Design, Synthesis, and Biological Evaluation of 2-Benzylpyrroles and 2-Benzoylpyrroles

Design, Synthesis, and Biological Evaluation of 2-Benzylpyrroles and 2-Benzoylpyrroles Based on Structures of Insecticidal Chlorfenapyr and Natural Pyrrolomycins

(Supporting information)

Yu-XiuLiu, Peng-Xiang Zhang, Yong-Qiang Li, Hai-Bin Song and Qing-Min Wang*

Tables of contents

I Synthesis of target compounds and characterization.

IIX-ray Diffraction of compound 20c.

III Biological Assay Methods.

IV References

V Copies of NMR spectrum of compound 16a–k, 17a–k,18a–i, 19b, 20b and 20c.

I Synthesis of target compounds and characterization.

Instruments.1H NMR spectra were obtained at 400 MHz using a Bruker AV400 spectrometer in CDCl3 or DMSO-d6 solution with tetramethylsilane as the internal standard. Chemical shift values (δ) are given in parts per million. Abbreviation for the signals: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet.HRMS data were obtained on an FTICR-MS instrument (Ionspec 7.0 T). The melting points were determined on an X-4 binocular microscope melting point apparatus and are uncorrected. N,N-dimethylformamide (DMF) was distilled from calcium hydride;acetonitrile and dichloromethane (DCM) were distilled on phosphorus pentoxide; tetrahydrofuran (THF) was distilled from metal sodium. Other solvents and reagents were used as received. Yields were not optimized.

Diphenylmethanimine (benzophenone imine, 11):S1To a solution of benzophenone (10)(36.4 g, 0.2 mol) in cyclohexane (400 mL) was bubbled dry ammonia gas, meanwhile titanium tetrachloride (38 g, 0.2 mol) was slowly added through dropping funnel within 4 h. After the addition, ammonia gas was bubbled for another 2 h. Then, to the reaction mixture was added saturated sodium bicarbonate (200 mL), stirred for 30 min, and filtered. The organic phase was separated, washed with water, brine, dried over sodium sulfate, and concentrated to give 11 as colorless thick oil, which was used in the next step without further purification.

Ethyl N-(diphenylmethy1ene)glycinate (12):S2Crude benzophenone imine(11)(0.2 mol) and ethyl glycinate hydrochloride (28.0 g, 0.2 mol) were dissolved in dichloromethane (400 mL)and stirred at room temperature for 12 h. The reaction mixture was washed with water and brine, dried over sodium sulfate, filtrated, and concentrated to give 12 as a white solid (49 g, 92.5% for two steps). Mp. 52−54°C. 1HNMR(400MHz, CDCl3):δ 7.68−7.64 (m, 2H), 7.49−7.30 (m, 6H), 7.20−7.17 (m, 2H,), 4.21(q, 3JHH = 7.2 Hz, 2H), 4.20 (s, 2H), 1.27 (t, 3JHH = 7.2 Hz, 3H ).

(Substituted-phenyl)alanine (14): General procedure:S3To a solution of ethylN-(diphenylmethy1ene)glycinate(12) (10.0 g, 0.037 mol) and (substituted)benzyl chloride or bromide (0.037 mol) in dichloromethane was added potassium carbonate (15.6 g, 0.11 mol), potassium hydroxide (3.1 g, 0.11 mol) andbenzyltriethylammonium bromide (TEBA) (0.85 g, 3.7 mmol).The mixture was stirred at room temperature for 24 h, and thenfiltered.The filtrate was condensed to give crude 13, which was redissolved in hydrochloric acid (6 mol/L, 200 mL) and refluxed for 6h. After cooling to room temperature, the solution was washed several times with ether, and the layers were separated. Water and excess hydrochloric acid were removed from the aqueous layer to give (substituted-phenyl)alanine hydrochloride as a white solid. The solid was dissolved in ethanol and refluxed for 0.5 h, and then propylene oxide (30 mL) was added and the mixture was further refluxed for another 15 min.Free (substituted-phenyl)alanine14was precipitated and collected when cooled. Due to low solubility, not all of the compounds could give a clear spectrum.

14c: 6.37 g, 85.7%.Mp. 225−226 °C.

