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.

项目摘要实际上，大多数（如果不是全部），实际上是由氟化氢（HF）。但是，HF的气态和腐蚀性将其排除在外没有特殊设备和培训的工作实验室。综合体 HF具有有机碱，例如吡啶-HF复合物（OLAH的试剂）和三乙胺-HF复合物已被广泛探索为氟的核螺旋来源，但使用这些有机物碱会降低系统的酸度，并可能干扰许多金属催化剂。到目前为止不是基于HF的核氟化试剂，它在酸或过渡金属中效果很好催化反应。我们的主要目标是开发新一代的基于HF的核系统氟化试剂与酸和金属催化剂兼容，基于有理设计。基于新的HX（X = CL，BR，I）的卤素也可以使用相同的策略试剂。氢键而不是离子相互作用已被确定为主要相互作用在吡啶-HF（OLAH的试剂）等复合物中的HF和有机碱之间。减少 HF复合物的挥发性（使其成为液体或在室温下固体），我们必须使用与HF复合物相关的良好氢键受体（HBA）。我们的假设是：强（良好的）氢键受体不需要坚固的基础（Brønsted或刘易斯基地）。这样，可以用作良好氢键受体的化合物（更好比吡啶或三乙胺），但预期较低的碱性将形成挥发性较小的复合物。和由于该HBA的碱性低，所得的HBA-HF复合物将与酸兼容催化剂或介体。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制备HBA-HX复合物。我们正在寻找 “异常” HBA，即良好的氢键受体，但Brønsted碱基弱。这氢键碱度和Brønsted碱度的定量描述如图1所示（基于劳伦斯和同事的氢键基础数据库）是我们的主要选择合适的氢键受体的指南。提出的核氟化试剂和使用的方法将实现氟胺，氟氢蛋白，氟胺的立体和区域选择性合成，立体和区域选择性合成通过氟氨基酸，氟脂肪族，烷烃，环状和杂环化合物通过新的合成协议，例如串联HF-ADDITION-METASESIS，HF捕获在阳离子中级联反应，应变释放核荧光，原位亲电荧光素 Markovnikov和抗Markovnikov氢氟化。将使用类似的策略开发基于设计的HX（X = Cl，BR，I）卤素化试剂。我们的试剂之一（DMPU-HF）已经在商业上可用，我们将商业化其他新开发的试剂使我们的方法可用于药物化学家全世界。

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）

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
影响因子：
0
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).