Synthesis, Structure and Antimicrobial Activity of 9,9-Dimethyl-9,10-dihydrospiro[benzo[a]-xanthene-12,3'-indoline]-2',11(8H)-dione

Du-Lin KONG Jie JIANG Lu-Yong WU Xiang-Hui WANG Zai-Feng SHI Ming-Shu WU Xin WANG Qiang LIN

Citation:  KONG Du-Lin, JIANG Jie, WU Lu-Yong, WANG Xiang-Hui, SHI Zai-Feng, WU Ming-Shu, WANG Xin, LIN Qiang. Synthesis, Structure and Antimicrobial Activity of 9,9-Dimethyl-9,10-dihydrospiro[benzo[a]-xanthene-12,3'-indoline]-2',11(8H)-dione[J]. Chinese Journal of Structural Chemistry, 2016, 35(12): 1849-1854. doi: 10.14102/j.cnki.0254-5861.2011-1249 shu

Synthesis, Structure and Antimicrobial Activity of 9,9-Dimethyl-9,10-dihydrospiro[benzo[a]-xanthene-12,3'-indoline]-2',11(8H)-dione

English

  • The compound with spirooxindole ring system found in a number of alkaloids (Fig. 1)[1, 2] has attracted considerable interest as antimicrobial and antitumor agents, and as an inhibitor of the human NKI receptor[3, 4]. The conformational restriction associated to the structural rigidity significantly affects their biological activities[5]. It has been reported that biological activity could be enhanced to a greater extent by sharing indole 3-carbon atom in the formation of spiroindoline derivatives[6, 7]. The literature is enumerated with several approaches prescribed for structurally diverse heterocyclic spirooxindoles during the past few years[8-15]. Most of them suffer from different drawbacks, such as long reaction time, low yield, tedious workup, higher temperature (130 ℃)[16], use of toxic solvents and expensive reagents.

    Figure 1

    Figure 1.  Some examples for alkaloid containing a heterocyclic spirooxindole scaffold

    Based on the above considerations and our interest in the design and development of novel and environmental benign synthetic methodologies[17-21], we successfully use indole moiety which has better biological activity[22-26] to construct a series of novel spirooxindole ring derivatives by one pot threecomponent condensation reaction in aqueous medium. Fortunately, one single crystal among the target products was obtained and characterized by single-crystal X-ray diffraction. Furthermore, the antimicrobial activities of spiro-compound (C26H21NO3) have also been tested.

    Unless otherwise noted, the reagents and solvents were used as received from commercial suppliers. Melting points were determined on a Yanaco apparatus and uncorrected. IR spectra were recorded on a FT-IR Thermo Nicolet Avatar 360 using KBr pellet. 1H and 13 C NMR spectra were recorded on an AVANCE 500 Bruker spectrometer (Bruker, Billerica, Massachusetts, USA) operating at 500 and 125 MHz in DMSO-d6, respectively, and chemical shifts were reported in ppm. Elemental analyses were performed on a Yanagimoton MT3CHN recorder (Yanagimoto, Saitama, Japan).

    The synthetic approach of the title compound is illustrated in Scheme 1. The title compound exists as a form of colorless crystal.

