Synthesis method and application of benzoxazepine and benzoxazole compounds

Abstract

The invention provides a synthesis method and application of a benzoxazepine and benzoxazole compound. In the formula I and the formula II, R1 is one of hydrogen, methyl, methoxyl, halogen, cyano group, aldehyde group and ester group, and R2 is one of p-methylbenzenesulfonyl, benzenesulfonyl, p-bromobenzenesulfonyl, p-chlorobenzenesulfonyl and p-nitrobenzenesulfonyl, and in the formula I and the formula II, R1 is one of hydrogen, methyl, methoxyl, halogen, cyano group, aldehyde group and ester group, and R2 is one of p-methylbenzenesulfonyl, benzenesulfonyl, p-bromobenzenesulfonyl and p-nitrobenzenesulfonyl. Under the catalysis of a palladium catalyst, a series of N-(2-(allyloxy) phenyl)-4-methylbenzenesulfonamide is subjected to Wacker reaction and hydrogen amination reaction adjustable synthesis; by optimizing the synthesis route and improving the reaction conditions, the synthesis efficiency and selectivity are improved, the yield is improved, and the generation of by-products is reduced. These compounds have anti-plant fungal activity.

Description

Technical Field

[0001] The present invention relates to the research fields of organic synthesis, drug synthesis and new drug research and development, and in particular to a synthesis method and application of benzoxazepine and benzoxazole compounds. Background Art

[0002] Plant fungal diseases are one of the important factors affecting global agricultural production, especially in warm and humid climates, where plant fungal diseases occur more frequently. Common plant fungal diseases such as rice blast, smut, powdery mildew, etc., not only seriously endanger the yield of crops, but may also reduce the quality of agricultural products and even cause significant economic losses. For example, diseases such as powdery mildew and gray mold are widely spread around the world, causing significant impacts on crops such as wheat, grapes, and vegetables. Especially in recent years, with the mutation of pathogens and the influence of environmental changes, the drug resistance of some plant fungi has gradually increased, bringing greater challenges to prevention and control.

[0003] At present, the prevention and control of fungal diseases of crops mainly rely on chemical pesticides, such as bactericides and antifungal agents. However, long-term reliance on chemical pesticides not only leads to the problem of drug resistance of pathogens, but also pollutes the environment. Therefore, finding new, efficient and low-toxic plant protection agents has become one of the research focuses in the agricultural field. Benzoxazepines and benzoxazoles have excellent antifungal activity, especially in the inhibition of plant fungi, showing good application potential and becoming a research hotspot in the field of plant protection.

[0004] Traditional synthetic methods usually rely on aromatic nucleophilic substitution reactions, transition metal-catalyzed aromatic halide coupling reactions, and condensation reactions of carboxylic acid derivatives. Cui and colleagues reported a method for the efficient synthesis of substituted benzo[b][1,4]oxazepines from aminoketones using Cs2CO3 as a promoter. Kawatsura reported the synthesis of benzo[b][1,4]oxazepines by copper-catalyzed hydrogenation of acetylenic ketone with 2-aminophenol in 1,4-dioxane at 100°C. Methods for the synthesis of benzoxazoles: (a) condensation reaction of carboxylic acids and their derivatives with 2-aminophenol; (b) metal-catalyzed oxidative intramolecular CO coupling reaction of 2-halogenated anilines and their analogs; (c) oxidative cyclization reaction of phenol Schiff base intermediates; (d) metal-catalyzed direct CH arylation reaction: Akkineni reported the combination of carbon monoxide, aryl halides and o-diaminobenzene or o-diaminophenol in the presence of FeCl2, and the reductive carbonylation reaction of aryl iodides using in situ generated aldehydes to generate benzimidazoles or benzoxazoles.

