[F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].[CH3:11][CH:12]1[CH2:17][C:16](=[O:18])[CH2:15][CH2:14][O:13]1.Cl>BrCCBr.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:16]2([OH:18])[CH2:15][CH2:14][O:13][CH:12]([CH3:11])[CH2:17]2)[CH:5]=[C:6]([F:8])[CH:7]=1A Grignard reagent was prepared from 3,5-difluorobromobenzene (0.772 g), 1,2-dibromoethane (2 drops), magnesium (0.106 g) and THF (5 ml). The mixture was stirred at ambient temperature for 15 minutes and then heated to 50° C. for 15 minutes. The mixture was allowed to recool to ambient temperature and a solution of 2-methyltetrahydropyran-4-one (J. Amer. Chem. Soc., 1982, 104, 4666) in THF (1 ml) was added dropwise. The mixture was stirred at ambient temperature for 1 hour. The mixture was poured into dilute aqueous hydrochloric acid and extracted with diethyl ether. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 9:1 v/v mixture of methylene chloride and diethyl ether as eluent. There was thus obtained a less polar isomer, (2RS,4SR)-4-(3,5-difluorophenyl)-4-hydroxy-2-methyltetrahydropyran (0.25 g, 36%), having the 2-methyl and 4-hydroxy substituents in a trans-relationship.
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