Design, synthesis, and insecticidal activity of some novel diacylhydrazine and acylhydrazone derivatives

Article abstract of DOI:10.3390/molecules20045625

In this study a series of diacylhydrazine and acylhydrazone derivatives were designed and synthesized according to the method of active group combination and the principles of aromatic group bioisosterism. The structures of the novel derivatives were dete

Full text of DOI:10.3390/molecules20045625

Molecules 2015, 20, 5625-5637; doi:10.3390/molecules20045625
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Design, Synthesis, and Insecticidal Activity of Some Novel
Diacylhydrazine and Acylhydrazone Derivatives
Jialong Sun and Yuanming Zhou *
College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University,
Qingdao 266109, China; E-Mail: sunjialong6289@163.com
* Author to whom correspondence should be addressed; E-Mail: zym7410@163.com;
Tel.: +86-532-86080147.
Academic Editor: Derek J. McPhee
Received: 26 February 2015 / Accepted: 25 March 2015 / Published: 30 March 2015
Abstract: In this study a series of diacylhydrazine and acylhydrazone derivatives were
designed and synthesized according to the method of active group combination and the
principles of aromatic group bioisosterism. The structures of the novel derivatives were
1
determined on the basis on H-NMR, IR and ESI-MS spectral data. All of the compounds
were evaluated for their in vivo insecticidal activity against the third instar larvae of
Spodoptera exigua Hiibner, Helicoverpa armigera Hubner, Plutella xyllostella Linnaeus
and Pieris rapae Linne, respectively, at a concentration of 10 mg/L. The results showed
that all of the derivatives displayed high insecticidal activity. Most of the compounds
presented higher insecticidal activity against S. exigua than the reference compounds
tebufenozide, metaflumizone and tolfenpyrad, and approximately identical insecticidal
activity against H. armigera, P. xyllostella and P. rapae as the references metaflumizone
and tolfenpyrad.
Keywords: diacylhydrazine; acylhydrazone; aromatic diamide; insecticidal activity; synthesis
1. Introduction
Synthetic pesticides have performed major functions in feed, food and fiber production for many
years. To a considerable extent, these pesticides may be expected to be used well into the future,

Molecules 2015, 20
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although the type of pesticides used may shift toward materials with novel modes of action and lower
risk to humans and other non-target organisms [1,2].
The phthalic diamide flubendiamide and the anthranilic diamides chlorantraniliprole and
cyantraniliprole were successively designed and synthesized by Japanese pesticide companies in 1998
and DuPont in 2001; these novel insecticides act on the ryanodine receptor (RyR) [3–7]. Bayer and
Syngenta have also developed the meta-amino benzamides A and B (Figure 1), both of which are
considered RyR pesticides [8–10]. Compounds A and B present excellent insecticidal activities against
pests of different orders, such as Lepidoptera, Diptera, Coleoptera, Hemiptera, and Isoptera, and
feature high selectivity, low mammalian toxicity, and environmental friendliness. As determined
through electrophysiological and Ca2+-release studies these insecticides act by activating insect RyR, a
non-voltage-gated calcium channel, to affect calcium release from intracellular stores by locking
channels in a partially opened state [3,11,12]. All of the RyR insecticides described above contain two
amide structures that are important to their insecticidal activity.
Tebufenozide
Diacylhydrazine moiety
O
N
N
H
O
O
O
Combination of
active groups
H
N
R1
N
N
R2
Aromatic group
bioisosterism
H
H
O
O
H
N
Diacylhydrazine derivatives
N
N
A
B
H
O
CF3
O
C3F7-n
C3F7-n
S
H
N
N
H
N
O
Cl
CN
Combination of
active groups
O
R2
H
Aromatic diamide moiety
N
Aromatic group
bioisosterism
R1
N
N
F3CO
H
O
O
N
N
N
CF3
CN
Acylhydrazone derivatives
H
H
Aromatic acylhydrazone moity
Metaflumizone
Figure 1. Design of the skeleton of diacylhydrazine and acylhydrazone derivatives.
Diacylhydrazines have been identified as one of the most important types of insect regulators since
the discovery of the N-tert-butyl-N,N'-diacylhydrazines in the mid-1980s by Rohm and Haas [13–15].
