3'-Bromoacetophenone → HCID 57825032, compound

Temperature

40 °C

Tetrahydrofuran (5 mL) was added to magnesium turnings (330 mg, 13.56 mmol) in a dried apparatus consisting of 250 mL 3-necked flask, addition funnel and reflux condenser. Then 5 mL of a solution of 4-bromo-2-methylanisole (2.5 g, 12.43 mmol) in tetrahydrofuran (15 mL) was added, followed by a drop of bromine. The exothermic reaction started instantaneously, and the 4-bromo-2-methylanisole solution was added at such a rate to maintain gentle reflux of the reaction mixture (25 min). After complete addition, the light-brown hazy Grignard solution was stirred for another 2 h at 40° C. The mixture was then cooled to 0° C. and a solution of 3-bromoacetophenone (1.42 mL, 11.3 mmol) in tetrahydrofuran (15 mL) was added dropwise over 30 min. After the addition was complete, the mixture was stirred overnight, followed by cooling in an ice bath and careful quenching with 0.5 N cold HCl. After further dilution with ethyl acetate (100 mL) and water (100 mL), the layers were separated and the aqueous layer extracted once more with ethyl acetate (50 mL). The organic layer was dried (magnesium sulfate), filtered and evaporated under reduced pressure. The residual material (tertiary alcohol) was dissolved in a mixture of acetic acid/sulfuric acid (4 mL of acetic acid, 0.12 mL of sulfuric acid) and the reaction mixture was stirred for 3 h at room temperature; then it was examined by LC-MS which showed the complete formation of desired product. The solution was quenched with ice and dichloromethane (20 mL) was added. The two phases formed and were separated. The organic layer was washed with a saturated solution of sodium bicarbonate and brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. Crude was purified by flash chromatography eluting with cyclohexane. 1.9 g of desired product was obtained as colorless oil (Yield: 55%).

1. additionconsisting of 250 mL 3-necked flask, addition funnel
2. temperaturereflux condenser
3. customThe exothermic reaction
4. temperatureto maintain gentle
5. temperaturereflux of the reaction mixture (25 min)
6. additionAfter complete addition
7. temperatureThe mixture was then cooled to 0° C.
8. additionAfter the addition
9. stirringthe mixture was stirred overnight
10. temperatureby cooling in an ice bath
11. customcareful quenching with 0.5 N cold HCl
12. customAfter further dilution with ethyl acetate (100 mL) and water (100 mL), the layers were separated
13. extractionthe aqueous layer extracted once more with ethyl acetate (50 mL)
14. dry with materialThe organic layer was dried (magnesium sulfate)
15. filtrationfiltered
16. customevaporated under reduced pressure
17. dissolutionThe residual material (tertiary alcohol) was dissolved in a mixture of acetic acid/sulfuric acid (4 mL of acetic acid, 0.12 mL of sulfuric acid)
18. stirringthe reaction mixture was stirred for 3 h at room temperature
19. customThe solution was quenched with ice and dichloromethane (20 mL)
20. additionwas added
21. customThe two phases formed
22. customwere separated
23. washThe organic layer was washed with a saturated solution of sodium bicarbonate and brine
24. dry with materialIt was then dried over anhydrous magnesium sulfate
25. filtrationfiltered
26. customevaporated under reduced pressure
27. customCrude was purified by flash chromatography
28. washeluting with cyclohexane

ORD record

ord-d495366d2bcd4126afbb64d8d666997f

Source dataset

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07989449B2