HETEROCYCLES

Short Paper | Regular issue | Vol. 92, No. 4, 2016, pp. 740-750
Received, 22nd January, 2016, Accepted, 23rd February, 2016, Published online, 2nd March, 2016.
DOI: 10.3987/COM-16-13412

■ Design, Synthesis And Biological Activity Of Novel Sulfonylurea Oxazolidines

Ying Fu, Jing-Xin Kang, Yun-Kai Wang, Jing Liu, Li-Xia Zhao, Shuang Gao, and Fei Ye*

Department of Applied Chemistry, College of Sciences, Northeast Agricultural University, No.59 Mucai Street Harbin 150030, Heilongjiang, China

Abstract

A series of N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine- 3-carboxamide 4 was synthesized by cycloaddition and acylation reaction with alkamine, ketones, and p-methylbenzenesulfonyl isocyanate as the starting materials. The structures of all the compounds were characterized by IR, 1H NMR, 13C NMR, MS, and elemental analysis. The configuration of 4d was determined by X-ray crystallography. The preliminary biological test showed that all compounds could protect maize against injury caused by chlorsulfuron to certain extent. The sulfonylurea oxazolidines were possible acted as antagonists of sulfonylureas herbicides at target enzyme pocket site by docking analysis.

Sulfonylureas (SUs) compounds have a wide range of practical applications such as insecticides,1 antimicrobial agents,2 anticancer agents,3 as well as herbicides.4 SUs are the very popular herbicides used for controlling a range of weeds and some grasses in a variety of crops and vegetables because of their good herbicidal activity, low mammalian toxicity, high selectivity, and benign environmental activity. However their phytotoxicities and the residues to succeeding crops have caused some concerns. Some sulfonylurea herbicides (such as Chlorsulfuron, Metsulfuron, Chlorimuron-ethyl) are long residual herbicides, and persistent in soil which is poisonous to susceptive crops.5 More and more novel safeners for SUs herbicides have been commercialized, such as Dimepiperate, Dymron, and Cyprosulfamide (Scheme 1).6
Structure-activity relationship theory (SAR) are very important in the search for bioactive materials because it provides useful molecular structure information that are necessary for the target bioactivity.7 Base on the SAR, active substructure combination, and bioisosteric replacement, the novel aniline derivatives of Chlorothalonil was designed and synthesized by substitution of Cl atom on Chlorothalonil with aryl amine moiety of Fluazinam, another commercially available agent (Scheme 2).8 Recently many such successful cases have been reported.9 In the same way, the safeners could be used as herbicide antidotes if the herbicides and their respective safeners are similar at the molecular level. Based on the above and continuous our previous work on N-containing heterocycles herbicide safeners,10 herein we designed a series of novel N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide utilizing active substructure combination and similarity theory (Scheme 3).

Several approaches had been developed to sulfonylurea derivatives with isocyanate11 or carbamic ester12 as the starting materials. Riehen reported the N-(2-methoxyethoxyphenylsulfony)-N`-(p-methoxy-6- methylpyrimidin-2-yl)urea being synthesized by acylation and aminolysis reaction with sulfonamide, dimethylformamide and 2-amino-4-methoxy-6-methylpyrimidine as the starting materials at low temperature with about 60% yield.13 Hagana reported the synthesis of Nicosulfuron by amidation reaction with aminopyrimidine, phosgene (which is highly toxic and the procedure is difficult to control) and phenyl carbamate as the starting materials at room temperature with the yield of 80%.14 Most of these reported methods required harsh reaction conditions, expensive materials, or phosgene. In view of the facts mentioned above, substituted N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide 4 were synthesized with alkamine, ketone and p-methylbenzenesulfonyl isocyanate as the starting materials via cyclization and acylation reactions (Scheme 4).

Several approaches had been developed to sulfonylurea derivatives with isocyanate11 or carbamic ester12 as the starting materials. Riehen reported the N-(2-methoxyethoxyphenylsulfony)-N`-(p-methoxy-6- methylpyrimidin-2-yl)urea being synthesized by acylation and aminolysis reaction with sulfonamide, dimethylformamide and 2-amino-4-methoxy-6-methylpyrimidine as the starting materials at low temperature with about 60% yield.13 Hagana reported the synthesis of Nicosulfuron by amidation reaction with aminopyrimidine, phosgene (which is highly toxic and the procedure is difficult to control) and phenyl carbamate as the starting materials at room temperature with the yield of 80%.14 Most of these reported methods required harsh reaction conditions, expensive materials, or phosgene. In view of the facts mentioned above, substituted N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide 4 were synthesized with alkamine, ketone and p-methylbenzenesulfonyl isocyanate as the starting materials via cyclization and acylation reactions (Scheme 4).

