Synthesis, Crystal Structure and Antifungal Activity of 2-((2-Fluorobenzyl)thio)-5-(pyridin-4-yl)-1,3,4-oxadiazole

Guo-Xiang SUN Yan-Xia SHI Zhi-Wen ZHAI Zhao-Hui SUN Jian-Quan WENG Cheng-Xia TAN Xing-Hai LIU Bao-Ju LI

Citation:  SUN Guo-Xiang, SHI Yan-Xia, ZHAI Zhi-Wen, SUN Zhao-Hui, WENG Jian-Quan, TAN Cheng-Xia, LIU Xing-Hai, LI Bao-Ju. Synthesis, Crystal Structure and Antifungal Activity of 2-((2-Fluorobenzyl)thio)-5-(pyridin-4-yl)-1,3,4-oxadiazole[J]. Chinese Journal of Structural Chemistry, 2016, 35(12): 1855-1859. doi: 10.14102/j.cnki.0254-5861.2011-1352 shu

Synthesis, Crystal Structure and Antifungal Activity of 2-((2-Fluorobenzyl)thio)-5-(pyridin-4-yl)-1,3,4-oxadiazole

English

  • In recent years, heterocycles have received significant attention due to their biological importance[1-3], especially 1, 3, 4-oxadiazole ring. The 1, 3, 4-oxadiazole derivatives often exhibit diversity biological activities including antifungal[4], antiviral[5], antimicrobial[6] and anti-cancer activity[7]. Also, pyridines displayed outstanding activity, such as antifungal[8-13], antimycobacterial[14], anti-alzheimer's disease[15], herbicidal[16, 17], and nematicidal activity[18, 19].

    In view of these facts mentioned above, and also as a part of our work[20-23] on the synthesis of bioactive lead compounds for drug discover, the title compounds were designed by introducing pyridine pharmacophore into 1, 3, 4-oxadiazole scaffold. A new 1, 3, 4-oxadiazole derivative was synthesized and characterized by 1H NMR, MS and elemental analysis. The single-crystal structure of the title compound was determined by X-ray diffraction. The antifungal activity of the title compound was tested.

    Melting points were determined using an X-4 apparatus and uncorrected. 1H NMR spectra were measured on a Bruker AV-400 instrument using TMS as an internal standard and CDCl3 as the solvent. Mass spectra were determined on a Thermo Finnigan LCQ Advantage LC/mass detector instrument. Elemental analyses were performed on a Vario EL elemental analyzer. Crystallographic data of the compound were collected on a Bruker APEX-II CCD diffractometer. All the reagents were of analytical grade or freshly prepared before use.

    The intermediates 1 and 2 were synthesized according to our previous work[4]. A CEM designed 10 mL pressure-rated vial was charged with DMF (5 mL), 2 (0.25 g, 1 mmol), 1-(chloromethyl)-2- fluorobenzene (1.1 mmol), and NaOH (0.05 g, 1.2 mmol). The mixture was irradiated in a CEM Discover Focused Synthesizer (150 w, 90 ℃, 200 psi, 15 min). The mixture was cooled to room temperature by passing compressed air through the microwave cavity for 2 min. It was poured into cold ice (40 mL) and the formed precipitate was filtered. The crude solid was recrystallized from EtOH to give 2-((2-fluorobenzyl) thio)-5-(pyridin-4-yl)- 1, 3, 4-oxadiazole, white crystal, yield 84%, m.p.: 119~122 ℃. 1H NMR (CDCl3, 400MHz), δ: 4.51(s, 2H, SCH2), 6.99~7.05(m, 2H, ArH), 7.19~7.25(m, 1H, ArH). 7.46~7.49(m, 1H, ArH), 7.83(s, 2H, Py), 8.74(s, 2H, Py). MS (ESI), m/z: 288 (M+1)+. Elemental anal. (%), calculated: C, 58.53; H, 3.51; N, 14.63. Found: C, 58.45; H, 3.46; N, 14.69%.

