N-chlorosuccinimide/sodium hydroxide-mediated synthesis of benzimidazoles from amidines under mild conditions

Article abstract of DOI:10.3987/COM-12-S(N)53

A convenient room-temperature one-pot procedure for the preparation of benzimidazoles derivatives from N-arylamidines has been developed. The reaction of N-aryl-N'-chloro amidines, generated by the treatment of N-arylamidines with N-chlorosuccinimide, in presence of sodium hydroxide provides benzimidazoles in good to excellent yields. Nitrogen anion generated in situ from succinimide (by-product of the chlorination step using NCS) and hydroxide anion was found to be highly effective as Bronsted base to promote the cyclization into benzimidazole of N-aryl-N'-chloroamidine.

Full text of DOI:10.3987/COM-12-S(N)53

HETEROCYCLES, Vol. 86, No. 1, 2012, pp. -. © The Japan Institute of Heterocyclic Chemistry
Received, 23rd June, 2012 Accepted, 27th July, 2012, Published online, 8th August, 2012
DOI: 10.3987/COM-12-S(N)53
N-CHLOROSUCCINIMIDE/SODIUM
HYDROXIDE-MEDIATED
SYNTHESIS OF BENZIMIDAZOLES FROM AMIDINES UNDER MILD
CONDITIONS
Thanh Binh Nguyen,* Ludmila Ermolenko, and Ali Al-Mourabit
Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances
Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
E-mail: nguyen@icsn.cnrs-gif.fr
Abstract – A convenient room-temperature one-pot procedure for the preparation
of benzimidazoles derivatives from N-arylamidines has been developed. The
reaction of N-aryl-N'-chloro amidines, generated by the treatment of N-aryl
amidines with N-chlorosuccinimide, in presence of sodium hydroxide provides
benzimidazoles in good to excellent yields. Nitrogen anion generated in situ from
succinimide (by-product of the chlorination step using NCS) and hydroxide anion
was found to be highly effective as Brønsted base to promote the cyclization into
benzimidazole of N-aryl-N'-chloroamidine.
INTRODUCTION
Compounds bearing benzimidazole moiety are frequently found in biologically active and therapeutically
useful molecules. Their significant importance to medicinal chemistry is obvious.1 For these reasons, a
simpler approach to the synthesis of these heterocyclics was thought to be of great value. The classical
methods for the preparation of benzimidazoles consist in condensing o-phenylenediamines with either
carboxylic acid derivatives2 under drastic conditions (strong acid/high temperature) or aldehydes3 under
oxidative conditions. There have been other procedures for the construction of benzimidazole
heterocycles starting from aniline derivatives making use of o-substitituents for cyclization.4 Although
these transformations are widely used in the preparation of benzimidazoles, further developments of
selective methods based on direct C-H functionalization transformation to this structure are of
considerable interest. These methods represent one of the most effective and atom economical approach
for C-N bond-forming reactions. The oxidative cyclization of N-arylamidines5 to benzimidazoles have
Dedicated to Prof. Ei-ichi Negishi on the occasion of his 77th birthday.

