Accessing Tricyclic Imines Comprising a 2-Azabicyclo[2.2.2]octane Scaffold by Intramolecular Hetero-Diels–Alder Reaction of 4-Alkenyl-Substituted N-Silyl-1,4-dihydropyridines

Abstract

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.

Synthesis of 1,5‐Ring‐Fused Imidazoles from Cyclic Imines and TosMIC – Identification of in situ Generated N‐Methyleneformamide as a Catalyst in the van Leusen Imidazole Synthesis

“…of the organometallic reagents were used in contrast to the literature procedure. [14a] As in related cases,, these reactions resulted in mixtures of the regioisomeric 1,2‐ and 1,4‐addition products, i.e. of 11a – 11f and 12a – 12f .…”

“…For the synthesis of these compounds, 13a – 13f , the synthetic procedure developed for the construction of related, but non‐symmetrically substituted tricyclic imines should be followed. [14a] Accordingly, in the first step appropriately 4,4‐disubstituted 1,4‐dihydropyridines should be prepared via reaction of N ‐silylpyridinium ions with bisorganomagnesium compounds. An acid catalyzed intramolecular hetero‐Diels‐Alder‐reaction of these 4,4‐disubstituted 1,4‐dihydropyridines – with one 4‐substituent exhibiting a double bond serving as dienophile – should finally furnish the respective tricyclic imines.…”

“…It is likely to be attributed to the limited availability of appropriate cyclic imines which are devoid of any additional unsaturation that cycloaddition reactions of this type of compounds with TosMIC for the preparation of the respective N ‐fused imidazoles have hardly been explored so far. We have repeatedly reported on the synthesis of this kind of alicyclic imines by acid catalyzed intramolecular cycloaddition reactions of 4,4‐disubstituted 1,4‐dihydropyridines (1,4‐DHPs) with one of the 4‐substituents serving as dienophile . The tricyclic imines resulting from these reactions exhibiting a highly defined geometry are to be considered as valuable building blocks for the construction of drug like compounds, as they represent scaffolds of high rigidity encompassing well defined trajectories for individual substituents.…”

Synthesis and biological evaluation of novel N-substituted nipecotic acid derivatives with tricyclic cage structures in the lipophilic domain as GABA uptake inhibitors

“…Then the respective aldehyde should be added to a mixture of imine and reducing agent, which was premixed to mediate imine reduction and to allow subsequent reductive amination of the aldehyde function of rac-12 or rac-13 with the formed amine. When in a test reaction aldehyde 13 was added to a mixture of an imine, structurally similar to imine 10c but with one of the methyl residues substituted by hydrogen (for a depiction of the structure see compound rac-14a in [49]), and NaBH 3 CN, that had proven well suited for the reduction of the imines 10 to the corresponding amines 14, besides the reductive amination product also the alcohol rac-15b resulting from the reduction of aldehyde rac-13 was obtained. However, when the mild reducing agent NaBH(OAc) 3 [62,63] in combination with acetic acid was used instead of NaBH 3 CN no such unfavorable reaction occurred.…”

“…Since no systematic study aiming at the development of GAT inhibitors with a polycyclic cage subunit as lipophilic domain has been presented so far, though this appears to be quite rewarding, we intended to carry out such a study. To this end, polycyclic cage structures based on a 2azabicyclo [2.2.2]octane scaffold should be used, as they are easily available by an efficient and straightforward synthesis recently reported by us [49,50]. For the present study the symmetric tricyclic imines 10 should be used (for general structure see Fig.…”