    The cube-shaped single crystal of the title compound was obtained by recrystallization from EtOH. The crystal with dimensions of 0.44mm × 0.34mm × 0.24mm was mounted on a Bruker APEX-II CCD diffractometer with a graphite-monochromated MoKα radiation (λ = 0.71073 Å) by using a Phi scan mode at 150(2) K in the range of 2.2≤θ≤24.7°. A total of 13921 reflections were collected, of which 3385 were independent (Rint = 0.0975) and 2198 were observed with I > 2σ(I). The structure was solved by direct methods using SHELXS-97[24] and refined by SHELXL-97[25] package. The calculations were performed with SHELXTL program[26]. The non-hydrogen atoms were refined anisotropically. The hydrogen atoms were determined with theoretical calculations and refined isotropically. The final full-matrix leastsquares refinement gave R = 0.0648 and wR = 0.1732 (w = 1/[σ2(Fo 2) + (0.1158P)2], where P = (Fo2 + 2Fc 2)/3), S = 0.97, (Δ/σ) max = 0.000, (Δρ) max = 0.509 and (Δρ) min = -0.508 e·Å-3.

    Antifungal activities of compound against Pythium ultimum, Phytophthora infestans, Corynespora cassiicola and Rhizoctonia solani were evaluated according to reference[4].

    The synthetic route for the preparation of the title 1, 3, 4-oxadiazole compound is depicted in Scheme 1. Many references reported the synthesis methods about 1, 3, 4-oxadiazole. Generally, the oxadiazole derivatives were often synthesized by cyclization from acylhydrazine derivatives. In this paper, we use acylhydrazine and CS2 as materials, then cyclized under base condition. At last, 5-(pyridin-4- yl)-1, 3, 4-oxadiazole-2-thiol and 1-(chloromethyl)- 2-fluorobenzene took place smoothly in the presence of NaOH in DMF under microwave irradiation, resulting in the formation of the final product in excellent yield. The separated solid was washed with water and followed by filtration, dried, and crystallized from EtOH to furnish analytically pure white yellow product, yield 84%.

    Figure Scheme 1

    Figure Scheme 1.  Synthetic route of the title compound

    The structure of the pure product 2-((2-fluorobenzyl) thio)-5-(pyridin-4-yl)-1, 3, 4-oxadiazole was confirmed by 1H NMR, and MS spectroscopic techniques. From the 1H NMR data, the signals at 8.74 and 7.83 ppm are assigned to the protons of pyridine ring. The -SCH2 protons connected to phenyl ring is found at 4.51 ppm. The compound showed a molecular ion peak at m/z 288 (M+H)+ in agreement with the molecular formula. The elemental analysis result is in accordance with the calculated results.

    The crystal belongs to monoclinic system with space group P21/n. The molecular structure of the title compound is shown in Fig. 1, and the packing diagram is in Fig. 2. The selected bond lengths and torsion angles are listed in Table 1.

    Figure 1

    Figure 1.  Single structure of compound 3

    Figure 2

    Figure 2.  Packing of the title compound 3

    Table 1

    Table 1.  Selected Bond Lengths (Å) and Bond Angles (°) for the Title Compound 3
    DownLoad: CSV
    BondÅAngle(°)S(1)–C(7)1.731(3)C(7)–S(1)–C(8)98.53(15)C(1)–C(2)1.382(4)O(1)–C(6)–C(3)120.0(2)
    S(1)–C(8)1.833(3)C(7)–O(1)–C(6)102.1(2)
    O(1)–C(7)1.364(3)C(1)–N(1)–C(5)116.8(2)
    O(1)–C(6)1.376(3)C(6)–N(2)–N(3)106.9(2)
    N(1)–C(1)1.335(4)C(7)–N(3)–N(2)105.3(2)
    N(1)–C(5)1.338(4)C(1)–C(2)–C(3)118.2(3)
    F(1)–C(10)1.363(3)N(1)–C(2)–C(1)124.3(3)
    N(2)–N(3)1.411(3)F(1)–C(10)–C(11)117.2(2)
    N(3)–C(7)1.301(4)N(3)–C(6)–O(1)120.0(2)

    Generally, the average bond lengths and bond angles of pyridine ring[27, 28] and 1, 3, 4-oxidiazole ring[29] are normal. The C (6)=N (2) bond (1.295(3) Å) is longer than the general C=N double bond in 1.27 Å. The bond angle of C (7)-S (1)-C (8) is 98.53(15)°. The torsion angle of thioether group C (7)-S (1)-C (8)-C (9) is -83.4(2)°. From Fig. 1, the 1, 3, 4-oxadiazole ring is nearly planar with the pyridine ring with a quite small angle (θ) of 9.6º. Meanwhile, the phenyl ring is nearly vertical with the 1, 3, 4-oxadiazole and pyridine rings with the angle (θ) of 110.1º and 108.7º, respectively. Intermolecular face-to-face π-π stacking pattern of the title compound (Fig. 2) exists between the two benzene rings and the oxidiazole rings of the adjacent molecule. The distances of the centroids are 3.321 and 3.703 Å, respectively. The hydrogen bonds and weak π-π interactions strengthen the integration of the 1D network. These interactions are estimated to play a role in stabilizing the crystal structure.

