Atroposelective interrupted CuAAC reaction using cyclic diaryliodoniums

Copper-catalyzed azide-alkyne cycloaddition (CuAAC) is a pivotal strategy for joining two fragments, including bioactive moieties under mild conditions. In recent years, "interrupted" CuAAC reaction has emerged by intercepting copper triazolide intermediates, thereby significantly broadening the scope of these transformations. However, asymmetric transformations based on the interruption of copper triazolide intermediates have remained elusive. In this work, we present an efficient and mild approach that intercepts a copper triazolide intermediate with a cyclic diaryliodonium reagent, enabling a three-component coupling of the cyclic diaryliodonium species, an alkyne, and an azide under atroposelective control. This method constitutes an asymmetric interrupted CuAAC reaction and furnishes a diverse array of structurally unique atropisomeric biaryl triazoles. Mechanistic investigations reveal an unusual secondary kinetic isotope effect for the terminal alkyne, while in situ calorimetry-based reaction progress kinetic analysis identifies the individual reaction orders of each substrate: formal 0.4th-order for cyclic diaryliodonium and first-order for both the alkyne and the azide. The overall rate is governed by copper-mediated cyclometallation of the alkyne and azide, as well as the oxidative addition of the copper triazolide intermediate to the cyclic diaryliodonium reagent.