Evaluation of some quinoline-based hydrazone derivatives as insecticidal agents

Abstract

In continuation of our program aimed at the discovery and development of efficient insecticidal agents, a series of quinoline-based hydrazone derivatives were synthesized and evaluated as insecticidal agents against three-day-old larvae of Spodoptera litura (Noctuidae: Lepidoptera), a polyphagous insect pest of many important crops, in vivo at 1 mg mL⁻¹. In particular, compounds 3c, 3e, 4g, 4h, and 6f showed potent insecticidal activity with 7 day mortality rates greater than 93%, and were comparable to that of the positive control toosendanin.

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Introduction

Spodoptera litura (Noctuidae: Lepidoptera) is a polyphagous insect pest of many important crops such as cotton, vegetables, soybean, cauliflower, castor and others.¹ Outbreaks of S. litura are frequently responsible for severe yield losses in many economically important crops, and recently various pesticides have been widely used to control S. litura. However, the extensive application of those agrochemicals over the years has led to the development of insecticide resistance in insect pest populations.^2–6 Therefore, research and development of new pesticides to efficiently control S. litura is highly desirable.

The quinoline skeleton (I, Fig. 1) occurs in various biologically active natural products and synthetic compounds, which exhibit a variety of interesting activities such as antiplasmodial activity,⁷ antimicrobial activity,⁸ anticancer activity,⁹ antiplasmodial activity,¹⁰ antimalarial activity,¹¹ and antioxidant activity.¹² Recently, we found that introduction of hydrazone fragments into podophyllotoxin, N-arylsulfonyl-3-acylindole or fraxinellone could result in more potent compounds as insecticidal agents, i.e., podophyllotoxin-based hydrazones (II, Fig. 1),¹³ N-arylsulfonyl-3-acylindole arylcarbonyl hydrazones (III, Fig. 1),¹⁴ and fraxinellone-based hydrazones (IV and V, Fig. 1),¹⁵ respectively. Encouraged by the above results, and in continuation of our program aimed at the discovery and development of novel pesticidal agents, here we prepared a series of quinoline-based hydrazone derivatives (VI, Fig. 1) by introduction of hydrazone moiety (Part A) into the quinoline skeleton (Part B). Their insecticidal activity was tested against the three-day-old larvae of S. litura in vivo.

Fig. 1 Design strategy of the target compounds VI.

Materials and methods

General procedure for synthesis of compounds 2a and 2b

2-Methylquinoline (1a) or 8-hydroxyquinaldine (1b, 1 mmol) reacted with SeO₂ (1.1 mmol) in dioxane (10 mL) at 80 °C. After 12 or 18 h, the mixture was cooled to room temperature. The precipitate was filtered and washed with CH₂Cl₂ (20 mL). The combined organic phases were concentrated and purified by preparative thin-layer chromatography (PTLC) to give compounds 2a [mp 68–70 °C (lit. 68 °C)¹⁶] or 2b [mp 94–96 °C (lit. 95–96 °C)¹⁷].

Synthesis of compound 2c

To a mixture of 1b (1 mmol) and K₂CO₃ (2 mmol) in DMF (20 mL) at room temperature, CH₃I (2 mmol) was added. Then the mixture was stirred at room temperature for 15 h. After the rest of CH₃I in the mixture was removed by evaporation, the mixture was diluted by water (15 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layer was dried over anhydrous Na₂SO₄, concentrated and purified by silica gel column chromatography (200–300 mesh) to afford compound 1c. Subsequently, the product 2c [mp 100–102 °C (lit. 103 °C)]¹⁸ was prepared from 1c by the same method as described above.

Synthesis of compound 2d

To a solution of 1b (1 mmol) in CH₂Cl₂ (10 mL) at 0 °C, benzenesulfonyl chloride (1.2 mmol) and triethylamine (1.5 mmol) were added in sequence. After addition, the above mixture was stirred at room temperature for 30 h. The solvent was removed under reduced pressure to give the residue, which was purified by PTLC to give compound 1d. Subsequently, the product 2d was prepared from 1d by the same method as described above.

