Transition Metal-Catalyzed Fluorination/ [18]fluorination and Decarbonylative Carbon Heteroatom Bond Formation

Abstract

The development of novel methods to incorporate fluorine and fluoroalkyl groups into organic molecules is highly desirable, as these substituents can impart unique stability, reactivity and biological properties. Over the past decade, tremendous efforts have been expended to develop transition metal-catalyzed aromatic fluorination methodologies. Nevertheless, carbon–fluorine bond formation remains challenging, especially in the context of general, functional group-tolerant late-stage fluorinations of arenes. Ultimately, gaining direct accessibility to highly functionalized and complex fluorinated pharmaceutical and radiopharmaceutical precursors is a central objective of this field. Chapter 1 describes the key challenges in the field C–F bond formation key considerations in industry, as well as the relevant history and precedent for the work detailed herein. Chapter 2 begins with our initial development of the copper-catalyzed fluorination of unsymmetrical diaryliodonium salts with KF. This transformation proceeds with high chemoselectivity and yields. Detailed computational and experimental mechanistic analyses established the key role of the solvent in catalysis and rationalized the chemoselectivity in Cu-catalyzed reactions of unsymmetrical iodonium salts. Chapter 3 describes detailed efforts into the translation of the Cu-catalyzed fluorination of diaryliodonium salts to radiofluorination. The fluorine-18 radionuclide is the most widely utilized for in vivo imaging by positron emission tomography. However, the lack of rapid, practical radiofluorination methods hinders newly developed radiotracers entering into clinic. We have identified conditions that rapidly incorporate fluorine-18 into electron-rich arenes in 20 minutes under mild conditions. Importantly this chemistry can be further applied to synthesize clinically important radiotracers. Chapter 4 details the exploration of the Cu-mediated radiofluorination of aryl boronates and aryl halides. Extensive studies on developing a new elution method allowed operationally simple, highly reproducible means to make anhydrous fluoride-18 effective for Cu catalysis. Chapter 5 investigates a novel Pa-catalyzed decarbonylative fluorintion method to incorporate a carbon-fluorine bond. The protocol aims to utilize aroyl fluorides as both the fluorine and arene source that oxidatively adds to metals in a single step, thereby minimizing the complexity and waste in this step of the synthesis. This work was further extended to form various carbon-heteroatom bonds, starting from acid chlorides in one pot.