Palladium mono-N-protected amino acid complexes: experimental validation of the ligand cooperation model in C-H activation.

Mechanistic proposals for the C-H activation reaction enabled by mono-N-protected amino acid ligands (MPAAs) have been supported by DFT calculations. The direct experimental observation of the ligand-assisted C-H activation has not yet been reported due to the lack of well-defined isolated palladium complexes with MPAAs that can serve as models. In this work, palladium complexes bearing chelating MPAAs (NBu4)[Pd(κ2-N,O-AcN-CHR-COO)(C6F5)py] (Ac = MeC(O); R = H, Me) and [Pd(κ2-N,O-MeNH-CH2-COO)(C6F5)py] have been isolated and characterized. Their evolution in a solution containing toluene leads to the C-H activation of the arene and the formation of the C6F5-C6H4Me coupling products. This process takes place only for the ligands with an acyl protecting group, showing the cooperating role of this group in a complex with a chelating MPAA, therefore experimentally validating this working model. The carboxylate group is inefficient in this C-H activation.

Palladium-Catalyzed Ortho C-H Arylation of Unprotected Anilines: Chemo- and Regioselectivity Enabled by the Cooperating Ligand [2,2'-Bipyridin]-6(1H)-one.

Metal-catalyzed C-H functionalizations on the aryl ring of anilines usually need cumbersome N-protection-deprotection strategies to ensure chemoselectivity. We describe here the Pd-catalyzed direct C-H arylation of unprotected anilines with no competition of the N-arylation product. The ligand [2,2'-bipyridin]-6(1H)-one drives the chemoselectivity by kinetic differentiation in the product-forming step, while playing a cooperating role in the C-H cleavage step. The latter is favored in an anionic intermediate where the NH moiety is deprotonated, driving the regioselectivity of the reaction toward ortho substitution.

[2,2'-Bipyridin]-6(1 H)-one, a Truly Cooperating Ligand in the Palladium-Mediated C-H Activation Step: Experimental Evidence in the Direct C-3 Arylation of Pyridine.

The ligand [2,2'-bipyridin]-6(1 H)-one (bipy-6-OH) has a strong accelerating effect on the Pd-catalyzed direct arylation of pyridine or arenes. The isolation of relevant intermediates and the study of their decomposition unequivocally show that the deprotonated coordinated ligand acts as a base and assists the cleavage of the C-H bond. Mechanistic work indicates that the direct arylation of pyridine with this ligand occurs through a Pd(0)/Pd(II) cycle. Because of this dual ligand-intramolecular base role, there is no need for an available coordination site on the metal for an external base, a difficulty encountered when chelating ligands are used in coupling reactions that involve a C-H cleavage step.