been reported earlier using oxidizing agents such as NaOCl/NaOH,5a,b Pb(OAc)4,5c hypervalent iodine
reagents.5d,e Although these methods can be applied to a wide range of substrates, the use of
stoichiometric amounts of toxic,5c expensive5d,e reagents along with possible formation of nuclear
chlorinated side products5a are major disadvantages. Recently, copper-6a,b and palladium-6c catalyzed C-N
aerobic oxidative cross-coupling methodologies have been applied successfully in the synthesis of
benzimidazole derivatives 2-substituted by an aryl,6a,c t-butyl6a or amino6b groups. While the use of
gaseous oxygen as oxidizing agent is an interesting feature, these catalyzed methods suffer from elevated
temperatures, long reaction times, use of solvents which are difficult to remove (DMSO,
N-methyl-2-pyrrolidone). Moreover, compared to older methods5 using stoichiometric amounts of
oxidizing reagents, 2-alkylbenzimidazoles (except t-butyl) could not be obtained by the metal-catalyzed
methods,6 and ortho-substituted benzamidine structure was required to ensure high conversion.6a
Our interest in the synthesis of benzimidazole moiety led us to reexamine the transformation of N-aryl-
amidines into benzimidazoles with the aim to limit these drawbacks.
Herein, we disclosed the results of our study on the synthesis of benzimidazoles via a 2-step sequence (i)
N-halogenation of N-arylamidines, (ii) base-promoted cyclization, which offers a simple synthetic method
for benzimidazoles derivatives under mild conditions (Scheme 1).
[X+]
H
N
H
N
B-
N
N
H
HN
XN
Scheme 1
RESULTS AND DISCUSSION
We started our investigation by studying the conversion of phenylbenzimidazole into its N-halogenated
derivative using N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), Br2,
I2, and chloramine-T. We found that both NCS and chloramine-T gave the N-chloro product in high
conversion (> 95%) under mild conditions (0 °C to rt) in short reaction time (less than 5 min) in different
solvents (CH2Cl2, MeCN, Et2O).7 N-Chloroamidine product was relatively stable and could be purified
by column chromatography without noticeable degradation. We next explored the one-pot cyclization
reaction by adding a base into the reaction mixture obtained from the reaction with NCS in MeCN.8 A
variety of weak organic bases, such as Et3N, pyridine, DABCO, DIPEA and aqueous inorganic bases,
such as NaHCO3, Na2CO3 were tested but without success. Interestingly, addition of an aqueous solution
of NaOH induced a rapid and clean cyclization of N-chloroamidine into 2-phenylbenzimidazole even at
low temperature (0 °C). After removal of volatiles in vacuo, the desire benzimidazole product was

obtained in high purity (87% yield) by simple trituration of the crude mixture with water in order to
remove by-product succinimide (as sodium salt) and other impurities.
The optimized conditions were next applied to a variety of substituted N-arylamidines (Table 1). To our
delight, several functional groups including halogens and electron-donating are tolerated well on the
N-arylring of the amidines. In contrast to the metal-catalyzed C-H functionalization,6 our method can be
extended to the synthesis of 2-alkylated benzimidazoles with methyl, n-propyl, i-propyl or benzyl
substituent (entries 9-12). When N-methyl-N-phenylamidine 1n was used as substrate (entry 13), the
N'-chlorinated intermediate could be obtained, but failed to cyclize under our conditions. Finally, in all
cases studied, no trace of nuclear chlorination was observed.
Table 1. One-pot synthesis of benzimidazoles from N-aryl amidines
H
N
H
N
R1
R1
NaOH
H2O
NCS
N
R2
R2
R2
R
MeCN
N
H
2b-l
HN
N
Cl
3b-n
1b-n
entry
1
substrate
product
yield (%)
90
H
N
N
Me
N
H
Me
HN
1b
2b
Me
N
Me
Me
H
N
Me
2
3
92
87
N
H
HN
1c
2c
Me
N
Me
H
N
Me
N
H
Me
HN
1d
2d
Me
Me
H
N
N
N
H
4
5
86
95
HN
Me
Me
1e
2e
Me
Me
H
N
N
HN
N
H
Me
Me
1f
2d

H
N
N
Cl
N
H
Cl
6
7
79
75
92
84
85
87
72
0
HN
1g
2f
H
N
N
MeO
N
H
MeO
HN
1h
2g
H
N
N
Br
Br
N
H
8
HN
1i
2h
H
N
N
Me
Me
N
H
9
HN
1j
2i
H
N
N
N
H
10
11
12
13
HN
1k
2j
H
N
N
N
H
HN
1l
2k
H
N
N
Bn
Me
N
H
Me
Ph
HN
2l
1m
H
N
N
N
Me
MeN
1n
2m
We tentatively propose the mechanism (Scheme 2) of the transformation based on literature precedent of
related process using NaOCl.5a Amidine 1 reacts with NCS to give N-chloroamidine A. The
dehydrochlorination of A promoted by a base would follow either path 1 to produce the nitrene
intermediate B, which undergoes cyclization to C and prototropic rearrangement to provide
benzimidazole 2 or path 2 to generate directly the cyclized product C. This dehydrochlorination seems
not impossible when N-methyl-N-phenyl benzamidine 1n was used. The reaction rate enhancement of the
transformation from A to 2 under our conditions (5 min, 0 ˚C to rt) compared to the literature reported
result (30 min, refluxing aqueous solution)5a could be explained by the involvement of succinimide in the

