Palladium-Mediated Arylation of 3-Aminopiperidines and 3-Aminopyrrolidines

This paper describes the palladium-catalyzed arylation of 1-substituted 3-aminopyrrolidines or
piperidines. Palladium(0) (1−2 mol %) in conjunction with “Buchwald's ligand” [2-(dimethylamino)-2‘-(dicyclohexylphosphine)biphenyl] was shown to be the catalyst of choice for the coupling with
aryl bromides or chlorides. When bromobenzene was used, a strong temperature effect was noticed.
Whereas no reaction occurred at 100 °C, yields higher than 85% were obtained at 130 °C for each
substrate. Such an effect was not observed when diphosphines were used. Whereas Xantphos and,
to a lesser extent BINAP, were moderately efficient in the coupling of all diamines, the palladium-mediated arylation in the presence of monophosphines was strongly dependent on the substrate.
The results suggest the participation of both nitrogens of the aminoheterocycle in the reactive
intermediate. This participation could also account for the highly selective arylation of the endocyclic
nitrogen of unsubstituted 3-aminopyrrolidine or piperidine. Optimal conditions were found for the
arylation using 2- or 4-substituted electron-poor or enriched aryl halides.