Mechanochemical Oxidative Mannich Reaction: Evaluation of Chemical and Mechanical Parameters for the Mild and Chemoselective Coupling of N-tert-butoxycarbonyltetrahydroquinolines and Ketones

A mechanochemical oxidative Mannich reaction of N-tert-butoxycarbonyl (Boc) tetrahydroquinolines and ketones was successfully developed under solvent-free ball-milling conditions. The reaction afforded the desired coupling products in satisfactory yields under mild and tractable oxidative conditions. Side reactions such as deprotection of the Boc group were prevented by carefully adjusting the milling parameters, including milling frequency, time, milling-ball filling degree, milling-ball size, and grinding auxiliary. Further examination of the scope indicated that the reaction system could also be applied to the N-benzyloxycarbonyl and N-aryl substrates to afford the corresponding products in moderate to good yields.