Synthesis of benzimidazoles by Cu2O-catalyzed cascade reactions between o-haloaniline and amidine hydrochlorides

Article abstract of DOI:10.1016/j.tet.2012.12.039

An efficient Cu₂O-catalyzed method for the synthesis of benzimidazole derivatives from amidine hydrochlorides and o-haloaniline has been developed. The cascade C-N coupling and intramolecular transamination reaction provided benzimidazole deriv

Full text of DOI:10.1016/j.tet.2012.12.039

Tetrahedron 69 (2013) 1717e1719
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Synthesis of benzimidazoles by Cu2O-catalyzed cascade reactions
between o-haloaniline and amidine hydrochlorides
*
Yanyang Qu, Lei Pan, Zhiqing Wu, Xiangge Zhou
Institute of Homogeneous Catalysis, College of Chemistry, Sichuan University, Chengdu 610064, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 August 2012
Received in revised form 7 October 2012
Accepted 14 December 2012
Available online 21 December 2012
An efficient Cu2O-catalyzed method for the synthesis of benzimidazole derivatives from amidine hy-
drochlorides and o-haloaniline has been developed. The cascade CeN coupling and intramolecular
transamination reaction provided benzimidazole derivatives in high yields up to 90%.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Copper
Catalysis
Cyclization
Heterocycle
Benzimidazole
1. Introduction
amidine hydrochlorides,12a Beifuss and co-workers synthesized
quinazolines by using benzamidines in water.12b In these cases, the
Benzimidazole and its derivatives have been studied exten-
sively because of their biological activities as potential bacteri-
cides,1 anti-carcinogens,2 and peptic ulcer agents.3 The traditional
synthetic methods involve the reactions between o-arylenedi-
amines and carboxylic acids,4 aldehydes,5 or alcohols,6 which
usually require strong acid, high temperature (>200 ꢀC), and
sometimes photoirradiation conditions, precious metal salts,7
molecular oxygen5d,e or 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ) as oxidant.5f
In the last decade, considerable progress has been made in the
area of palladium or copper catalyzed N-arylations, and several N-
heterocycles have been successfully synthesized based on this
strategy.8 Moreover, amidine has been recently applied as building
block for the formation of benzimidazole and other heterocycles
due to its good chemistry characteristic and excellent stability.9 For
example, Brain and co-workers pioneered this work by palladium
catalyzed intramolecular N-arylation with o-bromophenyl ami-
dine.10 Buchwald and Shi and co-workers made significant contri-
butions to construct this useful scaffold through Cu- or Pd-
catalyzed intramolecular CeH amination.11 Very recently, Fu and
co-workers developed an interesting protocol for the synthesis of
benzimidazoles via cascade reaction of o-haloacetoanilide with
existence of derivatives from amino group was essential to ob-
tained the desired product, which might limit its applications.
In continuation of our efforts in copper-catalyzed coupling re-
actions and construction of heterocycles,13 we envisioned here the
direct synthesis of the benzimidazole by the reaction of amidine
hydrochlorides and o-haloaniline.
Initially, benzamidine hydrochloride and 2-iodoaniline were
selected as model substrates to optimize the reaction conditions by
using CuI and L1 (DMEDA, N,N0-dimethylethanediamine) as cata-
lyst. Screening different solvents indicated DMF to be better than
others (Table 1, entries 1e6). Increasing reaction temperature also
benefited the catalysis. For example, when the temperature was
increased from 120 ꢀC, 130 ꢀCe140 ꢀC, the yields also increased
from 29%, 35%e54% (Table 1, entries 6e8). Several other copper
salts and ligands were also examined, and the catalyst consisting of
Cu2O and L1 was proven to be the most effective one in yield of 73%
(Table 1, entries 9e18). Therefore, the optimal reaction conditions
for the synthesis of benzimidazole consist of 10 mol % Cu2O and
20 mol % L1 as catalyst, 3 equiv of Cs2CO3 as the base, DMF as the
solvent, and the reaction was carried out at 140 ꢀC for 16 h.
Next, different o-haloanilines were tested, and the results are
summarized in Table 2. In general, most of the reactions proceeded
smoothly to give corresponding products in moderate to excellent
yields, and o-iodoanilines showed higher reactivities than bromo
analogs in yields ranging from 59% to 90%. However, o-chloroaniline
was not reactive during this reaction to give trace of product.
* Corresponding author. Tel./fax: þ86 28 85412026; e-mail address: zhoux-
iangge@scu.edu.cn (X. Zhou).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.039

