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

Herein, the first mechanochemical Fries rearrangement for the industrially important synthesis of para-hydroxyacetophenone, inside a ball mill and a twin-screw extruder, is presented. Our approach leads to a yield of 62 % in as little as 90 minutes while liquid-assisted grinding can shift the isomer ratio resulting in an excess of the desired para-product. The multigram scale-up by extrusion leads to 61 % yield in only three minutes while completely avoiding solvents. The extrusion temperature can even further be reduced by combining extrusion with a subsequent ageing step.