Synthesis, Crystal Structure and Biological Activity of N-cyanosulfoximine Derivative Containing 1,2,3-Thiadiazole①

MAO Wu-To ZONG Gung-Ning FAN Zhi-Jin LI Feng-Yun SONG Hi-Bin LI Jun-Jun Klinin A. Ttin Khzhiev InnLugovik KseniMorzherin Yu. YuryBelsky P. Ntliy

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Synthesis, Crystal Structure and Biological Activity of-cyanosulfoximine Derivative Containing 1,2,3-Thiadiazole①

MAO Wu-Taoa, bZONG Guang-NingaFAN Zhi-Jina②LI Feng-YunaSONG Hai-BinaLI Juan-JuanaKalinina A. TatianacKhazhieva InnacLugovik KseniacMorzherin Yu. YurycBelskaya P. Nataliyac②

a((),300071)b(473061)c()

The title compound-cyanosulfoximine derivative containing 1,2,3-thiadiazole (C6H8N4OS2,= 216.28) has been synthesized using 4-(chloromethyl)-5-methyl-1,2,3-thiadiazole as the starting material, and its structure was characterized by IR,1H NMR, HRMS, elemental analysis and single-crystal X-ray diffraction. The crystal of the title compound belongs to orthorhombic, space group21with= 14.730(6),= 5.478(2),=22.619(9) ?,= 8,= 1825.0(13) ?3,D= 1.574 g/cm3,= 0.547 mm-1,(000) = 896,= 0.0767 and(> 2())= 0.2064. X-ray analysis indicates that in this crystal double enantiomers are found as the basically asymmetrical unit and interactions between S(1)···N(3), S(3)···N(4) and S(3)···N(7) are observed. This kind of interactions extends the molecules into a one-dimensional double chain. The preliminary biological test showed that the title compound had insecticidal activity againstin a certain degree and also presented moderate potential bioactivity against tobacco mosaic virus (TMV).

1,2,3-thiadiazole, sulfoximine, crystal structure, synthesis, biological activity;

1 INTRODUCTION

Sap-feeding insects are one type of the most destructive pests for agricultural production, which not only destroy plants directly but also spread virus-causing disease. The current neonicotinoid insecticides are active agrochemicals to control this type of pests with broad spectrum[1-3].However, resistance has already reduced their efficacy and increased the application dosage. Sulfoxaflor is a new type of neonicotinoid insecticide containing a sulfoximine group which acts as a nicotinic acetyl- choline receptor (nAChR) without cross-resis- tance[3-7].Afterwards,more and more derivatives of sulfoxmine have been synthesized[8].

Plant elicitors are one typical measure for dealing with virus-causing disease. They can induce the plant systemic acquired resistance to produce a broad spectrum of defiance against pathogen by altering its physical and physiological innate de- fiance system[9]. Acibenzolar-S-methyl (BTH)[10]and tiadinil (TDL) are most active elicitors com- mercialized successfully with 1,2,3-thiadiazole active substructure. As one of the most important classes of sulfur containing heterocycles, molecules containing 1,2,3-thiadiazole ring exhibited various biological activities such as insecticidal[11], fungi- cidal[12], antiviral[13], herbicidal activity[14], and systemic acquired resistance[15]. More derivatives of 1,2,3-thiadiazole have been reported with various biological activities[16, 17]. To continue our studies to expand the novel pesticide lead, a-cyanosulfo- ximine derivative containing 1,2,3-thiadiazole ring was designedand synthesized here according to Scheme 1.

Scheme 1. Synthesis route of the title compound

2 EXPERIMENTAL

The starting material (compound 1) was synthesi- zed according to the reported literature[18], and all the other chemicals and reagents were of analytical grade and used without further purification. Melting point was determined on an XT-4A apparatus and the thermometer was uncorrected. Infrared spectra were recorded on a Bruker Equinox 55 Spec- trophotometer by a KBr pellet press.1H NMR spectra were measured on a Bruker AC-P500 Instrument (400MHz) with CDCl3as the solvent and TMS as the internal standard. The elemental analyses were performed on a Vario EL Elemental Analyzer. Mass spectra were obtained with a Thermo Scientific Finnigan LCQ advantage mass spectrometer equipped with standard electrospray ionization (ESI) apparatus. High-resolution mass spectrometry (HRMS) data were obtained on an FTICR-MS Varian 7.0T FTICR-MS instrument. The single-crystal structure was determined on a Rigaku Saturn724 CCD diffractometer.

