p-Toluensulfonic Acid and Cation Exchange Resin in Aprotic Solvent: Valuable Catalysts for Fischer Indolization

Abstract

p-Toluenesulfonic acid and cation exchange resin (Amberlyst-15) in aprotic solvent were found to serve as a good catalyst for Fischer indolization in many cases.With this condition ethyl indole-2-carboxylate was prepared more conveniently in better yield than by previous methods.Fischer indolizationla is the most valuable and widely-used method for synthesis of indoles, and thus numerous combination of mineral, organic, or Lewis acids with various solvents have been developedlb for the catalyst.However, there have not been so many examples lb" reported for the usage of aprotic solvents.We now wish to report that p-toluenesulfonic acid (TsOH) and cation exchange resin (Amberlyst-15) in aprotic solvent (benzene or toluene) have some advantages for practical synthesis of various indoles by Fischer indolization. 3In connection with our synthetic studies we needed a large amount of ethyl indole-2-carboxylate ( & ) , which is a stable equivalent of indole itself.Although the Reissert method is considered4 as a standard one for preparing the indole (1).the yield is neither satisfactory nor the procedure is necessarily convenient because of the use of dangerous metal potassium.We reinvestigated the Fischer indolization of ethyl pyruvate 2-(phenylhydrazone) (2) for the facile and improved preparation of the indole I&), as Fischer indolization is suitable for laboratory large scale experiment because of its easy-handling procedure.At first we tried the Fischer indolization of the phenylhydrazone (2) with H2S04/ ACOH as reported.'However, this reaction afforded the indole (1) in only 38.8% Yield.accompanied with ethyl 2-(2-ethoxycarbonylindol-3-y1)acrylate ()_) in 5.9%