Theoretical Investigations of Palladium‐Catalyzed [3+2] Annulation via Benzylic and meta C−H Bond Activation

DFT studies on the palladium-catalyzed reaction of aromatic amides with maleimides using 2-thiomethylphenyl as a directing group are reported. The results predict that the meta C−H bond activation step is the turnover frequency (TOF)-determining step.

Abstract

The palladium-catalyzed reaction of aromatic amides with maleimides results in the formation of a double C−H bond activation product, which occurs at both the benzylic and meta positions. Computational chemistry studies suggest that the first C−H bond activation unfolds via a six-membered palladacycle, maleimide insertion, protonation of the Pd−N bond, and then activation of the meta C−H bond. The process concludes with reductive elimination, producing an annulation product. The energy decomposition analysis (EDA) showed that the deformation energy favors the ortho C−H bond activation process. However, this route is non-productive. The interaction energy controls the site where the maleimide is inserted into the Pd−C(sp³) bond, which determines its site selectivity. The energetic span model indicates that the meta C−H bond activation step is the one that determines the turnover frequency. Regarding the directing group, it has been concluded that the strong Pd−S bonding and the destabilizing effect of the deformation energy allow the 2-thiomethylphenyl to function effectively as a directing group.

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