Synthesis method and application of N, 3-diphenyl-4 (2-thienyl) butyramide compound
The N,3-diphenyl-4(2-thienyl)butylamide compounds were synthesized by one pot method, using cheap and easy-to-get Bronst base catalyst and simple steps, and the synthesis problems in the prior art were solved, and environmentally friendly and efficient preparation of compounds was achieved.
Patent Information
- Application Number
- CN202411813068.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-10
- Publication Date
- 2025-06-20
AI Technical Summary
It is difficult to efficiently synthesize N,3-diphenyl-4(2-thienyl)butylamide compounds with wide applicability in the prior art, and the use of transition metal catalysts during the synthesis is not environmentally friendly.
N,N-dimethyl-3-phenyl-4-(2-thienyl)butylamide compounds were synthesized by one pot method, and the inexpensive and easy-to-get Bronst base LiN(SiMe3)2/CsN(SiMe3)2 was used as a catalyst, and reacted in an organic solvent, followed by HCl acidification and SOCl2 treatment to form N,3-diphenyl-4(2-thienyl)butylamide compounds.
It realizes simple and environmentally friendly compound synthesis, has a wide range of applicability, simplified synthesis steps, avoids extreme temperature operation, and is easy to obtain raw materials.
Smart Images
Figure CN120172952A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing N,3-diphenyl-4(2-thienyl)butyramide compounds and their uses. Background Art
[0002] As a protected form of amines, amides are important guiding groups for C-H bond functionalization. Due to their role as intermediates, the transformation of amides has many requirements in organic and pharmaceutical synthesis. N-aryl butanamides play an important role in promoting antifungal activity, and related analogues of 3,4-diphenylbutyric acid can be used as part of chemical fungicides (Arch. Pharm. 1999, 332, 333 - 336). Therefore, the present invention prepared a variety of butyramide compounds and carried out antibacterial screening on plant pathogenic fungi such as Gibberella zeae, Rhizoctonia solani, Rhizoctonia cerealis, Fusarium oxysporum f. sp. cucumerinum, Pythium aphanidermatum, Fusarium graminearum, Magnaporthe oryzae, and Sclerotinia sclerotiorum. Summary of the Invention
[0003] The purpose of the present invention is to design a pesticide molecular skeleton using a new synthesis method to provide technical support for the creation of new varieties of green pesticides. To provide the biological activities of N,3-diphenyl-4(2-thienyl)butyramide compounds in regulating agricultural, horticultural, sanitary, and forestry plant pathogens and their determination methods.
[0004] The technical solutions to achieve the above purposes are as follows:
[0005]
[0006] Step 1, N,N-dimethylcinnamamide compounds shown in Formula 1 and 2-methylthiophene shown in Formula 2 are mixed with an organic solvent (N,N-dimethylformamide) in the presence of a Bronsted base (LiN(SiMe3)2 / CsN(SiMe3)2) to react and synthesize N,N-dimethyl-3-phenyl-4-(2-thienyl)butyramide compounds shown in Formula 3;
[0007] Wherein R 1 is selected from phenyl, 4-phenoxyphenyl, 1-naphthyl.
[0008] Step 2, N,N-dimethyl-3-phenyl-4-(2-thienyl)butyramide compounds shown in Formula 3 are reacted in 6 mol / L HCl aqueous solution at 110 °C for 48 h to synthesize 3-phenyl-4-(2-thienyl)butyric acid compounds shown in Formula 4;
[0009] Wherein R 1 is selected from phenyl, 4-phenoxyphenyl, 1-naphthyl.
[0010] Step 3: A 3-phenyl-4-(2-thienyl)butyric acid compound shown in Formula 4 is mixed with SOCl2 (2.0 equiv) and a few drops of DMF and heated to 70 °C. After reacting for 1 hour, the mixture is cooled to room temperature. An aniline compound (1.1 equiv) and DMF (1 mL / mmol) are added dropwise to the reaction solution at 0 °C, and the mixture is stirred overnight at room temperature to synthesize an N,3-diphenyl-4(2-thienyl)butyramide compound shown in Formula 5;
[0011] wherein R 2 is selected from chlorine and sulfomethyl.
[0012] The method of the present invention uses a catalytic amount of Bronsted base (LiN(SiMe3)2 / CsN(SiMe3)2) to achieve a one-pot synthesis of an N,N-dimethyl-3-phenyl-4-(2-thienyl)butyramide compound shown in Formula 3; 3 can be acidified with HCl to generate a 3-phenyl-4-(2-thienyl)butyric acid compound shown in Formula 4; 4 is finally reacted with an aniline compound under the action of SOCl2 and DMF to synthesize an N,3-diphenyl-4(2-thienyl)butyramide compound shown in Formula 5. The raw materials used in this synthesis method are all cheap and easily available; R 1 and R 2 can have multiple choices, with a wider applicability.
[0013] Preferably, the reaction step 1 is carried out under the protection of an inert gas. Preferably, the inert gas is nitrogen.
[0014] Preferably, the Bronsted base in the reaction step 1 is lithium bis(trimethylsilyl)amide (LiN(SiMe3)2) and cesium bis(trimethylsilyl)amide (CsN(SiMe3)2), and CsN(SiMe3)2 can be obtained by the method of exchanging LiN(SiMe3)2 with a cesium salt (O′Hara, C.T. et al, Inorg. Chem. 2016, 55, 5719).
[0015] Preferably, the organic solvent in the reaction step 1 is N,N-dimethylformamide.
[0016] Preferably, the ratio of N,N-dimethylcinnamide shown in Formula 1, 2-methylthiophene shown in Formula 2 and the Bronsted base in the reaction step 1 is: 1:5:64.5; the reaction temperature is 110 °C.
[0017] Preferably, the acid in the reaction step 2 is 6 mol / L aqueous HCl solution; the reaction temperature is 110 °C.
[0018] Preferably, the ratio of 3-phenyl-4-(2-thienyl)butyric acid, aniline, SOCl2, and DMF shown in Formula 4 of Reaction Step 3 is: 1:1.1:2:1 to 1.2.
[0019] Preferably, by using the method of the present invention, the N,N-dimethyl-3-phenyl-4-(2-thienyl)butyramide compounds, 3-phenyl-4-(2-thienyl)butyric acid compounds, aniline compounds, and the product N,3-diphenyl-4(2-thienyl)butyramide compounds are one of the following Table 1:
[0020] Table 1 N,3-diphenyl-4(2-thienyl)butyramide compounds
[0021]
[0022]
[0023] Adopting the technical solution of the present invention can at least achieve one of the following beneficial effects:
[0024] The raw materials used in the synthesis method of the present invention are all cheap and easily available;
[0025] The synthesis method of the present invention does not use transition metal catalysts and is green and environmentally friendly;
[0026] The operation steps required by the present invention are relatively simple and do not require extreme heating or cooling;
[0027] R in the present invention 1 、R 2 There can be multiple choices, so the method of the present invention has a wider applicability and can synthesize various butyramide compounds. BRIEF DESCRIPTION OF THE DRAWINGS
[0028] The drawings are the hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectra of the products of each example. The serial numbers of the drawings correspond to the serial numbers of the examples. Figure A is the hydrogen spectrum nuclear magnetic resonance spectrum, and Figure B is the carbon spectrum nuclear magnetic resonance spectrum. For example Figure 1A is the hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 1, Figure 1B is the carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 1; Figure 2A is the hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 2, Figure 2B is the carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 2; Figure 3A is the hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 3, Figure 3B is the carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 3; Figure 4A is the hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 4, Figure 4B is the carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 4; SPECIFIC EXAMPLES
[0029] For the convenience of those skilled in the art to understand, the concept of the present invention will be further described below in conjunction with embodiments. The specific descriptions of the following embodiments are not limitations on the present invention, but only for the convenience of those skilled in the art to understand the technical solution. All kinds of raw materials involved in the specification are purchased from the market or simply synthesized, and other drugs are purchased from Anychem, Bidepharm, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta or J&K., and the nuclear magnetic resonance spectrometer model is Bruker 400M.
