Direct functionalization of aromatic rings using temporary dearomatization

许多有机天然产品和药物含有高度官能化的芳香族化合物，如果没有苛刻或强制的条件，很难从简单的芳香族化合物中创造出这样的主题。芳烃和杂环化合物是开发新的生物活性化合物的核心。因此，开发和扩展合成方法学，以创造更可持续和有效的新途径来构建药物基础，对药物发现的未来至关重要。开发芳环，特别是杂环的直接官能化方法，将允许对制药中常用的芳香族部分进行选择性后期官能化。使用催化技术来做到这一点，使我们的转变能够可持续地实现。该项目的目的是在多诺霍小组以前的一些工作的基础上，利用金属铑催化的借氢技术对吡啶进行直接功能化。为了更好地了解该反应的反应机理，我们首先研究了利用缺电子芳烃、易去除的活化基或新的杂芳烃活化技术来活化杂芳烃的各种方法。这些技术包括路易斯酸、相邻基团的金属络合、氮的质子化或使用环状类似物。我们还希望扩大在我们的过程中使用的亲电剂的范围。目前，该反应仅限于使用甲醛作为电泳剂和终端还原剂。未发表的工作表明，甲基乙烯基酮可能是一种合适的电泳剂，我们将使用各种迈克尔受体和羰基来测试反应范围。可以使用这种化学方法来生成一锅环化技术，其中通过临时脱芳构化添加的侧链然后可以用作亲核剂来攻击杂芳烃，从而在一步中生成新的相邻环。这一反应可能成为产生具有进一步衍生化潜力的产物的吡啶的一个非常普遍的环化过程。我们的第三条反应调整路线涉及研究还原剂，以便亲核分子可以在最终还原事件之前竞争攻击中间体，要么调整催化剂负载，要么使用不同的氢化物来源。一些令人兴奋的可能性包括使用内部亲核剂来攻击部分脱芳烃的吡啶，从而在一步中插入一条链并创建一个新的环，或者使用芳基硼酸或芳基卤化物，它们将转位到Rhodium催化剂上，并允许芳基加成到部分脱芳烃的吡啶中间体上。另一个有趣的探索方面是通过计算关键中间物种的电荷密度和分子轨道能量来更好地理解这一机制。用计算技术预测可能的活化基或潜在合适的杂芳烃是可能的。我们的方法建立在该小组多年的氢气借用专业知识的基础上，最近专注于杂芳烃的应用。杂芳烃的脱芳构化是一个很大的领域，发表了许多文献，但几乎所有的文献都将脱芳构化作为一种技术来获得二氢吡啶，而不是对生成的中间体进行再芳构化。已经发表了几篇使用临时脱芳烃技术的论文，但这些论文的范围都非常有限，只在特定的情况下有用。我们的方法旨在更普遍地适用于许多亲电化合物和杂芳烃化合物。该项目属于合成有机化学研究领域，属于EPSRC物理科学研究主题。该项目是与葛兰素史克合作进行的。

Numerous organic natural products and pharmaceuticals contain heavily functionalized aromatics, a motif which is difficult to create from simple aromatics without harsh or forcing conditions. Aromatics and heterocyclics are core to the development of new biologically active compounds. The development and expansion of synthetic methodology to create new more sustainable and effective routes to pharmaceutical building blocks is therefore essential for the future of drug discovery. Developing direct functionalization methods for aromatic rings, particularly heterocycles, will allow selective late-stage functionalization for aromatic moieties commonly used in pharmaceuticals. Using catalytic techniques to do so allows our transformations to be achieved sustainably. The project's aim is to expand upon some previous work from the Donohoe group on the direct functionalization of pyridines using Rhodium metal catalysed hydrogen-borrowing techniques. We wish to understand the mechanism of the reaction better, firstly by studying various methods of activating the heteroarene, using electron deficient arenes, easily removeable activating groups or new techniques for heteroarene activation. Such techniques include Lewis acids, metal chelation from neighbouring groups, protonation of the nitrogen or by using annulated analogues. We also wish to expand the scope of electrophiles used in our process. Currently the reaction is limited to using formaldehyde as both the electrophile and terminal reductant. Unpublished work suggests that methyl vinyl ketone could be a suitable electrophile and we will use various Michael acceptors and carbonyls to test the reaction scope. It may be possible to use this chemistry to generate one-pot annulation techniques where a side chain added via temporary dearomatization could then be used as a nucleophile to attack the heteroarene thereby generating a new adjacent ring in a single step. This reaction could become a very general annulation procedure for pyridines that create products with suitable potential for further derivatization. Our third route for reaction tuning involves investigating the reductant so that nucleophiles can compete to attack intermediates before the final reduction event, either by adjusting catalyst loading or using a different hydride source. Some exciting possibilities involve using an internal nucleophile to attack the partially dearomatized pyridine thereby inserting a chain and creating a new ring in a single step, or using aryl boronic acids or aryl halides that will transmetalate onto the Rhodium catalyst and allow aryl addition to the partially dearomatized pyridine intermediate. Another aspect that would be interesting to explore is using computation to better understand the mechanism by computing charge density and MO energies of the key intermediate species. Predictions of possible activating groups or potentially suitable heteroarenes will be possible with computational techniques. Our methodology builds on numerous years of hydrogen borrowing expertise in the group, more recently focused on applications to heteroarenes. Dearomatization of heteroarenes is a large field with many publications, but nearly all use dearomatization as a technique to access dihydro pyridines, not to rearomatize the resultant intermediate. A few papers using temporary dearomatization techniques have been published but all are very limited in their scope and are only useful for select circumstances. Our method aims to be more generally useful to many electrophiles and heteroarene compounds. This project falls within the Synthetic Organic Chemistry research area, within the EPSRC Physical sciences research theme. This project is conducted in collaboration with GSK.