Chiral Dicarboxamide Scaffolds Containing a Sulfiliminyl Moiety as

Jun 20, 2014 - The ryanodine receptor (RyR) represents an attractive biological target for insect control and shows great promise in integrated pest ...
1 downloads 0 Views 662KB Size
Download PDF
Article pubs.acs.org/JAFC

Chiral Dicarboxamide Scaffolds Containing a Sulfiliminyl Moiety as Potential Ryanodine Receptor Activators Sha Zhou, Zhehui Jia, Lixia Xiong, Tao Yan, Na Yang, Guiping Wu, Haibin Song, and Zhengming Li* State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, China 300071 ABSTRACT: To search for new environmentally benign insecticides with high activity, low toxicity, and low residue, novel chiral configurations introduced into dicarboxamide scaffolds containing N-cyano sulfiliminyl moieties were first studied. Four series of phthalamides with sulfur-containing side chains were designed, synthesized, and evaluated against oriental armyworm (Pseudaletia separata Walker) and diamondback moth (Plutella xylostella (L.)) for their insecticidal activities. All structures were characterized by 1H NMR, 13C NMR, and HRMS (or elemental analysis), and their configurations were confirmed by optical polarimetry. The biological assessment indicated that some title compounds exhibited significant insecticidal activities. For oriental armyworm, these stereoisomers exerted different impacts on biological activity following the sequence (Sc, Ss) ≥ (Sc, Rs) ≫ (Rc, Ss) > (Rc, Rs), and carbon chirality influenced the activities more strongly than sulfur. Compounds Ia and IIa reached as high an activity as commercial flubendiamide, with LC50 values of 0.0504 and 0.0699 mg L−1, respectively, lower than that of flubendiamide (0.1230 mg L−1). For diamondback moth, the sequence of activity was (Sc, Ss) > (Sc, Rs), and the sulfur chirality influenced the activities more greatly than carbon. Compound IIe exhibited even higher activity than flubendiamide, whereas Ie and Ic,d reached the activity of the latter. The results indicated that the improvement of insecticidal activity probably required a coordination of both carbon and sulfur chirality. Comparative molecular field analysis calculation indicated that stereoisomers with Sc configurations containing strong electron-withdrawing groups such as as CN are important in maintaining the high activity. The chiral scaffolds containing the N-cyano sulfiliminyl moiety are also essential for high larvicidal activity. Some title compounds could be considered as potential candidates for ryanodine receptor activators. KEYWORDS: optically active, sulfiliminyl, insecticidal activity

■

INTRODUCTION To cope with the global food shortage, scientists have been dedicated in discovering novel potent insecticides with new mechanisms of action and ecofriendly properties. The ryanodine receptor (RyR) represents an attractive biological target for insect control and shows great promise in integrated pest management strategies.1,2 As one of the recent successful discoveries, the diamides have been classified as a new group (28: ryanodine receptor modulators) by the Insecticide Resistance Action Committee (IRAC). The first commercial phthalic diamide,3−10 flubendiamide, targeted at the insect ryanodine receptor, has been applied against lepidopteran insects since 2007. Later, some modified structures (A, Figure 1) have been reported, which mainly focused on the phthaloyl moiety, the sulfonylalkyl group in the aliphatic amide moiety, or the heptafluoroisopropyl group in the anilide moiety.11

Recently the discovery of sulfoxaflor (B, Figure 1) aroused our interests in that the N-cyano sulfoximinyl moiety is interesting to consider during our molecular design stage.12−15 Considering its similarity to sulfoximines, the sulfimines have not been rightly examined in agrochemistry, although a few sulfiliminyl derivatives were reported to show some herbicidal activity.16 Sulfimines (where SNH) were postulated to have a small hydrophilic core, a hydrogen bond acceptor, and a hydrogen bond donor. This new approach might reveal unknown biological properties of these novel structures. In recent years, around one-third of all pesticides have chirality in their structures.17 It was reported that compound C (also called CMP; Figure 1) showed high activity with better selectivity and ecological impact.18 Thus, a new chiral sulfiliminyl moiety was introduced into dicarboxamide structures. Besides the introduction of a chiral sulfur atom, we also introduced another chiral carbon center into the new scaffold and studied the influence of these factors on bioactivity. The new optically active phthalamide derivatives were designed and synthesized as shown in Figure 2. Their insecticidal activities against oriental armyworm and diamondback moth were evaluated accordingly. Comparative molecular Received: Revised: Accepted: Published:

Figure 1. © 2014 American Chemical Society

6269

April 11, 2014 June 18, 2014 June 20, 2014 June 20, 2014 dx.doi.org/10.1021/jf501727k | J. Agric. Food Chem. 2014, 62, 6269−6277

Journal of Agricultural and Food Chemistry

Article

Figure 2.

field analysis (CoMFA) calculation was also undertaken. The structure−activity relationship (SAR) was concluded.

■

sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromagraphy.25−28 (S,R)-3-Iodo-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2-yl)N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, Ia: white solid; yield 70.3%; mp 116−119 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H, Ar−NH), 8.83 (d, J = 7.8 Hz, 1H, −CNH), 8.05 (d, J = 7.9 Hz, 1H, Ar−H), 7.79−7.75 (m, 2H, Ar−H), 7.54 (d, J = 7.3 Hz, 2H, Ar−H), 7.31 (t, J = 7.8 Hz, 1H, Ar−H), 4.24 (dt, J = 13.6, 6.8 Hz, 1H, −N−CH), 3.29 (dd, J = 12.7, 5.9 Hz, 1H, −SCH2), 3.18 (dd, J = 7.9, 4.9 Hz, 1H, −SCH2), 2.66 (s, 3H, −SCH3), 2.36 (s, 3H, ArCH3), 1.26 (d, J = 6.7 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 167.68, 165.45, 141.54, 140.92, 139.25, 135.59, 133.63, 130.31, 127.38, 127.20, 125.79, 123.33, 121.80, 120.48, 95.32, 54.77, 41.27, 32.01, 18.67, 17.94. Aanl. Calcd for C23H20F7IN4O2S: C, 40.75; H, 3.01; N, 8.13. Found: C, 40.84; H, 2.98; N, 8.28. HRMS calcd for C23H20F7IN4O2SH ([M + H]+): 677.0313. Found: 677.0310. [α]20D = −8.2 (c = 10, EtOAc). (S,R)-3-Fluoro-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2yl)-N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, Ib: white solid; yield 59.6%; mp 103−105 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H, Ar−NH), 8.96 (d, J = 7.9 Hz, 1H, −CNH), 7.75 (d, J = 8.1 Hz, 1H, Ar−H), 7.64 (m, 2H, Ar−H), 7.56 (d, J = 8.3 Hz, 2H, Ar−H), 7.53−7.46 (m, 1H, Ar−H), 4.40−4.22 (m, 1H, −N− CH), 3.43−3.27 (m, 1H, −SCH2), 3.20 (dd, J = 12.6, 6.9 Hz, 1H, −SCH2), 2.74 (s, 3H, −SCH3), 2.39 (s, 3H, ArCH3), 1.28 (d, J = 6.6 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 165.31, 163.06, 159.62, 157.17, 139.28, 136.62, 134.00, 130.95, 127.25, 126.20, 123.80, 123.34, 120.43, 118.18, 117.95, 54.90, 32.07, 18.90, 17.98. HRMS calcd for C23H20F8N4O2SH ([M + H]+): 569.1252. Found: 569.1256. [α]20D = −31.6 (c = 10, EtOAc). (S,R)-3-Chloro-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2yl)-N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, Ic: white solid; yield 61.2%; mp 120−122 °C; 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H, Ar−NH), 8.91 (s, 1H, −CNH), 7.72 (m, 3H, Ar−H), 7.58 (m, 3H, Ar−H), 4.28 (m, 1H, −N−CH), 3.19 (m, 2H, −SCH2), 2.70 (s, 3H, −SCH3), 2.37 (s, 3H, ArCH3), 1.25 (d, J = 6.0 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 165.31, 164.85, 139.23, 135.97 (d, J = 16.3 Hz), 133.85, 131.49, 130.69, 130.19, 127.16, 126.52, 126.01, 123.29, 121.84, 120.46, 54.84, 41.22, 31.96, 18.80, 17.96. HRMS calcd for C23H20ClF7N4O2SH ([M + H]+): 585.0957. Found: 585.0951. [α]20D = −28.0 (c = 10, EtOAc). (S,R)-3-Nitro-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2-yl)N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, Id: white solid; yield 69.8%; mp 121−123 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H, Ar−NH), 9.04 (d, J = 7.6 Hz, 1H, −CNH), 8.25 (d, J = 8.1 Hz, 1H, Ar−H), 8.12 (d, J = 7.4 Hz, 1H, Ar−H), 7.82 (dd, J = 16.2, 8.4 Hz, 2H, Ar−H), 7.57 (m, 2H, Ar−H), 4.22 (dt, J = 13.4, 6.6 Hz, 1H, −N−CH), 3.26 (dd, J = 12.8, 6.0 Hz, 1H, −SCH2), 3.15 (dd, J = 12.7, 6.7 Hz, 1H, −SCH2), 2.69 (s, 3H, −SCH3), 2.39 (s, 3H, ArCH3), 1.22 (d, J = 6.7 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 165.56, 164.14, 147.10, 139.58, 137.61, 135.84 (d, J = 354.8 Hz), 135.84 (d, J = 354.8 Hz), 138.43−131.64 (m), 131.19 (d, J = 85.7 Hz), 130.42−127.83 (m), 130.42−123.89 (m), 122.37, 120.37, 55.03, 41.82, 33.13, 19.91, 18.49. HRMS calcd for C23H20F7N5O4SH

