Full Paper

Received: 25 May 2014

Revised: 29 June 2014

Accepted: 14 July 2014

Published online in Wiley Online Library: 28 August 2014

(wileyonlinelibrary.com) DOI 10.1002/aoc.3195

L-Proline:

an efficient N,O-bidentate ligand for

copper-catalyzed intramolecular cyclization
reaction of 2-iodoanilines with nitriles for the
synthesis of benzimidazoles
Jiatao Yu, Yonggen Xia and Ming Lu*
A novel and highly efficient copper-catalyzed intramolecular cyclization reaction of 2-iodoanilines with nitriles for the synthesis of
benzimidazoles with L-proline as the ligand has been developed. A variety of substituted benzimidazole derivatives can be synthesized with high yields using this approach. Copyright 2014 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publishers web-site.
Keywords: benzimidazoles; intramolecular cyclization; copper; L-proline

Introduction

764

Among the various nitrogen-containing heterocycles, benzimidazole and its derivatives are common building blocks in biologically
active and therapeutically useful compounds. They exhibit significant pharmacological and biological activities such as anticonvulsant, anticancer, antiulcer, antihypertensive, antibacterial and
antihistaminic properties.[15] In addition, they have been applied
in other fields, such as chemosensing,[6] dyes,[7] fluorescence and
corrosion science.[8] Their synthesis is one of the most exciting
topics in practical organic synthesis. In general, benzimidazoles
have various reported syntheses, with two methods used extensively that employ o-phenylenediamine as starting material. One
is the coupling of carboxylic acids, and the other is the condensation of aldehydes. They both have some drawbacks: the former
requires strong acidic conditions, and sometimes high
temperature[913]; the latter requires a stoichiometric oxidant, involves the generation of environmentally hazardous/toxic byproducts and requires odorous and unstable aldehydes.[1420]
Therefore, developing new efficient and greener methods for the
synthesis of benzimidazoles is an important task.
In recent years, the synthesis of benzimidazoles from
2-iodoaniline as a practical and efficient method has aroused
great interest. These methods often involve the condensation
of 2-iodoaniline and aldehydes/NaN3[21] or benzamidine
hydrochloride.[22] However, these methods have some drawbacks,
such as requiring highly toxic NaN3 and unstable aldehydes, hygroscopic benzamidine hydrochloride and a nitrogen atmosphere.
Very recently, Cano et al.[23] developed an interesting protocol
for the synthesis of benzimidazoles via cascade reaction of
2-iodoaniline and amides. However, the yields were not very
satisfactory and the reaction time was too long. As we know,
amides can be prepared easily from nitriles by hydrolysis. Also,
in 2013, Xiang et al.[24] synthesized N-arylamides from aryl
halides and nitriles. The use of nitriles as nitrogen nucleophiles
can make the synthesis of N-arylamides simpler than that from
Appl. Organometal. Chem. 2014, 28, 764767

amides through in situ hydrolysis. A variety of N-arylamides

and benzoxazole derivatives can be synthesized according to
this approach. But its application in the catalytic synthesis of
heterocycles is limited. All of these facts stimulated us to
explore the feasibility of using nitriles as the reaction partners
instead of amides in the reaction to synthesize benzimidazoles (Scheme 1).
Herein we introduce a ligand-assisted copper-catalyzed direct
synthesis of benzimidazoles by the reaction of 2-iodoaniline with
nitriles. A series of substrates were used in this catalytic system
and afforded the products in good to excellent yields.

Results and Discussion

Our preliminary studies focused on the reaction between
2-iodoaniline and benzonitrile using CuI as the catalyst, N,Ndimethyl-1,2-ethanediamine (L1) as the ligand, Cs2CO3 and KOH
as the base, and H2O as the additive in DMSO at 100C for 24 h.
The desired product, 2-phenylbenzimidazole, is obtained in a yield
of 68% (Table 1, entry 1). When the reaction is conducted in the
absence of one or more of them, it results in large decreases of
the yields (entries 27). Other copper salts also had considerable
catalytic activity; among them, CuCl2 exhibited the highest activity (entries 1, 814). After screening different ligands, it is found
that the use of L-proline (L2) as the ligand with CuCl2 gives the
best result (entries 1, 1517). Solvent screening shows DMSO
to be better than other solvents (entries 15, 1820). The effect

* Correspondence to: Ming Lu, Nanjing University of Science and Technology,

College of Chemical Engineering, Nanjing, Jiangsu 210094, China. E-mail:
luming302@126.com
Nanjing University of Science and Technology, College of Chemical Engineering,
Nanjing, Jiangsu 210094, China

Copyright 2014 John Wiley & Sons, Ltd.

