Design,synthesis,and nematicidal activities of novel 1,3-thiazin(thiazol)-4-one derivatives against Meloidogyne incognita

Abstract

Four series of novel 1,3-thiazin(thiazol)-4-one derivatives were synthesized by Suzuki coupling. Preliminary bioassays showed that most of the synthesized compounds exhibited good inhibitory activity in vivo against root-knot nematodes, Meloidogyne spp. at 20 mg L⁻¹. Among the tested compounds, we found that two compounds displayed 46.4% and 41.4% inhibitory activity even at 1 mg L⁻¹, respectively.

Keywords

1 3-thiazin(thiazol)-4-one in vivo nematicide

Four series of novel 1, 3-thiazin(thiazol)-4-one derivatives were designed and synthesized. Preliminary bioassays showed that most of the synthesized compounds exhibited good inhibitory activity in vivo against Meloidogyne incognitaita at 20 mg L-1. This investigation suggested that this 1, 3-thiazin(thiazol)-4-one could be further optimized to explore novel, high-bioactivity nematicidal leads.

Introduction

Plant-parasitic nematodes (PPNs) cause approximately US$157 billion of annual crop losses globally¹. RKNs, Meloidogyne spp., are considered as the most damaging nematode group in the world as they result in approximately 5% of global crop loss to most cultivated plant species such as tomato, pepper, watermelons, and onions.^2–4 It is difficult to control RKNs because they spend their lives in the soil or plant roots. Different methods are used in the field to control nematodes, including crop rotation, conventional chemical, botanical nematicides, biological controls,⁵ soil solarization, and the use of resistant crop varieties. Among them, chemical nematicides have played a prominent role in the management of nematodes,⁶ which are efficacious and easy to apply, with rapid onset.⁷

For decades, the use of chemical nematicides is somewhat reduced, and many products have actually been phased-out from the market because their indiscriminate use affected nontarget organisms with consequential problems for the environment.^8,9 Such as methyl bromide, the most widely used fumigant, has prohibited to use in 2015 because of its ozone depletion and human health concern in most countries.^10,11 Although recently newly developed nematicides fluensulfone and tioxazafen were released to the market,^12–16 compared with the numbers of new insecticides, it is not enough to control various nematodes with serious resistance and meet the increasingly stringent regulatory requirements for protecting the environment and ensuring food safety. Thereby, the research and development of novel nematicides with higher safety and efficiency are necessary and pressing.¹⁷

Thiazinone ring structure is very popular in the field of pesticide and pharmaceutical applications, and compounds with a thiazinone ring are used to have antifungal activity (1-1), anticancer activity (1-2 and 1-4), antihyperglycemia and antihyperlipidemia activity (1-3), insecticidal activity (1-5), and so on (Figure 1).^18–23 Inspired by the reports above, 1,3-thiazin-4-one was introduced to generate a novel structure against Meloidogyne incognita.

Figure 1.

Application of thiazinone and thiazolidinone structure in pharmacy and pesticide.

Thiazolidinone, a class of heterocycle including nitrogen and sulfur atom, have been reported to have anticonvulsant activity, cardiovascular effects, antibacterial activity, anticancer activity, and anti-inflammatory activity.^24–27 Especially, Wang et al. reported that thiazolidinone compound 1–6 exhibited good inhibition rates against M. incognita, with inhibition rate of 100% at the concentration of 10.0 mg L⁻¹. Inspired by the reports above, 1,3-thiazol-4-one was introduced to generate a novel structure against M. incognita.

Biphenyl group is a polycyclic aromatic hydrocarbon which consists of two independent benzene rings, and combined with its unique chemical structure, it has some special physiological activity and is widely used in pharmaceuticals and pesticides,²⁸ such as bifonazole, felbinacethyl, brequinar, bifenazate, boscalid, and fluxapyroxad (Figure 2). It is well known that biphenyl ring is stable, which is not easy to be degraded in the soil. Another purpose of the introduction of the biphenyl structure is to imitate the ternary ring compound tioxazafen of Monsanto.

Figure 2.

Application of biphenyl structure in pharmacy and pesticide.

Integrating the structure characteristic, we designed four series of novel 1,3-thiazin(thiazol)-4-one derivatives (Figure 3(A)–(D)). Their in vivo biological activities against M. incognita were measured. In order to investigate the relationship between structure and nematicidal activity, two parts of contents were analyzed as follows: (a) first, different substituents were introduced into phenyl ring to explore the influence of substituents at different positions and (b) biphenyl group was introduced to replace the phenyl ring of lead structure and their effects on inhibitory activities were evaluated.

Figure 3.

The design strategy of title compounds.

Results and discussion

Synthesis

We used Suzuki coupling reaction to synthesize benzidine according to the literature.²⁹ Phenylboronic acid and 2-fluoro-4-iodoaniline reacted through the combination of oxidation addition, transfer metallization, and reduction elimination in one pot, catalyzed by Pd(dba)₂ [bis(dibenzylideneacetone) palladium] (Scheme 1).

Scheme 1.

Synthetic route of 4-aminobiphenyls.

