Metal-Free Chemoselective ortho-C(sp²)–F Bond Hydroxylation and N-Trifluoroacylation of Fluoroarylamines for Domino Synthesis of 2-(N-Trifluoroacyl)aminophenols

Abstract

A novel chemoselective reaction for the formation of C–O bonds by C(sp²)–F bond cleavage and concomitant N-trifluoroacylation of fluoroanilines using trifluoroacetic acid and Oxone^® is presented. This domino reaction gives o-hydroxy-N-trifluoroacetanilides in good yields under metal-free conditions in a single step. Selective ortho-directed monohydroxylation and N-trifluoroacylation of 2- and 6-fluoro- or 2,6-difluoro-substituted anilines takes place in this transformation.

Key words

C–F bonds - chemoselective reactions - C–O bonds - fluoroarylamine - hydroxylation

• References and Notes

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• 10 Synthesis of 2-Hydroxy-N-trifluoroacetamides; General Procedure: A Schlenk tube was charged with Oxone (0.398 g, 0.648 mmol) and trifloroacetic acid (0.099 mL, 1.296 mmol) in anhydrous dioxane (2 mL) under argon. To this mixture was added 2-fluoroaniline (0.06 g, 0.54 mmol), and the reaction mixture was heated to 90 °C under argon until starting material was consumed. As the reaction progressed, the color turned from light red to dark red. The mixture was then cooled to room temperature and washed with a saturated aqueous sodium bicarbonate. The mixture was extracted with EtOAc (2 × 20 mL) and the combined organic layers were dried over Na₂SO₄. After filtering and removal of the solvent under reduced pressure in vacuo, the residue was purified by silica gel (100–200 mesh) column chromatography (hexane–EtOAc, 9:1), to afford a pale-brown solid (65%) of 2-hydroxy-N-trifluoroacetanilides from 2-fluoroaniline (2a). 2-Hydroxy-N-trifluoroacetanilides from 2-Fluoroaniline (2a): Pale brown solid; mp 155–156 °C. IR (CHCl₃): 3389, 3248, 2923, 2851, 1690, 1597, 1562, 1465, 1194, 1159, 1101, 1041, 851, 749 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.51 (br s, 1 H), 9.94 (br s, 1 H), 7.31 (dd, J = 7.8, 1.4 Hz, 1 H), 7.16–7.12 (m, 1 H), 6.94 (d, J = 7.1 Hz, 1 H), 6.85–6.81 (m, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 154.9 (q, J = 36 Hz), 151.2, 127.9, 126.3, 122.2, 118.9, 115.9 (q, J = 287 Hz), 116.0. ¹⁹F NMR (376.50 MHz, CD₃OD): δ = –77.16 (s, 3 F). HRMS (ESI): m/z [M – H⁺]^– calcd for C₈H₅F₃NO₂: 204.0275; found: 204.0273. N-(3,4-Difluoro-2-hydroxyphenyl)-2,2,2-trifluoroacetamide (2b): Brownish semi-solid. ¹H NMR (400 MHz, acetone-d ₆): δ = 7.56–7.48 (m, 1 H), 6.89 (ddd, J = 10.0, 9.3, 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CD₃OD): δ = 152.7, 152.3 (d, J = 24 Hz), 143.2, 133.8, 120.9, 120.2, 117.3 (d, J = 256 Hz), 107.3 (d, J = 18.7 Hz). ¹⁹F NMR (376 MHz, CD₃OD): δ = –77.03 (s, 3 F), –141.09 (ddd, J = 20.3, 10.1, 5.4 Hz, 1 F), –160.66 to –164.19 (m, 1 F). GC-MS: m/z = 241.2 [M]⁺. N-(5-Chloro-2-hydroxyphenyl)-2,2,2-trifluoroacetamide (2d): Brownish