MATERIALS AND METHODS

Instruments and Materials. The melting points were determined on an X-4 binocular microscope melting point apparatus (Beijing Tech Instrument Co., Beijing, China) and are uncorrected. 1H NMR and 13 C NMR spectra were recorded at 300 MHz (Bruker AC-P 300 spectrometer) or 400 MHz (Bruker AV 400 spectrometer) in CDCl3 or DMSO-d6 solution with tetramethylsilane as internal standard, and chemical shift (δ) were recorded in parts per million. Elemental analyses were performed on a Vario EL elemental analyzer. HRMS data were obtained by Varian QFT-ESI. Optical rotations were measured with a PerkinElmer 341 polarimeter at 20 °C. GC-MS was recorded on HP 5973 MSD with 6890 GC flash chromatography with silica gel (200−300 mesh). All reagents were analytically pure. All solvents and liquid reagents were dried according to standard methods and distilled before use. Commercial insecticide flubendiamide was used only as contrast compound and synthesized according to the literature.19 3-Substituted anhydride compounds 4a−f,20,21 2-methyl4-(perfluoropropan-2-yl)aniline 6a,22 (S)-1-(methylthio)propan-2amine 3, and (R)-1-(methylthio)propan-2-amine 1023 were synthesized according to the methods reported in the cited literature. Synthesis of Intermediate Compounds. Synthesis of 1(methylthio)propan-2-amine 3: pale yellow liquid; yield 57.8%; 1H NMR (400 MHz, CDCl3-d6) δ 2.90 (dqd, J = 8.4, 6.3, 4.5 Hz, 1H, −CHNH2), 2.42 (dd, J = 13.2, 4.4 Hz, 1H, −SCH2−), 2.19 (dd, J = 13.2, 8.4 Hz, 1H, −SCH2−), 1.95 (s, 3H, −SCH3), 0.99 (d, J = 6.4 Hz, 3H, −C−CH3). (S)-1-(Methylthio)propan-2-amine 12: [α]20D +30.13 (c = 53.7, CHCl3). (R)-1-(Methylthio)propan-2-amine 13: [α]20D = −29.79 (c = 53.2, CHCl3). General Synthetic Procedure for Compounds 7a−f. These phthalamide derivatives were synthesized in moderate yield according to the method reported in the literature. The melting point and 1H NMR data were consistent with the literature.24 (S)-N 1 -(1-(Methylthio)propan-2-yl)-N 2 -(3-(trifluoromethyl)phenyl)phthalamide, 7f: 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H, Ar−NH), 8.36 (d, J = 7.7 Hz, 1H, −CNH), 8.22 (s, 1H, Ar−H), 7.90 (d, J = 7.1 Hz, 1H, Ar−H), 7.58 (m, 5H, Ar−H), 7.44 (d, J = 7.0 Hz, 1H, Ar−H), 4.08−3.98 (m, 1H, −N−CH), 2.66 (dd, J = 13.0, 6.3 Hz, 1H, −SCH2), 2.54 (m, 1H, −SCH2), 2.05 (s, 3H, −SCH3), 1.19 (d, J = 6.3 Hz, 3H, −CCH3). General Synthetic Procedure for Compounds Ia−e, IIa−e, IIIa−d, and IVa−d. A mixture of 1.0 mmol of 7a−f and 0.046 g (1.1 mmol) of cyanamide in 20 mL of acetonitrile was cooled below 0 °C. To this solution was added 0.322 g (1 mmol) of iodobenzene diacetate all at once. The reaction mixture was allowed to stir below 0 °C for 10 min and slowly warmed to room temperature over 1.5 h; the progress of the reaction was followed by TLC. Excess oxidant was destroyed by adding 5 mL of 2.5% aqueous sodium metabisulfite. The solution was washed with dilute hydrochloric acid, water, an aqueous sodium carbonate solution, and water, respectively, and dried over anhydrous 6270

