Design, Synthesis and Insecticidal Activity of Novel meta-Diamide Compounds Containing Methoxy Group

Abstract

This work is based on the precursor compound cyproflanilide and designs a series of methoxy containing meta-diamine compounds. By replacing the fluorine atom on the phenyl ring in cyproflanilide with methoxy group, 17 derivatives (12a-12q) were obtained with yields ranging from 46 to 92%, which were characterized by high-resolution mass spectrometry, and nuclear magnetic resonance (1H and ¹³C) spectroscopy and infrared. The insecticidal activities were evaluated against the Plutella xylostella and Spodoptera frugiperda. Compound N-(3-((2-bromopropane-4-(perfluoropropan-2-yl))-6-(trifluoromethyl)phenyl)methoxyphenyl)-N-(cyclopropylmethyl)-6-fluoronicotinamide (12q) showed significant insecticidal activity against the Plutella xylostella with a mortality rate of 97.67% at a concentration of 1 mg L^-1. It also exhibited moderate activity against the Spodoptera frugiperda at a concentration of 0.1 mg L^-1, which can be used as a template for structure modification to obtain higher insecticidal activity.

Keywords: methoxy group; meta-diamide compounds; insecticidal activity; structure-activity relationship

Introduction

Synthetic pesticides have been widely used to prevent pest infestations and greatly increased crop productivity since the emergence of modern agriculture. However, with the advancement of pesticide technologies and the increased focus on health and environmental protection, high insecticidal activity is no longer the sole criterion used to evaluate pesticide quality.¹,² Rather, it has become crucial to evaluate their safety and compatibility with the environment and human health. Organic farming, utilizing fewer synthetic pesticides and emphasizing eco-friendly farming practices, is popular to control pests. Today, low toxicity is also an important standard for pesticides. Thus, high insecticidal activity and low mammalian toxicity of insecticides are crucial for controlling the spread of pests and meeting the global food safety and reducing environmental pollution.³,⁴ It is true that the use of pesticides will inevitably add pest resistance,⁵,⁶ which creates a need for new insecticides with novel mechanisms of action.

Diamide insecticides with low mammalian toxicity and less cross resistance against other existing insecticides have shown great activity against lepidopteron pests and attracted worldwide attention.⁷,⁸,⁹ The reported diamide insecticides include flubendiamide (1; Figure 1), chlorantraniliprole (2; Figure 1), cyantraniliprole (3; Figure 1), tetrachlorantraniliprole (4; Figure 1) and cyclaniliprole (5; Figure 1).¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵ These insecticides mainly act on the insect’s fish nicotine receptor (RyR), continuously dredge the Ca²⁺ ion channel and infect insects.¹⁶,¹⁷,¹⁸,¹⁹,²⁰ However, due to the unreasonable use of pesticides, some lepidopteran pests have increased resistance to existing diamide insecticides, such as the Plutellidae Plutella and Spodoptera exigua.²¹,²²,²³,²⁴ Broflanilide (6; Figure 1) is a new and charming type of diamide insecticide developed. The structure of broflanilide contains a meta-positioned diamide group, which is the primary difference between it and traditional diamide insecticides. It acts on insect γ-aminobutyric acid (GABA) receptors and has been classified as a new group (group 30) by the Insecticide Resistance Action Committee (IRAC).²⁵,²⁶,²⁷ In 2019, it was reported a new insecticide, cyproflanilide (7; Figure 1), which demonstrated better effect against Diamondback moth and Chilo suppressalis than broflanilide.²⁸

Figure 1
Structure of some insecticides containing diamines and methoxy groups.

Recent studies had highlighted that most phenyl methoxy compounds exhibit good biological activities. For instance, Satoshi et al.²⁹ modified the methoxymethyl group of the 6-methoxy-2-methoxymethyl-3-(3,4-methylenedioxyphenyl)-1,4benzodioxan-7-yl with several alkyl groups (8; Figure1). The assay results indicated that the oxygen atom of the methoxymethyl group had a certain influence on its biological activity. Horty et al.³⁰ prepared a series of (E/Z)-2-arylstilbenes, and the assays results indicated that the (Z)-4-fluoro-3-methyl-2-(2,4-difluorostyryl)-4-fluoro-5-methoxy-1,1’-bipheny (9; Figure1) compound exhibit good activity in several pests, including Spodoptera exigua, Trichoplusia ni, Helicoverpa zea, Plutella xylostella, and Pseudoplusia includens. Xu et al.³¹ synthesized a series of monomethyl phthalate derivatives of podophyllotoxin (10; Figure 1), all the assays tested showed that the synthesized derivatives had good insecticidal activity. Structure activity relationship (SAR) indicated that the 4-methoxy group was an important structural property of podophyllotoxins for good insecticidal activity.

Inspired by the aforementioned view, we aimed to synthesize insecticides with high insecticidal activity against Plutella xylostella and Spodoptera frugiperda by replacing the fluorine atom on the benzene ring in the middle of cyproflanilide with a methoxy group and modifying the Q substituent (Figure 2).

Figure 2
Design strategy of the target compounds.

In the present study, a series of novel methoxy-containing meta-diamine compounds were synthesized based on the new mechanism of cyproflanilide and the extensive biological activity of methoxybenzene derivatives. The bioactivity of these compounds against Plutella xylostella and Spodoptera frugiperda was evaluated, and their structure-activity relationship was also discussed.

Experimental

General information

All reagents and solvents used in the work were purchased from Macklin (Shanghai, China) and Aladdin (Shanghai, China). The thin-layer chromatography (TLC) analyses were performed on 0.25 mm silica gel plates (GF254) and visualized with a ZF-20D ultraviolet. Flash column chromatographic separations were carried out on silica gel (200-300 mesh) using ethyl acetate and hexane as eluents.¹H and ¹³C nuclear magnetic resonance (NMR) were recorded at 400 and 101 MHz, respectively, using Bruker AV400 (Bruker Co., Switzerland) with tetramethylsilane as the internal standard in deuterated dimethyl sulfoxide (DMSO-d₆) solution. The chemical shift (δ) is given in ppm. The multiplicity is indicated by the following abbreviations: s (singlet), d (doublet), t (triplet), q (quarlet), dd (double of doublets), td (doublet of triplets), m (multiplet). All coupling constants (J values) were given in Hz. Infrared (IR) spectra in the range of 4000-500 cm^-1 were obtained using a Bruker INVENIO infrared spectrometer (Bruker Co., Germany). The melting points were measured using Hai Neng mp430 (Shanghai, China) video melting point apparatus. Mass spectra were obtained with an Agilent 1100 LC-MSD-Trap mass spectrometer (Agilent, CA, USA) equipped with standard electrospray ionization (ESI) apparatus.

Synthesis

Synthesis of intermediates 15-18

The intermediates 15, 17, 18 were synthesized according to the literature procedure.³²

Synthesis of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-nitrobenzamide (15)

2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl) aniline (10.03 g, 24.60 mmol) was combined with 2-fluoro-3-nitrobenzoyl chloride (5.0 g, 24.60 mmol), 4-dimethylaminopyridine (DMAP) (0.60 g, 4.92 mmol) and N,N-diisopropylethylamine (DIPEA) (6.36 g, 49.2 mmol) in a 50 mL three-necked flask with a magnetic stir bar. The reaction mixture was stirred magnetically at 120 °C for 7 h. After the reaction end, the pH was adjusted to 8 using 10% aqueous NaOH. The mixture was then extracted with ethyl acetate, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography using hexane-ethyl acetate (10:1 v v^-1) as an eluent. The compound 15 was obtained as a dark brown oil in a 46% yield (6.16 g, 10.73 mmol).

Synthesis of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-methoxy-3-nitrobenzamide (16)

Methanol (70 mL) and compound 15 (6.6 g, 11.48 mmol) were added to a 250 mL three-necked flask with magnetic stirrer. Then, sodium methoxide (0.86 g, 17.22 mmol) and K₂CO₃ (7.94 g, 57.4 mmol) were added to the solution in turn. After the reaction continued for 3 h at 80 °C, the reaction solution was extracted with water and ethyl acetate. The extract solution was removed under reduced pressure. The crude product was purified by silica gel column chromatography using hexane-ethyl acetate (5:1 v v^-1) as eluent. The compound 16 was obtained as a yellow solid in 87% yield (5.86 g, 10 mmol). The structure of compound 16 is confirmed by the data present below.

¹H NMR (400 MHz, DMSO-d₆) δ 3.94 (s, 3H), 7.53 (t, J 7.9 Hz, 1H), 7.94 (dd, J 7.7, 1.7 Hz, 1H), 7.98 (s, 1H), 8.15-8.12 (m, 1H), 8.45 (s, 1H), 10.88 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 64.1, 118.4 (d, J 273 Hz), 121.2 (d, J 27.9 Hz), 122.5 (dd, J 297 Hz), 122.8, 124.7, 126.3 (d, J 21.6 Hz), 127.3, 128.8, 130.7, 131.0, 131.3, 131.6, 133.8, 134.2 (d, J 10.6 Hz), 138.6, 144.2, 150.4, 164.3; HRMS (ESI) m/z, calcd. for C₁₈H₉BrF₁₀N₂O₄ [M + H]⁺: 585.9586, found: 585.9569.

Synthesis of 3-amino-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-methoxybenzamide (17)

To a 250 mL round bottom flask, compound 16 (5.86 g, 10 mmol), ethanol (60 mL), stannous chloride (9.0 g, 86.54 mmol) and concentrated hydrochloric acid (2 mL) were added sequentially. The reaction mixture was stirred magnetically for 3 h at 110 °C. TLC analysis confirmed the completion of the reaction. The solvent was removed under reduced pressure. Solution of water and ethyl acetate were added to the residue, adjusted to pH 10 by 10% aqueous NaOH. Then, the organic phase was concentrated. The residue was purified by silica gel column chromatography using hexane-ethyl acetate (3:1 v v^-1) as eluent. The compound 17 was obtained as a yellow solid in 59% yield (3.26 g, 5.86 mmol). The structure of compound 17 is confirmed by the data present below.

1H NMR (400 MHz, DMSO-d₆) δ 3.76 (s, 3H), 5.23 (s, 2H), 6.98-6.88 (m, 3H), 7.95 (s, 1H), 8.39 (s, 1H), 10.30 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 60.3, 116.4, 118.3, 118.6, 120.7, 121.3 (d, J 27.6 Hz), 122.1 (dd, J 267 Hz), 122.5, 124.3, 125.8 (d, J 21.4 Hz), 127.6, 129.0 (d, J 1.7 Hz), 130.9 (dd, J 4.0, 0.0 Hz), 133.9 (d, J 10.1 Hz), 139.8, 142.2, 144.1, 165.5; HRMS (ESI) m/z, calcd. for C₁₈H₁₁BrF₁₀N₂O₂ [M + H]⁺: 555.9844, found: 555.9823.

Synthesis of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-3-((cyclopropylmethyl)amino)-2-methoxybenzamide (18)

Compound 17 (2.0 g, 5.59 mmol), 1,2-dichloroethane 45 mL, trifluoroacetic acid (2.43 g, 21.31 mmol) and cyclopropyl formaldehyde (0.024 g, 3.33 mmol) were added to 250 mL three-neck flask. The reaction mixture was magnetic stirred for 1 h at room temperature. Sodium triacetoxyborohydride (2.27 g, 10.71 mmol) was slowly added and stirred for 3 h at room temperature. After the reaction completion the solution was adjusted to pH 8 by saturated sodium carbonate solution, extract with the solution of dichloromethane and water. After organic phase was concentrated the residue was purified by silica gel column chromatography using hexane-ethyl acetate (5:1 v v^-1) as eluent. The compound 18 was obtained as a yellow solid in 70% yield (2.26 g, 3.70 mmol). The structure of compound 18 is supported by the data present below.

IR (KBr) v / cm^-1 3357, 3308, 1674, 1598, 1584, 1480, 1451, 1423, 1341, 1321, 1304, 1276, 1238, 1202, 1165, 1146, 1120,1084, 1005, 985, 890, 845, 760, 748, 726, 706, 685, 430; ¹H NMR (400 MHz, DMSO-d₆) δ 0.27-0.21 (m, 2H), 0.46 (dd, J 8.0, 5.6 Hz, 2H), 1.12 (t, J 7.9 Hz, 1H), 3.04 (d, J 6.1 Hz, 2H), 3.78 (s, 3H), 5.40 (s, 1H), 6.90 (dd, J 18.0, 7.9 Hz, 2H), 7.07 (t, J 7.9 Hz, 1H), 7.96 (s, 1H), 8.41 (s, 1H), 10.35 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 3.3, 10.6, 47.0, 60.9, 113.5, 115.6, 118.4 (d, J 27.4 Hz), 121.3 (d, J 27.4 Hz), 122 (dd, J 272.5 Hz), 122.6, 123.4, 124.6, 125.8 (d, J 21.4 Hz), 127.5, 129.0 (d, J 1.5 Hz), 130.6 (d, J 31.4 Hz), 131.2 (d, J 30.0 Hz), 134.0 (d, J 9.9 Hz), 139.7, 142.2, 144.4, 165.7; HRMS (ESI) m/z, calcd. for C₂₂H₁₇BrF₁₀N₂O₂ [M + H]⁺: 610.0314, found: 610.0284.

