Oxadiazolyl 3(2H)-Pyridazinones
J. Agric. Food Chem., Vol. 51, No. 1, 2003 153
(5 mmol) and POCl3 (10 mL) was refluxed for 3 h. After being cooled
to room temperature, it was poured slowly into an ice and water mixture.
The resulting precipitate was filtered out, washed, dried, and recrystal-
Scheme 1. General Synthetic Route for 5-Aryl-2-(chloromethyl)-1,3,4-
oxadiazoles (I)
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lized from ethanol to produce the pure oxadiazole I (11). H NMR,
MS, and mp for the typical compounds: 5-(4-chlorophenyl)-2-
(chloromethyl)-1,3,4-oxadiazole, δ 4.78 (s, 2H, CH2), 7.50 (d, 2H, Ar
H), 8.04 (d, 2H, Ar H), MS m/z ) 228 (M+, 23), 139 (100), mp 81-
82 °C; 5-(4-dichloro-5-fluorophenyl)-2-(chloromethyl)-1,3,4-oxadiazole,
δ 4.80 (s, 2H, CH2), 7.65 (d, 1H, Ar H), 7.87 (d, 1H, Ar H), MS m/z
) 280 (M+, 16), 191(100), mp 100-101 °C; 5-(3,5-dimethylphenyl)-
2-(chloromethyl)-1,3,4-oxadiazole, δ 2.41 (s, 6H, 2CH3), 4.78 (s, 2H,
CH2), 7.19 (s, 1H, Ar H), 7.70 (d, 2H, Ar H), MS m/z ) 222 (M+, 27),
133 (100), mp 79-80 °C.
Scheme 2. General Synthetic Route for the Final Compounds IIIa−t
General Synthetic Procedure for 2-tert-Butyl-4-chloro-5-[5′-aryl-
2′-(1′,3′,4′-oxdiazolyl)methoxy (or methylmercapto)]-3(2H)-pyridazi-
nones (IIIa-t). A mixture of 2-tert-butyl-4-chloro-5-hydroxy (or
mercapto)-3(2H)-pyridazinone (II) (2.5 mmol), anhydrous potassium
carbonate (8 mmol), tetrabutylammonium bromide (0.2 mmol), and dry
DMF (5 mL) was stirred at 90 °C (X ) O) or 40 °C (X ) S) for 0.5
h. To the mixture was added 5-aryl-2-(chloromethyl)-1,3,4-oxadiazole
(I) (2.5 mmol) and dry DMF (5 mL). The reaction mixture was stirred
at 90 °C (X ) O) or 40 °C (X ) S) for 2-4 h. After cooling, the
mixture was treated with water (30 mL) and extracted with chloroform
(3 × 15 mL). The organic layer was washed with water, dried over
MgSO4, and concentrated. The residue was chromatographed over a
column of silica gel and eluted with petroleum ether (60-90 °C)-
ethyl acetate ) 2:1 (v/v). The desired product was determined by TLC.
The preparative and spectral data of IIIa-t are listed in Table 1 Data
for IIIa: 1H NMR δ 1.65 (s, 9H, (CH3)3C), 5.55 (s, 2H, CH2), 7.97 (s,
1H, Py H), 7.54 (m, 3H, Ar H), 8.08 (d, 2H, Ar H); IR (KBr, cm-1) ν
1650 (CdO); MS m/z ) 361 ([M + 1]+, 12), 325 (20), 304 (40), 268
(37), 159 (71), 105 (100). Anal. Calcd for C17H17ClN4O3: C, 56.59;
H, 4.75; N, 15.52. Found: C, 56.46; H, 4.72; N, 15.66.
Data for IIIb: 1H NMR δ 1.65 (s, 9H, (CH3)3C), 5.58 (s, 2H, CH2),
7.96 (s, 1H, Py H), 8.29 (d, 2H, Ar H), 8.42 (d, 2H, Ar H); IR (KBr,
cm-1) ν 1660 (CdO); MS m/z ) 406 ([M + 1]+, 24), 350 (51), 150
(87), 56 (100), 41 (54). Anal. Calcd for C17H16ClN5O5: C, 50.32; H,
3.97; N, 17.26. Found: C, 50.02; H, 4.13; N, 17.62.
Data for IIIc: 1H NMR δ 1.65 (s, 9H, (CH3)3C), 2.45 (s, 3H, CH3),
5.55 (s, 2H, CH2), 7.39-7.90 (m, 4H, Ar H), 7.98 (s, 1H, Py H); IR
(KBr, cm-1) ν 1630 (CdO); MS m/z ) 374 (M+, 13), 282 (12), 119
(100), 91 (40), 56 (34). Anal. Calcd for C18H19ClN4O3: C, 57.68; H,
5.11; N, 14.95. Found: C, 57.45; H, 5.11; N, 15.22.
4-chloro-5-hydroxy (or mercapto)-3(2H)-pyridazinones (II) with 5-aryl-
2-(chloromethyl)-1,3,4-oxadiazoles (I) at 80 °C in the presence of a
phase transfer catalyst (TBAB, tetrabutylammonium bromide) and
powdered K2CO3 in DMF (Scheme 2). It is a convenient and useful
method for the preparation of the title compounds.
Bioassays. The neem extracts “Azadirachtin”, an enriched and
formulated product (containing 3 mg of azadirachtin mL-1) extracted
from ground neem seed kernels, was obtained from Yunnan Chemical
Ind. Ltd. (Kunming, P. R. China). Compounds IIIa-t were compared
with Azadirachtin using a feeding bioassay. All the compounds were
tested using fifth-instar larvae of the Asiatic corn borer Ostrinia
furnacalis (Guenee). The newly moulted fifth instar larvae were
maintained on artificial diet containing the test compounds, with
untreated diet as control (12).