dx.doi.org/10.1021/jf501727k | J. Agric. Food Chem. 2014, 62, 6269−6277

Journal of Agricultural and Food Chemistry

Article

([M + H]+): 596.1197. Found: 596.1194. [α]20D = −18.8 (c = 3, MeOH). (S,R)-3-Bromo-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2yl)-N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, Ie: white solid; yield 71.2%; mp 116−118 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H, Ar−NH), 8.89 (d, J = 8.0 Hz, 1H, −CNH), 7.85 (d, J = 8.0 Hz, 1H, Ar−H), 7.78 (dd, J = 13.7, 8.2 Hz, 2H, Ar− H), 7.55 (d, J = 7.7 Hz, 2H, Ar−H), 7.51 (t, J = 7.9 Hz, 1H, Ar−H), 4.26 (dt, J = 13.7, 6.9 Hz, 1H, −N−CH), 3.30 (dd, J = 12.7, 5.9 Hz, 1H, −SCH2), 3.18 (dd, J = 12.7, 7.1 Hz, 1H, −SCH2), 2.69 (s, 3H, −SCH3), 2.37 (s, 3H, ArCH3), 1.26 (d, J = 6.8 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 165.77, 165.31, 139.24, 137.80, 136.15, 134.60, 133.75, 130.36, 127.55−126.83 (m), 125.91, 123.32 (d, J = 10.2 Hz), 121.79 (d, J = 20.5 Hz), 121.59−121.53 (m), 120.47, 120.06, 118.98, 118.71, 54.80, 41.24, 31.95, 18.75, 17.96. HRMS calcd for C23H20BrF7N4O2SH ([M + H]+): 629.0452. Found: 629.0453. [α]20D = −4.0 (c = 1.5, MeOH). (S,R)-N2-(1-(N-Cyano-S-methylsulfinimidoyl)propan-2-yl)-N1-(3(trifluoromethyl)phenyl)phthalamide, If: white solid; yield 79.7%; mp 74−78 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H, Ar−NH), 8.75 (s, 1H, −CNH), 8.21 (s, 1H, Ar−H), 7.91 (d, J = 7.8 Hz, 1H, Ar−H), 7.66−7.57 (m, 5H, Ar−H), 7.44 (d, J = 7.4 Hz, 1H, Ar−H), 4.35−4.25 (m, 1H, −N−CH), 3.38−3.36 (m, 1H, −SCH2), 3.29−3.21 (m, 1H, −SCH2), 2.83 (s, 3H, −SCH3), 1.29 (d, J = 5.6 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 167.39, 167.34, 140.14, 136.33, 135.58, 129.92, 129.67 (d, J = 32.5 Hz), 129.20, 127.67 (d, J = 18.9 Hz), 125.49, 123.06, 122.78, 120.55, 119.69, 115.54, 55.35, 41.27, 32.24, 19.44. HRMS calcd for C20H19F3N4O2SH ([M + H]+), 437.1254. Found: 437.1252. [α]20D = −29.8 (c = 10, MeOH). (S,S)-3-Iodo-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2-yl)1 N -(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, IIa: white solid; yield 29.7%; mp 116−118 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H, Ar−NH), 8.70 (d, J = 6.6 Hz, 1H, −CNH), 8.04 (d, J = 6.8 Hz, 1H, Ar−H), 7.82−7.74 (m, 2H, Ar−H), 7.55 (m, 2H, Ar−H), 7.31 (m, 1H, Ar−H), 4.23 (m, 1H, -N−CH), 3.28−3.20 (m, 1H, −SCH2), 3.16 (d, J = 11.1 Hz, 1H, −SCH2), 2.67 (s, 3H, −SCH3), 2.37 (s, 3H, ArCH3), 1.28 (d, J = 5.1 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 167.72, 165.51, 140.77, 141.58, 139.29, 135.86, 133.52, 130.29, 127.36, 125.67, 123.34, 121.50, 120.12, 95.101, 54.76, 41.15, 32.80, 19.62, 17.98. HRMS calcd for C23H20F7IN4O2SH ([M + H]+): 677.0313. Found: 677.0310. [α]20D = +51.2 (c = 10, EtOAc). (S,S)-3-Fluoro-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2yl)-N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, IIb: white solid; yield 40.4%; mp 106−107 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H, Ar−NH), 8.79 (d, J = 7.6 Hz, 1H, −CNH), 7.75 (d, J = 7.9 Hz, 1H, Ar−H), 7.61 (m, 2H, Ar−H), 7.54 (d, J = 9.2 Hz, 2H, Ar−H), 7.49 (d, J = 8.0 Hz, 1H, Ar−H), 4.27 (m, 1H, −N− CH), 3.23 (m, 2H, −SCH2), 2.76 (s, 3H, −SCH3), 2.38 (s, 3H, ArCH3), 1.27 (d, J = 6.4 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 165.38, 163.01, 159.54, 159.09, 139.32, 136.98, 133.91, 130.92 (d, J = 32.0 Hz), 127.18 (d, J = 44.0 Hz), 126.09, 124.91 (d, J = 79.6 Hz), 123.28 (d, J = 37.6 Hz), 121.78 (d, J = 80.4 Hz), 119.91, 117.91 (d, J = 87.6 Hz), 54.48, 41.20, 32.67, 19.90, 18.00. HRMS calcd for C23H20F8N4O2SH ([M + H]+): 569.1252. Found: 569.1256. [α]20D = +42.0 (c = 10, EtOAc). (S,S)-3-Chloro-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2yl)-N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, IIc: white solid; yield 38.8%; mp 83−86 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H, Ar−NH), 8.76 (d, J = 7.8 Hz, 1H, −CNH), 7.76 (dd, J = 14.4, 7.9 Hz, 2H, Ar−H), 7.70 (d, J = 7.9 Hz, 1H, Ar− H), 7.61−7.53 (m, 3H, Ar−H), 4.26 (m, 1H, −N−CH), 3.22 (m, 2H, −SCH2), 2.72 (s, 3H, −SCH3), 2.38 (s, 3H, ArCH3), 1.26 (d, J = 6.7 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 165.38, 164.88, 139.26, 136.32, 135.91, 133.76, 131.31, 130.62, 130.16, 127.19 (d, J = 11.2 Hz), 126.46, 125.87, 123.35, 121.83, 121.63, 120.04, 54.53, 41.06, 32.75, 19.73, 17.99. Aanl. Calcd for C23H20ClF7N4O2S: C, 47.23; H, 3.45; N, 9.58. Found: C, 46.98; H, 3.48; N, 9.68. HRMS calcd for C23H20ClF7N4O2SH ([M + H]+): 585.0957. Found: 585.0951. [α]20D = +68.4 (c = 10, MeOH).

