Whilst high-throughput technologies have dramatically advanced processes such as drug screening and protein crystallization, reaction setup and execution in synthetic chemistry has not changed significantly for decades. Application of related high-throughput experimentation practices have the potential to revolutionize chemical synthesis. The aim of this work was to develop a general high-throughput platform for reaction development.<br/>Using the TTP Mosquito®, a liquid handling robot, we sought to apply a copper-catalyzed C–N bond coupling reaction to a high-throughput format. Reagent stock solutions were transferred to a 1536-well plate where the reaction takes place in a total reaction volume of 2.5 μL. We established a novel protocol to efficiently screen four reaction parameters simultaneously: catalyst, base, ligand and substrate. Once the best combination was discovered, reagent equivalents were optimised. To aid this strategy, generic plate designs and excel based software were developed to facilitate stock solution preparation and source plate loading. Statistical tests assessed the robustness of the data generated. This unique simultaneous multi-parameter screening platform facilitates identification of ideal combinations unlike typical iterative batch optimisation and, therefore, can rapidly generate bespoke reaction conditions for multiple substrates.<br/>Optimal reaction conditions in DMSO at room temperature were found for the coupling of eight different boronic esters with one amine by screening six catalysts, eight bases and twelve ligands in a short timeframe. This proof-of-principal study further demonstrates the potential of the TTP Mosquito® for use in rapid chemical synthesis and optimization. The protocols we have developed are not specific for our chosen coupling but can be used for multiple chemical reactions illustrating the potential that high-throughput chemistry has in advancing chemical synthesis.

High-throughput synthesis: A platform for rapid reaction development

254th National Meeting (2017)

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