Synthesis of ferrocenyl pyrazoles by the reaction of (2-formyl-1-chlorovinyl)ferrocene with hydrazines Metin Zora * , Meral Go ¨ rmen Department of Chemistry, Faculty of Arts and Sciences, Middle East Technical University, 06531 Ankara, Turkey Received 23 June 2007; accepted 21 July 2007 Available online 27 July 2007 Abstract Synthesis of ferrocenyl-substituted pyrazoles via the reaction between (2-formyl-1-chlorovinyl)ferrocene and hydrazine derivatives is described. Depending upon the substitution pattern of hydrazine, the reaction affords 1-alkyl/aryl-5-ferrocenylpyrazoles and/or 1-alkyl/ aryl-3-ferrocenylpyrazoles. The reaction appears to be general for a variety of hydrazine derivatives. Ó 2007 Elsevier B.V. All rights reserved. Keywords: Ferrocene; Ferrocenyl; Pyrazole; Hydrazine; Hydrazinium salt; Hydrazide; Propenal; Density functional theory; B3LYP 1. Introduction Pyrazoles have occupied a unique position in the design and synthesis of novel biologically active agents that exert remarkable anticancer activities [1]. In fact, pyrazoles have been studied for over a century as an important class of heterocyclic compounds and still continue to attract con- siderable attention due to the broad range of biological activities they possess, including analgesic, antimicrobial, antiviral, anti-inflammatory, hypoglycemix, anti-hyperten- sive and antitumor properties [1,2]. Recent studies have shown that the integration of a ferrocenyl group into such structures may enhance their biological activities or gener- ate new medicinal properties [3,4]. Due to its unique structure, different membrane-permeation properties and anomalous metabolism, ferrocene is often incorporated into a compound in order to obtain unexpected or enhanced biological activities [3,4]. Thus, in recent years, considerable effort has been devoted to the synthesis of new ferrocene derivatives since the properly functionalized derivatives could be potential antitumor substances [5,6]. Although pyrazoles are among the most thoroughly stud- ied compounds [7], we were surprised that there has been very limited study of the ferrocenyl-substituted pyrazoles [8]. In this regard, as shown by Terent’ev and co-workers [9], the reaction between (2-formyl-1-chlorovinyl)ferrocene (1) and hydrazines (2) represents a rapid entry into ferroce- nyl pyrazoles (3)(Scheme 1), but this reaction was not studied in much detail and the low yields of ferrocenyl pyr- azoles 3 were obtained. As part of a program to synthesize new ferrocenyl-substituted heterocyclic compounds as potential pharmaceuticals, we have reinvestigated this reac- tion and improved the yields [10]. We herein report the results of this study. 2. Results and discussion 2.1. Synthesis of starting materials (2-Formyl-1-chlorovinyl)ferrocene (3-chloro-3-ferroce- nylpropenal) (1) was synthesized from acetylferrocene according to the well-known literature procedure [11], in which treatment of acetylferrocene with phosphorous oxy- chloride in DMF led to formation of (2-formyl-1-chlorovi- nyl)ferrocene (1). Acetylferrocene is readily available in large quantities from ferrocene according to a standard 0022-328X/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jorganchem.2007.07.029 * Corresponding author. Tel.: +90 312 2103213; fax: +90 312 2103200. E-mail address: zora@metu.edu.tr (M. Zora). www.elsevier.com/locate/jorganchem Journal of Organometallic Chemistry 692 (2007) 5026–5032