    The primary bioassay showed the title compound exhibits weak inhibiting activity towards Phytophthora infestans, Corynespora cassiicola and Rhizoctonia solani. Its inhibition rates to Phytophthora infestans, Corynespora cassiicola and Rhizoctonia solani reach -0.80%, -0.93% and 0% at 500 μg/mL, respectively. It is lower than that of the controls (dimethomorph, 97.76%; procymidone, 45.89%; Validamycin, 62.5%). Surprisingly, the title compound exhibited excellent activity against Pythium ultimum (100.00%); on the contrary, the control had no control effective against Pythium ultimum.

    1. [1]

      Liu X. H, Tan C. X, Weng J. Q. Synthesis, dimeric crystal, and fungicidal activity of 1-(4-methylphenyl)-2-(5-((3,5-dimethyl-1H-pyrazol-1-yl) methyl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)ethanone[J]. Phosphorus Sulfur Silicon Relat. Elem, 2011, 186:  558-564. doi: 10.1080/10426507.2010.508060

    2. [2]

      Liu X. H, Pan L, Ma Y, Weng J. Q, Tan C. X, Li Y. H, Shi Y. X, Li B. J, Li Z. M, Zhang Y. G. Design, synthesis, biological activities, and 3D-QSAR of new N,N?-diacylhydrazines containing 2-(2,4-dichlorophenoxy)propane moiety[J]. Chem. Biol. Drug Des, 2011, 78:  689-694. doi: 10.1111/jpp.2011.78.issue-4

    3. [3]

      Yan S. L, Yang M. Y, Sun Z. H, Min L. J, Tan C. X, Weng J. Q, Wu H. K, Liu X. H. Synthesis and antifungal activity of 1,2,3-thiadiazole derivatives containing 1,3,4-thiadiazole moiety[J]. Lett. Drug Des. Discov, 2014, 11:  940-943. doi: 10.2174/1570180811666140423222141

    4. [4]

      Sun G. X, Shi Y. X, Sun Z. H, Yang M. Y, Wu H. K, Weng J. Q, Tan C. X, Liu X. H, Li B. J, Zhang Y. G. Synthesis and bioactivities of novel 1,3,4-oxadiazole derivatives containing pyridine moiety[J]. Lett. Drug Des. Discov, 2014, 11:  1119-1123. doi: 10.2174/1570180811666140522002929

    5. [5]

      Gan X. H, Hu D. Y, Li P, Wu J, Chen X. W, Xue W, Song B. A. Design, synthesis, antiviral activity and three-dimensional quantitative structure-activity relationship study of novel 1,4-pentadien-3-one derivatives containing the 1,3,4-oxadiazole moiety[J]. Pest Manag. Sci, 2016, 72:  534-543. doi: 10.1002/ps.2016.72.issue-3

    6. [6]

      Salar U, Miana G. A, Khan K. M, Naz F, Siddiqui N. I, Taha M, Tauseef S, Khan S, Perveen S. Biology-oriented syntheses (BIOS) of novel santonic-1,3,4-oxadiazole derivatives under microwave-irradiation and their antimicrobial activity[J]. J. Chem. Soc. Pak, 2015, 37:  1020-1029.

    7. [7]

      Dawood K. M, Gomha S. M. Synthesis and anti-cancer activity of 1,3,4-thiadiazole and 1,3-thiazole derivatives having 1,3,4-oxadiazole moiety[J]. J. Heterocycl. Chem, 2015, 52:  1400-1405. doi: 10.1002/jhet.v52.5

    8. [8]

      Yang M. Y, Zhai Z. W, Sun Z. H, Yu S. J, Liu X. H, Weng J. Q, Tan C. X, Zhao W. G. A facile one-pot synthesis of novel 1,2,4-triazolo[4,3-a]pyridine derivatives containing the trifluoromethyl moiety using microwave irradiation[J]. J. Chem. Res, 2015, 39:  521-523. doi: 10.3184/174751915X14400874295745

    9. [9]

