A one-pot asymmetric sequential amination-alkylation of aldehydes: Expedient synthesis of aliphatic chiral amines

A one-pot asymmetric sequential amination-alkylation method has been developed for the synthesis of alkyl-alkyl' alpha-chiral primary amines (aliphatic primary amines with a chiral center adjacent to the nitrogen atom) from aldehydes. In situ aldimine formation from non-branched, alpha-branched, and beta-branched aliphatic aldehydes with (R)- or (S)-alpha-(methylbenzyl)amine [catalyzed by 5 mol-% Ti(OiPr)(4)] followed by reaction with a methyl, ethyl, or n-butyl cuprate complex in the presence of boron trifluoride or an allyl Grignard reagent provides good yield (77-88%) and diastereomeric excess (77-92 %) for amines 2 or 5. To further demonstrate the usefulness of this method, several of the secondary amine products (2d, 2e, and 5) were hydrogenolyzed, providing the corresponding enantioenriched alkyl-alkyl' alpha-chiral primary amines 3d, 3e, and 6 (86-96% yield). ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007).