Synthesis and Insecticidal Activity of New Quinoline Derivatives Containing Perfluoropropanyl Moiety

Article abstract of DOI:10.1002/jhet.3502

A series of new quinoline derivatives containing perfluoropropanyl moiety were designed and synthesized. Their structures were confirmed by ¹H-NMR, MS, and elemental analysis. The bioassay results showed that compound 4e exhibited good insecticidal activity against Plutella xylostella and Mythimna separata at 100?mg/L.

Full text of DOI:10.1002/jhet.3502

Month 2019
Synthesis and Insecticidal Activity of New Quinoline Derivatives
Containing Perfluoropropanyl Moiety
a,b
a,b
b
a
a
a
b
Long Cheng, Peng-Peng Cai, Rui-Rui Zhang, Liang Han, Cheng-Xia Tan, Jian-Quan Weng, Tian-Ming Xu, and
a
Xing-Hai Liu *
a
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China
b
Zhejiang Base of National Southern Pesticide Research Centre, Zhejiang Research Institute of Chemical Industry,
Hangzhou 310023, China
*E-mail: xhliu@zjut.edu.cn
Received August 6, 2018
DOI 10.1002/jhet.3502
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A series of new quinoline derivatives containing perfluoropropanyl moiety were designed and synthe-
1
sized. Their structures were confirmed by H-NMR, MS, and elemental analysis. The bioassay results
showed that compound 4e exhibited good insecticidal activity against Plutella xylostella and Mythimna
separata at 100 mg/L.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
but compound 4e exhibited good insecticidal activity
against Plutella xylostella and Mythimna separata at
100 mg/L. Even at 20 mg/L, the compound 4e still
exhibited moderate insecticidal activity against
P. xylostella and M. separata. These compounds and
their insecticidal activity had been published as patents
[36] by us.
Quinoline heterocycle is an important natural product
skeleton, which can be found in many plants. For
instance, the famous anti-malaria drug quinine is exacted
from the congeneric plants firstly. Neither natural
quinoline derivatives nor synthetic quinoline derivatives
always displayed diversity activities, such as antioxidant
activity [1], antitubercular agents [2], trypanocidal
activities [3], anticancer [4], antibacterial activity [5],
aromatase inhibitors [6], and multi-trypanosomatid
activity [7]. So the synthesis of novel quinoline
derivatives has been attracted by many organic chemists.
The tebufloquin is a novel quinoline compound with
outstanding control effect against Pyricularia oryae,
which is discovered by Meiji Seika Kaisha, Inc. [8].
RESULTS AND DISCUSSION
The synthetic route was shown in Scheme 2. Generally,
2-methyl-4-(perfluoropropan-2-yl)aniline was prepared
from 2-methyl aniline and 1,1,1,2,3,3,3-heptafluoro-2-
iodopropane reagent as starting materials according to our
previous work [9–13]. The mechanism [37] of the key
In our previous work [9–13], we found that the
perfluoropropanyl group on the quinoline ring can
increase the fungicidal activity, so in line with our
continued efforts to synthesize novel lead compounds for
drug discover [14–35], the fungicide tebufloquin was
selected as a lead compound, the t-Bu group was
replaced by perfluoropropanyl group, the methyl group
was replaced by chlorine atom, the fluorine atom was
replaced by methyl group, and the ether group was
replaced by ester carbonate. Our original strategy is
depicted in Scheme 1. Surprisingly, the title compounds
possessed no in vivo fungicidal activity against P. oryae,
intermediate
2-methyl-4-(perfluoropropan-2-yl)aniline
was shown in Scheme 3. For the synthesis of quinolone
structure, it is reported lots of methods, such as Camps
method [38], Skraup method [39], cyclized method [40],
Combes method [41], Niementowsld method [42],
Friedlander method [43], microwave method [44],
Pfitzinger method [45], and one pot method [46]. Among
them, Combes method was selected, which cyclized from
the starting material 2-methyl-4-(perfluoropropan-2-yl)
aniline and ethyl 3-oxobutanoate in the oxydibenzene
solution. In our previous work, the quinoline compounds
were synthesized under acid condition. For the target
©
2019 Wiley Periodicals, Inc.

L. Cheng, P.-P. Cai, R.-R. Zhang, L. Han, C.-X. Tan, J.-Q. Weng, T.-M. Xu, and X.-H. Liu
Vol 000
Scheme 1. The design strategy of title compounds. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 2. The synthetic route of title compounds. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 3. The mechanism of synthesis intermediate 1.
derivatives, the yield is low when tetrahydrofuran was used
The in vivo fungicidal activity against P. oryae was
determined. Unfortunately, all of target compounds
possessed no activity against P. oryae at 200 mg/L.
