Synthesis of a class of anethol-based 1,3,4-thiadiazole-thiourea compounds having herbicidal activity

Abstract

The application provides a synthesis method of an anisyl 1,3,4-thiadiazole-thiourea compound with herbicidal activity, which comprises the following steps: using trans-4-methoxycinnamaldehyde obtained by oxidation of anisyl alcohol as a starting material, then performing condensation reaction with aminothiourea to prepare an intermediate anisyl thiosemicarbazide, then performing oxidation and cyclization by using ferric chloride hexahydrate to prepare an intermediate anisyl 2-amino-1,3,4-thiadiazole, and finally performing nucleophilic addition of the intermediate with a series of isothiocyanate to synthesize 20 novel anisyl 1,3,4-thiadiazole-thiourea compounds. Herbicidal activity test results show that part of the compounds exhibit good inhibition activity on dicotyledonous plants such as rape. The application expands the application range of anisyl alcohol, and the compounds exhibit the potential as novel natural product-based green herbicide lead compounds.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and in particular to a method for synthesizing a novel bioactive compound based on anethole, 1,3,4-thiadiazole and thiourea—annethole-based 1,3,4-thiadiazole-thiourea compound. Background Technology

[0002] Herbicides play an indispensable role in ensuring crop yields in global agricultural production. However, the long-term and repeated use of traditional herbicides can have serious ecological consequences, not only severely polluting the environment but also leading to the gradual development of herbicide resistance in weeds. Against this backdrop, developing highly effective and low-toxicity alternatives to novel pesticides is a key approach to solving these problems. In particular, herbicides derived from natural products, with their abundant sources, diverse structures, easy degradation, and high safety, are becoming an important direction for replacing traditional herbicides.

[0003] Anethole is a natural phenylpropanoid compound, chemically named 1-methoxy-4-(1-propenyl)benzene, with the molecular formula C2. 10 H 12 Anethole (O) is a colorless to pale yellow oily liquid. This compound exists in two stereoisomers, cis and trans, with trans-anethole being the predominant form found in nature. It is mainly found in the essential oils of plants such as star anise and fennel. Due to its phenylpropanoid-derived C6-C3 conjugated molecular skeleton, anethole and its derivatives exhibit a wide range of biological activities, including anti-inflammatory, antioxidant, antifungal, and insecticidal effects. Therefore, it has good application potential in medicine and agriculture. Its activity can be enhanced through chemical modification. By chemically modifying the active sites of the anethole molecule and introducing bioactive groups, a series of novel anethole derivatives can be constructed, enriching molecular diversity and demonstrating potential biological activities.

[0004] On the other hand, 1,3,4-thiadiazole is a five-membered heterocyclic compound containing nitrogen and sulfur atoms. Due to the inductive effect of the sulfur atom, it is extremely weakly basic and highly aromatic, and has wide applications in the fields of medicine, agriculture, and materials. Studies have shown that 1,3,4-thiadiazole compounds have a wide range of biological activities, such as herbicides, antioxidants, anticancer agents, anti-inflammatory agents, and antifungals. By introducing the 1,3,4-thiadiazole active group into the structure of a lead compound, it can be converted into a highly effective insecticide or herbicide, such as the herbicides fluthiamethoxam and tebufenozide. In addition, thiourea compounds, due to their unique thiourea group active structure, are easy to modify and can interact with a variety of enzymes or metal ions in organisms, thus exhibiting rich and wide-ranging biological activities in the fields of medicine and pesticides, including insecticidal, antibacterial, antiviral, and antidiabetic effects, such as the fungicide methyl thiophanate and the acaricide difenoconazole.

[0005] This invention patent, based on a molecular strategy of active substructure splicing, introduces the bioactive groups of 1,3,4-thiadiazole and thiourea into the molecular skeleton of the natural product anethole for the first time. A novel anethole-based 1,3,4-thiadiazole-thiourea compound was synthesized using a highly efficient, simple, and effective method. Herbicidal activity tests show that some compounds exhibit good herbicidal activity and can serve as lead compounds for the development of novel natural product-based green herbicides. These substances are novel bioactive compounds, and their synthesis methods and herbicidal activities have not been reported in domestic or international literature to date. Summary of the Invention

[0006] The purpose of this invention is to provide a method for synthesizing a class of fenestrated 1,3,4-thiadiazole-thiourea compounds, the resulting products being low in cost and simple to prepare.

[0007] The present invention achieves the above objectives by adopting the following technical solutions:

[0008] A class of fenestrated 1,3,4-thiadiazole-thiourea compounds with the following general structural formula:

[0009]

[0010] Where R is ethylphenyl, phenyl, p-chlorophenyl, 3-chloro-5-fluorophenyl, 2,4-dimethylphenyl, p-bromophenyl, p-tert-butylphenyl, p-n-butylphenyl, p-fluorophenyl, p-nitrophenyl, p-methylphenyl, cyclohexyl, p-ethylphenyl, o-fluorophenyl, o-chlorophenyl, p-cyanophenyl, p-iodophenyl, m-fluorophenyl, 3,4-dichlorophenyl, p-trifluoromethylphenyl

[0011] The preparation method of the aforementioned class of anethole-based 1,3,4-thiadiazole-thiourea compounds comprises the following reaction:

[0012]

[0013] (1) Preparation of intermediate anisole-based thiourea compound

[0014] Aminothiourea (0.91 g, 10.0 mmol) and deionized water (20 mL) were added sequentially to a reaction flask, and the mixture was magnetically stirred in an oil bath at 65 °C. Separately, trans-4-methoxycinnamonaldehyde (1.62 g, 10.0 mmol) was completely dissolved in anhydrous ethanol (20 mL) and slowly added dropwise to the above reaction mixture through a constant-pressure dropping funnel. After the addition was complete, the reaction system was stirred at 65 °C for 15 min. The reaction solution was allowed to cool to room temperature, filtered to obtain a solid, and the filter cake was washed with 50% ethanol aqueous solution (20 mL × 3). The crude product was purified by recrystallization from ethanol to obtain a white solid product, namely, anethole-based aminothiourea.