Several commercial compounds, such as tebufenozide, methoxyfenozide, chromafenozide, and
halofenozide, are all classified as diacylhydrazines, and all of these insecticides affect the ecdysone

Molecules 2015, 20
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receptor complex, leading to precocious lethal molting, especially in caterpillars [16,17].
Diacylhydrazines have attracted significant attention because of their high insecticidal selectivity,
simple structure, and low toxicity to vertebrates [15].
Metaflumizone, a semicarbazone compound with a structure containing an acylhydrazone moiety, is
a novel sodium channel blocker insecticide recently introduced to the Chinese market in 2010 by
BASF. It provides excellent control of most economically important pests belonging to the orders
Lepidoptera, Coleoptera, Hymenoptera, Hemiptera, Isoptera, Diptera, and Siphonaptera. Metaflumizone
presents low risk to pollinators and beneficial insects, as well as humans and the environment.
Insect strains that are resistant to organophosphates, carbamates, and imidacloprid do not display
cross-resistance to metaflumizone. Thus, this insecticide demonstrates great potential use in Integrated
Pest Management (IPM) and resistance management strategies [2,18,19]. Moreover many other
acylhydrazone compounds also show strong insecticidal activity [20,21].
Plant pests, such as the beet armyworm (Spodoptera exigua Hiibner), diamondback moth
(Helicoverpa armigera Hubner), cotton bollworm (Plutella xyllostella Linnaeus), and cabbage
caterpillar (Pieris rapae Linne), are harmful to crops all over the world. Unfortunately, pest control of
these species has become increasingly difficult because of development of resistance to traditional
insecticides. Poor pest control leads to enormous losses of crop production because of long-term use of
conventional pesticides [3,22].
In the present work, we sought to incorporate an aromatic diamide unit into an aromatic
diacylhydrazine or acylhydrazone moiety according to the method of active group combination and the
principle of aromatic group bioisosterism. A total of four diacylhydrazine derivatives and 12
acylhydrazone derivatives were designed; the structures of these compounds combined a meta-amino
benzamide with diacylhydrazine or acylhydrazone active groups (Scheme 1) and they were identified
1
by IR, ESI-MS, and H-NMR spectroscopy. The insecticidal activities of the resulting compounds
against the third instarlarvae of beet armyworm, diamondback moth, cotton bollworm, and cabbage
caterpillar were screened. Combination of critical components is expected to improve the biological
activities of these pesticides.
2. Results and Discussion
2.1. Chemistry
Scheme 1 shows the route used successfully for the preparation of the four diacylhydrazine
derivatives 3a–3d and 12 acylhydrazone derivatives 4a–4l. The raw materials 3-aminoethyl benzoate
and acyl chlorides R1COCl (I) were dissolved in chloroform and heated to reflux to prepare the
3-acylamino ethyl benzoates 1a–1g. Using alcohol as a solvent, 3-acylaminobenzoyl hydrazines 2a–2g
were obtained by reaction of compounds 1a–1g with hydrazine hydrate. Then, compounds 2a–2g were
reacted with acyl chlorides R2COCl (II) in tetrahydrofuran at room temperature to prepare the
diacylhydrazine derivatives 3a–3d. Again using alcohol as a solvent and trifluoroacetic acid as a
catalyst, compounds 2a–2g were reacted with 2-(4-nitrilo)benzyl-1-substituedphenyl ketones II to
form acylhydrazone derivatives 4a–4l. The structures of all of the diacylhydrazine and acylhydrazone
derivatives were effectively determined through 1H-NMR, ESI-MS, and IR spectroscopy.

Molecules 2015, 20
5628
O
O
H
O
Ⅰ
NH2NH2
N
R1
Cl
R1
N
H
NH2
OC2H5
OC2H5
THF, Ref., 4 h
H2N
R1
O
N
H
Ref., 2 h
O
O
O
2a-2g
1a-1g
CN
Ⅱ
R2
MeOH, ref., 6 h
R2
Cl
Ⅲ
O
THF, r.t.,15 h
R2
O
O
O
CN
H
H
N
N
R2
N
R1
N
H
N
R1
N
H
H
O
O
3a-3d
4a-4l
Scheme 1. Synthesis of diacylhydrazine and acylhydrazone derivatives.
