Single electron transfer in organic synthesis targeted towards sustainable manufacture

  • Joshua Barham

Student thesis: Doctoral Thesis

Abstract

Single electron transfer technology has received considerable interest in organic synthesis in recent years. Single electron transfer gives rise to unconventional modes of reactivity and intermediates, thus serving as a platform for innovative bond constructions, deconstructions and functional group transformations. This is of key importance to the pharmaceutical industry, where the brevity of synthetic routes to small molecules both accelerates drug discovery and drives chemical efficiency in late-stage development. In many cases, single electron transfer chemistry unlocks reaction conditions which are milder, safer and more cost-effective than conventional chemistries. This Thesis investigates two fields of single electron transfer research and contributes new methodology and mechanistic understanding to both. Volume 1 investigates the N-functionalisation of tertiary amines, which is an important method for the elaboration of naturally occuring raw materials into pharmaceutically useful compounds. Two complementary methodologies driven by single electron oxidation were developed. The first method, using visible-light photoredox catalysis, achieved selective benzylic N-CHN₂ functionalisation of N-substituted tetrahydroisoquinolines. The second method, using stable radical cation salts, achieved selective N-CHN₃ functionalisation of trialkylamines. Volume 2 investigates transition metal-free C-H arylation reactions, which are of particular importance to the pharmaceutical industry, given the costly nature of transition metals typically used in catalysis and their long-term sustainability. These reactions are triggered by single electron reduction, effected by a combination of simple alkali metal alkoxide bases and cheap, readily available organic additives. The interplay of the alkoxide and the different organic additives is not fully understood but is key to unlocking milder reaction conditions and broadening substrate scope in these reactions.Comprehensive mechanistic studies were undertaken in this regard.
Date of Award1 Jan 2017
LanguageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde & Glaxo Smithkline (UK)
SupervisorJohn Murphy (Supervisor) & William Kerr (Supervisor)

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