[0015] (2) Preparation of the intermediate anethole-based 1,3,4-thiadiazole compound

[0016] In a reaction flask, 2.80 g (13.0 mmol) of anethole-based thiourea and 100 mL of deionized water were added sequentially. The mixture was heated to 65 °C with magnetic stirring and reacted for 10 min. A solution of ferric chloride hexahydrate (10.10 g, 38.0 mmol) and deionized water (pH = 2) was added dropwise. The reaction mixture was heated to 85 °C and stirred until complete, monitored by thin-layer chromatography. The reaction solution was cooled, quenched with 5% sodium thiosulfate solution, and then extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography [eluent: V (petroleum ether): V (ethyl acetate) = 2:1] to obtain a brown solid product, anethole-based 2-amino-1,3,4-thiadiazole.

[0017] (3) Synthesis of the final product, anethole-based 1,3,4-thiadiazole-thiourea compound

[0018] Anethole-based 2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). Methyl phenyl isothiocyanate (0.15 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. The solutions were then slowly added dropwise to the above reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was dissolved in ethyl acetate and recrystallized for purification. A white solid, namely anethole-based 1,3,4-thiadiazole-thiourea compound a, was obtained. The amount of this type of compound can be increased or decreased according to the corresponding proportions. Compounds b to t were synthesized using the above method.

[0019] The present invention also provides the herbicidal activity of the fenestrated 1,3,4-thiadiazole-thiourea compound against two common weeds, rapeseed and barnyardgrass.

[0020] The beneficial effects of this invention are:

[0021] This invention patent is based on a molecular design strategy of active substructure splicing. Using anethole aldehyde, obtained by allylic methyl oxidation of the natural renewable biomass resource anethole, as a starting material, a three-step reaction is used to introduce 1,3,4-thiadiazole and thiourea active groups into the molecular skeleton of anethole. The synthesis method is simple, efficient, easy to operate, and low in cost. Herbicidal activity tests revealed that some compounds exhibited good herbicidal activity against the tested weeds, providing experimental evidence for the high-value utilization of anethole, a unique and advantageous natural product resource in my country. Detailed Implementation

[0022] The technical solution of the present invention will be further described below through specific embodiments.

[0023] Example 1: Preparation of Anethole-based 1,3,4-thiadiazole-(ethyl)phenylthiourea (compound a)

[0024]

[0025] Anethole-based 2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). Benzyl isothiocyanate (0.15 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. The solutions were then slowly added dropwise to the above reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-based 1,3,4-thiadiazole-benzylthiourea was given as a white solid, yield 76.9%, mp 167.9 – 168.1 ℃; IR (KBr, ν / cm) -1 ): 3307 (NH), 3063, 3032, 2929, 2830 (Ar-CH,CH), 1650 (C=N,C=C), 1601, 1573, 1508 (Ar-C=C), 1171 (C=S), 649 (CSC); 1 HNMR (600 MHz, DMSO-d6) δ: 9.22 (s, 1H, N- H ), 7.64 (d, J = 8.3 Hz, 2H, Ar- H ), 7.39 – 7.33 (m, 2H, Ar- H ), 7.32 (s, 2H, Ar- H), 7.25 (d, J = 16.5 Hz, 1H, =C- H ), 7.22 (d, 1H, =C- H ), 6.96 (d, J = 8.2 Hz, 2H, Ar- H ), 4.79 (s, 2H, -C H 2-), 3.79 (s, 3H, Ar- H ); 13 C NMR (151 MHz, DMSO-d6) δ: 160.27, 157.67, 139.32,129.05, 128.93, 128.73, 127.83, 127.32, 117.69, 114.74, 55.69, 47.80; HRMS(APCI, m / z): calcd. for C 19 H 18 N4OS2 + ([M+H + ]) 381.0849, found 382.0922.

[0026] Example 2: Preparation of Anethole-based 1,3,4-thiadiazole-phenylthiourea (compound b)

[0027]

[0028] Anethole-2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). Phenyl isothiocyanate (0.14 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. The solutions were then slowly added dropwise to the above reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was dissolved in ethyl acetate and recrystallized for purification. The compound anethole-1,3,4-thiadiazole-phenylthiourea was given as a white solid, yield 76.3%, mp 172.8 – 173.3 ℃; IR (KBr, ν / cm) -1): 3296 (NH), 3024, 2963, 2842 (Ar-CH, CH), 1630 (C=N,C=C), 1601, 1572, 1548, 1511 (Ar-C=C), 1174 (C=S), 654 (CSC); 1 HNMR (600 MHz, DMSO-d6) δ: 10.51 (s, 1H, N- H ), 7.71 (d, J = 7.9 Hz, 2H, Ar- H ), 7.70 – 7.67 (m, 2H, Ar- H ), 7.35 (d, J = 4.9 Hz, 1H, =C- H ), 7.33 (d, J = 4.3Hz, 2H, Ar- H ), 7.25 (d, J = 16.5 Hz, 1H, =C- H ), 6.99 – 6.96 (m, 2H, Ar- H ),3.79 (s, 3H, -OC H 3); 13 C NMR (151 MHz, DMSO-d6) δ: 160.69, 140.16, 136.99,136.37, 131.07, 129.48, 129.40, 129.29, 128.86, 128.43, 119.23, 116.84,114.80, 55.73; HRMS (APCI, m / z): calcd. for C 19 H 17 N3OS2 + ([M+H + ]) 367.0693,found 367.0688.

