Reaction screening in multiwell plates: high-throughput optimization of a Buchwald–Hartwig amination

Cook, Adam; Clément, Roxanne; Newman, Stephen G.

doi:10.1038/s41596-020-00452-7

Cited by 28 publications

(22 citation statements)

References 30 publications

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“…High-throughput experimentation (HTE) involves running multiple reactions in parallel, which is a useful technique for quickly exploring chemical space in a systematic and standardized manner. − Traditionally, this process has been employed in the pharmaceutical industry for the parallel synthesis/assessment of chemical compounds on a variety of scales. This includes small, focused arrays of compounds for exploring structure–activity relationships (SAR) around a hit compound of interest, and the synthesis of thousands of compounds to populate high-throughput screening (HTS) libraries.…”

Section: Data-driven Optimizationmentioning

confidence: 99%

A Brief Introduction to Chemical Reaction Optimization

et al. 2023

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From the start of a synthetic chemist’s training, experiments are conducted based on recipes from textbooks and manuscripts that achieve clean reaction outcomes, allowing the scientist to develop practical skills and some chemical intuition. This procedure is often kept long into a researcher’s career, as new recipes are developed based on similar reaction protocols, and intuition-guided deviations are conducted through learning from failed experiments. However, when attempting to understand chemical systems of interest, it has been shown that model-based, algorithm-based, and miniaturized high-throughput techniques outperform human chemical intuition and achieve reaction optimization in a much more time- and material-efficient manner; this is covered in detail in this paper. As many synthetic chemists are not exposed to these techniques in undergraduate teaching, this leads to a disproportionate number of scientists that wish to optimize their reactions but are unable to use these methodologies or are simply unaware of their existence. This review highlights the basics, and the cutting-edge, of modern chemical reaction optimization as well as its relation to process scale-up and can thereby serve as a reference for inspired scientists for each of these techniques, detailing several of their respective applications.

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Section: Data-driven Optimizationmentioning

confidence: 99%

A Brief Introduction to Chemical Reaction Optimization

et al. 2023

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“…Data extraction of appropriate Buchwald–Hartwig amination reactions led to a similar distribution of articles to the SMCC data set (Figure ). From 57 articles and 69 reactions, ,,,,− the largest proportion, again, are localized in the lowest mol % category of 0–1 mol %. There are several sources that involve the use of other metal additives (CuI and Zn(OTf) 2 ), which skew the data, being used in 50 (0.5 equiv.)…”

Section: Buchwald–hartwig Aminationmentioning

confidence: 92%

Pd-Catalyzed Cross-Couplings: On the Importance of the Catalyst Quantity Descriptors, mol % and ppm

Horbaczewskyj

Fairlamb

2022

Org. Process Res. Dev.

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This Review examines parts per million (ppm) palladium concentrations in catalytic cross-coupling reactions and their relationship with mole percentage (mol %). Most studies in catalytic cross-coupling chemistry have historically focused on the concentration ratio between (pre)catalyst and the limiting reagent (substrate), expressed as mol %. Several recent papers have outlined the use of “ppm level” palladium as an alternative means of describing catalytic cross-coupling reaction systems. This led us to delve deeper into the literature to assess whether “ppm level” palladium is a practically useful descriptor of catalyst quantities in palladium-catalyzed cross-coupling reactions. Indeed, we conjectured that many reactions could, unknowingly, have employed low “ppm levels” of palladium (pre)catalyst, and generally, what would the spread of ppm palladium look like across a selection of studies reported across the vast array of the cross-coupling chemistry literature. In a few selected examples, we have examined other metal catalyst systems for comparison with palladium.

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“…Recent advances in high-throughput experimentation (HTE) enabled the fast examination of multiple reactions with minimum resources in a relatively short period of time. − Thus, the HTE approach has been successfully applied to pharmaceutical synthesis − and catalyst design. − Benefitting from the HTE logic and known accessibility to both Cp X - and LX-type compounds, we envisaged generating a wide array of Cp X M(LX) complexes in situ by simple premixing of [Cp X MCl 2 ] 2 and LX co-ligands. Moreover, we also envisioned additionally screening the metal centers and nitrenoid precursors (Scheme b, right).…”

Section: Introductionmentioning

confidence: 99%

Multidimensional Screening Accelerates the Discovery of Rhodium Catalyst Systems for Selective Intra- and Intermolecular C–H Amidations

et al. 2022

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We report herein a series of tailored CpXRh(LX)Cl catalyst systems for the outer-sphere C–H amidations discovered by high-throughput experimentation. Using a diverse repertoire of Cp-tunable group 9 [CpXMCl2]2 precatalysts in combination with bidentate LX-type co-ligands, we have established a premixing protocol for the fast and convenient in situ generation of an array of half-sandwich metal complexes. Benefitting from the designed multidimensional approach to simultaneously screen the metal center, CpX, LX-type co-ligands, and nitrene precursors, optimal CpXRh(III)(LX) catalysts were quickly identified for intra- and intermolecular C–H amidations and also for an enantioselective transformation using N-tosyloxycarbamates as the nitrenoid precursor.

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Reaction screening in multiwell plates: high-throughput optimization of a Buchwald–Hartwig amination

Cited by 28 publications

References 30 publications

A Brief Introduction to Chemical Reaction Optimization

A Brief Introduction to Chemical Reaction Optimization

Pd-Catalyzed Cross-Couplings: On the Importance of the Catalyst Quantity Descriptors, mol % and ppm

Multidimensional Screening Accelerates the Discovery of Rhodium Catalyst Systems for Selective Intra- and Intermolecular C–H Amidations

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