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

ABSTRACT 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(sp 3 )–C(sp 3 ) bond formation.