Mechanochemistry as an enabling technology for synthesis and catalysis

Williams, Matthew 2022. Mechanochemistry as an enabling technology for synthesis and catalysis. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

This thesis describes the investigations into solvent-minimised catalytic transformations, under mechanochemical conditions. Initially, the aza-Morita-Baylis-Hillman reaction was explored under ball-milling conditions, which built upon pioneering work from Mack and co-workers. This study revealed that the reaction could be carried out with decreased reaction times in comparison to solution-phase analogues and with the elimination of bulk reaction solvent, as toluene was used in liquid-assisted grinding quantities. A broad substrate scope was demonstrated, along with a scale up to 3 mmol. Additionally, asymmetric induction was performed using a cinchona-alkaloid derived tertiary amine catalyst. Finally, comparisons of the protocol to neat and solution-phase processes revealed the superiority of the reaction compared to these other techniques. Next, a nickel-catalysed cross-electrophile coupling reaction between heteroaryl halides and alkyl halides was investigated. This built on previous research within the Browne group, where cross-electrophile coupling was carried out mechanochemically. The key benefits of this previous work were the circumvention of inert atmospheres and mechanical activation of the terminal metal reductant (zinc or manganese). The previous work was expanded to tolerate this new class of substrate, due to the importance of heteroaromatic compounds in drug discovery. This process required a re-optimisation of the previous reaction conditions, revealing that an amidine ligand was best for effective cross-coupling. Broad scope of a variety of N-heteroaryl halides was demonstrated, along with a scale up to 6 mmol. Solution-phase comparisons revealed the vast improvements of the protocol, including the aforementioned circumvention of inert atmospheres and terminal reductant activation. Additionally, the process was shown to be effective irrespective of the form of the zinc reductant used, which can be an issue encountered in large-scale processes. iii The final research chapter describes the investigation into the nickel-catalysed intramolecular dicarbofunctionalisation of alkenes, which built on the previous cross�electrophile coupling work and was an unexplored type of reactivity under mechanochemical conditions. This reactivity allowed synthesis of 3,3-disubsituted heterocyclic compounds, namely oxindoles, using alkyl halides as a second coupling partner. Manganese was found to be a more effective terminal reductant than zinc and a higher filling degree of the milling jar had a positive effect on the product yield. Good substrate scope was demonstrated, including the tolerance of bromobenzene as an sp2 electrophile. The process was scaled up to 10 mmol, also, and asymmetric induction was demonstrated by using a chiral ligand, giving moderate enantioinduction. Finally, solution-phase comparisons revealed that the process is largely ineffective without the explicit activation of the manganese reductant, which was demonstrated by mechanochemically grinding the manganese before adding it to a solution reaction.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Chemistry
Date of First Compliant Deposit:	13 March 2023
Last Modified:	13 Mar 2024 02:30
URI:	https://orca.cardiff.ac.uk/id/eprint/157698

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