‘On Water’ Direct Aldol Reaction of Oxindoles with β,γ-Unsaturated α-Keto Esters for the Synthesis of 3-(α-Hydroxy-β-carbonyl)oxindoles

Abstract

An efficient ‘on water’ direct aldol reaction of oxindoles and β,γ-unsaturated α-keto esters was developed, giving 3-(α-hydroxy-β-carbonyl)oxindoles in high yields (up to 92%) and diastereoselectivities (up to >20:1). Compared with organic solvent, water as the solvent was crucial to the reaction and rate acceleration was observed in water.

Key words

aldol reaction - on water - oxindole - β,γ-unsaturated α-keto ester - 3-(α-hydroxy-β-carbonyl)oxindole

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• 9 Typical Procedure for the ‘On Water’ Direct Aldol Reaction of Oxindole with β,γ-Unsaturated α-Keto Ester: A mixture of oxindole (0.1 mmol), β,γ-unsaturated α-keto ester (0.12 mmol), and DABCO (0.02 mmol) in H₂O (1 mL) was stirred at room temperature. After stirring for the indicated time, the mixture was extracted with EtOAc. The combined organic phase was dried over Na₂SO₄ and concentrated in vacuo. The residue was further purified by washing with petroleum ether/EtOAc to afford the desired product 3a. Yield: 76%; white solid; diastereomeric mixture (dr >20:1). ¹H NMR (400 MHz, DMSO): δ = 10.38 (s, 1 H), 7.49 (d, J = 0.8 Hz, 2 H), 7.38 (t, J = 0.8 Hz, 2 H), 7.29 (t, J = 0.8 Hz, 1 H), 7.13 (t, J = 0.8 Hz, 2 H), 6.67-6.82 (m, 4 H), 5.79 (s, 1 H), 4.15 (q, J = 0.8 Hz, 2 H), 3.99 (s, 1 H), 1.18 (t, J = 0.8 Hz, 3 H). ¹³C NMR (100 MHz, DMSO): δ = 175.2, 171.9, 143.6, 136.0, 128.8, 127.8, 126.6, 126.1, 125.3, 120.5, 108.9, 78.6, 61.0, 52.8, 13.8. HRMS (ESI): m/z calcd for [C₂₀H₁₉NO₄ + H]⁺: 338.1392; found: 338.1395.