Focused Microwave-Assisted Parallel Synthesis of bis-Benzimidazoles

Abstract

Combinatorial parallel synthesis of bis-benzimidazoles by focused (mono-modal) microwave irradiation is described. Polymer immobilized o-phenylenediamines as a versatile template was synthesized under microwave irradiation. The resulting PEG bound diamines was N-acylated with 4-fluoro-3-nitrobenzoic acid selectively in primary aromatic amino moiety. Nucleophilic aromatic substitution of the amide obtained was performed with different amines then cyclized to benzimidazole in acidic condition. Successive reduction, cyclization with various aldehydes yielded 5-(benzimidazol-2-yl)benzimidazoles. The desired products were released from the polymer support to afford the tri-substituted bis-benzimidazoles in good yields and purity.

Key words

bis-benzimidazole - combinatorial chemistry - liquid-phase method - solid-phase method - scaffold

References

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15

All the microwave assisted polymer-supported reactions described here were performed in a 50 mL round bottom flask (attached to the reflux condenser) with CEM Discover Microwave System at a frequency of 2450 Hz (0-300 W).
A Typical Procedure for the Synthesis of 4:
A mixture of polyethylene glycol (MW χα. 6000, 0.1 mmol), DCC (N,N′-dicyclohexylcarbodiimide, 0.15 mmol), DMAP (5 µmol) and 4-fluoro-3-nitrobenzoic acid (0.15 mmol) in CH₂Cl₂ (10 mL) was irradiated under microwave cavity with an output at 300 W for 5 min. Upon completion of the reaction, Et₂O (30 mL) was added to the reaction mixture in an ice-water bath to precipitate out PEG-bound compound. The precipitate was then collected on sintered glass funnel and thoroughly washed with Et₂O (3 × 10 mL) following filtration. To 600 mg each of the above resin was added 3 equiv of primary amines and 10 mL CH₂Cl₂ at r.t. The reaction mixtures were irradiated in a microwave (300 W) for 5 min. After completion, polymer bound product was purified by precipitation method and was redissolved, precipitated twice and dried in vacuo. To 600 mg each of the above resin was added zinc (2.0 mmol) and NH₄Cl (0.56 mmol) in CH₃OH (10 mL) at r.t. The reaction mixtures were irradiated in microwave cavity with an output at 300 W for 6 min and the bright yellow color of the solution was observed to disappear. The same work-up procedure has been followed by precipitation to separate side products and desired polymer-supported diaminobenzene. The crude PEG product 4 was redissolved, precipitated twice and dried in vacuo for the next sequence.