Synthesis and fungicidal activities of perfluoropropan-2-yl-based novel quinoline derivatives

Article abstract of DOI:10.1515/hc-2019-0002

A series of novel perfluoropropan-2-yl-based quinoline derivatives was designed and synthesized utilizing tebufloquin as the lead compound. The structures of all the newly synthesized compounds were confirmed by spectroscopic data ¹HNMR, MS and elemental analysis. The results of bioassay indicated that these compounds exhibited potent fungicidal activities against Erysiphe graminis. Especially, compound 8c displayed excellent activity with EC₅₀ value at 1.48 mg / L, which was better than that of the commercialized fungicide-tebufloquin. The structure-activity relationship for these new compounds was also discussed.

Full text of DOI:10.1515/hc-2019-0002

Heterocycl. Commun. 2019; 25: 91–97
Research Article
Open Access
Zai Zhang, Minhua Liu, Weidong Liu, Jun Xiang, Jianming Li, Zhong Li, Xingping Liu,
Mingzhi Huang, Aiping Liu* and Xingliang Zheng*
Synthesis and fungicidal activities of
perfluoropropan-2-yl-based novel quinoline
derivatives
https://doi.org/10.1515/hc-2019-0002
the spread of human infectious diseases, increasingly
Received March 01, 2018; accepted April 26, 2018.
plays an important role in agriculture. World’s fungi-
Abstract: A series of novel perfluoropropan-2-yl-based qui- cide market is dominated by two kinds of compounds---
noline derivatives was designed and synthesized utilizing strobilurins and triazoles [1]. However, given the increased
tebufloquin as the lead compound. The structures of all the application dose and frequency of fungicide, fungi have
newly synthesized compounds were confirmed by spectro- gradually grown resistance to strobilurins and triazoles,
1
scopic data HNMR, MS and elemental analysis. The results and thus, it is imperative to develop new fungicides. Qui-
of bioassay indicated that these compounds exhibited noline derivatives are a group of nitrogen-containing hete-
potent fungicidal activities against Erysiphe graminis. Espe- rocyclic compounds, the spectra of which demonstrate
cially, compound 8c displayed excellent activity with EC5
biological activities in weeding [2], fungicidal [3], insecti-
0
value at 1.48 mg / L, which was better than that of the com- cidal [4-5], antitumor [6-7], antiviral [8-9], anti-tuberculo-
mercialized fungicide --- tebufloquin. The structure-activity sis [10-11] and antifungal [12-14]. With such an extensive
relationship for these new compounds was also discussed.
range of biological activities, quinoline derivatives have
strong existence in agriculture. For instance, tebufloquin
Keywords: perfluoropropan-2-yl-based quinoline derivatives; has been being used as a fungicide, in order to further
synthesis; fungicidal activity; structure-activity relationship improve the fungicidal activity of tebufloquin, a lot of work
has been done for the optimization of it [15-17]. Flometo-
quin in insecticides, and echinacol in herbicides. Besides
Introduction
Fungicide, with its multiple functions including pro-
tecting crops from fungicidal threats and preventing
a wide application, quinolines are also well known as
green pesticides due to their low residue and small harm
to the environment. Lastly, quinoline compounds were too
worth attention because of the special structure-activity
relationship: quinoline’s biological activities change as
the substituents on the quinoline ring and the number of
substituents vary. In order to obtain better new pesticides,
fluorine atoms and different substituents were introduced
to organic molecules of pesticides is our good idea.
*
Corresponding author: Aiping Liu, National Engineering Research
Center for Agrochemicals, Hunan Research Institute of Chemical
Industry, Changsha 410007, China; Hunan Province Key Laboratory for
Agrochemicals, Changsha 410014, China, e-mail:lapliu@yahoo.com
(
Aiping Liu) and Xingliang Zheng, School of Chemistry and Biological
In our optimization program, we used tebufloquin as
the lead compound because it has a broad spectrum of fun-
gicidal activity. We also introduced fluorine atom because
of its unique properties, such as electronic effect, infiltra-
tion effect, simulation effect and hindering effect. A series
of perfluoropropan-2-yl-based novel quinoline derivatives
were designed and synthesized through analog synthesis
and substructure theory. As shown in Figure 1, isobutyl
was substituted by perfluoropropan-2-yl and side chains
Engineering, Changsha University of Science and Technology,
Changsha 410114, e-mail: xingliangzheng@163.com (Xingliang Zheng);
Zai Zhang and Zhong Li, School of Chemistry and Biological
Engineering, Changsha University of Science and Technology,
Changsha 410114; National Engineering Research Center for
Agrochemicals, Hunan Research Institute of Chemical Industry,
Changsha 410007, China
Minhua Liu, Weidong Liu, Jun Xiang, Jianming Li, Xingping Liu
and Mingzhi Huang, National Engineering Research Center for
Agrochemicals, Hunan Research Institute of Chemical Industry,
Changsha 410007, China; Hunan Province Key Laboratory for
Agrochemicals, Changsha 410014, China
1
2
3
4
of R , R , R and R were revised until a more effective com-
bination was found. Bioassay results show that compound
Open Access. © 2019 Zai Zhang et al., published by De Gruyter.ꢀ
Attribution alone 4.0 License.
