Holistic Development of Nickel Catalysis for Sustainable Suzuki-Miyaura Cross Couplings: from Batch to Continuous Flow and Industrially Relevant Applications

Innovation in sustainable chemical synthesis is paramount to accomplish the ever-growing need to go green. Non-precious metal catalysis is a vibrant field of research, seeking to establish viable alternatives to typically unsustainable precious metal-based catalytic processes. The Suzuki-Miyaura cross coupling (SMCC) reaction, a cornerstone of pharmaceutical and fine chemical synthesis, exemplifies this challenge due to its typical reliance on palladium. While nickel catalysis has emerged as a promising, earth-abundant alternative, its widespread industrial adoption is hindered by several research challenges. This thesis addresses these barriers by integrating the development of a practical nickel catalysis protocol with modern, data-driven experimental strategies such as continuous flow chemistry and Design of Experiments (DoE).

Initially, a benchmark nickel-catalysed SMCC reaction was established in batch, where kinetic time-course studies and modelling revealed a marked performance decline at catalyst loadings below 2.5 mol%, likely due to poisoning and/ or deactivation of the nickel catalyst. By translating the benchmark reaction into continuous flow, a DoE optimisation successfully achieved high product yields at low catalyst loadings (1 mol%). The utility of the nickel-catalysed flow protocol was then demonstrated in industrially relevant SMCC reactions, the syntheses of active pharmaceutical ingredients (APIs), in both batch and flow. Further optimisation of the nickel-catalysed SMCC synthesis of the API Savolitinib was performed using DoE in batch, and a green process metric comparison highlighted the sustainability advantages of the nickel-based system compared with the established palladium-catalysed SMCC route. Finally, the reaction scope was expanded to a challenging regioselective SMCC. The nickel catalyst system displayed selectivity for the 4-arylated product over the 2-arylated product, diverging from the typical behaviour of palladium-catalysed systems, underscoring the unique synthetic potential of nickel catalysis. Thus, this thesis presents a holistic approach to furthering research in sustainable chemistry, demonstrating the integration of data-driven experimental methodologies with non-precious metal catalysis as an effective strategy to investigate industrially viable, sustainable processes.