Protection for Phenols

Historically, simple n-alkyl ethers formed from a phenol and a halide or sulfate were cleaved under rather drastic conditions (e.g., refluxing HBr). New ether protective groups have been developed that are removed under much milder conditions (e.g., via nucleophilic displacement, hydrogenolysis of benzyl ethers, or mild acid hydrolysis of acetal-type ethers) that often do not affect other functional groups in a molecule. 

Deuteromethyl ethers have been used to protect phenols to prevent the methyl hydrogens from participating in free-radical reactions.  

acetone, reflux, 6 h. This is a very common and often very efficient method for the preparation of phenolic methyl ethers. The method is also applicable to the formation of phenolic benzyl ethers. 

This method selectively protects phenols with pK 8 as a result of electron-withdrawing ortho- or para-substituents. 

or R2SO4, NaOH, CH2CI2, H2O, PhCH2N Bu3Br-, 25°, 2-13 h, 75-95% yield. 

Methyl, ethyl, and benzyl ethers have been prepared in the presence of tetraethylammonium fluoride as a Lewis base (alkyl halide, DME, 20°, 3 h, 60-85% yields).  

Phenols protected as r-BuMe2Si ethers can be converted directly to methyl or benzyl ethers (Mel or BnBr, KF, DMF, rt, 90% yield).  

acetone, reflux, 6 h. This is a very common and often very efficient method for the preparation of phenolic methyl ethers. The method is also applicable to the formation of phenolic benzyl ethers. Stronger bases are not required because of the increased acidity of a phenol versus a typical alcohol. In the following case the ortho OH is more acidic by about 1 pA), unit therefore more reactive.  

Li0H H20, M62S04 0.5 eq., THF, 70-100% yield. This method results in the transfer of both methyl groups, does not isomerize amino acid derivatives, and is selective for a PhOH in the presence of an amide.  

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PROTECTION FOR PHENOLS AND CATECHOLS 24. 4-Picolyl Ether ArOCH2-4-pyridyl (Chart 4) Formation /Cleavage ... 

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