Switchable Cycloadditions of Mesoionic Dipoles: Refreshing up a Regioselective Approach to Two Distinctive Heterocycles

Mesoionic rings are among the most versatile 1,3-dipoles, as witnessed recently by their incorporation into bio-orthogonal strategies, and capable of affording unconventional heterocycles beyond the expected scope of Huisgen cycloadditions. Herein, we revisit in detail the reactivity of thiazol-3-ium-4-olates with alkynes, leading to thiophene and/or pyrid-2-one derivatives. A structural variation at the parent mesoionic dipole alters sufficiently the steric outcome, thereby favoring the regioselective formation of a single transient cycloadduct, which undergoes chemoselective fragmentation to either five- or six-membered heterocycles. The synthetic protocol benefits largely from microwave (MW) activation, which enhances reaction rates. The mechanism has been interrogated with the aid of density functional theory (DFT) calculations, which sheds light into the origin of the regioselectivity and points to a predictive formulation of reactivity involving competing pathways of mesoionic cycloadditions.

Automated summary

This study revisits the reactivity of thiazol-3-ium-4-olates with alkynes, and demonstrates that the structural variation of mesoionic rings can influence the steric outcome, leading to the regioselective formation of either five- or six-membered heterocycles. Microwave activation is found to enhance reaction rates, and density functional theory calculations provide insights into the mechanism of the reaction.