English

• 1.   Introduction

  In the development courses of novel pesticides, several kinds of compounds were designed and synthesized based on the spirocyclic butenolide moiety using the strategy of diversity-oriented synthesis, ^[1-3] and most of compounds from our constructed molecular library (Scheme 1) were found to exhibit excellent fungicidal and insecticidal activities against several phytopathogens and harmful insects in our laboratory.^[4-12] These results showed that our compounds derived from the spirocyclic butenolide moiety by diversity-oriented synthesis strategy exhibit the wide-range bioactivities in both fungicide and insecticide.

  Scheme 1

  

  Scheme 1.  Spirocyclic butenolide molecular library constructed from the diversity-oriented synthesis strategy^[4-12]

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  4-Aminofuran-2(5H)-ones are of interest as the biologically active compounds and intermediates in the synthesis of natural products.^[13] For example, a novel insecticide 4-((N-2, 2-difluoroethyl)(N-6-chloropyridin-3-ylmethyl)-amino)-furan-2(5H)-one (flupyradifurone) with the 4- amino-furan-2(5H)-one and pyridin-3-ylmethyl moieties was available in the market since 2014, and it showed excellent activity against several harmful pests without the severe honeybee toxicity associating with the other neonicotinoid insecticides.^[14] The 3-acetyl-4-phenyl-1-oxaspiro[4, 5]dec-3-en-2-one oxime derivatives (Scheme 2, A) were synthesized based on the facts that lots of compounds containing oxime ether scaffolds have excellent fungicidal activities, ^[15-18] and 3-acetyl-5, 5-dimethyl-4-(methylami- no)furan-2(5H)-one and 3-acetyl-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (Scheme 2, B) were also found to exhibit good in vivo fungicidal activities against E. graminis, P. polysora and C. lagenarium in the previous reports.^[9-10] In order to improve the fungicidal activities against phytopathogens and enlarge the constructed molecular library, the C-4 phenyl group of 3-(1-iminoethyl)- 5, 5-disubstituted-4-phenylfuran-2(5H)-one was replaced with the methylamino group to design the novel molecule 3-(1-iminoethyl)-5, 5-disubstituted-4-(methylamino)furan-2(5H)-one (Scheme 2). The synthetic route of target compounds was showed in Scheme 3. The synthesis and their biological activities of them were presented.

  Scheme 2

  

  Scheme 2.  Design strategy of target molecules

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  Scheme 3

  

  Scheme 3.  Synthetic route of (E)-3-(1-iminoethyl)-5, 5-disubstituted-4-(methylamino)furan-2(5H)-one

  1A, 2A, 2a, 3A~3I, 4A~4I, 5A~5I: R¹=R²=CH₃; 1B, 2B, 2b, 3J~3R, 4J~4R, 5J~5R: R¹+R²=(CH₂)₅; 3A, 4A, 5A, 3J, 4J, 5J: R³=CH₃; 3B, 4B, 5B, 3K, 4K, 5K: R³=PhCH₂; 3C, 4C, 5C, 3L, 4L, 5L: R³=2-ClC₆H₄CH₂; 3D, 4D, 5D, 3M, 4M, 5M: R³=3-ClC₆H₄CH₂; 3E, 4E, 5E, 3N, 4N, 5N: R³=4-ClC₆H₄CH₂; 3F, 4F, 5F, 3O, 4O, 5O: R³=4-CH₃OC₆H₄CH₂; 3G, 4G, 5G, 3P, 4P, 5P: R³=4-NO₂C₆H₄CH₂; 3H, 4H, 5H, 3Q, 4Q, 5Q: R³=3, 4-Cl₂C₆H₃CH₂; 3I, 4I, 5I, 3R, 4R, 5R: R³=2-Cl-6-FC₆H₃CH₂
  Reagents and condition: (a) diketene, Et₃N, Na, toluene, 70 ℃, 90%~93%; (b) Me₃OBF₄, (1, 8-bis(dimethylamino)naphthalene, DCM, reflux; 30% methylamine solution, ethanol, reflux, 55%~60%; (c) and (d) O-methyl/benzylhydroxylamine, 4-methylbenzenesulfonic acid, r.t. or reflux, 66%~72%; (e) oxalyl dichloride, DMF, 0 ℃~r.t.; (f) 30% methylamine solution, THF, r.t., 61%~78%

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  2.   Results and discussion

  2.1   Synthesis and configuration of C=N double bond of oxime moiety

  When 2a and 2b were obtained, the direct oximination of 2a and 2b with O-benzylhydroxylamine or O-methyl- hydroxylamine in route 1 was performed under ambient or reflux temperature, but the raw materials were observed unchanged by thin-layer chromatography (TLC) check. The possible reason was that the proton of NH at C-4 formed strong six-membered hydrogen bond with the oxygen of carbonyl at C-3. In this case, the strategy was changed as indicated in route 2 in the Scheme 3. The direct oximination of intermediates 2A and 2B with O-benzyl- hydroxylamine or O-methyl hydroxylamine were going smoothly under reflux temperature and afforded oxime ether derivatives 3A~3R successfully. Then the oxime ether derivatives 3A~3R reacted with oxalyl dichloride using N, N'-dimethylformamide (DMF) as the catalyst to produce chlorinated products 4A~4R, which was utilized for the next reaction without purification. Finally, the target compounds 5A~5R were obtained by the reaction of 4A~4R with 30% (mass fraction) methylamine aqueous solution in 61%~78% overall yield for two steps from 3A~3R.