4-(Substituted-benzyl)-2-(trifluoromethyl)oxazol-5(2H)-one (15): General procedure:S2,S4To a refluxing solutionof trifluoromethyl anhydride (12.8 g, 0.06 mol) in acetonitrile (100 mL) was added (substituted-phenyl)alanine14 (0.03 mol), and the mixture was refluxed for another 0.5 h. After the solution was condensed in vacuo, the residue was redissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated to give 15 as pale yellow oil, which was used in the next step without further purification.

15a: yield 96%. 1H NMR (400 MHz, CDCl3) δ7.42−7.31 (m, 3H, ArH), 7.22(d, 3JHH = 7.2 Hz, 2H, ArH), 6.13−6.02 (m, 1H, CH-CF3), 4.14 (s, 2H, CH2).

15b: yield 99%. 1H NMR (400 MHz, CDCl3) δ7.19 (d, 3JHH = 8.4 Hz, 2H, ArH), 6.80 (d, 3JHH = 8.4 Hz, 2H, ArH), 6.10−6.05 (m, 1H, CH-CF3), 5.07 (s, 1H, OH), 3.96 (s, 2H, CH2).

15c: yield 99%. 1H NMR (400 MHz, CDCl3) δ7.33 (d, 3JHH = 8.4 Hz, 2H, ArH), 7.26 (d, 3JHH = 8.4 Hz, 2H, ArH), 6.13−6.09 (m, 1H, CH-CF3), 4.01 (s, 2H, CH2).

15d: yield 97%. 1H NMR (400 MHz, CDCl3) δ8.22 (d, 3JHH = 8.8 Hz, 2H, ArH), 7.52 (d, 3JHH = 8.8 Hz, 2H, ArH), 6.17−6.13 (m, 1H, CH-CF3), 4.16 (s, 2H, CH2).

15e: yield 91%. 1H NMR (400 MHz, CDCl3) δ7.32−7.28 (m, 2H, ArH), 7.07−7.02 (m, 2H, ArH), 6.13−6.08 (m, 1H, CH-CF3), 4.02 (s, 2H, CH2).

15f: yield 98%. 1H NMR (400 MHz, CDCl3) δ8.39 (d, 4JHH = 2.4 Hz, 1H, PyH), 7.69 (dd, 3JHH = 2.4 Hz, 1H, PyH), 7.37 (d, 3JHH = 8.4 Hz, 1H, PyH), 6.16−6.12 (m, 1H, CH-CF3), 4.05 (s, 2H, CH2).

15g: yield 99%. 1H NMR (400 MHz, CDCl3) δ7.44−7.41 (m, 1H, ArH), 7.36−7.33 (m, 1H, ArH), 7.29−7.27 (m, 2H, ArH), 6.14−6.09 (m, 1H, CH-CF3), 4.16 (s, 2H, CH2).

15h: yield 80%. 1H NMR (400 MHz, CDCl3) δ7.33−7.19 (m, 4H, ArH), 6.14−6.09 (m, 1H, CH-CF3), 4.01 (s, 2H, CH2).

15i: yield 90%. 1H NMR (400 MHz, CDCl3) δ7.45 (d, 4JHH = 1.6 Hz, 1H, ArH), 7.30−7.27 (m, 2H, ArH), 6.13−6.08 (m, 1H, CH-CF3), 4.12 (s, 2H, CH2).

15j: yield 76%. 1H NMR (400 MHz, CDCl3) δ7.86 (s, 1H, ArH), 7.59 (s, 1H, ArH), 6.13−6.10 (m, 1H, CH-CF3), 4.08 (s, 2H, CH2).

15k: yield 92%. 1H NMR (400 MHz, CDCl3) δ7.56 (s, 1H, ArH), 6.14−6.07 (m, 1H, CH-CF3), 4.37 (s, 2H, CH2).

2-(Substituted-benzyl)-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile (16): General procedure:S5To a solution of 15 (10 mmol) and 2-chloroacrylnitrile (20 mmol) in dry acetonitrile (40 mL) was added a solution oftriethylamine (10 mmol) in acetonitrile (5 mL) within 20 min under an ice-salt bath. The mixture was then stirred at room temperature, monitored by TLC and stirred until 15was not longer detected . After the solution was concentratedin vacuo, the resulting residue was redissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated.The crude was purified on a silica gel column (petroleum ether: ethyl acetate, 3:1) followed by recrystallization from petroleum etherand ethyl acetate to give 16 as pale yellow solid.