reaction. In the presence of hydroxide anion, succinimide (pKa = 9.66)9 is deprotonated into succinimide
anion. Due to its lower propensity to be solvated by water compared to OH–, succinimide anion could
participate in the dehydrochlorination of A more efficiently.10
O
-
H
N
N
N
O
R
Cl
R
path 1
N
N
nitrene intermediate
H
N
NCS
B
A
R
O
-
HN
electrocyclization
succinimide
N
H
N
1
N
N
N
O
prototropic
R
R
R
Cl
path 2
rearrangement
N
H
N
H
2
A
C
Scheme 2
In conclusion, we have developed a convenient room-temperature one-pot procedure for the preparation
of benzimidazoles derivatives 2 from N-aryl amidines 1 via N-aryl-N'-chloroamidine intermediate A.
Nitrogen anion generated in situ from succinimide (by-product of the chlorination step using NCS) and
NaOH was found to be highly effective as Brønsted base to promote the cyclization into benzimidazole 2
of N-aryl-N'-chloro amidine A.
EXPERIMENTAL
The 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded on a Bruker AC-300 or AC-500
spectrometer operating at 300 MHz or 500 MHz respectively. Flash chromatography was performed
using SDS silicagel 60 (35-70 !m). Thin layer chromatography (TLC) was carried out on plates with a
layer thickness of 0.25 mm (SDS Silicagel 60 F254). Visualization was achieved under a UVP
mineralight UVGL-58 lamp or with vanilline stain. All reagents were obtained from commercial suppliers
unless otherwise stated.
N-Arylamidines (1a-n) were prepared according to literature.6a
N-Phenylbenzamidine (1a). 1H NMR (CDCl3, 300 MHz) " 7.87 (d, J = 6.1 Hz, 2H), 7.48-7.42 (m, 3H),
7.35 (m, 2H), 7.05 (m, 1H), 6.98 (d, J = 7.4 Hz, 2H).
1
N-p-Tolylbenzamidine (1b). H NMR (CDCl3, 300 MHz) " 7.85 (d, J = 7.0 Hz, 2H), 7.49-7.40 (m, 3H),
7.14 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H).

