A green route for the one-pot synthesis of 1,2-disubstituted benzimidazoles using iron(III) phosphate under solventless conditions

Article abstract of DOI:10.1002/cjoc.201180461

1,2-Disubstituted benzimidazoles are selectively synthesized in high yields under extremely mild conditions via the condensation of o-phenylenediamine derivatives with aldehyde derivatives using catalytic amount of iron(III) phosphate under solvent-free conditions. The use of readily available iron(III) phosphate as a reusable and recyclable catalyst makes this process quite simple, convenient, and environment-friendly. Copyright

Full text of DOI:10.1002/cjoc.201180461

FULL PAPER
DOI: 10.1002/cjoc.201180461
A Green Route for the One-Pot Synthesis of 1,2-Disubstituted
Benzimidazoles Using Iron(III) Phosphate under Solventless
Conditions
Behbahani, F. K.*
Ziaei, Parisa
Department of Chemistry, Karaj Branch, Islamic Azad University, Karaj, Iran
1,2-Disubstituted benzimidazoles are selectively synthesized in high yields under extremely mild conditions via
the condensation of o-phenylenediamine derivatives with aldehyde derivatives using catalytic amount of iron(III)
phosphate under solvent-free conditions. The use of readily available iron(III) phosphate as a reusable and recycla-
ble catalyst makes this process quite simple, convenient, and environment-friendly.
Keywords 1,2-disubstituted benzimidazoles, iron(III) phosphate, solvent-free
Introduction
terms of operational simplicity, economic viability and
selectivity.
The most prominent benzimidazole compound in
nature is N-ribosyl-dimethylbenzimidazole, which
serves as an axial ligand for cobalt in vitamin B12,[1]
possessing selective neuropeptide YYl receptor antago-
nists,[2] 5-lipoxygenase inhibitors,[3] 5-HT3 antago-
nists,[4] poly(ADP-ribose) polymerase (PARP) inhibi-
tors[5] and factor Xa (Fxa) inhibitors.[6] In addition, they
exhibit significant activity against several viruses, such
as HIV, herpes (HSV-1), RNA influenza, and human
cytomegalovirus (HCMV).[7] Benzimidazole derivatives
have also found commercial applications in veterinarian
medicine.[8] Medicinal chemists would certainly classify
benzimidazoles as privileged substructures for drug de-
sign.[9] Consequently, a variety of methods have been
developed for the preparation of substituted benzimida-
zoles.[10] Of these, one of the most traditional methods
involves the condensation of an o-phenylenediamine
with carboxylic acid or its derivatives.[11] Subsequently,
several improved protocols have been developed for the
synthesis of benzimidazoles via the condensation of
o-phenylenediamines with aldehydes in the presence of
acid catalysts under various reaction conditions.[12]
However, many of these methods suffer from certain
drawbacks, including longer reaction times, unsatisfac-
tory yields, harsh reaction conditions, expensive agents,
tedious work-up procedures, co-occurrence of several
side reactions, and poor selectivity. Since benzimidazole
derivatives are useful and important in the field of drugs
and pharmaceuticals, the development of simple, con-
venient, high yielding and environmentally benign pro-
tocols is desirable. Therefore, the search continues for a
better catalyst for the synthesis of benzimidazoles, in
On the other hand, iron(III) phosphate is a relatively
cheap and safe catalyst that is prepared using Fe2(SO4)3
and disodium phosphate[13] and purchased commercially.
Iron(III) phosphate[14] is being petitioned for use as a
pesticide (molluscicide) to prevent extensive damage to
and/or destruction of vegetables, citrus and non-citrus
fruit, berries, field crops, ornamentals, greenhouse and
nursery plants, lawns, and gardens for seed production.
It is not harmful to human health. Chemically, iron(III)
phosphate is very stable and will not dissociate unless in
the presence of concentrated acid, which is not present
in natural surroundings, because of its low solubility in
the aqueous agro ecosystem, there is little contamination
beyond treated areas. Iron(III) phosphate has also been
employed for the selective oxidation of CH4 to
CH3OH[15] and benzene to phenol[16] and one-pot syn-
thesis of dihydropyrimidinones and thiones[17] and syn-
thesis of triarylated imidazoles[18] as a catalyst. There-
fore, ongoing previously our works to introduce the
green protocol for the synthesis of heterocyclic com-
pounds using eco-friendly catalyst,[19] herein iron(III)
phosphate is reported as a green, reusable, recyclable,
environmentally safe, inexpensive and commercially
available catalyst for the synthesis of 1,2-disubstituted
benzimidazole derivatives under solventless conditions
at room temperature (Scheme 1).