    Figure Scheme 1

    Figure Scheme 1.  Synthetic route for the title compound

    To a solution of sodium dodecyl sulfate/H2O (2 mL m/m = 1:9) were added isatin (1 mmol), 2-naphthol (1 mmol), 5, 5-dimrthyl-1, 3-cyclohexanedione (1 mmol) and p-methylbenzene sulfonic acid (0.1 mmol). The mixture was stirred at 80 ℃ for 3 hours and monitored by TLC. After the reaction completed, water (10 mL) was added to the mixture, and the precipitated product was separated by filtration, washed with water and hot ethanol and dried to afford the desired product. White solid. Yield: 80%, m. p. > 300 ℃. Anal. Calcd. (%) for C26H21NO3: C, 78.97; H 5.35; N, 3.54. Found (%): C, 79.02; H, 5.28; N, 3.61. IR (KBr) ν: 3141, 3079, 2960, 1716, 1239, 745 cm-1. 1H NMR (500 MHz, DMSO-d6) δ: 0.99 (s, 3H), 1.12 (s, 3H), 2.08 (d, 1H, J = 15 Hz), 2.26 (d, 1H, J = 15 Hz), 2.65 (d, 1H, J = 15 Hz), 2.76 (d, 1H, J = 15 Hz), 6.77~6.97 (m, 3H), 7.16~7.42 (m, 4H), 7.71 (d, 1H, J = 5 Hz), 7.89~ 7.97 (m, 2H), 10.97 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ: 26.64, 27.90, 31.54, 40.75, 49.05, 50.95, 109.36, 111.18, 113.87, 117.57, 121.91, 122.90, 123.66, 124.84, 127.22, 128.42, 129.22, 130.90, 130.97,131.45, 134.83, 142.84, 147.33, 163.86, 178.88, 194.98.

    The single crystal suitable for X-ray diffraction was obtained by slow evaporation from methanol solution of the title compound at room temperature.

    The molecule has been crystallized from methanol by a slow evaporation technique at room temperature. A white crystal of the title compound with dimensions of 0.28mm × 0.12mm × 0.10mm was mounted on the top of a glass fiber. Single-crystal X-ray diffraction data were collected on a Rigaku diffractometer with an Agilent Technologies Gemini An Ultra system (CuKα; λ = 0.71073 Å) at room temperature. In the range of 2.58≤θ≤25.01° (-10 ≤h≤10, -28≤k≤28, -7≤l≤11), a total of 9555 independent reflections were collected, of which 3517 with I > 2σ(I) (Rint = 0.1121) were considered to be observed and used in the succeeding structure determination and refinement. The data were processed using CrysAlispro. The structure was solved and refined using full-matrix least-squares based on F2 with program SHELXS-97 and SHELXL-97 within Olex2. All non-hydrogen atoms were refined with anisotropic thermal parameters, and the hydrogen atoms refined isotropically with riding model position parameters were located from difference Fourier map and added theoretically. H-atoms were placed in the calculated positions (C-H 0.93 Å, N-H 0.86 Å), and were included in the refinement in the riding model, with Uiso (H) = 1.2Ueq (C). The final refinement converged to R = 0.0801 and wR = 0.1824 (w = 1/[σ2(Fo 2) + (0.1102P)2 + 0.0000P], where P = (Fo2+ 2Fc 2)/3), (Δ/σ) max = 0.000, S = 1.028, Δρ(max) = 0.281 and Δρ(min) = -0.327 e/Å3.

    The title compound 1 crystallizes in monoclinic P21/c space group. The selected bond lengths and bond angles are summarized in Table 1. The hydro gen bond lengths and bond angles are listed in Table 2. The molecular structure and packing diagram of 1 are shown in Figs. 1 and 2, respectively. As shown in Fig. 1, the molecule contains five six-membered rings and one five-membered ring, of which the naphthol ring and one pyran ring are almost parallel. Because there are three carbon atoms (C (2), C (3) and C (4) of sp3 hybridization, the six-membered ring (C (1), C (2), C (3), C (4), C (5) and C (6)) is not located in one plane, deviating from their least-squares plane by -0.0284, -0.1818, 0.3241, -0.2530, 0.0391 and 0.1000 Å. Furthermore, the bond lengths of C (1)- C (2), C (2)-C (3), C (3)-C (4), C (4)-C (5), C (3)-C (25) and C (3)-C (26) are significantly longer than the normal C=C bonds. As shown in Fig. 1, the fivemembered pyrrole ring is nearly vertical with the pyran ring with the dihedral angle (θ) of 86.59°. The pyrrole ring (C (7), C (18), C (19), C (20) and N (1)) and phenyl ring (C (19), C (20), C (21), C (22), C (23) and C (24)) are fairly planar with plane equations of -7.6919x + 9.9888y + 0.3379z = 4.6202 and -7.5299x + 10.5720y + 0.0780z = 5.0110. The C (5)=O (2) (1.223(5) Å) and C (18)=O (3) (1.231(4) Å) bonds are longer than the normal C=O double bond (1.20 Å).

