CN111004208B

CN111004208B - 2-cyano-3-thiophene substituted valeramide derivative and application thereof

Info

Publication number: CN111004208B
Application number: CN201911357356.XA
Authority: CN
Inventors: 唐孝荣; 钱伟烽; 刘辉; 肖婷婷; 程玮; 陆童; 张婷婷; 蒋文静; 曾义; 张铭格; 陈彬贤
Original assignee: Xihua University
Current assignee: Xihua University
Priority date: 2019-12-25
Filing date: 2019-12-25
Publication date: 2020-11-24
Anticipated expiration: 2039-12-25
Also published as: CN111004208A

Abstract

The invention relates to a 2-cyano-3-thiophene substituted valeramide derivative and application thereof, belonging to the field of pesticides. The structural formula of the compound is shown as formula I; wherein R is₁Is methyl, methoxy, hydroxymethyl, chlorine or bromine; r₂Hydrogen, methyl, methoxy, chlorine, bromine or iodine. The compound of the invention has better control effect on plant pathogenic fungi and better promotion effect on the germination of vegetable seeds.

Description

2-cyano-3-thiophene substituted valeramide derivative and application thereof

Technical Field

The invention relates to a 2-cyano-3-thiophene substituted valeramide derivative and application thereof, belonging to the field of pesticides.

Background

The amide compounds have wide biological activity, including sterilization, antioxidation, plant growth regulation and the like. Therefore, extensive and intensive research on the compounds has been conducted over the past decades, and many novel and highly effective compounds have been discovered, and there have been continuously reported varieties which are novel in structure, unique in mode of action, excellent in performance, highly effective against harmful organisms, safe against non-target organisms, easily degradable in the environment, and safe to human health and ecological environment for degradation products.

Thiophene is an important member of heterocyclic compounds and plays a very important role. The study of thiophene derivatives also has a very major role in medicine and agrochemical chemistry. Thiophene derivatives have a wide variety of biological activities, for example, antibacterial, antiviral, antitumor, anti-inflammatory, insecticidal, herbicidal, and the like. Meanwhile, the thiophene ring-containing compounds generally have the characteristics of high efficiency, low toxicity, safety to non-target organisms, easiness in degradation in the environment, difficulty in generation of resistance by pests and the like, and compounds with novel structures and excellent performance are continuously published. Therefore, in the process of research and development of pesticides, compounds containing thiophene rings are more widely concerned and become hot spots and frontiers for creating new pesticides.

So far, no report of the use of 2-cyano-3-thiophene substituted valeramide derivatives as agricultural bactericides and vegetable seed germination promoters is found.

Disclosure of Invention

The invention solves the technical problem of providing a new compound which can be used as an agricultural bactericide and a seed germination promoter.

The structural formula of the compound of the invention is shown as formula I:

wherein R is₁Is methyl, methoxy, hydroxymethyl, chlorine or bromine; r₂Hydrogen, methyl, methoxy, chlorine, bromine or iodine.

Preferably: r₁Is chlorine, bromine or methoxy; r₂Hydrogen, methyl, methoxy, chlorine, bromine or iodine.

Preferably: r₁Is methyl, methoxy, hydroxymethyl, chlorine or bromine; r₂Is hydrogen or bromine.

More preferably: r₁Is chlorine, bromine or methoxy; r₂Is hydrogen or bromine.

Preferably, the compound has the structural formula:

the invention solves a second technical problem by providing the application of the compound in preparing agricultural fungicides.

Researches show that the compound has bactericidal activity and can be used as an agricultural bactericide.

Preferably, the bacteria controlled by the bactericide are fungi; more preferably, the bacteria controlled by the agricultural bactericide are cucumber downy mildew, wheat powdery mildew, wheat leaf rust, rice blast, cotton verticillium wilt or citrus anthracnose.

The second technical problem solved by the invention is to provide the application of the compound in preparing the seed germination promoter.

Researches show that the compound can promote seed germination and improve the seed germination rate, and can be prepared into a seed germination promoter.

Preferably, the seeds are vegetable seeds; more preferably, the yellow vegetable seed is cucumber seed, green pepper seed, tomato seed or celery seed.

The invention has the beneficial effects that:

1. the invention introduces thiophene ring into the molecular structure of valeramide to synthesize some 2-cyano-3-thiophene substituted valeramide derivatives, finds some active compounds or active lead compounds with novel structures and excellent activity, and lays a better foundation for the creation of new pesticides.

