Copper-Catalyzed Direct C-5 Fluorination of 8-Aminoquinolines by Remote C–H Activation

Abstract

A convenient method was developed for direct regioselective fluorination of 8-aminoquinolines at the C-5 position by copper-catalyzed remote C–H activation using Selectfluor as the electrophile fluorinating reagent. With this method, diverse fluorinated quinoline derivatives were facilely obtained under mild conditions with moderate yields.

Key words

fluorination - copper-catalyzed - 8-aminoquinolines - Selectfluor - remote C–H activation

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• 22 Fluorinated Product 2a–t, General Procedure 8-Aminoquinoline derivatives 1 (0.1 mmol, 1.0 equiv), Cu(OAc)₂ (0.02 mmol, 0.2 equiv), Selectfluor (0.15 mmol, 1.5 equiv), KH₂PO₄ (0.2 mmol, 2.0 equiv), and Na₂SO₄ (50 mg) were weighed into an oven-dried Schlenk tube, and MeOH (1 mL) was added. The reaction vessel was capped and vacuum-flushed with N₂ three times. The reaction was stirred under N₂ atmosphere at 80 °C, and the progress of the fluorination was monitored by TLC. Upon complete consumption of 1, the reaction was cooled to room temperature. Volatile solvent and reagents were removed by rotary evaporation, and the residue was purified by silica gel flash chromatography using PE/EtOAc (100:1 to 20:1) to afford fluorinated product 2. N-(5-Fluoroquinolin-8-yl)-4-methylbenzamide (2a) 45% yield, white solid. ¹H NMR (600 MHz, chloroform-d): δ = 10.52 (s, 1 H), 8.94–8.85 (m, 2 H), 8.47 (dd, J = 8.4, 1.7 Hz, 1 H), 8.01–7.94 (m, 2 H), 7.56 (dd, J = 8.4, 4.2 Hz, 1 H), 7.40–7.33 (m, 2 H), 7.30–7.27 (m, 1 H), 2.46 (s, 3 H). ¹³C NMR (151 MHz, chloroform-d): δ = 165.48 , 153.87 (d, J = 250.7 Hz), 149.22, 142.55, 139.09 (d, J = 3.0 Hz), 132.28, 131.35 (d, J = 3.0 Hz), 129.98 (d, J = 3.0 Hz), 129.62, 127.37, 121.87 (d, J = 3.0 Hz), 119.00 (d, J = 3.0 Hz), 116.09 (d, J = 7.6 Hz), 110.72 (d, J = 19.6 Hz), 21.71. ¹⁹F NMR (565 MHz, chloroform-d): δ = –129.22. HRMS (ESI): m/z calcd for C₁₇H₁₄ON₂F [M + H]⁺: 281.1090; found: 281.1086. 4-Fluoro-N-(5-fluoroquinolin-8-yl)benzamide (2g) 38% yield, white solid. ¹H NMR (600 MHz, chloroform-d): δ = 10.50 (s, 1 H), 8.91 (dd, J = 4.2, 1.6 Hz, 1 H), 8.87 (dd, J = 8.6, 5.3 Hz, 1 H), 8.48 (dd, J = 8.4, 1.7 Hz, 1 H), 8.12–8.06 (m, 2 H), 7.57 (dd, J = 8.4, 4.2 Hz, 1 H), 7.30–7.23 (m, 3 H). ¹³C NMR (151 MHz, chloroform-d): δ = 165.83, 164.23, 164.16, 153.89 (d, J = 252.2 Hz), 149.16, 138.92 (d, J = 3.0 Hz), 131.16 (d, J = 3.0 Hz), 130.96 (d, J = 4.5 Hz), 129.95 (d, J = 4.5 Hz), 129.64 (d, J = 9.1 Hz), 121.82 (d, J = 1.5 Hz), 118.90 (d, J = 18.1 Hz), 116.07 (d, J = 9.1 Hz), 115.97 (d, J = 22.6 Hz), 110.59 (d, J = 19.6 Hz). ¹⁹F NMR (565 MHz, chloroform-d): δ = –107.51, –128.74. HRMS (ESI): m/z calcd for C₁₆H₁₁ON₂F₂ [M + H]⁺: 285.0839; found: 285.0833. N-(5-Fluoroquinolin-8-yl)-2,6-dimethoxybenzamide (2i) 34% yield, white solid. ¹H NMR (600 MHz, chloroform-d): δ = 10.10 (s, 1 H), 8.99 (dd, J = 7.6, 1.3 Hz, 1 H), 8.78 (dd, J = 4.2, 1.7 Hz, 1 H), 8.18 (dd, J = 8.2, 1.7 Hz, 1 H), 7.61 (t, J = 7.9 Hz, 1 H), 7.56 (dd, J = 8.3, 1.4 Hz, 1 H), 7.45 (dd, J = 8.2, 4.2 Hz, 1 H), 7.14 (dd, J = 11.2, 9.1 Hz, 1 H), 6.64 (dd, J = 9.2, 3.3 Hz, 1 H), 4.01 (d, J = 1.9 Hz, 3 H), 3.83 (s, 3 H). ¹³C NMR (151 MHz, chloroform-d): δ = 162.92 (d, J = 3.0 Hz), 153.18 (d, J = 3.0 Hz), 150.80 (d, J = 241.6 Hz), 148.35, 145.77 (d, J = 12.1 Hz) 138.60, 136.44, 134.76, 128.10, 127.60, 121.97, 121.73, 117.79 (d, J = 21.1 Hz), 117.01, 106.10 (d, J = 7.6 Hz), 62.32 (d, J = 4.5 Hz), 56.49. ¹⁹F NMR (565 MHz, chloroform-d): δ = –139.30, –139.33. HRMS (ESI): m/z calcd for C₁₈H₁₆O₃N₂F [M + H]⁺: 327.1145; found: 327.1140. 2,3,4,5,6-Pentafluoro-N-(5-fluoroquinolin-8-yl)benzamide (2j) 23% yield, white solid. ¹H NMR (600 MHz, chloroform-d): δ = 10.19 (s, 1 H), 8.87 (ddd, J = 4.7, 3.0, 1.7 Hz, 1 H), 8.83 (ddd, J = 8.9, 5.3, 3.8 Hz, 1 H), 8.48 (ddd, J = 8.4, 4.2, 1.7 Hz, 1 H), 7.58 (ddd, J = 8.5, 4.2, 2.9 Hz, 1 H), 7.32–7.27 (m, 1 H). ¹³C NMR (151 MHz, chloroform-d): δ = 155.23, 154.61 (d, J = 253.7 Hz), 149.49, 145.35 (m), 143.66 (m), 141.81 (m), 138.65 (m), 136.98 (m), 130.07 (m), 122.08, 118.90 (dd, J = 18.4, 3.6 Hz), 116.99 (d, J = 9.1 Hz), 116.94 (m), 110.51(dd, J = 19.6, 2.8 Hz). ¹⁹F NMR (565 MHz, chloroform-d): δ = –126.79, –139.92 (d, J = 19.0 Hz), –149.94 (d, J = 20.9 Hz), –149.99, –159.64 (t, J = 19.2 Hz). HRMS (ESI): m/z calcd for C₁₆H₇ON₂F₆ [M + H]⁺: 357.0463; found: 357.0457.