Mild, one-pot preparation of 2-substituted benzimidazoles from organic halides

Article abstract of DOI:10.1080/00397911.2017.1287922

Alkyl halides are feasibly transformed into benzimidazoles by a domino reaction under solvent-free conditions. The organic halides react with o-phenylenediamines in stoichiometric amounts in the presence of pyridine-N-oxide to produce the desired substituted benzimidazoles. This domino synthesis does not require catalysts. The synthesis occurs in dry medium and the environmental impact is minimal. The method provides products without intermediate separation. A mechanism of benzimidazole synthesis is also proposed.

Full text of DOI:10.1080/00397911.2017.1287922

A Mild, One-Pot Preparation of 2-Substituted Benzimidazoles from Organic Halides
1
George Brătulescu
1
Department of Chemistry, University of Craiova, Craiova, Romania
Corresponding author George Brătulescu E-mail: kzpzk@yahoo.com
Abstract
Alkyl halides are feasibly transformed into benzimidazoles by an domino reaction under
solvent-free conditions. The organic halides react with orthophenylenediamines in
stoichiometric amounts in the presence of pyridine-N-oxide to produce the desired
substituted benzimidazoles. This domino synthesis does not requires catalysts. The
synthesis occurs in dry medium and the environmental impact is minimal. The method
provides products without intermediate separation. A mechanism of benzimidazole
synthesis is also proposed.
Graphical Abstract
KEYWORDS: benzimidazoles, domino reaction, oxidation, dry medium
INTRODUCTION
The benzimidazole ring is one of the most important pharmacophores in the design of
[
1]
modern synthetic drugs. The biological activity of benzimidazole compounds is quite
1

diverse, and many benzimidazole derivatives are used in various active pharmaceutical
[
2]
ingredients for human and veterinary use.
Benzimidazoles and their derivatives exhibit important pharmacological properties; for
[
4]
[4]
example, they act as histamine H(4) receptor binders, anti-ulcer agents, anti-
[
5]
[6]
hypertensive agents, anti-cancer agents, poly(ADP-ribose) phosphorylase
[7]
[8]
[9]
inhibitors, anti-viral agents, anti-tumour agents, anti-microbial and antifungal
[
10]
[11]
[12]
[13]
agents,
anti-parasitic agents,
anti-inflammatory agents
and HIV inhibitors.
Benzimidazole ligands are also found in biological molecules forming complexes with
[14]
transition metal ions.
From the medicinal chemistry point of view, only compounds
[15]
substituted in positions 1, 2 and 5 exhibit a wide range of pharmacological activities.
Typically, several different approaches have been used to synthesize substituted-1H-
[16]
benzo [d]imidazoles.
Traditional methods of synthesizing benzimidazoles consist of the reaction
[
17]
between orthophenylenediamines and carboxylic acids
or their functional derivatives
[
18]
(nitriles, imidates, orthoesters)
or cascade reactions of o-aminoanilines or
[
19]
naphthalene-1,8-diamines with terminal alkynes and p-tolylsulfonyl azide. However,
these methods have many disadvantages, such as a strong acidic medium, harsh
dehydrating reaction conditions, high temperatures and long reaction times (from 3 h to
2
3 h).
2

[
20]
The catalytic intramolecular N-arylation of N-(2-haloaryl) alkylimidamides,
[
21]
the condensation between arylamino oximes and dichloromethane
and the cascade
intermolecular addition/intramolecular C-N coupling process of o-haloarylcarbodiimides
[22]
with N- or O-nucleophiles produce benzimidazoles.
Nevertheless, many of the
protocols used to prepare substituted benzimidazoles require hazardous solvents (tertiary
amines, DMSO, DCM, DMEDA), expensive catalysts (e.g. palladium) and very long
reaction times (from 6 h to 30 h).
Oxidative procedures were developed by replacing the carboxylic acids with
aldehydes or alcohols in the synthesis of benzimidazoles from o-aminoanilines in the
[
23-30]
presence of an oxidant.
The oxidant performs cyclodehydrogenation of the
[
23]
corresponding aromatic amine Shiff bases intermediate. Such oxidants are H O ,
2
2
[24]
[25]
[26]
hypervalent iodine reagents,
potassium peroxymonosulfate,
MnO2,
[
27]
[28]
[29]
Pb(OAc)4,
NH VO ,
nitrogen dioxide and ozone (Kyodai nitration),
air and
4
3
[
30]
green catalysts.
These methods are not straightforward and require laborious workup
and purification procedures. The malign oxidants containing heavy metals generate toxic
byproducts and low isolation yields.
[31]
Recently,
a synthetic way to obtain substituted benzimidazoles has been
reported. The procedure uses 2-nitroanilines and aldehydes and involves a reductive
cyclization strategy. The protocol requires sodium dithionite (Na S O ), formic acid, iron
2
2
4
powder and NH Cl as additives to reduce the nitro group and accomplish the imidazole
4
3

