Home Synthesis and fungicidal activities of perfluoropropan-2-yl-based novel quinoline derivatives
Article Open Access

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

  • Zai Zhang , Minhua Liu , Weidong Liu , Jun Xiang , Jianming Li , Zhong Li , Xingping Liu , Mingzhi Huang , Aiping Liu EMAIL logo and Xingliang Zheng EMAIL logo
Published/Copyright: May 31, 2019
Download Article (PDF)
Heterocyclic Communications
From the journal Heterocyclic Communications Volume 25 Issue 1

Abstract

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.

Keywords: perfluoropropan-2-yl-based quinoline derivatives; synthesis; fungicidal activity; structure-activity relationship

Introduction

Fungicide, with its multiple functions including protecting crops from fungicidal threats and preventing the spread of human infectious diseases, increasingly plays an important role in agriculture. World’s fungicide market is dominated by two kinds of compounds---strobilurins and triazoles [1]. However, given the increased application dose and frequency of fungicide, fungi have gradually grown resistance to strobilurins and triazoles, and thus, it is imperative to develop new fungicides. Quinoline derivatives are a group of nitrogen-containing heterocyclic compounds, the spectra of which demonstrate biological activities in weeding [2], fungicidal [3], insecticidal [4, 5], antitumor [6, 7], antiviral [8, 9], anti-tuberculosis [10, 11] and antifungal [12, 13, 14]. With such an extensive range of biological activities, quinoline derivatives have strong existence in agriculture. For instance, tebufloquin has been being used as a fungicide, in order to further improve the fungicidal activity of tebufloquin, a lot of work has been done for the optimization of it [15, 16, 17]. Flometoquin in insecticides, and echinacol in herbicides. Besides 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.

In our optimization program, we used tebufloquin as the lead compound because it has a broad spectrum of fungicidal activity. We also introduced fluorine atom because of its unique properties, such as electronic effect, infiltration 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 of R1, R2, R3 and R4 were revised until a more effective combination was found. Bioassay results show that compound 8c has higher fungicidal activity against Erysiphe graminis 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 representative compound, and all the reactions were carried out under protective condition by using dry nitrogen or calcium chloride tubes. 1HNMR, MS and elemental analysis were used to identify and verify all synthesized target compounds.

Figure 1 Design strategy of the target compounds.
Figure 1

Design strategy of the target compounds.

The fungicidal activities against Erysiphe graminis of target compounds are shown in Table 1. The datum indicate 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, regression equations were calculated by selecting a portion of the compounds with high fungicidal activity. Concentrations of these compounds at their 50% maximal effect (EC50) values are shown in Table 1, and activity of tebufloquin is also presented 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 EC50 values of 1.48 mg/L against Erysiphe graminis, which has the most prominent effect.

Table 1

Fungicidal activity against Erysiphe graminis, and EC50 of title compounds.

CompoundInhibition of Erysiphe graminis (%)Regression equationCorrelationEC5095% confidence
500 mg/L200 mg/L100 mg/L50 mg/Lmg/Llimit (mg/L)
8a90.0090.0070.0060.00----
8b100.0095.20100.00100.00Y = 3.9621 + 1.5889x0.98084.503.04-6.65
8c95.00100.0095.0094.60Y = 4.7260 + 1.6045x0.99531.481.11-1.98
8d100.0099.0098.4083.10Y = 4.3748 + 1.5741x0.98712.501.85-3.36
8e95.0096.0096.7088.90Y = 4.4587 + 1.3837x0.96782.461.85-3.28
8f85.0095.1086.1050.40Y = 3.8727 + 1.4010x0.94586.374.52-8.99
8g95.00100.0093.1085.80Y = 3.7697 + 1.5457x0.97166.254.36-8.96
8h90.0070.0060.0020.00----
8i90.00100.0095.4092.40Y = 4.2558 + 1.8014x0.99122.581.82-3.69
9a60.00-------
9b95.0079.1072.1074.20----
9c90.0096.1085.5076.10-->20-
tebufloquin95.0089.3079.3048.50Y = 4.1733 + 1.1521x0.98565.223.88-7.02

Although it is hard to draw exact structure-activity relationship from these data, the compounds still follow the rule that fungicidal activities vary as R1, R2, R3 and R4 moieties of the title compound are optimized. From Table 1, the following pattern is observed: When R1=8-CH3, R2=CH3, R3=A1, fungicidal activity is the highest; When R1, R2 are kept invariant, the activity of R3 group is A1 > A2;

Scheme 1 Synthetic pathways for the target compounds.
Scheme 1

Synthetic pathways for the target compounds.