1718
Y. Qu et al. / Tetrahedron 69 (2013) 1717e1719
Table 1
Table 2
Optimization of reaction conditionsa
Cu2O-catalyzed synthesis of 2-arylbenzimidazoles from substituted o-haloaniline
with benzamidine hydrochloridea
NH. HCl
NH2
H
N
[Cu]/Ligand
NH2
Base, Solvent
N
I
NH
N
N
HN
N
N
L1
Entry
1
Haloaniline
Product
Yieldb [%]
L2
L3
73 (X¼I)
COOH
N
H
N
COOH
N
N
H
2
3
4
5
6
7
62 (X¼Br)
86 (X¼I)
56 (X¼Br)
83 (X¼I)
57 (X¼Br)
86 (X¼I)
L5
L6
L4
Entry
Copper source
Ligand
Solvent
Temp (ꢀC)
Yieldb [%]
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
d
L2
L3
L4
L5
L6
H2O
H2O
100
100
130
130
130
130
140
120
140
140
140
140
140
140
140
140
140
140
<5c
10
21
28
24
35
54
29
59
73
34
Trace
35
49
62
66
39
60
DMSO
Dioxane
Xylene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
9
CuBr
Cu2O
CuCl2
d
10
11
12
13
14
15
16
17
18
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
8
90 (X¼I)
66 (X¼Br)
89 (X¼I)
9
a
Reaction conditions: benzamidine hydrochloride (1.5 mmol), o-iodoaniline
(1.0 mmol), copper source (0.1 mmol), ligand (0.2 mmol), Cs2CO3 (3.0 mmol), sol-
vent (2 mL) under nitrogen atmosphere, reaction time 16 h.
10
b
Yields of isolated product.
c
The reaction was carried out in the air.
11
59 (X¼I)
Furthermore, the substrates with electron-withdrawing substituents
seemed to be more fitful for the catalysis. For example, chloro
substituted substrate gave yields around 90%, while only 70% yield
was obtained in the case of n-butyl substituted substrate (Table 2,
entries 8 and 15). Unfortunately, carboxylate substituted o-iodoani-
line resulted in only moderate yield 59% (Table 2, entry 11), which
might be caused by the side reaction between amidine and carbox-
ylate group.
12
13
14
79 (X¼I)
66 (X¼Br)
81 (X¼I)
Then, we examined the general applicability of this method-
ology by using a variety of amidine hydrochlorides. As shown in
Table 3, the substituted benzamidine hydrochlorides containing
electron-withdrawing groups also seemed to be beneficial to the
catalysis than the electron-donating groups. For example,
p-methyl and p-methoxy benzamidine hydrochlorides provided
51% and 43% yield, respectively (Table 3, entries 5 and 9), while
p-chloro benzamidine hydrochlorides gave as high as 84% yield
(Table 3, entries 3). Furthermore, the alkyl amidine hydrochlorides
resulted in moderate yield of 2-methyl-1H-benzoimidazole (Table
3, entry 10).
15
70 (X¼I)
a
Reaction conditions: benzamidine hydrochloride (1.5 mmol), o-haloaniline
(1.0 mmol), Cu2O (0.1 mmol), L1 (0.2 mmol), Cs2CO3 (3.0 mmol), DMF (2 mL) under
a nitrogen atmosphere, reaction time 16 h under nitrogen atmosphere.
b
Isolated yields.
2. General experimental procedure
Based on these results and literature,9,12 a possible reaction
pathway for the synthesis of benzimidazoles is proposed in Fig. 1.
Firstly, amidine hydrochloride is reacted with base to release free
amidine.12 Then, Cu-catalyzed intermolecular N-arylation between
amidine and haloaniline provides intermediate II, the following
intramolecular nucleophilic attack results in ring closure and
elimination of NH3 to give the target product III.9b,c
In conclusion, we have developed an efficient Cu2O-catalyzed
method for the synthesis of benzimidazole and its derivatives. A
broad range of benzimidazoles could be successfully synthesized in
moderate to excellent yields.
A flask was charged with Cu2O (14 mg, 0.1 mmol), Cs2CO3
(977 mg, 3 mmol), o-haloaniline (1 mmol) and amidine hydro-
chloride (1.5 mmol) in 2 mL DMF under nitrogen atmosphere. The
mixture was stirred at room temperature and DMEDA (20
mL,
0.2 mmol) was added via syringe. The reaction mixture was then
stirred in a preheated oil bath at 140 ꢀC for 16 h, and then cooled to
room temperature. The inorganic salt was filtered off and ethyl
acetate, water was added. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate. The combined or-
ganic layer was dried over Na2SO4, and concentrated in vacuum.
The residue was purified by column chromatography on silica gel

Y. Qu et al. / Tetrahedron 69 (2013) 1717e1719
1719
Table 3
using petroleum ether/ethyl acetate as eluent to provide the de-
sired product.
Cu2O-catalyzed synthesis of substituted 2-arylbenzimidazoles via reaction of o-
haloaniline with various benzamidine hydrochloridea
Acknowledgements
We appreciate the Natural Science Foundation of China (No.
21072132, 21272161), and Ministry of Education (NCET-10-0581)
for financial support, and the Analytical & Testing Centre of Sichuan
University for NMR analysis.
Entry
1
Amidine
Amine
Product
Yieldb [%]
76 (X¼I)
Supplementary data
2
3
4
5
6
7
8
9
68 (X¼Br)
84 (X¼I)
71 (X¼Br)
51 (X¼I)
40 (X¼Br)
56 (X¼I)
48 (X¼Br)
43 (X¼I)
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.12.039.
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Fig. 1. Proposed pathway for the synthesis of benzimidazoles.