103: Continuous-flow approaches to more sustainable synthesis of nitrogen-containing compounds via epoxide ring-opening and organocatalytic Povarov reactions

Abstract: The development of more efficient and sustainable synthetic methodologies remains a central objective in modern organic chemistry. Continuous-flow synthesis has emerged as a powerful platform to address these challenges while rethinking traditional batch-based practices. In this context, we describe two synthetic approaches aimed at re-evaluating reactions from a process-focused perspective. While these transformations were initially developed under batch conditions, current efforts focus on their translation into continuous-flow operation. The first centers on the regioselective ring-opening of styrene oxide with a sulfonamide nucleophile as a direct entry to functionalized phenethylamine derivatives under transition-metal-free conditions (Scheme 1a). Particular emphasis has been placed on reagent reuse and residence time optimization, aiming to enhance material efficiency and enable straightforward scalability under continuous-flow conditions. The second investigates the Povarov multicomponent reaction, a formal aza-Diels–Alder transformation enabling the construction of a tetrahydroquinoline from an aniline, an formaldehyde, and 2,3-dihydrofuran an electron-rich alkene (Scheme 1b). In our approach, this reaction is promoted by an organocatalyst under mild and metal-free conditions, providing a more sustainable platform while preserving synthetic efficiency. The reaction has been evaluated with emphasis on improving mixing efficiency and reducing reaction time with comparable yields. These efforts may facilitate access to compound libraries for biological evaluation and subsequent laboratory-scale scale-up of promising candidates. Collectively, these studies highlight the role of continuous-flow systems in advancing more sustainable synthetic methodologies.