A New Method for the Synthesis of 3-Substituted Indoles

Abstract

Starting from readily accessible nitrones and electron-deficient acetylenes, a highly efficient and versatile synthetic protocol for 3-substituted indoles has been developed.

Key words

indoles - nitrones - electron-deficient acetylenes - nucleo­philic addition - 1,3-dipolar additions

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• 8 General Procedure A 1:1 mixture (1 mmol each) of nitrone and acetylene in MeCN (10 mL) was stirred under reflux for 4 h. After complete consumption of starting materials, solvent was evaporated off, and the residue was redissolved in CH₂Cl₂ (10 mL) in the same flask. Oxalic acid (1 mmol) adsorbed on silica gel (1 g) was added to the same pot, and the mixture was stirred at r.t. for 1 h. After completion of the reaction, the solvent was removed, and the products were isolated by column chromatography over silica gel using mixtures of hexane and EtOAc as eluents. In all reactions, fluorenone was formed as a byproduct in yields comparable to those cited for the indoles. Nitrones were prepared by recycling the fluorenone.

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• 10 Characterization Data for 5b and 5c (E)-1-{2′,5′-Diphenyl-2′H-spiro[fluorene-9,3′-isoxazole]-4′-yl}-3-phenylprop-2-en-1-one (5b) Yellow solid, yield 16%; mp 105 °C. IR (KBr): ν_max = 3058 (=CH stretch), 1649 (C=O stretch) cm^–1. ¹HNMR (400 MHz, CDCl₃): δ = 7.89–7.86 (m, 2 H), 7.67 (d, J = 7.6 Hz, 2 H), 7.64–7.60 (m, 1 H), 7.57–7.53 (m, 4 H), 7.36–7.32 (m, 2 H), 7.27–7.16 (m, 6 H), 6.99–6.91 (m, 4 H), 6.81–6.76 (m, 1 H), 6.61–6.58 (m, 2 H), 6.36 (d, J = 15.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 183.9, 163.1, 145.9, 144.9, 140.8, 140.7, 134.9,131.7, 130.2, 129.8, 129.4, 128.8, 128.6, 128.1, 128.0, 127.9, 127.0, 125.4, 124.7, 123.6, 120.1, 118.3, 117.0, 84.9. MS: m/z = 503 [M⁺]. Anal. Calcd for C₃₆H₂₅NO₂: C, 85.86; H, 5.00, N, 2.78. Found: C, 85.82; H, 4.98; N, 2.75. 1-{2′,5′-Diphenyl-2′H-spiro[fluorene-9,3′-isoxazole]-4′-yl}ethanone (5c) Yellow solid, yield 18%, mp 124 °C. IR (KBr): ν_max = 3058 (=CH stretch), 1649 (C=O stretch) cm^–1. ¹HNMR (400 MHz, CDCl₃): δ = 7.84–7.81 (m, 2 H), 7.65–7.52 (m, 6 H), 7.37–7.33 (m, 2 H), 7.26–7.22 (m, 3 H), 6.93–6.89 (m, 2 H), 6.79–6.75 (m, 1 H), 6.56–6.53 (m, 2 H), 2.28 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 192.4, 163.4, 145.9, 144.9, 140.6, 131.4, 129.7, 129.4, 128.6, 128.3, 128.0, 127.9, 125.5, 123.6, 120.2, 117.3, 117.1, 84.5, 28.7. MS: m/z = 415 [M⁺]. Anal. Calcd for C₂₉H₂₁NO₂: C, 83.83; H, 5.09; N, 3.37. Found: C, 83.78; H, 5.05; N, 3.35
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