FULL PAPER DOI: 10.1002/ejoc.200701160 Three-Component Indium-Mediated Domino Allylation of 1H-Indole-3- carbaldehyde with Electron-Rich (Hetero)arenes: Highly Efficient Access to Variously Functionalized Indolylbutenes Francesca Colombo, [a] Giancarlo Cravotto, [b] Giovanni Palmisano,* [a] Andrea Penoni, [a] and Massimo Sisti [a] Keywords: Indium / Domino reactions / Aldehydes / Allylation / Heterocycles / Nitrogen heterocycles We have developed a three-component, one-pot domino re- action that combines the allylindation of 1H-indole-3-carbal- dehyde with the dehydrative alkylation of stabilized C nucleophiles (e.g., electron-rich heteroarenes, electron-rich Introduction The ubiquitous presence of the indole skeleton in a large number of naturally occurring and biologically important compounds has elicited intense research aimed to facilitate its synthesis and functionalization. Moreover, the indole unit has been recognized as a component of highly specific information-transmitting molecules, a role it plays because it can bind to many receptors with a high degree of affinity. Consequently, much efforts is being devoted to develop ef- ficient methods for the installation of a variety of functional groups on the indole scaffold. [1] Following our interest in this area we revisited the Barbier-type indium-mediated allylation [2,3] (hereafter called allylindation) of 1H-indole-3-carbaldehyde (1) in the presence of azoles (e.g., pyrazole). At variance with results previously reported by others, [4] we anticipated that adduct 2 could be obtained by a three-component, one-pot domino process (as shown in the Scheme 1) [5,6] Inspired by successful and ready reaction with N nucleo- philes, we proceeded to develop a C–C bond-forming reac- tion by merging allylindation with a dehydrative Friedel– Crafts-type alkylation. If successful, this approach would facilitate the access (via common intermediate 3) to a vari- ety of structurally diverse products by simply changing the C nucleophile chosen to react with it. The present report [a] Dipartimento di Scienze Chimiche e Ambientali, Università dell’Insubria, Via Valleggio 11, 22100 Como, Italy, Fax: +39-031-2386449 E-mail: giovanni.palmisano@uninsubria.it [b] Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via Giuria 9, 10125 Torino, Italy Supporting information for this article is available on the WWW under http://www.eurjoc.org or from the author. Eur. J. Org. Chem. 2008, 2801–2807 © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2801 aromatics, and stabilized enols) or N nucleophiles (e.g., azoles). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) Scheme 1. describes the results of this study and their applications to the synthesis of nonsymmetrical bis(indolyl)-, heteroaryl- (indolyl)-, and alkyl(indolyl)butenes. [6,7] Results and Discussion We started from the allylindation of 1 in the presence of indole (as a neutral C nucleophile, i.e. one possessing rela- tively high-lying HOMOs) to obtain the already-known in- dole 5; standard conditions were used as described by Ku- mar et al. [4] Treatment of 1 with allyl bromide (1 equiv.) and indole (1 equiv.) in the presence of indium metal (0.7 equiv.)