The Mechanochemical Fries Rearrangement: Manipulating Isomer Ratios in the Synthesis of p-Hydroxyacetophenone at Different Scales

Here, we present the first mechanochemical Fries rearrangement for the industrially important synthesis of para hydroxyacetophenone, inside a ball mill and a twin-screw extruder. Our approach leads to quantitive conversion in as little as 90 minutes. Furthermore, the utilisation of liquid-assisted grinding can shift the isomer ratio resulting in an excess of the desired para product. The multigram scale-up via a continuous extrusion process leads to similar results in only three minutes of residence time while completely avoiding solvents. The extrusion temperature of 75-100 °C can even further be reduced by combining extrusion at 50°C with a subsequent ageing step.