[0029] Example 3: Preparation of anisole-based 1,3,4-thiadiazole-(4'-chloro)phenylthiourea (compound c)

[0030]

[0031] Anethole-2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). 4-Chlorophenyl isothiocyanate (0.17 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. The solutions were then slowly added dropwise to the above reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-1,3,4-thiadiazole-(4'-chloro)phenylthiourea was given as a yellow solid, yield 72.1%, mp 175.1 – 176.5 ℃; IR (KBr, ν / cm) -1 ): 3331 (NH), 3006, 2930, 2836 (Ar-CH, CH), 1657 (C=N,C=C), 1601, 1541,1513, 1492 (Ar-C=C), 1173 (C=S),648 (CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 9.85 (s, 1H, N- H ), 7.80 (d, J = 8.3Hz, 2H, Ar- H ), 7.68 (d, J = 8.7 Hz, 2H, Ar- H ), 7.41 – 7.33 (m, 2H, Ar- H ),7.31 (d, J = 11.0 Hz, 1H, =C- H ), 7.26 (d, J = 16.4 Hz, 1H, =C- H ), 6.97 (d, J= 8.2 Hz, 2H, Ar- H ), 3.79 (s, 3H, -OC H 3); 13 C NMR (151 MHz, DMSO-d6) δ:160.58, 155.90, 139.45, 136.49, 129.36, 129.28, 129.23, 128.62, 123.93,120.63, 117.16, 116.80, 114.79, 55.72; HRMS (APCI, m / z): calcd. forC 18 H15 ClN4OS2 + ([M+H + ]) 401.0303, found 401.0298.

[0032] Example 4: Preparation of anisole-based 1,3,4-thiadiazole-(3'-chloro-5'-fluoro)phenylthiourea (compound d)

[0033]

[0034] Anethole-2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). 3-chloro-5-fluoro-phenyl isothiocyanate (0.19 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. These solutions were then slowly added dropwise to the reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was dissolved in ethyl acetate and recrystallized for purification. The compound anethole-1,3,4-thiadiazole-(3'-chloro-5'-fluoro)phenylthiourea was obtained as a yellow solid in 73.6% yield, mp 176.9–177.4 °C; IR (KBr, v / cm) -1 ): 3331 (NH), 2954, 2926,2854 (CH), 1629 (C=N,C=C), 1600, 1572, 1541, 1511 (Ar-C=C), 1172(C=S), 650(CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 9.24 (s, 1H, N- H ), 8.38 (dd, J = 7.1,2.7 Hz, 1H, Ar- H ), 7.78 – 7.74 (m, 1H, Ar- H ), 7.60 (d, J = 8.4 Hz, 2H, Ar- H ),7.25 (d, J = 9.6 Hz, 1H, Ar- H ), 7.23 – 7.21 (m, 1H, =C- H ), 7.08 (d, J = 16.4Hz, 1H, =C- H), 6.95 (d, J = 8.4 Hz, 2H, Ar- H ), 3.79 (s, 3H, -OC H 3); 13 C NMR(151 MHz, DMSO-d6) δ: 179.28, 171.92, 159.76, 157.60, 152.57, 132.44, 131.06,129.61, 128.51, 120.77, 119.78, 118.61, 116.45, 114.72, 114.04, 55.65; HRMS(APCI, m / z): calcd. for C 18 H 14 ClFN4OS2 + ([M+H + ]) 419.0209, found 419.0204.

[0035] Example 5: Preparation of anisole-based 1,3,4-thiadiazole-(2',4'-dimethyl)phenylthiourea (compound e)

[0036]

[0037] Anethole-2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). 2,4-methylphenyl isothiocyanate (0.17 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. These solutions were then slowly added dropwise to the reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was dissolved in ethyl acetate and recrystallized for purification. The compound anethole-1,3,4-thiadiazole-(2',4'-methyl)phenylthiourea was given as a white solid in 78.1% yield, mp 177.8–178.5 °C; IR (KBr, v / cm) was also obtained. -1 ): 3303 (NH), 3036, 3010,2938 (Ar-H, CH), 1653 (C=N,C=C), 1600, 1528,1511 (Ar-C=C), 1171(C=S), 652(CSC); 1H NMR (600 MHz, DMSO-d6) δ: 8.06 (s, 1H, N- H ), 7.59 (s, 1H, Ar- H ),7.57 (d, J = 8.6 Hz, 2H, Ar- H ), 7.19 (d, J = 16.4 Hz, 1H, Ar- H ), 7.02 (d, J =16.4 Hz, 1H, Ar- H ), 6.95 (s, 2H, Ar- H ), 6.94 (d, 1H, =C- H ), 6.92 (d, J = 8.0Hz, 1H, =C- H ), 3.78 (s, 3H, -OC H 3), 2.24 (s, 3H, -C H 3), 2.17 (s, 3H,-C H 3); 13 CNMR (151 MHz, DMSO-d6) δ: 159.63, 137.79, 132.32, 131.72, 130.73, 129.76,128.37, 126.43, 125.78, 120.04, 114.70, 55.63, 20.96, 18.56; HRMS (APCI, m / z): calcd. for C 20 H 20 N4OS2 + ([M+H + ]) 395.1006, found 395.1003.

