Phenol → 4-Methoxy-3-methylphenol

The synthesis for the phenol was a two step synthesis via the Vilsmer-Haack condensation to obtain the aldehyde and then by the Baeyer-Villiger oxidation to give the phenol. Phosphorus oxychloride (5.1 mL, 0.057 mol) was added the dropwise to a solution of 2-methylanisole (5.33 mL, 0.043 mol) in dimethylformamide (6 g) under nitrogen. After addition, the mixture was heated and refluxed for 4 h, cooled then added to 100 mL of water. An excess of 10% NaOH was added and the solution was extracted with 4×100 mL of ether. The ether layers were washed with water and then brine solution, dried over magnesium sulfate and evaporated under reduced pressure. The dark oil that remained (5.0 g, 77%) was purified by column chromatography (silica gel: 90% hexane, 10% ethyl acetate). The remaining oil (1.78 g, 28%) was dissolved in dichloromethane (100 mL) and then 3.03 g, (0.018 mol) 3-chloroperbenzoic acid was added. The mixture was refluxed under nitrogen for ˜5 h, cooled, and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The dark oil that remained was dissolved in 7 mL of methanol and 5.5 mL of 10% aqueous potassium hydroxide solution was added. The solution was stirred under nitrogen for ˜2 h, water was added, and the solution was extracted with ether. The ether layers were combined and washed with saturated sodium bicarbonate solution and then with water. The ether was dried over magnesium sulfate and evaporated under reduced pressure. The oil that remained (1.21 g, 74%) was recrystallized twice with hexane to give long white needles (0.34 g, <1%). The purity was assessed by NMR and GC-MS.

1. additionAfter addition
2. temperaturethe mixture was heated
3. temperaturerefluxed for 4 h
4. temperaturecooled
5. extractionthe solution was extracted with 4×100 mL of ether
6. washThe ether layers were washed with water
7. dry with materialbrine solution, dried over magnesium sulfate
8. customevaporated under reduced pressure
9. customwas purified by column chromatography (silica gel: 90% hexane, 10% ethyl acetate)
10. dissolutionThe remaining oil (1.78 g, 28%) was dissolved in dichloromethane (100 mL)
11. temperatureThe mixture was refluxed under nitrogen for ˜5 h
12. temperaturecooled
13. customevaporated under reduced pressure
14. dissolutionThe residue was dissolved in ethyl acetate
15. washwashed with aqueous saturated sodium bicarbonate
16. dry with materialThe organic layer was dried over magnesium sulfate
17. customevaporated under reduced pressure
18. dissolutionThe dark oil that remained was dissolved in 7 mL of methanol
19. addition5.5 mL of 10% aqueous potassium hydroxide solution was added
20. additionwater was added
21. extractionthe solution was extracted with ether
22. washwashed with saturated sodium bicarbonate solution
23. dry with materialThe ether was dried over magnesium sulfate
24. customevaporated under reduced pressure
25. customwas recrystallized twice with hexane

ORD-Eintrag

ord-898d9bb469c042dd995993578365621b

Quelldatensatz

uspto-grants-2003_11

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US06643591B1