2. The compound of the general formula (I) has a novel structure and excellent activity, has a better control effect on plant pathogenic fungi, has a better promotion effect on the germination of vegetable seeds, and is not reported in the currently known bactericides and seed germination promoters.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum of the compound of example 1.

FIG. 2 is a nuclear magnetic carbon spectrum of the compound of example 1.

FIG. 3 is a high resolution mass spectrum of the compound of example 1.

FIG. 4 is a nuclear magnetic hydrogen spectrum of the compound of example 2.

FIG. 5 is a nuclear magnetic carbon spectrum of the compound of example 2.

FIG. 6 is a high resolution mass spectrum of the compound of example 2.

FIG. 7 is a nuclear magnetic hydrogen spectrum of the compound of example 3.

FIG. 8 is a nuclear magnetic carbon spectrum of the compound of example 3.

FIG. 9 is a high resolution mass spectrum of the compound of example 3.

FIG. 10 is a nuclear magnetic hydrogen spectrum of the compound of example 4.

FIG. 11 is a nuclear magnetic carbon spectrum of the compound of example 4.

FIG. 12 is a high resolution mass spectrum of the compound of example 4.

FIG. 13 is a nuclear magnetic hydrogen spectrum of the compound of example 5.

FIG. 14 is a nuclear magnetic carbon spectrum of the compound of example 5.

FIG. 15 is a high resolution mass spectrum of the compound of example 5.

Detailed Description

The structural formula of the compound of the invention is shown as formula I:

Preferably, the compound has the structural formula:

the compound can be prepared by adopting a conventional chemical method;

preferably, the compound can be prepared by the following reaction process:

the compound of the general formula (I) has simple synthesis process, and adopts a one-pot method, namely, the intermediate is not separated out according to the traditional method and then subjected to the next reaction, but the next reaction is directly performed, so that the operation steps are reduced, the reaction efficiency is improved, and the energy conservation and consumption reduction are facilitated.

The fourth technical problem solved by the invention is to provide the application of the compound in preparing the seed germination promoter.

The following examples are provided to further illustrate the embodiments of the present invention and are not intended to limit the scope of the present invention.

Example 1:

compound (I)

Preparation of

0.01mol of 4-methoxyacetophenone was dissolved in 10mL of anhydrous ethanol, and 5mL of a 10% NaOH ethanol solution was added thereto. Under stirring in an ice bath, a mixed solution of 0.01mol of thiophene-2-carbaldehyde and 10mL of absolute ethanol was slowly dropped into the above mixed solution with a constant pressure dropping funnel, reacted at 0 to 5 ℃, and checked for completion with a thin layer silica gel plate (TLC). After completion of the reaction, 5mL of 10% NaOH ethanol solution was added to the reaction mixture, and a mixed solution of 0.02mol of cyanoacetamide and 10mL of anhydrous ethanol was slowly dropped into the mixture using a constant pressure dropping funnel, and the reaction was continued at 0 to 5 ℃ with TLC to check whether the reaction was completed. After the reaction is finished, adding a large amount of ice water into the solution, adjusting the pH value to be neutral by using a 10% hydrochloric acid solution, separating out a precipitate, filtering, washing, and recrystallizing by using absolute ethyl alcohol to obtain a target compound, wherein the physicochemical data are as follows: white crystals; yield: 85 percent; the hydrogen spectrum is shown in figure 1, the carbon spectrum is shown in figure 2, the high resolution mass spectrum is shown in figure 3, and particularly,¹H NMR(400MHz,DMSO-d₆)(ppm):7.92(2H,d,J＝8.8Hz),7.87(1H,s),7.63(1H,s),7.37(1H,d,J＝5.2Hz),7.06(1H,s),7.03(2H,s),6.94(1H,t,J＝4.8Hz),4.30-4.25(1H,m),4.19(1H,d,J＝7.6Hz),3.84(3H,s),3.64(1H,dd,J＝17.2,9.2Hz),3.33-3.28(1H,m)；¹³C NMR(100MHz,DMSO-d₆)(ppm):195.45,165.86,163.83,142.61,130.79,129.67,127.19,126.33,125.38,117.81,114.46,56.03,45.32,42.82,36.60；HRMS(ESI)m/z:Calcd for C₁₇H₁₆N₂O₃S[M+H]⁺:329.0954,Found:329.0962.

example 2:

compound (I)

