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Regioselective, Unconventional Pictet–Spengler Cyclization Strategy Toward the Synthesis of Benzimidazole-Linked Imidazoquinoxalines on a Soluble Polymer Support

Authors

  • Dr. Chih-Hau Chen,

    1. Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10 (Taiwan), Fax: (+886) 3-573-6007
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  • Jaren Kuo,

    1. Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10 (Taiwan), Fax: (+886) 3-573-6007
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  • Dr. Gorakh S. Yellol,

    1. Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10 (Taiwan), Fax: (+886) 3-573-6007
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  • Prof. Dr. Chung-Ming Sun

    Corresponding author
    1. Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10 (Taiwan), Fax: (+886) 3-573-6007
    • Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10 (Taiwan), Fax: (+886) 3-573-6007

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Abstract

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.

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