16a: yield 75%. Mp. 119−122 °C. 1H NMR (400 MHz, CDCl3) δ8.41 (s, 1H, NH), 7.41−7.31 (m, 3H, ArH), 7.23 (d, 3JHH = 7.2 Hz, 2H, ArH), 6.77 (s, 1H, Pyrrole-H), 4.14 (s, 2H, CH2).

16b: yield 75%. Mp. 184–185 °C. 1H NMR (400 MHz, CDCl3) δ8.31 (s, 1H, NH), 7.10 (d, 3JHH = 8.0 Hz, 2H, ArH), 6.84 (d, 3JHH = 8.0 Hz, 2H, ArH), 6.77 (s, 1H, Pyrrole-H), 4.76 (s, 1H, OH), 4.07 (s, 2H, CH2).

16c: yield 75%. Mp. 132−136 °C. 1H NMR (400 MHz, CDCl3) δ8.70 (s, 1H, NH), 7.35 (d, 3JHH = 8.4 Hz, 2H, ArH), 7.16 (d, 3JHH = 8.4 Hz, 2H, ArH), 6.78 (s, 1H, Pyrrole-H), 4.11 (s, 2H, CH2).

16d: yield 75%. Mp. 145−147 °C. 1H NMR (400 MHz, CDCl3) δ8.64 (s, 1H, NH), 8.23 (d, 3JHH = 8.4 Hz, 2H, ArH), 7.40 (d, 3JHH = 8.4 Hz, 2H, ArH), 6.83 (s, 1H, Pyrrole-H), 4.27 (s, 2H, CH2).

16e: yield 75%. Mp. 176−177 °C.1H NMR (400 MHz, CDCl3) δ8.53 (s, 1H, NH), 7.22−7.18 (m, 2H, ArH), 7.10−7.05 (m, 2H, ArH), 6.79 (s, 1H, Pyrrole-H), 4.12 (s, 2H, CH2).

16f: yield 75%. Mp. 150−152 °C. 1H NMR (400 MHz, CDCl3) δ11.06 (s, 1H, NH), 7.86 (s, 1H, PyH), 7.62 (dd, 4JHH = 2.4 Hz, 1H, PyH), 7.37 (d, 3JHH = 8.4 Hz, 1H, PyH), 6.81 (s, 1H, Pyrrole-H), 4.11 (s, 2H, CH2).

16g: yield 75%. Mp. 129−130 °C. 1H NMR (400 MHz, CDCl3) δ8.71 (s, 1H, NH), 7.45−7.42 (m, 1H, ArH), 7.35−7.28 (m, 3H, ArH), 6.76 (s, 1H, Pyrrole-H), 4.25 (s, 2H, CH2).

16h: yield 75%. Mp. 133−134 °C. 1H NMR (400 MHz, CDCl3) δ8.68 (s, 1H, NH), 7.34−7.26 (m, 2H, ArH), 7.22 (s, 1H, ArH), 7.13−7.10 (m, 1H, ArH), 6.79 (s, 1H, Pyrrole-H), 4.12 (s, 2H, CH2).

16i: yield 75%. Mp. 155−156 °C. 1H NMR (400 MHz, CDCl3) δ8.84 (s, 1H, NH), 7.45 (d, 4JHH = 1.6 Hz, 1H, ArH), 7.30−7.24 (m, 2H, ArH), 6.77 (s, 1H, Pyrrole-H), 4.22 (s, 2H, CH2).

16j: yield 75%. Mp. 102−103 °C. 1H NMR (400 MHz, CDCl3) δ8.20 (s, 1H, NH), 8.05 (s, 1H, ArH), 7.78 (s, 1H, ArH), 7.08 (s, 1H, Pyrrole-H), 4.17 (s, 2H, CH2).

16k: yield 75%. Mp. 219−210 °C. 1H NMR (400 MHz, CDCl3) δ8.68 (s, 1H, NH), 7.58 (s, 1H, ArH), 6.76 (s, 1H, Pyrrole-H), 4.48 (s, 2H, CH2).