Results and discussion
Initially, in order to ascertain a suitable condition,
we chose o-phenylenediamine (1 mmol) and benzalde-
hyde (2 mmol) to establish the conditions for the con-
*
E-mail: Farahnazkargar@yahoo.com; Tel.: 0098-0261-4418145; Fax: 0098-0261-4418156
Received December 17, 2010; accepted September 29, 2011.
Chin. J. Chem. 2012, 30, 65—70
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Behbahani & Ziaei
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Scheme 1 Synthesis of 1,2-disubstituted benzimidazoles using
FePO4
derivatives (2.5 mmol) and 2 mol% of FePO4 as a cata-
lyst under solvent-free conditions and ambient tem-
perature. In order to prove the generality of the opti-
mized reaction, a variety of aromatic aldehyde deriva-
tives and o-phenylenediamine derivatives were chosen.
As shown in Table 3; aromatic aldehydes reacted with-
out any significant difference in rate to give the corre-
sponding 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles in
good yields. The method has the ability to tolerate other
functional groups such as methyl, methoxy, nitro, hy-
droxyl, N,N-dimethylamino and halo groups. Conse-
quently several aromatic aldehydes with different sub-
stituents on the aromatic ring were subjected to the
condensation reaction. In all cases the yields were very
good and electron withdrawing groups were effective as
well as electron-donating groups on reaction rates (Ta-
ble 3). An aliphatic aldehyde such as hexanal was also
subjected under similar reaction condition, but 2-pentyl
benzimidazole was afforded.
R1
NH2
NH2
FePO4 (2 mol%)
solvent-free, r.t.
R2CHO
+
2
1
R1 = H, Me
R2 = Aryl, Heteroaryl
R1
R1
N
N
R2
R2
+
N
N
H
R2
4 (not formed)
3
densation reaction in the presence of 10 mol% of FePO4
without solvent and at room temperature. The reaction
mixture was stirred mechanically for appreciated time.
It was found that when benzaldehyde (2 mmol) was
stirred at room temperature in the presence of o-phe-
nylenediamine (1 mmol), the mixture of 1,2-disubsti-
tuted and 2-substituted benzimidazole derivatives (70∶
30, yield ratio) were obtained. To achieve 1,2-disubsti-
tuted benzimidazole as a target molecule, the reaction
was tested by 3 mmol of benzaldehyde. In this case,
1,2-disubstituted benzimidazole derivative was afforded
as the sole product respectively. For third time, the reac-
tion was performed by 2.5 mmol of benzaldehyde. In-
terestingly, we obtained the same product as with 2.5
mmol of benzaldehyde (Table 1).
Then we report FePO4 as a green, reusable, inexpen-
sive and environmentally benign catalyst for the synthe-
sis of 1,2-disubstituted benzimidazoles. It is necessary
to be mentioned that our group are researching on other
application of FePO4 in organic synthesis.
The plausible mechanism for the synthesis of 1,2-di-
substituted benzimidazoles may probably be imagined
to occur via reactions as revealed in Scheme 2. FePO4
activated the aldehydic carbonyl oxygen to form the
dibenzylidene-o-phenylene diamine and ring closure
leading to a five membered ring. Finally, 1,3-hydride-
transfer followed to produce 1,2-disubstituted benzimi-
dazoles.[20] Recently Jacob and et al.[27] proved when the
reaction in the presence of deuterated solvents such as
D2O and CH3OD was performed; any amount deuter-
ated benzimidazole was detected. The mechanism can
be enhanced that the reaction probably occurs according
to Scheme 2.
Table 1 Effect of varying amounts of benzaldehyde on the
synthesis of 1-benzyl-2-phenyl benzimidazole
Enrty Benzaldehyde/mmol Time/minYield/% (3/4)Conversion/%
1
2
3
2
20
20
20
70/30a
90/—b
90/—b
100
100
100
2.5 (10, 5, 2 mol% of
FePO4)
Experimental
3
a The yield refer to GC analysis. b Isolated yield.
Mps were measured by using the capillary tube
Scheme 2 The suggested mechanism for preparation of 1,2-di-
substituted benzimidazole derivatives
To obtain the optimized amount of the catalyst, we
set up reaction using 5 and 2 mol% of FePO4, 1 mmol
of o-phenylendiamine, 2.5 mmol of benzaldehyde. In
almost all the studied cases, the results were likely ob-
served at 20 min (Table 2).