  The structures of the target compounds 5A~5R were characterized by the ¹H NMR, ¹³C NMR, and HR-ESI-MS spectral data. In order to further confirm their structures and determine the configuration of C=N double bond of the oxime moiety in these molecules, the crystal of 5O was obtained from its ethanol/n-hexane solution, and the X-ray diffraction analysis result is depicated in Figure 1. This result indicated that the C=N double bond take E-configuration, and the proton of NH at C-4 formed strong six-membered hydrogen bond with the nitrogen atom of the oxime moiety at C-3. The intermolecular hexatomic hydrogen bond may contribute to stabilize the structure of B-conformation. The chemical shifts of the NH protons at C-4 were in the range of δ 8.40~8.80, the N-CH₃ in the range of δ 2.95~3.17 were splitted into doublets with coupling constants 5.7 Hz in their ¹H NMR spectra due to the presence of six-membered hydrogen bond. The δ_C of the C=N double bond of oxime moiety were in the range of 155.3~156.8, and the δ_C of N-CH₃ were in the range of 11.1~11.6 in their ¹³C NMR spectra.

  图 1

  

  图 1.  X-Ray structure and two possible conformations of compound 5O

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  2.2   Biological activity and structure-activity relation- ship of title compounds 5A~5R

  After completed these syntheses, the 4-methylamino analogues of 3-(1-iminoethyl)-5, 5-disubstituted-4-phenyl-furan-2(5H)-one were evaluated for their fungicidal and insecticidal activities against several phytopathogens and harmful insects using protocol in the previous report.^{[9-12, 19-20]} It was found that all of new compounds did not exhibit significant in vivo fungicidal activities (data do not give) against Pseudoperonospora cubensis, Erysiphe graminis, Puccinia polysora and Colletotriechum agenarium as those 3-(1-iminoethyl)-5, 5-disubstituted-4- phenylfuran-2(5H)-one in the previous report.^[9] This result indicated that the replacement of phenyl with methylamino at 4-position greatly decreased the in vivo fungicidal activities compared with that of 3-(1-iminoethyl)-5, 5-disub- stituted-4-phenylfuran-2(5H)-one. However some of them unexpectedly exhibited good insecticidal activities with 100% mortality against Plutella xylostella, Mythimna seprata and Myzus persicae, while they did not have acaricidal activities against Tetranychus cinnabarinus at the concentration of 600 µg/mL (Table 1). These results in Table 1 indicated that these compounds with 5, 5-germial dimethyl have better insecticidal activities than these compounds with 5, 5-spirocyclic, which implied that these bulky hindrance of 5, 5-spirocyclic group resulted in decreasing of insecticidal activity.^[12] In the other aspect, those compounds with Cl-substitutition in the benzene ring were beneficial to improve insecticidal activity, while OCH₃ and NO₂ substitutition resulted in decreasing of their insecticidal activities. Compounds 5C, 5D, 5F, 5I, 5L and 5Q still had 30%~60% and 0~40% mortality against P. xylostella when the concentrations were decreased to 100 and 10 µg/mL, which indicated that these compounds could be used as the lead compounds for the further modification.

  表 1

  

  表 1  Insecticidal activities (mortality/%) of title compounds 5A~5R at 600 µg/mL

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  Compd.	P. xylostella	M. separata	M. persicae	T. cinnabarinus
  5A	0	0	100, 0, a 0b	0
  5B	0	0	0	0
  5C	100, 50, a 40b	0	0	0
  5D	100, 50, a 20b	0	0	0
  5E	0	0	0	50
  5F	100, 30, a 0b	0	0	0
  5G	60	50	0	0
  5H	0	0	0	0
  5I	100, 60, a 40b	0	0	0
  5J	70	0	0	0
  5K	70	100, 0, a 0b	0	0
  5L	100, 30, a 0b	0	0	0
  5M	0	0	0	0
  5N	0	70	0	0
  5O	0	0	0	0
  5P	50	50	0	0
  5Q	100, 50, a 0b	100, 0, a 0b	0	0
  5R	0	0	0	0
  Imidacloprid	100b	100b	100b	100b
  a Activity at 100 µg/mL; b Activity at 10 µg/mL.

  3.   Conclusion

  In summary, eighteen novel (E)-3-(1-iminoethyl)-5, 5- disubstituted-4-(methylamino)furan-2(5H)-one compounds were designed and synthesized in 61%~78% yields through four-step reaction using methyl 2-hydroxy-2- methylpropanoate and methyl 1-hydroxycyclohexane-1- carboxylate as the raw materials. Their structures were characterized by ¹H NMR, ¹³C NMR, HR-ESI-MS data and confirmed by the X-ray diffraction of compound 5O. Compounds 5C, 5D, 5F, 5I, 5L and 5Q exhibited 100% mortality against P. xylostella, 5K and 5Q had 100% mortality against M. seprata, 5A had 100% mortality against M. persicae at the concentration of 600 μg/mL, respectively, while all of these compounds did not show significant in vivo fungicidal activities against phytopathogen P. cubensis, E. graminis, P. polysora and C. agenarium and acaricidal activities against T. cinnabarinus.

  4.   Experimental section

  4.1   General information

  Melting points (m.p.) were examined using a Yanagimoto apparatus without further corrected. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker DPX 300 spectrometer with CDCl₃ as the solvents and tetramethylsilane (TMS) as the internal standard. HR-ESI-MS data were acquired on a Linear Trap Quadropole (LTQ) Orbitrap instrument equipped with electrospray ionization source (ESI). Crystal structure was analyzed at a Thermo Fisher ESCALAB 250 X-ray diffractometry. All chemicals such as starting materials and reagents were purchased from commercial supplier (Energy Chemical) and used without further purification except as indicated. Organic solvents were concentrated under reduced pressure using a rotary evaporator or oil pump. All reactions were carried out using magnetic stirring. The silica gel chromatography was performed using 200~300 mesh flash silca gel (Qingdao Haiyang).

  4.2   Synthesis of compounds 5A~5R

  4.2.1   Synthesis of intermediates 2A and 2B, 2a and 2b

  Intermediates 2A and 2B, 2a and 2b were synthesized following the literature procedures, and their analytical data were consistent with the reported data^{[5, 10-11]}.