When R1 and R3 are kept constant, the activity of R2 group is CH3 > CH2CH2CH2CH3. In addition, to keep R2=CH3, R4=A3, the influence of R1 moiety on improved activity is as follows: 5-CH3 > 8-CH3 > H. Therefore, the fungicidal activities may be summarized as follows: 8c > 8e ≈ 8d ≈ 8i > 8g > 9c > 8a > 8h > 9a. Further research on the structure and biological activity of this series of compounds is in progress.

Conclusions

In order to find efficient fungicides, a series of perfluoropropan-2-yl-based new quinoline derivatives were designed and synthesized. Most synthetic compounds showed good fungicidal activity. In particular, EC50 of compound 8c against Erysiphe graminis was 1.48 mg/L, which was far superior to tebufloquin. Based on the above results, our research proved that this series of quinolines have great potential in fungicides development and worth further research.

Experimental

Materials and Methods

Unless otherwise noted, solvents and reagents were used as received from commercial suppliers. 1HNMR spectra were acquired with a Varian INOVA-300 spectrometer using TMS as the internal standard and CDCl3 as the solvent. Mass spectra were obtained using a Agilent 5973-6890 gas chromatography-mass spectrometer (GC-MS) and a Agilent 1100 series liquid chromatography-mass spectrometer (LC-MS). Column chromatography was performed using a 200–300 mesh silica gel. Elemental analysis data were obtained with a Vario EL III from Elementar. Uncorrected melting points were taken in the WRS-1B digital melting points apparatus.

Synthesis of Ethyl 2-methyl-3-oxobutanoate (2a) and its analogue (2b)

Sodium hydride (60%, 4.4g, 0.11mol) was added to a solution of ethyl 3-oxobutanoate (13.0 g, 0.10mol) in tetrahydrofuran (150 mL). Methyl iodide (15.6 g, 0.11 mol) was added dropwise at room temperature. The reaction mixture was stirred for 18h at the same temperature until the staring materials was comsumed (monitored by TLC). The reaction mixture was poured into ice water followed 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.

Synthesis of 2-Methyl-4-(perfluoropropan-2-yl)aniline (4b) and its analogue (4a, 4c and 4d)

To the mixture of tetrabutylammonium bromide (3.2g, 0.01mol) and methyl tert-butyl ether (90 mL) in water (100 mL), sodium dithionite (10.4g, 0.06mol), heptafluoroisopropyl iodide (35.5g, 0.12mol), o-methylaniline (10.7 g, 0.10 mol), anhydrous sodium carbonate (12.7 g, 0.12 mol) was added with stirring below 5°C. The reaction mixture was stirred for 4h in ice-bath. Then sodium dithionite (10.4g, 0.06mol) was added, and the reaction was stirred overninght at the same temperature until the staring materials was comsumed (monitored by TLC). The reaction mixture was poured into ice water followed by extracted with ethyl acetate. The combined organic layer was dried with anhydrous sodium sulfate, and solvent was evaporated under reduced pressure to afford 25.6g (89.1% yield, 95.6% purity) of a brown liquid. 1H NMR (CDCl3): 2.20 (s, 3H), 3.93 (bs, 2H), 6.71 (d, J=6.9 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 7.25 (s, 1H). LC-MS Pos [M+1]+=276; Anal. Calcd for C10H8F7N: C, 43.65; H, 2.93; N, 5.09; Found: C, 43.60; H, 2.96; N, 5.11. 4a, 4c and 4d were synthesized in a similar method.