2.2. Insecticidal Activities
Table 1 shows that all of the diacylhydrazine and acylhydrazone derivatives 3a–3d, 4a–4l display
strong insecticidal activity against the third instar larvae of beet armyworm (S. exigua) at a
concentration of 10 mg/L. Most of the synthesized compounds indicated higher insecticidal activity
than the reference compounds tebufenozide, metaflumizone, and tolfenpyrad. Among the synthesized
compounds, the mortality caused by compounds 3b, 4b, 4c, 4d, 4f and 4l exceeded 95% at the 72 h
time point. Moreover the third instar larvae of beet armyworm showed 100% mortality within 72 h
when treated with compounds 4b, 4d, and 4l. Table 1 further demonstrates that insect mortality
presents a positive relationship with administration time.
Table 2 presents the mortality data of cotton bollworm (H. armigera), diamondback moth
(P. xyllostella), and cabbage worm (P. rapae) exposed to acylhydrazone derivatives 4a–4l at a
concentration of 10 mg/L for 72 h. Compounds 4a–4l revealed strong insecticidal activity against the
third instar larvae of these species. Insect mortalities from exposure to these compounds were
approximately identical to those observed from exposure to the reference compounds metaflumizone
and tolfenpyrad. Among the synthesized acylhydrazone derivatives, 4b, 4c, 4d, 4f and 4l showed
100% mortalities against the third instar larvae of P. rapae. Compound 4f in particular displayed broad
spectrum insecticidal activity.
According to the data in Tables 1 and 2, it could be found that the presence of fluorine was
important for the insecticidal activity of the synthesized compounds. Comparing the differences
between the substituent groups and the position of the substituents on the benzene ring, it could be
presumed that relatively weak electron-withdrawing effects could strengthen the insecticidal activities
of the acylhydrazone derivatives, however electron-donating effects (such as seen in 4j) and strong
electron-withdrawing effects (such as in 4h and 4i) could not do so.

Molecules 2015, 20
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Table 1. Insecticidal activities of diacylhydrazine and acylhydrazone derivatives
(concentration, 10 mg/L) against the third instar larvae of beet armyworm.
Mortality (%)
24 h 48 h
Compound
3a
R1
R2
72 h
12.50
29.17 70.83
Cl
N
N
Cl
O
3b
3c
45.83
66.67 95.83
F3C
O
F
16.67
37.50 79.17
N
Cl
O
F
O
3d
4a
41.67
45.83
66.67 91.67
66.67 87.50
CF3
N
Cl
CF3
CF3
CF3
CF3
4b
4c
4d
4e
50.00
50.00
54.17
45.83
75.00 100.00
79.17 95.83
79.17 100.00
66.67 91.67
F3C
F3C
O
F
Cl
O
F
4f
4g
4h
4i
54.17
41.67
37.50
45.83
70.83 95.83
70.83 91.67
75.00 91.67
70.83 91.67
CF3
CF3
CF3
CF3
N
Cl
F3C
F3C
O
4j
37.50
66.67 87.50
CF3

Molecules 2015, 20
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Table 1. Cont.
Mortality (%)
24 h 48 h
Compound
4k
R1
R2
72 h
41.67
58.33
70.83 87.50
83.33 100.00
Cl
CF3
CF3
4l
F3CO
Reference Compounds
Tebufenozide
Metaflumizone
Tolfenpyrad
12.50
37.50
45.83
37.50 66.67
45.83 66.67
66.67 79.17
Table 2. Insecticidal activities of acylhydrazone derivatives (concentration, 10 mg/L;
treatment time, 72 h).
Mortality(%)
Compound
H. armigera P. xyllostella P. rapae
4a
87.50
91.67
91.67
95.83
79.17
95.83
87.50
83.33
87.50
83.33
91.67
79.17
87.50
91.67
79.17
95.83
87.50
87.50
83.33
100.0
87.50
87.50
75.50
83.33
70.83
95.83
83.33
91.67
91.67
100.0
100.0
100.0
91.67
100.0
95.83
95.83
91.67
91.67
91.67
100.0
87.50
95.83
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
Metaflumizone
Tolfenpyrad
3. Experimental Section
3.1. General Procedures
All reagents were chemically pure and solvents were dried according to standard methods. 1H-NMR
spectra were obtained on an AM-500 spectrometer (Bruker, Karlsruhe, Germany) with DMSO-d6
as the solvent. IR spectra were recorded on an IR-200 spectrophotometer (Nicolet, Thermo Electron,
Madison, WI, USA) using KBr disks. Mass spectra were recorded under ESI conditions on a Q-TOF
spectrometer (Micromass, Waters Corp., Manchester, UK). Melting points were measured on a
WRS-1A-type melting point apparatus (Shanghai, China) and are reported uncorrected. Analytical
TLC was carried out on pre-coated silica gel plates, and spots were visualized through UV illumination
(254 nm).

