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<p>We report a scalable and efficient flow method for the selective α-bromination of aromatic ketones using <i>N</i>-bromosuccinimide (NBS) activated by catalytic <i>p</i>-toluenesulfonic acid (<i>p</i>TsOH). The reaction conditions were optimized via a Design of Experiments (DoE) approach, enabling rapid identification of parameters that afford high conversions and selectivities. The methodology tolerates various electron-donating and electron-withdrawing substituents on the aromatic ring, with electron-rich substrates showing higher reactivity. Scale-up experiments confirmed the robustness and stability of the system, producing multi-gram quantities without loss of efficiency. This flow protocol offers a safe, practical, and environmentally friendly alternative to conventional batch bromination, with potential industrial applicability for the synthesis of pharmaceutically relevant α-bromo ketones.</p>

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Flow synthesis of aromatic alpha-bromo ketones: a DoE aided approach

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月17日

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  • Giulio Mancini,
  • Italo Franco Coelho Dias,
  • Claudio Santi,
  • Luca Sancineto

摘要

We report a scalable and efficient flow method for the selective α-bromination of aromatic ketones using N-bromosuccinimide (NBS) activated by catalytic p-toluenesulfonic acid (pTsOH). The reaction conditions were optimized via a Design of Experiments (DoE) approach, enabling rapid identification of parameters that afford high conversions and selectivities. The methodology tolerates various electron-donating and electron-withdrawing substituents on the aromatic ring, with electron-rich substrates showing higher reactivity. Scale-up experiments confirmed the robustness and stability of the system, producing multi-gram quantities without loss of efficiency. This flow protocol offers a safe, practical, and environmentally friendly alternative to conventional batch bromination, with potential industrial applicability for the synthesis of pharmaceutically relevant α-bromo ketones.