ORGANIC
LETTERS
2004
Vol. 6, No. 6
1037-1040
Synthesis of 3-Iodoindoles by
Electrophilic Cyclization of
N,N-Dialkyl-2-(1-alkynyl)anilines
Dawei Yue and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
Received January 15, 2004
ABSTRACT
A wide variety of N-alkyl-3-iodoindoles are readily prepared under very mild reaction conditions by the palladium/copper-catalyzed cross-
coupling of N,N-dialkyl-o-iodoanilines and terminal alkynes, followed by electrophilic cyclization by I2. Alkyl-, aryl-, and vinylic-substituted
alkynes all undergo iodocyclization in excellent yields.
The indole nucleus is prevalent in a wide variety of bio-
logically active natural and unnatural compounds.1 The syn-
thesis and functionalization of indoles have been the major
objectives of research for over one hundred years. Among
the most recent synthetic targets have been pharmacologically
active ergot alkaloids,2 the antitumor agents ellipticine3 and
mitomycin C,4 and more complex “dimeric” indole alkaloids,
such as vincristine and vinblastine.5 A number of synthetic
approaches to this class of compounds have been introduced
in recent years.6
ployed in the synthesis of indoles. However, some of these
approaches are either incompatible with functionality6f or
sometimes restricted by a lack of regioselectivity.6a Recent
success in the synthesis of benzo[b]furans,7 furopyridines,8
isoquinolines,9 and benzo[b]thiophenes10 by the electrophilic
(5) (a) Oikawa, Y.; Yonemitsu. J. Chem. Soc., Perkin Trans. 1 1976,
1479. (b) Tokuyama, H.; Fukuyama, T. Kagaku Kogyo 2001, 52, 416. (c)
Xiong, W. N.; Yang, C. G.; Jiang, B. Bioorg. Med. Chem. 2001, 9, 1773.
(6) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652. (c) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F. Tetrahedron
1994, 50, 437. (d) Cacchi, S.; Fabrizi, G.; Pace, P.; Marinelli, F. Synlett
1999, 5, 620. (e) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Moro, L. Eur. J. Org.
Chem. 1999, 64, 1137. (f) Rodriguez, A. L.; Koradin, C.; Dohle, W.;
Knochel, P. Angew. Chem., Int. Ed. Engl. 2000, 39, 2488. (g) Larock, R.
C. J. Organomet. Chem. 1999, 576, 111. (h) Takeda, A.; Kamijo, S.;
Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 5662. (i) Pete, B.; Toke, L.
Tetrahedron Lett. 2001, 42, 3373. (j) Kamijo, S.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2002, 41, 3230. (k) Kamijo, S.; Yamamoto, Y. J. Am. Soc.
Chem. 2002, 124, 11940. (l) Yasuhara, A.; Takeda, Y.; Suzuki, N.;
Sakamoto, T. Chem. Pharm. Bull. 2002, 50, 235. (m) Rossiter, S.
Tetrahedron Lett. 2002, 43, 4671. (n) Zhou, T.; Chen, Z. C. Synth. Commun.
2002, 32, 903. (o) Hegedus, L. S. Angew. Chem. 1988, 100, 1147. (p) Li,
J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Pergamon:
Oxford, UK, 2000; pp 73-187.
Many synthetic methods, including palladium-catalyzed
intermolecular annulation6a,b and transition metal catalyzed
intramolecular cyclization,6c-e have been successfully em-
(1) (a) McKay, M. J.; Carroll, A. R.; Quinn, R. J.; Hooper, J. N. A. J.
Nat. Prod. 2002, 65, 595. (b) Verpoorte, R. Alkaloids 1998, 397-433. (c)
Sundberg, R. J. Prog. Heterocycl. Chem. 1989, 1, 111. (d) Saxon, J. E.
Nat. Prod. Rep. 1986, 3, 357. Saxon, J. E. Nat. Prod. Rep. 1987, 4, 591.
Saxon, J. E. Nat. Prod. Rep. 1989, 6, 1. (e) Sundberg, R. J. Indoles. In Best
Synthetic Methods; Academic Press: San Diego, 1996. (f) Gribble, G. W.
J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(2) (a) Manske, R. H. F. The Alkaloids; J. Wiley: New York, 1959-
1979; Vols. 1-17. (b) Hesse, M. Indolalkaloids in Tabellin; Springer:
Berlin, Germany, 1964. (c) Glasby, J. S. Encyclopedia of Alkaloids; Plenum
Press: New York, 1975.
(7) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett
1999, 1432.
(3) Horwell, D. C. Tetrahedron 1980, 36, 3123.
(8) Arcadi, A.; Cacchi, S.; Giuseppe, S. D.; Fabrizi, G.; Marinelli, F.
Org. Lett. 2002, 4, 2409.
(9) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67,
3437.
(4) (a) Mangeney, P.; Andreanmialisoa, R.; Langlois, Y. J. Am. Chem.
Soc. 1979, 101, 2243. (b) Iyengar, B. S.; Remers, W. A.; Catino, J. J. J.
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10.1021/ol0498996 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/26/2004