Oxindole synthesis via polar-radical crossover of ketene-derived amide enolates in a formal [3 + 2] cycloaddition

Abstract

Herein we introduce a simple, efficient and transition-metal free method for the preparation of valuable and sterically hindered 3,3-disubstituted oxindoles via polar-radical crossover of ketene derived amide enolates. Various easily accessible N-alkyl and N-arylanilines are added to disubstituted ketenes and the resulting amide enolates undergo upon single electron transfer oxidation a homolytic aromatic substitution (HAS) to provide 3,3-disubstituted oxindoles in good to excellent yields. A variety of substituted anilines and a 3-amino pyridine engage in this oxidative formal [3 + 2] cycloaddition and cyclic ketenes provide spirooxindoles. Both substrates and reagents are readily available and tolerance to functional groups is broad.

Scheme 1. Selected strategies for the synthesis of oxindoles.

Scheme 2. Substrate scope – variation of substituents at the nitrogen. Reactions (0.20 mmol) were conducted under argon atmosphere. ^a For step 1 and 2 reaction time was 1 h.

Scheme 3. Substrate Scope – variation of anilines and ketenes. Reactions (0.20 mmol) were conducted under argon atmosphere. ^a Isolated as an inseparable mixture (1 : 1.4) with the protonated enolate 4fa (56% combined yield).

Scheme 4. Suggested mechanism.

Scheme 5. Mechanistic experiments. (a) (1) EtMgBr (1.1 equiv.), rt, 30 min, (2) 2a (1.5 equiv.), −78 °C, 30 min, (3) I₂ (1.2 equiv.), −78 °C, 15 min in THF (0.01 M). (b) Warm to room temperature in THF (0.01 M), 18 h. (c) NaI (1.2 equiv.) in acetone (0.77 M), rt, 18 h. (d) Irradiation with blue LED (40 W, 467 nm) in THF (0.01 M), rt, 8 h.