Studies On Synthesis Of Polysubstituted Tetrahydropyridens Via Multicomponent Reactions Of Brassard's Diene, Aldehydes And Anilines

Functionalized tetrahydropyridine and piperidine ring systems are widely found in biologically active natural products and pharmaceuticals. Among these methodologies that have been developed to construct these nitrogen-containing six-membered heterocycles, hetero Diels-Alder reaction has been proved to be one of the most powerful ones. The author of this paper dedicated to the reactions of Brassard's diene condensed with imines and happened to discover a synthesis of a new kind of polysubstituted tetrahydropyridine. The synthesis was achieved by a multicomponent reaction of Brassard's diene, benzaldehyde and aniline catalyzed by Lewis acid. The mechanism of the synthesis mentioned above was then investigated and a two-step condensation pathway (firstly aldol condensation and secondly aza Diels-Alder reaction) was proposed. Catalyst screening showed BF3·Et2O was the best catalyst. Further research found that this reaction proceeded smoothly under solvent-free and open-air conditions. Encouraged by the results obtained, a number of aldehydes, anilines and dienes were investigated. The three components condensation reaction proceeded smoothly to afford the corresponding tetrahydropyridines in moderate to excellent yields. A gram scale synthesis was achieved in 62% yield when increasing the amount of benzaldehyde from 0.2 mmol to 5 mmol. The relative stereochemistry of product 4a was assigned based on NOESY experiment, which shows that the C2 and C6 substituents of 4a are in trans relationship. Reactions of Brassard's diene condensed with imines were also investigated. Six different kinds of imines were introduced to the investigation and corresponding Mannich-type products were isolated. Asymmetric Mannich-type reaction research was tested but the result was disappointed.