Synthesis of 2,3,8-Trimethyl-6-(perfluoropropan-2-yl) quinolin-4-ol (5d) and its analogue (5a-5c and 5e-5f)

The mixture of compound 2a (8.6 g, 0.060 mol), compound 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 apparatus equipped with a water trap. The reaction was heated under reflux for 6h until the staring materials was comsumed (monitored by TLC). The resulting mixture was cooled to room temperature. Then the resulting mixture was poured into ice water, and the resulted solid was formed. The solid was collected by filtration and dried to give 8.4g (76.8% yield, 92.7% purity) as a white solid. mp 198.5-199.9°C; 1H NMR (CDCl3): 2.15 (s, 3H), 2.53 (s, 3H), 2.59 (s, 3H), 7.58 (s, 1H), 8.17 (s, 1H), 8.56 (s, 1H). LC-MS Pos [M+1]+=356; Anal. Calcd for C15H12F7NO: C, 50.71; H, 3.40; N, 3.94; Found: C, 50.64; H, 3.44; N, 3.97. 5a-5c and 5e-5f were synthesized in a similar method.

Tetrahydrofuran-3-yl carbonochloridate (7a) and its analogue (7b)

In 300ml of methylene chloride was dissolved diphosgene (117.6g, 0.60 mol) with stirring below -15°C. The mixture of pyridine (43.5g, 0.55 mol) and tetrahydrofuran-3-ol (44.0g, 0.50 mol) was added dropwise at the same temperature. The reaction mixture was stirred for 3-4h at -15°C. After the reaction was completed, dilute hydrochloric acid (40%, 50 ml) was added to remove the pyridine. Then the reaction mixture was poured into ice water followed by extracted with methylene chloride. The combined organic layer was dried with anhydrous sodium sulfate. Solvent was evaporated under reduced pressure to afford product of a light yellow liquid which was used directly without calculating the yield and purification. 7b was synthesized in a similar method.

Synthesis of Tetrahydrofuran-3-yl (2,3,8-trimethyl-6-(perfluoropropan-2-yl)quinolin-4-yl) carbonate (8c) and its analogue (8a-8b and 8d-8i)

The sodium hydride (60%, 1.6 g, 0.040 mol) was dissolved in N, N-dimethylformamide (100 mL) at room temperature. After stirring for 20 min, compound 5d (7.1 g, 0.020 mol) was added, and compound 7a (3.3 g, 0.022 mol) was added dropwise at the same temperature. The reaction mixture was stirred for 2h at room temperature until the staring materials was comsumed (monitored by TLC). The reaction mixture was poured into ice water followed by extracted 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 (25: 1 / 10: 1 by volume) as eluent to afford compound 8c. Compounds 8a-8b and 8d-8i were synthesized by the similar approach.

Synthesis of 2,3,8-trimethyl-6-(perfluoropropan-2-yl)-4-(prop-2-yn-1-yloxy)quinoline (9b) and its analogue (9a and 9c)

The sodium hydride (60%, 1.6 g, 0.04 mol) was dissolved in N, N-dimethylformamide (100 mL) at room temperature. After stirring for 20 min, compound 5d (7.1 g, 0.02 mol) was added, and 3-bromoprop-1-yne (3.5 g, 0.03 mol) was added dropwise at the same temperature. The reaction mixture was stirred for 2h at room temperature until the staring materials was comsumed (monitored by TLC). The reaction mixture was poured into ice water followed by extracted 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) as eluent to afford compound 9b. Compounds 9a and 9c were synthesized by the similar method.

All the synthesized intermediates 4 and 5 were confirmed by MS. Due to the structural similarity, only intermediates 4b and 5d were further characterized and confirmed by 1H NMR and elemental analysis respectively.

Structures of the title compounds were supported by spectroscopic data shown below. Due to the structural similarity of the title compounds, only some representative compounds 8c, 8e, 9a and 9b, were analyzed and confirmed by 13C NMR.

3-Butyl-2-methyl-6-(perfluoropropan-2-yl)quinolin-4-yl (tetrahydrofuran-3-yl) carbonate (8a)

Yield: 43.2%, light brown viscous solid; 1H NMR (CDCl3): 0.97 (t, J=2.1 Hz, 3H), 1.30-1.62 (m, 6H), 2.74 (t, J=7.8 Hz, 2H), 2.82 (s, 3H), 3.86-4.07 (m, 4H), 5.37-5.42 (m, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H), 8.15 (d, J=9.0 Hz, 1H); GC-MS M+=497 base peak: 71; Anal. Calcd for C22H22F7NO4: C, 53.12; H, 4.46; N, 2.82; Found: C, 53.18; H, 4.42; N, 2.79.

