Catalytic generation and harnessing of reactive intermediates

反应中间体的催化生成和利用

• 批准号: EP/M026221/1
• 负责人: Christopher Jones
• 金额: $ 86.03万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FM026221%2F1
• 关键词: Catalytic; generation; harnessing; reactive; intermediates

Reactive chemical intermediates are short-lived and high-energy molecules. Whilst it is inherently demanding to exploit the high levels of reactivity of these species, the potential benefits are compelling. Great opportunities are afforded to conduct powerful new chemical and biological processes, with applications in medicine and materials development amongst others. The goal of this proposal is to provide new methods to harness reactive intermediates and hence facilitate reactions of immense utility.We will focus on intermediates called arynes; molecules in which one of the three carbon-carbon (C-C) double bonds in a benzene ring has been replaced with a C-C triple bond. Incorporating this triple bond causes the ring to become highly strained and thus highly reactive. Arynes are extremely useful as they enable rapid generation of complex benzene ring-containing products that are common in pharmaceuticals, agrochemicals, materials and dyes. Despite recent advances, methods for an ideal scenario whereby arynes are prepared using a catalyst - a small amount of a substance that promotes a reaction but is not consumed and can thus be recycled - are extremely rare and no general procedure exists. As a result, our long term goal will be to develop a general strategy for catalytic aryne synthesis that also exploits abundant chemicals. There are myriad potential benefits, from the development of new chemical reactions for application in healthcare and manufacturing, to the environmental issues of reduced waste production and the use of more plentiful starting materials.One example of a cheap bulk chemical for this process is phenol (a benzene ring with an oxygen atom attached), with 60,000 commercially available analogues also offering great potential for structural diversification. By attaching an activating group to the oxygen, we will investigate strategies that enable the proximal addition of a catalyst onto the benzene ring. This catalyst can then interact with the adjacent activating group to aid elimination of the two species from the ring, producing an aryne. The catalyst will then be free to add to another activated phenol ring and thus the cycle is established.We will also look to subsequently exploit the reactivity of arynes in demanding reactions, such as manipulating the ubiquitous carbon-hydrogen (C-H) bond. Breaking a particular C-H bond and replacing that hydrogen with another atom is extremely desirable, as it means valuable compounds can be made directly from cheap hydrocarbon materials. However, this process is very difficult due to the strength of the C-H bond and most progress has been made using metal catalysts that can be expensive and toxic. Here we will utilise the high reactivity of arynes to develop new complementary metal-free methods for selective C-H bond breaking, involving an initial hydrogen ion transfer from the hydrocarbon compound onto the aryne. This novel process results in two oppositely charged molecules, and we propose that via the recombination of these charges, a new C-C bond will be made. Studies into hydrogen ion transfer onto an aryne will commence with systems where the two components are in the same molecule, tied together in close proximity to aid the reaction. As our understanding increases, we will see whether they can be part of different molecules, which is anticipated to be more challenging. Crucially, we have a preliminary result to support this unique concept.This research area has been chosen because arynes enable rapid construction of useful complex molecules. Developing these new methods will enable chemists to make drug, polymer, dye and agrochemical compounds more efficiently, and maybe even prepare molecules that are currently inaccessible. These advances can benefit wider society through the development of drugs to treat illnesses, herbicides and pesticides to improve global food production and by harnessing more sustainable chemical feedstocks.

