5574
G. M. Raghavendra et al. / Tetrahedron Letters 52 (2011) 5571–5574
T3P/DMSO
Ethyl acetate
References and notes
H2N
HS
OH
N
+
1. Tanious, F. A.; Hamelberg, D.; Bailly, C.; Czarny, A.; Boykin, D. W.; Wilson, W. D.
J. Am. Chem. Soc. 2004, 126, 143.
2. Kuhler, T. C.; Swanson, M.; Shcherbuchin, V.; Larsson, H.; Mellgard, B.;
Sjostrom, J. E. J. Med. Chem. 1998, 41, 1777.
oC to rt
S
0
14c
14b
1a
3. Mavrova, A.; Anichina, K. K.; Vuchev, D. I.; Tsenov, J. A.; Denkova, P. S.; Kondeva,
M. S.; Micheva, M. K. Eur. J. Med. Chem. 2006, 41, 1412.
4. Kohara, Y.; Kubo, K.; Imamiya, E.; Wada, T.; Inada, Y.; Naka, T. J. Med. Chem.
1996, 39, 5228.
Scheme 3. General approach for the synthesis of benzothiazoles.
5. Mederski, W. W.; Dorsch, D.; Anzali, S.; Gleitz, J.; Cezanne, B.; Tsaklakidis, C.
Bioorg. Med. Chem. Lett. 2004, 14, 3763.
6. Richards, M. L.; Lio, S. C.; Sinha, A.; Tieu, K. K.; Sircar, J. C. J. Med. Chem. 2004, 47,
6451.
7. Elmer, G. I.; Pieper, J. O.; Goldberg, S. R.; George, F. R. Psychopharmacology (Berl.)
1995, 117, 23.
8. Mader, M.; de Dios, A.; Shih, C.; Anderson, B. D. Bioorg. Med. Chem. Lett. 2008,
18, 179.
9. Arjmand, F.; Mohani, B.; Ahmad, S. Eur. J. Med. Chem. 2005, 40, 1103.
10. Gualtieri, F.; Brody, G.; Fieldsteel, A. H.; Skinner, W. A. J. Med. Chem. 1972, 15,
420.
11. Valdez, J.; Cedillo, R.; Hernandez-Campos, A.; Yepez, L.; Hernandez-Luis, F.;
Navarrete-Vazquez, G.; Tapia, A.; Cortes, R.; Hernandez, M.; Castillo, R. Bioorg.
Med. Chem. Lett. 2002, 12, 2221.
was observed. Increasing the volume of DMSO in the ratio
(EtOAc/DMSO) to 1:1, 1:2, 1:3, and 1:4 did not improve the yield.
The optimization studies of the experiments are provided in Table
1, (entries 5–10) which shows the effect of various solvents such as
EtOAc (entry 3, 90%), toluene (entry 5, 75%) and CH3CN (entry 8,
60%), in which ethyl acetate was chosen as the appropriate solvent
with consideration to yield. The optimum temperature of the
reaction was determined by conducting the experiments at 40,
50, 60, and 70 °C. The results showed that at these temperatures
the reaction time was drastically reduced, but with no significant
increase in the yield of benzimidazole 1c.
12. Tamm, I. Science 1957, 126, 1235.
13. Porcari, A. R.; Devivar, R. V.; Kucera, L. S.; Drach, J. C.; Townsend, L. B. J. Med.
Chem. 1998, 41, 1251.
14. Imidazole and Benzimidazole Synthesis; Grimmett, M. R., Ed.; Academic Press:
San Diego, 1997.
15. (a) Hornberger, K. R.; Adjabeng, G. M.; Dickson, H. D.; Davis-Ward, R. G.
Tetrahedron Lett. 2006, 47, 5359; (b) Wang, R.; Lu, X. X.; Yu, X. Q.; Shi, L.; Sun, Y.
J. Mol. Catal. A: Chem. 2007, 266, 198.
16. (a) Mukhopadhyay, C.; Tapaswi, P. K. Tetrahedron Lett. 2008, 49, 6237; (b) Lin,
C.; Lai, P. T.; Liao, S. K. S.; Hung, W.-T.; Yang, W.-B.; Fang, J.-M. J. Org. Chem.
2008, 73, 3848.
17. (a) Yang, D.; Fokas, D.; Li, J.; Yu, L.; Baldino, C. M. Synthesis 2005, 47; (b) Surpur,
C. M.; Singh, P. R.; Patil, S. B.; Samant, S. D. Synth. Commun. 2007, 37, 1375.
18. (a) Zou, B.; Yuan, Q.; Ma Angew. Chem., Int. Ed. 2007, 46, 2598; (b) Evindar, G.;
Batey, R. A. Org. Lett. 2003, 5, 133.
19. (a) Curini, M.; Epifano, F. Synlett 2004, 1832; (b) Wilfred, C. D.; Taylor, R. J. K.
Synlett 2004, 1628; (c) Ruiz, V. R.; Corma, A.; Sabater, M. J. Tetrahedron Lett.
2010, 66, 730; (d) Kondo, T.; Yang, S.; Huh, K. T.; Kobayashi, M.; Kotachi, S.;
Watanabe, Y. Chem. Lett. 1991, 1275; (e) Kim, J. W.; He, J.; Yamaguchi, K.;
Mizuno, N. Chem. Lett. 2009, 62, 1275; (f) Blacker, A. J.; Farah, M. M.; Hall, M. I.;
Marsden, S. P.; Saidi, O.; Williams, J. M. Org. Lett. 2009, 11, 2039; (g) Moorthy, J.
N.; Neogi, I. Tetrehedron Lett. 2011, 52, 3868; (h) Plumb, B.; Harper, D. J. Chem.
