Ruthenium-Free Preparation of 1,5-Disubstituted Triazoles by Alkylative Debenzylation of 1,4-Disubstituted Triazoles

Abstract

A method that cleanly converts the 1,4-disubstituted 1,2,3-triazole products of the copper-catalyzed ‘click’ dipolar cycloaddition reaction of benzyl azide with terminal alkynes into 1,5-disubstituted triazoles is described. Selective N-alkylation of 1,4-disubstituted 1,2,3-triazoles under microwave irradiation is followed by debenzylation of the resulting 1,3,4-trisubstituted triazolium cations by treatment with potassium tert-butoxide.

Key words

1,2,3-triazole - debenzylation - microwave - disubstituted - rearrangement

• References and Notes

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• 23 C₁₇H₁₈IN₃, M = 391.25, monoclinic, space group P2₁/c, a = 17.436(4), b = 7.723(2), c = 12.207(3) Å, V = 1628.2(6) ų, Z = 4, μ (Mo Kα) = 0.71075, 9847 independent reflections, (Rint = 0.0594), R1[I > 2σ(I)] = 0.0376, wR2 (all reflections) = 0.0874. CCDC 1479260 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
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• 28 General Procedure for the Formation of the Triazolium Salts from 1-Benzyl-4-phenyl 1,2,3-Triazoles 1-Benzyl-4-phenyl 1,2,3-triazole was dissolved in MeCN in a microwave vial, and the alkyl halide (5 equiv) was added. The reaction was irradiated in the microwave instrument for 3 h at 100 °C. Solvents were removed under reduced pressure to yield the triazolium salt. 1-Benzyl-3-methyl-4-phenyl-1H-1,2,3-triazolium Iodide (2) Prepared according to the general procedure from 1 (1.66 g, 7.07 mmol) and MeI (1.73 mL, 4.98 g, 35.10 mmol). Compound 2 was isolated as a pale yellow solid (2.79 g, 93%), mp 133–135 °C. IR (neat): 3467, 3040, 1611, 1493, 1455, 1155, 768, 746, 699 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.33 (s, 1 H), 7.69–7.60 (m, 4 H), 7.54–7.40 (m, 3 H), 7.37–7.33 (m, 3 H), 5.97 (s, 2 H), 4.26 (s, 3 H).¹³C NMR (126 MHz, CDCl₃): δ = 143.2, 132.2, 131.4, 130.1, 130.1, 129.8, 129.7, 129.6, 129.4, 121.7, 57.6, 39.6. General Procedure for the Debenzylation of Triazolium Salts Using t-BuOK 1-Benzyl-3-alkyl-4-phenyl triazolium iodide was dissolved in THF, and the solution cooled to 0 °C. t-BuOK (2.5 equiv) was added, and the reaction stirred overnight. H₂O was added, and the mixture was stirred for 30 min and filtered through Celite. The solution was extracted using EtOAc, and the solvents were removed under reduced pressure to give the desired 1,5-disubstituted triazole. 1-Methyl-5-phenyl-1H-1,2,3-triazole (6) Prepared according to the general procedure from 2 (0.78 g, 2.05 mmol), and t-BuOK (0.61 g, 5.46 mmol) was dissolved in THF (45 mL). The crude product was purified by column chromatography, eluting with EtOAC–petroleum ether (1:1), yielding the titled compound 6 as an orange oil (0.31 g, 93%). IR (neat): 3060, 3030, 2953, 1732, 1484, 1454, 1245, 767 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.73 (s, 1 H), 7.57–7.45 (m, 3 H), 7.45–7.35 (m, 2 H), 4.08 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 129.3, 128.7, 127.1, 35.7, 14.3 (quaternary signals not observed).