  4.2.2   Synthesis of intermediates 3A~3R

  Taking 3K as an example, intermediate 2B (630 mg, 3 mmol) was added into 50 mL of methanol in a 100 mL three-necked flask, then gradually O-benzylhydroxylamine (406 mg, 3.3 mmol) and 4-methylbenzenesulfonic acid hydrate (95 mg, 0.5 mmol) were added into the solution at the room temperature. The resulting mixture was stirred, heated and kept to reflux for 8 h. After cooled to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, the solution was washed with water (50 mL×3). The water phase was re-extracted with ethyl acetate (50 mL×2), and the organic phase was combined. Then the organic phase was dried over anhydrous Na₂SO₄. The solvent was removed, and the residue was subjected to flash column chromatography on silica gel and eluted with petroleum ether/EtOAc (V:V=1:1) to afford (E)-3-(1-((ben- zyloxy)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3K) (466 mg, yield 74%) as a white solid. Intermediates 3A~3R were prepared in the same protocol.

  (E)-3-(1-((Methoxy)imino)ethyl)-5, 5-dimethyl-4-hydro-xylfuran-2(5H)-one (3A): White solid, 358 mg, yield 72%. m.p. 85~87 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 4.56 (s, 1H, OH), 3.83 (s, 3H, OCH₃), 2.44 (s, 3H, N=CCH₃), 1.31 (s, 6H, 2×CH₃); HR-ESI-MS cacld for C₉H₁₄NO₄ [M+H]⁺ 200.0917, found 200.0912.

  (E)-3-(1-((Benzyloxy)imino)ethyl)-5, 5-dimethyl-4-hydroxyfuran-2(5H)-one (3B): Yellow solid, 481 mg, yield 70%. m.p. 63~64 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.45~7.33 (m, 5H, ArH), 5.03 (s, 2H, ArCH₂), 4.61 (s, 1H, OH), 2.55 (s, 3H, N=CCH₃), 1.40 (s, 6H, 2×CH₃); HR-ESI-MS cacld for C₁₅H₁₈NO₄ [M+H]⁺ 276.1230, found 276.1236.

  (E)-3-(1-((2-Chlorobenzyloxy)imino)ethyl)-5, 5-dimeth-yl-4-hydroxyfuran-2(5H)-one (3C): White solid, 533 mg, yield 69%. m.p. 92~93 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.49~7.28 (m, 4H, ArH), 5.16 (s, 2H, ArCH₂), 4.62 (s, 1H, OH), 2.43 (s, 3H, N=CCH₃), 1.45 (s, 6H, 2×CH₃); HR-ESI-MS cacld for C₁₅H₁₇ClNO₄ [M+H]⁺ 310.0841, found 310.0837.

  (E)-3-(1-((3-Chlorobenzyloxy)imino)ethyl)-5, 5-dimethyl-4-hydroxyfuran-2(5H)-one (3D): White solid 548 mg, yield 71%. m.p. 106~107 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.35~7.20 (m, 4H, ArH), 4.99 (s, 2H, ArCH₂), 4.60 (s, 1H, OH), 2.42 (s, 3H, N=CCH₃), 1.45 (s, 6H, 2×CH₃); HR-ESI-MS cacld for C₁₅H₁₇ClNO₄ [M+H]⁺ 310.0841, found 310.0842.

  (E)-3-(1-((4-Chlorobenzyloxy)imino)ethyl)-5, 5-dimeth-yl-4-hydroxylfuran-2(5H)-one (3E): White solid, 601 mg, yield 65%. m.p. 116~119 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.35~7.27 (m, 2H, ArH), 6.97~6.86 (m, 2H, ArH), 4.92 (s, 2H, ArCH₂), 4.62 (s, 1H, OH), 2.42 (s, 3H, N=CCH₃), 1.42 (s, 6H, 2×CH₃); HR-ESI-MS cacld for C₁₅H₁₇ClNO₄ [M+H]⁺ 310.0841, found 310.0847.

  (E)-3-(1-((4-Methoxybenzyloxy)imino)ethyl)-5, 5-di-methyl-4-hydroxylfuran-2(5H)-one (3F): White solid, 613 mg, yield 67%. m. p. 95~98 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.43~7.37 (m, 2H, ArH), 7.37~7.29 (m, 2H, ArH), 5.00 (s, 2H, ArCH₂), 4.60 (s, 1H, OH), 3.83 (s, 3H, OCH₃), 2.42 (s, 3H, N=CCH₃), 1.45 (s, 6H, 2×CH₃); HR-ESI-MS cacld for C₁₆H₂₀NO₅ [M+H]⁺ 306.1336, found 306.1332.

  (E)-3-(1-((4-Nitrobenzyloxy)imino)ethyl)-5, 5-dimethyl-4-hydroxylfuran-2(5H)-one (3G): Yellow solid, 624 mg, yield 65%, m.p. 79~80 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.27 (d, J=8.7 Hz, 2H, ArH), 7.56 (d, J=8.7 Hz, 2H, ArH), 5.16 (s, 2H, ArCH₂), 4.65 (s, 1H, OH), 2.46 (s, 3H, N=CCH₃), 1.45 (s, 6H, 2×CH₃); HR-ESI-MS cacld for C₁₅H₁₇N₂O₆ [M+H]⁺ 321.1081, found 321.1086.

  (E)-3-(1-((3, 4-Dichlorobenzyloxy)imino)ethyl)-5, 5-dimethyl-4-hydroxyfuran-2(5H)-one (3H): White solid, 611 mg, yield 71%, m.p. 112~114 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.51~7.47 (m, 2H, ArH), 7.26~7.22 (m, 1H, ArH), 4.97 (s, 2H, ArCH₂), 4.64 (s, 1H, OH), 2.42 (s, 3H, N=CCH₃), 1.46 (s, 6H, 2×CH₃); HR-ESI-MS cacld for C₁₅H₁₆Cl₂NO₄ [M+H]⁺344.0451, found 344.0455.

