CuBr-Catalyzed Oxidation/Coupling: An Efficient and Applicable Strategy for the Synthesis of 2-Aryl Benzimidazoles from 1-Fluoro-2-nitrobenzene and Benzylamines

Article abstract of DOI:10.1080/00397911.2014.971971

A novel and efficient route has been developed for the synthesis of benzimidazole derivatives via ligand-free CuBr-catalyzed oxidation and cyclization of 1,2-diamines derived from 1-fluoro-2-nitrobenzene and different arylamines as starting materials. GRAPHICAL ABSTRACT.

Full text of DOI:10.1080/00397911.2014.971971

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CuBr-Catalyzed Oxidation/Coupling: An Efficient
and Applicable Strategy for the Synthesis of 2-Aryl
Benzimidazoles from 1-Fluoro-2-nitrobenzene and
Benzylamines
Behrooz Mirzaa & Mohsen Zeeba
a Department of Applied Chemistry, Faculty of Science, Islamic Azad University, Tehran, Iran
Accepted author version posted online: 05 Nov 2014.
To cite this article: Behrooz Mirza & Mohsen Zeeb (2014): CuBr-Catalyzed Oxidation/Coupling: An Efficient and
Applicable Strategy for the Synthesis of 2-Aryl Benzimidazoles from 1-Fluoro-2-nitrobenzene and Benzylamines,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2014.971971
To link to this article: http://dx.doi.org/10.1080/00397911.2014.971971
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CuBr-Catalyzed Oxidation/Coupling: An Efficient and Applicable Strategy for the
Synthesis of 2-Aryl Benzimidazoles from 1-Fluoro-2-nitrobenzene and
Benzylamines
Behrooz Mirza1, Mohsen Zeeb1
1Department of Applied Chemistry, Faculty of Science, Islamic Azad University, Tehran,
Iran
Corresponding author.: E-mail: b_mirza@azad.ac.ir
Abstract
A novel and efficient route has been developed for the synthesis of benzimidazole
derivatives via ligand-free CuBr-catalyzed oxidation and cyclization of 1,2-diamines
derived from 1-fluoro-2-nitrobenzene and different arylamines as starting materials.
KEYWORDS: CuBr; oxidation/coupling; benzimidazoles; 1-fluoro-2-nitrobenzene.
INTRODUCTION
Benzimidazole and its derivatives are a very interesting class of compounds due to their
interesting biological activities and potential pharmaceutical applications in a large
1

number of pharmacological targets.[1,2] These nitrogen containing heterocycles were
found to possess important biological activities such as antibacterial,[3-9] anticancer,[10,11]
antidiabetic,[12] anthelmintic,[13] analgesic, anti-inflammatory,[14,15] and antioxidant[16] with
substitution at various positions. Regarding to their pivotal pharmacological properties,
great attention has been devoted to the synthesis of benzimidazole derivatives. The
condensation of 1,2-phenylenediamine with carboxylic acids or their derivatives under
strong acidic conditions and sometimes high temperature is the most common method to
synthesis of benzimidazole derivatives.[17] The other synthetic route is the cyclo-
dehydrogenation of aniline Schiff’s bases, which generated from the condensation of 1,2-
phenylenediamines and aldehydes,[18] follows by oxidation with different oxidants such
as Oxone,[19] I2:KI:K2CO3:H2O,[20] NaHSO3,[21] MnO2,[22] applying hexafluorophosphoric
acid under microwave condition,[23] and catalytic use of AlKIT-5.[24] Recently, copper-
catalyzed N-arylation has been reported as an efficient strategy for the cross coupling and
synthesis of N-heterocyclic compounds.[25-28]
Under these circumstances, this study was disclosed during the course of seeking for a
more efficient catalytic system on the preparation of different catalyst supporting agents
to synthesis of 2-Aryl Benzimidazoles. As part of our continuing efforts for the
expeditious synthesis of biologically relevant heterocyclic compounds,[29,30] herein we
describe an efficient and practical synthesis of benzimidazoles via copper-catalyzed
oxidation and cyclization reaction of o-phenylenediamines derived from 1-fluoro-2-
nitrobenzene and benzyl amines as starting materials.
2

