Novel Pd-NHC Catalyst for Suzuki–Miyaura Cross-Couplings Optimized by High-Throughput Experimentation

Palladium-catalyzed Suzuki–Miyaura (SM) and Buchwald–Hartwig (BH) cross-coupling reactions are highly valuable tools for the fine chemical industry. These methodologies enable chemoselective transformations under mild conditions, which are well-suited for efficient synthesis of complex pharmaceutical intermediates and active pharmaceutical ingredients. While phosphine-based catalysts have been widely used, Pd-NHC (N-heterocyclic carbene) complexes generally offer better stability and efficiency, and their reactivity can be tuned by modifying the substitution of the heterocyclic carbene. In this study, we evaluated a novel Pd-NHC-cinnamyl complex, NOVECAT G4–02, fully substituted on the heterocyclic ring. This complex displayed a very high catalytic performance in a range of SM cross-coupling experiments. High-throughput experimentation has been used to optimize reaction conditions across various substrates, enabling systematic screening of the base and solvent combinations. This led to high-yielding transformations with minimal Pd catalytic charge while highlighting very specific solvent systems, which could further be used by researchers from academia or industry with other Pd-NHC catalysts. The catalyst was then successfully used for BH coupling, for which HTE-based optimization led to improved results. It should be underlined that the catalytic loadings improved during this study match or exceed the best results described in the literature. The scalability of G4–02 was finally illustrated by BH and SM couplings performed successfully on scales up to 100 g.