Synthesis and Antifungal and Insecticidal Activities of Novel <i>N</i>-Phenylbenzamide Derivatives Bearing a Trifluoromethylpyrimidine Moiety

Yu, Xuetong; Lan, Wenjun; Chen, Meihang; Xu, Su; Luo, Xiaoxi; He, Shuhong; Chen, Haijiang; Fei, Qiang; Wu, Wenneng

doi:https://doi.org/10.1155/2021/8370407

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Advanced Catalysis and Synthesis for Sustainable and Environmental Processes

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Research Article | Open Access

Volume 2021 | Article ID 8370407 | https://doi.org/10.1155/2021/8370407

Synthesis and Antifungal and Insecticidal Activities of Novel N-Phenylbenzamide Derivatives Bearing a Trifluoromethylpyrimidine Moiety

Xuetong Yu,¹Wenjun Lan,¹Meihang Chen,²Su Xu,¹Xiaoxi Luo,¹Shuhong He,¹Haijiang Chen,¹Qiang Fei,¹and Wenneng Wu¹

Academic Editor: Yaqiong Su

Received27 Jun 2021

Revised23 Aug 2021

Accepted25 Aug 2021

Published16 Sept 2021

Abstract

Seventeen novel N-phenylbenzamide derivatives bearing a trifluoromethylpyrimidine moiety were synthesized via four-step reactions. Their antifungal and insecticidal properties were evaluated. Antifungal test results demonstrated that some of the synthesized compounds showed better in vitro bioactivities against Phomopsis sp., Botryosphaeria dothidea (B. dothidea), and Botrytis cinerea (B. cinerea) at 50 μg/mL than pyrimethanil. Unfortunately, the synthesized compounds revealed lower insecticidal activities against Spodoptera frugiperda (S. frugiperda) and Mythimna separata (M. separata) at 500 μg/mL than chlorantraniliprole.

1. Introduction

Plant fungal diseases and insect pests have drawn widespread attention because of their enormous damage toward agriculture [14]. The traditional commercial fungicides and insecticides used to prevent and control plant diseases could increase the yield, improve the quality of agricultural products, and also not reduced huge loss annually [5, 6]. However, the misuse of traditional fungicides and insecticides had speeded up the resistance of plant diseases, which is rapidly becoming a huge challenge in agriculture [7, 8]. Therefore, it is still an urgent and meaningful task to develop the novel, highly efficient, and promising pesticides.

Pyrimidine is one of best important chemical scaffolds for application in pesticide chemistry, medicinal chemistry, and material chemistry. Many of pyrimidine derivatives play an important role of bioactive compounds, such as antifungal [9, 10], antibacterial [11, 12], acaricidal [13, 14] insecticidal [15, 16], herbicidal [17, 18], and antiviral [19, 20] activities. Meanwhile, N-phenylbenzamide, a key active fragment in pesticide chemistry, is usually used as a pesticide active fragment and exhibit extensive biological activities, such as antiviral, antifungal, antibacterial, herbicidal, and insecticidal activities [21]. Our early work has reported a series of novel benzamide derivatives containing a pyrimidine moiety (Figure 1) with better antiviral, insecticidal, antifungal, and antibacterial activities [26–33].

Herein, to develop new highly bioactivity lead compounds, we replace benzamide to N-phenylbenzamide (Figure 2) to design a series of novel N-phenylbenzamide derivatives containing a trifluoromethylpyrimidine moiety and then evaluate their antifungal and insecticidal activities.

2. Experimental

2.1. Materials and Methods

The melting points were obtained by using an XT-4 binocular microscope (Beijing Tech. Instrument Co., China). NMR spectral recorded on a Bruker Avance NEO 600 NMR spectrometer (Bruker Corporation, MA, USA) using DMSO-d₆ as an solvent. HRMS data were obtained on a Thermo Scientific Q Exactive Fucus instrument (Thermo Fisher Scientific, CA, USA). Analytical TLC was performed on silica gel GF₂₅₄.

