One-pot synthesis of 2-substituted benzimidazoles catalyzed by anhydrous FePO4

Article abstract of DOI:10.1007/s10593-012-1093-0

Anhydrous FePO₄ has been employed as a catalyst for efficient synthesis of 2-substituted benzimidazoles. Simple and convenient procedure, easy purification and shorter reaction time are the advantages of this method, resulting in several known and three new compounds.

Full text of DOI:10.1007/s10593-012-1093-0

Chemistry of Heterocyclic Compounds, Vol. 48, No. 7, October, 2012 (Russian Original Vol. 48, No. 7, July, 2012)
ONE-POT SYNTHESIS OF 2-SUBSTITUTED BENZIMIDAZOLES
CATALYZED BY ANHYDROUS FePO4
Farahnaz K. Behbahani1* and Parisa Ziaei1
Anhydrous FePO4 has been employed as a catalyst for efficient synthesis of 2-substituted benzimidazoles.
Simple and convenient procedure, easy purification and shorter reaction time are the advantages of this
method, resulting in several known and three new compounds.
Keywords: 2-aldehyde, anhydrous FePO4, benzimidazole, o-phenylenediamine.
Benzimidazole structural motifs are found in numerous pharmaceutical agents possessing a wide range
of biological applications [1, 2], for example, as antihistamine, antiulcer agents, and topoisomerase inhibitors.
Due to the high profile of biological and industrial applications of compounds with benzimidazole structural
fragments, methods of their synthesis are extensively studied. Synthesis of benzimidazoles requires heating of
o-phenylenediamine and carboxylic acids or their derivatives (nitriles, chlorides, or orthoesters) [3-6] under
strong acidic conditions, sometimes combined with high temperatures in polyphosphoric acid or under
microwave irradiation. Another method for the synthesis of benzimidazoles involves cyclodehydration of
phenylenediamine and aldehydes by using various oxidative reagents [7-20]. Although a variety of
reagents/catalysts have been recently employed in this second route, many of these methods have drawbacks
such as harsh reaction conditions, low to moderate yields, long reaction times, tedious work-up procedures, and
occurrence of several by-products. The main disadvantage of the existing methods is that the catalysts are
destroyed under work-up conditions and cannot be recovered and reused. Therefore, the search continues for a
better catalyst for the synthesis of benzimidazoles in terms of operational simplicity, reusability, and economic
viability.
Iron(III) phosphate has been employed for the selective oxidation of methane to methanol [21], benzene
to phenol [22], one-pot synthesis of dihydropyrimidinones and thiones [23], and synthesis of triarylated
imidazoles [24]. We have recently reported a variety of organic transformations [25-27] using similar catalytic
systems. In this communication, we wish to introduce anhydrous FePO4 as a new catalyst for the preparation of
2-substituted benzimidazoles by an environmentally benign protocol at room temperature.
The main aim of this work was to provide a new catalytic and environmentally benign protocol for the
synthesis of 2-substituted benzimidazole derivatives. Hereby we report a simple and fast method for the
synthesis of 2-substituted benzimidazoles using anhydrous FePO4 at room temperature. In order to establish the
optimal conditions for this transformation, various quantities of FePO4 were examined to catalyze the model
reaction between o-phenylenediamine and benzaldehyde without a solvent (Table 1).
_______
*To whom correspondence should be addressed, e-mail: Farahnazkargar@yahoo.com.
1Department of Chemistry, Karaj Branch, Islamic Azad University, Karaj, Iran.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1088-1094, July, 2012. Original
article submitted December 15, 2010; revision submitted October 7, 2011.
0009-3122/12/4807-1011©2012 Springer Science+Business Media New York
1011

TABLE 1. Effect of Varying Amounts of Catalyst on the Yield of
2-Phenyl-1H-benzimidazole
CHO
NH2
N
FePO4, air
+
neat, room temp., 5 min
N
H
NH2
Entry
FePO4, mol%
Yield*, %
1
2
3
4
5
15
98
98
98
98
—
10
5
2
No catalyst
_______
*Yields of the isolated products from the reaction of benzaldehyde
(1.1 mmol) and o-phenylenediamine (1.0 mmol) in corresponding solvent
(5 ml) in the presence of anhydrous FePO4 (2.0 mol%) at room
temperature for 5 min.
An excellent yield was achieved already with 2 mol% of anhydrous FePO4. Noteworthy was that the
presence of catalyst was essential for the synthesis of 2-substituted benzimidazoles: We observed that only a
negligible amount of the desired product was formed in the absence of FePO4.
Next, the effect of solvent was studied for this reaction (Table 2). Unfortunately, use of any solvent
decreased the reaction yield.
TABLE 2. Effect of Solvent on the Yield of 2-phenyl-1H-benzimidazole
Entry
Solvent
Yield*, %
1
2
CH2Cl2
30
32
35
25
75
79
87
50
80
65
60
85
98
THF
3
CCl4
4
n-Hexane
MeCN
5
6
EtOH
7
Dioxane
Toluene
DMF
8
9
10
11
12
13
DMSO
H2O
H2O–EtOH (1:1)
Neat / no solvent
_______
* Yields of the isolated products from the reaction of benzaldehyde
(1.1 mmol) and o-phenylenediamine (1.0 mmol) in corresponding solvent
(5 ml) in the presence of anhydrous FePO4 (2.0 mol%) at room
temperature for 5 min.
In order to evaluate the scope and limitations of this work, we focused our attempts on the synthesis of
differently substituted benzimidazoles (Table 3). Aldehydes and o-phenylenediamine derivatives having
methoxy, chloro, nitro, and methyl substituents were converted into the corresponding 2-substituted
benzimidazoles in high yields and short reaction times. Aldehydes containing electron-withdrawing groups gave
1012

products in higher yields than those containing electron-donating groups. Using 2-methyl-, 3-hydroxy- and 3,5-
dichlorobenzaldehydes in the reaction with 4-methyl-substituted o-phenylenediamine gave three previously
undescribed benzimidazoles (Table 3, entries 22–24).
TABLE 3. Synthesis of 2- and 2,5-(Di)substituted Benzimidazoles
R1
R1
NH2
NH2
N
FePO4, air
R
RCHO
+
neat, room temp.
N
H
Time,
min
Mp, °C
Entry
R
R1
Yield, %
Found
>290
Reported [Ref.]
1
Ph
H
5
15
18
15
23
25
20
30
28
25
7
98
84
80
87
82
78
90
75
79
80
94
89
95
93
90
89
95
80
92
90
85
79
80
85
77
85
75
80
85
87
85
60
75
62
60
90
88
290-292 [28]
199-200 [9]
217-219 [29]
270-272 [28]
179-180 [30]
205-206 [30]
226 [28]
2
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
H
200-202
218-220
268-271
177-179
205-207
223-225
235-237
185-186
255-257
233-235
229-231
288-290
224-227
296-297
205-207
>312
3
H
4
H
5
H
6
H
7
H
8
3,4-(MeO)2C6H3
3-HOC6H4
4-HOC6H4
2-ClC6H4
H
236-238 [31]
182-183 [28]
254-255 [28]
233-234 [28]
230-232 [28]
292-293 [28]
227 [32]
9
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36*
37*
H
H
3-ClC6H4
H
10
5
4-ClC6H4
H
2,4-Cl2C6H3
3,5-Cl2C6H3
3-O2NC6H4
4-O2NC6H4
4-Me2NC6H4
Ph
H
7
H
10
10
7
296-298 [33]
206-207 [28]
312-314 [28]
264-266 [34]
242-243 [9]
224-225 [9]
200.5-203.7 [35]
—
H
H
H
32
3
265-267
240-242
223-225
200-201
145-147
230-232
137-139
205-206
279-280
231-233
290-293
260-262
200-201
217-220
170-173
173-174
153-155
160-162
>300
Me
Me
Me
Me
Me
Me
NO2
NO2
NO2
H
4-ClC6H4
5
2-MeOC6H4
2-MeC6H4
3-HOC6H4
3,5-Cl2C6H3
Ph
15
10
15
7
—
—
12
10
30
35
30
10
30
30
35
32
37
50
45
206-209 [36]
277-281 [37]
234-236 [36]
>300 [38]
4-ClC6H4
4-MeOC6H4
4-oxo-4H-chromen-2-yl
2-hydroxy-1-naphthyl
H
260 [39]
trans-styryl
H
199-202 [34]
218 [28]
2-pyridyl
H
H
H
172-173 [40]
174-176 [40]
156-158 [40]
162-163 [40]
>300 [41]
Me
H
n-Pr
H
n-C5H11
H
4-(benzimidazol-2-yl)phenyl
4-(5-methylbenzimidazol-
2-yl)phenyl
H
Me
>300
>300 [8]
_______
*Terephthalaldehyde (1.0 mmol) and corresponding o-phenylenediamine
(2.0 mmol) were used.
