Synthesis of Oxindoles by Brønsted Acid Catalyzed Radical Cascade Addition of Ketones

Abstract

Oxindoles bearing ketone side chains in the 3-position can be synthesized by Brønsted acid catalysis from N-aryl methacrylamides, ketones, and hydroperoxides. The cyclized products are presumably formed in a radical cascade reaction, initiated by decay of intermediate alkenyl peroxides. In the case of acrylic substrates that do not undergo cyclization, γ-peroxyketones were isolated instead, indicating that the final cyclization step of the cascade does not take place in these cases.

Key words

Brønsted acid catalysis - radicals - cyclization - heterocycles - peroxides

• References and Notes

• 1 University of Ioannina, Department of Chemistry, 45110 Ioannina, Greece.
• 2 Universität zu Köln, Department of Chemistry, Greinstraße 6, 50939 Köln, Germany.
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For related radical reactions, see:
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• 8 General Procedure for Reactions with Acetone In an oven-dried Schlenk flask, 2a (1.5 mmol, 1 equiv) and t-BuOOH (5.5 M solution in decane, 4.5 mmol, 3 equiv) were dissolved in acetone (7.5 mL). The resulting mixture was freeze-pump-thaw degassed and allowed to warm to r.t. Then, p-TsOH (0.30 mmol, 0.2 equiv) was added under a stream of argon, and the reaction mixture was allowed to react overnight at 50 °C. It was then diluted with acetone, a small amount of silica was added and solvent removed. The residue was purified by column chromatography on silica gel using mixtures of hexanes and EtOAc to afford the pure products.
• 9 General Procedure for Reactions with Other Ketones In an oven-dried Schlenk flask, 2a (1.5 mmol, 1 equiv), ketone (7.5 mmol, 5 equiv), and t-BuOOH (5.5 M solution in decane, 4.5 mmol, 3 equiv) were dissolved in dry CHCl₃ (7.5 mL). The resulting mixture was freeze–pump–thaw degassed and allowed to warm to r.t. Then, p-TsOH (0.30 mmol, 0.2 equiv) was added under a stream of argon and after closing the flask, the reaction mixture was allowed to react overnight at 50 °C. The reaction mixture was then diluted with CHCl₃, a small amount of silica was added and solvent removed. The resulting powder was purified by column chromatography on silica gel using mixtures of hexanes and EtOAc to afford the pure products.
• 10 Warning: Although we never experienced any problem in working with or handling the compounds described in this work, precautions against explosions should be taken when working with peroxides. In particular, neat peroxides should not be heated or brought into contact with metals or metal salts. Explosive triacetone triperoxide should not be formed under the reaction conditions described here, as tert-butyl hydroperoxide and not hydrogen peroxide is used. In addition, the reaction conditions described here lead to the consumption of hydroperoxides (as confirmed for hydrogen peroxide, see ref. 7a).
• 11 Characterization Data of Compound 1da Yellow oil. ¹H NMR (500 MHz, DMSO): δ = 6.98 (d, J = 2.5 Hz, 1 H), 6.93 (d, J = 8.5 Hz, 1 H), 6.83 (dd, J = 2.5, 8.5 Hz, 1 H), 3.73 (s, 3 H), 3.10 (s, 3 H), 2.10–1.85 (m, 4 H), 1.93 (s, 3 H), 1.24 (s, 3 H). ¹³C NMR (125 MHz, DMSO): δ = 207.4, 178.8, 155.6, 136.4, 134.3, 112.0, 110.3, 108.7, 55.5, 47.1, 37.9, 31.3, 29.7, 26.0, 23.3. HRMS (ESI⁺): m/z [M⁺] calcd for C₁₅H₁₉N₁O₃Na: 284.125712; found: 284.125640.
• 12 Characterization Data of Compound 1ea Yellow oil. ¹H NMR (500 MHz, DMSO): δ = 6.69 (s, 1 H), 6.64 (s, 1 H), 3.10 (s, 3 H), 2.28 (s, 3 H), 2.24 (s, 3 H), 2.15–2.08 (m, 1 H), 1.99–1.87 (m, 2 H), 1.88 (s, 3 H), 1.82–1.74 (m, 1 H), 1.29 (s, 3 H). ¹³C NMR (125 MHz, DMSO): δ = 207.3, 179.3, 143.4, 137.2, 133.5, 126.3, 125.2, 107.1, 47.4, 38.2, 29.7, 29.6, 26.0, 22.0, 21.1, 17.6. HRMS (ESI⁺): m/z [M⁺] calcd for C₁₆H₂₁N₁O₂Na: 282.146448; found: 282.146440.
• 13 Characterization Data of Compound 5b Clear oil. ¹H NMR (500 MHz, DMSO): δ = 7.48–7.43 (m, 2 H), 7.31–7.27 (m, 1 H), 7.14–7.10 (m, 2 H), 2.60 (app t, J = 7.8 Hz, 2 H), 2.17–2.10 (m, 1 H), 2.14 (s, 3 H), 2.05–1.99 (m, 1 H), 1.47 (s, 3 H), 1.23 (s, 9 H). ¹³C NMR (125 MHz, DMSO): δ = 207.3, 171.1, 150.5, 129.6, 125.9, 121.5, 82.7, 79.6, 36.7, 29.7, 28.8, 26.2, 19.9. HRMS (ESI⁺): m/z [M⁺] calcd for C₁₇H₂₄O₅Na: 331.151594; found: 331.151520.
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