Experimental and Computational Studies towards Chemoselective C-F over C-Cl Functionalisation: Reversible Oxidative Addition is the Key

Catalytic cross-coupling is a valuable tool for forming new carbon-carbon and carbon-heteroatom bonds, allowing access to a variety of structurally diverse compounds. However, for this methodology to reach its full potential, precise control over all competing cross-coupling sites in poly-functionalised building blocks is required. Carbon-fluorine bonds are one of the most stable bonds in organic chemistry, with oxidative addition at C-F being much more difficult than at other C-halide bonds. As such, the development of methods to chemoselectively functionalise the C-F position in poly-halogenated arenes would be very challenging if selectivity was to be induced at the oxidative addition step. However, metal-halide complexes exhibit different trends in reactivity to the parent haloarenes, with metal-fluoride complexes known to be very reactive towards transmetalation. In this current work we sought to exploit the divergent reactivity of Ni-Cl and Ni-F intermediates to develop a chemoselective C-F functionalisation protocol, where selectivity is controlled by the transmetalation step. Our experimental studies highlight that such an approach is feasible, with a number of nickel catalysts shown to facilitate Hiyama cross-coupling of 1-fluoronapthalene under base free conditions, while no cross-coupling with 1-chloronapthalene occurred. Computational and experimental studies revealed the importance of reversible C-Cl oxidative addition for the development of selective C-F functionalisation, with ligand effects on the potential for reversibility also presented.