A One-Pot Cascade Strategy toward Organocatalytic Enantioselective Construction of Fused Benzimidazoles

Abstract

Herein, we describe an asymmetric assembly of ortho-aromatic diamines and formyl tethered Michael acceptors forming chiral fused benzimidazoles. A cinchona-alkaloid-derived bifunctional squaramide catalyst enables the methodology through on-site dihydrobenzimidazole formation followed by an aza-Michael addition/oxidation cascade. This protocol stands out for its excellent catalytic efficiency over the background reaction and its mild conditions, making it more practical. Various Michael acceptors, including enones, ester, and thioester, were successful substrates in this study. Additionally, this methodology has demonstrated scalability and successfully showcased postsynthetic transformations.B enzimidazole is a privileged structural motif frequently found in marketed drug molecules, such as Omeprazole, Albendazole, Liarozole, Telmisartan, and Mibefradil. 1 This heterocyclic pharmacophore exhibits diverse biological properties, including anti-inflammatory, anticancer, antimicrobial, antiviral, antifungal, and so on. 2 Particularly, tricyclic and 1,2disubstituted chiral benzimidazole derivatives demonstrate a broad spectrum of pharmaceutical, biological activities (Figure 1A). 3 For instance, dihydropyrrole-fused benzimidazole

Umpolung Reactivity of in Situ Derived Aryl Hydrazones: An Asymmetric Brønsted Acid Catalyzed Strategy to Access Fused Pyrazolidines

“…These endeavors rely on utilizing formyl-tethered enones as a fundamental framework . Expanding on our prior research, we formulated a hypothesis to synthesize fused pyrazolidines by utilizing aryl hydrazine instead of TsNH 2 and ortho -aromatic diamines . Our vision entails a umpolung cascade pathway forming fused chiral pyrazolidines through on-site hydrazone generation followed by a formal (3 + 2) cycloaddition reaction (Scheme C).…”