[0030] Example 1
[0031] In a nitrogen-filled glove box, LiN(SiMe3)2 (1.7 mg, 0.01 mmol), CsN(SiMe3)2 (2.9 mg, 0.01 mmol), N,N-dimethylcinnamamide (17.5 mg, 0.1 mmol), 2-methylthiophene (0.05 mL, 0.5 mmol) and DMF (0.6 mL) were successively added to a dry microwave tube with a magnetic stirrer. The microwave tube was sealed with a lid and taken out of the glove box. The reaction mixture was heated in an oil bath at 110 °C for 12 hours. The flask was taken out of the oil bath, cooled to room temperature, exposed to air, and then three drops of water were slowly added to quench the reaction. The reaction mixture was passed through a short silica pad and washed with another 3 mL of ethyl acetate (3 x 1 mL), and the combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluted with petroleum ether:ethyl acetate = 5:1) to obtain product 3a (22.4 mg, 82% yield) as a yellow solid.
[0032] 3a (27.3 mg, 0.1 mmol) was added to a 30 mL round-bottom flask, and 6 M HCl aqueous solution (5 mL) was added at room temperature. The reaction solution was vigorously stirred at 110 °C for 48 h. After the reaction was completed, three drops of water were added to quench the reaction, and the mixture was extracted with DCM (3 x 5 mL), and the organic phase was washed with saturated aqueous NaHCO3 solution. The obtained organic phases were combined, acidified with 1 M HCl aqueous solution, and then the mixture was extracted with DCM (3 x 5 mL). The aqueous phase was separated, and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluted with petroleum ether:ethyl acetate = 5:1) to obtain product 4a (19.7 mg, 80% yield) as a brown liquid.
[0033] 4a (24.6 mg, 0.1 mmol), SOCl2 (14.5 μL, 0.2 mmol) and a few drops of DMF were added to a 5 mL round-bottom flask and stirred at 70 °C for 1 h. At 0 °C, the cooled mixture was added dropwise to a solution of 3-chloroaniline (11.6 μL, 0.11 mmol) and DMF (1 mL / mmol). After the addition was complete, the mixture was stirred at room temperature overnight. The reaction was quenched with water and washed with 3 mL of ethyl acetate (3 x 1 mL). The aqueous phase was separated, and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluted with petroleum ether:ethyl acetate = 10:1) to give the product 5a (19.5 mg, 55% yield) as a white solid. 1 1H NMR (400 MHz, CHCl3) δ 7.40 (s, 1H), 7.32 - 7.28 (m, 2H), 7.25 - 7.18 (m, 3H), 7.14 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 6.1 Hz, 2H), 7.01 (d, J = 7.7 Hz, 1H), 6.94 - 6.79 (m, 2H), 6.68 (d, J = 3.1 Hz, 1H), 3.56 - 3.45 (m, 1H), 3.27 - 3.16 (m, 2H), 2.76 (dd, J = 14.5, 5.5 Hz, 1H), 2.60 (dd, J = 14.5, 8.9 Hz, 1H). 13 C{ 1 1H} NMR (101 MHz, CDCl3) δ 169.6, 142.8, 141.6, 138.6, 134.5, 129.8, 128.8, 127.5, 127.1, 126.7, 125.8, 124.3, 123.8, 119.9, 117.8, 44.6, 43.8, 36.4 ppm.
[0034] The raw materials in Example 1 were changed, and the following 4 groups of experimental examples were designed. The first group of experiments was Example 1, and the nuclear magnetic resonance spectrum of the corresponding product was Figure 1. The serial numbers of the nuclear magnetic resonance spectra of the products in the remaining groups 2 - 4 corresponded to the serial numbers of the corresponding examples.