2-(Substituted-benzyl)-4-bromo-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile (17): General procedure:S6To a stirred solution of 16 (14 mmol) and DMF (0.16 g, 21 mmol) in dichloromethane (20 mL) was added dropwise a solution of bromine (0.33 g, 21 mmol) in chloroform (5 mL), and then the mixture was refluxed for 1 h. After cooling to room temperature, saturated aqueous sodium carbonate (10 mL) was added to the reaction mixture and stirred for another 0.5 h. When chloroform and part of water wereremoved by evaporation,yellow solid was precipitated. The solid was collected and recrystallized from petroleum ether and ethyl acetate to give 17.

17a: yield 96%. Mp. 200−202 °C. 1H NMR (400 MHz, CDCl3) δ8.46 (s, 1H, NH), 7.42−7.26 (m, 3H, ArH), 7.22 (d, 3JHH = 7.2 Hz, 2H, ArH), 4.13 (s, 2H, CH2); HRMS (ESI) m/z Calcd forC13H7BrF3N2−[M−H]−: 326.9750, found 326.9757.

17b: yield 80%. Mp. 237−238 °C. 1H NMR (400 MHz, CDCl3) δ9.84 (s, 1H, NH), 7.32 (s, 2H, ArH), 5.93 (s, 1H, OH), 4.03 (s, 2H, CH2);Anal. Calcd. for C13H6Br3F3N2O: C, 31.05, H, 1.20, N, 5.57; found C, 30.97, H, 1.25, N, 5.58.

17c: yield 84%. Mp. 206−207 °C. 1H NMR (400 MHz, CDCl3) δ8.61 (s, 1H, NH), 7.37 (d, 3JHH = 8.4 Hz, 2H, ArH), 7.17 (d, 3JHH = 8.4 Hz, 2H, ArH), 4.11 (s, 2H, CH2); Anal. Calcd. for C13H7BrClF3N2: C, 42.95; H, 1.94; N, 7.71; found C, 42.73; H, 1.98; N, 7.89.

17d: yield 98%. Mp. 183−185 °C. 1H NMR (400 MHz, CDCl3) δ8.84 (s, 1H, NH), 8.23 (d, 3JHH = 8.4 Hz, 2H, ArH), 7.41 (d, 3JHH = 8.4 Hz, 2H, ArH), 4.25 (s, 2H, CH2); Anal. Calcd. for C13H7BrClF3N2: C, 41.74; H, 1.89; N, 11.23; found C, 41.50; H, 1.86; N, 11.11.

17e: yield 36%. Mp. 218−220 °C. 1H NMR (400 MHz, CDCl3) δ8.47 (s, 1H, NH), 7.22−7.18 (m, 2H, ArH), 7.12-7.06 (m, 2H, ArH), 4.11 (s, 2H, CH2);Anal. Calcd. for C13H7BrF4N2: C, 44.98; H, 2.03; N, 8.07; found C, 44.74; H, 2.04; N, 8.18.

17f: yield 58%. Mp. 176−177 °C. 1H NMR (400 MHz, CDCl3) δ11.10 (s, 1H, NH), 7.88 (d, 4JHH = 2.4 Hz, 1H, PyH), 7.62 (dd, 4JHH = 2.4 Hz, 1H, PyH), 7.40 (d, 3JHH = 8.4 Hz, 1H, PyH), 4.10 (s, 2H, CH2); HRMS (ESI) m/z Calcd for C12H7BrClF3N3+[M+H]+:363.9458, found 363.9461

17g: yield 71%. Mp. 165−166 °C. 1H NMR (400 MHz, CDCl3) δ8.83 (s, 1H, NH), 7.47−7.42 (m, 1H, ArH), 7.37−7.28 (m, 3H, ArH), 4.24 (s, 2H, CH2);Anal. Calcd. for C13H7BrClF3N2: C, 42.95; H, 1.94; N, 7.71; found C, 42.72; H, 2.05; N, 7.72.

17h: yield 52%. Mp. 183−186 °C. 1H NMR (400 MHz, CDCl3) δ8.74 (s, 1H, NH), 7.34−7.32 (m, 2H, ArH), 7.22 (s, 1H, ArH), 7.14−7.10 (m, 1H, ArH), 4.11 (s, 2H, CH2);Anal. Calcd. for C13H7BrClF3N2: C, 42.95; H, 1.94; N, 7.71; found C, 42.98; H, 2.10; N, 7.75.

