Tetrahydrofuran → 2-[(3-Bromo-2,5-dichlorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene

Temperature

110 °C

6-chloro-2-fluoro-3-methylphenol (3.3 g, 20.55 mmol) and 18-crown-6 (1.086 g, 4.11 mmol) were dissolved in dry DMSO (50 mL) and treated with 20% potassium t-butoxide in THF (11.50 g, 20.55 mmol) for 15 minutes at room temperature. 1-bromo-2,5-dichloro-3-fluorobenzene (7.21 g, 29.6 mmol) was added in one portion and the reaction mixture heated at 110° C. for 3 days at which time LC-MS indicated nearly complete consumption of phenol and formation of a major new product. Addition of water to the reaction mixture resulted in a brown gummy oil which was extracted with EtOAc. The organic phase was isolated, washed with brine four times, dried over MgSO4, filtered and concentrated to dryness to give a brown syrup. This material was filtered through a plug of 45 g silica gel which was eluted with 500 mL DCM. The filtrate was concentrated to an amber oil and crystallized from EtOH and a few drops of water. This mixture was cooled in an ice bath, filtered, and the precipitate washed with three portions of cold EtOH to give 2-[(3-bromo-2,5-dichlorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (4.0 g, 10.40 mmol, 50.6% yield) as a cream solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.73 (s, 1H), 7.29-7.47 (m, 2H), 6.81 (s, 1H), 2.29 (s, 3H).

1. customconsumption of phenol and formation of a major new product
2. additionAddition of water to the reaction mixture
3. customresulted in a brown gummy oil which
4. extractionwas extracted with EtOAc
5. customThe organic phase was isolated
6. washwashed with brine four times
7. dry with materialdried over MgSO4
8. filtrationfiltered
9. concentrationconcentrated to dryness
10. customto give a brown syrup
11. filtrationThis material was filtered through a plug of 45 g silica gel which
12. washwas eluted with 500 mL DCM
13. concentrationThe filtrate was concentrated to an amber oil
14. customcrystallized from EtOH and a few drops of water
15. temperatureThis mixture was cooled in an ice bath
16. filtrationfiltered
17. washthe precipitate washed with three portions of cold EtOH

ORD record

ord-06ef025c872b4cad9c37a69a937efac7

Source dataset

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08304419B2