      Liu X. H, Tan C. X, Weng J. Q. Phase transfer-catalyzed, one-pot synthesis of some novel N-pyrimidinyl-N?-nicotinyl thiourea derivatives[J]. Phosphorus Sulfur Silicon Relat. Elem, 2011, 186:  552-557. doi: 10.1080/10426507.2010.508059

    10. [10]

      Liu X. H, Sun Z. H, Yang M. Y, Tan C. X, Weng J. Q, Zhang Y. G, Ma Y. Microwave assistant one pot synthesis, crystal structure, antifungal activities and 3D-QSAR of novel 1,2,4-triazolo[4,3-a]pyridines[J]. Chem. Biol. Drug Des, 2014, 84:  342-347. doi: 10.1111/cbdd.2014.84.issue-3

    11. [11]

      Zhai Z. W, Shi Y. X, Yang M. Y, Zhao W, Sun Z. H, Weng J. Q, Tan C. X, Liu X. H, Li B. J, Zhang Y. G. Microwave assisted synthesis and antifungal activity of some novel thioethers containing 1,2,4-triazolo[4,3-a]pyridine moiety[J]. Lett. Drug Des. Discov, 2016, 13:  521-525. doi: 10.2174/157018081306160618181757

    12. [12]

      Shen Z. H, Shi Y. X, Yang M. Y, Sun Z. H, Weng J. Q, Tan C. X, Liu X. H, Li B. J, Zhao W. G. Synthesis, crystal structure, DFT studies and biological activity of a novel schiff base containing triazolo[4,3-a]pyridine moiety[J]. Chin. J. Struct. Chem, 2016, 35:  457-464.

    13. [13]

      Zhai Z. W, Shi Y. X, Yang M. Y, Sun Z. H, Weng J. Q, Tan C. X, Liu X. H, Li B. J, Zhang Y. G. Synthesis, crystal structure, DFT studies and antifungal activity of 5-(4-cyclopropyl-5-((3-fluorobenzyl)sulfonyl)-4H-1,2,4-triazol-3-yl)-4-methyl-1,2,3-thiadiazole[J]. Chin. J. Struct. Chem, 2016, 35:  25-33.

    14. [14]

      Zampieri D, Mamolo M. G, Vio L, Romano M, Skoko N, Baralle M, Pau V, De Logu A. Antimycobacterial activity of new N-1-[1-[1-aryl-3-[4-(1H-imidazol-1-yl)phenyl]-3-oxo]propyl]-pyridine-2-carboxamidrazone derivatives[J]. Bioorg. Med. Chem. Lett, 2016, 26:  3287-3290. doi: 10.1016/j.bmcl.2016.05.053

    15. [15]

      Kroth H, Sreenivasachary N, Hamel A, Benderitter P, Varisco Y, Giriens V, Paganetti P, Froestl W, Pfeifer A, Muhs A. Synthesis and structure-activity relationship of 2,6-disubstituted pyridine derivatives as inhibitors of beta-amyloid-42 aggregation[J]. Bioorg. Med. Chem. Lett, 2016, 26:  3330-3335. doi: 10.1016/j.bmcl.2016.05.040

    16. [16]

      Liu X. H, Xu X. Y, Tan C. X, Weng J. Q, Xin J. H, Chen J. Synthesis, crystal structure, herbicidal activities and 3D-QSAR study of some novel 1,2,4-triazolo[4,3-a]pyridine derivatives[J]. Pest Manag. Sci, 2015, 71:  292-301. doi: 10.1002/ps.2015.71.issue-2

    17. [17]

      Liu X. H, Zhai Z. W, Xu X. Y, Yang M. Y, Sun Z. H, Weng J. Q, Tan C. X, Chen J. Facile and efficient synthesis and biological activity determination of novel 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one derivatives via microwave irradiation[J]. Bioorg. Med. Chem. Lett, 2015, 25:  5524-5528. doi: 10.1016/j.bmcl.2015.10.064

    18. [18]

      Liu X. H, Zhao W, Shen Z. H, Xing J. H, Yuan J, Yang G, Xu T. M, Peng W. L. Synthesis, nematocidal activity and docking study of novel chiral 1-(3-chloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives[J]. Bioorg. Med. Chem. Lett, 2016, 26:  3626-3628. doi: 10.1016/j.bmcl.2016.06.004

    19. [19]

