Synthesis and insecticidal activities of novel phthalic acid diamides

Article abstract of DOI:10.1002/cjoc.201100746

In order to discover novel insecticides with the new action mode on ryanodine receptor (RyR), a series of novel phthalic acid diamide derivatives were designed and synthesized. All compounds were characterized by ¹H NMR spectra and HRMS. The preliminary results of biological activity assessment indicated that some title compounds exhibited excellent insecticidal activities against Mythimna separata, Spodoptera exigua, and Plutella xylostella. The title compound 3-nitro-N-cyclopropyl-N′-[2-methyl-4-(perfluoropropan-2-yl) phenyl]phthalamide (4a) was more efficient against diamondback moths than the control (chlorantraniliprole). The effects of some title compounds on intracellular calcium of neurons from the Spodoptera exigua proved that the title compounds were RyR activators. Copyright

Full text of DOI:10.1002/cjoc.201100746

FULL PAPER
DOI: 10.1002/cjoc.201100746
Synthesis and Insecticidal Activities of Novel Phthalic Acid
Diamides
Yan, Tao(闫涛)
Li, Yuxin*(李玉新)
Li, Yongqiang(李永强)
Wang, Duoyi(王多义)
Chen, Wei(陈伟)
Liu, Zhuo(刘卓)
Li, Zhengming*(李正名)
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, China
In order to discover novel insecticides with the new action mode on ryanodine receptor (RyR), a series of novel
1
phthalic acid diamide derivatives were designed and synthesized. All compounds were characterized by H NMR
spectra and HRMS. The preliminary results of biological activity assessment indicated that some title compounds
exhibited excellent insecticidal activities against Mythimna separata, Spodoptera exigua, and Plutella xylostella.
The title compound 3-nitro-N-cyclopropyl-N'-[2-methyl-4-(perfluoropropan-2-yl)phenyl]phthalamide (4a) was
more efficient against diamondback moths than the control (chlorantraniliprole). The effects of some title com-
pounds on intracellular calcium of neurons from the Spodoptera exigua proved that the title compounds were RyR
activators.
Keywords phthalic acid diamides, insecticidal activity, ryanodine receptor, activators
Introduction
oriental armyworms (Mythimna separata), beet army-
worms (Spodoptera exigua) and diamondback moths
(Plutella xylostella) were tested accordingly. The effect
of these compounds on intracellular calcium concentra-
tion in the central neurons isolated from the third instar
of Spodoptera exigua was studied by calcium imaging
technique as well.[16]
In order to overcome resistance and ecobiological
problems associated with conventional insecticides,
there is an urgent need to discover novel potent insecti-
cides with a new action mode.[1] The ryanodine receptor
(RyR) represents a new target to study in integrated
strategies for pest management.[2,3] To date, there are
only three commercial products targeting the RyR,
namely: flubendiamide (Scheme 1, A),[4] chloran-
traniliprole (Rynaxypyr) (Scheme 1, B) and cyan-
traniliprole (Cyazypyr) (Scheme 1, C).[5,6] They stabilise
insect RyR channels to the open state, evoke massive
calcium release from intracellular stores and then dis-
rupt calcium homeostasis, and possess distinct pharma-
cological characteristics.[7]
Since the discovery of phthalic acid diamides, most
modifications can be categorized into three substruc-
tures (Scheme 1, D): the phthalic acid moiety (a), aro-
matic amide moiety (b) and aliphatic amide moiety
(c).[8] In previous work, most modifications are related
to parts a and b.[9-13] However, less research has been
devoted to the modification of part c, it has been re-
ported that the biological activity of such compounds
can be affected by changing the aliphatic amide skeleton
to a large extent.[12,14,15] In consideration of the above
viewpoints, a series of novel phthalic acid diamides
containing heptafluoroisopropylaniline were synthe-
sized as shown in Scheme 2. Their bioactivity against
Scheme 1 Chemical structures of compounds A—D
O
S
Br
N
H
N
I
O
O
O
H
N
NH
H
O
N
N
Cl
O
Cl
N
C3F7
B
A
R2
R1
(c)
N
Br
H
N
O
O
O
H
N
X
N
N
Cl
O
(a)
N
R3
NC
N
Ym
(b)
C
D
Experimental
Materials and instruments
1H NMR spectra were recorded on a Bruker 400
*
E-mail: nkzml@vip.163.com and liyx128@nankai.edu.cn; Tel.: 0086-022-23503732; Fax: 0086-022-23505948
Received December 31, 2011; accepted February 22, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201100746 or from the author.
Chin. J. Chem. 2012, XX, 1—8
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1

Yan et al.
FULL PAPER
sodium bicarbonate solution and brine. The resulting
solution was dried and evaporated to give the crude
residue, which was further purified by flash chromatog-
raphy on silica gel with petroleum/ethyl acetate (4∶1,
volume ratio) to afford the title compounds 4a—4c.
3-Nitro-N-cyclopropyl-N'-[2-methyl-4-(perfluoro-
propan-2-yl)phenyl]phthalamide (4a) Yield 61.7%,
MHz or 300 MHz nuclear magnetic resonance spec-
trometer with CDCl3 or DMSO-d6 as the solvent and
TMS as internal standard. High resolution mass spec-
trometry (HRMS) data were obtained on a Varian
QFT-ESI instrument. The melting points were deter-
mined on an X-4 melting point apparatus. All the re-
agents were of analytical grade.
1
white solid, m.p. 218—220 ℃; H NMR (400 MHz,
CDCl3) δ: 8.50 (s, 1H, Ar-NH), 8.28 (d, 3JHH＝8.10 Hz,
General procedure for the synthesis of intermediates
2 and 3
3
1H, Ar-H), 8.08 (d, JHH＝7.42 Hz, 1H, Ar-H), 7.69 (t,
3JHH＝7.90 Hz, 1H, Ar-H), 7.54—7.41 (m, 2H, Ar-H),
6.28 (s, 1H, NHCHCH2CH2), 2.86 — 2.77 (m, 1H,
CHCH2CH2), 2.42 (s, 3H, Ar-CH3), 0.84—0.74 (m, 2H,
CHCH2CH2), 0.59—0.50 (m, 2H, CHCH2CH2); 13C
NMR (100 MHz, DMSO-d6) δ: 165.1, 146.8, 139.2,
137.2, 133.6, 133.0, 131.5, 130.0, 127.1, 125.6, 125.5,
Synthetic route of the intermediates (compounds 2
and 3) was shown in Scheme 2. They were synthesized
according to the methods reported in the literature[13,17]
with some modification.
