Synthesis, Structure and Biological Activity of 3-Methyl-4-(3-nitrobenzylideneamino)-5- ethoxycarbonyl-methylsulfanyl-1,2,4-triazole 1

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1 34 卷 2 期结构化学 (JIEGOU HUAXUE) Vol. 34, No Chinese J. Struct. Chem Synthesis, Structure and Biological Activity of 3-Methyl-4-(3-nitrobenzylideneamino)-5- ethoxycarbonyl-methylsulfanyl-1,2,4-triazole 1 a, b2 YANG Qing-Cui SUN LIU Yuan-Fa d a, c2 Xiao-Hong CHEN Bang d MA Hai-Xia a JIN Ru-Yi a a (College of Chemical Engineering, Northwest University, Xi an , China) b (School of Science, Xi'an University of Architecture and Technology, Xi an , China) c (Chemical Research Institute, Northwest University, Xi an , China) d (College of Chemistry & Materials Science, Northwest University, Xi an , China) ABSTRACT A Schiff base was synthesized by 3-methyl-4-amino-5-ethoxycarbonyl-methylsulfanyl-1,2,4-triazole with 3-nitrobenzaldehyde. The structure was confirmed by 1 H NMR, IR, H RMS, TGA techniques and X-ray diffraction. The crystal belongs to monoclinic system, space group P2 1 /c, with a = 8.965(2), b = (5), c = 9.197(2) Å, β = (4), C 14 H 15 N 5 O 4 S, M r = , V = (6) Å 3, D c = g cm -3, Z = 4, F(000) = 728, μ = mm -1, the final R = and wr = for 2932 unique reflections with I > 2σ(I). Furthermore, the biological activity to four vegetable pathogens has been tested. The title compound exhibits better biological activity to four vegetable pathogens compared to the Schiff base without 5-ethoxycarbonyl and to Gibberlla saubinetti in EC 95 compared with triadimefon. Keywords: Schiff base, crystal structure, 4H-4-amino-1,2,4-triazole, biological activity DOI: /j.cnki INTRODUCTION It has been found that many 1,2,4-triazoles possess a wide spectrum activities including antibacterial, anticancer, antiviral, anti-infection and herbicidal activity [1-4]. As an important type of fungicides, Schiff bases derived from 1,2,4-triazole compounds attracted growing interest for their high effectiveness and low poisonousness [5-8]. In continuation of our interest in the synthesis and biological activity of 4H-4-amino-1,2,4-triazole Schiff bases [9-12]. In order to obtain higher biological activity compounds, we aimed to obtain new Schiff bases including 5- ethoxycarbonyl which may be more through cell wall of pathogens easily. The structure was confirmed by 1 H NMR,IR, H RMS and TGA techniques [13, 14]. The crystal structure and TGA analysis of the title compound are reported here. In addition, the biological activity of the compounds to four pathogens, containing Gibberlla nicotiancola, Pythium solani, Fusarium oxysporium f.s.p. niveum and Gibberlla saubinetii, has been tested. Received 6 August 2014; accepted 11 October 2014 (CCDC ) 1 This project was supported by the National Natural Science Foundation of China (No ) and the Shaanxi Provincial Education Department Foundation (No. 2013JK0666) 2 Corresponding authors. Yang Qing-Cui, majoring in organic synthesis and pesticide chemistry. yqcsrg@126.com; Sun Xiao-Hong, professor, research field: organic chemistry. xhsun888@sohu.com

2 YANG Q. C. et al.: Synthesis, Structure and Biological Activity of 3-Methyl (3-nitrobenzylideneamino)-5-ethoxycarbonyl-methylsulfanyl-1,2,4-triazole No. 2 2 EXPERIMENTAL 2. 1 Reagents and instruments All chemical reagents purchased were of chemical or analytical grade and used without further purification. The melting point determination was performed on a SMP3 melting point apparatus. 