Syn th esis of â- a n d γ-Ca r bolin es by th e P a lla d iu m /
Cop p er -Ca ta lyzed Cou p lin g a n d Cycliza tion of Ter m in a l
Acetylen es
Haiming Zhang and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received April 30, 2002
A variety of 3-substituted â- and γ-carbolines have been synthesized from N-substituted 3-iodoindole-
2-carboxaldehydes and 2-bromoindole-3-carboxaldehydes, respectively. The coupling of these
aldehydes with various terminal acetylenes with PdCl2(PPh3)2/CuI as the catalyst readily affords
the corresponding alkynylindole carboxaldehydes, which have subsequently been converted to the
corresponding tert-butylimines and cyclized to â- and γ-carbolines by either copper-catalyzed or
thermal processes.
In tr od u ction
laboratories, a variety of isoquinolines, pyridines, and
naphthyridines have been successfully synthesized by the
copper-catalyzed,6 the palladium-catalyzed,7 and the elec-
trophile-induced8 cyclization of alkynes having a tert-
butylimino group in close proximity to the carbon-carbon
triple bond.
Palladium-catalyzed annulation processes have re-
cently proven to be a powerful method for the construc-
tion of a wide variety of hetero- and carbocycles in our
own laboratories.1 In addition, the transition metal-
mediated,2 base-promoted,3 electrophile-induced,4 and
thermal5 cyclization of alkynes, which possess a nucleo-
phile in close proximity to the carbon-carbon triple bond,
have also been shown to be very effective for the synthesis
of a wide variety of hetero- and carbocycles. In our own
Pyrido[3,4-b]indoles and pyrido[4,3-b]indoles, com-
monly known as â- and γ-carbolines, respectively, are the
key structural units for a variety of biologically important
alkaloids.9 Numerous â- and γ-carbolines have been
studied extensively as antitumor agents.9 The isolation
and synthesis of naturally occurring carbolines and the
synthesis of â- and γ-carboline derivatives have received
considerable attention in the literature9,10 due to their
biological and pharmaceutical importance.
(1) For reviews, see: (a) Larock, R. C. J . Organomet. Chem. 1999,
576, 111. (b) Larock, R. C. Palladium-Catalyzed Annulation. In
Perspectives in Organopalladium Chemistry for the XXI Century; Tsuji,
J ., Ed.; Elsevier Press: Lausanne, Switzerland, 1999; pp 111-124. (c)
Larock, R. C. Pure Appl. Chem. 1999, 71, 1435. For recent reports,
see: (d) Larock, R. C.; Yum, E. K. J . Am. Chem. Soc. 1991, 113, 6689.
(e) Larock, R. C.; Yum, E. K.; Refvik, M. D. J . Org. Chem. 1998, 63,
7652. (f) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 1551. (g)
Roesch, K. R.; Larock, R. C. J . Org. Chem. 2001, 66, 412. (h) Larock,
R. C.; Yum, E. K.; Doty, M. J .; Sham, K. K. C. J . Org. Chem. 1995, 60,
3270. (i) Larock, R. C.; Doty, M. J .; Han, X. J . Org. Chem. 1999, 64,
8770. (j) Larock, R. C.; Han, X.; Doty, M. J . Tetrahedron Lett. 1998,
39, 5713. (k) Larock, R. C.; Doty, M. J .; Tian, Q.; Zenner, J . M. J . Org.
Chem. 1997, 62, 7536. (l) Larock, R. C.; Tian, Q. J . Org. Chem. 1998,
63, 2002. (m) Roesch, K. R.; Larock, R. C. J . Org. Chem. 1998, 63,
5306. (n) Roesch, K. R.; Zhang, H.; Larock, R. C. J . Org. Chem. 2001,
66, 8042.
(2) For recent leading references, see: (a) Takeda, A.; Kamijo, S.;
Yamamoto, Y. J . Am. Chem. Soc. 2000, 122, 5662. (b) Gabriele, B.;
Salerno, G.; Fazio, A. Org. Lett. 2000, 2, 351. (c) Roshchin, A. I.;
Bumagin, N. A. Chem. Heterocycl. Compd. 1999, 35, 171. (d) Cacchi,
S.; Fabrizi, G.; Moro, L. Tetrahedron Lett. 1998, 39, 5101. (e)
Chowdhury, C.; Chaudhuri, G.; Guha, S.; Mukherjee, A. K.; Kundu,
N. G. J . Org. Chem. 1998, 63, 1863. (f) Cacchi, S.; Fabrizi, G.; Moro,
L. J . Org. Chem. 1997, 62, 5327. (g) Arcadi, A.; Cacchi, S.; Del Rosario,
M.; Fabrizi, G.; Marinelli, F. J . Org. Chem. 1996, 61, 9280.
