Sustainable cross-couplings for pharmaceutical scale-up using aryldiazonium salts

  • Aymeric Pierre COLLEVILLE

Student thesis: Doctoral Thesis

Abstract

Cross-coupling reactions are some of the most important tools to form aryl-aryl bonds in modern organic chemistry because of the predominance of this motif in pharmaceuticals, agrochemicals and materials. In this context, aryldiazonium salts are very promising building blocks owing to their ability to release benign by-products (nitrogen gas, which represents 80% of the composition of the atmosphere). This characteristic makes them very attractive from a pharmaceutical development point of view and their high reactivity provides a unique opportunity to develop new types of reactivity involving transition metal catalysis. However, this high reactivity can also translate into instability, potentially to explosivity and as a consequence their use is not well established. This thesis aims to render aryldiazonium salts more accessible by presenting results of studies on preparation, stability and couplings focused on the sustainability, efficiency and novelty of the processes. The use of aryldiazonium salts as arylating agents was investigated from a process chemistry perspective and were found to be efficient in both palladium catalysed cross-couplings and radical C-H arylations. Both methodologies were optimised using statistical tools (Design of Experiment, Orthogonal Partial Least Square regression) and optimal reaction conditions were applied to a range of functionalised substrates. Ultimately, a full scale-up study was conducted for the kilogram-scale synthesis of a selected aryldiazonium salts and the subsequent palladium-mediated coupling to generate a valuable intermediate involved in the synthesis of important angiotensin II inhibitors. Valuable mechanistic insights were also obtained for the radical C-H arylation of N-oxide heterocyles through IR monitoring and X-ray crystallography which allowed the identification of a triazene intermediate and refuted the role of ascorbic acid as radical initiator in this transformation.
Date of Award1 Jan 2016
LanguageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde & Glaxo Smithkline (UK)
SupervisorNicholas Tomkinson (Supervisor) & (Supervisor)

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