Synthesis and insecticidal evaluation of novel N′-tert-butyl-N′-substitutedbenzoyl-N-5-chloro-6-chromanecarbohydrazide derivatives

Article abstract of DOI:10.1016/j.bmc.2007.09.018

A series of novel N′-tert-butyl- N′-substitutedbenzoyl-N-5-chloro-6-chromanecarbohydrazide derivatives were synthesized, and their larvicidal activities against Oriental armyworm were evaluated. The results of bioassays indicated that most of these title

Full text of DOI:10.1016/j.bmc.2007.09.018

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 488–494
Synthesis and insecticidal evaluation of novel
N0-tert-butyl-N0-substitutedbenzoyl-N-5-chloro-6-
chromanecarbohydrazide derivatives
Chun-Hui Mao,a,b Kai-Liang Wang,a Zi-Wen Wang,a
Xiao-Ming Ou,b Run-Qiu Huang,a Fu-Chun Bia and Qing-Min Wanga,*
aState Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, People’s Republic of China
bHunan Branch of National Pesticide R&D South Center, Hunan Research Institute of Chemical Industry, Changsha 410007,
Hunan Province, People’s Republic of China
Received 23 July 2007; revised 10 September 2007; accepted 11 September 2007
Available online 14 September 2007
Abstract—A series of novel N0-tert-butyl- N0-substitutedbenzoyl-N-5-chloro-6-chromanecarbohydrazide derivatives were synthe-
sized, and their larvicidal activities against Oriental armyworm were evaluated. The results of bioassays indicated that most of these
title compounds exhibit higher larvicidal activities than RH-5849, and several of them somewhat lower than the commercial insec-
ticide tebufenozide. The larvicidal activities are strongly associated with the types and patterns of substitution on the benzene, and
3,5-dimethyl, 2-nitro-4-chloro and 3-methyl derivatives are most prominent in increasing activity. Toxicity assays indicated that
these derivatives could induce a premature, abnormal, and lethal larval moult.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
believed that the activity strongly depended on the
substituents on the benzene ring of the benzohetero-
cyle moiety.8–11 Among them, N0-tert-butyl-N0-3,5-dim-
ethylbenzoyl-N-5-methyl-6-chromanecarbohydrazide
(Chromafenozide; ANS-118) (I) has been commercial-
ized as insecticide under the trade name Matric.12,13 In
the literature,9 it was also noticed that the insecticidal
activity against Spodoptera litura of N0-tert-butyl-N0-
3,5-dimethylbenzoyl-N-5-methyl-2,3-dihydro-1,4-benzo-
dioxine-6-carbohydrazide (II) (LC50 = 1.4 mg Lꢀ1) is
equal to that of N0-tert-butyl-N0-3,5-dimethylbenzoyl-
N-5-chloro-2,3-dihydro-1,4-benzodioxine-6-carbohyd-
razide (III) (LC50 = 1.4 mg Lꢀ1), which meant that
the chloride and the methyl should be bioisosterism.
Inspired by these reports, we developed an idea for
displacement of the methyl on the benzene ring of
5-methyl-6-chromane of Chromafenozide with the chlo-
ride. Therefore, in a search for new insect growth regu-
lators with improved profiles, we designed and
synthesized a series of novel N0-tert-butyl-N0-substitut-
edbenzoyl-N-5-chloro-6-chromanecarbohydrazide deri-
vatives (IV) as shown in Scheme 1.
A new class of insect growth regulators (IGRs), diacy-
lhydrazines, have been found to act as nonsteroidal
ecdysone agonists inducing, especially in Lepidoptera,
precocious molting, leading to death.1–5 Among those
nonsteroidal ecdysone agonists, N0-tert-butyl-N0-3,5-
dimethylbenzoyl-N-4-ethylbenzoylhydrazide (tebufe-
nozide; RH-5992) was first to be commercialized as a
leptidopteran-specific insecticide under the trade names
Mimic, Confirm, and Romdan in several countries.6,7
Recently, it has been reported that N0-benzoheterocycl-
ecarbonyl-N-tert-butyl-3,5-dimethylbenzohydrazide
analogs showed high insecticidal activities, some of them
equal to or superior to that of tebufenozide, and it was
Keywords: 5-Chloro-6-chromanecarboxilic acid; Insect growth regula-
tor; Diacylhydrazine; Larvicidal activity; Lethal larval moult.
*
Corresponding author. Tel./fax: +86 (0) 22 23499842; e-mail
addresses: wang98h@263.net; wangqingmin1970@ eyou.com
0968-0896/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.09.018

C.-H. Mao et al. / Bioorg. Med. Chem. 16 (2008) 488–494
489
CH3
O
O
Cl
O
O
O
N
N
O
O
N
NH
NH
NH
O
O
O
O
I
II
III
2. Results and discussion
2-tert-Buty-4-methyl-1-(prop-2-ynyloxy)benzene (a) was
obtained in excellent yields by the reaction of 2-tert-bu-
tyl-4-methylphenol with 3-bromoprop-1-yne using tetra-
butylammonium bromide as phase-transfer catalyst,
and the temperature of the above reaction should be
controlled under 60 °C, in order to avoid yielding
byproduct, 7-tert-butyl-3,5-dimethyl benzofuran. 7-
tert-Butyl-3,5-dimethyl benzofuran, 1H NMR d: 1.40
(s, 9H); 2.32 (s, 3H); 2.37 (s, 3H); 6.18 (s 1H); 6.82 (s
1H); 7.03 (s, 1H).
