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Steric parameters (e.g., the molecular length d and the ratio of the nonpolar surface area and polar
surface area V1/V2) and semiempirical quantum parameters (e.g., the molecular total energy Et
and the lowest unoccupied molecular orbital energy ELUMO and so on) of these compounds, as well
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made with an Italian MOD.1106 analyzer. Analytical thin- 8.80 Hz, 1H, CH), 2.29 (dd, J ) 8.80 Hz, 1H, CH), 1.30-1.40
layer chromatography (TLC) was carried out on precoated (6H, 2CH3); (trans) δ 7.74 (dd, J ) 1.19 and 3.67 Hz, 1H, ArH),
plates (silica gel 60 F254), and spots were visualized with 7.56 (dd, J ) 1.19 and 5.02 Hz, 1H, ArH), 7.18 (dd, J ) 3.67
ultraviolet (UV) light. and 5.02 Hz, 1H, ArH), 5.75 (d, J ) 8.07 Hz, 1H, Cl2CdCH),
General Synthetic Procedure for 2-[2,2-Dimethyl-3- 2.47 (dd, J ) 8.07 and 5.58 Hz, 1H, CH), 2.14 (d, J ) 5.58 Hz,
(2,2-dichlorovinyl)cyclopropyl]-5-substituted-1,3,4-oxa- 1H, CH), 1.30-1.40 (6H, 2CH3). Anal. Calcd (%) for C13H12-
diazoles (1-6). A mixture of 2,2-dimethyl-3-(2,2-dichlorovi- Cl2N2OS: C, 49.53; H, 3.84; N, 8.89. Found: C, 49.20; H, 3.70;
nyl)cyclopropanecarboxylic acid methyl ester (A) (2.23 g, 10 N, 8.90.
mmol) and hydrazine monohydrate (5 g, 100 mmol) was boiled Data for 3 (trans): yield 68%; obtained as white powdery
under reflux for 12 h. After the mixture had cooled to room crystals; mp 129.2-129.8 °C; Rf ) 0.77 (ethyl acetate/
temperature, a precipitate was collected, washed, and dried petroleum ether ) 1:2, v/v); IR (KBr, cm-1) υmax 3050, 2950,
to give a yellowish solid, 2,2-dimethyl-3-(2,2-dichlorovinyl)- 1590, 1570, 1480, 1380, 1100, 890, 830; 1H NMR (CDCl3) δ
cyclopropanecarboxylic acid hydrazide (B) (90% yield). Com- (trans) 7.97 (d, J ) 8.48 Hz, 1H, ArH), 7.59 (d, J ) 2.03 Hz,
pound B (without purification) (1.56 g, 7 mmol), NaHCO3 1H, ArH), 7.45 (dd, J ) 8.48 and 2.03 Hz, 1H, ArH), 5.77 (d,
(0.588 g, 7 mmol), THF (8 mL), and H2O (4 mL) were mixed. J ) 8.14 Hz, 1H, Cl2CdCH), 2.49 (dd, J ) 8.14 and 5.57 Hz,
To this mixture was added dropwise a solution of the corre- 1H, CH), 2.21 (d, J ) 5.57 Hz, 1H, CH), 1.34 (6H, 2CH3). Anal.
sponding acyl chloride (7 mmol) in THF (6 mL) over 30 min, Calcd (%) for C15H12Cl4N2O: C, 47.62; H, 3.17; N, 7.41.
with stirring. The reaction mixture was stirred for 3 h at room Found: C, 47.19; H, 3.14; N, 7.40.
