CN117088803A - 1-trifluoromethyl cyclopentadiene [ b ] indole compound and preparation method and application thereof - Google Patents

1-trifluoromethyl cyclopentadiene [ b ] indole compound and preparation method and application thereof Download PDF

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CN117088803A
CN117088803A CN202310829136.2A CN202310829136A CN117088803A CN 117088803 A CN117088803 A CN 117088803A CN 202310829136 A CN202310829136 A CN 202310829136A CN 117088803 A CN117088803 A CN 117088803A
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trifluoromethyl
indole
reaction
formula
indole compound
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饶卫东
滕玉玲
俞向栋
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Nanjing Forestry University
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Nanjing Forestry University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A01N43/38—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P3/00—Fungicides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system

Abstract

The application relates to the technical field of organic synthesis, in particular to a 1-trifluoromethyl cyclopentadiene [ b ] indole compound, a preparation method and application thereof. The preparation method of the compound comprises the steps of taking a simple and easily available trifluoromethyl 3-indole substituted allyl alcohol compound as a raw material, taking hexafluoroisopropanol as a solvent, and reacting at room temperature under the catalysis of a Bronsted acid p-toluenesulfonic acid monohydrate catalyst to obtain the 1-trifluoromethyl cyclopentadiene [ b ] indole compound. The method does not need to use a metal catalyst, does not need heating and anhydrous and anaerobic operation, and has the advantages of mild reaction conditions, simple operation, high yield, wider range of reaction substrates and the like; the 1-trifluoromethyl cyclopentadiene [ b ] indole compound prepared by the application has a good inhibition effect on plant pathogenic bacteria, and can be used for preventing and treating wheat scab and tomato gray mold.

Description

1-trifluoromethyl cyclopentadiene [ b ] indole compound and preparation method and application thereof
Technical Field
The application belongs to the technical field of organic compound synthesis, and particularly relates to a 1-trifluoromethyl cyclopentadiene [ b ] indole compound, and a preparation method and application thereof.
Background
Cyclopentadiene [ b ]]Indole compounds are an important branch of indole alkaloids, are widely used in bioactive natural products and bioactive compounds, and have important applications in the fields of medicines, pesticides, functional materials and the like. For example, terpendole E is a natural product extracted from soil, and Terpendole E has a good inhibitory effect on spindle kinesin (KSP, also known as Eg 5). Furthermore, it was found that the natural product Nostonone A isolated from cyanobacteria was demonstrated to inhibit chymotrypsin-like protease activity in vitro. Prostaglandin D 2 (PGD 2 ) Is the main cyclooxygenase metabolite of arachidonic acid, PGD, when mast cells respond to antigen challenge 2 Excessive production of (a) can lead to inflammation common in allergic diseases such as allergic rhinitis, asthma and atopic dermatitis. Fischer-Tropsch L pair PGD 2 Receptor antagonists act to alleviate various allergic diseases. The natural product brucelline E extracted from the root of the wall tree has potential medicinal value for treating various parasitic diseases including malaria. MK-0524 shows extremely strong inhibition against seasonal allergic rhinitis and other allergic diseases (such as allergic asthma, atopic dermatitis and allergic conjunctivitis), C thereof max 1100. Mu.M, 3900. Mu.M. The production of new metabolites by Clavipita has been well documented, most notably, the production of metabolites by Zostereum purpureus has long been associated with contamination of various cereals, whereas Paspaline has excellent inhibition of legumain with a MIC of 128 μg/mL.
The fluorine-containing organic compound is widely applied in the fields of medicines, pesticides, materials and the like, and the introduction of fluorine atoms or fluorine-containing functional groups into organic molecules has become an important strategy for the development of new drugs. Trifluoromethyl (CF) 3 ) Is a key pharmacophore, and introducing fluorine atom or fluorine-containing functional group into small organic molecule can obviously change physicochemical property, biological activity and bioavailability of the compound, and simultaneously trifluoromethyl functional group is also importantThe organic synthons of (2) are used for the construction of fluorine-containing and non-fluorine-containing functional molecules. 1-Trifluoromethylcyclopentadiene [ b ]]The synthetic methods for indole compounds are quite rare (chem. Commun.2014,50, 14797-14800), and therefore a synthetic method for 1-trifluoromethyl cyclopentadiene [ b ] was developed]The new method of indole compounds is of great significance.
Disclosure of Invention
This section is intended to outline some aspects of embodiments of the application and to briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section as well as in the description of the application and in the title of the application, which may not be used to limit the scope of the application.
