4318
S. Lin, L. Yang / Tetrahedron Letters 46 (2005) 4315–4319
O
air
dioxane
NH2
N
H
+
NH2
100 oC, 24 h
84%
N
H
(100 mmol)
(100 mmol)
Scheme 2. Synthesis of 2-phenyl-5-methylbenzimidazole.
under these conditions follows through the known7–17
intermediate SchiffÕs bases A, which exist in equilibrium
with the cyclic hydrobenzimidazoles B that were oxi-
dized to benzimidazoles byoxygen.
J. Med. Chem. 1978, 21, 613–623; (c) Fairley, T. A.;
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6. (a) Bourgrin, K.; Loupy, A.; Soufiaoui, M. Tetrahedron
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2467; (c) Ben-Alloum, A.; Bakkas, S.; Soufiaoui, M.
Tetrahedron Lett. 1998, 39, 4481.
In summary, efficient synthesis of benzimidazoles from
phenylenediamines and aldehydes using air as the oxi-
dant was investigated, and a simple and efficient proce-
dure using dioxane as the solvent was developed. The
salient features of this method include a simple proce-
dure, mild conditions, no coupling agents or commercial
oxidants/additives used, no waste produced (onlyby-
product being water), easypurification, and high
generality.
7. (a) Dubey, P. K.; Ratnam, C. V. Indian J. Chem. B 1979,
18, 428; (b) Yadagiri, B.; Lown, J. W. Syn. Commun. 1990,
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Y.; Luong, C.; Martelli, A.; Radika, K.; Rai, R.; She, M.;
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Acknowledgements
We would like to thank Drs. Min Ge, Changyou Zhou,
and Alexander Pasternak for helpful discussions.
9. (a) vanden Eynde, J. J.; Delfosse, F.; Lor, P.; van
Haverbeke, Y. Tetrahedron 1995, 51, 5813–5818; (b) Lee,
K. J.; Janda, K. D. Can. J. Chem. 2001, 79, 1556–1561.
10. Chikashita, H.; Nishida, S.; Miyazaki, M.; Morita, Y.;
Itoh, K. Bull. Chem. Soc. Jpn. 1987, 60, 737.
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14. Beaulieu, P. L.; Hache, B.; von Moos, E. Synthesis 2003,
11, 1683–1692.
15. (a) Weidner-Wells, M. A.; Ohemeng, K. A.; Nguyen, V.
N.; Fraga-Spano, S.; Macielag, M. J.; Werblood, H. M.;
Foleno, B. D.; Webb, G. C.; Barrett, J. F.; Hlasta, D. J.
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19. General procedure: A solution of 3,4-diaminotoluene
(0.25 mmol) and benzaldehyde (0.25 mmol) in 1 mL of
solvent or neat was placed in a 50 mL capped tube. The
tube was flushed with air, capped, and heated for 4 h at
refluxing or at 100 °C (see Table 1). The reaction mixture
was then cooled to room temperature, and diluted to
10 mL with methanol. The crude mixture was then
analyzed by a reverse-phase HPLC using a 0.025 M
methanol solution of 3,4-diaminotoluene and a 0.025 M
methanol solution of 2-phenyl-5-methylbenzimidazole as
the standards.
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20. The rate of oxidation bymere O was reported earlier to
2
be slow in acetonitrile and ÔinsufficientÕ for complete