2.1. Synthesis
The novel N0-tert-butyl-N0-substitutedbenzoyl-N-5-chloro-
6-chromanecarbohydrazide derivatives (IV1–IV29)
were synthesized by the reaction of various substituted-
benzoylchloride with N0-tert-butyl-5-chlorochroman-6-
carbohydrazide (i) in dichloromethane using triethyl-
amine as acid acceptor. N0-tert-Butyl-5-chlorochroman-6-
carbohydrazide (i) were obtained by the reaction of
5-chlorochroman-6-carbonyl chloride (h), which was
yielded by 5-chlorochromane-6-carboxylic acid (g)
refluxing in thionyl chloride, with tert-butylhydrazine
hydrochloride. The synthetic pathway of the key
intermediate 5-chlorochromane-6-carboxylic acid (g) is
outlined in Scheme 1.
Firstly, we attempted to oxidize 8-tert-butyl-5-chloro-6-
methylchromane (d) to 8-tert-butyl-5-chloro-4-oxochro-
mane-6-carboxylic acid (j), which further reduced to
8-tert-butyl-5-chlorochromane-6-carboxylic acid (k),
then de-tert-butylation provided the key intermediate
5-chlorochromane-6-carboxylic acid (g). However, we
Br
HO
O
O
a
b
Cl
SO2Cl2
Cr2O3
HAc
Pd-C
H2
O
O
d
c
Cl
Cl
Cl
CHO
CHO
COOH
AlCl3
Ag2O
O
O
O
g
f
e
Cl
O
Cl
O
NH
Cl
SOCl2
NH2NHC(CH3)3HCl
N
H
O
O
h
i
O
Cl
O
Cl
Rn
Rn
N
N
H
O
IV
O
Scheme 1. General synthetic route for compounds IV.

490
C.-H. Mao et al. / Bioorg. Med. Chem. 16 (2008) 488–494
Cl
Cl
O
O
Cl
COOH
COOH
[O]
[H]
X
O
O
d
j
k
Cl
O
Cl
O
Cl
COOH
OH
CHO
CrO3
HAc
+
+
+
O
O
O
O
O
e
n
l
m
Scheme 2.
Table 1. Larvicidal activities against Oriental armyworm of N0-tert-
butyl-N0-substitutedbenzoyl-N-5-chloro-6-chromanecarbohydrazide
derivatives, tebufenozide and RH-5849
cannot obtain 8-tert-butyl-5-chloro-4-oxochromane-6-
carboxylic acid (j). 8-tert-Butyl-5-chloro-6-methylchro-
mane (d) can be subjected to partial oxidation to obtain
8-tert-butyl-5-chlorochromane-6-carbaldehyde (e) using
chromium trioxide as oxidant. At the same time, a little
8-tert-butyl-5-chloro-6-methylchroman-4-one (l) and 8-
tert-butyl-5-chlorochromane-6-carboxylic acid (m) and
7b-tert-butyl-1a,2,5,6-tetrahydro-2-hydroxy-2-methyl-
4H-oxireno[2,3-h]chromen-3(7bH)-one (n) were also ob-
tained (as shown in Scheme 2). And it was unexpected
that the compound (n) would result from partial oxida-
tion of the aromatic ring, for it has been believed that
the aromatic ring is resistant to attack by chromium
(VI) that attack the alkyl side chain.14
Compound
LC50 (mg/L)
Y = a + bx
R
IV1
IV2
5.00
1.191 + 5.449x
1.145 + 2.576x
ꢀ3.678 + 2.976x
2.965 + 2.727x
3.272 + 2.174x
3.793 + 3.432x
1.00
0.99
0.99
0.99
0.99
0.99
31.33
2.78
5.57
IV3
IV4
IV5
IV6
6.14
2.25
IV7
IV8
>500
10.07
11.40
25.06
19.76
42.66
215.28
10.76
5.98
1.426 + 3.564x
0.496 + 4.263x
0.718 + 3.060x
ꢀ0.436 + 4.195x
1.358 + 2.234x
ꢀ3.491 + 3.639x
1.243 + 3.639x
2.910 + 2.690x
2.858 + 3.522x
ꢀ2.470 + 4.120x
ꢀ2.470 + 4.120x
0.98
0.97
0.99
0.99
0.99
0.99
0.99
0.99
0.99
0.98
0.99
IV9
IV10
IV11
IV12
IV13
IV14
IV15
IV16
IV17
IV18
IV19
IV20
IV21
IV22
IV23
IV24
IV25
IV26
IV27
IV28
IV29
Tebufenozide
RH-5849
1
Compound l: mp: 93–95 °C, H NMR d: 1.36 (s, 9H);
2.33 (s, 3H); 2.85 (t, 2H,J = 6.0 Hz); 4.49 (t, 2H,
J = 6.9 Hz); 7.30 (s, 1H). Anal. Calcd (%) for
C14H17ClO2: C: 66.53; H: 6.78. Found (%): C: 66.42;
H: 6.68.
4.06
4.11
4.11
Compound m: mp: 206–211 °C, 1H NMR d: 1.38 (s,
9H); 2.04–2.12 (m, 2H); 2.89 (t, 2H, J = 6.6 Hz); 4.24
(t, 2H, J = 5.1 Hz); 7.89 (s, 1H). Anal. Calcd (%) for
C14H17ClO3: C: 62.57; H: 6.38. Found (%): C: 62.66;
H: 6.38.
>500
2.73
8.47
3.614 + 3.178x
2.526 + 2.663x
0.97
0.99
>500
4.75
5.69
2.858 + 3.522x
3.103 + 2.513x
1.164 + 2.592x
ꢀ2.948 + 4.850x
2.359 + 3.239x
ꢀ1.267 + 2.409x
0.618 + 2.974x
4.397 + 2.990x
ꢀ4.687 + 6.982x
0.99
0.99
0.99
0.99
0.99
0.97
0.97
0.99
0.99
30.20
43.55
6.54
1
Compound n: mp: 71–72 °C, H NMR d: 1.13 (s, 9H);
1.33 (s, 3H); 1.77–2.10 (m, 3H); 2.54–2.66 (m, 1H);
3.68 (s, 1H); 3.70 (s, b, 1H); 3.95–4.03 (m, 1H); 4.40–
4.47 (m, 1H). Anal. Calcd (%) for C14H20O4: C: 66.65;
H: 7.99. Found (%): C: 66.45; H: 7.73.
