Fine-Tunable Tris(triazolyl)methane Ligands for Copper(I)- Catalyzed Azide-Alkyne Cycloaddition Reactions

• Published in: Advanced synthesis & catalysis Vol. 356; no. 4; pp. 857 - 869
• Main Authors: Ozkal, Erhan, Llanes, Patricia, Bravo, Fernando, Ferrali, Alessandro, Pericàs, Miquel A.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 10.03.2014; WILEY‐VCH Verlag; Wiley
• Subjects: alkynes; azides; Catalysis; Catalysts; Chemistry; Chemistry, Applied; Chemistry, Organic; click chemistry; copper; Cycloaddition; cycloaddition reactions; Ligands; Phenyls; Physical Sciences; Science & Technology; Solvents; Synthesis; Toluene; 1,3-DIPOLAR CYCLOADDITIONS; cycloaddition reactions; MECHANISM; alkynes; COMPLEXES; click chemistry; TERMINAL ALKYNES; azides; VERSATILE ROUTE; FUNCTIONALIZATION; SOLID-SUPPORTED ORGANOCATALYST; copper; CATALYSTS; WATER
• ISSN: 1615-4150; 1615-4169
• DOI: 10.1002/adsc.201300887

The preparation of a small library of modular tris(triazolyl)methane ligands for copper‐catalyzed azide–alkyne cycloaddition (CuAAC) reactions is reported. The synthesis of the first generation ligand, tris(1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)methanol (1a), suitable for work in aqueous systems, is reported at the 50–100 mmol scale through a one‐stage, environmentally benign procedure. One‐stage procedures for the synthesis of tris(aryltriazolyl)methanol structures (1b, phenyl; 1c, para‐trifluoromethylphenyl; 1d, para‐methoxyphenyl) designed for electronic fine‐tuning of catalytic properties, and of 1a‐derived ethers 2c (OBn) and 2d (OMe), designed for CuAAC reactions in organic solvents, are also reported. The complete set of ligands (1a–d, 2c–d) has been tested in the reaction of phenylacetylene with benzyl azide in six different solvents (water, hexane, toluene, dichloromethane, tetrahydrofuran, and acetonitrile), and this has allowed the identification of 1b, 1c and 2c as the ligands depicting the highest tolerance to changes in solvent polarity within the considered family. The comparative performance of ligands 1b–d and 2c in the cycloaddition of a small family of alkynes with benzyl azide in two very different reaction media (1:1 t‐BuOH/H2O and toluene) has been studied as a guide for catalyst selection in specific applications. The applicability of 1c in CuAAC reactions involving functional substrates in toluene has been explored under thermal and microwave‐accelerated (tandem azide formation plus CuAAC reaction) reaction conditions.