Mechanistic Study of Palladium-Catalyzed Chemoselective C(sp3)–H Activation of Carbamoyl Chloride

A theoretical study has been carried out on the palladium-catalyzed C(sp3)–H activation/amidation reaction of carbamoyl chloride precursors ( Takemoto Y. Angew. Chem. Int. Ed. 2012, 51, 2763 ). In Takemoto’s reaction, although the C(sp2)–H bond of naphthalene was present in the substrate, the benzylic C(sp3)–H bond was activated exclusively. Mechanistic calculations have been performed on the two possible pathways: the C(sp3)–H activation/amidation pathway (Path-sp3) and the C(sp2)–H activation/amidation pathway (Path-sp2). Calculation results show that both paths include three steps: oxidative addition (via the mono-phosphine mechanism), C–H activation involving the PivNHO– anion (via the CMD mechanism), and final reductive elimination. The calculations indicate that the Path-sp3 mechanism is kinetically favored, and the C(sp3)–H amidated product is predicted to be the main product. This conclusion is consistent with Takemoto’s experimental observations. The rate-determining step of Path-sp3 is the oxidative addition step, and the C(sp3)–H bond activation step determines the selectivity. Further examination on the origin of the selective C(sp3)–H activation shows that the higher acidity of the benzylic C(sp3)–H (in comparison to the naphthalene C(sp2)–H in this system) is the main reason for the chemoselectivity. The additive might promote the reaction by forming a more soluble organic base (PivNHOCs) via reaction with Cs2CO3.