[0005] At present, there are still some challenges in the synthesis of benzoxazepines and benzoxazole compounds. Existing synthesis methods mostly rely on high temperature and high pressure reaction conditions, or require the use of rare catalysts and reactants or dehydrating agents and toxic reagents, resulting in complex reaction processes, low yields and high costs, which are not environmentally friendly. Therefore, it is urgent to develop new and adjustable synthesis methods that can not only improve the selectivity and yield of the reaction, but also simplify the reaction conditions and reduce costs. Summary of the invention

[0006] The present invention provides a chemically selective palladium-catalyzed olefin functionalization method, which enhances the control of product selectivity by adjusting the catalyst and the protecting group. Under simple conditions, benzoxazepine is synthesized by Wacker reaction using the same substrate in the same reaction system, and benzoxazole is synthesized by intramolecular hydrogenation reaction, making it more suitable for drug synthesis, and the two types of compounds have certain antibacterial activity in antifungal activity screening.

[0007] Based on the above objectives, the first objective of the present invention is to provide a benzoxazepine compound and a benzoxazole compound, which have the general structural formulas shown in Ⅰ and Ⅱ respectively:

[0008]

[0009] Among them, R1 is one of hydrogen, methyl, methoxy, halogen, cyano, aldehyde, and ester, and R2 is one of p-toluenesulfonyl, benzenesulfonyl, p-bromobenzenesulfonyl, p-chlorobenzenesulfonyl, and p-nitrobenzenesulfonyl.

[0010] The second object of the present application is to provide a method for synthesizing the above-mentioned benzoxazepine and benzoxazole compounds, comprising the following process:

[0011] N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamide derivative, palladium catalyst, and ligand are dispersed in a solvent;

[0012] The mixture undergoes an intramolecular hydroamination reaction to obtain a benzoxazole compound;

[0013] When synthesizing benzoxazepine compounds, additives need to be added, and the mixture undergoes a Wacker reaction to obtain benzoxazepine compounds.

[0014] Wherein, the N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamide derivative has the structural formula shown in II:

[0015]

[0016] Wherein, R1 is one of hydrogen, methyl, methoxy, halogen, cyano, aldehyde, and ester, and R2 is one of p-toluenesulfonyl, benzenesulfonyl, p-bromobenzenesulfonyl, p-chlorobenzenesulfonyl, and p-nitrobenzenesulfonyl;

[0017] The palladium catalyst is bistriphenylphosphine palladium dichloride when synthesizing benzoxazepine compounds; and the palladium catalyst is palladium dichloride when synthesizing benzoxazole compounds.

[0018] The ligand is pyridine; compared with other ligands such as 2,2'-bipyridine, pyridine is preferably used as a ligand to increase the yield of the product.

[0019] The additive used in synthesizing benzoxazepine compounds is copper acetate; no additive is needed in synthesizing benzoxazole compounds.

[0020] The solvent is toluene; compared with other solvents such as N,N-dimethylformamide, toluene is preferably used as the solvent to increase the yield of the product.

[0021] The reaction was carried out under oil bath heating, the reaction time was 24 h, and the reaction temperature was 80°C;

[0022] In the Wacker reaction, the molar ratio of the N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamide derivative, bistriphenylphosphine palladium dichloride, pyridine, and copper acetate is 1:0.1:0.2:1.5;

[0023] The molar ratio of the N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamide derivative, palladium chloride and pyridine in the intramolecular hydroamination reaction is 1:0.1:0.2.

[0024] Further, the feeding amount of the toluene is C N-(2-(烯丙氧基)苯基)-4-甲基苯磺酰胺 =0.2M.

[0025] And, the benzoxazepine compounds and benzoxazole compounds prepared according to the above synthesis method.

[0026] The third objective of the present application is to provide the use of the above-mentioned benzoxazepine compounds and benzoxazole compounds in resisting agricultural forest pathogenic fungi.

[0027] Furthermore, the fungus is rice blast fungus, Fusarium graminearum, Rhizoctonia solani, Solanum solani, Concha sporeans, Fusarium oxysporum, and Botrytis cinerea.