Synthesis of compounds 12a-12q

Intermediate 18 (0.24 g, 0.39 mmol), tetrahydrofuran (4 mL), pyridine (0.5 mL) and benzoyl chloride (66 mg, 0.47 mmol) were added to a 50 mL single mouth bottle in turn. The solution was stirred at 80 °C for 4-5 h. After reaction completion, solution was neutralized to acid state with dilute hydrochloric acid, then extracted with water and ethyl acetate. After the organic phase was concentrated, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (5:1 v v^-1) as eluent to obtain compound 12a.

The compounds 12b-12q were synthesized using similar method of compound 12a. The structure of compounds 12b-12q were confirmed by the data present below.

N-(2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl) phenyl)-3-(N-(cyclopropylmethyl)benzamido)-2-methoxy-benzamide (12a)

Yield 85%; white solid; mp 113.7-115.1 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 0.15 (d, J 26.8 Hz, 2H), 0.43 (s, 2H), 1.07 (brs, 1H), 3.84 (s, 3H), 4.11 (s, 2H), 7.26 (d, J 42.2 Hz, 5H), 7.55 (d, J 35.4 Hz, 3H), 7.94 (s, 1H), 8.40 (s, 1H), 10.49 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 3.6, 4.6, 10.3, 29.8, 31.9, 53.4, 62.2, 118.8 (d, J 27.4 Hz), 121.0, 121.5, 121.8, 122.8 (dd, J 291.2 Hz), 123.1, 123.7 (d, J 8.3 Hz), 124.4, 124.7, 126.5 (d, J 21.5 Hz), 128.1, 128.3 (d, J 3.3 Hz), 129.4 (d, J 15.1 Hz), 130.0, 131.2 (d, J 32.3 Hz), 131.7, 133.7 (d, J 4.0 Hz), 134.5 (d, J 10.3 Hz), 136.9 (d, J 36.8 Hz), 139.5, 154.0 (dd, J 7.1, 3.1 Hz), 165.4, 170.4; HRMS (ESI) m/z, calcd. for C₂₉H₂₁BrF₁₀N₂O₃ [M + H]⁺: 714.0576, found: 714.0549.

N-(2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl) phenyl)-3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-methoxybenzamide (12b)

Yield 89%; white solid; mp 142-143.1 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 0.16 (s, 2H), 0.44 (s, 2H), 1.09 (s, 1H), 3.53-3.36 (m, 1H), 3.82 (s, 3H), 4.03 (q, J 7.1 Hz, 1H), 7.04 (s, 2H), 7.24 (s, 1H), 7.37 (s, 2H), 7.60 (dd, J 14.3, 7.3 Hz, 2H), 7.94 (s, 1H), 8.40 (s, 1H), 10.41 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 3.7, 4.5, 10.3, 53.7, 62.2, 114.8 (d, J 18.0 Hz), 118.7 (d, J 27.8 Hz), 120.8, 121.6 (d, J 28.2 Hz), 122.2 (dd, J 262.5 Hz), 123.5, 123.8, 126.3, 126.4, 126.6, 128.9, 129.5, 130.8, 131.1, 131.4, 132.9 (d, J 3.1 Hz), 134.2 (d, J 10.7 Hz), 137.2, 139.3, 153.8, 159.0 (d, J 261 Hz), 161.6, 164.1, 165.0, 169.5; HRMS (ESI) m/z, calcd. for C₂₉H₂₀BrF₁₁N₂O₃ [M + H]⁺: 732.0482, found: 732.0442.

N-(2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl) phenyl)-3-(4-chloro-N- (cyclopropylmethyl)benzamido)-2-methoxybenzamide (12c)

Yield 86%; white solid; mp 119-121.0 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 0.17 (s, 2H), 0.45 (s, 2H), 1.09 (s, 1H), 3.51-3.37 (m, 1H), 3.82 (s, 3H), 4.10-4.00 (m, 1H), 7.36-7.18 (m, 5H), 7.61 (t, J 8.2 Hz, 2H), 7.94 (s, 1H), 8.40 (s, 1H), 10.41 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 3.2, 4.1, 9.8, 53.2, 59.6, 61.8, 118.3 (d, J 27.9 Hz), 120.4, 121.1 (d, J 27.3 Hz), 121.7 (dd, J 270.8 Hz), 122.5, 123.1, 123.4, 126.1 (d, J 21.4 Hz), 127.4, 128.4, 129.2, 129.6, 130.4, 130.7, 131.0, 132.5, 133.7 (d, J 10.0 Hz), 134.3, 134.9, 136.6, 138.8, 153.4, 164.4, 169.0; HRMS (ESI) m/z, calcd. for C₂₉H₂₀BrClF₁₁N₂O₃ [M + H]⁺: 748.0186, found: 748.0072.

N-(2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl) phenyl)-3-(4-bromo-N-(cyclopropylmethyl)benzamido)-2-methoxybenzamide (12d)

Yield 68%; white solid; mp 83.4-84.9 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 0.18 (s, 2H), 0.45 (s, 2H), 1.09 (s, 1H), 3.49-3.37 (m, 1H), 3.82 (s, 3H), 4.10-3.99 (m, 1H), 7.25 (s, 3H), 7.46-7.35 (m, 2H), 7.68-7.55 (m, 2H), 7.94 (s, 1H), 8.40 (s, 1H), 10.40 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 2.9, 3.8, 9.5, 52.8, 61.6, 118.6 (d, J 26.6 Hz), 120.8, 121.5 (d, J 28.1 Hz), 122.1 (d, J 270.8 Hz), 123.2, 123.5 (d, J 7.7 Hz), 123.6,123.8, 126.2, 126.3 (d, J 21.5 Hz), 127.9 (d, J 4.2 Hz), 129.0, 129.4, 130.2, 130.8, 131.2, 133.0, 134.3 (d, J 10.5 Hz), 135.8, 136.8, 139.3, 153.7, 164.9, 169.4; HRMS (ESI) m/z, calcd. for C₂₉H₂₀Br₂F₁₀N₂O₃ [M + H]⁺: 791.9681, found: 791.9642.

N-(2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl) phenyl)-3-(N-(cyclopropylmethyl)-4-(trifluoromethyl) benzamido)-2-methoxybenzamide (12e)

Yield 46%; white solid; mp 73.5-74.9 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 0.21 (s, 2H), 0.48 (s, 2H), 1.14 (s, 1H), 3.50 (dd, J 12.8, 7.1 Hz, 1H), 3.84 (s, 3H), 4.05 (dq, J 14.2, 6.9 Hz, 1H), 7.26 (t, J 7.4 Hz, 1H), 7.74-7.46 (m, 6H), 7.92 (s, 1H), 8.39 (s, 1H), 10.28 (d, J 68.5 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 1.9, 2.6, 8.4, 51.7, 60.5, 116.8 (d, J 28.3Hz), 118.8 (d, J 5.1 Hz), 119.6 (d, J 27.4 Hz), 121.0 (d, J 21.3 Hz), 121.6, 122.2 (d, J 11.3 Hz), 122.9, 122.6 (d, J 281 Hz), 123.5 (d, J 18.5 Hz), 124.4 (d, J 21.7 Hz), 126.4 (dd, J 12.3, 5.5 Hz), 127.1 (d, J 19.7 Hz), 127.7 (dd, J 7.7, 2.2 Hz), 128.0 (d, J 5.2 Hz), 129.0 (d, J 3.5 Hz), 130.1 (d, J 16.2 Hz), 131.0 (d, J 4.3 Hz), 131.4 (d, J 4.8 Hz), 132.4 (d, J 9.8 Hz), 134.9, 136.5 (d, J 2.1 Hz), 137.5, 138.8, 151.8, 167.4; HRMS (ESI) m/z, calcd. for C₃₀H₂₀BrF₁₃N₂O₃ [M + H]⁺: 782.0450, found: 782.0411.

N-(2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl) phenyl)-3-(4-cyano-N-(cyclopropylmethyl)benzamido)-2-methoxybenzamide (12f)

Yield 55%; white solid; mp 79.7-81.8 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 0.21 (s, 2H), 0.48 (s, 2H), 1.12 (s, 1H), 3.50 (m, 1H), 3.82 (s, 3H), 4.09-3.97 (m, 1H), 7.26 (t, J 7.5 Hz, 1H), 7.45 (d, J 7.8 Hz, 2H), 7.61 (d, J 7.2 Hz, 1H), 7.68 (d, J 7.7 Hz, 3H), 7.94 (s, 1H), 8.40 (s, 1H), 10.32 (d, J 38.1 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 3.7, 4.4, 10.1, 53.5, 62.4, 112.1, 115.3, 118.5, 120.7, 121.3 (d, J 3.3 Hz), 121.4, 121.5 (d, J 1.3 Hz), 121.6 (d, J 2.3 Hz), 123.0 (d, J 297.9 Hz), 123.5, 124.0, 126.3 (d, J 21.6 Hz), 128.8, 129.0, 129.4, 130.2, 131.5 (d, J 57.0 Hz), 132.8 (d, J 22.6 Hz), 134.3 (d, J 10.0 Hz), 136.4, 139.2, 141.1, 153.6, 166.3, 169.0; HRMS (ESI) m/z, calcd. for C₃₀H₂₀BrF₁₀N₃O₃ [M + H]⁺: 739.0528, found: 739.0588.

N-(2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl) phenyl)-3-(N-(cyclopropylmethyl)-3-fluorobenzamido)-2-methoxybenzamide (12g)

Yield 89%; yellow solid; mp 91.6-93.4 °C; IR (KBr) v / cm^-1 3081, 1718, 1686, 1654, 1589, 1474, 1442, 1442, 1426, 1376, 1304, 1278, 1232, 1196, 1171, 1005, 985, 891, 795, 747, 728; ¹H NMR (400 MHz, DMSO-d₆) δ 0.19 (s, 2H), 0.47 (s, 2H), 1.10 (s, 1H), 3.54-3.44 (m, 1H), 3.82 (s, 3H), 4.03-3.95 (m, 1H), 7.08 (s, 1H), 7.44-7.19 (m, 2H), 7.74–7.52 (m, 2H), 7.85-7.78 (m, 1H), 7.94 (s, 1H), 8.40 (s, 1H), 10.34 (s, 1H), 10.38 (d, J 28.6 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 3.3, 4.0, 9.7, 53.3, 61.9, 116.4, 117.7 (d, J 17.9 Hz), 118.2 (d, J 17.2 Hz), 120.3, 121.0 (d, J 28.0 Hz), 122.0 (d, J 283.9 Hz), 122.5, 123.0, 123.5, 124.8, 125.8, 126.0, 126.7 (dd, J 7.7, 3.4 Hz), 128.5, 128.6, 132.1, 133.6, 133.8 (d, J 9.6 Hz), 138.9, 147.8 (d, J 13.1 Hz), 150.3 (d, J 13.1 Hz), 150.7 (d, J 248.0 Hz), 151.0 (d, J 12.5 Hz), 153.2, 153.6 (d, J 12.7 Hz), 165.3, 167.8; HRMS (ESI) m/z, calcd. for C₂₉H₂₀BrF₁₁N₂O₃ [M + H]⁺: 732.0482, found 733.0315.

N-(3-((2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-methoxyphenyl)-N-(cyclopropylmethyl)-2-fluorobenzamide (12h)

Yield 79%; white solid; mp 70.2-73.5 °C; IR (KBr) v / cm^-1 3308, 3083, 1690, 1654, 1614, 1582, 1490, 1454, 1426, 1382, 1306, 1279, 1229, 1204, 1169,1144, 1081, 1005, 985, 891, 757, 728, 702; ¹H NMR (400 MHz, DMSO-d₆) δ 0.25-0.12 (m, 2H), 0.47 (q, J 5.4 Hz, 2H), 1.17-1.04 (m, 1H), 3.90 (m, 4H), 4.12 (dd, J 14.0, 6.8 Hz, 1H), 7.04 (t, J 8.1 Hz, 2H), 7.16 (t, J 7.8 Hz, 1H), 7.35-7.24 (m, 1H), 7.40 (q, J 7.6 Hz, 1H), 7.52 (d, J 7.8 Hz, 1H), 7.59 (d, J 9.2 Hz, 1H), 7.94 (s, 1H), 8.39 (s, 1H), 10.47 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 2.7, 3.9, 9.5, 52.0, 61.5, 114.9 (d, J 21.1 Hz), 116.5 (d, J 22.2 Hz), 118.0 (d, J 28.9 Hz), 118.9 (d, J 10.2 Hz), 119.1 (d, J 259.6), 120.8 (d, J 28.8 Hz), 122.5, 123.4, 124.0 (d, J 3.8 Hz), 124.6 (d, J 16.8 Hz), 125.7 (d, J 21.5 Hz), 127.0, 128.5 (d, J 14.6 Hz), 128.9, 129.2, 130.2, 130.6, 130.8 (d, J 8.1 Hz), 131.5, 132.3, 133.7 (d, J 10.4 Hz), 134.0, 134.3 (d, J 8.9 Hz), 134.8, 138.8 (d, J 25.3 Hz), 153.6, 154.0, 156.1, 158.5, 159.0 (d, J 250 Hz), 159.5, 162.0, 164.7 (d, J 3.0 Hz), 165.6 (d, J 31.7 Hz); HRMS (ESI) m/z, calcd. for C₂₉H₂₀BrF₁₁N₂O₃ [M + H]⁺: 732.0482, found: 733.0315.

