Efficient Synthesis of Conformationally Constrained 5,5’-Bi-1,2,3-Triazole-Based Bis-Macrocycles

We report herein the synthesis and structural characterization of 5,5′-bi-1,2,3-triazole bis-macrocycles obtained via oxidative copper-catalyzed azide–alkyne cycloaddition (CuAAC) of acyclic precursors bearing azide and alkyne groups. Initially observed as by-products during the copper(I)-NHC-catalyzed CuAAC synthesis of a 1,2,3-triazole-based macrocycle, these compounds were selectively obtained in the present work after systematic optimization of the catalyst, ligand, reaction atmosphere, and precursor addition rate. The bis-macrocycles were characterized by NMR and HRMS, and in some cases, by single-crystal X-ray diffraction. Chiral HPLC experiments enabled enantiomer separation, confirming their configurational stability.

Publication History

Received: 03 June 2025

Accepted after revision: 15 July 2025

Accepted Manuscript online:
15 July 2025