3-Nitrophthalic anhydride (2) Yield 98.7%, yel-
low solid, m.p. 160—162 ℃ (lit. 163—165 ℃).[18]
2-(2-Methyl-4-(perfluoropropan-2-yl)phenyl)-4-
nitro-isoindoline-1,3-dione (3) Yield 91.5%, yellow
solid, m.p. 146—148 ℃; 1H NMR (400 MHz, CDCl3) δ:
123.2, 121.9, 121.7, 119.0, 118.7, 22.5, 18.0, 5.3.
＋
HRMS calcd for C21H16F7N3O4Na ([M ＋ Na]
)
530.0921, found 530.0934.
3
3
3-Nitro-N-butyl-N'-[2-methyl-4-(perfluoropropan-
2-yl)phenyl]phthalamide (4b) Yield 65.2%, white
8.25 (d, JHH＝7.50 Hz, 1H, Ar-H), 8.21 (d, JHH＝8.14
3
Hz, 1H, Ar-H), 8.02 (t, JHH＝7.80 Hz, 1H, Ar-H), 7.62
1
(s, 1H, Ar-H), 7.59 (d, 3JHH＝8.50 Hz, 1H, Ar-H), 7.36 (d,
3JHH＝8.42 Hz, 1H, Ar-H), 2.30 (s, 3H, Ar-CH3).
solid, m.p. 224—226 ℃; H NMR (400 MHz, CDCl3)
3
δ: 8.50 (s, 1H, Ar-NH), 8.37 (d, JHH＝8.82 Hz, 1H,
Ar-H), 8.30 (d, 3JHH＝8.40 Hz, 1H, Ar-H ), 8.13 (d, 3JHH
3
General procedure for the synthesis of compounds
4a—4c
＝7.74 Hz, 1H, Ar-H), 7.72 (t, JHH＝8.00 Hz, 1H,
3
Ar-H), 7.48 (d, JHH＝9.20 Hz, 1H, Ar-H), 7.44 (s, 1H,
Ar-H), 6.09 (s, 1H, NHCH2CH2CH2CH3), 3.41 (dd,
Synthetic route of title compounds was shown in
Scheme 2. The synthetic procedure was described below.
To a solution of compound 3 (0.50 mmol) and po-
tassium carbonate (10 mg) in 10 mL of tetrahydrofuran,
aliphatic amine (0.50 mmol) in 5 mL of tetrahydrofuran
was added dropwise at the room temperature. The re-
sulting mixture was then stirred for 1—12 h and moni-
tored by TLC. After evaporation, extracted twice with
20 mL of dichloromethane, the combined organic layer
was sequentially washed with 1 mol/L HCl, saturated
4
3JHH＝13.30, JHH＝6.82 Hz, 2H, CH2CH2CH2CH3),
2.40 (s, 3H, Ar-CH3), 1.47—1.40 (m, 2H, CH2CH2-
CH2CH3), 1.28—1.18 (m, 4H, CH2CH2CH2CH3), 0.73
3
(t, JHH＝7.30 Hz, 3H, CH2CH2CH2CH3); 13C NMR
(100 MHz, DMSO-d6) δ: 165.1, 163.7, 146.8, 139.2,
137.2, 133.0, 132.9, 131.4, 130.0, 127.2, 125.4, 125.0,
123.3, 121.6, 121.4, 118.7, 38.9, 30.5, 19.5, 17.9, 13.4.
＋
HRMS calcd for C21H16F7N3O4Na ([M ＋ Na]
)
546.1234, found 546.1242.
Scheme 2 Synthesis of compounds 4, 5, 6, 7
O
O
NO2
NO2
O
NO2
O
H2N
CF(CF3)2
COOH
COOH
R1
O
NH2
O
CF(CF3)2
N
O
O
3
1
2
I
O
O
R1
NaNO2
NH
NH
KI/NH2CONH2
NH2
O
O
R1
NO2
O
R1
H2 Pd / C
CF(CF3)2
NH
NH
NH
NH
O
6
R2
(CH3CO)2O or
(CF3CO)2O
NH
O
5
R1
CF(CF3)2
O
CF(CF3)2
NH
NH
4
-78 ℃ 25 ℃
O
CF(CF3)2
7
4a, 5a, 6a: R1 = cyclopropyl; 4b, 5b, 6b: R1 = n-butyl; 4c, 5c, 6c: R1 = i-amyl; 7a: R1 = cyclopropyl, R2 = CH3; 7b: R1 = n-butyl, R2 = CH3; 7c:
R1 = i-amyl, R2 = CH3; 7d: R1 = n-butyl, R2 = CF3; 7e: R1 = i-amyl, R2 = CF3
2
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Chin. J. Chem. 2012, XX, 1—8

Synthesis and Insecticidal Activities of Novel Phthalic Acid Diamides
3-Nitro-N-isopentyl-N'-[2-methyl-4-(perfluoro-
propan-2-yl)phenyl]phthalamide (4c) Yield 58.4%,
NHCH2CH2CH2CH3), 1.27 — 1.16 (m, 2H, NHCH2-
3
CH2CH2CH3), 0.71 (t, JHH＝7.20 Hz, 3H, NHCH2-
1
white solid, m.p. 230—231 ℃; H NMR (400 MHz,
CH2CH2CH3); 13C NMR (100 MHz, CDCl3) δ: 168.4,
168.0, 145.7, 138.5, 135.5, 130.9, 128.2, 127.8, 124.5,
122.6, 122.4, 121.2, 119.3, 118.6, 118.4, 117.2, 39.9,
31.5, 20.0, 17.9, 13.4. HRMS calcd for C21H16F7N3-
O4Na ([M＋Na]＋) 516.1492, found 516.1495.
