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

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.