13-(benzothiazol-2-yl)-6,12-cyclimine dibenzo[b,f][1,5]diazocine derivatives, their preparation and fungicidal activity

Abstract

The application discloses a 13-(benzothiazole-2-yl)-6,12-cycloimine dipyrido[b,f][1,5] diazocin derivative and preparation and fungicidal activity thereof, and relates to the technical field of organic synthesis. The 13-(benzothiazole-2-yl)-6,12-cycloimine dipyrido[b,f][1,5] diazocin derivative has the structural general formula as follows: wherein X is selected from H, halogen, C1-C4 alkyl and C1-C4 alkoxy; and Y is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy and nitro. The 13-(benzothiazole-2-yl)-6,12-cycloimine dipyrido[b,f][1,5] diazocin derivative is synthesized by a one-pot method, and has the characteristics of mild reaction condition, easy-to-obtain raw material and simple synthesis process. The compound has medium to good inhibitory activity on Valsa mali and Sclerotinia sclerotiorum.

Description

TECHNICAL FIELD

[0001] The present application relates to a 13-(benzothiazole-2-yl)-6,12-cycloimine dipyrido[b,f][1,5]diazocine derivative and its preparation and fungicidal activity, and relates to the technical field of organic synthesis. BACKGROUND

[0002] Nitrogen-containing heterocyclic compounds generally exhibit a broad spectrum of biological activity and are the most important members of the family of heterocyclic compounds. Whether in natural products or artificially synthesized compounds, nitrogen-containing heterocyclic structures are the most common molecular building blocks. With the deepening of research, organic chemists are committed to exploring and synthesizing a series of novel nitrogen-containing heterocyclic structures. 6,12-cycloimine dipyrido[b,f][1,5]diazocine is a novel nitrogen-containing heterocyclic compound with an imine bridge across the 6- and 12-positions, which folds the original eight-membered ring structure into two nearly perpendicular planes. This V-shaped rigid structure makes it have potential application value in the fields of biological medicine, pesticides, supramolecular chemistry, etc. At present, there are few reports on this kind of compound. In addition to the report by the research group of the present application, "N-pyrimidyl cycloimine dipyrido[1,5]diazocine derivative and its preparation and application (Patent No.: ZL202211161823.3)", there has been no report on introducing an aryl group on the cycloimine nitrogen. After discovering that 2-aminopyrimidine can react with o-aminobenzaldehyde to produce N-pyrimidyl cycloimine dipyrido[1,5]diazocine, the research group of the present application is committed to studying the reaction of other arylamines with o-aminobenzaldehyde. It is found that both aniline and 2-aminopyridine are difficult to obtain N-aryl-6,12-cycloimine dipyrido[b,f][1,5]diazocine when reacting with o-aminobenzaldehyde, but 2-aminobenzothiazole successfully produces 13-(benzothiazole-2-yl)-6,12-cycloimine dipyrido[b,f][1,5]diazocine. The present application intends to introduce the preparation of 13-(benzothiazole-2-yl)-6,12-cycloimine dipyrido[b,f][1,5]diazocine derivative and its fungicidal activity. SUMMARY

[0003] One of the purposes of the present application is to provide a class of 13-(benzothiazole-2-yl)-6,12-cycloimine dipyrido[b,f][1,5]diazocine derivatives.

[0004] To achieve the above-mentioned purposes, the technical solutions of the present application are as follows:

[0005] A 13-(benzothiazole-2-yl)-6,12-cycloimine dipyrido[b,f][1,5]diazocine derivative, the general structure of which is:

[0006]

[0007] In the general formula 1, X is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy; Y is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro.

[0008] Preferably, X is selected from H, F, Cl, Br, CH3, OCH3, and Y is selected from H, F, Cl, Br, CH3, OCH3, NO2.

[0009] Another object of the present application is to provide a method for preparing 13-(benzothiazol-2-yl)-6,12-cycloimine dipyrido[b,f][1,5]diazocine derivatives by one-pot reaction using 2-amino-m-X benzothiazole and 2-amino-n-Y benzaldehyde as raw materials, which comprises the following steps:

[0010] Step one: 2-amino-4-substituted benzaldehyde (2) and 2-amino-6-substituted benzothiazole (3) are added into an organic solvent, and heated to reflux under acid catalysis to obtain a reaction mixture containing general formula 1:

[0011]

[0012] Step two: the reaction mixture containing general formula 1 is rotary evaporated under reduced pressure, separated by column chromatography, and purified by recrystallization to obtain 13-(benzothiazol-2-yl)-6,12-cycloimine dipyrido[b,f][1,5]diazocine derivatives with general formula 1.

