An efficient and environmental benign synthesis of 2-benzimidazoles and 2-benzothiazoles using CeCl3-NaI as catalyst

Article abstract of DOI:10.3184/174751913X13575704209748

A one-pot condensation of an aldehyde with 1,2-phenylenediamine or 2-aminothiophenol in dimethyl carbonate at 100°C under O₂ in the presence of catalytic amounts of CeCl₃-NaI gave an imine intermediate, which cyclised and dehydrogenated to give 2-arylbenzimidazoles or 2-arylbenzothiazoles in good yields.

Full text of DOI:10.3184/174751913X13575704209748

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 119
FEBRUARY, 119–121
An efficient and environmental benign synthesis of 2-benzimidazoles and
2-benzothiazoles using CeCl3-NaI as catalyst
Xun Zhua,b and Yunyang Weia*
aSchool of Chemical Engineering, Nanjing University of Science andTechnology, 210094, Nanjing, P. R. China
bDepartment of Chemical Engineering, YanchengTextile VocationalTechnology College, 224005, Yancheng, P. R. China
A one-pot condensation of an aldehyde with 1,2-phenylenediamine or 2-aminothiophenol in dimethyl carbonate at
100 °C under O2 in the presence of catalytic amounts of CeCl3–NaI gave an imine intermediate, which cyclised and
dehydrogenated to give 2-arylbenzimidazoles or 2-arylbenzothiazoles in good yields.
Keywords: 2- benzimidazoles, 2-benzothiazoles, aldehydes, cerium(III) chloride
Benzimidazoles, benzoxazoles and benzothiazoles are impor-
tant heterocyclic compounds that have many applications
in pharmaceutical and biological chemistry.1 For example,
benzimidazole and derivatives are commonly encountered in
natural products and agrochemicals, and in pharmaceuticals2
such as anti-ulcer agents, anti-tumour agents and antiviral
agents.3 This widespread interest in benzimidazole-containing
structures has promoted extensive studies of their synthesis.
A conventional method for the synthesis of benzimidazole
and derivatives is the reaction of 1,2-phenylenediamine with
carboxylic acid derivatives in the presence of strong acid under
harsh conditions,4 sometimes in combination with microwave
irradiation.5 Another method for the preparation of benzimid-
azoles is oxidative cyclisation of the imine intermediate, which
is generated from condensation of an amine with an aldehyde.6
However, an excessive amount of an oxidant such as DDQ,7
MnO2,8 PhI(OAc)2,9 I2,10 and Na2S2O5 is usually required for
this oxidation.11
Moreover, volatile organic solvents such as toluene and
xylene are used in the traditional procedures. Environmental
pressures have been forcing chemists to search for more
efficient ways of performing chemical reactions using green
solvents and green catalysts.
Recently, some methods have also been reported for con-
structing the benzimidazole framework by using a catalyst
containing iridium,12 copper,13 nickel,14 palladium,15 cobalt16
iron,17 and activated carbon.18 In continuation of our previous
studies on the application of cerium(III) chloride as a Lewis
acid in organic chemistry,19,20 we now report a simple, inexpen-
sive and green method for the cerium(III) chloride-catalysed
synthesis of 2-alkyl- and 2-aryl-benzimidazoles and 2-alkyl-
and 2-aryl-benzothiazoles using O2 as oxidant in dimethyl
carbonate.
