Leveraging sulfinates for heterocycle cross-electrophile coupling

连接的杂芳基和杂芳基杂芳基基序，特别是基于吡啶的结构，在医药和农业化学中具有重要的地位，它们也是金属催化剂的关键配体。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，吡啶是仅次于哌啶的第二大环。然而，制药和农化工业用来制备连接芳烃的主要反应只有在使用杂环衍生偶联伙伴时才有效。这是由于制备困难，以及关键的起始原料的稳定性，这些原料是杂芳烃的硼酸。这在药物化学中产生了真正的后果，可能意味着需要更长的合成序列，这就耗费了大量的时间和资源，并导致了更多的废物产生，或者只是因为合成太具挑战性而没有制造分子。这项提议涉及开发一类可以作为杂芳烃硼酸替代品的分子。这些新试剂不是以硼为基础的，而是以硫为基础的，重要的是，它们是在关键的偶联反应中产生的，而不是孤立的中间产物。我们在早期的工作中已经证明，分离的亚硫酸盐试剂(我们将在反应过程中生成的基团)是交叉偶联化学的优秀试剂。在反应过程中生成这些试剂将有几个好处；最重要的是，它将从整个反应序列中省去两个合成步骤。步骤的减少将意味着产生的废物更少，所需的能量更少，目标分子的制备将在更短的时间内完成。它的优势还在于，起始材料(衬底)可以从许多商业供应商那里广泛获得。我们还将探索非贵金属的使用，如镍和铜，作为催化剂。与传统上用于此类反应的金属(如钯)相比，这些金属具有更大的丰度优势。

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.