A Study Of The Fischer Indole Synthesis PDF Download

To obtain the dienone-imine intermediate proposed in the Robinson mechanism of the Fischer indole synthesis, the reaction of cyclohexanone with Ń-alkyl-2,6 - dialkylphenylhydrazine and its hydrochloride was studied. When the above reactants were heated in refluxing dry benzene and water removed azeotropically, 8,9-dialkyl- 1 ,2 ,3 ,4-tetrahydrocarbazole could be obtained in good yield. Only two other products could be isolated from this reaction. They were ammonium chloride and alkylamine hydrochloride. The latter arose through the elimination of the alkyl group at the nitrogen atom and not from the alkyl group attached to the aromatic ring of the hydrazine. Although neither the eneliydrazine nor the dienone-imine intermediate could be isolated, the products of the reaction could be explained only- through their intermediacy. When the reaction of N'-methyl-2,6-dimethylphenylhydrazine with cyclohexanone was conducted at room temperature through the azeotropic removal of water under vacuum, an oil was obtained which gave an indication of the presence of the expected enehydrazine in it. All attempts to isolate this enehydr azine in pure form were unsuccessful. Further, when this oil was treated in benzene with maleic anhydride, no Diels-Alder adduct of the expected dienone - imine could be isolated. The inability to isolate or trap the dienone- imine intermediate was ascribed to the presence of an enolizeable hydrogen at a carbon atom - [symbol] to the imine carbon of the former cyclohexanone ring. When such an enolizeable hydrogen in the dienone-imine intermediate was eliminated by the use of isobutyraldehyde, and the latter allowed to react with N'-methyl-2,6-dimethylphenylhydr azine hydrochloride, a stable dienone-imine hydrochloride was obtained. This could be purified and converted to the free dienone-imine. This dienone-imine reacted with tetracyanoethylene and maleic anhydride to give the reactions of secondary amines rather than to form the corresponding Diels-Alder adducts. The reaction with acetyl chloride gave N-acetylation. However, this dienone-imine could not be converted to the corresponding indole. When a mixture of propionalde-hyde and N'-methyl-2 ,6-dimethylphenylhydrazine hydrochloride was heated in refluxing dry benzene for 20 hours, 1 ,3,7-trimethylindole (31%) was obtained. The latter was contaminated with 3 ,7-dimethyl- indole (~ 9%). When the above reactants were heated in refluxing dry benzene for only 10-12 minutes, a solid dienone-imine hydrochloride containing isomeric contaminants was obtained. When this material was again heated in refluxing dry benzene for 19 hours, the reaction mixture gave a 35% yield of 1 ,3,7-trimethylindole also contaminated with 3,7-dimethylindole (~9%). The isolation of a dienone-imine and its conversion to the corresponding indole supports the mechanism proposed by Robinson for the Fischer indole synthesis.