Ligand Control of Copper-Mediated Cycloadditions of Acetylene to Azides: Chemo- and Regio-Selective Formation of Deutero- and Iodo-Substituted 1,2,3-Triazoles

The participation of σ-monocopper and σ-bis-copper acetylide in mechanistic pathways for copper-catalyzed cycloaddition (CuAAC) reactions of acetylene with azides was probed by analysis of deuterium distributions in the 1,2,3-triazole product formed by deuterolysis of initially formed mono- and bis-copper triazoles. The results show that, when Cu(Phen)(PPh₃)₂NO₃ is used as the catalyst for reactions of acetylene with azides in DMF/D₂O, 1-substituted-5-deutero-1,2,3-triazoles are generated selectively. This finding demonstrates that the Cu(Phen)(PPh₃)₂NO₃-catalyzed cycloadditions utilize monocopper acetylide as the substrate and produce 5-copper-1,2,3-triazoles initially. Conversely, when DBU or Et₃N is the copper ligand, the process takes place through initial formation and cycloaddition of bis-copper acetylide to produce 4,5-bis-copper-triazole, which reacts with D₂O to form the corresponding 4,5-bis-deutero-triazole. Moreover, when C₂D₂ is used as the substrate, Cu(Phen)(PPh₃)₂NO₃ as the Cu ligand, and H₂O/DMF as the solvent, mono-C4-deutreo 1,2,3-triazoles are generated in high yields and excellent levels of regioselectivity. Lastly, CuAAC reactions of acetylene with azides, promoted by CuCl₂·2H₂O and NaI, yield 4,5-diiodo-1,2,3-triazoles with moderate to high efficiencies.