One-pot synthesis of benzimidazoles in water in the presence of SiO 2-OPO3H

Article abstract of DOI:10.1007/s10593-014-1445-z

Silica-bound phosphoric acid (SiO₂-OPO₃H), as an eco-friendly, reusable, and heterogeneous catalyst, was applied for synthesis of 2-substituted benzimidazoles in water at 70°C. Very short reaction times, clean work-up, and high yields are among the advantages of this protocol.

Full text of DOI:10.1007/s10593-014-1445-z

Chemistry of Heterocyclic Compounds, Vol. 50, No. 1, April, 2014 (Russian Original Vol. 50, No. 1, January, 2014)
ONE-POT SYNTHESIS OF BENZIMIDAZOLES
IN WATER IN THE PRESENCE OF SiO
2
–OPO H
3
1
2
1
*
B. F. Mirjalili , A. Bamoniri , and M. Rahimi Kazerouni
Silica-bound phosphoric acid (SiO –OPO H), as an eco-friendly, reusable, and heterogeneous catalyst,
2
3
was applied for synthesis of 2-substituted benzimidazoles in water at 70°C. Very short reaction times,
clean work-up, and high yields are among the advantages of this protocol.
Keywords: silica-bound phosphoric acid, 2-substituted benzimidazole, heterogeneous catalysis.
The benzimidazole moiety is encountered in vitamin B12, purine bases of DNA, caffeine [1], the
antihistamine astemizole [2], the anti-ulcerative esomeprazole [3], and the antiparasitic albendazole [4].
2
-Arylbenzimidazoles also exhibit anti-HIV [5], checkpoint kinase inhibitor [6], and Chlamydia pneumoniae
inhibitor [7] activities. The common protocol for benzimidazole synthesis is the reaction between an
o-phenylenediamine and carboxylic acid, nitrile, amidate, or orthoester under harsh dehydrating conditions [8].
Another method for the synthesis of these compounds is the one-pot reaction of o-phenylenediamine with
aldehydes in the presence of acidic catalyst and subsequent oxidation with air or other oxidants [9-14].
Silica-bound phosphoric acid (SiO –OPO H, also designated as P O /SiO ) is a reusable solid acid that
2
3
2
5
2
is a more efficient catalyst of similar syntheses than neat phosphoric acid [15].
Water as an inexpensive and environmentally benign solvent, as well as due to its specific properties,
can be very useful as a medium for organic synthesis. When organic compounds are suspended in water, their
relative insolubility causes them to associate, thus diminishing the water-hydrocarbon interface area. The
hydrophobic effect of water generates internal pressure and promotes the association of the reactants in the
solvent cavity during the activation process, thus accelerating the reaction [16].
The attenuated total reflectance FT-IR (ATR) spectra of silica gel, SiO –OPO H, and H PO ·SiO are
2
3
3
4
2
-
1
shown in Figure 1. In all ATR spectra, the Si–O–H and Si–O–Si stretching bands appear at 900-1100 cm . In
the ATR spectra of SiO –OPO H and H PO ·SiO , the P–OH, PO–H, P=O, and P–O stretching bands appear at
2
3
3
4
2
-
1
9
67, 2250-2300 and 2650-2750 (two bands), 1637, and 850 cm , respectively. According to above data, we
suggest the structure of SiO –OPO H as
2
3
O
O
P
O
O
Si
O
OH
n
_
*
______
To whom correspondence should be addressed, e-mail: fmirjalili@yazduni.ac.ir.
1
Yazd University, P. O. Box 8915813149, Yazd, I. R. Iran.
2
University of Kashan, Kashan, I. R. Iran; e-mail: bamoniri@kashanu.ac.ir.
_
________________________________________________________________________________________
Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 41-46, 2014. Original article
submitted November 16, 2012; revision submitted December 23, 2013.
009-3122/14/5001-0035©2014 Springer Science+Business Media New York
0
35

In continuation of our investigations on the applications of solid acids in organic synthesis [17-21], we
have studied the synthesis of benzimidazole derivatives in the presence of SiO –OPO H via condensation of
2
3
o-phenylenediamines and aldehydes. The reaction of o-phenylenediamine (1 mmol) with 4-nitrobenzaldehyde
(
1 mmol) was investigated for the optimization of the reaction conditions. The results revealed that the best
conditions were the use of SiO –OPO H in water as solvent at 70°C. These conditions are comparable to other
2
3
applied conditions (Table 1).