CDCl3) δ: 8.56 (s, 1H, Ar-NH), 8.36 (d, 3JHH＝8.72 Hz,
3
1H, Ar-H), 8.29 (d, JHH＝8.20 Hz, 1H, Ar-H), 8.10 (d,
3
3JHH＝7.70 Hz, 1H, Ar-H), 7.70 (t, JHH＝8.00 Hz, 1H,
3
Ar-H), 7.48 (d, JHH＝8.82 Hz, 1H, Ar-H), 7.44 (s, 1H,
Ar-H), 6.14 (t, 3JHH3 ＝ 5.62 Hz, 1H, NHCH2CH2-
CH(CH3)2), 3.42 (q, JHH＝6.60 Hz, 2H, NHCH2CH2-
CH(CH3)2), 2.40 (s, 3H, Ar-CH3), 1.54—1.48 (m, 1H,
3-Amino-N-isopentyl-N'-[2-methyl-4-(perfluoro-
propan-2-yl)phenyl]phthalamide (5c) Yield 81.7%,
1
white solid, m.p. 95—97 ℃; H NMR (400 MHz,
3
3
NHCH2CH2CH(CH3)2), 1.30 (q, JHH＝7.20 Hz, 2H,
DMSO-d6) δ: 9.33 (s, 1H, Ar-NH), 7.99 (dd, JHH
＝
3
4
NHCH2CH2CH(CH3)2), 0.72 (d, JHH＝6.60 Hz, 6H,
13.82, JHH＝7.3 Hz, 2H, Ar-H), 7.50 (s, 1H, Ar-H),
NHCH2CH2CH(CH3)2); 13C NMR (100 MHz, CDCl3) δ:
165.8, 164.6, 145.6, 138.0, 136.4, 134.5, 130.1, 128.0,
126.4, 124.2, 123.4, 123.2, 122.1, 121.8, 119.2, 119.0,
38.9, 37.7, 25.4, 22.0, 18.0. HRMS calcd for
C23H21F7N3O4 ([M－H]－) 536.1426, found 536.1421.
7.49 (d, JHH＝7.90 Hz, 1H, Ar-H), 7.17 (t, JHH＝7.80
3
3
Hz, 1H, NHCH2CH2CH(CH3)2), 6.83 (t, 3JHH＝7.50 Hz,
3
2H, Ar-H), 5.29 (s, 2H, Ar-NH2), 3.13 (q, JHH＝6.80
Hz, 2H, NHCH2CH2CH(CH3)2), 2.35 (s, 3H, Ar-CH3),
1.48—1.36 (m, 1H, NHCH2CH2CH(CH3)2), 1.15 (q,
3JHH＝7.00 Hz, 2H, NHCH2CH2CH(CH3)2), 0.63 (d,
3JHH ＝16.40, 6H, NHCH2CH2CH(CH3)2); 13C NMR
(100 MHz, CDCl3) δ: 168.4, 167.9, 145.7, 138.5, 135.5,
130.9, 128.0, 127.8, 124.5, 122.6, 122.4, 121.1, 119.3,
118.6, 118.4, 117.2, 38.4, 38.2, 25.5, 22.0, 17.9. HRMS
calcd for C21H16F7N3O4Na ([M＋Na]＋) 530.1649, found
530.1646.
General procedure for the synthesis of compounds
5a—5c
Synthetic route of title compounds was shown in
Scheme 2. The synthetic procedure was described be-
low.
Compounds 4 (0.50 mmol) in 200 mL methanol
were placed into a flask and stirred at 60 ℃ until dis-
solved completely and then 10% Pd/C (0.05 mmol) was
added. The mixture was intensively stirred under H2 at
60 ℃ for 1—4 h, monitored with TLC and then fil-
tered. The resulting solution was evaporated to give the
crude product. It was further purified by flash chroma-
tography on silica gel with petroleum/ethyl acetate (2∶
1, volume ratio) to afford the title compounds 5a—5c.
3-Amino-N-cyclopropyl-N'-[2-methyl-4-(perfluo-
General procedure for the synthesis of compounds
6a—6c
Synthetic route of title compounds was shown in
Scheme 2. The synthetic procedure was described be-
low.
To a solution of compound 5 (0.5 mmol) in 20 mL
20% diluted hydrochloric acid at 0 ℃, sodium nitrite
(1.00 mmol) dissolved in 5 mL of water was added
dropwise. The resulting mixture was stirred for 2 h and
0.1 g urea was added. After the mixture was intensively
stirred for 15 min, an aqueous solution of KI (0.6 mmol)
was added dropwise. The resulting mixture was then
stirred for 2 h at room temperature and monitored by
TLC. The solution was extracted with CH2Cl2 (30 mL×
3) and dried over Na2SO4. After filtration, the solvent
was evaporated to give the crude product. It was further
purified by flash chromatography on silica gel with pe-
troleum/ethyl acetate (4∶1, volume ratio) to afford the
title compounds 6a—6c.
ropropan-2-yl)phenyl]phthalamide (5a)
Yield
1
85.3%, white solid, m.p. 164—167 ℃; H NMR (300
3
MHz, CDCl3) δ: 8.31 (d, JHH＝8.50 Hz, 1H, Ar-NH),
7.54 (s, 1H, Ar-NH), 7.49 (d, 3JHH＝8.72 Hz, 1H, Ar-H),
3
7.43 (s, 1H, Ar-H), 7.24 (t, JHH＝8.00 Hz, 1H, Ar-H),
3
3
6.93 (d, JHH＝7.42 Hz, 1H, Ar-H), 6.81 (d, JHH＝8.10
Hz, 1H, Ar-H), 6.42 (s, 1H, NHCHCH2CH2), 4.66 (s,
2H, Ar-NH2), 2.74—2.86 (m, 1H, CHCH2CH2), 2.33 (s,
3H, Ar-CH3), 0.76—0.69 (m, 2H, CHCH2CH2), 0.30—
0.35 (m, 2H, CHCH2CH2); 13C NMR (100 MHz,
DMSO-d6) δ: 170.0, 168.0, 145.9, 138.3, 135.6, 131.0,
128.4, 127.8, 124.5, 122.8, 122.6, 121.3, 119.0, 118.5,
3-Iodo-N-cyclopropyl-N'-[2-methyl-4-(perfluoro-
propan-2-yl)phenyl]phthalamide (6a) Yield 22.8%,
118.0, 117.0, 23.1, 18.0, 6.4. HRMS calcd for
＋
1
C21H16F7N3O4Na ([M ＋ Na] ) 500.1179, found
white solid, m.p. 210—211 ℃; H NMR (400 MHz,
500.1174.