Dite-Choice Test. Certain amounts of pure IIIa,e-l and Azadirachtin
(3 mg of azadirachtin mL-1) were dissolved in acetone and added to
the ingredients of the diet prior to preparation. All compounds were
tested with diets containing 500 mg/kg IIIa,e-l and Azadirachtin. Five
replicates were prepared for this concentration with 10 fifth-instar larvae
in each replicate. Control diets were prepared in a similar way but with
only solvent. After 24 h, the deterrency index (%) for each treatment
was calculated as the following:
Data for IIId: 1H NMR δ 1.65 (s, 9H, (CH3)3C), 2.40 (s, 6H, 2CH3),
5.54 (s, 2H, CH2), 7.20 (s, 1H, Ar H), 7.69 (s, 2H, Ar H), 7.98 (s, 1H,
Py H); IR (KBr, cm-1) ν 1630 (CdO); MS m/z ) 388 (M+, 2.5), 187
(13), 133 (100), 105 (24). Anal. Calcd for C19H21ClN4O3: C, 58.69;
H, 5.44; N, 14.41. Found: C, 58.77; H, 5.48; N, 14.41.
Data for IIIe: 1H NMR δ 1.65 (s, 9H, (CH3)3C), 2.45 (s, 3H, CH3),
5.53 (s, 2H, CH2), 7.34 (d, 2H, Ar H), 7.97 (d, 2H, Ar H), 7.99 (s, 1H,
Py H); IR (KBr, cm-1) ν 1660 (CdO); MS m/z ) 374 (M+, 7), 282
(12), 282 (11), 173 (22), 119 (100), 91 (22), 56 (22). Anal. Calcd for
C18H19ClN4O3: C, 57.68; H, 5.11; N, 14.95.
deterrency index (%) ) [(C - T)/(C + T)] × 100
Here C and T are the amounts of control and treated diets eaten,
respectively.
Effect on Growth of LarVaes. The effect of compounds on weight
gain was further assessed using fifth-instar larvae with a diet-choice
test. Treated and untreated diets were prepared as previously described.
Three concentrations of IIIa,j and Azadirachtin were selected. Batches
of 10 of the larvae of Asiatic corn borer which had been starved for
4-6 h and weighed were then applied to each diet. Each batch of larvae
was reweighed after 5 days. Controls were treated as above, and each
treatment was replicated five times.
Synthesis of 2-tert-Butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone
(13, 14). A mixture of 2-tert-butyl-4,5-dichloro-3(2H)-pyridazinone (5
mmol), KOH (15 mmol), and glycol (20 mL) was stirred at 130 °C for
5 h. After cooling, it was poured into water, acidified with concentrated
HCl (10 mL). The white solid was collected, washed, and dried (yield
92%), mp 218-220 °C.
Synthesis of 2-tert-Butyl-4-chloro-5-mercapto-3(2H)-pyridazi-
none. To a stirred solution of 2-tert-butyl-4,5-dichloro-3(2H)-pyridazi-
none (5 mmol) in ethanol (20 mL) at 0 °C was added dropwise NaSH
(30%, 10 mmol). After the addition was completed, the reaction mixture
was stirred for 2 h. The mixture was acidified with concentrated HCl
(10 mL). The yellow solid was collected, washed, and dried (yield 90%),
mp 112-113 °C.
Found: C, 57.58; H, 5.04; N, 14.93.
Data for IIIf: 1H NMR δ 1.65 (s, 9H, (CH3)3C), 5.55 (s, 2H, CH2),
7.23 (m, 2H, Ar H), 8.00 (s, 1H, Py H), 8.10 (m, 2H, Ar H); IR (KBr,
cm-1) ν 1670 (CdO); MS m/z ) 379 ([M + 1]+, 4), 321 (20), 177
(25), 123 (100), 57 (33). Anal. Calcd for C17H16ClFN4O3: C, 53.90;
H, 4.26; N, 14.79. Found: C, 53.85; H, 4.15; N, 14.86.
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Data for IIIg: H NMR δ 1.26-1.29 (t, 3H, CH3), 1.64 (s, 9H,
(CH3)3C), 2.74 (q, 2H, CH2), 5.54 (s, 2H, CH2), 7.35 (d, 2H, Ar H),
8.00 (d, 2H, Ar H), 7.98 (s, 1H, Py H); IR (KBr, cm-1) ν 1640 (Cd
O); MS m/z ) 389 ([M + 1]+, 6), 297 (15), 187 (31), 133 (100), 77
(8), 56 (30). Anal. Calcd for C19H21ClN4O3: C, 58.69; H, 5.44; N,
14.41. Found: C, 58.66; H, 5.44; N, 14.47.
Data for IIIh: 1H NMR δ 1.65 (s, 9H, (CH3)3C), 5.55 (s, 2H, CH2),
7.52 (d, 2H, Ar H), 8.02 (d, 2H, Ar H), 8.03 (s, 1H, Py H); IR (KBr,
cm-1) ν 1640 (CdO); MS m/z ) 394 (M+, 10), 336 (15), 303 (11),
193 (32), 140 (100), 57 (38). Anal. Calcd for C17H16Cl2N4O3: C, 51.66;
H, 4.08; N, 14.18. Found: C, 51.50; H, 3.95; N, 14.18.
General Synthetic Procedure for 5-Aryl-2-(chloromethyl)-1,3,4-
oxadiazoles (I). The mixture of the N-chloroacetyl-N′-aroylhydrazine