Catalytic Behavior of Mono-N-Protected Amino-Acid Ligands in Ligand-Accelerated C-H Activation by Palladium(II).

Mono-N-protected amino acids (MPAAs) are increasingly common ligands in Pd-catalyzed C-H functionalization reactions. Previous studies have shown how these ligands accelerate catalytic turnover by facilitating the C-H activation step. Here, it is shown that MPAA ligands exhibit a second property commonly associated with ligand-accelerated catalysis: the ability to support catalytic turnover at substoichiometric ligand-to-metal ratios. This catalytic role of the MPAA ligand is characterized in stoichiometric C-H activation and catalytic C-H functionalization reactions. Palladacycle formation with substrates bearing carboxylate and pyridine directing groups exhibit a 50-100-fold increase in rate when only 0.05 equivalents of MPAA are present relative to PdII . These and other mechanistic data indicate that facile exchange between MPAAs and anionic ligands coordinated to PdII enables a single MPAA to support C-H activation at multiple PdII centers.

Palladium Catalyzed Hydrodefluorination of Fluoro-(hetero)arenes.

Palladium catalyzed hydrodefluorination was developed for fine-tuning the properties of fluoro-(hetero)aromatic compounds. The robust reaction can be set up in air, requires only commercially available components, and tolerates a variety of heterocycles and functionalities relevant to drug discovery. Given the prevalence of fluorine incorporation around metabolic hotspots, the corresponding deuterodefluorination reaction may prove useful for converting fluorinated libraries to deuterated analogues to suppress the oxidative metabolism by kinetic isotope effects.

Mono-N-protected amino acid ligands stabilize dimeric palladium(ii) complexes of importance to C-H functionalization.

Mono-protected amino acid (MPAA) ligands are used in a number of Pd-catalyzed C-H functionalization reactions. MPAAs have been proposed to bind to Pd(ii) via κ2-(N,O) coordination, but such binding has not yet been experimentally validated. Herein, we report the synthesis and detailed characterization of a series of MPAA complexes prepared via cyclopalladation of dimethylbenzylamine in the presence of MPAAs. The isolated complexes exist as µ-carboxylato (MPAA) bridged dimers and feature potential M-M cooperativity and secondary sphere hydrogen bonding. Selective MPAA coordination and relay of stereochemistry, previously suggested to uniquely result from κ2-(N,O) MPAA coordination, are both observed. The isolated MPAA complexes undergo C-C and C-X (X = Cl, Br, I) bond formation when treated with electrophiles used for catalytic C-H functionalization. Stoichiometric iodination of MPAA palladacycles was found to proceed via a dinuclear palladium species with one equivalent of iodine in the rate limiting transition structure, and the isolated complexes also served as viable precatalysts for catalytic C-H functionalization. Together, these results provide a number of insights into the reactivity of Pd-MPAA complexes relevant to C-H bond functionalization.