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

Dedication

Dedicated to Academician Marius Andruh on the occasion of his 70th anniversary.

Abstract

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)-N-Heterocyclic Carbenes (NHCs)–catalyzed CuAAC synthesis of a 1,2,3-triazole–based macrocycle, these compounds were selectively obtained after systematic optimization of the catalyst, ligand, reaction atmosphere, and precursor addition rate. The bis-macrocycles were characterized by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometry (HRMS), and in some cases, by single-crystal X-ray diffraction. Chiral High-Performance Liquid Chromatography (HPLC) experiments enabled enantiomer separation, confirming their configurational stability.

Keywords

5,5′-Bi-1,2,3-triazoles - Bis-macrocycles - CuAAC - Atropoisomer - N-Heterocyclic carbenes

Publication History

Received: 03 June 2025

Accepted after revision: 15 July 2025

Accepted Manuscript online:
15 July 2025

Article published online:
20 August 2025

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