Leveraging sulfinates for heterocycle cross-electrophile coupling

连接的杂芳基-芳基和杂芳基-杂芳基基，特别是基于吡啶的结构，在医药和农业化学项目中占有重要地位，它们也作为金属催化剂的配体发挥着关键作用。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%含有至少一个氮杂环，而吡啶是仅次于哌啶的第二常见环。然而，制药和农化工业用于制备连接芳烃的主要反应只有在采用杂环衍生偶联伙伴时才有效。这是由于制备困难，以及关键起始材料杂芳香硼酸的稳定性。这对药物化学产生了真正的影响，可能意味着需要更长的合成序列，这在时间和资源方面都是昂贵的，并导致更多的废物产生，或者因为合成太具有挑战性而无法制造分子。这个建议是关于开发一类分子，可以作为替代杂芳香硼酸。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中产生的，而不是分离的中间体。我们在早期的工作中已经表明，分离的亚硫酸盐试剂（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省去两个合成步骤。这种步骤的减少将意味着产生更少的废物，所需的能量更少，目标分子将在更短的时间内制备。它还有一个优点，即起始材料（基材）可以从许多商业供应商那里广泛获得。我们还将探索使用非贵金属，如镍和铜，作为催化剂。它们比传统上用于这类反应的金属（如钯）具有丰富得多的优势。

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.