Advanced strategies for efficient macrocyclic Cu(I)-catalyzed cycloaddition of azides.

An advanced strategy for efficient macrocyclic Cu(I)-catalyzed cycloaddition is described. The key features include employing azide-iodoalkyne cycloadditions (CuAiAC), low catalyst loadings, relatively high concentrations (30 mM → 300 mM), and application to continuous flow. The remarkably efficient new tool affords a variety of macrocyclic skeletons having either different alkyl, aryl, or amino acid spacers in high yields (70-97%). The macrocyclic CuAiAC process affords macrocycles having an iodotriazole moiety that can be further functionalized using standard Pd-catalyzed cross-couplings.