Synthesis of Advanced Aliphatic Amines via Catalytic C(sp3)-N Bond-Formation or C(sp3)-H Functionalization

Identifier:  TDX:4571

Handle: https://hdl.handle.net/20.500.11797/TDX4571

Authors:  Chen, Jinhong

Abstract:
Amines are highly ubiquitous in bioactive natural products, pharmaceuticals, and materials. Therefore, the development of new catalytic manifolds aimed at promoting de novo C–N bond-forming reactions operating with broad applicability and practicality would be particularly valuable in both pharmaceutical and industrial laboratories. In line with our ongoing interest in Ni-catalyzed cross-coupling reactions, this doctoral thesis focuses on two main areas: 1) nickel-catalyzed C(sp3)–N bond formation via functionalization of C(sp3)–H linkages or olefins via nitrene transfer, and 2) site-selective, diverse functionalization of C(sp3)–H bonds in aliphatic amines. The initial study unravels the possibility of conducting a site-selective C(sp3)–H amidation enabled by nickel-nitrenoid catalysis. The method is characterized by a predictable reactivity pattern by selective C–N bond formation at sp3 sites adjacent to heteroatoms via open-shell species. The following chapter focuses on stereodivergent N-glycosylation via nickel catalyzed hydroamidation of glycals. The protocol provides access to either α- or β-N-glycosides through forging C(sp3)–N glycosidic bonds on kinetic or thermodynamic grounds. On the other hand, we have developed a new platform for enabling remote functionalization of aliphatic amines via a site-selective bromination event at distal C(sp3)–H sites enabled by protonation of the amine function. The resulting brominated scaffolds serve as a synthetic linchpin that can be easily transformed to a series of carbon–carbon and carbon–heteroatom bonds, thus offering access to advanced sp3 architectures possessing valuable aliphatic amine moieties.