[0038] Example 6: Preparation of Anethole-based 1,3,4-thiadiazole-(4'-bromophenylthiourea) (compound f)

[0039]

[0040] Anethole-based 2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). 4-Bromophenyl isothiocyanate (0.19 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. These solutions were then slowly added dropwise to the reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-based 1,3,4-thiadiazole-(4'-bromo)phenylthiourea was given as a white solid, yield 78.1%, mp 187.0 – 187.9 ℃; IR (KBr, ν / cm) -1 ): 3331 (NH), 3030, 2987, 2931 (Ar-CH, CH), 1659, 1602 (C=N,C=C), 1583, 1548,15 1512 (Ar-C=C), 1173 (C=S),660 (CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 9.62 (s, 1H, N- H ), 7.85 (d, J = 9.1Hz, 1H, =C- H ), 7.62 (d, J = 8.9 Hz, 2H, Ar- H ), 7.56 (d, J = 8.7 Hz, 2H, Ar- H ), 7.32 (d, J = 8.8 Hz, 2H, Ar- H ), 7.21 (d, J = 16.4 Hz, 1H, =C- H ), 6.96 (d,J = 6.9 Hz, 2H, Ar- H ), 3.78 (s, 3H, -OC H 3); 13 C NMR (151 MHz, DMSO-d6) δ:176.06, 160.05, 159.58, 140.97, 133.91, 131.72, 129.13, 128.81, 120.37,118.28, 114.75, 112.82, 99.99, 55.67; HRMS (APCI, m / z): calcd. forC18 H 15 BrN4OS2 + ([M+H + ]) 444.9798, found 444.9792.

[0041] Example 7: Preparation of Anethole-based 1,3,4-thiadiazole-(4'-tert-butyl)phenylthiourea (compound g)

[0042]

[0043] Anethole-2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). 4-tert-butylphenyl isothiocyanate (0.19 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. These solutions were then slowly added dropwise to the reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-1,3,4-thiadiazole-(4'-tert-butyl)phenylthiourea was given as a white solid in 83.9% yield, mp 191.5–192.1 °C; IR (KBr, v / cm) was also obtained. -1 ): 3306 (NH), 3122, 3032,2960, 2833 (Ar-CH, CH), 1602 (C=N,C=C), 1537, 1574, 1512 (Ar-C=C), 1172 (C=S), 649 (CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 10.72 (s, 1H, N- H ), 7.67 (s, 2H,Ar- H ), 7.42 (s, 2H, Ar- H ), 7.31 (d, J = 35.1 Hz, 2H, Ar- H ), 6.97 (s, 2H, Ar- H ), 3.79 (s, 3H, -OC H 3), 1.28 (s, 9H, tC H 3); 13C NMR (151 MHz, DMSO-d6) δ: 160.53, 137.49, 136.30, 129.32, 128.61, 125.48, 122.73, 114.78, 34.56, 31.66; HRMS (APCI, m / z): calcd. for C 23 H 25 N3OS2 + ([M+H + ]) 423.1319, found 423.1317.

[0044] Example 8: Preparation of anisole-based 1,3,4-thiadiazole-(4'-n-butyl)phenylthiourea (compound h)

[0045]

[0046] Anethole-2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). 4-Butylphenyl isothiocyanate (0.19 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. These solutions were then slowly added dropwise to the reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was dissolved in ethyl acetate and recrystallized for purification. The compound anethole-1,3,4-thiadiazole-(4'-n-butyl)phenylthiourea was given as a white solid in 88.9% yield, mp 192.8–193.3 °C; IR (KBr, v / cm) was also obtained. -1 ): 3327 (NH), 3123, 3069,3026, 2954, 2927 (Ar-CH, CH), 1628 (C=N,C=C), 1572, 1541, 1511 (Ar-C=C),1172 (C=S), 651 (CSC); 1 H NMR (600 MHz, DMSO-d6) δ:10.47 (s, 1H, N- H ), 7.78–7.63 (m, 2H, Ar- H ), 7.63 – 7.49 (m, 2H, Ar- H ), 7.36 – 7.21 (m, 2H, Ar- H),7.13 (d, J = 5.4 Hz, 1H, =C- H ), 7.12 (t, J = 18.7 Hz, 1H, =C- H ), 7.03 – 6.89(s, 2H, Ar- H ), 3.79 (s, 3H, -OC H 3), 1.54 (t, 2H, -CH2-), 1.31 (t, 2H, -C H 2-), 0.90 (s, 3H, -C H 3); 13 C NMR (151 MHz, DMSO-d6) δ:160.63, 136.72, 129.41,128.60, 128.49, 116.94, 114.79, 55.73, 34.77, 33.66, 22.21, 14.26; HRMS(APCI, m / z): calcd. for C 22 H 24 N4OS2 + ([M+H + ]) 423.1319, found 423.1315.

[0047] Example 9: Preparation of Anethole-based 1,3,4-thiadiazole-(4'-fluoro)phenylthiourea (compound i)

[0048]

[0049] Anethole-based 2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). 4-fluorophenyl isothiocyanate (0.16 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. The solutions were then slowly added dropwise to the above reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-based 1,3,4-thiadiazole-(4'-fluoro)phenylthiourea was given as a yellow solid, yield 75.9%, mp 180.1–180.9 ℃; IR (KBr, ν / cm) -1): 3295 (NH), 3032, 2995, 2930 (Ar-CH, CH), 1630 (C=N,C=C), 1603, 1587, 1550, 1504 (Ar-C=C), 1173 (C=S), 661(CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 10.49 (s, 1H, N- H ), 7.80 (d, J = 8.3 Hz, 2H, Ar- H ), 7.68 (d, J = 9.0 Hz, 2H, Ar- H ), 7.36 (dd, J = 14.8, 8.5 Hz, 2H,Ar- H ), 7.33 (d, J = 5.4 Hz, 1H, =C- H ), 7.27 (t, J = 18.7 Hz, 1H, =C- H ), 6.97(d, J = 8.2 Hz, 2H, Ar- H ), 3.79 (s, 3H, -OC H 3); 13 C NMR (151 MHz, DMSO-d6) δ:160.58, 155.90, 139.45, 136.49, 129.36, 129.28, 129.23, 128.62, 123.93,120.63, 117.16, 116.80, 114.79, 55.72; HRMS (APCI, m / z): calcd. forC 18 H 15 FN4OS2 + ([M+H + ]) 385.0599, found 386.0597.

