The Photocatalytic α-C–H Alkylation of Unprotected Primary Amines: Methodology and Mechanism

  • Alison Ryder

Student thesis: Doctoral ThesisPhD


Aliphatic amines are abundant in bioactive molecules, including the α-tertiary amines motif,however despite their ubiquity there are limited examples of α-C–H functionalisation ofunprotected amines. The lack of a practical and scalable catalytic entry to α-tertiary primaryamines by C–H functionalisation was recently stressed as a key unsolved problem for syntheticchemistry and is the focus of this work. This thesis describes the research conducted into themethodology development and mechanistic understanding of a visible light promoted,photoredox catalysed α-C–H alkylation of unprotected primary amines.The first chapter introduces the concept of photoredox catalysis, the underlying theory, andphysical concepts, as well as introducing dual catalytic strategies. The importance of aliphaticamines in drug discovery and the need for new methodology to access α-tertiary amines is thenhighlighted. An overview of synthetic approaches to the synthesis of α-tertiary amines is given,organised by disconnection rather than methodology, and then focusing specifically on existingmethodology for the α-C–H functionalisation of amines.The second chapter describes the development of a visible-light photocatalysed α-C–Halkylation of unprotected, α-disubstituted primary aliphatic amines using an organicphotoredox catalyst in combination with a hydrogen atom transfer (HAT) catalyst. Thegenerality of this process as a practical, catalytic entry to α,α,α-trisubstituted (α-tertiary)primary amines and γ-lactams is then described, along with its translation from batch intocontinuous flow. The non-trivial extension of this reactivity to α-monosubstituted primaryaliphatic amines is presented in the third chapter and the use of a continuous flow reactor isexhibited as a further means of exerting control on the degree of alkylation. Several examplesof intentional α-dialkylation are also presented.The fourth chapter outlines the mechanistic investigations to probe the reaction discussed inchapters two and three. Evidence and rationale is discussed for each step of the proposedcatalytic cycle as well as considerations for the selectivity of the HAT with unprotected primaryamines, which is shown to be irreversible. A 1H NMR reaction monitoring study determinedthe overall order of reaction to be apparent pseudo first order although further study is neededto confirm that this is not an artifact of catalyst deactivation. Catalyst degradation wasuncovered in this experiment and is explored in the fifth chapter. This chapters outlines detailedinvestigations of this degradation process and attempts to establish the mechanistic pathwaysinvolved. It also describes the discovery of an improved photocatalyst (4DPAIPN) whichexhibits enhanced catalytic activity and stability. Finally, the sixth chapter describes theexperimental procedures relevant to the results discussed in chapters two to five.
Date of Award14 Feb 2022
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorAlex Cresswell (Supervisor), Salvador Eslava Fernandez (Supervisor), Simon Lewis (Supervisor), Catherine M Alder (Advisor), Lee J Edwards (Advisor) & Blandine S J McKay (Advisor)

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