反应性化学中间体是寿命短的高能分子。虽然开发这些物种的高反应性本身就要求很高，但潜在的好处是令人信服的。在医学和材料开发等方面的应用，为进行强大的新化学和生物工艺提供了巨大的机会。本提案的目标是提供利用反应中间体的新方法，从而促进具有巨大效用的反应。我们将重点关注被称为芳烃的中间体；苯环上三个碳-碳（C-C）双键中的一个被碳-碳三键取代的分子。结合这个三键使环变得高度紧张，因此反应性很强。Arynes非常有用，因为它们可以快速生成复杂的含苯环的产品，这些产品在制药、农用化学品、材料和染料中很常见。尽管最近取得了一些进展，但使用催化剂（少量促进反应的物质，但不消耗，因此可以回收利用）制备芳炔的理想方案的方法极其罕见，而且没有通用的程序。因此，我们的长期目标将是开发一种利用丰富化学物质的催化合成芳烃的总体策略。从开发用于医疗保健和制造业的新化学反应，到减少废物产生和使用更丰富的起始材料的环境问题，有无数潜在的好处。用于这一过程的廉价散装化学品的一个例子是苯酚（一种附着氧原子的苯环），它有6万种商业上可用的类似物，也为结构多样化提供了巨大的潜力。通过将一个活化基团连接到氧上，我们将研究在苯环上近端加成催化剂的策略。然后，该催化剂可以与相邻的激活基团相互作用，以帮助消除环上的两种物质，产生一个任何炔。然后，催化剂将自由地添加到另一个活化的酚环上，这样就建立了循环。随后，我们还将探索芳烃在复杂反应中的反应活性，例如操纵无处不在的碳氢键。打破一个特定的碳氢键并用另一个原子取代这个氢是非常可取的，因为这意味着有价值的化合物可以直接从廉价的碳氢化合物材料中制造出来。然而，由于C-H键的强度，这一过程非常困难，而且大多数进展都是使用昂贵且有毒的金属催化剂。在这里，我们将利用芳烃的高反应性来开发新的无金属互补的选择性C-H键断裂方法，包括初始氢离子从碳氢化合物转移到芳烃上。这个新过程产生了两个带相反电荷的分子，我们提出，通过这些电荷的重组，将形成一个新的C-C键。研究氢离子转移到炔上的方法将从两个组分在同一分子中，紧密结合在一起以促进反应的系统开始。随着我们了解的增加，我们将看到它们是否可以成为不同分子的一部分，预计这将更具挑战性。至关重要的是，我们有一个初步的结果来支持这个独特的概念。之所以选择这个研究领域，是因为芳烃能够快速构建有用的复杂分子。开发这些新方法将使化学家能够更有效地制造药物、聚合物、染料和农用化合物，甚至可能制备目前无法获得的分子。这些进步可以通过开发治疗疾病的药物、开发改善全球粮食生产的除草剂和杀虫剂以及利用更可持续的化学原料，使更广泛的社会受益。

项目成果

Aryne-Mediated Arylation of Hantzsch Esters: Access to Highly Substituted Aryl-dihydropyridines, Aryl-tetrahydropyridines and Spiro[benzocyclobutene-1,1'-(3',4'-dihydropyridines)]

芳炔介导的 Hantzsch 酯的芳基化：获得高度取代的芳基-二氢吡啶、芳基-四氢吡啶和螺[苯并环丁烯-1,1-(3,4-二氢吡啶)]

• DOI: 10.1055/s-0037-1611065
• 发表时间: 2018
• 期刊: Synthesis
• 作者: Jones C

Intermolecular Aryne Ene Reaction of Hantzsch Esters: Stable Covalent Ene Adducts from a 1,4-Dihydropyridine Reaction.

• DOI: 10.1021/acs.orglett.7b02272
• 发表时间: 2017-08
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Piera Trinchera;Weitao Sun;Jane E. Smith;D. Palomas;R. Crespo‐Otero;C. Jones

The Aryne Ene Reaction

芳烯反应

• DOI: 10.1055/a-1827-2987
• 发表时间: 2022
• 期刊: Synthesis
• 作者: Jones C

Selective access to dihydrophenanthridines and phenanthridinones via cyclisation of aryl amines onto N -tethered arynes

通过将芳基胺环化到 N-束缚芳烃上选择性获得二氢菲啶和菲啶酮

• DOI: 10.1039/d3cc03027j
• 发表时间: 2023
• 期刊: Chemical Communications
• 影响因子: 4.9
• 作者: Sun W

A Ring Expansion Route to Benzofused N-Heterocycles Through Aryne Insertion into 1,3-Diaza-heterocycles

• DOI: 10.1002/ejoc.201900570
• 发表时间: 2019-09
• 期刊: European Journal of Organic Chemistry
• 影响因子: 2.8
• 作者: Yun-Chin Yang;Yue Xu;C. Jones