Synthesis of benzimidazoles from 2-iodoanilines and nitriles

Scheme 1. Synthesis of benzimidazole and its derivatives from 2-iodoaniline

and nitriles catalyzed by CuCl2/L-proline.

of reaction temperature was also tested, and it is found that

the highest yield is obtained at 100C (entries 15, 2123). In
addition, we also investigated the amount of benzonitrile in
the reaction. It is found that the use of 1.2 equiv. of
benzonitrile gives the best results (entries 15, 2426). Furthermore, it is found that the amount of water has a great
influence on the yield of the reaction, and 10 equiv. of H2O
is a suitable amount and gives a good yield of 90% (entries
15, 2729). Also, we tested the influence of all loadings
including catalyst, ligand and base, and the result is that
10 mol% catalyst/ligand, 0.5 equiv. Cs2CO3 and 1.5 equiv.
KOH are the most suitable proportions (entries 3037).
Encouraged by the good catalytic activity of the L-prolineassisted CuCl2 catalytic system, the scope of the transformation
under investigation was extended to 2-haloaniline derivatives with
various aromatic nitriles. Initially, 2-haloaniline derivatives were
selected as reaction partners for the nitriles. 2-Iodoaniline,
2-bromoaniline and 2-chloroaniline can react with benzonitrile to
afford the desired product 2-phenylbenzimidazole in yields of
90%, 32% and trace, respectively (Table 2, entries 1ac). It is obvious
that 2-iodoaniline is the most suitable 2-haloaniline derivative for

Table 1. Conditions optimization for the preparation of benzimidazolesa

Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37

PhCN (equiv.)

Cu (mol%)

Ligand (mol%)

Base (equiv.)

H2O (equiv.)

Solvent

Temperature (C)

Yield (%)b

1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1.2
1.5
0.8
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2

CuI (10)
CuI (10)

CuI (10)
CuI (10)
CuI (10)
CuI (10)
Cu2O (10)
CuCl (10)
CuBr (10)
CuBr2 (10)
Cu(OAc)2 (10)
Cu(ClO4)2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (5)
CuCl2 (20)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)

L1 (10)

L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L2 (10)
L3 (10)
L4 (10)
L2 (10)
L2 (10)
L2 (10)
L2 (10)
L2 (10)
L2 (10)
L2 (10)
L2 (10)
L2 (10)
L2 (10)
L2 (10)
L2 (10)
L2 (10)
L2 (10)
L2 (5)
L2 (20)
L2 (10)
L2 (10)
L2 (10)
L2 (10)

Cs2CO3(0.5) + KOH (1.5)

Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
KOH (1.5)
Cs2CO3 (0.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(0.5) + KOH (1.5)
Cs2CO3(1) + KOH (1.5)
Cs2CO3(0.2) + KOH (1.5)
Cs2CO3(0.5) + KOH (1)
Cs2CO3(0.5) + KOH (2)

20
20
20
20
20
0
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
10
5
30
10
10
10
10
10
10
10
10

DMSO
DMSO
DMSO
DMSO
DMSO
DMSO

DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Dioxane
DMP
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO

100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
60
Room temp.
100
100
100
100
100
100
100
100
100
100
100
100
100
100

68
46
Trace
59
40
64
14
74
76
70
58
18
65
83
85
24
20
54
68
46
75
48
12
87
84
65
90
85
79
82
90
73
90
90
82
78
90

Appl. Organometal. Chem. 2014, 28, 764767

Copyright 2014 John Wiley & Sons, Ltd.

wileyonlinelibrary.com/journal/aoc

765

Reaction conditions: 2-iodoaniline (0.5 mmol), benzonitrile, Cu salt, ligand, base, H2O, solvent (1 ml) were mixed in a 5 ml three-necked flask, and then
stirred rapidly for several hours. The reaction progress was monitored by TLC.
b
Isolated yield.