ꢀThis work is licensed under the Creative Commons
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ꢁ
Z. Zhang et al.: Magnesium porphyrazine with peripheral methyl(3,5-dibromophenylmethyl)amino groups
9
2ꢁ
8
c has higher fungicidal activity against Erysiphe graminis
The fungicidal activities against Erysiphe graminis of
target compounds are shown in Table 1. The datum indi-
cate that most of title compounds has excellent fungicidal
activity against Erysiphe graminis at 500 mg/L and some
even have high fungicidal activity under 50 mg/L. For
example, compounds 8b, 8c, 8d, 8e and 8i have ≥ 95%
fungicidal activity at 100 mg/L, and compounds 8b, 8c
and 8i still have > 90% fungicidal activity at 50 mg/L. To
further assess the activity level of title compounds, regres-
sion equations were calculated by selecting a portion of the
compounds with high fungicidal activity. Concentrations of
these compounds at their 50% maximal effect (EC ) values
than tebufloquin does.
Results and discussion
The general synthetic method of the target compound is
shown in Scheme 1. Yields have not been optimized. The
synthesis of other compounds is similar to that of the repre-
sentative compound, and all the reactions were carried out
under protective condition by using dry nitrogen or calcium
chloride tubes. HNMR, MS and elemental analysis were
used to identify and verify all synthesized target compounds.
1
50
are shown in Table 1, and activity of tebufloquin is also pre-
sented in Table 1. As exhibited in Table 1, 8b, 8c, 8d, 8e
and 8i showed a significant control effect against Erysiphe
graminis, which was superior to tebufloquin. In particular,
compound 8c has EC values of 1.48 mg/L against Erysiphe
50
graminis, which has the most prominent effect.
Although it is hard to draw exact structure-activity
relationship from these data, the compounds still follow
1
2
3
the rule that fungicidal activities vary as R , R , R and
4
R moieties of the title compound are optimized. From
1
Table 1, the following pattern is observed: When R =8-CH ,
3
2
3
1
R =CH , R =A1, fungicidal activity is the highest; When R ,
R are kept invariant, the activity of R group is A1 > A2;
3
2
3
Figure 1ꢀDesign strategy of the target compounds.
Scheme 1ꢀSynthetic pathways for the target compounds.
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Z. Zhang et al.: Magnesium porphyrazine with peripheral methyl(3,5-dibromophenylmethyl)amino groupsꢁ
ꢁ93
Table 1ꢀFungicidal activity against Erysiphe graminis, and EC50 of title compounds.
Compound
Inhibition of Erysiphe graminis (%)
00 mg/L ꢂ00 mg/L ꢃ00 mg/L 50 mg/L
Regression equation
Correlation
EC
ꢁ5% confidence
limit (mg/L)
5
0
mg/L
5
ꢂa
ꢃꢄ.ꢄꢄ
ꢃꢄ.ꢄꢄ
ꢃꢈ.ꢉꢄ
ꢇꢄꢄ.ꢄꢄ
ꢃꢃ.ꢄꢄ
ꢃꢆ.ꢄꢄ
ꢃꢈ.ꢇꢄ
ꢇꢄꢄ.ꢄꢄ
ꢅꢄ.ꢄꢄ
ꢇꢄꢄ.ꢄꢄ
-
ꢅꢄ.ꢄꢄ
ꢇꢄꢄ.ꢄꢄ
ꢃꢈ.ꢄꢄ
ꢃꢂ.ꢋꢄ
ꢃꢆ.ꢅꢄ
ꢂꢆ.ꢇꢄ
ꢃꢊ.ꢇꢄ
ꢆꢄ.ꢄꢄ
ꢃꢈ.ꢋꢄ
-
ꢆꢄ.ꢄꢄ
ꢇꢄꢄ.ꢄꢄ
ꢃꢋ.ꢆꢄ
ꢂꢊ.ꢇꢄ
ꢂꢂ.ꢃꢄ
ꢈꢄ.ꢋꢄ
ꢂꢈ.ꢂꢄ
ꢉꢄ.ꢄꢄ
ꢃꢉ.ꢋꢄ
-
-
-
-
-
ꢂb
ꢇꢄꢄ.ꢄꢄ
ꢃꢈ.ꢄꢄ
ꢇꢄꢄ.ꢄꢄ
ꢃꢈ.ꢄꢄ
ꢂꢈ.ꢄꢄ
ꢃꢈ.ꢄꢄ
ꢃꢄ.ꢄꢄ
ꢃꢄ.ꢄꢄ
ꢆꢄ.ꢄꢄ
ꢃꢈ.ꢄꢄ
ꢃꢄ.ꢄꢄ
ꢃꢈ.ꢄꢄ
Y = ꢊ.ꢃꢆꢉꢇ + ꢇ.ꢈꢂꢂꢃx
ꢄ.ꢃꢂꢄꢂ
ꢄ.ꢃꢃꢈꢊ
ꢄ.ꢃꢂꢅꢇ
ꢄ.ꢃꢆꢅꢂ
ꢄ.ꢃꢋꢈꢂ
ꢄ.ꢃꢅꢇꢆ
-
ꢋ.ꢈꢄ
ꢇ.ꢋꢂ
ꢉ.ꢈꢄ
ꢉ.ꢋꢆ
ꢆ.ꢊꢅ
ꢆ.ꢉꢈ
-
ꢊ.ꢄꢋ-ꢆ.ꢆꢈ
ꢇ.ꢇꢇ-ꢇ.ꢃꢂ
ꢇ.ꢂꢈ-ꢊ.ꢊꢆ
ꢇ.ꢂꢈ-ꢊ.ꢉꢂ
ꢋ.ꢈꢉ-ꢂ.ꢃꢃ
ꢋ.ꢊꢆ-ꢂ.ꢃꢆ
-
ꢂc
Y = ꢋ.ꢅꢉꢆꢄ + ꢇ.ꢆꢄꢋꢈx
ꢂd
Y = ꢋ.ꢊꢅꢋꢂ + ꢇ.ꢈꢅꢋꢇx
ꢂe
Y = ꢋ.ꢋꢈꢂꢅ + ꢇ.ꢊꢂꢊꢅx
ꢂf
