Methods for the Functionalization of C-H Bonds

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Project Abstract Due to the unique physicochemical properties of fluorinated small molecules, fluorides stand as one of the simplest and sought after functional groups in medicinal chemistry. For example, the inclusion of fluorine in biologically active molecules increases the lipophilicity, bioavailability, and oxidative stability. This allows medicinal chemists to tune the metabolic stability and biodistribution of lead compounds. The primary goal of the proposed research is to develop directed H-atom abstraction as a versatile C–H fluorination strategy for synthesis. While extensive methodology has been developed for the functionalization of Csp2–H bonds, Csp3– H bonds remain challenging. The common approach of using noble metals for C–H activation is currently limited to only a few “privileged” directing groups that function under specialized conditions. The chemistry proposed here employs directed H-atom transfer to easily access Csp3–H bonds. The reactions arising from the proposed chemistry will complement and expand current C–H activation strategies through broadened directing-group compatibility and targetable Csp3–H bonds. In this project, iron-catalyzed reactions will allow a range of directing groups to selectively fluorinate specific Csp3–H bonds in a molecule. This paradigm will be employed in the fluorination of activated (Aim 1) and unactivated (Aim 2) Csp3–H bonds using readily available fluoride starting materials. These transformations will find application in the synthesis and derivatization of drug candidates, natural products, and biological probes.