A Highly Efficient Synthesis Route for the Rapid Generation of 1,2,5,6-Tetrasubstituted Benzimidazoles

Abstract

Herein we describe the facile generation of novel benzimidazoles starting from 5-chloro-4-iodo-2-nitroaniline. A synthesis protocol was established which allows the parallel synthesis of compound arrays as well as the rapid generation of single representatives thereof.

Key words

benzimidazoles - parallel synthesis - medicinal chemistry - palladium coupling - nucleophilic aromatic substitution

References and Notes

• 1 Bleicher KH. Nettekoven M. Peters J.-U. Wyler R. Chimia  2004,  58:  588 
• 2 Bleicher KH. Boehm H.-J. Mueller K. Alanine A. Nature Rev. Drug Discov.  2003,  2:  396 
• 3 Imidazole and Benzimidazole Synthesis   Ross Grimmett M. Academic Press; London: 1997. 
• 4 Wilson JG. Hunt FC. Austr. J. Chem.  1983,  36:  2317 
• 5a Adam G, Alanine A, Goetschi E, Mutel V, and Woltering TJ. inventors; WO  2001029011.  ; Chem. Abstr. 2001, 134, 311234
• 5b Adam G, Goetschi E, Mutel V, Wichmann J, and Woltering TJ. inventors; WO  2002083652.  ; Chem. Abstr. 2002, 137, 325447

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General Procedure for N-Alkylation Reactions
(5-Chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert-butyl ester (1, 1 mmol) was dissolved in DMF (10 mL) and alkylating agent (1 equiv) and Cs₂CO₃ was added. In case of benzyl chlorides, a catalytic amount of KI was added. The reaction mixture was stirred at r.t. overnight. After evaporation of the solvent, the crude was taken up in EtOAc and extracted with a sat. NaHCO₃ solution. The residue could be purified by column chromatography using SiO₂ or used directly in the following step.

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General Procedure for Nucleophilic Displacement Reactions
(5-Chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert-butyl ester (1, 10 mmol) was dissolved in DMSO and amine (5 equiv) added. The reaction mixture was stirred at 80 °C for 3 h. After addition of H₂O, the product precipitated from the solution and was filtered off, washed twice with H₂O and dried under vacuum. The residue could be purified by crystallization from MeOH or used directly in the following step.

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General Procedure for Suzuki Coupling Reactions
(5-Chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert-butyl ester (1, 2 mmol) was dissolved in DMF. Then, arylboronic acid (1.1 equiv), tetrakis(triphenylphosphine)-palladium (0.02 equiv), and sat. Na₂CO₃ solution (1.5 mL) were added. The reaction mixture was heated to 80 °C overnight. The crude product was extracted from EtOAc-H₂O. The residue could be purified by crystallization from MeOH or MeCN or used directly in the following step.

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General Procedure for Nitro Reductions
The corresponding nitroanilines were suspended in a mixture of MeOH and sat. aq NH₄Cl (2:1). An excess of zinc powder was added and the reaction mixture stirred at r.t. overnight. The remaining solid was filtered off. After evaporation of the organic solvent, EtOAc was added and the crude product extracted with H₂O. The residue could be purified by column chromatography using SiO₂ or used directly in the following step.

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General Procedure for Acylation Reactions
The corresponding anilines were dissolved in DMF and added to a mixture of carboxylate (1 equiv), HATU, and DIPEA. The reaction mixture was stirred at r.t. for 2 h. The solvent was evaporated and the resulting residue taken up in EtOAc and extracted with aq NaHCO₃. The crude product was not further purified.

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General Procedure for Cyclization Reactions
The crude products from the previous step were treated with neat TFA and stirred at r.t. for 2 h. Depending on the residues introduced, partial cyclization to the corresponding benzimidazole was observed. Full conversion was obtained after evaporation of the TFA, dissolution of the mixture in AcOH and heating to 80 °C overnight. All final library products were isolated by preparative HPLC and characterized via LC-MS.