1
N-(2,3-Dimethylphenyl)benzamidine (1c). H NMR (CDCl3, 300 MHz) " 7.90 (d, J = 6.7 Hz, 2H),
7.47-7.42 (m, 3H), 7.06 (dd, J = 7.7 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H), 2.29 (s,
3H), 2.10 (s, 3H).
1
N-(2,4-Dimethylphenyl)benzamidine (1d). H NMR (CDCl3, 300 MHz) " 7.88 (d, J = 6.5 Hz, 2H),
7.47-7.41 (m, 3H), 7.02 (s, 1H), 6.97 (d, J = 7.9 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 2.29 (s, 3H), 2.15 (s,
3H).
1
N-(2,5-Dimethylphenyl)benzamidine (1e). H NMR (CDCl3, 300 MHz) " 7.87 (d, J = 6.4 Hz, 2H),
7.49-7.40 (m, 3H), 7.09 (d, J = 7.5 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.69 (s, 1H), 2.29 (s, 3H), 2.15 (s,
3H).
1
N-(3,5-Dimethylphenylbenzamidine (1f). H NMR (CDCl3, 300 MHz) " 7.84 (d, J = 7.0 Hz, 2H),
7.45-7.40 (m, 3H), 6.69 (s, 1H), 6.60 (s, 2H), 2.29 (s, 6H).
1
N-(4-Chlorophenyl)benzamidine (1g). H NMR (CDCl3, 300 MHz) " 7.81 (d, J = 7.0 Hz, 2H),
7.47-7.39 (m, 3H), 7.29 (d, J = 8.5 Hz), 6.90 (d, J = 8.5 Hz, 2H).
N-(4-Methoxyphenyl)benzamidine (1h). 1H NMR (CDCl3, 300 MHz) " 7.82 (d, J = 7.0 Hz, 2H),
7.46-7.41 (m, 3H), 6.91-6.89 (m, 4H), 3.79 (s, 3H).
1
4-Bromo-N-phenylbenzamidine (1i). H NMR (CDCl3, 300 MHz) " 7.72 (d, J = 7.1 Hz, 2H), 7.55 (d, J
= 7.1 Hz, 2H), 7.34 (m, 2H), 7.06 (m, 1H), 6.95 (d, J = 7.9 Hz, 2H).
1
N-Phenylacetamidine (1j). H NMR (CDCl3, 500 MHz) " 7.32-7.29 (m, 2H), 7.05-7.02 (m, 1H),
6.89-6.87 (m, 1H), 4.50 (broad s, 2H), 2.05 (broad s, 3H).
1
N-Phenylbutyramidine (1k). H NMR (CDCl3, 300 MHz) " 7.26 (m, 2H), 6.98 (m, 1H), 6.69 (s, 1H),
6.84 (m, 2H), 2.25 (t, J = 7.3 Hz, 2H), 1.69 (sextuplet, J = 7.3 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H).
N-Phenylisobutyramidine (1l). 1H NMR (CDCl3, 300 MHz) " 7.27 (m, 2H), 6.98 (m, 1H), 6.69 (s, 1H),
6.84 (m, 2H), 2.52 (septuplet, J = 6.9 Hz, 1H), 1,23 (d, J = 6.9 Hz, 6H).
1
N-(p-Tolyl)phenylacetamidine (1m). H NMR (CDCl3, 500 MHz) " 7.34-7.24 (m, 5H), 7.09 (d, J = 7.9
Hz, 2H), 6.80 (d, J = 7.9 Hz, 2H), 4.19 (broad s, 2H), 3.65 (s, 2H), 2.28 (s, 3H).
1
N-Phenyl-N-methylbenzamidine (1n). H NMR (CDCl3, 300 MHz) " 7.31-7.27 (m, 2H), 7.22-7.14 (m,
5H), 7.04-6.98 (m, 3H), 3.53 (s, 3H).
General Procedure for the Synthesis of Benzimidazoles from N-arylamidines 1
To a cooled solution of N-aryl amidine 1 (1 mmol) in MeCN (4 mL) at 0 °C was added solid NCS (133.5
mg, 1mmol). After stirring at the same temperature for 5 min, an aqueous solution of NaOH (200 mg in
0.2 mL H2O) was added. The reaction mixture was stirred at 0 °C for 5 min, then concentrated in vacuo.
The residue was washed with H2O (3 ! 5 mL) and dried to afford the benzimidazole as light brown solid
(yields are reported in Table 1).