Data for 2d

Yield = 85%, white solid, mp 152–154 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.80 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.94–7.97 (m, 3H), 7.85 (dd, J = 8.0, 1.2 Hz, 1H), 7.80 (dd, J = 7.6, 1.6 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H).

General procedure for synthesis of compounds 3a–e, 4a–h, 5a–e, and 6a–f

A mixture of 2a, 2b, 2c or 2d (1 mmol), hydrazides or hydrazines (1 mmol), and two drops of HOAc in EtOH (10 mL) was refluxed. When the reaction was complete checked by TLC after 2–4 h, the resulting reaction mixture was cooled to room temperature until no more precipitate was observed. The crude solid was then collected by filtration, and washed with cooled ethanol and petroleum ether in sequence to afford the target compounds 3a–e, 4a–h, 5a–e, or 6a–f.

Data for 3a

CAS no. 7727-09-5. Yield = 91%, yellow solid, mp 202–204 °C (lit. 204 °C);¹⁹ IR cm⁻¹ (KBr): 3445, 1598, 1563; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.92 (s, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.93–7.97 (m, 2H), 7.71–7.75 (m, 1H), 7.53–7.57 (m, 1H), 7.27–7.31 (m, 2H), 7.18–7.21 (m, 2H), 6.83 (t, J = 7.2 Hz, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 155.60, 147.98, 144.99, 137.27, 136.50, 130.21, 129.76, 128.90, 128.36, 127.31, 126.68, 120.32, 117.72, 112.99; HRMS m/z calcd for C₁₆H₁₄N₃ ([M + H]⁺) 248.1182, found 248.1181.

Data for 3b

CAS no. 14148-37-9. Yield = 84%, yellow solid, mp 246–248 °C (lit. 247–248 °C);²⁰ IR cm⁻¹ (KBr): 3446, 1616, 1583, 1336, 1321; ¹H NMR (500 MHz, DMSO-d₆) δ: 11.81 (s, 1H), 8.86 (s, 1H), 8.80 (s, 1H), 8.39–8.42 (m, 2H), 8.19–8.23 (m, 2H), 8.03 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.78–7.80 (m, 1H), 7.62–7.65 (m, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 153.82, 149.38, 148.03, 144.69, 138.59, 137.16, 131.14, 130.54, 130.10, 129.48, 128.44, 128.41, 127.89, 123.14, 118.32, 117.72; HRMS m/z calcd for C₁₆H₁₂O₄N₅ ([M + H]⁺) 338.0884, found 338.0881.

Data for 3c

CAS no. 106869-10-7. Yield = 91%, yellow solid, mp 168–170 °C (lit. 187 °C);²¹ IR cm⁻¹ (KBr): 3445, 1674, 1621, 1585; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.66 (d, J = 8.8 Hz, 1H), 8.02–8.11 (m, 4H), 7.91–7.97 (m, 3H), 7.72–7.79 (m, 4H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 164.02, 154.31, 148.46, 147.87, 137.25, 133.69, 132.53, 130.58, 129.40, 129.08, 128.51, 128.41, 128.27, 127.82, 118.00; HRMS m/z calcd for C₁₇H₁₄ON₃ ([M + H]⁺) 276.1131, found 276.1130.

Data for 3d

CAS no. 894695-24-0. Yield = 95%, white solid, mp 265–266 °C (lit. not report);²² IR cm⁻¹ (KBr): 3450, 3243, 1657, 1607, 1545, 1150; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.13 (s, 1H), 11.60 (s, 1H), 8.62 (s, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.02–8.07 (m, 2H), 7.87–7.89 (m, 1H), 7.79 (t, J = 7.2 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 6.97–7.02 (m, 2H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 165.40, 159.12, 154.14, 149.04, 147.88, 137.31, 134.39, 130.62, 129.42, 129.38, 128.53, 128.45, 127.91, 119.55, 118.06, 117.71, 117.04; HRMS m/z calcd for C₁₇H₁₄O₂N₃ ([M + H]⁺) 292.1081, found 292.1079.

