Synthesis
General steps:
1. To a stirred solution of 4-bromoresorcinol (3.0 g, 15.87 mmol) in anhydrous acetone (60 mL) was added K2CO3 (10.97 g, 79.36 mmol, 5.0 eq.) and p-toluenesulfonyl chloride (TsCl, 3.18 g, 16.7 mmol, 1.05 eq.). The reaction mixture was refluxed for 16 hours and then cooled to room temperature.
2. To the reaction mixture was added iodomethane (MeI, 2.47 mL, 39.67 mmol, 2.5 eq.) and refluxed further for 12 hours. After cooling to room temperature, the precipitated solid was filtered.
3. The filtrate was concentrated under pressure and the residue was diluted with water and ethyl acetate (EtOAc, 1:1, 50 mL). Separate the aqueous layer and extract with EtOAc (2 x 30mL). The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated.
4. The residue was purified by silica gel column chromatography using petroleum ether/EtOAc (9:1 to 4:1) as eluent to afford 4-bromo-3-methoxyphenyl-4-methylbenzenesulfonate (5.05 g, 89%) as a white solid.
5. To a stirred solution of the above 4-bromo-3-methoxyphenyl-4-methylbenzenesulfonate (4.2 g, 11.76 mmol) in ethanol (30 mL) was added KOH (1.32 g, 23.52 mmol, 2.0 equiv). The reaction mixture was refluxed for 3 hours and then cooled to room temperature.
6. The solvent was evaporated under reduced pressure and the residue was diluted with water and EtOAc (1:1, 50 mL). The aqueous layer was separated and extracted with EtOAc (2 x 30mL). The organic extracts were combined, washed with brine, dried (Na2SO4) and concentrated.
7. The residue was purified by silica gel column chromatography using petroleum ether/EtOAc (4:1 to 7:3) as eluent to afford 4-bromo-3-methoxyphenol (2.1 g, 88%) as a white solid.
8. To a solution of anhydrous THF (30 mL) of the above 4-bromo-3-methoxyphenol (1.80 g, 8.87 mmol) was added NaH (0.277 g, 11.53 mmol, 1.3 eq.) at 0 °C and stirred for 15 min.
9. tert-Butyldimethylchlorosilane (TBDMSCl, 2.0 g, 13.31 mmol, 1.5 eq.) was added at 0 °C, then slowly warmed to room temperature and the reaction mixture was stirred for 12 hours.
10. Upon completion of the reaction, the reaction was terminated with saturated aqueous NaHCO3 solution (20 mL). The solvent was evaporated under reduced pressure and the aqueous layer was extracted with EtOAc (3 x 20 mL). The organic layers were combined, washed with water and brine, dried (Na2SO4) and concentrated.
11. The residue was purified by silica gel column chromatography using petroleum ether/EtOAc (9.5:0.5 to 9:1) as eluent to give the target product (2.75 g, 98%) as a colorless oil.
References
[1] Journal of the American Chemical Society, 2007, vol. 129, # 13, p. 3918 - 3929
[2] Tetrahedron Asymmetry, 2013, vol. 24, # 20, p. 1281 - 1285
[3] Journal of the American Chemical Society, 1991, vol. 113, # 24, p. 9293 - 9319
[4] Patent: WO2010/148650, 2010, A1. Location in patent: Page/Page column 36
