Nondirected Pd-Catalyzed C–H Perdeuteration and meta-Selective Alkenylation of Arenes Enabled by Pyrazolopyridone Ligands

Abstract

The development of ligands and the elucidation of their roles in the catalytic cycle are key to achieving high efficiency and selectivity in nondirected transition-metal-catalyzed C–H functionalization. In particular, careful ligand design can enable the functionalization of previously inaccessible substrate positions, which can lead to regiodivergent transformations of common reactants. In this study, a series of pyrazolopyridone (PzPyOH) ligands that can be easily prepared in a single step was developed for the Pd-catalyzed perdeuteration and meta-selective alkenylation of arenes. In this system, the 2-pyridone moiety was incorporated to function as an internal base, facilitating C–H cleavage and rendering C–H activation reversible, even at challenging sp2 C–H bonds, thus enabling perdeuteration. In addition, the reversible activation of the C–H bonds implies that site selectivity is determined during the migratory insertion step in the alkenylation reaction, thereby preferentially functionalizing the meta-positions rather than the typically more reactive ortho- and para-positions of anisole derivatives. Further, the electronic and structural properties of the pyrazole moiety provide flexibility in the ligand binding to Pd, enabling the facile coordination of an alkene coupling partner during alkenylation. In this process, the hydrogen bonding between pyridone and acetate ligands was crucial to stabilize intermediates, allowing for different types of binding modes, including L,L- and L,X-type bidentate and monodentate binding. Kinetic and computational studies support the proposed mechanisms for perdeuteration and alkenylation, and the findings reveal crucial factors in the design of ligands for Pd-catalyzed C–H functionalization, which will be useful for further development of pyrazole- and pyridone-containing ligands in transition metal catalysis.

Late‐Stage C−H Activation of Drug (Derivative) Molecules with Pd(ll) Catalysis

“…More recently, the Joo group developed non-directed CÀ H perdeuteration with pyrazolopyridone ligand that can be easily prepared in a single step (Scheme 21b). [79] They had previously developed a series of less Lewis basic pyrazole-containing ligands. [80] With this ligand series, electron-rich and sterically accessible positions in aromatic rings were rapidly deuterated, but CÀ H cleavage at the meta-positions of electron-rich arenes and all positions of electron-deficient arenes was not possible.…”