Synthesis of 2,3,5,6-tetrafluoro-pyridine derivatives from reaction of pentafluoropyridine with malononitrile, piperazine and tetrazole-5-thiol

Some pentafluoropyridine derivatives have been synthesized by the reaction of pentafluoropyridine with appropriate C, S and N-nucleophile such as malononitrile, 1-methyl-tetrazole-5-thiol and piperazine. These reactions provided 4-substituted 2,3,5,6-tetrafluoropyridine derivatives in good yields. All the compounds were characterized using 1H, 13C and 19F-NMR spectroscopy and X-ray crystallography.


Background
Pentafluoropyridine and related compounds in which all the hydrogen atom in heterocyclic ring have been replaced by fluorine atoms were synthesized by reaction of potassium fluoride with perchloro heteroaromatic (Ojima 2009). In pharmacology, it is common to substitute hydrogen with fluorine atoms for increases the lipophilicity and biological activity of the compounds (Chambers et al. 2008a, b). Pentafluoropyridine one of the most important perfluoroheteroaromatic compounds have been used for the synthesis of various drug-like systems (Gutov et al. 2010). These systems are highly active towards nucleophilic additions owing to the presence of electronegative fluorine atoms and the presence of the nitrogen heteroatom so all five fluorine atoms in pentafluoropyridine may be substituted by an appropriate nucleophile (Cartwright et al. 2010;Chambers et al. 2005). A nucleophilic substitution reaction of pentafluoropyridine occurs in two-step addition-elimination mechanism, so install nucleophile addition and in the end elimination flour ring nitrogen (Colgin et al. 2012). The site reactivity order of pentafluoropyridine is well known that, the order of activation toward nucleophilic attack follows these quence 4 (Para)-fluorine > 2 (Ortho)fluorine > 3 (Meta)-fluorine so the reactions of pentafluoropyridine with some nucleophilic occur selectively at the Para position as this site is most activated towards nucleophilic additions to afforded of 4-substited tetrafluoropyridine (Chambers et al. 2008a, b).
In basic condition, malononitrile 2a deprotonate and carbon nucleophile of malononitrile attack to Para position of pentafluoropyridine 1 and elimination of 4-fluor ring pyridine to give 5a. In 5a, hydrogen malononitrile very acidy so essay deprotonate in base solution to give potassium dicyano (perfluoropyridin-4-yl) methanide 6a (Fig. 2). Purification of 6a was achieved by recrystallization in ethanol/acetonitrile. In crystal 6a, two molecule chelate by potassium ion between flour and nitrogen. Identification of chelate 6a was done by F-NMR analysis, in which the resonance attributed to fluorines located Ortho to ring nitrogen has a chemical shift of -83.5 ppm and -84.4 ppm. The corresponding resonance for fluorines located Meta to ring nitrogen in chelate 6a occurred at −135.4 and −139.4 ppm. Four resonances by 19 F-NMR indicate displacement of fluorine atoms attached to the Para position of two pyridine ring. The 1 H-NMR spectra of compound 6a consisted of a H broad signal at δ = 7.29 ppm for CH malononitrile. X-ray crystallography confirmed the structure of chelate 6a (Figs. 3,4). A summary of the crystal data, experimental details and refinement results for 6a is given in Table 1.
Also, we examined the reaction of pentafluoropyridine 1 with piperazine 2c in the presence of sodium carbonate in CH 3 CN solvent gave 1,4-bis(perfluoropyridin-4-yl)piperazine 3c (Fig. 9). In basic condition, two nitrogen of the piperazine deprotonation and attack to Para position of pentafluoropyridine and elimination of 4-fluor pyridine ring to give 3e   (Fig. 10). Purification of 3c was achieved by recrystallization in acetonitrile. The structure of compounds 3c was confirmed by X-ray crystallography and by NMR spectroscopic data. In particular, 19 F-NMR spectroscopy shows the chemical shift of fluorine atoms attached to the Ortho and Meta position are observed respectively at −97.3 and −160.5 ppm. In 1 H-NMR, the protons of CH 2 piperazine, was observed at δ = 4.3 ppm. The 13 C-NMR spectrum of compound 3c showed 4 distinct resonances in agreement with the proposed structure. The structure of 3c was confirmed by X-ray crystallography (Figs. 11,12).

Conclusion
In conclusion, we showed that pentafluoropyridine can successfully react with a variety of nucleophiles to afford of 4-substited tetrafluoropyridine. The regioselectivity of nucleophilic substitution in this process may be explained by high nucleophilicity of sulfur, nitrogen or oxygen and activating influence of pyridine ring nitrogen that significantly activate the Para and Ortho sites to itself.

Experimental
All materials and solvents were purchased from Merck and Aldrich and were used without any additional purification. The melting points of the products were determined in open capillary tubes using BAMSTEAB Electrothermal apparatus model 9002. The 1H NMR spectra were recorded at 300 MHz. The 13 C-NMR spectra were recorded at 75 MHz. The 19 F-NMR spectra were recorded at 282 MHz. In the 19 F-NMR spectra, up field shifts were quoted as negative and referenced to CFCl 3 . Mass spectra were taken by a Micro mass Platform II: EI mode (70 eV). Silica plates (Merck) were used for TLC analysis.