399.02
29.72
1.59
24.38
2.2. Insecticidal activity
icity assays indicated that these derivatives could induce
a premature, abnormal, and lethal larval moult.
Table 1 shows the larvicidal activities against Oriental
armyworm of the title compounds, tebufenozide and
RH-5849. Most of the title compounds show higher
larvicidal activities than RH-5849, and several of them
somewhat lower than tebufenozide (LC50 = 1.59
mg Lꢀ1), for example, IV6 (LC50 = 2.25 mg Lꢀ1), IV20
(LC50 = 2.73 mg Lꢀ1), IV3 (LC50 = 2.78 mg Lꢀ1). Tox-
The larvicidal activities against Oriental armyworm of
the title compounds varied drastically, depending upon
the types and patterns of substitution on the benzene.
Among mono-substituted derivatives, compared to
non-substituent compound (IV1), substituents are

C.-H. Mao et al. / Bioorg. Med. Chem. 16 (2008) 488–494
491
unfavorable to activity except for methyl at meta or hal-
ogen at para. And the bulkier substituent, such as
C2H5O, I, and NO2 (except for NO2 at ortho), drastically
fluxed for 5 h. After cooling to room temperature, the
reaction mixture was diluted with ethyl acetate
(500 ml), and washed with hydrochloric acid
(2 mol Lꢀ1), water and brine, then dried over anhydrous
sodium sulfate. After the solvent was evaporated, the
residue was vacuum distilled (bp: 98–100 °C/85 Pa) to
give 173.5 g of 8-tert-butyl-6-methyl-2H-chromene (b)
decreased activity, for example, IV13 (LC50 > 200 mg Lꢀ1
)
and IV28 (LC50 > 300 mg Lꢀ1). Among multi-substi-
tuted compounds, 3,5-dimethyl and 2-nitro-4-chloro
derivatives are most prominent in increasing activity,
2,4-dichloro and 3,5-dichloro derivatives slightly in-
crease activity, while introduction of tri-substituted
groups results in rapidly decreasing activity, for exam-
ple, the activities of compounds IV7 and IV19 are too
low to be measured.
1
as a colorless oil. Yield (%): 85.9. H NMR d: 1.28 (s,
9H); 2.18 (s, 3H); 4.61–4.63 (m, 2H); 5.72–5.77 (m,
1H); 6.31–6.36 (m, 1H); 6.61–6.86 (m, 2H). Anal. Calcd
(%) for C14H18O: C: 83.12; H: 8.97. Found (%): C:
82.96; H: 8.79.
A mixture of 8-tert-butyl-6-methyl-2H-chromene (b)
(140.0 g, 0.69 mol), wet 10% palladium on activated car-
bon (12.0 g, 60% in water), and methanol (500 ml) was
stirred under 1 atm. of hydrogen at room temperature
for 5 h. The reaction mixture was filtered, the filtrate
was concentrated, and the residue was vacuum distilled
(bp: 92–95 °C/100 Pa) to give 126.0 g of 8-tert-butyl-6-
methylchromane (c) as a colorless oil. Yield (%): 89.5.
1H NMR d: 1.28 (s, 9H); 1.85–1.93 (m, 2H); 2.16 (s,
3H); 2.69 (t, 2H, J = 6.0 Hz); 4.07 (t, 2H, J = 5.1 Hz);
6.65 (s, 1H); 6.81 (s, 1H). Anal. Calcd (%) for
C14H20O: C: 82.30; H: 9.87. Found (%): C: 82.19; H:
9.78.
3. Conclusions
In summary, a series of novel N0-tert-butyl-N0-substitut-
edbenzoyl-N-5-chloro-6-chromanecarbohydrazide deriva-
tives were synthesized, and their larvicidal activities
were evaluated. The results of bioassays indicated that
most of these title compounds exhibit higher larvicidal
activities than RH-5849, and several of them somewhat
lower than tebufenozide. The larvicidal activities are
strongly associated with types and patterns of substitu-
tion on the benzene, 3,5-dimethyl, 2-nitro-4-chloro,
and 3-methyl derivatives are most prominent in increas-
ing activity.
SO2Cl2 (89.2 g, 0.66 mol) in dichloromethane (200 ml)
was added dropwise to 8-tert-butyl-6-methylchromane
(c) (126.0 g, 0.62 mol) in dichloromethane (200 ml) at
30–35 °C. After stirring at 30–35 °C for 3 h, the reaction
mixture was cooled and washed successively with water
and brine, then dried over anhydrous sodium sulfate.
The solvent was evaporated to give 115.3 g of 8-tert-bu-
tyl-5-chloro-6-methylchromane (d) as colorless crystal.
4. Experimental
4.1. Analysis and instruments
Proton NMR spectra were obtained at 300 MHz using a
Bruker AC-P300 spectrometer in CDCl3 solution with
TMS as internal standard. Chemical shift values (d)
were given in ppm. Elemental analyses were determined
on a Yanaca CHN Corder MT-3 elemental analyzer.
Melting points were taken on a Thomas–Hoover melt-
ing-point apparatus and were uncorrected. Yields were
not optimized.
1
Yield (%): 78.0. mp (°C): 44–46. H NMR d: 1.27 (s,
9H); 1.90–1.99 (m, 2H); 2.22 (s, 3H); 2.72 (t, 2H,
J = 6.9 Hz); 4.04 (t, 2H, J = 5.1 Hz); 6.90 (s, 1H). Anal.
