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Synlett 2007(19): 2991-2994  
DOI: 10.1055/s-2007-990969
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis and Reactivity of N-Hydroxy-2-Amino-3-Arylindoles

Michel Belley*, Daniel Beaudoin, Petar Duspara, Effiette Sauer, Gabriel St-Pierre, Laird A. Trimble
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 Trans-Canada Highway, Kirkland, QC, H9H 3L1, Canada
e-Mail: belley@merck.com;
Further Information

Publication History

Received 24 July 2007
Publication Date:
08 November 2007 (online)

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Abstract

Catalytic hydrogenation of 2-nitrophenylacetonitriles bearing an aromatic substituent α to the nitrile group, using Pd/C and (Ph3P)4Pd, affords unstable N-hydroxy-2-amino-3-arylindoles which, after autoxidation, yields 2-amino-3-aryl-3H-indol-3-ol 1-oxides.

Key words

N-hydroxyindoles - N-methoxyindoles - reductive cyclization - tetrakis(triphenylphosphine)palladium - catalytic hydrogenation

    References and Notes

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10

3-(4-Ethylphenyl)-6-(trifluoromethyl)-1 H -indole (3): 1H NMR (400 MHz, acetone-d 6): δ = 8.10 (d, J = 10.5 Hz, 1 H), 7.89 (s, 1 H), 7.83 (s, 1 H), 7.66 (d, J = 11.0 Hz, 2 H), 7.42 (d, J = 10.5 Hz, 1 H), 7.34 (d, J = 11.0 Hz, 2 H), 2.71 (q, J = 8.0 Hz, 2 H), 1.28 (t, J = 8.0 Hz, 3 H). IR (neat): 3393, 2972, 2923, 1549, 1511, 1127 cm-1. MS (APCI, -ve): m/z = 287.9 [M - 1].

11

[2-(Hydroxyamino)-4-(trifluoromethyl)phenyl](4-methoxyphenyl)acetonitrile (4): 1H NMR (500 MHz, acetone-d 6): δ = 8.12 (s, 1 H), 7.92 (s, 1 H), 7.67 (s, 1 H), 7.59 (d, J = 11.0 Hz, 1 H), 7.35 (m, 3 H), 7.00 (d, J = 9.0 Hz, 2 H), 6.68 (s, 1 H), 3.83 (s, 3 H). IR (neat): 2800-3500 (br), 2225 (CN) cm-1. MS (ESI, -ve): m/z = 381.1 [M + AcO-], 321.2 [M - 1], 303.1, 288.2.