In order to show the merits of this catalytic method in comparison with the reported protocols, we
compiled the results on the formation of 2-phenyl-1H-benzimidazole (Table 3, Entry 1) in the presence of a
1013

variety of catalysts, especially iron(III) salts and complexes. From the results given in Table 4, the advantages
of our method are evident, regarding the amounts of catalyst, as well as its easy separation from the reaction
mixture, which are especially important in the chemical industry.
TABLE 4. Synthesis of 2-Phenyl-1H-benzimidazole Catalyzed by Various
Catalytic Systems
Time,
min
Yield,
%
Entry
Catalyst (quantity)
Conditions
[Ref.]
1
Fe(NO3)3·9H2O (10 mol%), H2O2 (0.4 ml) Neat, 50°C
2
25
25
98
88
85
90
97
95
98
[42]
2
FeBr3 (5 mol%)
DMF, 60°C
DMF, 60°C
[43]
3
Fe(NO3)3·9H2O (10 mol%)
FeCl3/PANI
[43]
4*
5*2
6*3
7
EtOH, room temp. 30
EtOH, room temp. 30
EtOH, room temp. 90
[44]
T(o-Cl)PPFe(III)Cl (5 mol%)
T(o-Cl)PPFe(III)–SiO2 (5 mol%)
FePO4 (2.0 mol%), air
[28]
[28]
Neat, room temp.
5
This work
_______
*FeCl3/PANI = FeCl3-doped polyaniline.
*2T(o-Cl)PPFe(III)Cl = meso-tetrakis(o-chlorophenyl)porphyrin–Fe(III)Cl
complex.
*3T(o-Cl)PPFe(III)–SiO2 = meso-tetrakis(o-chlorophenyl)porphyrin–Fe(III)
complex supported on activated silica.
The reusability of the catalyst was also studied. At the end of the reaction, the catalyst was removed by
filtration and washed with diethyl ether. The recycled catalyst could be subjected to a new reaction run. In the
case of the model reaction, after three recycles the catalytic activity of FePO4 was almost the same as that of
fresh catalyst (Table 5).
O
FePO4
R
H
R1
N
R1
R
H
NH2
NH2
NH2
air/O2
H
N
R1
Fe(III)
Fe(II)
R1
N
H
R
R
N
H
N
H
TABLE 5. Reusability of the Catalyst in the Model Reaction
Entry
Run
Yield*, %
1
2
3
4
fresh
98
96
94
93
1st recycle
2nd recycle
3rd recycle
_______
* Yields of the isolated products from the reaction of benzaldehyde
(1.1 mmol) and o-phenylenediamine (1.0 mmol) without solvent in the
presence of catalyst (2.0 mol %) at room temperature for 5 min.
1014

The proposed mechanism for FePO4-catalyzed synthesis of 2-substituted benzimidazoles may be
illustrated by a sequence of reactions as depicted in the scheme above. This involves formation of benzylidene-
o-phenylenediamine via iminium catalysis, following ring closure into a five-membered ring and oxidation
of the dihydrobenzimidazole by FePO4 to benzimidazole. Also, air (oxygen) plays an important role in this
reaction by the reoxidation of Fe(II) into Fe(III) species. For instance, 2-phenyl-1H-benzimidazole was obtained
in 65% yield when this reaction was conducted in nitrogen atmosphere.
