Nucleophilic halogenation reagents

亲核卤化试剂

• 批准号: 10058844
• 负责人: GERALD B HAMMOND
• 金额: $ 29.26万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-06 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058844
• 关键词: Acidity; Acids; Agrochemicals; Alkenes; Amino Acids; Biological; Cations; Chemicals; Complex; Corrosives; Databases; Descriptor; Ethers; Fluorine; Generations; Goals; Guidelines; Heterocyclic Compounds; Hydrogen; Hydrogen Bonding; Hydrogen Fluoride; In Situ; Laboratories; Liquid substance; Mediating; Mediator of activation protein; Metabolic; Metals; Methodology; Methods; Nature; Pattern; Periodicity; Pharmaceutical Chemistry; Pharmaceutical Preparations; Preparation; Property; Protocols documentation; Reaction; Reagent; Research; Resistance; Solid; Source; Special Equipment; System; Temperature; Transition Elements; Work; alkalinity; base; case-by-case basis; catalyst; cyclic compound; design; drug discovery; equipment training; halogenation; organic base; pyridine; stereochemistry; triethylamine; virtual

Project Summary Most, if not all, fluorinating reagents (electrophilic or nucleophilic) are actually made from hydrogen fluoride (HF). However, the gaseous and corrosive nature of HF excludes it from working laboratories where special equipment and training are not available. The complexes of HF with organic bases like pyridine-HF complex (Olah's reagent) and triethylamine-HF complex have been explored extensively as nucleophilic sources of fluorine, but use of these organic bases reduce the acidity of the system and may interfere with many metal catalysts. So far there is no HF-based nucleophilic fluorination reagent that works well in acid or transition metal catalyzed reactions. Our primary goal is to develop a new generation of HF-based nucleophilic fluorination reagents that is compatible with acids and metal catalysts based on a rational design. The same strategy can also be used for new HX (X = Cl, Br, I)-based halogenation reagents. Hydrogen bonding, rather than an ionic interaction, has been identified as the major interaction between HF and an organic base in complexes such as pyridine-HF (Olah's reagent). To reduce the volatility of an HF complex (make it a liquid or solid at room temperature), we have to use a relatively good hydrogen bonding acceptor (HBA) to complex with HF. Our hypothesis is: a strong (good) hydrogen bonding acceptor is not necessarily a strong base (BrØnsted or Lewis base). In this way, a compound that serves as good hydrogen bonding acceptor (better than pyridine or triethylamine), but is less basic, is expected to form a less volatile complex. And due to the low basicity of this HBA, the resulting HBA-HF complex will be compatible with acid catalysts or mediators. In this manner, we may achieve unprecedented reactivity and selectivity in HF-participating reactions. The first part of our research is the preparation of HBA-HX complexes. We are seeking `anomaly' HBAs, that is, good hydrogen bond acceptors but weak BrØnsted bases. The quantitative descriptor of hydrogen bond basicity and BrØnsted basicity shown in Figure 1 (based on Laurence and co-workers' database of hydrogen-bond basicity) is our primary guideline for the selection of suitable hydrogen bonding acceptors. The nucleophilic fluorination reagents proposed and the methodologies for their use will enable diverse-oriented, stereo- and regio-selective synthesis of fluoroamines, fluorohydrins, fluoroaminoacids, fluorinated aliphatic, alkenes, cyclic and heterocyclic compounds, through new synthetic protocols such as tandem HF-addition-metathesis, HF trapping in cationic cascade reactions, strain-release nucleophilic fluorinations, in-situ electrophilic fluorine formation, Markovnikov and anti-Markovnikov hydrofluorinations. A similar strategy will be used to develop designer-HX based (X = Cl, Br, I) halogenation reagents. One of our reagents (DMPU-HF) is already commercially available, and we will commercialize other newly developed reagents to make our methods available to medicinal chemists worldwide.

项目摘要 大多数（如果不是全部的话）氟化试剂（亲电或亲核）实际上是由 氟化氢（HF）。然而，HF的气态和腐蚀性性质使其不被用于制备高纯度的HF。 在没有特殊设备和培训的实验室工作。配合物 HF与有机碱如吡啶-HF络合物（Olah试剂）和三乙胺-HF络合物 作为氟的亲核源进行了广泛的探索，但是使用这些有机化合物 碱降低了体系的酸度，并可能干扰许多金属催化剂。至今 是没有HF基亲核试剂，其在酸或过渡金属中工作良好 催化反应。我们的主要目标是开发新一代HF基亲核 与酸和金属催化剂相容的化学试剂， 设计同样的策略也可用于新的HX（X = Cl，Br，I）基卤化反应 试剂 氢键，而不是离子相互作用，已被确定为主要的相互作用 HF和有机碱之间的络合物，如吡啶-HF（Olah试剂）。减少 HF络合物的挥发性（使其在室温下为液体或固体），我们必须使用 相对较好的氢键受体（HBA）与HF络合。我们的假设是： 强（好）氢键受体不一定是强碱（Brunnsted或 刘易斯碱）。以这种方式，可以制备用作良好氢键结合受体的化合物（更好地 比吡啶或三乙胺），但碱性较低，预期形成挥发性较低的络合物。和 由于该HBA的低碱度，所得HBA-HF络合物将与酸相容 催化剂或介质。这样，我们可以实现前所未有的反应性和选择性 HF参与的反应。 本研究的第一部分是HBA-HX复合物的制备。我们正在寻求 “异常”，也就是说，良好的氢键受体，但弱布朗斯台德碱。的 图1所示的氢键碱度和布朗斯台德碱度的定量描述符 （基于Laurence和同事的氢键碱性数据库）是我们的主要 选择合适的氢键受体的指南。 提出的亲核试剂及其使用方法将使 氟胺，氟醇， 氟氨基酸、氟化脂族、烯烃、环状和杂环化合物， 新的合成方案，如串联HF加成复分解，HF捕获阳离子 级联反应，应变释放亲核氟化，原位亲电氟化 形成、Markovnikov和反Markovnikov氢氟化。将采用类似的策略 开发设计者HX（X = Cl，Br，I）卤化试剂。 我们的一种试剂（DMPU-HF）已经商业化，我们将商业化 其他新开发的试剂，使我们的方法可供药物化学家使用 国际吧

项目成果

Metal-Free and User-Friendly Regioselective Hydroxyfluorination of Olefins.

• DOI: 10.1021/acs.orglett.8b00681
• 发表时间: 2018-04-20
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Sedgwick DM;López I;Román R;Kobayashi N;Okoromoba OE;Xu B;Hammond GB;Barrio P;Fustero S
• 通讯作者: Fustero S

Chloride-Tolerant Gold(I)-Catalyzed Regioselective Hydrochlorination of Alkynes.

耐氯化物金 (I) 催化的炔烃区域选择性氢氯化反应

• DOI: 10.1021/acscatal.7b02567
• 发表时间: 2017-10-06
• 期刊: ACS catalysis
• 影响因子: 12.9
• 作者: Ebule R;Liang S;Hammond GB;Xu B
• 通讯作者: Xu B

Practical Synthesis of α-Trifluoromethylated Pyridines Based on Regioselective Cobalt-Catalyzed [2+2+2] Cycloaddition using Trifluoromethylated Diynes with Nitriles.

• DOI: 10.1002/adsc.202001433
• 发表时间: 2021-03-29
• 期刊: Advanced synthesis & catalysis
• 影响因子: 5.4
• 作者: Kumon T;Yamada S;Agou T;Fukumoto H;Kubota T;Hammond GB;Konno T
• 通讯作者: Konno T

HCl•DMPU-Assisted One-pot and Metal-free Conversion of Aldehydes to Nitriles.

• DOI: 10.1039/d0gc00757a
• 发表时间: 2020-07-07
• 期刊: Green chemistry : an international journal and green chemistry resource : GC
• 作者: Mudshinge SR;Potnis CS;Xu B;Hammond GB
• 通讯作者: Hammond GB

Synthesis and applications of S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium triflate (Umemoto reagent IV).

• DOI: 10.1016/j.jfluchem.2022.110015
• 发表时间: 2022-07
• 期刊: Journal of fluorine chemistry
• 影响因子: 1.9
• 作者: Sagar R. Mudshinge;G. Hammond;T. Umemoto