Aryl isothiocyanate was synthesized according to the literature.³⁰ First, in the presence of triethylene diamine, aryl anilines were treated with carbon disulfide to give corresponding salts of dithiocarbamic acid, and then, the corresponding salts of dithiocarbamic acid were dissolved in chloroform and a solution of bis(trichloromethyl)carbonate (BTC) in chloroform was added dropwise at 0 °C to obtain the compound (Scheme 2). This procedure efficiently yields (71%–95%). But it is difficult to synthesize aromatic isothiocyanates containing strongly electron-withdrawing groups such as nitro-trifluoromethyl and two or more halogen groups.³⁰

Scheme 2.

Synthetic route to aryl isothiocyanate.

The title compounds A-1–A-10, B-1–B-6, C-1−C-5, and D-1–D-12 were synthesized by the reaction of aryl isothiocyanate with methyl cyanoacetate and then treated with 3-bromopropionyl chloride in the presence of N,N-dimethylformamide (DMF; Scheme 3).

Scheme 3.

Synthetic route of title compounds.

Mohareb had reported that the final products A-1–A-10 and C-1–C-5 could have the alternative isomeric thiazolidin-5-one and 1,3-thiazin-6-one structures.³¹ But we obtained different structures. X-ray crystal structures of compounds A-1 (CCDC 1588188) and D-5 (CCDC 1588195) verified the position of C=O of our final compounds, which locates in the side of nitrogen atom of thiazolidinone and thiazinone ring instead of the side of sulfur atom (Scheme 4).

Scheme 4.

The monocrystalline of compounds A-1 and D-5 at 22% probability.

Nematicidal activity

The nematicidal activities of compound A-1–A-10, B-1–B-6, C-1–C-5, and D-1–D-12 are listed in Table 1, and the in vivo nematicidal activities of title compounds against M. incognita were initially evaluated at the concentration of 40.0 mg L⁻¹. Some compounds, such as B-1, B-2, B-5, and B-6, showed high nematicidal activities with inhibition rates of 100%, whereas some others were toxic to the plants and resulted in the death of plants because of their high concentration. To minimize the phytotoxicity of test compounds to plants, a lower treatment concentration was tried. When treated at the concentration of 20.0 mg L⁻¹, the phytotoxicity was significantly improved and quite a few compounds exhibited moderate to high nematicidal activities. Among them, compounds D-4, D-5, D-9, D-10, D-11, and D-12 were 100% inhibitory against M. incognita. When the treatment concentration was reduced further to 10.0 mg L⁻¹, all compounds were nematicidal without phytotoxicity and some of the tested compounds still showed moderate nematicidal activity. Among them, D-5 and D-11 displayed 46.4% and 41.4% inhibition rate against M. incognita at 1.0 mg L⁻¹, respectively, which are better than others. The detailed discussion on the nematicidal results is shown in supporting information.

Table 1.

Structure of the target compound.

Compound	n	R¹	R²	R³
A-1	1	2-F
A-2	1	3-F
A-3	1	4-F
A-4	1	2,4-diF
A-5	1	2,6-diF
A-6	1	2,3,5,6-tetraF
A-7	1	2-Cl
A-8	1	4-OCH₃
A-9	1	4-NO₂
A-10	1	2-F,4-OCH₃
B-1	2	2-F
B-2	2	4-CH₃
B-3	2	4-Br
B-4	2	2,3-diF
B-5	2	2-F,4-CH₃
B-6	2	2-F,4-OCH₃
C-1	1		H	H
C-2	1		2-F	2′-CH₃
C-3	1		2-F	2′-CN
C-4	1		2-F	3′-CF₃
C-5	1		2-F	4′-OCH₃
D-1	2		H	H
D-2	2		2-F	H
D-3	2		2,6-diF	H
D-4	2		2-F	2′-CF₃
D-5	2		2-F	3′-CF₃
D-6	2		2-F	4′-CF₃
D-7	2		2-F	4′-OCH₃
D-8	2		2-F	2′-OCH₃
D-9	2		2-F	3′-OCH₃
D-10	2		2-F	3′-CH₃
D-11	2		2-F	3′-CN
D-12	2		2-F	3′-NO₂

In conclusion, 33 1,3-thiazin(thiazol)-4-one derivatives were synthesized and their nematicidal activities against M. incognita in vivo were evaluated. Some of the tested compounds showed good nematicidal activity against M. incognita at 20 mg L⁻¹. Among them, compounds D-5 and D-11 displayed 46.4% and 41.4% inhibitory activities at 1 mg L⁻¹, respectively. This investigation suggested that this 1,3-thiazin(thiazol)-4-one structure could be further optimized to explore novel, high-bioactivity nematicidal leads. The relationships between structure and activity obtained in this study could be beneficial for discovering new nematicides, and further optimization of 1,3-thiazin(thiazol)-4-one derivatives is ongoing in our laboratory.

