11C‐Cyanation of Aryl Fluorides via Nickel and Lithium Chloride‐Mediated C−F Bond Activation

A radiosynthetic method for [¹¹C]aryl nitriles via nickel-mediated carbon-fluorine bond activation is reported. This method enables the efficient ipso-¹¹C-cyanation of a broad range of aryl fluorides, including pharmaceutical drugs. Stoichiometric reactions and theoretical studies indicate that LiCl greatly promotes the oxidative addition of aryl fluorides to a nickel(0) complex, affording aryl(chloro)nickel(II) complexes at room temperature.

Abstract

Aryl fluorides are expected to be useful as radiolabeling precursors due to their chemical stability and ready availability. However, direct radiolabeling via carbon-fluorine (C−F) bond cleavage is a challenging issue due to its significant inertness. Herein, we report a two-phase radiosynthetic method for the ipso-¹¹C-cyanation of aryl fluorides to obtain [¹¹C]aryl nitriles via nickel-mediated C−F bond activation. We also established a practical protocol that avoids the use of a glovebox, except for the initial preparation of a nickel/phosphine mixture, rendering the method applicable for general PET centers. This method enabled the efficient synthesis of diverse [¹¹C]aryl nitriles from the corresponding aryl fluorides, including pharmaceutical drugs. Stoichiometric reactions and theoretical studies indicated a significant promotion effect of lithium chloride on the oxidative addition, affording an aryl(chloro)nickel(II) complex, which serves as a precursor for rapid ¹¹C-cyanation.

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