Intramolecular Cyclization of δ-Iminoacetylenes: A New Entry to Pyrazino[1,2-a]indoles Giorgio Abbiati,* ,† Antonio Arcadi, ‡ Alessandra Bellinazzi, † Egle Beccalli, † Elisabetta Rossi, † and Simona Zanzola § Istituto di Chimica Organica “Alessandro Marchesini”, Facolta ` di Farmacia, Universita ` degli Studi di Milano Via Venezian 21, 20133 Milano, Italy, Dipartimento di Chimica, Ingegneria Chimica e Materiali, Facolta ` di Scienze, Universita ` de L’Aquila, Via Vetoio, 67010 Coppito due, L’Aquila, Italy, and Rotta Research Laboratorium SpA, Via Valosa di Sopra, 7, 20052 Monza (MI), Italy giorgio.abbiati@unimi.it Received February 4, 2005 The synthesis of the pyrazino[1,2-a]indole nucleus was achieved by intramolecular cyclization of several 2-carbonyl-1-propargylindoles in the presence of ammonia. The reaction conditions were optimized using microwave heating and a pool of catalysts. Cyclization of 1-alkynylindole-2- carbaldehydes was easily accomplished under standard heating conditions, whereas microwave heating contributed to reduced reaction times and improved overall yields. Moreover, a fine-tuning of the microwave irradiation time made possible the selective synthesis of both pyrazino[1,2-a]- indole isomers. TiCl 4 proved the catalytic system of choice to achieve pyrazinoindoles in satisfactory yields starting from 1-alkynyl-2-acetylindoles and 1-alkynyl-2-benzoylindole derivatives. Also in these cases, microwave heating contributed to faster reactions and improved yields. The uncatalyzed versus catalyzed reaction mechanism is discussed. Introduction Polycyclic indoles represent the framework of a large number of compounds characterized by a wide range of biological activities. 1 The isolation from natural sources, synthesis, and the study of the biological properties of these molecules is still a research field of great interest and continuous evolution. For instance, the explosive growth of the carbazole chemistry is demonstrated by the many reviews and monographs that appeared in the literature. 2 In addition, nitrogen analogues of carbazoles commonly called carbolinessare under active investiga- tion for their potential pharmacological activities, 3 in particular the  4 and γ 5 forms. Although a-fused aza- polycyclic indoles are less studied than the b-fused, recently some papers related to the chemistry and the pharmacology of pyrazino[1,2-a]indole nucleus have ap- peared in the literature. Whereas the synthesis of 1-ox- opyrazino[1,2-a]indole derivatives was widely explored, 6 the preparation of simple pyrazino- 7 and 3,4-dihydropy- razino[1,2-a]indoles 8 has been less examined. For ex- ample, Hegedus 7a prepared the pyrazinoindole nucleus * Corresponding author. Tel: +39-02-50314474. Fax: +39-02- 50314476. † Universita ` degli Studi di Milano. ‡ Universita ` de L’Aquila. § Rotta Research Laboratorium. (1) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970. (b) Sundberg, R. J. Indoles; Academic Press: London, 1996. (2) Kno ¨lker, H. J.; Reddy, K. R. Chem. Rev. 2002, 11, 4303-4428 and references cited therein. (3) See: Khorana, N.; Smith, C.; Herrick-Davis, K.; Purohit, A.; Teitler, M.; Grella, B.; Dukat, M.; Glennon, R. A. J. Med. Chem. 2003, 46, 3930-3937. (4) See: Condie, G. C.; Bergman, J. Eur. J. Org. Chem. 2004, 1286- 1297. (5) See: Zhang, H.; Larock, R. C. J. Org. Chem. 2003, 68, 5132- 5138. (6) (a) Suzuki, H.; Shinpo, K.; Yamazaki, T.; Niwa, S.; Yokoyama, Y.; Murakami, Y. Heterocycles 1996, 42, 83-86. (b) Barry, J. F.; Wallace, T. W.; Walshe, N. Tetrahedron 1995, 51, 12797-12806. (c) Boes, M.; Jenck, F.; Martin, J. R.; Moreau, J. L.; Mutel, V.; et al. Eur. J. Med. Chem. Chim. Ther. 1997, 32, 253-262. (d) Modi, N. T.; et al. J. Org. Chem. 1970, 35, 2228-2230. (e) Saxena, A. J. Heterocycl. Chem. 1977, 14, 595-597. (f) Voss, M. E.; Carter, P. H.; Tebben, A. J.; Scherle, P. A.; Brown, G. D.; Thompson, L. A.; Xu, M.; Lo, Y. C.; Yang, G.; Liu, R.-Q.; Strzemienski, P.; et al. Bioorg. Med. Chem. Lett. 2003, 13, 533- 538. (g) Tapia, R. A.; Prieto, Y.; Pautet, F.; Domard, M.; Sarciron, M.- E.; Walchshofer, N.; Fillion, H. Eur. J. Org. Chem. 2002, 23, 4005- 4010. (h) Campiani, G.; Butini, S.; Trotta, F.; Fattorusso, C.; Catalanotti, B.; Aiello, F.; Gemma, S.; Nacci, V.; Novellino, E.; Stark, J. A.; Cagnotto, A.; et al. J. Med. Chem. 2003, 46, 3822-3839. (7) (a) Hegedus, L. S.; Mulhern, T. A.; Asada, H. J. Am. Chem. Soc. 1986, 108, 6224-6228. (b) Kibalnyi, A. V.; Kikolyukin, Yu. A.; Dulenko, V. I. Chem. Heterocycl. Compd. 1994, 30, 1041-1047. (c) Grinev, A. N.; Shvedov, V. I.; Krichewskii, E. S.; Romanova, O. B.; Altukhova L. B. Pharm. Chem. J. 1984, 18, 94-98. 4088 J. Org. Chem. 2005, 70, 4088-4095 10.1021/jo0502246 CCC: $30.25 © 2005 American Chemical Society Published on Web 04/16/2005