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Synlett 2015; 26(09): 1258-1262
DOI: 10.1055/s-0034-1379905
DOI: 10.1055/s-0034-1379905
letter
Metal-Free Chemoselective ortho-C(sp2)–F Bond Hydroxylation and N-Trifluoroacylation of Fluoroarylamines for Domino Synthesis of 2-(N-Trifluoroacyl)aminophenols
Further Information
Publication History
Received: 31 October 2014
Accepted after revision: 25 February 2015
Publication Date:
24 March 2015 (online)
![](https://www.thieme-connect.de/media/synlett/201509/lookinside/thumbnails/st-2014-d0907-l_10-1055_s-0034-1379905-1.jpg)
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.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0034-1379905.
- Supporting Information
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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.
For recent reviews on metal-mediated aliphatic C–F bond activation, see: