Synthesis and insecticidal activity of N - Tert -Butyl- N, N ′-diacylhydrazines containing 1,2,3-thiadiazoles

Article abstract of DOI:10.1021/jf104004q

N-tert-Butyl-N,N′-diacylhydrazines are nonsteroidal ecdysone agonists used as environmental benign pest regulators. In this paper, two series of new N-tert-butyl-N,N′-diacylhydrazine derivatives containing 1,2,3-thiadiazole were designed and synthesized.

Full text of DOI:10.1021/jf104004q

628 J. Agric. Food Chem. 2011, 59, 628–634
DOI:10.1021/jf104004q
Synthesis and Insecticidal Activity of N-tert-Butyl-N,
N0-diacylhydrazines Containing 1,2,3-Thiadiazoles
†,
†,
§
H
UAN
W
ANG
,
Z
HIKUN
Y
ANG
,
Z
HIJIN
F
AN,*,† QINGJUN
W
U
,§ YOUJUN
†
Z
HANG
§
,
NA
MI
,† SHOUXIN
W
ANG,† ZHENGCAI
Z
HANG,† HAIBIN
S
ONG
,
AND
F
ENG
L
IU
†State Key Laboratory of Elemento-Organic Chemistry, Nankai University, No. 94 Weijin Road,
Nankai District, Tianjin 300071, People’s Republic of China, and §Institute of Vegetables and Flowers,
Chinese Academy of Agricultural Sciences, No. 12 South Zhongguancun Avenue, Haidian District,
Beijing 100081, People’s Republic of China. These authors contributed equally to this work.
N-tert-Butyl-N,N0-diacylhydrazines are nonsteroidal ecdysone agonists used as environmental
benign pest regulators. In this paper, two series of new N-tert-butyl-N,N0-diacylhydrazine derivatives
containing 1,2,3-thiadiazole were designed and synthesized. All structures of the synthesized com-
pounds were confirmed by proton nuclear magnetic resonance (1H NMR), infrared spectroscopy
(IR), and high-resolution mass spectrometry (HRMS). Bioasssay results indicated that most of the
synthesized compounds possessed good insecticidal activities against Plutella xylostella L. and
Culex pipiens pallens as compared with the positive control, tebufenozide. The results of this study
indicated that 1,2,3-thiadiazoles, as an important active substructure, could improve or maintain the
activity of the dicylhydrazines and favor novel pesticide development.
KEYWORDS: 4-Methyl-1,2,3-thiadiazole; diacylhydrazine; insect growth regulator
INTRODUCTION
Diacylhydrazines have been identified as one of the most
important insect regulators since the discovery of the N-tert-
butyl-N,N0-diacylhydrazines inthe mid-1980s byRohm and Haas
Co. (1, 2). They mimic the action of 20-hydroxyecdysone (3) and
therefore affect the ecdysone receptor, leading to lethal premature
molting. Currently, diacylhydrazines have attracted considerable
attention because of their unique action with high insecticidal
selectivity, simple structure, and lower toxicity to vertebrates (3-6).
Among nonsteroidal ecdysone agonists, N-tert-buyl-N,N0-diben-
zoylhydrazine (RH-5849) was the first thoroughly investigated
as an insecticide (1, 2, 7). However, N-tert-butyl-N0-(4-ethyl-
benzoyl)-3,5-dimethylbenzoylhydrazine (tebufenozide) was first
commercialized (8). At present, analogues of tebufenozide such
as methoxyfenozide (RH-2485), halofenozide (RH-0345), and
chromafenozide (ANS-118) have already been brought into the
agrochemical market (9, 10). In addition, JS-118, a furan deriva-
tive containing N-tert-butyl-N,N0-diacylhydrazine, has already
been registered in China as an insecticide (11). The corresponding
structures mentioned above are presented in Figure 1.
Heterocyclic compounds as the main sources of lead molecules
play an important role in agrochemicals. In the 1960s, Merck &
Co. Int. discovered and developed thiabendazole as a fungicide.
Afterward, many thiazoles including a number of widely used
fungicides (e.g., tricyclazole, probenazole, trifluzamide) and plant
elicitors (e.g., acibenzolar-S-methyl, BTH) have been introduced
into the pesticide market (12, 13). 1,2,3-Thiadiazoles as an
Figure 1. Structures of commercialized diacylhydrazines and their lead,
20-hydroxyecdysone.
important class of sulfur-containing compounds with various
interesting properties are becoming a rapidly growing and inde-
pendent branch of the chemistry of thiazoles (14, 15). They have
shown many biological activities such as anti-HIV (16, 17),
insecticidal (18), fungicidal (14, 19-22), and antiviral activ-
ities (23, 24), systemic acquired resistance (14, 25), and herbicidal
activity (26). More significantly, the structure of 1,2,3-thiadiazoles
*Author to whom correspondence should be addressed (phone
þ86-22-23499464; fax þ86-22-23503627; e-mail fanzj@nankai.
edu.cn).
pubs.acs.org/JAFC
Published on Web 12/17/2010
© 2010 American Chemical Society

Article
J. Agric. Food Chem., Vol. 59, No. 2, 2011 629
Scheme 1. Molecular Structures and Synthesis of the Target Compounds V
can be easily decomposed into lower molecular weight compounds
by releasing N2; the decomposed low molecular weight compounds
lost their activities, and this favors the use of its derivates as
environmentally benign pesticides with low toxicity and suitable
duration of efficiency to the target biology and half-life in the agro-
ecosystem (14). However, studies on the synthesis and biological
activity of 1,2,3-thiadazole are seldomly reported, and very limited
products are commercialized currently. In our previous studies,
some new 1,2,3-thiadizole compounds with fungicidal activity,
antiviral activity, and systemic acquired resistance were reported
(27-29). Encouraged by these results, we continued to investigate
the insecticidal activity of 1,2,3-thiadiazole-containing N-tert-butyl-
N,N0-diacylhydrazines, which were synthesized according to the
routine described in Scheme 1.
dichloromethane (20 mL) was added. The reaction mixture was washed
successively with water (3 ꢀ 20 mL) and brine (20 mL). The organic layer
was then dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated. The residue was then purified by recrystallization in ethyl
acetate or column chromatography on silica gel using ethyl acetate and
petroleum ether (60-90 °C) with 1:2 to 1:4 v/v as an eluent to obtain
compounds V, and yields were also not optimized (Scheme 1). The yields,
physical properties, and 1H NMR, HRMS, and IR data of the target
compounds V were as follows.
Data for V-1: white needle crystal; yield, 32%; mp, 194-196 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.57 (s, 9H, C(CH3)3), 2.32 (s, 3H, -CH3),
2.50 (s, 3H, thiadiazolyl-CH3), 7.08-7.24 (m, 4H, Ph-H), 7.94 (s, 1H, NH);
HRMS (m/z) (M þ H)þ, 333.1380, found, 333.1384; IR (KBr pellet press,
ν, cm-1), 3177 (NH, st), 2980, 1699 (CdO, st), 1627, 1456, 1376, 1317,
1276, 1201, 1150, 1018, 765.
Data for V-2: white needle crystal; yield, 43%; mp, 195-196 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.54 (s, 9H, C(CH3)3), 2.28 (s, 3H, -CH3),
2.50 (s, 3H, thiadiazolyl-CH3), 7.09-7.15 (m, 4H, Ph-H), 8.52 (s, 1H, NH);
HRMS (m/z) (M þ H)þ, 333.1380, found, 333.1372; IR (KBr pellet press,
ν, cm-1), 3185 (NH, st), 2982, 1691 (CdO, st), 1633, 1526, 1422, 1395,
1031, 980.
Data for V-3: white solid; yield, 44%; mp, 208-210 °C; 1H NMR
(CDCl3, 400 MHz), δ 1.57 (s, 9H, C(CH3)3), 2.33 (s, 3H, -CH3), 2.57
(s, 3H, thiadiazolyl-CH3), 7.12 (d, 2H, J=8.0 Hz, Ph-H), 7.32 (d, 2H, J =
8.0 Hz, Ph-H), 7.77 (s, 1H, NH); HRMS (m/z) (M þ H)þ, 333.1380, found,
333.1382; IR (KBr pellet press, ν, cm-1), 3198 (NH, st), 2974, 2929, 2360,
2341, 1698 (CdO, st), 1620, 1569, 1507, 1361, 1278, 1235, 1198, 1030, 874, 755.
Data for V-4: white needle crystal; yield, 44%; mp, 228-230 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.59 (s, 9H, C(CH3)3), 2.59 (s, 3H,
thiadiazolyl-CH3), 3.91 (s, 3H, -OCH3), 6.87 (d, 1H, J = 8.4 Hz,
Ph-H), 6.98 (t, 1H, J=7.2 Hz, Ph-H), 7.31 (t, 1H, J=7.6 Hz, Ph-H),
7.39 (d, 1H, J=7.2 Hz, Ph-H), 8.27 (s, 1H, NH); HRMS (m/z) (M þ Na)þ,
371.1148, found, 371.1154; IR (KBr pellet press, ν, cm-1), 3176 (NH, st),
2981, 1697 (CdO, st), 1636, 1560, 1537, 1490, 1462, 1319, 1268, 1020, 768.
Data for V-5: white needle crystal; yield, 45%; mp, 166-167 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.56 (s, 9H, C(CH3)3), 2.56 (s, 3H,
thiadiazolyl-CH3), 3.77 (s, 3H, -OCH3), 6.88-6.92 (m, 3H, Ph-H), 7.20
(t, 1H, J=8.0 Hz, Ph-H), 8.08 (s, 1H, NH); HRMS (m/z) (M þ Na)þ,
371.1148, found, 371.1149; IR (KBr pellet press, ν, cm-1), 3177 (NH, st),
2981, 2360, 2341, 1690 (CdO, st), 1630, 1580, 1529, 1376, 1316, 1204, 1051,
886, 767, 696.
MATERIALS AND METHODS
Equipment and Materials. Melting points of all compounds were
determined on an X-4 binocular microscope (Gongyi Tech. Instrument
Co., Henan, China), and the thermometer was not corrected. Proton NMR
spectra were obtained using a Bruker AVANCE-400 MHz spectrometer,
and chemical shift values (δ) were reported in parts per million with
deuterochloroform (CDCl3) as solvent and tetramethylsilane (TMS) as the
internal standard. High-resolution mass spectrometry (HRMS) data were
obtained on an FTICR-MS Varian 7.0T FTICR-MS instrument. IR was
recorded on a Bruker Vector 22 FTIR spectrometer using a KBr pellet
press. All solvents and reagents were of analytical reagent grade. Column
chromatography purification was carried out using silica gel.
General Synthetic Procedure for Compound III. 4-Methyl-1,2,3-
thiadiazole-5-carbonyl chloride (I) was synthesized from 4-methyl-1,2,3-
thiadiazole-5-carboxylic acid according to the method given in ref 27. To a
solution of tert-butylhydrazine hydrochloride (II, 50.0 g, 0.4 mol) in
dichloromethane (280 mL) was dropwise added a solution of sodium
hydroxide (25 g, 96%, 0.6 mol) in water (20 mL) in batches below 10 °C.
After 15 min of stirring, 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride
(I, 0.2 mol) was dropwise added in batches below 10 °C. After 0.5 h of
stirring in an ice-water bath, the mixture was permitted to stand for
another 1 h at room temperature. Then, the organic layer was washed
successively with water (3 ꢀ 15 mL) and brine (15 mL). The organic layer
was dried over anhydrous sodium sulfate. After filtration, the solvent was
removed under vacuum to give the white solid (III) (34.6 g) with a yield of
80.1%, which was not optimized (Scheme 1).
Data for V-6: white needle crystal; yield, 46%; mp, 176-177 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.55 (s, 9H, C(CH3)3), 2.58 (s, 3H,
thiadiazolyl-CH3), 3.79 (s, 3H, -OCH3), 6.79 (d, 2H, J=8.8 Hz, Ph-H),
7.36 (d, 2H, J=8.8 Hz, Ph-H), 8.09 (s, 1H, NH); HRMS (m/z) (M þ Na)þ,
371.1148, found, 371.1153; IR (KBr pellet press, ν, cm-1), 3186 (NH, st),
2979, 2604, 2498, 1686 (CdO, st), 1629, 1479, 1383, 1366, 1256, 1173,
1036, 850.
General Synthetic Procedure for Target Compounds V (1-15).
A
solution of substituted benzoyl chloride (IV, 5.2 mmol) in dichloro-
methane (10 mL) was added dropwise to a stirred mixture of N-tert-
butyl-N0-(4-methyl-1,2,3-thiadiazole)-5-formylhydrazine (III, 5.2 mmol),
triethylamine (0.56 g, 5.5 mmol), and dichloromethane (10 mL) in an ice
bath. After the reaction had been stirred at room temperature for 10 h,

630 J. Agric. Food Chem., Vol. 59, No. 2, 2011
Wang et al.
Data for V-7: white solid; yield, 53%; mp, 207-208 °C; 1H NMR
(CDCl3, 400 MHz), δ 1.59 (s, 9H, C(CH3)3), 2.59 (s, 3H, thiadiazolyl-
CH3), 7.22-7.39(m, 4H, Ph-H), 8.03 (s, 1H, NH); HRMS (m/z) (M -
H)-, 351.0688, found, 351.0685; IR (KBr pellet press, ν, cm-1), 3166 (NH,
st), 2982, 2359, 2341, 1701 (CdO, st), 1633, 1591, 1568, 1450, 1265, 768.
Data for V-8: white needle crystal; yield, 46%; mp, 202-204 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.57 (s, 9H, C(CH3)3), 2.61 (s, 3H, thiadiazolyl-
CH3), 7.27-7.38 (m, 4H, Ph-H), 7.95(s, 1H, NH); HRMS (m/z) (M - H)-,
351.0688, found, 351.0682; IR (KBr pellet press, ν, cm-1), 3188 (NH, st),
2981, 1689 (CdO, st), 1635, 1524, 1451, 1419, 1396, 1231, 1015, 632.
Data for V-9: light yellow crystal; yield, 57%; mp, 194-197 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.56 (s, 9H, C(CH3)3), 2.59 (s, 3H,
thiadiazolyl-CH3), 7.35 (d, 2H, J = 8.4 Hz, Ph-H), 7.52 (d, 2H, J = 8.4
Hz, Ph-H), 8.00 (s, 1H, NH); HRMS (m/z) (M þ H)þ, 353.0833, found,
353.0833; IR (KBr pellet press, ν, cm-1), 3193 (NH, st), 2981, 2932, 1685
(CdO, st), 1635, 1522, 1313, 1232, 1201, 1139, 825, 713.
Data for V-10: white needle crystal; yield, 23%; mp, 173-175 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.56 (s, 9H, C(CH3)3), 2.54 (s, 3H,
thiadiazolyl-CH3), 7.46-7.66 (m, 4H, Ph-H), 7.68 (s, 1H, NH); HRMS
(m/z) (M þ Na)þ, 409.0917, found, 409.0912; IR (KBr pellet press, ν,
cm-1), 3210 (NH, st), 2984, 1704 (CdO, st), 1643, 1530, 1385, 1316, 1266,
1182, 1124, 902, 772.
Data for V-11: white needle crystal; yield, 10%; mp, 165-168 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.71 (s, 9H, C(CH3)3), 2.60 (s, 3H,
thiadiazolyl-CH3), 7.49-7.76 (m, 4H, Ph-H), 8.38 (s, 1H, NH); HRMS
(m/z) (M þ Na)þ, 409.0917, found, 409.0914; IR (KBr pellet press, ν,
cm-1), 3315 (NH, st), 2937, 1629 (CdO, st), 1624, 1548, 1427, 1331, 1049,
893, 819, 568.
Data for V-12: white solid; yield, 33%; mp, 186-189 °C; 1H NMR
(CDCl3, 400 MHz), δ 1.57 (s, 9H, C(CH3)3), 2.51 (s, 3H, thiadiazolyl-
CH3), 7.49 (d, 1H, J = 8.0 Hz, Ph-H), 7.57 (d, 1H, J = 8.4 Hz, Ph-H), 8.12
(s, 1H, NH); HRMS (m/z) (M þ Na)þ, 409.0917, found, 409.0916; IR
(KBr pellet press, ν, cm-1), 3191 (NH, st), 2985, 1687 (CdO, st), 1640,
1526, 1408, 1327, 1276, 1171, 1133, 1017, 873, 758.
Data for V-13: white solid; yield, 20%; mp, 119-123 °C; 1H NMR
(CDCl3, 400 MHz), δ 1.20 (s, 9H, C(CH3)3), 2.99 (s, 3H, thiadiazolyl-
CH3), 3.81 (s, 1H, NH), 7.52-7.83 (m, 4H, Ph-H); HRMS (m/z) (M þ
H)þ, 364.1074, found, 364.1071; IR (KBr pellet press, ν, cm-1), 3182 (NH,
st), 2977, 2934, 1705 (CdO, st), 1677, 1653, 1574, 1532, 1476, 1381,1316,
1030, 864, 735.
sodium sulfate. After filtration, the solvent was evaporated. The residue
was then purified by recrystallization in ethyl acetate or by column
chromatography on silica gel using ethyl acetate and petroleum ether
(60-90 °C) with 1:2 to 1:4 v/v as an eluent to obtain the compounds VII,
and the yields were not optimized (Scheme 1). The yields, physical
properties, and 1H NMR, HRMS, and IR data of the target compounds
VII were as follows.
Data for VII-1: white needle crystal; yield, 13%; mp, 145-147 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.21 (s, 9H, C(CH3)3), 2.41 (s, 3H, -CH3),
2.85 (s, 3H, thiadiazolyl-CH3), 5.74 (s, 1H, NH), 7.24-7.43 (m, 4H, Ph-H);
HRMS (m/z) (M þ H)þ, 333.1380, found, 333.1375; IR (KBr pellet press,
ν, cm-1), 3314 (NH, st), 3028, 2972, 1686 (CdO, st), 1531, 1485, 1439,
1371, 1236, 1127, 1015, 932.
Data for VII-2: white needle crystal; yield, 30%; mp, 142-145 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.59 (s, 9H, C(CH3)3), 2.35 (s, 3H, -CH3),
2.79 (s, 3H, thiadiazolyl-CH3), 7.29-7.41 (m, 4H, Ph-H), 8.26 (s, 1H, NH);
HRMS (m/z) (M þ H)þ, 333.1380, found, 333.1373; IR (KBr pellet press,
ν, cm-1), 3345 (NH, st), 3007, 2930, 1667 (CdO, st), 1607, 1586, 1506,
1484, 1393, 1378, 1361, 1298, 1218, 1186, 647.
Data for VII-3: white solid; yield, 6%; mp, 143-144 °C; 1H NMR
(CDCl3, 400 MHz), δ 1.18 (s, 9H, C(CH3)3), 2.46 (s, 3H, -CH3), 2.92 (s,
3H, thiadiazolyl-CH3), 5.75 (s, 1H, NH), 7.32 (d, 2H, J = 8.0 Hz, Ph-H),
7.79 (d, 2H, J = 8.0 Hz, Ph-H); HRMS (m/z) (M þ H)þ, 333.1380, found,
333.1380; IR (KBr pellet press, ν, cm-1), 3348 (NH, st), 3024, 2928, 2866,
1699 (CdO, st), 1606, 1559, 1506, 1456, 1393, 1288, 1019, 934.
Data for VII-4: white solid; yield, 35%; mp, 141-142 °C; 1H NMR
(CDCl3, 400 MHz), δ 1.59 (s, 9H, C(CH3)3), 2.86 (s, 3H, thiadiazolyl-
CH3), 4.014 (s, 3H, -OCH3), 7.00-8.02 (m, 4H, Ph-H), 9.52 (s, 1H, NH);
HRMS (m/z) (M þ Na)þ, 371.1148, found, 371.1142; IR (KBr pellet press,
ν, cm-1), 3412 (NH, st), 2982, 1680 (CdO, st), 1600, 1506, 1483, 1436,
1386, 1248, 1168, 1116, 1021, 743.
Data for VII-5: white needle crystal; yield, 23%; mp, 151-152 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.59 (s, 9H, C(CH3)3), 2.81 (s, 3H,
thiadiazolyl-CH3), 3.81 (s, 3H, -OCH3), 7.06-7.33 (m, 4H, Ph-H), 8.13
(s, 1H, NH); HRMS (m/z) (M þ H)þ, 337.1129, found, 337.1131; IR (KBr
pellet press, ν, cm-1), 3364 (NH, st), 2931, 2851, 1657 (CdO, st), 1624,
1528, 1425, 1351, 1099, 898, 839, 800, 561.
