Di-tert-butyl dicarbonate → 5-bromo-2,3-dihydro-1H-isoindole hydrochloride

Temperature

0 °C

In a dried 500 mL three necked round bottom flask equipped with a reflux condenser and addition funnel was taken BH3-THF (160 mL) solution with dry THF (50 mL). The mixture was cooled to 0° C. To this cold solution 5-bromo-1H-isoindole-1,3(2H)-dione (8.0 g, 35.4 mmol) in dry THF (100 mL) was added gradually and allowed to warm to room temperature. After 10 min at room temperature the mixture was refluxed for 16 h. The reaction mixture was then cooled to 0° C. and quenched with methanol. (Caution: vigorous foaming will occur). 20-30 mL of 2N HCL was added and refluxed the mixture for 1 h. Cooled the mixture and basified with NaOH solution and extracted with ethyl acetate. Combined organic extracts were washed with water, saturated NaCl solution, dried over Na2SO4 and concentrated under vacuo. To the crude product in MeOH (150 mL), Et3N (12 mL) and di-tert-butyl dicarbonate (13.8 g, 63.23 mmol) were added and stirred at room temperature for 16 h. The reaction mixture was then concentrated under vacuo. The crude product was diluted with CH2Cl2 (200 mL), washed with water, saturated NaCl solution, and dried over Na2SO4. Crude product was purified by column chromatography using 20% ethyl acetate in hexanes as eluant to afford a colourless solid. To this dioxane-HCl was added at room temperature and stirred for 10 min, the solid obtained was then filtered and dried to give 3.0 g (42.8%) of 5-bromoisoindoline hydrochloride salt as an ash colour solid.

1. temperatureto warm to room temperature
2. temperatureAfter 10 min at room temperature the mixture was refluxed for 16 h
3. temperatureThe reaction mixture was then cooled to 0° C.
4. customquenched with methanol
5. addition20-30 mL of 2N HCL was added
6. temperaturerefluxed the mixture for 1 h
7. temperatureCooled the mixture
8. extractionextracted with ethyl acetate
9. washCombined organic extracts were washed with water, saturated NaCl solution
10. dry with materialdried over Na2SO4
11. concentrationconcentrated under vacuo
12. concentrationThe reaction mixture was then concentrated under vacuo
13. additionThe crude product was diluted with CH2Cl2 (200 mL)
14. washwashed with water, saturated NaCl solution
15. dry with materialdried over Na2SO4
16. customCrude product was purified by column chromatography
17. customto afford a colourless solid
18. stirringstirred for 10 min
19. customthe solid obtained
20. filtrationwas then filtered
21. customdried

ORD record

ord-e93c4438266d4fe980781df6598db808

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08354406B2