FePO4
+N
Ph
FePO4
+O
H
Eventually, we decided to go on the reactions using
o-phenylenediamine derivatives (1 mmol), aldehyde
N
H
H
Ph
FePO4
N
Table 2 The condensation reaction of benzaldehyde (2.5 mmole)
and o-phenylenediamine (1 mmol) using 2, 5, 10 mol% of FePO4
as a catalyst at 20 min and ambient temperature
H2N
H2N
Ph
FePO4
H
N
+
Ph
Entry
Aldehyde
Catalyst/mol%
Yielda/%
1
Benzaldehyde
10
5
90
90
90
N
2
—
—
Ph
N
3
2
a Isolated yield
Ph
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A Green Route for the One-Pot Synthesis of 1,2-Disubstituted Benzimidazoles
Table 3 Synthesis of 1,2-disubstituted benzimidazole derivatives using o-phenylenediamine derivatives and aldehyde derivatives in the
presence of iron(III) phosphate as catalyst
Entry
R1
Aldehyde
Time/min
20
Yielda/%
Ref.
12a
Product
N
N
1
H
C6H5CHO
90
Me
N
N
2
H
3-MeC6H4CHO
23
80
25
Me
N
N
Me
3
4
5
H
H
H
4-MeC6H4CHO
2-MeOC6H4CHO
4-MeOC6H4CHO
25
32
30
85
88
94
12a
Me
MeO
OMe
N
N
21
N
N
OMe
21
MeO
OMe
OMe
N
N
6
H
3,4-(MeO)2C6H3CHO
45
80
22
MeO
OMe
OH
N
N
7
8
H
H
3-HOC6H4CHO
55
50
85
89
22
22
OH
N
N
OH
4-HOC6H4CHO
HO
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Behbahani & Ziaei
FULL PAPER
Continued
Ref.
Entry
R1
Aldehyde
Time/min
20
Yielda/%
Product
Cl
N
N
9
H
2-ClC6H4CHO
87
12a
Cl
Cl
N
N
10
11
12
H
H
H
3-ClC6H4CHO
30
20
40
85
90
92
25
Cl
N
N
Cl
4-ClC6H4CHO
12a
Cl
Cl
N
N
Cl
3,5-(Cl)2C6H3CHO
NEW
Cl
Cl
NO2
N
N
13
H
3-NO2C6H4CHO
20
94
23
NO2
N
N
NO2
14
15
H
H
4-NO2C6H4CHO
10
40
96
92
21
O2N
N
N
NMe2
4-(Me)2NC6H4CHO
12a
Me2N
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Chin. J. Chem. 2012, 30, 65—70

A Green Route for the One-Pot Synthesis of 1,2-Disubstituted Benzimidazoles
Continued
Ref.
Entry
16
R1
Aldehyde
C6H5CHO
Time/min
15
Yielda/%
Product
H3C
N
N
CH3
80
24
NEW
26
MeO
N
H3C
N
17
18
CH3
2-MeOC6H4CHO
4-MeOC6H4CHO
28
25
80
85
OMe
H3C
N
OMe
N
CH3
MeO
H3C
OH
N
N
19
CH3
3-HOC6H4CHO
45
45
82
85
NEW
OH
N
N
N
2-Pyridinecarbaldehyde
20
H
24
N
a Isolated yield.
method with an electro thermal 9200 apparatus. IR
eluent, V(n-hexane) ∶V(ethylacetate) ＝3 ∶1], ethyl
acetate (20 ml) was added and the catalyst filtered off.
The crude product was afforded after evaporation of
solvent under reduced pressure. Next the residue was
directly recrystallized from ethanol.
spectra were recorded on Perkin Elmer FT-IR spec-
－
1
1
trometer scanned between 4000—400 cm . H NMR
and 13C NMR spectra were obtained on Bruker
DRX-400 MHZ NMR instrument in CDCl3 and DMSO.
Chemical shifts (δ) are reported relative to tetramethyl-
silane (δ 0.0) as internal standard. Elemental analyses
were performed by Elemental analyzer Vario EL. Ana-
lytical TLC of all reactions was performed on Merck
precoated plates (silica gel 60F-254 on aluminium). All
starting materials were purchased from Merck Com-
pany.