N-(2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl) phenyl)-3-(N-(cyclopropylmethyl)-3-(trifluoromethyl) benzamido)-2-methoxybenzamide (12i)

Yield 73%; white solid; mp 61.5-62.5 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 0.20 (s, 2H), 0.47 (s, 2H), 1.12 (s, 1H), 3.45 (dd, J 12.3, 6.7 Hz, 1H), 3.84 (s, 3H), 4.06 (d, J 16.5 Hz, 1H), 7.24 (s, 1H), 7.50-7.38 (m, 1H), 7.62 (m, 5H), 7.93 (s, 1H), 8.39 (s, 1H), 10.36 (d, J 42.7 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 2.5, 3.6, 9.4, 51.8, 61.4, 118.0 (d, J 29.7 Hz), 119.3, 119.8, 120.2, 120.8 (d, J 28.4 Hz), 122.5, 122.7, 122.9 (d, J 3.8 Hz), 123.6,124.7 (d, J 257 Hz), 125.1 (dt, J 7.9, 4.5 Hz), 125.7 (d, J 3.9 Hz), 125.8, 128.4 (d, J 8.1 Hz), 128.6, 128.7 (d, J 5.5 Hz), 128.9, 129.0-128.9 (m), 129.2, 129.7, 131.5, 132.8, 133.3 (d, J 6.0 Hz), 133.7 (d, J 8.9 Hz), 135.1, 135.4, 136.1, 136.6 (d, J 19.1 Hz), 138.7, 153.2, 164.7, 165.6, 169.2, 171.9; HRMS (ESI) m/z, calcd. for C₃₀H₂₀BrF₁₃N₂O₃ [M + H]⁺: 782.0450, found: 782.0410.

N-(3-((2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-methoxyphenyl)-N-(cyclopropylmethyl)-2,6-difluorobenzamide (12j)

Yield 78%; brown solid; mp 135-137 °C; IR (KBr) v / cm^-1 3009, 1695, 1663, 1626, 1590, 1478, 1420, 1308, 1275, 1236, 1204, 1169, 1131, 1020, 985, 920, 891, 804, 770, 728, 594; ¹H NMR (400 MHz, DMSO-d₆) δ 0.26-0.15 (m, 2H), 0.48 (d, J 12.3 Hz, 2H), 1.14-1.03 (m, 1H), 3.42 (s, 1H), 3.89 (d, J 10.6 Hz, 4H), 4.12-4.00 (m, 1H), 7.27-7.03 (m, 3H), 7.62 (t, J 6.5 Hz, 2H), 7.94 (s, 1H), 8.40 (s, 1H); 10.49 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 2.8, 3.9, 9.5, 52.1, 54.6, 110.7 (d, J 18.5 Hz), 111.4, 112.3-111.5 (m), 113.6 (d, J 24.4 Hz), 114.3 (t, J 22.4 Hz), 118.0 (d, J 28.7 Hz), 120.9 (d, J 29.5 Hz), 122.1 (d, J 297Hz), 122.4, 123.0 (d, J 9.7 Hz), 125.6, 125.9, 128.5 (d, J 14.4 Hz), 129.1, 129.5, 130.3 (d, J 12.6 Hz), 131.3 (t, J 10.0 Hz), 132.1-131.6 (m), 132.6 (t, J 10.4 Hz), 133.7, 138.7 (d, J 24.8 Hz), 153.9, 157.7 (d, J 7.1 Hz), 160.2 (d, J 6.9 Hz), 160.9 (d, J 21.4 Hz), 161.8 (d, J 265.5Hz), 164.5, 164.7; HRMS (ESI) m/z, calcd. for C₂₉H₁₉BrF₁₂N₂O₃ [M + H]⁺: 750.0387, found: 750.0039.

N-(3-((2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl) phenyl) carbamoyl)-2-methoxyphenyl)-N-(cyclopropylmethyl)-2,4,5-trifluorobenzamide (12k)

Yield 50%; white solid; mp 116.7-117.5 °C; IR (KBr) v / cm^-1 3325, 3078, 1654, 1629, 1582, 1517, 1490, 1448, 1426, 1381, 1321, 1304, 1279, 1231, 1203, 1170, 1146, 1081, 1005, 985, 891, 852, 811, 761, 750, 728, 701; ¹H NMR (400 MHz, DMSO-d₆) δ 0.22 (s, 2H), 0.58-0.44 (m, 2H), 1.10 (d, J 7.2 Hz, 1H), 3.51 (m, 1H), 3.87 (m, 3H), 4.03-3.96 (m, 1H), 7.27 (t, J 7.8 Hz, 1H), 7.51-7.33 (m, 2H), 7.71-7.57 (m, 2H), 7.94 (s, 1H), 8.40 (s, 1H), 10.38 (d, J 50.1 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) d 3.9, 4.3, 10.4, 54.4, 61.5, 106.3 (dd, J 28.7, 21.5 Hz), 108.1 (dd, J 29.2, 21.4 Hz), 116.8 (dt, J 12.3, 4.2 Hz), 118.3-117.7 (m), 118.8 (d, J 27.6 Hz), 120.1 (d, J 20.3 Hz), 121.9 (d, J 27.9 Hz), 122.2 (d, J 18.3 Hz), 123.1, 123.7, 123.9, 124.3 (d, J 283.7 Hz), 126.6 (d, J 21.4 Hz), 129.3 (d, J 13.8 Hz), 129.8, 134.5 (d, J 10.7 Hz), 135.7, 139.6 (d, J 24.9 Hz), 144.6 (d, J 13.0 Hz), 145.0 (dd, J 12.7, 3.7 Hz), 147.0, 147.1 (d, J 3.8 Hz), 147.5-147.3 (m), 148.8 (d, J 13.1 Hz), 151.6-151.0 (m), 152.4 (d, J 11.1 Hz), 153.9 (d, J 26.5 Hz), 154.9 (d, J 9.4 Hz), 156.4 (d, J 13.1 Hz), 158.1 (d, J 236 Hz), 159.0 (d, J 12.9 Hz), 163.8, 165.5, 170.8; HRMS (ESI) m/z, calcd. for C₂₉H₁₈BrF₁₃N₂O₃ [M + H]⁺: 768.0293, found: 769.0130.

