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

Heinrich‐Karl A Rudy,Klaus T Wanner,Peter Mayer

doi:10.1002/ejoc.202000280

Heinrich‐Karl A Rudy, Klaus T Wanner + Show 1 more

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https://doi.org/10.1002/ejoc.202000280

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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.

Highlights

Imidazole rings are a common structural motif present in many natural products, medicinal drugs, and chemical compounds.[1]
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] in the first step appropriately 4,4disubstituted 1,4-dihydropyridines should be prepared via reaction of N-silylpyridinium ions with bisorganomagnesium compounds
A small set of imidazoles fused with a cyclic system in 1- and 5-position, starting from saturated aliphatic tricycles incorporating an imine functional group and tosylmethyl isocyanide (TosMIC) has been synthesized

Summary

Introduction

Imidazole rings are a common structural motif present in many natural products, medicinal drugs, and chemical compounds.[1]. Exhibiting an imine subunit, pyrazine-2(1H)one derivatives have been employed in cycloaddition reactions with TosMIC yielding the corresponding ring fused systems that served as intermediates for the development of anticancer agents.[7] Further examples for the construction of 1,5-ring-fused imidazoles by means of TosMIC are found in syntheses of imidazobenzodiazepine and imidazo -carboline derivatives.[8,9,10] nitrogen containing heteroaromatic compounds like quinolone, isoquinoline, and quinoxaline formally displaying a C=N subunit have successfully been employed in the synthesis of the corresponding N-fused imidazo heterocycles employing TosMIC (Figure 2).[11]. 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.[14] 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

Results and Discussion

Conclusion

Experimental Section

NMR experiments