aldehydes (1 mmol) were allowed to react with 2-phenylenedi-
amine (1 mmol) or 2-aminothiophenol (1 mmol) in the pres-
ence of 10 mol% of CeCl3 and NaI at 100 °C. As can be seen
in Table 2, both aliphatic aldehydes and aromatic aldehydes
react with 2-phenylenediamine or 2-aminothiophenol to form
the corresponding 2-substituted benzimidazoles or benzothia-
zoles. Aromatic aldehydes having electron-withdrawing 4-
substituents such as nitro, chloro or bromo, were converted
into the corresponding benzimidazole in good yields (Table 2,
entries 3, 4, 5, 11 and 12). Reactions with aromatic aldehydes
having electron-donating group such as methoxy on the ben-
zene ring reduce the yield of the corresponding benzimidazole
(Table 2, entry 7 and 13). Heterocyclic aldehydes such as
2-furyl and 2-thiophene carboxaldehyde also gave moderate
yields of the corresponding benzimidazole (Table 2, entries 8
and 9). To our delight, aliphatic aldehydes also reacted with
2-phenylenediamine or 2-aminothiophenol smoothly to give
the corresponding 2-substituted benzimidazole or benzothia-
zole in moderate to good yields (Table 1, entries 1, 2, 15 and
16).
ApossiblemechanismwasproposedbyKhalilandSardaria23
and is shown in Scheme 1. Initially, halogen exchange between
CeCl3 and NaI gives a mixed cerium salt CeInCl3-n. As a good
Lewis acid, CeInCl3-n catalyses the reaction of aldehydes with
2-phenylenediamine or 2-aminothiophenol to form an imine
Table 1 Optimisation of the synthesis of
2-phenylbenzimidazoles and 2-phenylbenzothiazolesa
Results and discussion
Entry Reagent Solvent
Temp. Catalyst/mol % Yield/
b
Initial experiments were carried out with benzaldehyde
(1 equiv.) and 2-phenylenediamine (1 equiv.) or 2-aminothio-
phenol (1 equiv.) as model substrates. Solvent effects were
examined in the presence of 10 mol% of CeCl3 and NaI,
respectively (Table 1). Moderate yields (50–70%) of the
corresponding heterocycles were obtained in refluxing THF or
CH3CN or in dioxane at 100 °C (Table1, entries 1, 3, 4, 6, 8
and 9). When the reaction was carried out in dimethyl carbon-
ate or toluene at 100 °C for 12 h excellent yields (80–90%)
were obtained (Table 1, entries 2, 5, 7 and 10). As a control
experiment, the same reaction was carried out in the absence
of CeCl3–NaI and only 5% of benzothiazole was obtained
(Table 1, entry 11).
/°C
%
1
2
3
4
5
1a
1a
1a
1a
1a
Dioxane
Toluene
THF
100 CeCl3–NaI (10–10) 50
100 CeCl3–NaI (10–10) 81
Reflux CeCl3–NaI (10–10) 60
Acetonitrile Reflux CeCl3–NaI (10–10) 51
Dimethyl
carbonate
Dioxane
Toluene
THF
100 CeCl3–NaI (10–10) 81
6
7
8
9
1b
1b
1b
1b
1b
100 CeCl3–NaI (10–10) 60
100 CeCl3–NaI (10–10) 91
Reflux CeCl3–NaI (10–10) 70
Acetonitrile Reflux CeCl3–NaI (10–10) 63
10
Dimethyl
carbonate
Dimethyl
carbonate
100 CeCl3–NaI (10–10) 90
11
1b
100 None <5
With the initial results in hand, the scope and limitations of
the procedure were then tested. Various aliphatic and aromatic
a Reaction conditions: 2-phenylenediamine (1 mmol) or 2-
aminothiophenol (1 mmol) ; aldehyde (1 mmol); CeCl3-NaI
(10–10 mol%); solvent (5 mL); 12 h; under O2.
b GC-MS yield.
* Correspondent. E-mail: ywei@mail.njust.edu.cn

120 JOURNAL OF CHEMICAL RESEARCH 2013
Table 2 CeCl3–NaI catalysed synthesis of 2-alkyl- and
flame ionisation detector. GC-MS spectra were recorded on Thermo
Trace DSQ GC-MS spectrometer using TRB-5MS (30 m × 0.25 mm
× 0.25 µm) column. Melting points were determined using a XT-4
apparatus and are not corrected. The 1H NMR spectra were obtained
on a Bruker DRX500 (500 MHz) spectrometer using CDCl3 or
DMSO-d6 as solvent with TMS as internal standard. Progress of the
reactions was followed by TLC using silica-gel polygrams SIL G/UV
254 plates. Column chromatography was performed using Silicycle
(40–60 mm) silica gel. All products are known compounds and were
characterised by comparison of their physical and spectral properties
with literature data.