cyclization. However, this protocol consumes a very large amount of iron, with the
excess turning into waste iron oxides at the end of the reaction.
[
32]
[33]
Unconventional methods involving microwaves
been used to obtain substituted benzimidazoles.
and ultrasounds
have also
RESULTS AND DISCUSSION
Given the great medicinal and pharmaceutical importance of benzimidazole derivatives,
we developed a method that transforms organic halides and orthophenylenediamines into
substituted benzimidazoles. From what we know so far, this is the first direct synthesis of
benzimidazoles from halocarbons by domino reaction with the help of pyridine-N-oxide
in absence of catalysts and solvents (Scheme 1).
The pattern reaction between benzyl bromide, o-phenylenediamine and pyridine-N-oxide
in which the 2-phenylbenzimidazole product is obtained was used as a starting point in
our study. The reaction mixture was heated at different temperatures for varying periods
of time. Benzimidazole production depends strongly on the molar ratio of reactants,
temperature and time (Table 1). Thus, an excess of 25% pyridine-N-oxide gives a better
result compared to the stoichiometric molar ratio of the reaction. The reaction
temperature of 105 °C provided a good yield of 80% after 2 h (Table 1, entry 7).
We think that in the first stage, the halide is oxidized to aldehyde by pyridin-N-oxide
[
34]
(Scheme 2). This transformation is very similar to that of the Kornblum reaction
but
4

with the advantage of mild reaction conditions. Next, o-phenylenediamine gives a
1
condensation reaction with benzaldehyde to form the Schiff base N -benzylidene
benzene-1,2-diamine (II). The Schiff base turns into 2,3-dihydro-1H-benzoimidazole (III)
by an intramolecular cycloaddition, followed by oxidation with pyridin-N-oxide to 2-
phenylbenzimidazole (IV).
With this set of reaction conditions, a series of benzimidazoles derivatives was
obtained (Table 2). The synthesis of the products performs in high yields. The amount of
benzimidazole derivative depends on the experimental conditions, such as the work
reaction temperature, the molar ratio of reactants, the reaction time and the nature of the
halide and amine used.
Toxic by-products such as hydrogen bromide does not release from the synthesis because
+
-
results the salt of pyridinium bromide, [PyH] Br . Further, pyridine was fully recovered
from the filtrate (99.5%) using the well-known method of azeotropic distillation and
separation of sodium hydroxide. Pyridine was recycled in the synthesis of benzimidazole
derivatives by conversion into pyridine-N-oxide. Pyridine oxidation was achieved with
[
35]
peracetic acid using the existing protocol.
Although the carboxylic acids, aldehydes and alcohols are more affordable than organic
bromine compounds used in our protocol, the negative impact of the environment
constitute a strong drawback. The synthesis of benzimidazoles from aromatic amines and
aldehydes in excess is performed using harmful organic solvents (acetonitrile, DMSO,
5

DMF, dioxane) with large amounts of concentrated acid catalysts (350% excess of HCl
[
23]
[47]
3
5
7% and 600% excess of H O 30%),
heavy metal salts (CuCl),
IBX (in excess of
2
2
[
24]
[48]
0%),
H O 37% (300% excess) coupled with ceric ammonium nitrate . The
2 2
synthesis of benzimidazoles from amines and carboxylic acids requires a large amount of
[49]
[50]
carboxylic acid (200% excess),
organic solvents (DCM) and Lewis acids.
The
excess of aldehyde or carboxylic acid along with the catalysts and organic solvents
generate significant harmful wastes at the end of the synthesis.
[
51]
[52]
Recently, a patent
and a paper
published by the same authors describe the same
method of synthesis of benzimidazoles from organic halides, o-phenylenediamines and
DMSO with the help of copper halide and sodium bicarbonate as catalysts at temperature
of 120°C. This method requires 24 h reaction time and very large amount of hazardous
organic solvents.
All these known methods involve either hazardous catalysts or toxic organic
solvents as reaction medium. Moreover, the separation of benzimidazoles is carried out
by chromatographic techniques and require huge amounts of toxic organic solvents. Also,
chemistry metrics have strong drawbacks, as they have a high environmental E-factor and
low mass efficiency.
CONCLUSION
A rapid work-up and high-yielding benign protocol that uses organohalide and amine in
stoichiometric amounts without solvents and catalysts was developed for the domino
6