    Table 1

    Table 1.  Selected Bond Lengths (Å), B ond Angles (°) and Torsion Angles (°)
    DownLoad: CSV
    BondDist.BondDist.BondDist.Bond Angle(°)Bond Angle(°)Torsion Angle(°)C(18)-N(1)-C(19)111.7(3)O(1)-C(1)-C(2)110.6(3)C(9)-O(1)-C(1)-C(6)-2.6(6)C(20)-C(7)-C(8)109.3(3)C(23)-C(24)-H(24)121N(1)-C(19)-C(20)-C(7)-0.5(4)
    N(1)-C(18)1.367(5)O(1)-C(1)1.365(5)O(2)-C(5)1.223(5)
    N(1)-C(19)1.405(5)O(1)-C(9)1.405(5)O(3)-C(18)1.231(4)
    C(1)-O(1)-C(9)118.6(3)O(2)-C(5)-C(6)120.7(4)C(3)-C(4)-C(5)-O(2)-149.2(4)
    C(6)-C(1)-O(1)122.8(4)O(2)-C(5)-C(4)121.5(4)O(2)-C(5)-C(6)-C(1)179.4(4)
    O(3)-C(18)-C(7)125.2(3)N(1)-C(18)-C(7)108.5(3)C(7)-C(8)-C(9)-O(1)2.4(6)
    C(24)-C(19)-N(1)128.6(4)C(23)-C(22)-C(21)119.9(4)C(9)-O(1)-C(1)-C(2)176.7(3)
    C(8)-C(9)-O(1)124.4(3)C(23)-C(22)-H(22)120O(1)-C(1)-C(6)-C(5)176.9(3)
    O(1)-C(9)-C(10)111.7(3)C(21)-C(22)-H(22)120O(2)-C(5)-C(6)-C(7)-0.5(6)
    O(3)-C(18)-N(1)126.4(3)C(24)-C(23)-C(22)121.5(4)C(1)-O(1)-C(9)-C(8)2.9(6)
    C(20)-C(19)-N(1)110.2(3)C(24)-C(23)-H(23)119.2C(19)-N(1)-C(18)-C(7)-1.8(4)
    C(5)-C(6)-C(7)118.6(3)C(22)-C(23)-H(23)119.2C(8)-C(7)-C(18)-O(3)59.6(5)
    C(6)-C(7)-C(20)112.8(3)C(23)-C(24)-C(19)118.0(4)C(18)-N(1)-C(19)-C(20)1.5(4)

    Table 2

    Table 2.  Hydrogen Bond Len gths (Å) and Bond Angles (o)
    DownLoad: CSV
    D-H···Ad(D-H)d(H···A)d(D···A)∠DHAN(1)-H(1)···O(3)0.862.042.8425156C(14)-H(14)···N(1)0.932.463.2993151
    Symmetry transformation: -x, 1-y, -z

    Figure 2

    Figure 2.  Crystal structure of the title compound

    Figure 3

    Figure 3.  Packing of the molecule in a unit cell

    The intermolecular hydrogen-bonding interactions N (1)-H (1)…O (3) and C (14)-H (14)…N (1) in compound 1 link two molecules together. Moreover, they were further linked together to form an extensive network by C (4)-H (4A)…π (2.70 Å), C (14)-H (14)…π (2.29 Å) hydrogen bonds and face-to-face π-π stacking.

    The microplate reader was used in this assay to detect the antimicrobial activity against Micrococcus tetragenus, Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, S. albus and Escherichia coli in a sterile 96-well microtitre plate. The experimental procedure was referred to the method Chen Mo et al. used[27]. The values of antimicrobial activities of the title compound are listed in Table 3. Antibacterial assay indicated that the title compound exhibited activities against the tested bacteria of Micrococcus tetragenus, Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, S. albus and Escherichia coli with MIC to be 0.01, 0.008, 0.01, 0.007, 0.01 and 0.01 mg/mL, respectively.