[0013] Thus, 13-(benzothiazol-2-yl)-6,12-cycloimine dipyrido[b,f][1,5]diazocine derivatives are synthesized by one-pot method. The synthesis method of the present application has the characteristics of mild reaction conditions, easy-to-obtain raw materials, and simple synthesis process. Preferably, in step one, the organic solvent is a protic solvent and an aprotic solvent.

[0014] More preferably, the protic solvent is anhydrous ethanol or n-butanol, and the aprotic solvent is N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), toluene, acetonitrile, 1,4-dioxane or 1,2-dichloroethane (1,2-DCE). Preferably, in step one, the acid catalyst is a protic acid or a Lewis acid.

[0015] More preferably, the protic acid is acetic acid, triflic acid or p-toluenesulfonic acid, and the Lewis acid is ferric chloride, aluminum chloride, ytterbium triflate or scandium triflate.

[0016] Preferably, in step one, the amount of catalyst is in the range of 5-30 mol% of the amount of 2-amino-m-X benzothiazole.

[0017] More preferably, the amount of the catalyst is in the range of 5-20 mol%.

[0018] More preferably, the amount of the catalyst is in the range of 5-15 mol%.

[0019] Preferably, in step one, the heating reflux temperature is 60-100℃.

[0020] More preferably, the heating reflux temperature is 70-90℃.

[0021] Preferably, in step one, the molar ratio of the 2-amino-m-X benzothiazole to the 2-amino-n-Y benzaldehyde is 1:1-4.

[0022] More preferably, the molar ratio of the 2-amino-m-X benzothiazole to the 2-amino-n-Y benzaldehyde is 1:2-3. Preferably, in step one, the reaction time is 8-24h.

[0023] More preferably, the reaction time is 12-16h.

[0024] Preferably, in step two, the separation is column chromatography separation, using petroleum ether / ethyl acetate or petroleum ether / dichloromethane as the mobile phase [volume ratio (5-15):1]; and the purification is recrystallization, using a mixture of petroleum ether / ethyl acetate as the solvent.

[0025] More preferably, the column chromatography separation uses petroleum ether / ethyl acetate as the mobile phase [volume ratio (5-10):1].

[0026] Another object of the present application is to provide an application of the above-mentioned 13-(benzothiazol-2-yl)-6,12-cycloimine dibenzo[b,f][1,5]diazocine derivative as a bacterial disease fungicide for crops.

[0027] Preferably, the bacterial disease of the crops is one or several of tomato early blight, wheat scab, rape sclerotinia, rice sheath blight, apple ring rot, wheat sheath blight and rice seedling blight.

[0028] Advantages of the present application

[0029] The present application provides a 13-(benzothiazol-2-yl)-6,12-cycloimine dibenzo[b,f][1,5]diazocine derivative, a preparation method and an application thereof. The 13-(benzothiazol-2-yl)-6,12-cycloimine dibenzo[b,f][1,5]diazocine derivative of the present application has the following general structure: wherein X is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy; Y is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro. The 13-(benzothiazol-2-yl)-6,12-cycloimine dibenzo[b,f][1,5]diazocine derivatives are synthesized by "one-pot" method. The compounds of the present application have moderate to good inhibitory activity against Phaeoacremonium aleophilum and Sclerotinia sclerotiorum. The present application has the characteristics of mild reaction conditions, easy to obtain raw materials and simple synthesis process. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 The 1H NMR of 13-(benzothiazol-2-yl)-6H,12H-6,12-cycloimine dibenzo[b,f][1,5]diazocine (1cc).

[0031] Figure 2 The 13C NMR of 13-(benzothiazol-2-yl)-6H,12H-6,12-cycloimine dibenzo[b,f][1,5]diazocine (1cc).

[0032] Figure 3 The high resolution mass spectrum of 13-(benzothiazol-2-yl)-6H,12H-6,12-cycloimine dibenzo[b,f][1,5]diazocine (1cc). DETAILED DESCRIPTION

[0033] In order to better understand the present application, the present application will be further described in conjunction with the following examples, but the content of the present application is not limited thereto.