1 H NMR spectra were recorded on a Bruker INOVA-400MHz spectrometer with CDCl 3 -d 3 as the solvent and TMS as an internal standard. HRMS was obtained from microtof-q II mass spectrometer. Infrared spectra (IR) were recorded on an irprestige-21 FT-IR spectrometer. Thermogravimetric analysis (TGA) data were collected with a Mettler-toledo TGA/SDTA851 analyzer in N 2 at a heating rate of 10 min -1. The single-crystal structure of the title compound was determined on a Bruker Smart APEX II CCD diffractometer Synthesis of the title compound The title compound was synthesized by 3-methyl- 4H-4-amino-3-thiol-1,2,4-triazole according to the reference [14]. Yield: 64.2%, m.p ~ ESI-HRMS for C 14 H 15 N 5 O 4 S [M+H] + calcd.: ; found: IR (KBr, cm -1 ): 2942 (C H), 1736 (C=O), 1638 (C=N), (C=C), 1345 (C NO 2 ), 1301 (C N), 1228 (C S), 1185 (C O). 1 H NMR (CDCl 3, 400 MHz, TMS): δ (ppm) 8.87 (s, 1H), 8.71 (s, 1H), 8.44 (d, J = 18.7 Hz, 1H), 8.22 (d, J = 7.1 Hz, 1H), 7.73 (s, 1H), 4.29~ 3.96 (m, 4H), 2.56 (s, 4H), 1.27 (t, J = 6.9 Hz, 3H) Structure determination and refinement The crude product was recrystallized from absolute ethanol, and then the title compound dissolved in ethanol was stood at room temperature by slow evaporation. Transparent-yellow single crystal suitable for X-ray analysis was obtained after two months. A yellow single crystal with approximate dimensions of 0.39mm 0.25mm 0.20mm was selected for data collection. X-ray diffraction data were collected on a Bruker SMART APEX II CCD diffractometer equipped with a graphite-monochromated MoKα radiation (λ = Ǻ) by using an F-ω scan mode at 296(2) K. A total of 8184 reflec- tions with 2932 independent ones (R int = ) were collected in the ranges of 1.86<θ<25.10º, 10 h 10, 26 k 17 and 10 l 10, of which 2932 with I > 2σ(I) were used in the succeeding refinement. The structure was solved by direct methods with SHELXS-97 [15], and refined using the full-matrix least-squares technique on F 2 with anisotropic thermal parameters for all non-hydrogen atoms using SHELXL-97 [16]. All C-bound H atoms were placed in the geometrically idealized positions and refined isotropically in the riding model appro- ximation with C H = 0.93 to 0.97 Å and U iso (H) = 1.2 ~ 1.5U eq (C). The final refinement give R = and wr = , (Δ/σ) max = 0.000, S = 1.037, (Δρ) max = and (Δρ) min = e/å Biological activity test The biological activity of the title compound to four vegetable pathogens, containing Gibberlla nicotiancola (A), Pythium solani (B), Fusarium oxysporium f.s.p. niveum (C) and Gibberlla saub- inetii (D), was tested according to the method of the reference [13]. Triadimefon and the Schiff base without 5-ethoxycarbonyl were used as the com- parison compounds. 3 RESULTS AND DISCUSSION 3. 1 Thermogravimetric analysis (TGA) of the title compound The TGA data of the title compound with mg were collected on a Mettler-toledo TGA/SDTA851 analyzer in N 2 at a heating rate of 10 min -1. The TGA curve is illustrated in Fig. 1. TGA measurement was conducted to determine the thermal stability of the title compound. It can be found that the compound has an endothermic peak at , which corresponds to m.p ~ The TGA curve also reveals that the compound has an exothermic peak at , being ascribed to the loss of nitrobenzyl and ethoxycarbonyl (found: 64.65%; calcd: 64.47%) at ~ The remaining product weight is 32.31% when further heating at the range of ~418.71, which

3 2014 Vol. 33 结构化学 (JIEGOU HUAXUE)Chinese J. Struct. Chem. 199 can be ascribed to 3-methyl-4H-4-amino-1,2,4-triazole residue (calcd.: 32.05%). Fig. 1. TGA curve of the title compound at a heating rate 10 min Crystal structure A yellow single crystal of the title compound was cultured for X-ray diffraction analysis. The selected bond lengths and bond angles of the title compound are listed in Table 1. The molecular structure is shown in Fig. 2. The crystal packing of the com- pound is presented in Fig. 3. Fig. 2. Molecule structure of the title compound Fig. 3. Packing diagram of the title compound of a unit cell

