Tetrahedron Letters 50 (2009) 1495–1497

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Synthesis of 1,2-disubstitued benzimidazoles using SiO2/ZnCl2

a r t i c l e i n f o a b s t r a c t

Article history: A general and easy method for the synthesis of several 1,2-disubstituted benzimidazoles using SiO2/ZnCl2
Received 25 November 2008 and solvent-free conditions is described. This efficient and improved method furnishes selectively and in
Revised 13 January 2009 good yields the corresponding 1,2-bis(organyl)-benzimidazoles starting from o-phenylenediamine and
Accepted 14 January 2009
aromatic or aliphatic aldehydes. The catalytic system was re-used up three times and the use of focused
Available online 19 January 2009
microwaves accelerates the reaction.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Benzimidazole
Green-chemistry
Microwave

Benzimidazoles and their derivatives exhibit a number of results of the preparation of 1,2-disubstituted benzimidazoles
important pharmacological properties, such as antihistaminic,1 catalyzed by SiO2/ZnCl2 under solvent-free conditions at room
anti-ulcerative,2 antiallergic,3 and antipyretic.4 In addition, benz- temperature, or under microwave irradiation (MW) (Scheme 1).
imidazole derivatives are effective against the human cytomegalo- Initially, we chose o-phenylenediamine (1a; 1 mmol) and (R)-
virus (HCMV)5 and are also efficient selective neuropeptide Y Y1 citronellal (2a; 2 mmol) to establish the conditions for the conden-
receptor antagonists.6 Most of the described methods for the syn- sation reaction. We examined the temperature, SiO2/ZnCl2 ratio,
thesis of benzimidazoles make use of volatile organic solvents and and the irradiation with microwaves (MW).14,15 It was found that
involve solid-phase synthesis via o-nitroanilines7 or the condensa- when 1a (1 mmol) was stirred at room temperature in the pres-
tion of o-phenylenediamines with carboxylic acid derivatives,8 ence of 0.120 g of SiO2/ZnCl2 (10%), the reaction proceeded slowly
aldehydes,9 and aryl halides.10 Alternatively, the palladium- and to afford 2-[(R)-2,6-dimethylhept-5-enyl]-1-[(R)-3,7-dimethyloct-
copper-catalyzed intramolecular N-arylation starting from o-halo- 6-enyl]-1H-benzo[d]imidazole 3a in 57% yield after 8 h. When
anilines has been used.11 More recently, cleaner protocols have the ZnCl2 ratio was increased to 15%, 20%, and 25%, 3a was, respec-
been described, including solvent-free conditions9a–d and the use tively, obtained in 70%, 84%, and 86% yield. The stirring at room
of water8,9e,f and ionic liquid as green solvents.9g However, most temperature for further prolonged time (24 h) or the use of larger
of these protocols use expensive and toxic reagents and/or long amount of the catalytic system (0.240 g) afforded 3a in comparable
reaction times and are limited to aromatic carbonyl compounds. yield. Aiming to reduce the reaction time, the mixture was irradi-
This way, the development of clean, general, and selective routes ated with focused microwaves (300 W/65 °C, Method B) using a
to benzimidazole, including the use of new catalysts, alternative monomode reactor (CEM Explorer). Complete consumption of the
or non-solvents, renewable starting materials, and non-classical starting materials was observed after irradiation for 1.5 min, and
energy sources continues to attract the interest of synthetic organ- 3a was obtained in 92% yield (Table 1, entry 2). By using conven-
ic chemists. The naturally occurring aldehyde, citronellal, besides tional heating at 75 °C, stirring for 2 h was necessary inorder to
an important commodity in the flavor and fragrance industry, is consume the starting materials, and the product was obtained in
a key compound in organic synthesis.12 In recent times, our group just 69% yield. The excellent result observed with focused MW
developed new protocols using SiO2/ZnCl2 as solid-supported cata-
lyst under solvent-free conditions and microwave irradiation to NH2 N
SiO2/ZnCl2 (25%)
prepare isopulegol and octahydroacridines, starting from (R)- + RCHO R
r.t. or MW
citronellal.13 NH2 N
1 2a-i 3a-i R
In continuation of our studies toward the development of new
and cleaner methods for classical synthesis, we report herein the R = C6H5, C3H7, C4H9, 3-CH3C6H5, 4-CH3OC6H5
2-CH3OC6H5, (E)-C6H5CH=CH, 2-Furyl,

* Corresponding author. Tel./fax: +55 53 32757533.