Experimental

Chemistry

All reagents and solvents were obtained from commercial suppliers and used without further purification. All reactions were carried out without nitrogen protection unless otherwise noted. All melting points were obtained with a Büchi Melting Point B540 and are uncorrected. Nuclear Magnetic ¹H, ¹³C, and ¹⁹F nuclear magnetic resonance (NMR) spectra were recorded in dimethyl sulfoxide (DMSO)-d₆ on a Bruker AM-400 (400 MHz) spectrometer at ambient temperature and TMS as the internal standard. Chemical shifts were reported in parts per million (δ). Coupling constants (J) were reported in hertz (Hz). High-resolution electron mass spectra (electrospray ionization time-of-flight (ESI-TOF)) were performed on a Micromass liquid chromatography time-of-flight (LC-TOF) spectrometer using electrospray (ES) ionization modes (positive or negative). Analytical thin-layer chromatography (TLC) was carried out on precoated plates (silica gel 60 F₂₅₄), and spots were visualized with ultraviolet (UV) light. X-ray crystallography was carried out on Bruker CMOS. All infrared (IR) spectra were obtained with Nicolet Magna-IR 550 infrared spectrometer.

General procedure for compounds

General procedure for 4-aminobiphenyls 3 (carcinogenic)

Substituted 4-iodoaniline 2 (5 mmol) and substituted phenylboronic acid 1 (6 mmol), an orange solution of Pd(dba)₂ (2 mol%) and triphenylphosphine (6 mol%) were added in a tube, and the tube was evacuated and back-filled with argon.²⁹ Potassium carbonate (20 mmol) solution (10 mL, 2 mol L⁻¹) and ethanol (10 mL) were added using syringe, and the mixture was stirred and refluxed for 3–5 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, and water was added to the residue, which was extracted with CH₂Cl₂ three times. The organic layer was dried over anhydrous Na₂SO₄, concentrated, and purified with flash chromatography on silica gel, eluting with petroleum ether (60−90 °C)/EtOAc to afford substituted benzidine in yields of 65%–79%.

General procedure for Aryl Isothiocyanates 6

A mixture of 1,4-diazabicyclo[2.2.2]octane (DABCO; 15 mmol), substituted aromatic amine 4 (5 mmol), and carbon disulfide (25 mL) in acetone (5 mL) was stirred overnight at room temperature.³⁰ The precipitated solid was filtered. To a stirred solution of the solid in chloroform (20 mL) was added a solution of triphosgene (2 mmol) in chloroform (10 mL) dropwise over 30 min, and the stirring was continued for 4 h at room temperature. After the resulting mixture was filtered, the filtrate was concentrated under reduced pressure and purified with flash chromatography on silica gel, eluting with petroleum ether (60−90 °C)/EtOAc to afford compounds 6 in yields of 80%−95%.

General procedure for target compounds (A-1−A-10, B-1−B-6, C-1−C-5, and D-1−D-12)

To a cold suspension of finally divided KOH (4 mmol) in dry DMF (5 mL) was added the methyl cyanoacetate 7 (2 mmol) followed by aryl isothiocyanate 6 (2 mmol).^32–34 The mixture was stirred at room temperature for 15–30 min. After completion of the reaction and then cooled again to 0 °C, 3-bromopropionyl chloride (2.4 mmol) was added and left to stand overnight at room temperature. The mixture was poured into ice-cold water, and the reaction solution was extracted three times with CH₂Cl₂. The combined organic phases were dried over Na₂SO₄, and the solvent was removed under reduced pressure. Crystallized from ethanol to give target compounds in 68%–80% yield. The data of compounds A1−A10, B1−B6, C1−C5 and D1−D12 are shown as follows.

Methyl 2-cyano-2-[3-(2-fluorophenyl)]-4-oxo-1,3-thiazol-2-ylidene]acetate A-1)

Yield: 73%. m.p. 169.3–169.5 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.65–7.55 (m, 2H), 7.43 (t, J = 9.0 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 4.20 (ABq, J_gem = 18.8 Hz, 2H), 3.73 (s, 3H).¹⁹F NMR (376 MHz, DMSO-d₆): δ −122.55 to −122.67 (m). High-resolution mass spectrometry (HRMS; ESI) calcd for C₁₃H₉FN₂O₃S (M + Na)⁺, 315.0216; found: 315.0218. IR (KBr): ν = 2938, 2219, 1752, 1690, 1505, 1460, and 1395 cm⁻¹.

Methyl 2-cyano-2-[3-(3-fluorophenyl)]-4-oxo-1,3-thiazol-2-ylidene]acetate A-2)

Yield: 65%. m.p. 179.3–179.5 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.59–7.53 (m, 1H), 7.41 (t, J = 8.0 Hz, 2H), 7.30 (d, J = 7.6 Hz, 1H), 4.13–3.99 (m, 2H), 3.71 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −111.83 (dt, J₁ = 10.2 Hz, J₂ = 2.6 Hz). HRMS (ESI) calcd for C₁₃H₉FN₂O₃S (M + Na)⁺, 315.0216; found: 315.0217. IR (KBr): ν = 2987, 2223, 1741, 1681, 1585, 1499, 1357, and 1233 cm⁻¹.