Molecules 2015, 20
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3.2. General Procedure for the Preparation of 1a–1g
3-Aminoethyl benzoate (30 mmol) was dissolved in chloroform (25 mL) in an ice-water bath. Then,
an acyl chloride R1COCl (I, 30 mmol) was dissolved in chloroform (25 mL) and added dropwise to
this solution. The mixture was reacted at 25 °C in a water bath for 5 h and then refluxed for 2 h.
The reaction mixture was subsequently cooled to room temperature and filtered under vacuum to
obtain the 3-acylaminoethyl benzoates 1a–1g with yields of 85%–95%.
3.3. General Procedure for the Preparation of 2a–2g
A mixture of 3-acylaminoethyl benzoates 1a–1g (20 mmol), 80% hydrazine hydrate (100 mmol),
and ethanol (100 mL) was stirred and heated under reflux for 4 h. The reaction mixture was cooled to
room temperature and filtered under vacuum. The solid obtained was washed with water (50 mL) to
provide the 3-acylaminobenzoyl hydrazines 2a–2g in yields of 80%–95%.
3.4. General Procedure for Preparation of 3a–3d and 4a–4l
3-Acylaminobenzoyl hydrazines 2a–2g (5 mmol) and NaOH (5.7 mmol) were dissolved in dry
tetrahydrofuran (50 mL). Acyl chlorides R2COCl (II, 5.7 mmol) dissolved in dry tetrahydrofuran
(30 mL) were then dropped slowly into the above solution at 0 °C in an ice-water bath. The solution
was reacted at room temperature for 15 h. After completion of the reaction, the reaction mixture was
concentrated in vacuo and mixed with saturated NaHCO3 solution (25 mL). The mixture was stirred
for 30 min and then filtered under vacuum. The filtrate was recrystallized with DMF and water
(volume ratio, 2:1) to afford the target compounds 3a–3d.
3-Acylaminobenzoyl hydrazines 2a–2g (2 mmol), 2-(4-nitrilo)benzyl-1-substituted phenyl ketones
(III, 2 mmol), and two or three drops of trifluoroacetic acid were dissolved in methanol (15 mL) and
n-hexane (2 mL). This solution was stirred and heated under reflux for 6 h, after which the reaction
mixture was concentrated in vacuo and filtered under vacuum. The filtrate was recrystallized with
methanol to yield the target compounds 4a–4l. All 16 compounds are novel compounds and their
physical and spectral data are listed below.
N-(2-Chloropyridyl-3-formyl)-3-(2-chloropyridyl-3-formylamino)benzoyl hydrazine (3a). White needle-like
crystals, yield 75.2%, m.p. 253.0–253.2 °C. HR-ESI-MS m/z: 430.0471 [M+H]+ (calcd for
1
C19H14Cl2N5O3, 430.0468). H-NMR (DMSO-d6) δ: 10.84, 10.73, 10.61 (each s, 1H, NH), 8.54 (d,
J = 2.4Hz, 2H,), 8.26 (s, 1H), 8.10 (dd, J =7 .5, 1.7 Hz, 1H), 7.98 (dd, J = 7.5, 1.7 Hz, 1H), 7.87 (d,
J = 8.0 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.60–7.48 (m, overlapped, 3H). IR (KBr): ν 3246, 2360,
1701, 1656, 1580, 1492, 1400, 1283, 1268, 912, 750, 653 cm−1.
N-(3-Phenoxy)benzoyl-3-(3-phenoxylbenzoylamino)benzoyl hydrazine (3b). White powder, yield
76.6%, m.p. 239.6–240.8 °C. HR-ESI-MS m/z: 520.1474 [M+H]+ (calcd for C28H21F3N3O4, 520.1479).
