Intramolecular (3+2) Cycloaddition Reactivity Between Heteroatom-Substituted Alkynes and Tethered Alkynes: Thermal and Catalytic Routes

Abstract

While 1,3-dipolar three-atom components are widely used in (3+2) cycloaddition chemistry, their exotic counterparts of neutral three-atom components are significantly less studied. These neutral three-atom components have a large synthetic potential, as their resulting (3+2) cycloadducts are zwitterionic and unstable in nature, providing new opportunities for functionalization and diversification. In this thesis, the participation of heteroatom-substituted alkynes, a unique class of neutral three-atom components, in intramolecular (3+2) cycloadditions with tethered alkyne is described and further explored. Specifically, alkyne-tethered ynamides and alkynyl sulfides were found to produce fused pyrroles and thiophenes, respectively. On the basis of experimental and theoretical studies, this thermally promoted process is proposed to occur through the stepwise formation of a (3+2) cycloadduct via diradical intermediates. These zwitterionic cycloadducts are highly reactive and provide a diverse array of pyrroles and thiophenes depending strongly on both scaffold substitution and reaction conditions. Additionally, similar (3+2) cycloaddition processes involving ynamides or alkynyl sulfides tethered with terminal alkynes can be catalyzed at much lower temperatures in the presence of copper and silver salts. This catalytic process is suggested to employ mechanisms reminiscent of that of copper-catalyzed azide-alkyne couplings.