Methyl 2-cyano-2-[3-(4-fluorophenyl)]-4-oxo-1,3-thiazol-2-ylidene]acetate A-3)

Yield: 69%. m.p. 188.4–188.8 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.48 (dd, J₁ = 8.0 Hz, J₂ = 4.0 Hz, 2H), 7.34 (t, J = 8.0 Hz, 2H), 4.05 (s, 2H), 3.71 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ 110.70–110.77 (m). HRMS (ESI) calcd for C₁₃H₉FN₂O₃S (M + Na)⁺, 315.0216; found: 315.0216. IR (KBr): ν = 2988, 2219, 1738, 1696, 1597, 1507, 1386, and 1229 cm⁻¹.

Methyl 2-cyano-2-[3-(2,4-difluorophenyl)]-4-oxo-1,3-thiazol-2-ylidene]acetate A-4)

Yield: 74%. m.p. 171.0–171.4 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.72 (dd, J₁ = 17.3 Hz, J₂ = 8.4 Hz, 1H), 7.44 (dt, J₁ = 20.2 Hz, J₂ = 6.5 Hz, 2H), 4.22 (ABq, J_gem = 11.0 Hz, 2H), 3.74 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 173.22, 171.97, 165.42, 150.44, 147.57, 127.37, 125.68, 124.10, 120.87, 112.58, 76.52, 53.05, 32.51; ¹⁹F NMR (376 MHz, DMSO-d₆): δ −137.38 (ddd, J₁ = 14.8, J₂ = 9.7, J₃ = 4.2 Hz), −145.86 (dt, J₁ = 21.9, J₂ = 6.2 Hz); HRMS (EI) calcd for C₁₃H₈F₂N₂O₃S(M + Na)⁺, 333.0122; found: 333.0127. IR (KBr): ν = 2997, 2217, 1745, 1683, 1588, 1497, 1386, and 1211 cm⁻¹.

Methyl 2-cyano-2-[3-(2,6-difluorophenyl)]-4-oxo-1,3-thiazol-2-ylidene]acetate A-5)

Yield: 77%. m.p. 175.3–175.8 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.78–7.70 (m, 1H), 7.39 (t, J = 8.8 Hz, 2H), 4.37 (s, 2H), 3.75 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ 119.03 (t, J = 8.3 Hz). HRMS (ESI) calcd for C₁₃H₈F₂N₂O₃S (M + Na)⁺, 333.0122; found: 333.0129. IR (KBr): ν = 2997, 2220, 1744, 1695, 1591, 1491, 1352, 1299 cm⁻¹.

Methyl 2-cyano-2-[3-(2,3,5,6-tetrafluorophenyl)]-4-oxo-1,3-thiazol-2-ylidene]acetate A-6)

Yield: 80%. m.p. 202.2–202.8 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 8.44–8.37 (m, 1H), 4.40 (s, 2H), 3.77 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 172.28, 170.50, 164.82, 150.76, 147.11, 112.51, 111.04, 98.46, 76.88, 53.32, 32.26; ¹⁹F NMR (376 MHz, DMSO-d₆): δ −117.47 (dd, J₁ = 15.7 Hz, J₂ = 9.1 Hz), −135.00 to −141.03 (m), −142.23 to −146.76 (m), −156.09 (d, J = 15.9 Hz); HRMS (EI) calcd for C₁₃H₆F₄N₂O₃S(M)⁺, 346.0034; found: 346.0035. IR (KBr): ν = 2219, 1760, 1685, 1519, 1440, 1299, and 1260 cm⁻¹.

Methyl 2-cyano-2-[3-(2-chlorophenyl)]-4-oxo-1,3-thiazol-2-ylidene]acetate A-7)

Yield: 67%. m.p. 158.2–158.3 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.67–7.57 (m, 3H), 7.50 (td, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 4.22 (ABq, J_gem = 18.8 Hz, 2H), 3.72 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 173.19, 171.63, 165.62, 133.31, 133.24, 132.41, 132.18, 130.28, 128.85, 112.28, 76.40, 53.02, 32.28. HRMS (ESI) calcd for C₁₃H₉ClN₂O₃S (M + Na)⁺, 330.9920; found: 330.9927. IR (KBr): ν = 3010, 2222, 1740, 1684, 1602, 1507, 1391, and 1214 cm⁻¹.

Methyl 2-cyano-2-[3-(4-methoxyphenyl)]-4-oxo-1,3-thiazol-2-ylidene]acetate A-8)

Yield: 74%. m.p. 128.3–129.7 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.30 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 4.04 (s, 2H), 3.80 (s, 3H), and 3.70 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 174.01, 173.67, 166.02, 161.09, 131.00, 127.81, 114.91, 112.72, 76.25, 55.91, 52.81, and 32.51. HRMS (ESI) calcd for C₁₄H₁₃N₂O₄S (M + H)⁺, 305.0597; found: 305.0597. IR (KBr): ν = 2955, 2213, 1755, 1682, 1603, 1434, 1398, and 1288 cm⁻¹.