RESULTS AND DISCUSSION
By virtue of the aforementioned advantages of benzimidazoles, the synthetic route to
target compounds namely 2-aryl-1H-benzo[d]imidazole derivatives 5a-h from 1-fluoro-
2-nitrobenzene was studied (Scheme 1). Initially, the selective aromatic nuclephilic
substitution reaction of 1-fluoro-2-nitrobenzene by a primary amine was carried out to
obtain the corresponding o-nitroaniline. As known, the displacement of the substituent at
1-position is faster when the aromatic ring contains electron-withdrawing substituents at
ortho or/and para positions.[31] To determine the best operative reaction condition, the
later reaction was tried with benzylamine 2a in various solvents and bases. The N-
phenylmethyl-o-nitroaniline 3a was obtained in excellent yields (> 90%) using K2CO3 at
80 °C and in DMF as solvent.[32] In the next step, the obtained o-nitroaniline was afforded
to 2-N-phenylmethylaniline 4a via treatment with Zinc and ammonium chloride (Zn-
NH4Cl) in methanol at room temperature within 8-15 min.[33] The work-up of the
products and purification were simple and excellent yields were obtained (~95%).
In the last step of our designed synthesis, we investigated 2-N-phenylmethylaniline 4a as
the model substrate in the presence of CuBr, K2CO3, and DMSO, as catalyst, base, and
solvent, respectively. The reaction was accomplished under air (1 atm) in order to
synthesize 2-phenyl-1H-benzo[d]imidazole 5a via the sequential copper-catalyzed
aerobic oxidation, and an intramolecular nucleophilic addition process without the
addition of any ligand and additive.[34]
3

After the optimization, we realized that CuBr (0.1 equiv) as catalyst with 3 equiv of
K2CO3 (relative to amount of substrate) in DMSO as the solvent at 120 °C provided the
highest yield (Table 1). Other bases such as Cs2CO3 and NaOAc were screened which
K2CO3 showed the best activity.
To reveal the generality and utility of the protocol, various arylamines 2a-h were
subjected to the reaction with 1 according to the reaction conditions of Scheme 1 which
the results are summarized in Table 2. Using this designed synthetic protocol, an array of
arylamines 2a-h having different substitutions reacted with 1 and the corresponding
benzimidazoles 5a-h were prepared in high yields 70-88%.
A possible mechanism for the preparation of benzimidazole derivatives is proposed in
Scheme 2 owing to the obtained results. The reaction of 1-fluoro-2-nitrobenzene with
benzyl amine leads o-nitroaniline 3a which formed by the displacement of fluorine in
quantitative yields in the presence of K2CO3 as base. Then the coupled nitroarene is
reduced to 4a using Zn–NH4Cl (aq) as reducing agent. Then 4a is converted to
intermediate 6a containing a C=N bond using copper-catalyzed aerobic oxidation
reaction, and the intramolecular nucleophilic addition of the amino nitrogen to the C=N
bond in 6a leads to corresponding 2,3-dihydro-2-phenyl-1H-benzo[d]imidazole
benzimidazoles 7a. Afterward, the intermediate 7a is converted to 2-phenyl-1H-
benzo[d]imidazole 5a using copper-catalyzed aerobic oxidation reaction. The
interestingly, no ligand or additive is required in this reaction system.
4

The presented protocol for the synthesis of benzimidazole derivatives shows good
potential as a method of choice for large-scale preparation of these scaffolds. To confirm
this capability, the preparation of 5a was scaled-up to provide multi-gram quantities of
this compound (67% total yield).
CONCLUSION
In summary, we have introduced a simple and efficient method for the synthesis of 2-aryl
substituted benzimidazole derivatives from 1-fluoro-2-nitrobenzene and aryl amines as
starting materials in acceptable yields. This synthetic route utilizes cheap and readily
available catalysts and starting materials, and also is an economical and environmentally
friendly manner due to the usage of air as the oxidant. This protocol can be a useful
example of constructing N-heterocycles via the coupling of 1-fluoro-2-nitrobenzene with
different aryl amines, sequential aerobic oxidation, and intramolecular nucleophilic
addition process under air. The mild reaction conditions, cost-effective, simple workup
procedure and acceptable yields as well as the scope for using air as a green oxidant made
our methodology a valuable contribution to the preparation of benzimidazole derivatives.
EXPERIMENTAL
Commercially available chemicals and solvents were purchased from Merck and Fluka
chemical company and used without further purification. Melting points are measured
with a Kofler hot stage apparatus and are uncorrected. 1H and 13C NMR spectra were run
on a Bruker FT-250 using DMSO-d6 and TMS as solvent and internal standard,
5