Preparation of

0.01mol of 4-bromoacetophenone was dissolved in 10mL of anhydrous ethanol, and 5mL of a 10% NaOH ethanol solution was added thereto. Under stirring in an ice bath, a mixed solution of 0.01mol of thiophene-2-carbaldehyde and 10mL of absolute ethanol was slowly dropped into the above mixed solution with a constant pressure dropping funnel, reacted at 0 to 5 ℃, and checked for completion with a thin layer silica gel plate (TLC). After completion of the reaction, 5mL of 10% NaOH ethanol solution was added to the reaction mixture, and a mixed solution of 0.02mol of cyanoacetamide and 10mL of anhydrous ethanol was slowly dropped into the mixture using a constant pressure dropping funnel, and the reaction was continued at 0 to 5 ℃ with TLC to check whether the reaction was completed. After the reaction is finished, adding a large amount of ice water into the solution, adjusting the pH value to be neutral by using a 10% hydrochloric acid solution, separating out a precipitate, filtering, washing, and recrystallizing by using absolute ethyl alcohol to obtain a target compound, wherein the physicochemical data are as follows:

a gray powder; yield: 76%; the hydrogen spectrum is shown in fig. 4, the carbon spectrum is shown in fig. 5, the high resolution mass spectrum is shown in fig. 6, and particularly,¹H NMR(400MHz,DMSO-d₆)(ppm):7.88(1H,s),7.86(2H,s),7.75(2H,d,J＝8.8Hz),7.64(1H,s),7.38(1H,d,J＝4.4Hz),7.05(1H,d,J＝3.2Hz),6.95(1H,dd,J＝4.8,3.6Hz),4.29-4.25(1H,m),4.19(1H,d,J＝7.6Hz),3.70(1H,dd,J＝17.2,9.2Hz),3.41(1H,dd,J＝17.6,4.4Hz)；¹³C NMR(100MHz,DMSO-d₆)(ppm):196.51,165.74,142.37,135.66,132.36,130.46,128.14,127.23,126.42,125.48,117.73,45.27,43.25,36.37；HRMS(ESI)m/z:Calcd for C₁₆H₁₃BrN₂O₂S[M+H]⁺:376.9954,Found:376.9953.

example 3:

compound (I)

Preparation of

0.01mol of 4-methoxyacetophenone was dissolved in 10mL of anhydrous ethanol, and 5mL of a 10% NaOH ethanol solution was added thereto. Under stirring in an ice bath, a mixed solution of 0.01mol of 5-bromothiophene-2-carbaldehyde and 10mL of absolute ethyl alcohol was slowly dropped into the mixed solution by using a constant pressure dropping funnel, the reaction was carried out at 0 to 5 ℃, and whether the reaction was completed or not was checked by using a thin layer silica gel plate (TLC). After completion of the reaction, 5mL of 10% NaOH ethanol solution was added to the reaction mixture, and a mixed solution of 0.02mol of cyanoacetamide and 10mL of anhydrous ethanol was slowly dropped into the mixture using a constant pressure dropping funnel, and the reaction was continued at 0 to 5 ℃ with TLC to check whether the reaction was completed. After the reaction is finished, adding a large amount of ice water into the solution, adjusting the pH value to be neutral by using a 10% hydrochloric acid solution, separating out a precipitate, filtering, washing, and recrystallizing by using absolute ethyl alcohol to obtain a target compound, wherein the physicochemical data are as follows: yellow crystals; yield: 89 percent; the hydrogen spectrum is shown in fig. 7, the carbon spectrum is shown in fig. 8, the high resolution mass spectrum is shown in fig. 9, and specifically,¹H NMR(400MHz,DMSO-d₆)(ppm):7.95(2H,d,J＝8.8Hz),7.88(1H,s),7.66(1H,s),7.07-7.05(3H,m),6.90(1H,d,J＝3.6Hz),4.22(2H,d,J＝2.4Hz),3.85(3H,s),3.69-3.63(1H,m),3.38-3.33(1H,m)；¹³C NMR(100MHz,DMSO-d₆)(ppm):195.33,165.68,163.91,144.58,130.84,130.38,129.53,127.34,117.63,114.49,110.29,56.06,44.87,42.26,36.67；HRMS(ESI)m/z:Calcd for C₁₇H₁₅BrN₂O₃S[M+H]⁺:407.0060,Found:407.0055.

example 4:

compound (I)

