38
S. Kamijo et al. / Tetrahedron Letters 45 (2004) 35–38
Marinelli, F. J. Organomet. Chem. 1994, 475, 289–296;
(d) Kondo, Y.; Shiga, F.; Murata, N.; Sakamoto, T.;
Yamanaka, H. Tetrahedron 1994, 50, 11803–11812.
4. For the reactions using Cu(I) catalyst, see: (a) Castro, C.
E.; Gaughan, E. J.; Owsley, D. C. J. Org. Chem. 1966, 31,
4071–4078; (b) Sakamoto, T.; Kondo, Y.; Iwashita, S.;
Nagano, T.; Yamanaka, H. Chem. Pharm. Bull. 1988, 36,
1305–1308.
5. For the reactions using Cu(II) catalyst, see: (a) Saulnier,
M. G.; Frennesson, D. B.; Deshpande, M. S.; Vyas, D. M.
Tetrahedron Lett. 1995, 36, 7841–7844; (b) Hiroya, K.;
Itoh, S.; Ozawa, M.; Kanamori, Y.; Sakamoto, T.
Tetrahedron Lett. 2002, 43, 1277–1280.
available to which pathway is operative. According to
the observations that the reactions are completed in
shorter times when electron-donating groups are intro-
duced at either the R1 or R3 positions of the starting
imines 1, and that even acidic alcohols such as phenols
2e, 2f, and trifluoroethanol 2g afford the corresponding
indoles 3x, 3y, and 3z, it might be that cycle (b) is the
favorable pathway. However, more detailed investiga-
tions are needed to clarify the mechanism for the present
indole forming reaction.
In conclusion, we have achieved the synthesis of N-
(alkoxybenzyl)indoles 3 via the copper-catalyzed tandem
reaction between 2-alkynyl-N-arylideneanilines 1 and
alcohols 2. Awide variety of N-(alkoxybenzyl)indole
derivatives can be synthesized by utilizing this protocol,
since the derived indoles are essentially formed by the
four-component assemblies of aldehydes, 2-iodoanilines,
terminal alkynes, and alcohols. Studies of the reaction
mechanism and synthetic applications are now in pro-
gress.
6. Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem.
Soc. 2000, 122, 5662–5663.
7. (a) Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2002,
124, 11940–11945; (b) For the different type of the
palladium catalyzed cyclizations of isocyanides, see:
Onitsuka, K.; Suzuki, S.; Takahashi, S. Tetrahedron Lett.
2002, 43, 6197–6199.
8. Kamijo, S.; Yamamoto, Y. Angew. Chem., Int. Ed. 2002,
41, 3230–3233.
9. Kamijo, S.; Yamamoto, Y. J. Org. Chem. 2003, 68, 4764–
4771.
10. The starting imines 1 were prepared in two steps. The
Sonogashira coupling reaction between 2-iodoanilines
Acknowledgements
and terminal alkynes under
a catalytic amount of
This work was supported by a Grant-in-Aid for
Encouragement of Young Scientists (B) from the Japan
Society for the Promotion of Science. We thank mem-
bers in the Instrumental Analysis Center for Chemistry
at Tohoku University for measurements of mass spectra
and elemental analyses.
Pd(PPh3)4 and CuI in Et2NH furnished 2-(1-alkynyl)ani-
lines in high yields. Dehydration between the 2-(1-
alkynyl)anilines and aldehydes in the presence of MS
ꢀ
4 Aafforded the 2-(1-alkynyl)- N-arylideneanilines 1.
11. The transition metal catalysts, such as [(g3-C3H5)PdCl]2,
CuCl, CuBr, [IrCl(cod)]2, and [RuCl(cod)]2, showed a
catalytic activity.
12. Typical procedure for the copper-catalyzed indole form-
ing reaction. To a toluene solution (1 mL) of 2-(1-
pentynyl)-N-(p-methylbenzylidene)aniline 1a (130.7 mg,
0.5 mmol) and CuCl (2.5 mg, 0.025 mmol) was added
MeOH 2a (41 lL. 1 mmol) and the mixture was stirred
at 100 °C for 2.5 h. After consumption of 1a, the
reaction mixture was filtered through a Florisil pad
and the eluent was concentrated. Purification with silica
gel chromatography (n-hexane/ether) gave N-(1-meth-
oxy-(p-tolyl)methyl)-2-propylindole 3a in 70% yield
(102.3 mg).
13. (a) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y.
J. Am. Chem. Soc. 2002, 124, 764–765; (b) Nakamura, I.;
Bajracharya, G. B.; Mizushima, Y.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2002, 41, 4328–4331.
14. (a) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.;
Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12650–
12651; (b) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y.
J. Am. Chem. Soc. 2003, 125, 10921–10925; (c) Asao, N.;
Kasahara, T.; Yamamoto, Y. Angew. Chem., Int. Ed.
2003, 42, 3504–3506.
References and Notes
1. Reviews on indole chemistry, see: (a) Sundberg, R. J.
Indoles; Academic: London, 1996; (b) Katritzky, A. R.;
Pozharskii, A. F. In Handbook of Heterocyclic Chemistry;
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Transformations); Thomas, E. J., Ed.; Georg Thieme:
Stuttgart, 2000; Vol. 10, pp 361–652; (d) Li, J. J.; Gribble,
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