Enyne Amides to Fused Pyridones: Scope and Limitations

Herein we present an investigation into the scope and mechanism for the synthesis of cyclopentyl and heterocyclic fused pyridones from the corresponding enyne amides. In the presence of a secondary amine, cyclization proceeds smoothly to form 5,6-bicyclic pyridones in 12-90% yield. The cyclization fails with enyne amides of six-membered and larger ring systems. The ring closure reaction is catalytic in nature with respect to the secondary amine and proceeds via sequential 1,6-addition of the amine, 6-exo-trig ring closure of the iminium intermediate, and subsequent elimination of the secondary amine. Computations show reduced conjugation between the enyne and amide for six-membered and larger systems, thereby providing an explanation for the inability of such enyne amides to form fused pyridones.

Automated summary

This investigation demonstrates that enyne amides can smoothly undergo cyclization to form pyridones in the presence of a secondary amine, but fails with six-membered and larger ring systems. The ring closure reaction is catalytic, involving sequential 1,6-addition of the amine, 6-exo-trig ring closure of the iminium intermediate, and subsequent elimination of the secondary amine.