Leveraging sulfinates for heterocycle cross-electrophile coupling

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.