Kinetics and Mechanism of N-Boc Cleavage: Evidence of a Second-Order Dependence upon Acid Concentration

The kinetics of the HCl-catalyzed deprotection of the Boc-protected amine, thioester 2 to liberate AZD3409 1 have been studied in a mixture of toluene and propan-2-ol. The reaction rate was found to exhibit a second-order dependence upon the HCl concentration. This behavior was found to have a degree of generality as the deprotection of a second Boc-protected amine, tosylate 3 to yield amine 4 using HCl, sulfuric acid, and methane sulfonic acid showed the same kinetic dependence. In contrast the deprotection of tosylate 3 with trifluoroacetic acid required a large excess of acid to obtain a reasonable rate of reaction and showed an inverse kinetic dependence upon the trifluoroacetate concentration. These observations are rationalized mechanistically in terms of a general acid-catalyzed separation of a reversibly formed ion-molecule pair arising from the fragmentation of the protonated tert-butyl carbamate.