Synthesis
General procedure for the synthesis of tert-butyl 5-hydroxyisoindoline-2-carboxylate by the reaction of 5-hydroxyisoindole-1,3-dione with di-tert-butyl dicarbonate:
1. Preparation of 2,3-dihydro-5-hydroxy-1H-isoindole (7): 750 mL of 1 M borane/THF solution was added dropwise to 300 mL of dry THF containing 20 mL (125 mmol) of 5-hydroxyisoindole-1,3-dione at -5 °C for 60 min. Subsequently, the reaction mixture was stirred at 22°C for 2 hours and then at 80°C for 16 hours.
2. Upon completion of the reaction, the mixture was cooled to 0 °C and 100 mL of methanol (note exothermic) and 100 mL of 2M hydrochloric acid were slowly added. The resulting mixture was stirred at 80°C for 3 hours, then cooled to 22°C and 100 mL of water was added.
3. The aqueous solution was extracted three times with dichloromethane (150 mL each time). To the aqueous solution was added 27.8 g (125 mmol) of di-tert-butyl dicarbonate and 12.6 g (125 mmol) of triethylamine, and the mixture was stirred at 22°C for 30 minutes.
4. The reaction mixture was again extracted three times with dichloromethane (100 mL each time). The organic phases were combined, dried over sodium sulfate, filtered, and the filtrate evaporated to dryness under vacuum.
5. The crude product was ground with petroleum ether to give 6.7 g (22% yield) of light beige crystals of tert-butyl 5-hydroxyisoindoline-2-carboxylate (6).
1H-NMR (500 MHz, DMSO-d6/TFA-d1, 90 °C): δ [ppm] 7.093 (m, 1H), 6.709 (m, 2H), 4.486 (m, 4H), 1.457 (s, 9H); Molecular Weight (MW) 235.3.