[0028] The present invention is to synthesize a series of benzoxazepine compounds and benzoxazole compounds in an adjustable manner by a Wacker reaction and a hydrogenation reaction of a series of N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamides under the catalysis of a palladium catalyst; by optimizing the synthesis route and improving the reaction conditions, the synthesis efficiency and selectivity are improved, the yield is increased, and the generation of by-products is reduced. At the same time, the present invention will also conduct a systematic study on the anti-plant fungal activity of these compounds, provide theoretical support and practical basis for their application in agricultural prevention and control, especially the potential to combat common plant fungal diseases, and provide new prevention and control schemes. After screening of rice blast fungus, graminearum Fusarium, Rhizoctonia solani, black rot fungus, pinecone spore fungus, oxysporum Fusarium, and botrytis cinerea, the activity screening results show that these compounds have certain antifungal activity, providing a new direction for pest control. DETAILED DESCRIPTION

[0029] The invention discloses benzoxazepine and benzoxazole compound derivatives, synthesis methods and antifungal activities thereof.

[0030] The synthesis methods of benzoxazepine compounds and benzoxazole compound derivatives disclosed in the present invention are completed in one step, that is, under toluene as a solution, bistriphenylphosphine palladium dichloride is used as a catalyst, pyridine is used as a ligand, and copper acetate is used as an additive, and N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamide compounds undergo Wacker reaction to generate benzoxazepine compounds; palladium chloride is used as a catalyst, pyridine is used as a ligand, and N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamide compounds undergo intramolecular hydrogen amination reaction to generate benzoxazole compounds. The reaction equation is shown in the following reaction formula:

[0031]

[0032] The present invention is further described in detail below in conjunction with specific examples. This implementation case is implemented based on the technology of the present invention, and a detailed implementation method and specific operation process are now given to illustrate that the present invention is creative, but the protection scope of the present invention is not limited to the following examples.

[0033] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0034] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0035] The substrates used in the following examples were prepared according to the following two schemes:

[0036]

[0037] Example 1 Preparation of benzobenzoxazepine compounds

[0038] Synthesis method: N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamide (0.2mmol, 1.0eq.), bistriphenylphosphine palladium dichloride (0.02mmol, 0.1eq.), pyridine (0.04mmol, 0.2eq.), copper acetate (0.3mmol, 1.5eq.) were placed in a 10mL Shrek tube equipped with a magnetic stirrer, 2ml of toluene was added, and the mixture was heated to 80°C in an oil bath for 12h. After the reaction was completed, the reaction mixture was concentrated in vacuo to remove the solvent. The residue was purified by silica gel column chromatography to obtain the corresponding product. All reactions were repeated 2-3 times, and the average yield was given.

[0039] The specific added components, reaction products and yields of the N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamide derivative are shown in Table 1; the nuclear magnetic resonance spectrum, characterization data and standard nomenclature of the reaction product are shown in Table 2.

[0040] Table 1

[0041]

[0042]

[0043]

[0044] Table 2

[0045]

[0046]

[0047]

[0048]

[0049]

[0050] Example 2 Preparation of benzoxazole derivatives

[0051] Synthesis method: N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamide (0.2mmol, 1.0eq.), palladium chloride (0.02mmol, 0.1eq.), pyridine (0.04mmol, 0.2eq.) were placed in a 10mL Shrek tube equipped with a magnetic stirrer, 2ml of toluene was added, and the mixture was heated to 80°C in an oil bath for 12h. After the reaction was completed, the reaction mixture was concentrated in vacuo to remove the solvent. The residue was purified by silica gel column chromatography to obtain the corresponding product. All reactions were repeated 2-3 times, and the average yield was given.

[0052] The specific added components, reaction products and yields of the N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamide derivative are shown in Table 3; the nuclear magnetic resonance spectrum, characterization data and standard nomenclature of the reaction product are shown in Table 4.