2,3-Dimethyl-6-(perfluoropropan-2-yl)quinolin-4-yl (tetrahydrofuran-3-yl) carbonate (8b)

Yield: 37.9%, brown viscous liquid; 1H NMR (CDCl3): 2.05-2.25 (m, 2H), 2.36 (s, 3H), 2.82 (s, 3H), 4.94-5.25 (m, 4H), 5.39-5.42 (m, 1H), 7.85 (d, J=8.4 Hz, 1H), 8.08 (s, J=1.8 Hz, 1H), 8.24 (s, 1H); GC-MS M+=455 base peak: 71; Anal. Calcd for C19H16F7NO4: C, 50.12; H, 3.54; N, 3.08; Found: C, 50.16; H, 3.49; N, 3.03.

Tetrahydrofuran-3-yl (2,3,8-trimethyl-

6-(perfluoropropan-2-yl)quinolin-4-yl) carbonate (8c)

Yield: 47.7%, light yellow viscous liquid; 1H NMR (CDCl3): 2.23-2.28 (m, 2H), 2.33 (s, 3H), 2.76 (s, 3H), 2.84 (s, 3H), 3.93-4.01(m, 4H), 5.39 (s, 1H), 7.65 (s, 1H), 7.90 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ : 12.51, 18.32, 24.51, 32.69, 66.90, 72.76, 80.23, 93.96, 114.65 (qd, J=286, 28 Hz), 116.94 (d, J=12.6 Hz), 120.49 (d, J=145 Hz), 122.43, 123.77 (d, J=27 Hz), 124.66 (d, J=8.0 Hz), 138.55, 146.73, 151.44, 151.91, 161.50. LC-MS Pos [M+1]+=470; Anal. Calcd for C20H18F7NO4: C, 51.18; H, 3.87; N, 2.98; Found: C, 51.23; H, 3.81; N, 2.94.

Tetrahydrofuran-3-yl (2,3,7-trimethyl-

6-(perfluoropropan-2-yl)quinolin-4-yl) carbonate (8d)

Yield: 40.6%, yellow viscous liquid; 1H NMR (CDCl3): 2.15-2.28 (m, 2H), 2.31 (s, 3H), 2.75 (s, 3H), 2.85 (s, 3H), 3.86-4.01 (m, 4H), 5.22-5.24 (m, 1H), 7.69 (s, 1H), 7.98 (d, J=1.2 Hz, 1H); LC-MS Pos [M+1]+=470; Anal. Calcd for C20H18F7NO4: C, 51.18; H, 3.87; N, 2.98; Found: C, 51.21; H, 3.83; N, 2.96.

8-Ethyl-2,3-dimethyl-6-(perfluoropropan-2-yl)quinolin-4-yl(tetrahydrofuran-3-yl) carbonate (8e)

Yield: 36.8%, yellow viscous solid; 1H NMR (CDCl3): 1.35 (t, J=7.5 Hz, 3H), 2.22-2.31 (m, 2H), 2.33 (s, 3H), 2.76 (s, 3H), 3.29 (q, J=7.5 Hz, 2H), 3.90-4.07 (m, 4H), 5.37-5.40 (m, 1H), 7.64 (s, 1H ), 7.89 (d, J=1.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ : 12.54, 14.85, 24.54, 24.75, 32.70, 66.93, 72.79, 80.22, 109.68, 114.65 (qd, J=286, 28 Hz), 116.81 (d, J=12.6 Hz), 120.56 (d, J=136 Hz), 122.37, 123.14 (d, J=8.6 Hz), 123.95 (d, J=20 Hz), 144.17, 146.12, 151.50, 151.94, 161.37; LC-MS Pos [M+1]+=484; Anal. Calcd for C21H20F7NO4: C, 52.18; H, 4.17; N, 2.90; Found: C, 52.10; H, 4.22; N, 2.83.

Cyclopentyl (2,3,8-trimethyl-6-(perfluoropropan-2-yl) quinolin-4-yl) carbonate (8f)

Yield: 55.6%, light yellow viscous solid; 1H NMR (CDCl3): 1.65-1.97 (m, 8H), 2.32 (s, 3H), 2.33 (s, 3H), 2.76 (s, 3H), 5.22-5.29 (m, 1H), 7.80 (s, 1H), 7.91 (d, J=1.5 Hz, 1H); LC-MS Pos [M+1]+=468; Anal. Calcd for C21H20F7NO3: C, 53.97; H, 4.31; N, 3.00; Found: C, 53.86; H, 4.29; N, 3.07.

