Selective Thermal Deprotection of N-Boc Protected Amines in Continuous Flow

Thermal N-Boc deprotection of a range of amines is readily effected in continuous flow, in the absence of an acid catalyst. While the optimum results were obtained in methanol or trifluoroethanol, deprotection can be effected in a range of solvents of different polarities. Sequential selective deprotection of N-Boc groups has been demonstrated through temperature control, as exemplified by effective removal of an aryl N-Boc group in the presence of an alkyl N-Boc group. As a proof of principle, a telescoped sequence involving selective deprotection of an aryl N-Boc group from 9h followed by benzoylation and deprotection of the remaining alkyl N-Boc group to form amide 13 proved successful.