Synthesis of 2,3,5,6-tetrafluoro-pyridine derivatives from reaction of pentafluoropyridine with malononitrile, piperazine and tetrazole-5-thiol
© Beyki et al. 2015
Received: 8 September 2015
Accepted: 2 November 2015
Published: 4 December 2015
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.
KeywordsPentafluoropyridine Heterocycle Nucleophilic Substitution Synthesis 19F-NMR
Pentafluoropyridine and related compounds in which all the hydrogen atom in heterocyclic ring have been replaced by fluorine atoms were synthesized by reaction of potassium fluoride with perchloro heteroaromatic (Ojima 2009).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).
Results and discussion
Crystal data for 6a, 5b and 3c
C8 F4 K N3
C9 H8 F3 N5 O S
C14 H8 F8 N4
P b c a
Unit cell dimensions (Å)
a = 11.882 (2)
b = 18.857 (4)
c = 7.7561 (15)
α = 90
β = 108.369 (3)
γ = 90
a = 9.0254 (9)
b = 7.5269 (8)
c = 17.9941 (19)
α = 90
β = 99.1260 (10)
γ = 90
a = 8.8425 (5)
b = 11.0779 (4)
c = 14.5459 (7)
α = 90
β = 90
γ = 90
Density (calculated) g cm−1
0.469 × 0.196 × 0.165
0.309 × 0.240 × 0.151
Θ range for data
−17 < h < 17
−28 < k < 28
−11 < l < 11
−12 < h < 12
−10 < k < 10
−25 < l < 25
−11 < h < 11
−14 < k < 13
−19 < l < 18
Absorption coefficient mm−1
Final R 1 a . wR 2 b (Obs. data)
Final R 1 a , wR 2 b (all data)
Goodness of fit on F 2 (S)
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.
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 13C-NMR spectra were recorded at 75 MHz. The 19F-NMR spectra were recorded at 282 MHz. In the 19F-NMR spectra, up field shifts were quoted as negative and referenced to CFCl3. Mass spectra were taken by a Micro mass Platform II: EI mode (70 eV). Silica plates (Merck) were used for TLC analysis.
Preparation of 2-(perfluoropyridin-4-yl)malononitrile 6a
Pentafluoropyridine 1 (0.1 g, 0.6 mmol), malononitrile 2a (0.04 g, 0.6 mmol) and potassium carbonate (0.11 g, 1.0 mmol) were stirred together in DMF (5 mL) at reflux temperature for 3 h. The reaction mixture was evaporated to dryness than the solid product was recrystallisation from acetonitrile to give 2-(perfluoropyridin-4-yl)malononitrile (0.22 g, 86 %) as a red crystals; mp 260 °C dec, 19F NMR (acetone): 1H NMR (acetone): δ (ppm) 7.79 (s, 1H, CH); δ (ppm) −83.5 (m, 2F, F-2,6), −84.4 (m, 2F, F-2′,6′), −135.4 (m, 2F, F-3,5), −139.4 (m, 2F, F-3′,5′). MS (EI), m/z (%) = 508 (M+), 440, 364, 291, 180, 147, 121, 105, 91, 77, 57, 43.
Preparation of 2-ethoxy-3,5,6-trifluoro-4-((1-methyl-1H-tetrazol-5-yl)thio)pyridine 5b
Pentafluoropyridine 1 (0.1 g, 0.6 mmol), 1-methyl-1H-tetrazole-5-thiol 2b (0.09 g, 0.6 mmol) and sodium hydrogencarbonate (0.11 g, 1.0 mmol) were stirred together in CH3CN (5 mL) at reflux temperature for 4 h (monitored by TLC). The solvent was evaporated; water (5 mL) was added and extracted with dichloromethane and ethyl acetate (3 × 5 mL). Solvent evaporation and recrystallisation from ethanol gave 2-ethoxy-3,5,6-trifluoro-4-((1-methyl-1H-tetrazol-5-yl)thio)pyridine 5b (0.2 g, 75 %) as a white crystal; mp 130 °C dec. 1H NMR (acetone): δ (ppm) 1.37 (3H, m, CH3), 3.90 (3H, s, N-CH3), 4.3 (2H, m, CH2); 19F NMR (acetone): δ (ppm) −88.6 (1F, m, F-2), −131.4 (1F, m, F-3), −154.8 (1F, m, F-5); 13C NMR (acetone): δ (ppm) 14.6, 35.5, 63.2, 64.4, 139.2, 140.5, 142.6, 143.7, 145.9 ppm. MS (EI), m/z (%) = 292 (M+), 263, 235, 219, 180, 132, 100, 83, 43.
Preparation of 1,4-bis(perfluoropyridin-4-yl)piperazine 3c
Pentafluoropyridine 1 (0.1 g, 0.6 mmol), piperazine 2c (0.03 g, 0.5 mmol) and sodium hydrogencarbonate (0.11 g, 1.0 mmol) were stirred together in CH3CN (5 mL) at reflux temperature for 5 h. After complicated reaction, the solvent was evaporated; water (5 mL) was added and extracted with dichloromethane and ethyl acetate (3 × 5 mL). Solvent evaporation and recrystallization from CH3CN gave 1,4-bis(perfluoropyridin-4-yl)piperazine 3c (0.2 g, 52 %) as a white crystal; mp 288 °C dec. 1H NMR (acetone): δ (ppm) 4.30 (8H, s, CH2); 19F NMR (acetone): δ (ppm) −97.3 (4F, m, F-2,6), −160.5 (4F, m, F-3,5). 13C-NMR (acetone): δ (ppm) 60.3, 123.7, 127.1, 131.3 ppm. MS (EI), m/z (%) = 384 (M+), 317, 292, 263, 235, 219, 180, 152, 132, 116, 100, 83, 63, 43.
KB, RH and MTM were involved in the study design and manuscript preparation, data collection, data analysis and revisions. All authors read and approved the final manuscript.
The authors wish to thank Evan Sarina from University of California for the partial support of this work.
None declared under financial, general, and institutional competing interests. I wish to disclose a competing interest(s) such as those defined above or others that may be perceived to influence the results and discussion reported in this paper.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Cartwright MW, Parks EL, Pattison G, Slater R, Sandford G, Wilson I, Yufit DS, Howard JAK, Christopher JA, Miller DD (2010) Tetrahedron 66:3222–3227View ArticleGoogle Scholar
- Chambers RD, Khalil A, Murray CB, Sandford G, Batsanov AS, Howard JAK (2005) J Fluor Chem 126:1002–1008View ArticleGoogle Scholar
- Chambers RD, Martin PA, Sandford G, Williams DLH (2008a) J Fluor Chem 129:998–1002View ArticleGoogle Scholar
- Chambers RD, Martin PA, Sandford G, Williams DLH (2008b) J Fluor Chem 129:998–1004View ArticleGoogle Scholar
- Colgin N, Tatum NJ, Pohl E, Cobb S, Sandford G (2012) J Fluor Chem 133:33–37View ArticleGoogle Scholar
- Gutov AV, Rusanov EB, Ryabitskii AB, Chernega AN (2010) J Fluor Chem 131:278–281View ArticleGoogle Scholar
- Ojima I (2009) Fluorine in medicinal chemistry and chemical biology. Blackwell, LondonView ArticleGoogle Scholar