17i: yield 94%. Mp. 191−192 °C. 1H NMR (400 MHz, CDCl3) δ8.86 (s, 1H, NH), 7.47 (d, 4JHH = 1.6 Hz, 1H, ArH), 7.47−7.26 (m, 2H, ArH), 4.20 (s, 2H, CH2); Anal. Calcd. for C13H6BrCl2F3N2: C, 39.23; H, 1.52; N, 7.04; found C, 39.12; H, 1.57; N, 7.14.

17j: yield 57%. Mp. 195−197 °C. 1H NMR (400 MHz, CDCl3) δ12.91 (s, 1H, NH), 8.05 (s, 1H, ArH), 7.76 (s, 1H, ArH), 4.17 (s, 2H, CH2);HRMS (ESI) m/z Calcd for C13H4Br4F3N2−[M−H]−: 560.7066, found 560.7067.

17k: yield 96%. Mp. 208−210 °C. 1H NMR (400 MHz, CDCl3) δ8.73 (s, 1H, NH), 7.59 (s, 1H, ArH), 4.47 (s, 2H, CH2); HRMS (ESI) m/z Calcd for C13H4BrCl4F3N2Na+[M+Na]+:486.8156, found 486.8179.

2-(Substituted-benzyl)-4-bromo-1-ethoxymethyl-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile (18): General procedure:S6,S7

To a stirred solution of 17 (1.7 mmol) in THF (20 mL) under the ice-salt bath was added sodium hydride (0.2 g, 4.3 mmol)in batches. After the mixture was stirred at room temperature for 10 min, chloromethyl ethyl ether (0.47 g, 5.1 mmol) was added, and the mixture was refluxed for 0.5 h. Then, solvent was removed by evaporation, and the resulting residue was redissolved in ethyl acetate and successively washed with water and brine, dried over sodium sulfate, and concentrated. The crude was purified on a silica gel column (petroleum ether: ethyl acetate, 5:1) followed by recrystallization from petroleum etherand ethyl acetate to give 18 as a white solid.

18a: yield 70%. Mp. 46−47 °C. 1H NMR (400 MHz, CDCl3) δ7.35−7.26 (m, 3H, ArH), 7.16 (d, 3JHH = 7.2 Hz, 2H, ArH), 5.15 (s, 2H, NCH2), 4.25 (s, 2H, ArCH2), 3.38 (q, 3JHH = 7.2 Hz, 2H, OCH2CH3), 1.12 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3);Anal. Calcd. for C16H14BrF3N2O: C, 49.63, H, 3.64, N, 7.23; found C, 49.62, H, 3.73, N, 7.03.

18b: yield 90%. Mp. 137−138 °C. 1H NMR (400 MHz, CDCl3) δ7.28 (s, 2H, ArH), 5.88 (s, 1H, OH), 5.19 (s, 2H, NCH2), 4.14 (s, 2H, ArCH2), 3.44 (q, 3JHH = 7.2 Hz, 2H, OCH2CH3), 1.15 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3);Anal. Calcd. for C16H12Br3F3N2O2: C, 34.26, H, 2.16, N, 4.99; found C, 34.29, H, 2.27, N, 5.00.

18c: yield 64%. Mp. 62−64 °C. 1H NMR (400 MHz, CDCl3) δ7.31 (d, 3JHH = 8.4 Hz, 2H, ArH), 7.11 (d, 3JHH = 8.4 Hz, 2H, ArH), 5.15 (s, 2H, NCH2), 4.22 (s, 2H, ArCH2), 3.41 (q, 3JHH = 7.2 Hz, 2H, OCH2CH3), 1.13 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3);Anal. Calcd. for C16H13BrClF3N2O: C, 45.58, H, 3.11, N, 6.64; found C, 45.58, H, 3.05, N, 6.68.

18d: yield 60%. Mp. 97−98 °C. 1H NMR (400 MHz, CDCl3) δ8.21 (d, 3JHH = 8.4 Hz, 2H, ArH), 7.37 (d, 3JHH = 8.4 Hz, 2H, ArH), 5.19 (s, 2H, NCH2), 4.37 (s, 2H, ArCH2), 3.43 (q, 3JHH = 7.2 Hz, 2H, OCH2CH3), 1.09 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3);Anal. Calcd. for C16H13BrF3N3O3: C, 44.46, H, 3.03, N, 9.72; found C, 44.31, H, 3.19, N, 9.51.