[0050] Example 10: Preparation of Anethole-based 1,3,4-thiadiazole-(4'-nitro)phenylthiourea (compound j)

[0051]

[0052] Anethole-based 2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). Meanwhile, 4-nitrophenyl isothiocyanate (0.18 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. The solutions were then slowly added dropwise to the reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-based 1,3,4-thiadiazole-(4'-nitro)phenylthiourea was given as a yellow solid, yield 78.9%, mp 190.7–191.2 ℃; IR (KBr, ν / cm) -1 ): 3383 (NH), 3020, 2931 (Ar-CH, CH), 1632 (C=N,C=C), 1602, 1552, 1511 (Ar-C=C), 1174 (C=S), 667 (CSC); 1 HNMR (600 MHz, DMSO-d6) δ: 11.37 (s, 1H, N- H ), 7.69 (d, J = 8.4 Hz, 2H, Ar- H ),7.62 (d, J = 8.4 Hz, 2H, Ar- H ), 7.42 (d, J = 8.5 Hz, 2H, Ar- H ), 7.29 (d, J =16.4 Hz, 1H, =C- H ), 7.16 (d, J = 16.4 Hz, 1H, =C- H ), 6.97 (d, J = 8.3 Hz, 2H,Ar- H ), 3.79 (s, 3H, -OC H 3); 13 C NMR (151 MHz, DMSO-d6) δ: 176.06, 160.05,159.58, 156.80, 140.97, 133.91, 129.13, 128.81, 120.37, 118.28, 114.75,112.82, 55.67; HRMS (APCI, m / z): calcd. for C 18 H 15N5O3S2 + ([M+H + ]) 412.0544,found 412.0540.

[0053] Example 11: Preparation of Anethole-based 1,3,4-thiadiazole-(4'-methyl)phenylthiourea (compound k)

[0054]

[0055] Anethole-based 2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). Meanwhile, 4-methylphenyl isothiocyanate (0.15 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. These solutions were then slowly added dropwise to the reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-based 1,3,4-thiadiazole-(4'-methyl)phenylthiourea was obtained as a white solid with a yield of 86.5%, mp 182.8 – 183.1 ℃; IR (KBr, ν / cm) -1 ): 3302 (NH), 3024, 2931 (Ar-CH,CH), 1629 (C=N,C=C), 1601, 1573, 1540, 1510 (Ar-C=C), 1172 (C=S), 651 (CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 10.41 (s, 1H, N- H ), 7.68 (d, J = 8.3 Hz, 2H,Ar- H ), 7.56 (d, J = 8.0 Hz, 2H, Ar- H ), 7.35 – 7.31 (m, 1H, =C- H ), 7.25 (d, J= 16.5 Hz, 1H, =C- H ), 7.14 (d, J = 8.0 Hz, 2H, Ar- H ), 6.98 (d, J = 8.3 Hz, 2H, Ar- H ), 3.79 (s, 3H, -OC H3), 2.28 (s, 3H, -C H 3); 13 C NMR (151 MHz, DMSO-d6)δ 160.64, 137.65, 136.79, 129.44, 129.43, 129.27, 128.46, 116.92, 114.79,55.72, 21.00; HRMS (APCI, m / z): calcd. for C 19 H 18 N4OS2 + ([M+H + ]) 381.0849, found381.0847.

[0056] Example 12: Preparation of Anethole-based 1,3,4-thiadiazole-cyclohexylthiourea (compound 1)

[0057]

[0058] Anethole-based 2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). Cyclohexyl isothiocyanate (0.14 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. The solutions were then slowly added dropwise to the above reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-based 1,3,4-thiadiazole-cyclohexylphenylthiourea was given as a yellow solid, yield 80.3%, mp 177.1 – 178.0 °C; IR (KBr, ν / cm) -1 ): 3472 (NH), 3183, 3030 (Ar-CH,CH), 1668, 1631 (C=N,C=C), 1604, 1579, 1513 (Ar-C=C), 1173 (C=S), 655 (CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 9.16 (s, 1H, N- H ), 7.63 (d, J = 8.2 Hz, 2H,Ar- H ), 7.25 (s, 1H, =C- H), 7.24 (s, 1H, =C- H ), 6.96 (d, J = 8.2 Hz, 2H, Ar- H ), 3.78 (s, 3H, -OC H 3), 1.55 (d, J = 7.1 Hz, 1H, -C H -), 1.31 – 1.22 (m,10H, -C H 2-); 13 C NMR (151 MHz, DMSO-d6) δ: 181.74, 164.72, 160.24, 157.99,134.95, 128.99, 128.95, 117.69, 114.73, 55.68, 44.64, 31.74, 29.16, 22.58;HRMS (APCI, m / z): calcd. for C 18 H 22 N4OS2 + ([M+H + ]) 373.1162, found 373.1158.

[0059] Example 13: Preparation of Anethole-based 1,3,4-thiadiazole-(4'-ethyl)phenylthiourea (compound m)

[0060]

[0061] Anethole-based 2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). 4-ethylphenyl isothiocyanate (0.16 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. These solutions were then slowly added dropwise to the reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-based 1,3,4-thiadiazole-(4'-ethyl)phenylthiourea was given as a white solid, yield 87.9%, mp 197.8 – 198.2 ℃; IR (KBr, ν / cm) -1): 3292 (NH), 371, 3026, 2955 (Ar-CH, CH), 1652, 1629 (C=N,C=C), 1603, 1574,1529, 1512 (Ar-C=C), 1172 (C=S),649 (CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 9.18 (s, 1H, N- H ), 7.74 (d, J = 8.5Hz, 2H, Ar- H ), 7.61 (d, J = 8.7 Hz, 2H, Ar- H ), 7.24 (d, J = 16.3 Hz, 1H, =C- H ), 7.10 (d, J = 16.4 Hz, 1H, =C- H ), 7.06 (d, J = 8.6 Hz, 2H, Ar- H ), 6.96 (d,J = 8.8 Hz, 2H, Ar- H ), 3.79 (s, 3H, -OC H 3), 2.54 (q, J = 7.5 Hz, 2H, -C H 2-), 1.18 – 1.15 (m, 3H, -C H 3); 13 C NMR (151 MHz, DMSO-d6) δ: 159.83, 139.81,132.72, 129.24, 128.58, 128.54, 127.68, 120.86, 119.50, 119.37, 114.73,55.65, 28.09, 16.36; HRMS (APCI, m / z): calcd. for C 20 H 20 N4OS2 + ([M+H + ])395.1006, found 395.1002.