J. Yu, Y. Xia and M. Lu

Table 2. Ligand-assisted copper-catalyzed synthesis of benzimidazoles
from 2-iodoaniline with different nitrilesa

Entry

Time (h)

Yield (%)b

1a
1b
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19

I
Br
Cl
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I

H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-Cl
4-NO2
H
H

C6H5
C6H5
C6H5
4-BrC6H4
4-ClC6H4
2-ClC6H4
2-, 4-ClC6H3
4-NO2C6H4
4-MeOC6H4
4-Me2NC6H4
4-IsopropylC6H4
3,4,5-MeOC6H2
1-Naphthyl
Styryl
2-Furyl
5-Methyl-2-furyl
Pyridin-2-yl
C6H5
C6H5
n-C7H15
n-C11H23

24
36
36
24
24
24
24
20
24
24
24
24
24
28
30
30
30
26
32
24
24

90
32
Trace
81
83
62
79
94
91
87
85
82
83
42
65
71
68
84
80
Trace
Trace

Scheme 2. Hydrolysis of nitriles.

Scheme 3. Condensation of amide and 2-iodoaniline.

Reaction conditions: 2-iodoaniline (0.5 mmol), nitriles (0.6 mmol), CuCl2

(10 mol%), L-proline (10 mol%), Cs2CO3 (0.25 mmol), KOH (0.75 mol), H2O
(5 mmol), DMSO (1 ml) were mixed in a 5 ml three-necked flask, and then
stirred rapidly at 100C for several hours. The reaction progress was
monitored by TLC.
b
Isolated yield.

Scheme 4. Intramolecular coupling of aryl iodide and amine.

766

this reaction. Then a series of aromatic nitriles was selected to

react with 2-iodoaniline. The results are given in Table 2. In
most cases, 2-iodoaniline reacts with various aromatic nitriles
smoothly to give the corresponding products in good to excellent yields, regardless of the presence of electron-donating or
electron-withdrawing functionalities. It seems that aromatic nitriles bearing electron-deficient aromatic rings at the paraposition give higher yields of products than those bearing
electron-rich aromatic rings (entries 2, 3, 69). The reason may
be that the strong electron-withdrawing groups (NO2) enhance
the reaction rate (entry 6). The steric hindrance of the
substituted aromatic nitriles also influences the reaction. For example, the more sterically hindered o-chlorobenzonitrile reacts Scheme 5. Proposed reaction mechanism.
with 2-iodoaniline furnishing the target product in lower yield
than p-chlorobenzonitrile (entries 3 and 4). 1-Naphthonitrile
was tested in the reaction and the yield is also very good (entry
in good yields (entries 16 and 17). To demonstrate the scope of
11). However, when 3-phenylacrylonitrile is used in the reaction,
the present method, this catalytic system was then extended to
the yield is lower than with other aromatic nitriles (entry 12).
the synthesis of benzimidazoles with 2-iodoaniline and aliphatic
Heteroarylnitriles were used in the reaction, and the yields are
nitriles, such as octanenitrile and dodecanenitrile (entries 18 and
satisfactory (entries 1315). In addition, 5-chloro-2-iodoaniline and
19). However, the yields are trace and this transformation cannot
5-nitro-2-iodoaniline were also employed in the reaction, resulting
be realized.

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Copyright 2014 John Wiley & Sons, Ltd.

Appl. Organometal. Chem. 2014, 28, 764767

Synthesis of benzimidazoles from 2-iodoanilines and nitriles

Preliminary mechanistic studies of the reaction were also
conducted. As a first step, we turn our attention to the hydrolysis
of nitriles. The results are shown in Scheme 2. We find that the
nitriles can be only hydrolyzed under basic conditions without
the aid of copper catalyst.
The second step is the condensation of amide and 2-iodoaniline.
We find that the reaction can occur without any catalyst and additives, as shown in Scheme 3.
The last step is the intramolecular coupling of aryl iodide and
amine, as shown in Scheme 4. We find that CuCl2 and L-proline
are extremely important. The reaction does not proceed in the
absence of CuCl2 and L-proline.
Based on these results and the reported literature,[2124] a possible
reaction pathway for the synthesis of benzimidazoles is proposed,
as shown in Scheme 5. Initially, the hydrolysis of nitriles 1 under
basic conditions produces the amide salt A, which transforms to
the Schiff base salt B through condensation with 2-iodoaniline.
Then the copper catalyst C reacts with B to generate the metallic
intermediates D. Subsequently, intramolecular iodine undergoes
an oxidative addition to intermediates to form the metallic intermediates E,[25] which produce the final products 2 through a reductive
elimination reaction and release of the catalyst to complete the
catalytic cycle.