[0035] The structural formulas of the products in Examples 1 - 4 are listed in Table 2. The last column lists the yields of the products in each example, and the specific implementation conditions of each example are marked. The specific meanings of the implementation conditions of each example are shown below the table.
[0036] Table 2 Yields of N,3-diphenyl-4(2-thienyl)butyramide compounds
[0037]
[0038] Example 2
[0039] In a nitrogen-filled glove box, LiN(SiMe3)2 (1.7 mg, 0.01 mmol), CsN(SiMe3)2 (2.9 mg, 0.01 mmol), N,N-dimethylcinnamamide (17.5 mg, 0.1 mmol), 2-methylthiophene (0.05 mL, 0.5 mmol) and DMF (0.6 mL) were successively added to a dry microwave tube equipped with a magnetic stir bar. The microwave tube was sealed with a lid and removed from the glove box. The reaction mixture was heated in an oil bath at 110 °C for 12 h. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then quenched by slowly adding three drops of water. The reaction mixture was passed through a short pad of silica gel and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solutions were concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (eluted with petroleum ether:ethyl acetate = 5:1) to give product 3a (22.4 mg, 82% yield) as a yellow solid.
[0040] 3a (27.3 mg, 0.1 mmol) was added to a 30 mL round-bottom flask, and 6 M aqueous HCl solution (5 mL) was added at room temperature. The reaction solution was vigorously stirred at 110 °C for 48 h. After the reaction was completed, the reaction was quenched by adding three drops of water, and the mixture was extracted with DCM (3 x 5 mL), and the organic phase was washed with saturated aqueous NaHCO3 solution. The obtained organic phases were combined, acidified with 1 M aqueous HCl solution, and then the mixture was extracted with DCM (3 x 5 mL). The aqueous phase was separated, and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (eluted with petroleum ether:ethyl acetate = 5:1) to give product 4a (19.7 mg, 80% yield) as a brown liquid.
[0041] 4a (24.6 mg, 0.1 mmol), SOCl2 (14.5 μL, 0.2 mmol) and a few drops of DMF were added to a 5 mL round-bottom flask and stirred at 70 °C for 1 h. At 0 °C, the cooled mixture was added dropwise to a solution of 4-(methylthio)aniline (12.4 μL, 0.11 mmol) and DMF (1 mL / mmol). After the addition was complete, the mixture was stirred at room temperature overnight. The reaction was quenched with water and washed with 3 mL of ethyl acetate (3 x 1 mL). The aqueous phase was separated, and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (eluted with petroleum ether:ethyl acetate = 10:1) to give product 5b (26.8 mg, 73% yield) as a white solid. 11H NMR (400 MHz, CHCl3) δ 7.34 - 7.27 (m, 2H), 7.24 - 7.14 (m, 6H), 7.07 (d, J = 5.0 Hz, 1H), 6.91 - 6.72 (m, 2H), 6.69 (s, 1H), 3.57 - 3.46 (m, 1H), 3.32 - 3.13 (m, 2H), 2.87 - 2.70 (m, 1H), 2.65 - 2.56 (m, 1H), 2.43 (s, 3H). 13 C{ 1 13C{1H} NMR (101 MHz, CDCl3) δ 169.4, 142.9, 141.7, 135.2, 133.6, 128.8, 127.9, 127.6, 127.0, 126.7, 125.8, 123.7, 120.6, 44.7, 36.3, 16.7 ppm.
