Copper Catalyzed Fluorination of Aryl Halides

铜催化芳基卤化物的氟化

• 批准号: 10115518
• 负责人: Liam Shin Sharninghausen
• 金额: $ 6.64万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115518
• 关键词: Address; Agrochemicals; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Area; Complex; Copper; Development; Diagnosis; Disease; Electrons; Enzyme Inhibitor Drugs; Fluorides; Fluorine; High temperature of physical object; Imaging Device; Imaging Techniques; Label; Lead; Ligands; Mediating; Metals; Methods; Parkinson Disease; Periodicity; Pharmacologic Substance; Positron-Emission Tomography; Process; Property; Protocols documentation; Radioisotopes; Reaction; Reporting; Research; Salts; Series; Source; System; Tracer; Transition Elements; Work; analog; aryl halide; base; carbene; catalyst; cost; functional group; improved; in vivo imaging; metal complex; non-invasive imaging; novel; prevent; radiotracer; scaffold

Project Summary. The aryl fluoride motif is prevalent in a range of important compounds. >25% of agrochemicals and >20% of pharmaceuticals contain fluorine, often in the form of aryl fluoride. Additionally, 18F is the favored radioisotope in Positron Emission Tomography (PET), an in-vivo imaging technique used in the diagnosis and treatment of diseases such as Alzheimer's and Parkinson's. Despite the widespread use of aryl fluorides in these areas, there are currently very few robust and functional group tolerant methods for their synthesis. Developing more efficient methods to introduce fluorine into organic molecules is therefore a priority. One promising method is the transition metal catalyzed synthesis of aryl fluorides from readily available aryl halides. However, there are few reported systems for this transformation. The two prior Cu-based systems use simple Cu salts and pose significant drawbacks that need to be addressed, such as the requirement for high temperatures, an excess of expensive fluoride source (AgF), supersoichiometric Cu, or limitation to specific directing groups. Developing systems that overcome these limitations is therefore an extremely important unsolved problem in the field. In order to improve on these systems, we aim to address key challenges inherent to Cu: (i) the instability of most CuIF complexes to disproportionation to form inactive Cu0 and CuF2 and (ii) the difficulty of the oxidative addition step. To overcome these issues we will move from simple Cu salts to well-defined copper complexes supported by N-heterocyclic carbenes (NHCs), cyclic alkyl amino carbene (CAACs), or related ligands. We hypothesize that these ligands will stabilize CuI intermediates, as well as favor oxidative addition, leading to more efficient catalysts. Specifically, we aim to use carbene-supported Cu complexes to: (1) study the effects of ligand properties on stoichiometric fluorination of aryl halides, (2) develop catalytic fluorination of a range of pharmaceutically relevant aryl halide scaffolds (3) synthesize 18F labeled tracer molecules for use in PET imaging. Completion of these aims will result in improved systems for the fluorination of aryl halides that can be applied to synthesis of pharmaceuticals, agrochemicals and PET tracers. Preliminary results have been obtained that support the feasibility of each proposed aim.

项目摘要。 芳基氟基序普遍存在于一系列重要的化合物中。 >25% 的农用化学品和 >20% 的药物含有氟，通常以芳基氟的形式存在。另外，18F是首选 正电子发射断层扫描（PET）中的放射性同位素，一种用于诊断和治疗的体内成像技术 治疗阿尔茨海默氏症和帕金森氏症等疾病。尽管芳基氟化物广泛用于 在这些领域，目前很少有稳健且官能团耐受的合成方法。 因此，开发更有效的方法将氟引入有机分子是当务之急。一 有前途的方法是过渡金属催化从容易获得的芳基卤化物合成芳基氟化物。 然而，关于这种转变的系统报道很少。之前的两个基于铜的系统使用简单的 铜盐并带来了需要解决的重大缺点，例如对高 温度、过量昂贵的氟化物源 (AgF)、超化学计量的铜或限制到特定的 指导小组。因此，开发克服这些限制的系统极为重要 领域未解决的问题。为了改进这些系统，我们的目标是解决关键挑战 Cu 固有的特性：(i) 大多数 CuIF 络合物对歧化形成不活泼的 Cu0 和 CuF2 的不稳定性 (ii)氧化加成步骤的难度。为了克服这些问题，我们将不再使用简单的铜盐 到由 N-杂环卡宾 (NHC)、环烷基氨基卡宾支持的明确铜配合物 （CAAC）或相关配体。我们假设这些配体将稳定 CuI 中间体，并有利于 氧化加成，导致更有效的催化剂。具体来说，我们的目标是使用卡宾支撑的铜 配合物：(1) 研究配体性质对芳基卤化物化学计量氟化的影响，(2) 开发 催化氟化一系列药学相关的芳基卤化物支架 (3) 合成 18F 标记 用于 PET 成像的示踪分子。完成这些目标将导致改进系统 芳基卤化物的氟化，可应用于药物、农用化学品和PET示踪剂的合成。 已经获得的初步结果支持每个拟议目标的可行性。

项目成果

Copper-Mediated Radiocyanation of Unprotected Amino Acids and Peptides.

• DOI: 10.1021/jacs.2c01959
• 发表时间: 2022-04-27
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Sharninghausen, Liam S.;Preshlock, Sean;Joy, Stephen T.;Horikawa, Mami;Shao, Xia;Winton, Wade P.;Stauff, Jenelle;Kaur, Tanpreet;Koeppe, Robert A.;Mapp, Anna K.;Scott, Peter J. H.;Sanford, Melanie S.
• 通讯作者: Sanford, Melanie S.

Sequential Ir/Cu-Mediated Method for the Meta-Selective C-H Radiofluorination of (Hetero)Arenes.

（杂音）领域的元选择性C-H射荧光的顺序IR/CU介导的方法。

• DOI: 10.1021/jacs.1c00523
• 发表时间: 2021-05-12
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Wright JS;Sharninghausen LS;Preshlock S;Brooks AF;Sanford MS;Scott PJH
• 通讯作者: Scott PJH

Tandem Iridium-Catalyzed C-H Borylation/Copper-Mediated Radiofluorination of Aromatic C-H Bonds with [18F]TBAF.

[18F]TBAF 串联铱催化 C-H 硼化/铜介导的芳香族 C-H 键放射性氟化。

• DOI: 10.1007/978-1-0716-3499-8_4
• 发表时间: 2024
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Morales,Maria;Preshlock,Sean;Sharninghausen,LiamS;Wright,JayS;Brooks,AllenF;Sanford,MelanieS;Scott,PeterJH
• 通讯作者: Scott,PeterJH

Copper-Mediated Late-stage Radiofluorination: Five Years of Impact on Pre-clinical and Clinical PET Imaging.

• DOI: 10.1007/s40336-020-00368-y
• 发表时间: 2020-06
• 期刊: Clinical and translational imaging
• 影响因子: 2.1
• 作者: Wright JS;Kaur T;Preshlock S;Tanzey SS;Winton WP;Sharninghausen LS;Wiesner N;Brooks AF;Sanford MS;Scott PJH
• 通讯作者: Scott PJH

Copper-Mediated Fluoroalkylation of Aryl Bromides and Chlorides Enabled by Directing Groups.

• DOI: 10.1021/acs.organomet.3c00066
• 发表时间: 2023-03
• 期刊: Organometallics
• 影响因子: 2.8
• 作者: Jonathan R. Hall;Isaac M Blythe;Liam S. Sharninghausen;M. Sanford