Conformation-driven C3-C(sp3)–H arylation of saturated azacycles using Pd catalyst

Directed Pd-catalysed site-selective C(sp3)–H activation offers an effective route to functionalized amines that are highly valued yet synthetically challenging in drug discovery. Despite the central importance of diverse saturated azacycles in biologically active molecules, a general strategy harnessing native endocyclic nitrogen that only works for specific types of conformation as the directing element for C–H activation of these scaffolds has remained unsolved due to conformational constraints imposed by transannular transition states. Here we report a Pd-catalysed, site- and diastereo-selective C3-C(sp3)–H arylation of saturated azacycles, enabled by temporarily converting the endocyclic nitrogen into an N-oxide directing group and a bifunctional ligand. This one-bond extension strategy enables favourable five-membered cyclopalladation, with axial N-oxide orientation being crucial for overcoming transannular ring strain as to reach the syn-axial C3-C(sp3)–H bond. The C–H activation of secondary and tertiary amines under directed Pd(II) catalysis remains challenging. Now the authors report a Pd-catalysed, site- and diastereoselective C3-C(sp3)–H arylation of saturated azacycles, enabled by conversion of the endocyclic nitrogen as N-oxide directing group and a bifunctional ligand.