A Convenient Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles via 1,3-Dipolar Cycloaddition/Coupling of Alkynes, Phenylboronic Acids, and Sodium Azide Catalyzed by Cu(I)/Cu(II)

Abstract

A series of 1,4,5-trisubstituted 1,2,3-triazoles was prepared simply and conveniently via 1,3-dipolar cycloaddition/coupling reaction of terminal alkynes, phenylboronic acids and sodium azide in 1,4-dioxane-water using CuI/CuSO₄ as catalyst.

triazole - cycloaddition/coupling - phenylboronic acid - copper catalyst - alkyne

References and Notes

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16

Synthesis of 4-(4-Methoxyphenyl)-5-[2-(4-methoxy-phenyl)ethynyl]-1-phenyl-1 H -1,2,3-triazole ( 4a); Typical Procedure: A mixture of 1a (50.0 mg, 0.41 mmol), 2a (118.9 mg, 0.90 mmol), sodium azide (3; 40.3 mg, 0.62 mmol), CuI (7.8 mg, 0.041 mmol) and CuSO₄·5H₂O (20.5 mg, 0.082 mmol) in 1,4-dioxane (10 mL) and H₂O (5 mL) was stirred overnight. Then, the reaction mixture was diluted with H₂O (20 mL) and was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic extracts were dried over MgSO₄, filtered and concentrated. The residue was purified by column chromatography (PE-EtOAc, 10:1) to afford 4a (98.5 mg, 63%) as a white solid; mp 86-88 °C. IR (KBr): 2216 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.83 (s, 3 H), 3.87 (s, 3 H), 6.89 (d, J = 9.3 Hz, 2 H), 7.03 (d, J = 8.7 Hz, 2 H), 7.40 (d, J = 8.7 Hz, 2 H), 7.50-7.60 (m, 3 H), 7.88 (d, J = 8.1 Hz, 2 H), 8.21 (d, J = 9.3 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 55.3 (CH₃), 55.4 (CH₃), 75.4 (C), 102.0 (C), 113.6 (C), 114.1 (CH), 114.3 (CH), 116.3 (C), 122.9 (C), 123.7 (CH), 127.8 (CH), 129.2 (CH), 129.7 (CH), 133.0 (CH), 136.7 (C), 148.1 (C), 160.0 (C), 160.6 (C). EI-MS: m/z = 381 [M⁺], 353 [M - N₂]⁺. Anal. Calcd for C₂₄H₁₉N₃O₂: C, 75.57; H, 5.02; N, 11.02. Found: C, 75.50; H, 4.99; N, 10.98.
1,4-Diphenyl-5-(2-phenylethynyl)-1 H -1,2,3-triazole ( 4b): white solid; mp 105-107 °C. IR (KBr): 2215 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.38-7.60 (m, 11 H), 7.88 (d, J = 8.4 Hz, 2 H), 8.28 (d, J = 7.5 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 76.4 (C), 102.0 (C), 116.8 (C), 121.4 (C), 123.8 (CH), 126.5 (CH), 128.6 (CH), 128.7 (CH), 128.7 (CH), 129.2 (CH), 129.4 (CH), 129.6 (CH), 130.1 (C), 131.4 (CH), 136.5 (C), 148.5 (C). EI-MS: m/z = 321 [M⁺], 293 [M -N₂]⁺. Anal. Calcd for C₂₂H₁₅N₃: C, 82.22; H, 4.70; N, 13.08. Found: C, 82.16; H, 4.71; N, 13.04.
5-(Hept-1-ynyl)-4-pentyl-1-phenyl-1 H -1,2,3-triazole ( 4c): liquid. IR (KBr): 2236 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 0.87-0.94 (m, 6 H), 1.26-1.42 (m, 8 H), 1.53-1.60 (m, 2 H), 1.76-1.81 (m, 2 H), 2.45 (t, J = 7.0 Hz, 2 H), 2.79 (t, J = 7.6 Hz, 2 H), 7.44-7.53 (m, 3 H), 7.78 (d, J = 6.9 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 13.87 (CH₃), 13.94 (CH₃), 19.6 (CH₂), 22.1 (CH₂), 22.3 (CH₂), 25.4 (CH₂), 27.7 (CH₂), 28.5 (CH₂), 30.9 (CH₂), 31.4 (CH₂), 66.9 (C), 103.1 (C), 118.7 (C), 123.3 (CH), 128.8 (CH), 129.0 (CH), 136.8 (C), 151.2 (C). EI-MS: m/z = 309 [M⁺], 281 [M - N₂]⁺. Anal. Calcd for C₂₀H₂₇N₃: C, 77.63; H, 8.79; N, 13.58. Found: C, 77.56; H, 8.77; N, 13.55.