N-(3-((2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-methoxyphenyl)-N-(cyclopropylmethyl)-2-fluoroisonicotinamide (12l)

Yield 65%; yellow solid; mp 67.8-68.8 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 0.20 (s, 2H), 0.53–0.44 (m, 2H), 1.10 (s, 1H), 3.47 (dd, J 12.9, 7.3 Hz, 1H), 3.85 (s, 3H), 4.09-3.99 (m, 1H), 7.07 (s, 1H), 7.18 (d, J 4.7 Hz, 1H), 7.27 (t, J 7.9 Hz, 1H), 7.64 (d, J 7.2 Hz, 1H), 7.71 (d, J 7.6 Hz, 1H), 7.94 (s, 1H), 8.09 (d, J 5.0 Hz, 1H), 8.40 (s, 1H), 10.47 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 3.4, 4.2, 9.8, 53.1, 62.2, 108.0 (d, J 39.3 Hz), 109.3 (d, J 39.2 Hz), 118.4 (d, J 26.1 Hz), 120.5, 121.3, 121.8 (d, J 261.1 Hz), 123.0 (d, J 47.5 Hz), 123.6, 126.1 (d, J 21.4 Hz), 128.8, 129.7, 131.0, 132.7, 134.1 (d, J 9.6 Hz), 135.3, 139.0, 147.4 (d, J 14.5 Hz), 148.9 (d, J 15.0 Hz), 149.8 (d, J 7.4 Hz), 153.6, 161.3, 163.6, 164.1 (d, J 235.5Hz), 164.8, 167.0; HRMS (ESI) m/z, calcd. for C₂₈H₁₉BrF₁₁N₃O₃ [M + H]⁺: 733.0434, found: 733.0399.

N-(3-((2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-methoxyphenyl)-N-(cyclopropylmethyl)isonicotinamide (12m)

Yield 78%; white solid; mp 154.2-155.5 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 0.18 (s, 2H), 0.47 (d, J 7.4 Hz, 2H), 1.09 (s, 1H), 3.41 (dd, J 12.9 Hz, 7.4 Hz, 1H), 3.85 (s, 3H), 4.07 (dd, J 14.0, 6.9 Hz, 1H), 7.23 (dd, J 12.9, 6.0 Hz, 3H), 7.63 (s, 2H), 7.94 (s, 1H), 8.40 (s, 1H), 8.44 (d, J 4.9 Hz, 2H), 10.48 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 3.9, 4.8, 10.4, 53.6, 62.6, 118.9, 119.1 (d, J 4.9 Hz), 121.2, 121.7 (d, J 5.7 Hz), 122.4, 123.0 (d, J 257.5 Hz), 123.4, 124.0 (d, J 14.9 Hz), 126.7 (d, J 21.5 Hz), 129.5, 130.2, 131.4 (d, J 30.3 Hz), 133.6, 134.7 (d, J 10.8 Hz), 136.3, 138.7, 139.6, 144.4, 149.9, 151.3, 154.3, 165.4, 166.8, 168.8; HRMS (ESI) m/z, calcd. for C₂₈H₂₀BrF₁₀N₃O₃ [M + H]⁺: 715.0528, found: 715.0489.

N-(3-((2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl) phenyl)carbamoyl)-2-methoxyphenyl)-2-chloro-N-(cyclopropylmethyl)isonicotinamide (12n)

Yield 64%; white solid; mp 121-123.2 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 0.20 (s, 2H), 0.54-0.43 (m, 2H), 1.09 (s, 1H), 3.51-3.41 (m, 1H), 3.85 (s, 3H), 4.01 (dd, J 12.9, 6.8 Hz, 1H), 7.23 (d, J 4.6 Hz, 1H), 7.27 (t, J 7.9 Hz, 1H), 7.40 (s, 1H), 7.64 (d, J 6.9 Hz, 1H), 7.72 (d, J 7.7 Hz, 1H), 7.94 (s, 1H), 8.26 (d, J 5.0 Hz, 1H), 8.40 (s, 1H), 10.49 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 3.6, 9.1, 52.5, 61.6, 117.8 (d, J 26.9 Hz), 119.9, 120.4 (d, J 10.1 Hz), 120.7, 121.6 (d, J 270.0 Hz), 121.9 (d, J 35.3 Hz), 122.6, 122.9 (d, J 10.8 Hz), 123.6, 125.6, 127.2, 129.1, 130.2 (d, J 29.7 Hz), 132.1, 133.4 (d, J 9.9 Hz), 134.7, 138.4, 141.3, 146.8, 149.0, 150.5, 153.0, 164.1 (d, J 23.9 Hz), 166.2; HRMS (ESI) m/z, calcd. for C₂₈H₁₉BrClF₁₀N₃O₃ [M + H]⁺: 749.0139, found: 749.0101.

N-(3-((2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-methoxyphenyl)-N-(cyclopropylmethyl)nicotinamide (12o)

Yield 79%; white solid; mp 139.4-140.6 °C; IR (KBr) v / cm^-1 3369, 1685, 1663, 1588, 1487, 1455, 1425, 1396, 1377, 1345, 1304,1277, 1233, 1204, 1163, 1133, 1080, 1024, 983, 890, 767, 728, 708, 692; ¹H NMR (400 MHz, DMSO-d₆) δ 0.18 (s, 2H), 0.46 (s, 2H), 1.10 (s, 1H), 3.46 (d, J 20.6 Hz, 1H), 3.83 (s, 3H), 4.04 (dd, J 12.8, 5.1 Hz, 1H), 7.26 (d, J 6.4 Hz, 2H), 7.66 (td, J 17.8, 14.5, 7.2 Hz, 3H), 7.94 (s, 1H), 8.39 (s, 1H), 8.45 (s, 2H), 10.48 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 2.7, 3.5, 9.23, 55.9, 61.3, 117.8 (d, J 27.3 Hz), 119.9, 120.6 (d, J 27.9 Hz), 122.4-122.0 (m), 123.0 (t, J 27.3 Hz), 124.0 (d, J 263.8 Hz), 125.5 (d, J 21.6 Hz), 127.3, 128.5 (d, J 44.9 Hz), 130.2 (d, J 30.1 Hz), 131.6, 132.1, 133.5 (d, J 11.1 Hz), 134.9, 135.6, 136.3, 138.4, 147.7, 149.6 (d, J 10.4 Hz), 152.8 (d, J 9.2 Hz), 164.2, 165.7, 167.5, 171.4; HRMS (ESI) m/z, calcd. for C₂₈H₂₀BrF₁₀N₃O₃[M + H]⁺: 715.0528, found: 716.0363.