Methyl 2-cyano-2-[3-(4-nitrophenyl)]-4-oxo-1,3-thiazol-2-ylidene]acetate A-9)

Yield: 78%. m.p. 189.7–190.5 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 8.40 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H), 4.09 (s, 2H), 3.72 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 173.68, 172.68, 165.67, 148.91, 140.96, 131.79, 125.00, 113.09, 76.23, 52.95, and 32.89. HRMS (ESI) calcd for C₁₃H₉N₃O₅S (M + Na)⁺, 342.0161; found: 342.0165. IR (KBr): ν = 2219, 1735, 1696, 1527, 1505, 1350, and 1297 cm⁻¹.

Methyl 2-cyano-2-[3-(2-fluoro-4-methoxyphenyl)]-4-oxo-1,3-thiazol-2-ylidene]acetate A-10)

Yield: 83%. m.p. 145.6–145.9 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.44 (t, J = 8.8 Hz, 1H), 7.05 (dd, J₁ = 12.0 Hz, J₂ = 2.8 Hz, 1H), 6.91 (dd, J₁ = 8.4 Hz, J₂ = 2.4 Hz, 1H), 4.17 (ABq, J_gem = 18.8 Hz, 2H), 3.83 (s, 3H), 3.73 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −120.26 (t, J = 11.6 Hz). HRMS(ESI) calcd for C₁₄H₁₁FN₂O₄S (M + Na)⁺, 345.0322; found: 345.0321. IR (KBr): ν = 2989, 2224, 1751, 1682, 1599, 1487, 1386, and 1228 cm⁻¹.

Methyl 2-cyano-2-[3-(2-fluorophenyl)]-4-oxo-1,3-thiazin-2-ylidene]acetate B-1)

Yield: 84%. m.p. 222.0–222.5 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.46 (dd, J₁ = 13.2 Hz, J₂ = 7.2 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.31–7.19 (m, 2H), 3.80 (s, 3H), 3.23–3.17 (m, 2H), 3.15–3.10 (m, 2H). ¹⁹F NMR (376 MHz, CDCl₃): δ −116.15 to −116.13 (m). HRMS (ESI) calcd for C₁₄H₁₂N₂O₃FS (M + H)⁺, 307.0553; found: 307.0554. V_max (KBr)/cm⁻¹ 2207 (–CN), 16991 (–CON–), and 1748 (–COOMe).

Methyl 2-cyano-2-[3-(4-methylphenyl)]-4-oxo-1,3-thiazin-2-ylidene]acetate B-2)

Yield: 78%. m.p. 232.9–233.3 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.27 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 3.80 (s, 3H), 3.20–3.14 (m, 2H), 3.11–3.04 (m, 2H), 2.40 (s, 3H). HRMS (ESI) calcd for C₁₅H₁₅N₂O₃S (M + H)⁺, 303.0803; found: 303.0804. V_max (KBr)/cm⁻¹ 2214 (–CN), 16,993 (–CON–), 1716 (–COOMe).

Methyl 2-cyano-2-[3-(4-bromophenylphenyl)]-4-oxo-1,3-thiazin-2-ylidene]acetate B-3)

Yield: 71%. m.p. 232.4–233.0 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.59 (dt, J₁ = 8.8 Hz, J₂ = 2.4 Hz, 2H), 7.21 (dt, J₁ = 8.8 Hz, J₂ = 2.4 Hz, 2H), 3.81 (s, 3H), 3.20–3.16 (m, 2H), 3.10–3.06 (m, 2H). HRMS (ESI) calcd for C₁₄H₁₂N₂O₃S⁷⁹Br (M + H)⁺, 366.9752; found: 366.9758; calcd for C₁₄H₁₂N₂O₃S⁸¹Br (M + H)⁺, 368.9732; found: 368.9746. V_max (KBr)/cm⁻¹ 2216 (–CN), 16,995 (–CON–), and 1712 (–COOMe).

Methyl 2-cyano-2-[3-(2,3-difluorophenyl)]-4-oxo-1,3-thiazin-2-ylidene]acetate B-4)

Yield: 67%. m.p. 210.0–210.7 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.32–7.25 (m, 1H), 7.23–7.17 (m, 1H), 7.12 (t, J = 7.2 Hz, 1H), 3.81 (s, 3H), 3.22–3.18 (m, 2H), 3.16–3.13 (m, 2H). ¹⁹F NMR (376 MHz, CDCl₃): δ −135.37 to −135.44 (m, 1F), −138.62 (dt, J₁ = 22.0 Hz, J₂ = 6.8 Hz, 1F). HRMS (ESI) calcd for C₁₄H₉N₂O₃F₂S (M − H)⁻, 323.0302; found: 323.0305. V_max (KBr)/cm⁻¹ 2211 (–CN), 16,991 (–CON–), and 1712 (–COOMe).