respectively. IR spectra were recorded on a Shimadzu 470 spectrophotometer (KBr
disks).
General Procedure For Synthesis Of 2-Aminoaniline Derivatives 4a-H
To a stirred solution of 2-nitroaniline (1mmol) in MeOH and saturated NH4Cl solution (4
ml, 1:1) was added zinc dust (10 mmol) portion-wise over 15 min at 0 C. completion of
the reaction (TLC), the reaction mixture was filtered through Celite, and the MeOH
waremoved under vacuo, then the aqueous residue was extracted with Et2O. Next, the
organic solvent was dried (Na2SO4) and concentrated. The crude product was purified by
column chromatography over silica gel.
General Procedure For Synthesis Of Benzimidazole Derivatives 5a-H
A solution of 2-aminoaniline 4a-h (0.2 mmol), K2CO3 (0.6 mmol, 83 mg) and CuBr (0.02
mmol, 2.8 mg) in DMSO (2 mL) was provided. The mixture was allowed to stir under air
(1atm) at 120 °C for 14 h. After completion of the reaction, the resulting solution was
cooled to room temperature and filtered. Afterward, the filtrate was evaporated using a
rotary evaporator. Then the residue was purified by column chromatography on silica gel
using petroleum ether/ethyl acetate (3:1 to 2:1) as eluent to provide 5a-h. All the products
1
were identified and characterized by comparison of mp, IR, and HNMR and 13CNMR
spectroscopy with those reported in literatures.[35]
Selected Data
2-Phenyl-1H-Benzimidazole (5a)
6

Colorless solid; mp 282-284 °C; IR (KBr); υ(cm-1): 1620 (C=N); 1H NMR (DMSO-d6,
250 MHz): δ = 7.14–7.25 (m, 2 H), 7.44–7.61 (m, 5 H), 8.20 (d, J = 7.2 Hz, 2 H), 12.94
(s, 1 H, NH) ppm; 13C NMR (DMSO-d6): δ = 122.1, 126.4, 128.4, 128.9, 129.2, 129.8,
130.1, 151.2.
2-(4-Chlorophenyl)-1H-Benzimidazole (5b)
Colorless solid; mp 292–293 °C; IR (KBr); υ(cm-1): 1626 (C=N); 1H NMR (DMSO-d6,
250 MHz): δ = 7.18–7.21 (m, 2 H), 7.60 (m, 4 H), 8.17 (d, J = 8.6 Hz, 2 H), 12.99 (s, 1
H, NH) ppm; 13C NMR (DMSO-d6): δ = 111.4, 118.9, 121.9, 122.7, 128.1, 129, 134.5
150.1.
ACKNOWLEDGMENTS
Support of this investigation by the Islamic Azad University Tehran South Branch
through grant is gratefully acknowledged.
SUPPORTING INFORMATION
Full experimental details, 1H and 13C NMR spectra for this article can be accessed on the
publisher’s website.
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Table 1. The optimal reaction condition for the synthesis of benzimidazoles 5a.
Entry
Basea
CuBr (equiv) Solvent
Temp.(°C) Time (h) Yield (%)
1
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
___
0.1
0.1
0.2
0.2
0.2
DMSO
DMSO
DMSO
DMSO
CH3CN
DMF
120
120
120
120
80
24
24
12
12
12
12
12
12
12
12
trace
81
88
74
25
34
45
63
21
18
2
3
4
5
6
100
120
120
120
120
7
Cs2CO3 0.1
Cs2CO3 0.2
NaOAc 0.1
NaOAc 0.2
DMSO
DMSO
DMSO
DMSO
8
9
10
a( 3 equiv)
11

Table 2. The synthesis of benzimidazoles 5a-h from 1-fluoro-2-nitrobenzene and
arylamines.
Entry
Ar-
Product
4a
Yield (%)a
1
2
3
4
5
6
7
8
Ph-
88
73
80
81
71
70
75
77
4-Cl-Ph-
4-CH3-Ph-
4-NO2-Ph-
4-MeO-Ph-
2-Cl-Ph-
4-OH-Ph-
4-CN-Ph-
4b
4c
4d
4e
4f
4g
4h
a Isolated yields
12

Scheme 1. The synthesis route of 2-phenyl-1H-benzo[d]imidazole 5a.
13

Scheme 2. The plausible mechanism for the synthesis of 5a.
14