[0042] Example 3
[0043] In a nitrogen-filled glove box, LiN(SiMe3)2 (1.7 mg, 0.01 mmol), CsN(SiMe3)2 (2.9 mg, 0.01 mmol), N,N-dimethyl-3-(1-naphthyl)acrylamide (22.5 mg, 0.1 mmol), 2-methylthiophene (0.05 mL, 0.5 mmol) and DMF (0.6 mL) were successively added to a dry microwave tube equipped with a magnetic stir bar. The microwave tube was sealed with a lid and taken out of the glove box. The reaction mixture was heated in an oil bath at 110 °C for 12 h. The flask was taken out of the oil bath, cooled to room temperature, exposed to air, and then quenched by slowly adding three drops of water. The reaction mixture was passed through a short pad of silica gel and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (eluted with petroleum ether:ethyl acetate = 5:1) to give product 3b (13.9 mg, 43% yield) as a yellow solid.
[0044] 3b (32.3 mg, 0.1 mmol) was added to a 30 mL round-bottom flask, and 6 M aqueous HCl solution (5 mL) was added at room temperature. The reaction solution was vigorously stirred at 110 °C for 48 h. After the reaction was completed, three drops of water were added to quench the reaction, and the mixture was extracted with DCM (3 x 5 mL). The organic phase was washed with saturated aqueous NaHCO3 solution. The obtained organic phases were combined, acidified with 1 M aqueous HCl solution, and then the mixture was extracted with DCM (3 x 5 mL). The aqueous phase was separated, and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (eluted with petroleum ether:ethyl acetate = 5:1) to give product 4b (24.0 mg, 81% yield) as a brown liquid.
[0045] 4b (29.6 mg, 0.1 mmol), SOCl2 (14.5 μL, 0.2 mmol) and a few drops of DMF were added to a 5 mL round-bottom flask and stirred at 70 °C for 1 h. At 0 °C, the cooled mixture was added dropwise to a solution of 3-chloroaniline (11.6 μL, 0.11 mmol) and DMF (1 mL / mmol). After the addition was complete, the mixture was stirred at room temperature overnight. The reaction was quenched with water and washed with 3 mL of ethyl acetate (3 x 1 mL). The aqueous phase was separated and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting with petroleum ether:ethyl acetate = 10:1) to give the product 5c (27.6 mg, 68% yield) as a white solid. 1 1H NMR (400 MHz, CHCl3) δ 8.21 (d, J = 8.4 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.80 - 7.74 (m, 1H), 7.55 - 7.38 (m, 4H), 7.14 - 6.98 (m, 4H), 6.87 - 6.79 (m, 2H), 6.72 (d, J = 3.5 Hz, 1H), 4.55 - 4.37 (m, 1H), 3.47 - 3.35 (m, 2H), 2.89 - 2.79 (m, 2H). 13 13 1 C{
[0046] Example 4
[0047] In a nitrogen-filled glove box, LiN(SiMe3)2 (1.7 mg, 0.01 mmol), CsN(SiMe3)2 (2.9 mg, 0.01 mmol), N,N-dimethyl-3-(4-phenoxyphenyl)acrylamide (26.7 mg, 0.1 mmol), 2-methylthiophene (0.05 mL, 0.5 mmol) and DMF (0.6 mL) were successively added to a dry microwave tube equipped with a magnetic stir bar. The microwave tube was sealed with a lid and removed from the glove box. The reaction mixture was heated in an oil bath at 110 °C for 12 h. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then quenched by slowly adding three drops of water. The reaction mixture was passed through a short pad of silica gel and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (eluted with petroleum ether:ethyl acetate = 5:1) to give the product 3c (25.9 mg, 71% yield) as a yellow solid.
[0048] 3c (36.5 mg, 0.1 mmol) was added to a 30 mL round-bottom flask, and 6 M aqueous HCl solution (5 mL) was added at room temperature. The reaction solution was vigorously stirred at 110 °C for 48 h. After the reaction was completed, the reaction was quenched by adding three drops of water, and the mixture was extracted with DCM (3 x 5 mL), and the organic phase was washed with saturated aqueous NaHCO3 solution. The obtained organic phases were combined, acidified with 1 M aqueous HCl solution, and then the mixture was extracted with DCM (3 x 5 mL). The aqueous phase was separated, and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (eluted with petroleum ether:ethyl acetate = 5:1) to give the product 4c (25.3 mg, 75% yield) as a brown liquid.