The structures of all the target compounds 4 were supported by MS, IR, 1H NMR, 13C NMR spectral data and elemental analysis. The IR spectra of compounds 4a-k showed bands at 3268-3350 cm-1 due to N-H; 1665-1699 cm-1 due to C=O, 1134-1167 and 1354-1370 cm-1 due to S=O, which confirmed the formation of urea bridge. The 1H NMR spectra of compounds 4a-k exhibited a single signal in the range δ 10.41-10.79 for the proton of N-H; multiplet in the range δ 3.99-3.50 for the proton of oxazolidine. The elemental analysis of 4a-k agreed with the molecular formula of all these compounds.
Finally, the single crystal of 4d was obtained by dissolving it in CH2Cl2 and light petroleum, followed by slow evaporation at room temperature. The diffraction data of 4d was collected with a Bruker AXSⅡ CCD area detector using a graphite monochromated Mo Kα radiation (λ=0.71073 Å) at 293(2) K. The structure was solved by direct methods using SHELXS-97,15 and refined by full matrix least squares on F2, SHELXL-97.16
The molecular structure of compound 4d is shown in Figure 1. In the structure the oxazolidine, phenethyl and p-methylphenylsulfonylamine groups are not in a coplane. The dihedral angle of oxazolidine and phenethyl is 63.3°, and the dihedral angle of phenethyl group and p-methylphenylsulfonylamine group is 42.0°.
As depicted in the crystal packing of compound 4d, two molecules are connected by one intermolecular hydrogen bond (C5-H5…O3) in Figure 2. Intermolecular and adjacent molecules are assembled through strong C-H…π stacking interaction in Figure 3. No significant π-π interactions were found in the crystal structure.

The bioactivity determination of all the novel compounds 4a-k was carried out on maize from the injury of Chlorsulfuron. The results were summarized in Table 1. The recovery rates of the growth index could be attained almost 50% with 10 mg/kg of the 4a-k when the concentration of Chlorsulfuron in the soil was 2 μg/kg. Among the compounds tested, 4j and 4k showed the best activity against the injury of Chlorsulfuron, similar as the commercial safener R-28725. Further bioassay was carrying out to probe the structure-activity relationship.
For the structural similarity of safener and herbicide, the competition of the target enzyme was probed. The acetolactate synthetase (ALS) crystal structure data was taken from the PDB data bank (PDB ID: 1N0H). Docking calculations were performed by using Docking Suite. Molecular structure of 4k was constructed and optimized using SKETCH and MINIMIZE option, and Gasteiger−Hückel charges were calculated for them. Geometry optimization was carried out using Triops force field supplied within SYBYL, with convergence criterion set at 0.005 kcal/(Å mol), and iterations criterion set at 1000. Docking calculations were performed on the two molecules using Docking Suite option. The protein was prepared with BIOPOLYMER option. Docked structure was scored by the built-in scoring function and clustered by 0.8 Å of root-mean-square deviation (RMSD) criterions. The best binding modes were determined by docking scores and also the comparison to available complex crystal structure of ALS. Standard Amber FF99 force field parameters were assigned to protein, and general AMBER force field (gaff) was assigned to ligand. The safener 4k was binding by hydrogen bonds with two active site residues (Ser163 and Ala117). The cofactor FAD 701 and AYD 700 were surrounding the active site pocket (Figure 4). The urea linkage moiety was binding by two active site residues at the entrance of the pocket. The oxazolidine moiety was deeply buried in the active site pocket (Figure 5). Based on the SAR, active substructure combination, docking analysis and the bioactivity data, the sulfonylurea oxazolidine safeners were possible acted as antagonists of SUs herbicides at target enzyme pocket site.

In conclusion, we have developed an efficient, fast and convenient method for the preparation of N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide derivatives. The advantages of this method were readily available starting materials, mild reaction conditions, and good yields. The preliminary bioactivity results showed that compound 4j and 4k attained the best herbicide safener activity to Chlorsulfuron. The sulfonylurea oxazolidine were possible acted as antagonists of sulfonylureas herbicides at target enzyme pocket site by docking analysis.

