Synthesis of enantiomerically pure α-[4-(1-substituted)-1,2,3-triazol-4-yl]-benzylacetamides via microwave-assisted click chemistry: towards new potential antimicrobial agents

Chiral 1-phenyl-2-propynylamines are important building blocks for the synthesis of antifungal and antiaromatase agents related to bifonazole. In this report, a microwave-assisted Cu(I)-catalyzed ‘click chemistry’ approach has been employed to easily generate a small library of enantiomerically pure α-[4-(1-substituted)-1,2,3-triazol-4-yl]benzylacetamides starting from racemic propargylamines. These compounds could represent easily accessible intermediates for the synthesis of new antimicrobial agents.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

(S)-N-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-phenyl-methyl]-acetamideC18H18N4OEe 91%[α]D20=-9.2 (c 0.6, MeOH).Source of chirality: (R)-N-acetyl-1-phenyl-2-propynylamineAbsolute configuration: (S)

(S)-N-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-(4-fluorophenyl)-methyl]-acetamideC18H17FN4OEe 93%[α]D20=-7.9 (c 1.1, CHCl3)Source of chirality: (R)-N-acetyl-1-(4-fluorophenyl)-2-propynylamineAbsolute configuration: (S)

(S)-N-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-(4-bromophenyl)-methyl]-acetamideC18H17BrN4OEe 95%[α]D20=-10.0 (c 0.6, CHCl3)Source of chirality: (R)-N-acetyl-1-(4-bromophenyl)-2-propynylamineAbsolute configuration: (S)

(S)-N-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-(4-chlorophenyl)-methyl]-acetamideC18H17ClN4OEe 99%[α]D20=-10.9 (c 1.0, CHCl3)Source of chirality: (R)-N-acetyl-1-(4-chlorophenyl)-2-propynylamineAbsolute configuration: (S)

(S)-N-[Phenyl-(1-phenyl-1H-[1,2,3]triazol-4-yl)-methyl]-acetamideC17H16N4OEe 95%[α]D20=-9.4 (c 1.0, CHCl3)Source of chirality: (R)-N-acetyl-1-phenyl-2-propynylamineAbsolute configuration: (S)

(S)-N-[4-Fluorophenyl-(1-phenyl-1H-[1,2,3]triazol-4-yl)-methyl]-acetamideC17H15FN4OEe 95%[α]D20=-6.6 (c 0.9, CHCl3)Source of chirality: (R)-N-acetyl-1-(4-fluorophenyl)-2-propynylamineAbsolute configuration: (S)

(S)-N-[4-Bromophenyl-(1-phenyl-1H-[1,2,3]triazol-4-yl)-methyl]-acetamideC17H15BrN4OEe 89%[α]D20=-6.8 (c 1.7, CHCl3)Source of chirality: (R)-N-acetyl-1-(4-bromophenyl)-2-propynylamineAbsolute configuration: (S)

(S)-N-[4-Chlorophenyl-(1-phenyl-1H-[1,2,3]triazol-4-yl)-methyl]-acetamideC17H15ClN4OEe 79%[α]D20=-9.8 (c 1.0, CHCl3)Source of chirality: (R)-N-acetyl-1-(4-chlorophenyl)-2-propynylamineAbsolute configuration: (S)