16

Typical Experimental Procedures: 4-(2-Amino-6-fluoro-1-hydroxy-1 H -indol-3-yl)benzo-nitrile (2e): To a solution of 4-[cyano(4-fluoro-2-nitro-phenyl)methyl]benzonitrile (1e; 210 mg, 0.75 mmol) in a mixture of EtOAc-AcOH (4:1, 12 mL) were added 10% Pd/C (40 mg, 0.05 equiv) and (Ph3P)4Pd (13 mg, 0.015 equiv). This mixture was degassed and stirred under an atmosphere of hydrogen for 4 h. The solids were removed by a filtration through Celite and the solvents were evaporated. Flash chromatography of the residue on silica gel using a gradient from 5% to 40% EtOAc-hexane afforded 2e (162 mg, 81% yield) as a light orange powder; mp 146-147 °C (dec.). 1H NMR (400 MHz, acetone-d 6): δ = 10.21 (s, 1 H), 7.76 (m, 4 H), 7.57 (dd, J = 4.9, 8.6 Hz, 1 H), 7.02 (br s, 1 H), 6.82 (br s, 1 H), 5.66 (br s, 2 H). IR (KBr): 3348, 3210, 2923, 2226, 1670, 1631, 1601, 1510, 1493, 1479, 1466 cm-1. MS (ESI, -ve): m/z = 532.8 (2 × M - 1), 266.1 (M - 1), 248.1.
4-(2-Amino-6-fluoro-3-hydroxy-1-oxido-3 H -indol-3-yl)benzonitrile (6e): The N-hydroxyindole 2e (78.9 mg, 0.216 mmol) was dissolved in EtOAc (2.5 mL) and this solution was stirred for 3 d at r.t. under open air. The solid 6e (44.3 mg) was separated by filtration and the residue from the filtrate was purified by flash chromatography on silica gel eluting with 10% MeOH-CH2Cl2 to afford a second crop of 6e (18.3 mg, overall yield 75%) as a white solid; mp 188.5-189.5 °C (dec.). 1H NMR (400 MHz, MeOH-d 4): δ = 7.78 (d, J = 10.5 Hz, 2 H), 7.60 (d, J = 10.5 Hz, 2 H), 7.05-7.25 (m, 2 H), 6.91 (dd, J = 1.8, 11.0 Hz, 1 H), 4.61 (br s, 1 H). 13C NMR (100 MHz, DMSO-d 6): δ = 163.92 (d, J C-F = 243.3 Hz), 157.30, 148.30 (d, J C-F = 11.7 Hz), 146.24, 133.03 (2 × C), 130.72, 126.80 (2 × C), 124.24 (d, J C-F = 9.5 Hz), 119.05, 111.28, 111.02 (d, J C-F = 23.0 Hz), 99.34 (d, J C-F = 27.8 Hz), 77.65. IR (KBr): 3287, 2233, 1699, 1630, 1610, 1491, 1183 cm-1. MS (ESI, +ve): m/z = 283.8 [M + 1]. Anal. Calcd for C15H10N3FO2·0.4EtOAc: C, 62.60; H, 4.18; N, 13.19. Found: C, 62.24; H, 3.82; N, 12.80. HRMS: m/z [M + H] calcd for C15H11N3FO2: 284.0830; found: 284.0837.
4-(2-Amino-6-fluoro-1-methoxy-1 H -indol-3-yl)benzo-nitrile (5e): To a solution of the N-hydroxyindole 2e (78.9 mg, 0.216 mmol) in EtOAc (2.5 mL) was added an ethereal solution of CH2N2. This mixture was stirred at r.t. for about 30 min and the excess CH2N2 was quenched with AcOH. The solvents were evaporated and the residue was purified by flash chromatography on silica gel with 10% EtOAc-toluene to obtain 5e (73.3 mg, 87%) as a yellow solid; mp 136-137 °C (dec.). 1H NMR (400 MHz, acetone-d 6): δ = 7.70-7.90 (m, 4 H), 7.50-7.65 (m, 1 H), 7.12 (dd, J = 1.1, 9.5 Hz, 1 H), 6.88 (dd, J = 2.4, 9.5 Hz, 1 H), 5.82 (br s, 2 H), 4.15 (s, 3 H). 13C NMR (100 MHz, acetone-d 6): δ = 158.28 (d, J C-F = 232.8 Hz), 141.84, 140.76, 132.53 (2 × C), 130.19 (d, J C-F = 11.9 Hz), 127.15 (2 × C), 119.56, 119.10, 116.81 (d, J C-F = 9.2 Hz), 108.21 (d, J C-F = 23.3 Hz), 106.56, 94.50 (d, J C-F = 27.7 Hz), 88.32, 64.27. IR (KBr): 3457, 3353, 2222, 1620, 1599 cm-1. MS (ESI, +ve): m/z = 282.1 [M + 1]. Anal. Calcd for C16H12N3FO: C, 68.32; H, 4.30; N, 14.94. Found: C, 68.40; H, 4.08; N, 14.86.
6-Chloro-3-(4-chlorophenyl)-1,3-dihydroxy-1,3-dihydro-2 H -indol-2-one (7b): 2-Amino-6-chloro-3-(4-chlorophenyl)-3H-indol-3-ol 1-oxide (6b; 149 mg, 0.481 mmol) was diluted into MeOH-THF-H2O (3:1:2, 13.5 mL) to give a cloudy yellow mixture. Addition of 10 N NaOH (0.27 mL, 5.6 equiv) resulted in a clear red solution that was heated to reflux (65 °C) for 16 h. The reaction was then quenched with sat. NH4Cl, extracted with isopropyl acetate, dried over Na2SO4 and concentrated. Trituration of the residue in dichloromethane afforded 7b (92 mg, 62% yield) as a yellow solid; mp 162-163 °C (dec.). 1H NMR (500 MHz, DMSO-d 6): δ = 11.10 (s, 1 H), 7.43 (d, J = 8.5 Hz, 2 H), 7.30 (d, J = 8.5 Hz, 2 H), 7.19 (d, J = 8.0 Hz, 1 H), 7.12 (dd, J = 1.7, 8.0 Hz, 1 H), 7.07 (m, 2 H). 13C NMR (100 MHz, acetone-d 6): δ = 173.05, 144.95, 140.01, 135.91, 134.33, 129.19, 128.27, 126.68, 123.78, 108.93, 76.39, 14.60. IR: 3140, 1710, 1610 cm-1. MS (APCI, -ve): m/z = 310.1, 308.1 [M - 1], 272.1.
6-Chloro-3-(4-chlorophenyl)-2,1-benzisoxazole (8b): The oxindole 7b (50 mg, 0.161 mmol) was dissolved in MeOH-THF-H2O (3:1:2, 4.5 mL). Addition of 10 N NaOH (90 µL, 5.6 equiv) resulted in a clear yellow solution that was heated to 90 °C overnight in a sealed tube. The reaction was then quenched with sat. NH4Cl, extracted with isopropyl acetate, dried over Na2SO4 and concentrated. Purification by flash chromatography on silica gel eluting with 2% EtOAc-hexanes afforded 8b (21 mg, 50% yield) as a yellow solid; mp 152.0-153.5 °C. 1H NMR (500 MHz, acetone-d 6): δ = 8.17 (d, J = 7.8 Hz, 2 H), 8.12 (d, J = 9.1 Hz, 1 H), 7.75 (d, J = 1.8 Hz, 1 H), 7.72 (d, J = 7.8 Hz, 2 H), 7.17 (dd, J = 1.8, 9.1 Hz, 1 H). IR (KBr): 1640 cm-1. MS (ESI, +ve): m/z = 266.1, 264.1 [M + 1].
6-Chloro-3-(4-chlorophenyl)-3-hydroxy-1-methoxy-1,3-dihydro-2 H -indol-2-one (9): The oxindole 7b (39.9 mg, 0.129 mmol) was dissolved in THF (2 mL) and treated with an ethereal solution of diazomethane at r.t. for 2.5 h. The excess CH2N2 was quenched with AcOH, the solvents were evaporated and the residue was purified by flash chromatog-raphy on silica gel eluting with 10% EtOAc-toluene to obtain 9 (27.8 mg, 66% yield) as an oil. 1H NMR (500 MHz, acetone-d 6): δ = 7.46 (d, J = 8.6 Hz, 2 H), 7.41 (d, J = 8.6 Hz, 2 H), 7.30 (d, J = 7.0 Hz, 1 H), 7.20 (dd, J = 2.0, 7.0 Hz, 1 H), 7.18 (d, J = 2.0 Hz, 1 H), 6.06 (s, 1 H), 4.05 (s, 3 H). MS (ESI, -ve): m/z = 384.2, 382.1 [M + AcO-], 324.1, 322.1 [M - 1], 290.2 [M - MeOH - 1].