[3-(4-Methoxy-phenyl)-isoxazol-5-yl]-methanol

Synthesis

General procedure for the synthesis of [3-(4-methoxyphenyl)-5-isoxazolyl]methanol from 2-propyn-1-ol and α-chloro-4-methoxybenzaldehyde oxime: N-chlorosuccinimide (NCS) (in small amount) was slowly added to a solution of (E)-4-methoxybenzaldehyde oxime (790.0 mg, 5.3 mmol) in DMF (15.8 mL). If the reaction temperature did not increase, 1 N HCl (50.0 μL) was added to promote the reaction. Subsequently, NCS (774.2 mg, 5.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and the progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction was quenched by the addition of ether (20.0 mL) and washed with NaCl solution (2 × 20.0 mL). The organic phase was dried with anhydrous Na2SO4 and the solvent was subsequently removed by rotary evaporation. The resulting carboxyiminocarbonyl chloride was dissolved in t-BuOH:H2O (1:1, 3.8 mL), followed by sequential addition of ethynyl alcohol (340.0 μL, 5.8 mmol), CuSO4 (7.5 mg, dissolved in 50.0 μL of water), sodium ascorbate (104.40 mg, 0.5 mmol) and NaHCO3 (1.3 g, 15.8 mmol). The reaction mixture was stirred for 4 h, after which it was diluted with ethyl acetate (20.0 mL) and washed with H2O (2 × 20.0 mL). The organic phase was dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. Purification by column chromatography [eluent: hexane:ethyl acetate, 8:2 (v/v)] afforded the target compound [3-(4-methoxyphenyl)-5-isoxazolyl]methanol (d1) as a pale yellow solid (890.0 mg, 4.3 mmol, 82% yield). Melting point: 90-92 °C. Rf value: 0.40 [Expanding agent: hexane:ethyl acetate, 60:40 (v/v)]. IR (KBr, cm-1): 3352, 2837, 1610, 1527, 1431, 1259, 1082, 840, 802. 1H NMR (400 MHz, CDCl3) δ: 7.74 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 6.52 (s, 1H), 4.81 (s, 2H), 3.86 (s, 3H).13C NMR (100 MHz, CDCl3) δ: 171.5, 162.1, 161.0, 128.2, 121.4, 114.3, 99.8, 56.7, 55.4. 55.4.

References

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[2] Journal of the Chinese Chemical Society, 2007, vol. 54, # 3, p. 643 - 652
[3] Synthesis, 2002, # 12, p. 1663 - 1668
[4] Patent: EP2308838, 2011, A1. Location in patent: Page/Page column 79-80
[5] Letters in Organic Chemistry, 2011, vol. 8, # 4, p. 278 - 281