Nickel- and palladium-catalysed deprotonative cross-couplings

Abstract

Transition metal-catalysed cross coupling chemistry is a valuable tool for synthetic organic chemistry, enabling the preparation of compounds of great interest. The catalytic metal of choice is usually palladium, which generally offer better performances in term of catalytic activity and easy handling. On the other hand, the use of nickel in this class of reactions is gaining attention, as it would provide more economically and environmentally sustainable processes. Deprotonative cross couplings are a subgroup of these reactions, in which the nucleophile is generated in situ by direct deprotonation of a (relatively) acidic C–H bond, for example those of an enolizable ketone or an imine. The reaction products often represent intermediates towards more complex molecular architectures, by virtue of the well-known carbonyl chemistry. The development of a Pd-catalysed methodology for the prototypical deprotonative coupling, the a-arylation of ketones, is reported in this thesis. It requires significantly lower catalyst loadings compared to previous reports, and displays good tolerance towards functionalised substrates. A related protocol for the intramolecular a-arylation of imines towards indoles was subsequently disclosed: as it requires low catalyst loadings and displays good scalability and simple setup, this methodology is a promising hit for industrial applications. The parallel development of nickel-catalysed protocols afforded an efficient method for the a-arylation of ketones, using chloroarenes as electrophile for the first time in the literature. The method was further optimised for the synthesis of an intermediate towards a commercial medicinally active compound. Building up on these findings, the first nickel-catalysed protocol for the deprotonative arylation of benzylaminederived imines was also developed. Last, the first aqueous palladium-catalysed protocol for the a-arylation of ketones was investigated. The method proved flexible, showing excellent functional group tolerance: compounds containing base-sensitive functional groups, halogenated small-molecule drugs, and Boc-protected amino acids were all suitable substrates.