In conclusion, we have developed a simple and efficient one-pot synthetic approach for 2-substituted
benzimidazoles by the condensation of various o-phenylenediamine derivatives and aldehydes in the presence
of anhydrous FePO4 at room temperature under solvent-free conditions. The described method offers very
attractive features such as reduced reaction times, high yields, and atom efficiency, as well as easy product
separation, which allows us to consider it as a useful strategy for the preparation of various biologically
important benzimidazoles simply by changing different substrates. The operational simplicity of the procedure
is also attractive from the green chemistry point of view.
EXPERIMENTAL
1
IR spectra were recorded on a Perkin Elmer FT-IR spectrometer in KBr pellets. H and 13C NMR
spectra were obtained on a Bruker DRX-300 NMR instrument (300 and 75 MHz, respectively) in DMSO-d6,
internal standard TMS. GC/mass spectra were recorded on an Agilent 6890 GC apparatus, Hp-5 capillary
30 m×530 µm×1.5 µm, operating at ionization potential of 70 eV (EI). Elemental analyses were performed on a
Carlo Erba 106 Perkin-Elmer model 240 Analyzer. Melting points were measured using the capillary tube
method with an Electrothermal 9200 apparatus. Analytical TLC of all reactions was performed on Merck
precoated plates (silica gel 60 F-254 on aluminum) using n-hexane–EtOAc (8:1) as eluent. All starting materials
were purchased from Merck and Acros Companies.
Synthesis of 2-Substituted 1H-Benzimidazole Derivatives (General Method). A mixture of the
corresponding o-phenylenediamine (1.0 mmol) and aldehyde (1.1 mmol) was mechanically blended without
solvent in the presence of anhydrous FePO4 (2.0 mol%) at room temperature within the times defined in Table 3.
The progress of the reaction was monitored by TLC. After completion of the reaction, hot EtOH (10 ml) was
added, and the catalyst was filtered off. Then ice-water (30 ml) was poured into the stirred filtrate. The
precipitated product was separated by filtration, washed with water, and dried to give the corresponding pure
benzimidazole as the only product. An identical procedure was employed using o-phenylenediamine (2.0 mmol)
and terephthalaldehyde (1.0 mmol) to yield bis-benzimidazoles (Table 3, entries 36 and 37).
The analytical data of previously obtained compounds were in accordance with those described in the
literature.
5-Methyl-2-(2-methylphenyl)-1H-benzimidazole (Table 3, Entry 22). Light-brown solid. IR spectrum,
1
, cm-1: 3420 (N–H), 1619 (C=N). H NMR spectrum, δ, ppm: 2.42 (3H, s, 5-CH3); 2.58 (3H, s, 2'-CH3);
6.69-7.72 (7H, m, H Ar); 12.45 (1H, s, NH). 13C NMR spectrum, δ, ppm: 144.2 (NH–C=N); 138.2 (2C); 136.5;
135.7; 132.4; 129.3; 128.4; 127.1; 126.2; 125.6; 115.1 (2C); 24.1; 17.5. Mass spectrum, m/z (Irel, %): 223
[M+H]+ (40), 222 [M]+ (62), 207 (36), 149 (35), 105 (18), 83 (33), 55 (100). Found, %: C 80.92; H 6.15;
N 12.45. C15H14N2. Calculated, %: C 81.05; H 6.35; N 12.60.
