Synthesis of 2-tetrafluoropyridyl-4,5-disubstituted 1,2,3-triazoles

Abstract 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. Graphical Abstract


Background
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Pentafluoropyridine in which all the hydrogen atoms in pyridine ring have been replaced by fluorine atoms are highly susceptible towards nucleophilic attack owing to the presence of several highly electronegative fluorine atoms and nitrogen hetero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).
In 19 F NMR analyze of 2a exhibited two peaks for fluorine's, a peak is observed at down field of doublet of doublet at δ = −89.54 (J = 24, 28 Hz) for F-2,6 (ortho positions) and also, a doublet of doublet is remarked at up field −144.83 (J = 20, 8 Hz) for F-3,5 (meta positions). A part of the 19 F NMR spectrum of 2a is shown in Fig. 3. 19 F NMR analysis of 2a confirmed that the nucleophilic substitution had occurred at the 4-position of pyridine ring. The mass spectrum of 2a displayed molecular ion peak (M + ) at m/z = 399, which is consistent with the proposed structure. Other ion peak are shown in mass spectra of 2a (Fig. 4).
The structure of compounds 2b was confirmed by NMR spectroscopic data. In particular, 19 F-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 1 H NMR spectra of compound 2b showed an H broad signal at 4.5 ppm for OCH 3 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.   Fig. 2 The mechanism for the formation of 2-tetrafluoropyridyl-4,5-disubstituted 1,2,3-triazoles

Experimental
All reagents and solvents were purchased from Aldrich and Merck were used without further purification. The 1 H and 13 C NMR spectra were obtained on Bruker with DMSO as a solvent ( 1 H NMR at 300 MHz and 13 C NMR at 75 MHz). In the 19 F-NMR spectra (282 MHz), 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).

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.