CDCl3) δ: 8.58 (s, 1H, Ar-NH), 8.11 (d, 3JHH＝8.42 Hz,
1H, Ar-H), 7.90 (d, 3JHH＝7.70 Hz, 1H, Ar-H), 7.65 (d,
3JHH＝7.42 Hz, 1H, Ar-H), 7.42 (s, 2H, Ar-H), 7.13 (t,
3JHH＝7.70 Hz, 1H, Ar-H), 6.63 (s, 1H, NHCHCH2-
CH2), 2.87—2.76 (m, 1H, CHCH2CH2), 2.38 (s, 3H,
Ar-CH3), 0.85—0.75 (m, 2H, CHCH2CH2), 0.66—0.56
(m, 2H, CHCH2CH2); 13C NMR (100 MHz, DMSO-d6)
δ: 166.5, 154.6, 143.4, 139.4, 135.8, 135.0, 132.4, 131.5,
128.8, 127.1, 125.3, 123.2, 121.2, 121.0, 119.0, 115.8,
31.5, 17.8, 6.2. HRMS calcd for C21H16F7N3O4Na ([M
＋Na]＋) 611.0037, found 611.0039.
3-Amino-N-butyl-N'-[2-methyl-4-(perfluoropro-
pan-2-yl)phenyl]phthalamide (5b)
white solid, m.p. 159—161 ℃; H NMR (400 MHz,
Yield 95.6%,
1
3
CDCl3) δ: 8.42 (d, JHH＝8.62 Hz, 1H, Ar-H), 7.61 (s,
1H, Ar-NH), 7.51 (d, 3JHH＝8.80 Hz, 1H, Ar-H), 7.44 (s,
3
1H, Ar-H), 7.31 (d, JHH＝7.34 Hz, 1H, Ar-H), 7.00 (d,
3JHH＝7.34 Hz, 1H, Ar-H), 6.85 (d, JHH＝7.90 Hz, 1H,
3
Ar-H), 6.27 (s, 1H, NHCH2CH2CH2CH3), 4.63 (s, 2H,
Ar-NH2), 3.33 (q, JHH＝6.50 Hz, 2H, NHCH2CH2-
CH2CH3), 2.35 (s, 3H, Ar-CH3), 1.38—1.31 (m, 2H,
3
Chin. J. Chem. 2012, XX, 1—8
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3

Yan et al.
FULL PAPER
3-Iodo-N-butyl-N'-[2-methyl-4-(perfluoropropan-
2-yl)phenyl]phthalamide (6b) Yield 76.4%, white
solid, m.p. 210—212 ℃; 1H NMR (400 MHz, CDCl3) δ:
8.49 (s, 1H, Ar-NH), 8.36 (d, 3JHH＝8.70 Hz, 1H, Ar-H),
MHz, DMSO-d6) δ: 168.8, 167.2, 166.5, 139.6, 136.1,
135.1, 133.2, 130.4, 128.9, 127.2, 126.8, 125.1, 124.0,
123.3, 121.4, 121.2, 119.0, 23.4, 22.5, 17.9, 5.6. HRMS
calcd for C21H16F7N3O4Na ([M＋Na]＋) 542.1285, found
542.1279.
3
3
7.99 (d, JHH＝7.92 Hz, 1H, Ar-H), 7.81 (d, JHH＝7.74
Hz, 1H, Ar-H), 7.46 (d, 3JHH＝8.90 Hz, 1H, Ar-H), 7.42
(s, 1H, Ar-H), 7.23 (t, 3JHH＝8.00 Hz, 1H, Ar-H), 6.02 (t,
3JHH＝5.60 Hz, 1H, NHCH2CH2CH2CH3), 3.40 (q, 3JHH
＝6.70 Hz, 2H, NHCH2CH2CH2CH3), 2.38 (s, 3H,
Ar-CH3), 1.51—1.41 (m, 2H, NHCH2CH2CH2CH3),
3-Acetamido-N-butyl-N'-[2-methyl-4-(perfluoro-
propan-2-yl)phenyl]phthalamide (7b) Yield 96.8%,
1
white solid, m.p. 190—192 ℃; H NMR (400 MHz,
CDCl3) δ: 9.00 (s, 1H, Ar-NH), 8.35 (d, 3JHH＝8.22 Hz,
3
1H, Ar-H), 8.31 (d, JHH＝8.62 Hz, 1H, Ar-H), 7.66 (s,
3
1.30—1.21 (m, 2H, NHCH2CH2CH2CH3), 0.73 (t, JHH
1H, NHCOCH3), 7.52—7.42 (m, 3H, Ar-H), 7.33 (d,
＝7.30 Hz, 3H, NHCH2CH2CH2CH3); 13C NMR (100
MHz, CDCl3) δ: 170.0, 165.2, 141.9, 140.2, 138.5,
135.2, 130.9, 129.2, 129.1, 127.9, 124.3, 122.8, 122.6,
121.5, 119.3, 93.5, 40.2, 31.1, 20.0, 18.1, 13.4. HRMS
calcd for C21H16F7N3O4Na ([M＋Na]＋) 627.0350, found
627.0357.