Calcd (%) for C14H19ClO: C: 70.43; H: 8.02. Found (%):
C: 70.32; H:7.95.
A mixture of chromium trioxide (24.0 g, 0.24 mol), ace-
tic acid (80 ml), and water (40 ml) was added dropwise
to a stirred solution of 8-tert-butyl-5-chloro-6-meth-
ylchromane (d) (19.2 g, 0.08 mol) in acetic acid
(100 ml) under 15 °C. After stirring under 15 °C for
4 h, the reaction mixture was poured into iced water
and extracted with ethyl acetate, the organic layer was
washed successively with a solution of sodium bicarbon-
ate, water, and brine, then dried over anhydrous sodium
sulfate. After evaporation of the solvent, the residue was
purified by column chromatography on silica gel to give
3.66 g of 8-tert-butyl-5-chlorochromane-6-carbaldehyde
(e) as colorless crystal. Yield (%): 18.1. mp (°C): 174–
4.2. General synthetic procedure for N0-tert-butyl-N-5-
chlorochroman-6-carbohydrazide (i)
3-Bromoprop-1-yne (42.0 g, 1.20 mol) was added drop-
wise to a stirred mixture of 2-tert-butyl-4-methylphenol
(164.0 g, 1.0 mol), toluene (200 ml), sodium hydroxide
(150.0 g, 32%, 1.20 mol), and tetrabutylammonium
bromide (32.2 g, 0.01 mol) in an ice bath. After stirring
at 35–40 °C for 4 h, the reaction mixture was cooled
and diluted with ethyl acetate (1000 ml), the separated
organic layer was washed successively with water, and
brine, then dried over anhydrous sodium sulfate. The
solvent was evaporated to give 196.4 g of 2-tert-buty-
4-methyl-1-(prop-2-ynyloxy)benzene (a) as a yellow
1
175. H NMR d: 1.37 (s, 9H); 2.05–2.13 (m, 2H); 2.87
(t, 2H, J = 6.9 Hz); 4.28 (t, 2H, J = 4.5 Hz); 7.77 (s,
1H); 10.39 (s, 1H). Anal. Calcd (%) for C14H17ClO2:
C: 66.53; H: 6.78. Found (%): C: 66.48; H: 6.70.
1
oil. Yield (%): 97.2. H NMR d: 1.31 (s, 9H); 2.21 (s,
3H); 2.39 (t, 1H, J = 2.4 Hz); 4.62 (d, 2H,
J = 2.4 Hz); 6.78 (d, 1H, J = 8.1 Hz); 6.89ꢀ7.02 (m,
2H).
8-tert-Butyl-5-chlorochromane-6-carbaldehyde (7.6 g,
0.03 mol) (e) in dichloromethane (60 ml) was added
dropwise to a stirred suspension of aluminum chloride
(8.01 g, 0.06 mol) in dichloromethane (60 ml) in an ice
2-tert-Buty-4-methyl-1-(prop-2-ynyloxy)benzene (a)
(202.0 g, 1.0 mol) in N,N-diethylaniline (150 ml) was re-

492
C.-H. Mao et al. / Bioorg. Med. Chem. 16 (2008) 488–494
bath. After stirring at room temperature for 2 h, the
reaction mixture was poured into hydrochloric acid
(1 mol Lꢀ1; 50 ml), the organic layer was washed succes-
sively with a solution of sodium bicarbonate, water, and
brine, then dried over anhydrous sodium sulfate. After
evaporation of the solvent, the residue was purified by
column chromatography on silica gel to give 3.82 g of
5-chlorochromane-6-carbaldehyde (f) as colorless crys-
tion. The resulting white solid was recrystallized from
70% ethanol to give 6.96 g of 5-chlorochromane-6-car-
boxylic acid (g) as a white solid. Yield (%): 91.0. mp
(°C): 202–205. H NMR d: 1.98–2.14 (m, 2H); 2.85 (t,
2H, J = 6.3 Hz); 4.20 (t, 2H, J = 5.4 Hz); 6.79 (d, 1H,
J = 8.4 Hz); 7.85 (d, 1H, J = 8.4 Hz). Anal. Calcd (%)
for C10H9ClO3: C: 56.49; H: 4.27. Found (%): C:
56.47; H: 4.44.
1
1
tal. Yield (%): 65.0. mp (°C): 63–65. H NMR d: 2.04–
2.12 (m, 2H); 2.84 (t, 2H, J = 6.0 Hz); 4.23 (t, 2H,
J = 5.4 Hz); 6.82 (d, 1H, J = 8.4 Hz); 7.73 (d, 1H,
J = 8.4 Hz); 10.37 (s, 1H). Anal. Calcd (%) for
C10H9ClO2: C: 61.08; H: 4.61. Found (%): C: 60.96;
H: 4.45.
