Pyridinium N-(20-azinyl)aminides: regioselective synthesis of N-(2-pyridyl) substituted polyamines

The regioselective alkylation of pyridinium-N-(20-pyridyl)aminide with alkyl dihalides under mild conditions, followed by N–N bond reduction of the corresponding bis-salts, allowed an easy preparation of N,N0-bis(2-pyridyl)diamines. The same methodology has been applied to the synthesis of N,N0,N00-tris(2-pyridyl)triamines. q 2002 Elsevier Science Ltd. All rights reserved. The role of polyamines in biological systems is well recognized and, over the last two decades, many functions of prokaryotic and eukaryotic cells have been shown to be polyamine dependent. – 3 Natural and synthetic polyamines are potent cation-channel blockers and templates for the design of synthetic vectors with potential application in gene therapy. A number of polyamine analogues have shown promise as anticancer agents and a platinum complex linked by a bridging diamine showed biological activity against various human cancer cell lines. The synthetic approaches to polyamine chemistry have been recently reviewed, being the N-alkylation of amines the most widely used reaction in polyamine synthesis. To avoid polyalkylation, excess of amine or a suitable protecting group have to be used but, in the field of diamines and polyamines, mono N-alkylation has been achieved using cesium hydroxide. In the last years, we have been interested in heteroaryl-stabilized cycloiminium ylides 1, as building blocks for the synthesis of heterocyclic derivatives – 15 and, more recently, we are exploring the synthetic utility of pyridinium N-(20-azinyl)aminides 2 (Scheme 1). – 21 Some of our work in this field has been concerned with alkylation processes and in a preceding paper we reported the regioselective synthesis of 2-alkylaminoazines 4 in a two-step method. As it is well known, the direct alkylation of heterocyclic amidines 5 is unsatisfactory as a preparative method, because mixtures of N-endosubstituted 6 and N-exosubstituted 7 derivatives are obtained and, usually, alkylation mainly occurs at the most basic endocyclic nitrogen (Scheme 1). However, when permanent nitride species, such as the pyridinium N-(20azinyl)aminides 2, are used, regioselective alkylation takes place at the exocyclic nitrogen, and the salts 3 are 0040–4020/02/$ see front matter q 2002 Elsevier Science Ltd. All rights reserved. PII: S0 04 0 -4 02 0 (0 2) 00 9 01 -8 Tetrahedron 58 (2002) 8573–8579