N-bromobutanimide → 6-(2-Bromoacetyl)isochroman-1-one

Temperature

80 °C

6-Bromo-3,4-dihydro-1H-isochromen-1-one (6.90 g, 30.4 mmol), tributyl(1-ethoxyethenyl)stannane (10.8 mL, 31.9 mmol, 1.05 equiv), and PdCl2(PPh3)2(1.07 g, 1.52 mmol, 0.05 equiv) were weighed into a 250 mL round bottom flask. To this was added dioxane (70 mL) and the resulting mixture stirred at 80° C. for 4 h. The reaction was not complete by HPLC, therefore another 0.1 equiv of tin reagent was added. After 30 min 6-bromo-3,4-dihydro-1H-isochromen-1-one had been fully consumed as indicated by HPLC. The reaction mixture was cooled to 0° C. and 35 mL THF followed by 14 mL H2O were added. To this was introduced solid N-bromosuccinimide (5.68 g, 31.9 mmol, 1.05 equiv), added in portions over 5 min. After stirring for 30 min there was still evidence of remaining enol ether, therefore NBS was added in small portions (˜300 additional mg added) until it was consumed as evidenced by HPLC. Water was then added and the mixture extracted with EtOAc. The aqueous layer was extracted 2 additional times with EtOAc, the combined organics dried with MgSO4, filtered and concentrated in vacuo. This was transferred with EtOAc to a 100 mL round bottom flask, the resulting solution concentrated to ˜25 mL total volume, at which point hexane (50 mL) was added dropwise. When complete the heterogeneous mixture was stirred for 30 min, then cooled to 0° C. and stirred for 10 min, then filtered and washed twice with hexanes. The desired product was dried under a nitrogen bag, then purified by flash chromatography (12 to 100% EtOAc/Hex) to provide the title compound.

1. customAfter 30 min 6-bromo-3,4-dihydro-1H-isochromen-1-one had been fully consumed
2. temperatureThe reaction mixture was cooled to 0° C.
3. additionwere added
4. additionadded in portions over 5 min
5. stirringAfter stirring for 30 min there
6. customwas consumed
7. additionWater was then added
8. extractionthe mixture extracted with EtOAc
9. extractionThe aqueous layer was extracted 2 additional times with EtOAc
10. dry with materialthe combined organics dried with MgSO4
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. customThis was transferred with EtOAc to a 100 mL round bottom flask
14. concentrationthe resulting solution concentrated to ˜25 mL total volume, at which point hexane (50 mL)
15. additionwas added dropwise
16. stirringWhen complete the heterogeneous mixture was stirred for 30 min
17. temperaturecooled to 0° C.
18. stirringstirred for 10 min
19. filtrationfiltered
20. washwashed twice with hexanes
21. dry with materialThe desired product was dried under a nitrogen bag
22. custompurified by flash chromatography (12 to 100% EtOAc/Hex)

ORD record

ord-d6cef1b93a72472db26cadc04e710250

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09206199B2