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<p>The α-functionalization of unprotected cyclic amines <i>via</i> 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 <i>in</i>-<i>situ</i> 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&#xa0;°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&#xa0;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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月2日

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  • Lara J. Nolan,
  • Ailbhe A. Ryan,
  • Seán Dempsey,
  • Megan Smyth,
  • Thomas S. Moody,
  • Scott Wharry,
  • Karen Fahey,
  • Paul Dingwall,
  • David W. Rooney,
  • Jillian M. Thompson,
  • Mark J. Muldoon,
  • Peter C. Knipe

摘要

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.

Graphical Abstract