Data for 3e

CAS no. 92869-04-0. Yield = 94%, white solid, mp 194–196 °C (lit. 197 °C);²² IR cm⁻¹ (KBr): 3428, 1662, 1598, 1558; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.42 (s, 1H), 8.82–8.84 (m, 2H), 8.63 (s, 1H), 8.45 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.02–8.08 (m, 2H), 7.86–7.88 (m, 2H), 7.80–7.84 (m, 1H), 7.65–7.68 (m, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 162.52, 153.98, 150.92, 149.65, 147.86, 140.70, 137.38, 130.65, 129.46, 128.53, 128.50, 127.99, 122.10, 118.03; HRMS m/z calcd for C₁₆H₁₃ON₄ ([M + H]⁺) 276.1032, found 276.1030.

Data for 4a

Yield = 72%, yellow solid, mp 164–166 °C; IR cm⁻¹ (KBr): 3361, 3287, 1598, 1566, 1250; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.94 (s, 1H), 9.62 (s, 1H), 8.23 (d, J = 9.0 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 8.10 (s, 1H), 7.35–7.40 (m, 2H), 7.28 (t, J = 7.5 Hz, 2H), 7.20 (d, J = 7.5 Hz, 2H), 7.08 (d, J = 6.5 Hz, 1H), 6.83 (t, J = 7.5 Hz, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 153.59, 144.91, 138.40, 137.25, 136.45, 129.76, 128.47, 127.57, 120.26, 118.27, 117.97, 112.96, 112.92, 112.15; HRMS m/z calcd for C₁₆H₁₄ON₃ ([M + H]⁺) 264.1131, found 264.1129.

Data for 4b

Yield = 72%, yellow solid, mp 280–282 °C; IR cm⁻¹ (KBr): 3399, 3266, 1609, 1576, 1316, 1248; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.71 (s, 1H), 9.75 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.25 (s, 1H), 8.16–8.21 (m, 3H), 7.38–7.46 (m, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.11 (dd, J = 7.2, 1.6 Hz, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 153.32, 152.12, 150.19, 141.96, 139.42, 138.21, 136.41, 128.54, 127.94, 126.21, 117.90, 117.77, 112.09; HRMS m/z calcd for C₁₆H₁₃O₃N₄ ([M + H]⁺) 309.0982, found 309.0981.

Data for 4c

CAS no. 439294-17-4. Yield = 82%, pale yellow solid, mp 222–224 °C (lit. 221 °C);²³ IR cm⁻¹ (KBr): 3359, 3318, 1684, 1602, 1546, 1266; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.27 (s, 1H), 9.88 (s, 1H), 8.68 (s, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 7.0 Hz, 2H), 7.63 (t, J = 7.0 Hz, 1H), 7.56–7.59 (m, 2H), 7.42–7.49 (m, 2H), 7.15 (d, J = 7.5 Hz, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 164.05, 153.91, 152.23, 148.37, 138.60, 137.09, 133.72, 132.50, 129.32, 129.05, 128.80, 128.29, 118.31, 118.18, 112.66; HRMS m/z calcd for C₁₇H₁₄O₂N₃ ([M + H]⁺) 292.1081, found 292.1079.

Data for 4d

Yield = 51%, white solid, mp 166–168 °C; IR cm⁻¹ (KBr): 3408, 3183, 2834, 1649, 1585, 1557, 1373, 1128; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.21 (s, 1H), 9.85 (s, 1H), 8.67 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.41–7.55 (m, 5H), 7.20 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 6.8 Hz, 1H), 3.86 (s, 3H) ¹³C NMR (125 MHz, DMSO-d₆) δ: 163.70, 159.76, 153.90, 153.73, 152.23, 148.50, 138.55, 137.11, 135.07, 130.27, 129.32, 128.81, 120.46, 118.37, 118.18, 113.62, 112.55; 55.89; HRMS m/z calcd for C₁₈H₁₆O₃N₃ ([M + H]⁺) 322.1186, found 322.1185.

