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Synlett 2007(19): 2999-3002  
DOI: 10.1055/s-2007-990970
LETTER
© Georg Thieme Verlag Stuttgart · New York

A New General Synthesis of N-Hydroxyindoles

Michel Belley*, Daniel Beaudoin, Gabriel St-Pierre
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 30 August 2007
Publication Date:
08 November 2007 (online)

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Abstract

Catalytic hydrogenation of 2-nitrobenzyl aldehydes, ketones and amides, using Pd/C and (Ph3P)4Pd, affords N-hydroxyindoles in good to excellent overall yields.

Key words

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

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Most of the substrates used for the reductive cyclization were prepared by aromatic electrophilic substitution, either with NaH in DMF15 (1a-c, 4 and 9c) or NaOH/TBAHS/toluene18 (9a,b). Compounds 11a-c, 14 and 17 were commercially available and 20 was prepared via a Pd-catalyzed arylation of a ketone enolate.9

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Typical Experimental Procedures:
2- tert -Butyl-1-hydroxy-6-(trifluoromethyl)-1 H -indole-3-carbonitrile (10b): To a solution of 4,4-dimethyl-2-[2-nitro-4-(trifluoromethyl)phenyl]-3-oxopentanenitrile (9b; 236 mg, 0.75 mmol) in a mixture of EtOAc and 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 of EtOAc-hexane (0-25%) as eluent afforded 10b (204 mg, 96% yield) as a light beige powder; mp 144 °C (dec.). 1H NMR (400 MHz, acetone-d 6): δ = 11.07 (s, 1 H), 7.84 (s, 1 H), 7.81 (d, J = 8.3 Hz, 1 H), 7.58 (dd, J = 1.3, 8.3 Hz, 1 H), 1.69 (s, 9 H). 13C NMR (100 MHz, acetone-d 6): δ = 153.78, 133.02, 126.60, 125.14 (q, J C-F = 32 Hz), 124.91 (q, J C-F = 269 Hz), 119.19, 118.34 (q, J C-F = 4 Hz), 115.47, 106.68 (q, J C-F = 4 Hz), 78.60, 34.48, 28.51. IR (KBr): 3127, 2977, 2229 (CN), 1365, 1324, 1272, 1119 cm-1. MS (ESI, +ve): m/z = 283.0 [M + 1]. Anal. Calcd for C14H13F3N2O: C, 59.57; H, 4.64; N, 9.92. Found: C, 59.47; H, 4.68; N, 9.55.
Ethyl 1,2-Dimethoxy-6-(trifluoromethyl)-1 H -indole-3-carboxylate (6): The reductive cyclization of ethyl 3-amino-2-[2-nitro-4-(trifluoromethyl)phenyl]-3-oxopropanoate (4; 270 mg, 0.75 mmol) was performed as described above. The crude material obtained after filtration was redissolved into THF and treated with an ethereal solution of CH2N2 at r.t. for 45 min. The excess CH2N2 was quenched with AcOH, the solvents were evaporated and the residue was purified by flash chromatography on silica gel using a gradient of EtOAc-hexane (0-10%) as eluent to give dimethoxyindole 6 (191 mg, 80%) as a light beige powder; mp 76 °C. 1H NMR (400 MHz, acetone-d 6): δ = 8.25 (d, J = 8.4 Hz, 1 H), 7.78 (s, 1 H), 7.52 (dd, J = 1.3, 8.4 Hz, 1 H), 4.40 (q, J = 7.1 Hz, 2 H), 4.38 (s, 3 H), 4.24 (s, 3 H), 1.43 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, acetone-d 6): δ = 162.69, 155.17, 126.75, 125.10 (q, J C-F = 269 Hz), 123.91 (q, J C-F = 32 Hz), 123.75, 121.65, 118.50 (q, J C-F = 4 Hz), 105.28 (q, J C-F = 4 Hz), 88.54, 66.29, 63.39, 59.53, 13.90. IR (KBr): 2987, 2949, 1703, 1555, 1459 cm-1. MS (ESI, +ve): m/z = 318.0 [M + 1], 289.1, 229.0. Anal. Calcd for C14H14F3NO4: C, 53.00; H, 4.45; N, 4.41. Found: C, 53.20; H, 4.13; N, 4.30.