  (E)-3-(1-((2-Chloro-6-flurobenzyloxy)imino)ethyl)-5, 5-dimethyl-4-hydroxyfuran-2(5H)-one (3I): White solid, 572 mg, yield 70%. m.p. 115~117 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.34~7.23 (m, 2H, ArH), 7.08~7.00 (m, 1H, ArH), 5.21 (s, 2H, ArCH₂), 4.62 (s, 1H, OH), 2.38 (s, 3H, N=CCH₃), 1.45 (s, 6H, 2×CH₃); HR-ESI-MS cacld for C₁₅H₁₆FClNO₄ [M+H]⁺ 328.0746, found 328.0750.

  (E)-3-(1-((Methoxy)imino)ethyl)-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (3J): White solid, 430 mg, yield 72%. m.p. 82~85 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 4.56 (s, 1H, OH), 3.83 (s, 3H, OCH₃), 2.43 (s, 3H, N=CCH₃), 1.87~1.12 (m, 10H, 5×CH₂); HR-ESI-MS cacld for C₁₂H₁₈NO₄ [M+H]⁺ 240.1230, found 240.1235.

  (E)-3-(1-((Benzyloxy)imino)ethyl)-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (3K): White solid, 543 mg, yield 69%, m.p. 120~122 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.43~7.31 (m, 5H, ArH), 5.02 (s, 2H, ArCH₂), 4.60 (s, 1H, OH), 2.43 (s, 3H, N=CCH₃), 1.74~1.08 (m, 10H, 5×CH₂); HR-ESI-MS cacld for C₁₈H₂₂NO₄ [M+H]⁺ 316.1543, found 316.1548.

  (E)-3-(1-((2-Chlorobenzyloxy)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3L): Yellow solid, 595 mg, yield 68%. m.p. 131~134 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.47~7.25 (m, 4H, ArH), 5.15 (s, 2H, ArCH₂), 4.62 (s, 1H, OH), 2.43 (s, 3H, N=CCH₃), 1.72~1.01 (m, 10H, 5×CH₂); HR-ESI-MS cacld for C₁₈H₂₁ClNO₄ [M+ H]⁺ 350.1154, found 350.1147.

  (E)-3-(1-((3-Chlorobenzyloxy)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3M): Yellow solid, 601 mg, yield 70%. m.p. 115~118 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.38~7.26 (m, 4H, ArH), 4.97 (s, 2H, ArCH₂), 4.61 (s, 1H, OH), 2.40 (s, 3H, N=CCH₃), 1.71~1.03 (m, 10H, 5×CH₂); HR-ESI-MS cacld for C₁₈H₂₁ClNO₄ [M+H]⁺350.1154, found 350.1151.

  (E)-3-(1-((4-Chlorobenzyloxy)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3N): White solid, 578 mg, yield 66%. m.p. 132~135 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.44~7.30 (m, 4H, ArH), 5.03 (s, 2H, ArCH₂), 4.64 (s, 1H, OH), 2.39 (s, 3H, N=CCH₃), 1.72~1.00 (m, 10H, 5×CH₂); HR-ESI-MS cacld for C₁₈H₂₁ClNO₄ [M+H]⁺350.1154, found 350.1148.

  (E)-3-(1-((4-Methoxybenzyl)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3O): White solid, 604 mg, yield 70%. m.p. 93~95 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.37 (d, J=8.7 Hz, 2H, ArH), 6.95 (d, J=8.7 Hz, 2H, ArH), 5.01 (s, 2H, ArCH₂), 4.61 (s, 1H, OH), 3.75 (s, 3H, OCH₃), 2.37 (s, 3H, N=CCH₃), 1.71~1.23 (m, 10H, 5×CH₂); HR-ESI-MS cacld for C₁₉H₂₄NO₅ [M+H]⁺346.1649, found 346.1642.

  (E)-3-(1-((4-Nitrobenzyloxy)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3P): Yellow solid, 603 mg, yield 67%. m.p. 75~78 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.32~8.24 (m, 2H, ArH), 7.61~7.54 (m, 2H, ArH), 5.19 (s, 2H, ArCH₂), 4.64 (s, 1H, OH), 2.41 (s, 3H, N=CCH₃), 1.71~1.02 (m, 10H, 5×CH₂); HR-ESI-MS cacld for C₁₈H₂₁N₂O₆ [M+H]⁺ 361.1394, found 361.1388.

  (E)-3-(1-((3, 4-Dichlorobenzyloxy)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3Q): Yellow solid, 653 mg, yield 68%. m.p. 99~102 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.54~7.48 (m, 2H, ArH), 7.31~7.22 (m, 1H, ArH), 5.02 (s, 2H, ArCH₂), 4.60 (s, 1H, OH), 2.39 (s, 3H, N=CCH₃), 1.81~1.03 (m, 10H, 5×CH₂); HR-ESI- MS cacld for C₁₈H₂₀Cl₂NO₄ [M+H]⁺ 384.0764, found 384.0769.

  (E)-3-(1-((2-Chloro-6-flurobenzyloxy)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3R): White solid, 607 mg, yield 66%. m.p. 89~91 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.39~7.24 (m, 2H, ArH), 7.13~7.02 (m, 1H, ArH), 5.27 (s, 2H, ArCH₂), 4.62 (s, 1H, OH), 2.35 (s, 3H, N=CCH₃), 1.84~1.01 (m, 10H, 5×CH₂); HR-ESI-MS cacld for C₁₈H₂₀FClNO₄ [M+H]⁺ 368.1059, found 368.1065.