[0062] Example 14: Preparation of Anethole-based 1,3,4-thiadiazole-(2'-fluoro)phenylthiourea (compound n)

[0063]

[0064] Anethole-2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). 2-fluorophenyl isothiocyanate (0.15 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. The solutions were then slowly added dropwise to the above reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-1,3,4-thiadiazole-(2'-fluoro)phenylthiourea was given as a yellow solid, yield 70.9%, mp 174.9–175.3 ℃; IR (KBr, ν / cm) -1 ): 3465 (NH), 3034, 2991, 2931 (Ar-CH, CH), 1662 (C=N,C=C), 1602, 1580,1548, 1512 (Ar-C=C), 1174 (C=S), 658(CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 8.46 (s, 1H, N- H ), 7.66 (s, 1H, Ar- H ),7.63 (d, J = 8.8 Hz, 2H, Ar- H ), 7.48 (m, 1H, Ar- H ), 7.33 – 7.29 (m, 1H, Ar- H ), 7.26 (d, J = 16.4 Hz, 1H, Ar- H ), 7.18 (d, J = 16.5 Hz, 1H, =C- H ), 7.08 –7.02 (m, 1H, =C- H ), 6.96 (d, J = 8.2 Hz, 2H, Ar- H ), 3.79 (s, 3H, -OC H 3); 13CNMR (151 MHz, DMSO-d6) δ: 180.81, 172.55, 160.05, 157.60, 129.34, 129.25,128.81, 127.73, 124.86, 124.04, 118.83, 114.74, 55.67; HRMS (APCI, m / z):calcd. for C 18 H 15 FN4OS2 + ([M+H + ]) 386.0671, found 386.0671.

[0065] Example 15: Preparation of Anethole-based 1,3,4-thiadiazole-(2'-chloro)phenylthiourea (compound o)

[0066]

[0067] Anethole-2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). 2-chlorophenyl isothiocyanate (0.15 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. The solutions were then slowly added dropwise to the reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-1,3,4-thiadiazole-(2'-chloro)phenylthiourea was given as a yellow solid, yield 84.8%, mp 179.5–180.3 ℃; IR (KBr, v / cm) -1 ): 3331 (NH), 3006, 2930, 2836 (Ar-CH, CH), 1657 (C=N,C=C), 1601, 1541,1513, 1492 (Ar-C=C), 1173 (C=S), 650(CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 8.46 (s, 1H, N- H ), 7.63 (d, J = 8.3 Hz, 2H, Ar- H ), 7.45 (dd, J = 8.0, 1.4 Hz, 1H, Ar- H), 7.33 – 7.29 (m, 1H, Ar- H ),7.26 (d, J = 16.4 Hz, 1H, Ar- H ), 7.18 (d, J = 16.4 Hz, 1H, =C- H ), 7.05 (t, J= 7.9 Hz, 1H, =C- H ), 6.96 (d, J = 8.2 Hz, 2H, Ar- H ), 3.79 (s, 3H, -OC H 3); 13 CNMR (151 MHz, DMSO-d6) δ: 180.81, 172.55, 160.05, 157.60, 129.34, 129.25,128.81, 127.73, 124.86, 124.04, 118.83, 114.74, 55.67; HRMS (APCI, m / z):calcd. for C 19 H 16 ClN3OS2 + ([M+H + ]) 401.0303, found 401.0299.

[0068] Example 16: Preparation of Anethole-based 1,3,4-thiadiazole-(4'-cyano)phenylthiourea (compound p)

[0069]

[0070] Anethole-2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). 4-cyanophenyl isothiocyanate (0.15 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. The solutions were then slowly added dropwise to the above reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-1,3,4-thiadiazole-(4'-cyano)phenylthiourea was given as a yellow solid, yield 83.5%, mp 195.8 – 196.0 ℃; IR (KBr, v / cm) -1): 3317 (NH), 3032, 3004, 2933 (Ar-CH, CH), 1660 (C=N,C=C), 1601, 1536, 1511 (Ar-C=C), 1174 (C=S), 653 (CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 10.80 (s, 1H, N- H ), 7.75 (d, J = 3.9 Hz, 2H, Ar- H ), 7.74 (d, 2H, Ar- H ), 7.67 (dd, J = 20.1, 8.3 Hz, 2H, Ar- H ), 7.33(d, J = 23.1 Hz, 1H, =C- H ), 7.27 (t, J = 16.8 Hz, 1H, =C- H ), 6.98 – 6.96 (m,2H, Ar- H ), 3.79 (s, 3H, -OC H 3); 13 C NMR (151 MHz, DMSO-d6) δ: 160.75, 144.48,137.32, 136.66, 133.75, 133.23, 129.53, 129.35, 128.36, 121.59, 119.76,119.06, 116.70, 114.80, 55.72; HRMS (APCI, m / z): calcd. for C 19 H 15 N5OS2 + ([M+H + ]) 392.0645, found 392.0644.

