Encouraging the Exploration of Nickel Catalysis in Pharmaceutical Manufacturing Processes: A Case Study of Catalyst Screening and Process Optimization of Mono-Arylation of Ammonia

Reports of new ligands or precatalysts based on non-platinum group metal (pgm) catalysis, as well as the number of publications describing new methodology that relies on non-pgm catalysts, are at an all-time high. Catalyst screening groups and process chemists are now beginning to seriously investigate and evaluate non-pgm based processes when carrying out route scouting and process optimization. The million dollar question is how many already established manufacturing processes and how many launched drugs may have benefitted from the use of non-pgm catalysis, had it been available and considered at the time of process optimization and launch? We wanted to explore one such example and identified a previously reported palladium-catalyzed selective formal mono-arylation of ammonia, from the process to make abemaciblib, as a suitable model reaction. This article describes our work where this specific reaction was evaluated in a high-throughput screening study with the aim of exploring whether nickel catalysis can be an alternative to palladium catalysis, in this particular case. The preformed complex (NHP-DalPhos)Ni(o-tol)Cl) Cat5 was identified as the best-performing catalyst, and provided the desired primary amine 2 in 82% conversion. We achieved a better understanding of the ligand parameters that proved to be important for a highly active and selective catalyst. A structure-activity relationship model based on three distinct catalyst descriptors (buried volume, P-Ni-P bond angle and electron richness) was uncovered. This has previously not been described for nickel catalysis, whilst being known in broad terms for palladium catalysis, and could fill a gap as an up-until-now missing insight for the successful implementation of nickel-catalyzed reactions. We also demonstrated that this understanding can lead to rapid identification of optimized reaction conditions to be explored in further scale-up exercises.