Palladium-Mediated C(sp3)-H Bond Activation of N-Methyl-N-(pyridin-2-yl)benzamide: Direct Arylation/Alkylation and Mechanistic Investigation

Herein, we present a facile syntheticmethodology toproduce arange of N-(CH2-aryl/alkyl)-substituted N-(pyridin-2-yl)benzamides via palladium-mediated C(sp(3))-H bond activation. The N-methyl-N-(pyridin-2-yl)benzamide precursor was first reacted withpalladium(II) acetate in a stoichiometric manner to obtain the keydinuclear palladacycle intermediates, whose structures were elucidatedby mass spectrometric, NMR spectroscopic, and X-ray crystallographicstudies in detail. The subsequent C(sp(3))-H bondfunctionalizations on the N-methyl group of the startingsubstrate show facile productions of the corresponding N-(CH2-aryl/alkyl)-substituted N-(pyridin-2-yl)benzamideswith good functional group tolerance. A plausible mechanism was proposedbased on density functional theory calculations in conjunction withkinetic isotope effect experiments. Finally, the synthetic transformationfrom the prepared N-(CH2-aryl)-N-(pyridin-2-yl)benzamides through debenzoylation to N-(CH2-aryl)-2-aminopyridine was successfullydemonstrated.