temperature. The solvent was removed in vacuo, and the solid Data for 4 (cis/trans ) 28.1:71.9): yield 63%; obtained as
obtained was washed and dried to give N-acyl-N′-[2,2-dimeth- white needle crystals; mp 120.5-137.6 °C; Rf ) 0.74 (ethyl
yl-3-(2,2-dichlorovinyl)cyclopropanecarbonyl]hydrazines (C1- acetate/petroleum ether ) 1:2, v/v); IR (KBr, cm-1) υmax 3050,
C6) in ∼92% yield, which was submitted to the cyclization 2950, 1610, 1590, 1570, 1490, 1410, 1090, 890, 830, 730; 1H
reaction without further purification. The mixture of the NMR (CDCl3) δ (cis) 8.00 (d, J ) 8.55 Hz, 2H, 2ArH), 7.55 (d,
hydrazine C1-C6 (5 mmol) and POCl3 (10 mL) was refluxed J ) 8.55 Hz, 2H, 2ArH), 6.30 (d, J ) 8.76 Hz, 1H, Cl2CdCH),
for 3 h. After cooling to room temperature, it was poured slowly 2.40 (d, J ) 8.76 Hz, 1H, CH), 2.29 (dd, J ) 8.76 Hz, 1H, CH),
into an ice and water mixture. The resulting precipitate was 1.31-1.41 (6H, 2CH3); (trans) δ 8.00 (d, J ) 8.55 Hz, 2H,
filtered, washed, dried, and recrystallized from ethanol twice 2ArH), 7.55 (d, J ) 8.55 Hz, 2H, 2ArH), 5.76 (d, J ) 8.02 Hz,
to produce the pure oxadiazoles 1-6. The recrystallized yields 1H, Cl2CdCH), 2.49 (dd, J ) 8.02 and 5.52 Hz, 1H, CH), 2.15
for cyclization reactions are listed below. (d, J ) 5.52 Hz, 1H, CH), 1.31-1.41 (6H, 2CH3). Anal. Calcd
Data for 1 (trans): yield 55%; obtained as white needle (%) for C15H13Cl3N2O: C, 52.40; H, 3.79; N, 8.15. Found: C,
crystals; mp 163.1-163.9 °C; Rf ) 0.68 (ethyl acetate/ 51.88; H, 3.66; N, 8.22.
petroleum ether ) 1:2, v/v); IR (KBr, cm-1) υmax 3050, 2950, Data for 5 (cis/trans ) 23.4:76.6): yield 61%; obtained as
1650, 1570, 1560, 1490, 1450, 890, 830; 1H NMR (CDCl3) δ white needle crystals; mp 154.9-165.6 °C; Rf ) 0.80 (ethyl
8.03 (m, 2H, 2ArH), 7.52 (m, 3H, 3ArH), 5.74 (d, J ) 8.09 Hz, acetate/petroleum ether ) 1:2, v/v); IR (KBr, cm-1) υmax 3050,
1H, Cl2CdCH), 2.47 (dd, J ) 8.09 and 5.56 Hz, 1H, CH), 2.15 2950, 1610, 1590, 1570, 1500, 1470, 1270, 1030, 890, 830; 1H
(d, J ) 5.56 Hz, 1H, CH), 1.29-1.32 (6H, 2CH3). Anal. Calcd NMR (CDCl3) δ (cis) 7.98 (d, J ) 8.77 Hz, 2H, 2ArH), 7.02 (d,
(%) for C15H14Cl2N2O: C, 58.25; H, 4.53; N, 9.06. Found: C, J ) 8.77 Hz, 2H, 2ArH), 6.31 (d, J ) 8.81 Hz, 1H, Cl2CdCH),
58.25; H, 4.47; N, 9.03. 3.90 (s, 3H, OCH3), 2.39 (d, J ) 8.81 Hz, 1H, CH), 2.26 (dd, J
Data for 2 (cis/trans ) 6.6:93.4): yield 60%; obtained as ) 8.81 Hz, 1H, CH), 1.30-1.40 (6H, 2CH3); δ (trans) 7.98 (d,
white powdery crystals; mp 149.0-150.2 °C; Rf ) 0.74 (ethyl J ) 8.77 Hz, 2H, 2ArH), 7.02 (d, J ) 8.77 Hz, 2H, 2ArH), 5.75
acetate/petroleum ether ) 1:2, v/v); IR (KBr, cm-1) υmax 3050, (d, J ) 8.11 Hz, 1H, Cl2CdCH), 3.90 (s, 3H, OCH3), 2.47 (dd,
2950, 1600, 1560, 1495, 1430, 830, 710; 1H NMR (CDCl3) δ J ) 8.11 Hz and 5.55 Hz, 1H, CH), 2.15 (d, J ) 5.55 Hz, 1H,
(cis) 7.74 (dd, J ) 1.19 and 3.67 Hz, 1H, ArH), 7.56 (dd, J ) CH), 1.30-1.40 (6H, 2CH3). Anal. Calcd (%) for C16H16-
1.19 and 5.02 Hz, 1H, ArH), 7.18 (dd, J ) 3.67 and 5.02 Hz, Cl2N2O2: C, 56.64; H, 4.72; N, 8.26. Found: C, 56.71; H, 4.64;
1H, ArH), 6.29 (d, J ) 8.80 Hz, 1H, Cl2CdCH), 2.38 (d, J ) N, 8.40.