[0034] Example 1:

[0035] A preparation method of 13-(benzothiazol-2-yl)-6,12-cycloimine dibenzo[b,f][1,5]diazocine derivatives, the specific scheme is shown in formula 1.

[0036]

[0037] Experimental scheme of formula 1

[0038] The synthesis method is illustrated by taking compound 1cc (X=H, Y=H) shown in formula 1 as an example, and the synthesis methods of other compounds are similar.

[0039] The specific synthesis steps and characterization are as follows:

[0040] The reaction of 2-aminobenzaldehyde (2c) and 2-aminobenzothiazole (3c) is taken as an example to illustrate the experimental process. Into a 100 mL three-necked flask was added 0.2423 g (2 mmol) of 2-aminobenzaldehyde, 0.1502 g (1 mmol) of 2-aminobenzothiazole, 0.0172 g of p-toluenesulfonic acid (10 mol%) and 4 mL of 1,2-dichloroethane, heated to 80°C, and reacted for 12 hours. After the reaction was completed, column chromatography was used for separation and purification with petroleum ether: ethyl acetate = 8:1 as the eluent, the eluent was removed by rotary evaporation, and white powder solid 13-(benzothiazol-2-yl)-6,12-cyclamidinodibenzo[b,f][1,5]diazocin was obtained by double solvent (petroleum ether / ethyl acetate) recrystallization, with a yield of 40%.

[0041] The structure was characterized by nuclear magnetic resonance hydrogen spectrum Figure 1 ), carbon spectrum Figure 2 ) and mass spectrum Figure 3 ), and the following results were obtained: 1 H NMR (500 MHz, DMSO-d6) δ 7.84 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 4.1 Hz, 2H), 7.31 (dd, J = 13.0, 7.9 Hz, 3H), 7.15 (t, J = 7.6 Hz, 1H), 6.75 - 6.68 (m, 2H), 6.66 (s, 2H), 6.30 (d, J = 3.9 Hz, 2H); 13 C NMR (126 MHz, DMSO-d6) δ 165.57, 151.36, 143.03, 132.77, 131.07, 129.92, 126.11, 122.45, 121.58, 121.53, 119.53, 116.95, 114.32, 63.19; High resolution mass spectrum result was HRMS (ESI) m / z: [M+H] + calcd for C 21 H 16 N4S 357.1169, found 357.1173. The results showed that the obtained product was the target compound.

[0042] According to the above method, 35 target compounds were synthesized.

[0043] Specifically, the names and structural characterization of the 35 synthesized 13-(benzothiazol-2-yl)-6,12-cyclamidinodibenzo[b,f][1,5]diazocin derivatives are shown in Table 1.

[0044] Table 1 Structure and nuclear magnetic information of compounds

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051] Example 2:

[0052] The fungicidal activity of 35 13-(benzothiazol-2-yl)-6,12-cyclamidinylbenzo[b,f][1,5]diazocane derivatives in Example 1 was tested. The test compounds were used to prevent tomato early blight, wheat scab, cabbage sclerotinia, rice sheath blight, apple ring rot, wheat sheath blight, and rice sheath blight.

[0053] Experimental method:

[0054] 1) 3 mg of compound was weighed and dissolved in 100 μL of DMSO to prepare a 30000 ppm mother solution, which was diluted with 1% Tween water to a 500 ppm compound solution;

[0055] 2) 1 mL of the solution was taken with a pipette and placed in a sterilized plate, and 9 mL of PDA medium was taken with a pipette and placed in the plate to mix, to prepare a corresponding concentration of drug-containing plate;

[0056] 3) The edge of the pathogenic colony (cultured) was cut with a sterilized puncher (4 mm in diameter) to obtain a fungus cake. After the medium solidified, different strains were inoculated (the blank control was the medium containing the same volume of sterile water). After 72 hours of incubation in an incubator, the colony diameter was observed and measured;

[0057] The above operations were all carried out under sterile conditions, and the PDA medium and the like were all sterile.

[0058] Experimental results:

[0059] The fungicidal activity, i.e. the inhibition efficiency, was calculated using formula (2);

[0060]

[0061] Note: 4 mm in formula (2) is the diameter of the fungus cake.

[0062] The fungicidal activity of 13-(benzothiazol-2-yl)-6,12-cyclen dibenzo[b,f][1,5] diazocine derivatives at a concentration of 50 μg / mL is listed in Table 2.

