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

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.PhDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/133480/1/naokoi_1.pd

Automated synthesis of PET radiotracers by copperâ mediated 18Fâ fluorination of organoborons: Importance of the order of addition and competing protodeborylation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142980/1/jlcr3583_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142980/2/jlcr3583.pd

Pd-Catalyzed Decarbonylative Cross-Couplings of Aroyl Chlorides

This report describes a method for Pd-catalyzed decarbonylative cross-coupling that enables the conversion of carboxylic acid derivatives to biaryls, aryl amines, aryl ethers, aryl sulfides, aryl boronate esters, and trifluoromethylated arenes. The success of this transformation leverages the Pd⁰/Brettphos-catalyzed decarbonylative chlorination of aroyl chlorides, which can then participate in diverse cross-coupling reactions <i>in situ</i> using the same Pd catalyst

Palladium- and Nickel-Catalyzed Decarbonylative C–S Coupling to Convert Thioesters to Thioethers

This Letter describes the development of a catalytic decarbonylative C–S coupling reaction that transforms thioesters into thioethers. Both Pd- and Ni-based catalysts are developed and applied to the construction of diaryl, aryl alkyl, and heterocycle-containing thioethers

Mechanistic Investigations of Cu-Catalyzed Fluorination of Diaryliodonium Salts: Elaborating the Cu^I/Cu^III Manifold in Copper Catalysis

A combination of experimental and density functional theory (DFT) investigations suggests that the Cu-catalyzed fluorination of unsymmetrical diaryliodonium salts with general structure [Mes­(Ar)­I]⁺ in <i>N</i>,<i>N</i>′-dimethylformamide proceeds through a Cu^I/Cu^III catalytic cycle. A low concentration of fluoride relative to combined iodonium reagent plus copper ensures that [Mes­(Ar)­I]⁺ is available as the reactive species for oxidative “Ar⁺” transfer to a Cu^I center containing one or two fluoride ligands. A series of different possible Cu^I active catalysts (containing fluoride, triflate, and DMF ligands) have been evaluated computationally, and all show low-energy pathways to fluorinated products. The oxidation of these Cu^I species by [Mes­(Ar)­I]⁺ to form <i>cis</i>-Ar­(F)­Cu^III intermediates is proposed to be rate-limiting in all cases. Ar–F bond-forming reductive elimination from Cu^III is computed to be very facile in all of the systems examined. The conclusions of the DFT experiments are supported by several experimental studies, including tests showing that Cu^I is formed rapidly under the reaction conditions and that the fluoride concentration strongly impacts the reaction yields/selectivities

Cu-Catalyzed Fluorination of Diaryliodonium Salts with KF

A mild Cu-catalyzed nucleophilic fluorination of unsymmetrical diaryliodonium salts with KF is described. This protocol preferentially fluorinates the smaller aromatic ligand on iodine(III). The reaction exhibits a broad substrate scope and proceeds with high chemoselectivity and functional group tolerance. DFT calculations implicate a Cu^I/Cu^III catalytic cycle

Copper-Catalyzed [¹⁸F]Fluorination of (Mesityl)(aryl)iodonium Salts

A practical, rapid, and highly regioselective Cu-catalyzed radiofluorination of (mesityl)­(aryl)­iodonium salts is described. This protocol utilizes [¹⁸F]­KF to access ¹⁸F-labeled electron-rich, -neutral, and -deficient aryl fluorides under a single set of mild conditions. This methodology is applied to the synthesis of protected versions of two important radiotracers: 4-[¹⁸F]­fluorophenylalanine and 6-[¹⁸F]­fluoroDOPA

Synthesis of [¹⁸F]Arenes via the Copper-Mediated [¹⁸F]Fluorination of Boronic Acids

A copper-mediated radiofluorination of aryl- and vinylboronic acids with K¹⁸F is described. This method exhibits high functional group tolerance and is effective for the radiofluorination of a range of electron-deficient, -neutral, and -rich aryl-, heteroaryl-, and vinylboronic acids. This method has been applied to the synthesis of [¹⁸F]­FPEB, a PET radiotracer for quantifying metabotropic glutamate 5 receptors