Y = ꢊ.ꢂꢅꢉꢅ + ꢇ.ꢋꢄꢇꢄx
ꢂg
Y = ꢊ.ꢅꢆꢃꢅ + ꢇ.ꢈꢋꢈꢅx
ꢂh
-
ꢂi
Y = ꢋ.ꢉꢈꢈꢂ + ꢇ.ꢂꢄꢇꢋx
ꢄ.ꢃꢃꢇꢉ
-
ꢉ.ꢈꢂ
-
ꢇ.ꢂꢉ-ꢊ.ꢆꢃ
-
ꢃa
-
ꢃb
ꢅꢃ.ꢇꢄ
ꢃꢆ.ꢇꢄ
ꢂꢃ.ꢊꢄ
ꢅꢉ.ꢇꢄ
ꢂꢈ.ꢈꢄ
ꢅꢃ.ꢊꢄ
ꢅꢋ.ꢉꢄ
ꢅꢆ.ꢇꢄ
ꢋꢂ.ꢈꢄ
-
-
-
-
ꢃc
-
-
>ꢉꢄ
ꢈ.ꢉꢉ
-
tebufloquin
Y = ꢋ.ꢇꢅꢊꢊ + ꢇ.ꢇꢈꢉꢇx
ꢄ.ꢃꢂꢈꢆ
ꢊ.ꢂꢂ-ꢅ.ꢄꢉ
1
3
2
When R and R are kept constant, the activity of R group is gas chromatography-mass spectrometer (GC-MS) and a
2
4
CH > CH CH CH CH . In addition, to keep R =CH , R =A3, Agilent 1100 series liquid chromatography-mass spectro-
3
2
2
2
3
3
1
the influence of R moiety on improved activity is as follows: meter (LC-MS). Column chromatography was performed
-CH > 8-CH > H. Therefore, the fungicidal activities may using a 200–300 mesh silica gel. Elemental analysis data
5
3
3
be summarized as follows: 8c > 8e ≈ 8d ≈ 8i > 8g > 9c > 8a were obtained with a Vario EL III from Elementar. Uncor-
>
8h > 9a. Further research on the structure and biological rected melting points were taken in the WRS-1B digital
activity of this series of compounds is in progress.
melting points apparatus.
Synthesis of Ethyl 2-methyl-3-oxobutanoate (2a) and its
analogue (2b).
Conclusions
In order to find efficient fungicides, a series of perfluoropro- Sodium hydride (60%, 4.4g, 0.11mol) was added to a
pan-2-yl-based new quinoline derivatives were designed and solution of ethyl 3-oxobutanoate (13.0 g, 0.10mol) in tet-
synthesized. Most synthetic compounds showed good fun- rahydrofuran (150 mL). Methyl iodide (15.6 g, 0.11 mol)
gicidal activity. In particular, EC of compound 8c against was added dropwise at room temperature. The reaction
50
Erysiphe graminis was 1.48 mg/L, which was far superior mixture was stirred for 18h at the same temperature until
to tebufloquin. Based on the above results, our research the staring materials was comsumed (monitored by TLC).
proved that this series of quinolines have great potential in The reaction mixture was poured into ice water followed
fungicides development and worth further research.
by extracted with ethyl acetate. The combined organic
layer was dried with anhydrous sodium sulfate, and
solvent was evaporated under reduced pressure to afford
12.5g ( 82.3% yield, 94.7% purity) of a yellow liquid. 2b
was synthesized in a similar method.
Experimental
Materials and Methods
Synthesis of 2-Methyl-4-(perfluoropropan-2-yl)aniline
Unless otherwise noted, solvents and reagents were used
(
4b) and its analogue (4a, 4c and 4d)
1
as received from commercial suppliers. HNMR spectra
were acquired with a Varian INOVA-300 spectrometer using To the mixture of tetrabutylammonium bromide
TMS as the internal standard and CDCl as the solvent. (3.2g, 0.01mol) and methyl tert-butyl ether (90 mL) in
3
Mass spectra were obtained using a Agilent 5973-6890 water (100 mL), sodium dithionite (10.4g, 0.06mol),
Unauthenticated
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Z. Zhang et al.: Magnesium porphyrazine with peripheral methyl(3,5-dibromophenylmethyl)amino groups
9
4ꢁ
heptafluoroisopropyl iodide (35.5g, 0.12mol), o-methyla- liquid which was used directly without calculating the yield
niline (10.7 g, 0.10 mol), anhydrous sodium carbonate (12.7 and purification. 7b was synthesized in a similar method.
