Radical Benzylic C-H Fluorinatioin: The Use of Unprotected Amino Acids as Radical Precursors, Pyridines as Halogen Bond Acceptors, and the Development of a Novel Hydrogen Atom Transfer Agent

Author(s): Hua, Alyssa Minh Doan | Advisor(s): Baxter, Ryan D.; Hratchian, Hrant P. | Abstract: Benzylic C–H bonds are ubiquitous in pharmaceutical and other biologically active compounds. The low BDE of the benzylic C–H bond has made it a target for further functionalization, where the original bond may be replaced with a C–C bond, C–O bond, C–N bond, or C–X bond, (where X = halogen). While the functionalization of benzylic C–H bonds to C–C/O/N bonds are relatively well established, selective halogenation proves to be more challenging. Halogenation typically refers to chlorination, bromination, and iodination, but has recently come to include fluorination. Achieving fluorination has traditionally been cumbersome. Classical methods of generating a C–F bond typically require harsh conditions with highly toxic reagents. C–F bond formation has increasingly become of interest primarily for its advantageous biological features. The focus of this dissertation will be method development and mechanistic investigation of silver(I)-catalyzed benzylic C–H fluorination via radical pathways. Recent developments of new fluorinating reagents have afforded methods that no longer require highly toxic chemicals; however, current radical fluorination still require harsh reagents, (e.g. strong oxidants), or have a limited substrate scope. Utilizing the idea of radical decarboxylative fluorination, and the demonstrated utility of radical decarboxylation of unprotected amino acids, a novel radical decarboxylative benzylic fluorination pathway was designed where unprotected amino acids were used as radical precursors to facilitate HAT at the benzylic site, and ultimately allow for subsequent fluorination. Upon further mechanistic investigation of the unprotected amino acids system, it was found that radical benzylic fluorination was achievable in the absence of an amino acid, so long as a free nitrogen-bearing compound, such as pyridine, was present. Through experimental and theoretical investigations, it was proposed that halogen bonding between the pyridine and fluorinating agent was facilitating the more efficient radical benzylic fluorination pathway by producing a stronger HAT agent.