Data for 4e (E/Z = 3/2)

Yield = 74%, pale yellow solid, mp 192–194 °C; IR cm⁻¹ (KBr): 3427, 3173, 1666, 1594, 1566, 1373, 1129; ¹H NMR (400 MHz, CDCl₃) δ: 12.43 (s, 0.2H), 12.32 (s, 0.3H), 9.90 (s, 0.3H), 9.87 (s, 0.2H), 8.49 (s, 0.6H), 8.36 (d, J = 8.8 Hz, 0.6H), 8.30 (s, 0.4H), 8.18 (d, J = 8.4 Hz, 0.4H), 8.10 (d, J = 8.8 Hz, 0.6H), 7.31–7.67 (m, 6.4H), 7.10–7.15 (m, 1H); HRMS m/z calcd for C₁₇H₁₃O₂N₃Cl ([M + H]⁺) 326.0691, found 326.0686.

Data for 4f

Yield = 91%, white solid, mp 168–170 °C; IR cm⁻¹ (KBr): 3428, 3277, 1665, 1651, 1553, 1379, 1087; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.32 (s, 1H), 9.86 (s, 1H), 8.65 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.42–7.50 (m, 2H), 7.14 (d, J = 7.2 Hz, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 162.55, 153.77, 152.09, 148.92, 138.55, 137.18, 135.64, 133.85, 132.35, 131.10, 129.38, 128.90, 128.00, 127.16, 118.36, 118.23, 112.64; HRMS m/z calcd for C₁₇H₁₃O₂N₃Cl ([M + H]⁺) 326.0691, found 326.0689.

Data for 4g

CAS no. 1184997-85-0. Yield = 73%, yellow solid, mp 246–248 °C (lit. 245–247 °C);²³ IR cm⁻¹ (KBr): 3465, 3252, 1644, 1608, 1532, 1224; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.18 (s, 1H), 11.64 (s, 1H), 9.87 (s, 1H), 8.65 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.42–7.50 (m, 3H), 7.15 (d, J = 7.2 Hz, 1H), 6.98–7.03 (m, 2H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 165.49, 159.18, 153.95, 152.02, 148.98, 138.64, 137.16, 134.37, 129.38, 129.35, 128.92, 119.52, 118.33, 118.22, 117.72, 117.04, 112.68; HRMS m/z calcd for C₁₇H₁₄O₃N₃ ([M + H]⁺) 308.1030, found 308.1024.

Data for 4h

CAS no. 298218-46-9. Yield = 71%, yellow solid, mp 160–162 °C (lit. 162–164 °C);²³ IR cm⁻¹ (KBr): 3446, 1679, 1616, 1548, 1281; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.46 (s, 1H), 9.90 (s, 1H), 8.83 (d, J = 7.0 Hz, 2H), 8.67 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 6.8 Hz, 2H), 7.42–7.51 (m, 2H), 7.15 (d, J = 7.2 Hz, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 162.60, 153.42, 151.04, 150.69, 140.53, 139.71, 138.74, 137.40, 129.64, 129.10, 123.86, 122.31, 118.53, 113.45; HRMS m/z calcd for C₁₆H₁₃O₂N₄ ([M + H]⁺) 293.1033, found 293.1031.

Data for 5a

Yield = 74%, yellow solid, mp 108–110 °C; IR cm⁻¹ (KBr): 3445, 2916, 1615, 1553, 1384, 1121; ¹H NMR (500 MHz, DMSO-d₆) δ: 15.49 (s, 1H), 8.41 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.573 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 6.92 (t, J = 7.5 Hz, 1H), 4.15 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 154.34, 152.20, 144.74, 137.33, 137.25, 130.07, 128.39, 128.01, 127.58, 122.44, 121.30, 119.58, 113.26, 109.53, 56.68; HRMS m/z calcd for C₁₇H₁₆ON₃ ([M + H]⁺) 278.1288, found 278.1286.

Data for 5b

Yield = 72%, white solid, mp 206–208 °C; IR cm⁻¹ (KBr): 3449, 2834, 1660, 1604, 1558, 1377, 1105; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.18 (s, 1H), 8.62 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 7.6 Hz, 2H), 7.54–7.64 (m, 5H), 7.23 (d, J = 7.2 Hz, 1H), 4.00 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 164.09, 155.65, 152.83, 148.58, 139.63, 137.03, 133.82, 132.49, 129.46, 129.10, 128.30, 128.26, 119.90, 118.35, 109.54, 56.18; HRMS m/z calcd for C₁₈H₁₆O₂N₃ ([M + H]⁺) 306.1237, found 306.1235.

