Regioselective, unconventional Pictet-Spengler cyclization strategy toward the synthesis of benzimidazole-linked imidazoquinoxalines on a soluble polymer support.

A novel strategy for an unconventional Pictet-Spengler reaction has been developed for the regioselective cyclization of the imidazole ring system at the C2 position. The developed strategy was utilized to develop a diversity-oriented parallel synthesis for bis(heterocyclic) skeletal novel analogs of benzimidazole-linked imidazoquinoxalines on a soluble polymer support under microwave conditions. Condensation of polymer-immobilized o-phenylenediamines with 4-fluoro-3-nitrobenzoic acid followed by nucleophilic aromatic substitution with an imidazole motif affords bis(heterocyclic) skeletal precursors for the Pictet-Spengler reaction. The unconventional Pictet-Spengler cyclization with various aldehydes was achieved regioselectively at the C2 position of the imidazole ring to furnish rare imidazole-fused quinoxaline skeletons. During the Pictet-Spengler cyclization, aldehydes bearing electron-donating groups afford 4,5-dihydro-imidazoquinoxalines, which then auto-aromatize into benzimidazole-linked imidazo[1,2-a]quinoxalines. However, interestingly, aldehydes bearing electron-withdrawing groups directly provide aromatized imidazo[1,2-a]quinoxalines, which unexpectedly afford novel benzimidazole-linked 4-methoxy-4,5-dihydro-imidazo[1,2-a]quinoxalines after polymer cleavage.

Enantioselective synthesis of benzimidazolyl quinoxalinones on soluble polymer support using focused microwave irradiation.

Focused microwave irradiation has been applied to a multistep synthetic sequence of reactions designed to generate benzimidazolyl quinoxalinones using a soluble polymer support. They were obtained by the ipso-fluoro (S(N)Ar) displacement of the immobilized ortho-nitro fluoro benzimidazoles with chiral alpha amino esters under microwave irradiation. Intermediate chiral organic-polymer conjugates when subjected to neutral reduction underwent a spontaneous intramolecular ring closure. Cleavage of the polymer support, at room temperature, did not cause any significant racemization resulting in the generation of a chiral molecular library with two points of structural diversity.