2.2. General Procedure for the Preparation of Intermediates 1 and 2

Trifluoroacetoacetate (0.1 mol) with ethanol (200 mL) was added to a 500 mL round bottom flask. Then, formamidine hydrochloride (0.1 mol) or acetamidine hydrochloride (0.1 mol) and 1,8-diazabicyclo[5.4.0]undecane-7-ene (DBU, 0.15 mol) were added to the mixture and reacted for 10 h at reflux temperature. After completion, the mixture was cooled to room temperature, acidified with 1 mol/L HCl to pH 7, extracted with ethyl acetate, and evaporated under vacuum to produce intermediate 1. Then, intermediate 1 (0.1 mol), POCl₃ (0.2 mol), and CH₃CN (240 mL) were added to a 500 mL round bottom flask and reacted for 0.5 h at reflux temperature. After that, diisopropylethylamine (0.12 mol) was added dropwise and continuously reacted for 8 h. After completion, excess POCl₃ and CH₃CN were removed by distillation, and then ice-water mixture (120 mL) was added. Finally, the mixture was alkalified with 5 mol/L NaOH to pH 9 and extracted using CH₂Cl₂ to give intermediate 2.

2.3. General Procedure for the Preparation of the Key Intermediate 3

To a 100 mL round bottom flask, intermediate 2 (0.012 mol) dissolved in acetone (10 mL), Cs₂CO₃ (0.02 mol), and 4-hydroxybenzoic acid (0.01 mol) were added and reacted for 2-3 h at room temperature. After the completion of reaction, the excess solvent was removed, and the residue was added to distilled water (50 mL) and acidified with concentrated HCl to pH 2-3. The precipitate was filtered and recrystallized from ethanol to give key intermediate 3. The structures of intermediate 3 were confirmed by ¹H NMR and ¹³C NMR. The physical characteristics and ¹H NMR and ¹³C NMR data for intermediate 3 are shown as follows.

2.3.1. 4-((6-(Trifluoromethyl)pyrimidine-4-yl)oxy)benzoic acid (3a)

White solid; yield: 80.1%; m.p. 147-148°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 9.02 (s, 1H, pyrimidine-H), 8.41 (s, 1H, pyrimidine-H), 8.21 (d, 1H, J = 8.4 Hz, Ph-H), 7.86 (d, J = 8.4 Hz, 1H, Ph-H), 7.70 (t, J = 7.2 Hz, 1H, Ph-H), 7.70 (t, J = 7.8 Hz, 1H, Ph-H); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.34, 159.75, 156.12(q, J = 36.0 Hz), 143.24, 129.97, 128.63, 126.01, 121.53 (q, J = 272.85 Hz), 120.46, 109.99, 105.44.

2.3.2. 4-((2-Methyl-6-(trifluoromethyl)pyrimidine-4-yl)oxy)benzoic acid (3b)

White solid; yield: 70.0%; m.p. 145-146°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 12.56 (s, 1H, COOH), 7.80 (d, J = 8.4 Hz, 2H, Ph-H), 7.48 (s, 1H, pyrimidine-H), 6.83 (d, J = 8.4 Hz, 2H, Ph-H), 2.35 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 167.63, 162.69, 162.06, 151.96 (q, J = 35.25 Hz), 131.98, 122.09 (q, J = 273.00 Hz), 121.82, 115.56, 111.07, 25.90.

2.4. General Procedure for the Preparation of the Target Compounds (4a–4q)

To a 50 mL round bottom flask, the key intermediate 3 (0.024 mol), dichloromethane (20 mL), aromatic amides (0.02 mol), dimethylaminopyridine (DMAP, 0.0004 mol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 0.03 mol) were added, respectively. The reaction was carried out at room temperature for 8–10 h. After the completion of the reaction, the solvent was evaporated under vacuum condition and then the residue was recrystallized from ethanol to give pure target compounds 4a–4q. The physical characteristics, ¹H NMR, ¹³C NMR, and HRMS data for all the target compounds are shown in Supplementary Materials.