126 J. Agric. Food Chem., Vol. 49, No. 1, 2001 Shi et al.
Table 1. Structure Formulas, Molecular Parameters, and Experimental and Calculated Inecticidal Activities of
Synthesized or Cited Oxadiazoles
a Calculated by eq 1. b Calculated by eq 7. c Calculated by eq 8. *The values in parentheses are the percentage killed at that concenration.
# The double bond in 6 is the E configuration.
Synthesis of New 2,5-Disubstituted-1,3,4-oxadiazoles J. Agric. Food Chem., Vol. 49, No. 1, 2001 127
Data for 6 (cis/trans ) 33.1:66.9): yield 66%; obtained as 2H, 2ArH), 5.25 (s, 2H, OCH2). Anal. Calcd (%) for C14H9-
white needle crystals; mp 120.8-134.4 °C; Rf ) 0.77 (ethyl Cl2N3O2: C, 52.20; H, 2.82; N, 13.04. Found: C, 52.43; H, 2.78;
acetate/petroleum ether ) 1:2, v/v); IR (KBr, cm-1) υmax 3080, N, 13.12.
3050, 2950, 1650, 1570, 1530, 1450, 970, 890, 830, 750; 1H Data for 10: yield 30%; obtained as small off-white ball
NMR (CDCl3) δ (cis) 7.57 (m, 2H, ArH), 7.50 (d, J ) 16.22 Hz, crystals; mp 186.2-186.6 °C; Rf ) 0.50 (dichloromethane); 1H
1H, CdCH), 7.43 (m, 3H, ArH), 7.02 (d, J ) 16.22 Hz, 1H, NMR (CDCl3) δ 8.55 (d, J ) 5.05 Hz, 1H, ArH), 8.25 (d, J )
CdCH), 6.30 (d, J ) 8.76 Hz, 1H, Cl2CdCH), 2.37 (d, J ) 8.76 2.25 Hz, 1H, ArH), 7.56 (d, J ) 5.05 and 2.25 Hz, 1H, ArH),
Hz, 1H, CH), 2.27 (dd, J ) 8.76 Hz, 1H, CH), 1.31-1.40 (6H, 7.37 (d, J ) 9.00 Hz, 2H, 2ArH), 7.05 (d, J ) 9.00 Hz, 2H,
2CH3); δ (trans) 7.57 (m, 2H, ArH), 7.50 (d, J ) 16.22 Hz, 1H, 2ArH), 4.75 (s, 2H, OCH2). Anal. Calcd (%) for C14H9Cl2N3O2:
CdCH), 7.43 (m, 3H, ArH), 7.02 (d, J ) 16.22 Hz, 1H, Cd C, 52.20; H, 2.82; N, 13.04. Found: C, 52.19; H, 2.74; N, 13.01.
CH), 5.75 (d, J ) 8.10 Hz, 1H, Cl2CdCH), 2.48 (dd, J ) 8.10 Data for 11: yield 40%; obtained as brilliant yellow needle
and 5.33 Hz, 1H, CH), 2.12 (d, J ) 5.33 Hz, 1H, CH), 1.31- crystals; mp 100.6-101.5 °C; Rf ) 0.57 (dichloromethane); IR
1.40 (6H, 2CH3). Anal. Calcd (%) for C17H16Cl2N2O: C, 60.90; (KBr, cm-1) υmax 3100, 2910, 1580, 1490, 1240, 1070, 870, 830,
H, 4.78; N, 8.36. Found: C, 61.05; H, 4.69; N, 8.48. 780, 720; 1H NMR (CDCl3) δ 7.85 (m, 1H, ArH), 7.75 (m, 1H,
General Synthetic Procedure for Substituted Phe- ArH), 7.50 (m, 1H, ArH), 7.28 (m, 1H, ArH), 7.25 (d, J ) 8.70
noxyacetic Acid Hydrazides (F1-F3). The substituted Hz, 2H, 2ArH), 6.95 (d, J ) 8.70 Hz, 2H, 2ArH), 5.50 (s, 2H,
phenol (D1-D3) (100 mmol) was dissolved by anhydrous OCH2). Anal. Calcd (%) for C15H10ClFN2O2: C, 59.13; H, 3.31;
acetone (30 mL). To the solution were added ethyl chloroac- N, 9.20. Found: C, 59.30; H, 3.28; N, 9.26.