Data for 5c (E/Z = 3/2)

Yield = 81%, white solid, mp 220–221 °C; IR cm⁻¹ (KBr): 3449, 2838, 1694, 1591, 1552, 1378, 1105; ¹H NMR (400 MHz, CDCl₃) δ: 12.38 (s, 0.3H), 12.28 (s, 0.45H), 18.43 (s, 0.6H), 8.38 (d, J = 8.8 Hz, 0.6H), 8.25 (s, 0.4H), 8.19 (d, J = 8.8 Hz, 0.4H), 8.12 (d, J = 8.8 Hz, 0.6H), 7.40–7.67 (m, 6.4H), 7.20–7.25 (m, 1H), 3.99 (s, 1.8H), 3.97 (s, 1.2H); HRMS m/z calcd for C₁₈H₁₅O₂N₃Cl ([M + H]⁺) 340.0847, found 340.0844.

Data for 5d

Yield = 58%, white solid, mp 176–178 °C; IR cm⁻¹ (KBr): 3446, 2836, 1666, 1614, 1562, 1378, 1106; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.25 (s, 1H), 8.60 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.55–7.64 (m, 3H), 7.23 (dd, J = 7.2, 1.2 Hz, 1H), 4.00 (s, 3H); 162.66, 155.69, 152.68, 149.18, 139.67, 137.07, 135.83, 133.88, 132.31, 131.13, 129.52, 128.37, 127.95, 127.10, 119.92, 118.37, 109.62, 56.23; HRMS m/z calcd for C₁₈H₁₅O₂N₃Cl ([M + H]⁺) 340.0847, found 340.0845.

Data for 5e (E/Z = 2/1)

Yield = 93%, yellow solid, mp 232–234 °C; IR cm⁻¹ (KBr): 3446, 2830, 1647, 1618, 1589, 1384, 1137; ¹H NMR (400 MHz, CDCl₃) δ: 15.63 (s, 0.6H), 12.07 (s, 0.3H), 11.78 (s, 0.6H), 11.55 (s, 0.3H), 8.60 (d, J = 8.4 Hz, 1H), 8.37 (d, J = 8.8 Hz, 0.3H), 7.85–8.14 (m, 2.6H), 7.44–7.69 (m, 3H), 7.35 (d, J = 7.6 Hz, 0.7H), 7.23 (d, J = 7.6 Hz, 0.34H), 6.97–7.12 (m, 2H), 4.00 (s, 1H), 3.94 (s, 2H); HRMS m/z calcd for C₁₈H₁₆O₃N₃ ([M + H]⁺) 322.1186, found 322.1185.

Data for 6a

Yield = 65%, yellow solid, mp 141–142 °C; IR cm⁻¹ (KBr): 3447, 1598, 1568, 1244, 1184; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.97 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.90–7.94 (m, 3H), 7.77 (s, 1H), 7.71–7.50 (m, 1H), 7.53–7.61 (m, 4H), 7.28–7.32 (m, 2H), 7.19 (d, J = 7.6 Hz, 2H), 6.85 (t, J = 7.6 Hz, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 155.86, 144.79, 144.64, 140.84, 136.74, 136.40, 135.70, 135.12, 129.78, 129.68, 129.09, 128.91, 127.89, 126.22, 123.57, 120.58, 118.48, 113.12; HRMS m/z calcd for C₂₂H₁₈O₃N₃S ([M + H]⁺) 404.1063, found 404.1062.

Data for 6b

Yield = 72%, yellow solid, mp 260–262 °C; IR cm⁻¹ (KBr): 3445, 1616, 1581, 1312, 1271, 1161; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.03 (s, 1H), 9.08 (d, J = 2.0 Hz, 1H), 8.83 (s, 1H), 8.59–8.62 (m, 2H), 8.38–8.40 (m, 2H), 8.183–8.16 (m, 3H), 7.83–7.88 (m, 3H), 7.75–7.79 (m, 2H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 154.06, 148.72, 145.12, 144.59, 140.93, 138.79, 137.18, 135.82, 134.98, 131.34, 130.09, 129.74, 129.69, 128.89, 127.85, 127.53, 123.49, 123.12, 119.05, 117.78; HRMS m/z calcd for C₂₂H₁₆O₇N₅S ([M + H]⁺) 494.0765, found 494.0762.