(3) (a) Rodriguez, A. L.; Koradin, C.; Dohle, W.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 2488. (b) Yasuhara, A.; Kanamori, Y.; Kaneko,
M.; Numata, A.; Kondo, Y.; Sakamoto, T. J . Chem. Soc., Perkin Trans.
1 1999, 529.
(5) (a) Sakamoto, T.; Numata, A.; Saitoh, H.; Kondo, Y. Chem.
Pharm. Bull. 1999, 47, 1740. (b) Kanekiyo, N.; Choshi, T.; Kuwada,
T.; Sugino, E.; Hibiho, S. Heterocycles 2000, 53, 1877. (c) Kanekiyo,
N.; Kuwada, T.; Choshi, T.; Nobuhiro, J .; Hibiho, S. J . Org. Chem. 2001,
66, 8793. (d) Abbiati, G.; Beccalli, E. M.; Marchesini, A.; Rossi, E.
Synthesis 2001, 2477. (e) Numata, A.; Kondo, Y.; Sakamoto, T.
Synthesis 1999, 306. (f) Sakamo, T.; Kondo, Y.; Miura, N.; Hayashi,
K.; Yamanaka, H. Heterocycles 1986, 24, 2311. (g) Prikhod’ko, T. A.;
Vasilevskii, S. F.; Shvartsberg, M. S. Bull. Acad. Sci. USSR, Div. Chem.
Sci. 1984, 33, 2383.
(6) (a) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 553. (b) Roesch,
K. R.; Larock, R. C. J . Org. Chem. 2002, 67, 86.
(7) (a) Dai, G.; Larock, R. C. Org. Lett. 2001, 3, 4035. (b) Dai, G.;
Larock, R. C. Org. Lett. 2002, 4, 193.
(8) Huang, Q.; Hunter, J . A.; Larock, R. C. Org. Lett. 2001, 3, 2973.
(9) (a) Hino, T.; Nakagawa, M. J . Heterocycl. Chem. 1994, 31, 625.
(b) Baker, B. J . Alkaloids: Chem. Biol. Perspect. 1996, 10, 357. (c) Love,
B. E. Org. Prep. Proced. Int. 1996, 28, 1. (d) Magnier, E.; Langlois, Y.
Tetrahedron 1998, 43, 6201. (e) Nakagawa, M. J . Heterocycl. Chem.
2000, 37, 567. (f) Ohmoto, T.; Koike, K. In The Alkaloids; Brossi, A.,
Ed.; Academic Press: San Diego, CA, 1989; Vol. 36, pp 135-170. (g)
Matsukura, N.; Kawachi, T.; Morino, K.; Ohgaki, H.; Sugimura, T.;
Takayama, S. Science 1981, 213, 346. (h) Hibino, S.; Sugino, E.; Ogura,
N.; Shintani, Y.; Sato, K. Heterocycles 1990, 30, 271. (i) Gribble, G. W.
In The Alkaloids; Brossi, A., Ed.; Academic Press: San Diego, CA, 1990;
Vol. 39, Chapter 7. (j) Tan, G. T.; Pezzuto, J . M. In Chemistry and
Toxicology of Diverse Classes of Alkaloids; Blum, M. S., Ed.; Alaken,
Inc.: Ft. Collins, CO, 1996; pp 1-119. (k) Nguyen, C. H.; Lavelle, F.;
Riou, J .-F.; Bissery, M.-C.; Huel, C.; Bisagni, E. Anti-Cancer Drug Des.
1992, 7, 235.
(4) (a) Larock, R. C.; Yue, D. Tetrahedron Lett. 2001, 42, 6011. (b)
Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3, 651. (c)
Barluenga, J .; Romanelli, G. P.; Alvarez-Garc´ıa, L. J .; Llorente, I.;
Gonza´lez, J . M.; Garc´ıa-Rodr´ıguez, E.; Garc´ıa-Granda, S. Angew.
Chem., Int. Ed. 1998, 37, 3136. (d) Goldfinger, M. B.; Crawford, K. B.;
Swager, T. M. J . Am. Chem. Soc. 1997, 119, 4578.
10.1021/jo0258857 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/30/2002
7048
J . Org. Chem. 2002, 67, 7048-7056