‘Click’ Chemistry on Sugar-Derived Alkynes: A Tandem ‘Click-Click’ Approach to Bistriazoles

Abstract

Development of a tandem ‘click-click’ approach to the formation of successive 1,4-disubstituted 1,2,3-triazole linkages and ‘click chemistry’ on sugar-derived alkynes are described.

Key words

C-glycoside - triazole - ‘click’ reaction - alkyne - azide - azido-alkyne - bistriazole

References and Notes

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For an updated list, see: http://www.scripps.edu/chem/sharpless/click.html

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Typical procedure for the simple ‘click’ reaction: To a solution of alkyne 3 (0.050 g, 0.19 mmol) and azide 5 (0.026 g, 0.19 mmol) in MeCN (1.9 mL) were added CuI (0.0746 g, 0.38 mmol) and DIPEA (0.1 mL, 0.57 mmol) successively at r.t. After stirring for 30 min, the reaction was quenched by adding sat. aq NH₄Cl (10 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 20 mL). After washing with brine (20 mL), the organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo to give the crude product, which was purified by recrystallisation from CH₂Cl₂-hexanes. The mother liquor was further purified by column chromatography (hexanes-EtOAc, 1.5:1) to afford triazole 12 (0.065 g, 85%). R _f  = 0.62 (EtOAc-hexanes, 1:1); mp 155-157 ˚C; [a]^²0 _D -83.880 (c 0.21, CHCl₃); ^¹H NMR (400 MHz, CDCl₃): δ = 7.53 (s, 1 H), 7.38-7.25 (m, 5 H), 5.59 (d, J = 11.6 Hz, 1 H), 5.57 (d, J = 1.2 Hz, 1 H), 5.43 (d, J = 14.8 Hz, 1 H), 5.18 (d, J = 2 Hz, 1 H), 4.70 (dd, J = 8.0, 2.4 Hz, 1 H), 4.36 (dd, J = 4.8, 2.4 Hz, 1 H), 1.59 (s, 3 H), 1.41 (s, 3 H), 1.35 (s, 3 H), 1.31 (s, 3 H); ^¹³C NMR (100 MHz, CDCl₃): δ = 145.5, 134.5, 128.9, 128.5, 128.0, 123.0, 109.1, 108.9, 96.4, 72.5, 70.6, 70.5, 64.6, 54.0, 26.1, 25.8, 24.8, 24.1; IR (KBr): 3019, 2923, 2395, 1966, 1651, 1374, 1259, 1215, 1069 cm^-¹; HRMS (EI): m/z calcd for C₂₀H₂₆N₃O₃: 388.1872; found: 388.1892.

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Typical procedure for the double ‘click’ reaction: To methyl propiolate 32 (0.024 mL, 0.27 mmol) in MeCN
(1.5 mL) was added CuI (0.105 g, 0.552 mmol) and DIPEA (0.147 mL, 0.82 mmol). The reaction mixture became a clear solution. The azido-alkyne 31 (0.050 g, 0.27 mmol) was added and the reaction was stirred for 1 h (reaction moni-tored by TLC). Then, azide 6 (0.27 mmol) was added and the reaction was stirred for 15 minutes. The reaction was quenched by the addition of sat. aq NH₄Cl (10 mL), the organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 20 mL). After washing with brine (20 mL), the organic layer was dried over Na₂SO₄ and concentrated in vacuo to give the crude product, which was purified by recrystallization from CH₂Cl₂-hexanes. The mother liquor was purified by column chromatography (hexanes-EtOAc, 1:1.5) to afford triazole 35 (0.050 g, 46%). Compound 35: R _f  = 0.54 (EtOAc); mp 218-220 ˚C; [a]^²0 _D
-55.148 (c 0.38, CHCl₃); ^¹H NMR (300 MHz, CDCl₃): δ = 8.32 (s, 1 H), 7.97 (s, 1 H), 7.59 (d, J = 8.5 Hz, 2 H), 7.33 (d, J = 8.1 Hz, 2 H), 4.95-4.64 (m, 4 H), 3.96 (s, 3 H), 2.43 (s, 3 H), 1.51 (s, 3 H), 1.39 (s, 3 H); ^¹³C NMR (75 MHz, CDCl₃): δ = 145.8, 135.0, 130.2, 129.2, 129.1, 128.9, 128.2, 122.3, 109.3, 78.2, 72.1, 54.3, 52.2, 50.4, 26.7, 26.7, 21.1. IR (KBr): 3135, 3019, 2953, 2400, 1714, 1545, 1450, 1436, 1372, 1357, 1334, 1239, 1216, 1174, 1123, 1110, 1073, 1047 cm^-¹; HRMS (EI): m/z calcd for C₁₉H₂₃N₆O₄: 399.5706; found: 399.5701. Compound 36: R _f  = 0.68 (EtOAc); mp 134-136 ˚C; ^¹H NMR (CDCl₃, 400 MHz): δ = 8.47 (s, 1 H), 7.63 (d, J = 8.5 Hz, 2 H), 7.35 (d, J = 8.1 Hz, 2 H), 3.99 (s, 3 H), 2.44 (s, 3 H); ^¹³C NMR (75 MHz, CDCl₃): δ = 145.8, 135.0, 130.2, 121.5, 120.6, 109.3, 52.0, 21.1; IR (KBr): 3019, 2928, 2857, 1726, 1552, 1521, 1434, 1259, 1215, 1148, 1038 cm^-¹; HRMS (EI): m/z calcd for C₁₁H₁₂ N₃O₂: 218.0861; found: 218.0865.