Direct functionalization of aromatic rings using temporary dearomatization

许多有机天然产品和药物含有高度功能化的芳烃，这是一个很难从简单的芳烃中产生的基序，没有苛刻或强制的条件。芳烃和杂环化合物是开发新型生物活性化合物的核心。因此，发展和扩大合成方法，以创造新的更可持续和更有效的药物构建方法，对药物发现的未来至关重要。开发芳香环，特别是杂环的直接功能化方法，将允许对药物中常用的芳香部分进行选择性的后期功能化。使用催化技术这样做可以使我们的转变可持续地实现。该项目的目的是在Donohoe小组先前使用铑金属催化的借氢技术直接功能化吡啶的一些工作的基础上进行扩展。为了更好地了解这一反应的机理，我们首先研究了各种激活杂环芳烃的方法，利用缺电子芳烃、易移除的激活基团或新技术来激活杂环芳烃。这些技术包括路易斯酸、邻近基团的金属螯合、氮的质子化或使用环状类似物。我们还希望扩大在我们的工艺中使用的亲电试剂的范围。目前该反应仅限于甲醛作为亲电试剂和末端还原剂。未发表的研究表明甲基乙烯酮可能是一种合适的亲电试剂，我们将使用各种迈克尔受体和羰基来测试反应范围。利用这种化学反应可以产生一锅环化技术，其中通过临时脱芳化添加的侧链可以用作亲核试剂来攻击杂芳烃，从而在一步中产生一个新的相邻环。这个反应可以成为吡啶的一个非常普遍的环化过程，产生具有进一步衍生化潜力的产物。我们调整反应的第三条途径是研究还原剂，以便通过调整催化剂负载或使用不同的氢化物源，使亲核试剂在最终还原事件发生之前能够竞争攻击中间体。一些令人兴奋的可能性包括使用内部亲核试剂攻击部分去芳化的吡啶，从而插入一条链并在一步中形成一个新的环，或者使用芳基硼酸或芳基卤化物，它们会在铑催化剂上发生金属转移，并允许芳基加成到部分去芳化的吡啶中间体上。另一个值得探索的有趣方面是，通过计算关键中间物质的电荷密度和MO能，利用计算来更好地理解反应机理。利用计算技术可以预测可能的活化基团或可能合适的杂芳烃。我们的方法建立在集团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。杂环芳烃的脱芳化是一个很大的领域，有许多出版物，但几乎所有的脱芳化技术都是为了获得二氢吡啶，而不是为了得到中间体的再芳化。一些使用临时脱芳技术的论文已经发表，但它们的范围都非常有限，只对特定的情况有用。我们的方法旨在对许多亲电试剂和杂芳烃化合物更普遍地有用。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GSK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.