(S,S)-3-Nitro-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2-yl)N -(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, IId: white solid; yield 30.2%; mp 99−102 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H, Ar−NH), 8.88 (d, J = 7.1 Hz, 1H, −CNH), 8.26 (d, J = 7.7 Hz, 1H, Ar−H), 8.10 (d, J = 7.0 Hz, 1H, Ar−H), 7.84 (d, J = 7.6 Hz, 2H, Ar−H), 7.57 (m, 2H, Ar−H), 4.19 (m, 1H, −N−CH), 3.26− 3.18 (m, 1H, −SCH2), 3.14 (m, 1H, −SCH2), 2.68 (s, 3H, −SCH3), 2.40 (s, 3H, ArCH3), 1.25 (d, J = 5.7 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 166.25, 164.84, 147.80, 140.27, 138.30, 134.77, 134.28, 132.31, 131.46, 128.43 (d, J = 10.5 Hz), 126.91 (d, J = 19.0 Hz), 124.47, 122.98 (d, J = 20.5 Hz), 121.07, 55.73, 42.53, 33.84, 20.60, 19.18. HRMS calcd for C23H20F7N5O4SH ([M + H]+): 596.1197. Found: 596.1194. [α]20D = +23.6 (c = 2, MeOH). (S,S)-3-Bromo-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2yl)-N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, IIe: white solid; yield 28.8%; mp 94−96 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.05 (d, J = 12.5 Hz, 1H, Ar−NH), 8.76 (t, J = 8.1 Hz, 1H, −CNH), 7.74−7.69 (m, 3H, Ar−H), 7.60−7.47 (m, 3H, Ar−H), 4.25 (m, 1H, −N−CH), 3.27−3.16 (m, 2H, −SCH2), 2.71 (d, J = 5.9 Hz, 3H, −SCH3), 2.37 (s, 3H, ArCH3), 1.25 (d, J = 6.7 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO) δ 165.61, 164.89, 139.28, 137.83, 136.34, 135.93, 134.43, 133.77, 131.32, 130.63, 130.17, 127.25−126.47 (m), 125.88, 123.35, 121.73 (d, J = 20.7 Hz), 121.53−121.35 (m), 120.06, 54.52, 41.07, 32.79 (d, J = 8.3 Hz), 19.74, 18.00. HRMS calcd for C23H20BrF7N4O2SH ([M + H]+): 629.0452. Found: 629.0453. [α]20D = +2.6 (c = 0.5, MeOH). (S,S)-N2-(1-(N-Cyano-S-methylsulfinimidoyl)propan-2-yl)-N1-(3(trifluoromethyl)phenyl)phthalamide, IIf: white solid; yield 20.3%; mp 85−87 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H, Ar−NH), 8.58 (d, J = 7.2 Hz, 1H, −CNH), 8.20 (m, 1H, Ar−H), 7.89 (m, 1H, Ar−H), 7.59 (d, J = 5.9 Hz, 5H, Ar−H), 7.44 (d, J = 7.2 Hz, 1H, Ar− H), 4.27 (m, 1H, −N−CH), 3.29 (d, J = 9.6 Hz, 2H, −SCH2), 2.81 (s, 3H, −SCH3), 1.27 (d, J = 6.6 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 167.43, 167.23, 140.17, 136.43, 135.62, 129.84 (d, J = 10.9 Hz), 129.50, 129.19, 127.70 (d, J = 23.9 Hz), 125.50, 123.05, 120.08, 119.63, 115.54, 54.24, 41.01, 32.67, 19.88. HRMS calcd for C20H19F3N4O2SH ([M + H]+): 437.1254. Found: 437.1252. [α]20D = +45.1 (c = 10, MeOH). (R,S)-3-Iodo-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2-yl)N 1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, IIIa: white solid; yield 70.3%; mp 116−118 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H, Ar−NH), 8.83 (d, J = 7.8 Hz, 1H, −CNH), 8.05 (d, J = 7.9 Hz, 1H, Ar−H), 7.79−7.75 (m, 2H, Ar−H), 7.54 (d, J = 7.3 Hz, 2H, Ar−H), 7.31 (t, J = 7.8 Hz, 1H, Ar−H), 4.24 (dt, J = 13.6, 6.8 Hz, 1H, −N−CH), 3.29 (dd, J = 12.7, 5.9 Hz, 1H, −SCH2), 3.18 (dd, J = 7.9, 4.9 Hz, 1H, −SCH2), 2.66 (s, 3H, −SCH3), 2.36 (s, 3H, ArCH3), 1.26 (d, J = 6.7 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 167.68, 165.45, 141.54, 140.92, 139.25, 135.59, 133.63, 130.31, 127.38, 127.20, 125.79, 123.33, 121.80, 120.48, 95.32, 54.77, 41.27, 32.01, 18.67, 17.94. Anal. Calcd for C23H20F7IN4O2S: C, 40.75; H, 3.01; N, 8.13. Found: C, 40.84; H, 2.98; N, 8.28. HRMS calcd for C23H20F7IN4O2SH ([M + H]+): 677.0313. Found: 677.0310. [α]20D = +8.3 (c = 10, EtOAc). (R,S)-3-Fluoro-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2yl)-N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, IIIb: white solid; yield 59.6%; mp 106−108 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H, Ar−NH), 8.96 (d, J = 7.9 Hz, 1H, −CNH), 7.75 (d, J = 8.1 Hz, 1H, Ar−H), 7.64 (m, 2H, Ar−H), 7.56 (d, J = 8.3 Hz, 2H, Ar−H), 7.53−7.46 (m, 1H, Ar−H), 4.40−4.22 (m, 1H, −N− CH), 3.43−3.27 (m, 1H, −SCH2), 3.20 (dd, J = 12.6, 6.9 Hz, 1H, −SCH2), 2.74 (s, 3H, −SCH3), 2.39 (s, 3H, ArCH3), 1.28 (d, J = 6.6 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 165.31, 163.06, 159.62, 157.17, 139.28, 136.62, 134.00, 130.95, 127.25, 126.20, 123.80, 123.34, 120.43, 118.18, 117.95, 54.90, 32.07, 18.90, 17.98. HRMS calcd for C23H20F8N4O2SH ([M + H]+): 569.1252. Found: 569.1256. [α]20D = +30.9 (c = 10, EtOAc). (R,S)-3-Chloro-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2yl)-N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, IIIc: white solid; yield 61.2%; mp 121−122 °C; 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H, Ar−NH), 8.91 (s, 1H, −CNH), 7.72 (m, 1

6271

dx.doi.org/10.1021/jf501727k | J. Agric. Food Chem. 2014, 62, 6269−6277

Journal of Agricultural and Food Chemistry

Article

Scheme 1

3H, Ar−H), 7.58 (m, 3H, Ar−H), 4.28 (m, 1H, −N−CH), 3.19 (m, 2H, −SCH2), 2.70 (s, 3H, −SCH3), 2.37 (s, 3H, ArCH3), 1.25 (d, J = 6.0 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 165.31, 164.85, 139.23, 135.97 (d, J = 16.3 Hz), 133.85, 131.49, 130.69, 130.19, 127.16, 126.52, 126.01, 123.29, 121.84, 120.46, 54.84, 41.22, 31.96, 18.80, 17.96. HRMS calcd for C23H20ClF7N4O2SH ([M + H]+): 585.0957. Found: 585.0951. [α]20D = +28.1 (c = 10, EtOAc). (R,S)-3-Nitro-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2-yl)1 N -(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, IIId: white solid; yield 69.8%; mp 119−121 °C; 1H NMR (400 MHz,

DMSO-d6) δ 10.22 (s, 1H, Ar−NH), 9.04 (d, J = 7.6 Hz, 1H, −CNH), 8.25 (d, J = 8.1 Hz, 1H, Ar−H), 8.12 (d, J = 7.4 Hz, 1H, Ar−H), 7.82 (dd, J = 16.2, 8.4 Hz, 2H, Ar−H), 7.57 (m, 2H, Ar−H), 4.22 (dt, J = 13.4, 6.6 Hz, 1H, −N−CH), 3.26 (dd, J = 12.8, 6.0 Hz, 1H, −SCH2), 3.15 (dd, J = 12.7, 6.7 Hz, 1H, −SCH2), 2.69 (s, 3H, −SCH3), 2.39 (s, 3H, ArCH3), 1.22 (d, J = 6.7 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 165.56, 164.14, 147.10, 139.58, 137.61, 135.84 (d, J = 354.8 Hz), 135.84 (d, J = 354.8 Hz), 138.43−131.64 (m), 131.19 (d, J = 85.7 Hz), 130.42−127.83 (m), 130.42−123.89 (m), 122.37, 120.37, 55.03, 41.82, 33.13, 19.91, 18.49. HRMS calcd for C23H20F7N5O4SH 6272

dx.doi.org/10.1021/jf501727k | J. Agric. Food Chem. 2014, 62, 6269−6277

Journal of Agricultural and Food Chemistry

Article

deviations of the tested biological values were ±5%. LC50 and LC95 values were calculated by probit analysis.30 Larvicidal Activity against Oriental Armyworm (Mythimna separata Walker). The larvicidal activity of the title compounds and commercial flubendiamide against oriental armyworm was tested according to the leaf-dip method using the reported procedure.31 Leaf disks (about 5 cm) were cut from fresh corn leaves and were dipped into the test solution for 3−5 s. After drying, the treated leaf disks were placed individually into a glass-surface vessel (7 cm). Each dried treated leaf disk was infested with 10 third-instar oriental armyworm larvae. Percentage mortalities were evaluated 4 days after treatment. Leaves treated with acetone were provided as controls. Each treatment was performed three times. The larvicidal activities of Ia, IIIa, Va, and flubendiamide against oriental armyworm are listed in Table 2. The insecticidal activity is summarized in Table 3. LC50 values of compounds Ia,b, IIa,b, IId, IIIa,b, and IVa,b and flubendiamide against oriental armyworm are listed in Table 4. Larvicidal Activity against Diamondback Moth (Plutella xylostella L.). The larvicidal activity of the title compounds and flubendiamide against diamondback moth was tested by the leaf-dip method using the reported procedure.32,33 Leaf disks (5 cm × 3 cm) were cut from fresh cabbage leaves and then dipped into the test solution for 3 s. After air-drying, the treated leaf disks were placed individually into boxes (80 cm). Each dried treated leaf disk was infested with 30 second-instar diamondback moth larvae. Percentage mortalities were evaluated 3 days after treatment. Each treatment was performed three times. The insecticidal activity is summarized in Table 5.