18e: yield 71%. Mp. 48−49 °C. 1H NMR (400 MHz, CDCl3) δ7.17−7.13 (m, 2H, ArH), 7.05−7.00 (m, 2H, ArH), 5.16 (s, 2H, NCH2), 4.22 (s, 2H, ArCH2), 3.40 (q, 3JHH = 6.8 Hz, 2H, OCH2CH3), 1.13 (t, 3JHH = 6.8 Hz, 3H, OCH2CH3);Anal. Calcd. for C16H13Br3F4N2O: C, 47.43, H, 3.23, N, 6.91; found C, 47.41, H, 3.22, N, 6.83.

18f: yield 59%. Mp. 76−78 °C. 1H NMR (400 MHz, CDCl3) δ8.29 (d, 4JHH = 2.4 Hz, 1H, PyH), 7.50 (dd, 3JHH = 8.4 Hz, 4JHH = 2.4 Hz, 1H, PyH), 7.32 (d, 3JHH = 8.4 Hz, 1H, PyH), 5.20 (s, 2H, NCH2), 4.23 (s, 2H, ArCH2), 3.43 (q, 3JHH = 6.8 Hz, 2H, OCH2CH3), 1.11 (t, 3JHH = 6.8 Hz, 3H, OCH2CH3);Anal. Calcd. for C15H12BrClF3N3O: C, 42.63, H, 2.86, N, 9.92; found C, 42.98, H, 3.33, N, 9.42.

18g: yield 75%. Mp. 83−85 °C. 1H NMR (400 MHz, CDCl3) δ7.42 (dd, 4JHH = 1.6 Hz, 1H, ArH), 7.28−7.19 (m, 2H, ArH), 7.01−7.98 (m, 1H, ArH), 5.18 (s, 2H, NCH2), 4.34 (s, 2H, ArCH2), 3.39 (q, 3JHH = 6.8 Hz, 2H, OCH2CH3), 1.10 (t, 3JHH = 6.8 Hz, 3H, OCH2CH3);Anal. Calcd. for C16H13BrClF3N2O: C, 45.58, H, 3.11, N, 6.64; found C, 45.69, H, 3.15, N, 6.54.

18h: yield 47%. Mp. 54−55 °C. 1H NMR (400 MHz, CDCl3) δ7.28−7.26 (m, 2H, ArH), 7.16 (s, 1H, ArH), 7.07−7.05 (m, 1H, ArH), 5.17 (s, 2H, NCH2), 4.22 (s, 2H, ArCH2), 3.41 (q, 3JHH = 6.8 Hz, 2H, OCH2CH3), 1.13 (t, 3JHH = 6.8 Hz, 3H, OCH2CH3);Anal. Calcd. for C16H13BrClF3N2O: C, 45.58, H, 3.11, N, 6.64; found C, 45.35, H, 3.15, N, 6.55.

18i: yield 38%. Mp. 125−127 °C. 1H NMR (400 MHz, CDCl3) δ7.45 (d, 4JHH = 2.0 Hz, 1H, ArH), 7.22 (dd, 3JHH = 8.0 Hz, 4JHH = 2.0 Hz, 1H, ArH), 6.95 (d, 3JHH = 8.0 Hz, 1H, ArH), 5.18 (s, 2H, NCH2), 4.30 (s, 2H, ArCH2), 3.41 (q, 3JHH = 7.2 Hz, 2H, OCH2CH3), 1.10 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3);Anal. Calcd. for C16H12BrCl2F3N2O: C, 35.51, H, 2.45, N, 4.87; found C, 35.53, H, 2.47, N, 4.89.

2-(Substituted-benzoyl)-4-bromo-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile (19):General procedure: S8

To a stirred solution of 17 (1 eq.) in dichloromethane was added freshly distilled sulfonyl dichloride(1.5 eq.), and the mixture was stirred at room temperature for 12 h. Water was added, and the mixture was stirred for another 0.5 h. When dichloromethane was removed by evaporation, white solid was precipitated and collected, which was recrystallized from petroleum ether and dichloromethane to give 19.

19a: from 17a, yield 83%. Mp. 208−209 °C. 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H, NH), 7.89 (d, 3JHH = 7.2 Hz, 2H, ArH), 7.76-7.70 (m, 1H, ArH), 7.59 (t, 3JHH = 6.8 Hz, 2H, ArH); HRMS (ESI) m/z Calcd for C13H5BrF3N2O−[M−H]−: 340.9543, found 340.9535.