The present application has been made in view of the above-mentioned or existing problems occurring in the prior art.
One of the purposes of the application is to provide a 1-trifluoromethyl cyclopentadiene [ b ] indole compound, which fills the technical blank in the aspect of synthesizing the trifluoromethyl cyclopentadiene [ b ] indole compound.
In order to solve the technical problems, the application provides the following technical scheme: a1-trifluoromethyl cyclopentadiene [ b ] indole compound has a structural formula shown in a formula (I):
wherein R is 1 、R 2 、R 3 R is a group independent of each other 1 One of hydrogen, halogen, ester group, methoxy, methyl, aldehyde group, benzyloxy, pivaloyloxy, allyloxy, methyl acrylate group and phenyl group;
R 2 one selected from C1-C6 straight-chain alkyl;
R 3 selected from one of phenyl and halogen substituted phenyl.
The application also aims to provide a preparation method of the 1-trifluoromethyl cyclopentadiene [ b ] indole compound, which comprises the steps of taking a compound shown in a formula (II) as a raw material, and reacting in a solvent at normal temperature under the catalysis of a Bronsted acid catalyst to obtain the compound shown in the formula (I);
wherein R in formula (II) 1 、R 2 、R 3 And R in formula (I) 1 、R 2 、R 3 The correspondence is consistent.
As a preferable mode of the process for producing a 1-trifluoromethylcyclopentadiene [ b ] indole compound of the present application, there is provided a process wherein: the bronsted acid catalyst is selected from p-toluenesulfonic acid monohydrate or trifluoromethanesulfonic acid; the preferred catalyst is p-toluenesulfonic acid monohydrate.
As a preferable mode of the process for producing a 1-trifluoromethylcyclopentadiene [ b ] indole compound of the present application, there is provided a process wherein: the molar ratio of the Bronsted acid catalyst to the compound shown in the formula (II) is 0.1-0.3:1; the preferred molar ratio is 0.3:1.
As a preferable mode of the process for producing a 1-trifluoromethylcyclopentadiene [ b ] indole compound of the present application, there is provided a process wherein: the concentration of the 1-trifluoromethyl cyclopentadiene [ b ] indole compound in the solvent hexafluoroisopropanol is 0.05-0.2 mol/L; the concentration is preferably 0.1mol/L.
As a preferable mode of the process for producing a 1-trifluoromethylcyclopentadiene [ b ] indole compound of the present application, there is provided a process wherein: the solvent is hexafluoroisopropanol or a mixed solvent of dichloroethane and hexafluoroisopropanol; preferably the solvent is hexafluoroisopropanol; wherein the volume ratio of dichloroethane to hexafluoroisopropanol is 1-2:1.
As a preferable mode of the process for producing a 1-trifluoromethylcyclopentadiene [ b ] indole compound of the present application, there is provided a process wherein: the reaction is carried out at normal temperature, and the reaction time is 4-24 hours.
As a preferable mode of the process for producing a 1-trifluoromethylcyclopentadiene [ b ] indole compound of the present application, there is provided a process wherein: the normal temperature reaction process also comprises the steps of tracking the reaction by thin plate chromatography until the reaction is complete, removing the solvent by rotary evaporation after the reaction is finished, and carrying out silica gel column chromatography on the crude product.
It is another object of the present application to provide the use of a 1-trifluoromethyl-cyclopentadiene [ b ] indole compound as described above for inhibiting gibberella and/or botrytis; or in the preparation of medicines for inhibiting wheat scab and/or tomato gray mold.
Compared with the prior art, the application has the beneficial effects that:
the synthesis method of the 1-trifluoromethyl cyclopentadiene [ b ] indole compound uses cheap p-toluenesulfonic acid monohydrate as a catalyst, and does not need to use a metal catalyst, thereby realizing the efficient synthesis of the 1-trifluoromethyl cyclopentadiene [ b ] indole compound. The method has the advantages of easily available raw materials, mild conditions, high yield, wide substrate range, high atom economy and the like.
