A New, Direct Method for Selective Demethylation of N⁺-Methyl Quaternary Ammonium Iodides

Abstract

N⁺-Methyl quaternary ammonium salts occur naturally in several families of alkaloids¹ and occur occasionally as undesired by-products in some reactions of tertiary amines.² Three general methods have been developed for demethylation of these ammonium salts:³ transfer of the quaternary methyl group to ethanolamine used as solvent, pyrolysis of the salts, and tertiary amine displacement by attack of an external nucleophile on the quaternary methyl group. Each of these methods has been used successfully in certain cases, but each also has some limitations. Methyl group transfer to ethanolamine, for example, is often accompanied by side reactions such as O-demethylation of methoxyl groups.⁴ Pyrolysis of methochlorides requires high (e.g., 200° or higher) temperatures;⁵ methacetates are pyrolyzed to the corresponding tertiary amines, but methacetates are usually highly hygroscopic and therefore hard to handle;⁶ pyrolysis of heteroaromatic methiodides occurs in dimethylformamide solution, but this demethylation process appears to be limited to heteroaromatic N⁺-methyl ammonium salts;⁷ and pyrolysis of methomercaptides causes demethylation as well as cleavage of ester groups present in the metho salt.⁸ Finally, tertiary amine displacement has been achieved by nucleophilic attack of lithium aluminum