School of Chemistry - Theses

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Start date: 2020 × End date: 2021 × Subject: Flow Chemistry ×

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    Visible-Light Promoted Carbonylation of Unactivated Alkyl Halides and Inert C(sp3)-H Bonds in Continuous Flow
    Forni, Jose Augusto ( 2021)
    Multicomponent carbonylations with carbon monoxide gas is an increasingly important strategy to generate carbonyl-rich scaffolds, such as amides and ketones. Traditionally, carbonylation reactions are catalysed by transition metals in a 2-electron pathway. While the carbonylation of aromatic substrates is well established, methodology to C(sp3) hybridised substrates remains underdeveloped. The p-acidity of carbon monoxide renders the metal catalyst less reactive towards an oxidative addition to alkyl halides and completive b-hydride elimination precludes product formation. Successful C(sp3) carbonylation has been achieved via transition-metal catalysed C(sp3)-H activation. These reactions, however, require elevated temperatures which could negatively affect selectivity and cause degradation of the starting materials and/or products. Additionally, this approach generally requires prolongated reaction times and stoichiometric amounts of external oxidants. Radical chemistry has emerged as an important alternative to overcome the limitation of the 2- electron carbonylation reactions. In this approach, the reactivity of carbon centred radicals towards carbon monoxide to form carbonyl compounds is explored. In the context of carbonylation reactions, alkyl radicals have been generated mainly from alkyl halides by means of explosive and toxic radical initiators or UV radiation. Direct C(sp3)-H alkylation is also reported, however, available methodologies required the use of toxic lead salts and prolonged reaction times. With the advent of visible light photoredox catalysis, safer and milder conditions to generate radicals have emerged. In the context of carbonylation reactions, the low redox potential of alkyl halides (Ered = -1.90 to -2.90 V vs SCE) greatly limited the use of this technique. This constrain of traditional photoredox methods can be overcome by the recently developed multiphoton catalytic systems and electrochemical methods, which both remain underexplored. Additionally, a visible light photocatalysed method for direct carbonylation of C(sp3)-H bonds remains unreported. In this PhD thesis, visible light multiphoton photoredox catalysis was explored to discover new C(sp3) carbonylation reactions. Implementation of continuous flow technology allowed for short residence times, safe handling of toxic gases and ready scalability. In chapter one, an introduction to transition-metal catalysed and radical C(sp3) carbonylation is provided. In this section, the current examples and limitations are highlighted. Next, the principles of conventional and multiphoton photoredox catalysis are discussed. The general objectives of this PhD thesis are subsequently elaborated followed by an introduction to flow chemistry. In chapter two, a new visible light promoted aminocarbonylation of unactivated alkyl iodides with carbon monoxide gas is reported. The reaction harnesses the highly reducing capabilities of the multiphoton tandem catalytic cycle of the [Ir(ppy)2(dtb-bpy)]+ photocatalyst to engage energy demanding substrates in an oxidative quenching cycle. The reaction presented excellent functional group tolerance and a broad substrate scope. This new methodology allowed for the late-stage functionalisation of natural products, in which five new cholesterol derivatives were synthetized in good to excellent yields. Steady state quenching experiments confirmed operation of the tandem photocatalytic cycle and DFT calculations led to the conclusion that the reaction proceeds via radical chain propagation. The use of continuous flow allowed short reaction times, safe handling of CO gas and scalability of the reaction. In chapter three, the tandem photoredox of the [Ir(ppy)2(dtb-bpy)]+ photocatalyst was explored in the first visible-light promoted radical carbonylative hydroacylation of alkenes with unactivated alkyl iodides and bromides. Optimisation studies showed this transformation benefits from the presence of water in the reaction mixture. The reaction showed broad substrate scope, good functional group tolerance and was high yielding. Deuterium labelling experiments studies demonstrated that this transformation proceeds via a radical polar cross over mechanism. The anionic intermediate was subsequently trapped with carbon dioxide leading to the synthesis of 1,4-keto esters and furanones via a 4 component multi-gas reaction. In chapter four, various substrates and photocatalytic systems were investigated to promote the carbonylation of inert C(sp3)-H bonds via an intramolecular hydrogen atom transfer process. The desired product could be obtained, however in low yield. The limitation of the photocatalytic methods motivated investigation of an electrochemical approach. During this study, it was discovered a new unexpected electrochemical arylation of inert C(sp3)-H bonds, which was fully developed in the subsequent chapter. In chapter five, a new electrochemical and catalyst-free arylation of arylation of inert C(sp3)-H bonds of aryl sulfonamides is reported. This reaction harnesses the ability of electron deficient cyanoarenes to function as both mediators and arylating reagent. Mechanistic studies demonstrated that the cathodic cyanoarene radical anion promotes single electron reduction of the halogenated aryl sulfonamide leading to aryl radical formation. Subsequent intramolecular hydrogen atom transfer led to the arylation of the remote C(sp3)-H arylation. An extensive study was conducted to optimise this reaction. Substrate scope was limited as the reaction was very sensitive to the nature of the cyanoarene and substitution on the sulfonamide.
