Metal-free couplings for molecules, materials and bioactive targets

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Synthetic chemistry powers scientific advances on many fronts as molecules and materials are vital to the work of millions of scientists around the world: if we can't make the molecular systems we need, we can't advance science and benefits for society will be lost. In particular, the selective formation of carbon-carbon bonds in aromatic and heteroaromatic systems is one of the most important goals in synthesis as aromatic scaffolds form the structural basis of many pharmaceuticals, agrochemicals and materials.A range of metal-catalyzed cross-coupling processes - now familiar to every practising chemist worldwide - have been developed to address the formation of these particular carbon-carbon bonds and the resultant benefits for society have been remarkable. In recognition, the 2010 Nobel Prize in Chemistry was awarded jointly to Heck, Negishi and Suzuki "for palladium-catalyzed cross couplings in organic synthesis". More recently, methods for the formation of carbon-carbon bonds to sites on an aromatic ring with substitution of a C-H bond, rather than a halide (so called "C-H activation") have been developed. Such processes are highly desirable as the starting materials are often more available, inexpensive and processes usually generate less waste.The majority of these 'classical' and 'cutting-edge' cross-coupling processes have one thing in common: they are mediated by expensive late transition metals (e.g. ruthenium, rhodium, palladium and platinum). Unfortunately, the supply of these metals is at risk and their use will become unsustainable in the future. An important course, therefore, involves the development of coupling reactions that do not involve the use of a metal. Such an approach has additional benefits, as trace metal contamination in products arising from metal-catalyzed processes is a major problem in industry - particularly the pharmaceutical and organic electronic industries.During my Fellowship project I will develop metal-free processes that complement existing metal-catalyzed cross-coupling technologies and could eventually lead to their replacement. Readily-accessible aromatic and heteroaromatic systems will be used in metal-free cross-couplings with electron-rich carbon-based partners. Our strategy will use a sulfoxide directing group on the aromatic ring to orchestrate carbon-carbon bond formation at the position next door: sulfur will catch the incoming carbon coupling partner before passing it to the aromatic ring. Thus, an easy carbon-sulfur bond forming event will be used to trigger the formation of a more-challenging carbon-carbon bond, with substitution of a hydrogen on the aromatic ring (so called "C-H substitution"). The aromatic and heteroaromatic sulfoxide starting materials are very easy to make by oxidation of a wide-range of commercially available sulfides. Importantly, the sulfur directing group in our approach can be viewed as a 'safety-catch' directing group: the sulfur in the starting material lies dormant and only upon oxidation to the sulfoxide is the substrate 'switched on' and becomes receptive to metal-free cross-coupling. During the coupling, the sulfur directing group is reduced and the directing effect is 'switched-off'. This 'safety-catch' feature leads to many advantages: for example, premature reaction or over reduction of the substrate is impossible.The products of the metal-free couplings are of high value in their own right and are also ripe for manipulation. For example, metal-free conversion to industrially-important benzothiophene motifs is possible. To illustrate the great potential of our metal-free approach to cross-coupling we will apply the technology in the synthesis and modification of functional molecules, organic materials and bioactive targets: syntheses that would usually be carried out using supply-risk late transition metals.