Microwave Irradiation as an Effective Means of Synthesizing Unsubstituted N-Linked 1,2,3-Triazoles from Vinyl Acetate and Azides

Abstract

N-Linked 1,2,3-triazoles have been prepared by a reaction of azides with vinyl acetate under microwave irradiation. Additionally, a microwave-assisted, two-step, one-pot procedure from halides involving azide substitution in diethyl ether, followed by ­reaction with vinyl acetate, has effectively been employed.

Key words

1,2,3-triazole - vinyl acetate - microwave irradiation - one-pot reaction - 1,3-dipolar cycloaddition

References and Notes

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• 15 Microwave-Assisted Preparation of Alkyl Azides; General Procedure Alkyl halide (1 equiv) and NaN₃ (1.1 equiv) in DMF was mixed in a Biotage vial of 0.5-2.0 mL. The vial was sealed, and irradiated at 100 ˚C for 10-60 min. When the reaction was complete as monitored by TLC analysis, the reaction mixture was diluted with Et₂O and the organic phase was washed several times with H₂O and brine and dried over MgSO₄. The solvent was removed at atmospheric pressure and room temperature (as small organic azides do not tolerate vacuum evaporation), and the isolated alkyl azide was sufficiently pure for the next reaction. WARNING: organic azides are potentially explosive substances and proper safety precautions such as a blast shield should be taken when handling these compounds. Benzyl Azide (1a): BnCl (1.20 mL, 10.4 mmol) and NaN₃ (726 mg, 11.2 mmol) in DMF (12 mL) were irradiated for 10 min at 100 ˚C to give benzyl azide as a colorless oil (1.17 g, 84%). ^¹H NMR (CDCl₃): δ = 7.40-7.31 (m, 5 H), 4.35 (s, 2 H). NMR spectral data was in accordance with literature values, see: Ju Y. Kumar D. Varma RS. J. Org. Chem.  2006,  71:  6697 
• 16 Microwave-Assisted 1,2,3-Triazole Formation from Azides; General Procedure Alkyl azide (0.24-0.58 mmol) and vinyl acetate (1.50 mL) were mixed in a Biotage vial (0.5-2.0 mL). The vial was sealed and irradiated at 120 ˚C until full conversion was achieved as monitored by TLC analysis. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash column chromatography on silica gel. 1-Benzyl-1 H -1,2,3-triazole (2b): Benzyl azide (1b; 68 mg, 0.51 mmol) in vinyl acetate (1.5 mL) was irradiated at 120 ˚C for 5 h. Column chromatography (EtOAc-CH₂Cl₂, 1:9; R _f = 0.41) afforded the triazole as colorless crystals (81 mg, 99%). ^¹H NMR (CDCl₃): δ = 7.71 (s, 1 H), 7.47 (d, J = 0.8 Hz, 1 H), 7.40-7.32 (m, 3 H), 7.28-7.24 (m, 2 H), 5.57 (s, 2 H). NMR spectral data was in accordance with literature values, see: Chuprakov S. Chernyak N. Dudnik AS. Gevorgyan V. Org. Lett.  2007,  9:  2333 
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Microwave-Assisted One-Pot Formation of 1,2,3-Triazole from Alkyl Halides; General Procedure WARNING : Excess azide can potentially react with acetic acid to form explosive hydrazoic acid. Thus, vinyl acetate should not be added before the azidation reaction has run to completion, and proper safety precautions should be taken when handling these compounds. Alkyl halide (1 equiv) and tetrabutylammonium azide (1.05 equiv) were dissolved in diethyl ether (1 mL) in a sealed Biotage vial and irradiated at 100 ˚C until TLC analysis indicated full consumption of the starting material. Vinyl acetate (10 equiv) was then added and the reaction mixture was irradiated at 120 ˚C until TLC analysis showed disappearance of the intermediate azide. The reaction mixture was then diluted with diethyl ether and the organic phase was washed with H₂O and brine then dried over MgSO₄, concentrated under reduced pressure and purified by column chromatography on silica gel.
1-Benzyl-1 H -1,2,3-triazole: BnCl (50 µL, 0.35 mmol) and TBAN (104 mg, 0.36 mmol) in Et₂O (1.0 mL) was irradiated at 100 ˚C for 15 min. Vinyl acetate (0.32 mL, 3.5 mmol) was added and the reaction mixture was irradiated at 120 ˚C for 9 h. Flash column chromatography (EtOAc-CH₂Cl₂, 1:9;
R _f = 0.41) afforded the triazole as colorless crystals (36 mg, 64%).