N-(3-((2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl) phenyl)carbamoyl)-2-methoxyphenyl)-6-chloro-N-(cyclopropylmethyl)nicotinamide (12p)

Yield 81%; white solid; mp 165.8-166.8 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 0.20 (s, 2H), 0.47 (d, J 6.9 Hz, 2H), 1.12-1.02 (m, 1H), 3.55 (dd, J 12.9, 7.2 Hz, 1H), 3.81 (s, 3H), 3.97 (dd, J 14.2, 7.1 Hz, 1H), 7.30 (t, J 7.8 Hz, 1H), 7.38 (d, J 8.2 Hz, 1H), 7.66 (t, J 8.2 Hz, 1H), 7.74 (t, J 9.1 Hz, 2H), 7.93 (s, 1H), 8.25 (s, 1H), 8.39 (s, 1H), 10.40 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 3.9, 9.7, 54.7, 62.0, 118.3, 120.3, 121.0 (d, J 27.5 Hz), 121.8 (d, J 268.8 Hz), 122.5, 123.2, 123.7, 124.3, 125.8, 126.0 (d, J 10.3 Hz), 128.6, 129.3 (d, J 30.1 Hz), 130.6 (d, J 30.4 Hz), 132.0, 133.8 (d, J 10.5 Hz), 136.0, 138.8, 140.2, 148.4, 150.5 (d, J 18.0 Hz), 152.8, 153.8, 164.3, 165.2, 166.9; HRMS (ESI) m/z, calcd. for C₂₈H₁₉BrClF₁₀N₃O₃ [M + H]⁺: 749.0139, found: 749.0098.

N-(3-((2-Bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-methoxyphenyl)-N-(cyclopropylmethyl)-6-fluoronicotinamide (12q)

Yield 92%; white solid; mp 162.5-164.0 °C; IR (KBr) v / cm^-1 3373, 1686, 1663, 1594, 1487, 1456, 1426, 1401, 1375, 1346, 1305, 1276, 1232, 1205, 1164, 1128, 1081, 1024, 1003, 983, 891, 838,770, 727, 702; ¹H NMR (400 MHz, DMSO-d₆) δ 0.20 (s, 2H), 0.47 (d, J 6.2 Hz, 2H), 1.11 (s, 1H), 3.55 (dd, J 12.8, 7.1 Hz, 1H), 3.81 (s, 3H), 3.98 (dd, J 14.1, 7.0 Hz, 1H), 7.05 (d, J 7.4 Hz, 1H), 7.34-7.26 (m, 1H), 7.68 (dd, J 33.4, 7.2 Hz, 2H), 7.92 (d, J 12.5 Hz, 2H), 8.10 (s, 1H), 8.39 (s, 1H), 10.39 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 3.2, 3.7, 9.5, 53.0, 61.7, 108.4 (d, J 35.0 Hz), 109.4 (d, J 37.8 Hz),120.1, 121.1 (d, J 273.0 Hz), 122.4, 122.8, 123.5, 125.6, 128.4, 128.8, 130.4 (d, J 4.3 Hz), 131.8 (d, J 5.1 Hz), 133.6 (d, J 10.1 Hz), 136.0, 138.6, 141.4 (d, J 6.7 Hz), 142.8 (d, J 9.6 Hz), 146.6 (d, J 16.3 Hz), 149.2 (d, J 16.9 Hz), 152.7, 164.2 (d, J 248 Hz), 164.8, 166.7; HRMS (ESI) m/z, calcd. for C₂₈H₁₉BrF₁₁N₃O₃ [M + H]⁺: 733.0434, found: 733.0401.

Biological assay

The tested insects Plutella xylostella and Spodoptera frugiperda were 3^rd instar larvae supported by Shanghai International Trading Co., Ltd. They were continuously fed indoors during the experiment. The leaf-dip method³² was used to test the insecticidal activity of the target compounds against Plutella xylostella and Spodoptera frugiperda. Commercially available cyproflanilide was used as a positive control. To prepare the target compound, 10 mg was dissolved in 1 mL of N,N-dimethylformamide (DMF) to make a 10000 mg L^-1 mother liquor. The required concentration solution for testing was obtained by diluting the mother liquor with 0.05% warm water.

The experiment was conducted as follows: the leaf plates were immersed in the solution for 10 s and dried in Petri dishes. Four plates were placed in each dish with filter paper to moisturize. 10 3^rd instar Plutella xylostella larvae were placed in each Petri dish, and the experiment was repeated 3 times. The Petri dishes were placed in a light incubator at 25 °C for 14 h. The number of Plutella xylostella larvae deaths was recorded after 1, 2, and 3 days, and the lethality rate was calculated. Lethality rate were corrected using Abbott’s formula. The testing method for Spodoptera frugiperda was the same as that for Plutella xylostella.

Overall, the study aimed to evaluate the insecticidal activity of the target compounds on Plutella xylostella and Spodoptera frugiperda using the leaf-dip method. Commercially available cyproflanilide was used as the positive control, and the target compounds were tested in various concentrations. The experiments were conducted using the third instar larvae, and lethality rate were calculated over a 3-day period. The study results could offer significant information on the potential of the target compounds as insecticides.

Results and Discussion

The target compounds 12a-12q were prepared in five steps according to the synthesis route shown in Scheme 1. In the first step, 2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)aniline was reacted with 2-fluoro-3-nitrobenzoyl chloride in the presence of 4-dimethylaminopyridine (DMAP) to prepare intermediates 15 with yield 46%.³³ In the second step, compound 15 was reacted with sodium methanol to prepare compound 16 with 87% yield. In the third step, compound 16 was involved in the reduction of nitro group by SnCl₂·2H₂O to obtain intermediate 17,³³ which then reacted with cyclopropanecarbaldehyde to produce intermediate 18.³³ In the last step, in order to evaluate the effect of methoxy-substituted Q group on the biological activity of the compounds, 17 new compounds were synthesized by amide condensation reaction with yields ranging from 46 to 92%.