EXPERIMENTAL
The IR spectra were taken on a KJ-IN-27G infrared spectrophotometer in KBr pellets. The 1H NMR and 13C NMR spectra were recorded on Bruker AVANVE 300 MHz or 400 MHz, respectively, with CDCl3 or DMSO-d6 as the solvent and TMS as the internal standard. The elemental analysis was performed on FLASH EA1112 elemental analyzer. The mass spectrum was recorded on a Waters Xevo TQ spectrometer. X-Ray diffraction data were collected on a Brukcr AXSⅡ CCD area-detector diffractometer, Mo Kα. The melting points were determined on a Beijing Taike melting point apparatus(X-4) and are uncorrected. All the reagents were of analytical reagents grade.
General procedure for the preparation of N-[(p-Methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide(4a-k)
Solution of p-methylbenzenesulfonyl isocyanate (1.98g, 0.01 mol, in 10 mL anhydrous benzene) was added dropwise to a stirred mixture of oxazolidine 3 (0.01 mol) and anhydrous benzene (50 mL) at 10-12 °C for 3 h. After the reaction completed, the product was recovered by filtration, extraction and drying, the crude product 4 was received. The pure product was obtained by soaking and filtration with a mixture of benzene and a little of CH2Cl2.
2,2-Dimethyl-N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide (4a). Yield 84%. White solid, mp 95-96 °C. IR (KBr, cm-1): ν 3268 (N-H), 1696 (C=O), 1166, 1364 (S=O); 1H NMR (DMSO-d6, 300MHz): δ 7.34-7.77 (m, 4H, Ph-H), 3.88 (t, 2H, J=6.1Hz, N-CH2), 3.51 (t, 2H, J=6.3Hz, O-CH2), 2.37 (s, 3H, Ph-CH3), 1.34 (s, 6H, C-(CH3)2); 13C NMR (DMSO-d6, 75MHz): δ 151.93, 144.06, 137.96, 129.92, 127.72, 60.15, 42.27, 21.53; ESI-MS: 299 [M+H+]. Anal. Calcd for C13H18N2O4S: C 52.33, H 6.08, N 9.39, S 10.75. Found: C 52.48, H 6.02, N 9.31, S 10.65.
2-Ethyl-2-methyl-N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide (4b). Yield 72%. White solid, mp 98-99 °C. IR (KBr, cm-1): ν 3274 (N-H), 1699 (C=O), 1165, 1363 (S=O); 1H NMR (DMSO-d6, 300MHz): δ 10.60 (s, 1H, N-H), 7.35-7.76 (m, 4H, Ph-H), 3.79-3.98 (m, 2H, N-CH2), 3.45-3.64 (m, 2H, O-CH2), 2.37 (s, 3H, Ph-CH3), 0.59-1.86 (m, 8H, C-CH2 and C-CH3); 13C NMR (DMSO-d6, 75MHz): δ 149.49, 143.27, 138.98, 129.59, 127.74, 96.05, 63.37, 46.49, 29.89, 23.27, 21.52, 7.82; ESI-MS: 313 [M+H+]. Anal. Calcd for C14H20N2O4S: C 53.83, H 6.45, N 8.97, S 10.26. Found: C 53.75, H 6.52, N 8.88, S 10.32.
