TiCl4-promoted condensation of methyl acetoacetate, isobutyraldehyde, and indole: a theoretical and experimental study

Andrea Renzetti; Alessandro Marrone; Stéphane Gérard; Janos Sapi; Hiroshi Nakazawa; Nazzareno Re; Antonella Fontana

doi:10.1039/C4CP05412A

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TiCl₄-promoted condensation of methyl acetoacetate, isobutyraldehyde, and indole: a theoretical and experimental study†

Andrea Renzetti,‡*^a Alessandro Marrone,‡*^b Stéphane Gérard,^c Janos Sapi,^c Hiroshi Nakazawa,^a Nazzareno Re^b and Antonella Fontana^b

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* Corresponding authors

^a Department of Chemistry, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, 558-8585 Osaka, Japan
E-mail: renzetti@sci.osaka-cu.ac.uk

^b Dipartimento di Farmacia, Università “G. d'Annunzio” di Chieti-Pescara, via dei Vestini 33, I-66100 Chieti, Italy
E-mail: a.marrone@unich.it

^c Institut de Chimie Moléculaire de Reims, UMR CNRS 7312, Université de Reims Champagne-Ardenne, Faculté de Pharmacie, 51 rue Cognacq-Jay, F-51096 Reims, France

Abstract

The mechanism of the TiCl₄-promoted condensation of methyl acetoacetate, isobutyraldehyde, and indole was studied by a combination of theoretical and experimental techniques. The energy profile of plausible reaction paths was evaluated by DFT calculations, and various reaction intermediates were isolated or observed in solution by NMR spectroscopy. Theoretical and experimental results indicate that the reaction proceeds in three steps, all promoted by titanium: (1) formation of the enolate ion of methyl acetoacetate, (2) Knoevenagel condensation of the enolate ion and aldehyde, and (3) Michael addition of indole to the Knoevenagel adduct. The study sheds light on the role of titanium in the reaction, providing a mechanistic model for analogous reactions.

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Article information

DOI: https://doi.org/10.1039/C4CP05412A
Article type: Paper
Submitted: 20 Nov 2014
Accepted: 20 Feb 2015
First published: 09 Mar 2015

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Phys. Chem. Chem. Phys., 2015,17, 8964-8972

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TiCl₄-promoted condensation of methyl acetoacetate, isobutyraldehyde, and indole: a theoretical and experimental study

A. Renzetti, A. Marrone, S. Gérard, J. Sapi, H. Nakazawa, N. Re and A. Fontana, Phys. Chem. Chem. Phys., 2015, 17, 8964 DOI: 10.1039/C4CP05412A

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