A mixture of 5-chlorochromane-6-carboxylic acid (g)
(1.1 g, 5 mmol) and thionyl chloride (1 ml) was heated
under reflux for 1 h. After excess thionyl chloride was
removed under reduced pressure, the residue was dis-
solved in dichloromethane (5 ml). The solution was
added dropwise to a stirred mixture of tert-butylhydr-
azine hydrochloride (1.25 g, 10 mmol), sodium hydrox-
ide (0.70 g, 25 mmol), dichloromethane (15 ml), and
water (5 ml) in an ice bath. After stirring for 6 h at room
temperature, ethyl acetate (50 ml) was added to the reac-
tion mixture. The organic layer was separated and
washed successively with water and brine, and then
dried over anhydrous sodium sulfate. After evaporation
of the solvent, the residue was washed with cold diethyl
ether to give 1.1 g of N0-tert-butyl-5-chlorochroman-6-
carbohydrazide (i) as white solid. Yield (%): 78.6. mp
A solution of silver nitrate (6.14 g, 0.036 mol) in water
(30 ml) was added to sodium hydroxide (1.6 g,
0.04 mol) in water (15 ml). The mixture was stirred
for 5 min, and the silver oxide was collected in a fun-
nel with suction and washed free of nitrates with
water. The wet, freshly precipitated silver oxide was
transferred to a breaker, covered with water (70 ml),
and treated with sodium hydroxide (3.3 g, 0.083 mol)
with vigorous stirring. The mixture was warmed to
55–60 °C, 5-chlorochromane-6-carbaldehyde (7.10 g,
0.036 mol) (f) was added, stirring was continued for
15 min, the mixture was filtered, and the precipitated
silver was washed with hot water, and the resulting
solution was poured into hydrochloric acid (40 ml),
and the resulting precipitate was collected by filtra-
1
(°C): 117–120. H NMR d: 1.18 (s, 9H); 2.01–2.09 (m,
2H); 2.81 (t, 2H, J = 6.6 Hz); 4.17 (t, 2H, J = 5.1 Hz);
6.79 (d, 1H, J = 8.1 Hz); 7.40 (d, 1H, J = 8.1 Hz) Anal.
Calcd (%) for C14H19ClN2O2: C: 59.47; H: 6.77. Found
(%): C: 59.22; H: 6.70.
Table 2. Physical properties and elemental analyses of N0-tert-butyl-N0-substitutedbenzoyl-N-5-chloro-6-chromanecarbohydrazide derivatives
Compound
Rn
Mp (°C)
Yield (%)
Formula
Analysis calcd (found, %)
C
H
N
IV1
IV2
H
2-Me
247–248
256–257
235–237
252–253
194–195
259–261
272–273
201–202
201–202
243–245
221–223
230–231
213–214
236–237
232–233
243–246
142–145
253–255
245–247
215–216
182–185
233–234
228–230
165–166
249–251
247–249
261–264
259–260
230–232
76.2
76.2
80.9
85.7
77.3
55.2
56.5
72.7
77.3
72.0
83.3
84.0
78.3
81.8
68.2
80.5
75.0
70.8
58.8
48.0
60.0
64.3
66.7
68.2
74.1
77.8
85.0
75.0
70.0
C
21H23ClN2O3
65.20(64.96)
65.91(65.88)
65.91(65.77)
65.91(65.72)
66.58(66.57)
66.58(66.50)
67.20(66.98)
63.38(63.30)
63.38(63.45)
63.38(63.21)
61.81(61.89)
60.44(60.33)
64.11(63.98)
59.87(59.70)
59.87(59.86)
59.87(59.70)
55.34(55.34)
55.34(55.30)
51.45(51.44)
54.09(53.91)
54.09(53.92)
50.45(50.48)
62.30(62.16)
59.65(59.67)
49.19(49.00)
49.19(48.90)
58.40(58.31)
58.40(58.21)
58.40(58.18)
5.99(6.02)
6.29(6.18)
6.29(6.37)
6.29(6.18)
6.56(6.74)
6.56(6.48)
6.81(7.01)
6.04(5.99)
6.04(6.07)
6.04(5.98)
6.09(6.17)
6.13(6.16)
6.32(6.23)
5.26(5.19)
5.26(5.38)
5.26(5.33)
4.64(4.74)
4.64(4.74)
4.11(4.23)
4.54(4.70)
4.54(4.62)
3.85(3.92)
5.48(5.43)
5.01(4.96)
4.32(4.40)
4.32(4.50)
5.13(5.16)
5.13(5.07)
5.13(5.11)
7.24(7.37)
6.99(7.03)
6.99(6.98)
6.99(7.15)
6.75(6.94)
6.75(6.82)
6.53(6.74)
6.72(6.80)
6.72(6.74)
6.72(6.59)
6.27(6.63)
5.87(6.06)
6.50(6.52)
6.65(6.60)
6.65(6.65)
6.65(6.59)
6.15(6.25)
6.15(6.15)
5.71(5.73)
9.01(9.11)
9.01(8.87)
5.35(5.19)
6.92(7.03)
6.62(6.90)
5.46(5.36)
