Epibatidine Alkaloid Chemistry 5. Domino-Heck Reactions of Azabicyclic and Tricyclic Systems.docVIP

Molecules 2006, 11, 603-614 molecules ISSN 1420-3049 Full Paper Epibatidine Alkaloid Chemistry: 5. Domino-Heck Reactions of Azabicyclic and Tricyclic Systems ? ?igdem Yolacan 1, Emine Bagdatli 1, Nüket ?cal 1,* and Dieter E. Kaufmann 2,* 1 Y?ld?z Technical University, Faculty of Art and Sciences, Department of Chemistry, Davutpasa Campus, 34210, Istanbul, Turkey 2 Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstr. 6, D-38678 Clausthal-Zellerfeld, Germany ? For the preceding paper in this series, see ref. [4] * Authors to whom correspondence may be addressed; e-mails: nocal@.tr; dieter.kaufmann@tu-clausthal.de Received: 26 July 2006; in revised form: 11 August 2006 / Accepted: 12 August 2006 / Published: 16 August 2006 Abstract: Palladium-catalyzed hydroarylations and additional domino reactions of aza- bicyclic and tricyclic norbornene derivatives were investigated and a series of new epibatidine analogues were synthesized. Keywords: Epibatidine, Palladium, Hydroarylation, Domino Reactions, Heck Reactions, Alkynes, Heterocycles. Introduction Epibatidine (1), a novel class of amphibian alkaloid, was first isolated by Daly in trace amounts from the skin of the Ecuadorian poison frog Epipedobates tricolor [1]. The very high analgesic activity of 1 is a consequence of its high potency as an agonist towards nicotinic acetylcholine receptors (nAChRs) in the central and autonomic nervous systems [2]. The exciting biological properties and unique structure of 1, combined with its scarcity in Nature (ca. 1 mg were obtained from some 750 frogs) have aroused the interest of synthetic chemists [3].  Molecules 2006, 11 604 N H Cl N 1 Despite the large number of syntheses of epibatidine published to date [4, 5], only a few analogues with modified pyridine rings have been prepared by reductive Heck reactions [6, 7]. In conjuction with this work we became interested in the poss