Unravelling mechanistic underpinnings of organometallic nickel chemistry and applications into medicinal chemistry

Identifier:  TDX:4301

Handle: https://hdl.handle.net/20.500.11797/TDX4301

Authors:  Odena Juan, Carlota

Abstract:
Nickel, leveraging its inherent chemical properties, offers versatile reactivity patterns while being earth-abundant and more affordable than other noble-metals as palladium or rhodium. Moreover, stoichiometric organometallic nickel chemistry holds great promise for the development of novel reactivities, overcoming challenges in catalytic strategies as well as the study of mechanisms. In the first project, a general protocol for the synthesis of nickel oxidative addition complexes of drug-like molecules and their potential for C(sp2)–C(sp3) diversification is depicted. These bench-stable complexes could be readily employed as coupling partners in Negishi couplings as well as reductive couplings. Moreover, the successful application of the Negishi coupling in an end-to-end automated workflow was shown. The second project presents the synthesis, characterization, and studies on metal migration over aromatic backbones of dinuclear(I) nickel oxidative addition complexes. A formal 1,2-Ni shift was proposed via a 1,2-hydride transfer based on the experimental work and DFT studies. Finally, the nickel migration was harnessed for promoting C(sp2)–C(sp2) bond formation at remote C(sp2)–H sites. The last project summarizes the results on the synthesis of Ni(I)– and Ni(II)–alkyl complexes with a phenanthroline-type ligand containing an alkyl ligand with -hydrogens. These complexes are postulated intermediates in Ni-catalysed chain-walking reactions and the aim of the ongoing project is to elucidate the still opaque mechanism of chain-walking reactions and to obtain fundamental understanding of the involved organometallic intermediates. All in all, this doctoral thesis has showcased the potential of organometallic nickel chemistry as a platform to overcome challenges in catalytic strategies, uncover novel reactivity patterns and unravel fundamental insights on the transformations.