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
0
21
Trace
28
60
82
88
86
46
28
97
92
79
89
97
9
DMF
10
11
12
13c
14d
15e
Dioxane
Toluene
Benzyl alcohol
Toluene
Toluene
Toluene
a
Reaction conditions: benzyl alcohol (0.9 mmol), o-nitroaniline (0.3 mmol), catalysts (0.015 mmol), solvent (1 mL), at 150–170 °C for 24 h in a sealed tube under nitrogen
atmosphere.
b
c
Isolated yields.
Catalysts (0.009 mmol).
Benzyl alcohol (0.6 mmol).
Benzyl alcohol (1.2 mmol).
d
e
Table 2
Synthesis of benzimidazoles from benzyl alcohols and o-nitroanilinea
Entry
1
Benzyl alcohol
Product
Yieldb (%)
97
2
3
96
81
4
5
97
96
6
7
8
9
78
92
85
80

X. Li et al. / Tetrahedron Letters 57 (2016) 4645–4649
4647
Table 2 (continued)
Entry
Benzyl alcohol
Product
Yieldb (%)
10
82
11
12
79
74
76
13
a
Reaction conditions: benzyl alcohols (0.9 mmol), o-nitroaniline (0.3 mmol), Pd(dppf)Cl2 (0.015 mmol), toluene (1 mL), 24 h, 160 °C, under nitrogen atmosphere.
Isolated yields.
b
Table 3
o-nitroanilines (Scheme 1, Eq. d). In this process, no additional
additive (acid, base, oxidant, or reductant) was required.
Synthesis of benzimidazoles from o-nitroanilines and benzyl alcohola
Our initial study was focused on the reaction of benzyl alcohol
(1a) and o-nitroaniline (2a) as the model substrates (Table 1).
Firstly, various iron and palladium catalysts were screened for
the reaction. No product or poor yield was observed in the pres-
ence of either iron or palladium catalyst solely (entries 1–4). The
reaction yield could be improved to 60% when dppf was used
(entry 5). 3a was obtained in 82% yield under the catalysis of Pd
(dppf)Cl2 (5 mol %, entry 6). It suggested that the synergetic effects
of palladium and iron improved the catalytic activities signifi-
cantly. The reactions conducted at 150 and 170 °C resulted in lower
yields than at 160 °C (entries 6–8). Solvents also influenced the
reaction efficiency. Among the tested solvents (entries 9–12),
toluene showed the best efficiency and 3a was provided in 97%
yield (in the Ref. 8b, the optimal yield using dppf is only 74%).
The reaction was also conducted under the solvent-free
condition, but resulted in a slight lower yield (92%, entry 12).
The desired product 3a could only be obtained in 79% yield when
we decreased the catalyst loading to 3 mol % (entry 13). When
the amount of benzyl alcohol was decreased from 3.0 equiv to
2.0 equiv, the yield of 3a was decreased to 89% (entry 14).
However, 4.0 equiv of benzyl alcohol did not change the yield of
the product (entry 15). The optimized reaction conditions were
obtained in Table 1 (entry 11): 3.0 equiv of benzyl alcohol (1a),
1.0 equiv of o-nitroaniline (2a), 0.05 equiv (5 mol %) of Pd(dppf)
Cl2 in toluene (1 mL) at 160 °C with stirring for 24 h.
Entry
1
o-Nitroaniline
Product
Yieldb (%)
90
2
3
4
5
6
7
89
83
81
87
80
78
With the optimized conditions in hand, the scope of the benzyl
alcohols and o-nitroanilines in the reaction were extended. Benzyl
alcohols bearing substituents at the aromatic ring reacted
smoothly and gave the products in good to excellent yields
(78–97%, Table 2), regardless of the electronic properties of the
substituents. These substituents range from methyl, methoxyl, to
halogens. However, the steric hindrance of the substituents had a
negative influence on the reaction. A slightly lower yield (81%,
78%) was obtained when 2-methylbenzyl alcohol 1c or
2-chlorobenzyl alcohol 1f was used as the substrates (entries 3
and 6). Cinnamyl alcohol 1j also smoothly coupled with 2a and
afforded 3ja in 82% yield (entry 9). Notably, several heteroaromatic
products bearing a 2-thienyl, 2-pyridyl, or 2-furyl substituent were
readily obtained under the standard reaction conditions (entries
11–13).
8
88
a
Reaction conditions: benzyl alcohol (0.9 mmol), o-nitroanilines (0.3 mmol), Pd
(dppf)Cl2 (0.015 mmol), toluene (1 mL), 24 h, 160 °C, under nitrogen atmosphere.
b
Isolated yields.
product yield is improved (Scheme 1, Eq. c).5 Inspired by this and
some literatures, we inferred that complex catalyst would be more
efficient for this kind of reaction.10 Iron has been proven to be fea-
sible catalyst for this kind of reaction. Pd catalysts is efficient in
redox reactions and it can act as a capacitors and accelerate the
electron transfer.11 Herein, we wish to describe a one-pot method
catalyzed by [1,10-bis(diphenylphosphino)ferrocene]dichloropalla-
dium(II) (Pd(dppf)Cl2) to synthesize benzimidazoles in excellent
yields from inexpensive and readily available benzyl alcohols and
To further explore the application of this reaction, various
o-nitroanilines were employed to react with 1a under the opti-
mized conditions (Table 3). A series of functional groups on the
aromatic ring including methyl, methoxyl, and halogens were well
tolerated, and the desired products were obtained in good to

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X. Li et al. / Tetrahedron Letters 57 (2016) 4645–4649
Scheme 2. Control experiments.
potentially be complementary to the existing methods for the
synthesis of benzimidazoles. Application of the method is under
way in our laboratory and will be reported in due course.
Acknowledgments
We thank to the National Natural Science Foundation of China
(Grant No. 21072095), National High Technology Research and
Development Program of China (863 Program 2014AA022100),
Six Talent Peaks Project in Jiangsu Province (No. 2015-SWYY-
016) and Graduate Student Innovation Project in Jiangsu Province
(Grant No. SJZZ15_0100) for supporting this research.
Supplementary data
Scheme 3. Proposed mechanism.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.09.
018.
excellent yields (entries 1–5). 80% yield was achieved when 3,4-
difluoro-2-nitroaniline 2g was used (entry 6). 4-Amino-3-
nitrobenzonitrile 2h was suitable substrate for the reaction and
3ah was afforded in 78% yield (entry 7). It was worth noting that
2-nitro-N-phenylbenzamide 2i was successfully employed as the
substrate to give the corresponding product 3ai in 88% yield (entry
8).
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To further clarify the mechanism for this reaction, some control
experiments were carried out under standard conditions
(Scheme 2). When benzaldehyde was employed as the substrate
to react with o-nitroaniline (Eq. a), or o-phenylenediamine was
employed as the substrate to react with benzyl alcohol (Eq. b), only
a trace amount of the desired product was obtained at both situa-
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benzaldehyde could give the desired product in 85% yield (Eq. c).
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a
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o-nitroaniline 2a is reduced to o-phenylenediamine B via hydrogen
transfer in the presence of Pd(dppf)Cl2 catalyst. Then A is con-
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drogenation of D affords the desired product 3a.
In summary, Pd(dppf)Cl2 is found to be efficient catalyst to syn-
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gen-transfer between benzyl alcohols and o-nitroanilines. This
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