etate (15 g, 120 mmol) and anhydrous potassium carbonate Data for 12: yield 45%; obtained as light brown thin flake
(22.7 g, 200 mmol). The reaction mixture obtained was refluxed crystals; mp 126.2-126.8 °C; Rf ) 0.50 (dichloromethane); IR
for 20 h, with stirring. When hot, the reaction mixture was (KBr, cm-1) υmax 3090, 2910, 1610, 1580, 1490, 1240, 1090,
filtered under aspirator pressure. The solvent was removed 1040, 880, 830, 730, 680; 1H NMR (CDCl3) δ 7.90 (d, JH,F )
from the filtrate under reduced pressure to give the crude 6.93 Hz, 1H, ArH), 7.65 (d, JH,F ) 9.10 Hz, 1H, ArH), 7.30 (d,
substituted phenoxyacetic acid ethyl esters (E1-E3). A mix- J ) 8.90 Hz, 2H, 2ArH), 7.00 (d, J ) 8.90 Hz, 2H, 2ArH), 5.70
ture of the above ester (E1-E3) (without further purification), (s, 2H, OCH2); MS, m/z (relative intensity) 374 (M+, 7), 245
hydrazine monohydrate (42.30 g, 0.83 mol), and ethanol (50 (41), 194 (75), 191 (100), 165 (11), 128 (10), 111 (10), 99 (16).
mL) was refluxed for 14 h. After the mixutre had cooled to Anal. Calcd (%) for C15H8Cl3FN2O2: C, 48.22; H, 2.16; N, 7.50.
room temperature, the resulting precipitate was filtered, Found: C, 47.91; H, 1.96; N, 7.54.
washed, and dried to give the crude products, which were Data for 13: yield 33%; obtained as white needle crystals;
recrystallized from ethanol to produce the pure substituted mp 160.9-162.5 °C; Rf ) 0.55 (dichloromethane); 1H NMR
phenoxyacetic acid hydrazides (F1-F3). The total yields for (DMSO-d6) δ 8.00 (s, 1H, ArH), 7.90 (d, J ) 1.85 Hz, 1H, ArH),
two-step reactions are given below. 7.70 (s, 1H, ArH), 7.65 (d, J ) 1.85 Hz, 1H, ArH), 7.45 (d, J )
Data for F1: yield 67%; obtained as a white floc; mp 110.5- 1.40 Hz, 1H, ArH), 7.43 (d, J ) 1.40 Hz, 1H, ArH), 5.65 (s,
111.1 °C; Rf ) 0.20 (ethyl acetate). Anal. Calcd (%) for C8H9- 2H, OCH2). Anal. Calcd (%) for C15H8Cl4N2O2: C, 46.19; H,
ClN2O2: C, 47.89; H, 4.52; N, 13.96. Found: C, 47.81; H, 4.45; 2.07; N, 7.18. Found: C, 46.19; H, 2.05; N, 7.23.
N, 13.90. Data for 14: yield 32%; obtained as a white floc; mp 164.6-
Data for F2: yield 74%; obtained as white needle crystals; 165.0 °C; Rf ) 0.50 (dichloromethane); 1H NMR (DMSO-d6) δ
mp 159.8-162.6 °C (Volovel’skii and Soedin, 1965); Rf ) 0.15 8.15 (d, JH,F ) 6.71 Hz, 1H, ArH), 8.05 (d, JH,F ) 9.15 Hz, 1H,
(ethyl acetate); IR (KBr, cm-1) υmax 3320, 1680, 1490, 1240, ArH), 7.65 (d, J ) 2.14 Hz, 1H, ArH), 7.40-7.45 (m, 2H, 2ArH),
840. Anal. Calcd (%) for C8H9ClN2O2: C, 47.89; H, 4.52; N, 5.65 (s, 2H, OCH2). Anal. Calcd (%) for C15H7Cl4FN2O2: C,
13.96. Found: C, 47.69; H, 4.47; N, 13.84. 44.12; H, 1.72; N, 6.86. Found: C, 44.18; H, 1.68; N, 6.96.
Bioassays. Insecticidal Activities against Armyworm (P.
Data for F3: yield 66%; obtained as white powdery crystals;
separata Walker). A test solution was made by dissolving the
mp 155.8-157.4 °C (Zhang et al., 1989); Rf ) 0.17 (ethyl
compound in a small amount of DMF, then adding a few drops
acetate). Anal. Calcd (%) for C8H8Cl2N2O2: C, 40.85; H, 3.40;
of surfactant, and finally adding water to a proper volume.
N, 11.91. Found: C, 40.53; H, 3.28; N, 11.85.
