Exploiting the Nucleophilicity of the Nitrogen Atom of Imidazoles: One-Pot Three-Component Synthesis of Imidazo-Pyrazines

Abstract

A novel one-pot multicomponent reaction to synthesize substituted imidazopyrazines is described. In brief, 1H-(imidazol-5-yl)-N-substituted methanamines react with aldehydes and isocyanides in methanol at room temperature to give imidazopyrazine derivatives in excellent yields. The imidazole nitrogen atom was able to intercept the nascent nitrilium ion, channeling the reaction toward to the sole formation of imidazopyrazines, suppressing the competitive formation of other possible side products deriving from the reaction with the high-energy nitrilium ion. The number of examples and the variability of the nature of isocyanides, aldehydes, and amine components herein employed, witness the robustness of this novel methodology.

New Histamine-Related Five-Membered N-Heterocycle Derivatives as Carbonic Anhydrase I Activators

“…The synthesis of Schiff bases was thereafter performed from 8, the lower homolog of HST (Scheme 3A). After neutralization of the hydrochloride salt with KOH, the reaction with benzaldehyde, salicylaldehyde and p-anisaldehyde smoothly afforded good yields of the corresponding imines 17-19, which were then reduced with sodium borohydride to 20-22 [39,40]. The reaction of 4-imidazole-carbaldehyde with benzylamine yielded the Schiff base 23 [41] (Scheme 3B).…”

Copper-Catalyzed Conjugate Additions to Isocyanoalkenes

“…The title compound was prepared following a modification of the published procedure . An ethanolic solution (0.2 M) of N -[(1 H -imidazol-5-yl)­methyl]-1-phenylmethanamine (12 mg, 60 μmol), paraformaldehyde (1.8 mg, 50 μmol), and isocyanide 16b (20 mg, 60 μmol) was stirred at rt.…”

“…The title compound was prepared following a modification of the published procedure. 41 An ethanolic solution (0.2 M) of N-[(1H-imidazol-5-yl)methyl]-1-phenylmethanamine (12 mg, 60 μmol), paraformaldehyde (1.8 mg, 50 μmol), and isocyanide 16b (20 mg, 60 μmol) was stirred at rt. After 90 h, the reaction mixture was concentrated under reduced pressure and then purified (2 cm × 10 cm silica gel column, eluent of 3% MeOH/CH 2 Cl 2 ) to afford 26 mg (82%) of benzoimidazopyrazine 22 as a yellow oil: IR (ATR) 3029, 2952, 2822, 1731 cm −1…”