2-aryl-benzimidazoles and 2-alkyl- and 2-aryl-benzothiazolesa
Entry
X
R
Yield/% b
1
2
NH
NH
NH
NH
NH
NH
NH
NH
NH
S
H
61
67
89
88
85
81
65
63
61
90
92
92
75
82
85
79
General experimental procedure
CH3(CH2)3
4-NO2C6H4
4-ClC6H4
4-BrC6H4
C6H5
2-Phenylenediamine (1 mmol) or 2- aminothiophenol (1 mmol), and
benzaldehyde (1 mmol) in dimethyl carbonate (5 mL), were stirred
for 20 min at RT, CeCl3 (0.0246 g, 0.1 mmol) and NaI (0.0150 g,
0.1 mmol) were then added and the mixture was stirred at 100 °C
under O2 for 12h. The reaction mixture after cooling was poured into
water and the aqueous solution was extracted with ethyl acetate (3 ×
8 mL). Evaporation of the solvent gave a crude product which was
purified on a small silica gel column with EtOAc: petroleum ether
(1:8) as eluent, prior to recrystallisation.
3
4
5
6
7
4-CH3OC6H4
2-C4H3S
2-C4H3O
C6H5
4-ClC6H4
4-NO2C6H4
4-CH3OC6H4
4-CH3C6H4
CH3(CH2)2
CH3(CH2)3
8
9
10
11
12
13
14
15
16
S
Benzimidazole: M.p. 170–172 °C (EtOH) (lit.9 174 °C); H NMR
1
S
S
(DMSO-d6): δ 12.47 (s, 1H), 8.22 (s, 1H), 7.60 (s, 2H), 7.19 (d, J =
4.0 Hz, 2H).
S
2-(4-Nitro-phenyl)-benzimidazole: M.p. 315–317 °C (EtOH) (lit.21
S
1
S
316 °C); H NMR (DMSO-d6): δ 8.34 (d, J = 9.0 Hz, 2H), 8.26 (d,
a Reaction conditions: 2-phenylenediamine (1 mmol) or 2-
aminothiophenol (1 mmol) ; aldehyde (1 mmol); CeCl3–NaI
(10 mol%-10 mol%); dimethyl carbonate (5 mL); 12 h; under O2.
b Isolated yield.
J = 8.5 Hz, 2H), 7.23–7.25 (m, 1H), 7.00–7.03 (m, 1H), 6.74–6.76 (m,
1H), 6.55–6.59 (m, 1H).
2-(4-Chloro-phenyl)-benzimidazole: M.p. 292–294 °C (EtOH)
1
(lit.21 294 °C); H NMR (DMSO-d6): δ 12.99 (s, 1H), 8.19 (m, 2H),
7.54–7.65 (m, 4H), 7.22 (s, 2H).
2-(4-Bromo-phenyl)-benzimidazole: M.p. 298–299 °C (EtOH) (lit.9
1
299–300 °C); H NMR (DMSO-d6): δ 12.99 (s, 1H), 8.12 (d, J =
intermediate. CeInCl3-n then promotes cyclisation to a bicyclic
intermediate, dehydrogenation of which gives the final prod-
uct. According to this mechanism, aromatic aldehydes bearing
an electron withdrawing group would be highly reactive since
they possess a more electrophilic carbonyl carbon which is
beneficial for the attack of the amino group to form the imine
intermediate which is itself very reactive towards the subse-
quent attack of the amino or hydroxyl group to form, after
dehydrogenation, the final product.