Methyl 2-cyano-2-[3-(2-fluoro-4-methylphenyl)]-4-oxo-1,3-thiazin-2-ylidene]acetate B-5)

Yield: 72%. m.p. 214.7–215.0 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.21 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 10.4 Hz, 2H), 3.80 (s, 3H), 3.21–3.16 (m, 2H), 3.14–3.10 (m, 2H), 2.41 (s, 3H).¹⁹F NMR (376 MHz, CDCl₃): δ −117.45 (dd, J₁ = 10.8 Hz, J₂ = 8.4 Hz). HRMS (ESI) calcd for C₁₅H₁₄N₂O₃FS (M + H)⁺, 321.0709; found: 321.0710. V_max (KBr)/cm⁻¹ 2210 (–CN), 16,989(–CON–), and 1708 (–COOMe).

Methyl 2-cyano-2-[3-(2-fluoro-4-methoxyphenyl)]-4-oxo-1,3-thiazin-2-ylidene]acetate B-6)

Yield: 69%. m.p. 228.8–229.0 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.22 (t, J = 8.8 Hz, 1H), 6.81–6.72 (m, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.20–3.15 (m, 2H), 3.13–3.08 (m, 2H). ¹⁹F NMR (376 MHz, CDCl₃): δ −114.19 (dd, J₁ = 12.0 Hz, J₂ = 9.2 Hz). HRMS (ESI) calcd for C₁₅H₁₄N₂O₄FS (M + H)⁺, 337.0658; found: 337.0660. V_max (KBr)/cm⁻¹ 2216 (–CN), 16,984 (–CON–), and 1721 (–COOMe).

Methyl 2-cyano-2-[3-([1,1′-biphenyl])-4-yl)-4-oxo-1,3-thiazol-2-ylidene]acetate C-1

Yield: 76%. m.p. 235.1–235.5 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.82 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 7.2 Hz, 2H), 7.51 (t, J = 8.0 Hz, 4H), 7.43 (t, J = 7.2 Hz, 1H), 4.10 (s, 2H), 3.72 (s, 3H). HRMS (ESI) calcd for C₁₉H₁₄N₂O₃S (M + H)⁺, 351.0803; found: 351.0802. IR (KBr): ν = 2938, 2208, 1746, 1691, 1634, 1507, 1417, and 1276 cm⁻¹.

Methyl 2-cyano-2-[3-(2-fluoro-2′-methyl[1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazol-2-ylidene]acetate C-2

Yield: 70%. m.p. 198.6–198.9 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.63(t, J = 8.0 Hz, 1H), 7.44 (d, J = 10.8 Hz, 1H), 7.33–7.26 (m, 5H), 4.25 (ABq, J_gem = 18.8 Hz, 2H), 3.75 (s, 3H), 2.26 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −122.72 (t, J = 9.4 Hz), HRMS (ESI) calcd for C₂₀H₁₅FN₂O₃S (M + H)⁺, 383.0866; found: 383.0868. IR (KBr): ν = 2967, 2212, 1751, 1688, 1619, 1526, 1434, and 1257 cm⁻¹.

Methyl 2-cyano-2-[3-(2-fluoro-2′-cyano[1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazol-2-ylidene]acetate C-3

Yield: 75%. m.p. 179.8–180.4 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 8.01 (d, J = 7.6 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.75 (dd, J₁ = 7.2 Hz, J₂ = 2.4 Hz, 2H) 7.68–7.61 (m, 3H), 4.25 (ABq, J_gem = 18.8 Hz, 2H), 3.75 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −121.43 (t, J = 11.5 Hz). HRMS (ESI) calcd for C₂₀H₁₂FN₃O₃S (M + H)⁺, 394.0662; found: 394.0655. IR (KBr): ν = 2979, 2215, 1755, 1639, 1597, 1529, 1449, and 1231 cm⁻¹.

Methyl 2-cyano-2-[3-(2-fluoro-3′-trifluoromethyl[1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazol-2-ylidene]acetate C-4

Yield: 67%. m.p. 194.5–194.7 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.89 (d, J = 7.6 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.70–7.64 (m, 2H), 7.46 (d, J = 12.0 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 4.24(ABq, J_gem = 18.4 Hz, 2H), 3.75 (s, 3H), 3.36 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −55.25 (s), −122.50 (t, J₁ = 11.1 Hz, J₂ = 2.2 Hz), HRMS (ESI) calcd for C₂₀H₁₂F₄N₂O₃S (M + H)⁺, 437.0583; found: 437.0590. IR (KBr): ν = 2958, 2214, 1759, 1688, 1601, 1527, 1450, and 1279 cm⁻¹.

Methyl 2-cyano-2-[3-(2-fluoro-4′-methoxy[1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazol-2-ylidene]acetate C-5

Yield: 73%. m.p. 220.1–220.5 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.59 (t, J = 8.0 Hz, 2H), 7.50 (dd, J₁ = 8.4 Hz, J₂ = 1.6 Hz, 1H), 7.43 (td, J₁ = 8.0 Hz, J₂ = 1.6 Hz, 1H), 7.37 (dd, J₁ = 7.2 Hz, J₂ = 1.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 4.24 (ABq, J_gem = 18.8 Hz, 2H), 3.82 (s, 3H), and 3.75 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −123.08 (dd, J₁ = 12.8 Hz, J₂ = 8.5 Hz), HRMS (ESI) calcd for C₂₀H₁₅FN₂O₄S (M + H)⁺, 399.0815; found: 399.0814. IR (KBr): ν = 2955, 2216, 1751, 1695, 1621, 1566, 1431, and 1281 cm⁻¹.