The 1-trifluoromethyl cyclopentadiene [ b ] indole compound prepared by the application has good inhibition effect on plant pathogenic bacteria, especially gibberella and botrytis cinerea, and can be used for preventing and treating wheat scab and tomato gray mold.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are needed in the description of the embodiments will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present application, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art. Wherein:
FIG. 1 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the target product 1a prepared in example 1 of the present application;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the target product 1a prepared in example 1 of the present application;
FIG. 3 is a nuclear magnetic resonance fluorine spectrum of the target product 1a prepared in example 1 of the present application;
Detailed Description
Various exemplary embodiments of the application will now be described in detail, which should not be considered as limiting the application, but rather as more detailed descriptions of certain aspects, features and embodiments of the application. In order that the above-recited objects, features and advantages of the present application will become more apparent, a more particular description of the application will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present application, but the present application may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present application is not limited to the specific embodiments disclosed below.
Further, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic can be included in at least one implementation of the application. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
The starting pivaloyl-protected trifluoromethyl-indole-substituted allylic alcohol compounds used in the examples were prepared as reported in the reference (Tetrahedron, 2017,73 (16), 2283-2289;Journal of the American Chemical Society,2002,124 (44): 13179-13184).
Example 1
10mL eggplant-shaped bottle is taken, pivaloyl-protected trifluoromethyl 3-indole substituted allyl alcohol 2a (0.2 mmol) and p-toluenesulfonic acid monohydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (2 mL) is added under the atmosphere, the reaction is carried out for 4h under normal temperature (thin plate chromatography tracking reaction is carried out until the reaction is complete), after the reaction is finished, the reaction mixture is concentrated in a rotating way to remove the solvent, and crude products are separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain target products 1a (47.6 mg, yellow solid, yield 76%).
The reaction equation is as follows:
the target product 1a is characterized, the nuclear magnetic resonance hydrogen spectrum is shown in fig. 1, the nuclear magnetic resonance carbon spectrum is shown in fig. 2, and the nuclear magnetic resonance fluorine spectrum is shown in fig. 3:
1 H NMR(600MHz,CDCl 3 )δ8.06(s,1H),7.71(d,J＝7.9Hz,1H),7.59–7.54(m,4H),7.51–7.47(m,1H),7.36(d,J＝8.1Hz,1H),7.25(t,J＝7.6Hz,1H),7.19(t,J＝7.6Hz,1H),4.11(d,J＝9.3Hz,1H),2.36(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ147.7,139.2,137.5,135.1,133.2,129.0,128.2,128.1,126.5(q,J＝279.1Hz),124.3,120.9,120.8,118.3,112.5(q,J＝2.6Hz),112.1,51.2(q,J＝29.6Hz),14.5；
19 F NMR(565MHz,CDCl 3 )δ-66.43(d,J＝9.3Hz).
example 2
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indole substituted allyl alcohol 2b (0.2 mmol) protected by pivaloyl and p-toluenesulfonic acid monohydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (2 mL) is added under the atmosphere to react for 4h (thin plate chromatography tracking reaction is carried out until the reaction is complete), after the reaction is finished, the reaction mixture is concentrated in a rotating way to remove the solvent, and crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain target product 1b (39.1 mg, yellow solid, yield is 59%).
The reaction equation is as follows:
characterization of the above target product 1 b:
1 H NMR(600MHz,CDCl 3 )δ8.19(s,1H),7.53(t,J＝7.5Hz,2H),7.51–7.48(m,2H),7.44(t,J＝7.2Hz,1H),7.14(d,J＝8.1Hz,1H),7.05–7.01(m,1H),6.86(dd,J＝10.7,7.9Hz,1H),4.19(q,J＝8.9Hz,1H),2.30(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ155.0(d,J＝247.1Hz),148.1,141.6(d,J＝11.3Hz),139.0,134.7,133.0,129.1,128.3,128.2,121.3,121.3,114.0(q,J＝22.2Hz),108.0(q,J＝3.4Hz),106.3,106.2,51.8(q,J＝29.7Hz),14.8；
19 F NMR(565MHz,CDCl 3 )δ-66.23(dd,J＝19.5,8.9Hz),-120.54–-120.74(m).
example 3
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indole substituted allyl alcohol 2c (0.2 mmol) protected by pivaloyl and p-toluenesulfonic acid monohydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (2 mL) is added under the atmosphere to react for 4h (thin plate chromatography tracking reaction is carried out until the reaction is complete), after the reaction is finished, the reaction mixture is concentrated in a rotating way to remove the solvent, and crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain target product 1c (73.9 mg, yellow solid, yield 92%).
