Continuous Flow Br/Li Exchange Enables Scalable Synthesis of Chiral N , P Ligands for Asymmetric Catalysis

Abstract Chiral N, P ligands represent privileged scaffolds in asymmetric catalysis, yet their scalable synthesis suffers from traditional batch constraints: ultra-cryogenic conditions (−100 to −120 °C), competitive benzyne formation, low yields, and poor scalability. Herein, a concise continuous-flow protocol for the efficient synthesis of (S)-DPPNH2-derived chiral N, P ligands via sequential Br/Li exchange is reported. Precise spatiotemporal control in a microreactor system enables selective monolithiation, phosphination, and stereoselective nucleophilic addition at a mild −70 °C, with a total residence time of only 17.8 s. This flow platform effectively suppresses benzyne side reactions and eliminates the need for ultra-cryogenic infrastructure while maintaining a low in-process inventory of hazardous intermediates. The corresponding ligand precursors are obtained in yields of up to 71% with good to excellent diastereoselectivities (up to 98:2 dr). Preparative-scale synthesis (1.17 g in a 2 min collection) and subsequent acid-catalyzed deprotection highlight the potential for further scale-up. This modular continuous-flow strategy offers a practical route to diverse chiral N, P ligands, addressing key manufacturing challenges in asymmetric catalyst development.