The mechanistic origins of unconventional selectivity in palladium catalyzed cross-couplings of dihalo(hetero)arenes

Abstract

This dissertation presents synthetic strategies for achieving unconventional selectivity in Pd-catalyzed cross-couplings of dihalo(hetero)arenes, emphasizing the crucial role of ligands in determining selectivity. The findings have significant implications in pharmaceutical, agrochemical, and materials industries, as halogenated (hetero)arenes are common starting materials for synthesizing high-value compounds such as drugs, pesticides, and polymeric materials used for energy storage. One selectivity challenge in the cross-coupling of dihalogenated arenes is controlling the degree of functionalization, mono vs di functionalization. Previous reports have shown that sterically hindered NHC ligands such as IPr and IPent can preferentially ring-walk across the monocross-coupled product pi-system to the other reactive site. This effect can reduce yields and complicate product isolation in catalytic reactions requiring bulky ligands. Part I of this dissertation examines the origin of ligand effects governing overarylation in dichloroarenes. Selectivity between mono- and di-functionalization is determined by competition between Pd displacement from the monocross-coupled product and a second oxidative addition that initiates another cross-coupling cycle. The presence of a coordinating additive can favor Pd displacement via a bimolecular mechanism, leading to mono-functionalization. However, increased steric bulk around Pd disfavors this process. With Pd/NHC complexes, dibromoarenes deviate from expected trends, as the Br? byproduct can displace the Pd/NHC catalyst from the monocross-coupled product, forming anionic [Pd(NHC)Br]? and favoring mono-functionalization. This study further highlights the unique ability of Pd/NHC complexes to support anionic Pd species. The final section of this dissertation discusses a novel approach to achieving C2-selective thiolations of 2,4-dihalopyrimidines using the bulky catalyst Pd/IPent. To extend this selectivity to other nucleophiles, a mechanistic investigation was conducted with a focus on kinetic studies. While the exact origin of C2-selectivity remains unresolved, an interplay between C4-selective SNAr and C2-selective catalysis was examined, revealing a dependence on thiolate concentration. Additionally, conditions were identified that completely inhibit SNAr even in the absence of Pd. Overall, this work provides mechanistic insights into unconventional selectivity in Pd-catalyzed cross-coupling reactions, expanding the understanding of ligand effects and nucleophile-dependent reactivity in selective functionalization.