g, 0.12 mol) was added with stirring below 5°C. The reac-
tion mixture was stirred for 4h in ice-bath. Then sodium Synthesis of Tetrahydrofuran-3-yl (2,3,8-trimethyl-
dithionite (10.4g, 0.06mol) was added, and the reaction 6-(perfluoropropan-2-yl)quinolin-4-yl) carbonate (8c)
was stirred overninght at the same temperature until the and its analogue (8a-8b and 8d-8i)
staring materials was comsumed (monitored by TLC). The
reaction mixture was poured into ice water followed by The sodium hydride (60%, 1.6 g, 0.040 mol) was dissolved
extracted with ethyl acetate. The combined organic layer in N, N-dimethylformamide (100 mL) at room tempera-
was dried with anhydrous sodium sulfate, and solvent ture. After stirring for 20 min, compound 5d (7.1 g, 0.020
was evaporated under reduced pressure to afford 25.6g mol) was added, and compound 7a (3.3 g, 0.022 mol) was
1
(
89.1% yield, 95.6% purity) of a brown liquid. H NMR added dropwise at the same temperature. The reaction
(
CDCl ): 2.20 (s, 3H), 3.93 (bs, 2H), 6.71 (d, J=6.9 Hz, 1H), mixture was stirred for 2h at room temperature until the
3
+
7
.06 (d, J=7.2 Hz, 1H), 7.25 (s, 1H). LC-MS Pos [M+1] =276; staring materials was comsumed (monitored by TLC). The
Anal. Calcd for C H F N: C, 43.65; H, 2.93; N, 5.09; Found: reaction mixture was poured into ice water followed by
10
8 7
C, 43.60; H, 2.96; N, 5.11. 4a, 4c and 4d were synthesized extracted with ethyl acetate. The combined organic layer
in a similar method.
was dried with anhydrous sodium sulfate, and solvent was
evaporated under reduced pressure. The residue material
Synthesis of 2,3,8-Trimethyl-6-(perfluoropropan-2-yl) was purified by silica gel column chromatography using
quinolin-4-ol (ꢄd) and its analogue (ꢄa-ꢄc and ꢄe-ꢄf)
petroleum ether and ethyl acetate (25: 1 / 10: 1 by volume)
as eluent to afford compound 8c. Compounds 8a-8b and
The mixture of compound 2a (8.6 g, 0.060 mol), com- 8d-8i were synthesized by the similar approach.
pound 4b (8.2 g, 0.030 mol) and p-toluenesulfonic acid
(
6.2 g, 0.033 mol) in xylene (150 mL) was added to reaction Synthesis of 2,3,8-trimethyl-6-(perfluoropropan-2-yl)-4-
apparatus equipped with a water trap. The reaction was (prop-2-yn-1-yloxy)quinoline (9b) and its analogue
heated under reflux for 6h until the staring materials was (9a and 9c)
comsumed (monitored by TLC). The resulting mixture
was cooled to room temperature. Then the resulting The sodium hydride (60%, 1.6 g, 0.04 mol) was dissolved
mixture was poured into ice water, and the resulted solid in N, N-dimethylformamide (100 mL) at room temperature.
was formed. The solid was collected by filtration and dried After stirring for 20 min, compound 5d (7.1 g, 0.02 mol) was
to give 8.4g (76.8% yield, 92.7% purity) as a white solid. added, and 3-bromoprop-1-yne (3.5 g, 0.03 mol) was added
1
mp 198.5-199.9°C; H NMR (CDCl ): 2.15 (s, 3H), 2.53 (s, 3H), dropwise at the same temperature. The reaction mixture
3
2
.59 (s, 3H), 7.58 (s, 1H), 8.17 (s, 1H), 8.56 (s, 1H). LC-MS Pos was stirred for 2h at room temperature until the staring
+
[
3
M+1] =356; Anal. Calcd for C H F NO: C, 50.71; H, 3.40; N, materials was comsumed (monitored by TLC). The reac-
15
12 7
.94; Found: C, 50.64; H, 3.44; N, 3.97. 5a-5c and 5e-5f were tion mixture was poured into ice water followed by ext-
synthesized in a similar method.
racted with ethyl acetate. The combined organic layer was
dried with anhydrous sodium sulfate, and solvent was
evaporated under reduced pressure. The residue material
was purified by silica gel column chromatography using
petroleum ether and ethyl acetate (50: 1 / 30: 1 by volume)
Tetrahydrofuran-3-yl carbonochloridate (7a) and its
analogue (7b)
In 300ml of methylene chloride was dissolved diphosgene as eluent to afford compound 9b. Compounds 9a and 9c
117.6g, 0.60 mol) with stirring below -15°C. The mixture of were synthesized by the similar method.
pyridine (43.5g, 0.55 mol) and tetrahydrofuran-3-ol (44.0g, All the synthesized intermediates 4 and 5 were confir-
(
0
.50 mol) was added dropwise at the same temperature. med by MS. Due to the structural similarity, only interme-
The reaction mixture was stirred for 3-4h at -15°C. After the diates 4b and 5d were further characterized and confirmed
1
reaction was completed, dilute hydrochloric acid (40%, 50 by H NMR and elemental analysis respectively.
ml) was added to remove the pyridine. Then the reaction
Structures of the title compounds were supported by
mixture was poured into ice water followed by extracted spectroscopic data shown below. Due to the structural
with methylene chloride. The combined organic layer was similarity of the title compounds, only some representa-
dried with anhydrous sodium sulfate. Solvent was evapora- tive compounds 8c, 8e, 9a and 9b, were analyzed and
1
3
ted under reduced pressure to afford product of a light yellow confirmed by C NMR.
