The general procedure for the synthesis of 4-fluoro-2,3-indolinediones from 4-fluoroindoles was as follows: 10.0 g (0.0723 mol) of 4-fluoroindole and 200 mL of DMSO were added to a reaction vessel equipped with a stirring device, a thermometer, and a reflux condenser tube under the protection of nitrogen and stirred until complete dissolution. Subsequently, the reaction system was evacuated to 800 mbar and 26.5 g (0.149 mol) of N-bromosuccinimide (NBS) was slowly added. The reaction temperature was raised to 80 °C and the reaction progress was monitored by liquid chromatography (LC, Agilent 1200) and gas chromatography-mass spectrometry (GC-MS, Shimadzu GC-MS 2010 PLUS). When the peak of the monobromo product (4-fluoro-3-bromoindole) completely disappeared (about 3 h after the start of the reaction), 29.3 g (0.37 mol) of pyridine was added as a reaction terminator and stirring was continued for 2 h. The mixture was then cooled down for 2 h. The reaction was then stopped and the reaction was completed. After completion of the reaction, the mixture was cooled to room temperature, 500 mL of ethyl acetate was added, and then washed with 3% aqueous sodium thiosulfate. The organic layer was separated, dried with magnesium sulfate, filtered and concentrated. Finally, the target product 4-fluoro-2,3-indolinedione was purified by silica gel column chromatography (eluent ratio of toluene:ethyl acetate=4:1). In Example 2, the synthesis of 4-fluoro-2,3-indolinedione was carried out in the same manner as the above steps, and only the raw material 4-fluoroindole was replaced with 4-fluoroindole E obtained in Example 1.
