Synthesis Of N-methyl-n-alkylamine Derivatives

Amines and their derivatives are prevalent functionalities in various natural products and unnatural synthetic targets. Due to its unique biological properties, the amine moiety has played a central role in chemotherapeutics of numerous diseases. In particular, the synthesis of secondary amines has long been of interest because of their potential as robust pharmacophores and as useful synthetic intermediates.Direct N-alkylation appears deceptively simple, but it is well known that the synthetic value of this method is limited due to the concomitant overalkylation, giving rise to mixtures of primary, secondary, and tertiary amines, as well as quaternary ammonium salts. So in order to reduce amine nucleophilicity, protection-deprotection strategy was used to synthesize N-methyl-N-alkylamine derivatives.In this paper a simple method was developed for the mono-N-methylation of primary amine. Methyl amine was firstly treated with ethyl acetate to afford N-methylacetamide. Subsequent treatment with n-butyl bromide gave Ac-protected N-butyl methylamine. It was found that the yield of N-alkylation reaction was affected by the amount of base and catalyst, reaction time and temperature. The optimum conditions were obtained finally. Then several alkyl halides were employed to react under the optimum conditions, which upon hydrolysis removal of acetyl group in basic conditions yielded N-methylamine derivatives.