2.4.1. N-(4-fluorophenyl)-4-((6-(trifluoromethyl)pyrimidine-4-yl)oxy)benzamide (4a)

White solid; yield: 35.0%; m.p. 172–174°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.37 (s, 1H, CONH), 8.98 (s, 1H, pyrimidine-H), 8.05 (d, J = 8.7 Hz, 2H, Ph-H), 7.86 (s, 1H, pyrimidine-H), 7.79 (dd, J₁ = 9.1 Hz, J₂ = 5.0 Hz, 2H, Ph-H), 7.45 (d, J = 8.7 Hz, 2H, Ph-H), 7.20 (t, J = 8.9 Hz, 2H, Ph-H); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.38, 165.13, 159.74, 156.24 (q, J = 35.60 Hz), 154.57, 135.94, 133.17, 130.07, 122.59, 122.52, 122.17, 121.92, 121.82 (q, J = 272.30 Hz), 115.79, 115.57, 107.03; HRMS (ESI) calcd. for C₁₈H₁₂F₄N₃O₂ [M + H]⁺: 378.3061, found: 378.0851.

2.4.2. N-(4-chlorophenyl)-4-((6-(trifluoromethyl)pyrimidine-4-yl)oxy)benzamide (4b)

White solid; yield: 42.5%; m.p. 176–179°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.43 (s, 1H, CONH), 8.98 (s, 1H, pyrimidine-H), 8.05 (d, J = 8.5 Hz, 2H, Ph-H), 7.85 (s, 1H, pyrimidine-H), 7.82 (d, J = 8.8 Hz, 2H, Ph-H), 7.45 (d, J = 8.6 Hz, 2H, Ph-H), 7.41 (d, J = 8.8 Hz, 2H, Ph-H); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.26, 162.10, 159.38, 156.24 (q, J = 35.60 Hz), 143.29, 137.81, 134.89, 134.83, 134.81, 133.75, 132.50, 126.97, 126.96, 126.92, 122.21 (q, J = 273.60 Hz), 106.95; HRMS (ESI) calcd. for C₁₈H₁₂ClF₃N₃O₂ [M + H]⁺: 394.0565, found: 394.0563.

2.4.3. N-(4-bromophenyl)-4-((6-(trifluoromethyl)pyrimidine-4-yl)oxy)benzamide (4c)

White solid; yield: 26.8%; m.p. 168–171°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.42 (s, 1H, CONH), 8.99 (s, 1H, pyrimidine-H), 8.04 (dd, J₁ = 8.6, J₂ = 6.3 Hz, 2H, Ph-H), 7.84 (s, 1H, pyrimidine-H), 7.76 (d, J = 8.9 Hz, 2H, Ph-H), 7.54 (dd, J₁ = 8.8, J₂ = 1.3 Hz, 2H, Ph-H), 7.45 (d, J = 8.7 Hz, 1H, Ph-H), 7.41 (d, J = 8.7 Hz, 1H, Ph-H); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.37, 165.36, 164.09, 159.73, 156.25 (q, J = 34.6 Hz), 151.28, 139.01, 138.98, 133.07, 132.44, 131.93, 130.15, 122.60, 122.21 (q, J = 273.65 Hz), 121.94, 115.85, 107.00; HRMS (ESI) calcd. for C₁₈H₁₁BrF₃N₃O₂ [M + H]⁺: 438.0060, found: 438.0057.

2.4.4. N-(4-methoxyphenyl)-4-((6-(trifluoromethyl)pyrimidine-4-yl)oxy)benzamide (4d)

White solid; yield: 62.1%; m.p. 143–145°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.20 (s, 1H, CONH), 8.99 (s, 1H, pyrimidine-H), 8.06 (d, J = 9.0 Hz, 2H, Ph-H), 7.85 (s, 1H, pyrimidine-H), 7.70 (d, J = 8.4 Hz, 2H, Ph-H), 7.46 (d, J = 8.4 Hz, 2H, Ph-H), 6.95 (d, J = 9.0 Hz, 2H, Ph-H), 3.76 (s, 3H, CH₃O); ¹³C NMR (125 MHz, DMSO-d₆, ppm) δ 17041, 169.77, 159.76, 156.20 (q, J = 34.95 Hz), 156.06, 154.43, 133.45, 132.65, 129.98, 122.22, 122.09, 121.81 (q, J = 272.85 Hz), 114.23, 107.00, 55.65; HRMS (ESI) calcd. for C₁₉H₁₅F₃N₃O₃ [M + H]⁺: 390.1060, found: 390.1060.