Preparation of

0.01mol of 4-chloroacetophenone was dissolved in 10mL of anhydrous ethanol, and 5mL of a 10% NaOH ethanol solution was added thereto. Under stirring in an ice bath, a mixed solution of 0.01mol of 5-bromothiophene-2-carbaldehyde and 10mL of absolute ethyl alcohol was slowly dropped into the mixed solution by using a constant pressure dropping funnel, the reaction was carried out at 0 to 5 ℃, and whether the reaction was completed or not was checked by using a thin layer silica gel plate (TLC). After completion of the reaction, 5mL of 10% NaOH ethanol solution was added to the reaction mixture, and a mixed solution of 0.02mol of cyanoacetamide and 10mL of anhydrous ethanol was slowly dropped into the mixture using a constant pressure dropping funnel, and the reaction was continued at 0 to 5 ℃ with TLC to check whether the reaction was completed. After the reaction is finished, adding a large amount of ice water into the solution, adjusting the pH value to be neutral by using a 10% hydrochloric acid solution, separating out a precipitate, filtering, washing, and recrystallizing by using absolute ethyl alcohol to obtain a target compound, wherein the physicochemical data are as follows: a white powder; yield: 73 percent; the hydrogen spectrum is shown in fig. 10, the carbon spectrum is shown in fig. 11, the high resolution mass spectrum is shown in fig. 12, and specifically,¹H NMR(400MHz,DMSO-d₆)(ppm):7.99(2H,dd,J＝8.4,2.8Hz),7.88(1H,s),7.66-7.58(3H,m),7.07(1H,dd,J＝7.6,4.0Hz),6.91(1H,dd,J＝10.4,3.6Hz),4.22(1H,s),4.13(1H,d,J＝7.2Hz),3.83-3.69(1H,m),3.55-3.43(1H,m)；¹³C NMR(100MHz,DMSO-d₆)(ppm):196.18,165.60,145.23,144.36,139.02,135.21,130.42,129.41,127.44,117.56,110.38,44.84,42.71,36.43；HRMS(ESI)m/z:Calcd for C₁₆H₁₂BrClN₂O₂S[M+H]⁺:410.9564,Found:410.9563.

example 5:

compound (I)

Preparation of

0.01mol of 4-bromoacetophenone was dissolved in 10mL of anhydrous ethanol, and 5mL of a 10% NaOH ethanol solution was added thereto. Under stirring in an ice bath, a mixed solution of 0.01mol of 5-bromothiophene-2-carbaldehyde and 10mL of absolute ethyl alcohol was slowly dropped into the mixed solution by using a constant pressure dropping funnel, the reaction was carried out at 0 to 5 ℃, and whether the reaction was completed or not was checked by using a thin layer silica gel plate (TLC). After the reaction was completed, 5mL of 10% NaOH solution in ethanol was added to the reaction mixture, and the mixture was dropped with a constant pressureA mixed solution of 0.02mol of cyanoacetamide and 10mL of anhydrous ethanol was slowly dropped into the mixture from the funnel, and the reaction was continued at 0 to 5 ℃ and the completion of the reaction was checked by TLC. After the reaction is finished, adding a large amount of ice water into the solution, adjusting the pH value to be neutral by using a 10% hydrochloric acid solution, separating out a precipitate, filtering, washing, and recrystallizing by using absolute ethyl alcohol to obtain a target compound, wherein the physicochemical data are as follows: white crystals; yield: 70 percent; the hydrogen spectrum is shown in fig. 13, the carbon spectrum is shown in fig. 14, the high-resolution mass spectrum is shown in fig. 15, and specifically,¹H NMR(400MHz,DMSO-d₆)(ppm):7.90(2H,d,J＝8.4Hz),7.88(1H,s),7.76(2H,d,J＝8.4Hz),7.66(1H,s),7.07(1H,d,J＝3.6Hz),6.92(1H,d,J＝4.0Hz),4.21(2H,s),3.75-3.69(1H,m),3.48-3.43(1H,m)；¹³C NMR(100MHz,DMSO-d₆)(ppm):196.39,165.59,144.35,135.53,132.37,130.51,128.25,127.44,127.08,117.55,110.38,44.84,42.68,36.41；HRMS(ESI)m/z:Calcd for C₁₆H₁₂Br₂N₂O₂S[M+Na]⁺:476.8878,Found:476.8869.

test example 1 measurement of inhibitory Activity of the Compound of the present invention against plant pathogenic fungi

(1) Test for plant pathogenic fungi

Cucumber downy mildew, wheat powdery mildew, wheat leaf rust, rice blast, cotton verticillium wilt and citrus anthracnose.

