A New General Strategy for Pyridine Functionalization via Dearomatized Intermediates

项目摘要。 本项目的目标是引入一种新的合成策略来功能化吡啶杂环。吡啶类化合物 是FDA批准的药物中第二常见的氮杂环，这一事实并不令人惊讶，因为 它们的氢键倾向和一系列有价值的物理化学性质，如水 溶解度、净极性和抗氧化性。合成方法直接和选择性地 功能化的吡啶在药物发现工作中至关重要，因为药物开发者需要在 位置选择性，支架上不同的碳和杂原子基团在它们的 空间和电子性质。然而，将吡啶C-H键转化为有价值的 衍生品匮乏。在这项建议中，我们概述了一种通过将吡啶转化为锌的脱芳烃策略。 亚胺和亚胺加合物。实际上，这些加合物使吡啶的反应类似于一系列烯烃，而不是 芳香族体系，从而打开了以前与烯烃相关的过多反应 对吡啶类药物本身无效。我们将展示吡啶现在可以参与许多过程， 例如卤化反应，与sp2-碳亲电自由基反应，这些反应要么不可行，要么 在极端反应条件下工作。这一进程将在区域选择性的排他性控制下进行。 对于Zincke中间体的3-位，也可以根据Zincke加合物的 结构。在许多情况下，开环-功能化-闭环可序列化为一锅过程。 我们还将利用Zincke平台获取用于ADME研究的吡啶同位素和形成 氮氧化物。我们计划将这一策略应用于简单的积木吡啶、类药物中间体和 含复杂吡啶类药物的后期功能化。

Project Abstract. The goal of this project is to introduce a new synthetic strategy to functionalize pyridine heterocycles. Pyridines are the second most common nitrogen heterocycle found in FDA approved drugs, an unsurprising fact because of their propensity for hydrogen bonding and suite of valuable physiochemical properties such as aqueous solubility, net polarity, and resistance to oxidative metabolism. Synthetic methods to directly and selectively functionalize pyridines are critical in drug discovery efforts because drug-developers require variation in positional selectivity, various carbon- and heteroatom bearing groups on the scaffold a wide variance in their steric and electronic properties. However, general approaches to transform pyridine C–H bonds into valuable derivatives are lacking. In this proposal, we outline a dearomatization strategy by converting pyridines into Zincke imine and iminium adducts. In effect, these adducts make pyridines react like a series of alkenes rather than an aromatic system and thus open up the plethora of reactions associated with olefins that were previously ineffective on pyridines themselves. We will show that pyridines can now participate in numerous processes, such as halogenation, reaction with sp2-carbon electrophiles radical reactions that were either not viable or operated under extreme reaction conditions. The processes will occur with exclusive control of regioselectivity for the 3-position of Zincke intermediates and are also switchable to the 5-position based on the Zincke adduct's structure. The ring-opening-functionalization-ring-closing is sequencable into one-pot processes in many cases. We will also use the Zincke platform to access pyridine isotopologs for ADME studies and new methods to form N–oxides. We plan to employ this strategy for simple building block pyridines, drug-like intermediates and for late-stage functionalization of complex pyridine-containing drugs.