4 YANG Q. C. et al.: Synthesis, Structure and Biological Activity of 3-Methyl (3-nitrobenzylideneamino)-5-ethoxycarbonyl-methylsulfanyl-1,2,4-triazole No. 2 Table 1. Selected Bond Lengths (Å) and Bond Angles ( ) Determined by X-ray Diffraction Bond Dist. Bond Dist. Bond Dist. S(1) C(9) 1.731(3) N(4) C(9) 1.306(3) C(2) C(3) 1.380(4) S(1) C(10) 1.793(3) N(4) N(5) 1.405(3) C(3) C(4) 1.360(4) N(1) O(2) 1.216(3) N(5) C(8) 1.302(3) C(4) C(5) 1.394(4) N(1) C(2) 1.465(4) O(3) C(11) 1.197(4) C(5) C(6) 1.384(4) N(2) C(7) 1.264(3) O(4) C(11) 1.314(4) C(6) C(7) 1.469(4) N(2) N(3) 1.388(3) O(4) C(12) 1.467(6) C(8) C(14) 1.471(4) N(3) C(9) 1.374(4) C(1) C(2) 1.373(4) C(10) C(11) 1.494(5) N(3) C(8) 1.392(3) C(1) C(6) 1.386(4) C(12) C(13) 1.424(7) Angle ( ) Angle ( ) Angle ( ) C(9) S(1) C(10) 97.53(15) C(2) C(1) C(6) 118.5(3) N(5) C(8) N(3) 108.1(3) O(2) N(1) O(1) 122.6(3) C(1) C(2) C(3) 122.6(3) N(5) C(8) C(14) 123.8(3) O(2) N(1) C(2) 118.9(3) C(1) C(2) N(1) 118.7(3) N(3) C(8) C(14) 128.1(3) O(1) N(1) C(2) 118.5(3) C(3) C(2) N(1) 118.7(3) N(4) C(9) N(3) 110.5(3) C(7) N(2) N(3) 121.1(2) C(4) C(3) C(2) 118.5(3) N(4) C(9) S(1) 127.9(2) C(9) N(3) N(2) 117.5(2) C(3) C(4) C(5) 120.6(3) N(3) C(9) S(1) 121.6(2) C(9) N(3) C(8) 105.7(2) C(6) C(5) C(4) 120.0(3) C(11) C(10) S(1) 114.7(3) N(2) N(3) C(8) 136.6(3) C(5) C(6) C(1) 119.8(3) O(3) C(11) O(4) 123.9(4) C(9) N(4) N(5) 106.2(2) C(5) C(6) C(7) 119.9(3) O(3) C(11) C(10) 127.0(3) C(8) N(5) N(4) 109.5(2) C(1) C(6) C(7) 120.3(3) O(4) C(11) C(10) 109.1(3) C(11) O(4) C(12) 119.2(3) N(2) C(7) C(6) 118.8(3) C(13) C(12) O(4) 109.9(5) According to Table 1, the bond length of 1.264(3) Å between atoms N(2) and C(7) is similar to those observed in other Schiff bases [17], indicating it is a double bond. The results indicate that the carbonnitrogen bond lengths on the triazole ring are also intermediate between typical C N single (1.47 Å) and C=N double (1.27 Å) bonds [18] from the better conjugated effect of triazole ring. It can be found that the C S bond lengths are almost within the typical C S single bond (1.82 Å) [12] from the effect of triazole ring and ethoxycarbonyl. It can be calculated that the torsion angle of N(3) N(2) C(7) C(6) is 177.1, indicating that the triazole and benzene rings are almost coplanar in the molecular structure. The C H N and C H O hydrogen bonds in Table 2 contribute to the stability and packing of the structure (Fig. 3). It can be found that the title compound has different hydrogen bond connections compared with N H S connections of the Schiff base without 5-ethoxycarbonyl [12] and it could be beneficial to further study the relationship between the structure and properties. Table 2. Hydrogen Bond Lengths (Å) and Bond Angles ( ) for the Compound D H A d(d H) d(h A) d(d A) DHA C(3) H(3) N(5) (4) 151 C(5) H(5) O(3) (5) 160 C(10) H(10A) O(1) (5) 160 C(10) H(10B) N(4) (5) 102 C(12) H(12B) O(3) (6) 105 C(14) H(14B) N(4) (4) Biological activity In this study, we focus our attention on the structural activity relationship. The biological activity test data are given in Table 3. The results indicate that the tested compounds exhibit different antifungal activity to the four plant pathogens. It is interesting to note that the EC 50 and EC 95 values of the title compound are significantly less than the Schiff base without 5-ethoxycarbonyl. It can be also found that the EC 95 value of the title compound to Gibberlla saubinetti is less than triadimefon. All of this means that the title compound