[0049] 4c (33.8 mg, 0.1 mmol), SOCl2 (14.5 μL, 0.2 mmol) and a few drops of DMF were added to a 5 mL round-bottom flask, and the mixture was stirred at 70 °C for 1 h. At 0 °C, the cooled mixture was added dropwise to a solution of 3-chloroaniline (11.6 μL, 0.11 mmol) and DMF (1 mL / mmol). After the addition was complete, the mixture was stirred at room temperature overnight. The reaction was quenched with water and washed with 3 mL of ethyl acetate (3 x 1 mL). The aqueous phase was separated, and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (eluted with petroleum ether:ethyl acetate = 10:1) to give the product 5d (30.0 mg, 67% yield) as a white solid. 11H NMR (400 MHz, ) δ 7.37 - 7.27 (m, 2H), 7.16 (d, J = 6.5 Hz, 4H), 7.11 - 7.01 (m, 4H), 6.98 - 6.90 (m, 4H), 6.86 (dd, J = 5.1, 3.4 Hz, 1H), 6.70 (s, 1H), 3.51 (dt, J = 13.6, 7.3 Hz, 1H), 3.28 - 3.09 (m, 2H), 2.76 (dd, J = 14.5, 5.5 Hz, 1H), 2.59 (dd, J = 14.0, 8.9 Hz, 1H). 13 13C NMR (101 MHz, ) δ 169.6, 157.1, 156.1, 141.5, 138.7, 137.6, 134.6, 129.9, 129.7, 128.8, 126.7, 125.8, 124.4, 123.8, 123.2, 119.9, 119.1, 118.8, 117.8, 43.9, 43.8, 36.5, 14.5 ppm.
[0050] Example 5 Determination results of the antibacterial activities of N,N-dimethyl-3-phenyl-4-(2-thienyl)butyramide compounds of the present invention:
[0051] The codes and names of the common phytopathogenic fungi tested in the present invention are as follows: G.z: Gibberella zeae, its Latin name is Gibberella zeae; R.s: Rhizoctonia solani Kühn, its Latin name is Rhizoctonia solani kühn; R.c: Rhizoctonia cerealis, its Latin name is Rhizoctonia cerealis; F.o: Fusarium oxysporum f.sp., its Latin name is Fusarium oxysporum f.sp.; P.a: Pythium aphanidermatum, its Latin name is Pythium aphanidermatum; F.g: Fusarium graminearum, its Latin name is Fusarium graminearum; M.o: Magnaporthe oryzae, its Latin name is Magnaporthe oryzae; B.c: Botrytis cinerea, its Latin name is Botrytis cinerea; C.a: Cercospora arachidicola, its Latin name is Cercospora arachidicola; P.p: Physalospora piricola, its Latin name is Physalospora piricola; A.s: Alternaria solani, its Latin name is Alternaria solani; S.s: Sclerotinia sclerotiorum, its Latin name is Sclerotinia sclerotiorum. These strains are highly representative and can represent most of the pathogen genera occurring in the fields during agricultural production.
[0052] The results of the determination by the mycelial growth rate method are shown in Table 3. Table 3 shows that at 100 μg / mL, all N,3-diphenyl-4(2-thienyl)butyramide compounds synthesized in the present invention have bactericidal activities to varying degrees, and some N,3-diphenyl-4(2-thienyl)butyramide compounds of the present invention have good bactericidal activities. The bactericidal activity of 5a against Botrytis cinerea is 80.58%; the bactericidal activities of 5b against Gibberella zeae and Fusarium graminearum are relatively ideal, being 84.48% and 88.75% respectively; the bactericidal activity of 5c against Gibberella zeae can be as high as 93.10%; 5d shows good bactericidal activities against Fusarium graminearum and Botrytis cinerea, being 95% and 83.50% respectively.
