Deciphering Complexity in Pd–Catalyzed Cross-Couplings

Understanding complex reaction systems and networks is critical in chemistry. While synthetic methods for the selective formation of products are highly sought after, oftentimes it is the full signature of a specific reaction, i.e. the complete profile of products/side-products, that informs mechanistic rationale and acceler-ates discovery chemistry. Moreover, understanding the triggers and sensitivities, under different reaction conditions, that can lead to different products assists with enhanced robustness and safety understanding. In this study we report a methodology using high-throughput experimentation methods and multivariate data analysis that can be used to take the full signature of a chemical reaction, to accelerate an understand-ing of the most complex reaction chemistries. To exemplify our approach, we selected a model Pd-catalyzed reaction system which forms many products – the reaction of two molecules of 2-bromo-N-phenylbenzamide, which affords primarily N-phenyl phenanthridinone. The reaction is a standout bench-mark model for gaining insight on a plethora of side-products. Principal component analysis, correspond-ence analysis and heatmaps with hierarchical clustering have allowed us to examine the factors contrib-uting to the variance in product distributions and show associations between solvents and reaction prod-ucts. Using robust data from experiments performed with eight solvents for four different reaction times at five different temperatures, we have been able to correlate side-products to the major dominant N-phenyl phenanthridinone product, and the post-chemical modification of other side products. Complementary stoichiometric organopalladium studies allowed examination of the Pd precatalyst activation pathway, gaining insight into likely Pd reaction intermediates, particularly an oxidative addition intermediate and downstream PdII intermediates. Automated reaction screening and advanced data analysis tools are transforming the way we examine cata-lytic and synthetic processes. Our study offers a unique and complementary approach to revealing im-portant reaction data on what is arguably one of the most complicated Pd catalyzed transformations known in the chemical literature.