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Synthesis of Arylethylamines via C(sp3)–C(sp3) Palladium-Catalyzed Cross-Coupling

Cite this: J. Org. Chem. 2021, 86, 4, 3583–3604
Publication Date (Web):January 29, 2021
https://doi.org/10.1021/acs.joc.0c02958
Copyright © 2021 American Chemical Society

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    Abstract

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    Substituted arylethylamines represent a key structural motif in natural, pharmaceutical, and agrochemical compounds. Access to such scaffolds has been the subject of long-standing synthetic interest. Herein, we report the synthesis of such scaffolds via a palladium-catalyzed C(sp3)–C(sp3) coupling between (chloromethyl)aryls and air-/moisture-stable N,N-dialkylaminomethyltrifluoroborate salts. Rapid hit identification was achieved using microscale high-throughput experimentation and was followed by millimolar-scale reaction parameter optimization. A range of structurally and electronically varied arylethylamine products were obtained in moderate to excellent yields (27–96%, >60 examples). The reaction mechanism is proposed to proceed via formation of a trialkylbenzylammonium species prior to oxidative addition.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.0c02958.

    • Detailed procedures for high-throughput experimentation, preparation, and characterization of compounds; and 1H and 13C{1H} NMR spectra of compounds and procedures for monitoring of trifluoroborate salt hydrolysis rates (PDF)

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    Cited By

    This article is cited by 5 publications.

    1. Emily E. Freeman, Randy Jackson, Jessica Luo, Rajen Somwaru, Alex A. Sons, Andrew Bean, Ronald N. Buckle, R. Jason Herr. A Three-Step Method for the Preparation of N-Substituted 3,4-Dihydroisoquinolin-1(2H)-ones and Heteroaryl-Fused 3,4-Dihydropyridin-2(1H)-ones from 2-Bromobenzoate Precursors. The Journal of Organic Chemistry 2023, 88 (4) , 2589-2598. https://doi.org/10.1021/acs.joc.2c02670
    2. Efrey A. Noten, Cody H. Ng, Robert M. Wolesensky, Corey R. J. Stephenson. A general alkene aminoarylation enabled by N-centred radical reactivity of sulfinamides. Nature Chemistry 2024, 6 https://doi.org/10.1038/s41557-023-01404-w
    3. Valentyn Pozhydaiev, Cyprien Muller, Joseph Moran, David Lebœuf. Catalytic Synthesis of β‐(Hetero)arylethylamines: Modern Strategies and Advances. Angewandte Chemie International Edition 2023, 62 (41) https://doi.org/10.1002/anie.202309289
    4. Valentyn Pozhydaiev, Cyprien Muller, Joseph Moran, David Lebœuf. Catalytic Synthesis of β‐(Hetero)arylethylamines: Modern Strategies and Advances. Angewandte Chemie 2023, 135 (41) https://doi.org/10.1002/ange.202309289
    5. Efrey A. Noten, Rory C. McAtee, Corey R. J. Stephenson. Catalytic intramolecular aminoarylation of unactivated alkenes with aryl sulfonamides. Chemical Science 2022, 13 (23) , 6942-6949. https://doi.org/10.1039/D2SC01228F

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