Visible-Light Promoted Carbonylation of Unactivated Alkyl Halides and Inert C(sp3)-H Bonds in Continuous Flow

Abstract

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.