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

Abstract

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 degrees C, yields higher than 85% were obtained at 130 degrees 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.

Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors

“…19a – d were prepared through Suzuki coupling as described above, and 19e – g were obtained in 70–85% yield by Ullmann coupling of 3-bromobenzaldehyde with an excess of the appropriate amines 20e – g [49]. The Buchwald coupling of protected 3-bromobenzaldehyde with amines 20h – j proceeded smoothly in toluene with NaO t -Bu as base by using a Pd 2 (dba) 3 / rac -BINAP catalysis system [50]. …”

Bite angle effects of diphosphines in C–C and C–X bond forming cross coupling reactions

“…In contrast to the last reaction, for the synthesis of the BOC-protected 3-(N-arylamino)piperidine 30 the wide bite angle forming Xantphos turned out to be the best diphosphine (entry 7). 101 Better results, by far, were obtained using phosphines such as DavePhos or 2-(dicyclohexylphosphino)-obiphenyl (90 and 98% yield).…”

Design, Synthesis, and Characterization of Novel Small Molecules as Broad Range Antischistosomal Agents

“…Starting from commercially available 4-bromo-2-nitrobenzoic acid 5 , reduction with BH 3 -THF followed by protection of the resulting alcohol as a TBS ether produced the desired compound 6 . Compound 6 was then used as a common intermediate for Buchwald–Hartwig amination conditions , with a variety of commercially available N-Boc-protected diamines, producing a diverse set of cyclic amine templates (compound 7 ) in moderate to good yields (50–80%).…”