N-methyl-N-(2-nitrophenyl)acetamide → 1,2-Dimethylbenzimidazole

Temperature

100 °C

Time

2 h

Other

One-pot sequence: nitro reduction to aniline -> intramolecular cyclization of the aniline nitrogen onto the acetyl carbonyl -> dehydrative aromatization to the benzimidazole. Fe(0) powder (100 mesh, 6-8 equiv), glacial acetic acid as solvent, 95-100 degC, 2-4 h (2 h for model substrate 8a-acetyl -> product 10). Per general methods, reactions were run under N2.

Step 3 (reductive cyclization) of a three-step synthesis. A solution of N-methyl-N-(2-nitrophenyl)acetamide (8a, 150 mg) in glacial acetic acid (6 mL) was heated to 90 degC; 100-mesh iron powder (6-8 equiv) was added with vigorous stirring and a condenser fitted, then heated at 95-100 degC for 2-4 h (2 h for the model substrate 8a-acetyl). After cooling, the stir bar and unreacted iron were removed, the mixture concentrated under vacuum, the residue taken up in EtOAc and washed with H2O, 1 M aq. NaOH and sat. aq. NaCl, then dried (MgSO4) and concentrated to give 1,2-dimethyl-1H-benzo[d]imidazole (10). (Experimental Section 3.3, Molecules 2026, 31(12), 2150.)

Records the isolated Step 3 (reductive cyclization-aromatization) of the 3-step synthesis of 1,2-disubstituted benzimidazoles from 2-fluoro-1-nitrobenzene (Nevels, Germond, Bunce, Molecules 2026). For the model substrate N-methyl-N-(2-nitrophenyl)acetamide (8a-acetyl), the cyclization to 1,2-dimethylbenzimidazole (10) proceeded in nearly quantitative yield (>98%); the reported isolated two-step yield (acylation of 7a + cyclization) for product 10 is 88%. No competing acyl transfer was observed.

Source note

Nevels, N. E.; Germond, M. E.; Bunce, R. A. Reductive Cyclization of N-Alkyl- and N-Aryl-N-(2-Nitrophenyl) Amides to 1,2-Disubstituted Benzimidazoles. Molecules 2026, 31(12), 2150.

Source type

Literature

DOI

10.3390/molecules31122150