The Integration of Continuous Flow Technology with Strained Cyclic Systems

Since the emergence of continuous flow in the past twenty years, it has become an enabling technology renowned for its inherent advantages over traditional batch syntheses. Its use as a more efficient, safer, and easily scaled synthesis method has enriched current literature and continues to provide access to new chemical space in both academic and industrial lab settings. The work described in this thesis aims to revitalise both the synthesis and exploitation of strained cyclic systems via their integration with continuous flow technology. Chapter 2 presents the development of a continuous flow thermal Baldwin rearrangement and its comparison to traditional batch mode, for the synthesis of valuable aziridine molecules. A thermal batch process was initially developed for the forgotten Baldwin rearrangement but suffered from long reaction times, moderate yields, and a limited substrate scope. Solvent superheating was utilised to translate the process to continuous flow and this process intensification resulted in short residence times of just 5-10 minutes, improved yields, and a broader substrate scope than the corresponding batch procedure, which even enabled the synthesis of some substrates that had failed in batch. The robustness of the process in flow was demonstrated with two 1 g scale up examples, resulting in throughputs of up to 20.5 g/h achieved. The results of this study were subsequently published in a special flow chemistry edition of Organic Process Research & Development. The work described in chapter 3 investigates the synthesis and synthetic utility of the sp3-rich heterocyclic scaffold present in antiviral drug tecovirimat. Initially the high temperature polycyclic cascade process for the synthesis of this scaffold was explored in the development of batch, flow, and microwave processes, which were all more efficient than current literature and patent procedures. A 15 min flow-mediated synthesis of the API tecovirimat was then developed – resulting in throughputs of 1.3 g/h on a 1 g scale – and a telescoped solvent switch experiment investigated. Desymmetrisation of the polycyclic scaffold was performed and related sp3-rich hydrazine derivatives were synthesised, which lead to different cyclic products, depending on the hydrazine substitution pattern. The work presented in this chapter was published in Organic & Biomolecular Chemistry. Finally, chapter 4 explores the use of continuous flow in the photocarboxylations of 2H-azirines. This chapter combines the use of photochemistry and gases in flow for the revitalisation of CO2 as a cheap and abundant coupling partner with 2H-azirines, which has remained unresearched since the 1970s. The 2H-azirine starting materials were synthesised via the thermal decomposition of vinyl azides, with both electron rich and electron poor azirines well tolerated in their 365 nm-mediated catalyst-free cycloaddition with CO2. The resulting mixtures of unstable oxazolone isomers were subsequently aromatised to oxazole products, yielding these products as single isomers in good yields. The scalability of the process was developed with a 1 g scale up of the model substrate, with the scale-up yield comparing well with the original smaller scale yield. At the time of writing, the associated manuscript for this chapter is being drafted.