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.
Pharmaceutical Development, AstraZeneca R&D, S41/18 PR&D Building, Silk Road Business Park, Charter Way, Macclesfield, Cheshire, SK10 2NA, United Kingdom. ian.ashworth@astrazeneca.com
Ian W
IW
Ashworth
Brian G
BG
Cox
Brian
B
Meyrick
D000143:Acids / Q000737:chemistry*; D002219:Carbamates / Q000737:chemistry*; D002384:Catalysis; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure
D000143:Acids; D002219:Carbamates