Transition metal-catalyzed intermolecular C(sp³)-H animation reactions

Nitrogen is a fundamental element in almost every area of chemistry, playing an essential role in biological systems, pharmaceuticals, agrochemicals, and material science. In organic synthesis, the development of efficient methods to introduce nitrogen-based functionalities in a chemo- regio- and stereoselective manner is a major challenge. In this context, transition metals complexes have been studied and designed to directly functionalize ubiquitous C–H bonds, with a number of attractive and straightforward methods to forge new C–N bonds without the need of pre-functionalized materials. Indeed, C(sp3)–H amination reactions have recently emerged as powerful tools for the synthesis of nitrogen-containing pharmaceutical fragments and natural products.
This thesis focuses on the development of novel transition metal-catalyzed intermolecular C(sp3)–H amination reactions.
Specifically, we explored the design and synthesis of a safe and highly reactive amidating reagent for the direct and selective synthesis of vicinal aminoalcohols and diamines. The studied reagent, in combination with an iridium-based catalytic system, promotes the C(sp3)–H amination of alcohols and diamines under mild and practical conditions. Furthermore, the high reactivity of iridium nitrenoids was employed for the development of an intermolecular protocol for the C(sp3)–H amination of benzylic and aliphatic substrates.
Next, we discovered that catalytic amounts of abundant and benign FeCl2 can promote the site-selective C(sp3)–H amination of pharmaceutically relevant N-heterocycles, in an appealing late stage functionalization logic. The developed method was then applied to the total synthesis of the reported structure of senobtusin, an atypical alkaloid with an amidine moiety. In addition, kinetic studies helped gaining insights in the reaction’s mechanism.
Altogether, the research presented in this thesis contributes to the growing field of C–H amination, offering novel, sustainable and atom-economical strategies for the synthesis of amines.