Leveraging sulfinates for heterocycle cross-electrophile coupling

利用亚磺酸盐进行杂环交叉亲电子偶联

• 批准号: EP/X020525/1
• 负责人: Michael Willis
• 金额: $ 36.82万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX020525%2F1
• 关键词: Leveraging; sulfinates; heterocycle; cross; electrophile

Linked heteroaryl-aryl and heteroaryl-heteroaryl motifs, particularly pyridine-based structures, feature prominently in medicinal and agrochemistry programs, and they also play key roles as ligands for metal catalysts. A recent analysis showed that 59% of drugs approved by the US Federal Drug Administration up to 2012 contained at least one nitrogen heterocycle, and that pyridine was the second most common ring after piperidine. However, the workhorse reaction used by the pharmaceutical and agrochemical industries to prepare linked arenes is only poorly effective when heterocycle derived coupling partners are employed. This is due to difficulties in the preparation, and the stability of the key starting materials, which are heteroaromatic boronic acids. This has real consequences in medicinal chemistry, and can mean that longer synthetic sequences are needed, which is costly in terms of time and resource, and results in greater waste production, or that molecules are simply not made because the synthesis is too challenging. This proposal is concerned with exploiting a class of molecule that can function as replacements for heteroaromatic boronic acids. Instead of being based on boron, these new reagents are sulfur-based, and importantly, are generated during the key coupling reactions, and are not isolated intermediates. We have shown in earlier work that isolated sulfinate reagents (the group we will generate during the reactions) are excellent reagents for cross-coupling chemistry. Generating these reagents in the course of the reaction will have several advantages; most significantly it will remove two synthetic steps from the overall reaction sequence. This reduction in steps will mean less waste is produced, less energy is needed, and the target molecules will be prepared in a shorter time. It also has advantages in that the starting materials (the substrates) are widely available from many commercial suppliers. We will also explore the use of non-precious metals, such as nickel and copper, as catalysts. These have advantages of far greater abundance than metals that are traditionally used in these types of reactions, such as palladium.

连接的杂芳基-芳基和杂芳基-杂芳基基序，特别是基于吡啶的结构，在医药和农业化学项目中具有突出的特征，并且它们作为金属催化剂的配体也发挥着关键作用。最近的一项分析显示，截至 2012 年，美国联邦药物管理局批准的药物中有 59% 至少含有一个氮杂环，而吡啶是仅次于哌啶的第二常见环。然而，当使用杂环衍生的偶联配偶体时，制药和农业化学工业用于制备连接芳烃的主力反应效果不佳。这是由于制备困难以及关键起始原料杂芳族硼酸的稳定性造成的。这对药物化学产生了真正的影响，并且可能意味着需要更长的合成序列，这在时间和资源方面是昂贵的，并导致更多的废物产生，或者由于合成太具有挑战性而根本无法制造分子。该提案涉及开发一类可以替代杂芳族硼酸的分子。这些新试剂不是基于硼，而是基于硫，重要的是，它们是在关键偶联反应过程中产生的，而不是孤立的中间体。我们在早期的工作中已经证明，分离的亚磺酸盐试剂（我们将在反应过程中产生的基团）是交叉偶联化学的优秀试剂。在反应过程中生成这些试剂有几个优点：最重要的是，它将从整个反应序列中删除两个合成步骤。步骤的减少意味着产生的废物更少，需要的能量更少，并且可以在更短的时间内制备目标分子。它的优点还在于起始材料（基材）可以从许多商业供应商处广泛获得。我们还将探索使用镍和铜等非贵金属作为催化剂。它们的优点是比传统上用于此类反应的金属（例如钯）丰度更高。