Uncovering Competing Cross-Coupling Catalytic Cycles Through Rich Data Analysis of Reaction Outcomes Gained by High-throughput Experiment Screening

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Pd-catalyzed Suzuki-Miyaura Cross-Coupling (SMCC) reactions are widely employed in the pharmaceutical sector, from research discovery and scale-up processes through to manufacture. Despite extensive work on Pd-catalyzed SMCC reactions, involving substrate scoping, catalyst development, and mechanistic work, there remain significant challenges when new cross-coupling substrates (reagents) are tested. The reasons for lower than expected yields of products are typically associated with competing side reactions, especially protodeborylation, protodehalogenation and hydrolysis processes. To understand these competing processes better we will employ a Chemspeed ISYNTH robotic system, combining high throughput experimentation (HTE) and data analytics, with the primary aim of generating a large number of reaction outcomes (leading to the creation of a valuable dataset). We are then able to integrate the data from the reaction outcomes using a bespoke design of experiment approach. There we will assess both quantitative (amounts) and categorical (groupings) variables for the different SMCC reactions (employing various substrate reactivity profiles). We expect trends to emerge in the reactivity profiling. As a consequence, this research project will directly address the urgent need to identify rules governing the reactivity of libraries of pi-rich and pi-deficient organic substrates. As a secondary off-shoot from our work, the approaches developed in HTE and data analytics will be broadly transferable to other catalytic processes.