Nucleus- and side-chain fluorinated 3-substituted indoles by a suitable combination of organometallic and radical chemistry Francesca Bellezza a , Antonio Cipiciani a , Renzo Ruzziconi b, * , Sara Spizzichino b a CEMIN, ‘‘Centro di Eccellenza Materiali Innovativi Nanostrutturati’’, via Elce di Sotto, 8, 06123 Perugia, Italy b Dipartimento di Chimica, Universita ` di Perugia, via Elce di Sotto, 8, 06123 Perugia, Italy Received 27 July 2007; received in revised form 1 September 2007; accepted 9 September 2007 Available online 14 September 2007 Abstract Regioselectively fluoro-, trifluoromethyl- and trifluoromethoxy-substituted 3-methyleneindolines have been prepared using a four-step procedure involving metalation/bromination of fluorinated Boc-protected anilines, N-propargylation of the resulting o-bromoarylcarbamate and reductive radical cyclization of the product with tributyltin hydride/AIBN. 3-Methyleneindolines, as valuable, versatile intermediates, can be transformed into highly functionalized 3-substituted indoles by ene-type reactions using different enophiles. Thus, fluoro-, trifluoromethyl- and trifluoromethoxy-substituted diethyl 2-hydroxy-2-[(1H-indol-3-yl)methyl]malonates, ethyl 2-hydroxy-3-(1H-indol-3-yl)propionates and ethyl 2-hydroxy-3-(1H-indol-3-yl)-2-trifluormethylpropionates were obtained in 77–86% yield by simply heating the corresponding tert-butyl 3-methyleneindoline-1-carboxylate with an equimolar amount of diethyl ketomalonate, ethyl glyoxalate and ethyl 3,3,3-trifluoropyruvate, respectively, at 100 8C, without solvent, for 0.5–4 h. # 2007 Elsevier B.V. All rights reserved. Keywords: Fluorinated indolines; Indole derivatives; Arylcarbamate metalation; Radical cyclization; Carbonyl-ene reactions 1. Introduction It is now recognized that fluorine can change the properties of a biologically active molecule by influencing its metabolism. Its ability to increase lipophilicity, its high electronegativity and its reduced van der Waals radius, which make it like to an OH group, with, however, a scarce propensity to form hydrogen bonds, make fluorine a unique, valuable resource for increasing the therapeutic efficacy of biologically active organic molecules, especially when it is located in specific positions [1]. Besides the fluorine atom, the introduction of a CF 3 [2], or the less common OCF 3 group [3], into an aromatic ring appears to be a successful combination for the biological activity of a molecule to make the undertaking extremely attractive. The indolic nucleus is involved in a variety of natural products also by controlling essential biological functions both in the animal and plant kingdom [4]. For the above reasons, it should not be surprising if the introduction of fluorine or fluorinated substituents into a strategic position of the indole nucleus substantially affects the biological activity of this class of molecules leading to unexpected pharmacokinetic or pharma- codynamic properties [1e,f,5]. Although many methods have been developed to synthesize indole derivatives [6], fluorinated analogues of indole-based, biologically active molecules are not as well known. Trifluoromethyl-substituted indoles are somewhat rare. Some of them have been prepared starting from commercially available (trifluoromethyl)aniline by complex procedures [7]. Direct electrophilic trifluoromethylation of indoline and oxindoles was recently attempted and gave access to regioselectively substituted 6-(trifluoromethyl)oxindoles, in moderate to good yields [8]. To our knowledge, only two examples of 3-substituted indoles bearing a trifluoromethoxy group are known to date [8,9]. We therefore found attractive to develop a simple, general method for preparing regioselectively nucleous- and side-chain fluoro-, trifluoromethyl- and trifluoromethoxy-substituted indoles functionalyzed at the 3 position, based on a suitable combination of organometallic and radical chemistry. The results of this research are presented in this paper. www.elsevier.com/locate/fluor Journal of Fluorine Chemistry 129 (2008) 97–107 * Corresponding author. Fax: +39 075 5855262. E-mail address: ruzzchor@unipg.it (R. Ruzziconi). 0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2007.09.003