Nickel- and palladium-catalysed deprotonative cross-couplings

Organic compounds--Synthesis;Metal catalysts

Marelli, Enrico ; Nolan, Steven P. ; Nolan, Steven P.

University:University of St Andrews

Department:Chemistry (School of)

关键词: Organic compounds--Synthesis;    Metal catalysts;   

Others  :  https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/15603/EnricoMarelliPhDThesis.pdf?sequence=2&isAllowed=y

来源: DR-NTU

【 摘 要 】

Transition metal-catalysed cross coupling chemistry is a valuable tool for syntheticorganic chemistry, enabling the preparation of compounds of great interest. Thecatalytic metal of choice is usually palladium, which generally offer betterperformances in term of catalytic activity and easy handling. On the other hand, theuse of nickel in this class of reactions is gaining attention, as it would provide moreeconomically and environmentally sustainable processes.Deprotonative cross couplings are a subgroup of these reactions, in which thenucleophile is generated in situ by direct deprotonation of a (relatively) acidic C–Hbond, for example those of an enolizable ketone or an imine. The reaction productsoften represent intermediates towards more complex molecular architectures, by virtueof the well-known carbonyl chemistry.The development of a Pd-catalysed methodology for the prototypical deprotonativecoupling, the a-arylation of ketones, is reported in this thesis. It requires significantlylower catalyst loadings compared to previous reports, and displays good tolerancetowards functionalised substrates. A related protocol for the intramolecular a-arylationof imines towards indoles was subsequently disclosed: as it requires low catalystloadings and displays good scalability and simple setup, this methodology is apromising hit for industrial applications.The parallel development of nickel-catalysed protocols afforded an efficient method forthe a-arylation of ketones, using chloroarenes as electrophile for the first time in theliterature. The method was further optimised for the synthesis of an intermediatetowards a commercial medicinally active compound. Building up on these findings,the first nickel-catalysed protocol for the deprotonative arylation of benzylaminederivedimines was also developed.Last, the first aqueous palladium-catalysed protocol for the a-arylation of ketones wasinvestigated. The method proved flexible, showing excellent functional grouptolerance: compounds containing base-sensitive functional groups, halogenated small-moleculedrugs, and Boc-protected amino acids were all suitable substrates.