Synthetic Strategies to Control C–N Atropisomerism in Acyclic Amines and Amides

Abstract

Atropisomeric molecules are a privileged class of stereogenic material that have important applications in catalysis, materials science and medicines. To date, the majority of work has been focused upon biaryl and heterobiaryl scaffolds involving restricted rotation between a pair of cyclic fragments, but C–N atropisomeric molecules based upon amines and amides where the nitrogen atom is not part of a ring system are rapidly emerging as an important class of stereogenic molecules. This is the focus of this Short Review article, which begins by discussing the factors which influence the configurational stability of such molecules and provides a historical background to their synthesis. This is followed by a detailed discussion of state-of-the-art catalytic asymmetric strategies that are now available to access C–Nacyclic atropisomers including carboxamides, sulfonamides, sulfinamides, phosphamides and diarylamines. A variety of different synthetic approaches are discussed including kinetic resolution/desymmetrization, amination, C–H functionalization, N-functionalization, and annulation.

Synthesis, structure and stereodynamics of atropisomeric N-chloroamides

“…the herbicide metolachlor). 4 However, in contrast to biaryls, atropisomerism in anilides is complicated by the possibility of rotation about multiple bonds. Although several studies have interrogated the impact of structural modifications on the configurational stability of anilides, 5,6 it is not established whether racemization occurs via direct Ar–N bond rotation or in correlation with rotation about the N–CO bond as reported by Clayden and co-workers for C–C atropisomeric benzamides.…”

Regio- and Stereoselective α-Allylation with Enolates Prepared from N–C Axially Chiral Thiolactam and Lactam

“…Recently, catalytic enantioselective syntheses of N–C axially chiral compounds (atropisomers owing to the rotational restriction about an N–C single bond) have been reported by many groups . Most N–C axially chiral compounds, which were prepared through a catalytic asymmetric method, are either carboxamide derivatives or nitrogen-containing aromatic heterocycles.…”