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    The Synthesis and α-Functionalisation of Amines via Visible Light Mediated Catalysis
    van As, Dean Joseph ( 2020)
    The ubiquity of amines in pharmaceutical, agrochemical and advanced materials has incentivised modern synthetic chemists to develop novel and innovative methods for their synthesis and functionalisation. Specifically, the direct alpha-C-H functionalisation of aliphatic amines represents one such transformation which demands further development and improvement of current methodology. Visible-light mediated catalysis has presented a powerful platform to facilitate this transformation, with several pathways established to achieve the alpha-functionalisation of amines. This thesis is an exploration of the visible-light mediated functionalisation of aliphatic amines. Specifically, it explores the formal alpha-functionalisation of amines via the generation of alpha-amino radicals as key intermediates and investigates subsequent pathways of reactivity. The methodologies developed have been applied to the synthesis of biologically relevant amine scaffolds. Upon optimisation, continuous flow protocols were established to enhance the photochemical reaction conditions. Chapter 1 summarises the protocols for the alpha-functionalisation of amines. A brief history of this transformation is explored, highlighting several methodologies and is accompanied by a critical evaluation of their benefits and limitations. The concept and principles of photoredox catalysis are introduced and notable examples examined within the context of photocatalytic protocols for amine alpha-functionalisation. Finally, flow chemistry is presented detailing its advantages with emphasis towards photoredox catalysis. Chapter 2 establishes a visible-light mediated transfer hydrogenation of diarylmethimines. This process makes use of the single electron reduction of imines to engender alpha-amino radicals with triethylamine functioning as both a sacrificial reductant and hydrogen source. The developed conditions enabled the synthesis of a series of diarylmethamines to be synthesised with excellent chemoselectivity. A plausible mechanism was established, highlighting the dual role of triethylamine. Flow engineering enabled this procedure to be efficiently scaled to synthetically useful quantities with retention of the chemoselectivity established in batch. Chapter 3 details the development of the decarboxylative alpha-alkylation of fused heterocyclic amines. This process engages fused heterocyclic amines and N-hydroxy phthalimide esters as radical surrogates to simultaneously establish both alpha-amino and alkyl radicals. Upon in situ generation of alpha-amino and alkyl radicals, radical-radical coupling produces the desired alpha-alkylated amine. The addition of co-reductant, diphenylamine is believed to facilitate a second mechanistic pathway that proceeds concurrently and improves the efficiency of this transformation. A flow protocol established more favourable reaction conditions, enabling conjugation of a variety of biologically active derivatives in typically good yields. Chapter 4 introduces the concept of the tandem photocatalytic cycle revealing that in situ generation of a highly reducing iridium species establishes an effective pathway for single electron reduction of energy demanding substrates. This chapter further extends the knowledge of the tandem photoredox cycle, applying this mechanism towards the radical-radical coupling of alpha-amino and alkyl radicals. Accessing a highly reducing species enabled the single electron reduction of energy demanding alkyl halides; substrates previously difficult to access. This chapter further investigates the tandem photocatalytic cycle and establishes an alternative protocol for alpha-amino sp3 C-C bond formation.