Alkylation of Phenols
The alkylation reaction of phenols can be accomplished by the reaction of phenol with diazo alkane, the reaction of phenol with alkyl halide, sulfuric acid, or sulfurous acid in the presence of base, or the reaction of phenol with olefin under acid catalysis.
- Diazoalkane Alkylation
Diazoalkane reacts quickly with phenol in an inert solvent to form an alkyl ether with very few by-products. For example, excess diazomethane reacts with protocatechuic acid to generate dimethoxy derivatives. If the amount of diazomethane is controlled, the more acidic para-hydroxyl can be selectively methylated.
The catechol group reacts with boric acid or its salt in an aqueous solution to form a boric acid cyclic ester compound that is no longer methylated by diazomethane. Therefore, flavonol rhamnetin can be prepared from flavonoid rutin.
- Alkylation of Haloalkane with Sulfate
The most commonly used phenol alkylation method is to react alkyl halide or sulfate with phenol or acylated phenol in the presence of base. This type of reaction is the nucleophilic substitution of the alkyl group by the phenoxide anion or the phenol itself.
The monomethylation of catechol and resorcinol is best reacted with a limited amount of dimethyl sulfate at pH=8~9.
The hydroxyl group in the ortho position of the carboxyl group or the hydroxyl group forming a strong hydrogen bond, like diazomethane, is not easily methylated by haloalkane or sulfate.
In polyphenol compounds, when it is necessary to protect the ortho-position bisphenol group, it can be realized by double-coordinating methine, isopropylidene, or diphenylmethine. The reaction is carried out according to the general alkylation procedure.
Dealkylation of Phenol Ethers
- Acid Reagent
Almost all alkyl phenol ethers can be broken by acidic reagents under suitable conditions. The order of stability of various alkyl groups is as follows:
－OCH2R>－OCH(CH3)2,－OCH2Ph>－C(CH3)3,－OCH2OCH3,－O－Tetrahydropyranyl.
Generally speaking, methyl ether is the most stable, while oxymethyl ether and tetrahydropyran ether with an acetal structure are easier to remove.
Because tert-butyl ether is easy to crack, it has been used to synthesize pseudouridine from pyrimidine. When methanol hydrochloride is used, the protective ether group can be removed by heating for 2 minutes at 60 oC, but the furan ring structure of sugar will not be changed under this condition.
- Oxidation Reagent
P-dimethoxybenzene compounds are oxidized by nitric acid, chromic anhydride, or cerium sulfate to demethylate to p-quinone, which is reduced to p-dihydroxyl structure. For example, the 6-hydroxy derivative of iso-anisolactone to bergamot lactone is to remove the protective group by oxidant, and the last step takes advantage of the instability of benzyl ether and methyl ether to acid.
- Boron Halide and Aluminum Halide
Boron trihalide and aluminum trihalide are the most effective reagents for dealkylation, especially demethylation.
Because the ether group at the 2-position of 1,2,3-glucinol trimethyl ether is sensitive to acid, but under controlled conditions, aluminum bromide and aluminum chloride can selectively remove the ortho-position and para-position of the carbonyl or meta-ether groups:
- Grignard Reagent and Magnesium Iodide
Grignard reagents can split alkyl phenyl ethers and have selectivity.
The role of the Grignard reagent comes from the magnesium halide in the molecule; after that, magnesium iodide is used as the deether reagent, which has a selective removal effect on the methoxy group at the meta-position of the carbonyl group.
- Nucleophiles and Base Catalysis
The deetherization of acid, halogenated boron, and aluminum chloride can be classified as catalysis: they can form coordination bonds with the lone electron pairs of oxygen in the ether, thus contributing to the nucleophilic attack of alkyl groups. In the absence of these catalysts, strong nucleophiles such as -SPh, -NH2, -PPh2, -AsPh2, and-SC2H5 can be used as dealkylation agents under specific conditions. When the resulting phenol salt is an anion stabilized by the conjugation effect, only the hydroxyl ion is sufficient for dealkylation.
- Reducing Agent
Benzyl ethers can be hydrogenolyzed not only by acid reagents but also by acid reagents, so benzyl groups can be selectively removed from an ether compound containing benzyl and methyl groups, which is often used to synthesize partially methylated polyphenols.