solid; mp 190–191 °C. IR (CHCl₃): 3391, 2922, 2852, 1688, 1597, 1158, 1047, 871 cm^–1. ¹H NMR (400 MHz, acetone-d ₆): δ = 9.97 (s, 1 H), 9.45 (s, 1 H), 7.98 (d, J = 2.4 Hz, 1 H), 7.14 (dd, J = 8.7, 2.5 Hz, 1 H), 7.03 (d, J = 8.7 Hz, 1 H). ¹³C NMR (101 MHz, acetone-d ₆): δ = 155.6 (d, J = 37.6 Hz), 148.2, 127.2, 125.6, 124.4, 123.1, 117.5, 116.8 (q, J = 286 Hz). ¹⁹F NMR (376 MHz, acetone-d ₆): δ = 101.19 (s). GC-MS: m/z = 239.2 [M]⁺. N-(4-Bromo-2,3-difluoro-6-hydroxyphenyl)-2,2,2-trifluoroacetamide (2k): Pale brown solid; 187–188 °C. IR (CHCl₃): 3391, 2924, 1690, 1594, 1429, 1255, 1122, 1020, 868 cm^–1. ¹H NMR (400 MHz, acetone-d ₆): δ = 7.92 (d, J = 10.0 Hz, 1 H), 7.25 (d, J = 6.4 Hz, 1 H), 3.04 (s, 1 H), 2.98 (s, 2 H). ¹³C NMR (126 MHz, CDCl₃): δ = 154.1, 151.7, 146.0, 124.9, 119.8, 116.7 (q, J = 285 Hz), 111.1 (d, J = 35 Hz), 105.1 (d, J = 27.5 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = –75.68 (s), –119.92 (d, J = 6.8 Hz). HRMS (ESI): m/z [M – H⁺]^– calcd for C₈H₃BrF₄NO₂: 299.9285; found: 299.9284. 2,2,2-Trifluoro-N-(5-fluoro-2-hydroxyphenyl)acetamide (2o): Light-brown solid; mp 192–195 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.94 (s, 1 H), 8.80 (s, 1 H), 7.99 (dd, J = 9.4, 2.0 Hz, 1 H), 6.91 (dd, J = 8.4, 5.0 Hz, 1 H), 6.76 (t, J = 7.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃ + acetone-d ₆): δ = 157.4, 154.5 (dd, J = 72.0, 34.5 Hz), 142.3, 124.7 (d, J = 11.5 Hz), 115.7 (d, J = 286 Hz), 115.5, 112.1 (d, J = 23.3 Hz), 108.1 (d, J = 29.3 Hz). ¹⁹F NMR (376 MHz, CD₃OD): δ = –77.23 (s), –122.99 to –128.86 (m). GC-MS: m/z = 223.2 [M]⁺. 2,2,2-Trifluoro-N-(2-hydroxy-5-methoxyphenyl)acetamide (2q): Brown solid; mp 168–169 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.45 (s, 1 H), 7.68 (d, J = 2.2 Hz, 1 H), 6.84 (d, J = 8.7 Hz, 1 H), 6.68 (d, J = 2.6 Hz, 1 H), 5.53 (s, 1 H), 3.78 (s, 3 H). ¹⁹F NMR (376 MHz, CDCl₃): δ = –75.61. ¹³C NMR (101 MHz, CD₃OD): δ = 154.2, 143.9, 124.9, 118.8, 117.0, 116.0, 113.5, 110.0, 56.2. ESI-MS: m/z = 234 [M – H]⁺. 2,2,2-Trifluoro-N-(2-hydroxy-6-methoxyphenyl)acetamide (2r): Brown solid; mp 221–222 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.48 (s, 1 H), 7.42 (d, J = 7.8 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 6.99 (dd, J = 21.3, 7.8 Hz, 1 H), 6.17 (s, 1 H), 3.91 (s, 3 H). ¹⁹F NMR (376.50 MHz, CDCl₃): δ = –75.41 (s, 3 F). ¹³C NMR (100 MHz, CDCl₃): δ = 151.4, 145.6, 126.7, 125.8, 121.2, 120.8, 111.1, 96.4, 55.7. MS (ESI): m/z = 234 [M – H]⁺. N-(2-Chloro-6-hydroxyphenyl)-2,2,2-trifluoroacetamide (2s): Reddish brown solid; mp 225–226 °C. IR (CHCl₃): 3388, 3220, 2920, 2853, 1687, 1565, 1419, 1199, 1154, 1018, 850 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.21 (s, 1 H), 8.09 (d, J = 8.9 Hz, 1 H), 7.52 (s, 1 H), 6.96 (s, 1 H), 6.80 (dd, J = 9.0, 2.1 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 154.0, 130.9, 128.8, 125.2, 125.1, 123.4, 116.4, 114.9. ¹⁹F NMR (376 MHz, CDCl₃): δ = –75.74. HRMS (ESI): m/z [M – H⁺]^– calcd for C₈H₄ClF₃NO₂: 237.9893; found: 237.9883. N-(2-Bromo-4-fluoro-6-hydroxyphenyl)-2,2,2-trifluoroacetamide (2t): Reddish brown solid; mp 195–196 °C. IR (CHCl₃): 3293, 2923, 2852, 1730, 1432, 1152, 1118, 857 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.32 (s, 1 H), 7.81 (s, 1 H), 7.02 (dd, J = 7.3, 2.7 Hz, 1 H), 6.82 (dd, J = 9.5, 2.6 Hz, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 163.1, 161.1, 156.3 (d, J = 38.6 Hz), 152.0 (d, J = 13.3 Hz), 117.9 (d, J = 12.7 Hz), 115.5 (q, J = 285 Hz), 112.86 (d, J = 26.4 Hz), 107.62 (d, J = 24.5 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = –74.54 (s, 3 F), –110.09 (dd, J = 9.3, 7.4 Hz, 1 F). GC-MS: m/z = 301.2 [M]⁺, 303.2 [M⁺ + 2] (1:1 ratio). 2,2,2-Trifluoro-N-(2-hydroxy-6-iodophenyl)acetamide (2u): Light-brown solid; mp 232–233 °C. ¹H NMR (400 MHz, CD₃OD): δ = 7.27 (dd, J = 7.4, 1.6 Hz, 1 H), 6.89–6.76 (m, 2 H). ¹³C NMR (125 MHz, CD₃OD + acetone-d ₆): δ = 157.5 (q, J = 36.2 Hz), 155.5, 132.0, 130.9, 125.9, 118.9, 117.5, 100.9. ¹⁹F NMR (376 MHz, CD₃OD): δ = –76.60 (s). HRMS (ESI): m/z [M – H⁺]^– calcd for C₈H₄F₃INO₂: 329.9245; found: 329.9239. N-(2-Bromo-6-hydroxyphenyl)-2,2,2-trifluoroacetamide (2v): Light-brown solid; mp 315–316 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.43 (s, 1 H), 7.68 (d, J = 6.0 Hz, 1 H), 7.38 (d, J = 40.4 Hz, 1 H), 7.20–7.01 (m, 1 H), 6.81 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 156.4 (q, J = 38 Hz), 151.1, 134.1, 130.0, 128.2, 125.6, 119.8 (q, J = 277 Hz), 119.5. ¹⁹F NMR (376 MHz, CDCl₃): δ = –75.66 (s). HRMS (ESI): m/z [M – H⁺]^– calcd for C₈H₄BrF₃NO₂: 283.9365; found: 283.9534. 2,2,2-Trifluoro-N-(2-fluoro-6-hydroxyphenyl)acetamide (2w): Light-brown solid; mp 155–156 °C. IR (CHCl₃): 3436, 2918, 1619, 1474, 1383, 1200, 1158, 1021, 785 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.27 (s, 1 H), 7.20 (dd, J = 14.9, 7.6 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H), 6.77 (t, J = 9.1 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 156.4 (q, J = 39 Hz), 153.9, 150.6, 128.9, 115.6 (q, J = 285 Hz), 116.0, 112.1, 112.0, 107.3. ¹⁹F NMR (376 MHz, CDCl₃): δ = –74.51 (s, 3 F), –125.35 (d, J = 7.9 Hz, 1 F). HRMS (ESI): m/z [M – H⁺]^– calcd for C₈H₄F₄NO₂: 222.0187; found: 272.0178. N-(2,4-Difluoro-6-hydroxyphenyl)-2,2,2-trifluoroacetamide (2x): Light-brown solid; mp 195–196 °C. IR (CHCl₃): 436, 2923, 2852, 1619, 1452, 1384, 1240, 1157, 1054, 1021, 840 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.20 (s, 1 H), 6.62–6.49 (m, 2 H). ¹³C NMR (126 MHz, CDCl₃): δ = 163.1 (d, J = 15.7 Hz), 161.4–160.2 (m), 157.2–154.4 (m), 152.1 (dd, J = 14.6, 4.1 Hz), 115.5 (q, J = 287.1 Hz), 102.7 (dd, J = 25.0, 3.3 Hz), 96.6 (dd, J = 27.5, 24.3 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = –74.5 (s), –109.4 (ddd, J = 710.6, 163.3, 9.1 Hz), –120.6 (d, J = 6.6 Hz). HRMS (ESI): m/z [M – H⁺]^– calcd for C₈H₃F₅NO₂: 240.0065; found: 240.0084.