Chemoselectivity switch by mechanochemistry in the base-catalysed dione-acylation

The mechanochemistry of small molecules is an exponentially growing area of investigation relevant to developing sustainable synthesis to reduce waste and energy consumption, with great potential in large-scale chemical manufacturing. Occasionally, mechanochemical processes exhibit different reactivities, resulting in varying product selectivity compared to solution processes. In this study, we investigate the catalytic mechanism of a solvent-free one-pot acylation reaction of dimedone and 3-phenylpropanoic acid using a solvent-free ball-mill approach. The mechanochemical procedure afforded complete chemoselectivity towards a single acylation product after short milling, contrary to solution studies that previously reported product mixtures. Selectivity towards a single acylation product is controlled by the choice of the catalytic base. Under these mechanical process conditions, 4-dimethylaminopyridine (DMAP) is the only base that promotes the formation of the more desirable C-acylation product, whereas other bases exclusively afford the O-acylation product. Based on experimental findings, supported by theoretical modeling, we provide a mechanistic understanding of the base-dependent chemoselectivity, which leads to an enolate esterification that, in the case of DMAP, is converted to the thermodynamic product via Fries rearrangement. Finally, we explore the reaction scope with additional dicarbonyl compounds and carboxylic acids.