Indoles via Knoevenagel-Hemetsberger reaction sequence

A series of substituted indoles have been synthesized by the sequential reaction of aromatic aldehydes with ethyl azidoacetate in the presence of sodium ethoxide to form the corresponding ethyl alpha-azido-beta-arylacrylates (Knoevenagel process) followed by a solvent mediated thermolysis (Hemetsberger process). The isolated yields of the ethyl alpha-azido-beta-arylacrylates were significantly increased when employing the sacrificial electrophile ethyl trifluoroacetate. H-1 NMR and coupled H-1-C-13 NMR analysis of the ethyl alpha-azido-beta-arylacrylates indicate that the condensation is stereospecific-only the Z-isomer could be detected. Solvent mediated thermal treatment of the meta-substituted ethyl alpha-azido-beta-arylacrylates resulted in the formation of both the 5- and 7-substituted indoles-the 5-regioisomer being slightly favored over the 7-regioisomer. Analogous thermal treatment of (2Z, 2Z')-diethyl 3,3'-(1,3-phenylene)bis(2-azidoacrylate) and (2Z, 2Z')-diethyl 3,3'-(1,4-phenylene)bis(2-azidoacrylate) exclusively produced pyrroloindoles, diethyl 1,5-dihydropyrrolo[2,3-f]indole-2,6-dicarboxylate and diethyl 1,5-dihydropyrrolo[2,3-f] indole-2,6-dicarboxylate, respectively. Results are also reported which indicate that the alpha-azido-beta-arylacrylates can be used in the subsequent Hemetsberger indolization process without prior purification.