Nucleophilic halogenation reagents

亲核卤化试剂

基本信息

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
项目类别：
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

项目摘要

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.

项目概要大多数（如果不是全部）氟化试剂（亲电或亲核）实际上是由氟化氢 (HF) 然而，HF 的气态和腐蚀性使其无法使用。没有特殊设备和培训的工作实验室。 HF 与有机碱，如吡啶-HF 络合物（奥拉试剂）和三乙胺-HF 络合物作为氟的亲核来源已被广泛探索，但使用这些有机碱会降低系统的酸度，并可能干扰许多金属催化剂。不是在酸或过渡金属中效果良好的 HF 基亲核氟化试剂我们的主要目标是开发新一代基于 HF 的亲核反应。基于合理的与酸和金属催化剂相容的氟化试剂相同的策略也可用于基于 HX (X = Cl、Br、I) 的新型卤化。试剂。氢键而非离子相互作用已被确定为主要相互作用 HF 和有机碱之间的络合物，如吡啶-HF（奥拉试剂）。 HF络合物的挥发性（使其在室温下为液体或固体），我们必须使用与 HF 复合的相对较好的氢键受体 (HBA) 我们的假设是：a 强（好）氢键受体不一定是强碱（BrØnsted 或通过这种方式，化合物可以作为良好的氢键受体（更好）。吡啶或三乙胺），但碱性较低，预计会形成挥发性较低的络合物。由于该 HBA 的碱度较低，生成的 HBA-HF 复合物将与酸相容通过这种方式，我们可以实现前所未有的反应性和选择性。在 HF 参与反应中。我们研究的第一部分是我们正在寻找HBA-HX复合物的制备。 “异常”HBA，即良好的氢键受体但弱布朗斯特碱。氢键碱度和布朗斯台德碱度的定量描述符如图1所示（基于劳伦斯和同事的氢键碱度数据库）是我们的主要选择合适的氢键受体的指南。所提出的亲核氟化试剂及其使用方法将使氟胺、氟醇的多样化定向立体和区域选择性合成氟氨基酸、氟化脂肪族、烯烃、环状和杂环化合物，通过新的合成方案，例如串联 HF 加成复分解、阳离子捕获 HF 级联反应、应变释放亲核氟化、原位亲电氟形成、马尔可夫尼科夫和反马尔可夫尼科夫氢氟化将使用类似的策略。开发基于设计者-HX（X = Cl、Br、I）的卤化试剂。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全世界。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Chlorinating Reagent Yields Vinyl Chlorides with High Regioselectivity under Heterogeneous Gold Catalysis.

一种氯化试剂在多相金催化下产生具有高区域选择性的氯乙烯。

DOI：
发表时间：
2017-09-01
期刊：
影响因子：
5.2
作者：
Liang, Shengzong;Ebule, Rene;Hammond, Gerald B;Xu, Bo
通讯作者：
Xu, Bo

Multifaceted Ion Exchange Resin-Supported Hydrogen Fluoride: A Path to Flow Hydrofluorination.

多面离子交换树脂负载氟化氢：流动氢氟化的途径。

DOI：
10.1039/c8gc03166e
发表时间：
2019-05-07
期刊：
Green chemistry : an international journal and green chemistry resource : GC
影响因子：
0
作者：
Zhichao Lu;Bhv;ip S. Bajwa;ip;O. Otome;G. Hammond;Bo Xu
通讯作者：
Bo Xu

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

基于区域选择性钴催化的α-三氟甲基化吡啶的实际合成[2 2 2] 使用三氟甲基化二炔与腈进行环加成。

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

Self-Sustaining Fluorination of Active Methylene Compounds and High-Yielding Fluorination of Highly Basic Aryl and Alkenyl Lithium Species with a Sterically Hindered N-Fluorosulfonamide Reagent.

使用空间位阻 N-氟磺酰胺试剂进行活性亚甲基化合物的自持氟化以及高碱性芳基和烯基锂物种的高产率氟化。

DOI：
发表时间：
2022-10-24
期刊：
影响因子：
0
作者：
Yang, Yuhao;Hammond, Gerald B;Umemoto, Teruo
通讯作者：
Umemoto, Teruo

Cobalt-Catalyzed C-H Activation/Annulation of Benzamides with Fluorine-Containing Alkynes: A Route to 3- and 4-Fluoroalkylated Isoquinolinones.

钴催化苯甲酰胺与含氟炔烃的 C-H 活化/环化：生成 3- 和 4- 氟烷基化异喹啉酮的路线。

DOI：
10.1021/acs.joc.1c00080
发表时间：
2021-03-16
期刊：
The Journal of organic chemistry
影响因子：
0
作者：
Tatsuya Kumon;Jian‐Yi Wu;M. Shimada;S. Yamada;T. Agou;Hiroki Fukumoto;T. Kubota;G. Hammond;T. Konno
通讯作者：
T. Konno