Development of Aromatic and Aliphatic C–H Functionalizations via Photoredox Catalysis Public Deposited

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  • March 21, 2019
  • Margrey, Kaila
    • Affiliation: College of Arts and Sciences, Department of Chemistry
  • Carbon–hydrogen (C–H) bonds are ubiquitous in organic compounds, and the ability to functionalize C–H bonds selectively is a powerful strategy for late-stage derivatizations. The direct C–H functionalization of electron-rich arenes with azole coupling partners was demonstrated using an acridinium photoredox catalyst and a nitroxyl radical cocatalyst under an aerobic atmosphere, occurring via the intermediacy of an arene cation radical. High levels of site selectivity were observed with this methodology, and it proved applicable to a wide variety of arene and azole coupling partners, including complex bioactive molecules. Anilines could be constructed using ammonium carbamate as the nucleophilic coupling partner. The ability to predict the site of C–H functionalization on complex arenes is nontrivial, and for this reason, a predictive model was developed. This enabled the extension of our aryl amination to a wide variety of heterocyclic arenes that are common motifs in pharmaceuticals. Using electron density calculations, we could predict the major site of functionalization for over 60 arene substrates. We sought to extend this arene functionalization methodology toward aliphatic amine coupling partners. We demonstrated this capability with a wide variety of amino acid and primary amine coupling partners with arene substrates. Site selectivity was dependent on sterics of the arene, unlike our previous work with azoles. We also disclose the functionalization of arenes that cannot be oxidized by the acridinium catalyst, such as benzene and toluene, supporting a reactive amine cation radical intermediate. A modular functionalization of unactivated aliphatic C–H bonds was developed utilizing an acridinium photoredox catalyst, phosphate base, and several diverse radical traps. The development of a C–H azidation reaction highlighted good site selectivity on alkanes for tertiary functionalization exclusively. Through modifications of this system, a C–H diversification allowed for the formation of C–F, C–Br, C–Cl, C–SCF3, and C–C bonds.
Date of publication
Resource type
  • Alexanian, Erik
  • Gagne, Michel
  • Leibfarth, Frank
  • Meek, Simon
  • Nicewicz, David
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2018

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