100927-02-4

1. To a stirred solution of 4-hydroxy-3-methylacetophenone (3.0 g, 19.98 mmol) in acetone (60 mL) at 0 °C were sequentially added K2CO3 (13.8 g, 99.89 mmol) and BnBr (8.3 mL, 69.92 mmol). The reaction mixture was heated to reflux for 1 h and then cooled to room temperature and the reaction was terminated by the addition of water. The reaction mixture was extracted with ethyl acetate (AcOEt) and the organic phases were combined and washed with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography using hexane/ethyl acetate (1:4 v/v) as eluent to afford benzyl ether (5.01 g, quantitative yield) as a white solid. 2. To a stirred solution of benzyl ether (4.91 g, 20.43 mmol) in dichloromethane (CH2Cl2, 100 mL) was added sequentially NaHCO3 (3.43 g, 40.86 mmol) and m-chloroperoxybenzoic acid (mCPBA, 5.88 g, 70%, 24.52 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 6 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic phases were combined and washed with saturated brine. To the concentrated residue was added a methanol solution of 10% KOH (adjusted pH to 9-10) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, diluted with water, acidified with 10% aqueous HCl to pH < 7 and extracted with ethyl acetate. The organic phases were combined and washed sequentially with saturated aqueous NaHCO3 and saturated saline. The organic phases were concentrated and purified by silica gel column chromatography using hexane/ethyl acetate (7:3 v/v) as eluent to afford the target product 4-(benzyloxy)-3-methylphenol (4.57 g, quantitative yield) as a white solid. Physical properties: melting point 58.1 °C (recrystallized from benzene); IR (pure) 3311, 1697, 1505, 1454, 1217, 1020, 742 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.24 (3H, s), 4.30 (1H, br s, D2O-exchangeable, OH), 5.01 (2H, s), 6.59 (1H, dd, J = 2.8 and 8.4 Hz), 6.67 (1H, d, J = 3.2 Hz), 6.75 (1H, d, J = 8.4 Hz), 7.29-7.44 (5H, m); 13C NMR (100 MHz, CDCl3) δ 16.4 (CH3), 70.9 (CH2), 112.6 (CH) 113.3 (CH), 118.0 (CH), 127.2 (CH), 127.7 (CH), 128.4 (CH), 128.8 (Cq), 137.7 (Cq), 149.3 (Cq), 151.1 (Cq); HRMS (ESI) m/z calculated value C14H14O2Na [M + Na]+ 237.0891 , measured value 237.0882.

[1] Tetrahedron, 2011, vol. 67, # 26, p. 4758 - 4766
[2] Tetrahedron Letters, 2007, vol. 48, # 39, p. 6933 - 6936
[3] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4528 - 4532
[4] Patent: US6124323, 2000, A