A new synthesis of pyrrolo[3,2-b]quinolines by a tandem electrocyclization–oxidation process Thomas Boisse a, y , Philippe Gautret a, * , Benoı ˆt Rigo a, * , Laurence Goossens b , Jean-Pierre He ´ nichart b , Laurent Gavara a, y a Groupe de Recherche sur l’Inhibition de la Prolife ´ration Cellulaire, EA 2692, Ecole des Hautes Etudes d’Inge´nieur,13 rue de Toul, 59046 Lille, France b Groupe de Recherche sur l’Inhibition de la Prolife ´ration Cellulaire, EA 2692, Institut de Chimie Pharmaceutique Albert Lespagnol, Universite´ de Lille 2, 3 rue du Professeur Laguesse, B.P. 83, 59006 Lille, France article info Article history: Received 7 April 2008 Received in revised form 14 May 2008 Accepted 15 May 2008 Available online 21 May 2008 Keywords: Benzoazaindole Electrocyclization Bredereck’s reagent Methyl transfer abstract A new synthesis of pyrrolo[3,2-b]quinolines is described. Condensation of anilines with dimethyl 4- oxopyrrolidine-1,3-dicarboxylate yields enaminoesters, which upon reaction with Bredereck’s reagent produce the title compounds. A possible reaction mechanism is briefly discussed. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Heterocycles containing the azaindole ring system have been reported to show a wide range of biological activities 1 (Fig. 1). Among them, a few natural products have been found, such as harmine derivatives (MAO inhibitors), 2 the DNA intercalator cryp- tolepine, 3 or the antileukemic canthin-6-one. 4 In this context, we became interested in the less studied pyrrolo[3,2-b]quinolines 1 , which possess the 4-azaindole core. This scaffold affords a wide range of modulation allowing its chemical structure to fit with a variety of targets involved in tumor progression, such as kinases, growth factor receptors, or DNA itself. To the best of our knowledge, a very few pyrrolo[3,2-b]quino- lines have been prepared and only three synthetic routes leading to this family have been described (Scheme 1). 5 The main method involves the cyclocondensation of 3-amino-2-methylquinoline 2 with triethyl orthoformate, 5a Vilsmeier reagent, 5b or acylation fol- lowed by treatment with Cu/NaOEt. 5b Pyrrolo[3,2-b]quinolines 1b can be obtained by rearrangement of 2-amino-5-phenyl-3H-1,4- benzodiazepines 3 with 1,3-dicarbonyl compounds 4. 5c Moreover, the reduced 1H-pyrrolo[3,2-b]quinoline 5, accompanied with isomer 6, can be obtained by Friedla ¨nder reaction of cyclic ketone 7 . 6 A review describing the main accesses to 4-, 5- or 6-azaindoles has recently been published. 7 Because of our interest in new chemical structures targeting tumor progression, we have been paying attention to the synthesis of highly functionalized pyrrolo[3,2-b]quinolines 1 allowing easy further dressing. We now wish to report a new practical general method for the synthesis of such a scaffold. 2. Results and discussion 2.1. Chemical context A classical synthesis of quinolines is based on the Friedla ¨ nder condensation. In the pyrroloquinoline series, this method has been extensively used for the preparation of precursors of the antitu- moral alkaloid camptothecin and some of its derivatives (last synthesis of Scheme 1). 8 In order to introduce various substituents on the phenyl ring, substituted aminobenzaldehydes would be required. However, it is well established that these aldehydes are often unstable due to self-condensation, 9 and Friedla ¨ nder con- densation may require harsh conditions (high temperature, strong acidic medium). 10 We did not consider this method since it would hardly be applied to highly functionalized compounds. Ring closure of azahexatrienes 8 via electrocyclization repre- sents another alternative method leading to quinoline scaffold 9. * Corresponding authors. Tel.: þ33 3 28 38 48 58; fax: þ33 3 28 38 48 04. E-mail addresses: philippe.gautret@hei.fr (P. Gautret), rigo@hei.fr (B. Rigo). y Both authors contributed equally to this work. Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.05.071 Tetrahedron 64 (2008) 7266–7272