Development of Practical Fluorination Methods and Selective C-H Borylation of Methane

Abstract

Fluorinated (hetero)arenes are finding increasing importance in pharmaceuticals and agrochemicals. As a result, the development of mild, inexpensive, and practical methods for the formation of aryl fluorides has been highly sought. Over the past few decades, transition metal-catalyzed methods as well as mild SNAr fluorination methods have emerged as approaches for the generation of aryl‒F bonds. Despite considerable progress in this field, current methods generally suffer from the use of expensive reagents (catalysts, fluoride sources), harsh reaction conditions, poor generality to electronically diverse substrates, and inapplicability of industrial scale processes. Chapters 2‒4 of this thesis describe several approaches to overcome some of the remaining challenges in this field. Chapter 1 describes the importance of fluorinated arenes, the remaining challenges for the formation of these bonds, and the relevant precedent for the work detailed herein. Chapter 2 focuses on the development of a mild SNAr fluorination method for the conversion of (hetero)aryl chlorides and nitroarenes to the (hetero)aryl fluoride using anhydrous tetramethylammonium fluoride (NMe4F). The reagent effectively converts aryl‒X (X = Cl, Br, I, NO2, OTf) to aryl‒F with the relative rates of reactions varying with X. These mild conditions can be used for the fluorination of electron-deficient (hetero)aromatics. Chapter 3 details a mild deoxyfluorination method for the conversion of phenols to aryl fluorides through an aryl fluorosulfonate (ArOFs) intermediate. The reaction of ArOFs with NMe4F proceeds under mild conditions for many electronically diverse and functional group rich substrates. The method is then extended to a one-pot transformation of phenols to aryl fluorides with the combination of sulfuryl fluoride (SO2F2) and NMe4F. Experimental and computational studies provide insight into the mechanism of the reaction that ultimately lead to the extension of this deoxyfluorination reaction to the fluorination of aryl triflates (ArOTf). Chapter 4 is focused on the development and optimization of a mild copper(II)-mediated fluorination reaction of aryl trifluoroborates using potassium fluoride (KF). The reaction shows a broad substrate scope including application to heteroarenes. Attempts to render the reaction catalytic in copper(II) proved challenging. A system involving directing group assistance to achieve copper-catalyzed fluorination of aryl halides was investigated but reactivity remained low. Chapter 5 details the extension of the copper(II)-mediated fluorination reaction to the use of other nucleophiles to produce a wide array of functionalized products under ambient conditions. Weakly nucleophilic coupling partners react with aryl trifluoroborates in the presence of Cu(OTf)2 to form C‒O, C‒N, and C‒halide bonds. Preliminary studies point toward the importance of copper salts bearing noncoordinating counterions for this mild reactivity. Another outstanding challenge for synthetic chemists is the functionalization of the C‒H bonds of methane. While recent progress has been made in the selective functionalization of liquid alkane C‒H bonds, few of these methods have been extended to the functionalization of methane. Chapter 6 describes the development and optimization of a transition metal-catalyzed method for the C‒H borylation of methane. Formation of mono-borylated methane over di-borylated methane can be tuned as a function of catalyst with a ruthenium dimer providing the highest selectivity. Furthermore, several transition metal catalysts are shown to be more selective for methane over ethane. Examination of boron reagents reveals that bis(pinacolborane) (B2pin2) and a diboron reagent derived from pinene were most reactive and selective in this C‒H borylation reaction.