Selectfluor-Promoted Direct Fluorination at the 4- or 5-Position of Imidazole Derivatives

Abstract

Facile fluorination of imidazole derivatives at the 4- or 5-position has been achieved successfully by Selectfluor. This is the first report of a technique for preparing fluoroimidazoles in one step.

Key words

Selectfluor - fluorination - imidazole - regioselectivity - heterocycles

• References and Notes

• 1 These authors contributed equally to the manuscript.
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• 13 General Procedure for the Fluorination at the 4- or 5-Position of Imidazole DerivativesTo a stirred solution of imidazole derivative (0.5 mmol) in anhyd MeCN (5 mL) was added Selectfluor (1.5 equiv, 0.75 mmol). After complete conversion of the starting material monitored by TLC, H₂O (15 mL) was added, and then, the mixture was extracted using CH₂Cl₂ (10 mL). The organic phase was dried over Na₂SO₄. After the solvent was removed in vacuo, the crude product was purified by flash chromatography (10% of EtOAc in hexanes) to yield the fluoroimidazoles.Compound 2aWhite solid. ¹H NMR (300 MHz, CDCl₃): δ = 9.91 (s, 1 H), 4.37 (q, 2 H, J ₁ = 7.2 Hz), 3.93 (d, 3 H, J = 0.9 Hz), 1.36 (t, 3 H, J = 7.2 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 159.8 (s), 157.1 (q, J = 38.1 Hz), 142.48 (d, J = 279.5 Hz), 127.5 (d, J = 13.0 Hz), 117.5 (q, J = 286.5 Hz), 114.6 (d, J = 6.75 Hz), 63.7 (s), 33.6 (s), 15.9 (s). ¹⁹F NMR (282 MHz, CDCl₃): δ = –75.3 (s, 3 F), –137.5 (s, 1 F). ESI-MS: m/z calcd for C₉H₉F₄N₃O₃: 283.06; found: 284.27 [M + 1].Compound 2bWhite solid. ¹H NMR (300 MHz, CDCl₃): δ = 8.57 (br, 1 H), 4.36 (q, 2 H, J ₁ = 6.9 Hz), 3.97 (s, 3 H), 2.14 (s, 3 H) 1.37 (t, 3 H, J = 7.2 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 170.6 (s), 160.0 (s), 142.6 (d, J = 278.3 Hz), 126.6 (d, J = 5.9 Hz), 117.3 (d, J = 6.1 Hz), 63.4 (s), 33.5 (s), 24.7 (s), 16.0 (s). ¹⁹F NMR (282 MHz, CDCl₃): δ = –139.2 (s, 1 F). ESI-MS: m/z calcd for C₉H₁₂FN₃O₃: 229.09; found: 230.14 [M + 1].Compound 2cWhite solid. ¹H NMR (300 MHz, CDCl₃): δ = 7.97–7.78 (m, 4 H), 4.31 (q, 2 H, J = 7.2Hz), 3.84 (d, 3 H, J ₁ = 0.9 Hz), 1.21 (t, 3 H, J = 7.5 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 168.3 (s), 160.2 (s), 146.4 (d, J = 280.3 Hz), 136.5 (s), 133.6 (s), 125.9 (s), 101.8 (s), 63.7 (s), 33.8 (s), 16.1 (s). ¹⁹F NMR (282 MHz, CDCl₃): δ = –141.4 (s, 1 F). ESI-MS: m/z calcd for C₁₅H₁₂FN₃O₄: 317.08; found: 318.26 [M + 1].Compound 2dWhite solid. ¹H NMR (300 MHz, CDCl₃): δ = 6.74 (d, 1 H, J = 7.5 Hz), 4.40 (q, 2 H, J ₁ = 6.9 Hz), 3.87 (d, 3 H, J = 0.9 Hz), 1.41 (t, 3 H, J = 6.9 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 