19b: from 17d, yield 95%. Mp. 220−222 °C. 1H NMR (400 MHz, CDCl3) δ10.70 (s, 1H, NH), 8.39 (d, 3JHH = 8.8 Hz, 2H, ArH), 8.08 (d, 3JHH = 8.8 Hz, 2H, ArH); HRMS (ESI) m/z Calcd for C13H4BrF3N3O3−[M−H]−: 385.9388, found 385.9390.

19c: from 17c, yield 91%. Mp. 195−196 °C. 1H NMR (400 MHz, CDCl3) δ 10.51 (s, 1H, NH), 7.84 (d, 3JHH = 8.4 Hz, 2H, ArH), 7.56 (d, 3JHH = 8.4 Hz, 2H, ArH); HRMS (ESI) m/z Calcd for C13H4BrClF3N2O−[M−H]−: 374.9153, found 374.9153.

2-(Substituted-benzoyl)-4-bromo-1-ethoxymethyl-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile (20): The synthetic procedure is the same as for 18.

20b: from 19b, yield 60%. Mp. 97−99 °C. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, 3JHH = 8.4 Hz, 2H, ArH), 8.03 (d, 3JHH = 8.4 Hz, 2H, ArH), 5.67 (s, 2H, NCH2), 3.47 (q, 3JHH = 6.8 Hz, 2H, OCH2CH3), 1.06 (t, 3JHH = 6.8 Hz, 3H, OCH2CH3); Anal. Calcd. for C16H11BrF3N3O4: C, 43.07, H, 2.48, N, 9.42; found C, 42.98, H, 2.45, N, 9.22.

20c: from 19c, yield 44%. Mp. 108−109 °C. 1H NMR (400 MHz, CDCl3) δ7.83 (d, 3JHH = 8.4 Hz, 2H, ArH), 7.54 (d, 3JHH = 8.4 Hz, 2H, ArH), 5.62 (s, 2H, NCH2), 3.42 (q, 3JHH = 7.2 Hz, 2H, OCH2CH3), 1.04 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3); Anal. Calcd. for C16H11BrClF3N2O2: C, 44.11, H, 2.55, N, 6.43; found C, 43.91, H, 2.75, N, 6.30.

IIX-ray Diffraction of compound 20c.

The crystal structure20cwas determined. 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. The crystallographic data have been deposited with the Cambridge Crystallographic Data Centre with the deposition No. 960562 (for 20c), respectively. Copies of the data can be obtained free of charge via

III Biological Assay Methods.

All bioassays were performed on representative test organisms reared in the laboratory.

Stock solutions of each test compound was prepared in dimethylformamide at a concentration of 200 mg L-1 and then diluted to the required concentration (100, 50, 25, 10 and 5 mg L-1) with water containing TW-20.

Insecticidal ActivityAssay.

Stomach Toxicity against Oriental Armyworm (Mythimna separata). The insecticidal activities of the test compounds against oriental armyworm were evaluated by foliar application. Individual corn leaves were placed on moistened pieces of filter paper in Petri dishes. The leaves were then sprayed with the test solution and allowed to dry. The dishes were infested with 10 fourth-instar oriental armyworm larvae. Percentage mortalities were evaluated 4 days after treatment. Evaluations were based on a percentage scale of 0–100, where 0 equals no activity and 100 equals total kill. Each treatment was performed three times. Error of the experiments was about 5%. In order to calculate IC50, at least two mortalities at different concentrations were lower than 50%. The IC50 was taken from a graph plotting percentagemortality (y-axis) against compound concentration (x-axis); the IC50 is the concentration where the mortality crossed 50%.

Acaricidal ActivityAssay.

Acaricidal activity against eggs of spider mite (Tetranychus cinnabarinus).Sieva bean plants (Phaseolus Vulgaris L.) with two primary leaves expanded to 10 cm were selected and cut back to one plant per pot. The female mites were taken from the main colony and placed on leaves of the test plants using a fine brush, each leaf had seven mites. About 24 hours later removed the adult mites and obtained about 60-100 mites per plant. The leaves were kept for no more than 24 h before treatment. The mite-egg-infested leaf were dipped into the test solution for 3 s with agitation got rid of the remaining liquid, then were placed in a tube (10 cm inner diameter) lined with a piece of filter paper. Percentage mortalities were evaluated 4 days after treatment, and three replicates were carried out.The IC50 was taken from a graph plotting percentagemortality (y-axis) against compound concentration (x-axis); the IC50 is the concentration where the mortality crossed 50%.