5 2014 Vol. 33 结构化学 (JIEGOU HUAXUE)Chinese J. Struct. Chem. 201 showed a good activity compared to the Schiff base without 5-ethoxycarbonyl and to Gibberlla saubi- netti in EC 95 compared with triadimefon. Table 3. Biological Activity Test Results of the Compound to Four Vegetable Pathogens Compd. Pathogen Regression equation R a EC 50 b /(g L -1 ) EC 95 c /(g L -1 ) Triadimefon A B C D Y = x Y = x Y = x Y = x A Y = x Methyl-4-(3-nitro- B Y = x benzylideneamino)-5- C Y = x thiol-1,2,4-triazole D Y = x A Y = x B Y = x Compound C Y = x D Y = x a R represents correlation coefficient, b EC 50 represents 50% effective concentration, c EC 95 represents 95% effective concentration REFERENCES (1) Uzgoren-Baran, A.; Tel, B. C.; Sarigol, D.; Ozturk, E. I.; Kazkayasi, I.; Okay, G.; Ertan, M.; Tozkoparan, B. Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: novel non-steroidal anti-inflammatory agents with favorable gastrointestinal tolerance. Eur. J. Med. Chem. 2012, 57, (2) Eweiss, N. F.; Bahajaj, A. A.; Elsherbini, E. A. Synthesis of heterocycles. Part VI [l]. Synthesis and antimicrobial activity of some amino-5-aryl-l,2,4-triazole-3-thiones and their derivatives. J. Heterocyclic Chem. 1986, 23, (3) Liu, X. L.; Liu, Y. H.; Shi, Y. C.; Guan, P. Y. Application of Schiff bases in organic synthesis. Chin. J. Org. Chem. 2002, 22, (4) Khanmohammadi, H.; Abnosi, M. H.; Hosseinzadeh, A.; Erfantalab, M. Synthesis, biological and computational study of new Schiff base hydrazones bearing 3-(4-pyridine)-5-mercapto-1,2,4-triazole moiety. Spectrochim Acta Part A 2008, 71, (5) Isloor, A. M.; Kalluraya, B.; Shetty, P. Regioselective reaction: synthesis, characterization and pharmacological studies of some new Mannich bases derived from 1,2,4-triazoles. Eur. J. Med. Chem. 2009, 44, (6) Chohan, Z. H.; Sumrra, S. H.; Youssoufi, M. H.; Hadda, T. B. Metal based biologically active compounds: design, synthesis, and antibacterial/antifungal/cytotoxic properties of triazole-derived Schiff bases and their oxovanadium(iv) complexes. Eur. J. Med. Chem. 2010, 45, (7) Bektas, H.; Karaali, N.; Sahin, D.; Demirbas, A.; Karaoglu, A. S.; Demirbas, N. Synthesis and antimicrobial activities of some new 1,2,4-triazol-ederivatives. Molecules. 2010, 15, (8) Eswaran, S.; Adhikari, A. V.; Shetty, N. S. Synthesis and antimicrobial activities of novel quinoline derivatives carrying 1,2,4-triazole moiety. Eur. J. Med. Chem. 2009, 44, (9) Sun, X. H.; Tao, Y.; Liu, Y. F.; Jia, Y. Q.; Chen, B.; Yang, J. W. Synthesis and biological activities of N-(5-Alkyl-2,4-dihydro-3-thioxo-1,2,4-tria-zol-4-yl) Schiff bases. Chin. J. Org. Chem. 2008, 28, (10) Sun, X. H.; Bai, Y.; Liu, Y. F.; Chen, B. Synthesis, structure and biological activities of 3-substituted phenoxymethyl-4-amino-1,2,4-triazol-5-thione Schiff bases. Acta Chim. Sinica. 2010, 68, (11) Lu, W. T.; Sun, X. H.; Liu, Y. F.; Jin, R. Y. Synthesis and biological activities of 4-amino-5-benzyl-3-mercapto-1,2,4-triazole Schiff bases. Chin. J. Chem. 2012, 75, (12) Jin, R. Y.; Sun, X. H.; Liu, Y. F.; Chen, B.; Shen, S. Q.; Ma, H. X. Synthesis, structure and biological activity of 5-benzyl-4-amino-1,2,4-triazole-3-thione Schiff base. Chin. J. Struct. Chem. 2014, 33, (13) Yand, Q. C.; Sun, X. H.; Liu, Y. F.; Jin, R. Y.; Ma, H. X. Synthesis and biological activity of Schiff base derivatives of 3-methyl-4-amino-5-ethoxycarbonyl-methylsulfanyl-1,2,4-triazole. Chin. J. Chem. 2013, 76, (14) Yand, Q. C.; Sun, X. H.; Liu, Y. F.; Chen, B.; Shen, S. Q. Synthesis and fungicidal activity of Schiff bases

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