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Z. Zhang et al.: Magnesium porphyrazine with peripheral methyl(3,5-dibromophenylmethyl)amino groupsꢁ
ꢁ9ꢄ
3
-Butyl-2-methyl-6-(perfluoropropan-2-yl)quinolin-4-yl
Hz), 120.56 (d, J=136 Hz), 122.37, 123.14 (d, J=8.6 Hz), 123.95
(tetrahydrofuran-3-yl) carbonate (8a):
(d, J=20 Hz), 144.17, 146.12, 151.50, 151.94, 161.37; LC-MS Pos
+
[
M+1] =484; Anal. Calcd for C H F NO : C, 52.18; H, 4.17;
2
1
20
7
4
1
Yield: 43.2%, light brown viscous solid; H NMR (CDCl ): N, 2.90; Found: C, 52.10; H, 4.22; N, 2.83.
3
0
.97 (t, J=2.1 Hz, 3H), 1.30-1.62 (m, 6H), 2.74 (t, J=7.8 Hz,
2
H), 2.82 (s, 3H), 3.86-4.07 (m, 4H), 5.37-5.42 (m, 1H), 7.82 Cyclopentyl (2,3,8-trimethyl-6-(perfluoropropan-2-yl)
(
d, J=9.3 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H), 8.15 (d, J=9.0 Hz, 1H); quinolin-4-yl) carbonate (8f):
+
GC-MS M =497 base peak: 71; Anal. Calcd for C H F NO :
2
2
22
7
4
1
C, 53.12; H, 4.46; N, 2.82; Found: C, 53.18; H, 4.42; N, 2.79.
Yield: 55.6%, light yellow viscous solid; H NMR (CDCl ):
3
1
.65-1.97 (m, 8H), 2.32 (s, 3H), 2.33 (s, 3H), 2.76 (s, 3H), 5.22-
2
,3-Dimethyl-6-(perfluoropropan-2-yl)quinolin-4-yl
5.29 (m, 1H), 7.80 (s, 1H), 7.91 (d, J=1.5 Hz, 1H); LC-MS Pos
+
(
tetrahydrofuran-3-yl) carbonate (8b):
[M+1] =468; Anal. Calcd for C H F NO : C, 53.97; H, 4.31;
2
1
20
7
3
N, 3.00; Found: C, 53.86; H, 4.29; N, 3.07.
1
Yield: 37.9%, brown viscous liquid; H NMR (CDCl ): 2.05-
3
2
.25 (m, 2H), 2.36 (s, 3H), 2.82 (s, 3H), 4.94-5.25 (m, 4H), Cyclopentyl (2,3-dimethyl-6-(perfluoropropan-2-yl)
.39-5.42 (m, 1H), 7.85 (d, J=8.4 Hz, 1H), 8.08 (s, J=1.8 Hz, quinolin-4-yl) carbonate (8g):
5
+
1
H), 8.24 (s, 1H); GC-MS M =455 base peak: 71; Anal. Calcd
1
for C H F NO : C, 50.12; H, 3.54; N, 3.08; Found: C, 50.16; Yield: 62.5%, light yellow viscous solid; H NMR (CDCl ):
19
16
7
4
3
H, 3.49; N, 3.03.
1.65-1.99 (m, 8H), 2.34 (s, 3H), 2.76 (s, 3H), 5.22-5.27 (m, 1H),
7
.80 (d, J=9.0 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 8.12 (d, J=9.0 Hz,
+
Tetrahydrofuran-3-yl (2,3,8-trimethyl-
6
1H); LC-MS Pos [M+1] =454; Anal. Calcd for C H F NO : C,
2
0
18
7
3
-(perfluoropropan-2-yl)quinolin-4-yl) carbonate (8c):
52.99; H, 4.00; N, 3.09; Found: C, 52.92; H, 4.03; N, 3.07.
