C–H Functionalization Catalysis via Transition Metal Stabilized Ligand-Based Radicals

Abstract

Two catalytic systems exploiting the capability of introducing functionalities into C–H bonds using transition metal stabilized ligand-based radicals were explored. The first system utilizes sterically accessible bidentate LX-type ligand platforms (dipyrrin: AdFL: 1,9-di-adamantyl-5-(perfluorophenyl)-dipyrromethene; anionic bisoxazoline: TrHBOX: bis((S)-4-trityl-4,5-dihydrooxazol-2-yl)methane) featuring a compressed ligand field that engenders a N-based iminyl radical broken-symmetry formulation when supporting Ni–N multiply bonded units. The proposed electronic structure is corroborated by electron paramagnetic and N K-edge X-ray absorption spectroscopies in conjunction to density functional theory calculations. The catalytic pyrrolidine formation via single-electron intramolecular C–H bond amination capitalizing the high reactivity of these iminyl radicals were probed both synthetically and mechanistically. The BOX variant further unlocks our ability to impart enantioselectivity to the catalytic scheme. The mechanistic evaluation suggests a radical recombination step with comparable rate to that of carboradical rotation, suggesting both the H-atom abstraction and radical capture as enantio-determining steps. In addition to pyrrolidine synthesis, intramolecular catalytic C–H alkoxylation mediated by Fe-stabilized vinyl carboradicals for O-heterocycle preparations was investigated. The transformation features commercially available ferrous acetylacetonate [Fe(acac)2] as the active catalyst and readily preparable ɑ-diazo-β-keto esters as the substrate to stereoselectively yield (Z)-2-alkylidene dihydrofuran derivatives. Mechanism of the reaction is probed using isotopic labelling study, ring-opening of radical clock substrate, Hammett analysis, and further corroborated by density functional theory (DFT) calculations. Heightened reactivity is observed for electron-rich C–H bonds (tertiary, ethereal), while greater catalyst loadings or elevated reaction temperatures are required for fully converting substrates with benzylic, secondary, and primary C–H bonds. The transformation is highly functional group tolerant and operates under mild reaction conditions to provide rapid access to complex structures such as spiro and fused bi/tricyclic O-heterocycles from readily available precursors.