Data for VII-6: white needle crystal; yield, 30%; mp, 135-137 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.59 (s, 9H, C(CH3)3), 2.81 (s, 3H,
thiadiazolyl-CH3), 3.85 (s, 3H, -OCH3), 6.90 (d, 2H, J = 8.4 Hz, Ph-
H), 7.59 (d, 2H, J = 8.0 Hz, Ph-H), 8.20 (s, 1H, NH); HRMS (m/z) (M þ
H)þ, 349.1329, found, 349.1327; IR (KBr pellet press, ν, cm-1), 3218 (NH,
st), 2970, 2934, 1688 (CdO, st), 1660, 1608, 1521, 1488, 1396, 1376, 1362,
1264, 1211, 1182, 1012, 936, 750.
Data for V-14: white needle crystal; yield, 45%; mp, 202-205 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.61 (s, 9H, C(CH3)3), 2.63 (s, 3H, thia-
diazolyl-CH3), 7.54-8.25(m, 4H, Ph-H), 8.04 (s, 1H, NH); HRMS (m/z)
(M þ H)þ, 364.1074, found, 364.1074; IR (KBr pellet press, ν, cm-1), 3190
(NH, st), 2987, 1689 (CdO, st), 1636, 1616, 1533, 1397, 1374, 1351, 1227, 630.
Data for VII-7: white solid; yield, 20%; mp, 165-169 °C; 1H NMR
(CDCl3, 400 MHz), δ 1.62 (s, 9H, C(CH3)3), 2.80 (s, 3H, thiadiazolyl-
CH3), 7.11-7.40 (m, 4H, Ph-H), 8.15 (s, 1H, NH); HRMS (m/z) (M þ
H)þ, 353.0833, found, 353.0834; IR (KBr pellet press, ν, cm-1), 3193 (NH,
st), 2984, 1701 (CdO, st), 1628, 1558, 1519, 1455, 1367, 1208, 617.
Data for VII-8: white needle crystal; yield, 40%; mp, 138-142 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.59 (s, 9H, C(CH3)3), 2.79 (s, 3H,
thiadiazolyl-CH3), 7.33-7.59 (m, 4H, Ph-H), 8.33 (s, 1H, NH); HRMS
(m/z) (M- H)-, 351.0688, found, 351.0685; IR (KBr pellet press, ν, cm-1),
3346 (NH, st), 2981, 1683 (CdO, st), 1632, 1519, 1471, 1397, 1368, 1264,
1234, 1032, 651.
1
Data for V-15: white needle crystal; yield, 18%; mp, 99-101 °C; H
NMR (CDCl3, 400 MHz), δ 1.41 (s, 9H, C(CH3)3), 1.55 (s, 3H,
thiadiazolyl-CH3), 5.29 (s, 1H, NH), 8.20 (d, 2H, J = 8.4 Hz, Ph-H),
8.28 (d, 2H, J = 8.4 Hz, Ph-H); HRMS (m/z) (M - H)-, 362.0929, found,
362.0931; IR (KBr pellet press, ν, cm-1), 3406 (NH, st), 2987, 2927, 1715
(CdO, st), 1608, 1525, 1279, 1099, 875, 840, 718.
General Synthetic Procedure for Compounds VI (1-15). To a
solution of tert-butylhydrazine hydrochloride (II, 1.2 g, 10 mmol) in
dichloromethane (20 mL) was dropwise added a solution (water, 5 mL) of
sodium hydroxide (0.7 g, 96%, 15 mmol) in batches below 10 °C. After
15 min of stirring, substituted benzoyl chloride (IV, 5 mmol) was dropwise
added in batches below 10 °C. After stirring in an ice-water bath for 0.5 h,
the mixture was permitted to stand for another 1 h at room temperature.
Then, the organic layer was washed successively with water (3 ꢀ 10 mL)
and brine (10 mL). The mixture was then dried over anhydrous sodium
sulfate. After filtration, the solvent was removed under vacuum to give the
compounds VI; the yields were not optimized (Scheme 1).
General Synthetic Procedure for the Target Compounds VII
(1-15). A solution of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride (I,
5.2 mmol) in dichloromethane (10mL) was added dropwise to a mixture of
N-tert-butyl-N0-benzoyl formyl hydrazine (VI, 5.2 mmol), triethylamine
(0.56 g, 5.5 mmol), and dichloromethane (10 mL) in an ice bath. After 10 h
of stirring at room temperature, the reaction mixture with an addition of
dichloromethane (20 mL) was washed successively with water (3 ꢀ 20 mL)
and brine (20 mL). The organic layer was then dried over anhydrous
1
Data for VII-9: white solid; yield, 55%; m.p.: 137-139 °C; HNMR
(CDCl3, 400 MHz): δ1.58(s, 9H, C(CH3)3), 2.76(s, 3H, thiadiazolyl-CH3),
7.38(d, 2H, J = 8.4 Hz, Ph-H), 7.55(d, 1H, J = 8.4 Hz, Ph-H), 8.60(s, 1H,
NH); HRMS (m/z): (MþH)þ: 353.0833, found:353.0833; IR (KBr pellet
press, ν, cm-1): 3714(NH, st), 2976, 1699(CdO, st), 1660, 1593, 1361,
1284, 1267, 1190, 1092, 1009, 946, 874.
