New Way of Mono-BOC Protection of Diamines
The calculated pKa values could serve good interpretation for the selective reaction of different diamines in acidic medium. Summarizing the basic requirement for mono protection is 5 difference between the pKa values of the two amino groups. The lower is the pKa of the free amine of the mono-Boc species the higher is the yield of the mono-boc product. Isolated diamines can be reacted according to the following rule: in acidic medium the lower in neutral medium the greater pKa valued nitrogen can be protected with acceptable selectivity. Alkyl chain longer than 3 carbons reduces the favorable neighborhood effect. Over 8 pKa difference value the amines can be reacted selectively in chemical reactions.
There are certain problems which this model overlooks:
1. Stability of the protected amines vs. pH and temperature
2. Stability of the heterocyclic systems vs. pH and temperature
The bulky Boc O is very sensitive to the steric hindrance, which is confirmed by regioselectivity of the Boc-protection and the sensitivity of the reaction velocity to the steric hindrance.
Advancing Library Design and Organic Synthesis, La Jolla, California, February 24-27, 2003