2-Methyl-N-[(p-methylphenyl)sulfonyl]-2-propyl-1,3-oxazolidine-3-carboxamide (4c). Yield 52%. White solid, mp 90-91 °C. IR (KBr, cm-1): ν 3342 (N-H), 1700, 1673 (C=O), 1157, 1364 (S=O); 1H NMR (DMSO-d6, 300MHz): δ 10.65 (s, 1H, N-H), 7.36-7.76 (m, 4H, Ph-H), 3.80-3.96 (m, 2H, N-CH2), 3.41-3.61 (m, 2H, O-CH2), 2.37 (s, 3H, Ph-CH3), 0.69-1.82 (m, 10H, C-CH2 and C-CH3); 13C NMR (DMSO-d6, 75MHz): δ 149.00, 143.61, 138.42, 129.65, 127.85, 95.91, 63.39, 46.26, 23.38, 21.52, 16.51, 14.33; ESI-MS: 327 [M+H+]. Anal. Calcd for C15H22N2O4S: C 55.19, H 6.79, N 8.58, S 9.82. Found: C 55.26, H 6.66, N 8.48, S 9.96.
2-Methyl-N-[(p-methylphenyl)sulfonyl]-2-(2-phenylethyl)-1,3-oxazolidine-3-carboxamide (4d). Yield 85%. White solid, mp 115-116 °C. IR (KBr, cm-1): ν 3344 (N-H), 1698 (C=O), 1161, 1361 (S=O); 1H NMR (DMSO-d6, 300MHz): δ 10.74 (s, 1H, N-H), 6.81-7.82 (m, 9H, Ph-H), 3.86-4.05 (m, 2H, N-CH2), 3.51-3.66 (m, 2H, O-CH2), 1.78-2.43 (m, 4H, (CH2)2), 1.34 (s, 3H, C-CH3); 13C NMR (DMSO-d6, 75MHz): δ 148.99, 143.73, 142.10, 138.27, 129.70, 128.81, 128.66, 128.59, 128.01, 126.09, 95.66, 63.55, 46.31, 29.61, 23.47, 21.56; ESI-MS: 389 [M+H+]. Anal. Calcd for C20H24N2O4S: C 61.83, H 6.23, N 7.21, S 8.25. Found: C 61.78, H 6.26, N 7.39, S 8.14.
Crystal data for compound 4d: C20H24N2O4S, monoclinic, space group P21/c, a=9.3912(19) Å, b=19.483(4) Å, c=10.837(2) Å, V=1933.7(7) Å3, β= 102.78(3), Z=4, Dc=1.334 cm-3, μ=0.196 mm-1, F(000)= 824. Independent reflections were obtained in the range of 3.05° < θ < 27.48, 4369. The final least-square cycle gave R1= 0.0385, ωR2 = 0.0960 for 3412 reflections with I > 2σ(I). The maximum and minimum differences of peak and hole are 0.509 and -0.289 e/Å3, respectively.
N-[(p-Methylphenyl)sulfonyl]-1-oxa-4-aza-spiro[4.4]nonane-4-carboxamide (4e). Yield 68%. White solid, mp 102-103 °C. IR (KBr, cm-1): ν 3276 (N-H), 1695 (C=O), 1165, 1364 (S=O); 1H NMR (DMSO-d6, 300MHz): δ 10.72 (s, 1H, N-H), 7.37-7.76 (m, 4H, Ph-H), 3.84-3.86 (m, 2H, N-CH2), 2.94-3.48 (t, 2H, O-CH2), 2.38 (s, 3H, Ph-CH3), 1.48-2.32 (m, 8H, C4H8); 13C NMR (DMSO-d6, 75MHz): δ 163.81, 157.62, 140.34, 129.64, 128.69, 127.77, 127.35, 103.43, 63.39, 60.86, 45.92, 34.75, 24.24, 21.53, 21.38; ESI-MS: 325 [M+H+]. Anal. Calcd for C15H20N2O4S: C 55.54, H 6.21, N 8.64, S 9.88. Found: C 55.44, H 6.30, N 8.68, S 9.75.
N-[(p-Methylphenyl)sulfonyl]-1-oxa-4-aza-spiro[4.5]decane-4-carboxamide (4f). Yield 92%. White solid, mp 105-106 °C. IR (KBr, cm-1): ν 3275 (N-H), 1693 (C=O), 1165, 1361 (S=O); 1H NMR (DMSO-d6, 400MHz): δ 7.34-7.75 (m, 4H, Ph-H), 3.85 (t, 2H, J=3.0Hz, N-CH2), 3.50 (t, 2H, J=6.0Hz, O-CH2), 2.36 (s, 3H, Ph-CH3), 1.35-2.13 (m, 10H, C5H10); 13C NMR (DMSO-d6, 100MHz): δ 151.94, 151.87, 149.98, 144.07, 143.25, 139.05, 137.93, 137.88, 129.60, 127.86, 95.04, 62.98, 45.93, 32.27, 23.29, 21.52; ESI-MS: 339 [M+H+]. Anal. Calcd for C16H22N2O4S: C 56.78, H 6.55, N 8.28, S 9.47. Found: C 56.72, H 6.64, N 8.35, S 9.41.