3JHH＝7.62 Hz, 1H, Ar-H), 6.73 (t, JHH＝6.50 Hz, 1H,
3
NHCH2CH2CH2CH3), 3.32 (q, 3JHH ＝ 6.50 Hz, 1H,
CHCH2CH2CH3), 2.32 (s, 3H, Ar-CH3), 2.18 (s, 3H,
NHCOCH3), 1.41—1.28 (m, 2H, CHCH2CH2CH3), 1.24
3
—1.15 (m, 2H, CHCH2CH2CH3), 0.71 (t, JHH＝7.30
Hz, 3H, CHCH2CH2CH3); 13C NMR (100 MHz,
DMSO-d6) δ: 168.8, 166.5, 165.9, 139.6, 136.0, 135.1,
132.5, 130.3, 128.8, 127.1, 126.7, 124.6, 124.0, 123.3,
3-Iodo-N-isopentyl-N'-[2-methyl-4-(perfluoropro-
pan-2-yl)phenyl]phthalamide (6c)
Yield 58.5%,
1
white solid, m.p. 198—200 ℃; H NMR (400 MHz,
121.2, 120.1, 119.0, 38.8, 30.9, 23.4, 19.5, 17.9, 13.4.
＋
CDCl3) δ: 8.57 (s, 1H, Ar-NH), 8.26 (d, 3JHH＝8.42 Hz,
HRMS calcd for C21H16F7N3O4Na ([M ＋ Na]
)
3
1H, Ar-H), 7.94 (d, JHH＝7.90 Hz, 1H, Ar-H), 7.72 (d,
558.1598, found 558.1598.
3
3JHH＝7.70 Hz, 1H, Ar-H), 7.43 (d, JHH＝8.84 Hz, 1H,
3-Acetamido-N-isopentyl-N'-[2-methyl-4-(perfluo-
ropropan-2-yl)phenyl]phthalamide (7c) Yield
93.4%, white solid, m.p. 195—197 ℃; H NMR (400
3
Ar-H), 7.42 (s, 1H, Ar-H), 7.17 (t, JHH＝7.80 Hz, 1H,
1
Ar-H), 6.35 (s, 1H, NHCH2CH2CH(CH3)2), 3.41 (q,
3JHH＝6.70 Hz, 2H, NHCH2CH2CH(CH3)2), 2.38 (s, 3H,
Ar-CH3), 1.56—1.46 (m, 1H, NHCH2CH2CH(CH3)2),
3
MHz, CDCl3) δ: 9.01 (s, 1H, Ar-NH), 8.37 (t, JHH
＝
8.02 Hz, 2H, Ar-H), 7.67 (s, 1H, NHCOCH3), 7.54—
3
1.33 (q, JHH＝7.10 Hz, 2H, NHCH2CH2CH(CH3)2),
7.42 (m, 3H, Ar-H), 7.35 (d, 3JHH＝7.60 Hz, 1H, Ar-H),
3
3
0.73 (d, JHH＝16.40, 6H, NHCH2CH2CH(CH3)2); 13C
6.69 (t, JHH＝5.20 Hz, 1H, NHCH2CH2CH(CH3)2),
3
NMR (100 MHz, CDCl3) δ: 170.0, 165.2, 141.9, 140.2,
3.35 (q, JHH＝6.20 Hz, 2H, NHCH2CH2CH(CH3)2),
138.5, 135.2, 130.9, 129.1, 129.0, 127.9, 124.3, 122.8,
2.34 (s, 3H, Ar-CH3), 2.19 (s, 3H, NHCOCH3), 1.53—
3
122.6, 121.4, 119.3, 93.5, 38.7, 38.0, 25.5, 22.0, 18.0.
1.43 (m, 1H, NHCH2CH2CH(CH3)2), 1.25 (q, JHH
＝
＋
3
HRMS calcd for C21H16F7N3O4Na ([M ＋ Na]
)
7.20 Hz, 2H, NHCH2CH2CH(CH3)2), 0.74 (d, JHH
＝
13
641.0506, found 641.0509.
6.60, 6H, NHCH2CH2CH(CH3)2); C NMR (100 MHz,
CDCl3) δ: 169.1, 167.4, 167.3, 138.3, 135.9, 134.9,
130.6, 128.7, 127.9, 125.1, 124.8, 124.4, 123.4, 123.1,
General procedure for the synthesis of compounds
7a—7c
122.9, 121.7, 119.3, 38.6, 38.0, 25.6, 24.6, 22.1, 17.9.
＋
Synthetic route of title compounds was shown in
Scheme 2. The synthetic procedure was described be-
low.
Compound 5 (0.50 mmol) in 10 mL acetic anhydride
was stirred at room temperature for 10 min. The reaction
mixture was filtered and the residue was dissolved in
ethyl acetate. The solution was sequentially washed with
saturated sodium bicarbonate solution, brine and dried
over Na2SO4. After filtration, the solvent was evapo-
rated to give the products 7a—7c.
HRMS calcd for C21H16F7N3O4Na ([M ＋ Na]
)
572.1755, found 572.1755.
General procedure for the synthesis of compounds
7d and 7e
Synthetic route of title compounds was shown in
Scheme 2. The synthetic procedure was described be-
low.
Compound 5 (0.50 mmol) and 15 mL tetrahydro-
furan were placed into a flask and stirred at －78 ℃
and then trifluoroacetic anhydride (0.6 mmol) was
added dropwise. The temperature of the reaction mix-
ture was warmed to room temperature within 4 h and the
mixture was then stirred for another 4 h, monitored by
TLC. The reaction mixture was poured into the water
and filtered. The residue was dissolved in ethyl acetate.
The solution was sequentially washed with saturated
sodium bicarbonate solution, brine and dried over
Na2SO4. After filtration, the solvent was evaporated to
give the products 7d and 7e.
