Butyl vinyl ether → Methyl 4-acetyl-3-methylbenzoate

Temperature

90 °C

Methyl 4-bromo-methylbenzoate (2.146 g, 9.368 mmol), 1,3-bis(diphenylphosphino)propane (0.21 g, 0.52 mmol), sodium carbonate (2.19 g, 20.6 mmol) and palladium (II) acetate (0.10 g, 0.47 mmol) were combined in a vial and purged with argon. Methanol (10.7 mL, 265 mmol) and n-butyl vinyl ether (4.83 mL, 37.5 mmol) were added by syringe. The resulting mixture was further sonicated under argon flow for several minutes then heated at 90° C. overnight. Upon cooling to room temperature, the reaction was diluted with methanol (10 mL). Celite (2 g) was added, the mixture thoroughly homogenized and filtered. The filter cake was washed with several mL of methanol. To the red/brown methanolic filtrate was added 6M aqueous HCl (6.5 mL). The solution turned yellow and then turbid white over stirring at room temperature (0.3 h). The solvent was removed under reduced pressure and the residue obtained was partitioned between ethyl acetate (75 mL) and water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL). The extracts were combined, washed with saturated aqueous sodium bicarbonate then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was dried in vacuo to remove butanol. The residue was purified by silica gel chromatography (5-20% EtOAC/hexanes gradient) to afford the title compound as an off-white solid (1.49 g, 83%). LC-MS: (FA) ES+ 193; 1H NMR (400 MHz, DMSO) δ 7.89-7.83 (m, 3H), 3.86 (s, 3H), 2.57 (s, 3H), 2.44 (s, 3H).

1. custompurged with argon
2. customThe resulting mixture was further sonicated under argon flow for several minutes
3. temperatureUpon cooling to room temperature
4. additionCelite (2 g) was added
5. filtrationfiltered
6. washThe filter cake was washed with several mL of methanol
7. additionTo the red/brown methanolic filtrate was added 6M aqueous HCl (6.5 mL)
8. stirringover stirring at room temperature (0.3 h)
9. customThe solvent was removed under reduced pressure
10. customthe residue obtained
11. customwas partitioned between ethyl acetate (75 mL) and water (30 mL)
12. extractionThe aqueous phase was extracted with ethyl acetate (30 mL)
13. washwashed with saturated aqueous sodium bicarbonate
14. dry with materialbrine, dried over sodium sulfate
15. filtrationfiltered
16. concentrationconcentrated under reduced pressure
17. dry with materialThe crude residue was dried in vacuo
18. customto remove butanol
19. customThe residue was purified by silica gel chromatography (5-20% EtOAC/hexanes gradient)

ORD record

ord-32f96f145d9d49a7a7b257bc97355947

Source dataset

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09382197B2