4-Ethyl-2,2-dimethyl-N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide (4g). Yield 80%. White solid, mp 120-121 °C. IR (KBr, cm-1): ν 3283(N-H), 1686 (C=O), 1167, 1363 (S=O); 1H NMR (DMSO-d6, 300MHz): δ 10.70 (s, 1H, N-H), 7.36-7.75 (m, 4H, Ph-H), 4.01 (s, 1H, N-CH), 3.74-3.84 (m, 2H, O-CH), 2.37 (s, 3H, Ph-CH3), 0.86-1.60 (m, 11H, C-CH2 and C-CH3); 13C NMR (DMSO-d6, 75MHz): δ 148.77, 143.59, 138.62, 129.71, 127.83, 94.45, 66.45, 57.26, 27.20, 25.86, 23.68, 21.53, 10.42; ESI-MS: 327 [M+H+]. Anal. Calcd for C15H22N2O4S: C 55.19, H 6.79, N 8.58, S 9.82. Found: C 55.32, H 6.71, N 8.49, S 9.84.
2,4-Diethyl-2-methyl-N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide (4h). Yield 53%. White solid, mp 121-122 °C. IR (KBr, cm-1): ν 3301 (N-H), 1695 (C=O), 1153, 1367 (S=O); 1H NMR (DMSO-d6, 300MHz): δ 10.68 (s, 1H, N-H), 7.36-7.78 (m, 4H, Ph-H), 3.96 (m, 1H, N-CH), 3.76-3.86 (m, 2H, O-CH2), 2.37 (s, 3H, Ph-CH3), 0.88-1.88 (m, 13H, C-CH2 and C-CH3); 13C NMR (DMSO-d6, 75MHz): δ 148.61, 143.58, 138.57, 139.70, 127.80, 96.89, 66.24, 57.09, 31.00, 26.07, 21.74, 21.53, 10.66, 8.55; ESI-MS: 341 [M+H+]. Anal. Calcd for C16H24N2O4S: C 56.45, H 7.11, N 8.23, S 9.42. Found: C 56.54, H 7.22, N 8.15, S 9.35.
4-Ethyl-2-methyl-N-[(p-methylphenyl)sulfonyl]-2-(2-phenylethyl)-1,3-oxazolidine-3-carboxamide　(4i). Yield 23%. White solid, mp 117-118 °C. IR (KBr, cm-1): ν 3281 (N-H), 1686 (C=O), 1156, 1354 (S=O); 1H NMR (DMSO-d6, 300MHz): δ 10.79 (s, 1H, N-H), 6.81-7.78 (m, 9H, Ph-H), 3.72-4.00 (m, 3H, O-CH and N-CH2), 2.34 (s, 3H, Ph-CH3), 1.40-2.23 (m ,4H, C(CH2)2-Ph), 0.89-1.25 (m, 5H, CH2CH3); 13C NMR (DMSO-d6, 75MHz): δ 148.99, 143.60, 142.33, 138.58, 129.68, 128.63, 127.91, 126.12, 96.33, 68.04, 66.33, 57.17, 30.32, 26.19, 21.52, 10.71; ESI-MS: 417 [M+H+]. Anal. Calcd for C22H28N2O4S: C 63.44, H 6.78, N 6.73, S 7.70. Found: C 63.52, H 6.65, N 6.77, S 7.62.
3-Ethyl-N-[(p-methylphenyl)sulfonyl]-1-oxa-4-aza-spiro[4.4]nonane-4-carboxamide (4j). Yield 45%. White solid, mp 108-109 °C. IR (KBr, cm-1): ν 3259 (N-H), 1688 (C=O), 1160, 1370 (S=O); 1H NMR (DMSO-d6, 300MHz): δ 10.78 (s, 1H, N-H), 7.36-7.77 (m, 4H, Ph-H), 4.03 (s, 1H, N-CH), 3.74 (m, 2H, O-CH2), 2.37 (s, 3H, Ph-CH3), 0.85-2.23 (m, 13H, 5×CH2 and C-CH3); 13C NMR (DMSO-d6, 75MHz): δ 149.21, 142.33, 138.85, 129.63, 127.68, 103.78, 66.78, 56.79, 36.22, 34.09, 25.53, 24.41, 24.11, 21.52, 10.16; ESI-MS: 353 [M+H+]. Anal. Calcd for C17H24N2O4S: C 57.93, H 6.86, N 7.95, S 9.10. Found: C 57.85, H 6.96, N 7.91, S 9.13.