Surprisingly, compound 4e exhibited good insecticidal
activity and result was shown in Table 1. These
compounds displayed 100% inhibitory against
Lepidoptera pests at 500 and 100 mg/L, but they
exhibited no activity against Aphis craccivora Koch and
as solvent and Et N used as base. At last, these compounds
3
were synthesized in acetone under K CO3 as base
2
condition, the yield is high and purification is easy. All
the target compounds were characterized and identified
1
by H-NMR, MS, and ESI-HRMS. The title compounds
+
exhibited the M + H peak in the ESI-MS and ESI-
HRMS results.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Quinolines with Insecticidal Activity
Table 1
The insecticidal activity of some compounds (%, inhibitory).
Concentration
mg/L
Aphis craccivora
Tetranychus
cinnabarinus
Plutella
xylostella
Mythimna
separata
No.
Structure
Koch
4e
500
0
0
0
0
0
0
100
100
30
100
100
60
1
00
2
0
Tetranychus cinnabarinus. For the P. xylostella and
M. separata, the compound 4e exhibited 30% and 60%
inhibitory at 20 mg/L, respectively.
to afford the red brown oil (328.02 g, yield 71%) without
further purification.
Synthesis of 2,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-
4
-ol 2. In a 500 mL of three neck bottom, the 2-methyl-
4
3
-(perfluoropropan-2-yl) aniline (20 g, 0.073 mol), ethyl
-oxobutanoate (9.49 g, 0.073 mol), and oxydibenzene
CONCLUSION
(100 mL) were stirred at 240°C for 2 h. Then, the
mixture was cooled to 70°C; the petroleum ether was
added into the mixture; lots of solid were given, filtered,
To explore higher active compounds with antifungal
activity and insecticidal activity, some new 6-
perfluoropropanyl quinoline derivatives were designed
and synthesized. Only compound 4e possessed good
insecticidal activity against P. xylostella and M. separata.
The structure can be recognized as new lead insecticidal
compounds with further structure modification.
and dried (yield 91.8%). White solid, m.p. 321–323°C,
1
H-NMR (400 MHz, CDCl ) δ: 10.70 (s, 1H, Py-OH),
3
8
.20 (s, 1H, Ph-H), 6.07 (s, 1H, Py-H), 2.62 (s, 3H,
pyridyl-CH ), 2.43 (s, 3H, Ph-CH ); ESI-MS: 341
3
3
+
[
M + H] .
Synthesis of 3-chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)
quinolin-4-ol 3. In a 250 mL of three neck bottom, the
2
,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-4-ol (15 g,
EXPERIMENT
0
.044 mol), N-chlorosuccinimide (6.38 g, 0.048 mol),
and dimethylformamide (50 mL) were stirred at room
temperature. TLC monitored, after the reaction is
completed, the mixture was poured into water; lots of
Instrument. Melting points were measured on a Taike
X-4 apparatus and uncorrected. H-NMR data were
1
determined by Bruker AV-400 instrument. ESI-MS data
were determined by LCQ-Advantage Thermofinngen
instrument. The elemental analysis data were measured
by a Perkin-Elmer 240C elemental analyzer. All the thin-
layer chromatography (TLC) or chemical reagents are
purchased (analytical grade).
solid was given, filtered, and dried (yield 90.5%). White
1
solid, m.p. 281–283°C, H-NMR (400 MHz, CDCl ) δ:
3
1
0.84 (s, 1H, Py-OH), 8.27 (s, 1H, Ph-H), 7.77 (s, 1H,
Py-H), 2.90 (s, 3H, pyridyl-CH ), 2.74 (s, 3H, Ph-CH );
3
3
+
ESI-MS: 375 [M + H] .
Synthesis of target compounds 4a–4o. To a solution of 3-
chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-4-ol
General
procedure. Synthesis
of
2-methyl-4-
(
perfluoropropan-2-yl)aniline 1.
To a solution of o-
methylaniline (180 g, 1.68 mol) in MeOBu-t solution
800 mL) and H O (800 mL), the mixture of
(
0.525 g, 1.4 mmol) and K CO (0.19 g, 1.4 mmol) in
2 3
acetone (50 mL), the substituted benzyl carbonochloridate
(1.4 mmol) was dropwised. TLC monitored, after the
reaction is completed, the mixture was filtered and
evaporated. The target compound was purified by
chromatography on a silica gel using petroleum ether and
ethyl acetate (V(EA):V(PE) = 1:8) as the eluent to afford the
compounds 4a–4o.
