Synthesis of novel ferrocenyl-containing pyrazolo[4,3-c]quinolines Günseli Turgut Cin * , Seda Demirel, Abban Cakici Department of Chemistry, Faculty of Art and Sciences, Akdeniz University, Antalya, Turkey article info Article history: Received 7 June 2010 Received in revised form 27 September 2010 Accepted 1 October 2010 Available online 14 October 2010 Keywords: Ferrocene Pyrazolo[4,3-c]quinoline Pyrazole Quinoline PicteteSpengler reaction Cyclization abstract Synthesis of novel ferrocenyl-substituted pyrazolo[4,3-c]quinolines via the PicteteSpengler reaction is reported. Iminium intermediate formed by the condensation of pyrazole-based arylamine substrates with ferrocenecarboxaldehyde in acidic medium, undergoes 6-endo cyclization with sufficiently reactive aromatic moiety to form a pyrazolo[4,3-c]quinoline ring. Ó 2010 Elsevier B.V. All rights reserved. 1. Introduction Pyrazolo[4,3-c]quinolines and their derivatives are known as high-affinity benzodiazepine receptor ligands [1],A 3 adenosine receptor antagonists [1], interleukin 1 [2], acetylcholinesterase [2], NMDA receptor [3] and phosphodiesterase 4 (PDE4) inhibitors [3], anti-cancer [4], anti-inflammatory [2,5] and anti-ulcer [6] agents. Therefore, novel substituted pyrazolo[4,3-c]quinolines represent attractive synthetic targets. On the other hand, metallocenes are also known to exhibit a wide range of biological activity. Among them, ferrocene has become a useful organometallic compound in the field of pharmaceutical sciences due to its unique structure, different membrane-perme- ation properties and anomalous metabolism [7,8]. Many ferrocenyl compounds display interesting cytotoxic, anti-tumor, anti-malarial, antifungal and DNA-cleaving activities [9]. Recent studies have suggested that combination of a ferrocenyl moiety with heterocyclic structures may increase their biological activities or create new medicinal properties [7,8,10]. For example, structural variations of established drugs with the ferrocenyl moiety were reported, such as anti-malarial drugs chloroquine (termed ferroquine) [7c,11], quinine, mefloquine, and artemisinin and the anti-cancer drug tamixofen to give ferrocifen [8c,12]. The synthesis of such ferrocene-derived compounds allows the opening up of a potential area of research in designing and synthesizing multifunctional drugs. Although pyrazolo[4,3-c]quinolines are among intensely studied compounds [1e6,13], surprisingly, ferrocenyl-containing pyrazolo[4,3-c]quinolines have not been encountered in the liter- ature. Therefore, we envisioned the synthesis of novel ferrocenyl- containing pyrazolo[4,3-c]quinoline derivatives that may have significant biological activities. Numerous methods have been developed for the synthesis of substituted pyrazolo[4,3-c]quino- lines. In these methods, the pyrazole moiety is typically built up at a later stage of the sequence making the synthetic route lengthy and non-flexible. For instance, condensation of ethyl 4-chloro- quinoline-3-carboxylates [1a,13b], 2,3-dihydro-1H-quinolin-4- ones [4a] or o-chloro-derivatives of cyano quinolines [5c,d] with various arylhydrazines affords pyrazolo[4,3-c]quinoline ring systems. In contrast to these methods, Kundu et al. [14] described a modified PicteteSpengler reaction which involves the generation of quinoline ring onto the pyrazole to form pyrazolo[4,3-c]quino- lines. In general, a typical PicteteSpengler reaction is based on the condensation of an aldehyde with an aliphatic amine to form an iminium intermediate which undergoes 6-endo cyclization with sufficiently reactive aromatic moiety to form an N-heterocyclic ring in acidic medium [15]. Kundu and his coworkers [14] modified the general procedure of PicteteSpengler reaction by using designed aromatic amines having an activated heterocyclic ring instead of traditional aliphatic amines. They reported that the iminium ion derived from the arylamine is more electrophilic than the aliphatic * Corresponding author. Tel.: þ90 242 3102306; fax: þ90 242 2278911. E-mail addresses: gturgut@akdeniz.edu.tr (G.T. Cin), sedademirel@akdeniz.edu. tr (S. Demirel), abban@akdeniz.edu.tr (A. Cakici). Contents lists available at ScienceDirect Journal of Organometallic Chemistry journal homepage: www.elsevier.com/locate/jorganchem 0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jorganchem.2010.10.006 Journal of Organometallic Chemistry 696 (2011) 613e621