5.46(5.23)
9.73(9.90)
9.73(9.94)
9.73(9.93)
C22H25ClN2O3
C22H25ClN2O3
C22H25ClN2O3
C23H27ClN2O3
IV3
IV4
3-Me
4-Me
IV5
IV6
2,4-di-Me
3,5-di-Me
2,4,6-tri-Me
2-MeO
3-MeO
4-MeO
3,4-di-MeO
3,4,5-tri-MeO
4-C2H5O
2-Cl
C23H27ClN2O3
C24H29ClN2O3
IV7
IV8
C
C
22H25ClN2O4
22H25ClN2O4
IV9
IV10
IV11
IV12
IV13
IV14
IV15
IV16
IV17
IV18
IV19
IV20
IV21
IV22
IV23
IV24
IV25
IV26
IV27
IV28
IV29
C22H25ClN2O4
C23H27ClN2O5
C24H29ClN2O6
C23H27ClN2O4
C21H22Cl2N2O3
C21H22Cl2N2O3
C21H22Cl2N2O3
3-Cl
4-Cl
2,4-di-Cl
3,5-di-Cl
2,4,6-tri-Cl
2-NO2-4-Cl
2-Cl-4-NO2
2,6-di-Cl-4-CF3
2-F
C
21H21Cl3N2O3
C21H21Cl3N2O3
21H20Cl4N2O3
C
C21H21Cl2N3O5
C21H21Cl2N3O5
C22H20Cl3F3N2O3
C
21H22ClFN2O3
C21H21ClF2N2O3
21H22ClIN2O3
2,4-di-F
3-I
4-I
C
C21H22ClIN2O3
C21H22ClIN3O5
C21H22ClIN3O5
C21H22ClIN3O5
2-NO2
3-NO2
4-NO2

C.-H. Mao et al. / Bioorg. Med. Chem. 16 (2008) 488–494
493
1
Table 3. H NMR Data of N0-tert-Butyl-N0-substitutedbenzoyl-N-5-chloro-6-chromanecarbohydrazide derivatives
Compound 1H NMR
IV1
1.60 (s, 9H); 1.94–2.04 (m, 2H); 2.70 (t, 2H, 3JHH = 6.9 Hz); 4.10 (t, 2H, 3JHH = 4.5 Hz); 6.28 (d, 1H, 3JHH = 8.4 Hz); 6.52 (d, 1H,
3JHH = 8.4 Hz); 7.28–7.46 (m, 5H); 7.74 (s, 1H, NH)
IV2
1.60 (s, 9H); 1.93–2.01 (m, 2H); 2.35 (s, 3H); 2.69 (t, 2H, 3JHH = 6.6 Hz); 4.09 (t, 2H, 3JHH = 5.1 Hz); 6.03 (d, 1H, 3JHH = 8.1 Hz);
3
6.48 (d,1H, JHH = 8.1 Hz); 7.08–7.27 (m, 4H); 7.67 (s, 1H, NH)
IV3
1.58 (s, 9H); 1.94–2.04 (m, 2H); 2.31 (s, 3H); 2.70 (t, 2H, 3JHH = 6.0 Hz); 4.10 (t, 2H, 3JHH =5.1 Hz); 6.27 (d, 1H, 3JHH = 8.1 Hz);
3
6.52 (d, 1H, JHH = 8.1 Hz); 7.16–7.26 (m, 4H); 7.84 (s, 1H, NH)
IV4
1.58 (s, 9H); 1.95–2.04 (m, 2H); 2.34 (s, 3H); 2.71 (t, 2H, 3JHH = 6.0 Hz); 4.11 (t, 2H, 3JHH = 5.1 Hz); 6.34 (d, 1H, 3JHH = 8.4 Hz);
3
6.54 (d,1H, JHH = 8.4 Hz); 7.23 (m, 4H); 7.77 (s, 1H, NH)
IV5
1.61 (s, 9H); 1.90–2.05 (m, 2H); 2.22–2.40 (m, 6H); 2.64–2.76 (m, 2H); 4.04–4.17 (m, 2H); 6.05–6.15 (m, 1H); 6.46–6.56 (m, 1H);
6.88–7.16 (m, 3H); 7.49 (s, 1H, NH)
IV6
1.60 (s, 9H); 1.95–2.04 (m, 2H); 2.27 (s, 6H); 2.72 (t, 2H, 3JHH = 6.0 Hz); 4.11 (t, 2H, 3JHH = 5.4 Hz); 6.34 (d, 1H, 3JHH = 9.3 Hz);
3
6.56 (d, 1H, JHH = 9.3 Hz); 6.99 (s, 1H); 7.06 (s, 2H); 7.56 (s, 1H, NH)
IV7
1.64 (s, 9H); 1.94–2.02 (m, 2H); 2.21 (s, 3H); 2.26 (s, 3H); 2.35 (s, 3H); 2.70 (t, 2H, 3JHH = 6.0 Hz); 4.11 (t, 2H, 3JHH = 4.5 Hz); 5.95
3
3
(d, 1H, JHH = 8.4 Hz); 6.49 (d, 1H, JHH = 8.4 Hz); 6.9–6.88 (m, 2H); 7.70 (s, 1H, NH)
IV8
1.62 (s, 9H); 1.95–2.05 (m, 2H); 2.71 (t, 2H, 3JHH = 6.6 Hz); 3.82 (s, 3H); 4.11 (t, 2H, 3JHH = 5.1 Hz); 6.14 (d, 1H, 3JHH = 6.0 Hz);
3
6.52 (d, 1H, JHH = 6.0 Hz); 6.84–7.45 (m, 4H); 8.01 (s, 1H, NH)
IV9
1.58 (s, 9H); 1.94–2.02 (m, 2H); 2.70 (t, 2H, 3JHH = 6.9 Hz); 3.77 (s, 3H); 4.11 (t, 2H, 3JHH = 5.4 Hz); 6.36 (d, 1H, 3JHH = 8.1 Hz);
3
6.54 (d, 1H, JHH = 8.1 Hz); 6.88–7.23 (m, 4H); 7.75 (s, 1H, NH)
IV10
IV11
IV12
IV13
IV14
IV15
IV16
IV17
IV18
IV19
IV20
IV21
IV22
IV23
IV24
IV25
IV26
IV27
IV28
IV29
1.58 (s, 9H); 1.95–2.05 (m, 2H); 2.71 (t, 2H, 3JHH = 6.9 Hz); 3.79 (s, 3H); 4.11 (t, 2H, 3JHH = 5.4 Hz); 6.50 (d, 1H, 3JHH = 8.4 Hz);
3
6.58 (d, 1H, JHH = 8.4 Hz); 7.13 (m, 4H); 7.83 (s, 1H, NH)
3
1.60 (s, 9H); 1.96–2.04 (m, 2H); 2.72 (t, 2H, JHH = 6.0 Hz); 3.86 (s, 3H); 3.87 (s, 3H); 4.12 (t, 2H, JHH =5.1 Hz); 6.60–7.13 (m,
3
5H); 7.73 (s, 1H, NH)
3
3
1.60 (s, 9H); 1.96–2.03 (m, 2H); 2.71 (t, 2H, JHH = 6.9 Hz); 3.82 (s, 6H); 3.84 (s, 3H); 4.13 (t, 2H, JHH = 5.4 Hz); 6.60–6.76 (m,
4H); 7.67 (s, 1H, NH)
1.40 (t, 3H, 3JHH = 6.9 Hz); 1.58 (s, 9H); 1.95–2.04 (m, 2H); 2.72 (t, 2H, 3JHH = 6.9 Hz); 4.02 (q, 2H, 3JHH = 6.9 Hz); 4.11 (t, 2H,