2. 1 Synthesis

To a solution of 4-(chloromethyl)-5-methyl-1,2,3- thiadiazole (0.74 g, 5.00 mmol) in ethanol (20 mL) was added aqueous sodium thiomethoxide (20%, 2.10 g, 6.00 mmol) dropwise at 0 °C, and then the solution was stirred at ambient temperature for 3 h. The reaction mixture was quenched by 80 mL ice water, after which the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated and purified by flash chro- matography on silica gel using petroleum ether (60～90 °C) and ethyl acetate (v/v = 15:1) as the eluent to give 5-methyl-4-((methylthio)methyl)-1,2,3-thiadia- zole (2) as a yellow liquid with the yield of 79%.1H NMR (400 MHz, CDCl3):3.95 (s, 2H, CH2), 2.82 (s, 3H, S-CH3), 2.73 (s, 3H, thiadiazole-CH3).

Iodobenzene diacetate (2.4 g, 7.5 mmol) was added to a solution of sulfide (2, 0.49 g, 3 mmol) and cyanamide (0.25 g, 6 mmol) in tetrahydrofuran (THF) cooling to 0 °C in one portion. The reaction mixture was allowed to warm to ambient tempera- ture over 1 h, and stirred for additional 5 h. The solvent was removedand the residue was purified by silica gel column chromatography (ethyl acetate/acetone v/v = 3:1) to afford the sulfilimine intermediate (3) as a pale yellow solid in 54% yield.1H NMR (400 MHz, CDCl3):4.74 (AB system,= 13.6Hz, 2H, thiadiazole-CH2), 2.94 (s, 3H, S-CH3), 2.77 (s, 3H, CH3). IR (KBr, cm-1): 2144 (CN). Anal. Calcd. for C6H8N4S2: C, 35.98; H, 4.03; N, 27.97. Found: C, 35.85; H, 4.31; N, 28.11. ESI/MS Calcd: [M+Na]+223.0,found 223.0.

To a stirred solution of-chloroperbenzoic acid (85%, 0.61 g, 3 mmol) in ethanol (5 mL) at 0 °C, a solution of potassium carbonate (0.83 g, 6 mmol) in 4 mL water was added. The resulting mixture was stirred at 0 °C for 20 mins. Then, the solution of compound 3 (0.3 g, 1.5 mmol) in ethanol (8 mL) was added in one portion. The resulting mixture was stirred for 1 hour, and saturated aqueous sodium bisulfite (5 mL) was added to quench the excess peracid. The resulting mixture was extracted with ethyl acetate (30 mL × 3) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by chromatography on silica gel using petroleum ether (60～90 °C) and ethyl acetate (= 1:1) as the eluent to afford the title compound as a pale yellow solid with the yield of 60%. m.p. 110～112 °C.1H NMR (400 MHz, CDCl3):5.11 (AB system,= 14.8Hz, 2H, thiadiazole-CH2), 3.31 (s, 3H, S-CH3), 2.78 (s, 3H, thiadiazole-CH3). IR (KBr, cm-1): 2189 (CN). HR-MS (ESI): m/z calcd. for C6H8N4OS2Na [M+Na]+239.0037, Found 239.0034.