[0053] Table 3

[0054]

[0055]

[0056]

[0057] Table 4

[0058]

[0059]

[0060]

[0061]

[0062]

[0063] Example 3 Antifungal Activity Test of Benzoxazepine Compounds and Benzoxazole Compounds

[0064] Test targets: substrates 8 and 15; target compounds 1a and 3a prepared in Example 1; target compounds 13b and 16b prepared in Example 2;

[0065] Test method: The mycelium growth rate method was used to determine the inhibitory activity of the target compound against 7 plant pathogens at 25 μg / mL. The test species were Magnaporthe oryzae, Fusarium graminearum, Rhizoctonia solani, Valsa sordida Nit, Sphaeropsis-sapinea, Fusarium oxysporum, and Botrytis Cinerea.

[0066] Experimental results: as shown in Table 3

[0067] Table 3

[0068]

[0069]

[0070] Result analysis: At a concentration of 25 μg / ml, the six compounds we tested had moderate inhibitory activity against Magnaporthe grisea, Fusarium graminearum, Rhizoctonia solani, Cordyceps sinensis, Conchoceras pinecone, Fusarium oxysporum, and Botrytis cinerea.

[0071] Finally, it should be noted that the above implementation cases are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred implementation cases, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution of the present invention, which should be included in the scope of the claims of the present invention.

Claims

1. Benzoxazepine and benzoxazole compounds, characterized in that: They have the general structural formulas shown in Ⅰ and Ⅱ respectively: Among them, R1 is one of hydrogen, methyl, methoxy, halogen, cyano, aldehyde, and ester, and R2 is one of p-toluenesulfonyl, benzenesulfonyl, p-bromobenzenesulfonyl, p-chlorobenzenesulfonyl, and p-nitrobenzenesulfonyl.

2. The method for synthesizing benzoxazepine and benzoxazole compounds according to claim 1, characterized in that: The process includes the following: N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamide derivative, palladium catalyst, and ligand are dispersed in a solvent; The mixture undergoes an intramolecular hydroamination reaction to obtain a benzoxazole compound; When synthesizing benzoxazepine compounds, additives need to be added, and the mixture undergoes a Wacker reaction to obtain benzoxazepine compounds.

3. The method for synthesizing benzoxazepine and benzoxazole compounds according to claim 2, characterized in that: The N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamide derivative has the structural formula shown in II: Among them, R1 is one of hydrogen, methyl, methoxy, halogen, cyano, aldehyde, and ester, and R2 is one of p-toluenesulfonyl, benzenesulfonyl, p-bromobenzenesulfonyl, p-chlorobenzenesulfonyl, and p-nitrobenzenesulfonyl.

4. The method for synthesizing benzoxazepine and benzoxazole compounds according to claim 2, characterized in that: The palladium catalyst is bistriphenylphosphine palladium dichloride when synthesizing benzoxazepine compounds; and the palladium catalyst is palladium dichloride when synthesizing benzoxazole compounds.

5. The method for synthesizing benzoxazepine and benzoxazole compounds according to claim 2, characterized in that: The ligand is pyridine.

6. The method for synthesizing benzoxazepine and benzoxazole compounds according to claim 2, characterized in that: The additive is copper acetate.

7. The method for synthesizing benzoxazepine and benzoxazole compounds according to claim 2, characterized in that: The solvent is toluene.

8. The method for synthesizing benzoxazepine and benzoxazole compounds according to claim 2, characterized in that: The reaction was carried out under oil bath heating, the ultrasonic time was 24 h, and the reaction temperature was 80°C.

9. The method for synthesizing benzoxazepine and benzoxazole compounds according to claim 2, characterized in that: In the Wacker reaction, the molar ratio of the N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamide derivative, palladium catalyst, ligand, and additive is 1:0.1:0.2:1.5; The molar ratio of the N-(2-(allyloxy)phenyl)-4-methylbenzenesulfonamide derivative, the palladium catalyst, and the ligand in the intramolecular hydroamination reaction is 1:0.1:0.2; The amount of solvent added is C N-(2-(烯丙氧基)苯基)-4-甲基苯磺酰胺 =0.2M.

10. The benzoxazepine and benzoxazole compounds according to claim 1 are used for combating fungi of agricultural and forestry origin.

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