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

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.


General Procedure (GP4) for the preparation of Oxindoles (3aa-ha):
To a solution of a N-monosubstituted aniline (1.0 equiv., 0.20 mmol) in anhydrous THF (0.01 M) ethyl magnesium bromide (3.0 M solution in Et2O, 1.1 equiv.) was added at room temperature and the reaction mixture was stirred for 30 minutes. Subsequently, the ketene (1.5 equiv.) was added dropwise and stirring was continued. After further 30 minutes, iodine (2.2 equiv.) was added and the reaction was stirred overnight at room temperature. Sodium sulfite (sat. aq. solution) was added until the brown colour disappeared and the phases were separated. The aqueous phase was extracted with EtOAc (3 x), the combined organic phases dried over MgSO4 and concentrated in vacuo. Purification by reversed-phase MPLC (MeOH/H2O or MeCN/H2O) led to isolation of the desired oxindoles.

Analytical Data of compounds
S-4

Synthesis of N-monosubstituted anilines (R)-N-(1-Phenylethyl)aniline (1g):
The title compound was prepared following the general procedure GP1 using iodobenzene (1.12 mL, 10  The analytical data are consistent with those reported in literature. 5

Methylphenylketene (2b):
Methylphenylketene 2b was prepared following general procedure GP3 using The analytical data are consistent with those reported in the literature. 11

2-(4-Bromophenyl)but-1-en-1-one (2c):
Following a modified procedure from the literature 12  1.0 equiv.) in THF (20) was added slowly. The suspension was stirred for one hour at 0 °C, then ethyliodide (2.41 mL, 30.0 mmol, 1.5 equiv.) was added slowly. The reaction mixture was allowed to reach room temperature overnight and then adjusted to pH 1 by addition of hydrochloric acid (2 N aqueous solution, 7 mL). EtOAc (50 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (3 x 50 mL), the combined organic phases were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo.
n-BuLi (1.6 M in hexanes, 23.4 mL, 37.5 mmol, 2.5 equiv.) was added slowly at 0 °C and the mixture was stirred at room temperature for 30 minutes. After cooling to 0 °C, a solution of 4-iodophenylacetic acid (3.93 g, 15.0 mmol, 1.0 equiv.) in THF (15) was added slowly. The suspension was stirred for one hour at 0 °C, then ethyliodide (1.81 mL, 22.5 mmol, 1.5 equiv.) was added slowly. The reaction mixture was allowed to reach room temperature overnight and then adjusted to pH 1 by addition of hydrochloric acid (2 N aqueous solution, 5 mL). EtOAc (50 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (3 x 50 mL), the combined organic phases were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo.

Diphenylketene (2g):
Diphenylketene 2ig was prepared following general procedure GP3 using 2,2-diphenylacetic acid ( The analytical data are consistent with those reported in the literature. 14

Cycloheptylidenemethanone (2h):
Ketene 2h was prepared following general procedure GP3 using The analytical data are consistent with those reported in the literature. 14

Analytical Data of compounds
S-12

3-Ethyl-1-methyl-3-phenylindolin-2-one (3aa)
The title compound was prepared following the general procedure GP4 using The analytical data are consistent with those reported in literature. 15

1,3-Diethyl-3-phenylindolin-2-one (3ab)
The title compound was prepared following the general procedure GP4 using The analytical data are consistent to those reported in the literature. 16

1-Benzyl-3-ethyl-3-phenylindolin-2-one (3af)
The title compound was prepared following the general procedure GP4 using  The analytical data are consistent with those reported in literature. 17

1,3-Dimethyl-3-phenylindolin-2-one (3ba)
The title compound was prepared following the general procedure GP4 using  The analytical data are consistent with those reported in the literature. 19

diphenylbutanamide (4fa)
The title compounds were prepared following the general procedure GP4 using N-methylaniline 1a ( The analytical data are consistent with those reported in the literature. 21

1-Methyl-3,3-diphenylindolin-2-one (3ga)
The title compound was prepared following the general procedure GP4 using  The analytical data are consistent with those reported in the literature. 22 5 The signal of the quaternary α-C-atom is not resolved.

Analytical Data of compounds
S-27

Synthesis of Amides
S-28

Synthesis of Amides
S-29