The reaction equation is as follows:
characterization of the above target product 1 c:
1 H NMR(600MHz,CDCl 3 )δ8.14(s,1H),7.58(s,1H),7.53(t,J＝7.5Hz,2H),7.48(d,J＝6.9Hz,2H),7.44(t,J＝7.3Hz,1H),7.24(d,J＝8.6Hz,1H),7.07(dd,J＝8.6,2.0Hz,1H),4.06(q,J＝9.2Hz,1H),2.30(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ149.2,138.5,137.5,135.0,132.9,129.1,128.3,128.1,126.6,126.3(q,J＝279.1Hz),125.2,121.1,117.8,112.9,112.0,51.3(q,J＝29.8Hz),14.6；
19 F NMR(565MHz,CDCl 3 )δ-66.43(d,J＝9.0Hz).
example 4
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indole substituted allyl alcohol 2d (0.2 mmol) protected by pivaloyl and p-toluenesulfonic acid monohydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (2 mL) is added under the atmosphere to react for 6h (thin plate chromatography tracking reaction is carried out until the reaction is complete), after the reaction is finished, the reaction mixture is concentrated in a rotating way to remove the solvent, and crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain target product 1d (78.7 mg, yellow solid, yield 99%).
The reaction equation is as follows:
characterization of the above target product 1 d:
1 H NMR(600MHz,CDCl 3 )δ8.02(s,1H),7.54–7.51(m,4H),7.44(s,2H),7.25(d,J＝8.4Hz,1H),6.98(d,J＝8.2Hz,1H),4.07(q,J＝9.3Hz,1H),2.49(s,3H),2.31(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ147.8,137.5,137.3,135.2,133.3,130.2,129.0,128.2,128.1,124.5,122.5,118.1,111.7,51.3(q,J＝29.9Hz),21.6,14.5；
19 F NMR(565MHz,CDCl 3 )δ-66.37(d,J＝9.3Hz).
example 5
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indole substituted allyl alcohol 2e (0.2 mmol) protected by pivaloyl and p-toluenesulfonic acid monohydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (2 mL) is added under the atmosphere, the reaction is carried out for 4h under normal temperature (thin plate chromatography tracking reaction is carried out until the reaction is complete), after the reaction is finished, the reaction mixture is concentrated in a rotating way to remove the solvent, and crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether=1/100-1/20, V/V) to obtain target product 1e (80.3 mg, yellow solid, yield 93%).
The reaction equation is as follows:
characterization of the above target product 1 e:
1 H NMR(600MHz,CDCl 3 )δ8.13(s,1H),7.74(s,1H),7.53(t,J＝7.5Hz,2H),7.48(d,J＝6.9Hz,2H),7.44(t,J＝7.3Hz,1H),7.20(s,2H),4.06(q,J＝9.2Hz,1H),2.30(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ149.0,138.6,137.8,135.0,132.8,129.1,128.3,128.1,126.3(q,J＝279.0Hz),125.8,123.7,120.8,114.3,113.3,111.9(q,J＝3.5Hz),51.3(q,J＝30.1Hz),14.6；
19 F NMR(565MHz,CDCl 3 )δ-66.41(d,J＝9.2Hz).
example 6
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indole substituted allyl alcohol 2f (0.2 mmol) protected by pivaloyl and p-toluenesulfonic acid monohydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (2 mL) is added under the atmosphere, the reaction is carried out for 4h under normal temperature (thin plate chromatography tracking reaction is carried out until the reaction is complete), after the reaction is finished, the reaction mixture is concentrated in a rotating way to remove the solvent, and crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain target product 1f (87.4 mg, yellow solid, yield 99%).
The reaction equation is as follows:
characterization of the above target product 1 f:
1 H NMR(600MHz,CDCl 3 )δ8.13(s,1H),7.74(s,1H),7.53(t,J＝7.5Hz,2H),7.48(d,J＝6.9Hz,2H),7.44(t,J＝7.3Hz,1H),7.20(s,2H),4.06(q,J＝9.2Hz,1H),2.30(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ148.6,138.5,138.3,134.9,132.8,129.3,129.1,128.3,128.1,127.1,126.5,113.9,84.8,51.3(q,J＝29.9Hz),14.6；
19 F NMR(565MHz,CDCl 3 )δ-66.41(d,J＝9.2Hz).
example 7
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indole substituted allyl alcohol protected by pivaloyl (0.2 mmol) and p-toluenesulfonic acid monohydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (2 mL) is added under the atmosphere to react for 5h (thin plate chromatography tracking reaction is carried out until the reaction is complete), after the reaction is finished, the reaction mixture is concentrated in a rotating way to remove the solvent, and crude products are separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether=1/100-1/20, V/V) to obtain target products for 1h (45.7 mg, white solid, yield 67%).