[0063] Table 2 Fungicidal activity of 13-(benzothiazol-2-yl)-6,12-cyclen dibenzo[b,f][1,5] diazocine derivatives

[0064]

[0065]

[0066] As can be seen from Table 2, the 13-(benzothiazol-2-yl)-6,12-cyclen dibenzo[b,f][1,5] diazocine derivatives of the present example have a moderate to good inhibitory effect on V. mali, with the inhibitory rate of compounds 1bc, 1bd, 1cf and 1fd being higher than 80%. The target compounds have a moderate fungicidal effect on Sclerotinia sclerotiorum, with the highest inhibitory activity being 75%; the inhibitory rate on Gaeumannomyces graminis is up to 73.5%; the fungicidal effect on Xanthomonas oryzae is general, but the inhibitory rate of compound 1fc is as high as 92.5%. The fungicidal effect of these compounds on several other bacterial diseases of crops is general.

[0067] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present application and not to limit the protection scope of the present application. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the spirit and scope of the present application.

Claims

1. A 13-(benzothiazol-2-yl)-6,12-cycloiminodibenzo[b,f][1,5]diazacyclooctane derivative having the general structural formula: In Formula 1, X is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy; Y is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, and nitro.

2. The 13-(benzothiazol-2-yl)-6,12-cycloiminodibenzo[b,f][1,5]diazacyclooctane derivative according to claim 1, characterized in that: X is selected from H, F, Cl, Br, CH3, OCH3; Y is selected from H, F, Cl, Br, CH3, OCH3, NO2.

3. A method for preparing a 13-(benzothiazol-2-yl)-6,12-cycloiminodibenzo[b,f][1,5]diazacyclooctane derivative according to claim 1, wherein the preparation of the compound of formula 1 comprises the following steps: Step 1: Dissolve compounds 2 and 3 in an organic solvent and heat under reflux under acid catalysis to obtain a reaction mixture containing the general formula 1: Step 2: Separating, purifying and drying the reaction mixture having the general formula 1 to obtain a 13-(benzothiazol-2-yl)-6,12-cycloiminodibenzo[b,f][1,5]diazacyclooctane derivative having the general formula 1.

4. The method for preparing a 13-(benzothiazol-2-yl)-6,12-cycloiminodibenzo[b,f][1,5]diazacyclooctane derivative according to claim 3, characterized in that: In step 1, the organic solvent is anhydrous ethanol, n-butanol, acetonitrile, toluene, 1,2-dichloroethane or N,N-dimethylformamide (DMF).

5. The method for preparing a 13-(benzothiazol-2-yl)-6,12-cycloiminodibenzo[b,f][1,5]diazacyclooctine derivative according to claim 3, characterized in that: In step 1, the acid catalyst is a protonic acid or a Lewis acid, the protonic acid is acetic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid, and the Lewis acid is ferric chloride, aluminum chloride, scandium trifluoromethanesulfonate or ytterbium trifluoromethanesulfonate; the amount of the catalyst is in the range of 5-30 mol% of the amount of the compound 3.

6. The method for preparing a 13-(benzothiazol-2-yl)-6,12-cycloiminodibenzo[b,f][1,5]diazacyclooctane derivative according to claim 3, characterized in that: In step 1, the reaction temperature is 60-100° C., and the reaction time is 8-24 h.

7. The method for preparing a 13-(benzothiazol-2-yl)-6,12-cycloiminodibenzo[b,f][1,5]diazacyclooctane derivative according to claim 3, characterized in that: In step 1, the molar ratio of compound 3 to compound 2 is 1:1-4.

8. The method for preparing a 13-(benzothiazol-2-yl)-6,12-cycloiminodibenzo[b,f][1,5]diazacyclooctane derivative according to claim 3, characterized in that: In step 2, the separation is performed by column chromatography using petroleum ether / ethyl acetate or petroleum ether / dichloromethane as the mobile phase in a volume ratio of (5-15):1; the purification is performed by recrystallization using a mixture of petroleum ether / ethyl acetate as the solvent.

9. Use of the 13-(benzothiazol-2-yl)-6,12-cycloiminodibenzo[b,f][1,5]diazacyclopine derivative according to any one of claims 1 to 2 as a fungicide for bacterial diseases of crops, characterized in that: The bacterial diseases of crops are one or more of tomato early blight, wheat scab, rapeseed sclerotinia, rice sheath blight, apple ring rot, wheat sheath blight and rice bakanae.

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