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 C=C bond of the molecule with the aminomethyl fragment at one atom and hydrogen or heteroatom at the other. This paper describes a three-step approach to the aminomethylation of electron-deficient alkenes, facilitating their α,β-difunctionalization and an introduction of two aminomethyl fragments into both positions of the alkene. The initial [3+2]-cycloaddition reaction of nonstabilized azomethine ylide at the C=C double bond of enones and subsequent treatment with alkyl halides lead to the formation of a key intermediate of the process – quaternary ammonium salt of 3-acylpyrrolidine. Heating of such 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.