Novel Synthesis Of Benzofuran Derivatives Via FeCl₃-Mediated Intramolecular Cyclization

Benzofuran derivatives are important compounds, and the benzofuran moiety is abundant in both natural and artificial molecules possessing potent biological activities. So much attention was devoted to the novel development of general methods for the assembly of substituted benzofurans. Based on our previous method for the construction of indole ring, we proposed a unique method to synthesize benzofuran derivatives via ferric chloride-mediated intramolecular cyclization. This method involves the aryl carbon-oxygen bond formation via the direct C-H functionalization.Using substituted aryl nitriles and esters as starting materials,α-aryl-β-ketonitriles andα-aryl-β-carbonyl-carboxylates were synthesized as substrates. In order to investigate the effect of benzylic cyano group or carboxylic ester group in the cyclization step, other types of substrates were synthesized for comparision purpose. A series of benzofuran derivarives were synthesized via intramolecular cyclization in the presence of ferric chloride in 1,2-dichloroethane, usingα-aryl-β-ketonitriles orα-aryl-β-carbonyl-carboxylates as substrates. The reaction condition is mild, and the workup procedure is simple and moderate yields were achieved. The substituents on the benzene ring have strong effects in the cyclization under the reaction condition.The results of the experiment indicate that 3,4-dimethoxy group or 3,4-dideutomethoxy group on the benzene ring facilitates the cyclization. Replacing the benzene ring with the naphthalene ring, naphthofuran was obtained. It was also found that the cyano group or carboxylic ester group at the benzylic position is indispensable.A series of benzofuran derivatives were synthesized using this method, and the structures of the compounds were chracterized by 1H NMR spectra, LRMS and X-ray analysis. Mechanisms were studied for the reaction process, and two possible mechanisms were proposed.