[0071] Example 17: Preparation of Anethole-based 1,3,4-thiadiazole-(4'-iodo)phenylthiourea (compound q)

[0072]

[0073] Anethole-based 2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). 4-Iodophenyl isothiocyanate (0.26 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. These solutions were then slowly added dropwise to the reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-based 1,3,4-thiadiazole-(4'-iodo)phenylthiourea was given as a pale yellow solid, yield 75.1%, mp 172.5 – 173.1 ℃; IR (KBr, ν / cm) -1 ): 3328 (NH), 3036, 2994, 2993 (Ar-CH, CH), 1660 (C=N,C=C), 1603, 1547, 1512 (Ar-C=C), 1174 (C=S), 655 (CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 10.49 (s, 1H, N- H ), 7.80 (d, J = 8.4 Hz, 2H, Ar- H ), 7.67 (dd, J = 12.9, 8.1 Hz, 2H, Ar- H ), 7.35 (q, J = 11.0, 7.1 Hz, 2H, Ar- H ), 7.31 (d, J = 10.7 Hz, 1H, =C- H ), 7.26 (d, J = 16.5 Hz, 1H, =C- H ),6.97 (d, J = 8.2 Hz, 2H, , Ar- H ), 3.79 (s, 3H, -OC H 3); ); 13C NMR (151 MHz, DMSO-d6) δ: 160.59, 155.91, 139.46, 136.49, 129.37, 129.24, 128.63, 128.57,123.92, 120.64, 117.16, 116.81, 114.79, 55.72; HRMS (APCI, m / z): calcd. forC 18 H 15 IN4OS2 + ([M+H + ]) 492.9659, found 492.9655.

[0074] Example 18: Preparation of Anethole-based 1,3,4-thiadiazole-(4'-iodo)phenylthiourea (compound r)

[0075]

[0076] Anethole-2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). 3-fluorophenyl isothiocyanate (0.15 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. These solutions were then slowly added dropwise to the reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-1,3,4-thiadiazole-(3'-fluoromethyl)phenylthiourea was given as a yellow solid, yield 70.5%, mp 169.8 – 170.2 ℃; IR (KBr, ν / cm) -1 ): 3318 (NH), 3085, 3057, 3026,2904, 2835 (Ar-CH, CH), 1662 (C=N,C=C), 1602, 1573,1551, 1512 (Ar-C=C),1173 (C=S), 655 (CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 10.45 (s, 1H, N- H ), 7.90(dt, J = 12.1, 2.3 Hz, 1H, Ar- H ), 7.68 (d, J = 8.9 Hz, 2H, Ar-H ), 7.54 (ddd,J = 8.2, 2.0, 0.9 Hz, 1H, Ar- H ), 7.33 (d, J = 8.0 Hz, 1H, Ar- H ), 7.30 (d, J =14.9 Hz, 2H Ar- H ), 6.98 (d, J = 8.8 Hz, 2H Ar- H ), 6.86 (td, J = 8.6, 2.6 Hz,=C- H ), 3.80 (s, 3H, -OC H 3); 13 C NMR (151 MHz, DMSO-d6) δ:183.77, 167.65,161.68, 160.56, 155.95, 142.42, 136.35, 134.59, 130.24, 129.34, 128.86,128.60, 117.29, 114.79, 114.73, 55.71; HRMS (APCI, m / z): calcd. forC 18 H 15 FN4OS2 + ([M+H + ]) 385.0599, found 385.0596.

[0077] Example 19: Preparation of anethole-based 1,3,4-thiadiazole-(3',4'-dichloro)phenylthiourea (compound S)

[0078]

[0079] Anethole-2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). 3,4-dichlorophenyl isothiocyanate (0.15 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. These solutions were then slowly added dropwise to the reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was dissolved in ethyl acetate and recrystallized for purification. The compound anethole-1,3,4-thiadiazole-(3',4'-dichloro)phenylthiourea was given as a yellow solid in 72.6% yield, mp 179.5–180.1 °C; IR (KBr, v / cm) was also obtained. -1 ): 3288 (NH), 3096, 3040,2999, 2929 (Ar-CH, CH), 1629 (C=N,C=C), 1603, 1582, 1531, 1513 (Ar-C=C),1173 (C=S), 659 (CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 9.37 (s, 1H, N- H ), 8.49(d, J = 2.5 Hz, 1H, Ar- H ), 7.83 (dd, J = 8.9, 2.5 Hz, 1H, Ar- H ), 7.61 (d, J =8.8 Hz, 2H, Ar- H ), 7.42 (d, J = 8.9 Hz, 1H, Ar- H ), 7.27 (d, J = 16.4 Hz, 1H,=C- H ), 7.11 (d, J = 16.4 Hz, 1H, 1H, =C- H ), 6.96 (d, J = 8.8 Hz, 2H, Ar- H ),3.79 (s, 3H, -OC H 3); 13C NMR (151 MHz, DMSO-d6) δ: 179.24, 171.82, 159.81,157.76, 142.47, 132.61, 130.72, 130.14, 129.59, 128.56, 121.54, 120.63,119.73, 119.58, 114.74, 55.66; HRMS (APCI, m / z): calcd. for C 18 H 14 Cl2N4OS2 + ([M+H + ]) 434.9913, found 434.9911.

[0080] Example 20: Preparation of anisole-based 1,3,4-thiadiazole-(4'-trifluoromethyl)phenylthiourea (compound t)

[0081]

[0082] Anethole-2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). Methylphenyl isothiocyanate (0.15 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. The solutions were then slowly added dropwise to the above reaction mixture. The reaction mixture was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was purified by recrystallization from ethyl acetate. The compound anethole-1,3,4-thiadiazole-(4'-trifluoromethyl)phenylthiourea was given as a white solid, yield 81.2%, mp 178.8–179.3 ℃; IR (KBr, ν / cm) -1 ): 3330 (NH), 3028, 2840 (Ar-CH, CH), 1667 (C=N,C=C), 1601, 1538, 1550, 1514 (Ar-C=C), 1175 (C=S), 659 (CSC); 1 H NMR (600 MHz, DMSO-d6) δ: 9.45 (s, 1H, N- H ), 7.61 (d, J = 8.3 Hz, 2H,Ar- H ), 7.52 (d, 2H, Ar- H), 7.50 (s, 2H, Ar- H ), 7.28 (d, J = 16.4 Hz, 1H, =C- H ), 7.12 (d, J = 16.4 Hz, 1H, =C- H ), 6.96 (d, J = 8.2 Hz, 2H, Ar- H ), 3.79 (s,3H, -OC H 3); 13 C NMR (151 MHz, DMSO-d6) δ: 179.52, 159.82, 157.74, 145.72,132.64, 129.59, 128.55, 126.30, 125.45, 124.51, 121.79, 119.70, 119.32,114.74, 55.64; HRMS (APCI, m / z): calcd. for C 19 H 15 F3N4OS2 + ([M+H + ]) 435.0567,found 435.0562.