0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.076
1496 R. G. Jacob et al. / Tetrahedron Letters 50 (2009) 1495–1497

Table 1
Condensation of o-phenylenediamine derivatives with aldehydes

Entry Aldehydes Products 3 Methoda Time Yieldb (%)

1 CHO A 8h 86
N

2a 3a

2 2a 3a B 1.5 min 92
3 2a 3ª C 1.5 min 90

4 C6H5CHO 2b N A 20 min 72

3b

5 2b 3b B 0.5 min 90
6 2b 3b C 0.5 min 87

N O

7 2-Furyl 2c N A 20 min 75
O

3c

N
C 3H 7
8 C3H7CHO 2d N A 30 min 78
3d C 3H 7

9 3-CH3C6H4CHO 2e N A 15 min 82

3e

N
OCH3
10 4-CH3OC6H4CHO 2f N A 15 min 35

3f OCH3

CH3O
N

11 2-CH3OC6H4CHO 2 g N A 15 min 40
3g

CH3O

N
C 4H 9
12 C4H9CHO 2 h N
A 30 mim 82
3h C 4H 9

13 (E)-C6H5CH@CHCHO 2i N A 15 min 65

3i

a
Method A: the experiments were performed at room temperature. Method B: the experiments were performed under MW irradiation (300 W) using a MW reactor.
Method C: the experiments were performed under MW irradiation (420 W) using a domestic MW oven.
b
Yields of pure products isolated by column chromatography (hexanes/AcOEt). Compounds 3b–i were identified by mass spectrometry, 1H, 13C NMR and their spectral data
were compared with the literature.9a,c–e,g

was also obtained using an unmodified domestic MW oven at a confirmed by analysis of its NMR spectra, including 2D NOESY,
higher power (420 W, Method C, entry 3). When the same protocol COSY, and 1H–13C HMQC.
was performed at reduced MW power (280 W), the formation of 3a Besides the naturally occurring aldehyde 2a, our protocol was
was observed after a longer reaction time (6 min) in 45% yield. The extended to other aldehydes, including aromatic and aliphatic
exclusive formation of the 1,2-disubstituted benzimidazole 3a was ones. A large difference in the reactivity of unbranched aliphatic
 R. G. Jacob et al. / Tetrahedron Letters 50 (2009) 1495–1497 1497