The reaction equation is as follows:
characterization of the above target product 1 h:
1 H NMR(600MHz,CDCl 3 )δ10.00(s,1H),8.72(s,1H),8.11(s,1H),7.69(dd,J＝8.4,1.2Hz,1H),7.58–7.48(m,4H),7.46(d,J＝8.4Hz,1H),7.45–7.40(m,1H),4.15(q,J＝9.2Hz,1H),2.32(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ192.8,149.8,142.8,138.9,135.0,132.7,130.4,129.1,128.4,128.2,126.2(q,J＝279.1Hz),124.1,123.2,121.3,113.8(q,J＝3.3Hz),112.7,51.5(q,J＝30.0Hz),14.6；
19 F NMR(565MHz,CDCl 3 )δ-66.39(d,J＝9.2Hz).
example 8
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indole substituted allyl alcohol 2i (0.2 mmol) protected by pivaloyl and p-toluenesulfonic acid monohydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (2 mL) is added under the atmosphere, the reaction is carried out for 4h under normal temperature (thin plate chromatography tracking reaction is carried out until the reaction is complete), after the reaction is finished, the reaction mixture is concentrated in a rotating way to remove the solvent, and crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain target product 1i (74.5 mg, yellow solid, yield 99%).
The reaction equation is as follows:
characterization of the above target product 1 i:
1 H NMR(600MHz,CDCl 3 )δ8.20(s,1H),7.55–7.48(m,5H),7.44(t,J＝7.2Hz,1H),7.32(d,J＝1.5Hz,1H),7.13(dd,J＝8.5,1.7Hz,1H),4.06(q,J＝9.3Hz,1H),2.30(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ148.5,139.5,138.0,135.1,132.9,129.0,128.2,128.1,126.4,122.9,121.5,118.9,112.5,112.0,51.3(q,J＝30.3Hz),14.5；
19 F NMR(565MHz,CDCl 3 )δ-66.46(d,J＝9.3Hz).
example 9
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indole substituted allyl alcohol 2j (0.2 mmol) protected by pivaloyl and p-toluenesulfonic acid monohydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (2 mL) is added under the atmosphere, the reaction is carried out for 5h under normal temperature (thin plate chromatography is carried out until the reaction is complete), after the reaction is finished, the reaction mixture is concentrated in a rotating way to remove the solvent, and crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain target product 1j (56.3 mg, yellow solid, yield 96%).
The reaction equation is as follows:
characterization of the above target product 1 j:
1 H NMR(600MHz,CDCl 3 )δ8.09(s,1H),7.53(t,J＝7.5Hz,2H),7.50–7.44(m,5H),7.27(dd,J＝8.4,1.8Hz,1H),4.07(q,J＝9.3Hz,1H),2.29(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ148.4,139.9,138.2,135.0,132.9,129.1,128.3,128.1,126.3(q,J＝279.1Hz),124.1,123.1,119.4,114.9,113.9,112.6(q,J＝2.8Hz),51.3(q,J＝29.9Hz),14.6；
19 F NMR(565MHz,CDCl 3 )δ-66.46(d,J＝9.3Hz).
example 10
10mL eggplant-shaped bottle is taken, pivaloyl-protected trifluoromethyl 3-indole substituted allyl alcohol 2k (0.2 mmol) and p-toluenesulfonic acid monohydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (2 mL) is added under the atmosphere, the reaction is carried out for 4h under normal temperature (thin plate chromatography tracking reaction is carried out until the reaction is complete), after the reaction is finished, the reaction mixture is concentrated in a rotating way to remove the solvent, and crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether=1/100-1/10, V/V) to obtain target product 1k (58.1 mg, yellow solid, yield 85%).
The reaction equation is as follows:
characterization of the above target product 1 k:
1 H NMR(600MHz,CDCl 3 )δ8.01(s,1H),7.54–7.46(m,5H),7.44–7.39(m,1H),6.88(d,J＝2.1Hz,1H),6.85(dd,J＝8.7,2.2Hz,1H),4.05(q,J＝9.4Hz,1H),3.83(s,3H),2.28(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ155.6,146.7,140.0,135.9,135.3,133.4,129.0,128.2,128.0,126.6(q,J＝278.9Hz),119.1,118.8,112.7(q,J＝2.6Hz),110.1,96.3,55.8,51.3(q,J＝29.7Hz),14.4；
19 F NMR(565MHz,CDCl 3 )δ-66.54(d,J＝9.4Hz).
example 11
10mL eggplant-shaped bottle is taken, 2L (0.2 mmol) of trifluoromethyl 3-indole substituted allyl alcohol protected by pivaloyl and p-toluenesulfonic acid monohydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (2 mL) is added under the atmosphere to react for 4h (thin plate chromatography tracking reaction is carried out until the reaction is complete), after the reaction is finished, the reaction mixture is concentrated in a rotating way to remove the solvent, and crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain 1L (91.3 mg, yellow solid, yield 95%) of target product.