Cyclopentyl (2,3-dimethyl-6-(perfluoropropan-2-yl) quinolin-4-yl) carbonate (8g)

Yield: 62.5%, light yellow viscous solid; 1H NMR (CDCl3): 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, 1H); LC-MS Pos [M+1]+=454; Anal. Calcd for C20H18F7NO3: C, 52.99; H, 4.00; N, 3.09; Found: C, 52.92; H, 4.03; N, 3.07.

3-Butyl-2-methyl-6-(perfluoropropan-2-yl)quinolin-4-yl cyclopentyl carbonate (8h)

Yield: 39.1%, brown viscous solid; 1H NMR (CDCl3): 0.96 (t, J=7.2 Hz, 3H), 1.43-1.98 (m, 12H), 2.75 (t, J=5.1 Hz, 2H), 2.81 (s, 3H), 5.23-5.27 (m, 1H), 7.81 (d, J=9.0 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 8.14 (d, J=9.0 Hz, 1H). GC-MS M+=495 base peak: 340; Anal. Calcd for C23H24F7NO3: C, 55.76; H, 4.88; N, 2.83; Found: C, 55.69; H, 4.92; N, 2.88.

Cyclopentyl (2,3,7-trimethyl-6-(perfluoropropan-2-yl) quinolin-4-yl) carbonate (8i)

Yield: 50.1%, light yellow viscous liquid; 1H NMR (CDCl3): 1.64-1.97 (m, 8H), 2.30 (s, 3H), 2.73 (s, 3H), 2.85 (s, 3H), 5.22-5.25 (m, 1H), 7.64 (d, J=9.3 Hz,1H), 7.89 (d, J=9.0 Hz, 1H); LC-MS Pos [M+1]+=468; Anal. Calcd for C21H20F7NO3: C, 53.97; H, 4.31; N, 3.00; Found: C, 53.88; H, 4.37; N, 3.03.

2,3-dimethyl-6-(perfluoropropan-2-yl)-4-(prop-2-yn-1-yloxy)quinoline (9a)

Yield: 55.1%, light yellow solid, mp 117.9-119.5°C; 1H NMR (CDCl3): 2.44 (s, 3H), 2.50 (t, J=2.4 Hz, 1H), 2.74 (s, 3H), 4.77 (d, J=2.7 Hz, 2H), 7.79 (d, J=9.0 Hz, 1H), 8.10 (d, J=9.0 Hz, 1H), 8.43 (d, J=1.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ : 12.87, 24.30, 61.83, 77.00, 77.65, 114.66 (qd, J=286, 28 Hz), 116.35, 121.24 (d, J=12.0 Hz), 122.31(d, J=102 Hz), 123.08, 123.09 (d, J=22 Hz), 124.75 (d, J=9.7 Hz), 129.31, 147.77, 159.16, 163.33; LC-MS Pos [M+1]+=380; Anal. Calcd for C17H12F7NO: C, 53.84; H, 3.19; N, 3.69; Found: C, 53.90; H, 3.16; N, 3.67.

2,3,8-trimethyl-6-(perfluoropropan-2-yl)-4-(prop-2-yn-1-yloxy)quinoline (9b)

Yield: 49.2%, light yellow solid, mp 89.0-89.6°C; 1H NMR (CDCl3): 2.43 (s, 3H), 2.51 (s, 1H), 2.73 (s, 3H), 2.82 (s, 3H), 4.74 (d, J=2.1 Hz, 2H), 7.62 (s, 1H), 8.26 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ : 12.79, 18.36, 24.61, 61.74, 76.74, 77.82, 91.66, 114.48 (qd, J=286, 26 Hz), 118.90 (d, J=11.5 Hz), 119.05, 122.11 (d, J=68 Hz), 122.52 (d, J=17 Hz), 124.37 (d, J=9.1 Hz), 138.04, 147.10, 159.11, 161.94; LC-MS Pos [M+1]+=394; Anal. Calcd for C18H14F7NO: C, 54.97; H, 3.59; N, 3.56; Found: C, 54..91; H, 3.60; N, 3.59.

