Optimizing Reactions in Reactive Extrusion by a Bayesian Approach: the Case of Thermal Amidation

A solvent-free thermo-mechanochemical synthesis of amides from carboxylic acids and amines, performed by reactive extrusion, in the absence of coupling agents, additives or catalyst is reported. We developed a Bayesian optimization approach able to handle holistically various parameters (temperature, reaction time, excess starting material) as well as setting a target for sustainability. The methodology proved to be straightforward, high yielding, sustainable and easily optimized for each set of starting materials with a reduced number of experiments. It was applied to the facile and efficient preparation of various amides including bioactive macamides and API moclobemide.