ORGANIC
LETTERS
2003
Vol. 5, No. 4
435-438
A Novel Microwave-Mediated One-Pot
Synthesis of Indolizines via a
Three-Component Reaction
Utpal Bora, Anil Saikia, and Romesh C. Boruah*
Medicinal Chemistry DiVision, Regional Research Laboratory, Jorhat-785006, India
Received November 19, 2002
ABSTRACT
The microwave-mediated three-component reaction of acyl bromide, pyridine, and acetylene is catalyzed by basic alumina to give corresponding
indolizines in excellent yields in a one-pot reaction.
The design of multicomponent reactions (MCR) is an
important field of research from the point of view of
combinatorial chemistry.1 Being a one-pot reaction, generally
multicomponent reactions afford good yields and are fun-
damentally different from two-component reactions in several
aspects.2 Although the first MCR dates back to the Strecker
synthesis3 of R-amino acid in 1850, the MCR strategy has
been utilized successfully in Robinson’s synthesis of alkaloid
tropinone4 and Hantsch’s synthesis of 1,4-dihydropyridines.5
Consequently, in the past decade there has been tremendous
development in three- and four-component reactions involv-
ing Passerini-,6 Ugi-,7 and Mannich-type reactions8 which
led to the renaissance of MCRs. Unfortunately, despite the
enormous scope of MCR, only the 3-CRs with isocyanide
have been developed into popular organic reactions. Nev-
ertheless, great efforts have been and still are being made to
find and develop new MCRs.9
The indolizines constitute the core structure of many
naturally occurring alkaloids, viz., (-)-slaframine,10 (-)-
dendroprimine,11 indalozin 167B,12 and coniceine.13 The
synthesis of biologically active indolizines14 continues to
attract the attention15 of organic chemists. The indolizines
(9) (a) Shestopalov, A. M.; Emeliyanova, Y. M.; Shestopalov, A. A.;
Rodinovskaya, L. A.; Niazimbetova, Z. I.; Evans, D. H. Org. Lett. 2002,
423. (b) List, B.; Castello, C. Synlett 2001, 1687. (c) Nair, V.; Vinod, A.
U.; Rajesh, C. J. Org. Chem. 2001, 66, 4427. (d) Bagley, M. C.; Dale, J.
W.; Bower, J. Chem. Commun. 2002, 1682. (e) Kappe, C. O. Tetrahedron
1993, 49, 6973. (f) Cheng, J. F.; Chen, M.; Arrhenius, T.; Nadzen, A.
Tetrahedron Lett. 2002, 43, 6293. (g) Huma, H. Z. S.; Halder, R.; Kalra,
S. S.; Das, J.; Iqbal, J. Tetrahedron Lett. 2002, 43, 6485. (h) Bertozzi, F.;
Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 3147. (i) Yuan, Y.; Li, X.;
Ding, K. Org. Lett. 2002, 4, 3309.
(10) (a) Pourashraf, M.; Delair, P.; Rasmussen, M. O.; Greene, A. E. J.
Org. Chem. 2000, 65, 6966. (b) Cossy, J.; Willis, C.; Bellosta, V.; Jalmes,
L. S. Synthesis 2002, 951.
(11) Diederich, M.; Nubbemeyer, U. Synthesis 1999, 286.
(12) Chalard, P.; Remuson, R.; Mialhe, Y. G.; Gramain, J. C.; Canet, I.
Tetrahedron Lett. 1999, 40, 1661.
(1) (a) Weber, L.; Illegen, K.; Almstetter, M. Synlett 1999, 366. (b)
Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating,
T. A. Acc. Chem. Res. 1996, 29, 123.
(2) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(3) Strecker, A. Liebigs Ann. Chem. 1850, 75, 27.
(4) Robinson, R. J. Chem. Soc. (London) 1917, 111, 876.
(5) Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1.
(6) (a) Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R. Tetrahedron
Lett. 1997, 38, 2519. (b) Bossio, R.; Marcaccini, S.; Pepino, R.; Torroba,
T. Synthesis 1993, 783. (c) Kobayashi, K.; Matoba, T.; Susumu, I.; Takashi,
M.; Morikawa, O.; Konishi, H. Chem. Lett. 1998, 551. (d) Bossio, R.;
Marcaccini, S.; Pepino, R.; Torroba, T. J. Chem. Soc., Perkin Trans. 1 1996,
229.
(7) (a) Yamada, T.; Omote, Y.; Yamanaka, Y.; Miyazawa, T.; Kuwata,
S. Synthesis 1998, 991. (b) Keating, T. A.; Armstrong, R. W. J. Am. Chem.
Soc. 1995, 117, 7842. (c) Groger, H.; Hatam, M.; Martens, J. Tetrahedron
1995, 51, 7173. (d) Ross, G. F.; Herdtweck, E.; Ugi, I. Tetrahedron 2002,
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Asymmetry 2001, 12, 2621.
(14) (a) Gubin, J.; Lucchetti, J.; Mahaux, J.; Nisato, D.; Rosseels, G.;
Clinet, M.; Polster, P.; Chatelain, P. J. Med. Chem. 1992, 35, 981. (b) Gubin,
J.; Descamps, M.; Chatelain, P. P.; Nisato, D. European Patent EP, 235,111,
1988. (c) Okada, S.; Sawada, K.; Kuroda, A.; Watanabe, S.; Tanaka, H.
European Patent EP, 519353, 1993; Chem Abstr. 1993, 118, 212886.
10.1021/ol020238n CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/23/2003