Data for 6c

Yield = 67%, white solid, mp 200–201 °C; IR cm⁻¹ (KBr): 3447, 1657, 1593, 1572, 1171; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.22 (s, 1H), 8.43 (d, J = 9.2 Hz, 2H), 8.07 (d, J = 8.8 Hz, 1H), 7.97–8.00 (m, 3H), 7.89 (d, J = 7.6 Hz, 2H), 7.70 (t, J = 7.6 Hz, 1H), 7.57–7.61 (m, 7H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 163.94, 154.50, 147.95, 144.88, 140.77, 137.31, 135.41, 135.23, 133.56, 132.65, 129.80, 129.72, 129.12, 128.91, 128.32, 128.08, 127.54, 123.80, 118.70; HRMS m/z calcd for C₂₃H₁₈O₄N₃S ([M + H]⁺) 432.1013, found 432.1004.

Data for 6d (E/Z = 3/2)

Yield = 74%, white solid, mp 199–200 °C; IR cm⁻¹ (KBr): 3449, 1664, 1590, 1554, 1189; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.42 (s, 0.4H), 12.32 (s, 0.6H), 8.44 (d, J = 8.8 Hz, 0.6H), 8.26 (d, J = 8.8 Hz, 0.4H), 8.17 (s, 0.6H), 8.06 (d, J = 8.8 Hz, 0.6H), 8.00–8.02 (m, 0.6H), 7.97 (s, 0.4H), 7.87–7.89 (m, 2.4H), 7.47–7.73 (m, 9H), 7.32 (d, J = 8.4 Hz, 0.4H); HRMS m/z calcd for C₂₃H₁₇O₄N₃ClS ([M + H]⁺) 466.0623, found 466.0620.

Data for 6e

Yield = 78%, white solid, mp 206–208 °C; IR cm⁻¹ (KBr): 3445, 3277, 1640, 1609, 1533, 1228, 1160; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.44 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.99 (dd, J = 7.2, 1.6 Hz, 1H), 7.90–7.92 (m, 3H), 7.70 (t, J = 7.6 Hz, 1H), 7.64–7.67 (m, 2H), 7.56–7.60 (m, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.00–7.05 (m, 2H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 165.29, 158.96, 154.31, 148.39, 144.92, 140.74, 137.37, 135.44, 135.20, 134.43, 129.79, 129.74, 129.53, 128.96, 128.10, 127.63, 123.89, 119.63, 118.75, 117.71, 117.20; HRMS m/z calcd for C₂₃H₁₈O₅N₃S ([M + H]⁺) 448.0962, found 448.0963.

Data for 6f

Yield = 76%, white solid, mp 230–232 °C; IR cm⁻¹ (KBr): 3444, 3340, 1650, 1609, 1548, 1275, 1179; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.41 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 6.0 Hz, 1H), 7.97 (dd, J = 7.6, 2.0 Hz, 1H), 7.87–7.91 (m, 4H), 7.70 (t, J = 7.6 Hz, 1H), 7.57–7.67 (m, 4H), 6.92 (d, J = 8.4 Hz, 2H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 163.56, 161.52, 154.70, 144.86, 140.77, 137.21, 135.41, 135.21, 130.56, 130.50, 129.79, 129.66, 128.90, 128.06, 127.41, 123.93, 123.74, 118.66, 115.59; HRMS m/z calcd for C₂₃H₁₈O₅N₃S ([M + H]⁺) 448.0962, found 448.0961.