Scheme 1
General synthetic procedure for target compounds 12a-12q. (i) N,N-Diisopropylethylamine (DIPIA), DMAP, 120 °C, (yield 46%); (ii) NaOMe, K₂CO₃, 80 °C, (yield 87%); (iii) EtOH, SnCl₂·2H₂O, HCl, 110 °C, (yield 59%); (iv) cyclopropanecarbaldehyde, 35 °C, (yield 70%); (v) pyridine, tetrahydrofuran (THF), 80 °C, (yield 46-92%).

After being synthesized and characterized, the biological activities of compounds 12a-12q were tested, and the results are presented in Table 1. The insecticidal activity of cyproflanilide was evaluated under the same conditions.

Table 1
The insecticidal activities of compounds 12a-12q

Compound	Q	3-Day mortality / %
		Plutella xylostella			Spodoptera frugiperda
		1 mg L-1	0.1 mg L-1	0.01 mg L-1	0.1 mg L-1
12a		83.33	3.33	3.33	8.33
12b		63.33	6.67	0.00	4.17
12c		0.00	3.33	0.00	0.00
12d		0.00	12.33	0.00	0.00
12e		0.00	0.00	0.00	8.33
12f		33.33	6.67	3.33	25.00
12g		43.33	3.33	0.00	12.50
12h		3.33	6.67	0.00	4.17
12i		6.67	3.33	0.00	16.67
12j		3.33	6.67	0.00	4.17
12k		0.00	0.00	0.00	0.00
12l		73.33	3.33	0.00	4.17
12m		10.00	3.33	3.33	4.17
12n		26.67	0.00	0.00	4.17
12o		30.00	3.33	0.00	0.00
12p		33.33	0.00	0.00	20.83
12q		96.67	12.33	0.00	58.33
Cyproflanilide	—	100.00	80.00	20.00	100.00

Insecticidal activities against Plutella xylostella

The biological activity test results showed that compounds 12a and 12b exhibited certain insecticidal activity, with lethality rates of 83.33 and 63.33%, respectively, at a concentration of 1 mg L^-1. The effect of different substituents at the para-position of the phenyl ring on insecticidal activity was compared. When the para-position of the phenyl ring was substituted with halogen atoms Cl or Br, corresponding compounds 12c and 12d behaved no biological activity and the lethality rate was 0.00% at a concentration of 1 mg L^-1. Studies³⁴,³⁵ have found that bulky and polarizable halogen atoms can occupy available pockets and interact with the binding site of biological targets through halogen bonding. Therefore, the lack of insecticidal activity in compounds 12c and 12d may be due to the large size and steric hindrance of the Cl and Br atoms. Based on the lethality rates results, the activity order of introducing halogen atoms on the phenyl ring is 12b (para-F) > 12c (para-Cl) and 12d (para-Br). This is contrary to the results of da Silva et al.,³⁵,³⁶ who showed good biological activity when polarizable halogen substituents were introduced at the para-position of the phenyl ring. When CF₃ and CN groups were introduced at the para-position of the phenyl ring, corresponding compounds 12e had no biological activity, with lethality rates of 0.00 and 33.33%, respectively, at a concentration of 1 mg L^-1. Based on the results of para-substitution on the phenyl ring, moderate insecticidal activity was observed when the para-position was substituted with an F atom. In order to investigate the effect of introducing a fluorine atom on the insecticidal activity, we introduced fluorine atoms at the meta- and para-positions of the phenyl ring, corresponding to compounds 12g (43.33%, 1 mg L^-1) and 12h (3.33%, 1 mg L^-1), respectively. However, from the lethality rates results, there was no improvement in insecticidal activity. Increasing the number of fluorine substitutions on the phenyl ring, compounds 12j (3.33%, 1 mg L^-1) and 12k (0.00%, 1 mg L^-1) had almost no insecticidal activity. This may be due to the increased number of fluorine atoms substituted on the benzene ring leads to excessive steric hindrance, which may reduce the insecticidal activity. In our previous work,³⁷ changing the position of the fluorine atom substitution on the phenyl ring and increasing the number of fluorine substitutions also led to a reduction of insecticidal activity of the compounds.

When the Q substituent was a pyridine ring, compounds 12m and 12o had low insecticidal activity with lethality rates of 10.00 and 30.00%, respectively, at a concentration of 1 mg L^-1. When Cl atoms were introduced at the 2-position of pyridine-4-yl and 6-position of pyridine-3-yl, compounds 12n (26.67%, 1 mg L^-1) and 12p (33.33%, 1 mg L^-1) had low insecticidal activity. However, when F atoms were introduced at the 2-position of pyridine-4-yl and 6-position of pyridine-3-yl, surprisingly, compounds 12l and 12q had lethality rates of 73.33 and 96.67%, respectively, at a concentration of 1 mg L^-1. Especially compound 12q had a lethality rate close to that of cyproflanilide (100%) against Plutella xylostella larvae. It shows that the introduction of para-fluorine can improve the insecticidal activity because it may resonate with the aromatic ring and modification of electron-withdrawing group.³⁸ Since fluorine atom is a good hydrogen bond receptor with ideal hydrophilicity and metabolic stability of C–F bond,³⁰,³⁹,⁴⁰,⁴¹,⁴² the introduction of fluorine atom may increase the affinity of parent compounds to insect receptors.

Insecticidal activities against Spodoptera frugiperda

The insecticidal activity of compounds 12a-12q against Spodoptera frugiperda showed similarly structure-activity relationship as Plutella xylostella. It is further proved that the introduction of fluorine atoms is beneficial to the improvement of the insecticidal activity of the target compounds.

Conclusions

Overall, this study successfully synthesized a series of meta-diamine compounds containing methoxy group and conducted corresponding biological activity tests. Among them, compound 12q showed good insecticidal activity and promising application value. This result provides valuable idea to design novel insecticides with excellent activity.

Supplementary materials

Supplementary information (NMR and high-resolution mass spectra) is available free of charge at http://jbcs.sbq.org.br as PDF file.

Acknowledgments

We are grateful to Scientific Research Project of Hunan Provincial Department of Education (grant numbers 20A019); and Hunan Postgraduate Research and Innovation Project (grant number CX20200889). Project supported by the Changsha Science and Technology Project (Nos. kq1801163, kq1801052) and the Hunan Provincial Engineering Research Center for Food Processing of Aquatic Biotic Resources (No. 2018KJY08).

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Edited by

• Editor handled this article: Brenno A. D. Neto

Publication Dates

• Publication in this collection
  05 Feb 2024
• Date of issue
  Feb 2024

History

• Received
  23 Mar 2023
• Accepted
  10 July 2023