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

Publikationsverlauf

Eingereicht: 03. Juni 2025

Angenommen nach Revision: 15. Juli 2025

Accepted Manuscript online:
15. Juli 2025

Artikel online veröffentlicht:
20. August 2025

• References

• 1 Tornøe CW, Christensen C, Meldal M. J Org Chem 2002; 67: 3057-3064
• 2 Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew Chem, Int Ed 2002; 41: 2596-2599
• 3 Meldal M, Tornøe CW. Chem Rev 2008; 108: 2952-3015
• 4 Hein JE, Fokin VV. Chem Soc Rev 2010; 39: 1302-1315
• 5 Meldal M, Diness F. Trends Chem 2020; 2: 569-584
• 6 Liang L, Astruc D. Coord Chem Rev 2011; 255: 2933-2945
• 7 Kaur J, Saxena M, Rishi N. Bioconjugate Chem 2021; 32: 1455-1471
• 8 Xu Z, Bratlie KM. ACS Biomater Sci Eng 2018; 4: 2276-2291
• 9 Angell Y, Burgess K. Angew Chem, Int Ed 2007; 46: 3649-3651
• 10 González J, Pérez VM, Jiménez DO, Lopez-Valdez G, Corona D, Cuevas-Yañez E. Tetrahedron Lett 2011; 52: 3514-3517
• 11 Kwon M, Jang Y, Yoon S, Yang D, Jeon HB. Tetrahedron Lett 2012; 53: 1606-1609
• 12 Li L, Fan X, Zhang Y, Zhu A, Zhang G. Tetrahedron 2013; 69: 9939-9946
• 13 Reissig C-Y, Yu F. Beilstein J Org Chem 2023; 19: 1399-1407
• 14 Zheng Z-J, Ye F, Zheng L-S, Yang K-F, Lai G-Q, Xu L-W. Chem Eur J 2012; 18: 14094-14099
• 15 Brassard CJ, Zhang X, Brewer CR, Liu P, Clark RJ, Zhu L. J Org Chem 2016; 81: 12091-12105
• 16 García MA, Ríos ZG, González J. et al. Lett Org Chem 2011; 8: 701-706
• 17 Zheng Z-J, Wang D, Xu Z, Xu L-W. Beilstein J Org Chem 2015; 11: 2557-2576
• 18 Etayo P, Escudero-Adán EC, Pericàs MA. Catal Sci Technol 2017; 7: 4830-4841
• 19 Santana-Martínez I, Bautista-Renedo JM, Ayala-Bueno SV. et al. J Mol Struct 2022; 1270: 133969
• 20 Santana-Martínez I, Ramírez-Palma MT, Sánchez-Escalera J. et al. Struct Chem 2020; 31: 191-201
• 21 Goyard D, Praly J-P, Vidal S. Carbohydr Res 2012; 362: 79-83
• 22 Goyard D, Chajistamatiou AS, Sotiropoulou AI, Chrysina ED, Praly J-P, Vidal S. Chem Eur J 2014; 20: 5423-5432
• 23 Del Hoyo AM, Latorre A, Díaz R, Urbano A, Carreño MC. Adv Synth Catal 2015; 357: 1154-1160
• 24 Cucuiet TA, Anghel CC, Bogdan E. et al. Rev Roum Chim 2020; 65: 567-572
• 25 Anghel CC, Cucuiet TA, Hădade ND, Grosu I. Beilstein J Org Chem 2023; 19: 1776-1784
• 26 Teyssot ML, Nauton L, Canet JL, Cisnetti F, Chevry A, Gautier A. Eur J Org Chem 2010; 3507-3515
• 27 Shi Q, Wang X, Liu B, Qiao P, Li J, Wang L. Chem Commun 2021; 57: 12379-12405
• 28 Díez-González S, Correa A, Cavallo L, Nolan SP. Chem Eur J 2006; 12: 7758-7764
• 29 Sheldrick GM. Acts Crystallogr, Sect C: Struct Chem 2015; C71: 3-8
• 30 DIAMOND. Visual Crystal Structure Information System. Postfach 1251, 53002 Bonn, Germany: CRYSTAL IMPACT; 2001