3-Acetamido-N-cyclopropyl-N'-[2-methyl-4-(per-
fluoropropan-2-yl)phenyl]phthalamide (7a) Yield
1
95.6%, white solid, m.p. 204—206 ℃; H NMR (400
3
MHz, CDCl3) δ: 9.07 (s, 1H, Ar-NH), 8.36 (d, JHH
＝
8.20 Hz, 1H, Ar-H), 8.26 (d, 3JHH＝8.92 Hz, 1H, Ar-H),
7.59 (s, 1H, NHCOCH3), 7.50 (d, JHH＝7.42 Hz, 1H,
3
3
Ar-H), 7.46 (d, JHH＝10.80 Hz, 2H, Ar-H), 7.31 (d,
3JHH＝7.5 Hz, 1H, Ar-H), 6.78 (s, 1H, NHCHCH2CH2),
2.87—2.78 (m, 1H, CHCH2CH2), 2.33 (s, 3H, Ar-CH3),
2.19 (s, 3H, NHCOCH3), 0.79—0.72 (m, 2H, CHCH2-
13
CH2), 0.45—0.37 (m, 2H, CHCH2CH2); C NMR (100
3-Trifluoroacetamido-N-butyl-N'-[2-methyl-4-
4
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Chin. J. Chem. 2012, XX, 1—8

Synthesis and Insecticidal Activities of Novel Phthalic Acid Diamides
(perfluoropropan-2-yl)phenyl]phthalamide
(7d)
Percentage mortalities were evaluated 2 d after treat-
ment. Each treatment was replicated three times.
1
Yield 67.1%, white solid, m.p. 200—202 ℃; H NMR
(400 MHz, CDCl3) δ: 10.74 (s, 1H, NHCOCF3), 8.52 (d,
3
3JHH＝8.30 Hz, 1H, Ar-H), 8.31 (d, JHH＝8.52 Hz, 1H,
Larvicidal activity against beet armyworms
3
3
The larvicidal activities of compounds 4a—6a, 6b
and chlorantraniliprole were tested by the artificial
feeddip method.[21] At first, a solution of each test sam-
ple in DMSO (AR, purchased from AlfaAesar) at a
concentration of 200 mg/L was prepared and then di-
luted to the required concentration with water (distilled).
2 g feed was placed individually into beakers and then
was sprayed with the test solution. The resulting feed
was infested with ten third-instar beet armyworms lar-
vae. Percentage mortalities were evaluated 2 d after
treatment. Each treatment was performed three times.
Ar-H), 7.61 (t, JHH＝8.00 Hz, 1H, Ar-H), 7.52 (d, JHH
＝11.20 Hz, 1H, Ar-H), 7.50 (s, 1H, Ar-NH), 7.47—
7.40 (m, 2H, Ar-H), 6.92 (t, 3JHH ＝4.84 Hz, 1H,
NHCH2CH2CH2CH3), 3.36 (q, 3JHH ＝ 6.80 Hz, 1H,
CHCH2CH2CH3), 2.32 (s, 3H, Ar-CH3), 1.41—1.31 (m,
2H, CHCH2CH2CH3), 1.24—1.14 (m, 2H, CHCH2-
3
CH2CH3), 0.71 (t, JHH＝7.30 Hz, 3H, CHCH2CH2-
CH3); 13C NMR (100 MHz, DMSO-d6) δ: 166.2, 165.1,
155.3, 139.5, 136.7, 133.0, 132.1, 131.8, 129.5, 128.4,
127.1, 126.9, 125.0, 123.2, 121.4, 121.2, 119.0, 114.4,
38.8, 30.8, 19.5, 17.9, 13.3. HRMS calcd for C21H16F7-
N3O4Na ([M＋Na]＋) 612.1315, found 612.1319.
Larvicidal activity against diamondback moths
3-Trifluoroacetamido-N-isopentyl-N'-[2-methyl-
4-(perfluoropropan-2-yl)phenyl]phthalamide (7e)
The larvicidal activity of compounds 4a and the con-
trol chlorantraniliprole was tested by the leafdip method.
At first, a solution of each test sample in DMF (AR,
purchased from AlfaAesar) at a concentration of 200
mg/L was prepared and then diluted to the required con-
centration with water (distilled). Leaf disks (6 cm×2
cm) were cut from fresh cabbage leaves and then were
sprayed with the test solution for 3 s and allowed to dry.
The resulting leaf disks were placed individually into
glass tubes. Each disk was infested with seven second-
instar diamondback moth larvae. Percentage mortalities
were evaluated 2 d after treatment. Each treatment was
performed three times.
1
Yield 58.4%, white solid, m.p. 177—179 ℃; H NMR
(400 MHz, CDCl3) δ: 10.73 (s, 1H, NHCOCF3), 8.51 (d,
3
3JHH＝8.02 Hz, 1H, Ar-H), 8.32 (d, JHH＝7.64 Hz, 1H,
3
Ar-H), 7.60 (t, JHH＝5.84 Hz, 1H, Ar-H), 7.51 (s, 2H,
Ar-H), 7.46 (s, 1H, Ar-NH), 7.43 (d, 3JHH＝6.82 Hz, 1H,
Ar-H), 6.87 (s, 1H, NHCH2CH2CH(CH3)2), 3.37 (q,
3JHH＝5.30 Hz, 2H, NHCH2CH2CH(CH3)2), 2.32 (s, 3H
Ar-CH3), 1.50—1.37 (m, 1H, NHCH2CH2CH(CH3)2),
3
1.24 (q, JHH＝5.70 Hz, 2H, NHCH2CH2CH(CH3)2),
3
0.72 (d, JHH＝4.12, 6H, NHCH2CH2CH(CH3)2); 13C
NMR (100 MHz, DMSO-d6) δ: 166.2, 165.1, 155.3,
139.5, 136.7, 133.0, 132.6, 132.2, 129.5, 128.4, 127.2,
126.6, 124.7, 123.3, 121.3, 121.1, 117.3, 114.4, 37.5,
37.2, 24.7, 22.0, 17.9. HRMS calcd for C21H16F7N3O4-
Na ([M＋Na]＋) 626.1472, found 626.1469.
