New Strategies and Transformations for the alpha-Functionalization of Amines to Access Chiral Amines

New methodologies to prepare alpha-functionalized amines, especially chiral amines have been studied in this work. Specifically, we focused our work on introducing alpha-functionalization to amines through C–C forming processes. This thesis work is inspired by the vitamin B6 transamination process: forming ketimines or aldimines to increase the acidities of alpha-C–H protons of amines, thereby enabling the alpha-C–H deprotonation accessible under mild reaction conditions for further derivation. Based on this known process mechanism, we first explored the umpolung functionalization of amines through deprotonation of ketimines/aldimines, then a migratory insertion process from metal-hydrides to 2-azadienes have been further developed. Of these processes, this thesis work will specifically focus on the research exploration of three synthons: 2-azaallyl anion, 2-azaaalyl radical and 2-azadiene.

We began investigating processes to access alpha-amino anions directly through alpha-deprotonation of imines (formation of 2-azaallyl anions). The alpha-amino anion was then utilized in two further reactions: 1. enantiospecific ring-opening of aziridines to access 1,3-diamines and 2. enantioselective Pd-catalyzed allylation to obtain homoallylic amines.

Following our research of 2-azaallyl anions, we developed a metal-free cross-coupling reaction between 2-azaallyl radicals and single-electron acceptors such as 1,4-dicyanobenzene. The reaction efficiently delivered the desired two-component product at room temperature without additional catalysts. This reaction indicated the formation of radical pairs : 2-azaallyl radicals from 2-azaallyl anions and radical anions from the single-electron acceptors. We then examined a few plausible three-component coupling reactions to utilize alkene to intercept the radical pairs to prepare more complicated functionalized amines.

In the last part, we have developed 2-azadienes as platforms to access functionalized amines via alpha-amino transition metal species. Through migratory insertion of a copper hydride into 2-azadienes, we could access alpha-aminoalkyl metal species, which could be further used in reactions with various electrophiles. Two applications were examined in this chapter: 1) addition to ketones to access 1,2-amino tertiary alcohols and 2) addition to aldimines/ketimines to access 1,2-diamines.