Direct catalytic synthesis of β-acylamino cyclobutanones via three-component Mannich reactions

Herein, a versatile, robust, and solvent-free method is reported for the synthesis of novel β-acylamino cyclobutanone derivatives exploiting a Cu(OTf)₂/TIPSCl-promoted Mannich-type three-component approach. The present work expands the utilization of a ring-strained ketone as well as various amide derivatives as amine equivalents, which has remained relatively underexplored due to their low reactivity profile. Following a rapid optimization of the reaction conditions, a relevant set of β-acylamino cyclobutanone derivatives has been designed and generated. Furthermore, the synthetic utility of our process has been demonstrated via a dual Au(I)/Ag(I)-catalyzed intramolecular hydroxygenation reaction to showcase a representative post-Mannich transformation.