In conclusion, a new method for the synthesis of 2-alkyl- or
2-aryl-benzimidazoles and 2-alkyl- or 2-aryl-benzothiazoles
from aldehydes and 2-phenylenediamine or 2-aminothiophe-
nol in the presence of 10% CeCl3–NaI is reported. The one-pot
synthesis was carried out in dimethyl carbonate at 100 °C
using O2 as the oxidant. The procedure is suitable for the syn-
thesis of 2-substituted benzimidazoles and benzothiazoles
from aliphatic, aromatic or heteroaromatic aldehydes.
8.5 Hz, 2H), 7.77 (d, J = 9.0 Hz, 2H), 7.67 (d, J = 6.5 Hz, 1H), 7.54
(d, J = 7.5 Hz, 1H), 7.22 (s, 2H).
2-Phenyl-benzimidazole: M.p. 289–291 °C (EtOH) (lit.21 292 °C);
1H NMR (DMSO-d6): δ = 12.90 (s, 1H), 8.18 (d, J = 8.5 Hz, 2H),
7.50–7.57 (m, 5H), 7.21–7.22 (m, 2H).
2-(4-Methoxy-phenyl)- benzimidazole: M.p. 224–226 °C (EtOH)
1
(lit.21 226 °C); H NMR (DMSO-d6): δ 12.79 (s, 1H), 8.12 (d, J =
9.0 Hz, 2H), 7.55 (s, 2H), 7.11–7.18 (m, 4H), 3.84 (s, 3H).
2-(2-Furyl)-1H-benzimidazole: M.p. 287–288 °C (EtOH) (lit.21
1
288 °C); H NMR (DMSO-d6): δ 12.92 (s, 1H), 7.95 (s, 1H), 7.50–
7.62 (m, 2H), 7.19–7.20 (m, 3H), 6.73–6.74 (m, 1H).
2-(2-Thienyl)-1H-benzimidazole: M.p. 329–331 °C (EtOH) (lit.10
330 °C); 1H NMR (DMSO-d6): δ 12.93 (s, 1H), 7.83 (d, J = 3.0 Hz,
1H), 7.73 (d, J = 5.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.50 (d,
J = 7.5 Hz, 1H), 7.16–7.24 (m, 3H);
2-Phenyl-benzothiazole: M.p. 113–114 °C (EtOH) (lit.22 112–114
1
°C); H NMR (CDCl3) δ 7.95 (m, 2H), 7.52 (m, 3H), 7.34 (d, 1H,
J = 8.5 Hz), 7.23 (t, 1H, J = 8.5 Hz), 7.05 (d, 1H, J = 8.5 Hz), 6.94 (t,
1H, J = 8.5 Hz); MS (EI) m/z 210.94 (M+).
2-(4-Chloro-phenyl)-benzothiazole: M.p. 116–118 °C (EtOH) (lit.22
116–117 °C); 1H NMR (CDCl3) δ = 8.02 (d, 2H, J = 8.0 Hz), 7.73 (d,
1H, J = 8.0 Hz), 7.58 (t, 1H, J = 8.0 Hz), 7.49 (d, 2H, J = 8. Hz), 7.43
(t, 1H, J = 8.5 Hz), 7.20 (d, 1H, J = 8.5 Hz).
Experimental
All chemicals (AR grade) were obtained from commercial resources
and used without further purification. Gas chromatography analysis
was performed on an Agilent GC-6820 chromatograph equipped
with a 30m×0.32mm×0.5µm HP-Innowax capillary column and a
2-(4-Nitro-phenyl)-benzothiazole: M.p. 226–228 °C (EtOH) (lit.22
1
226–228 °C); H NMR (CDCl3) δ 8.37 (d, 2H, J = 8.5 Hz), 8.11 (d,
Scheme 1 Possible mechanism and tentative intermediates in the synthesis of 2-arylbenzimidazoles (X=NH) and
2-arylbenzothiazoles (X=S).23

JOURNAL OF CHEMICAL RESEARCH 2013 121
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Received 31 October 2012; accepted 31 December 2012
Paper 1201602 doi: 10.3184/174751913X13575704209748
Published online: 13 February 2013
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