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

Abstract

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.

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

“…Actually, despite treatment with NaBH(OAc) 3 imines 10e-f remained unchanged, indicating that they are less reactive than compounds 10a-d. This is likely to be due to a more severe shielding of the imine function by the adjacent R 1 groups as a result of the larger "upper" bridge (m = 2) in 10e-f as it was claimed before in cycloaddition reactions performed with these compounds [51]. To overcome this problem the aforementioned procedure was changed as follows: Instead of NaBH (OAc) 3 NaBH 3 CN was employed for the reduction of imines 10e-f to the amines 14e-f. Then, when the conversion to the amines 14e-f had gone to completion according to TLC, excess reducing agent was removed by basic-aqueous workup and the crude amines were reacted with NaBH(OAc) 3 and the aldehydes rac-12-13 in analogy to the original procedure.…”

“…Though these polycyclic imines 10 display the same 2-azabicyclo [2.2.2]octane skeleton, the size of the bridge between the two substituted bridgehead atoms and thus the size of the tricyclic scaffold but also the orientation of the bridgehead substituents may be varied [51], thus allowing to study the impact of these two parameters on the inhibitory potency of the target compounds. As bridgehead substituents initially exclusively methyl and phenyl residues should be used as the synthesis of the respective symmetric tricyclic imines is known [51]. For the connection of these tricyclic cage units via their amino nitrogen, resulting from reduction of the imine function, with the amino nitrogen of racemic nipecotic acid (rac-4) a plain alky chain linker of varying length should be used.…”