synthesis of benzimidazoles. The reaction occurs in dry heterogeneous medium without
separation of the intermediates and their purification. The method is an alternative to the
expensive and poisonous catalysts, hazardous solvents, and strong acids usually used in
all current protocols for the preparation of benzimidazoles. The benefits of domino
sequences cover reduction of waste generated and atom economy.
EXPERIMENTAL
Organic bromide, orthophenylenediamine, pyridine-N-oxide are commercial compounds.
The synthesized products were identified by TLC (EtOAc-petroleum ether), elemental
1
13
analysis, H-NMR, C-NMR, and IR spectra. The NMR spectra were recorded on a
1
13
BRUKER ARX instrument (300 MHz for H and 75 MHz for C). DMSO-d was used
6
as the solvent and tetramethylsilane as an internal standard. The infrared spectra were
recorded using an Alpha Bruker Optics spectrometer. Microanalyses were carried out on
a Carlo Erba CHN analyzer, model 1106. The melting points were determined on a
Gallenkamp digital melting point apparatus.
General Procedure For The Synthesis Of 2-Substituted Benzimidazoles
Primary alkyl bromide derivative (5 mmol), pyridine-N-oxide (12.5 mmol) and
orthophenylenediamine derivative (5 mmol) are well mixed in a 25 mL round bottomed
flask and placed in an oil bath on a magnetic stirrer hot plate at required temperature. The
mixture was heated to selected temperature for required time (Table 2). After completion
of the reaction (TLC, AcOEt-petroleum ether), the organic mixture was washed with
dilute NaOH and filtered off. The filtrate was collected for recovery of pyridine. The
7

resulting residue was recrystallized from EtOH-H O to give the desired benzimidazole
2
products. Pyridine was recovered from the filtrate (99.5%) by azeotropic distillation (bp.
9
2.6°C) and separation on sodium hydroxide. Resulting pyridine was oxidized with
[35]
peracetic acid to the pyridine-N-oxide
which was then reused in reaction. All of the
[36-46]
products are known compounds
and their identity was easily confirmed by
1
13
comparison with authentic samples (mp, H-NMR, C-NMR).
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[
1
1
1

Table 1. Screening of reaction conditions for 2-phenylbenzimidazole synthesis.
Entry Molar ratio
PhCH Br Pyridine-N-
Time
min.]
T [°C]
Yield
[%]
[
o-
2
oxide
1
Phenylenediamine
1
2
3
4
5
6
7
8
9
1
1
1
1
160
130
120
140
120
130
120
130
120
140
150
100
110
105
110
105
100
105
105
105
110
110
34
78
56
59
76
73
80
80
79
70
80
1
1
2
1
1.5
1
1
1.5
1
1
2
1
1
2.5
2.5
2.5
2.5
2.5
2.5
1
1
1
1
1
1
1.5
1
0
1
1.5
1
2
1
2

a
Table 2 Synthesis of benzimidazole derivatives in dry heterogeneous medium.
b
No Product
Time [min] T [°C] Yield [%]
I
II
III
IV
V
1
120
105
80
2
3
4
120
120
130
105
110
105
78
83
73
5
6
190
120
110
110
62
76
7
8
9
120
120
120
105
110
110
85
77
74
1
1
0
1
120
120
110
110
64
79
1
2
120
105
76
a -The products were characterized by comparison of their spectroscopic and physical
data with authentic samples synthesized by reported procedures.
1
3

b - Isolated and unoptimized yields.
1
4

Scheme 1. Conversion of primary alkyl halides to benzimidazoles.
1
5

Scheme 2. Presumed reaction mechanism of formation of 2-phenyl benzimidazole.
1
6