Synthesis of new azocine derivatives and their functionalization by nucleophilic addition to their iminium salts.

Abstract

A route to the eight-membered nitrogen heterocycles 20a,b is described starting from the 3-alkyl-N-benzylpyridinium salts 14a,b. These azocine derivatives were converted into their respective iminium salts 11 by treatment with methanesulfonic acid. A study concerning the regioselectivity of nucleophilic additions to these salts is presented. Nucleophiles like Introduction Azocine derivatives are an important and diverse class of compounds that are found in a range of natural and nonnatural products. These eight-membered nitrogen heterocycles are present in complex structures of many natural substances such apparicine (1),[1] magallanesine (2),[2] and manzamine A (3),[3] an important antitumoral marine alkaloid (Figure 1). Among the nonnatural products, the more commonly found azocines are substituted and fully or partly reduced. These compounds have found application as therapeutic agents in view of their various biological properties, for example as antimalarials, antitussives, nasal decongestants, antihypertensives, and analgesics.[4] Another large and much-studied class of compounds containing the azocine ring is synthetic benzofuroazocines (4), which, due their structure close to that of hypnoanalgesics, possess important activity in the central nervous system (CNS).[5] Finally, these monocyclic medium rings have also found use as synthetic intermediates, for example, in the synthesis of the pyrrolizidine ring system,[6] and they constitute important medium-size cycles in conformational studies. [a] Departamento de Química, ICEx, UFMG Av. Antônio Carlos, 6627, Belo Horizonte, MG, Brazil Fax: +55-031-3499-5700 E-mail: rossi@ciclope.lcc.ufmg.br [b] Departamento de Farmácia, SCS, UFPR, Av. Pref. Lothário Meissner, 3400, Jd. Botânico, Curitiba, PR, Brazil [c] Departamento de Química, ICEB, UFOP, Campus Morro do Cruzeiro, Ouro Preto, MG, Brazil [d] Institut de Chimie des Substances Naturelles, Avenue de la Terrasse, 91198, Gif-sur-Yvette, France © 2005 Wiley-VCH Verlag GmbH & Co. 1052 KGaA, Weinheim DOI: 10.1002/ejoc.200400728 Eur. J. Org. Chem. 2005, 1052–1057 hydride or Grignard reagents react selectively in the 2-position to give adducts such as 22 and 23, while azide and phenylthiolate attack the 6-position to give 24 and 25, respectively.