MW-Assisted Synthesis of Eight New 6-Nitrilmethyl Pyrrolo[3,4-b]pyridin-5-Ones via a Domino Process: aza Diels–Alder/N-Acylation/Aromatization

Abstract

An efficient Microwave (MW)-assisted synthesis of eight new 6-nitrilmethyl-pyrrolo[3,4-b]pyridin-5-ones via a domino process: aza Diels–Alder/N-acylation/aromatization (dehydration–decarboxylation) from their corresponding 2-aminonitrile-oxazoles and maleic anhydride are described. The use of MW as a heat source and scandium (III) triflate as a catalyst to promote the cycloaddition process was crucial to construct these polyfunctionalized products in very good yields (51–79%), considering both their molecular complexity and that only one domino-type experimental procedure was required for their synthesis. It is worth noting that all products reported herein have not been synthesized nor isolated anywhere. However, they can be of high interest for the synthetic and medicinal chemistry community because pyrrolo[3,4-b]pyridin-5-one is the structural core of various bioactive compounds. In the same context, it can be considered as a privileged aza analogue of the isoindolin-1-one, which in turn is the core of numerous anticancer agents.

Synthesis of Pyrrolo[3,4-b]pyridin-5-ones via Multicomponent Reactions and In Vitro–In Silico Studies Against SiHa, HeLa, and CaSki Human Cervical Carcinoma Cell Lines

“…In this context, stepwise methodologies have been reported in synthesizing novel pyrrolo[3,4- b ]pyridin-5-ones, for example, Devasthale and co-workers synthesized a panel of pyrrolo[3,4- b ]pyridin-5-ones, evaluating in vitro their properties as inhibitors of the dipeptidyldipentidase-4 (DPP-4) [26]. However, one efficient, versatile, and robust method to construct this polyheterocyclic core is through a one-pot cascade sequence Ugi–3CR/ aza Diels–Alder cycloaddition/ N –acylation/decarboxylation/dehydration, reported first by Zhu and co-workers [27], and further optimized by us many times [22,23,28,29,30,31,32,33,34]. Thus, for the in vitro assays against SiHa, HeLa, and CaSki cell lines, we synthesized some of our previously reported pyrrolo[3,4- b ]pyridin-5-ones 1a – j [22,32], and the new ones 1k – l , specifically prepared for the present study (Figure 1).…”