Methyl 2-cyano-2-[3-([1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazin-2-ylidene] acetate D-1

Yield: 81%. m.p. 185.8–186.3 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.72–7.66 (m, J = 7.6 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.48–7.44 (m, 2H), 7.41–7.36 (m, 3H), 3.82 (s, 3H), 3.25–3.07 (m, 4H). ¹³C NMR (100 MHz, CDCl₃): δ 171.27, 167.73, 164.73, 141.51, 139.92, 138.44, 128.80, 128.67, 127.74, 127.48, 127.25, 113.34, 91.73, 52.77, 35.67, and 23.54. HRMS (ESI) calcd for C₂₀H₁₇N₂O₃S (M + H)⁺, 365.0960; found: 365.0961. V_max (KBr)/cm⁻¹ 2213 (–CN), 1700 (–CON–), and 1720 (–COOMe).

Methyl 2-cyano-2-[3-(2-fluoro[1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazin-2-ylidene]acetate D-2

Yield: 83%. m.p. 198.6–199.1 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.62 (d, J = 8.0 Hz, 2H), 7.52–7.36 (m, 6H), 3.82 (s, 3H), 3.27–3.11 (m, 4H). ¹⁹F NMR (376 MHz, CDCl₃): δ −116.11 to −116.12 (m, 1F). HRMS (ESI) calcd for C₂₀H₁₆N₂O₃FS (M + H)⁺, 383.0866; found: 383.0867. V_max (KBr)/cm⁻¹ 2213 (–CN), 1701 (–CON–), and 1729 (–COOMe).

Methyl 2-cyano-2-[3-(2,6-difluoro[1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazin-2-ylidene]acetate D-3

Yield: 77%. m.p. 207.1–208.0 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.60 (d, J = 7.6 Hz, 2H), 7.46 (dt, J = 19.2 Hz, 6.8 Hz, 3H), 7.33–7.27 (m, 2H), 3.83 (s, 3H), and 3.20–3.14 (m, 4H). ¹⁹F NMR (376 MHz, CDCl₃): δ −114.16 (d, J = 9.8 Hz, 2F). HRMS (ESI) calcd for C₂₀H₁₅N₂O₃F₂S (M + H)⁺, 401.0771; found: 401.0772. V_max (KBr)/cm⁻¹ 2202 (–CN), 16996 (–CON–), and 1729 (–COOMe).

Methyl 2-cyano-2-[3-(2-fluoro-2′-trifluoromethyl[1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazin-2-ylidene]acetate D-4

Yield: 74%. m.p. 188.9–199.5 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.43–7.36 (m, 2H), 7.22 (t, J = 8.4 Hz, 2H), 3.82 (s, 3H), 3.26–3.10 (m, 4H). ¹⁹F NMR (376 MHz, CDCl₃): δ −56.70 (s, 3F), −116.36 to −116.48 (m, 1F). HRMS (ESI) calcd for C₂₁H₁₅N₂O₃F₄S (M + H)⁺, 451.0740; found: 451.0742. V_max (KBr)/cm⁻¹ 2214 (–CN), 16994 (–CON–), and 1712 (–COOMe).

Methyl 2-cyano-2-[3-(2-fluoro-3′-trifluoromethyl[1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazin-2-ylidene]acetate D-5

Yield: 73%. m.p. 177.9–188.2 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.86 (s, 1H), 7.82–7.76 (m, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.53–7.42 (m, 3H), 3.82 (s, 3H), 3.26–3.13 (m, 4H). ¹⁹F NMR (376 MHz, CDCl₃): δ −62.65 (s, 3F), −115.24 to −115.29 (m, 1F). HRMS (ESI) calcd for C₂₁H₁₅N₂O₃F₄S (M + H)⁺, 451.0740; found: 451.0743. V_max (KBr)/cm⁻¹ 2220 (–CN), 16,999 (–CON–), and 1715 (–COOMe).

Methyl 2-cyano-2-[3-(2-fluoro-4′-trifluoromethyl[1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazin-2-ylidene]acetate D-6

Yield: 65%. m.p. 151.3–152.0 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.76–7.68 (m, 4H), 7.51–7.44 (m, 3H), 3.82 (s, 3H), 3.23–3.14 (m, 4H). ¹⁹F NMR (376 MHz, CDCl₃): δ 62.56 (s, 3F), −115.27 to −115.32 (m, 1F). HRMS (ESI) calcd for C₂₁H₁₅N₂O₃F₄S (M + H)⁺, 451.0740; found: 451.0742. V_max (KBr)/cm⁻¹ 2216 (–CN), 1708 (–CON–), and 1720 (–COOMe).