(2) Experimental methods

The test compound is dissolved in dimethyl sulfoxide, added into tap water containing 0.1% Tween-80, and mixed uniformly to prepare a test solution of 20 mg/L. The solution was added to sterilized PDA medium, and streptomycin was added at a concentration of 50mg/L as a medium containing toxins. The corresponding solution without the test compound is used as a blank control, and a control culture medium with uniform thickness is prepared for standby application and is repeated three times. Selecting a fungus cake with phi 5mm, good growth, no pollution and uniform growth by using a sterilized puncher, inoculating the fungus cake into centers of a toxic culture medium and a control culture medium (one fungus cake is inoculated on each plate) under an aseptic condition, and culturing at the constant temperature of 28 +/-1 ℃. When the colony diameter of the blank control grows to about 50mm, the diameter of the colony is measured by a cross method, the average value is taken, and the inhibition rate is calculated by the following formula:

(3) results of the experiment

The results of the measurement of the inhibitory activity of the compounds of the present invention against phytopathogenic fungi are shown in Table 1.

TABLE 1 inhibitory Activity of the Compounds of examples 1-5 on phytopathogenic fungi at 20mg/L

^a: average of three replicates.

As is clear from Table 1, the compounds 1 to 5 of examples have a good inhibitory effect on all of the above 6 types of pathogens.

Test example 2 measurement of the Germination-promoting Effect of the Compound of the present invention on vegetable seeds

(1) Test seeds

Cucumber seeds (Zhongnong No. 8), green pepper seeds (Fengyuan No. 8), tomato seeds (Dongfeng No. 4), and celery seeds (Jinnanshi No. 1).

(2) Measurement method

The test compounds were dissolved in dimethyl sulfoxide and diluted to 20mg/L in tap water containing 0.1% Tween-80 for use. 10 g of cucumber seeds, 10 g of green pepper seeds, 5 g of tomato seeds and 5 g of celery seeds are respectively weighed. Respectively soaking the test solution into 20mL of the test solution, stirring for 30 minutes, fishing out the test solution into a small sieve, washing the test solution for 3-4 times by using tap water, and air-drying the test solution for later use. The corresponding solution without test compound was used as a blank. 100 seeds with uniform size and no defect treated by the liquid medicine are respectively selected and are horizontally placed in a culture dish (9cm) paved with double-layer filter paper. The water adding amount for the 1 st time is as follows: 9mL of cucumber, 7mL of green pepper, 5mL of tomato and 5mL of celery are put into a constant temperature box (25 +/-2 ℃) for accelerating germination, observed for 1 time every day and quantitatively supplemented when water is deficient. Each treatment was repeated 3 times. The germination of cucumber was checked after 1 day, the germination of green pepper after 5 days, the germination of tomato after 3 days, and the germination of celery after 9 days, and the average germination percentage was calculated for 3 replicates.

(3) Results of the experiment

The germination-promoting effect of the compounds of the present invention on vegetable seeds is shown in table 2.

TABLE 2 accelerating effect of the compounds of examples 1 to 5 on seed germination at 20mg/L

^a: average of three replicates.

It is understood that the compounds 1 to 5 of the examples have a good accelerating effect on the germination of the seeds of the above 4 kinds of vegetables.

In conclusion, the compound can be prepared into an agricultural bactericide which has a good inhibition effect on plant pathogenic fungi, and can also be prepared into a seed germination promoter which has a good promotion effect on the germination of vegetable seeds.

Claims

1. A compound having the structural formula I:

wherein R is₁Is methoxy, chlorine or bromine; r₂Is hydrogen or bromine.

2. The compound of claim 1, having the formula:

3. use of a compound according to claim 1 or 2 for the preparation of an agricultural fungicide.

4. The use of a compound according to claim 3 in the preparation of an agricultural fungicide, wherein the fungus controlled by the agricultural fungicide is a fungus.

5. The use of the compound according to claim 3 in the preparation of an agricultural fungicide, wherein the fungus to be controlled by the agricultural fungicide is cucumber downy mildew, wheat powdery mildew, wheat leaf rust, rice blast, cotton verticillium or citrus anthracnose.

6. Use of the compound according to claim 1 or 2 for the preparation of a seed germination promoter.

7. Use of a compound according to claim 6 for the preparation of a seed germination promoter, wherein the seed is a vegetable seed.

8. Use of a compound according to claim 7 for the preparation of a seed germination promoter, wherein the vegetable seed is cucumber seed, green pepper seed, tomato seed or celery seed.