Eng. News 1990, 3.
The reactions were carried out using ethyl acetate at 0–25 °C by
taking 1:1.1 mol ratio mixture of o-phenylenediamine, and
different alcohols in the presence of ÒT3P to get the desired prod-
uct in excellent yield (Scheme 2) the results in Table 2 show that
aromatic, aliphatic, and heterocyclic alcohols react without any
significant difference to provide their corresponding benzimidaz-
oles and benzothiazoles in good yield. This method can tolerate
protecting group like Boc and other functional groups such as ester,
halide, nitrile, allylic, and methoxy. The scope and the generality of
this procedure is illustrated with respect to various aliphatic, aro-
matic, and heterocyclic alcohols and the results are summarized in
Table 2.
To generalize our reagent system, the applicability of the ÒT3P/
DMSO system was examined for their reactions with a series of
aromatic, aliphatic, and heterocyclic alcohols with 1,2-phenylendi-
amines under the optimized conditions (Table 2). As shown, a vari-
ety of alcohols bearing electron-donating (entries 8–9) and
electron withdrawing (entries 4–7), heterocyclic (10–11), and ali-
phatic (12–13) substituents were successfully employed to prepare
the corresponding benzimidazole derivatives in excellent yields.
This procedure is applicable to substituted 1,2-phenylenediamines,
which produced the corresponding 2-arylbenzimidazoles simply in
excellent yields. 2-Aminothiophenol also underwent the reaction,
affording the corresponding 2-arylbenzothiazoles (Scheme 3) in
excellent yields (Table 2, entries 14–20). The 2-amiophenol did
not produce the desired products in the reaction.
In conclusion, we have developed an expedient and direct
method for the synthesis of benzimidazoles and benzothiazoles
in excellent yields, starting directly from a variety of alcohols
1,2-phenylenediamine and 2-aminothiophenol derivatives. The
protocol involves ÒT3P-DMSO mediated oxidation of alcohols to
aldehydes followed by cyclocondensation with 1,2-phenylenedi-
amine and o-aminothiolphenol, to afford benzimidazoles and ben-
zothiazoles in one-pot operation with excellent yield. ÒT3P is low
in toxicity, and commercially available at moderate price. The
range of benzimidazoles and benzothiazoles were produced in high
yields without the need for any additional oxidants.
20. Chandrappa, S.; Vinaya, K.; Ananda Kumar, C. S.; Rangappa, K. S. Tetrhedron Lett.
2010, 51, 6493.
21. Raghavendra, G. M.; Harsha, K. B.; Vinaya, K.; Mantelingu, K.; Rangappa, K. S.
Synth. Commun. 2011, 41, 2296.
22. Revanna, C. N.; Swaroop, T. R.; Raghavendra, G. M.; Bhadre Gowda, D. G.;
Mantelingu, K.; Rangappa, K. S.; J. Heterocycl. Chem. in press, doi:00880.
23. Chandrappa, S.; Vinaya, K.; Ramakrsihanappa, T.; Rangappa, K. S. Synlett 2010,
20, 3019.
24. Llanes Garcia, A. L. Synlett 2007, 1328.
25. (a) Burkhart, F.; Hoffmann, M.; Kessler, H. Angew. Chem., Int. Ed. 1997, 36, 1191;
(b) Zumpe, F. L.; Melanie, F.; Schmitz, K.; Lender, A. Tetrahedron Lett. 2007, 48,
1421; (c) Augustine, J. K.; Atta, R. N.; Ramappa, B. K.; Boodappa, C. Synlett 2009,
3378; (d) Augustine, J. K.; Vairaperumal, V.; Narasimhan, S.; Alagarsamy, P.;
Radhakrishnan, A. Tetrahedron 2009, 65, 9989; (e) James, M.; Crawforth, J. M.;
Paoletti, M. Tetrahedron Lett. 2009, 50, 4916; (f) Basavaprabhu, N. N.; Ravi, S. L.;
Sureshbabu, V. V. Tetrehedron. Lett. 2010, 51, 3002; (g) Meudt, A.; Scherer. S.;
Böhm, C. PCT Int. Appl. WO 2005102978, 2005.; (h) Chem. Abstr. 2005, 143,
440908.; (i) Augustine, J. K.; Sharmila, V. V.; Alagarsamy, N. P.; Radhakrishnan,
A. Tetrahedron 2009, 65, 9989.
26. General procedure for the one-pot synthesis of benzimidazoles and
benzothiazoles: to a solution of alcohol (1.1 mmol) in a mixture of solvents
ethyl acetate (4 mL) and DMSO (2 mL), was added ÒT3P (2 mmol, 50% solution
in ethyl acetate) at 0 °C and the resulting reaction mixture was stirred at room
temperature for 1–2 h under nitrogen atmosphere. The reaction was
monitored by TLC, 1,2-phenylenediamine (1 mmol) was added and stirred
further for 1–2 h. After completion of the reaction, the mixture was diluted
with water (20 mL) and neutralized with 10% NaHCO3 solution. The product
was extracted with ethyl acetate (10 mL) and the combined organic phase was
washed with water (10 mL) and brine solution. The organic phase was dried
over anhydrous Na2SO4. The solvent was dried under reduced pressure to
afford a crude product, which was purified on silica gel using ethyl acetate and
petroleum ether. For the conversion of alcohols to benzothiazoles the same
procedure as above was followed except the use of o-aminothiophenol, instead
of 1,2-phenylenediamine.
Acknowledgment
The authors are grateful to the UGC, Govt., of India for financial
support to K.M. for the projects vide No. F.No.39-710/2011 (SR) da-
ted 21-01-2011.