Tandem continuous-flow α-C-H functionalization of pyrrolidine with aryl bromide-derived organolithium reagents

Le résumé fourni par la source

The α-functionalization of unprotected cyclic amines via organolithium reagents presents significant challenges for scale-up due to the extreme reactivity of the intermediates and the requirement for cryogenic control. A continuous-flow platform has been developed that enables the in-situ generation and telescoped use of organolithium reagents for the oxidative C–H functionalization of cyclic amines with organolithium reagents. The lithiation, oxidation, and nucleophilic addition sequence proceeds efficiently at − 10 °C, offering precise thermal management and reproducible steady-state operation. The system furnishes α-aryl-substituted pyrrolidines in up to 54% yield with a productivity of ~ 40 g h⁻¹. Scope studies revealed solubility-limited precipitation for certain aryl lithium reagents, identifying solvent polarity as a critical design parameter for future expansion. This work establishes a safe, modular framework for executing highly energetic organolithium transformations under continuous-flow conditions, providing valuable guidance for translation to manufacturing scale.

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