In recent years, the development of remote functionalization methods is necessary to expand the transformations available in the organic molecules. Nitrogen-centered radicals seem an important strategy to access significant compounds, allowing the formation of key C-N bonds in organic molecules. The Hofmann-Löffler reaction represents the earliest example of nitrogen-centered radical generation to functionalize organic molecules selectively. The transformation consists in the formation of the nitrogen-centered radicals by photochemical decomposition, which through intramolecular 1,5-hydrogen atom transfer (1,5-HAT) process, generates the carbon-centered radical. Different functionalities could trap this carbon-centered radical. Typically, the transformation finishes with the formation of the pyrrolidine ring in the structure. This doctoral thesis will be focused on the applications of the Hofmann-Löffler reaction to functionalize C(sp3)-H bonds. In the first part, we developed the concept of ‘interrupted Hofmann-Löffler’ reaction to the multiple halogenation of compounds. This strategy consists in the use of sulfonamides or sulfamates esters as perfect candidates to direct the C(sp3)-H halogenation to cyclic and acyclic molecules. Moreover, sequential halogenation gave us access to introduce different halogen atoms in the same molecule.

On the other hand, the pyrrolidine core is a common structural motif in many natural products and bioactive compounds. In the second part, we investigated the use of the catalytic iodine-mediated Hofmann-Löffler discovered by our group to construct the pyrrolidine ring in the late-stage amination to synthesize nicotine and some analogs. Finally, the last project focused on applying the HLR to more complex systems such as the enantioselective synthesis of the hasubanan core.

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