Synthesis of 3-Borylated Pyrrolidines by 1,3-Dipolar Cycloaddition of Alkenyl Boronates and Azomethine Ylide |
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Authors: | Oleksandr S. Liashuk Ihor A. Ryzhov Dr. Oleksandr V. Hryshchuk Bohdan V. Vashchenko Pavlo V. Melnychuk Prof. Dr. Yulian M. Volovenko Prof. Dr. Oleksandr O. Grygorenko |
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Affiliation: | 1. Enamine Ltd., Chervonotkatska Street 78, Kyiv, 02094 Ukraine;2. Enamine Ltd., Chervonotkatska Street 78, Kyiv, 02094 Ukraine Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv, 01601 Ukraine;3. Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv, 01601 Ukraine |
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Abstract: | A scalable and efficient process for the preparation of 3-borylated pyrrolidines by 1,3-dipolar cycloaddition of N-benzyl azomethine ylide generated in situ has been developed. The optimized method included the use of LiF in DMSO at 110 °C and was suitable for α-mono-, α,β-di-, and α,β,β-trialkyl-, β,β-(hetera)cycloalkylidene-, CO2Et-, as well as most β-(het)aryl-substituted alkenyl boropinacolates. The 1,3-dipolar reaction proceeded on a multigram scale providing 3-borylated pyrrolidines with diverse substitution patterns (including fused and spirocyclic ones) in a diastereoselective manner. The Pd(OH)2-mediated N-debenzylation of pyrrolidine hydrochlorides was successfully performed to give the corresponding bifunctional building blocks on an up to 130 g scale, thus providing a substantial expansion of the synthetic and medicinal chemist's toolbox. Other reactions included the preparation of trifluoroborates, Zweifel-Aggarwal sp3-sp2 coupling, and oxidative deborylation as an example of C-heteroatom bond formation. |
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Keywords: | boronate boronic acid cycloadditions C−C coupling pyrrolidine |
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