Selective synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles in water at ambient temperature

Article abstract of DOI:10.1016/j.tetlet.2006.02.049

A highly selective synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles from the reaction of o-phenylenediamines and aromatic aldehydes in the presence of silica sulfuric acid is reported. The reactions were performed in ethanol or water and the catalys

Full text of DOI:10.1016/j.tetlet.2006.02.049

Tetrahedron Letters 47 (2006) 2557–2560
Selective synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles
in water at ambient temperature
Peyman Salehi,a,* Minoo Dabiri,b Mohammad Ali Zolfigol,c
Somayeh Otokeshb and Mostafa Baghbanzadehb
aDepartment of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, PO Box 19835-389,
Evin, Tehran, Iran
bDepartment of Chemistry, Faculty of Sciences, Shahid Beheshti University, Evin, Tehran, Iran
cDepartment of Chemistry, Faculty of Sciences, Bu-Ali Sina University, Hamadan, Iran
Received 22 November 2005; revised 1 February 2006; accepted 9 February 2006
Abstract—A highly selective synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles from the reaction of o-phenylenediamines and
aromatic aldehydes in the presence of silica sulfuric acid is reported. The reactions were performed in ethanol or water and the cat-
alyst could be reused for several runs.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
orthoesters) under harsh dehydrating conditions.8 Benz-
imidazoles have also been prepared on solid-phase to
provide a combinatorial approach.9 The most popular
strategies for their synthesis utilise o-nitroanilines as
intermediates or resort to direct N-alkylation of an
unsubstituted benzimidazole.10 A number of synthetic
protocols that involve intermediate o-nitroanilines have
evolved to include the synthesis of benzimidazoles on
solid support.11–17 Another method for the synthesis of
these compounds is the reaction of o-phenylenediamine
with aldehydes in the presence of acidic catalysts under
various reaction conditions.18–22
The benzimidazole nucleus is of significant importance
to medicinal chemistry. Several publications report
benzimidazole-containing compounds showing biologi-
cal activities such as selective neuropeptide YY1 recep-
tor antagonism,1 and as 5-lipoxygenase inhibitors for
use as novel antiallergic agents,2 factor Xa (FXa) inhib-
itors,3 poly (ADP-ribose) polymerase (PARP) inhibi-
tors4 and as human cytomegalovirus (HCMV)
inhibitors.5 Substituted benzimidazole derivatives have
found commercial applications in veterinarian medicine
as anthelmintic agents and in diverse human therapeutic
areas such as treatment of ulcers and as antihistaminics.6
In light of the affinity they display towards a variety of
enzymes and protein receptors, medicinal chemists
would certainly classify them as ‘privileged sub-struc-
tures’ for drug design.7
In continuation of our interest in catalysed solid support
reactions,23 we report a selective synthesis of 2-aryl-1-
arylmethyl-1H-1,3-benzimidazoles in ethanol and water.
When o-phenylenediamine derivatives 1 and aromatic
aldehydes 2 in the presence of silica sulfuric acid24 and
different organic solvents, were allowed to react at room
temperature, both expected products were obtained
whose ratios depended on the nature of the solvent
(Scheme 1, 3 and 4). As can be seen in Table 1, the best
overall yields and selectivities were obtained in ethanol,
in which only N-substituted benzimidazoles 3 were pro-
duced. Consequently several aromatic aldehydes with
different substituents on the aromatic ring were sub-
jected to the condensation reaction. In all cases the
yields were high and 3 was formed selectively rather
than 4 (Table 2).
The traditional synthesis of benzimidazoles involves
the reaction between an o-phenylendiamine and a
carboxylic acid or its derivatives (nitriles, amidates,
Keywords: Heterocycles; Benzimidazole; Heterogenous catalysis;
Water; Silica sulfuric acid.
Corresponding author. Tel./fax: +98 21 2241 8679; e-mail: p-salehi@
sbu.ac.ir
*
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.049