([M + H]+): 596.1197. Found: 596.1194. [α]20D = +19.2 (c = 3, MeOH). (R,R)-3-Iodo-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2-yl)1 N -(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, IVa: white solid; yield 29.7%; mp 116−118 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H, Ar−NH), 8.70 (d, J = 6.6 Hz, 1H, −CNH), 8.04 (d, J = 6.8 Hz, 1H, Ar−H), 7.82−7.74 (m, 2H, Ar−H), 7.55 (m, 2H, Ar−H), 7.31 (m, 1H, Ar−H), 4.23 (m, 1H, −N−CH), 3.28−3.20 (m, 1H, −SCH2), 3.16 (d, J = 11.1 Hz, 1H, −SCH2), 2.67 (s, 3H, −SCH3), 2.37 (s, 3H, ArCH3), 1.28 (d, J = 5.1 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 167.72, 165.51, 140.77, 141.58, 139.29, 135.86, 133.52, 130.29, 127.36, 125.67, 123.34, 121.50, 120.12, 95.101, 54.76, 41.15, 32.80, 19.62, 17.98. HRMS calcd for C23H20F7IN4O2SH ([M + H]+): 677.0313. Found: 677.0310. [α]20D = −50.9 (c = 10, EtOAc). (R,R)-3-Fluoro-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2yl)-N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, IVb: white solid; yield 40.4%; mp 105−106 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H, Ar−NH), 8.79 (d, J = 7.6 Hz, 1H, −CNH), 7.75 (d, J = 7.9 Hz, 1H, Ar−H), 7.61 (m, 2H, Ar−H), 7.54 (d, J = 9.2 Hz, 2H, Ar−H), 7.49 (d, J = 8.0 Hz, 1H, Ar−H), 4.27 (m, 1H, −N− CH), 3.23 (m, 2H, −SCH2), 2.76 (s, 3H, −SCH3), 2.38 (s, 3H, ArCH3), 1.27 (d, J = 6.4 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 165.38, 163.01, 159.54, 159.09, 139.32, 136.98, 133.91, 130.92 (d, J = 32.0 Hz), 127.18 (d, J = 44.0 Hz), 126.09, 124.91 (d, J = 79.6 Hz), 123.28 (d, J = 37.6 Hz), 121.78 (d, J = 80.4 Hz), 119.91, 117.91 (d, J = 87.6 Hz), 54.48, 41.20, 32.67, 19.90, 18.00 (s). HRMS calcd for C23H20F8N4O2SH ([M + H]+): 569.1252. Found: 569.1256. [α]20D = −41.5 (c = 10, EtOAc). (R,R)-3-Chloro-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2yl)-N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, IVc: white solid; yield 38.8%; mp 85−87 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H, Ar−NH), 8.76 (d, J = 7.8 Hz, 1H, −CNH), 7.76 (dd, J = 14.4, 7.9 Hz, 2H, Ar−H), 7.70 (d, J = 7.9 Hz, 1H, Ar− H), 7.61−7.53 (m, 3H, Ar−H), 4.26 (m, 1H, −N−CH), 3.22 (m, 2H, −SCH2), 2.72 (s, 3H, −SCH3), 2.38 (s, 3H, ArCH3), 1.26 (d, J = 6.7 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 165.38, 164.88, 139.26, 136.32, 135.91, 133.76, 131.31, 130.62, 130.16, 127.19 (d, J = 11.2 Hz), 126.46, 125.87, 123.35, 121.83, 121.63, 120.04, 54.53, 41.06, 32.75, 19.73, 17.99. Aanl. Calcd for C23H20ClF7N4O2S: C, 47.23; H, 3.45; N, 9.58. Found: C, 46.98; H, 3.48; N, 9.68. HRMS calcd for C23H20ClF7N4O2SH ([M + H]+): 585.0957. Found: 585.0951. [α]20D = −67.9 (c = 10, EtOAc). (R,R)-3-Nitro-N2-(1-(N-cyano-S-methylsulfinimidoyl)propan-2-yl)1 N -(2-methyl-4-(perfluoropropan-2-yl)phenyl)phthalamide, IVd: white solid; yield 30.2%; mp 99−101 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H, Ar−NH), 8.88 (d, J = 7.1 Hz, 1H, −CNH), 8.26 (d, J = 7.7 Hz, 1H, Ar−H), 8.10 (d, J = 7.0 Hz, 1H, Ar−H), 7.84 (d, J = 7.6 Hz, 2H, Ar−H), 7.57 (m, 2H, Ar−H), 4.19 (m, 1H, −N− CH), 3.26−3.18 (m, 1H, −SCH2), 3.14 (m, 1H, −SCH2), 2.68 (s, 3H, −SCH3), 2.40 (s, 3H, ArCH3), 1.25 (d, J = 5.7 Hz, 3H, −CCH3); 13C NMR (101 MHz, DMSO-d6) δ 166.25, 164.84, 147.80, 140.27, 138.30, 134.77, 134.28, 132.31, 131.46, 128.43 (d, J = 10.5 Hz), 126.91 (d, J = 19.0 Hz), 124.47, 122.98 (d, J = 20.5 Hz), 121.07, 55.73, 42.53, 33.84, 20.60, 19.18. HRMS calcd for C23H20F7N5O4SH ([M + H]+): 596.1197. Found: 596.1194. [α]20D = −22.9 (c = 2, MeOH). X-ray Diffraction. The crystal structure of compound If was determined, and X-ray intensity data were recorded on a Bruker SMART 1000 CCD diffraction meter using graphite monochromated Mo Kα radiation (λ = 0.71073 Å). All calculations were refined anisotropically. All hydrogen atoms were located from a difference Fourier map and were placed at calculated positions and were included in the refinements in the riding mode with isotropic thermal parameters. Biological Assay. All bioassays were performed on representative test organisms reared in the laboratory. The bioassay was repeated at 25 ± 1 °C according to statistical requirements. Assessments were made on a dead/alive basis, and mortality rates were corrected using Abbott’s formula.29 Evaluations were based on a percentage scale of 0−100, in which 0 = no activity and 100 = total kill. The standard

■

RESULTS AND DISCUSSION Synthesis. The method of oxidative imination based on a sulfide was followed to prepare these sulfilimines. Cyanogen amine was used as a nitrogen source, and hypervalent iodinane such as PhI(OAc)2 was used as a mild oxidant. The reaction of the sulfide with cyanogen amine in the presence of PhI(OAc)2 was carried out in 1,4-dioxane. The preferred reaction temperature ranged from −5 to 0 °C. N-Cyanosulfilimines were obtained in 95−99% yield with the ratio of diastereoselectivity 7:3. The title compounds were synthesized as shown in Scheme 1. The title compounds have been characterized by melting point, 1H NMR, 13C NMR, elemental analyses (or highresolution mass spectrometry), and optical polarimetry. All spectral and analytical data were consistent with the assigned structures. Physical parameters of each pair of enantiomers were alike, except with the opposite specific optical rotation signs. Compared with each diastereoisomer in I and II, the value of HRMS was the same, whereas differences were found in the melting points and proton signals of −NHCO− in the aliphatic amide moiety. As shown in Table 1, the melting point of isomer in I was approximately equal to or lower than that of the corresponding diastereoisomer in II. As for the proton signals of −NHCO− in the aliphatic amide moiety, the former was 0.14−0.16 ppm higher than the later, as well as in III and IV. Specific optical rotation values were negative (I), positive (II), positive (III), and negative (IV), respectively (Table 1). In 1 H NMR spectra of all title compounds, the proton signals of −NHCO− on the amide bridge were observed at δ 8.26−10.84 and 7.96−8.90 as a singlet or doublet, respectively. In all title compounds, the methyne proton appeared at δ 4.23−4.53 as a multiplet, and the methylene protons attached to the sulfur atom appeared at δ 3.52−4.16 and 2.97−3.89 as a couple of doublets due to respective chemical environment. Meanwhile, in the 1H NMR of aliphatic amide moiety, methyl protons attached to tertiary carbon were observed as a doublet as well. 6273

dx.doi.org/10.1021/jf501727k | J. Agric. Food Chem. 2014, 62, 6269−6277

Article

99−101 −22.9 (c = 3) 596.1197

Crystal Structure Analysis. To identify the chiral characteristic of each isomer, the colorless crystal (0.20 mm × 0.10 mm × 0.10 mm) structure of compound If was obtained in DMSO, which was suitable for X-ray single-crystal diffraction as shown in Figure 3 with the following crystallographic

105−106 −41.5 (c = 10) 569.1252

Figure 3. Crystal structure of compound If.

parameters: a = 5.0807(10) Å, b = 21.298 (4) Å, c = 19.011(4) Å, α = 90°, β = 90.17 (3)°, γ = 90°, V = 2057.1(7) Å3, Z = 4, Dc = 1.409 mg m−3, μ = 0.208 mm−1, F (100) = 904, R = 0.0717, wR = 0.0908, final R factor = 4.37%, final wR factor = 7.98%, absolute structure parameter = 0.02 (7). Structure−Activity Relationship (SAR). Larvicidal Activity against Oriental Armyworm. To explore the impact of carbon chirality on larvicidal activity, Va (the racemic compound of Ia and IIIa) was evaluated against oriental armyworm for its insecticidal activity. As shown in Table 2, Va displayed 60, 40, and 20% larvicidal activities at concentration of 0.5, 0.25, and 0.1 mg L−1, respectively, which showed better activity than IIIa (0.5 mg L−1, 20%) and weaker activity than Ia (0.1 mg L−1, 60%). These observations clearly revealed that the Sc configuration of Ia improved the bioactivity greatly. Furthermore, carbon chirality resulted from the aliphatic amine, which can easily be derived from the obtained (L)alanine. The larvicidal activities of compounds Ia−e, IIa−e, IIIa−d, and IVa−d and flubendiamide against oriental armyworm are listed in Tables 3 and 4. Most compounds exhibited good to excellent activity against oriental armyworm. Generally, the sequence of each configuration’s biological activity is (Sc, Ss) ≥ (Sc, Rs) ≫ (Rc, Ss) > (Rc, Rs). For example, IId (Sc, Ss) showed 60% insecticidal activity at 0.25 mg L−1 (0.5 mg L−1, 100%), whereas Id (Sc, Rs) gave a death rate of 60% at only 1 mg L−1. It is worth noting that the Sc configurations showed much better than Rc configurations. At a higher concentration of 10 mg L−1, we can see that IIId (Rc, Ss) (50%) showed better activity than IVd (Rc, Rs) (30%). As seen for other substituents in the phthaloyl moiety, (Sc, Ss) II was most active followed by (Sc, Rs) I and (Rc, Ss) III, and the (Rc, Rs) IV was almost inactive. The results indicated that the improvement of insecticidal activity required a reasonable coordination of both carbon and sulfur chirality and that a probable synergistic effect was involved. In comparison, Sc configurations (Ia vs IIa, Ib vs IIb, Ie vs IIe) and Rc configurations (IIIb vs IVb, IIIc vs IVc, IIId vs

116−118 +8.3 (c = 10) 677.0313 mp (°C) [α]20D HMRS (M + H)

106−108 +30.9 (c = 10) 569.1252

121−122 +28.1 (c = 10) 585.0957

119−121 +19.2 (c = 3) 596.1197

116−117 −50.9 (c = 10) 677.0313

85−86 −67.9 (c = 10) 585.0957

99−102 +23.6 (c = 3) 596.1197 IVd 84−86 +68.4 (c = 10) 585.0957 IVc 104−106 +42.0 (c = 10) 569.1252 IVb 116−118 +51.2 (c = 10) 677.0313 IVa 117−119 −8.2 (c = 10) 677.0313 IIIa mp (°C) [α]20D HMRS (M + H)

103−105 −31.6 (c = 10) 569.1252 IIIb

120−122 −28.0 (c = 10) 585.0957 IIIc

121−123 −18.8 (c = 3) 596.1197 IIId

IIb Ic Ib Ia

Table 1. Some Physical Parameters of Ia−e, IIa−e, IIIa−d, and IVa−d

Id

IIa

IIc

IId

Journal of Agricultural and Food Chemistry

6274

dx.doi.org/10.1021/jf501727k | J. Agric. Food Chem. 2014, 62, 6269−6277

Journal of Agricultural and Food Chemistry

Article

Table 2. Insecticidal Activities of Compounds Ia, IIIa, and Va and Flubendiamide against Oriental Armyworm larvicidal activity (%) at concn of compd

200 mg L−1

Ia 100 IIIa 100 Va 100 fubendiamide

100 mg L−1

50 mg L−1

25 mg L−1

10 mg L−1

5 mg L−1

2.5 mg L−1

1 mg L−1

0.5 mg L−1

0.25 mg L−1

0.1 mg L−1

100 100 100

100 100 100 100

100 100 100 100

100 100 100 100

100 100 100 100

100 100 100 100

100 100 100 100

100 20 60 100

100 0 40 100

60 20 50

Table 3. Insecticidal Activities of Ia−e, IIa−e, IIIa−d, IVa−d, and Flubendiamide against Oriental Armyworm larvicidal activity (%) at concn of compd

200 mg L−1

Ia 100 Ib 100 Ic 100 Id 100 Ie 100 IIa 100 IIb 100 IIc 100 IId 100 IIe 100 IIIa 100 IIIb 100 IIIc 100 IIId 100 IVa 100 IVb 100 IVc 100 IVd 100 flubendiamide

100 mg L−1

50 mg L−1

25 mg L−1

10 mg L−1

5 mg L−1

2.5 mg L−1

1 mg L−1

0.5 mg L−1

0.25 mg L−1

0.1 mg L−1

100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

100 100 100 100 100 100 100 100 100 100 100 20 60 50 100 10 40 30 100

100 100 100 100 100 100 100 100 100 100 100

100 100 100 100 100 100 100 100 100 100 100

100 40 60 40 60 100 70 100 100 100 100

100

100

60

100

100

48

100 100 60 20

60 60

100

60

100

100

100

100

100

0

50

Table 4. LC50 Values of Compounds Ia,b, IIa,b, IId, IIIa,b, and IVa,b and Flubendiamide against Oriental Armyworm LC50 (mg L−1) y = a + bx

compd Ia Ib IIa IIb IId IIIa IIIb IVa IVb flubendiamide

y y y y y y y y y y

= = = = = = = = = =

7.4089 5.2469 7.5886 5.6952 7.5067 6.5079 2.2365 4.2267 1.2531 7.4237

+ + + + + + + + + +

1.8566x 1.8142x 2.2397x 2.2259x 3.9160x 3.5344x 1.9655x 3.5772x 2.4626x 2.6428x

R

LC50

LC95

0.9885 0.9331 0.9402 0.9939 0.9541 0.9351 0.9882 0.9282 0.9688 0.9945

0.0504 (0.0326−0.0699) 0.7310 0.0699 (0.0536−0.0878) 0.4872 0.2290 0.3744 25.4675 1.6450 33.2304 0.1230 (0.0958−0.1503)

0.3877 (0.2400−1.0199) 5.8963 0.3790 (0.2488−0.8174) 2.6709 0.6024 1.0933 174.9238 4.7423 154.6959 0.5160 (0.3733−0.8966)

showed excellent activities comparable to that of flubendiamide. These results indicated that compounds with the iodine substituent in each configuration showed the best larvicidal activity, which was consistent with the previous study.19 A Cl substituent as well as NO2, Br, and F possessed inferior insecticidal activity against oriental armyworm. From Table 4, it is worth noting that the LC50 values of Ia and IIa were 0.0504 and 0.0699 mg L−1, respectively, lower than that of flubendiamide (0.1230 mg L−1). In addition, the LC50 values of compounds IIb, IId, and IIIa were 0.4872, 0.2290, and 0.3744 mg L−1, respectively. Larvicidal Activity against Diamondback Moth. The larvicidal activities of compounds Ib−e, IIa−e, and IVa and flubendiamide against diamondback moth are listed in Table 5. Most compounds possessed excellent activities. In comparison

IVd), these diastereoisomers reached the same activity level. For example, Ia and IIa showed similar activity at 0.1 mg L−1. IIc displayed 60% insecticidal activity at 0.25 mg L−1, whereas Ic gave a death rate of only 60% at 1 mg L−1, as did Id and IId. These observations showed that chiral sulfur had an influence on the larvicidal activity. However, carbon chirality influenced the activities more strongly than sulfur, as seen in comparison of compounds in Rs configurations such as Ia versus IIIa, Ib versus IIIb, Ic versus IIIc, and Id versus IIId) and in Ss configurations such as IIa versus IVa, IIb versus IVb, IIc versus IVc, and IId versus IVd. As shown in Table 3, all compounds showed a mortality of 100% at 10 mg L−1, except IIIb−d, IVb, IVd. Particularly (Sc, Rs) Ia−e, (Sc, Ss) IIa−e, (Rc, Ss) VIIa, and (Rc, Rs) VIIIa exhibited 100% larvicidal activities at 2.5 mg L−1. Ia and IIa 6275

dx.doi.org/10.1021/jf501727k | J. Agric. Food Chem. 2014, 62, 6269−6277

Journal of Agricultural and Food Chemistry

Article

Table 5. Insecticidal Activities of Compounds Ib−e, IIa−e, IVa, Va, Ve , and VIa−c and Flubendiamide against Diamondback Moth larvicidal activity (%) at compd

100 mg L−1

10 mg L−1

1 mg L−1

10−1 mg L−1

10−2 mg L−1

10−3 mg L−1

100 100 100 100 100 100 100 100 100 100

100 100 100 100 100 100 100 100 100 100 100

100 100 100 100 100 100 100 100 100 100 100

100 100 100 100 100 100 100 100 100 100 100

90 90 60 100 90 40 100 100 100 70 100

40 75 40 60 50 0 80 80 100 30 50

Ib Ic Id Ie IIa IIb IIc IId IIe IVa flubendiamide

10−4 mg L−1

10−5 mg L−1

90

40

0

declines in larvicidal activity. The yellow area indicates a less bulky substituent enhances activity. It is worth noting that the chiral carbon atom is located near the yellow area, and chirality (Rc or Sc) causes a difference in the orientation of the methyl group, which is bulkier than H atom. Thus, the methyl groups with Rc configurations (III and IV) come closer to the yellow area and have a poorer activity than Sc configurations. Finally, the red area surrounding the CN group indicates more electronegativity is favorable here, whereas Rc configurations on chiral carbon atoms cause the CN group to stay out of the red area, which leads to a decrease in activity. This is in accordance with SARs described in this paper. Partial least-squares analysis gives an excellent linear relationship between predicted and actual activities (R2 = 1.000), which indicates a valid CoMFA model. In summary, this is the first report of the novel optically active configuration incorporated into dicarboxamides containing N-cyano sulfiliminyl moieties. Four chiral series of novel phthalamide derivatives with sulfur-containing groups were designed, synthesized, and evaluated against oriental armyworm and diamondback moth for their insecticidal activities. All structures were characterized by 1H NMR, 13C NMR, and HRMS (or elemental analysis), and their relative absolute configurations were confirmed by optical polarimetry. For oriental armyworm, these stereoisomers exhibited different impacts on biological activity following the sequence (Sc, Ss) ≥ (Sc, Rs) ≫ (Rc, Ss) > (Rc, Rs); carbon chirality influenced the activities more strongly than sulfur. Compounds Ia and IIa reached activity as high as that of commercial flubendiamide, with LC50 values of 0.0504 and 0.0699 mg L−1, respectively, lower than that of flubendiamide (0.1230 mg L−1). For diamondback moth, the sequence of activity was (Sc, Ss) > (Sc, Rs), and the sulfur chirality influenced the activities greater to a greater extent than carbon. Compound IIe had an even higher activity than flubendiamide, whereas Ie and Ic,d reached the activity of the latter. The results indicated that the improvement of insecticidal activity required a reasonable coordination of both carbon and sulfur chirality. Probable synergistic influence was involved. CoMFA calculation indicated that stereoisomers with Sc configurations containing a strong electron-withdrawing group such as CN are important to retain their high activity. The N-cyano sulfiliminyl substituent was also essential for high larvicidal activity. Our research indicated that some of the title compounds could be potential candidates as ryanodine receptor activators.

of Sc configurations I and II, the sequence of activity was (Sc, Ss) > (Sc, Rs), except in the case of Ib (10−2 mg L−1, 90%), which displayed better activity than IIb (10−2 mg L−1, 40%). For the pair of enantiomers, it is worth noting that IIa and IVa reached similar activity levels. We conclude that in these cases the sulfur chirality influenced the activities more greatly than carbon. When different substituents in the phthaloyl scaffold were compared, it was found that Br showed the best activity. Ie and IIc,d reached the same activity as flubendiamide. In particular, IIe gave higher activity than flubendiamide with a mortality of 40% at low 10−5 mg L−1, whereas flubendiamide showed only 50% at 10−3 mg L−1. CoMFA Analysis by SYBYL. A brief CoMFA analysis for compounds Ia,b, IIa,b, IId, IIIa,b, and IVa,b was performed with SYBYL.34 The conformations with minimum energy were calculated with Tripos force field and Gasteiger−Hukel charges in advance. The activity data were reported as pLC50, and the negative logarithms of the LC50 data are in Table 2. Thus, a larger number of pLC50 indicates a higher activity. Details are shown in Figure 4. From the results of CoMFA, the green area near the I substituent suggests a bulkier group is favorable, as Cl or F