Data for VII-10: white solid; yield, 20%; mp, 198-199 °C; 1H NMR
(CDCl3, 400 MHz), δ 1.60 (s, 9H, C(CH3)3), 2.98 (s, 3H, thiadiazolyl-
CH3), 5.80 (d, 1H, J = 7.6 Hz, NH), 7.46-7.75 (m, 4H, Ph-H); HRMS (m/
z) (M þ H)þ, 387.1097, found, 387.1097; IR (KBr pellet press, ν, cm-1),
3233 (NH, st), 2990, 1699 (CdO, st), 1648, 1371, 1316, 1270, 1130, 1054,
905, 771, 662.
Data for VII-11: white solid; yield, 28%; mp, 200-203 °C; 1H NMR
(CDCl3, 400 MHz), δ 1.59 (s, 9H, C(CH3)3), 2.78 (s, 3H, thiadiazolyl-
CH3), 7.56 (t, 1H, J = 8.0 Hz, Ph-H), 7.78 (q, 2H, J = 7.6 Hz, Ph-H), 7.89

Article
J. Agric. Food Chem., Vol. 59, No. 2, 2011 631
Scheme 2. Regular Synthesis Methods for the Diacylhydrazines
(s, 1H, Ph-H), 8.55 (s, 1H, NH); HRMS (m/z) (M þ H)þ, 387.1097, found,
387.1097; IR (KBr pellet press, ν, cm-1), 3230 (NH, st), 2981, 1674 (CdO,
st), 1522, 1488, 1357, 1336, 1271, 1175, 1130, 1071, 913, 759, 700, 665, 420.
Data for VII-12: white needle crystal; yield, 46%; mp, 149-151 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.59 (s, 9H, C(CH3)3), 2.78 (s, 3H,
thiadiazolyl-CH3), 7.69 (m, 4H, Ph-H), 8.49 (s, 1H, NH); HRMS (m/z)
(M þ H)þ, 387.1097, found, 387.1091; IR (KBr pellet press, ν, cm-1), 3235
(NH, st), 2971, 2935, 1704 (CdO, st), 1658, 1486, 1334, 1268, 1212, 1129,
1012, 898, 852, 763, 671.
Data for VII-13: white needle crystal; yield, 25%; mp, 193-195 °C; 1H
NMR (CDCl3, 400 MHz), δ 1.65 (s, 9H, C(CH3)3), 2.74 (s, 6H,
thiadiazolyl-CH3), 6.39 (d, 1H, J = 7.6 Hz, Ph-H), 7.51-7.60 (m, 2H,
Ph-H), 8.02 (d, 1H, J = 8.0 Hz, Ph-H), 8.23 (s, 1H, NH); HRMS (m/z)
(M þ H)þ, 364.1074, found, 364.1074; IR (KBr pellet press, ν, cm-1), 3321
(NH, st), 3072, 2982, 1699 (CdO, st), 1655, 1533, 1506, 1351, 1298, 1264,
932, 847, 733.
Data for VII-14: white solid; yield, 54%; mp, 167-176 °C; 1H NMR
(CDCl3, 400 MHz), δ 1.61 (s, 9H, C(CH3)3), 2.78 (s, 3H, thiadiazolyl-
CH3), 7.64-8.46(m, 4H, Ph-H), 9.05(s, 1H, NH); HRMS (m/z) (M þ H )þ,
364.1074, found, 364.1066; IR (KBr pellet press, ν, cm-1), 3317 (NH, st),
2984, 1689 (CdO, st), 1639, 1533, 1398, 1286, 1001, 907, 837.
Data for VII-15: white solid; yield, 20%; mp, 152-155 °C; 1H NMR
(CDCl3, 400 MHz), δ 1.59 (s, 9H, C(CH3)3), 2.77 (s, 3H, thiadiazolyl-
CH3), 7.77 (d, 2H, J = 8.8 Hz, Ph-H), 8.24 (d, 1H, J = 8.8 Hz, Ph-H), 8.78
(s, 1H, NH); HRMS (m/z) (M þ H)þ, 364.1074, found, 364.1069; IR (KBr
pellet press, ν, cm-1), 3209 (NH, st), 3193, 3007, 2975, 1705 (CdO, st),
1659, 1522, 1483, 1359, 1321, 1298, 1212, 1106, 1009, 942, 812.
Crystal Structure Determination for Compound VII-2. The crystal
of compound VII-2 was cultured from the mixture of dichloromethane
and petroleum (crystal data are given in the Supporting Information).
X-ray intensity data were recorded on a Bruker SMART 1000CCD
diffraction meter using graphite monochromated Mo KR radiation
(λ = 0.71073 A). A total of 11153 reflections were measured, of which
2956 were unique (Rint = 0.0737) in the range of 2.56° e θ e 25.02°(h, -13
to 13; k, -11 to 10; l, -18 to 14), and 2073 observed reflections with I >
2σ(I) were used in the refinement on F2. The structure was solved by direct
methods with the SHELXS-97 program. All of the non-H atoms were
refined anisotropically by full-matrix least-squares to give the final R =
0.0547 and wR = 0.1246 (w = 1/[σ2((Fo2) þ (0.0684P)2 þ 0.0000P], where
˚
2
2
P = (Fo þ 2Fc )/3 with (Δ/σ)max = 1.000 and S = 1.052 by using the
SHELXL program. The hydrogen atoms were located from a difference
Fourier map and refined isotropically.