Isolation of neural cells
Spodoptera exigua were initially obtained from
shallot fields in Tianjin City, China and reared indoors
in climatic chambers on an agar-based semisynthetic
diet at (27±1) ℃, (75±5)% relative humidity, and a
LD 16∶8 h photocycle.[22] The insects were reared for
two generations prior to the experiment. Third instar
larvae of S. exigua were first anaesthetized with 70%
ethanol and their thoracic and abdomen ganglia were
removed and placed in saline. The thoracic and abdo-
men ganglia were transferred to a solution containing
0.3% trypsin for 6 min at 28 ℃, plated into a 35 mm
culture dish containing 1 mL of improved L-15 Leibo-
vitz culture medium supplemented with fetal calf serum
(15%, V∶V)[23] and then mechanically dissociated by
repeated trituration using a fire-polished Pasteur pipette.
The cultures were maintained at 27 ℃ for 2 h to allow
the cell to adhere to the dish. All procedures were car-
ried out under sterile conditions.
Biological assay
Insecticidal activities against oriental armyworms,
beet armyworms and diamondback moths were per-
formed on test organisms reared in a greenhouse. The
bioassay was replicated at 25 ℃ according to statistical
requirements. Assessments were made on a dead/alive
basis, and mortality rates were corrected applying Ab-
bott’s formula.[19] Evaluation was based on a percentage
scale of 0—100, where 0 equals no activity and 100
equals total kill. Error of the experiments was 5%. For
comparative purposes, chlorantraniliprole was tested as
control under the same conditions. The insecticidal ac-
tivity is summarized in Tables 1, 2 and 3.
Larvicidal activity against oriental armyworms
The insecticidal activities of compounds 4a—4c, 5a
—5c, 6a—6c, 7a—7e and chlorantraniliprole were
evaluated using the reported procedure.[20] The insecti-
cidal activity against oriental armyworms was tested by
foliar application; individual corn (Tangyu 10, Zeamays
L.) leaves were placed on moistened pieces of filter pa-
per in Petri dishes. The leaves were then sprayed with
the test solution and allowed to dry. The dishes were
infested with 10 fourth-instar oriental armyworm larvae.
Calcium imaging
Calibration of the fluorescence signal was achieved
by using the method of Takahashi et al.[24] with some
modifications. The attached neurones were rinsed in
－
1
standard physiological saline [(mmol•L ): 150 NaCl, 4
KCl, 2 MgCl2, 2 CaCl2, 10 HEPES, buffered to pH 6.9]
and then incubated in the dark for 45 min at 28 ℃ in
Chin. J. Chem. 2012, XX, 1—8
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Yan et al.
FULL PAPER
standard external saline containing the dye fluo-3-AM
halogen substituents. For example, the trend of bioactiv-
ity is 4a＞6a＞5a. Also, when the substituents of the
3-substituted position were acetyl or trifluoroacetyl
groups, their activities were comparably low, which in-
dicated that the larger substituents in the 3-substituted
position were negative on the activity. The cyclopro-
panamine, n-butylamine, isopentylamine were intro-
duced to examine their different effects on the activity.
It was observed that the cyclopropanamine showed the
best activity.
－
1
(Sigma, 10 µmol•L ) or incubated in the dark for 5 h at
－
1
28 ℃ in external saline [(mmol•L ): 150 NaCl, 4 KCl,
2 MgCl2, 2 EGTA, 10 HEPES, buffered to pH 6.9] con-
－
1
taining the dye fluo-5N (Invitrogen, 5 µmol•L ). After
dye loading cells were again rinsed in physiological sa-
line twice. For full depletion of thapsigargin-sensitive
stores, cells were incubated with 1 µmol•L－ thapsigar-
1
gin for 10 min. Calcium ratio imaging studies were
conducted using the imaging system coupled to an in-
verted fluorescence microacope with a Fluor 40× oil
immersion objective (Olympus IX71). Cells were ex-
cited at 488 nm and the 530 nm fluorescence emission
acquired using a CCD (Image Pro-6.0) data analysis.
Each experiment was repeated at least six times. The
data were analysed using Spss Inc, version 17.0 and
Microcal Origin, version 8.0 (Origin Lab Corp.,
Northampton, MA). Results were expressed as mean±
SD (n＝number of cells). Statistical significance was
determined by using Student’s paired or unpaired t-tests.
Fluorescence values were expressed as F/F0, F0 being
the resting (or baseline) fluorescence, and F the change
in fluorescence from baseline after the drug application.
Table 1 Insecticidal activities of title compounds against orien-
tal armyworms
O
R1
O
R
R2
NH
O
O
NH
NH
R
NH
NH
O
C3F7
C3F7
Larvicidal activity/%
200 mg/L 100 mg/L 50 mg/L
Comp. R
R1 R2
100c
Results and Discussion
4a
cyclopropyl NO2
100
100
b
b
4b
4c
n-butyl
i-amyl
NO2
NO2
80
40
—
—
Synthesis
b
b
—
—
The synthetic procedures of the title compounds
were shown in Scheme 2. The intermediates 2 and 3
were synthesized referring to a reported methods.[13,17]
Compound 3 reacted with the aliphatic amides to give
compounds (4a—4c) regioselectively, which was result
of the electron-withdrawing effect of the nitro-group.
However, the syntheses of compounds 4 and 5 were
significantly influenced by the structures of the aliphatic
amides. The reactions would not be progressed when the
aliphatic amide is tert-butylamine. Finally, the com-
pounds (7a—7c) were successfully obtained at room
temperature in high yields, but the compounds (7d, 7e)
were obtained at －78 ℃ in moderate yields. The dif-
ferent reaction conditions and yields suggested that the
electron withdrawing effect of anhydride significantly
influenced the reactions.
b
5a
cyclopropyl NH2
100
40
—
b
b
5b
5c
n-butyl
i-amyl
NH2
NH2
80
—
—
b
b
60
—
—
6a
cyclopropyl I
100
100
100
80
60
6b
6c
n-butyl
i-amyl
I
I
100
b
b
10
—
—
b
7a
cyclopropyl
n-butyl
i-amyl
CH3CO 100
CH3CO 40
CH3CO 20
CF3CO 40
CF3CO 50
100
60
—
b
b
7b
7c
—
—
b
b
—
—
b
b
7d
n-butyl
i-amyl
—
—
b
b
7e
controla
—
—
100c
100
a Chlorantraniliprole. b Not tested. c 10 mg/L.
