LIGHT-DRIVEN STRATEGIES FOR THE GENERATION OF N-OXAZOLIDINONE RADICALS AND THE SYNTHESIS OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
Recent advances in radical chemistry have opened new opportunities in synthetic methodology, enabling the resolution of challenges that more conventional methodologies have historically encountered. This PhD thesis work aims to investigate two different research topics as outlined in Figure I: (A) the light-promoted regioselective addition of novel N-oxazolidinone radicals to arenes and heteroarenes, achieved under both photocatalytic and photocatalyst-free conditions in batch and continuous-flow systems; and (B) the application of the photo-Favorskii rearrangement as a key step in the synthesis of active pharmaceutical ingredients (APIs) under continuous and scalable reaction conditions. In particular, Chapter 1 provides an overall introduction to the main topics encountered in this work, namely photochemistry and flow chemistry, outlining their fundamental principles and relevance in modern synthetic chemistry. Chapter 1.1, focused on the former, introduces the fundamental concepts of photochemistry and then specifically addresses photoredox catalysis, highlighting its role as a powerful and versatile strategy for enabling redox reactions under mild conditions through visible-light activation. This is followed by a section devoted to electron donor–acceptor (EDA) complexes, emphasizing their formation, photochemical behaviour, and synthetic applications. Subsequently, intramolecular rearrangements are discussed, illustrating how photoinduced processes can promote structural reorganizations with high efficiency and selectivity. Chapter 1.2 introduces flow chemistry, presenting continuous-flow methodologies as an effective alternative to traditional batch processes. It discusses the key parameters governing flow systems and highlights the main advantages of flow chemistry, including enhanced scalability and reproducibility. Finally, the integration of photochemical transformations within flow reactors is addressed, emphasizing how the combination of light-driven reactions and flow technology enables better irradiation efficiency and improved reaction control. N-centered radicals are introduced and classified in Chapter 2.1, which provides a historical overview of the literature with particular emphasis on the reactivity of amidyl radicals. Chapter 2.2 focuses on the results obtained using previously unexplored N-oxazolidinone radicals. Initially, these species were generated photocatalytically under visible-light irradiation, employing both a metal-based catalyst and an organic dye, enabling a novel, efficient, sustainable, and scalable C–H functionalization of arenes and heteroarenes. Importantly, the implementation of continuous-flow technology was found to offer additional advantages over conventional batch conditions, thereby expanding the potential applicability of this transformation. Furthermore, during the reaction investigation, it was discovered that under specific conditions – namely the use of highly polar aprotic solvents or suitable external additives – the N-oxazolidinone radical can be generated by direct light irradiation, allowing the reaction to proceed in the absence of a photocatalyst. As a result, the regioselective radical addition of N-oxazolidinone radicals to the selected substrates affords the desired functionalized products through a highly sustainable and cost-effective process. Chapter 3 instead focuses on the synthesis of pharmaceutically relevant arylpropionic acids via photoinduced intramolecular rearrangement strategies. After introducing the Favorskii and photo-Favorskii rearrangements in Chapter 3.1, Chapter 3.2 begins by validating the photochemical set-up through reproduction of the literature synthesis of Ibuprofen, thereby confirming the reliability and reproducibility of the process. The photo-Favorskii approach was then applied to Carprofen, providing access to a key intermediate, but revealing limitations in terms of both efficiency and sustainability. In contrast, an efficient and scalable total synthesis of Pelubiprofen was developed, combining a Friedel-Crafts acylation with a photo-Favorskii rearrangement performed under both batch and continuous-flow conditions. The photochemical step proved to be operationally simple and readily scalable, while subsequent oxidation and Claisen-Schmidt condensation completed the synthesis. Overall, this work reports the first photochemical route to Pelubiprofen, highlighting the potential of photo-Favorskii chemistry for the synthesis of arylpropionic acid-based APIs.
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