(
2
Bu NH HSO (50.5 g, 1.68 mol), Na CO (125.16 g,
4
4
4
2
3
1
.68 mol), and hydrosulfite (259.42 g, 1.68 mol) was
added dropwisely at 25°C. Then, the (CF ) CFI
3
2
(
497.28 g, 1.68 mol) was dropwised slowly at 0°C. TLC
monitored, after the reaction is completed, subsequently,
the reaction mixture was diluted with H O (200 mL), and
2
the organic layer was separated. Then, the residue
solution was extracted three times with ethyl acetate
3-Chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-
4-yl (trichloromethyl) carbonate 4a.
133~134°C, yield 33.1%, H-NMR (400 MHz, CDCl ) δ:
White solid, m.p.
1
(200 mL). The combined organic phases were washed
3
with brine, dried over magnesium sulfate and evaporated
8.33 (s, 1H, Ph-H), 7.74 (s, 1H, Ph-H), 2.91 (s, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L. Cheng, P.-P. Cai, R.-R. Zhang, L. Han, C.-X. Tan, J.-Q. Weng, T.-M. Xu, and X.-H. Liu
Vol 000
pyridyl-CH ), 2.86 (s, 3H, Ph-CH ); ESI-MS: 535
3
3
3-Chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-
+
[
M + H] ; Elemental anal. calculated for C H Cl F NO
3
4-yl isobutyrate 4g.
23.5%, H-NMR (400 MHz, CDCl ) δ: 7.87 (s, 1H, Ph-H),
White solid, m.p. 104~105°C, yield
1
6
8
4
7
1
(
1
%): C, 35.78; H, 1.50; N, 2.61; found: C, 35.49; H,
.24; N, 2.44.
3
7
.70 (s, 1H, Ph-H), 2.91~3.12 (m, 1H, -CH (CH ) ), 2.88
3 2
(
s, 3H, pyridyl-CH ), 2.84 (s, 3H, Ph-CH ), 1.48 (d, 6H,
3 3
Butyl
(3-chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)
White solid, m.p.
4~35°C, yield 32.2%, H-NMR (400 MHz, CDCl ) δ: 7.99
+
J = 7.2 Hz, -CH (CH ) ); ESI-MS: 446 [M + H] ;
Elemental anal. calculated for C H ClF NO (%): C,
4
3
2
quinolin-4-yl) carbonate 4b.
3
18
15
7
2
1
3
8.50; H, 3.39; N, 3.14; found: C, 48.67; H, 3.65; N, 3.23.
(s, 1H, Ph-H), 7.70 (s, 1H, Ph-H), 4.39 (t, 2H, J = 6.4 Hz, -
OCH CH CH CH ), 2.88 (s, 3H, pyridyl-CH ), 2.83 (s, 3H,
3-Chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-
4-yl pivalate 4h. White solid, m.p. 108~109°C, yield
40.9%, H-NMR (400 MHz, CDCl ) δ: 7.88 (s, 1H, Ph-
2
2
2
3
3
Ph-CH3), 1.70~1.81 (m, 2H, -OCH CH CH CH ),
2
2
2
3
1
1
.39~1.50 (m, 2H, -OCH CH CH CH ), 0.99 (t, 3H,
2 2 2 3
3
J
=
7.6 Hz, -OCH CH CH CH ); ESI-MS: 476
H), 7.72 (s, 1H, Ph-H), 2.89 (s, 3H, pyridyl-CH ), 2.86
2
2
2
3
3
+
[M + H] ; Elemental anal. calculated for C H ClF NO
(s, 3H, Ph-CH ), 1.54 (s, 9H, À(CH ) ); ESI-MS: 460
20
19
7
3
3
3 3
+
(%): C, 47.96; H, 3.60; N, 2.94; found: C, 48.06; H, 3.88;
[
M + H] ; Elemental anal. calculated for C H ClF NO
19 17 7 2
N, 3.09.
(%): C, 49.63; H, 3.73; N, 3.05; found: C, 49.76; H,
.87; N, 3.04.
