Synthesis of Polyheterocyclic Pyrrolo[3,4-b]pyridin-5-ones via a One-Pot (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization/SN2) Process. A Suitable Alternative towards Novel Aza-Analogues of Falipamil

Abstract

We describe the one-pot synthesis of twenty polyheterocyclic pyrrolo[3,4-<i>b</i>]pyridin-5-ones <i>via</i> a cascade process (Ugi-3CR/aza Diels-Alder/<i>N</i>-acylation/aromatization) in 20 to 95% overall yields, as well as four pharmacologically promising analogues <i>via</i> an improved cascade process (Ugi-3CR/aza Diels-Alder/<i>N</i>-acylation/aromatization/S_N2): two piperazine-linked pyrrolo[3,4-<i>b</i>]pyridin-5-ones in 33 and 34%, and a couple of Falipamil aza-analogues in 30 and 35% overall yields. It is worth highlighting the good substrate scope found, because final products are furnished with alkyl, aryl, and heterocyclic substituents. The use of chain-ring tautomerizable isocyanides (as key reagents for the Ugi-type three component reaction) allowed for a rapid and efficient assembly of the polysubstituted oxindoles, which were used in situ toward the complex products, conferring features like robustness, sustainability, and the one-pot approach to this synthetic methodology.