1H-NMR (DMSO-d6) δ: 10.67, 10.57, 10.52 (each s, 1H, NH), 8.30 (s, 1H), 8.18 (d, J = 8.1 Hz, 2H),
8.01 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H),
7.50–7.54 (m, overlapped, 3H), 7.43 (t, J = 7.8 Hz, 2H), 7.25 (d, J = 8.1 Hz, 1H), 7.19 (t, J = 7.4 Hz,
1H), 7.08 (d, J = 8.1 Hz, 2H).

Molecules 2015, 20
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N-(4-Fluoro-3-phenoxy)benzoyl-3-(2-chloropyridyl-3-formylamino)benzoyl hydrazine (3c). White
1
powder, yield 78.3%, m.p. 185.6–186.4 °C. H-NMR (DMSO-d6) δ: 10.89, 10.60, 10.46 (each s, 1H,
NH), 8.55 (dd, J= 4.0, 1.6 Hz, 1H), 8.28 (s, 1H), 7.99 (dd, J = 6.2, 1.6 Hz, 1H), 7.95 (dd,
J = 6.7, 1.0 Hz, 1H), 7.92 (m, 1H), 7.82 (dd, J = 6.5, 1.8 Hz, 1H), 7.66 (d, J = 6.6 Hz, 1H), 7.56–7.61
(m, overlapped, 2H), 7.49 (t, J = 6.6 Hz, 1H), 7.42 (dd, J = 7.1, 6.6 Hz, 2H),7.17 (t, J = 6.1 Hz, 1H),
7.06 (d, J = 6.5 Hz, 2H). IR (KBr): ν 3478, 3411, 1704, 1615, 1577, 1392, 1388, 1164, 902, 714 cm−1.
N-(4-Fluoro-3-phenoxy)benzoyl-3-(3-phenoxybenzoylamino)benzoyl hydrazine (3d). White powder,
yield 72.6%, m.p. 221.8–222.1 °C. HR-ESI-MS m/z: 562.1777 [M+H]+ (calcd for C33H25FN3O5,
1
562.1773). H-NMR (DMSO-d6) δ: 10.60, 10.51, 10.47 (each s, 1H, NH), 8.55 (s, 1H), 8.26 (s, 1H),
7.99 (d, J = 7.6 Hz, 1H), 7.84–7.76 (m, overlapped, 2H), 7.67 (d, J = 7.9 Hz, 1H), 7.59 (m, 4H), 7.40–7.50
(m, overlapped, 5H), 7.24 (d, J = 8.1 Hz, 1H), 7.19 (t, J = 7.4 Hz, 2H), 7.08 (d, J = 8.1 Hz, 3H). IR
(KBr): ν 3296, 3222, 3072, 1648, 1612, 1580, 1545, 1477, 1274, 900, 685 cm−1.
N-[3-(2-Chloropyridyl-3-formylamino)]benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)phenyl ethanone
hydrazone (4a). White needle-like crystals, yield 63.4%, m.p. 253.0–253.2 °C. HR-ESI-MS m/z:
562.1256 [M+H]+ (calcd for C29H20ClF3N5O2, 562.1252). 1H-NMR (DMSO-d6) δ: 11.39, 10.86 (each s,
1H, NH), 8.55 (dd, J = 4.8,1.7 Hz, 1H), 8.16 (d, J = 6.2 Hz, 1H), 8.10 (dd, J = 7.5, 1.6 Hz, 1H), 8.03 (s,
1H), 7.92 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 6.0 Hz, 1H), 7.72–7.82 (overlapped, 4H), 7.58(dd, J = 7.5,
4.9 Hz, 1H), 7.52 (s, 1H), 7.51 (d, J = 7.1 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 4.58 (s, 2H, -CH2-). IR
(KBr): ν 3275, 2230,1671, 1550, 1400, 1309,1103, 1068, 841, 750 cm−1.
