Metal-Free, Acid-Promoted Synthesis of Imidazole Derivatives via a Multicomponent Reaction

Abstract

An expedient and metal-free synthetic route has been developed for the construction of tri- and tetrasubstituted imidazole derivatives via acid promoted multicomponent reaction methodology. The reaction proceeded smoothly with a range of functionalities to produce the imidazole scaffolds in good to excellent yields.

Metal‐Free [2+2+1] Annulation of Alkynes, Nitriles and Nitrogen Atoms from Iminoiodanes for Synthesis of Highly Substituted Imidazoles

“…Although a metal-free multicomponent approach to highly substituted imidazoles from internal alkynes, aldehydes, and ammonium acetate with or without anilines has been reported very recently, this procedure was demonstrated only for the synthesis of 4,5-diarylimidazoles. [8] We have been engaged in the synthesis of heterocyclic systems through the activation of alkynes by iod-A C H T U N G T R E N N U N G ine(III) reagents, [9] which have gained much attention as eco-friendly oxidants. [10] As a part of our studies, an oxidative [2+2+1] annulation of alkynes, nitriles and oxygen atoms from iodosylbenzene (PhIO) was recently reported for the facile, metal-free and regioselective construction of 2,4-disubstituted and 2,4,5-trisubstituted oxazoles.…”

“…PhINTs, the yield of 2a was improved up to 84% at room temperature for 4 h (entry 5). It should be mentioned that other BF 3 complexes and HBF 4 ·OEt 2 were ineffective (entries [6][7][8]. Unfortunately, the use of 10 equiv.…”

“…Unfortunately, diphenylacetylene was not converted to the 4,5-diphenylA C H T U N G T R E N N U N G imidazole in a similar manner, even at 80 8C for 20 h. On the other hand, the present reaction conditions have a tolerance for deuterium and d-2a was obtained with a high deuteration rate (> 99% D, entry 7). Furthermore, by the use of other BF 3 ·nitrile complexes (BF 3 ·R 3 CN), [18] the reactions with various nitriles (propionitrile, isovaleronitrile, benzonitrile) in the place of MeCN proceeded smoothly giving rise to the functionalized imidazoles 4-6 (entries [8][9][10][11][12][13]. In all cases shown in Table 1 and Table 2, imidazoles 2 and 4-6 were obtained as a single isomer with the illustrated structures.…”

Current advances in the synthesis and biological potencies of tri- and tetra-substituted 1H-imidazoles

“…The metal-free, acid-promoted synthesis of tri-substituted imidazole derivatives was reported through a simple, efficient, and ecofriendly multicomponent methodology by Wang and co-workers in 2013 [168]. The reaction was performed easily using a variety of functionalities to create the imidazole scaffolds in good to high yields.…”

“…The reactions of suitable amines, aldehydes, and internal alkynes 199 (diphenylacetylene), PivOH and NH 4 OAc in (DMSO/H 2 O = 1:1) yield diverse products [168]. In addition, the properties of these analogs were investigated for their fluorescence emission and UV absorption, and compound 206k [211,222] was found to show high potency for photodynamic therapy (PDT) of skin cancer [223] and is a good candidate for being used in organic electroluminescent devices (Scheme 69) [224,225].…”