      Zhao W, Shen Z. H, Xu T. M, Peng W. L, Liu X. H. Synthesis, nematocidal activity and docking study of novel chiral 1-(3-chloropyridin-2-yl)-3-(difluoromethyl)-1H-pyrazole-4-carboxamide derivatives[J]. J. Heterocycl. Chem, 2016, :  . doi: 10.1002/jhet.2753

    20. [20]

      Liu X.H, Zhao W, Shen Z.H, Xing J.H, Xu T.M, Peng W.L. Synthesis, nematocidal activity and SAR study of novel difluoromethylpyrazole carboxamide derivatives containing flexible alkyl chain moieties[J]. Eur. J. Med. Chem, 2017, :  . doi: 10.1016/j.ejmech.2016.10.017

    21. [21]

      Liu X. H, Wang Q, Sun Z. H, Wedge D. E, Becnel J. J, Estep A. S, Tan C. X, Weng J. Q. Synthesis and insecticidal activity of novel pyrimidine derivatives containing urea pharmacophore against[J]. Aedes aegypti. Pest Manag Sci, 2016, :  . doi: 10.1002/ps.4370

    22. [22]

      Zhao W, Xing J. H, Xu T. M, Peng W. L, Liu X. H. Synthesis and in vivo nematocidal evaluation of novel N-substituted 3-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives[J]. Front. Chem. Sci. Eng, 2016, :  . doi: 10.1007/s11705-016-1595-x

    23. [23]

      Zhao W, Shen Z.H, Xu T.M, Peng W.L, Liu X.H. Synthesis and nematocidal activity of novel pyrazole carboxamide derivatives against Meloidogyne incognita[J]. Lett. Drug Des. Discov, 2017, 14:  . doi: 10.2174/1570180813666160930164327

    24. [24]

      Sheldrick, G. M. SHELXS97. Program for Crystal Structure Solution. University of Göttingen, Germany, 1997.

    25. [25]

      Sheldrick, G. M. SHELXL97. Program for Crystal Structure Refinement. University of Göttingen, Germany, 1997.

    26. [26]

      Sheldrick G. M. A short history of SHELX[J]. Acta Crystallogr, 2008, A64:  112-122.

    27. [27]

      Wang Q, Zhai Z. W, Sun Z. H, Liu X. H, Tan C. X, Weng J. Q. Synthesis, crystal structure and antifungal activity of 8-chloro-3-((4-chlorobenzyl)thio)[1,2,4]triazolo[4,3-a]pyridine[J]. Chin. J. Struct. Chem, 2016, 35:  651-655.

    28. [28]

      Yang M. Y, Zhao W, Liu X. H, Tan C. X, Weng J. Q. Synthesis, crystal structure and antifungal activity of 4-(5-((2,4-dichlorobenzyl)thio)-4-phenyl-4H-1,2,4-triazol-3-yl)pyridine[J]. Chin. J. Struct. Chem, 2015, 34:  203-207.

    29. [29]

      Chen M, Yang C. L. Synthesis, crystal structure and biological activity of 5-(2-methylphenyl)-1,3,4-oxadiazol-2(3H)-one derivatives[J]. Chin. J. Struct. Chem, 2015, 34:  189-196.

  • Scheme 1  Synthetic route of the title compound

    Figure 1  Single structure of compound 3

    Figure 2  Packing of the title compound 3

    Table 1.  Selected Bond Lengths (Å) and Bond Angles (°) for the Title Compound 3

    BondÅAngle(°)S(1)–C(7)1.731(3)C(7)–S(1)–C(8)98.53(15)C(1)–C(2)1.382(4)O(1)–C(6)–C(3)120.0(2)
    S(1)–C(8)1.833(3)C(7)–O(1)–C(6)102.1(2)
    O(1)–C(7)1.364(3)C(1)–N(1)–C(5)116.8(2)
    O(1)–C(6)1.376(3)C(6)–N(2)–N(3)106.9(2)
    N(1)–C(1)1.335(4)C(7)–N(3)–N(2)105.3(2)
    N(1)–C(5)1.338(4)C(1)–C(2)–C(3)118.2(3)
    F(1)–C(10)1.363(3)N(1)–C(2)–C(1)124.3(3)
    N(2)–N(3)1.411(3)F(1)–C(10)–C(11)117.2(2)
    N(3)–C(7)1.301(4)N(3)–C(6)–O(1)120.0(2)
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  • 收稿日期:  2016-07-05
  • 接受日期:  2016-10-17
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