Catalysing 3 routes to C-H Borylation using Earth-abundant Metals

The ability to construct rapidly new molecular architectures is essential across multiple fields. For example, pharmaceutical development requires a library of building blocks to maximise diversity at the early stage of drug discovery. Likewise, materials science is built on the ability to polymerise new building blocks with functional potential.

Aryl boronic acids and esters satisfy this need and are some of the most commonly used building blocks. They are air-stable and easy to manipulate with many well-established routes for functionalisation. However, the current routes to form aryl boronic esters rely on inefficient chemistry that is over 50-years old or require the use of toxic and scarce (thus unsustainable and expensive) precious metal catalysts.

This proposal seeks to replace these technologies with new methods using Earth-abundant aluminium- and zinc-complexes. More specifically, we will use aluminium and zinc based catalysts to achieve the direct (one step from simple precursors) borylation of simple (early stage) and complex (late stage) molecules.

The use of catalysis is essential in ensuring the sustainability of processes as this minimises the energy input requirements and amount of material needed for each transformation. Catalysis offers the single most applicable method to ensure a sustainable future for chemical synthesis and the use of Earth-abundant metals for catalysis greatly improves this prospect.

The use of aluminium and zinc is also driven by their low-toxicity relative to many other catalysts used in direct borylation (e.g. Co, Ir based catalysts). Zinc and aluminium have high daily permitted exposure limits enabling their use late in pharmaceutical manufacturing without the need for exhaustive metal removal required when using precious metal catalysts.

This project will specifically target the borylation of arene C-H bonds. Arenes are commodity chemicals with great structural diversity, but they lack handles for further functionalisation. We will develop aluminium- and zinc catalysts capable of introducing a boronic functional handle to these substrates.

Aluminium and zinc benefit from many similar properties including, size, substrate (arene) affinity, electronegativity and, to some extent, coordination preferences, but they differ based on their charge (valency) in compounds (+3 Vs +2). We will utilise both metals within common frameworks to enable the effect of unit charge variation to be studied to determine key structure activity relationships.

This deep understanding will enable broad scope borylation of arene C-H bonds to be achieved. The aryl boronic ester products are among the most common synthetic building blocks used by academia and industry so this will ensure the high impact of our developed methods.

We will transfer our initial breakthroughs through to operationally simple processes that can be readily used by the broadest academic and industrial synthetic community. Throughout we will be supported by GSK and Dr Andrew Dominey (GSK Process Chemistry, Stevenage), who as a co-Investigator on this project will be essential to enable the development of a truly useful process.

Regular meetings and placements at GSK will be carried out to ensure cohesive progression, technology transfer and imbedding of our new developed methods at GSK. Alongside this, the GSK placements offer a unique chance for real-world testing and benchmarking of our new developed methods. Placements at Stevenage will enable application of our new reaction to specific pharmaceutical targets.