Evaluation of Insecticidal Activity. The insecticidal activity of the
target compounds V and VII was conducted according to the standard
operation practice (SOP) as described in ref 27 and the following
procedures.
Insecticide Activity of the Target Compounds against Plutella xylostella L.
The larvicidal activities of the target compounds V and VII and the
positive control tebufenozide against P. xylostella L. were tested by leaf
film feeding method, which was operated as follows: fresh cabbage
leaves were dipped into the 200 μg/mL test water solution, which was
prepared with 5% of acetone to help the compounds dissolve, for 10 s.
After air-drying to evaporate off the acetone and water, the treated
leaves were cut into small pieces and placed in Petri dishes of 9 cm
diameter. Ten individuals of second-instar larvae of P. xylostella L.
were then transferred into 10 cm diameter Petri dishes. The Petri dishes
were finally fastened with rubber bands and placed in the standard
culturation room for 96 or 120 h at 25 °C and 80% humidity. The
percentage of mortalities was evaluated according to the corresponding
CK, which uses water to dispose only. The insects that had no reaction
when touched by a brush pen were regared as dead. Each treatment was
repeated three times. The data for the mortality regression lines of the
active compounds were subjected to probit analysis by POLO for the
median lethal concentration (LC50) determination.

632 J. Agric. Food Chem., Vol. 59, No. 2, 2011
Wang et al.
Insecticide Activity of the Target Compounds against Larval Culex
pipiens pallens. The larvicidal activities of the target compounds V and VII
against C. pipiens pallens were evaluated by the following procedures. Each
compound of 2 mg was weighed into a panicilin bottle; 10 mL of acetone
was added to dissolve the compound to prepare 200 μg/mL of mother
solution. The working solution of 2 μg/mL was prepared by diluting 1 mL
of mother solution with 89 mL of water and 10 mL of feeding solution into
a 100 mL beaker. Ten individuals of fourth-instar larvae of C. pipiens
pallens were transferred into the beaker. Thereafter, the beakers with
mosquito larvae were put into the standard conditioned rooms for further
cultivation with temperature of 25 °C and humidity of 80%. After 24 or
96 h of cultivation, the mortalities of the larvae were calculated by the
corresponding CK, which was prepared by 1 mL of acetone for substitut-
ing 1 mL of mother solution; the observation was conducted until all of the
larvae metamorphosized into pupation or died. Tebufenozide was chosen
as a positive control.
RESULTS AND DISCUSSION
Figure 2. X-ray structure of the title compound VII-2.
Synthetic Chemistry of the Title Compounds. As nonsteroidal
ecdysone agonists, the N-tert-butyl-N,N0-diacylhydrazine motif
has attracted extensive attention. Four widely applied methods
for the synthesis of N-tert-butyl-N,N0-diacylhydrazine were re-
ported. The first method is acylation of protected alkyl hydrazine.
This method can be used for synthesizing the asymmetric diacyl-
hydrazine with a high purity by using tert-butyloxycarbonyl
(Boc) or carbobenzyloxy (Cbz) as protection of the alkyl hydra-
zine. However, when the benzene ring possesses the substitution
of halogen or nitro, Cbz protection is unsuitable (7, 30). The
second method is the reduction of N-carbonyl hydrazones, with
the catalysis of acetic acid, trifluoroacetic acid, and oxalic acid for
aldehyde condensation. The reducing agent commonly used is
sodium cyanoborohydride or sodium borohydride (30). The third
method is 1,3,4-oxadiazole ring-opening; however, harsh reaction
conditions such as strong acid catalyst (e.g., sulfuric acid) are
usually required (31). The last method is alkyl hydrazine acyla-
tion, which is also used herein, and this convenient synthesis
method is the most commonly used and accepted method in the
laboratory or even in industry (7, 30) (Scheme 2).
All of the title compounds were synthesized according to
Scheme 1. The intermediate (i.e., 4-methyl-1,2,3-thiadiazole-5-
carbonyl chloride, I) was synthesized according to the method
given in ref 27. The reaction conditions were not optimized.
Because of the moisture in the solvents, yields of some target
compounds were low. All structures of the target compounds were
confirmed by 1H NMR, IR, and HRMS determination. For
further validation of these kinds of compounds, compound
VII-2 was cultured and determined by X-ray single-crystal diffraction
in this study (Figure 2). Bond lengths and angles within the
heterocyclic system agreed well with the standard values for
compound VII-2. This compound is nonplanar with a dihedral
angle of 65.48° between the two rings.