2558
P. Salehi et al. / Tetrahedron Letters 47 (2006) 2557–2560
R1
R1
R1
R1
R1
R1
NH2
NH2
N
N
N
Silica sulfuric acid
Solvent, rt
R2
R2CHO
R2
+
+
N
H
R2
1
2
3
4
Scheme 1.
lowed by ring closure.22 Finally, aromatisation took
place via deprotonation and 1,3-hydride transfer.
Table 1. Effect of solvent on the time and yield of the reaction of
o-phenylenediamine and p-chlorobenzaldehyde in the presence of
a catalytic amount of silica sulfuric acid
Yielda (%)
The production of monosubstituted benzimidazole 4 in
some cases could be visualised to occur by condensation
of o-phenylenediamine with the aldehyde followed by air
oxidation of the dihydrobenzimidazole derivative, as
previously reported.26
Solvent
Time (h)
3
4
EtOH
1
2
2.5
4.5
2
90
78
40
30
50
85
0
2
15
10
0
CH3CN
CH3OH
C6H5CH3
H2O
The recyclability of the catalyst was investigated using a
model reaction between o-phenylenediamine and 4-chlo-
robenzaldehyde in the presence of 30 mol % of the cata-
lyst in ethanol. After completion of the reaction, the
mixture was filtered to separate the catalyst. The recy-
cled catalyst was used for further runs and its activity
did not show any significant decrease even after five
runs.
H2O+LiClb
1.5
0
a Isolated yield based on the aromatic aldehyde.
b Reaction was performed in 1 M aqueous LiCl.
There is an urgent need to develop alternative solvents
and technologies due to pressure from governmental
organisations and other regulatory bodies to protect
the environment. Use of green solvents like water show
both economical and synthetic advantages. To the best
of our knowledge there is no pervious report on the syn-
thesis of 1,2-disubstituted benzimidazoles in aqueous
media at room temperature. Thus, we decided to inves-
tigate the reaction in water. Unfortunately, the yield was
not satisfactory even at reflux, but the selectivity for the
production of 3 was high. To increase the reaction yield
in water, LiCl was added in order to increase the dielec-
tric constant of the medium.25 As expected the reaction
time became shorter and yields were increased whilst
maintaining the selectively.
In summary, we have reported a new and effective meth-
odology for the eco-compatible preparation of 2-aryl-1-
arylmethyl-1H-1,3-benzimidazoles. The easy purifica-
tion of the products by simple filtration and crystallisa-
tion, the use of water as the solvent and silica sulfuric
acid as a heterogeneous and reusable catalyst suggest
good prospects for the applicability of this process.
Also, the problem of obtaining two possible products
was overcome using this new method.
2. General procedure for the synthesis of 2-aryl-1-
arylmethyl-1H-1,3-benzimidazoles in organic solvents
As described before, compound 3 may be produced
through a tandem sequence of reactions starting with
the formation of dibenzylidene-o-phenylenediamine fol-
Aromatic aldehyde (2 mmol), o-phenylenediamine deri-
vative (1 mmol) and silica sulfuric acid (0.11 g equal to
Table 2. Reaction of aromatic aldehydes with o-phenylenediamines in the presence of silica sulfuric acid in water and ethanol
Product
R1
R2
Time (h)
Yieldb (%)
Mpc (°C)
Ethanol
Watera
Ethanol
Watera
3a
3b
3c
3d
3e
3f
H
H
H
H
H
H
H
H
H
H
CH3
CH3
C6H5
1.5
2
1
1
2
1.5
2
1.5
1
1.5
1
1.5
2
75
78
95
90
75
67
88
70
94
75
84
78
71
78
90
82
70
60
75
72
85
71
78
75
13210
4-MeOC6H4
4-MeC6H4
4-ClC6H4
2-MeOC6H4
2-ClC6H4
2-Furyl
4-Me2NC6H4
4-iPrC6H4
2-Pyridyl
4-ClC6H4
4-MeC6H4
2.5
1.5
2
3
2
2.5
3
2
3.5
2
3
129–13022
128–13010a
13610b
15322
16310a
9422
3g
3h
3i
25510a
17610a
13022
3j
3k
3l
19027
17727
a Reactions were performed in 1 M aqueous LiCl.
b Isolated yield based on the aromatic aldehyde.
c The products were characterised by comparison of their spectroscopic and physical data with authentic samples synthesised by reported procedures.

