Direct functionalization of aromatic rings using temporary dearomatization

使用临时脱芳构化对芳环进行直接官能化

• 批准号: 2605101
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2605101
• 关键词: Direct; functionalization; aromatic; rings; using

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 Unpublished work suggests that methyl vinyl ketone could be a suitable electrophile and we will use various Michael acceptors and carbonyls to test the reaction scope.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.

许多有机天然产物和药物含有高度官能化的芳香族化合物，这是一种在没有苛刻或强制条件的情况下难以从简单芳香族化合物产生的基序。芳香族化合物和杂环化合物是开发新的生物活性化合物的核心。因此，开发和扩大合成方法以创造新的更可持续和更有效的药物构建途径对药物发现的未来至关重要。开发用于芳环，特别是杂环的直接官能化方法将允许用于药物中常用的芳族部分的选择性后期官能化。使用催化技术这样做可以使我们的转型可持续地实现。该项目的目的是扩展Donohoe小组以前的一些工作，即使用铑金属催化的氢借用技术直接官能化吡啶。为了更好地理解反应机理，我们首先研究了各种活化杂芳烃的方法，使用缺电子芳烃，容易去除的活化基团或新的杂芳烃活化技术。此类技术包括刘易斯酸、来自相邻基团的金属螯合、氮的质子化或通过使用环状类似物。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，该反应仅限于使用甲醛作为亲电试剂和末端还原剂。未发表的工作表明，甲基乙烯基酮可能是一个合适的亲电试剂，我们将使用各种迈克尔受体和羰基来测试反应范围。可以使用这种化学方法来产生一锅成环技术，其中通过暂时脱芳构化添加的侧链然后可以用作亲核试剂来攻击杂芳烃，从而在单个步骤中产生新的相邻环。该反应可能成为吡啶类化合物的一种非常普遍的环化过程，产生具有进一步衍生化潜力的产物。我们的第三种反应调节途径涉及研究还原剂，以便亲核试剂可以通过调节催化剂负载或使用不同的氢化物源在最终还原事件之前竞争攻击中间体。一些令人兴奋的可能性涉及使用内部亲核试剂攻击部分脱芳构化的吡啶，从而在一个步骤中插入一个链并产生一个新的环，或者使用芳基硼酸或芳基卤化物，其将金属转移到铑催化剂上并允许芳基加成到部分脱芳构化的吡啶中间体。另一个值得探索的方面是通过计算关键中间体物种的电荷密度和MO能量，使用计算来更好地理解机制。预测可能的活化基团或潜在的合适的杂芳烃将有可能与计算技术。我们的方法建立在该集团多年的氢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，有许多出版物，但几乎所有的使用脱芳构化作为一种技术，以获得二氢吡啶，而不是rearomatize所得的中间体。已经发表了几篇使用临时脱芳构化技术的论文，但所有这些论文的范围都非常有限，并且仅适用于选定的情况。我们的方法旨在更普遍地适用于许多亲电试剂和杂芳烃化合物。该项目福尔斯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。