Experimental and computational studies towards chemoselective C-F functionalisation

Cross-coupling reactions of organohalides with organometallic reagents offers a highly efficient modular approach to carbon-carbon bond formation, however limitations still exist in the scope of coupling partners. Organofluorides are particularly difficult to couple due to the strength of the C-F bond, however functionalization of C-F bonds under mild conditions could allow efficient late stage functionalisation of complex compounds. In addition, the unique reactivity of the metal-fluoride intermediate allows for base-free approaches and thus the potential for chemoselectivity, as other Ni-X species (X = Cl, Br, I) generated from oxidative addition to the metal centre would be unreactive.

As such, this work describes the development of a base-free Hiyama cross coupling reaction of 1-fluoronaphthalene and trimethoxy(phenyl)silane. After extensive screening and reaction optimisation, the coupling product was achieved in excellent yield under mild reaction conditions using a Ni(COD)2/PCy3 catalytic system. While control experiments with 1-chloronaphthalene highlighted the feasibility of the new chemoselectivity approach proposed in this Thesis, competition experiments with a mixture of 1-fluoronaphthalene and 1-chloronaphthalene failed to demonstrate the expected chemoselectivity. Density functional theory calculations were employed to gain mechanistic insight, as well as to provide some direction for the rational design of phosphine ligands to achieve chemoselectivity.