Reductive Cyclization of N-Alkyl- and N-Aryl-N-(2-Nitrophenyl) Amides to 1,2-Disubstituted Benzimidazoles

A new three-step strategy for the preparation of 1,2-disubstituted 1H-benzo[d]imidazoles has been developed. The approach involved (1) S_NAr addition-elimination of alkyl- or arylamines to 1-fluoro-2-nitrobenzene to give N-alkyl- or N-aryl-2-nitroanilines, (2) acylation of these adducts with acid chlorides to afford N-alkyl- or N-aryl-N-(2-nitrophenyl) amides, and (3) reduction of the aromatic nitro with iron in acetic acid at 95-100 °C, followed by closure of the resulting amine on the amide carbonyl to produce 1,2-disubstituted benzimidazoles in high yields. The sequence gave the benzimidazole products in NMR-pure form with only one purification after Step 2. Thirty-seven derivatives were prepared, providing a broad selection of 1,2-disubstituted benzimidazoles. Interestingly, the reaction of the aniline nitrogen derived from the reduction of the nitro group afforded the final product by addition to the acyl carbonyl, followed by dehydrative aromatization with no competing rearrangement, acyl transfer, or side products.