2,3,5-trimethyl-6-(perfluoropropan-2-yl)-4-(prop-2-yn-1-yloxy)quinoline (9c)

Yield: 53.7%, light yellow solid, mp 118.5-119.9°C; 1H NMR (CDCl3): 2.44 (s, 3H), 2.46 (s, 1H), 2.70 (s, 3H), 2.98 (d, J=8.7 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 C18H14F7NO: C, 54.97; H, 3.59; N, 3.56; Found: C, 54.93; H, 3.58; N, 3.61.

6-(tert-butyl)-8-fluoro-2,3-dimethylquinolin-4-yl acetate (tebufloquin)

White solid, mp 65.7-67.6°C; 1H NMR (CDCl3): 1.38 (s, 9H), 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

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, 19, 20, 21].

Fungicidal activity

The fungicidal activities were tested using our previously reported method [22].

Acknowledgements

The authors sincerely thank for the financial support of the National Natural Science Foundation of China (No. 21572050, 21672057).

References

[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 2-Heteroatomthiazole-based Carboxanilides. J. Heterocyclic. Chem. 2017, 54(2), 1625-1629.10.1002/jhet.2668Search in Google Scholar

[2] Hubele, A. Use of quinoline derivatives for the protection of cultivated plants from herbicides. US4902340. 1990.Search in Google Scholar

[3] Kessabi, F.; Beaudegnies, R.; Quaranta, L.; Lamberth, C.; Synthesis of conformationally locked analogs of quinolin-6-yloxyacetamide fungicides. Tetrahedron. Lett. 2016, 57(49), 5511-5513.10.1016/j.tetlet.2016.10.104Search in Google Scholar

[4] Yan, C.; Xu, J.; Weng, Y.; Li, J.; Wang, Y.; Chen, H. A series of ethyl 6-arylmethoxy-7-alkoxy-4-hydroxy-3-quinolinecarboxylates: synthesis and anticoccidial activity against Eimeria tenella. Chem. Biol. Drug. Des. 2008, 72(4), 314–319.10.1111/j.1747-0285.2008.00700.xSearch in Google Scholar

[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. PesticBiochemPhys 2009, 93(2), 85-90.10.1016/j.pestbp.2008.11.005Search in Google Scholar

[6] Valkó, K. Application of high-performance liquid chromatography based measurements of lipophilicity to model biological distribution. J. ChromatogrA. 2004, 1037(1-2), 299-310.10.1016/j.chroma.2003.10.084Search in Google Scholar

[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 2009, 274(2), 243-249.10.1016/j.canlet.2008.09.032Search in Google Scholar

[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. 2006, 49(5), 1506-1508.10.1021/jm0600139Search in Google Scholar

[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. BioorganMedChem 2009, 17(5),1948-1956.10.1016/j.bmc.2009.01.038Search in Google Scholar

[10] Eswaran, S.; Adhikari, A.; Chowdhury, I.; Pal, K.; Thomas, K. New quinoline derivatives: synthesis and investigation of antibacterial and antituberculosis properties. EurJMedChem 2010, 45(8), 3374-3383.10.1016/j.ejmech.2010.04.022Search in Google Scholar

[11] Jain, R.; Vaitilingam, B.; Nayyar, A.; Palde, P. Substituted 4-Methylquinolines as a New Class of anti-Tuberculosis Agents. BioorgMedChemLett 2003, 13(6), 1051-105410.1016/S0960-894X(03)00074-XSearch in Google Scholar

[12] Solomon, V.; Haq, W.; Srivastava, K.; Sunil, K.; Katti, S. Synthesis and Antimalarial Activity of Side Chain Modified 4-Aminoquinoline Derivatives. J. Med. Chem. 2007, 50(2), 394-398.10.1021/jm061002iSearch in Google Scholar PubMed

[13] Jampilek, J.; Dolezal, M.; Kunes, J.; Buchta, V.; Silva, L.; Kralova, K. Quinaldine derivatives: preparation and biological activity. Medicinal. Chemistry. 2005, 1(6), 591-599.10.2174/157340605774598108Search in Google Scholar PubMed