2-(3-Hydroxyphenyl)-5-methyl-1H-benzimidazole (Table 3, Entry 23). Brown solid. IR spectrum, ,
1
cm-1: 3276 (N–H, O–H), 1620 (C=N). H NMR spectrum, δ, ppm (J, Hz): 2.41 (3H, s, 5-CH3); 6.90 (1H, d,
J = 7.8, H-6); 7.03-7.05 (1H, m, H Ar); 7.32 (1H, d, J = 7.8, H-7); 7.45-7.74 (4H, m, H Ar); 9.65 (1H, s, OH);
12.54 (1H, s, NH). 13C NMR spectrum, δ, ppm: 154.7; 148.2 (NH–C=N); 138.4; 135.5; 132.2 (2C); 130.4;
124.3; 120.0; 114.5 (3C); 111.9; 23.7. Mass spectrum, m/z (Irel, %): 225 [M+H]+ (8), 224 [M]+ (15), 211 (15),
149 (53), 129 (17), 117 (19), 90 (42), 77 (40), 55 (100). Found, %: C 74.78; H 5.28; N 12.30. C14H12N2O.
Calculated, %: C 74.98; H 5.39; N 12.49.
1015

2-(3,5-Dichlorophenyl)-5-methyl-1H-benzimidazole (Table 3, Entry 24). Light-brown solid. IR
1
spectrum, , cm-1: 3446 (N–H), 1627 (C=N). H NMR spectrum, δ, ppm (J, Hz): 2.42 (3H, s, 5-CH3); 7.02-7.09
(1H, m, H Ar); 7.45 (1H, d, J = 7.4, H Ar); 7.55-7.59 (1H, m, H Ar); 7.61 (1H, d, J = 1.9, H Ar); 7.78 (1H, d,
J = 1.8, H Ar); 7.94 (1H, d, J = 3.7, H Ar); 12.62 (1H, s, NH). 13C NMR spectrum, δ, ppm: 150.7 (NH–C=N);
137.7; 135.6 (3C); 133.1; 132.2; 130.4; 124.1 (3C); 114.8 (2C); 24.0. Mass spectrum, m/z (Irel, %): 279 [M+2H]+
(28), 278 [M+H]+ (64), 277 [M]+ (16), 232 (12), 217 (26), 207 (45), 113 (8), 54 (88). Found, %: C 60.47; H 3.54;
N 10.01. C14H10Cl2N2. Calculated, %: C 60.67; H 3.64; N 10.11.
REFERENCES
1.
2.
W. A. Craigo, B. W. LeSueur, and E. B. Skibo, J. Med. Chem., 42, 3324 (1999).
K. S. Gudmundsson, J. Tidwell, N. Lippa, G. W. Koszalka, N. van Dranen, R. G. Ptak, J. C. Drach, and
L. B. Townsend, J. Med. Chem., 43, 2464 (2000).
3.
4.
5.
A. Czarny, W. D. Wilson, and D. W. Boykin, J. Heterocycl. Chem., 33, 1393 (1996).
R. R. Tidwell, J. D. Geratz, O. Dann, G. Volz, D. Zeh, and H. Loewe, J. Med. Chem., 21, 613 (1978).
T. A. Fairley, R. R. Tidwell, I. Donkor, N. A. Naiman, K. A. Ohemeng, R. J. Lombardy, J. A. Bentley,
and M. Cory, J. Med. Chem., 36, 1746 (1993).
6.
H. Foks, D. Pancechowska-Ksepko, W. Kuzmierkiewicz, Z. Zwolska, E. Augustynowicz-Kopec, and
M. Janowiec, Khim. Geterotsikl. Soedin., 697 (2006). [Chem. Heterocycl. Compd., 42, 611 (2006).]
Y. Tagawa, K. Yamagata, and K. Sumoto, Heterocycles, 75, 415 (2008).
K. Bahrami, M. M. Khodaei, and I. Kavianinia, Synthesis, 547 (2007).
L.-H. Du and Y.-G. Wang, Synthesis, 675 (2007).
7.
8.
9.
10.
11.
12.
13.
B. Das, H. Holla, and Y. Srinivas, Tetrahedron Lett., 48, 61 (2007).
R. Varala, A. Nasreen, R. Enugala, and S. R. Adapa, Tetrahedron Lett., 48, 69 (2007).
H. Ma, Y. Wang, J. Li, and J. Wang, Heterocycles, 71, 135 (2007).
R. R. Nagawade and D. B. Shinde, Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem., 46B, 349
(2007).
