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Copper-Catalyzed Azide-Alkyne Cycloaddition of Hydrazoic Acid Formed In Situ from Sodium Azide Affords 4-Monosubstituted-1,2,3-Triazoles

Dominik Jankovič, Miha Virant and Martin Gazvoda*

*Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia, Email: martin.gazvodafkkt.uni-lj.si

D. Jankovič, M. Virant, M. Gazvoda, J. Org. Chem., 2022, 87, 4018-4028.

DOI: 10.1021/acs.joc.1c02775



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Abstract

The use of polydentate N-donor chelating ligands enables a copper-catalyzed cycloaddition of hydrazoic acid with terminal alkynes to provide 4-substituted-1H-1,2,3-triazoles in high yields at room temperature. Hydrazoic acid was formed in situ from sodium azide under mildly acidic conditions in <6% concentrations at which it is safe to handle.

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(BimH)3



Synthesis of 4-monosubstituted-1,2,3-triazoles - Method C:

Into a 5 mL round bottom flask stirring bar, alkyne (0.5 mmol, 1 equiv.), CuSO45H2O (6.2 mg, 0.025 mmol, 5 mol%), sodium ascorbate (25 mg, 0.125 mmol, 0.25 equiv.), tris(2-benzimidazolylmethyl)amine ((BimH)3) (10 mg, 0.025 mmol, 5 mol%), NaN3 (49 mg, 0.75 mmol, 1.5 equiv.), solvent MeOH:H2O 3:1 (v/v, 0.6 mL) and CH3COOH (189 μL, 198 mg, 3.3 mmol, 6.6 equiv) were added in that order. After the addition of acetic acid flask was capped with glass stopper and the reaction mixture was stirred for 24 hours at room temperature. Then, the reaction flask was uncapped and the reaction mixture was filtered trough a short pad of silica gel using ethyl acetate as eluent. Resulting filtrate was concentrated with the aid of rotary evaporator and the crude product was purified by silica gel column chromatography.

Caution! Hydrazoic acid (HN3) is toxic if inhaled, and can be explosive if concentrated. It was reported that hydrazoic acid at concertation above 20% (w/w) can be explosive, although ignition source (e.g. spark) is required for detonation of its vapours. Hydrazoic acid solutions with concentration under 10% (w/w) are safe to store and handle. Therefore, to minimize its potential hazards, reactions were performed on low scale (0.5 - 1.5 mmol) and at low concentration of NaN3 / hydrazoic acid (max. 6% (w/w)), in closed systems inside the fume hood.


Key Words

1,2,3-triazoles, click chemistry


ID: J42-Y2022