[14] Giordani, A.; Mandelli, S.; Zanzola, S. Amidine derivatives of 2-heteroaryl-quinazolines and quinolines; potent analgesics and anti-inflammatory agents. US7968558. 2011.Search in Google Scholar

[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 ManagSci 2017, 73, 1900-1907.10.1002/ps.4556Search in Google Scholar PubMed

[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 Quinoline Derivatives. JHeterocyclChem 2018, 55, 240-245.10.1002/jhet.3031Search in Google Scholar

[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. LettDrug DesDiscov 2018, doi: 10.2174/157018081566618 031312173510.2174/157018081566618Search in Google Scholar

[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. 2017, 23, 455-460.10.1515/hc-2017-0110Search in Google Scholar

[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.Search in Google Scholar

[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. 2009, 65, 229-234.10.1002/ps.1673Search in Google Scholar PubMed

[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. JAgrFoodChem 2015, 63(34), 7469-7475.10.1021/acs.jafc.5b02279Search in Google Scholar PubMed

[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. JAgrFoodChem 2008, 56(15), 6562-6566.10.1021/jf800651zSearch in Google Scholar PubMed

Received: 2018-03-01
Accepted: 2018-04-26
Published Online: 2019-05-31

© 2019 Zai Zhang et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 Public License.

Articles in the same Issue

  1. Research Article
  2. Magnesium porphyrazine with peripheral methyl (3,5-dibromophenylmethyl)amino groups – synthesis and optical properties
  3. Synthesis and fungicidal activity of novel imidazo[4, 5-b]pyridine derivatives
  4. Synthesis of indazolo[5,4-b][1,6]naphthyridine and indazolo[6,7-b][1,6]naphthyridine derivatives
  5. Zinc Chloride Catalyzed Amino Claisen Rearrangement of 1-N-Allylindolines: An Expedient Protocol for the Synthesis of Functionalized 7-Allylindolines
  6. Synthesis and Biological Evaluation of (E)-N’-Benzylidene-7-methyl-2-propyl-1H-benzo[d] imidazole-5-carbohydrazides as Antioxidant, Anti-inflammatory and Analgesic agents
  7. Efficient synthesis, reactions and spectral characterization of pyrazolo[4’,3’:4,5]thieno[3,2-d] pyrimidines and related heterocycles
  8. Asymmetric Mannich Reaction: Synthesis of Novel Chiral 5-(substituted aryl)-1,3,4-Thiadiazole Derivatives with Anti-Plant-Virus Potency
  9. Synthesis and antitubercular activity of new N-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-(nitroheteroaryl)carboxamides
  10. Remarkable electronic effect on the total stereoselectivity of the cycloaddition reaction of arylnitrile oxides with pyrrol-2-one derivatives
  11. Preliminary Communications
  12. Crystal structure and molecular docking studies of new pyrazole-4-carboxamides
  13. Research Article
  14. Synthesis of polycyclic phosphonates via an intramolecular Diels-Alder reaction of 2-benzoylbenzalaldehyde and alkenyl phosphites
  15. Asymmetric total synthesis of filamentous fungi related resorcylic acid lactones 7-epi-zeaenol and zeaenol
  16. The first in situ synthesis of 1,3-dioxan-5-one derivatives and their direct use in Claisen-Schmidt reactions
  17. Synthesis and fungicidal activities of perfluoropropan-2-yl-based novel quinoline derivatives
  18. Combined XRD-paramagnetic 13C NMR spectroscopy of 1,2,3-triazoles for revealing copper traces in a Huisgen click-chemistry cycloaddition. A model case
  19. Cytotoxic and antimicrobial activities of some novel heterocycles employing 6-(1,3-diphenyl-1H-pyrazol-4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
  20. Substrate-controlled Diastereoselective Michael Addition of Alkylidene Malonates by Grignard Reagents
  21. Synthesis of 1,2,3 triazole-linked benzimidazole through a copper-catalyzed click reaction
  22. Synthesis and spectral characteristics of N-(1-([1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)carboxamides
  23. Facile One-pot Protocol of Derivatization Nitropyridines: Access to 3-Acetamidopyridin-2-yl 4-methylbenzenesulfonate Derivatives
