Tricyclic imines inheriting a 2-azabicyclo[2.2.2]octane (isoquinuclidine) scaffold were provided with high regioselectivity in moderate to very good yields by a smooth, broadly applicable intramolecular hetero-Diels–Alder reaction of various 4-ω-alkenyl-substituted 1,4-dihydropyridines (DHPs) under trifluoroacetic acid catalysis. The required 4,4-disubstituted 1,4-DHPs were obtained by introduction of ω-alkenyl moieties of varying chain length via diorganomagnesium reagents into the 4-position of diversely 4-substituted pyridines after prior N-activation with triisopropylsilyltriflate.
Imidazoles fused with a cyclic system in 1,5‐position were synthesized via the van Leusen imidazole synthesis employing saturated aliphatic tricycles including an imine function in the base catalyzed cycloaddition reaction with p‐toluenesulfonyl‐methyl isocyanide (TosMIC). Thereby, N‐(tosylmethyl)formamide, a decomposition product of TosMIC, was found to act as a promoter of this reaction leading to considerably reduced reaction times and improved yields. Mechanistic studies revealed that N‐(tosylmethyl)formamide is transformed into N‐methyleneformamide acting as a catalyst in this reaction under the applied basic conditions. Being a Michael acceptor, the employed imines add to this compound, thus being transformed into iminium ions. The so formed intermediates facilitate the first step of the van Leusen imidazole synthesis, which is the addition of deprotonated TosMIC to the iminium subunit. N‐methyleneformamide is finally reformed during the overall reaction and can thus be considered as an organocatalyst of the studied cycloaddition reaction.
A new class of GABA reuptake inhibitors with sterically demanding, highly rigid tricyclic cage structures as the lipophilic domain was synthesized and investigated in regard to their biological activity at the murine GABA transporters (mGAT1–mGAT4). The construction of these compounds, consisting of nipecotic acid, a symmetric tricyclic amine, and a plain hydrocarbon linker connecting the two subunits via their amino nitrogens, was accomplished via reductive amination of a nipecotic acid derivative with an N-alkyl substituent displaying a terminal aldehyde function with tricyclic secondary amines. The target compounds varied with regard to spacer length, the bridge size of one of the bridges, and the substituents of the tricyclic skeleton to study the impact of these changes on their potency. Among the tested compounds nipecotic acid ethyl ester derivates with phenyl residues attached to the cage subunit showed reasonable inhibitory potency and subtype selectivity in favor of mGAT3 and mGAT4, respectively.
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