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

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

[发布机构] University of Michigan

[效力级别] copper

[关键词] fluorination;copper;PET;Chemistry;Science;Chemistry