2.4.5. N-(4-methyphenyl)-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)benzamide (4e)

White solid; yield: 62.1%; m.p. 162–164°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.24 (s, 1H, CONH), 8.99 (s, 1H, pyrimidine-H), 8.18 (d, J = 8.4 Hz, 2H, Ph-H), 7.86 (s, 1H, pyrimidine-H), 7.68 (d, J = 8.4 Hz, 2H, Ph-H), 7.46 (d, J = 8.4 Hz, 2H, Ph-H), 7.18 (d, J = 7.8 Hz, 2H, Ph-H), 2.29 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.41, 165.01, 159.76, 156.20 (q, J = 35.25 Hz), 154.48, 140.34, 137.07, 133.45, 133.14, 130.05, 129.49, 122.10, 121.81(q, J = 272.85 Hz), 120.80, 106.99, 20.97; HRMS (ESI) calcd. for C₁₉H₁₅F₃N₃O₂ [M + H]⁺: 374.1113, found: 374.1110.

2.4.6. N-(3-chloro-4-fluorophenyl)-4-((6-(trifluoromethyl)pyrimidine-4-yl)oxy)benzamide (4f)

White solid; yield: 25.6%; m.p. 178-179°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.58 (s, 1H, CONH), 9.06 (s, 1H, pyrimidine-H), 8.18–8.12 (m, 3H, Ph-H), 7.93 (s, 1H, pyrimidine-H), 7.82–7.78 (m, 1H, Ph-H), 7.56–7.48 (m, 3H, Ph-H); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.33, 165.34, 159.71, 156.23 (q, J = 35.0 Hz), 155.01, 154.73, 152.60, 136.82, 132.77, 130.12, 121.83 (q, J = 272.85 Hz), 122.23, 121.01, 119.55, 119.37, 117.40, 107.04; HRMS (ESI) calcd. for C₁₈H₁₀F₄ClN₃O₂ [M + Na]⁺: 434.0293, found: 434.0290.

2.4.7. N-(4-bromo-3-chlorophenyl)-4-((6-(trifluoromethyl)pyrimidine-4-yl)oxy)benzamide (4g)

White solid; yield: 32.7%; m.p. 187–189°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.57 (s, 1H, CONH), 8.99 (s, 1H, pyrimidine-H), 8.18 (d, J = 2.4 Hz, 1H, Ph-H), 8.08 (d, J = 9.0 Hz, 2H, Ph-H), 7.87 (s, 1H, pyrimidine-H), 7.75 (d, J = 9.0 Hz, 1H, Ph-H), 7.73–7.66 (m, 1H, Ph-H), 7.49 (d, J = 9.0 Hz, 2H, Ph-H); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.37, 167.43, 165.56, 159.75, 156.41(q, J = 34.8 Hz), 154.86, 140.34, 134.27, 133.40, 132.72, 132.17, 131.99, 130.23, 129.13, 122.62, 122.25(q, J = 272.55 Hz), 120.02, 115.83, 115.36, 110.00, 103.75; HRMS (ESI) calcd. for C₁₈H₉F₃ClBrN₃O₂ [M + Na]⁺: 470.9592, found: 470.9590.