Acaricidal activity against larvae of spider mite (Tetranychus cinnabarinus). Keep the mite-egg-infested leaves (choose the eggs which were laid at the same day) at 25 °C for 4 days. Then get them out and put on the leaves of tested plant as above. After one day, the larvae were hatched and moved to the fresh leaves. Each leaf was about 60-100 mites. The leaf was cut and dipped into the test solution for 3 s and got rid of the remaining liquid, then was placed in a tube (10 cm inner diameter) lined with a piece of filter paper. Percentage mortalities were evaluated 4 days after treatment, and three replicates were carried out.The IC50 was taken from a graph plotting percentagemortality (y-axis) against compound concentration (x-axis); the IC50 is the concentration where the mortality crossed 50%.

Acaricidal activity against adult of spider mite (Tetranychus cinnabarinus).The acaricidal activities of the test compounds against adult of spider mite were evaluated using reported procedure. Sieva bean plants (Phaseolus Vulgaris L.) with two primary leaves expanded to 10 cm were selected and cut back to one plant per pot. The female mites were taken from the main colony and placed on leaves of the test plants using a fine brush, each leaf had about 60-100 mites per plant. The leaves were kept for no more than 24 h before treatment. The leaves were dipped into the test solution for 3 s with agitation got rid of the remaining liquid, then were placed in a tube (10 cm inner diameter) lined with a piece of filter paper. Percentage mortalities were evaluated 24 hours after treatment, and three replicates were carried out.The IC50 was taken from a graph plotting percentagemortality (y-axis) against compound concentration (x-axis); the IC50 is the concentration where the mortality crossed 50%.

Fungicidal ActivityAssay.

In vitro assay. Selected compounds were evaluated in mycelial growth tests in artificial media against Cercospora arachidicola Hori, Alternaria solani, Physalospora piricola, Fusarium oxysporiumf.sp.cucumeris and Fusarium graminearumat rate of 50 mgL−1.

Test compound was dissolvedwithin a suitable amount of acetone and diluted withwater containing 0.1% TW-80 to the concentration of 500 mg L-1.To each petri dish was added 1 mLsuch solution and 9 mLculture medium to make a 50 mg L-1of medicated tablet, whereas to anotherpetri dish was added1 mL sterilizedwaterand 9 mLculture mediumas blank control. A diameter of 4 mmof hyphae wascutby a hole puncher along thehyphae for bacteria to the outer plate and moved to the medicated tablet.Each treatment was performed three times.The dishes were stored in controlled environment cabinets (24±1°C) for 48 h, after which the diameter of mycelia growth was investigated and percentage inhibition wascalculated.

Percentage inhibition (%) = (averaged diameter of mycelia in blank controls− averaged diameter of mycelia in medicatedtablets) / averaged diameter of mycelia in blank controls

In vivo assay:the compounds were evaluated in leaf-piece assays at rate of 200 mg L−1 forPseudoperonospora cubensison cucumber,Botrytis cinereaon cucumber and Blumeria graminis f. sp. Triticion wheat.

Afterthe first true leaf of cucumberwas fully unfolded, test solution (1 mL) was sprayedwith the spray pressure of 0.7 kg/cm2 and the spray distance of 15 cm. For wheat the spray was performed at leaf stage.24 Hours after the treatment, the sporangium suspension of Pseudoperonospora cubensis and Botrytis cinerea (5 x 105 / mL) was inoculated to the back of the cucumber leaf until the leaf was fully wet. The plant was first cultivated in dark and humid environment for 24 h and then moved to normal cultivation in greenhouse for 48 h, after which the disease inhibition was assessed. For Blumeria graminis f. sp. Tritici on wheat, 7 days wereneeded before investigation. Evaluations were based on a percentage scale of 0–100, where 100 means 100% inhibition (no disease) and 0 means 0% inhibition (with the serious disease).Each treatment was performed three times, and the errors were about 10%.

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V Copies of NMR spectrum of compound 16, 17,18, 19 and 20.