  4.2.3   Synthesis of target compounds 5A~5R

  Taking 5K as an example, intermediate 3K (315 mg, 1 mmol) was added into 20 mL of CH₂Cl₂ in a 50 mL three- necked flask. After the mixture was cooled down to 0 ℃ in water-ice bath, 170 μL (2 mmol) of oxalyl dichloride and 15 μL (0.2 mmol) of DMF were dropped in a stirred condition. Then the reaction mixture was back to room temperature, and stirred for 4 h. 20 mL of water was added into the solution, and the organic phase was separated. The water phase was re-extracted with CH₂Cl₂ (20 mL×2), and the organic phase was combined. Then the organic phase was dried over anhydrous Na₂SO₄. The solvent was removed, and the crude product 4K was obtained and utilized for the next reaction without further purification.

  Product 4K was dissolved in tetrahydrofuran (THF) (20 mL), 30% (mass fraction) methylamine aqueous solution (265 μL, 2.5 mmol) was added gradually into the solution. The mixture was stirred and reacted for 6 h at ambient temperature. Then the solvent was removed, and the residue was dissolved in 50 mL of ethyl acetate. The organic mixture was washed with NaHCO₃ solution, and the water phase was re-extracted with ethyl acetate (50 mL×2), and the organic phase was combined. Then the organic phase was dried over anhydrous Na₂SO₄. The solvent was removed, and the residue was subjected to flash column chromatography on silica gel and eluted with petroleum ether/EtOAc (V:V=4:1) to afford (E)-3-(1-((benzyl- oxy)imino)ethyl)-4-methyl-amino-1-oxaspiro[4.5]dec-3-en-2-one (5K) (213 mg, yield 65%) as a white solid. The target compounds 5A~5R were synthesized in the same procedure.

  (E)-3-(1-((Methoxy)imino)ethyl)-5, 5-dimethyl-4-(methylamino)furan-2(5H)-one (5A): White solid, 155 mg, yield 78%. m.p. 102~103 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.80 (brs, 1H, NH), 3.84 (s, 3H, OCH₃), 3.15 (d, J=5.7 Hz, 3H, NCH₃), 2.29 (s, 3H, N=CCH₃), 1.63 (s, 6H, 2×CH₃); ¹³C NMR (75 MHz, CDCl₃) δ: 172.1, 170.0, 155.4, 88.0, 78.1, 61.3, 30.5, 24.5, 11.2; HR-ESI-MS cacld for C₁₀H₁₇N₂O₃ [M+H]⁺ 213.1234, found 213.1236.

  (E)-3-(1-((Benzyloxy)imino)ethyl)-5, 5-dimethyl-4-(methylamino)furan-2(5H)-one (5B): Yellow liquid, 232 mg, yield 70%. ¹H NMR (300 MHz, CDCl₃) δ: 8.51 (brs, 1H, NH), 7.42~7.30 (m, 5H, ArH), 5.05 (s, 2H, ArCH₂), 2.95 (d, J=5.7 Hz, 3H, NCH₃), 2.35 (s, 3H, N=CCH₃), 1.59 (s, 6H, 2×CH₃); ¹³C NMR (75 MHz, CDCl₃) δ: 172.0, 170.0, 155.5, 137.9, 128.1, 127.9, 127.5, 88.3, 78.1, 75.3, 30.2, 24.4, 11.5; HR-ESI-MS cacld for C₁₆H₂₁N₂O₃ [M+H]⁺ 289.1547, found 289.1546.

  (E)-3-(1-((2-Chlorobenzyloxy)imino)ethyl)-5, 5-dimeth-yl-4-(methylamino)furan-2(5H)-one (5C): White solid, 197 mg, yield 61%. m.p. 102~103 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.59 (brs, 1H, NH), 7.46~7.24 (m, 4H, ArH), 5.18 (s, 2H, ArCH₂), 3.04 (d, J=5.4 Hz, 3H, NCH₃), 2.37 (s, 3H, N=CCH₃), 1.60 (s, 6H, 2×CH₃); ¹³C NMR (75 MHz, CDCl₃) δ: 172.1, 170.0, 156.1, 135.6, 133.0, 129.8, 129.1, 128.7, 126.5, 88.1, 78.1, 72.0, 30.4, 24.5, 11.5; HR-ESI-MS cacld for C₁₆H₂₀ClN₂O₃ [M+H]⁺323.1157, found 323.1154.

  (E)-3-(1-((3-Chlorobenzyloxy)imino)ethyl)-5, 5-dimeth-yl-4-(methylamino)furan-2(5H)-one (5D): White solid, 203 mg, yield 63%. m.p. 85~87 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.47 (brs, 1H, NH), 7.38~7.23 (m, 4H, ArH), 5.00 (s, 2H, ArCH₂), 3.00 (d, J=5.7 Hz, 3H, NCH₃), 2.35 (s, 3H, N=CCH₃), 1.60 (s, 6H, 2×CH₃); ¹³C NMR (75 MHz, CDCl₃) δ: 172.1, 169.9, 156.0, 140.1, 133.9, 129.5, 127.9, 127.6, 125.9, 88.2, 78.1, 74.4, 30.3, 24.4, 11.5; HR-ESI-MS cacld for C₁₆H₂₀ClN₂O₃ [M+H]⁺ 323.1157, found 323.1152.

  (E)-3-(1-((4-Chlorobenzyloxy)imino)ethyl)-5, 5-dimeth-yl-4-(methylamino)furan-2(5H)-one (5E): White solid, 209 mg, yield 65%. m.p. 128~130 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.46 (brs, 1H, NH), 7.37~7.26 (m, 4H, ArH), 5.01 (s, 2H, ArCH₂), 2.98 (d, J=5.7 Hz, 3H, NCH₃), 2.34 (s, 3H, N=CCH₃), 1.60 (s, 6H, 2×CH₃); ¹³C NMR (75 MHz, CDCl₃) δ: 172.1, 169.9, 155.9, 136.5, 133.3, 129.1, 128.2, 88.2, 78.1, 74.4, 30.3, 24.4, 11.5; HR-ESI-MS cacld for C₁₆H₂₀ClN₂O₃ [M+H]⁺ 323.1157, found 323.1162.

