Nucleophilic halogenation reagents

项目摘要 大多数氟化试剂(亲电性或亲核性)实际上是由 氟化氢(HF)。然而，氢氟酸的气态和腐蚀性将其排除在 没有特殊设备和培训的工作实验室。的复合体 含有机碱的HF，如吡啶-HF络合物(Olah‘s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 碱降低了体系的酸度，可能会干扰许多金属催化剂。到目前为止，那里 不是在酸性或过渡金属中工作良好的基于HF的亲核氟化试剂 催化反应。我们的主要目标是开发基于氢氟酸的新一代亲核试剂 与酸和金属催化剂相容的氟化试剂 设计。同样的策略也可用于基于新的HX(X=氯、溴、碘)的卤化反应 试剂。 氢键，而不是离子相互作用，被认为是主要的相互作用 在氢氟酸和有机碱之间的络合物，如吡啶-氢氟酸(奥拉试剂)。减少 对于HF络合物的挥发性(在室温下使其成为液体或固体)，我们必须使用 氢键受体(HBA)与HF形成较好的络合物。我们的假设是：A 强(好)氢键受体不一定是强碱(BR？nsted或 Lewis碱基)。通过这种方式，作为良好氢键受体的化合物(更好 与吡啶或三乙胺相比)，但碱性较差，预计会形成挥发性较低的络合物。和 由于这种HBA的低碱度，生成的HBA-HF络合物将与酸相容 催化剂或中介者。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参与的反应中。 我们研究的第一部分是HBA-HX络合物的制备。我们正在寻找 “异常”HBA，即良好的氢键受体但弱的Brnsted碱。这个 氢键碱度和Brnsted碱度的定量描述符如图1所示 (基于Laurence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。 建议的亲核氟化试剂及其使用方法将使 多向、立体和区域选择性地合成氟胺、氟代烃、 含氟氨基酸，含氟脂肪族、烯烃、环状和杂环化合物 串联氢氟化氢加成复分解、阳离子捕获氢氟化氢等新合成方法 级联反应、应变释放亲核氟化、原位亲电氟化 形成、马尔科夫尼科夫和反马尔科夫尼科夫氢氟化。将使用类似的策略 开发Designer-HX类(X=氯、溴、碘)卤代试剂。 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。

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.