2-Phenyl-1H-benzo[d]imidazole (2a).1m mp 298–300 °C. 1H NMR (DMSO-d6, 300 MHz) " 12.90 (broad
s, 1H), 8.19 (d, J = 7.4 Hz, 2H), 7.60-7.48 (m, 5H), 7.22-7.19 (m, 2H). 13C NMR (DMSO-d6, 75 MHz) "
151.5, 144.1, 135.2, 130.5, 130.1, 129.2, 126.7, 122.7, 122.0, 119.1, 111.5.
1
4-Methyl-2-phenyl-1H-benzo[d]imidazole (2b).1m mp 242–244 °C. H NMR (DMSO-d6, 300 MHz) "
8.37 (broad s, 1H), 8.21-8.189 (m, 2H), 7.49-7.35 (m, 4H), 7. 30 (m, 1H), 6.91 (dd, J = 8.1, 1.5 Hz, 1H),
13
2.39 (s, 3H). C NMR (DMSO-d6, 75 MHz) " 153.0, 141.1, 139.8, 132.1, 129.8, 128.8, 128.6, 126.3,
122.4, 115.1, 114,6, 21.4.
4,5-Dimethyl-2-phenyl-1H-benzo[d]imidazole (2c).1m 1H NMR (DMSO-d6, 300 MHz) " 8.25-8.22 (m,
2H), 7.40-7.25 (m, 2H), 7.30-7.25 (m, 2H), 7.13 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 2.46 (s, 3H),
13
2.28 (s, 3H). C NMR (DMSO-d6, 75 MHz) " 155.3, 144.4, 141.7, 135.0, 128.1, 127.3, 126.3, 125.2,
122.6, 121.6, 112.1, 19.2, 13.8.
4,6-Dimethyl-2-phenyl-1H-benzo[d]imidazole (2d).1m 1H NMR (DMSO-d6, 300 MHz) " 12.50 (broad s),
8.26 (d, J = 7.1 Hz, 1H), 7.57-7.48 (m, 3H), 6.88 (s, 2H), 2.53 (s, 6H). 13C NMR (DMSO-d6, 75 MHz) "
150.3, 130.5, 129.5, 128.7, 126.6, 122.5, 16.7.
1
4,7-Dimethyl-2-phenyl-1H-benzo[d]imidazole (2e). H-NMR (DMSO-d6, 300 MHz) " 12.48 (broad s,
1H), 8.29- 8.26 (m, 2H), 7.59-7.47 (m, 3H), 6.90 (s, 2H), 2.55 (s, 6H). 13C NMR (DMSO-d6, 75 MHz) "
150.3, 130.4, 129.5, 128.7, 126.6, 122.6, 16.7.
1
5-Chloro-2-phenyl-1H-benzo[d]imidazole (2f).1m mp 211–213 °C. H-NMR (DMSO-d6, 300 MHz) "
13
12.95 (br s, 1H), 8.15 (d, J = 7.5 Hz, 2H), 7.61-7.49 (m, 5H), 7.17 (d, J = 8.0 Hz, 1H); C NMR
(DMSO-d6, 75 MHz) " 153.1, 130.6, 130.2, 129.5, 127.1, 122.8.
1
5-Methoxy-2-phenyl-1H-benzo[d]imidazole (2g).1m mp 148-150 °C. H-NMR (DMSO-d6, 300 MHz) "
12.50 (broad s, 1H), 8.11 (d, J = 6.5 Hz, 2H), 7.52-7.40 (m, 4H), 7.02 (br s, 1H), 6.80 (d, J = 6.5 Hz, 1H),
3.76 (s, 3H). 13C NMR (DMSO-d6, 75 MHz) " 156.0, 150.7, 130.5, 129.7, 129.0, 126.3, 111.5, 55.7.
1
2-(4-Bromophenyl)-1H-benzo[d]imidazole (2h). H NMR (DMSO-d6, 300 MHz) " 8.14- 8.09 (m, 2H),
7.79-7.74 (m, 2H), 7.63-7.57 (m, 2H), 7.24-7.18 (m, 2H). 13C NMR (DMSO-d6, 75 MHz) " 150.3, 131.9,
129.5, 129.2, 128.3, 123.1, 122.2, 115.2 (broad peak).
1
2-Methyl-1H-benzo[d]imidazole (2i). H NMR (MeOD, 300 MHz) " 7.47-7.44 (m, 2H), 7.17-7.14 (m,
2H), 2.54 (s, 4H). 13C NMR (MeOD, 75 MHz) " 153.1, 139.7, 123,2, 115.3 (broad peak), 14.4.
1
2-Propyl-1H-benzo[d]imidazole (2j). H NMR (MeOD, 300 MHz) " 7.49-7.46 (m, 2H), 7.18-7.15 (m,
2H), 2.85 (t, J = 7.3 Hz, 2H), 1.85 (sextuplet, J = 7.3, 2H), 0.99 (t, J = 7.3 Hz, 3H). 13C NMR (MeOD, 75
MHz) " 156.9, 139.7, 123,2, 115.5 (broad), 31.8, 22.8, 14.2.
1
2-Isopropyl-1H-benzo[d]imidazole (2k). H NMR (DMSO-d6, 300 MHz) " 12.11 (broad s, 1H),
7.47-7.44 (m, 2H), 7.11-7.08 (m, 2H), 3.13 (septuplet, J = 6.9 Hz, 1H), 1.34 (d, J = 6.9 Hz, 6H). 13C NMR
(DMSO-d6, 75 MHz) " 160.0, 121.0, 28.3, 21.3.

1
2-Benzyl-5-methyl-1H-benzo[d]imidazole (2l). H NMR (CDCl3, 300 MHz) " 10.38 (broad s, 1H), 7.44
(d, J = 8.3 Hz, 1H), 7.32 (d, J = 1.3 Hz, 1H), 7.26-7.19 (m, 5H), 7.09 (dd, J = 8.3, 1.3 Hz, 1H), 4.19 (s,
13
2H), 2.49 (s, 3H). C NMR (CDCl3, 75 MHz) " 153.8, 138.8, 137.2, 137.0, 132.0, 129.0, 128.8, 127.0,
123.7, 114.8, 114.5, 35.7, 21.7.
ACKNOWLEDGEMENTS
We thank Imma Arco and Minh Quan Tran for technical assistance.
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