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Issue 32, 2013
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Indolesvia Knoevenagel–Hemetsberger reaction sequence

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Abstract

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 α-azido-β-arylacrylates (Knoevenagel process) followed by a solvent mediated thermolysis (Hemetsberger process). The isolated yields of the ethyl α-azido-β-arylacrylates were significantly increased when employing the sacrificial electrophile ethyl trifluoroacetate. 1H NMR and coupled 1H–13C NMR analysis of the ethyl α-azido-β-arylacrylates indicate that the condensation is stereospecific—only the Z-isomer could be detected. Solvent mediated thermal treatment of the meta-substituted ethyl α-azido-β-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 α-azido-β-arylacrylates can be used in the subsequent Hemetsberger indolization process without prior purification.

Graphical abstract: Indoles via Knoevenagel–Hemetsberger reaction sequence

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Supplementary files

Article information


Submitted
16 Apr 2013
Accepted
31 May 2013
First published
31 May 2013

RSC Adv., 2013,3, 13232-13242
Article type
Paper

Indoles via Knoevenagel–Hemetsberger reaction sequence

W. L. Heaner IV, C. S. Gelbaum, L. Gelbaum, P. Pollet, K. W. Richman, W. DuBay, J. D. Butler, G. Wells and C. L. Liotta, RSC Adv., 2013, 3, 13232
DOI: 10.1039/C3RA42296H

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