Thesis

Iron-catalysed cross-couplings of secondary alkyl Grignard reagents

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2017
Thesis identifier
  • T15956
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Traditional methods for the preparation of secondary alkyl substituted aryl and heteroaryl chlorides are often poorly selective and have limited functional group tolerance. This thesis describes the use of process chemistry tools such as statistical design of experiments and high throughput chemistry to develop mild and sustainable methods to carry out sp2-sp3 cross-coupling reactions using iron catalysis. The early work is related to the discovery of an effective procedure for the preparation of iso-propyl substituted (hetero)arenes with minimal iso-propyl to n-propyl isomerisation. The reaction tolerates electronically diverse aryl chloride coupling partners, with excellent conversion observed for strongly electron deficient aromatic rings, such as esters and amides. Electron rich systems, including methyl and methoxy substituted aryl chlorides, were found to be less reactive. Furthermore, the reaction was found to be most successful when heteroaryl chlorides were submitted to the cross-coupling protocol. By mapping substituent effects on reaction selectivity, we were able to develop some mechanistic insight, helping to explain the requirement for electron-deficient aryl chlorides in these reactions. Through the estimation of the electron affinity of each aryl chloride, we were also able to develop a computational model which may be used to predict reactivity in the new cross-coupling procedure. Moderate isolated yields were achieved with selected aryl chlorides, and moderate to good isolated yields were obtained in all cases with heteroaryl chlorides. The final chapter discusses the search for an alternative to 1-methyl-2-pyrrolidinone, the reprotoxic solvent/additive used in almost all iron-catalysed cross coupling reactions. A simple protocol for the preparation of cyclopropyl substituted heteroarenes was discovered through the combination of high throughput chemistry and statistical design of experiments.
Advisor / supervisor
  • Percy, Jonathan M.
  • Nelson, David
  • Dominey, Andrew
Resource Type
Note
  • Previously held under moratorium in Chemistry department (GSK) from 10/05/2018 to 18/06/2021.
DOI
Funder
Embargo Note
  • This thesis is restricted to Strathclyde users only until 1st June 2023.

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