P. Salehi et al. / Tetrahedron Letters 47 (2006) 2557–2560
2559
0.3 mmol H+) were placed in a round bottomed flask.
Then 5 mL of solvent was added and the mixture was
stirred magnetically. After completion of the reaction
(TLC, eluent, n-hexane/ethyl acetate, 3/1), the mixture
was filtered, the solvent evaporated and the crude prod-
uct was recrystallised from ethanol.
9. (a) Wu, Z.; Rea, P.; Wickam, G. Tetrahedron Lett. 2000,
41, 9871–9874, and references cited therein; (b) Mazurov,
A. Bioorg. Med. Chem. Lett. 2000, 10, 67–70.
10. (a) Kim, B. H.; Han, R.; Kim, J. S.; Jun, Y. M.; Baik, W.;
Lee, B. M. Heterocycles 2004, 63, 41–54; (b) Itoh, T.;
Nagata, K.; Ishikawa, H.; Ohsawa, A. Heterocycles 2004,
63, 2769–2783.
11. Mazurov, A. Bioorg. Med. Chem. Lett. 2000, 10, 67.
12. Tumelty, D.; Cao, K.; Holmes, C. P. Org. Lett. 2001, 3,
83–86.
13. Tumelty, D.; Schwarz, M. K.; Needels, M. C. Tetrahedron
Lett. 1998, 38, 7467–7470.
3. General procedure for the synthesis of 2-aryl-1-
arylmethyl-1H-1,3-benzimidazoles in water
14. Mayer, J. P.; Lewis, G. S.; Mc Gee, C.; Bankaitis-Davis,
D. Tetrahedron Lett. 1998, 39, 6655–6658.
15. Huang, W.; Scarborogh, R. M. Tetrahedron Lett. 1999,
40, 2665–2668.
16. Smith, J. M.; Krchnak, V. Tetrahedron Lett. 1999, 40,
7633–7636.
17. Kilburn, J. P.; Lau, J.; Jones, R. C. F. Tetrahedron Lett.
2000, 41, 5419–5421.
18. Pertry, R. J.; Wilson, B. D. J. Org. Chem. 1993, 58, 7016–
7021.
19. Esser, F.; Ehrengart, P.; Ignanatow, H. P. J. Chem. Soc.,
Perkin Trans. 1 1999, 1153–1154.
Silica sulfuric acid (0.11 g equal to 0.3 mmol H+),
o-phenylenediamine (1 mmol), aromatic aldehyde (2
mmol) and 0.02 g of LiCl were added to 5 mL of water
and the reaction stirred in a round bottomed flask for
the appropriate time (see Table 2). The solvent was dec-
anted, hot ethanol (5 mL) was added and the mixture
was then filtered. The resulting solution was condensed
under reduced pressure. Finally the crude product was
recrystallised from ethanol.
20. Anastasiou, D.; Campi, E. M.; Chaouk, H.; Jackson, W.
R. Tetrahedron 1992, 48, 7467–7478.
Acknowledgement
21. Brain, C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43,
1893–1895.
22. Perumal, S.; Mariappan, S.; Selvaraj, S. Arkivoc 2004, 8,
46–51.
Financial support from the Research Council of Shahid
Beheshti University is gratefully acknowledged.
23. (a) Dabiri, M.; Salehi, P.; Mohammadi, A. A.; Baghban-
zadeh, M. Synth. Commun. 2005, 35, 279–287; (b) Salehi,
P.; Dabiri, M.; Zolfigol, M. A.; Baghbanzadeh, M. Synlett
2005, 1155–1157; (c) Dabiri, M.; Salehi, P.; Mohammadi,
A. A.; Baghbanzadeh, M.; Kozehgiry, Gh. J. Chem. Res.
(S) 2004, 570–572.
24. (a) Zolfigol, M. A. Tetrahedron 2001, 57, 9509–9511; (b)
Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Bodaghi Fard, M.
A. Tetrahedron Lett. 2003, 44, 2889–2891; (c) Zolfigol, M.
A.; Shirini, F.; Ghorbani Choghamarani, A.; Moham-
madpoor Baltork, I. Green Chem. 2002, 4, 562–564; (d)
Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Bodaghi Fard, M.
A. J. Braz. Chem. Soc. 2004, 15, 773–776; (e) Salehi, P.;
Dabiri, M.; Zolfigol, M. A.; Bodaghi Fard, M. A.
Heterocycles 2003, 60, 2435–2440; (f) Salehi, P.; Dabiri,
M.; Zolfigol, M. A.; Baghbanzadeh, M. Tetrahedron Lett.
2005, 46, 7051–7053.
25. (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159–164; (b)
