Copper-catalysed enantioconvergent N-alkylation of hydrazines with racemic α-haloamides to access enantioenriched hydrazines.

Abstract

Chiral hydrazines are important building blocks in chiral drug molecules, N-amino peptides, and aza-heterocycles. The catalytic enantioconvergent N-alkylation of readily available hydrazine derivatives with various racemic alkyl halides offers a highly attractive route to chiral hydrazines. However, this process remains challenging due to the lack of efficient asymmetric catalytic systems and the difficulty in achieving regioselectivity at the N¹/N² positions of hydrazine derivatives. Herein, we demonstrate a general copper-catalysed enantioconvergent N-alkylation of hydrazine derivatives with racemic α-haloamides. This strategy provides a modular approach for the synthesis of diverse enantioenriched hydrazines with excellent regio- and enantioselectivity. The key to success lies in the development of a radical-polar crossover nucleophilic substitution process and the employment of suitable hydrazine nucleophiles. Furthermore, this method provides a versatile platform to access a series of enantioenriched aza-heterocycles through facile subsequent transformations. It also enables the stereodivergent synthesis of all four possible stereoisomers of N-amino dipeptides bearing two stereocenters, with excellent stereoselectivity.