Synthesis of 2-tetrafluoropyridyl-4,5-disubstituted 1,2,3-triazoles
© The Author(s) 2016
Received: 3 June 2016
Accepted: 27 September 2016
Published: 11 November 2016
By cycloaddition reaction of sodium azide with chalcone in the presence of CuO as a catalyst in DMF a 1,2,3-triazole are prepared in reaction with pentafluoropyridine to give 2-(tetrafluoropyridin-4-yl)-1,2,3-triazole derivatives in good yields and high regioselectivity. The regioselectivity of the compounds are confirmed by 19F-NMR and other spectroscopy.
KeywordsPentafluoropyridine Chalcone 1,2,3-Triazoles CuO 19F-NMR
Recently, perfluorocarbons have been used as building blocks in the pharmaceutical industry and in material science due to their unique properties (Kenneth 2006; Bruce 2001). In pharmacology and medicinal researches, it is common to substitute hydrogen with fluorine atom for increasing the physiochemical (e.g. solubility, stability) and biological activity (e.g. absorption, distribution, metabolism, elimination and toxicity) of drugs (Iwao 2009).
Pentafluoropyridine in which all the hydrogen atoms in pyridine ring have been replaced by fluorine atoms are highly susceptible towards nucleophilic attack owing to the presence of several highly electronegative fluorine atoms and nitrogen hetero atom; consequently, the chemistry of pentafluoropyridine is dominated by nucleophilic aromatic substitution processes and new chemistry continues to emerge (Iwao 2009; Reza et al. 2008; Mark et al. 2013; Van Ba and Donald 2012). The order of nucleophilic attack for pentafluoropyridine is established to be para > ortho > meta positions, so the reactions of pentafluoropyridine with some nucleophile occur selectively at the para position as this site is most activated towards nucleophilic additions to afford of 4-substited tetrafluoropyridine (Hadjar et al. 2001; Matthew et al. 2010; Jingjing et al. 2014).
Earlier, we reported the synthesis of 4-substituted-2,3,5,6-tetrafluoropyridine derivatives by the reaction of pentafluoropyridine with malononitrile, 1-tetrazole-5-thiol, piperazine (Khalil et al. 2015), hydroxylated naphtoquinones and hydroxylated antraquinones (Khalil et al. 2016).
Results and discussion
In this research, we describe the synthesis of 2-tetrafluoropyridyl-4,5-disubstituted-1,2,3-triazoles via Diels–Alder cycloaddition reaction of sodium azide and 1,3-diphenylprop-2-en-1-one (chalcone) and then nucleophilic substitution reactions with pentafluoropyridine in DMF as solvent.
Purification of 2a was achieved by column chromatography using ethyl acetate/n-hexane (2:10). The melting point, 19F, 1H, 13C NMR and mass spectra of the obtained product clearly indicated the formation of (2-(perfluoropyridin-4-yl)-5-phenyl-2H-1,2,3-triazol-4-yl)(phenyl)methanone 2a. For example, in the 1H NMR spectrum of compound 2a, the aromatic proton resonances were observed as multiplets at δ = 7.60–8.61 ppm. The 13C NMR spectrum of compound 2a showed 20 distinct resonances consistent with the recommended structure.
The structure of compounds 2b was confirmed by NMR spectroscopic data. In particular, 19F-NMR spectroscopy show the chemical shift of fluorine atoms attached to the ortho and meta position are observed respectively at −95 and −153 ppm. The 1H NMR spectra of compound 2b showed an H broad signal at 4.5 ppm for OCH3 group, and the protons of the phenyl ring were observed at δ = 7.6–8.6 ppm. The mass spectrum of 2b displayed the molecular ion peak (M − 1) at m/z = 427, which is consistent with the proposed structure.
All reagents and solvents were purchased from Aldrich and Merck were used without further purification. The 1H and 13C NMR spectra were obtained on Bruker with DMSO as a solvent (1H NMR at 300 MHz and 13C NMR at 75 MHz). In the 19F-NMR spectra (282 MHz), 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).
General procedure for the preparation of 2-(tetrafluoropyridin-4-yl)-1,2,3-triazole
A mixture of chalcone (1 mmol), sodium azide (1 mmol) and CuO (2.5 mol%) were stirred in DMF (3 mL) for 20 h at 100 °C. After completion of the reaction as indicated by TLC pentafluoropyridine (1 mmol) was added to the mixture and the reaction continued at 100 °C for 5 h. Following, to the reaction mixture was added water 4 mL, and extracted with ethyl acetate and dichloromethane (3 × 5 mL). The solvent was removed in vacuo, and the crude product was purified by column chromatography using ethyl acetate/n-hexane (2/10) to give the pure product.
(0.24 g, 65 %) as brown solid; mp 240–245 °C decompose. 1H NMR (DMSO): δ (ppm) 7.96–8.41 (10H, m, Ar–H); 19F NMR (DMSO): δ (ppm) −89.5 (2F, m, JFF 23, F-2,6), −144.8 (2F, m, JFF 20, F-3,5); 13C NMR (DMSO): δ (ppm) 126.81, 126.96, 127.40, 128.14, 128.18, 128.24, 128.29, 128.66, 128.74, 128.86, 128.92, 129.23, 129.44, 129.52, 129.77, 129.86, 170.31 ppm. MS (EI), m/z (%) = 415 [M+NH3]+, 399 (M), 384, 360, 343, 316, 286, 268, 248, 220, 199, 169, 141, 119, 101, 86, 58, 42.
(0.20 g, 60 %) as a yellow solid; mp 265–270 °C decompose. 1H NMR (DMSO): δ (ppm) 4.5 (3H, OCH3) 7.60–8.61 (10H, m, Ar–H); 19F NMR (DMSO): δ (ppm) −95.0 (2F, m, F-2,6), −153.0 (2F, m, F-3,5); 13C NMR (DMSO): δ (ppm) 114.29, 115.54, 121.54, 122.94, 123.23, 127.82, 130.35, 130.85, 140.85, 141.22, 157.44 ppm. MS (EI), m/z (%) = 427 [M−1], 321, 282, 165, 91.
Diels–Alder cycloaddition reaction of chalcone with azide in the presence of CuO as catalyst gives 4,5-disubstituted 1,2,3-triazoles, in reaction with pentafluoropyridine give 4,5-disubstituted-2 tetrafluoropyridyl-1,2,3-triazoles.
Acquisition of data: from articles and books: Analysis and interpretation of data: by RH and KB. Drafting of manuscript: KB. Critical revision: MTM. All authors read and approved the final manuscript.
The authors gratefully acknowledge partial support of this work by the Research Affairs Office of Sistan and Balouchestan University.
The authors declare that they have no competing interests.
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