3
3
4
-Chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-
-yl propyl carbonate 4c. White solid, m.p. 25~26°C,
3-Chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-
4-yl acetate 4i. White solid, m.p. 96~97°C, yield
1
yield 67.3%, H-NMR (400 MHz, CDCl ) δ: 7.99 (s, 1H,
Ph-H), 7.70 (s, 1H, Ph-H), 4.35 (t, 2H, J = 6.8 Hz, -
3
1
34.6%, H-NMR (400 MHz, CDCl ) δ: 7.87 (s, 1H, Ph-
3
OCH CH CH CH ), 2.88 (s, 3H, pyridyl-CH ), 2.83 (s,
H), 7.67 (s, 1H, Ph-H), 2.86 (s, 3H, pyridyl-CH ), 2.82
2
2
2
3
3
3
3
1
4
H, Ph-CH ), 1.74~1.89 (m, 2H, -OCH CH CH CH ),
(s, 3H, Ph-CH ), 2.54 (s, 3H, -COCH ); ESI-MS: 418
[M + H] ; Elemental anal. calculated for C H ClF NO
16 11 7 2
(%): C, 46.01; H, 2.65; N, 3.35; found: C, 46.07; H,
2.87; N, 3.43.
3
2
2
2
3
3
3
+
.04 (t, 3H, J = 7.6 Hz, -OCH CH CH CH ); ESI-MS:
2
2
2
3
+
62 [M
+
H] ; Elemental anal. calculated for
C H ClF NO (%): C, 46.82; H, 3.27; N, 3.03; found:
1
8
15
7
3
C, 46.77; H, 3.24; N, 3.07.
3
-Chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-
4-yl (2-chloroethyl) carbonate 4j. White solid, m.p.
47~48°C, yield 35.8%, H-NMR (400 MHz, CDCl ) δ:
8.01 (s, 1H, Ph-H), 7.71 (s, 1H, Ph-H), 4.63 (d, 2H,
J = 5.6 Hz, -OCH CH Cl), 3.84 (d, 2H, J = 5.6 Hz, -
OCH CH Cl), 2.88 (s, 3H, pyridyl-CH ), 2.84 (s, 3H,
Ph-CH ); ESI-MS: 482 [M + H] ; Elemental anal.
calculated for C17 NO (%): C, 42.35; H, 2.51;
N, 2.90; found: C, 42.35; H, 2.22; N, 3.01.
3
4
1
7
-Chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-
1
-yl dimethylcarbamate 4d. White solid, m.p.
3
1
20~121°C, yield 20.1%, H-NMR (400 MHz, CDCl ) δ:
3
.97 (s, 1H, Ph-H), 7.66 (s, 1H, Ph-H), 3.30 (s, 3H, -
2
2
CON (CH ) ), 3.12 (s, 3H, -CON (CH ) ), 2.86 (s, 3H,
2
2
3
3
2
3 2
+
pyridyl-CH ), 2.84 (s, 3H, Ph-CH ); ESI-MS: 447
3
3
3
+
[M
+
H] ; Elemental anal. calculated for
H12Cl
2
F
7
3
C H ClF N O (%): C, 45.70; H, 3.16; N, 6.27; found:
1
7
14
7 2 2
C, 45.98; H, 3.43; N, 6.23.
3
-Chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-4-
yl ethyl carbonate 4k. White solid, m.p. 63~64°C, yield
45.3%, H-NMR (400 MHz, CDCl ) δ: 7.98 (s, 1H, Ph-H),
7.69 (s, 1H, Ph-H), 4.43 (q, 2H, J = 7.2 Hz, -OCH CH ),
2.87 (s, 3H, pyridyl-CH ), 2.83 (s, 3H, Ph-CH ), 1.45 (t,
3H, J = 7.2 Hz, -OCH CH ); ESI-MS: 448 [M + H] ;
Elemental anal. calculated for C17 NO (%): C,
45.60; H, 2.93; N, 3.13; found: C, 45.77; H, 3.03; N, 3.25.
3
4
-Chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-
-yl phenyl carbonate 4e. White solid, m.p. 93~94°C,
1
3
1
yield 39.2%, H-NMR (400 MHz, CDCl ) δ: 7.35~8.11
2
3
3
(m, 7H, Ar-H), 2.92 (s, 3H, pyridyl-CH ), 2.86 (s, 3H,
3
3
3
+
+
Ph-CH ); ESI-MS: 496 [M + H] ; Elemental anal.
2
3
3
calculated for C H ClF NO (%): C, 50.88; H, 2.64; N,
H13ClF
7
3
21
13
7
3
2.83; found: C, 50.90; H, 2.54; N, 2.56.
3
4
7
7
-Chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-
Allyl
(3-chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)
-yl (1-chloroethyl) carbonate 4f.
