Abstract
Acylation reactions are ubiquitous in the synthesis of natural products and biologically active compounds. Unfortunately,t hese reactions often require the use of large quantities of volatile and/or toxic solvents, either for the reaction,p urification or isolationo ft he products. Herein we describea nd discusst he possibility of completely eliminating the use of organic solventsf or the synthesis, purification and isolation of products resulting from the acylation of aminesa nd other nucleophiles. Thus,u tilisation of N,N'-carbonyldiimidazole(CDI) allowse fficient coupling between carboxylic acids and variousn ucleophiles under solvent-free mechanical agitation, and water-assisted grinding enables both the purification and isolation of pure products. Critical parameters such as the physicals tate and water solubility of the products, milling material, type of agitation (vibratory or planetary) as wella sc ontamination from wear are analysed and discussed. In addition, original organic-solvent-free conditionsa re proposed to overcome the limitations of this approach. Thec alculations of various green metrics are included, highlighting the particularly low environmental impact of this strategy.