The reaction equation is as follows:
characterization of the above target product 1 l:
1 H NMR(600MHz,CDCl 3 )δ8.03(s,1H),7.66(d,J＝7.9Hz,1H),7.54(t,J＝7.5Hz,2H),7.49(d,J＝7.0Hz,2H),7.45(t,J＝7.3Hz,1H),7.35(d,J＝8.0Hz,1H),7.20(t,J＝7.5Hz,1H),7.14(t,J＝7.5Hz,1H),4.28(q,J＝9.2Hz,1H),2.79–2.73(m,1H),2.62–2.55(m,1H),1.76–1.70(m,1H),1.61–1.56(m,1H),1.35–1.28(m,6H),0.89(t,J＝7.0Hz,4H)；
13 C NMR(150MHz,CDCl 3 )δ147.8,143.0,139.2,135.4,133.5,129.0,128.2,128.1,126.5(q,J＝279.2Hz),124.4,121.0,120.9,118.3,112.7(q,J＝2.9Hz),112.0,48.5(q,J＝29.8Hz),31.5,30.7,29.1,28.0,22.6,14.0；
19 F NMR(565MHz,CDCl 3 )δ-66.58(d,J＝9.3Hz).
example 12
10mL eggplant-shaped bottle is taken, 2m (0.2 mmol) of trifluoromethyl 3-indole substituted allyl alcohol protected by pivaloyl and p-toluenesulfonic acid monohydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (2 mL) is added under the atmosphere to react for 5h (thin plate chromatography tracking reaction is carried out until the reaction is complete), after the reaction is finished, the reaction mixture is concentrated in a rotating way to remove the solvent, and crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether=1/100-1/6, V/V) to obtain a target product 1m (42.0 mg, yellow solid, yield 53%).
The reaction equation is as follows:
characterization of the above target product 1 m:
1 H NMR(600MHz,CDCl 3 )δ8.30(s,1H),7.84(d,J＝15.9Hz,1H),7.76(s,1H),7.56–7.45(m,4H),7.43(t,J＝7.1Hz,1H),7.38–7.30(m,2H),6.43(d,J＝15.9Hz,1H),4.11(q,J＝9.2Hz,1H),3.81(s,3H),2.30(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ168.0,149.0,146.6,140.5,138.4,135.1,132.9,129.1,128.3,128.2,127.5,126.3(q,J＝279.0Hz),124.5,120.7,119.4,115.1,113.0(q,J＝2.4Hz),112.5,51.5,51.4(q,J＝30.5Hz),14.6；
19 F NMR(565MHz,CDCl 3 )δ-66.40(d,J＝9.2Hz).
example 13
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indole substituted allyl alcohol 2n (0.2 mmol) protected by pivaloyl and p-toluenesulfonic acid monohydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (2 mL) is added under the atmosphere, the reaction is carried out for 4h under normal temperature (thin plate chromatography tracking reaction is carried out until the reaction is complete), after the reaction is finished, the reaction mixture is concentrated in a rotating way to remove the solvent, and crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether=1/100-1/25, V/V) to obtain target product 1n (71.2 mg, white solid, yield 96%).
The reaction equation is as follows:
characterization of the above target product 1 n:
1 H NMR(600MHz,CDCl 3 )δ8.80(s,1H),8.37(s,1H),7.83(dd,J＝8.6,1.5Hz,1H),7.51–7.46(m,4H),7.42–7.36(m,2H),4.10(q,J＝9.2Hz,1H),3.89(s,3H),2.30(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ168.3,149.3,142.0,138.4,135.0,132.8,129.0,128.2,128.1,128.1(q,J＝279.1Hz),123.8,122.6,122.3,120.8,113.3,111.8,51.9,51.3(q,J＝29.9Hz),14.5；
19 F NMR(565MHz,CDCl 3 )δ-66.34(d,J＝9.2Hz).
example 14
In order to verify the practicability of the application, gram-scale amplification experiments are also carried out, and when the trifluoromethyl 3-indole substituted allyl alcohol 2a serving as a raw material is amplified to 3mmol (1.25 g), the expected product can still be obtained in 80% yield when the loading of the p-toluenesulfonic acid monohydrate catalyst is 30mol%, so that the practicability of the application is fully shown.
