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2005 | 3 | 2 | 288-294
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Parallel synthesis of novel benzimidazoles on a soluble polymer support

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Liquid phase combinatorial synthesis using a soluble polyethylene glycol (PEG) polymer support and commercially available 3-nitro-4-fluoro benzoic acid is carried out in order to create a molecular library of trisubstituted benzimidazoles. The PEG-ester conjugate of 3-nitro-4-fluoro benzoic acid is subjected to ipso-fluoro displacement by various primary amines. The nitro group is reduced under neutral conditions using excess zinc and ammonium chloride, producing the polymer-boundo-phenylene diamines. Reaction of the diamines with different aldehydes results in cyclisation to benzimidazoles. The polymer support is cleaved releasing the desired products in high yields and purity. All reactions are performed at room temperature. [...]
Physical description
1 - 6 - 2005
1 - 6 - 2005
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  • [24] A detailed experimental procedure for the first 3 steps of the sequence has been published in reference [18]. In a typical experiment, the polymer boundo-phenylene diamine 4 (500 mg) was stirred with three equivalents of an aldehyde (R2−CHO) in dichloromethane at room temperature for overnight. The solution was concentrated by rotary evaporation, and the reaction mixture was precipitated by addition of ether while stirring. The polymer-bound product was then filtered under aspirator pressure using a fritted funnel and washed several times with ethanol to obtain the precusor benzimidazole conjugates 5. The transesterification of the disubstituted benzimidazole in NaOMe/methanol is representative of the cleavage procedure: 540 mg of the benzimidazole-polymer conjugate was dissolved in 5 ml methanol containing 27 mg of sodium methoxide and stirred at room temperature for 3h. The solvent was evaporated under vacuum, and the polymer bound product was precipitated in ethanol. The polymer was filtered, and the combined filtrate was evaporated to give the crude product as pale yellow solid (35–43 mg, crude yield; 75–95%); The crude purity of the compounds was determined by HPLC analysis.1H-NMR spectral data (300 MHz, CDCl3) for 6c is as follows σ 8.52 (s, 1H); 8.00 (dd, J=8.7, 1.5 Hz, 1H); 7.67–7.63 (m, 3H); 7.54 (t, J=3.3 Hz, 3H); 4.87–4.79 (m, J=6.9 Hz, 1H); 3.96 (s, 3H); 1.66 (d, J=6.9 Hz, 6H).
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