Reaction of hydroxyl-quinoline with pentafluoropyridin

Abstract

Reaction of pentafluoropyridine with 2 or 8-hydroxyl-quinoline under basic conditions in acetonitrile gives 4-oxy quinoline 2,3,5,6-tetrafluoropyridine derivatives in good yields. All the compounds were characterized using ¹H, ¹³C, ¹⁹F-NMR and MS spectroscopy.

Background

The unique properties of fluorine atom make organofluorine compounds find many different applications, ranging from pharmaceuticals and agrochemicals to advanced materials and polymers. Circa 20 % of pharmaceuticals contain a fluorine atom (Hunter 2010; Champagne et al. 2015). The fluorinated groups in these systems lead to remarkable changes in their physical properties, chemical reactivity, and physiological activity (Iwao 2009). Pentafluoropyridine, as one of the simplest members of electron-deficient species of perfluoroheteroaromatic compounds, has been investigated into since the early 1960s (Fox et al. 2013). The most important reaction of pentafluoropyridines involves the replacement of the para-fluorine atom by nucleophilic reagents for the synthesis of new organofluorine compounds, such as heterocyclic and macrocyclic perfluoro systems (Cartwright et al. 2010; Chambers et al. 2005; Ranjbar-Karimi et al. 2015). In this paper, we have recently reported the reaction of pentafluoropyridine with hydroxyl-quinoline. This allows the synthesis of a wide range of 4-substituted 2,3,5,6-tetrafluoropyridine (Additional file 1).

Results and discussion

In this short report, we describe nucleophilic substitution of pentafluoropyridine with 2 or 8-hydroxyl-quinoline and how the resulting products of 4-quinoline-perfluoropyridine derivatives. Reaction of pentafluoropyridine 1 with 2-hydroxyl quinoline 2 under basic conditions (NaHCO₃) in acetonitrile at reflux temperature gave a single product of 2-(perfluoropyridin-4-yloxy)quinoline 2a (Fig. 1). In 2-hydroxyl quinoline 2, the hydroxyl group deprotonate by base and attacks at the most active para position of pentafluoropyridine to give 2a.

Fig. 1

Reaction of pentafluoropyridine with 2-hydroxyl quinoline

The structures of 2a were characterized by ¹⁹F, ¹H, ¹³C NMR and mass spectra. In ¹⁹F NMR spectroscopy of 2a observed two peaks for fluorine’s, a peak is observed as multiple at δ = −86.4 for fluorine atom located in the ortho position towards the ring nitrogen and also, a multiple is remarked at up field δ = −154.8 for fluorine atom located in the meta position towards the ring nitrogen.

The two resonances by ¹⁹F NMR and their chemical shift of them indicate that displacement of fluorine atoms attached to the para position of pyridine ring. In the ¹H NMR spectrum of compound 2a, the aromatic proton resonances were observed as doublets at δ = 7.01–8.01 ppm. Other spectroscopic techniques were consistent with the structures proposed. The mass spectrum of 2a compound displayed molecular ion peaks at peak (M-1) at m/z = 293, and any initial fragmentation involved the loss of the other molecules which is consistent with the proposed structure.

Also, we examined the reaction of pentafluoropyridine 1 with 8-hydroxyl quinoline 3 in the presence of sodium hydrogen carbonate in CH₃CN as a solvent gave 8-(perfluoropyridin-4-yloxy) quinoline 3a (Fig. 2). In basic condition, hydroxyl group of the quinoline deprotonation and attack to Para position of pentafluoropyridine and elimination of 4-fluor pyridine ring to give 3a. The purification of 3a was achieved by column chromatography using ethyl acetate/n-hexane (1:8).

Fig. 2

Reaction of pentafluoropyridine with 8-hydroxyl quinoline

8-(perfluoropyridin-4-yloxy) quinoline 3a was characterized by ¹⁹F NMR, in which the resonance attributed to the fluorine located in the ortho position towards the ring nitrogen has a chemical shift of −65.7 ppm and the fluorine resonance located in meta position occurs at −139.1 ppm. In ¹H NMR of 3a, the spectra protons of the aryl ring were observed at 6.8–7.9 ppm. The mass spectrum of 3a displayed the molecular ion peak (M⁺) at m/z = 294, which is consistent with the proposed structure. Other spectroscopic techniques were consistent with the structures proposed.

Conclusion

In conclusion, we showed that hydroxyl group in quinoline can react with pentafluoropyridine to afford of 2,3,5,6-tetrafluoropyridine quinoline characterized spectroscopically.

Experimental

All materials and solvents were purchased from Merck and Aldrich and were used without any additional purification. Mass spectra were taken by a Micro mass Platform II: EI mode (70 eV). Silica plates (Merck) were used for TLC analysis.

Typical procedure for preparation of 4-oxy quinoline 2,3,5,6-tetrafluoropyridine

Pentafluoropyridine (0.17 g, 1 mmol), hydroxyl-quinoline (0.16 g, 1 mmol) and sodium hydrogen carbonate (0.08 g, 1.0 mmol) were stirred together in CH₃CN (5 mL) at reflux temperature for 4 h. After completion of the reaction (indicated by TLC), reaction mixture was evaporated to dryness and water (10 mL) was added and extracted with dichloromethane (2 × 10 mL) and ethylacetate (2 × 10 mL). The mixture was filtered, volatiles evaporated and the residue purified by column chromatography on silica gel using ethyl acetate/n-hexane (1:8).

2-(perfluoropyridin-4-yloxy)quinoline 2a (0.2 g, 77 %) as yellow solid; mp 195 °C; ¹H NMR (DMSO): δ (ppm) 7.01–8.01 (6H, m, Ar–H). ¹⁹F NMR (CDCl₃): δ (ppm) −86.4 (2F, m, F-2,6), −154.8 (2F, m, F-3,5).¹³C NMR (CDCl₃): δ (ppm) 110.9, 112.6, 113.3, 122.3, 123.3, 128.7, 130.8, 148.2, 156.0, 161.1, 163.9, 165.1 MS (EI), m/z (%) = 293 (M⁺−1) 275, 253, 235, 213, 147, 83, 43.

8-(perfluoropyridin-4-yloxy) quinoline 3a (0.23 g, 80 %) as brown solid; mp 180 °C; ¹H NMR (DMSO): δ (ppm) 6.84–7.92 (6H, m, Ar–H). ¹⁹F NMR (CDCl₃): δ (ppm) −65.7 (2F, m, F−2,6), −139.1 (2F, m, F−3,5). ¹³C NMR (DMSO): δ (ppm) 110.9, 112.6, 113.3, 122.3, 123.3, 128.7, 130.8, 131.3, 148.2, 150.0, 161.1, 163.9, 165.1 MS (EI), m/z (%) = 294 (M⁺) 282, 275, 246, 227, 167, 122, 101, 85, 58, 43.