  24. Naphthalene substituted benzo[c]coumarins: Synthesis, characterization and evaluation of antibacterial activity and cytotoxicity
  25. A Green Synthesis and Antibacterial Activity of N-Arylsulfonylhydrazone Compounds
  26. Preliminary Communications
  27. Facile Synthesis of Spiro[cyclohexane-1,3’-indoline]-2,2’-diones
  28. Research Article
  29. Synthesis and AChE inhibitory activity of N-glycosyl benzofuran derivatives
  30. [DMImd-DMP]: A highly efficient and reusable catalyst for the synthesis of 4H-benzo[b]pyran derivatives
https://doi.org/10.1515/hc-2019-0002
Keywords for this article
perfluoropropan-2-yl-based quinoline derivatives; synthesis; fungicidal activity; structure-activity relationship
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Article
  2. Magnesium porphyrazine with peripheral methyl (3,5-dibromophenylmethyl)amino groups – synthesis and optical properties
  3. Synthesis and fungicidal activity of novel imidazo[4, 5-b]pyridine derivatives
  4. Synthesis of indazolo[5,4-b][1,6]naphthyridine and indazolo[6,7-b][1,6]naphthyridine derivatives
  5. Zinc Chloride Catalyzed Amino Claisen Rearrangement of 1-N-Allylindolines: An Expedient Protocol for the Synthesis of Functionalized 7-Allylindolines
  6. Synthesis and Biological Evaluation of (E)-N’-Benzylidene-7-methyl-2-propyl-1H-benzo[d] imidazole-5-carbohydrazides as Antioxidant, Anti-inflammatory and Analgesic agents
  7. Efficient synthesis, reactions and spectral characterization of pyrazolo[4’,3’:4,5]thieno[3,2-d] pyrimidines and related heterocycles
  8. Asymmetric Mannich Reaction: Synthesis of Novel Chiral 5-(substituted aryl)-1,3,4-Thiadiazole Derivatives with Anti-Plant-Virus Potency
  9. Synthesis and antitubercular activity of new N-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-(nitroheteroaryl)carboxamides
  10. Remarkable electronic effect on the total stereoselectivity of the cycloaddition reaction of arylnitrile oxides with pyrrol-2-one derivatives
  11. Preliminary Communications
  12. Crystal structure and molecular docking studies of new pyrazole-4-carboxamides
  13. Research Article
  14. Synthesis of polycyclic phosphonates via an intramolecular Diels-Alder reaction of 2-benzoylbenzalaldehyde and alkenyl phosphites
  15. Asymmetric total synthesis of filamentous fungi related resorcylic acid lactones 7-epi-zeaenol and zeaenol
  16. The first in situ synthesis of 1,3-dioxan-5-one derivatives and their direct use in Claisen-Schmidt reactions
  17. Synthesis and fungicidal activities of perfluoropropan-2-yl-based novel quinoline derivatives
  18. Combined XRD-paramagnetic 13C NMR spectroscopy of 1,2,3-triazoles for revealing copper traces in a Huisgen click-chemistry cycloaddition. A model case
  19. Cytotoxic and antimicrobial activities of some novel heterocycles employing 6-(1,3-diphenyl-1H-pyrazol-4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
  20. Substrate-controlled Diastereoselective Michael Addition of Alkylidene Malonates by Grignard Reagents
  21. Synthesis of 1,2,3 triazole-linked benzimidazole through a copper-catalyzed click reaction
  22. Synthesis and spectral characteristics of N-(1-([1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)carboxamides
  23. Facile One-pot Protocol of Derivatization Nitropyridines: Access to 3-Acetamidopyridin-2-yl 4-methylbenzenesulfonate Derivatives
  24. Naphthalene substituted benzo[c]coumarins: Synthesis, characterization and evaluation of antibacterial activity and cytotoxicity
  25. A Green Synthesis and Antibacterial Activity of N-Arylsulfonylhydrazone Compounds
  26. Preliminary Communications
  27. Facile Synthesis of Spiro[cyclohexane-1,3’-indoline]-2,2’-diones
  28. Research Article
  29. Synthesis and AChE inhibitory activity of N-glycosyl benzofuran derivatives
  30. [DMImd-DMP]: A highly efficient and reusable catalyst for the synthesis of 4H-benzo[b]pyran derivatives
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 7.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/hc-2019-0002/html
Scroll to top button