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。 芳基氟化物基序在一系列重要的化合物中普遍存在。 > 25％的农产品和 > 20％的药物含有氟，通常是芳基氟化物的形式。另外，18F是受欢迎的 正电子发射断层扫描（PET）中的放射性同位素，这是一种用于诊断和诊断和 治疗阿尔茨海默氏症和帕金森氏症等疾病。尽管广泛使用芳基氟化物 这些领域，目前很少有可靠和功能性的耐受性方法用于其合成。 因此，开发更有效的方法将氟引入有机分子是一个优先级。一 有希望的方法是从容易获得的芳基卤化物中催化的催化金属合成。 但是，对于这种转换，很少有报道的系统。两个先前的基于CU的系统使用简单 Cu盐和构成需要解决的重大缺点，例如高度要求 温度，昂贵的氟化物来源（AGF），超化学计量计或特定的限制 导演组。因此，开发克服这些限制的系统是极其重要的 现场未解决的问题。为了改善这些系统，我们旨在应对关键挑战 Cu固有的：（i）大多数CUIF复合物与形成不活跃的Cu0和Cuf2的不算力的不稳定性 （ii）氧化添加步骤的难度。为了克服这些问题，我们将从简单的铜盐中转移 到定义明确的铜络合物，并由N-杂环碳烯（NHC），环烷基氨基碳纤维支撑 （CAAC）或相关配体。我们假设这些配体将稳定CUI中间体，并偏爱 氧化添加，导致更有效的催化剂。具体而言，我们的目标是使用卡宾支持的铜 复合物至：（1）研究配体特性对芳基卤化物化学计量荧光的影响，（2）发展 一系列药物相关的芳基卤化物支架的催化氟化（3）合成18F标记的 示踪剂分子用于PET成像。这些目标的完成将导致改进的系统 芳基卤化物的氟化，可用于合成药物，农业化学和宠物示踪剂。 已经获得了支持每个提议的目标的可行性的初步结果。

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.

• 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

Strategies for the Production of [11C]LY2795050 for Clinical Use.

临床用[11C]LY2795050 的生产策略。

• DOI: 10.1021/acs.oprd.2c00388
• 发表时间: 2023
• 期刊: Organic process research & development
• 影响因子: 3.4
• 作者: Kaur,Tanpreet;Shao,Xia;Horikawa,Mami;Sharninghausen,LiamS;Preshlock,Sean;Brooks,AllenF;Henderson,BradfordD;Koeppe,RobertA;DaSilva,AlexandreF;Sanford,MelanieS;Scott,PeterJH
• 通讯作者: Scott,PeterJH