Biological assay

The insecticidal activity of compounds 3a–e, 4a–h, 5a–e and 6a–f against the three-day-old larvae of Spodoptera litura was assessed by leaf-dipping method.¹⁴ Toosendanin, isolated from Melia azedarach, was used as a positive control. For each compound, 30 three-day-old larvae (10 larvae per group) were used. Acetone solutions of all the above tested compounds, and toosendanin were prepared at the concentration of 1 mg mL⁻¹. Small circular leaf discs were cut from fresh castor leaves using a cork borer (1.0 cm in diameter) and dipped into the corresponding solution for 5 s, then taken out and dried in a room. Leaf discs treated with acetone alone were used as a blank control group. Several treated leaf discs were kept in each dish (9.0 cm in diameter), where every 10 larvae were raised. If the treated leaves were consumed, additional treated leaves were added to the dish. After 48 h, compound-soaked leaves were removed, and the larvae were fed with untreated fresh wheat leaves thereafter. The experiment was carried out at 28 ± 2 °C and on 16 h/8 h (light/dark) photoperiod. The insecticidal activities of the tested compounds against the three-day-old larvae of S. litura after 2, 3 and 7 days were calculated by the following formula:

Corrected mortality rate (%) = (T − C) × 100/(100% − C)

where T is the mortality rate in the treated group expressed as a percentage and C is the mortality rate in the untreated group expressed as a percentage.

Results and discussion

Synthesis

As shown in Scheme 1, first, oxidation of 2-methylquinoline (1a) or 8-hydroxyquinaldine (1b) with SeO₂ gave 2-formylquinoline (2a)¹⁶ and 2-formyl-8-hydroxyquinoline (2b),¹⁷ respectively. Then compounds 2a and 2b reacted with hydrazines or hydrazides to afford quinoline-based hydrazones 3a–e and 4a–h. Another quinoline-based hydrazones 5a–e and 6a–f were prepared as follows (Scheme 2): compound 1b firstly reacted with methyl iodide or benzenesulfonyl chloride to give 2-methyl-8-methoxyquinoline (1c) and 2-methyl-8-benzenesulfonyloxyquinoline (1d), respectively. Subsequently, compounds 1c and 1d were oxidized by SeO₂ to produce 2-formyl-8-methoxyquinoline (2c)¹⁸ and 2-formyl-8-benzenesulfonyloxyquinoline (2d), respectively. Finally, compounds 2c and 2d reacted with hydrazines or hydrazides to afford 5a–e and 6a–f.

Scheme 1 The synthetic route for preparation of 3a–e and 4a–h.

Scheme 2 The synthetic route for preparation of 5a–e and 6a–f.

Insecticidal activity

The insecticidal activity of compounds 3a–e, 4a–h, 5a–e and 6a–f against the three-day-old larvae of S. litura was evaluated by leaf-dipping method at a concentration of 1 mg mL⁻¹. Toosendanin, a commercial botanical insecticide isolated from Melia azedarach, was used as the positive control at 1 mg mL⁻¹. Leaves treated with acetone alone were used as a blank control group. As shown in Table 1, compounds 3c, 3e, 4g, 4h, and 6f showed potent insecticidal activity with 7 day mortality rates greater than 93%, and were comparable to that of toosendanin. Additionally, their structure–activity relationships were also observed. Among compounds 3a–e, 4a–h and 5a–e, the hydrazine derivatives were generally less active compared with the corresponding hydrazide ones (e.g., 3a vs. 3c; 4a vs. 4c; 5a vs. 5c). To derivatives 3a–e, compounds 3c (containing benzoylhydrazone moiety) and 3e (containing pyrid-4-ylcarbonylhydrazone moiety) exhibited potent insecticidal activity with 7 day mortality rates of 96.6%. Whereas introduction of a hydroxyl group on the phenyl ring of 3c led to less active compound 3d (7 day mortality rate: 69%). To compounds 4a–h, introduction of 2-hydroxybenzoylhydrazone or pyrid-4-ylcarbonylhydrazone moiety into 8-hydroxyquinoline afforded potent derivatives 4g and 4h with 7 day mortality rates of 96.6%, and 100%, respectively. Obviously, once pyrid-4-ylcarbonylhydrazone moiety was introduced into quinoline or 8-hydroxyquinoline, the corresponding compounds 3e and 4h all showed the potent insecticidal activity. However, all 8-methoxyquinoline hydrazones (5a–e) displayed less potent insecticidal activity. It demonstrated that to obtain the promising quinoline-based hydrazone derivatives, the hydroxyl group of 8-hydroxyquinoline should not be methylated. Among compounds 6a–f, 4-hydroxybenzoylhydrazone derivative 6f exhibited the most potent insecticidal activity with the 7 day mortality rate of 93.1%; whereas the 7 day mortality rates of 6c–e were 55.2%, 72.4%, and 82.8%, respectively. It suggested, for 8-benzenesulfonyloxyquinoline-based benzoylhydrazone derivatives, introduction of a hydroxyl group on the phenyl ring of 6c was necessary for obtaining potent compounds (e.g., 6c vs. 6e and 6f).