2.4.8. 4-((2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)oxy)-N-phenylbenzamide (4h)

White solid; yield: 30.0%; m.p. 167–169°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.32 (s, 1H, CONH), 8.07 (d, J = 8.4 Hz, 2H, Ph-H), 7.79 (d, J = 7.8 Hz, 2H, Ph-H), 7.60 (s, 1H, pyrimidine-H), 7.45 (d, J = 9.0 Hz, 2H, Ph-H), 7.30 (t, J = 7.8 Hz, 2H, Ph-H), 7.12 (t, J = 7.2 Hz, 2H, Ph-H), 2.52 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.30, 169.70, 165.24, 156.39 (q, J = 35.1 Hz), 155.94, 154.64, 139.62, 130.12, 129.11, 124.20, 122.01, 121.83 (q, J = 272.85 Hz), 120.81, 103.80, 25.93; HRMS (ESI) calcd. for C₁₉H₁₄F₃N₃O₂ [M + H]⁺: 372.0964, found: 372.0954.

2.4.9. 4-((2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)oxy)-N-(2-methyphenyl)benzamide (4i)

White solid; yield: 21.5%; m.p. 168–170°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 9.96 (s, 1H, CONH), 8.11 (d, J = 8.4 Hz, 2H, Ph-H), 7.59 (s, 1H, pyrimidine-H), 7.45 (d, J = 9.0 Hz, 2H, Ph-H), 7.37 (d, J = 7.2 Hz, 2H, Ph-H), 7.29 (d, J = 7.2 Hz, 2H, Ph-H), 7.23 (t, J = 6.0 Hz, 2H, Ph-H), 7.19 (t, J = 7.2 Hz, 2H, Ph-H), 2.53 (s, 3H, CH₃), 2.26 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.30, 169.71, 164.96, 156.60, 155.41(q, J = 34.6 Hz), 156.18, 155.94, 154.63, 136.83, 134.22, 132.72, 130.79, 130.07, 127.07, 126.51, 122.21 (q, J = 273.8 Hz), 122.03, 103.76, 25.90, 18.39; HRMS (ESI) calcd. for C₂₀H₁₆F₃N₃O₂ [M + H]⁺: 386.1121, found: 386.1111.

2.4.10. N-(4-fluorophenyl)-4-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)oxy)benzamide (4j)

White solid, yield: 38.4%, m.p. 175–178°C;¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.38 (s, 1H, CONNH), 8.04 (d, J = 8.7 Hz, 2H, Ph-H), 7.79 (dd, J₁ = 9.1, J₂ = 5.1 Hz, 2H, Ph-H), 7.58 (s, 1H, pyrimidine-H), 7.43 (d, J = 8.7 Hz, 2H, Ph-H), 7.19 (t, J = 8.9 Hz, 2H, Ph-H), 2.51 (s, 3H, CH₃);¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.22, 169.66, 165.12, 159.95, 157.54, 156.39 (q, J = 34.8 Hz), 154.62, 135.95, 132.96, 130.06, 122.60, 122.52, 122.24 (q, J = 273.3 Hz), 122.02, 115.77, 115.55, 103.75, 25.88; HRMS (ESI) calcd. for C₁₉H₁₄F₄N₃O₂ [M + H]⁺: 392.1017, found: 392.1014.

2.4.11. N-(4-chlorophenyl)-4-((2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)oxy)benzamide (4k)

White solid; yield: 42.5%; m.p. 172–174°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.37 (s, 1H, CONH), 8.05 (d, J = 8.8 Hz, 2H, Ph-H), 7.79 (dd, J₁ = 3.2, J₂ = 6.0 Hz, 2H, Ph-H),7.60 (s, 1H, pyrimidine-H), 7.45 (d, J = 8.7 Hz, 2H, Ph-H), 7.20 (t, J = 8.9 Hz, 2H, Ph-H), 2.51 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.24, 169.66, 165.32, 156.40 (q, J = 34.6 Hz), 154.71, 138.56, 132.86, 132.47, 130.13, 129.79, 129.02, 127.76, 122.25 (q, J = 273.6 Hz), 122.05, 103.78, 25.90; HRMS (ESI) calcd. for C₁₉H₁₄ClF₃N₃O₂ [M + H]⁺: 408.0721, found: 408.0720.