Conclusions
We have developed an efficient CuCl2/L-proline-catalyzed method
for the synthesis of benzimidazole and its derivatives from
2-iodoaniline and aromatic nitriles. A wide variety of benzimidazoles could be successfully synthesized in moderate to excellent
yields. On the whole, this approach is an extension of the work of
Xiang et al.[24] and using nitriles as the reaction partners for the
synthesis of benzimidazoles.

Experimental
All starting materials were purchased from commercial sources and
used without further treatment. Melting points were determined
with a Thomas Hoover capillary apparatus and were uncorrected.
All known compounds were identified by appropriate techniques such as 1H NMR and compared with previously reported
data. 1H NMR (500 MHz) spectra were recorded using a Bruker
500 spectrometer with tetramethylsilane as an internal standard.
Mass spectra were recorded using an Agilent Technologies 6110
quadrupole LC/MS equipped with an electrospray ionization
probe operating in positive ion mode. Analytical TLC was
performed on precoated silica gel 60 F254 plates. Yields refer
to the isolated yields of the products after purification by silicagel column chromatography (300 mesh).
Typical Procedure for the Synthesis of Benzimidazoles

Appl. Organometal. Chem. 2014, 28, 764767

References
[1] W. A. Denny, G. W. Rewcastle, B. C. Bauley, J. Med. Chem. 1990, 33, 814.
[2] T. Gngr, A. Fouquet, J.-M. Eulon, D. Provost, M. Cazes, A. Cloarec,
J. Med. Chem. 1992, 35, 4455.
[3] E. Seyhan, N. Sultan, A. Nilgun, N. Noyanalpan, Arzneim.-Forsch. 1997,
47, 410.
[4] L. Hu, M. L. Kully, D. W. Boykin, N. Abood, Bioorg. Med. Chem. Lett. 2009,
19, 3374.
[5] a) R. Schiffmann, A. Neugebauer, C. D. Klein, J. Med. Chem. 2006, 49,
511; b) R. P. Verma, Bioorg. Med. Chem. 2005, 13, 1059; c)
K.-J. Soderlind, B. Gorodetsky, A. K. Singh, N. Bachur, G. G. Miller,
J. W. Loun, Anti-Cancer Drug Des. 1999, 14, 19; d) D. A. Horton,
G. T. Bourne, M. L. Smythe, Chem. Rev. 2003, 103, 893; e) T. Roth,
M. L. Morningstar, P. L. Boyer, S. H. Hughes, R. W. Buckheit Jr.,
C. J. Michejda, J. Med. Chem. 1997, 40, 4199.
[6] N. Singh, D. O. Jang, Org. Lett. 2007, 9, 1991.
[7] J. A. Asensio, P. Gomez-Romero, Fuel Cells 2005, 5, 336.
[8] a) P. Chaudhuri, B. Ganguly, S. Bhattacharya, J. Org. Chem. 2007, 72,
1912; b) A. Sannigrahi, D. Arunbabu, R. M. Sankar, T. Jana,
Macromolecules 2007, 40, 2844; c) Y. Ooyama, T. Nakamura,
K. Yoshida, New J. Chem. 2005, 29, 447.
[9] Y. Wang, K. Sarris, D. R. Sauer, S. W. Djuric, Tetrahedron Lett. 2006, 47, 4823.
[10] a) W. Huang, R. M. Scarborough, Tetrahedron Lett. 1999, 40, 2665; b)
Y.-C. Chi, C.-M. Sun, Synlett 2000, 591; c) D. Kumar, M. R. Jacob,
M. B. Reynolds, S. M. Kerwin, Bioorg. Med. Chem. 2002, 10, 3997; d)
B. Gong, F. Hong, C. Kohm, L. Bonham, P. Klein, Bioorg. Med. Chem.
Lett. 2004, 14, 1455; e) S.-T. Huang, I.-J. Hsei, C. Chen, Bioorg. Med.