A50 mL round bottom flask is taken, trifluoromethyl 3-indole substituted allyl alcohol 2a (3 mmol,1.25 g) and p-toluenesulfonic acid monohydrate (0.9 mmol) are sequentially added, hexafluoroisopropanol (15 mL) is added under the atmosphere, the reaction is carried out for 5h (thin plate chromatography tracking reaction until the reaction is complete), after the reaction is finished, the solvent is removed by rotary evaporation of the reaction mixture, and crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain a target product 1a (0.94 g, yellow solid, yield 80%).
The reaction equation is as follows:
example 15
On the basis of example 1, the reaction conditions such as acid catalyst, solvent and reaction time were optimized, and the specific optimization results are shown in the following table 1:
TABLE 1
Catalyst (30 mol%) Solvent (0.1M) Time (h) Yield (%)
1 TsOH·H 2 O DCE 24 -
2 TsOH·H 2 O Toluene 24 -
3 TsOH·H 2 O THF 24 -
4 TsOH·H 2 O HFIP 5 96
5 TfOH HFIP 5 77
6 TsOH·H 2 O DCE:HFIP＝1:1 13 86
7 TsOH·H 2 O DCE:HFIP＝2:1 10 88
As can be seen from Table 1, tsOH.H 2 O is used as a catalyst, a target product cannot be obtained in the solvent DCE, toluene, THF, and the target product can only react in the solvent containing HFIP; the target product can be obtained in the mixed solvent of DCE and HFIP, but the reaction time is longer; using HFIP as the solvent can shorten the reaction time and can obtain the highest yield. Replacement of the catalyst with TfOH in HFIP solvent also gives good yields.
Therefore, the application provides a high-efficiency method for synthesizing 1-trifluoromethyl cyclopentadiene [ b ] indole compound, which adopts a nonmetallic catalyst and has the advantages of simple operation, wide substrate range, high yield and the like.
Example 16
Gibberella is a worldwide important plant pathogen which damages crops and can cause symptoms such as seedling blight, spike rot, stem basal rot, stalk rot and the like of crops. Botrytis cinerea, ash mold, also known as Botrytis cinerea, is a broad-host-range, capable of causing cataplexy, fallen leaves, flower rot, rotten fruits and rotten pits of various plant seedlings, fruits and storage organs. The surface layer of the affected part produces a large number of gray mold layers (conidiophores and conidia) when wet, called gray mold. The plant seed is widely distributed in the air, so that field crops can be infected, and huge losses can be caused to the postharvest stage of plants.
The compounds 1a to 1m prepared in examples 1 to 13 were subjected to test experiments for inhibition of sclerotinia and gray mold, and the specific procedures are as follows:
the plant fungi used in this experiment were the laboratory strains gibberella and botrytis cinerea that were stored at 4 ℃. The culture medium is potato agarose culture medium (PDA for short). PDA culture medium formula comprises potato (peeled) 200g, glucose 20g, agar 15g, distilled water 1000mL, and preparation method: cleaning potato, peeling, weighing 200g, cutting into small pieces, adding water, boiling for 20-30 min, tearing by a glass rod, filtering with eight layers of gauze, adding 15-20 g of agar according to experimental requirements, adding 20g of glucose, stirring uniformly, cooling slightly after full dissolution, supplementing water to 1000mL, sterilizing at 121 ℃ for 30 min, and cooling for later use.
The experimental method comprises the following steps: the growth rate method is adopted.
(1) Firstly, 2 plant fungi are cultured on a PDA flat plate at 25 ℃ for about 3-6 days for standby;
(2) Heating and dissolving a PDA culture medium, cooling to 45-50 ℃, adding a compound (1 a) to be tested with the concentration of 50mg/L to prepare a culture medium containing 50mg/L of liquid medicine, and respectively pouring the culture medium into a culture dish for cooling, wherein Chlorothalonil and thiram (Tetramethylthiuram Disulfide) are used as positive controls;
(3) Taking circular fungus cakes (with the diameter of 0.50 cm) from the edge of hypha of each strain cultivated for 6d (the growth condition is as consistent as possible) by using a puncher through aseptic operation procedures, picking the circular fungus cakes to the center of a medicine-containing flat plate by using an inoculating needle, and then inverting the culture dish to be cultivated in an incubator (28 ℃);
(4) Observing and measuring the growth condition of hyphae at different times after treatment, measuring the diameter by adopting a crisscross method, processing data, and calculating the inhibition rate;
(5) Inhibition ratio (%) = (control hypha diameter-treated hypha diameter)/(control hypha diameter-0.5) ×100;
(6) Each treatment was repeated 3 times.
