A New General Synthesis of N-Hydroxyindoles

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.

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

References and Notes

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For reviews on N-hydroxyindoles, see:

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14

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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17

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.

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