Figure 4. CoMFA results for Ia. 6276

dx.doi.org/10.1021/jf501727k | J. Agric. Food Chem. 2014, 62, 6269−6277

Journal of Agricultural and Food Chemistry

■

Article

(15) Babcock, J. M.; Gerwick, C. B.; Huang, J. X.; Loso, M. R.; Nakamura, G. E.; Nolting, S.; Rogers, R. B.; Sparks, T. C.; Thomas, J.; Watson, G. B.; Zhu, Y. Biological characterization of sulfoxaflor, a novelinsecticide. Pest Manag. Sci.. 2011, 67, 328−334. (16) Furukawa, N.; Oae, S. Sulfilimines. Synthetic applications and potential utilizations. Ind. Eng. Chem. Prod. Res. Dev. 1981, 20, 260− 270. (17) Lamberth, C.; Jeanmart, S.; Luksch, T.; Plant, A. Current challenges and trends in the discovery of agrochemicals. Science 2013, 134, 742−746. (18) Nakao, H.; Matsuzaki, Y.; Fujioka, S.; Morimoto, M.; Tohnishi, M.; Fisher, R.; Funke, C.; Malsam, O. WO 2006022225, 2006. (19) Tohnishi, M.; Nakao, H.; Furuya, T.; et al. Flubendiamide, a novel insecticide highly active against lepidopterous insect pests. J. Pestic. Sci. 2005, 30, 354−360. (20) Soucy, C.; Favreau, D.; Kayser, M. M. The regioselectivity of metal hydride reductions of 3-substituted phthalic anhydrides. J. Org. Chem. 1987, 52, 129−134. (21) Wei, R. B.; Li, S. W.; Lu, J. K.; Zheng, S. H.; Hu, W. H. Synthesis of organic pigment intermediate N,N′-bisacetylaceto-2,5dimethyl-1,4-phenylenediamine. Dyestuff Ind. 2000, 37, 16−18. (22) Masanobu, O.; Akihiko, Y.; Eiji, K. Process for the Production of perfluoroalkylated aniline derivatives. EP 1006102, 2000. (23) Pazenok, S. Preparation of thioalkylamines with high yields. WO 2007022900, 2007. (24) Blaschke, H.; Pazenok, S. Chiral 3-halophthalic acid derivatives. WO 2006024402, 2006. (25) Loso, M. R.; Nugent, B. M.; Huang, J. X.; Rogers, R. B.; Zhu Y.; Rogers, R. B.; et al. Preparation of insecticidal N-substituted (6haloalkylpyridin-3-yl) alkyl sulfoximines. WO 2007095229, 2007. (26) Podhorez, D. E.; Ross, R., Jr.; McConnell, J. R. Process for the preparation of certain substituted sulfilimines.U.S. 20080207910, 2008. (27) Bland, D. C.; Adaway, T. J.; Podhorez, D. E. Process for the preparation of certain substituted sulfilimines. U.S. 819322, 2012. (28) Huang, J. X.; Rogers, R. B.; Orr, N.; Sparks, T. C.; Clifford, J. M.; Loso, M. R.; Zhu Y.; Meade, T. A method to control insects resistant to common insecticides. WO 2007149134, 2007. (29) Abbott, W. S. A method of computing the effectiveness of an insecticide. J. Econ. Entomol. 1925, 18, 265−267. (30) Raymond, M. Presentation d’un programme Basic d’analyse logprobit pour miero-ordinateur. Cah. ORSTOM Ser. Ent. Med. Parasitol. 1985, 23, 117−121. (31) Wu, Y. D.; Shen, J. L.; Chen, J.; Lin, X. W.; Li, A. M. Evaluation of two resistance monitoring methods in Helicoverpa armigera: topical application method and leaf dipping method. Plant Prot. 1996, 22 (5), 3−6. (32) Ma, H.; Wang, K. Y.; Xia, X. M.; Zhang, Y.; Guo, Q. L. The toxicity testing of five insecticides to different instar larvae of Spodoptera exigua. Modern Agrochem. 2006, 5, 44−46. (33) Busivine, J. R. Recommended methods for measurement of pest resistance to pesticides. FAO Plant Production and Protection Paper 21; FAO: Rome, Italy, 1980; pp 3−13 and 119−122. (34) SYBYL 6.9, Tripos Associates, St. Louis, MO, USA.

AUTHOR INFORMATION

Corresponding Author

*(Z.L.) Phone: +86-22-23503732. E-mail: [email protected]. Funding

This work was supported by the project supported by the National Basic Research Program of China (No. 2010CB126106) and the National Key Technologies R&D Program (No. 2011BAE06B05) . Notes

The authors declare no competing financial interest.

■

REFERENCES

(1) Lahm, G. P.; Selby, T. P.; Frendenberger, J. H.; Stevenson, T. M.; Myers, B. J.; Seburyamo, G.; Smith, B. K.; Flexner, L.; Clark, C. E.; Cordova, D. Insecticidal anthranilicdiamides: a new class of potent ryanodine receptor activators. Bioorg. Med. Chem. Lett. 2005, 15, 4898−4906. (2) Feng, Q.; Liu, Z. L.; Xiong, L. X.; Wang, M. Z.; Li, Y. Q.; Li, Z. M. Synthesis and insecticidal activities of novel anthranilicdiamides containing modified N-pyridylpyrazoles. J. Agric. Food Chem. 2010, 58, 12327−12336. (3) Nakao, H.; Harayama, H.; Yamaguchi, M.; Tohnishi, M.; Morimoto, M.; Fujioka, S. Preparation of phthalamide derivatives as insecticides. WO 2002088074, 2002. (4) Harayama, H.; Tohnishi, M.; Morimoto, M.; Fujioka, S. Preparation of phthalamide derivatives as insecticides. WO 2002088075, 2002. (5) Mochizuki, K.; Inoue, S.; Hatanaka, T. Optically active phthalamide derivative, agricultural or horticultural insecticide, and method of using the same. U.S. 2008260440, 2008. (6) Tohnishi, M.; Nakao, H.; Kohno, E.; Nishida, T.; Furuya, T.; Shimizu, T.; Seo, A.; Sakata, K.; Fujioka, S.; Kanno, H. Preparation of phthalic acid diamides as agricultural and horticultural insecticides. EP 0919542, 1999. (7) Tohnishi, M.; Nakao, H.; Kohno, E.; Nishida, T.; Furuya, T.; Shimizu, T.; Seo, A.; Sakata, K.; Fujioka, S.; Kanno, H. Preparation of phthalamides as agrohorticultural insecticides. EP 1006107, 2000. (8) Tozai, M.; Morimoto, M.; Fujioka, N.; Seo, A. Preparation of phthalic diamides and insecticides for agriculture and horticulture. JP 2001335559, 2001. (9) Wada, K.; Gomibuchi, T.; Yoneta, Y.; Otsu, Y.; Shibuya, K.; Matsuo, H.; Fischer, R. Preparation of phthalamide derivatives as insecticides. WO 2004000796, 2003. (10) Wada, K.; Gomibuchi, T.; Yoneta, Y.; Otsu, Y.; Shibuya, K.; Nakakura, N.; Fischer, R. Preparation of pyrazolylmethylmethylphenyl phthalamides and related compounds as insecticides. WO 2005095351, 2005. (11) Seo, A.; Tohnishi, M.; Nakao, H.; Furuya, T.; Kodama, H.; Tsubata, K.; Fujioka, S.; Kodama, H.; Nishimatsu, T.; Hirooka, T. Flubendiamide, a new insecticide characterized by its novel chemistry and biology. In Pesticide Chemistry: Crop Protection, Public Health, Environmental Safety; Ohkawa, H., Miyagawa, H., Lee, P. W., Eds.; Wiley-VCH Verlag: Weinheim, Germany, 2007; pp 127−135. (12) Zhu, Y.; Loso, M. R.; Watson, G. B.; Sparks, T. C.; Rogers, R. B.; Hunag, J. X.; Gerwick, B. C.; Babcock, J. M.; Kelley, D.; Hegde, V. B.; Nugent, B. M.; Renga, J. M.; Denholm, I.; Gorman, K.; DeBoer, G. J.; Hasler, J.; Meade, T.; Thomas, J. D. Discovery and characterization of sulfoxaflor, a novel insecticide targeting sap-feeding pests. J. Agric. Food Chem. 2011, 59, 2950−2957. (13) Sparks, T. C.; Watson, G. B.; Loso, M. R.; Geng, C.; Babcock, J. M.; Thomas, J. D. Sulfoxaflor and the sulfoximine insecticides: chemistry, mode of action and basis for efficacy on resistant insects. Pestic. Biochem. Physiol. 2013, 107, 1−7. (14) Babcock, J. M.; Gerwick, B.; Hunag, J. X.; Loso, M. R.; Nakamura, G.; Nolting, S. P.; Rogers, R. B.; Sparks, T. C.; Thomas, J.; Watson, G. B.; Zhu, Y. Biological characterization of sulfoxaflor, a novel insecticide. Pest Manag. Sci. 2011, 67, 328−334.

■

NOTE ADDED AFTER ASAP PUBLICATION In the third from last sentences of both the abstract and final paragraph of the text, the stereoisomer configuration has been corrected from Rs in the original publication of June 26, 2014, to Sc, as corrected on June 27, 2014.

6277

dx.doi.org/10.1021/jf501727k | J. Agric. Food Chem. 2014, 62, 6269−6277