Hydrochloric Acid → 3-Methoxy-1-methylnaphthalene

Temperature

42.5 °C

A solution of t-BuOH (44.5 g, 600 mmol) in dry THF (240 mL) was added dropwise to a suspension of NaNH2 (84.4 g, 2.2 mmol) in dry THF (480 mL) under nitrogen. The resulting mixture was heated for 2 h at 40-45° C. After the mixture was cooled, a solution of 4-methoxypent-3-en-2-one (68.5 g, 600 mmol) in dry THF (480 mL) was added dropwise at 30-40° C. The resulting mixture was stirred at 45° C. for 2 h. A solution of bromobenzene (47.1 g, 300 mmol) in dry THF (240 mL) was added and the mixture was stirred at 55° C. for 6 h. The mixture was allowed to cool to room temperature overnight. The mixture was poured into ice, acidified with an aqueous 3 M HCl solution to pH 4-5 and extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, and the residue was diluted with acetone (480 mL) and stirred with conc. HCl solution (24 mL) for 10 min. The mixture was diluted with EtOAc (200 mL) and washed with saturated brine (200 mL). The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash chromatography (700 g silica gel with dry-loading, eluting by 2% EtOAc in heptanes to give orange oil (19 g, yield: 37%).

1. temperatureAfter the mixture was cooled
2. stirringthe mixture was stirred at 55° C. for 6 h
3. temperatureto cool to room temperature overnight
4. additionThe mixture was poured into ice
5. extractionextracted with EtOAc
6. concentrationThe combined organic extracts were concentrated under reduced pressure
7. additionthe residue was diluted with acetone (480 mL)
8. stirringstirred with conc. HCl solution (24 mL) for 10 min
9. additionThe mixture was diluted with EtOAc (200 mL)
10. washwashed with saturated brine (200 mL)
11. extractionThe aqueous layer was extracted with EtOAc
12. dry with materialthe combined organic layers were dried over sodium sulfate
13. filtrationfiltered
14. concentrationconcentrated
15. customwith dry-loading
16. washeluting by 2% EtOAc in heptanes

ORD record

ord-a74b2126dbf941dca5cad66d0db60d99

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08802659B2