5~76°C, yield 41.3%, H-NMR (400 MHz, CDCl ) δ:
White solid, m.p.
quinolin-4-yl) carbonate 4l. White solid, m.p.
49~50°C, yield 54.3%, H-NMR (400 MHz, CDCl ) δ:
7.99 (s, 1H, Ph-H), 7.70 (s, 1H, Ph-H), 4.43 (q, 2H,
J = 7.2 Hz, -OCH CH ), 2.87 (s, 3H, pyridyl-CH ), 2.83
(s, 3H, Ph-CH ), 1.45 (t, 3H, J = 7.2 Hz, -OCH CH );
ESI-MS: 460 [M + H] ; Elemental anal. calculated for
NO (%): C, 47.03; H, 2.85; N, 3.05; found:
C, 47.23; H, 3.01; N, 3.02.
1
1
3
3
.98 (s, 1H, Ph-H), 7.74 (s, 1H, Ph-H), 6.57 (q, 1H,
J = 5.6 Hz, -CHClCH ), 2.91 (s, 3H, pyridyl-CH ), 2.87
2
3
3
3
3
(s, 3H, Ph-CH ), 2.01 (d, 3H, J = 5.6 Hz, -CHClCH );
3
2
3
3
3
+
+
ESI-MS: 482 [M + H] ; Elemental anal. calculated for
C H Cl F NO (%): C, 42.35; H, 2.51; N, 2.90; found:
C, 42.34; H, 2.87; N, 2.99.
C
18
H
13ClF
1
7
12
2
7
3
7
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Quinolines with Insecticidal Activity
Insecticidal activity against Aphis craccivora.
aphids were dipped according to a slightly modified Food
Bean
Benzyl
(3-chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)
quinolin-4-yl) carbonate 4m.
White solid, m.p.
1
83~84°C, yield 67.2%, H-NMR (400 MHz, CDCl ) δ:
and Agriculture Organization (FAO) dip test. The tender
shoots of soybean with 40–60 healthy apterous adult
aphids were dipped in the diluted solutions of the
compounds for 5 s, and the superfluous fluid was
removed and placed in the conditioned room. Mortality
was calculated 48 h after treatment. Each treatment was
performed three times. The data for the mortality-
regression lines of the compounds were subjected to
probit analysis by Finney’s method.
3
7.36~7.95 (m, 7H, Ph-H), 5.38 (s, 2H, -OCH Ph), 2.87
2
(
[
(
s, 3H, pyridyl-CH ), 2.83 (s, 3H, Ph-CH ); ESI-MS: 510
M + H] ; Elemental anal. calculated for C H ClF NO
3
%): C, 51.83; H, 2.97; N, 2.75; found: C, 51.98; H,
3 3
+
2
2
15
7
3.12; N, 2.88.
3
4
7
7
1
3
-Chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-
-yl isopropyl carbonate 4n.
2~73°C, yield 77.4%, H-NMR (400 MHz, CDCl ) δ:
.98 (s, 3H, Ph-H), 7.70 (s, 3H, Ph-H), 5.02~5.11 (m,
H, -OCH (CH ) ), 2.88 (s, 3H, pyridyl-CH ), 2.83 (s,
H, Ph-CH ), 1.44 (d, 6H, J = 6.4 Hz, -OCH (CH ) );
White solid, m.p.
1
3
Acknowledgments. This work was funded by Zhejiang Provincial
Natural Science Foundation of China (LY19C140002) and
Research Fund of Department of Education of Zhejiang Province
(Y201840646).
3
2
3
3
3 2
+
ESI-MS: 462 [M + H] ; Elemental anal. calculated for
C H ClF NO (%): C, 46.82; H, 3.27; N, 3.03; found:
1
8
15
7
3
C, 46.98; H, 3.33; N, 3.05.
CONFLICT OF INTEREST
3
4
-Chloro-2,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-
-yl methyl carbonate 4o. White solid, m.p. 82~84°C,
The authors declare no competing financial interest.
1
yield 78%, H-NMR (400 MHz, CDCl ) δ: 7.99 (s, 3H,
3
Ph-H), 7.70 (s, 3H, Ph-H), 4.04 (s, 3H, -OCH ), 2.88 (s, 3H,
3
+
pyridyl-CH ), 2.83 (s, 3H, Ph-CH ); ESI-MS: 434 [M + H] ;
REFERENCES AND NOTES
3
3
Elemental anal. calculated for C H ClF NO (%): C,
16
11
7
3
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
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[
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet