Transition metal catalyzed C−H amination/amidation is a desirable method to construct C-N bonds from C-H bonds. While significant advances have been made with selective functionalization of sp2 C-H bonds, the selective functionalization of sp3 C-H bonds has often lagged behind. Site-selectivity of sp3 C-H functionalization typically follows C-H bond strengths, with weaker C-H bonds (allylic, benzylic) functionalized in preference to the stronger C-H bonds giving rise to 3° C-H selectivity over 2° and 1° C-H bonds. Accordingly, selective functionalization of 1° and 2° sp3 C−H bonds in the presence of weaker 3° C−H bonds remains a key challenge in this field. Methods for catalytic functionalization of 1° C–H bonds typically rely on directing groups that require specialized substrates which may not be present in a chosen substrate. Herein, we report the rational design and synthesis of a sterically encumbered β−diketiminato Cu(I) catalyst that leads to undirected, regioselective intermolecular amidation of unactivated sp3 C−H bonds. By limiting access of weaker, yet more hindered 3° C-H bonds to sterically protected copper nitrene intermediates derived from benzoyl azides, C-H amidation selectively takes place at stronger, yet more open 1° and 2° C-H bonds. This catalyst system functionalizes complex molecules with high levels of methylene site selectivity over 3° C−H bonds.

Cu catalyzed sp3 C-H amidation: Catalyst controlled site selectivity

254th National Meeting (2017)

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