2,5-Dimethoxybromobenzene1To a stirred solution of potassium bromide (26.7g, 224 mmol) and 1,4-dimethoxybenzene (30.0g, 210 mmol) in a mixture of water (150ml) and ethanol (300ml) was added sulfuric acid (10 M, 38 mL). The solution was heated (gently) to reflux before hydrogen peroxide (90 mL, 30%) was added dropwise over 30 min. After a further 45 min at reflux, water (150 ml) was added to the hot mixture, which was then allowed to stand at room temp overnight. The solution was decanted and the solvent was evaporated. The residue was extracted with ethyl acetate (3x200mL) and the combined extracts were washed with dilute sodium thiosulfate (3x200ml), water (200ml), dried and evaporated. Flash pad chromatography
3 of the residue using a gradient solvent system of ether/light petroleum followed by distillation gave 2,5-Dimethoxybromobenzene (30.1g, 62%) as a colorless oil, bp 107°C/0.2mmHg (Lit.
2 164-166°C/55mmHg).
2,5-Dimethoxyphenylmagnesiumbromide1A solution of 2,5-Dimethoxybromobenzene (3.19g, 14.7 mmol) in dry tetrahydrofuran (15 mL) was added gradually with stirring, to magnesium turnings (0.36g, 14.8 mmol) which had been activated by heating together with an iodine crystal, and the mixture was then heated at reflux for 4h and then cooled to room temperature.
Stereoselective ring-opening of an epoxide with the Grignard reagent, catalyzed by Li2CuCl41The above grignard reagent was added dropwise to a solution of 11.3 mmol of a terminal (R)-oxirane in tetrahydrofuran (15 ml) containing a catalytic amount of dilithium tetrachlorocuprate (0.1M, 1.0 mL, 0.10 mmol) at -78°C. The mixture was allowed to slowly return to room temperature and then stirred for 18h. The reaction mixture was quenched with saturated ammonium chloride (30 ml) and the organic phase extracted into ether (3x70 mL). The combined extracts was washed with saturated sodium hydrogen carbonate (3x60 mL), brine (3x60 mL), water (80 mL), dried and concentrated under reduced pressure. Flash pad chromatography
3 of the residue using a gradient solvent system of ether/light petroleum gave, after the evaporation of the solvent under reduced pressure, the optically pure alcohol in 92% yield.
References[1] Aust. J. Chem. 53, 245-256 (2000)
[Kudos to Chimimanie for finding this ref, and to ChemisTris for retrieving it][2] Aust. J. Sci. Res. Ser. A, 2, 595 (1949)
[3] Leonard & Lygo & Procter, "Advanced Practical Organic Chemistry" 2nd Ed, Stanley Thornes (1998), pp 215-216;
Aldrichimica Acta 18, 25 (1985)
Edit: Ref 1 came from ChemisTris' Bee Library
(http://www.crosswinds.net/~blibrary/chemistry/index.html)