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The demethylation reaction of methyl ethers (converting methyl ethers into alcohols or phenols) is an important transformation process in organic synthesis. Depending on the reaction conditions and substrate types, it can be classified into the following four categories: 1. Acidic conditions; 2. Lewis acid conditions; 3. Sulfide salt conditions; 4. Redox conditions. Additionally, there are other special conditions such as enzyme catalysis or photo-catalysis.
1. Demethylation under acidic conditions is the most classic method, suitable for substrates that are stable to acids.
HBr (48% aqueous solution or acetic acid solution): Reaction carried out under reflux, generating alcohols and halogenated methanes. HI: More reactive, capable of breaking methyl ethers, benzyl ethers, etc. The potassium iodide/phosphoric acid system is often used instead of pure HI.
2. Lewis acid:
BBr₃: Mild conditions, high selectivity (especially suitable for generating phenols from aromatic methyl ethers), the reaction is carried out at low temperatures (-78°C to room temperature). BBr₃ preferentially breaks the ether bonds with lower steric hindrance.
AlCl₃ / NaI: Reaction carried out in reflux in acetonitrile, generating HI in situ.
TMSI (trimethylsilyl iodide): Strong de-methylating reagent, mild conditions (room temperature), especially suitable for substrates sensitive to acids (such as sugars). The mechanism is that the iodide ion undergoes nucleophilic attack on the methyl group.
3. Sulfide salt method:
NaSEt or PhSH with Lewis acid (such as AlCl₃): Reaction carried out at high temperatures, the sulfide salt undergoes nucleophilic attack on the methyl group. Suitable for substrates that are unstable to acids (such as sugars).
4. Oxidative demethylation:
CAN (sodium ceric ammonium nitrate): Suitable for electron-rich aromatic methyl ethers (such as aromatic ethers), oxidized to quinone intermediates in acetonitrile/water solution, then hydrolyzed to phenols.
DDQ (dichlorodicyanobenzoquinone): Similar to CAN, mild conditions.
