Reactions affording novel pyrrolidines catalysed by palladium

Robinson, Joshua and Doulcet, Julien (2025) Reactions affording novel pyrrolidines catalysed by palladium. PhD thesis, Lancaster University.

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Abstract

Pyrrolidines are privileged motifs in drug discovery, ranked among the top five most common non-aromatic N-heterocycles and featured in 37 FDA-approved drugs. Transition metal-catalysed cross-coupling reactions are widely employed by medicinal chemists for drug synthesis and late-stage functionalization of complex molecules. In this work, we present a palladium-catalysed (hetero)arylation/reduction cascade reaction that provides access to 3-aryl pyrrolidines, potent and selective ligands for serotonin and dopamine receptors. The optimized protocol is highly reproducible, uses bench-stable reagents and avoids the need for glovebox or anhydrous conditions. This reaction demonstrates broad scope, accommodating diverse (hetero)aryl bromides and 1-benzyl-3-pyrroline as coupling partners, enabling direct synthesis of bioactive pyrrolidines from readily available precursors. Notably, it also affords indane-fused pyrrolidines in high yields from 2-bromoarylaldehydes, 2-bromoarylketones and 2-bromoaryl Michael acceptors, highlighting its versatility. Mechanistic studies suggest a Heck-type arylation pathway, whereby the reactive enamine intermediate (Mizoroki-Heck product) undergoes protonation to form a reactive iminium species, which is reduced to yield 3-aryl pyrrolidines. Alternatively, intramolecular nucleophilic attack by the enamine on an aldehyde moiety results in the formation of indane-fused pyrrolidines. This mechanistic insight expands the understanding of palladium-catalysed transformations for the synthesis of novel heterocycles.