3-Ethyl-N-[(p-methylphenyl)sulfonyl]-1-oxa-4-aza-spiro[4.5]decane-4-carboxamide (4k). Yield 90%. White solid, mp 164-165 °C. IR (KBr, cm-1): ν 3284 (N-H), 1687 (C=O), 1165, 1366 (S=O); 1H NMR (DMSO-d6, 300MHz): δ 10.41 (s, 1H, N-H), 7.35-7.75 (m, 4H, Ph-H), 3.99 (s, 1H, N-CH), 3.49-3.76 (s, 2H, O-CH2), 2.37 (s, 3H, Ph-CH3), 0.85-1.90 (m, 15H, 6×CH2 and C-CH3); 13C NMR (DMSO-d6, 75MHz): δ 149.21, 143.37, 138.93, 129.65, 127.80, 95.64, 66.20, 57.28, 35.20, 30.17, 26.07, 24.73, 23.45, 21.52, 10.50; ESI-MS: 367 [M+H+]. Anal. Calcd for C18H26N2O4S: C 58.99, H 7.15, N 7.64, S 8.75. Found: C 59.06, H 7.21, N 7.52, S 8.71.
1-(2’-Hydroxyethyl)-3-p-methylphenyl)sulfonylurea (6). White solid, mp 136-137 °C. IR (KBr,cm-1): ν 3338 (N-H), 1673 (C=O), 1157, 1335 (S=O). 1H NMR (DMSO-d6, 400MHz): δ 10.42 (s,1H, SO2N-H), 7.36-7.74 (m, J=8.4Hz, 8H, Ph-H), 6.43 (t, J=5.2Hz, 1H, O-H), 4.68 (s, 1H, N-H),3.29 (s, 2H, OH), 2.98 (t, J=5.6Hz, 2H, N-CH2), 2.36 (s, 3H, Ph-CH3); 13C NMR (DMSO-d6, 100MHz): δ 151.89, 144.03, 137.94, 129.89, 129.89, 127.68, 127.68, 60.12, 42.24, 21.49. Anal. Calcd for C10H14N2O4S: C 46.50, H 5.46, N 10.85, S 12.41. Found: C 46.44, H 5.52, N 10.78, S 12.55.
1,3-Bis(p-methylphenyl)sulfonylurea (7). White solid, mp 69-70 °C. IR (KBr, cm-1): ν 3299-3181 (N-H), 1701, 1748 (C=O), 1348 (S=O). 1H NMR (CDCl3, 400MHz): δ 8.86 (s, 2H, N-H), 7.25-7.79 (m, 8H, Ph-H), 2.38 (s, 6H, 2×Ph-CH3); 13C NMR (DMSO-d6, 100MHz): δ 172.06, 147.02, 147.02, 145.58, 145.58, 135.24, 135.24, 129.93, 129.93, 129.93, 129.93, 127.95, 127.95, 127.95,127.95, 60.81, 21.68, 21.68, 14.14. Anal. Calcd for C15H16N2O5S2: C 48.90, H 4.38, N 7.60, S 17.41. Found: C 48.88, H 4.42, N 7.68, S 17.56.
Biological activity: Maize (Dongnong 253) seeds were moistened with warm water about 30 min. The untreated or safener-treated maize were soaked by title compounds (10 mg/kg) for 12 h, and then germinated for 24 h at 26.5 °C. The seeds were planted 1.5 cm deep in plastic trays, in which soil was treated with 2 μg/kg Chlorsulfuron. Trays were incubated at 28 °C for 7 days. The effects of the title compound on the detoxification of Chlorsulfuron in soil were determined by testing the growth level.
SUPPLEMENTARY MATERIAL
Crystallographic data for the structural analysis of 4d has been deposited with the Cambridge Crystallographic Data Centre (CCDC 1044046). These data can be obtained free of charge from The Cambridge Crystallographic Data via www.ccdc.cam.ac.uk/data_request/cif.

ACKNOWLEDGEMENTS
This work was supported by the National Nature Science Foundation of China (No. 31401787), Natural Science Foundation of Heilongjiang Province (No. B201303), the Research Science Foundation in Technology Innovation of Harbin (No. 2015RAYXJ010), and Young Talents Project of Northeast Agricultural University (No. 14QC38).

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