1
Yield: 47.7%, light yellow viscous liquid; H NMR (CDCl ): 3-Butyl-2-methyl-6-(perfluoropropan-2-yl)quinolin-4-yl
3
2
.23-2.28 (m, 2H), 2.33 (s, 3H), 2.76 (s, 3H), 2.84 (s, 3H), 3.93- cyclopentyl carbonate (8h):
13
4
.01(m, 4H), 5.39 (s, 1H), 7.65 (s, 1H), 7.90 (s, 1H); C NMR
1
(
CDCl , 75 MHz) δ : 12.51, 18.32, 24.51, 32.69, 66.90, 72.76, Yield: 39.1%, brown viscous solid; H NMR (CDCl ): 0.96
3
3
8
0.23, 93.96, 114.65 (qd, J=286, 28 Hz), 116.94 (d, J=12.6 (t, J=7.2 Hz, 3H), 1.43-1.98 (m, 12H), 2.75 (t, J=5.1 Hz, 2H),
Hz), 120.49 (d, J=145 Hz), 122.43, 123.77 (d, J=27 Hz), 124.66 2.81 (s, 3H), 5.23-5.27 (m, 1H), 7.81 (d, J=9.0 Hz, 1H), 8.01
+
(
d, J=8.0 Hz), 138.55, 146.73, 151.44, 151.91, 161.50. LC-MS (d, J=1.8 Hz, 1H), 8.14 (d, J=9.0 Hz, 1H). GC-MS M =495 base
+
Pos [M+1] =470; Anal. Calcd for C H F NO : C, 51.18; H, peak: 340; Anal. Calcd for C H F NO : C, 55.76; H, 4.88; N,
2
0
18
7
4
23 24
7
3
3
.87; N, 2.98; Found: C, 51.23; H, 3.81; N, 2.94.
2.83; Found: C, 55.69; H, 4.92; N, 2.88.
Tetrahydrofuran-3-yl (2,3,7-trimethyl-
Cyclopentyl (2,3,7-trimethyl-6-(perfluoropropan-2-yl)
quinolin-4-yl) carbonate (8i):
6
-(perfluoropropan-2-yl)quinolin-4-yl) carbonate (8d):
1
1
Yield: 40.6%, yellow viscous liquid; H NMR (CDCl ): 2.15- Yield: 50.1%, light yellow viscous liquid; H NMR (CDCl ):
3
3
2
.28 (m, 2H), 2.31 (s, 3H), 2.75 (s, 3H), 2.85 (s, 3H), 3.86- 1.64-1.97 (m, 8H), 2.30 (s, 3H), 2.73 (s, 3H), 2.85 (s, 3H),
.01 (m, 4H), 5.22-5.24 (m, 1H), 7.69 (s, 1H), 7.98 (d, J=1.2 Hz, 5.22-5.25 (m, 1H), 7.64 (d, J=9.3 Hz,1H), 7.89 (d, J=9.0 Hz,
H); LC-MS Pos [M+1] =470; Anal. Calcd for C H F NO : C, 1H); LC-MS Pos [M+1] =468; Anal. Calcd for C H F NO : C,
1.18; H, 3.87; N, 2.98; Found: C, 51.21; H, 3.83; N, 2.96.
4
+
+
1
2
0
18
7
4
21 20
7
3
5
53.97; H, 4.31; N, 3.00; Found: C, 53.88; H, 4.37; N, 3.03.
8
-Ethyl-2,3-dimethyl-6-(perfluoropropan-2-yl)quinolin-
2,3-dimethyl-6-(perfluoropropan-2-yl)-4-(prop-2-yn-1-
yloxy)quinoline (9a):
4
-yl(tetrahydrofuran-3-yl) carbonate (8e):
1
1
Yield: 36.8%, yellow viscous solid; H NMR (CDCl ): 1.35 Yield: 55.1%, light yellow solid, mp 117.9-119.5°C; H NMR
3
(
(
(
t, J=7.5 Hz, 3H), 2.22-2.31 (m, 2H), 2.33 (s, 3H), 2.76 (CDCl ): 2.44 (s, 3H), 2.50 (t, J=2.4 Hz, 1H), 2.74 (s, 3H), 4.77
3
s, 3H), 3.29 (q, J=7.5 Hz, 2H), 3.90-4.07 (m, 4H), 5.37-5.40 (d,J=2.7Hz,2H),7.79(d,J=9.0Hz,1H),8.10(d,J=9.0Hz,1H),
13
13
m, 1H), 7.64 (s, 1H ), 7.89 (d, J=1.8 Hz, 1H); C NMR (CDCl , 8.43 (d, J=1.8 Hz, 1H); C NMR (CDCl , 75 MHz) δ : 12.87,
3
3
7
5 MHz) δ : 12.54, 14.85, 24.54, 24.75, 32.70, 66.93, 72.79, 24.30, 61.83, 77.00, 77.65, 114.66 (qd, J=286, 28 Hz),
8
0.22, 109.68, 114.65 (qd, J=286, 28 Hz), 116.81 (d, J=12.6 116.35, 121.24 (d, J=12.0 Hz), 122.31(d, J=102 Hz), 123.08,
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Download Date | 7/1/19 8:02 PM

ꢁ
Z. Zhang et al.: Magnesium porphyrazine with peripheral methyl(3,5-dibromophenylmethyl)amino groups
9
6ꢁ
1
1
23.09 (d, J=22 Hz), 124.75 (d, J=9.7 Hz), 129.31, 147.77, References
+
59.16, 163.33; LC-MS Pos [M+1] =380; Anal. Calcd for
C H F NO: C, 53.84; H, 3.19; N, 3.69; Found: C, 53.90;
[1] Liu, A.; Wang, X.; Liu, X.; Li, J.; Chen, H.; Hu, L.; Yu, W.; He, L.;
Liu, W.; Huang, M. Synthesis and Fungicidal Activity of Novel
17
12
7
H, 3.16; N, 3.67.
2
-Heteroatomthiazole-based Carboxanilides. J. Heterocyclic.