  (E)-3-(1-((4-Methoxybenzyloxy)imino)ethyl)-5, 5-dime-thyl-4-(methylamino)furan-2(5H)-one (5F): White solid, 194 mg, yield 61%. m.p. 117~119 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.59 (brs, 1H, NH), 7.31~7.24 (m, 2H, ArH), 6.94~6.84 (m, 2H, ArH), 4.97 (s, 2H, ArCH₂), 3.81 (s, 3H, OCH₃), 3.00 (d, J=5.4 Hz, 3H, NCH₃), 2.32 (s, 3H, N=CCH₃), 1.60 (s, 6H, 2×CH₃); ¹³C NMR (75 MHz, CDCl₃) δ: 172.0, 169.9, 159.0, 155.3, 130.0, 129.5, 113.5, 88.4, 78.1, 75.0, 55.0, 30.3, 24.5, 11.5; HR-ESI-MS cacld for C₁₇H₂₃N₂O₄ [M+H]⁺ 319.1652, found 319.1656.

  (E)-3-(1-((4-Nitrobenzyloxy)imino)ethyl)-5, 5-dimethyl-4-(methylamino)furan-2(5H)-one (5G): Yellow solid, 151 mg, yield 69%. m.p. 111~113 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.42 (brs, 1H, NH), 8.24~8.21 (m, 2H, ArH), 7.53~7.50 (m, 2H, ArH), 5.15 (s, 2H, ArCH₂), 3.00 (d, J=5.7 Hz, 3H, NCH₃), 2.38 (s, 3H, N=CCH₃), 1.60 (s, 6H, 2×CH₃); ¹³C NMR (75 MHz, CDCl₃) δ: 172.3, 169.7, 156.8, 147.2, 145.5, 127.8, 123.3, 88.1, 78.2, 73.9, 30.4, 24.4, 11.6; HR-ESI-MS cacld for C₁₆H₂₀N₃O₅ [M+H]⁺ 334.1397, found 334.1393.

  (E)-3-(1-((3, 4-Dichlorobenzyloxy)imino)ethyl)-5, 5-di-methyl-4-(methylamino)furan-2(5H)-one (5H): White solid, 232 mg, yield 65%. m.p. 106~108 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.45 (brs, 1H, NH), 7.47~7.43 (m, 2H, ArH), 7.23~7.19 (m, 1H, ArH), 4.98 (s, 2H, ArCH₂), 3.02 (d, J=5.7 Hz, 3H, NCH₃), 2.35 (s, 3H, N=CCH₃), 1.61 (s, 6H, 2×CH₃); ¹³C NMR (75 MHz, CDCl₃) δ: 172.2, 169.8, 156.4, 138.3, 132.1, 131.5, 130.2, 129.6, 127.1, 88.2, 78.2, 73.8, 30.4, 24.4, 11.5; HR-ESI-MS cacld for C₁₆H₁₉Cl₂- N₂O₃ [M+H]⁺ 357.0767, found 357.0765.

  (E)-3-(1-((2-Chloro-6-flurobenzyloxy)imino)ethyl)-5, 5-dimethyl-4-(methylamino)furan-2(5H)-one (5I): White solid, 211 mg, yield 62%. m.p. 128~130 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.76 (brs, 1H, NH), 7.31~7.21 (m, 2H, ArH), 7.05~6.98 (m, 1H, ArH), 5.23 (s, 2H, ArCH₂), 3.11 (d, J=5.7 Hz, 3H, NCH₃), 2.30 (s, 3H, N=CCH₃), 1.60 (s, 6H, 2×CH₃); ¹³C NMR (75 MHz, CDCl₃) δ: 172.1, 169.9, 161.8 (d, ¹J_FC=248.1 Hz), 156.2, 136.1 (d, ³J_FC=5.7 Hz), 130.1 (d, ³J_FC=9.8 Hz), 125.3 (d, ⁴J_FC=3.4 Hz), 123.5 (d, ²J_FC=17.8 Hz), 113.7 (d, ²J_FC=23.1 Hz), 87.9, 78.0, 65.3 (d, ³J_FC=2.1 Hz), 30.3, 24.4, 11.1; HR-ESI-MS cacld for C₁₆H₁₉ClFN₂O₃ [M+H]⁺ 341.1063, found 341.1068.

  (E)-3-(1-((Methoxy)imino)ethyl)-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (5J): White solid, 187 mg, yield 74%. m.p. 118~120 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.85 (brs, 1H, NH), 3.82 (s, 3H), 3.17 (d, J=5.5 Hz, 3H, NCH₃), 2.28 (s, 3H, N=CCH₃), 1.99~1.23 (m, 10H, 5×CH₂); ¹³C NMR (75 MHz, CDCl₃) δ: 171.9, 170.3, 155.6, 88.7, 80.1, 61.3, 32.5, 30.6, 24.3, 21.4, 11.3. HR-ESI-MS cacld for C₁₃H₂₁N₂O₃ [M+H]⁺253.1547, found 253.1542.

  (E)-3-(1-((Benzyloxy)imino)ethyl)-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (5K): White solid, 213 mg, yield 65%. m.p. 164~166 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.57 (brs, 1H, NH), 7.40~7.30 (m, 5H, ArH), 5.04 (s, 2H, ArCH₂), 2.99 (d, J=5.5 Hz, 3H, NCH₃), 2.36 (s, 3H, N=CCH₃), 1.94~1.22 (m, 10H, 5×CH₂); ¹³C NMR (75 MHz, CDCl₃) δ: 171.9, 170.3, 155.7, 138.0, 128.1, 127.9, 127.5, 89.0, 80.1, 75.2, 32.5, 30.4, 24.3, 21.4, 11.6; HR-ESI-MS cacld for C₁₉H₂₅N₂O₃ [M+H]⁺ 329.1860, found 329.1865.

