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-b]pyridin-5-ones via a cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization) in 20 to 95% overall yields, as well as four pharmacologically promising analogues via an improved cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization/SN2): two piperazine-linked pyrrolo[3,4-b]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.

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 our research group, we hold an ongoing program to develop short and versatile MCR-based strategies toward novel and complex polyheterocycles of interest in various fields, like optics [21] and medicinal chemistry [22]. One polyheterocyclic system that we can synthesize à la carte is the pyrrolo[3,4- b ]pyridin-5-one [23], which is considered as a privileged aza-analogue of the isoindolin-1-one [24], the latter being the structural core of various natural and synthetic anticancer agents [25].…”

“…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).…”

“…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). Thus, 4-chlorobenzaldehyde ( 2a ) or benzaldehyde ( 2b ) were combined sequentially with the 3-morpholinopropan-1-amine ( 3 ), the corresponding isocyanides 4a – b , and maleic anhydride ( 5 ) via the strategy mentioned before, using benzene as solvent, scandium (III) triflate as Lewis-acid catalyst, and microwaves (MW) as heat source to afford the polyheterocycles 1k – l in 46% ( 1k ) and 45% ( 1l ) yields, respectively, which are excellent considering the molecular complexity of the products, and that only one experimental procedure was needed in their synthesis (Scheme 1).…”

“…[a] Synthesis reported in Reference [32]. [b] Synthesis reported in Reference [22]. [c] New pyrrolo[3,4- b ]pyridin-5-ones.…”

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

“…Most of the reported methods to assemble pyrrolo [3,4-b]pyridin-5one based architectures involve multistep strategies as well as the use of harsh conditions-see for example the synthetic methodology reported by Devasthale et al [2]. However, various multicomponent reaction (MCR)-based synthetic strategies toward series of novel pyrrolo [3,4b]pyridin-5-one-containing polyheterocycles have been reported in the last decade by us [7][8][9][10][11][12][13][14] as an integral part of our ongoing research program. It is important to note that MCRs are highly convergent one-pot processes in which three or more reagents are combined sequentially to assemble complex products [15] like polyheterocycles [16], eventually in good yields, obeying most of the green chemistry principles [17].…”