Liquid-assisted mechanochemical synthesis of thioamide building blocks with the Lawesson reagent: ex situ monitoring and detection of intermediate polymorphs†

Thioamidation of various classes of carboxamide substrates with Lawesson's reagent under liquid-assisted mechanical activation for the synthesis of relevant building blocks including aromatic thioamides, thiopeptides, thiolactams, and thioenones is described. A thorough analysis of the effect of the specific material of milling jars and milling balls was carried out. The effect of different additives for liquid-assisted grinding (LAG) and the potential of the synthetic protocol for scale-up were explored. The simple and mild reaction conditions involved in this solvent-minimized mechanochemical protocol proved rather effective with a wide variety of substrates. Comparison with the corresponding reactions in solution shows comparable or better yields under mechanochemical activation. Ex situ powder X-ray diffraction (PXRD) monitoring with analysis at multiple points was performed in order to compare the diffraction patterns of reagents and products, to detect potential morphological changes of the reagents induced by milling prior to the reaction, and to perceive the occurrence of phase transitions during the mechanochemical reaction.