1-(4-Chlorophenyl)-4-(4-methoxyphenyl)-5-[2-(4-methoxyphenyl)ethynyl]-1 H -1,2,3-triazole ( 4d): white solid; mp 150-152 °C. IR (KBr): 2214 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.84 (s, 3 H), 3.87 (s, 3 H), 6.91 (d, J = 9.0 Hz, 2 H), 7.02 (d, J = 8.7 Hz, 2 H), 7.41 (d, J = 9.0 Hz, 2 H), 7.54 (d, J = 8.7 Hz, 2 H), 7.84 (d, J = 9.0 Hz, 2 H), 8.20 (d, J = 9.3 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 55.3 (CH₃), 55.4 (CH₃), 75.2 (C), 102.4 (C), 113.3 (C), 114.1 (CH), 114.4 (CH), 116.2 (C), 122.7 (C), 124.8 (CH), 127.8 (CH), 129.4 (CH), 133.1 (CH), 135.1 (C), 135.2 (C), 148.3 (C), 160.0 (C), 160.7 (C). EI-MS: m/z = 415 [M⁺], 387 [M - N₂]⁺. Anal. Calcd for C₂₄H₁₈ClN₃O₂: C, 69.31; H, 4.36; N, 10.10. Found: C, 69.27; H, 4.32; N, 10.08.
1-(4-Chlorophenyl)-4-phenyl-5-(2-phenylethynyl)-1 H -1,2,3-triazole ( 4e): white solid; mp 95-97 °C. IR (KBr): 2219 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.39-7.57 (m, 10 H), 7.85 (d, J = 8.1 Hz, 2 H), 8.26 (d, J = 8.4 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 76.1 (C), 102.4 (C), 116.7 (C), 121.2 (C), 124.9 (CH), 126.5 (CH), 128.7 (CH), 128.7 (CH), 128.9 (CH), 129.5 (CH), 129.8 (CH), 129.9 (C), 131.5 (CH), 135.0 (C), 135.3 (C), 148.7 (C). EI-MS: m/z = 355 [M⁺], 327 [M - N₂]⁺. Anal. Calcd for C₂₂H₁₄ClN₃: C, 74.26; H, 3.97; N, 11.81. Found: C, 74.21; H, 3.96; N, 11.77.
1-(4-Acetylphenyl)-4-(4-methoxyphenyl)-5-[2-(4-methoxyphenyl)ethynyl]-1 H -1,2,3-triazole ( 4f): white solid; mp 126-128 °C. IR (KBr): 2214, 1685 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.67 (s, 3 H), 3.84 (s, 3 H), 3.87 (s, 3 H), 6.91 (d, J = 8.4 Hz, 2 H), 7.03 (d, J = 8.4 Hz, 2 H), 7.43 (d, J = 8.1 Hz, 2 H), 8.06 (d, J = 8.4 Hz, 2 H), 8.16 (d, J = 8.1 Hz, 2 H), 8.20 (d, J = 8.1 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 26.7 (CH₃), 55.3 (CH₃), 55.4 (CH₃), 75.2 (C), 102.7 (C), 113.2 (C), 114.1 (CH), 114.4 (CH), 116.0 (C), 122.5 (C), 123.2 (CH), 127.8 (CH), 129.4 (CH), 133.0 (CH), 137.0 (C), 140.0 (C), 148.5 (C), 160.1 (C), 160.8 (C), 196.8 (C). EI-MS: m/z = 423 [M⁺], 395 [M -N₂]⁺. Anal. Calcd for C₂₆H₂₁N₃O₃: C, 73.74; H, 5.00; N, 9.92. Found: C, 73.71; H, 5.02; N, 9.89.
1-(4-Acetylphenyl)-4-phenyl-5-(2-phenylethynyl)-1 H -1,2,3-triazole ( 4g): white solid; mp 138-140 °C. IR (KBr): 2215, 1680 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.69 (s, 3 H), 7.41-7.55 (m, 8 H), 8.08 (d, J = 8.7 Hz, 2 H), 8.18 (d, J = 9.0 Hz, 2 H), 8.28 (d, J = 7.8 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 26.7 (CH₃), 76.1 (C), 102.7 (C), 108.3 (C), 121.2 (C), 123.4 (CH), 126.6 (CH), 128.73 (CH), 128.77 (CH), 129.0 (CH), 129.5 (CH), 129.83 (C), 129.91 (CH), 131.5 (CH), 137.3 (C), 139.9 (C), 149.1 (C), 196.8 (C). EI-MS: m/z = 363 [M⁺], 335 [M - N₂]⁺. Anal. Calcd for C₂₄H₁₇N₃O: C, 79.32; H, 4.72; N, 11.56. Found: C, 79.30; H, 4.69; N, 11.51.