Insecticidal Activity of the Target Compounds V and VII. The
results of insecticidal screening are given in Table 1. Data in
Table 1 show that most of the title compounds exhibited good
insecticidal activities against P. xylostella L. and C. pipiens
pallens when compared with the positive control. For insecti-
cidal activity against P. xylostella L., compounds V-5, V-7,
and V-11 exhibited 37, 79, and 46% insecticidal activity at 200 μg/
mL, respectively. Compound V-13 exhibited 45% insecticidal
activity at 400 μg/mL. Compounds VII-1, VII-3, VII-11, VII-
14, and VII-15 displayed 68, 37, 32, 34, and 33% insecticidal
activity at 200 μg/mL, respectively. Compound VII-9 exhib-
ited 43% insecticidal activity at 400 μg/mL. These data
indicate that compounds V-7 and VII-1 possessed a higher
insecticidal activity as compared with the positive control,
tebufenozide, at the same concentration. Compounds V-5,
Table 1. Insecticidal Activities of Target Compounds V and VII
mortality (%)
mortality (%)
compd
R
PXLa CPPb compd
R
PXLa CPPb
V-1
V-2
o-CH3
m-CH3
p-CH3
o-OCH3
m-OCH3
p-OCH3
o-Cl
8
0
20
20
10
10
20
10
10
30
100
10
40
30
10
30
10
100
VII-1
VII-2
VII-3
VII-4
VII-5
VII-6
VII-7
VII-8
VII-9
o-CH3
m-CH3
p-CH3
o-OCH3
m-OCH3
p-OCH3
o-Cl
68
12
100
20
0
V-3
V-4
15
30c
37
25
79
0
37
29
10
10
10
20
0
V-5
V-6
10c
28c
24
V-7
V-8
m-Cl
p-Cl
m-Cl
p-Cl
25
V-9
25
15
46
5
45c
23c
5
43c
ND
32
20
ND
100
40
20
10
30
V-10
V-11
V-12
V-13
V-14
V-15
tebufenozide
o-CF3
m-CF3
p-CF3
o-NO2
m-NO2
p-NO2
_
VII-10 o-CF3
VII-11 m-CF3
VII-12 p-CF3
VII-13 o-NO2
VII-14 m-NO2
VII-15 p-NO2
13
16
34
33
40
a PXL, Plutella xylostella L., 96 h, 200 μg/mL. b CPP, Culex pipiens pallens,
2 μg/mL. c Results of 400 μg/mL.
Table 2. Determination of LC50 of V-7 against Plutella xylostella L.
compd
96 h LC50 value (μg/mL)
slope ( SD
χ-square
V-7
tebufenozide
28 (7-67)a
26 (1-64)a
0.483 ( 0.164
0.774 ( 0.190
0.071
4.089
a 95% confidence limits are expressed in parentheses.
V-11, VII-3, VII-11, VII-14, and VII-15 showed the same
insecticidal activity as compared with tebufenozide at the
same concentration. Although compound V-7 possessed a
higher insecticidal activity than tebufenozide at only one
concentration, later precision toxicological study results of
compounds V-7 and tebufenozide indicated that the insecti-
cidal activity of compound V-7 was at the same level as that of
tebufenozide with very close LC50 values of 28 and 26 μg/mL,
respectively (Table 2). It is noteworthy that methoxyfe-
nozide (RH-2485) was 3-5-fold more potent than tebufeno-
zide against the susceptible Egyptian cotton leaf worm
Spodoptera littoralis and 7-14-fold more potent against its
field strain (32); to avoid skipping any potential active new
compounds synthesized, here we chose the moderately active
compound tebufenozide as positive control.
The compounds V-9, VII-1, VII-11, and tebufenozide showed
100% insecticidal activity against C. pipiens pallens at 1 μg/mL
(Table 1),

Article
J. Agric. Food Chem., Vol. 59, No. 2, 2011 633
Table 3. Death Rate of Compounds Active against Culex pipiens pallens
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concn
(μg/mL)
death
rate (%)
concn
(μg/mL)
death
rate (%)
compd
compd
VII-11
V-9
2
100
100
10
2
100
100
0
1
0.5
1
0.5
VII-1
2
100
100
30
tebufenozide
2
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100
60
1
0.5
1
0.5
and so did the tebufenozide. When the concentration was
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V-9, VII-1, VII-11 and tebufenozide decreased dramatically,
ranging from 10 to 60% (Table 3).
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the benzoyl ring near the tert-butyl and another series with the
5-methyl-1,2,3-thiadiazole near the tert-butyl are shown in
Scheme 1. According to the results, the structure-activity relation-
ship via parallel activity contrasting between the two series of
compounds against P. xylostella L. at the same concentration
(200 μg/mL) can be evaluated. Most of the contrasting results
between the two series had almost equal insecticidal activities as a
whole. However, compounds VII showed a better insecticidal
avtivity. Moreover, in compounds V when the R group was
substituted with chloride, the newly synthesized compounds had
comparable good insecticidal activities. In compounds VII, when
the R group was substituted with strong electron-withdrawing
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the insecticidal activity as compared with positive control. Promis-
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Received for review October 14, 2010. Revised manuscript received
November 24, 2010. Accepted November 24, 2010. This study was
funded in part by grants from the National Natural Science
Foundation of China (No. 20872071, 20911120069, and 20672062),
the Tianjin Natural Science Foundation (10JCZDJC17500), the
National Key Project for Basic Research (2010CB126105), the
National Key Technology Research and Development Program
(2011BAE06B05), the Key Laboratory of Pesticide Chemistry and
Application, Ministry of Agriculture (MOA), Beijing, People’s
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