N-[3-(4-Trifluoromethyl)benzoylamino]benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)phenyl ethanone
hydrazone (4b). Off-white powder, yield 68.6%, m.p. 217.9–218.5 °C. 1H-NMR (DMSO-d6) δ: 11.35,
10.65 (each s, 1H, NH), 8.16 (d, J = 7.8 Hz, 3H), 7.99 (s,1H), 7.93 (s, 1H), 7.92 (d, J =8.8 Hz, 3H),
7.76 (d, J = 8.0 Hz, 2H), 7.60 (s, 1H), 7.50 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H),
4.58 (s, 2H, -CH2-). IR (KBr): ν 3222, 2360, 2227, 1651, 1550, 1321, 1162, 862, 685 cm−1.
N-[3-(3-Trifluoromethyl)benzoylamino]benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)phenyl ethanone
hydrazone (4c). Off-white powder, yield 77.9%, m.p. 184.0–184.5 °C. HR-ESI-MS m/z: 595.1560
1
[M+H]+ (calcd for C31H21F6N4O2, 595.1563). H-NMR (DMSO-d6) δ: 11.36, 10.67 (each s, 1H, NH),
8.33 (s, 1H), 8.29 (d, J = 7.9 Hz, 1H), 8.23 (s, 1H), 8.03 (overlapped, 2H), 7.99 (d, J = 7.9 Hz, 1H),
7.55–7.82 (m, overlapped, 5H), 7.52 (s, 1H), 7.51 (d, J = 6.7 Hz, 1H),7.39 (d, J = 8.2 Hz, 2H), 4.59 (s,
2H, -CH2-). IR (KBr): ν 3225, 2357, 2227, 1680, 1651, 1550, 1336,1108, 853, 697 cm−1.
N-(4-Fluoro-3-phenoxylbenzoylamino)benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)phenyl
ethanone hydrazone (4d). Off-white powder, yield 74.3%, m.p.196.3–196.8 °C. HR-ESI-MS m/z:
1
637.1858 [M+H]+ (calcd for C36H25F4N4O3, 637.1857). H-NMR (DMSO-d6) δ: 11.34, 10.46 (each s,
1H, NH), 8.18 (s, 1H), 8.08 (s, 1H), 7.88–7.98 (m, 3H), 7.65–7.85 (m, 4H), 7.58–7.70 (m, 2H), 7.48 (s,
1H), 7.36–7.47 (m, 3H), 7.18 (m, 1H), 7.06 (d, J = 7.3 Hz, 2H), 4.59 (s, 2H, -CH2-). IR (KBr): ν 2360,
2227, 1671, 1648, 1559, 1333, 1277, 1212, 1135, 876, 750 cm−1.

Molecules 2015, 20
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N-(4-Chlorobenzoylamino)]benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)phenyl ethanone hydrazone (4e).
White powder, yield 70.3%, m.p. 197.0–197.3 °C. HR-ESI-MS m/z: 561.1298 [M+H]+ (calcd for
C30H21ClF3N4O2, 561.1300). 1H-NMR (DMSO-d6) δ: 11.35, 10.52 (each s, 1H, NH), 8.23 (s, 1H), 8.17
(s, 1H), 8.01 (d, J = 8.4 Hz, 3H), 7.94 (s, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.5 Hz, 3H), 7.49
(s, 1H), 7.48 (d, J = 6.7 Hz,1H), 7.40 (d, J = 8.2 Hz, 2H), 4.60 (s, 2H, -CH2-). IR (KBr): ν 3255, 2227,
1659, 1542, 1341, 1109, 1074, 826, 750 cm−1.
N-(4-Fluoro-3-phenoxylbenzoylamino)benzoyl-1-(4-trifluoromethyl)phenyl-2-(4-cyano)phenyl
ethanone
hydrazone (4f). Off-white powder, yield 74.3%, m.p. 187.1–187.4 °C. HR-ESI-MS m/z: 637.1859
1
[M+H]+ (calcd for C36H25F4N4O3, 637.1858). H-NMR (DMSO-d6) δ: 11.33, 10.45 (each s,1H, NH),
8.18 (s, 1H), 7.90–8.10 (m, 4H), 7.70–7.82 (m, 5H), 7.60 (m,1H), 7.35–7.50 (m, 6H), 7.18 (t, J = 7.3 Hz,
1H), 7.06 (d, J = 8.1 Hz, 2H), 4.57 (s, 2H, -CH2-). IR (KBr): ν 3187, 2369, 2225, 1677, 1648, 1556,
1503, 1324, 1271.3, 1212, 1132, 753, 691 cm−1.