1-(4-Acetylphenyl)-4-pentyl-5-(hept-1-ynyl)-1 H -1,2,3-triazole ( 4h): liquid. IR (KBr): 2235, 1689 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 0.88-0.93 (m, 6 H), 1.31-1.39 (m, 8 H), 1.57-1.64 (m, 2 H), 1.76-1.81 (m, 2 H), 2.49 (t, J = 6.8 Hz, 2 H), 2.67 (s, 3 H), 2.79 (t, J = 7.5 Hz, 2 H), 7.98 (d, J = 8.7 Hz, 2 H), 8.11 (d, J = 8.1 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 13.88 (CH₃), 13.94 (CH₃), 19.6 (CH₂), 22.1 (CH₂), 22.3 (CH₂), 25.3 (CH₂), 26.6 (CH₃), 27.7 (CH₂), 28.5 (CH₂), 31.0 (CH₂), 31.3 (CH₂), 66.7 (C), 104.0 (C), 118.6 (C), 122.8 (CH), 129.3 (CH), 136.8 (C), 140.3 (C), 151.8 (C), 196.8 (C). EI-MS: m/z = 351 [M⁺], 323 [M - N₂]⁺. Anal. Calcd for C₂₂H₂₉N₃O: C, 75.18; H, 8.32; N, 11.96. Found: C, 75.11; H, 8.33; N, 11.93.
1-(2-Methoxyphenyl)-4-(4-methoxyphenyl)-5-[2-(4-methoxyphenyl)ethynyl]-1 H -1,2,3-triazole ( 4i): white solid; mp 96-98 °C. IR (KBr): 2217 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.81 (s, 3 H), 3.84 (s, 3 H), 3.87 (s, 3 H), 6.84 (d, J = 8.7 Hz, 2 H), 7.02 (d, J = 8.7 Hz, 2 H), 7.12 (t, J = 7.5 Hz, 2 H), 7.28 (d, J = 9.3 Hz, 2 H), 7.50 (d, J = 7.2 Hz, 2 H), 8.22 (d, J = 9.0 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 55.3 (CH₃), 55.3 (CH₃), 55.9 (CH₃), 75.1 (C), 101.0 (C), 112.2 (CH), 113.8 (C), 114.0 (CH), 114.2 (CH), 118.9 (C), 120.6 (CH), 123.2 (C), 125.4 (C), 127.6 (CH), 128.3 (CH), 131.5 (CH), 133.0 (CH), 146.8 (C), 154.3 (C), 159.8 (C), 160.3 (C). EI-MS: m/z = 411 [M⁺], 383 [M - N₂]⁺. Anal. Calcd for C₂₅H₂₁N₃O₃: C, 72.98; H, 5.14; N, 10.21. Found: C, 72.93; H, 5.10; N, 10.20.
1-(2-Methoxyphenyl)-4-phenyl-5-(2-phenylethynyl)-1 H -1,2,3-triazole ( 4j): white solid; mp 84-86 °C. IR (KBr): 2219 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.83 (s, 3 H), 7.10-7.52 (m, 12 H), 8.30 (d, J = 8.4 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 55.8 (CH₃), 76.1 (C), 101.0 (C), 112.1 (CH), 119.4 (C), 120.6 (CH), 121.6 (C), 125.1 (C), 125.8 (CH), 126.3 (CH), 128.2 (CH), 128.5 (CH), 128.6 (CH), 129.3 (CH), 130.3 (C), 131.3 (CH), 131.7 (CH), 147.1 (C), 154.2 (C). EI-MS: m/z = 351 [M⁺], 323 [M - N₂]⁺. Anal. Calcd for C₂₃H₁₇N₃O: C, 78.61; H, 4.88; N, 11.96. Found: C, 78.55; H, 4.91; N, 11.94.

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18

Crystal data: C₂₂H₁₅N₃, MW = 321.37, T = 294(2) K, λ = 0.71073 Å, monoclinic, space group P2₁/c, a = 7.6038(2) Å, b = 18.6814(6) Å, c = 12.1815(4) Å, α = 90.00°, β = 91.356 (2)°, γ = 90.00°, V = 1729.89(9) ų, Z = 4, D = 1.234 g/cm³, µ = 0.074 mm^-1, F(000) = 672.0. Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC-626008.