Concentration is defined as mass (micrograms) of the com-
General Synthetic Procedure for 2-Substituted Phe- pound per milliliter of solution. A moderate amount of mealie
noxymethyl-5-substituted-aryl-1,3,4-oxadiazoles (7-14). leaves, which were treated with the above test solution, was
A mixture of the substituted phenoxyacetic acid hydrazide placed on moistened filter paper in three broad bottles. Each
(F1-F3) (10 mmol), the corresponding substituted aromatic bottle was infested with 10 second-instar larvae of the
carboxylic acid (10-20 mmol), and POCl3 (10 mL) was refluxed southern armyworm. The treated mealie leaves were added
for 5-6 h. After cooling, it was poured into broken ice. The everyday. All treatments were maintained at ∼20 °C in a well-
resulting precipitate was filtered, washed with diluted sodium ventilated room. The percent mortality was determined by the
hydrate water solution and then water, dried, and recrystal- number and size of live larvae in the treated bottles relative
lized from ethanol to give the desired products (7-14). to that in the untreated controls in 5 days. Insecticidal activity
Data for 7: yield 40%; obtained as light brown powdery data of the compounds were taken as the dependent variable
crystals; mp 119.5-120.0 °C; Rf ) 0.52 (dichloromethane); 1H and were expressed as pLC50 (i.e., -log LC50). The standard
NMR (DMSO-d6) δ 8.15 (d, JH,F ) 6.70 Hz, 1H, ArH), 8.05 (d, deviation in pLC50 found among three replicate measurements
JH,F ) 9.31 Hz, 1H, ArH), 7.35-7.45 (m, 3H, 3ArH), 7.05 (dd, for a compound should be <0.05; otherwise, the value of pLC50
J ) 6.75 and 2.44 Hz, 1H, ArH), 5.65 (s, 2H, OCH2). Anal. for the compound must be remeasured. These data of pLC50
Calcd (%) for C15H8Cl3FN2O2: C, 48.22; H, 2.16; N, 7.50. are presented in Table 1 along with the activity of 10
Found: C, 48.08; H, 2.08; N, 7.68. oxadiazoles cited. Compound 20, that is, DCPO, was included
Data for 8: yield 31%; obtained as white needle crystals; mp for reference purposes.
130.2-130.5 °C; Rf ) 0.55 (dichloromethane); 1H NMR (DMSO- Descriptor Variables. The molecular shape parameter V1/
d6) δ 8.00 (d, J ) 7.80 Hz, 1H, ArH), 7.92 (s, 1H, ArH), 7.68 V2, where V1 and V2 stand for the nonpolar surface area and
(d, J ) 7.80 Hz, 1H, ArH), 7.38 (d, J ) 7.56 Hz, 2H, 2ArH), polar surface area (Å2) of water solvation shell, respectively,
7.15 (d, J ) 7.56 Hz, 2H, 2ArH), 5.50 (s, 2H, OCH2). Anal. and the molecular length d (Figure 1) were calculated by using
Calcd (%) for C15H9Cl3N2O2: C, 50.66; H, 2.55; N, 7.88. a molecular modeling program, PCMODEL (4th ed., June
Found: C, 50.71; H, 2.47; N, 7.96. 1990) of Serena software. Before the above parameters of a
Data for 9: yield 31%; obtained as light brown needle compound were calculated, its spatial molecular conformation
crystals; mp 129.5-130.0 °C; Rf ) 0.48 (dichloromethane); IR was optimized with PCMODEL to acquire its most relaxed
(KBr, cm-1) υmax 3080, 2880, 1580, 1490, 1230, 1120, 1030, 830, conformation. The parameter d indicates the maximally
760; 1H NMR (CDCl3) δ 8.98 (d, J ) 2.40 Hz, 1H, ArH), 8.26 extended molecular length between two end atoms in the most
(dd, J ) 2.40 and 5.45 Hz, 1H, ArH), 7.43 (d, J ) 5.45 Hz, 1H, relaxed conformation, including hydrogen atoms if present. For
ArH), 7.20 (d, J ) 6.30 Hz, 2H, 2ArH), 6.85 (d, J ) 6.30 Hz, electronic parameters the molecular total energy (Et) and the
128 J. Agric. Food Chem., Vol. 49, No. 1, 2001 Shi et al.
Table 3. Development of Equation 2 (2) m-fluorine, d > 14.5 Å, and (3) 2,4-dichlorophe-
intercept V1/V2 Et n r s F noxymethyl, d > 14.5 Å, were treated as synthons,
having activity contributions of Q1, Q2, and Q3, respec-
-7.867 1.022 8 0.967 0.303 73.07
-8.603 0.804 -0.0237 7 0.994 0.148 161.00 tively. Equation 3 can be written as eq 4.