cat 2. Scott, L. J.; Dunn, C. J.; Mallarkey, G.; Sharpe, M. Drugs 2002, 62, 1503.
path A cat
cat 3. Nakano, H.; Inoue, T.; Kawasaki, N.; Miyataka, H.; Matsumoto, H.; Taguchi, T.;
cat N R N N
R Inagaki, N.; Nagai, H.; Satoh, T. Bioorg. Med. Chem. 2000, 8, 373.
O R
N H N
4. Cohn, G. Ber. 1899, 32, 2242.
N R
R H 5 R R
5. Zhu, Z.; Lippa, B.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 2000, 43, 2430.
3
H 6. Zarrinmayeh, H.; Nunes, A. M.; Ornstein, P. L.; Zimmerman, D. M.; Arnold, M. B.;
N B B Schober, D. A.; Gackenheimer, S. L.; Bruns, R. F.; Hipskind, P. A.; Britton, T. C.;
NH2 H H
R Cantrell, B. E.; Gehlert, D. R. J. Med. Chem. 1998, 41, 2709.
N N N
N H 7. For a review on the synthesis and reactivity of benizimidazoles, see: (a)
NH2 R
4 H R N
Preston, P. N. Chem. Rev. 1974, 74, 279; (b) Huang, W.; Scarborough, R. M.
N N
R H R
Tetrahedron Lett. 1999, 40, 2665; (c) Kilburn, J. P.; Lau, J.; Jones, R. C. F.
path B R R 6
D Tetrahedron Lett. 2000, 41, 5419; (d) Tumelty, D.; Cao, K.; Holmes, C. P. Org. Lett.
O sol D D
2001, 3, 83; (e) Vourloumis, D.; Takahashi, M.; Simonsen, K. B.; Ayida, B. K.;
cat
Barluenga, S.; Winters, G. C.; Hermann, T. Tetrahedron Lett. 2003, 44, 2807; (f)
Mazurov, A. Bioorg. Med. Chem. Lett. 2000, 10, 67; (g) Wu, Z.; Rea, P.; Wickham,
Scheme 2. G. Tetrahedron Lett. 2000, 41, 9871.
8. Dudd, L. M.; Venardou, E.; Garcia-Verdugo, E.; Licence, P.; Blake, A. J.; Wilson,
C.; Poliakoff, M. Green Chem. 2003, 5, 187.
and aromatic aldehydes compared with that of citronellal was ob- 9. (a) Perumal, S.; Mariappan, S.; Selvaraj, S. ARKIVOC 2004, 46; (b) Trivedi, R.; De,
S. K.; Gibbs, R. A. J. Mol. Catal. A: Chem. 2006, 245, 8; (c) Oskooie, H. A.; Heravi,
served. Aromatic aldehydes, butanal and pentanal reacted almost M. M.; Sadnia, A.; Behbahani, F. K.; Jannati, F. Chin. Chem. Lett. 2007, 18, 1357;
instantaneously, and the products were isolated after stirring for (d) Landge, S. M.; Török, B. Catal. Lett. 2008, 122, 338; (e) Salehi, P.; Dabiri, M.;
a few minutes at room temperature (Table 1, entries 4–13). Zolfigol, M. A.; Otokesh, S.; Baghbanzadeh, M. Tetrahedron Lett. 2006, 47, 2557;
(f) Ravi, V.; Ramu, E.; Vijay, K.; Rao, A. S. Chem. Pharm. Bull. 2007, 55, 1254; (g)
In almost all the studied cases, the 1,2-disubstituted benzimi- Dabiri, M.; Salehi, P.; Baghbanzadeh, M.; Nikcheh, M. S. Synth. Commun. 2008,
dazoles 3 were selectively obtained in moderate to good yields. 38, 4272; (h) Varala, R.; Nasreen, A.; Enugala, R.; Adapa, S. R. Tetrahedron Lett.
However, when 5-halopyridine-2,3-diamines were employed in- 2007, 48, 69; (i) Xiangming, H.; Huiqiang, M.; Yulu, W. ARKIVOC 2007, 150.
10. Perry, R. J.; Wilson, B. D. J. Org. Chem. 1993, 58, 7016.
stead of o-phenylenediamines 1, in the reaction with (R)-citronellal
11. (a) Zheng, N.; Buchwald, S. L. Org. Lett. 2007, 9, 4749; (b) Brain, C. T.; Brunton, S.
2a, only a trace amount of the respective condensation product 3 A. Tetrahedron Lett. 2002, 43, 1893.
was detected by GC/MS. The main isolated product in these reac- 12. Lenardão, E. J.; Botteselle, G. V.; Azambuja, F.; Perin, G.; Jacob, R. G. Tetrahedron
tions was isopulegol, obtained from the intramolecular ene-cycli- 2007, 63, 6671.
13. (a) Jacob, R. G.; Perin, G.; Loi, L. N.; Pinno, C. S.; Lenardão, E. J. Tetrahedron
zation of citronellal.13a The solid-supported catalyst was re-used Lett. 2003, 44, 3605; (b) Jacob, R. G.; Perin, G.; Botteselle, G. V.; Lenardão, E.
in a new condensation reaction up to three cycles without signifi- J. Tetrahedron Lett. 2003, 44, 6809; (c) Lenardão, E. J.; Mendes, S. R.; Ferreira,
cant lost of activity. After new treatment with ZnCl2, the supported P. C.; Perin, G.; Silveira, C. C.; Jacob, R. G. Tetrahedron Lett. 2006, 47, 7439.
14. The solid-supported catalyst (SiO2/ZnCl2, 25%) was prepared by the following
