Novel Strategies for the Assembly of Carbon-Boron Bonds via the Photoinduced Generation of Boryl-Radicals

含硼有机小分子化合物是现代合成化学中最重要的一类化合物，因为它们在诺贝尔奖获得者硼氢化-氧化和Suzuki交叉偶联中的应用。硼化结构单元通常用于制备学术界和工业界的高价值材料。因此，以前所未有的方式形成C-B键的新型化学反应的发明对于促进影响我们社会的分子的发现、进化和制造具有战略重要性。通常，硼基官能团通过双电子过程引入到有机分子中，如Grignards与B-亲电试剂的反应或使用过渡金属催化的芳香族C-H硼基化反应。该项目的首要目标是探索一种互补的方法，其中C-B键通过B中心自由基（硼基自由基）的反应性组装。这些活性中间体的使用和应用还相当落后，但可以为当前离子和金属介导的硼化策略提供许多正交和互补的解决方案。该项目分为三个目标，将针对与硼化材料制备相关的特定挑战。我们开发了一种光化学方法，用于从胺硼烷（一类稳定且丰富的材料）生成硼基自由基。这些开壳层中间体将用于实现N-杂环的直接和选择性的C-H硼基化，这是药物和农业化学材料中最重要的基序之一。这种反应性将提供一种新的方法来官能化这些高价值的分子，其选择性与当前金属催化方法所显示的选择性正交。我们还将通过将其应用于一系列具有工业利益的“现实世界”底物来衡量化学的适用性，这些底物将通过与杨森制药公司的合作提供。此外，我们将评估这些新型硼基化材料在主流交叉偶联反应中的应用。目标2.在这里，我们将开发不同的多组分反应的基础上的分子内环化硼自由基。我们将利用我们在自由基级联方面的知识，提供前所未有的硼基化-官能化过程。这种化学反应涉及生成高烯丙基胺-硼基自由基，其将经历分子内环化，然后通过与广泛的捕获剂的最终反应进行多样化。我们将评估这种反应性的全部范围和限制，并将其应用于制备重磅炸弹药物类似物。目标3.这种烯烃硼基化-官能化的策略将通过将其与镍催化剂合并来扩展。这将使一个创新的双光氧化还原-镍平台的串联自由基硼化和交叉偶联，将产生在一个不同的方式复杂和密集的功能化材料的发展。一个相关的方面将调查的可扩展性的各种工艺，我们将开发。该项目的这一部分将通过与杨森制药公司的合作来执行，这将允许使用他们最先进的流动化学设施。总的来说，该项目将为C-B键的形成提供新的反应模式，探索硼基自由基在光氧化还原催化中的反应性。鉴于硼化结构单元在合成、生物有机、医药和材料化学中的重要性，该项目将促进高价值材料的发现、开发和制造，对英国社会的福祉产生全面影响。

Boron-containing small organic molecules are one of the most important class of compounds in modern synthetic chemistry due to their use in the Nobel Prize-winning hydroboration-oxidation and Suzuki cross-coupling. Borylated building-blocks are routinely used in the preparation of high-value materials both in academia and industry. Therefore, the invention of novel chemical reactions that form C-B bonds in unprecedented ways is of strategic importance to facilitate the discovery, evolution and manufacture of molecules that impact our society.In general, boron-based functionalities are introduced into organic molecules using two-electron processes like the reaction of Grignards with B-electrophiles or the aromatic C-H borylation using transition metal catalysis. The overarching aim of this project is to explore a complementary approach where C-B bonds are assembled through the reactivity of B-centred radicals (boryl radicals). The use and application of these reactive intermediates is considerably underdeveloped but can provide many orthogonal and complementary solutions to current ionic and metal-mediated borylation strategies.The project is divided in three Aims that will target specific challenges relevant to the preparation of borylated materials.Aim 1. We develop a photochemical approach for the generation of boryl radicals from amine-boranes, a class of stable and abundant materials. These open-shell intermediates will be used to achieve direct and selective C-H borylation of N-heterocycles, one of the most important motifs in pharmaceutical and agrochemical materials. This reactivity will provide a novel approach to functionalise these high-value molecules with a selectivity orthogonal to the one displayed by current metal-catalysed methodologies. We will also benchmark the applicability of the chemistry by applying it to a series of "real-world" substrates of industrial interest that will be provided through a collaboration with Janssen Pharmaceutical. Furthermore, we will evaluate the use of these novel borylated materials in main-stream cross-coupling reactions. Aim 2. Here we will develop divergent multicomponent reactions based on the intramolecular cyclization of boryl radicals. We will use our knowledge in radical cascades to provide unprecedented borylation-functionalization processes. This chemistry involves the generation of homo-allylic amine-boryl radicals that will undergo an intramolecular cyclization followed by a diversification through a final reaction with a broad range of trapping agents. We will evaluate the full scope and limitation of this reactivity and also apply it to the preparation of blockbuster drug analogues. Aim 3. This strategy for olefin borylation-functionalization will be expanded by merging it with nickel catalysis. This will enable the development of an innovative dual photoredox-nickel platform for tandem radical borylation and cross-coupling that will generate in a divergent manner complex and densely functionalised materials.A relevant aspect will be investigating the scalability of the various processes that we will develop. This part of the project will be executed through a collaboration with Janssen Pharmaceutical that will allow to use their state-of-the-art flow-chemistry facilities.Overall, this project will provide novel reactivity modes for the formation of C-B bonds exploring the reactivity of boryl radicals in photoredox catalysis. Given the importance of borylated building blocks in a synthetic, bio-organic, medicinal and material chemistry, this project will facilitate the discovery, development and manufacture of high-value materials with overall impact to the well-being of UK society.