Ligand-Switched Regiodivergent Fluoroallylic Alkylation of Secondary Nitroalkanes via an Unusual Inner-Sphere Pathway.

As one of the cornerstones of modern organic synthesis, the Tsuji-Trost reaction is fundamentally governed by the "hard-soft" characteristics of nucleophiles, which confine nitroalkanes as "soft" pronucleophiles to classical outer-sphere substitution pathway. Here we report a palladium-catalyzed fluoroallylic alkylation of secondary nitroalkanes with gem-difluorocyclopropanes that overturns this long standing reactivity paradigm by enabling their engagement through an inner-sphere pathway. This strategy enables the switchable regiodivergence between linear and branched allylic nitroalkanes-an outcome unattainable under classical Tsuji-Trost conditions and unprecedented for secondary nitroalkanes. This method exhibits excellent functional-group and heterocycle tolerance and is readily applicable to the late-stage modification of structurally complex bioactive molecules. Moreover, its synthetic utility has been further highlighted by various downstream derivatizations of the resulting 2-fluoroallylic α-tertiary nitroalkanes. DFT studies indicate that ligand-controlled oxygen coordination to electrophilic fluoro-π-allyl-Pd intermediates enables an inner-sphere 3,3'-reductive elimination, thereby accounting for the excellent regioselectivity in C(sp3)-C(sp3) bond formation.