The test results are shown in Table 2.
TABLE 2
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As can be seen from the data in table 2, the compounds have certain inhibition activity on plant pathogenic fungi of gibberella and botrytis cinerea (also called botrytis cinerea), wherein the activity of a compound 1e with bromine substitution at the position of indole C5 and a compound 1f with iodine substitution at the position of indole C5 is best, and the inhibition effect of the compounds 1e and 1f on gibberella is obviously stronger than that of positive controls of thiram and chlorothalonil; and the inhibition effect of the compounds 1e and 1f on the gray mold is obviously stronger than that of positive control thiram and slightly weaker than that of chlorothalonil.
It should be noted that the above embodiments are only for illustrating the technical solution of the present application and not for limiting the same, and although the present application has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present application may be modified or substituted without departing from the spirit and scope of the technical solution of the present application, which is intended to be covered in the scope of the claims of the present application.

Claims (10)

1. A 1-trifluoromethyl cyclopentadiene [ b ] indole compound characterized in that: the structural formula of the compound is shown as formula (I):
wherein R is 1 、R 2 、R 3 R is a group independent of each other 1 One of hydrogen, halogen, ester group, methoxy, methyl, aldehyde group, benzyloxy, pivaloyloxy, allyloxy, methyl acrylate group and phenyl group;
R 2 one selected from C1-C6 straight-chain alkyl;
R 3 selected from one of phenyl and halogen substituted phenyl.
2. The process for producing a 1-trifluoromethylcyclopentadiene [ b ] indole compound according to claim 1, wherein: the method comprises the steps of taking a compound shown in a formula (II) as a raw material, and reacting in a solvent at normal temperature under the catalysis of a Bronsted acid catalyst to obtain the compound shown in the formula (I);
wherein R in formula (II) 1 、R 2 、R 3 And R in formula (I) 1 、R 2 、R 3 The correspondence is consistent.
3. The process for producing a 1-trifluoromethylcyclopentadiene [ b ] indole compound according to claim 2, wherein: the bronsted acid catalyst is selected from p-toluenesulfonic acid monohydrate or trifluoromethanesulfonic acid.
4. A process for the preparation of a 1-trifluoromethyl-cyclopentadiene [ b ] indole compound according to claim 2 or 3, wherein: the molar ratio of the Bronsted acid catalyst to the compound shown in the formula (II) is 0.1-0.3:1.
5. The process for producing a 1-trifluoromethylcyclopentadiene [ b ] indole compound according to claim 4, wherein: the concentration of the compound shown in the formula (II) in the solvent is 0.05-0.2 mol/L.
6. The process for producing a 1-trifluoromethylcyclopentadiene [ b ] indole compound according to claim 5, wherein: the concentration of the compound shown in the formula (II) in the solvent is 0.1mol/L.
7. The process for producing a 1-trifluoromethylcyclopentadiene [ b ] indole compound according to claim 5 or 6, wherein: the solvent is hexafluoroisopropanol or a mixed solvent of dichloroethane and hexafluoroisopropanol.
8. The process for producing a 1-trifluoromethylcyclopentadiene [ b ] indole compound according to claim 7, wherein: the volume ratio of dichloroethane to hexafluoroisopropanol is 1-2:1.
9. A process for the preparation of 1-trifluoromethylcyclopentadiene [ b ] indole compounds according to any one of claims 2, 3, 5, 6, 8, wherein: the reaction is carried out at normal temperature for 4 to 24 hours.
10. Use of a 1-trifluoromethyl-cyclopenta [ b ] indole compound according to claim 1 for inhibiting gibberella and/or botrytis; or in the preparation of medicines for inhibiting wheat scab and/or tomato gray mold.
CN202310829136.2A 2023-07-07 2023-07-07 1-trifluoromethyl cyclopentadiene [ b ] indole compound and preparation method and application thereof Pending CN117088803A (en)

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