catalyst was regenerated.14 procedure: To a 100-mL beaker, silica gel 60 (7.5 g), ZnCl2 (2.5 g), and water
A possible mechanism to explain the formation of the 1,2- (3.0 mL) were added. The suspension was stirred for 15 min at room
disubstituted benzimidazoles 3a–i from o-phenylenediamine 1 temperature, dried at 80 °C for 3 h and for additional 15 h at 150 °C in an
oven and then cooled in a desiccator.
and aldehydes 2 is depicted in Scheme 2. Aiming to speculate if 15. General procedure for the synthesis of benzimidazoles: Method A: To a mixture of
the dihydrobenzimidazole 4 was involved, as suggested by Zelenin aldehyde (2 mmol) and o-phenylenediamine (1 mmol) was added 0.120 g of
et al.,16 we performed the reaction in the presence of deuterated SiO2/ZnCl2, and the whole mixture was stirred at room temperature. The
reaction progress was followed by TLC. After stirring for 5.0 min–8 h (Table 1),
solvents, such as D2O and CH3OD (path B). However, any amount ethyl acetate (10 mL) was added, and the organic solution was separated of the
of deuterated benzimidazole 6 was detected. This can be indicative SiO2/ZnCl2 by filtration. The solvent was evaporated under reduced pressure,
that the reaction probably occurs via the path A, with formation of and the residue was purified by column chromatography over silica gel eluting
with hexanes/AcOEt 9:1 mixture, yielding the products. Method B: In a typical
dialkylidene (R = alkyl) or dibenzilidene-o-phenylenediamine 5
procedure, aldehydes (2.0 mmol), o-phenylenediamines (1 mmol), and the
(R = aryl), followed by 1,3-hydride transfer, according to previous catalyst (0.120 g) were placed in a 10-mL glass tube. The vessel was then
suggestions.9a,c,f,h sealed with a septum, placed into the microwave cavity and irradiated with
In conclusion, we have presented here an improved methodol- stirring under a maximum potency of 300 W for the time given in Table 1. After
allowing the mixture to cool to room temperature, the reaction vessel was
ogy for the selective synthesis of 1,2-disubstituted benzimidazoles opened and the product was purified according to that described in Method A.
by the condensation of o-phenylenediamine and aldehydes using Method C: The aforementioned whole mixture was previously stirred for 1 min
solid-supported catalyst. This general, simple, fast, and clean pro- and then irradiated with microwaves (used a domestic Panasonic model
Piccolo NN-S42BK, operating at 2.45 MHz) at 420 W17 for 0.5–1.5 min (Table
tocol minimizes the organic solvent and energy demands, as well 1). The reaction progress was followed by TLC, and the product was purified
as, the reaction time could be reduced from hours to a few minutes according to that described in Method A. Compound 3a: ½a20 D 3.0 (1, CHCl3);
1
using MW. H NMR (400 MHz, CDCl3) d (ppm) 7.71–7.73 (m, 1H); 7.25–7.30 (m, 1H); 7.19–
7.23 (m, 2H); 5.06–5.11 (m, 2H); 4.01–4.12 (m, 2H); 2.86 (dd, J = 14.8 and
5.6 Hz, 1H); 2.65 (dd, J = 14.8 and 8.8 Hz, 1H); 1.68 (s, 3H); 1.67 (s, 3H); 1.59 (s,
Acknowledgments 6H); 1.03 (d, J = 6.0 Hz, 3H); 1.00 (d, J = 6.0 Hz, 3H); 1.20–2.24 (m, 12H); 13C
NMR (50 MHz, CDCl3) d (ppm) 154.3, 143.0, 135.1, 131.9, 131.7, 124.5, 124.4,
122.0, 121.8, 119.4, 109.3, 42.1, 37.5, 37.0, 35.2, 32.7, 30.7, 25.9, 25.8, 25.6,
This project is funded by CNPq, CAPES, and FAPERGS. Sá, M. M. 20.0, 19.8, 17.9. HRMS (ESI): m/z calcd for C26H40N2 [M+H]+: 381.3270; found:
(UFSC-Brazil) is thanked for making available the MW focused 381.3362.
reactor. 16. Zelenin, K. N.; Ukraintsev, I. V.; Alekseev, V. V. Chem. Heterocycl. Compd. 1998,
34, 329.
17. The oven power was determined according to the method described by:
References and notes Kingston, H. M. In Introduction to Microwave Sample Preparation—Theory
and Practice; Jassie, L. B., Ed.; American Chemical Society: Washington,
1. Al Muhaimeed, H. J. Int. Med. Res. 1997, 25, 175. 1988.