Rapid cleavage of cyclic tertiary amides of Kemp's triacid: Effects of ring structure

Article abstract of DOI:10.1016/j.bmcl.2004.06.024

The piperidyl and prolyl amides of Kemp's triacid (7 and 8, respectively) have been prepared and their rates of intramolecular acylolysis measured as a function of pD. The piperidyl derivative 7 reacts approximately four-times faster (e.g., t_1/2=3min at 20°C and pD7.7) than the previously reported pyrrolidyl and methylphenethyl amide derivatives, while the prolyl derivative 8 reacts two-times more slowly (e.g., t_1/2=30min at 20°C and pD7.8). Molecular-mechanics calculations indicate that the nonbonded interactions in the piperidyl derivative 7 are distinct from those in the prolyl, pyrrolidyl, and methylphenethyl amide derivatives, a result that supports the suggestion that ground-state pseudoallylic strain contributes to the enormous reactivity of Kemp's triacid tertiary amides. In sum, the results reported indicate that the Kemp's triacid scaffolding provides a general means of activating tertiary amide derivatives.