Recent advances in the synthesis of regioselectively fluorinated homo- and heterocyclic compounds by complementary cyclization methods Renzo Ruzziconi *, Federica Buonerba Dipartimento di Chimica, Universita ` di Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy 1. Introduction Fluorine is increasingly becoming a protagonist in synthetic organic chemistry. It is a subtle yet efficacious tool to engineer molecular properties. No wonder that it plays a crucial role in the life sciences in general and in drug design in particular. Its electron-withdrawing power, combined with its high carbon– fluorine bond energy, significantly enhances the metabolic stability of the host molecule and at the same time increases its lipophilic character facilitating cell-membrane permeation. Due to its unique and surprising properties, fluorine, the only element capable of mimicking hydrogen in virtue of its comparable size, is increasingly being used as a substituent in the synthesis of significant pharmacologically active compounds. Nowadays, fluo- rinated drugs are employed in a vast range of therapeutic applications – from anesthetics to chemotherapeutics, from corticoids to neuroleptics – and are relative newcomers in the area of cardiovascular drugs [1]. The proven utility of fluorine in a variety of fields, other than in the pharmaceutical sciences, has driven the development of ever more effective synthetic methods of incorporating fluorine into aromatic systems [2]. From a historical point of view, one effective, though dated, method of putting a fluorine atom into an aromatic ring consists in decomposing the corresponding aryldiazonium fluoborate obtained by diazotation of aniline in the presence of the fluoborate anion (Schiemann reaction) (Scheme 1) [3]. The absolute regioselectivity of this reaction is, however, counterbalanced by less than spectacular yields, especially in the presence of acid-sensitive functional groups in the molecule. Variants, such as the use of different fluorinated anions, or different reagents and solvents, were gradually introduced in the original protocol thus allowing the yields to be substantially increased [4]. The use of alkaline fluoride constitutes a valid alternative in the fluorination of aromatic rings by nucleophilic aromatic substitu- tion. The success of this method depends on the presence of strong electron-withdrawing groups in the aromatic ring. Nevertheless, the yield can be sensibly increased by the use of suitable cation- coordinating crown ethers or anhydrous tetrabutylammonium fluoride in dipolar aprotic solvents (Scheme 2) [5]. Aromatic fluorination was also successfully accomplished by using ‘‘electrophilic fluorine’’ reagents, such as N-fluorodisulfoni- mides or the well-known selectfluor 1 and deoxofluor 1 , either by direct electrophilic fluorination of electron-rich aromatic rings (Scheme 3a) [6] or by reacting regioselectively lithiated aromatic rings with an electrophilic fluorinating reagent (Scheme 3b) [7]. The most advanced frontier of the aryl fluorination involves transition metal catalysis which has palladium and copper as the elective transition metals to perform aromatic fluorination in very good yields and regioselectivity (Scheme 4) [7e,8]. Research in the field of fluoroaromatics compounds was not limited to simple arenes, instead, it was also extended to the development of an impressive number of methods for the selective Journal of Fluorine Chemistry xxx (2013) xxx–xxx * Corresponding author. Tel.: +39 075 5855543; fax: +39 075 5855262. E-mail address: ruzzchor@unipg.it (R. Ruzziconi). A R T I C L E I N F O Article history: Received 18 January 2013 Received in revised form 30 April 2013 Accepted 4 May 2013 Available online xxx Keywords: Fluoroaromatic compounds Fluorinated naphthalenes Phenanthrenes Quinolones Quinolines isoquinolines A B S T R A C T A survey of some recent synthetic approaches to regioselectively fluorinated six member condensed homo- and heteropolycyclic aromatic compounds by complementary cyclization methods is reported. ß 2013 Elsevier B.V. All rights reserved. G Model FLUOR-8101; No. of Pages 17 Please cite this article in press as: R. Ruzziconi, F. Buonerba, J. Fluorine Chem. (2013), http://dx.doi.org/10.1016/j.jfluchem.2013.05.001 Contents lists available at SciVerse ScienceDirect Journal of Fluorine Chemistry jo ur n al h o mep ag e: www .elsevier .c om /loc ate/f luo r 0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jfluchem.2013.05.001