From benzofuro-, benzothieno- and 10-methylindolo-[2,3-b]-fused benzothiopyrano[4,3,2-de]quinolines to the corresponding benzothiopyrano[4,3,2-de]1,8-naphthyridines: synthesis and properties of these hexacyclic heteroaromatic compounds

Abstract

Polycyclic heterocycles such as 1- and 2-aminothioxanthones are important precursors to molecules endowed with different properties and original syntheses are always required. Here, 1-aminothioxanthone was obtained either in four steps from commercially available thioxanthone, or in five steps from 3-fluoroaniline. As for 2-aminothioxanthone, direct N-arylation using commercial 2-chlorothioxanthone gave its Boc-protected derivative. From 1-aminothioxanthone, original 10-methylbenzothiopyrano[4,3,2-de]indolo[2,3-b]quinoline was synthesized by tandem N-arylation-cyclization using 2-iodo-N-methylindole in the presence of copper. However, this approach being less efficient with 2-iodobenzothiophene, we also studied another strategy. Our efforts were next concentrated on the synthesis of benzofuro-, benzothieno- and indolo[2,3-b]benzothiopyrano[4,3,2-de]1,8-naphthyridines which are original hexacycles of helical nature. Different approaches were designed and we achieved our goal from 2-chloro-4-fluoropyridine, in five steps. The original polycyclic compounds obtained were evaluated as protein kinase inhibitors, and the results were rationalized by molecular modeling experiments. Finally, their photophysical properties were measured for the purpose of structure-property relationships.