    Table 3

    Table 3.  Antimicrobial Activities with Mi nimum Inhibitory Concentration (mg/mL)
    DownLoad: CSV
    Testes samplesMicrococcus tetragenusBacillus cereusBacillus subtilisStaphylococcus aureusS.albusEscherichia coliMIC0.010.0080.010.0070.010.01
    (Antimicrobial activities tested by Key Laboratory of Tropical Medicinal Plant Chemistry of the Ministry of Education)
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  • Figure 1  Some examples for alkaloid containing a heterocyclic spirooxindole scaffold

    Scheme 1  Synthetic route for the title compound

    Figure 2  Crystal structure of the title compound

    Figure 3  Packing of the molecule in a unit cell

    Table 1.  Selected Bond Lengths (Å), B ond Angles (°) and Torsion Angles (°)

    BondDist.BondDist.BondDist.Bond Angle(°)Bond Angle(°)Torsion Angle(°)C(18)-N(1)-C(19)111.7(3)O(1)-C(1)-C(2)110.6(3)C(9)-O(1)-C(1)-C(6)-2.6(6)C(20)-C(7)-C(8)109.3(3)C(23)-C(24)-H(24)121N(1)-C(19)-C(20)-C(7)-0.5(4)
    N(1)-C(18)1.367(5)O(1)-C(1)1.365(5)O(2)-C(5)1.223(5)
    N(1)-C(19)1.405(5)O(1)-C(9)1.405(5)O(3)-C(18)1.231(4)
    C(1)-O(1)-C(9)118.6(3)O(2)-C(5)-C(6)120.7(4)C(3)-C(4)-C(5)-O(2)-149.2(4)
    C(6)-C(1)-O(1)122.8(4)O(2)-C(5)-C(4)121.5(4)O(2)-C(5)-C(6)-C(1)179.4(4)
    O(3)-C(18)-C(7)125.2(3)N(1)-C(18)-C(7)108.5(3)C(7)-C(8)-C(9)-O(1)2.4(6)
    C(24)-C(19)-N(1)128.6(4)C(23)-C(22)-C(21)119.9(4)C(9)-O(1)-C(1)-C(2)176.7(3)
    C(8)-C(9)-O(1)124.4(3)C(23)-C(22)-H(22)120O(1)-C(1)-C(6)-C(5)176.9(3)
    O(1)-C(9)-C(10)111.7(3)C(21)-C(22)-H(22)120O(2)-C(5)-C(6)-C(7)-0.5(6)
    O(3)-C(18)-N(1)126.4(3)C(24)-C(23)-C(22)121.5(4)C(1)-O(1)-C(9)-C(8)2.9(6)
    C(20)-C(19)-N(1)110.2(3)C(24)-C(23)-H(23)119.2C(19)-N(1)-C(18)-C(7)-1.8(4)
    C(5)-C(6)-C(7)118.6(3)C(22)-C(23)-H(23)119.2C(8)-C(7)-C(18)-O(3)59.6(5)
    C(6)-C(7)-C(20)112.8(3)C(23)-C(24)-C(19)118.0(4)C(18)-N(1)-C(19)-C(20)1.5(4)
    下载: 导出CSV

    Table 2.  Hydrogen Bond Len gths (Å) and Bond Angles (o)

    D-H···Ad(D-H)d(H···A)d(D···A)∠DHAN(1)-H(1)···O(3)0.862.042.8425156C(14)-H(14)···N(1)0.932.463.2993151
    Symmetry transformation: -x, 1-y, -z
    下载: 导出CSV

    Table 3.  Antimicrobial Activities with Mi nimum Inhibitory Concentration (mg/mL)

    Testes samplesMicrococcus tetragenusBacillus cereusBacillus subtilisStaphylococcus aureusS.albusEscherichia coliMIC0.010.0080.010.0070.010.01
    (Antimicrobial activities tested by Key Laboratory of Tropical Medicinal Plant Chemistry of the Ministry of Education)
    下载: 导出CSV
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