Continuous Flow Synthesis of Aryl Ketones by Lithium–Bromine Exchange: From Lab‐Scale Optimization to Pilot‐Scale Production

Lithium–halogen exchange is a powerful method for the generation of highly reactive organolithium intermediates, but its implementation at scale remains challenging because of cryogenic requirements, strong exothermicity, and competing side reactions. Herein, we report the continuous flow process intensification of a lithium–bromine exchange/addition sequence for the synthesis of aryl ketones from aryl bromides and N ‐Boc‐protected lactams. Initial batch experiments highlighted the main selectivity limitation of the transformation, namely overaddition of the aryllithium intermediate to the desired ketone product, leading to tertiary alcohol byproducts. Translation to a lab‐scale microfluidic platform enabled precise residence‐time and thermal control, affording a model aryl ketone in 74% yield with excellent 98:2 ketone/alcohol selectivity, and a productivity of 1.0 g min ⁻¹ . The process was subsequently transferred to a pilot‐scale platform using a commercial mesofluidic flow reactor, delivering the model target ketone in 77% yield, with improved 99:1 selectivity, and a productivity of 1.1 kg h ⁻¹ without further purification. In‐line IR spectroscopy was integrated as a process analytical technology (PAT) tool to monitor steady‐state operation. The methodology was further applied to a small library of aryl bromides and N ‐Boc‐protected lactams, demonstrating the synthetic utility and current limitations of the intensified flow process.