Synthesis of Heterocyclic Fused [1,5]naphthyridines by Intramolecular HDA Reactions

Povarov reaction [1] can be considered as an example of HDA reactions and represents an excellent method for the preparation of nitrogen-containing heterocyclic compounds [2]. When aldimines, derived from aromatic amines and unsaturated functionalized aldehydes, are treated with a Lewis acid, the Povarov reaction takes place intramolecularly [3].

In this work, the synthesis of new families of heterocyclic fused [1,5]naphthyridines is reported. In this way, via an efficient and straightforward intramolecular Povarov reaction catalyzed by boron trifluoride etherate, tetrahydro-6H-chromeno[4,3-b][1,5]naphthyridines and tetrahydro-6H-quinolino[4,3-b][1,5]naphthyridines are obtained. Dehydrogenation of tetrahydroderivatives with DDQ gives compounds 6H-chromeno[4,3-b][1,5]naphthyridine and 6H-quinolino[4,3-b][1,5]naphthyridine.

This methodology allows access to novel compounds with biological activity. Based on the success of camptothecin (CPT) and its derivatives as inhibitors of Topoisomerase I (TopI) [4], as well as our results obtained with naphthyridine derivatives [5], we report here that these novel heterocyclic compounds are possible candidates, some of them showing excellent activity as TopI inhibitors. The cytotoxic effect on several cancer and noncancer cell lines was also screened.