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

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. The catalytic enantioconvergent N-alkylation of hydrazine derivatives with alkyl halides offers an attractive route to chiral hydrazines, but remains challenging due to the lack of efficient asymmetric catalytic systems and the difficulty in achieving regioselectivity. Herein, the authors report the copper-catalyzed enantioconvergent N-alkylation of hydrazine derivatives with racemic α-haloamides.