N-[3-(2-Chloropyridyl-3-formylamino)]benzoyl-1-(4-trifluoromethyl)phenyl-2-(4-cyano)phenyl ethanone
hydrazone (4g). White powder, yield 65.7%, m.p. 244.4–245.2 °C. HR-ESI-MS m/z: 562.1254 [M+H]+
1
(calcd for C29H20ClF3N5O2, 562.1252). H-NMR (DMSO-d6) δ: 11.39, 10.85 (each s, 1H, NH), 8.55
(dd, J = 4.4 Hz, 1H), 8.16 (s, 2H), 8.10 (m, 2H), 7.90 (d,J = 5.8 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.72
(d, J = 8.1 Hz, 1H), 7.62 (s, 1H), 7.58 (dd, J = 7.4, 4.9 Hz, 1H), 7.46–7.54 (m, 2H), 7.40 (d, J = 8.0 Hz,
2H), 4.59 (s, 2H, -CH2-). IR (KBr): ν 3275, 3249, 2227, 1671, 1527, 1397, 1350, 1168, 1103, 1068,
747, 547 cm−1.
N-(4-Trifluoromethylbenzoylamino)benzoyl-1-(4-trifluoromethyl)phenyl-2-(4-cyano)phenyl ethanone
hydrazone (4h). Off-white powder, yield 78.3%, m.p. 228.7–229.0 °C. HR-ESI-MS m/z: 595.1568
1
[M+H]+ (calcd for C31H21F6N4O2, 595.1563). H-NMR (DMSO-d6) δ: 11.36, 10.67 (each s, 1H, NH),
8.24 (s, 1H), 8.18 (d, J = 8.0 Hz, 2H), 8.00 (s, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.70–7.82 (m, 5H), 7.49–7.55
(m, 2H), 7.40 (d, J = 8.3 Hz, 2H), 4.59 (s, 2H, -CH2-). IR (KBr): ν 3228, 2233, 1683, 1656, 1559,
1324, 1130, 1065, 853 cm−1.
N-(3-Trifluoromethylbenzoylamino)benzoyl-1-(4-trifluoromethyl)phenyl-2-(4-cyano)phenyl ethanone
hydrazone (4i). White powder, yield 72.5%, m.p. 190.5–190.8 °C. HR-ESI-MS m/z: 595.1565 [M+H]+
1
(calcd for C31H21F6N4O2, 595.1563). H-NMR (DMSO-d6) δ: 11.35, 10.66 (each s, 1H, NH), 8.32 (s,
1H), 8.29 (d, J = 7.2 Hz, 2H), 8.23 (s, 1H), 8.18 (s, 1H), 7.96–8.05 (overlapped, 4H), 7.75–7.84
(m, overlapped, 4H), 7.63 (s, 1H), 7.52 (s, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 4.60
(s, 2H, -CH2-). IR (KBr): ν 3267, 2230, 1659, 1512, 1336, 1142, 1074, 823, 553 cm−1.
N-(3-Phenoxylbenzoylamino)benzoyl-1-(4-trifluoromethyl)phenyl-2-(4-cyano)phenyl ethanone hydrazone
(4j). Off-white powder, yield 70.3%, m.p. 189.4–189.6 °C. HR-ESI-MS m/z: 619.1949 [M+H]+ (calcd
1
for C36H26F3N4O3, 619.1952). H-NMR (DMSO-d6) δ: 11.34, 10.47 (each s, 1H, NH), 8.22 (s, 1H),
7.95–8.10 (m, 3H), 7.71–7.82 (overlapped, 5H), 7.61 (s, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.48 (s, 1H),
7.47 (d, J = 6.5 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.25 (dd, J = 8.0, 1.9 Hz,
1H), 7.19 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 4.58 (s, 2H,-CH2-). IR (KBr): ν 3187, 2225,
1677, 1648, 1539, 1480, 1327, 1271, 1235, 1124, 868, 750 cm−1.

