Abreu, Bruna
(2021)
Continuous flow photooxidation of p-substituted phenols using singlet oxygen in supercritical CO2 applied to telescoped syntheses.
PhD thesis, University of Nottingham.
Abstract
Interest in photochemical processes both in academia and industry is increasing, but uptake is still limited due to low efficiency and/or scalability of current processes. Photochemical synthesis of highly reactive hydroperoxides so-called ‘p-peroxyquinols’ is of particular interest for synthetic organic chemistry and pharmaceutical manufacturing, given their involvement in the synthesis of antimalarial drugs and complex natural products. Batch synthesis of p-peroxyquinols in large scale can be challenging, given its instability in flammable solvents and long reaction times of up to 48 h. Continuous flow photooxidation of p-substituted phenols using singlet oxygen and supercritical CO2 could be a suitable alternative. In this Thesis, this methodology is explored in telescoped syntheses of compounds with potential pharmaceutical interest.
Chapter 1 gives an introduction to flow chemistry including an overview of parameters and concepts used in the field. It highlights the advantages, challenges, and applications of flow chemistry both in academia and industry. A brief description of continuous flow photochemistry is also given, including recent advances using singlet oxygen in supercritical CO2. Chapter 2 describes the high-pressure batch and flow reactors used in this work, as well as the Standard Operating Procedures (SOP) for each system.
Chapters 3 and 4 explore the continuous flow dearomatisation of p-substituted phenols using singlet oxygen in supercritical CO2 (Chapter 3) and its applications in the telescoped synthesis of 1,2,4-trioxanes, a scaffold present in antimalarial drugs such as Artemisinin (Chapter 4). The dearomatisation of p-substituted phenols was carried out using a photosensitiser and Light Emitting Diodes (LEDs) to generate singlet oxygen. 1,2,4-trioxanes were then synthesised via an acid catalysed acetalization/oxa-Michael addition cascade with aldehydes. The substrate scope was expanded to a variety of p-peroxyquinols and 1,2,4- trioxanes, investigating functional group robustness, degree of substitution, and type of substituent.
Chapter 5 reports the telescoped synthesis of 2-substituted-1,4-benzoquinones, an important class of compounds with a variety of medicinal properties. The p-peroxyquinols formed through dearomatisation of p-substituted phenols, following the methodology developed in Chapter 3, were converted into 2-substituted-1,4-benzoquinones via acid- catalysed 1,2-alkyl shift of p-peroxyquinols. Optimisation of reaction conditions was initially carried out in batch, and the best conditions were then transferred to the continuous flow
system. Several packed bed reactor designs were investigated in order to optimise the reaction yields.
Chapters 6 and 7 present studies for the telescoped synthesis of 1,2,4-dioxazinanes and 1,3-oxazolidines, respectively. For both target compounds, an aminalisation/aza-Michael addition step using either a N-sulfinyl imine or N-sulfonyl imine was involved in the process. In Chapter 6, the synthesis of 1,2,4-dioxazinanes was investigated as this scaffold has been shown to have antimalarial activity, but synthetic methodologies to produce these compounds are scarce in the literature. The reaction conditions for both the asymmetric and racemic synthesis of 1,2,4-dioxazinanes were attempted in batch using a p-peroxyquinol and N-sulfonyl/sulfinyl imines previously synthesised. In Chapter 7, a synthetic route was designed for the asymmetric synthesis of 1,3-oxazolidines in four steps starting from the dearomatisation of p-substituted phenols. The reduction of p-peroxyquinols was examined in batch, and subsequent experiments were carried out to make 1,3-oxazolidines from p- quinols and N-sulfinyl imines.
In Chapter 8, a summary of the work developed in this Thesis is outlined, highlighting the main findings and challenges in exploring the continuous flow photooxidation of p- substituted phenols in telescoped syntheses. The discussion is guided by the Thesis aims defined in the introduction chapter. Ideas for potential future work are also presented.
Author name: Bruna Abreu Millard and Bruna Millard
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