Chem. 2ꢅ17, 54(2), 1625-1629.
2
,3,8-trimethyl-6-(perfluoropropan-2-yl)-4-(prop-2-yn-1-
[
2] Hubele, A. Use of quinoline derivatives for the protection of
cultivated plants from herbicides. US4902340. 1990.
3] Kessabi, F.; Beaudegnies, R.; Quaranta, L.; Lamberth, C.;
Synthesis of conformationally locked analogs of quinolin-6-
yloxyacetamide fungicides. Tetrahedron. Lett. 2ꢅ16, 57(49),
yloxy)quinoline (9b):
[
1
Yield: 49.2%, light yellow solid, mp 89.0-89.6°C; H NMR
CDCl ): 2.43 (s, 3H), 2.51 (s, 1H), 2.73 (s, 3H), 2.82 (s, 3H),
(
3
5511-5513.
1
3
4
.74 (d, J=2.1 Hz, 2H), 7.62 (s, 1H), 8.26 (s, 1H); C NMR
[
4] Yan, C.; Xu, J.; Weng, Y.; Li, J.; Wang, Y.; Chen, H. A series of
ethyl 6-arylmethoxy-7-alkoxy-4-hydroxy-3-quinolinecarbo-
xylates: synthesis and anticoccidial activity against Eimeria
tenella. Chem. Biol. Drug. Des. 2ꢅꢅ8, 72(4), 314–319.
(
CDCl , 75 MHz) δ : 12.79, 18.36, 24.61, 61.74, 76.74, 77.82,
3
9
1.66, 114.48 (qd, J=286, 26 Hz), 118.90 (d, J=11.5 Hz), 119.05,
1
1
22.11 (d, J=68 Hz), 122.52 (d, J=17 Hz), 124.37 (d, J=9.1 Hz),
+
[5] Wang, Y.; Yan, C.; Weng, Y.; Jin, H.; Chen, H. Synthesis and
anticoccidial activities of novel ethyl 6-aryloxy-7-bromo-4-
hydroxy-3-quinolinecarboxylate against Eimeria tenella. Pestic.
Biochem. Phys. 2ꢅꢅ9, 93(2), 85-90.
38.04, 147.10, 159.11, 161.94; LC-MS Pos [M+1] =394; Anal.
Calcd for C H F NO: C, 54.97; H, 3.59; N, 3.56; Found: C,
18
14 7
5
4..91; H, 3.60; N, 3.59.
[
6] Valkó, K. Application of high-performance liquid chromatography
2
,3,ꢄ-trimethyl-6-(perfluoropropan-2-yl)-4-(prop-2-yn-1-
based measurements of lipophilicity to model biological
distribution. J. Chromatogr. A. 2ꢅꢅ4, 1037(1-2), 299-310.
7] Claassen, G.; Brin, E.; Crogangrundy, C.; Vaillancourt, M.;
Zhang, H.; Gai, S.; Drewe, J.; Tseng, B.; Kasibhatla, S. Selective
activation of apoptosis by a novel set of 4-aryl-3-(3-aryl-1-oxo-
2-propenyl)-2(1H)-quinolinones through a Myc-dependent
pathway. Cancer Letters, 2ꢅꢅ9, 274(2), 243-249.
yloxy)quinoline (9c):
[
1
Yield: 53.7%, light yellow solid, mp 118.5-119.9°C; H NMR
(
CDCl ): 2.44 (s, 3H), 2.46 (s, 1H), 2.70 (s, 3H), 2.98 (d, J=8.7
3
Hz, 3H), 4.51 (d, J=2.7 Hz, 2H), 7.65 (d, J=9.0 Hz, 1H), 7.87
+
(
d, J=9.3 Hz, 1H). LC-MS Pos [M+1] =394; Anal. Calcd for
[8] Sato, M.; Motomura, T.; Aramaki, H.; Matsuda, T.; Yamashita,
M.; Ito, Y.; Kawakami, H.; Matsuzaki, Y.; Watanabe, W.;
Yamataka, K. Ikeda, S.; Kodama, E.; Matsuoka, M.; Shinkai,
Hisashi. Novel HIV-1 integrase inhibitors derived from
quinolone antibiotics. J. Med. Chem. 2ꢅꢅ6, 49(5), 1506-1508.
C H F NO: C, 54.97; H, 3.59; N, 3.56; Found: C, 54.93; H,
18
14 7
3
.58; N, 3.61.
6
-(tert-butyl)-8-fluoro-2,3-dimethylquinolin-4-yl acetate
[
9] Chen, S.; Chen, R.; He, M.; Pang, R.; Tan, Z.; Yang, M. Design,
synthesis, and biological evaluation of novel quinoline
derivatives as HIV-1 Tat–TAR interaction inhibitors. Bioorgan.
Med. Chem. 2ꢅꢅ9, 17(5),1948-1956.
(
tebufloquin):
1
White solid, mp 65.7-67.6°C; H NMR (CDCl ): 1.38 (s, 9H),
3
[
10] Eswaran, S.; Adhikari, A.; Chowdhury, I.; Pal, K.; Thomas, K.
New quinoline derivatives: synthesis and investigation of
antibacterial and antituberculosis properties. Eur. J. Med.
Chem. 2ꢅ1ꢅ, 45(8), 3374-3383.
