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

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.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/138679/1/schimles_1.pd

Novel Organocobalt Anticancer Agents: Synthesis and Studies of the Mode of Action

Inorganic medicinal chemistry is a current area of important research. While platinum containing compounds like cisplatin have wide use in cancer chemotherapy, organometallic compounds are an underscreened population which may have useful medicinal properties. Novel organometallic anticancer compounds are being designed such that they exhibit a different mode of action from cisplatin, as many of the side effects associated with this compound are a result of its interaction with DNA. Recently, a class of compounds consisting of hexacarbonyl dicobalt bound to an alkyne has been found to exhibit notable anticancer activity. In order to evaluate the role of the hexacarbonyl dicobalt and the ligand in the bioactivity, a series of novel cobalt-alkyne complexes have been synthesized from propargyl aryl ethers and dicobalt octacarbonyl, and the cytotoxic properties of these compounds were assayed. Studies on the mode of action of these compounds were performed using flow cytometry, including the ability of the compounds to induce apoptosis, the effect of these compounds on the production of reactive oxygen species (ROS), the effect on the mitochondria, and the effect on the cell cycle. The most active of these compounds, (propargyl p-nitrophenyl ether) hexacarbonyldicobalt (Co-NO2), showed strong antiproliferative activity against the MDA-MB-231 breast cancer cell line. Further synthetic studies showed that this ligand and the cobalt-alkyne complex were essential for the antiproliferative activity. This compound has been shown to initiate apoptosis in this cell line as observed by the loss of plasma membrane asymmetry. Furthermore, Co-NO2 increases intracellular levels of ROS and disrupts the mitochondrial transmembrane potential. Co-NO2 affects the cell cycle in such a way that fewer cells are undergoing mitosis, indicating that this compound is having an effect on the ability of these compounds to proliferate. Co-NO2 represents a novel compound to the field of organometallic anticancer compounds

Cu(OTf)₂‑Mediated Fluorination of Aryltrifluoroborates with Potassium Fluoride

This Communication describes the Cu­(OTf)₂-mediated fluorination of aryltrifluoroborates with KF. The reaction proceeds under mild conditions (at 60 °C over 20 h) and shows a broad substrate scope and functional group tolerance. The Cu is proposed to play two separate roles in this transformation: (1) as a mediator for the aryl–F coupling and (2) as an oxidant for accessing a proposed Cu^III(aryl)­(F) intermediate

Acyl Azolium Fluorides for Room Temperature Nucleophilic Aromatic Fluorination of Chloro- and Nitroarenes

The reaction of acid fluorides with <i>N</i>-heterocyclic carbenes (NHCs) produces anhydrous acyl azolium fluorides. With appropriate selection of acid fluoride and NHC, these salts can be used for the room temperature S_NAr fluorination of a variety of aryl chlorides and nitroarenes

Anhydrous Tetramethylammonium Fluoride for Room-Temperature S_NAr Fluorination

This paper describes the room-temperature S_NAr fluorination of aryl halides and nitroarenes using anhydrous tetramethylammonium fluoride (NMe₄F). This reagent effectively converts aryl-X (X = Cl, Br, I, NO₂, OTf) to aryl-F under mild conditions (often room temperature). Substrates for this reaction include electron-deficient heteroaromatics (22 examples) and arenes (5 examples). The relative rates of the reactions vary with X as well as with the structure of the substrate. However, in general, substrates bearing X = NO₂ or Br react fastest. In all cases examined, the yields of these reactions are comparable to or better than those obtained with CsF at elevated temperatures (i.e., more traditional halex fluorination conditions). The reactions also afford comparable yields on scales ranging from 100 mg to 10 g. A cost analysis is presented, which shows that fluorination with NMe₄F is generally more cost-effective than fluorination with CsF