[0053] Table 3 Antibacterial activities of N,3-diphenyl-4(2-thienyl)butyramide compounds of the present invention (Inhibition / % at 100 μg / mL)
[0054]
[0055] a Activity is preventive value (%), 100% complete killing, 0% zero killing; G.z: Gibberella zeae; R.s: Rhizoctonia solani kühn; R.c: Rhizoctonia cerealis; F.o: Fusarium oxysporum f.sp.; P.a: Pythium aphanidermatum; F.g: Fusarium graminearum; M.o: Magnaporthe oryza; B.c: Botrytis cinerea; C.a: Cercospora arachidicola; P.p: Physalospora piricola; A.s: Alternaria solani; S.s: Sclerotinia sclerotiorum.
Claims
1. A method for synthesizing N,3-diphenyl-4 (2-thienyl) butanamide compounds, characterized in that: Step 1, using the N, N-dimethylcinnamamide compound shown in Formula 1 and the 2-methylthiophene shown in Formula 2 to react with an organic solvent in the presence of a Bronsted base to synthesize the N, N-dimethyl-3-phenyl-4-(2-thienyl)butanamide compound shown in Formula 3; the Bronsted base is bis(trimethylsilyl)lithium amide (LiN(SiMe3)2) and bis(trimethylsilyl)cesium amide (CsN(SiMe3)2), and CsN(SiMe3)2 can be obtained by exchanging LiN(SiMe3)2 with a cesium salt (O′Hara, CT et al, Inorg. Chem. 2016, 55, 5719); wherein R 1 Selected from phenyl, 4-phenoxyphenyl, 1-naphthyl; Step 2, using the N, N-dimethyl-3-phenyl-4-(2-thienyl)butyramide compound shown in Formula 3 to react in a 6 mol / L HCl aqueous solution at 110° C. for 48 h to synthesize the 3-phenyl-4-(2-thienyl)butyric acid compound shown in Formula 4; wherein R 1 Selected from phenyl, 4-phenoxyphenyl, 1-naphthyl; Step 3, using the 3-phenyl-4-(2-thienyl)butyric acid compound shown in Formula 4, mixed with SOCl2 (2.0 equiv) and a few drops of DMF and heated to 70°C, reacting for 1 hour, cooling the mixture to room temperature, adding aniline compounds (1.1 equiv) and DMF (1 mL / mmol) dropwise at 0°C, stirring at room temperature overnight, and reacting to synthesize the N, 3-diphenyl-4 (2-thienyl) butyramide compound shown in Formula 5; wherein R 2 Selected from chlorine, thiomethyl.
2. The synthesis method according to claim 1, characterized in that The reaction in step 1 is carried out under the protection of an inert gas, wherein the inert gas is nitrogen.
3. The synthesis method according to claim 1, characterized in that The organic solvent in step 1 is N,N-dimethylformamide.
4. The synthesis method according to claim 1, characterized in that In the reaction of step 1, the ratio of N,N-dimethylcinnamamide shown in formula 1, 2-methylthiophene shown in formula 2 and Bronsted base is 1:5:64.5; and the reaction temperature is 110°C.
5. The synthesis method according to claim 1, characterized in that The acid in step 2 is 6 mol / L HCl aqueous solution; the reaction temperature is 110°C.
6. The synthesis method according to claim 1, characterized in that The ratio of the 3-phenyl-4-(2-thienyl)butyric acid compound represented by formula 4 described in step 3, the aniline compound, SOCl2, and DMF is 1:1.1:2:1-1.
2.
7. The synthesis method according to claim 1, characterized in that The N,N-dimethyl-3-phenyl-4-(2-thienyl)butyramide compounds, 3-phenyl-4-(2-thienyl)butyric acid compounds, aniline compounds and the product N,3-diphenyl-4(2-thienyl)butyramide compounds are as shown in one of the following tables: