New Chemical Process to Selectively Functionalize Pyridines, Diazines and Pharmaceuticals

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和二氮杂环。 吡啶是FDA批准的药物中发现的第二种最常见的氮杂环，还有 在这些结构中有许多二氮杂物的例子。这种广泛的事件的发生是由于 杂环及其取代基的影响。关键的药物-受体相互作用通常由氢组成。 杂环N-孤子对与生物靶标之间的键。这些杂环也是极性的，可以 参与p堆积相互作用，并抵抗氧化代谢。取代基能够调节 杂环的空间和电子环境，以及作为额外的结合位点。因此， 药物化学家要求化学过程可以直接和选择性地将一系列取代基安装在 从C-H前体药物发现的不同阶段。在这个提案中，我们将开发三种不同的方法 用于氮杂环丙烷功能化。首先，我们将安装杂环膦盐并开发其独特的反应性 发展与胺、硫代苯酚、半胱氨酸分子和炔烃的偶联反应。vbl.使用 具有侧链官能团的膦将能够与水和氨偶联。第二，直接耦合 将利用NTF-吡啶盐与亲核试剂之间的反应形成C-杂原子键。 附加物该平台将实现与脂肪胺、苯胺、酰胺和磺胺的直接偶联。 第三，我们将使用硫亲核试剂改变亲核加成反应的区域选择性，从4-位 将吡啶类化合物引入支架的2位。一旦嵌入到底物中，这些硫亲核试剂也可以 作为一种多功能的官能团，使其他转化可以生成C-N、C-O和C-F键。

Project Abstract. The goal of this project is to introduce a new synthetic strategy to functionalize pyridine and diazine heterocycles. Pyridines are the second most common nitrogen heterocycle found in FDA approved drugs, and there are numerous examples of diazines in these structures. The widespread occurrence arises because of a combined effect of the heterocycle and its substituents. The key drug-receptor interaction is often comprised of a hydrogen bond between the heterocycles N-lone pairs and the biological target. These heterocycles are also polar, can engage in p-stacking interactions and are resistant to oxidative metabolism. The substituents enable tuning of the steric and electronic environment of the heterocycle as well as serving as additional binding sites. As such, medicinal chemists require chemical process that can directly and selectively install a range of substituents at various stages of drug discovery from C–H precursors. In this proposal we will develop three different approaches for azine functionalization. First, we will install heterocyclic phosphonium salts and exploit their unique reactivity to develop coupling reactions with amines, thiophenols, cysteine containing molecules and alkynes. Using phosphines with pendant functional groups will enable coupling with water and ammonia. Second, direct coupling reactions between NTf-pyridinium salts and nucleophiles will be exploited for C–Heteroatom bond formation. additionsThis platform will enable direct coupling with aliphatic amines, anilines, amides and sulfonamides. Third, we will use sulfur nucleophile to change the regioselectivity of nucleophilic addition from the 4-position of pyridines to the 2-position of the scaffold. Once embedded in the substrate, these sulfur nucleophiles also serve as versatile functional group the enable other transformations to make C–N, C–O and C–F bonds.