5-sulfanyl-1,3-dihydroindol-2-one

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under reaction conditions analogous to preparation of 5-mercaptooxindole, chlorosulfonylation of 4-methyloxindole 3.15 g (21.40 mmol) with neat chlorosulfonic acid 25 mL provided 4.55 g of 5-chlorosulfonyl-4-methyloxindole (86.5% Y, 95% isomeric purity by 1H-NMR, in d6-acetone) which was reduced with triphenyl phosphine 17.0 g (65 mmol) in anhydrous dichloromethane, to provide a crude thiol 2.573 g (75% Y) which was then methylated with excess of methyl iodide (1.50 mL; 24 mmol) to provide a crude methylthio intermediate 2.722 g (98% Y, 90% pure), by using conditions analogous to preparation of 5-methylsulfoxyoxindole. Under reaction conditions

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under reaction conditions analogous to the preparation of 5-methylsulfoxyoxindole, alkylation of 5-mercaptooxindole 1.99 g (12.05 mmol) with ethyl iodide 1.35 mL (16.7 mmol) in aqueous methanol at 50° C. in the presence of hydrogen phosphate provided 2.152 g of 5-ethylthiooxindole (92.5%). Under reaction conditions

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The 5-chlorosulfonyl oxindole from the previous step, 42.23 g (182.3 mmol) was suspended in anhydrous dichloromethane (100 mL) in a 1 L round flask. The mixture was cooled on ice slush bath and a solution of triphenylphosphine 167.5 g (638 mmol, 3.5 eq.) in anhydrous dichloromethane (300 mL) was dropwise added from an addition funnel under nitrogen with cooling over a 45 min period. After complete addition the flask was removed from the cooling bath and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by water addition, 200 mL. The flask with the biphasic mixture was placed on a 50° C. water bath and the mixture was refluxed under nitrogen for 1 hour, then cooled on ice. The precipitated product was collected by filtration, washed thoroughly with ice-chilled dichloromethane and ice water, then dried by suction and on highvac, to provide 19.58 g of a pure product. The biphasic filtrates were de-oxygenated by argon/vacuum purge (3 times). The mixture was made strongly alkaline by addition of 50% aq. NaOH solution, shaken under Ar and then rapidly separated. The organic phase was re-extracted with water. The aqueous phases were promptly washed with fresh dichloromethane (200 mL). The combined aqueous extracts were made acidic by addition of 6M HCl, the mixture was cooled on ice, the precipitated product was collected by filtration, washed with ice-cold water, dried by suction and on highvac, to provide a second crop of the product, 7.15 g. The combined yield was 26.73 g (88.5% th) of a light tan solid. 1H-NMR (d6-DMSO, 400 MHz): 10.339 (s, 1H), 7.151 (s, 1H), 7.108 (m, 1H), 6.707 (d, 8.0 Hz, 1H), 5.109 (s, 1H), 3.436 (s, 2H) The mixture was cooled on ice slush bath with cooling over a 45 min period After complete addition the flask was removed from the cooling bath The reaction was quenched by water addition, 200 mL was placed on a 50° C. the mixture was refluxed under nitrogen for 1 hour cooled on ice The precipitated product was collected by filtration washed thoroughly with ice- chilled dichloromethane and ice water dried by suction