Recycling and reusing of FePO4
After completion of the reaction, FePO4 was filtrated,
washed by CH2Cl2, dried at 50 ℃ for 1 h and reused
for four runs. As it has been shown in Table 4, the reac-
tions were carried out without observation of apprecia-
ble loss in catalyst activity.
New compounds data
General
procedure
for
the
synthesis
of
1,2-disubstituted benzimidazole derivatives
1-(3,5-Dichlorobenzyl)-2-(3,5-dichlorophenyl)-
1H-1,3-benzimidazole (Entry 12) Pale yellow solid;
m.p. 155—157 ℃; 1H NMR (CDCl3, 400 MHz) δ: 5.30
(s, 2H), 7.26—7.50 (m, 8H), 7.86—8.19 (m, 2H); 13C
NMR (CDCl3, 400 MHz) δ: 153.5, 138.9, 136.2, 130.4,
125.5, 115.3, 48.0; GC/mass m/z: (422, M＋). Anal.
calcd for C20H12Cl4N2: C 56.90, H 2.871, Cl 33.59, N
In a beaker, aldehyde (2.5 mmol), and o-phenylene-
diamine (1 mmol) were mixed mechanically for 1 min
without solvent and at room temperature. To this mix-
ture then FePO4 (2 mol%) was added and the reaction
mixture was stirred for the indicated time (Table 3).
After completion of the reaction [monitored by TLC;
Chin. J. Chem. 2012, 30, 65—70
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69

Behbahani & Ziaei
FULL PAPER
[6] Zhao, Z. S.; Arainz, D. O.; Greidel, B.; Sakata, S.; Dallas, J. L.;
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Table 4 Recycling and reusing of the catalyst
Entry
Runs
Fresh
Aldehyde
4-Chlorobenzaldehyde
—
Time/min Yielda/%
1
2
20
20
90
90
[7] (a) Tebbe, M. J.; Spitzer, W. A.; Victor, F.; Miller, S. C.; Lee, C. C.;
Sattelberg, T. R.; Mckinney, E.; Tang, C. J. J. Med. Chem. 1997, 40,
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3
4
5
Second
Third
Fourth
—
—
—
20
20
20
87
87
85
a Isolated yield.
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6.44; C 56.65, H 2.67, Cl 33.45, N 6.44.
1-(2-Methoxybenzyl)-2-(2-methoxyphenyl)-5-me-
thyl-1H-1,3-benzimidazole (Entry 17) Solid light
brown, m.p. 185—187 ℃; 1H NMR (CDCl3, 400 MHz)
δ: 2.49 (s, 3H, CH3), 3.60 (s, 3H, OCH3), 3.79 (s, 3H,
OCH3), 5.22 (s, 2H, CH2), 6.69—7.75 (m, 11H, ArH);
13C NMR (CDCl3, 400 MHz) δ: 160.0, 157.7, 153.3,
138.8, 132.7, 131.3, 125.8, 123.0, 114.2, 55.9, 49.0,
24.3; GC/mass m/z: (358, M ＋ ). Anal. calcd for
C23H22N2O2: C 77.07, H 6.19, N 7.82; found C 76.87, H
6.11, N 7.63.
1-(3-Hydroxybenzyl)-2-(3-hydroxyphenyl)-5-me-
thyl-1H-1,3-benzimidazole (Entry 19) Solid brown;
m.p. 215—219 ℃; H NMR (DMSO-d6, 400 MHz) δ:
2.39 (s, 3H, CH3), 5.43 (s, 2H, CH2), 6.64—7.53 (m,
11H, ArH), 9.3 (s, 1H), 9.65 (s, 1H); 13C NMR
(DMSO-d6, 400 MHz) δ: 158.4, 153.3, 137.7, 134.3,
130.1, 123.0, 115.3, 112.9, 49.3, 27.3. GC/mass m/z:
(330, M＋). Anal. calcd for C21H18N2O2: C 76.34, H 5.49,
N 8.48; found C 76.25, H 5.31, N 8.39.
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Conclusions
In summary, the present work has reported a general,
efficient, convenient, catalytic and improved methodol-
ogy for the selective synthesis of 1,2-disubstituted ben-
zimidazole derivatives by the condensation of o-phe-
nylenediamines and aldehydes using FePO4 catalyst.
This general, simple, fast and clean protocol removed
the organic solvent and energy demands, as well as the
reaction time could be reduced from hours to a few
minutes under solvent free conditions at room tempera-
ture.
[14] TAP report for Iron(III) phosphate, July, 2004.
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70
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