Harnessing Secondary Coordination Sphere Interactions That Enable the Selective Amidation of Benzylic C-H Bonds

Abstract

Engineering site-selectivity is highly desirable especially in C-H functionalization reactions. We report a new catalyst platform that is highly selective for the amidation of benzylic C-H bonds controlled by pi-pi interactions in the secondary coordination sphere. Mechanistic understanding of the previously developed iridium catalysts that showed poor regioselectivity gave rise to the recognition that the pi-cloud of an aromatic fragment on the substrate can act as a formal directing group through an attractive noncovalent interaction with the bidentate ligand of the catalyst. On the basis of this mechanism-driven strategy, we developed a cationic (eta(5)-C5H5)Ru(II) catalyst with a neutral polypyridyl ligand to obtain record-setting benzylic selectivity in an intramolecular C-H lactamization in the presence of tertiary C-H bonds at the same distance. Experimental and computational techniques were integrated to identify the origin of this unprecedented benzylic selectivity, and robust linear free energy relationship between solvent polarity index and the measured site-selectivity was found to clearly corroborate that the solvophobic effect drives the selectivity. Generality of the reaction scope and applicability toward versatile gamma-lactam synthesis were demonstrated.