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Title: Ru-catalysed C-H arylation of (hetero)arenes and decarboxylative bromination of benzoic acids
Author: Cannas, Diego
ISNI:       0000 0004 9354 2457
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2020
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In the last few decades the direct functionalisation of C-H bonds has attracted a great deal of attention; the long-overlooked C-H bond is now regarded as a proper functional group. Compared to traditional cross-couplings, this methodology allows to streamline synthesis and reduce waste by avoiding the pre-functionalization of the starting material. Amongst the functionalities that can be installed through this synthetic tool, the synthesis of biaryls has always been of primary interest for the scientific community due to their widespread presence across pharmaceuticals, agrochemicals and high-technology materials. In chapter 1, an overview of the most successful strategies for the synthesis of the biaryl core through C-H activation, is provided, with particular attention to the mechanistic implications. The direct arylation of C-H bonds would in principle be ideally suited for the late-stage derivatisation and diversification of compounds of pharmaceutical interest. In practice however, C-H arylation methodologies are generally not compatible with highly functionalised arenes due to harsh reaction conditions and low tolerance towards polar functionalities. In chapter 2 we re-examined the ruthenium catalysed direct arylation of N-chelating substrates with aryl(pseudo)halides pioneered by Oi and co-workers nearly two decades ago. A thorough mechanistic investigation revealed that the widely accepted mechanistic picture was incomplete, as an elusive bis-cyclometalated Ru(II) complex was missing. The mechanistic insight let led to the discovery of mono-cyclometalated Ru(II) complexes as superior catalysts for the late-stage arylation of pharmaceutically relevant compounds. Aromatic carboxylic acids present several features that makes them desirable substrates in direct arylation as they are generally cheap, non-toxic and bench stable. Moreover, the carboxylic moiety can be then removed by protodecarboxylation or exploited for further functionalization. Due to its relatively low coordinating ability compared to nitrogen-containing directing groups, developing efficient C-H arylation methodologies remain a challenge. The majority of the reported procedures for the direct arylation of aromatic carboxylic acids employ a palladium catalyst along with a silver salt as halide scavenger. In chapter 3 we detail the development of a phospine free Ru(II)-catalysed direct arylation of aromatic carboxylic acids with aryl (pseudo)halides. Our protocol allows for the arylation of hindered benzoic acids, can be applied to indole carboxylic acids to access C-4, C-5, C-6 and C-7 arylated substrates overriding the classical reactivity at C-2 and C-3 position. Aryl bromides are recognised as a highly valuable class of substrates due to their use in a variety of transformations, notably featuring traditional cross-couplings and direct arylation. One strategy to synthesise aryl bromides is the decarboxylative halogenation of aromatic carboxylic acid. This transformation, known as aromatic Hunsdiecker reaction, date back to 1950 and classically require the presence of a silver or mercury salt. In chapter 4 we re-examined the aromatic Hunsdiecker reaction and developed a transition-metal free protocol for the decarboxylative bromination of electron-rich aromatic acids, which are poor substrates under classical Hunsdiecker-type conditions. Moreover, in contrast with the classical Hunsdiecker-type mechanism, our mechanistic studies suggest that radical intermediates are not involved.
Supervisor: Greaney, Michael ; Larrosa, Igor Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: ruthenium ; decarboxylation ; bromination ; carboxylic acid ; C-H activation ; catalysis ; arylation ; late-stage functionalisation ; indole