Highly Efficient and Scalable Process for Demethylation of 6-(2,4-Dimethoxybenzoyl)chromen-2-one and Other Aryl Methyl Ethers

Abstract

Demethylation of 6-(2,4-dimethoxybenzoyl)chromen-2-one and some other aryl methyl ethers was achieved with pyridinium bromide as demethylating agent and sulfolane as solvent. Compared with other demethylation methods, this combination offers advantages of clean conversion, excellent yields, easy operation and workup, and manageable reaction temperatures. This process could be particularly useful for large-scale production because it avoids use of corrosive or moisture-sensitive reagents.

Rapid and Mild Cleavage of Aryl‐Alkyl Ethers to Liberate Phenols

“…Other Lewis acidic reagents like AlCl 3 have been explored but are rarely used due to significant health and environmental burdens posed by the side-products. [10] Strong nucleophiles such as thiolates can be used for deprotection, but are limited by extreme air sensitivity. [13] Pyridinium halides are limited in their substrate compatibility due to the necessity for molten salts that require temperatures of ~200 °C.…”

“…Several methods have been developed for O ‐demethylation. For example, hydrohalic acids such as HBr are commonly used [10] . Hydrohalic acids can be applied as concentrated solutions or in tandem with glacial acetic acid [11] .…”

“…Subsequent hydrolysis forms the desired phenol alongside boric and hydrobromic acids. Despite this being a common procedure, BBr 3 is typically only used for small scale laboratory synthesis due to its high moisture sensitivity, volatility, variable yield, and corrosive nature [10] . This necessitates stringent reaction conditions that include cooling to −78 °C, flame‐dried glassware, and strict avoidance of atmospheric moisture.…”

“…Other Lewis acidic reagents like AlCl 3 have been explored but are rarely used due to significant health and environmental burdens posed by the side‐products [10] . Strong nucleophiles such as thiolates can be used for deprotection, but are limited by extreme air sensitivity [13] .…”

“…[8] These are stable, atomefficient, and tolerant of many chemical transformations. [9,10] However, their stability makes demethylation of aryl methyl ethers challenging and often impractical.…”