Methyl 2-cyano-2-[3-(2-fluoro-4′-methoxy[1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazin-2-ylidene]acetate D-7

Yield: 80%. m.p. 215.0–215.8 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.55 (d, J = 8.4 Hz, 2H), 7.40–7.35 (m, 3H), 6.99 (d, J = 8.4 Hz, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.24–3.11 (m, 4H). ¹⁹F NMR (376 MHz, CDCl₃): δ −116.32 to −116.37 (m, 1F). HRMS (ESI) calcd for C₂₁H₁₈N₂O₄FS (M + H)⁺, 413.0971; found: 413.0973. V_max (KBr)/cm⁻¹ 2202 (–CN), 1704 (–CON–), and 1730 (–COOMe).

Methyl 2-cyano-2-[3-(2-fluoro-2′-methoxy[1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazin-2-ylidene]acetate D-8

Yield: 83%. m.p. 219.8–220.5 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.44 (t, J = 9.2 Hz, 2H), 7.37 (t, J = 8.0 Hz, 3H), 7.08–6.98 (m, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.24–3.09 (m, 4H). ¹⁹F NMR (376 MHz, CDCl₃): δ −117.45 to −117.50 (m, 1F). HRMS (ESI) calcd for C₂₁H₁₈N₂O₄FS (M + H)⁺, 413.0971; found: 413.0973. V_max (KBr)/cm⁻¹ 2213 (–CN), 16,994 (–CON–), and 1725 (–COOMe).

Methyl 2-cyano-2-[3-(2-fluoro-3′-methoxy[1,1′-biphenyl])-4-yl)-4-oxo-1,3-thiazin-2-ylidene]acetate D-9

Yield: 78%. m.p. 180.9–181.0 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.43–7.38 (m, 4H), 7.20 (d, J = 7.6 Hz, 1H), 7.13 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), and 3.25–3.09 (m, 4H). ¹⁹F NMR (376 MHz, CDCl₃): δ −116.07 to −116.12 (m, 1F). HRMS (ESI) calcd for C₂₁H₁₈N₂O₄FS (M + H)⁺, 413.0971; found: 413.0973. V_max (KBr)/cm⁻¹ 2211 (–CN), 16,996 (–CON–), and 1727 (–COOMe).

Methyl 2-cyano-2-[3-(2-fluoro-3′-methyl[1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazin-2-ylidene]acetate D-10

Yield: 76%. m.p. 199.1–192.2 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.48–7.46 (m, 2H), 7.44–7.33 (m,4H), 7.24–7.21 (m, 1H), 3.81 (s, 3H), 3.25–3.09 (m, 4H), 2.44 (s, 3H). ¹⁹F NMR (376 MHz, CDCl₃): δ −116.17 to −116.51 (m, 1F). HRMS (ESI) calcd for C₂₁H₁₈N₂O₃FS (M + H)⁺, 397.1022; found: 397.1033. V_max (KBr)/cm⁻¹ 2206 (–CN), 1704 (–CON–), and 1728 (–COOMe).

Methyl 2-cyano-2-[3-(2-fluoro-3′-cyano[1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazin-2-ylidene]acetate D-11

Yield: 79%. m.p. 217.7–218.4 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.89 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.50–7.39 (m, 3H), 3.82 (s, 3H), 3.27–3.16 (m, 4H). ¹⁹F NMR (376 MHz, CDCl₃): δ −114.80 to −114.83 (m, 1F). HRMS (ESI) calcd for C₂₁H₁₅N₃O₃FS (M + H)⁺, 408.0818; found: 408.0821. V_max (KBr)/cm⁻¹ 2228, 2208 (–CN), 1704 (–CON–), and 1727 (–COOMe).

Methyl 2-cyano-2-[3-(2-fluoro-3′-nitro[1,1′-biphenyl]-4-yl)-4-oxo-1,3-thiazin-2-ylidene]acetate D-12

Yield: 81%. m.p. 209.1–210.7 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.48 (t, J = 2.0 Hz, 1H), 8.27 (ddd, J = 8.0, 2.0, and 0.8 Hz, 1H), 7.94 (ddd, J = 8.0, 1.6, and 1.0 Hz, 1H), 7.67 (dd, J = 10.4 and 6.0 Hz, 1H), 7.57–7.46 (m, 3H), 3.82 (s, 3H), and 3.19 (m, 4H). ¹⁹F NMR (376 MHz, CDCl₃): δ −114.72 to −114.77 (m, 1F). HRMS (ESI) calcd for C₂₀H₁₅N₃O₅FS (M + H)⁺, 428.0716; found: 428.0715. V_max (KBr)/cm⁻¹ 2213 (–CN), 1710 (–CON–), and 1736 (–COOMe).

Footnotes

Acknowledgements

We are very thankful to Dr Bingli Gao and his co-workers in Huzhou Modern Agricultural Biotechnology Innovation Center, Chinese Academy of Sciences, China, for the discussion of nematicidal evaluation.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was financially supported by the National Natural Science Foundation of China (21672061) and National Key Research Program of China (2018YFD0200105). This work was also supported by the Fundamental Research Funds for the Central Universities (222201718004).

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