| The abundance of synthetic and natural molecules with nitrogen-based functional groups has stimulated the advance of new chemical methods for C-N bond formation. The majority of existing methods involve the attack of a nucleophilic nitrogen species on an electrophilic carbon-center. The rhodium-catalyzed C-H amination methods developed in the Du Bois labs offer an important alternative approach whereby an electrophilic nitrogen species oxidizes a C-H bond. The work presented in this dissertation made key extensions to these methods. Namely, the existing methodology provided a powerful tool for the synthesis of complex nitrogen-rich molecules, but its use has been limited to intramolecular cases involving insertion into 3° sites or C-H bonds activated by adjacent electron-rich aromatic groups. The mechanistic work described in this dissertation supports the formation of a rhodium-bound nitrene as the reactive oxidant effecting C-H amination in a concerted, asynchronous event. Consistent with this mechanism, a strong preference for insertion into 3° and alpha-ethereal C-H bonds was uncovered through chemoselectivity experiments. Finally, kinetics studies have shed light on the steps of the reaction prior to nitrene formation.; These valuable insights enabled the development of two robust and important new methods. First, a method was developed to selectively aminate alpha-ethereal C-H bonds, forming N,O-acetals that can be coupled to a variety of nucleophiles. Second, an intermolecular version of the sulfamate insertion reaction was developed to provide access to benzylic amines in one step. The mechanism of this intermolecular C-H amination reaction was investigated and as with the intermolecular reaction, a nitrenoid species was implicated as the active oxidant. Analytical work also uncovered a competing radical-based pathway that leads to catalyst decomposition and undesired side products. It is anticipated that further improvements in catalyst design, coupled with these new mechanistic insights, will enable the continued development of highly efficient and robust C-H oxidation processes. |