[11] Jain, R.; Vaitilingam, B.; Nayyar, A.; Palde, P. Substituted
-Methylquinolines as a New Class of anti-Tuberculosis Agents.
2
.26 (s, 3H), 2.52 (s, 3H), 2.76 (s, 3H), 7.37 (d, J=1.8 Hz, 1H),
+
7
.41 (dd, J=1.8, 12.6 Hz, 1H). LC-MS Pos [M+1] =290.
Biological Assay
4
Bioorg. Med. Chem. Lett. 2ꢅꢅ3, 13(6), 1051-1054
12] Solomon, V.; Haq, W.; Srivastava, K.; Sunil, K.; Katti, S.
Synthesis and Antimalarial Activity of Side Chain Modified
Test Compounds
[
Stock solution of every test compound was prepared in
DMF at a concentration of 1.0 g/L and then diluted to the
required test concentrations (50-500 mg/L) with water
containing Tween 80 (0.4 mg/L) [18-21].
4
-Aminoquinoline Derivatives. J. Med. Chem. 2ꢅꢅ7, 50(2),
394-398.
[13] Jampilek, J.; Dolezal, M.; Kunes, J.; Buchta, V.; Silva,
L.; Kralova, K. Quinaldine derivatives: preparation and
biological activity. Medicinal. Chemistry. 2ꢅꢅꢄ, 1(6),
Fungicidal activity
The fungicidal activities were tested using our previously
reported method [22].
5
91-599.
[
14] Giordani, A.; Mandelli, S.; Zanzola, S. Amidine derivatives of
2
-heteroaryl-quinazolines and quinolines; potent analgesics
and anti-inflammatory agents. US7968558. 2011.
15] Liu, X.H.; Fang, Y.M.; Xie, F.; Zhang, R.R.; Shen, Z.H.; Tan,
C.X.; Weng, J.Q.; Xu, T.M.; Huang, H.Y. Synthesis and in vivo
fungicidal activity ofsome new quinoline derivatives against
rice blast. Pest Manag. Sci. 2ꢅ17, 73, 1900-1907.
[
Acknowledgements: The authors sincerely thank for the
financial support of the National Natural Science Founda-
tion of China (No. 21572050, 21672057).
Unauthenticated
Download Date | 7/1/19 8:02 PM

Z. Zhang et al.: Magnesium porphyrazine with peripheral methyl(3,5-dibromophenylmethyl)amino groupsꢁ
ꢁ97
[
16] Fang, Y.M.; Zhang, R.R.; Shen, Z.H.; Wu, H.K.; Tan, C.X.;
Weng, J.Q.; Xu, T.M.; Liu, X.H. Synthesis, Antifungal Activity,
and SAR Study of Some New 6-Perfluoropropanyl
[19] Yu, Y.; Wu, D.; Huang, M.; He, L.; Li, J.; Hu, L.; Gao, G.; Liu, A.
Synthesis and Fungicidal Activity of N-Biaryl Amides. Fine.
Chem. Intermediates. 2013, 43(1), 15-19.
[20] Liu, A.; Wang, X.; Chen, C.; Pei, H.; Mao, C.; Wang, Y.; He,
H.; Huang, L.; Liu, X.; Hu, Z.; Ou, X.; Huang, M.; Yao, J. The
discovery of HNPC-A3066: a novel strobilurin acaricide. Pest.
Manag. Sci. 2ꢅꢅ9, 65, 229-234.
[21] Liu, A.; Yu, W.; Liu, M.; Bai, J.; Liu, W.; Liu, X.; Pei, H.; Hu, L.;
Huang, M.; Wang, X. Synthesis and Insecticidal Activity of
Novel Nitropyridyl-Based Dichloropropene Ethers. J. Agr. Food.
Chem. 2ꢅ1ꢄ, 63(34), 7469-7475.
[22] Liu, A.; Wang, X.; Ou, X.; Huang, M.; Chen, C.; Liu, S.; Huang, L.;
Liu, X.; Zhang, C.; Zheng, Y.; Ren, Y.; He, L.; Yao, J. Synthesis and
fungicidal activities of novel bis(trifluoromethyl)phenyl-based
strobilurins. J. Agr. Food. Chem. 2ꢅꢅ8, 56(15), 6562-6566.
Quinoline Derivatives. J. Heterocycl. Chem. 2ꢅ18, 55,
2
40-245.
[
17] Fang, Y.M.; Zhang, R.R.; Shen, Z.H.; Tan, C.X.; Weng, J.Q.;
Xu, T.M.; Liu, X.H.; Huang, H.Y.; Wu, H.K. Synthesis and
Antifungal Activity of Some 6-tert-butyl-8-chloro-2,
3
-dimethylquinolin-4-ol Derivatives against Pyricularia oryae.
Lett. Drug Des. Discov. 2ꢅ18, doi: 10.2174/157018081566618
313121735
0
[
18] Huang, D.; Liu, A.; Liu, W.; Liu, X.; Ren, Y.; Zheng, X.; Pei, H.;
Xiang, J.; Huang. M.; Wang, X. Synthesis and insecticidal
activities of novel 1H-pyrazole-5-carboxylic acid derivatives.
Heterocycl. Commun. 2ꢅ17, 23, 455-460.
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