Fig. 1. ATR spectra of a) silica gel, b) SiO –OPO H, and c) H PO ·SiO
2
3
3
4
2
TABLE 1. Synthesis of 2-(4-Nitrophenyl)benzimidazole in Various Conditions
CHO
NH2
NH2
H
N
Cat.
+
NO2
N
NO2
Entry
Catalyst / mol% (g)
Time
Temperature, °C
Solvent
Yield*, %
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
SiO
SiO
SiO
SiO
SiO
SiO
SiO
SiO
SiO
SiO
SiO
2
2
2
2
2
2
2
2
2
2
2
(0.05)
180 s
60 s
30 s
30 s
3 h
4 min
30 s
20 min
5 min
60 s
70
70
70
70
H
H
H
H
H
H
H
2
2
2
2
2
2
2
O
100
90
100
100
80
100
100
100
100
100
90
95 [9]
95 [10]
91 [11]
99 [12]
91 [13]
91 [14]
–OPO
–OPO
–OPO
–OPO
–OPO
–OPO
–OPO
–OPO
–OPO
–OPO
3
3
3
3
3
3
3
3
3
H (0.02)
H (0.05)
H (0.07)
H (0.05)
H (0.05)
H (0.05)
H (0.05)
H (0.05)
O
O
O
O
O
O
room temp.
40
reflux
70
70
70
70
room temp.
90
room temp.
90
room temp.
100
EtOH
EtOAc
nd
0
1
2
3
4
5
6
7
H (0.05), 2 run
H (0.05), 3 run
H
2
H
2
H
2
H
2
O
O
O
O
rd
3
90 s
In(OTf)
I , KI / 25
2
3
/ 5
30 min
30 min
4 h
6 h
20 min
4 h
+
–
Me
2
S BrBr / 50
MeCN
Perfluorodecalin
EtOH
2
Yb(OPf)
3
/ 0.2 *
/ 10
NH
air
4
VO
3
DMF
_
*
*
______
Conversion yield.
2
Yb(III) perfluorooctane sulfonate.
3
6

TABLE 2. Synthesis of Benzimidazole Derivatives in Water at 70°C in the
Presence of SiO –OPO H
2
3
X
NH2
X
RCHO
N
R
SiO –OPO H, H O, 70°C
NH2
2
3
2
N
H
Entry
R
X
Time, s
Mp, °C
Yield*, %
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
2,3-(HO)
4-ClC
2
C
6
H
3
H
H
H
H
H
H
H
H
Me
Me
NO
NO
NO
H
25
240
90
300
40
40
40
30
70
201-202
98
6
H
4
290-292 (291-293 [12])
250-252 (250-252 [22])
287-289 (293-294 [9])
191-194
87 [12]
98 [22]
91 [9]
90
4-BrC
Ph
6 4
H
4-MeOCOC
6
H
4
2
*
>300
82
3-NO
4-NO
2
2
C
C
6
6
H
H
4
206-207 (198-200 [23])
315-316 (312-314 [12])
282-283
234-236
206-207
214-215
255-256
240-242
225-227 (225-227 [22])
246-247
98 [23]
98 [12]
87
95
98
98
97
91
87 [22]
92
4
4-Me
4-NO
2
NC
6
H
4
0
1
2
3
4
5
6
2
C
6
H
4
15
2,3-(HO)
2,4-Cl
4-NO
4-HOC
4-MeC
PhCH CH
2
C
6
H
3
2
2
2
150
150
60
200
180
300
2
C
6
H
3
2
C
6
H
4
6
H
4
6
H
4
H
H
2
2
_
______
*
Isolated yield.
2
*
2,2'-Benzene-1,4-diylbis(1H-benzimidazole) obtained from o-phenyl-
enediamine and benzene-1,4-dialdehyde.
The reusability of the SiO –OPO H catalyst was also examined. After each run, the combined
2
3
precipitate of product and catalyst was filtered and washed with hot ethanol to dissolve the product. The
insoluble catalyst was washed with chloroform and dried at 200°C, and then reused (Table 1, entries 10 and 11).
The applicability of the present method to a scaled-up process was examined with 20 mmol of
o-phenylenediamine and 20 mmol of 4-nitrobenzaldehyde in water at 70°C, which gave 2-(4-nitro-
phenyl)benzimidazole in 85% yield.
Consequently several aromatic aldehydes with different substituents at the aromatic ring were subjected
to the condensation reaction with o-arenediamines to form 2-substituted benzimidazoles in the presence of
1
SiO –OPO H in water at 70°C (Table 2). The products were characterized by IR and H NMR spectra and by
2
3
comparison of their physical properties with those reported in the literature.
In some reports, 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles were obtained as the chief product by
using 2 mmol of aldehyde and 1 mmol of o-phenylenediamine [24, 25]. When we used 2 mmol of aldehyde and
1
2
mmol of o-phenylenediamine in our protocol, only 2-substituted benzimidazoles were produced, and no
-aryl-1-arylmethyl-1H-1,3-benzimidazoles were detected.
In conclusion, we have demonstrated a simple method for the synthesis of 2-substituted benzimidazoles
in water using SiO
2
–OPO H as a reusable, eco-friendly, inexpensive, and efficient catalyst. The method is
3
characterized by short reaction times, high yield, simplicity of operation, and easy work-up.
3
7

EXPERIMENTAL
1
13
ATR IR spectra were recorded on a Bruker Equinox 55 spectrometer in KBr pellets. H and C NMR
spectra were recorded on a Bruker Avance DRX-400 Ultrashield spectrometer (400 and 100 MHz, respectively)
with TMS as internal standard. Mass spectra were obtained on a Shimadzu QP 1100 EX gas chromatograph/
mass spectrometer (EI, 70 eV). Elemental analyses were done using a Costech ECS 4010 CHNS-O analyzer.
Chlorine content was determined by sodium fusion and AgCl gravimetry. Melting points were determined on a
Buchi B-540 melting point apparatus. H PO ·SiO was prepared via mixing 1 g of SiO and 0.5 ml of
3
4
2
2
commercial H PO . Chemicals were purchased from Fluka and Merck.
3
4
Synthesis of Benzimidazole Derivatives (General Method). A mixture of o-phenylenediamine
1 mmol), aldehyde (1 mmol), water (5 ml), and SiO –OPO H [15] (0.056 g) was heated at 70C. The progress
(
2
3
of the reaction was monitored by TLC on silica gel using EtOAc–petroleum ether, 3:7, as eluent. As the reaction
progresses, the formed benzimidazole derivative was precipitated in medium. After completion of the reaction,
the mixture, containing product and catalyst, was filtered and washed with water. The precipitate was dried and
then dissolved in hot ethanol and filtered to separate insoluble catalyst. By evaporation of ethanol in the filtrate,
the benzimidazole derivatives were obtained in 87-98% yields.
-
1
(
1H-Benzimidazol-2-yl)benzene-1,2-diol (Table 2, entry 1). IR spectrum, ν, cm : 3453 (O–H), 1618
1
(
C=N), 1580, 1543, 1460 (C=C), 1210 (C–O), 1032, 763 (=C–H). H NMR spectrum (DMSO-d ), δ, ppm (J,
6
Hz): 12.91 (1H, s, NH); 9.27 (1H, s, OH); 8.86 (1H, s, OH); 7.09 (1H, d, J = 6.4, H Ar); 7.44 (4H, br. s, H Ar);
.92 (1H, d, J = 6.4, H Ar); 6.77 (1H, t, J = 7.6, H Ar). Found, %: С 69.13; Н 4.35; N 12.44; O 14.08.
С H N O . Calculated, %: С 69.02; Н 4.46; 20.40; N 12.38; O 14.14.
6
1
3
10
2
2
-
1
Methyl 4-(1H-benzimidazol-2-yl)benzoate (Table 2, entry 5). IR spectrum, ν, cm : 1719 (C=O), 1610
1
(
C=N), 1434 (C=C), 1279 (C–N), 1105 (C–O), 750 (C–H). H NMR spectrum (DMSO-d ), δ, ppm (J, Hz):
6
1
2.89 (1H, s, NH); 8.03 (2H, d, J = 8.2, H Ar); 7.95 (2H, J = 8.2, H Ar); 7.62-7.30 (4H, m, H Ar); 3.89 (s,
+
OCH ). Mass spectrum, m/z (I , %): 252 [М] (44), 233 (90), 232 (100), 221 [M-OMe] (35), 193 [M-COOMe]
3
rel
(
34), 90 (10). Found, %: С 71.30; Н 4.85; N 11.16. С H N O . Calculated, %: С 71.42; Н 4.79; N 11.10.
15
12
2
2
-
1
2
,2'-Benzene-1,4-diylbis(1H-benzimidazole) (Table 2, entry 6). IR spectrum, ν, cm : 3400 (N–H),
1
1
8
655 (C=N), 1442 (N–H, =C–H), 735 (=C–H). H NMR spectrum (acetone-d ), δ, ppm (J, Hz): 12.93 (2H, s, NH);
6
.42 (4H, s, H Ar); 7.68 (2H, br. d, J = 7.6, H Ar); 7.56 (2H, br. d, J = 7.6, H Ar); 7.20-7.31 (4H, m, H Ar).
+
Mass spectrum, m/z (I , %): 310 [М] (15), 105 (100), 77 (95). Found, %: С 77.35; Н 4.58; N 18.09. С H N .
rel
20 14
4
Calculated, %: С 77.42; Н 4.55; N 18.05.
-1
2-(4-Dimethylaminophenyl)-5-methyl-1H-benzimidazole (Table 2, entry 9). IR spectrum, ν, cm : 3400
1
(
N–H), 1611 (C=N), 1445 (N–H), 1058 (C–N). H NMR spectrum (DMSO-d ), δ, ppm (J, Hz): 12.95 (1H, s, NH);
6
8
.21 (2H, d, J = 8.2, H Ar); 7.61 (1H, d, J = 7.8, H Ar); 7.52 (1H, s, H Ar); 7.31 (1H, d, J = 8.1, H Ar); 6.72
+
(
2H, d, J = 8.1, H Ar); 3.12 (6H, s, N(CH ) ); 2.31 (3H, s, ArCH ). Mass spectrum, m/z (I , %): 251 [М] (100),
3
2
3
rel
2
50 (45), 119 (60). Found, %: С 75.92 Н 6.35; N 17.70. С H N . Calculated, %: С 76.46; Н 6.82; N 16.72.
1
6
17
3
-1
5-Methyl-2-(4-nitrophenyl)-1H-benzimidazole (Table 2, entry 10). IR spectrum, ν, cm : 3423 (N–H),
1
1
603 (C=N, C=C) 1520, 1344 (NO ). H NMR spectrum (DMSO-d ), δ, ppm: 13.33 (1H, s, NH); 8.40-8.45 (4H,
2
6
m, H Ar); 7.45-7.64 (2H, m, H Ar); 7.12 (1H, s, H Ar); 2.43 (3H, s, CH ). Mass spectrum, m/z (I , %): 253
3
rel
+
[
М] (100), 252 (20), 207(50), 121 (25), 116 (5), 105 (20). Found, %: С 66.56; Н 4.46; N 16.67. С H N O .
1
4
11
3
2
Calculated, %: С 66.40; Н 4.38; N 16.59.
-1
3-(6-Nitro-1H-benzimidazol-2-yl)benzene-1,2-diol (Table 2, entry 11). IR spectrum, ν, cm : 3391 (N–H
1
and O–H), 1603 (C=N and C=C), 1459 (C=C), 1530 and 1338 (NO ), 1264 (C–O). H NMR spectrum
2
(
DMSO-d ), δ, ppm (J, Hz): 12.51 (1H, s, NH); 8.96 (1H, s, OH); 8.04 (1H, s, OH); 7.92 (1H, d, J = 8.4, H Ar);
6
7
.89 (1H, s, H Ar); 7.21 (1H, d, J = 7.6, H Ar); 7.04 (1H, d, J = 7.6, H Ar); 6.98 (1H, d, J = 8.8, H Ar); 6.91
+
(
1H, t, J = 7.6, H Ar). Mass spectrum, m/z (I , %): 271 [М] (100), 162 (90), 137 (10), 121 (34), 107 (35).
rel
Found, %: С 57.75; Н 3.43; N 15.58. С H N O . Calculated, %: С 57.57; Н 3.34; N 15.49.
1
3
9
3
4
3
8

-
1
2
-(2,4-Dichlorophenyl)-5-nitro-1H-benzimidazole (Table 2, entry 12). IR spectrum, ν, cm : 3428 (N–
1
H), 1629 (C=N), 1459 (C=C), 1107 (C–N), 803 (C–H). H NMR spectrum (DMSO-d ), δ, ppm (J, Hz): 13.92
1H, s, NH); 8.42 (1H, d, J = 7.9, H Ar); 8.15 (1H, s, H Ar); 7.62 (1H, d, J = 7.5, H Ar); 7.44 (1H, s, H Ar);
.36 (1H, d, J = 7.5, H Ar); 7.23 (1H, d, J = 7.9, H Ar). Found, %: С 50.92; Н 2.23; Cl 23.11; N 13.39; O 10.35.
6
(
7
С H Cl N O . Calculated, %: С 50.67; Н 2.29; Cl 23.01; N 13.64; O 10.39.
1
3
7
2
3
2
-1
5
-Nitro-2-(4-nitrophenyl)-1H-benzimidazole (Table 2, entry 13). IR spectrum, ν, cm : 1605 (C=N and
1
C=C), 1522 and 1344 (NO ), 759 (=C–H). H NMR spectrum (DMSO-d ), δ, ppm: 13.94 (1H, s, NH); 8.42-8.51
2
6
(
1H, m, H Ar); 8.39-8.42 (4H, m, H Ar); 8.10-8.13 (1H, m, H Ar); 7.78-7.81 (1H, m, H Ar). Found, %: С 54.71;
Н 2.93; N 19.74; O 22.62. С H N O . Calculated, %: С 54.93; Н 2.89; N 19.71; O 22.52.
1
3
8
4
4
-
1
4
-(1H-Benzimidazol-2-yl)phenol (Table 2, entry 14). IR spectrum, ν, cm : 3401 (N–H, O–H), 1609
1
(
(
3
1
C=N, C=C), 1425 (C=C), 1126 (C–O), 758 (=C–H). H NMR spectrum (DMSO-d ), δ, ppm (J, Hz): 12.98
6
1H, s, NH); 7.98 (2H, d, J = 8.4, H Ar); 7.54 (2H, m, H Ar); 7.38 (2H, m, H Ar); 6.92 (2H, d, J = 8.4, H Ar);
1
3
.52 (1H, br. s, OH). C NMR spectrum (DMSO-d ), δ, ppm: 160.4; 151.6; 137.9; 129.1; 123.0; 119.6; 116.4;
6
14.9. Found, %: С 74.22; Н 4.81; N 13.38; O 7.59. С H N O. Calculated, %: С 74.27; Н 4.79; N 13.33;
1
3
10
2
O 7.61.
-
1
2
-(4-Methylphenyl)-1H-benzimidazole (Table 2, entry 15). IR spectrum, ν, cm : 3449 (N–H), 1430
1
(
C=C), 748 (=C–H). H NMR spectrum (DMSO-d ), δ, ppm (J, Hz): 12.91 (1H, s, NH); 8.05 (2H, d, J = 7.6,
6
H Ar); 7.57 (2H, dd, J = 5.6, J = 2.8, H Ar); 7.35 (2H, d, J = 7.6, H Ar); 7.19 (2H, dd, J = 5.6, J = 2.8, H Ar);
3
.17 (3H, s, CH ). Found, %: С 80.82; Н 5.78; N 13.40. С H N . Calculated, %: С 80.74; Н 5.81; N 13.45.
3
14 12
2
-1
2
-(2-Phenylethyl)benzimidazole (Table 2, entry 16). IR spectrum, ν, cm : 3160 (=C–H), 1600 (C=N),
1
1
6
9
575 (C–N). H NMR spectrum (DMSO-d ), δ, ppm (J, Hz): 3.11-3.21 (1H, m) and 3.25-3.55 (3H, m, (CH ) );
6
2 2
+
.50-7.10 (5H, m, H Ph); 7.10-7.80 (5H, m, H Ar, NH). Mass spectrum, m/z (I , %): 222 [М] (10), 119 (100),
rel
1 (20). Found, %: С 80.75; Н 6.90; N 12.21. С H N . Calculated, %: С 81.05; Н 6.35; N 12.60.
1
5
14
2
The Research Council of Yazd University is gratefully acknowledged for financial support of this work.
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