2.4.12. N-(4-bromophenyl)-4-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)oxy)benzamide (4l)

White solid; yield: 42.5%; m.p. 172–174°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.44 (s, 1H, CONH), 8.06 (d, J = 8.8 Hz, 2H, Ph-H), 7.78 (d, J = 8.8 Hz, 2H, Ph-H), 7.60 (s, 1H, pyrimidine-H), 7.56 (d, J = 9.2 Hz, 2H, Ph-H), 7.46 (d, J = 8.8 Hz, 2H, Ph-H), 2.52 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.19, 169.64, 165.33, 156.41 (q, J = 34.6 Hz), 155.01, 154.80, 152.59, 136.83, 132.55, 130.11, 122.21 (q, J = 273.0 Hz), 121.03, 119.55, 119.37, 117.18, 103.79, 25.96; HRMS (ESI) calcd. for C₁₈H₁₁BrF₃N₃O₂ [M + H]⁺: 450.0068, found: 450.0065.

2.4.13. N-(4-methoxyphenyl)-4-((2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)oxy)benzamide (4m)

White solid; yield: 56.2%; m.p. 154–155°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.21 (s, 1H, –CONH–), 8.04 (d, J = 8.6 Hz, 2H, Ph-H), 7.68 (d, J = 9.0 Hz, 2H, Ph-H), 7.57 (s, 1H, pyrimidine-H), 7.42 (d, J = 8.7 Hz, 2H, Ph-H), 6.92 (d, J = 9.0 Hz, 2H, Ph-H), 3.74 (s, 3H, CH₃O), 2.51 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.26, 169.67, 164.75, 156.39 (q, J = 34.8 Hz), 156.00, 154.46, 133.22, 132.63, 129.95, 122.36, 122.24 (q, J = 273.2 Hz), 121.94, 114.18, 103.74, 55.59, 25.88; HRMS (ESI) calcd. for C₂₀H₁₇F₃N₃O₂ [M + Na]⁺: 425.1195, found: 425.1196.

2.4.14. 4-((2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)oxy)-N-(4-methyphenyl)benzamide (4n)

White solid; yield: 39.9%; m.p. 167–168°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.24 (s, 1H, CONH), 8.04 (d, J = 8.4 Hz, 2H, Ph-H), 7.65 (d, J = 8.0 Hz, 2H, Ph-H), 7.56 (s, 1H, pyrimidine-H), 7.42 (d, J = 8.4 Hz, 2H, Ph-H), 7.15 (d, J = 7.6 Hz, 2H, Ph-H), 2.50 (s, 3H, CH₃), 2.26 (s, 3H, CH); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.22, 169.66, 165.01, 156.40 (q, J = 34.8 Hz), 154.49, 136.97, 133.16, 130.00, 129.45, 122.23 (q, J = 273.3 Hz), 121.94, 120.81, 103.68, 25.86, 20.92; HRMS (ESI) calcd. for C₁₉H₁₄ClF₃N₃O₂ [M + H]⁺: 408.0721, found: 408.0723.

2.4.15. 4-((2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)oxy)-N-(4-(trifluoromethoxy)phenyl) benzamide (4o)

White solid; yield: 26.2%; m.p. 164–167°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.51 (s, 1H, CONH), 8.07 (d, J = 8.4 Hz, 2H, Ph-H), 7.92 (d, J = 8.4 Hz, 2H, Ph-H), 7.61 (s, 1H, pyrimidine-H), 7.46 (d, J = 8.4 Hz, 2H, Ph-H), 7.38 (d, J = 8.4 Hz, 2H, Ph-H), 2.53 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.25, 169.69, 165.38, 156.65, 156.41 (q, J = 35.25 Hz), 154.77, 144.37, 138.83, 132.82, 130.17, 122.09, 122.05, 121.96, 121.82 (q, J = 272.85 Hz), 121.48 (q, J = 254.25 Hz), 103.76, 25.80; HRMS (ESI) calcd. for C₂₀H₁₃F₆N₃O₃ [M + Na]⁺: 480.0756, found: 480.0753.