1
The synthetic compounds were confirmed by H
NMR and HRMS. All spectral and analytical data were
consistent with the assigned structures.
Larvicidal activities against beet armyworms
The insecticidal activities of compounds 4a—6a and
6b against beet armyworms were shown in Table 2.
Most of them had higher activity against beet army-
worms than against oriental armyworms. Meanwhile,
the activity of 4a was 40% at 2.5 mg/mL, higher than
that of the other listed compounds, which indicated that
the compound 4a was also the most sensitive compound
against beet armyworms.
Larvicidal activities against oriental armyworm
The larvicidal activity against oriental armyworms
was summarized in Table 1. In general, most of the
compounds showed moderate potency against oriental
armyworms at 200 mg/L. Compound 4a exhibited the
best activity (100% mortality at 10 mg/L). In order to
study different substituents in the 3-substituted position
of the phthalic acid moiety (Scheme 1, D) on the activ-
ity, five kinds of substituents were introduced. When R
were fixed as one aliphatic group, the nitro-substituent
showed comparably higher activity than amino and
Larvicidal activities against diamondback moths
The insecticidal activity and LC50 values of com-
pound 4a against diamondback moth were listed in Ta-
ble 3. The activity of 4a was 86% at 0.05 mg/L and
6
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—8

Synthesis and Insecticidal Activities of Novel Phthalic Acid Diamides
Table 2 Insecticidal activities of title compounds against beet
armyworms
It indicated that compounds 4a and 5a could activate the
calcium release channel in the endoplasmic reticulum
(ER) membrane. Figure 1 also indicated that the re-
corded [Ca2＋]i treated with 4a was in a concentra-
tion-dependent manner and the activities had a good
positive correlation with the F/F0.
Larvicidal activity (%) at a concentration of (mg/L)
Comp.
200
100
100
100
100
100
100
100
100
100
100
50
25
10
5
2.5
100
100
100
100
100
100
100
100
100
100
100
90
100
70
40
90
100
40
4a
5a
6a
6b
There were two kinds of calcium release channels in
10
＋
the ER membrane, namely RyR and IP3R Ca2
channels.[25] After dye loading with fluo-5N, primary
cultured neurones incubated with 1 µmol•L－1 thapsigar-
gin 10 min were pretreated with heparin (10 mg/mL, a
60
20
100
100
30
controla 100
100
competitive antagonist of IP3) to test which pathway
a Chlorantraniliprole.
＋
was involved in elevation of [Ca2 ]i. When external
＋
Ca2 was free, blockade of IP3 receptors with heparin
Table 3 Insecticidal activities (%) and LC50 values of title
compound 4a against diamondback moths
and depletion of intracellular calcium store with thapsi-
gargin, compound 4a 100 mg/L and 200 mg/L induced
＋
[Ca2 ]i decrease to (81.25±4.26)% and (89.34±5.76)%,
Larvicidal activity
LC50
LC50
Comp.
b
1b
0.1b 0.05b y＝a＋bx
R
respectively. These data proved that compound 4a
＋
stimulated [Ca2 ]i via RyR pathway in the central neu-
100
Controla 100
86
100 71
a Chlorantraniliprole. b in mg/L.
86
y＝8.05＋1.61x 0.0127 0.9913
y＝8.77＋2.34x 0.0246 0.9924
4a
rones of S. exigua third larvae.
the LC50 value was 0.0127 mg/L, higher than that of
chlorantraniliprole (71% at 0.05 mg/L and LC50 value
was 0.0246 mg/L). It was indicated that the title com-
pound 4a was more sensitive against diamondback
moths than the chlorantraniliprole.
The effects of 4a, 5a and 7b on intracellular calcium
of neurons from the Spodoptera exigua
＋
Figure 1 illustrated the change of [Ca2 ]i vs. re-
cording time when the neurons were treated with 4a, 5a
＋
and 7b. The peak values of [Ca2 ]i were (131.163±
Figure 2 Effect of treatments with different concentrations of
＋
＋
4a on intracellular Ca2 at different time when extracellular Ca2
3.48)%, (114.049±4.37)%, (105.883±4.81)% and
(96.6±5.69)% of the initial value by the end of 10 min
recording when the cells were treated with 200 mg/L 4a,
100 mg/L 4a, 100 mg/L 5a and 100 mg/L 7b respec-
was in absence (EGTA replace Ca2＋). Panel indicated that intra-
＋
cellular Ca2 decreased by 100 mg/L and 200 mg/L of 4a. It
means the ryanodine receptor would be the action target of 4a.
tively. Compared with the control [(99.91±2.56)%],
＋
compounds 4a and 5a induced [Ca2 ]i increase without
＋
Conclusions
extracellular Ca2 (n＝6) and compound 7c at 100 mg/L
In conclusion, four novel series of phthalic acid dia-
mides (14 compounds) were synthesized, and their
structures were characterized and confirmed by 1H
NMR and HRMS. The biological activities of new
compounds were evaluated. The results indicated that
some compounds especially compound 4a exhibited
favorable larvicidal activities against oriental army-
worms and beet armyworms. Meanwhile, the LC50 value
of compound 4a against diamondback moth was lower
than the control indicating that the title compound 4a
was more efficient against diamondback moths than the
control. The effects of some title compounds on intra-
cellular calcium of neurons from the Spodoptera exigua
proved that the title compounds were the activators of
the RyR. Also, the experiment of intracellular calcium
of neurons provided us a new rapid detection method of
the target compound activities.
has no effect on intracellular calcium concentration.
Figure 1 Effect of different concentrations of 4a, 5a and 7b on
＋
[Ca2 ]i in the central neurones of S. exigua when extracellular
calcium was in absence.
Chin. J. Chem. 2012, XX, 1—8
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
7

Yan et al.
FULL PAPER
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Acknowledgement
This work was supported by the National Natural
Science Foundation of China (No. 20872069), National
Basic Research Program of China (No. 2010CB126106),
the National Key Technologies R&D Program (No.
2011BAE06B05) and Tianjin Natural Science Founda-
tion (No. 11JCYBJC08600)
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