Table 1 Insecticidal activity of compounds 3a–e, 4a–h, 5a–e and 6a–f against three-day-old larvae of S. litura on leaves treated with a concentration of 1 mg mL⁻¹

Compound	Corrected mortality rate (%)
	2 days	3 days	7 days
3a	33.3 ± 5.8	43.3 ± 5.8	48.3 ± 10.0
3b	6.7 ± 11.6	30.0 ± 17.3	51.7 ± 11.6
3c	36.7 ± 5.8	50.0 ± 10.0	96.6 ± 5.8
3d	6.7 ± 11.6	36.7 ± 11.6	69.0 ± 10.0
3e	30.0 ± 10.0	83.3 ± 11.6	96.6 ± 5.8
4a	0 ± 0	3.3 ± 5.8	20.7 ± 5.8
4b	3.3 ± 5.8	6.7 ± 5.8	51.7 ± 11.6
4c	0 ± 0	6.7 ± 11.6	58.6 ± 10.0
4d	3.3 ± 5.8	6.7 ± 5.8	69.0 ± 10.0
4e	20.0 ± 10.0	26.7 ± 5.8	65.5 ± 5.8
4f	20.0 ± 10.0	33.3 ± 5.8	55.2 ± 11.6
4g	16.7 ± 5.8	73.3 ± 11.6	96.6 ± 5.8
4h	40.0 ± 20.0	76.7 ± 5.8	100.0 ± 0.0
5a	3.3 ± 5.8	10.0 ± 17.3	38.0 ± 10.0
5b	0 ± 0	0 ± 0	48.3 ± 0.0
5c	3.3 ± 5.8	10.0 ± 10.0	65.5 ± 5.8
5d	3.3 ± 5.8	16.7 ± 5.8	48.3 ± 10.0
5e	0 ± 0	10.0 ± 10.0	62.1 ± 5.8
6a	26.7 ± 11.6	43.3 ± 15.3	69.0 ± 10.0
6b	26.7 ± 15.3	63.3 ± 5.8	82.8 ± 5.8
6c	26.7 ± 11.6	36.7 ± 11.6	55.2 ± 5.8
6d	43.3 ± 5.8	56.7 ± 5.8	72.4 ± 15.3
6e	36.7 ± 5.8	53.3 ± 5.8	82.8 ± 5.8
6f	23.3 ± 5.8	56.7 ± 5.8	93.1 ± 11.6
Toosendanin	90.0 ± 10.0	96.7 ± 5.8	100.0 ± 0
Blank control	0 ± 0	0 ± 0	3.3 ± 5.8

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Conclusions

In summary, a series of quinoline-based hydrazones were prepared, and evaluated for their insecticidal activity against three-day-old larvae of S. litura. Especially compounds 3c, 3e, 4g, 4h, and 6f showed potent insecticidal activity with 7 day mortality rates greater than 93% at 1 mg mL⁻¹. It suggested that the pyrid-4-ylcarbonylhydrazine derivatives could be hybridized with quinolines at the C-2 position for preparation of promising insecticidal candidates in the future.

Acknowledgements

The present research was supported by National Natural Science Foundation of China (No. 31171896), and the Special Funds of Central Colleges Basic Scientific Research Operating Expenses (YQ2013008).

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Footnote

† Electronic supplementary information (ESI) available: ¹H-NMR and ¹³C-NMR spectra for the some typical target compounds. See DOI: 10.1039/c6ra00993j

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