One-Pot Synthesis of 1,4-Disubstituted 1,2,3-Triazoles from Aldehydes and Amines

Abstract

A one-pot, three-step synthesis of 1,4-disubstituted 1,2,3-triazoles from aldehyde and amine has been developed by in situ transformation of aldehyde into alkyne, followed by diazo-transfer of amine into azide and subsequent cycloaddition. This procedure allowed the synthesis of fluorescent amino acid derivatives as well as glycoconjugate mimetics.

Key words

aldehydes - amines - cycloadditions - one-pot reaction - triazoles

References and Notes

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28

General Procedure
To a solution of aldehyde (1 equiv) in a mixture MeOH-CH₂Cl₂ (4 mL/4 mL for 0.5 mmol of aldehyde) were added K₂CO₃ (4 equiv) and the Bestmann-Ohira reagent (1.8 equiv). The mixture was stirred at r.t. until complete conversion of aldehyde to alkyne (TLC monitoring -
6 h maximum). Amine hydrochloride salt (1.2 equiv), CuSO₅˙5H₂O (1.2 equiv) and the imidazole-1-sulfonyl azide (1.2 equiv) were then added to the reaction mixture and stirred at r.t. to transform the amine into the azide intermediate. Reaction was judged to be complete when imidazole-1-sulfonyl azide spot disappeared on TLC (4 h maximum). Finally, ascorbic acid (4 equiv) was added, and the reaction was stirred at r.t. overnight. The mixture was filtered through a pad of Celite, washed with MeOH, and the solvents evaporated under vacuum. The residue was purified by column chromatography on silica gel (40-63 µM) to afford the triazoyl compound.
Analytical Data for Selected Compounds Compound 12: mp 191 ˚C; R _f  = 0.55 (EtOAc-cyclohexane = 1:1); [α]_D -89.2 (c 0.48, CH₂Cl₂). ^¹H NMR (400 MHz, CDCl₃): δ = 3.89 (s, 3 H), 5.37 (s, 2 H, CH₂), 8.01-8.29 (m, 9 H), 8.67 (d, 1 H, J = 9.2 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 51.0 (CH₂), 53.3 (CH₃), 124.3, 124.7, 125.0, 125.3, 126.2, 127.3, 127.5, 128.0, 128.4, 128.7 (CH), 131.0, 131.4, 131.5, 148.0, 166.9 (C). ESI-HRMS: m/z calcd for C₂₁H₁₅N₃NaO₂: 364.1062; found: 364.1057.
Compound 29: mp 114 ˚C; R _f  = 0.48 (EtOAc); [α]_D -35.2 (c 0.47, CH₂Cl₂). ^¹H NMR (400 MHz, CDCl₃): δ = 1.31 (s, 3 H), 1.36 (s, 3 H), 1.45 (s, 3 H), 1.60 (s, 3 H), 1.83 (s, 3 H), 1.83-2.01 (m, 2 H), 3.52-3.53 (m, 1 H), 3.61-3.63 (m, 1 H), 3.67 (dd, 1 H, J = 6.4, 10.1 Hz), 3.90 (dd, 1 H, J = 7.4, 10.1 Hz), 3.95-3.97 (m, 1 H), 4.11-4.13 (m, 1 H), 4.25 (t, 1 H, J = 6.8 Hz), 4.37 (dd, 1 H, J = 2.8, 5.0 Hz), 4.39-4.51 (m, 6 H), 4.55-4.59 (m, 3 H), 4.70 (dd, 1 H, J = 2.3, 7.8 Hz), 5.19 (d, 1 H, J = 1.8 Hz), 5.60 (d, 1 H, J = 5.0 Hz), 6.60 (d, 1 H, J = 9.6 Hz), 7.20-7.33 (m, 15 H), 7.65 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 23.4, 24.3, 25.1, 26.1, 26.3 (CH₃), 32.4, 46.9 (CH₂), 47.8, 64.7, 65.3 (CH); 67.6 (CH₂), 70.8, 70.9 (CH); 72.0, 72.3 (CH₂), 72.7, 73.2 (CH), 73.4 (CH₂), 74.2, 75.1, 77.3 (CH), 96.7 (CH), 109.0, 109.3 (C), 123.6, 127.8, 127.9, 128.6, 128.7 (CH), 137.3, 137.5, 138.2, 145.1, 170.0 (C). ESI-HRMS: m/z calcd for C₄₄H₅₄N₄NaO₁₀: 821.3738; found: 821.3732.