Gajewski, J. J. Acc. Chem. Res. 1997, 30, 219–225; (c)
Otto, S.; Engberts, J. B. F. N. Org. Biomol. Chem. 2003, 1,
2809–2820; (d) Pratt, L. R.; Pohrille, A. Chem. Rev. 2002,
102, 2671–2692; (e) Ludwig, R. Angew. Chem., Int. Ed.
2001, 40, 1808–1827; (f) Berslow, R. Acc. Chem. Res. 2004,
37, 471–478; (g) Narayan, S.; Muldoon, J.; Fin, M. G.;
Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 2005, 44, 3275–3279.
References and notes
1. Zarrinmayeh, H.; Nunes, A. M.; Ornstein, P. L.; Zimmer-
man, D. A.; Gackenheimer, S. L.; Bruns, R. F.; Hipskind,
P. A.; Britton, T. C.; Cantrell, B. E.; Gehlert, D. R. J.
Med. Chem. 1998, 41, 2709–2719.
2. Nakano, H.; Inoue, T.; Kawasaki, N.; Miyataka, H.;
Matsumoto, H.; Taguchi, T.; Inagaki, N.; Nagai, H.;
Satoh, T. Bioorg. Med. Chem. 2000, 8, 373–380.
3. Zhao, Z. S.; Arnaiz, D. O.; Griedel, B.; Sakata, S.; Dallas,
J. L.; Whitlow, M.; Trinh, L.; Post, J.; Liang, A.;
Morrissey, M. M.; Shaw, K. J. Bioorg. Med. Chem. Lett.
2000, 10, 963–966.
4. White, A. W.; Almassy, R.; Calvert, A. H.; Curtin, N. J.;
Griffin, R. J.; Hostomsky, Z.; Maegley, K.; Newell, D. R.;
Srinivasan, S.; Golding, B. T. J. Med. Chem. 2000, 43,
4084–4097.
5. Zhu, Z.; Lippa, B.; Drach, J. C.; Townsend, L. B. J. Med.
Chem. 2000, 43, 2430–2437.
6. Spasov, A. A.; Yozhitsa, I. N.; Bugaeva, L. I.; Anisimova,
V. A. Pharm. Chem. J. 1999, 33, 232–243.
7. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; Dipardo, R.
M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.;
Veber, D. F.; Anderson, P. S.; Chang, R. S.; Chang, R. S.
L.; Lotti, V. J.; Gerino, D. J.; Chen, T. B.; Kling, P. J.;
Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem.
1988, 31, 2235–2246; (b) Mason, J. S.; Morize, I.; Menard,
P. R.; Cheney, D. L.; Hume, C.; Labaudiniere, R. F. J.
Med. Chem. 1999, 42, 3251–3264.
8. (a) Preston, P. N. In Chemistry of Heterocyclic Com-
pounds; Weissberger, A., Taylor, E. C., Eds.; John Wiley
and Sons, 1981; Vol. 40; (b) Chi, Y.-C.; Sun, C.-M. Synlett
2000, 591–594; (c) Huang, W.; Scarborough, R. M.
Tetrahedron Lett. 1999, 40, 2665–2668; (d) Dudd, L. M.;
Venardou, E.; Garcia-Verdugo, E.; Licence, P.; Blake, A.
J.; Wilson, C.; Poliakoff, M. Green Chem. 2003, 5, 187–
192.
26. Curini, M.; Epifano, F.; Montanari, F.; Rosati, O.;
Taccone, S. Synlett 2004, 1832–1834.
27. Compound (3k) (C22H18Cl2N2): Pale yellow solid; mp
190 °C; IR (KBr) (mmax, cmÀ1): 3100, 2965, 1505, 1457,
1379; 1H NMR (300 MHz, DMSO-d6) d = 2.36 (3H, s,
CH3), 2.40 (3H, s, CH3), 5.43 (2H, s, CH2), 7.00–7.72
(10H, m, Ar–H) ppm; 13C NMR (75 MHz, CDCl3)
d = 20.3, 20.7, 48.0, 110.7, 118.9, 127.1, 129.4, 129.5,
130.5, 133.4, 134.6, 133.9, 134.1, 137.2, 150.7 ppm; MS
(EI, 70 eV) (m/z, %): 381 (M+, 2), 256 (20), 125 (100).
Compound (3l) (C24H24N2): White solid; mp 177 °C; IR
(KBr) (mmax, cmÀ1): 3020, 2900, 1507, 1436, 1381; 1H
NMR (300 MHz, CDCl3) d = 2.33 (3H, s, CH3), 2.36 (3H,

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P. Salehi et al. / Tetrahedron Letters 47 (2006) 2557–2560
s, CH3), 2.40 (3H, s, CH3), 2.41 (3H, s, CH3), 5.38 (2H, s,
119.4, 125.7, 126.4, 129.1, 129.5, 129.7, 132.0, 132.4, 133.4,
134.3, 137.4, 140.2, 153.0 ppm; MS (EI, 70 eV) (m/z, %):
340 (M+, 15), 236 (20), 105 (100).
CH2), 6.99–7.66 (10H, m, Ar–H) ppm; 13C NMR
(75 MHz, CDCl3) d = 20.3, 20.6, 21.1, 21.4, 48.1, 110.6,