Chem. 2006, 14, 6106.
[11] a) D. W. Dunwell, D. Evans, C. E. Smith, W. R. N. Williamson, J. Med. Chem.
1975, 18, 692; b) I. B. Dzvinchuk, A. V. Vypirailenko, M. O. Lozinskii, Russ.
J. Org. Chem. 1998, 34, 685.
[12] a) E. Barni, P. J. Savarino, J. Heterocycl. Chem. 1979, 16, 1583; b)
J. B. Hendrickson, M. S. Hussoin, J. Org. Chem. 1987, 52, 4137; c)
T. Gungor, A. Fouquet, J.-M. Teulon, D. Provost, M. Cazes, A. Cloarec,
J. Med. Chem. 1992, 35, 4455; d) A. W. White, R. Almassy, A. H. Calvert,
N. J. Curtin, R. J. Griffin, Z. Hostomsky, K. Maegley, D. R. Newell,
S. Srinivasan, B. T. Golding, J. Med. Chem. 2000, 43, 4084; e)
B. Biasotti, S. Dallavalle, L. Merlini, C. Farina, S. Gagliardi, C. Parini,
P. Belfiore, Bioorg. Med. Chem. 2003, 11, 2247.
[13] a) K. Bougrin, A. Loupy, M. Soufiaoui, Tetrahedron 1998, 54, 8055; b)
A. Ben-Alloum, S. Bakkas, M. Soufiaoui, Tetrahedron Lett. 1998, 39,
4481; c) G. V. Reddy, V. V. V. N. S. R. Rao, B. Narsaiah, P. S. Rao, Synth.
Commun. 2002, 2467; d) Z. Mao, Z. Wang, J. Li, X. Song, Y. Luo, Synth.
Commun. 2010, 40, 1963.
[14] F. F. Stephens, J. D. Bower, J. Chem. Soc. 1949, 2971.
[15] R. L. Lombardy, F. A. Tanious, K. Ramachandran, R. R. Tidwell,
W. D. Wilson, J. Med. Chem. 1996, 39, 1452.
[16] K. Bahrami, M. M. Khodaei, A. Nejati, Green Chem. 2010, 12, 1237.
[17] a) J. J. Vanden Eynde, F. Delfosse, P. Lor, Y. Van Haverbeke,
Tetrahedron 1995, 51, 5813; b) K. J. Lee, K. D. Janda, Can. J. Chem.
2001, 79, 1556.
[18] I. Bhatnagar, M. V. George, Tetrahedron 1968, 24, 1293.
[19] P. L. Beaulieu, B. Hache, E. von Moos, Synthesis 2003, 1683.
[20] K. Bahrami, M. M. Khodaei, I. Kavianinia, Synthesis 2007, 547.
[21] Y. Kim, M. R. Kumar, N. Park, Y. Heo, S. Lee, J. Org. Chem. 2011, 76, 9577.
[22] Y. Qu, L. Pan, Z. Wu, X. Zhou, Tetrahedron 2013, 69, 1717.
[23] R. Cano, D. J. Ramon, M. Yus, J. Org. Chem. 2011, 76, 654.
[24] S.-K. Xiang, D.-X. Zhang, H. Hu, J.-L. Shi, L.-G. Guo, C. Feng, B.-Q. Wang,
K.-Q. Zhao, P. Hu, H. Yang, W.-H. Yu, Adv. Synth. Catal. 2013,
355, 1495.

Supporting Information
Additional supporting information may be found in the online
version of this article at the publishers web-site.

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767

A mixture of 2-iodoaniline (0.5 mmol), benzonitrile (0.6 mmol),

CuCl2 (10 mol%), L-proline (10 mol%), Cs2CO3 (0.25 mmol), KOH
(0.75 mol), H2O (5 mmol), DMSO (1 ml) was added to a 5 ml
three-necked flask, and then stirred rapidly at 100C for several
hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature. The mixture was partitioned between ethyl acetate and
brine. The organic layer was separated, and the aqueous layer
was extracted twice with ethyl acetate. The combined organic

layers were dried over MgSO4, and concentrated in vacuo. The

crude product was purified using chromatography with hexane
ethyl acetate (7:3) as eluent.