2.4.16. N-(4-bromo-3-chlorophenyl)-4-((2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)oxy)benzamide (4p)

White solid; yield: 48.0%; m.p. 166–169°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.57 (s, 1H, CONH), 8.18 (d, J = 2.4 Hz, 1H, Ph-H), 8.07 (d, J = 9.0 Hz, 2H, Ph-H), 7.76 (d, J = 9.0 Hz, 1H, Ph-H), 7.73–7.66 (m, 1H, Ph-H), 7.61 (s, 1H, pyrimidine-H), 7.47 (d, J = 9.0 Hz, 2H, Ph-H), 2.51 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.23, 169.68, 167.43, 165.54, 156.42 (q, J = 34.9 Hz), 155.01, 154.93, 140.35, 134.25, 133.40, 132.50, 132.17, 131.98, 130.22, 129.13, 122.12, 122.24 (q, J = 273.3 Hz), 122.08, 121.03, 119.55, 117.40, 117.18, 103.79, 25.88. HRMS (ESI) calcd. for C₁₉H₁₂BrClF₃N₃O₂ [M + H]⁺: 485.9826, found: 485.9825.

2.4.17. N-(3-chloro-4-(trifluoromethoxy)phenyl)-4-((2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)oxy)benzamide (4q)

White solid; yield: 29.0%; m.p. 176–178°C; ¹H NMR (600 MHz, DMSO-d₆, ppm) δ 10.66 (s, 1H, CONH), 8.20 (d, J = 2.4 Hz, 1H, Ph-H), 8.08 (d, 2H, J = 8.4 Hz, Ph-H), 7.86 (dd, J₁ = 2.4 Hz, J₂ = 6.6 Hz, 1H, Ph-H), 7.59–7.57 (m, 2H, Ph-H and pyrimidine-H), 7.47 (d, J = 9.0 Hz, 2H, Ph-H), 2.53 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆, ppm) δ 170.21, 169.69, 165.59, 156.42 (q, J = 34.8 Hz), 154.95, 139.92, 132.42, 130.24, 126.44, 123.99, 122.11, 121.99, 121.81 (q, J = 273.3 Hz), 121.41 (q, J = 256.35 Hz), 120.53, 103.78, 25.88. HRMS (ESI) calcd. for C₂₀H₁₃F₆ClN₃O₃ [M + H]⁺: 492.0551, found: 492.0544.

2.5. In Vitro Antifungal Activity Test

The in vitro antifungal activities against Phomopsis sp., B. dothidea, and B. cinerea of the target compounds 4a–4q at 50 μg/mL were evaluated by the mycelium growth rate technique [32]. Each compound was dissolved in 1 mL DMSO and 9 mL 0.1% Twain aqueous solution, and then the mixture solution was added to 90 mL potato dextrose agar (PDA) medium to obtain 100 mL mixed PDA medium with the test compound concentration of 50 μg/mL. The mixed PDA mediums were poured into 6 dishes and cooled to room temperature to prepare PDA plates. Then, approximately 0.4 cm diameter mycelia dishes were cut from culture medium and transferred to the middle of PDA plates with a germfree inoculation needle. After that, the inoculated PDA plates were fostered at 27 ± 1°C for 3-4 days. Three replicates were conducted for each treatment. The following formula (1) was used to calculate the inhibition rates I (%), where C (cm) represents the diameter of fungi growth on untreated PDA and T (cm) represents the diameter of fungi on treated PDA:

2.6. Insecticidal Activity Test

The insecticidal activities against S. frugiperda and M. separata of the target compounds 4a–4q at 500 μg/mL were performed according to the reported methods [33]. Each compound was added to 0.1 mg/L NP-10 solvent to prepare the test compound solution with 500 µg/mL concentration. Then, approximately 5 cm length maize leaves and 3 cm diameter sweet corn leaves were soaked into the mixed solutions for 10 s and then dried at room temperature and placed in the Petri dish. After that, 30 larvae of second-instar S. frugiperda and M. separata were transferred into the Petri dish and cultivated in the incubator at 27 ± 1°C for 48 h. Three replicates were performed for each treatment. The mortality rates were determined using Abbott’s formula.

