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

• Published in: European journal of organic chemistry Vol. 2020; no. 24; pp. 3599 - 3612
• Main Authors: Rudy, Heinrich‐Karl A., Mayer, Peter, Wanner, Klaus T.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 30.06.2020; Wiley Subscription Services, Inc
• Subjects: Aliphatic compounds; Catalysts; Chemistry; Chemistry, Organic; Cyclic Imine; Cycloaddition; Imidazole; Imines; Nitrogen heterocycles; Organocatalysis; Physical Sciences; Science & Technology; TosMIC; Tricycles; AGENT; Cycloaddition; Nitrogen heterocycles; FUNGICIDE; Cyclic Imine; TosMIC; SULFONYLMETHYL ISOCYANIDES; Organocatalysis; DERIVATIVES
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202000280

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. An organocatalyst for the synthesis of 1,5‐ring‐fused imidazoles from cyclic imines and TosMIC via the van Leusen imidazole synthesis has been identified. Mechanistic studies provided insight into the formation of the catalyst from a pre‐catalyst and its mode of action.