Development and Molecular Understanding of a Pd-Catalyzed Cyanation of Aryl Boronic Acids Enabled by High-Throughput Experimentation and Data Analysis |
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Authors: | Jordan De Jesus Silva Niccolò Bartalucci Benson Jelier Samantha Grosslight Tobias Gensch Claas Schünemann Bernd Müller Paul C J Kamer Christophe Copéret Matthew S Sigman Antonio Togni |
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Institution: | 1. Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 1–5, CH-8093 Zürich, Switzerland;2. Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112 United States;3. Leibniz-Institute for Catalysis e. V., Albert-Einstein-Straße 29a, DE-18059 Rostock, Germany |
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Abstract: | A synthetic method for the palladium-catalyzed cyanation of aryl boronic acids using bench stable and non-toxic N-cyanosuccinimide has been developed. High-throughput experimentation facilitated the screen of 90 different ligands and the resultant statistical data analysis identified that ligand σ-donation, π-acidity and sterics are key drivers that govern yield. Categorization into three ligand groups – monophosphines, bisphosphines and miscellaneous – was performed before the analysis. For the monophosphines, the yield of the reaction increases for strong σ-donating, weak π-accepting ligands, with flexible pendant substituents. For the bisphosphines, the yield predominantly correlates with ligand lability. The applicability of the designed reaction to a wider substrate scope was investigated, showing good functional group tolerance in particular with boronic acids bearing electron-withdrawing substituents. This work outlines the development of a novel reaction, coupled with a fast and efficient workflow to gain understanding of the optimal ligand properties for the design of improved palladium cross-coupling catalysts. |
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Keywords: | aryl boronic acids cyanation data analysis high-throughput experimentation ligand design palladium |
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