  (E)-3-(1-((2-Chlorobenzyloxy)imino)ethyl)-4-(methyl-amino)-1-oxaspiro[4.5]dec-3-en-2-one (5L): Yellow solid, 236 mg, yield 65%. m.p. 160~161 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.64 (brs, 1H, NH), 7.45-7.22 (m, 4H, ArH), 5.17 (s, 2H, ArCH₂), 3.07 (d, J=5.7 Hz, 3H, NCH₃), 2.38 (s, 3H, N=CCH₃), 1.97~1.14 (m, 10H, 5×CH₂); ¹³C NMR (75 MHz, CDCl₃) δ: 171.9, 170.3, 156.3, 135.6, 133.0, 129.8, 129.0, 128.7, 126.5, 88.8, 80.1, 72.0, 32.5, 30.5, 24.3, 21.4, 11.6; HR-ESI-MS cacld for C₁₉H₂₄ClN₂O₃ [M+H]⁺ 363.1470, found 363.1466.

  (E)-3-(1-((3-Chlorobenzyloxy)imino)ethyl)-4-(methyl-amino)-1-oxaspiro[4.5]dec-3-en-2-one (5M): Yellow solid, 243 mg, yield 67%. m.p. 117~118 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.53 (brs, 1H, NH), 7.35~7.23 (m, 4H, ArH), 4.99 (s, 2H, ArCH₂), 3.03 (d, J=5.7 Hz, 3H, NCH₃), 2.35 (s, 3H, N=CCH₃), 1.96~1.13 (m, 10H, 5×CH₂); ¹³C NMR (75 MHz, CDCl₃) δ: 171.9, 170.2, 156.2, 140.1, 133.9, 129.5, 127.9, 127.6, 125.9, 88.9, 80.2, 74.4, 32.5, 30.5, 24.3, 21.4, 11.6. HR-ESI-MS cacld for C₁₉H₂₄ClN₂O₃ [M+H]⁺ 363.1470, found 363.1473.

  (E)-3-(1-((4-Chlorobenzyloxy)imino)ethyl)-4-(methyl-amino)-1-oxaspiro[4.5]dec-3-en-2-one (5N): White solid, 225 mg, yield 62%. m.p. 139~140 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.52 (brs, 1H, NH), 7.36~7.26 (m, 4H, ArH), 5.00 (s, 2H, ArCH₂), 3.01 (d, J=5.7 Hz, 3H, NCH₃), 2.35 (s, 3H, N=CCH₃), 1.96~1.15 (m, 10H, 5×CH₂); ¹³C NMR (75 MHz, CDCl₃) δ: 171.9, 170.2, 156.1, 136.5, 133.3, 129.1, 128.2, 88.9, 80.2, 74.4, 32.5, 30.4, 24.3, 21.4, 11.6; HR-ESI-MS cacld for C₁₉H₂₄ClN₂O₃ [M+H]⁺ 363.1470, found 363.1476.

  (E)-3-(1-((4-Methoxybenzyloxy)imino)ethyl)-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (5O): White solid, 189 mg, yield 73%. m.p. 135~137 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.65 (brs, 1H, NH), 7.32~7.26 (m, 2H, ArH), 6.93~6.88 (m, 2H, ArH), 4.96 (s, 2H, ArCH₂), 3.81 (s, 3H), 3.04 (d, J=5.7 Hz, 3H, NCH₃), 2.33 (s, 3H, N=CCH₃), 1.96~1.17 (m, 10H, 5×CH₂); ¹³C NMR (75 MHz, CDCl₃) δ: 171.8, 170.3, 159.0, 155.6, 130.0, 129.5, 113.5, 89.0, 80.1, 74.9, 55.0, 32.5, 30.4, 24.3, 21.4, 11.6; HR-ESI-MS cacld for C₂₀H₂₇N₂O₄ [M+H]⁺ 359.1965, found 359.1969.

  (E)-3-(1-((4-Nitrobenzyloxy)imino)ethyl)-4-(methyl-amino)-1-oxaspiro[4.5]dec-3-en-2-one (5P): Yellow solid, 228 mg, yield 61%. m.p. 128~129 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.46 (brs, 1H, NH), 8.24~8.20 (m, 2H, ArH), 7.53~7.50 (m, 2H, ArH), 5.15 (s, 2H, ArCH₂), 3.02 (d, J=5.7 Hz, 3H, NCH₃), 2.39 (s, 3H, N=CCH₃), 1.96~1.14 (m, 10H, 5×CH₂); ¹³C NMR (75 MHz, CDCl₃) δ: 172.1, 170.1, 156.9, 147.2, 145.5, 127.8, 123.3, 88.8, 80.2, 73.9, 32.5, 30.5, 24.3, 21.4, 11.7; HR-ESI-MS cacld for C₂₀H₂₇N₂O₄ [M+H]⁺ 359.1965, found 359.1969.

  (E)-3-(1-((3, 4-Dichlorobenzyloxy)imino)ethyl)-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (5Q): Yellow solid, 270 mg, yield 68%. m.p. 131~133 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.49 (brs, 1H, NH), 7.46~7.43 (m, 2H, ArH), 7.22~7.18 (m, 1H, ArH), 4.97 (s, 2H, ArCH₂), 3.05 (d, J=5.7 Hz, 3H, NCH₃), 2.35 (s, 3H, N=CCH₃), 1.96~1.18 (m, 10H, 5×CH₂); ¹³C NMR (75 MHz, CDCl₃) δ: 172.0, 170.1, 156.5, 138.3, 132.1, 131.5, 130.2, 129.6, 127.1, 88.8, 80.2, 73.8, 32.5, 30.5, 24.3, 21.4, 11.6; HR-ESI-MS cacld for C₁₉H₂₃Cl₂N₂O₃ [M+H]⁺ 397.1080, found 397.1075.

