Three-step alkylaminomethylative α,β-difunctionalization of enones†

Abstract

Aminomethylation of alkenes is a convenient methodology for the synthesis of aliphatic amines. This direction encompasses various methods, mainly allowing functionalization of the CC bond of the molecule with the aminomethyl fragment at one atom and hydrogen or a heteroatom at the other. This paper describes a three-step approach for the aminomethylation of electron-deficient alkenes, facilitating their α,β-difunctionalization and the introduction of two aminomethyl fragments into both positions of the alkene. The initial [3 + 2]-cycloaddition reaction of the nonstabilized azomethine ylide at the CC double bond of enones and subsequent treatment with alkyl halides lead to the formation of a key intermediate of the process – a quaternary ammonium salt of 3-acylpyrrolidine. Heating of such a salt in a polar solvent in the presence of a nucleophile results in a tandem Hofmann elimination/Michael addition to give 2-heteromethyl-4-aminobutan-1-ones with high diastereoselectivity and good to high overall yields. The proposed method benefits from inexpensive and available reagents, does not require noble metal catalysis and provides opportunities to apply a wide range of nucleophiles and alkyl halogenides, resulting in broad customization of the introduced heteromethyl moieties.