Copper-catalyzed N-demethylation Of Amides

The C-N bond is one of the most common chemical bonds in nature,and it is widely found in organic macromolecules and biomolecules.How to break the C-N bond greenly and efficiently has always been a hot issue in the discipline of chemistry.The N-demethylation reaction is a form of C-N bond breaking,and the efficient N-demethylation reaction is of great significance for chemical synthesis,alkaloid derivation,and drug synthesis.Amide is a common compound that occupies an important position in medicine,dyes,pesticides,and chemicals.At present,amide drugs account for about 25% of registered drugs.Compared with amines,amides are more difficult to undergo oxidation and nucleophilic substitution reactions,so the N-demethylation of amides has always been a problem in organic synthesis.In this paper,a new method for N-demethylation of amides is established.The reaction uses N-fluorobisbenzenesulfonamide(NFSI)as the oxidant and copper acetylacetonate as the catalyst to convert N-methylamides to the corresponding carbonolamines through a successive single electron transfer-hydrogen atom transfer-hydrolysis process,and carbonolamines decompose to N-demethylated amides.In this paper,through a series of optimization experiments,the best reaction conditions are obtained.Using the best reaction conditions,N-demethylation experiments were carried out on more than 30 different N-methylamides.Through cyclicvoltammetry,high-resolution mass spectrometry,nuclear magnetic resonance spectroscopy,isotope labeling and other methods,the mechanism of the reaction was speculated and proved.The reaction has the characteristics of mild reaction conditions and wide applicability of substrates.This method solves the problem that it is difficult for amide to undergo N-demethylation reaction.