3. Results and Discussion

3.1. Chemistry

The synthetic route for the target compounds is summarized in Scheme 1. Firstly, using ethyl trifluoroacetoacetate, formamidine hydrochloride, and acetamidine hydrochloride as raw materials, 2-substituted-4-chloro-6-(trifluoromethyl)pyrimidine (2) was synthesized including cyclization and chlorination reactions. Next, the key intermediate 2-substituted-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)benzoic acid (3) was synthesized from 2-substituted-4-chloro-6-(trifluoromethyl)pyrimidine (2) reacting with 4-hydroxybenzoic acid and cesium carbonate in acetone under reflux conditions. Finally, the target compounds 4a–4q were obtained from 2-substituted-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)benzoic acid (3) and aromatic amines by amidation reaction.

3.2. Antifungal Activity Test in Vitro

Table 1 showed that compounds 4a, 4j, 4o, and 4q exhibited higher antifungal activity against B. dothidea, with the inhibition rates of 89.8%, 85.9%, 93.1%, and 98.5%, respectively, which were even better than pyrimethanil (84.4%). Meanwhile, compounds 4o and 4q exhibited higher antifungal activity against Phomopsis sp., with the inhibition rates of 89.0% and 92.0%, respectively, which were even better than pyrimethanil (85.1%). Furthermore, compounds 4a, 4f, 4g, 4o, 4p, and 4q revealed excellent antifungal activity against B. cinerea, with the inhibition rates of 90.3%, 91.7%, 86.8%, 96.7%, 83.8%, and 98.5%, respectively, which were even better than pyrimethanil (82.8%). Especially, compound 4q revealed the best antifungal activity against B. dothidea (98.5%), Phomopsis sp. (92.0%), and B. cinerea (98.5%) than those of pyrimethanil and the other target compounds.

According to the antifungal activity data, the difference of R₁ and R₂ substituent groups was related to the antifungal activity of the target compounds. When the R₂ was the same group, with the presence of -H at R₁, the target compound revealed higher antifungal activity than compound with the R₁ was -CH₃. When R₁ was H, compounds with the presence of -F and -OCF₃ at R₂ represented higher antifungal activity compared with the other target compounds.

3.3. Insecticidal Activity Test

Table 2 shows that the target compounds 4a–4p indicated lower insecticidal activities against S. frugiperda (10.0–86.7%) and M. separata (13.3–90.0%) at 500 µg/mL than those of chlorantraniliprole. Especially, compound 4h demonstrated an excellent mortality rate of 90.0% against M. separata as well as compounds 4o and 4q revealed moderate insecticidal activity against S. frugiperda with the mortality rates of 83.3% and 86.7%, respectively.

4. Conclusion

In summary, 17 novel N-phenylbenzamide derivatives containing a trifluoromethylpyrimidine moiety were prepared, and their structures were confirmed by ¹H NMR, ¹³C NMR, and HRMS. Biological activity results indicated that most of the target compounds exhibited moderate to good antifungal and insecticidal activities. Among them, compound 4q revealed the best antifungal activities against Phomopsis sp., B. dothidea, and B. cinerea than those of pyrimethanil and the other target compounds. This study provided hope for discovery, development, design, and synthesis of novel N-phenylbenzamide derivatives containing a trifluoromethylpyrimidine.

Data Availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Conflicts of Interest

All authors state that there are no conflicts of interest.

Acknowledgments

The authors acknowledge funds from the Science and Technology Fund Project of Guizhou (nos. [2020]1Z023, [2019]1454, and [2019]1015), National Natural Science Foundation of China (nos. 31701821 and 21762037), Young Sci-Tech Talents Growth Program from the Department of Education of Guizhou Province (nos. QJHKYZ[2018]297 and QJHKYZ[2018]303), Guiyang Science and Technology Bureau and Guiyang University (no. GYU-KY-[2021], and Undergraduate Innovation and Entrepreneurship Training Program (nos. 2018520773 and 2018520841).

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