3JHH = 5.4 Hz); 6.50 (d, 1H, JHH = 9.3 Hz); 6.58 (d, 1H, JHH = 9.3 Hz); 7.12 (m, 4H); 7.79 (s, 1H, NH)
1.62 (s, 9H); 1.95–2.03 (m, 2H); 2.70 (t, 2H, 3JHH = 6.9 Hz); 4.11 (t, 2H, 3JHH = 5.4 Hz); 6.30 (d, 1H, 3JHH = 8.4 Hz); 6.55 (d, 1H,
3JHH = 8.4 Hz); 7.28–7.46 (m, 4H); 7.81 (s, 1H, NH)
3
3
1.58 (s, 9H); 1.95–2.04 (m, 2H); 2.71 (t, 2H, 3JHH = 6.9 Hz); 4.12 (t, 2H, 3JHH = 4.5 Hz); 6.52–6.61 (m, 2H); 7.21–7.43 (m, 4H); 7.86
(s, 1H, NH)
1.59 (s, 9H); 1.96–2.05 (m, 2H); 2.72 (t, 2H, 3JHH = 6.6 Hz); 4.13 (t, 2H, 3JHH = 5.4 Hz); 6.57–6.64 (m, 2H); 7.36 (m, 4H); 7.74 (s,
1H, NH)
1.61 (s, 9H); 1.97–2.04 (m, 2H); 2.72 (t, 2H, 3JHH = 6.6 Hz); 4.13 (t, 2H, 3JHH = 5.1 Hz); 6.59–6.66 (m, 2H); 7.26–7.45 (m, 3H); 7.91
(s, 1H, NH)
1.59 (s, 9H); 1.97–2.05 (m, 2H); 2.73 (t, 2H, 3JHH = 6.9 Hz); 4.14 (t, 2H, 3JHH =5.4 Hz); 6.67 (d, 1H, 3JHH =9.0 Hz); 6.81 (d, 1H,
3JHH =9.0 Hz); 7.33–7.36 (m, 3H); 7.78 (s, 1H, NH)
1.63 (s, 9H); 1.97–2.05 (m, 2H); 2.73 (t, 2H, 3JHH = 6.6 Hz); 4.14 (t, 2H, 3JHH =5.4 Hz); 6.68 (d, 1H, 3JHH =9.3 Hz); 6.81 (d, 1H,
3JHH =9.3 Hz); 7.26–7.34 (m, 2H); 7.82 (s, 1H, NH)
1.62 (s, 9H); 1.93–2.03 (m, 2H); 2.68 (t, 2H, 3JHH = 6.9 Hz); 4.13 (t, 2H, 3JHH = 5.4 Hz); 6.67 (d, 1H, 3JHH = 8.4 Hz); 6.85 (d, 1H,
3JHH = 8.4 Hz); 7.57–7.66 (m, 2H); 7.92 (s, 1H, NH); 8.07 (s, 1H)
1.62 (s, 9H); 1.95–2.03 (m, 2H); 2.68 (t, 2H, 3JHH = 6.6 Hz); 4.13 (t, 2H, 3JHH = 5.1 Hz); 6.65 (d, 1H, 3JHH = 9.0 Hz); 6.86 (d, 1H,
3JHH = 9.0 Hz); 7.67–8.25 (m, 4H)
1.65 (s, 9H); 1.96–2.04 (m, 2H); 2.70 (t, 2H, 3JHH = 6.6 Hz); 4.13 (t, 2H, 3JHH = 5.4 Hz); 6.64 (d, 1H, 3JHH = 8.1 Hz); 6.75 (d, 1H,
3JHH = 8.1 Hz); 7.51 (s, 1H); 7.58 (s, 1H); 7.80 (s, 1H, NH)
1.59 (s, 9H); 1.96–2.04 (m, 2H); 2.72 (t, 2H, 3JHH = 6.6 Hz); 4.12 (t, 2H, 3JHH = 5.1 Hz); 6.56–6.63 (m, 2H); 6.97–7.52 (m, 4H); 7.72
(s, 1H, NH)
1.60 (s, 9H); 1.99–2.04 (m, 2H); 2.72 (t, 2H, 3JHH = 6.6 Hz); 4.13 (t, 2H, 3JHH = 5.1 Hz); 6.61–6.92 (m, 4H); 7.53–7.61 (m, 1H); 8.01
(s, 1H, NH)
1.58 (s, 9H); 1.96–2.04 (m, 2H); 2.72 (t, 2H, 3JHH = 6.6 Hz); 4.13 (t, 2H, 3JHH =5.1 Hz); 6.56–6.64 (m, 2H); 7.03–7.08 (m, 1H); 7.45
3
3
(d, 1H, JHH = 7.5 Hz); 7.69 (d, 1H, JHH = 6.9 Hz); 7.76 (s, 1H); 7.78 (s, 1H, NH)
1.57 (s, 9H); 1.95–2.04 (m, 2H); 2.72 (t, 2H, 3JHH = 6.9 Hz); 4.13 (t, 2H, 3JHH = 5.1 Hz); 6.47 (d, 1H, 3JHH = 8.4 Hz); 6.61 (d, 1H,
3JHH = 8.4 Hz); 7.40 (m, 4H); 7.95 (s, 1H, NH)
3
3
1.64 (s, 9H); 1.93–2.01 (m, 2H); 2.65 (t, 2H, JHH = 6.0 Hz); 4.10 (t, 2H, JHH = 5.4 Hz); 6.58 (s, 2H); 7.47–7.68 (m, 3H); 7.92 (s,
3
1H, NH); 8.09 (d, 1H, JHH = 8.4 Hz)
1.62 (s, 9H); 1.92–2.05 (m, 2H); 2.68 (t, 2H, 3JHH = 6.0 Hz); 4.11 (t, 2H, 3JHH =5.4 Hz); 6.64 (d, 1H, 3JHH = 8.1 Hz); 6.75 (d, 1H,
3JHH = 8.1 Hz); 7.52 (t, 4H, JHH = 7.5 Hz); 7.90–7.95 (m, 2H); 8.17–8.28 (m, 2H)
3
1.61 (s, 9H); 1.93–2.05 (m, 2H); 2.69 (t, 2H, 3JHH = 6.6 Hz); 4.12 (t, 2H, 3JHH = 5.1 Hz); 6.63 (d, 1H, 3JHH = 9.0 Hz); 6.78 (d, 1H,
3JHH = 9.0 Hz); 7.83 (s, 1H, NH); 7.91 (m, 4H)
4.3. General synthetic procedure for N0-tert-butyl-N0-
substitutedbenzoyl-N-5-chloro-6-chromanecarbohydraz-
ide derivatives (IV1–IV29)
red mixture of N0-tert-butyl-5-chlorochroman-6-carbo-
hydrazide (i) (150 mg, 0.53 mmol), triethylamine
(64 mg, 0.64 mmol), and dichloromethane (5 ml) in an
ice bath. After stirred at room temperature for 3 h, ethyl
acetate (50 ml) was added to the reaction mixture. The
organic layer was separated and washed successively
The solution of substitutedbenzoylchloride (0.53 mmol)
in dichloromethane (1 ml) was added dropwise to a stir-