2. 2 Crystal data and structure determination

The colorless prism of the title compound with dimensions of 0.20mm × 0.20mm × 0.14mm was selected for X-ray diffraction analysis. The data were collected by a Bruker Smart 1000 CCD diffrac- tometer equipped with a graphite-monochromatic Moradiation (= 0.71073 ?) using a-scan mode at 113(2) K. In the range of 1.80≤≤25.00°, a total of 13825 reflections were collected with 3175 unique ones (int= 0.1018), of which 3092 were observed with> 2() and used in the succeeding refinements. Intensity data were corrected forfactors and empirical absorption. The structure was solved by direct methods with the SHELXS-97 program[19]. Refinements were done by full-matrix least-squares techniques on2with SHELXL-97[20]. All of the non-hydrogen atoms were located with successive difference Fourier syntheses. The structure was refined by full-matrix least-squares techniques on2using anisotropic thermal para- meters for all non-hydrogen atoms. The hydrogen atoms were added according to theoretical models. The final full-matrix least-squares refinement converged at= 0.0767,= 0.2064 (= 1/[2(F2) + (0.1805)2+ 2.1913], where= (F2+ 2F2)/3),= 1.057, (Δ)max= 1.796, (Δ)min=–0.686 e/?3and (Δ/)max= 0.001.

3 RESULTS AND DISCUSSION

The molecular structure of the title compound is shown in Fig. 1. The selected bond lengths and bond angles are listed in Table 1.

Fig. 1. Molecular structure of the title compound

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

Bond lengths and bond angles within the hetero- cyclic system agree well with the values reported[21]. In the crystal structure, double enantiomers can be found, explaining no optical activity of the title compound. Of both enantiomers, one has a chiral center (S(2) atom) withconfiguration, and the other has a chiral center (S(4) atom) with S con- figuration. Although both S(2) and S(4) atoms have a3hybridization station, the tetrahedral con- figuration of these two chiral centers has been signi- ficantly distorted. For example, the angle of O(1)–S(2)–N(3) is 118.1(3)o, which is significantly higher than that of normal tetrahedral configuration. The bond lengths of N(4)–C(6) and N(8)–C(12) are 1.180(9) and 1.135(9) ?, respectively, which agree well with the values of typical C≡N triple bond. The N(4)–C(6)–N(3) and N(8)–C(12)–N(7) angles are 175.3(8)° and 173.5(7)° respectively, indicatinghybridization station of C(6) and C(12). Due to the steric effects of the bigger sulfoximine group, the bond length of C(3)–C(4) (1.487(8) ?) is slightly longer than that of C(1)–C(2) (1.477(8) ?). The intermolecular distances of both S(1)···N(3) and S(3)···N(7) are 3.25 ?, which are slightly shorter than the sum of van der Waal radii (3.35 ?)[22]. The data reveal the crystal structure involves weak interactions at S(1)···N(3) and S(3)···N(7), which link the adjacent molecules to form two one-dimen- sional chains. Furthermore, the intermolecular distance of both S(3)···N(4) is 3.32 ?, so weak interactions appear at S(3)···N(4), and they connect the above two one-dimensional chains together (Fig. 2). This type of weak interactions stabilizes the crystal structure.

4 BIOLOGICAL ACTIVITY

The insecticidal activities of the title compound and compound 3 againstwere evaluated at 100 μg/mL according to the reported proce- dures[23]; and the data are shown in Table 2. The anti-TMV activities including protection, inactiva- tion, curative activity, and systemic acquired resis- tance of the title compound and 3 against TMV were evaluated at 100 μg/mL according to literatures[24]; the data are listed in Table 3. The title compounds not only exhibited insecticidal activity againstin a certain degree but also presented good potential bioactivity against TMV at 100 μg/mL, this will be valuable for insect control and virus disease control in agricultural practice.

Fig. 2. Intermolecular interactions in crystal structure viewed along thedirection

Table 2. Insecticidal Activity of the Target Compounds against M. persicae at 100 μg/mL

Table 3. Anti-TMVActivity of the Target Compounds at 100 μg/mL

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① This study was funded in part by the National Natural ScienceFoundationof China (21372132) and Nataliya P. Belskayathanks Russian State Task of Ministry Education and Science No. 4.560.2014/K. Kalinina A. Tatiana thanks RFBF № 13-03-00137

. Fan Zhi-Jin, born in 1968, professor. E-mail: fanzj@nankai.edu.cn;Nataliya P. Belskaya. Born in 1956, professor. E-mail: n.p.belskaya@urfu.ru

10.14102/j.cnki.0254-5861.2011-0665

10 February 2015; accepted 9 July 2015 (CCDC 885805)