Sulfoxides as substrate activators: New cross-couplings for making materials and medicines

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Synthetic chemistry is the engine that drives the advance of science and technology as man-made molecules and materials are vital to the work of millions of scientists around the world. In particular, the selective formation of carbon-carbon bonds, so-called 'cross-coupling', lies at the heart of almost any synthetic endeavour and is crucial for the discovery of tomorrow's pharmaceuticals, agrochemicals and advanced materials.A suite of cross-coupling reactions using metal catalysts has been developed for carbon-carbon bond formation and these methods are routinely used in every chemistry laboratory in the world. The resulting, positive impact of cross-coupling technology on science and on society has been remarkable. Unfortunately, the majority of cross-coupling is mediated by platinum group metals (e.g. rhodium, palladium, iridium and platinum) and the supply of these costly metals is at risk, thus making their use unsustainable. It is against the backdrop of an uncertain future that the search for new cross-coupling methods that do not use a metal or use a low-cost metal catalyst has gripped the global synthetic community. The world's leading scientists now share a vision of a chemical community less reliant on platinum group metals.There is an additional problem with the current methods for cross-coupling. Molecule-makers traditionally use starting, chemical feedstocks that are already 'functionalised'; i.e. they contain a 'handle' that facilitates chemical manipulation. If simpler, non-functionalised feedstocks could be used instead, shorter, less expensive chemical processes that generate less waste could be developed. With the promise of more sustainable chemistry in the future, the global synthetic community are eager to move away from 'functionalised' feedstocks to simpler starting materials that are functionalised and chemically transformed as part of a single process. Finally, metal-free cross-coupling has an additional key benefit. Trace metal contamination in products arising from metal-catalysed processes is a major problem in industry, particularly the pharmaceutical and organic electronic industries, where products are for human consumption or for use in devices where performance can be compromised by 'undetectable' levels of metal contaminant.In this project we will develop metal-free and low-cost metal catalysed cross-coupling processes that could eventually replace ubiquitous metal-catalysed technologies that use expensive platinum group metals. Our approach to this challenge is unique and is based on the proposal that sulfur can replace metals in; (i) activating substrates by functionalising them in situ, and (ii) providing a center around which coupling partners can be assembled prior to carbon-carbon bond-formation. More specifically, we will use readily-available and tuneable, organosulfur species, called sulfoxides, as reagents and catalysts to active simple feedstocks for direct use in new cross-couplings that deliver high value products. Crucially, our approach does not require pre-functionalised feedstocks for cross-coupling as activated substrates will be formed in situ and used directly in the same reaction vessel. At the heart of our proposal lies the so-called Interrupted Pummerer reaction, a little-known and seldom exploited chemical process in which a nucleophile adds to the sulfur of a sulfoxide to give a sulfonium salt. Our groundbreaking strategies will either be metal-free or will use inexpensive base-metal catalysts, thus avoiding the need for expensive, supply-risk, and contaminating platinum group metals.Applications in the synthesis and modification of materials and pharmaceuticals will be used throughout the project to showcase the utility of our new technology to molecule makers and end-users, thus plotting a course to future impact. Our track record in innovative cross-coupling processes using sulfoxides leaves us uniquely placed to meet this challenge.