494
C.-H. Mao et al. / Bioorg. Med. Chem. 16 (2008) 488–494
2. Hsu, A. C. -T.; Aller, H. E.; Murphy, R. A.; Le, D. P.;
Hamp, D. W.; Weinstein, B. US Patent 5,117,057, 1993.
3. Hsu, A. C.-T. In Synthesis and chemistry of agrochemicals
II; Baker, B. R., Fenyes, J. G., Moberg, W. K., Eds.; ACS
Sympoisum Series; American Chemical Society: Washing-
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with water and brine, and then dried over anhydrous
sodium sulfate. After evaporation of the solvent, the
residue was purified by recrystallization or column
chromatography on silica gel to afford compounds
IV1–IV29 as colorless crystals. The physical properties
and elemental analyses of new compounds (IV1–IV29)
1
are listed in Table 2, and their H NMR is listed in
Table 3.
4.4. Biological assay
6. Dhadialla, T. S.; Jansson, R. K. Pestic. Sci. 1999, 55, 357–
359.
The larvicidal activities of the novel N0-tert-butyl-N0-
substitutedbenzoyl-N-5-chloro-6-chromanecarbohyd-
razide derivatives (IV1–IV29) were evaluated using a
previously reported procedure.2,15–20 The larvicidal
activity was tested against Oriental armyworm [Mythi-
mna(=Pseudaletia) separata(Walker)] by foliar applica-
tion. For the foliar armyworm tests, 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 in-
fested with ten fourth-instar armyworm larvae. Percent-
age mortalities were evaluated 4 days after treatment.
Each treatment was performed in triplicate. The larvi-
cidal activity was expressed in terms of the LC50, and
LC50 values were obtained by the Probit method. For
comparative purposes, RH-5849 (N-tert-butyl-N,N0-dib-
enzoylhydrazine) and tebufenozide was tested under the
same condition. The larvicidal activity is summarized in
Table 1.
7. Heller, J. J.; Mattioda, H.; Klein, E.; Sagenmuller, A.
Brighton Crop Prot. Conf. Pests Dis. 1992, 1, 59–66.
8. Sawada, Y.; Yanai, T.; Nakagawa, H.; Tsukamoto, Y.;
Yokoi, S.; Yanagi, M.; Toya, T.; Sugizaki, H.; Kato, Y.;
Shirakura, H.; Watanabe, T.; Yajima, Y.; Kodama, S.;
Masui, A. Pest Manag. Sci. 2003, 59, 25–35.
9. Sawada, Y.; Yanai, T.; Nakagawa, H.; Tsukamoto, Y.;
Yokoi, S.; Yanagi, M.; Toya, T.; Sugizaki, H.; Kato, Y.;
Shirakura, H.; Watanabe, T.; Yajima, Y.; Kodama, S.;
Masui, A. Pest Manag. Sci. 2003, 59, 36–48.
10. Sawada, Y.; Yanai, T.; Nakagawa, H.; Tsukamoto, Y.;
Tamagawa, Y.; Yokoi, S.; Yanagi, M.; Toya, T.; Sugizaki,
H.; Kato, Y.; Shirakura, H.; Watanabe, T.; Yajima, Y.;
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H.; Watanabe, T.; Yajima, Y.; Kodama, S.; Masui, A.;
Yanai, T.; Tsukamoto, Y.; Sawada, Y.; Yokoi, S. EP
patent 496342, 1992.
12. Yanagi, M.; Watanabe, T.; Masui, A. Brighton Crop Prot.
Conf. Pests Dis. 2000, 2, 27–32.
13. Marketing Department, Agrochemicals Division, Agro &
Specialty Chemicals Group Nippon Kayaku Co., Ltd and
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2002, 27, 323–327.
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Acknowledgments
This work was supported by the National Key Project
for Basic Research (2003CB114400) and the National
Natural Science Foundation of China (20672064 and
20421202) and Program for New Century Excellent Tal-
ents in University (NCET-04-0228) and the Foundation
for the Author of National Excellent Doctoral Disserta-
tion of PR China (200255).
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L.; Liu, Y. X.; Shang, J. J. Agric. Food Chem. 2004, 52,
6737–6741.
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