Molecules 2015, 20
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N-(4-Chlorobenzoylamino)]benzoyl-1-(4-trifluoromethyl)phenyl-2-(4-cyano)phenyl ethanone hydrazone
(4k). White powder, yield 70.3%, m.p. 208.5–208.7 °C. HR-ESI-MS m/z: 561.1304 [M+H]+ (calcd for
1
C30H21ClF3N4O2, 561.1300). H-NMR (DMSO-d6) δ: 11.36, 10.52 (each s, 1H, NH), 8.23 (s, 1H),
7.95–8.10 (overlapped, 5H), 7.70–7.82 (overlapped, 4H), 7.63 (d, J = 8.5 Hz, 2H), 7.50 (s, 1H), 7.49
(d, J = 6.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 4.58 (s, 2H, -CH2-). IR (KBr): ν 3225, 2233, 1680, 1645,
1559, 1486, 1327, 1127, 1065, 850, 753, 600 cm−1.
N-(4-Trifluoromethoxy benzoylamino)]benzoyl-1-(4-trifluoromethyl) phenyl-2-(4-cyano) phenyl
ethanone hydrazone (4l). White powder, yield 70.3%, m.p. 249.5–249.8 °C. HR-ESI-MS m/z: 611.1518
1
[M+H]+ (calcd for C31H21F6N4O3, 611.1512). H-NMR (DMSO-d6) δ: 11.45, 10.58 (each s, 1H, NH),
8.35 (s, 1H), 8.19 (s, 1H), 8.16 (d, J = 7.9 Hz, 2H), 8.08 (s, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.91 (d,
J = 9.0 Hz, 2H), 7.77 (d, J = 7.8 Hz, 2H), 7.68 (t, J = 7.7 Hz, 1H), 7.64 (s, 1H), 7.35–7.45 (m,
overlapped, 4H), 4.61 (s, 2H, -CH2-). IR (KBr): ν 3222, 2230, 1683, 1645, 1536, 1509, 1256, 1171,
853, 697 cm−1.
3.5. Insecticidal Activity Bioassays
Wheat leaf discs measuring 0.5 cm × 0.5 cm were treated with 5 μL of 1.0 mg of test samples
dissolved in 100 mL of acetone. Acetone was used as a negative control, whereas tebufenozide,
metaflumizone, and tolfenpyrad were used as positive controls. The third instar larvae of S. exigua
were allowed to feed on the discs. Cohorts of 24 beet armyworms were treated each time and bioassays
were replicated three times. After 24, 48, and 72 h, the numbers of knocked-down larvae (indications:
the larvae were narcotized, their bodies were very soft and immobile, and responses to stimuli
disappeared completely) were recorded [23,24]. Insecticidal activity results are listed in Table 1.
Bioassays for insecticidal activity against cotton bollworm, diamondback moth, and cabbage worm
was performed according to the method described above, except that the third instar larvae of S. exigua
were replaced by the third instar larvae of H. armigera, P. xyllostella, and P. rapae. Metaflumizone
and tolfenpyrad were used as positive controls, and the numbers of knocked-down larvae were recorded
72 h after exposure. Bioassay results are listed in Table 2.
4. Conclusions
In conclusion, four novel diacylhydrazine 3a–3d and 12 acylhydrazone derivatives 4a–4l were
designed and synthesized according to the method of active group combination and the principle of
aromatic group bioisosterism. The resultant analogs were evaluated (concentration, 10 mg/L) for their
insecticidal activity against the third instar larvae of S. exigua, H. armigera, P. xyllostella, and
P. rapae in vivo. Bioassays of these analogs showed high insecticidal activity. Most of the synthesized
compounds presented higher insecticidal activity against S. exigua than the reference compounds
tebufenozide, metaflumizone, and tolfenpyrad. Insecticidal activities against H. armigera, P. xyllostella,
and P. rapae similar to that of the reference compounds metaflumizone and tolfenpyrad were also
obtained. The results above motivate us to further explore novel diacylhydrazine and acylhydrazone
derivatives as insecticidal agents; new findings will be reported in future work.

Molecules 2015, 20
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Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/04/5625/s1.
Acknowledgments
This work was supported by the Wheat Innovation Team of the Modern Agricultural Industry
Technology System of Shandong Province and High Level Talents Fund of Qingdao Agricultural
University (No. 6631110).
Author Contributions
Jialong Sun designed the research; Jialong Sun and Yuanming Zhou performed the research and
analyzed the data; Yuanming Zhou wrote the paper. All authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 3a–3d and 4a–4l are available from the authors.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/4.0/).