Utilization of Cyclic Amides as Masked Aldehyde Equivalents in Reductive Amination Reactions

J Org Chem. 2019 Jun 21;84(12):7936-7949. doi: 10.1021/acs.joc.9b00816. Epub 2019 May 31.

Abstract

An operationally simple protocol has been discovered that couples primary or secondary amines with N-aryl-substituted lactams to deliver differentiated diamines in moderate to high yields. The process allows for the partial reduction of a lactam in the presence of Cp2ZrHCl (Schwartz's reagent), followed by a reductive amination between the resulting hemiaminal and primary or secondary amine. These reactions can be telescoped in a one-pot fashion to significantly simplify the operation. The scope of amines and substituted lactams of various ring sizes was demonstrated through the formation of a range of differentiated diamine products. Furthermore, this methodology was expanded to include N-aryl pyrrolidinone substrates with an enantiopure ester group at the 5-position, and α-amino piperidinones were prepared with complete retention of stereochemical information. The development of this chemistry has enabled the consideration of lactams as useful synthons.

Publication types

  • Research Support, Non-U.S. Gov't