  (E)-3-(1-((2-Chloro-6-flurobenzyloxy)imino)ethyl)-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (5R): White solid, 256 mg, yield 68%. m.p. 133~134 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.81 (brs, 1H, NH), 7.31~7.20 (m, 2H, ArH), 7.05~6.98 (m, 1H, ArH), 5.22 (s, 2H, ArCH₂), 3.14 (d, J=5.7 Hz, 3H, NCH₃), 2.31 (s, 3H, N=CCH₃), 1.99~1.15 (m, 10H, 5×CH₂); ¹³C NMR (75 MHz, CDCl₃) δ: 171.9, 170.2, 161.8 (d, ¹J_FC=247.9 Hz), 156.5, 136.2 (d, ³J_FC=5.5 Hz), 130.0 (d, ³J_FC=9.7 Hz), 125.2 (d, ⁴J_FC=3.3 Hz), 123.5 (d, ²J_FC=17.8 Hz), 113.6 (d, ²J_FC=22.8 Hz), 88.6, 80.0, 65.3 (d, ³J_FC=2.1 Hz), 32.5, 30.4, 24.3, 21.4, 11.2; HR-ESI-MS cacld for C₁₉H₂₃ClFN₂O₃ [M+H]⁺ 381.1376, found 381.1379.

  4.3   X-Ray diffraction analysis of title compound 5O

  The crystal of 5O was obtained from ethanol/n-hexane (V:V=1:20) solution. Its structure parameters were shown as following: crystal size: 0.40 mm×0.35 mm×0.30 mm, formula C₂₀H₂₆N₂O₄, M=358.43, triclinic, a=0.76597(5) nm, b=0.99514(7) nm, c=1.28118(8) nm, α=100.566(5)°, β=101.600(5)°, γ=100.749(6)°, V=0.91476(10) nm³, ρ=1.301 mg/mm³, space group P-1, Z=2, μ(Mo Kα)=0.091 mm^－1, F(000)=384, S=1.033. Totally 7790 reflections were measured at T=112.00 K, 4241 unique reflections (R_int=0.0260) were used for all calculations and structure refinement. The final R₁=0.0551, wR₂=0.1071 (all data). The crystallographic data of 5O have been deposited with the Cambridge Crystallographic Data Centre with the accession number (CCDC 1999989). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam. ac.uk/data_request/cif.

  4.4   Biological activity evaluation of title compounds 5A~5R

  The fungicidal and insecticidal activities were evaluated using the protocols in the previous reports^{[9-12, 19-20]}.

  Supporting information  The ¹H NMR, ¹³C NMR of 5A~5R, and X-ray diffraction data of 5O. The Supporting information is available free of charge via the Internet at http://sioc-journal.cn.

  
  
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  Scheme 1  Spirocyclic butenolide molecular library constructed from the diversity-oriented synthesis strategy^[4-12]

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  Scheme 2  Design strategy of target molecules

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  Scheme 3  Synthetic route of (E)-3-(1-iminoethyl)-5, 5-disubstituted-4-(methylamino)furan-2(5H)-one

  1A, 2A, 2a, 3A~3I, 4A~4I, 5A~5I: R¹=R²=CH₃; 1B, 2B, 2b, 3J~3R, 4J~4R, 5J~5R: R¹+R²=(CH₂)₅; 3A, 4A, 5A, 3J, 4J, 5J: R³=CH₃; 3B, 4B, 5B, 3K, 4K, 5K: R³=PhCH₂; 3C, 4C, 5C, 3L, 4L, 5L: R³=2-ClC₆H₄CH₂; 3D, 4D, 5D, 3M, 4M, 5M: R³=3-ClC₆H₄CH₂; 3E, 4E, 5E, 3N, 4N, 5N: R³=4-ClC₆H₄CH₂; 3F, 4F, 5F, 3O, 4O, 5O: R³=4-CH₃OC₆H₄CH₂; 3G, 4G, 5G, 3P, 4P, 5P: R³=4-NO₂C₆H₄CH₂; 3H, 4H, 5H, 3Q, 4Q, 5Q: R³=3, 4-Cl₂C₆H₃CH₂; 3I, 4I, 5I, 3R, 4R, 5R: R³=2-Cl-6-FC₆H₃CH₂
  Reagents and condition: (a) diketene, Et₃N, Na, toluene, 70 ℃, 90%~93%; (b) Me₃OBF₄, (1, 8-bis(dimethylamino)naphthalene, DCM, reflux; 30% methylamine solution, ethanol, reflux, 55%~60%; (c) and (d) O-methyl/benzylhydroxylamine, 4-methylbenzenesulfonic acid, r.t. or reflux, 66%~72%; (e) oxalyl dichloride, DMF, 0 ℃~r.t.; (f) 30% methylamine solution, THF, r.t., 61%~78%

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  图 1  X-Ray structure and two possible conformations of compound 5O

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  表 1  Insecticidal activities (mortality/%) of title compounds 5A~5R at 600 µg/mL

  Compd.	P. xylostella	M. separata	M. persicae	T. cinnabarinus
  5A	0	0	100, 0, a 0b	0
  5B	0	0	0	0
  5C	100, 50, a 40b	0	0	0
  5D	100, 50, a 20b	0	0	0
  5E	0	0	0	50
  5F	100, 30, a 0b	0	0	0
  5G	60	50	0	0
  5H	0	0	0	0
  5I	100, 60, a 40b	0	0	0
  5J	70	0	0	0
  5K	70	100, 0, a 0b	0	0
  5L	100, 30, a 0b	0	0	0
  5M	0	0	0	0
  5N	0	70	0	0
  5O	0	0	0	0
  5P	50	50	0	0
  5Q	100, 50, a 0b	100, 0, a 0b	0	0
  5R	0	0	0	0
  Imidacloprid	100b	100b	100b	100b
  a Activity at 100 µg/mL; b Activity at 10 µg/mL.

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