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​Benzyl ether protection of an alcohol; ​Ether

SyntheticPage 309
DOI: 10.1039/SP309
Submitted May 27, 2009, published May 27, 2009
Akshat Rathi (akshat.rathi@chem.ox.ac.uk)
A contribution from Donohoe Group, Oxford


			Reaction Scheme: ​Benzyl ether protection of an alcohol

Chemicals Used

Benzyl trichloroacetimidate (Aldrich)
Trifluoromethanesulfonic acid (Alfa Aesar)
Dichloromethane (Distilled over Calcium Hydride)
Cyclohexane (Fischer Scientific)
Roche ester (Aldrich)

Procedure

Benzyl 2,2,2-trichloroacetimidate (2.23 mL, 12.0 mmol, 1.2 equiv.) was added dropwise to a stirred solution of (S)-3-hydroxy-2-methylpropionic acid methyl ester (1.11 mL, 10.0 mmol) in cyclohexane:dicholoromethane (2:1, 15 mL) at 0 °C. Trifluoromethanesulfonic acid (53 µL, 1 mmol, 0.1 equiv.) was then added dropwise and the reaction mixture was slowly allowed to warm to rt. After stirring for 20 h, the reaction mixture was filtered and washed with dicholoromethane (2 × 15 mL). The filtrate was washed with sat. aq. sodium bicarbonate (20 mL) and sat. brine (20 mL), then dried (magnesium sulphate), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (Petrol:Ether, 99:1 to 98:2) to afford (S)-methyl 3-(benzyloxy)-2-methylpropanoate (2.05 g, 98%) as a clear oil.

Author's Comments

Further addition of benzyl trichloroacetimidate (0.2 to 0.8 equiv.) helps accelerate the reaction. The major side product is trichloroacetamide which is a white crystalline solid and if polarity is increased beyond 98:2 (Petrol:Ether) during silica gel chromatography then it co-runs with the product.

Data

1H(400 MHz, Chloroform) 1.20 (3H, d, J 7.0), 2.72 - 2.89 (1H, m), 3.51 (1H, dd, J 9.0, 6.0), 3.67 (1H, dd, J 9.0, 7.5), 3.71 (3H, s), 4.53-4.55 (2H, m), 7.28-7.38 (5H, m); 13C(101 MHz, Chloroform) 14.0, 40.1, 51.7, 71.9, 73.1, 127.6, 127.6, 128.3, 138.1, 175.3.

Lead Reference

Zampella, A.; Sorgente, M.; D'Auria, M. V., Tetrahedron: Asymmetry, 2002, 13, 681 - 685 doi:10.1016/S0957-4166(02)00178-7

Other References

Iversen, T.; Bundle, K. R., J. Chem. Soc., Chem. Commun., 1981, 1240 doi:10.1039/c39810001240
White, J. D.; Reddy, G. N.; Spessard, G. O., J. Am. Chem. Soc., 1988, 110, 1624 doi:10.1021/ja00213a047

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