158.3 (s), 149.4 (d, J = 276.5 Hz), 126.6 (d, J = 7.7 Hz), 117.6 (d, J = 8.8 Hz), 61.1 (s), 30.7 (s), 13.8 (s). ¹⁹F NMR (282 MHz, CDCl₃): δ = –144.9 (s, 1 F). ESI-MS: m/z calcd for C₇H₉FN₂O₂: 172.06; found: 172.94 [M + 1].Compound 4aWhite solid. ¹H NMR (300 MHz, CDCl₃): δ = 9.06 (s, 1 H), 4.40 (q, 2 H, J ₁ = 6.9 Hz), 3.82 (s, 3 H), 1.39 (t, 3 H, J = 6.9 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 159.9 (s), 159.2 (q, J = 37.8 Hz), 150.7 (d, J = 239.9 Hz), 129.5 (d, J = 13.8 Hz), 117.2 (q, J = 285.8 Hz), 109.0 (d, J = 33.8 Hz), 64.0 (s), 34.5 (s), 15.9 (s). ¹⁹F NMR (282 MHz, CDCl₃): δ = –75.0 (s, 3 F), –132.2 (s, 1 F). ESI-MS: m/z calcd for C₉H₉F₄N₃O₃: 283.06; found: 284.21 [M + 1].Compound 4bWhite solid. ¹H NMR (300 MHz, CDCl₃): δ = 8.32 (s, 1 H), 4.09 (q, 2 H, J ₁ = 6.9 Hz), 3.60 (s, 3 H), 1.87 (s, 3 H) 1.10 (t, 3 H, J = 7.2 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 168.8 (s), 158.2 (s), 140.8 (d, J = 276.5 Hz), 124.7 (d, J = 5.9 Hz), 115.4 (d, J = 5.9 Hz), 61.5 (s), 31.7 (s), 22.8 (s), 14.2 (s). ¹⁹F NMR (282 MHz, CDCl₃): δ = –131.2 (s, 1 F). ESI-MS: m/z calcd for C₉H₁₂FN₃O₃: 229.09; found: 229.95 [M + 1].Compound 4cWhite solid. ¹H NMR (300 MHz, CDCl₃): δ = 8.02–7.86 (m, 4 H), 4.43 (q, 2 H, J = 7.2 Hz), 3.83 (s, 3 H), 1.43 (t, 3 H, J = 6.9 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 167.6 (s), 167.2 (s), 160.2 (s), 152.4 (d, J = 243.8 Hz), 137.1 (s), 133.3 (s), 126.4 (s), 101.8 (s), 63.8 (s), 34.7 (s), 16.0 (s). ¹⁹F NMR (282 MHz, CDCl₃): δ = –129.5 (s, 1 F). ESI-MS: m/z calcd for C₁₅H₁₂FN₃O₄: 317.08; found: 318.11 [M + 1].Compound 5aWhite solid. ¹H NMR (300 MHz, DMSO-d ₆): δ = 10.65 (s, 1 H), 8.65 (s, 1 H), 4.30 (q, 2 H, J = 6.9 Hz), 4.01 (s, 3 H), 3.84 (s, 3 H), 1.30 (t, 3 H, J = 6.9 Hz). ¹³C NMR (75 MHz, DMSO): δ = 160.3 (s), 159.4 (s), 146.8 (s), 143.8 (d, J = 276.8 Hz), 139.0 (s), 129.2 (s), 127.3 (s), 115.9 (d, J = 6.0 Hz), 63.2 (s), 38.8 (s), 34.0 (s), 16.3 (s). ¹⁹F NMR (282 MHz, DMSO): δ = –141.6 (s, 1 F). ESI-MS: m/z calcd for C₁₂H₁₃FN₆O₅: 340.09; found: 341.15 [M + 1].Compound 6aWhite solid. ¹H NMR (300 MHz, DMSO-d ₆): δ = 10.60 (s, 1 H), 10.20 (s, 1 H), 8.66 (s, 1 H), 4.29 (q, 2 H, J = 7.2 Hz), 4.02 (s, 3 H), 3.88 (s, 3 H), 3.83 (s, 3 H), 1.29 (t, 3 H, J = 6.9 Hz). ¹³C NMR (75 MHz, DMSO): δ = 160.3 (s), 159.7 (s), 159.6 (s), 146.8 (s), 144.4 (d, J = 274.5 Hz), 144.0 (d, J = 275.3 Hz), 139.0 (s), 129.3 (s), 127.1 (d, J = 7.6 Hz), 116.2 (d, J = 6.0 Hz), 114.6 (d, J = 6.0 Hz), 101.8 (s), 63.1 (s), 38.8 (s), 33.9 (s), 33.7 (s), 16.3 (s). ¹⁹F NMR (282 MHz, DMSO): δ = –137.1 (s, 1 F), –139.0 (s, 1 F). ESI-MS: m/z calcd for C₁₇H₁₇F₂N₉O₆: 481.13; found: 482.27 [M + 1].