[0083] Example 21: The herbicidal activity of the 1,3,4-thiadiazole-thiourea compounds a~t prepared in Examples 1 to 20 was tested. The test methods and corresponding results are as follows.

[0084] The inhibitory activity of the compounds against two common weeds was evaluated using the rapeseed petri dish method and the barnyard grass small cup method, with the commercial herbicide propyzamide used as a positive control. Based on the relative inhibition rate (%), the activity was divided into four levels: Level A (≥80%), Level B (60%-79%), Level C (40%-59%), and Level D (<40%). The specific operational steps are as follows:

[0085] Rapeseed petri dish method: A 5.6 cm diameter filter paper was placed in a 6 cm diameter petri dish, and 2 mL of the target compound test solution of the set concentration was added. Ten rapeseed seeds that had been soaked for 4 h were then evenly sown. The petri dishes were placed in a dark environment at (28±1)℃ for 72 h, and the radicle length was then measured. The herbicidal activity was evaluated using the inhibition rate of the target compound on rapeseed radicle growth under dark conditions. Two test concentrations were set up: 10 μg / mL and 100 μg / mL. Each concentration treatment was repeated in two replicates. The rapeseed radicle growth inhibition rate (%) was calculated using the following formula:

[0086]

[0087] Barnyardgrass small-cup method: A suitable amount of glass beads and a sheet of filter paper were placed in a 50 mL beaker, followed by 6 mL of the test compound solution of the predetermined concentration. Ten barnyardgrass seeds with emerging radicles were then sown. The seeds were cultured under light conditions at (28±1)℃ for 72 h, and the seedling height was measured. The inhibition rate of the compound on barnyardgrass seedling height under light conditions was used as an indicator to evaluate its herbicidal activity. The relative inhibition rate (%) of the test compound on barnyardgrass radicle growth was calculated by comparing the length of the radicles in the blank control and the test compound solution.

[0088] The herbicidal activity tests showed that, at concentrations of 10 μg / mL and 100 μg / mL, the 20 target compounds a~t exhibited varying degrees of inhibitory effects on rapeseed. Among them, compounds b (R = Ph), r (R = 3-FPh), and k (R = 4-CH3Ph) showed relative inhibition rates of 87.4%, 84%, and 79.3% on rapeseed radicle growth, respectively (the first two reaching Grade A activity levels), all of which were superior to the positive control propyzamide (inhibition rate 61.0%).

[0089] Test results:

[0090]

Claims

1. A class of anethole-based 1,3,4-thiadiazole-thiourea compounds, with the specific compound structures as follows: Compound a Compound b Compound C Compound D Compound e Compound f Compound g Compound h Compound i Compound j Compound k Compound l Compound m Compound n Compound O Compound P Compound q Compound r Compounds s and t.

2. The method for synthesizing a class of anethole-based 1,3,4-thiadiazole-thiourea compounds according to claim 1, characterized in that... The overall synthetic route is: 。 The preparation method of the compounds a~t includes the following steps: (1) Thiourea aminothiourea (0.91 g, 10.0 mmol) and deionized water (20 mL) were added sequentially to a reaction flask and the mixture was magnetically stirred in an oil bath at 65 °C. Meanwhile, trans-4-methoxycinnamonaldehyde (1.62 g, 10.0 mmol) was completely dissolved in anhydrous ethanol (20 mL) and slowly added dropwise to the above reaction mixture through a constant-pressure dropping funnel. After the addition was complete, the reaction system was stirred at 65 °C for 15 min. The reaction solution was allowed to cool to room temperature, filtered to obtain a solid, and the filter cake was washed with 50% ethanol aqueous solution (20 mL × 3). The crude product was purified by recrystallization from ethanol to obtain a white solid product, namely, anethole-based thiourea. (2) Add 2.80 g, 13.0 mmol of anethole-based thiourea and 100 mL of deionized water to the reaction flask in sequence. Heat to 65 °C with magnetic stirring and react for 10 min. Add a solution of 10.10 g, 38.0 mmol of ferric chloride hexahydrate and deionized water (pH = 2). Heat the reaction mixture to 85 °C and stir until the reaction is complete, monitoring the reaction by thin-layer chromatography. After cooling and quenching with 5% sodium thiosulfate solution, extract with ethyl acetate (20 mL × 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography [eluent: V (petroleum ether): V (ethyl acetate) = 2:1] to obtain a brown solid product, anethole-based 2-amino-1,3,4-thiadiazole. (3) Anethole-based 2-amino-1,3,4-thiadiazole (0.24 g, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL), and benzyl isothiocyanate (0.15 g, 1.0 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) at room temperature. The solution was then slowly added dropwise to the above reaction solution. The reaction solution was heated to reflux with continuous stirring, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, unreacted sodium hydroxide was removed by hot filtration. The resulting filtrate was concentrated under reduced pressure to remove the solvent. The crude product obtained after concentration was dissolved in ethyl acetate and recrystallized for purification. A white solid, namely anethole-based 1,3,4-thiadiazole-thiourea compound a, was obtained. The amount of this type of compound can be increased or decreased according to the corresponding proportion. Compounds b~t were synthesized using the above method.

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