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
D. B. Ramachary and G. B. Reddy, Org. Biomol. Chem., 4, 4463 (2006).
H. Ma, Y. Wang, and A. Wang, Heterocycles, 68, 1669 (2006).
S. Lin and L. Yang, Tetrahedron Lett., 46, 4315 (2005).
M. Curini, F. Epifano, F. Montanari, O. Rosati, and S. Taccone, Synlett, 1832 (2004).
T. Itoh, K. Nagata, H. Ishikawa, and A. Ohsawa, Heterocycles, 63, 2769 (2004).
K. Nagata, T. Itoh, H. Ishikawa, and A. Ohsawa, Heterocycles, 61, 93 (2003).
P. L. Beaulieu, B. Hache, and E. von Moos, Synthesis, 1683 (2003).
K. Otsuka and Y. Wang, Appl. Catal., A, 222, 145 (2001).
T. Ren, L. Yan, X. Zhang, and J. Suo, Appl. Catal., A, 244, 11 (2003).
M. M. Heravi, F. K. Behbahani, V. Zadsirjan, and H. A. Oskooie, Heterocycl. Commun., 12, 369
(2006).
24.
25.
26.
27.
28.
29.
30.
31.
32.
F. K. Behbahani, T. Yektanezhad, and A. R. Khorrami, Heterocycles, 81, 2313 (2010).
F. K. Behbahani, M. Farahani, and H. A. Oskooie, J. Korean Chem. Soc., 55, 633 (2011).
F. K. Behbahani and M. Farahani, Lett. Org. Chem., 81, 431 (2011).
F. K. Behbahani, P. Ziaei, Z. Fakhroueian, and N. Doragi, Monatsh. Chem., 142, 901 (2011).
H. Sharghi, M. H. Beyzavi, and M. M. Doroodmand, Eur. J. Org. Chem., 4126 (2008).
D. W. Hein, R. J. Alheim, and J. J. Leavitt, J. Am. Chem. Soc., 79, 427 (1957).
L. S. Gadekar, B. R. Arbad, and M. K. Lande, Chin. Chem. Lett., 21, 1053 (2010).
B. Das, B. S. Kanth, K. R. Reddy, and A. S. Kumar, J. Heterocycl. Chem., 45, 1499 (2008).
S. D. Sharma and D. Konwar, Synth. Commun., 39, 980 (2009).
1016

33.
34.
35.
I.-S. H. Lee, E. H. Jeoung, and M. M. Kreevoy, J. Am. Chem. Soc., 119, 2722 (1997).
X. Han, H. Ma, and Y. Wang, Zh. Org. Khim., 44, 872 (2008). [Russ. J. Org. Chem., 44, 863 (2008).]
G. Navarrete-Vázquez, H. Moreno-Diaz, S. Estrada-Soto, M. Torres-Piedra, I. León-Rivera,
H. Tlahuext, O. Muñoz-Muñiz, and H. Torres-Gómez, Synth. Commun., 37, 2815 (2007).
B. C. Raju, N. D. Theja, and J. A. Kumar, Synth. Commun., 39, 175 (2009).
S. Rostamizadeh, R. Aryan, H. R. Ghaieni, and A. M. Amani, J. Heterocycl. Chem., 46, 74 (2009).
K. R. S. Reddy, G. Srimannarayana, and N. V. Subba Rao, J. Indian Chem. Soc., 63, 600 (1986).
V. Luxami and S. Kumar, New J. Chem., 32, 2074 (2008).
J. Lu, B. Yang, and Y. Bai, Synth. Commun., 32, 3703 (2002).
N. J. Coville and E. W. Neuse, J. Org. Chem.,42, 3485 (1977).
K. Bahrami, M. M. Khodaei, and F. Naalia, Synlett, 569 (2009).
H. Ma, X. Han, Y. Wang, and J. Wang, Heterocycles, 71, 1821 (2007).
36.
37.
38.
39.
40.
41.
42.
43.
44.
M. Abdollahi-Alibeik and M. Moosavifard, Synth. Commun., 40, 2686 (2010).
1017