C2 spiro indolone compound as well as preparation method and application thereof

Abstract

The invention discloses a C2 spiro indolone compound as well as a preparation method and application thereof, simple and easily available N-indole connected o-alkynyl nitrobenzene compound is used as a raw material, and the C2 spiro indolone compound is obtained by heating reaction in a solvent under the catalysis of a cheap metal copper catalyst. The C2 spiro indolone compound prepared by the invention has a relatively good inhibition effect on phytopathogen, and can be used for preventing and treating botrytis cinerea, sclerotinia rot of colza and botryosphaeria dothidea; the preparation method does not need to use an expensive metal catalyst, does not need an additional reducing agent, and has the advantages of simple operation, high chemical selectivity, wide reaction substrate range and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic compound synthesis, and particularly relates to a C2 spirocyclic indolone compound, a preparation method and application thereof. BACKGROUND

[0002] C2 spirocyclic indolone compounds exist widely in natural products and drug molecules, and have been proved to have various biological activities such as antibacterial, anticholinesterase, insecticidal and potent opioid agonist. Austamide is isolated from the metabolite of Aspergilus ustus, and has certain antibacterial, insecticidal and insect repellent activities (Tetrahedron Lett., 1971, 36, 3331-3334); Fluorocarpamin is a spirocyclic indole alkaloid isolated from the plant of Catharanthus roseus (Planta. Med., 1983, 49, 124-125); Brevianamide A is isolated from the fungus Penicilium brevicompactum, and has good insecticidal activity on Spodoptera frugiperda and Heliothis virescens (J. Chem. Soc. D., 1969, 12, 644-645; Tetrahedron, 1970, 26, 2329-2344); Monoterpenoid indole alkaloids Ervaoffine B and Iboluteine extracted from the plant of Ervatamia have wide pharmacological effects such as anti-addiction, antifungal, antilipase and anti-HIV-1 activities (J. Nat. Prod. 2014, 77, 1839-1846); Melokhanine E is a natural product isolated from the plant of Kopsia Melokhanine, and has antibacterial activity, and shows significant antibacterial activity on various gram-positive and gram-negative bacteria, Pseudomonas aeruginosa, Microsporon canis and the like (J. Nat. Prod. 2016, 79, 2158-2166).

[0003]

[0004] In addition, these skeletons have also been proven to be versatile molecular building blocks for the synthesis of other members of the indole alkaloid natural products. At present, there are many methods for synthesizing C2 spirooxindole compounds, most of which rely on oxidative rearrangement or de-annulation cyclization of corresponding indole derivatives, [3+2] cycloaddition of N-heterocyclic carbene (NHC) catalyzed azapine and enal, phosphine / protic acid synergistic cascade cyclization reaction of 2-nitrophenyl propionamide, high-valence iodine-mediated cascade oxidation cyclization reaction, and rhodium or ruthenium-catalyzed C(sp2)-H activation tandem cyclization reaction. However, most of these reactions require noble metal catalysts, complicated preparation of substrates, addition of certain stoichiometric oxidants and / or additives, and narrow substrate range.

[0005] Therefore, it is of great significance to rapidly and efficiently construct C2 spirooxindole compounds from simple and readily available raw materials. SUMMARY

[0006] This section is intended to summarize some aspects of the embodiments of the present application and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of the specification of the present application in order to avoid obscuring the purpose of this section, the abstract and the title, and such simplifications or omissions cannot be used to limit the scope of the present application.

[0007] In view of the above and / or problems existing in the prior art, the present application is proposed.

[0008] One of the purposes of the present application is to provide a C2 spirooxindole compound which has good inhibitory effect on plant pathogenic fungi such as Botrytis cinerea, Sclerotinia sclerotiorum and Botryosphaeria dothidea, and can be potentially applied to the prevention and control of plant pathogenic fungi.

[0009] To solve the above technical problems, the present application provides the following technical scheme: a C2 spirooxindole compound, the structure of the compound is shown as formula (I):

[0010]

[0011] wherein, R 1 is selected from one of hydrogen, methyl, halogen or aldehyde group;

[0012] R 2 is selected from one of hydrogen, methyl, benzyl, CH2CH2CO2Me, CH2CH2OAc or CH2CH2NHBoc;

[0013] R 3 is selected from one of hydrogen, halogen, methyl, ethyl, methoxy, aldehyde group or methoxy ester group.

[0014] Another object of the present application is to provide a preparation method of the C2 spirocyclic indolinone compound as described above, comprising, taking the o-alkynyl nitrobenzene compound shown in formula (II) as raw material, heating reaction in a solvent under the catalysis of a metal catalyst to obtain the compound shown in formula (I).

[0015] The compound is shown in formula (II):

[0016]

[0017] In formula (II), R 1 , R 2 , R 3 correspond to R 1 , R 2 , R 3 in formula (I).

[0018] As a preferred scheme of the preparation method of the C2 spirocyclic indolinone compound of the present application, the metal catalyst is selected from one of indium tribromide, copper triflate, cuprous triflate, tetra(acetonitrile)cuprous triflate, tetra(acetonitrile)cuprous tetrafluoroborate or tetra(acetonitrile)cuprous hexafluorophosphate.

[0019] As a preferred scheme of the preparation method of the C2 spirocyclic indolinone compound of the present application, the molar ratio of the metal catalyst to the compound shown in formula (II) is 0.1-0.2:1.

[0020] As a preferred scheme of the preparation method of the C2 spirocyclic indolinone compound of the present application, the solvent is selected from one of dichloroethane, toluene, fluorobenzene, chlorobenzene or trifluorotoluene.

[0021] As a preferred scheme of the preparation method of the C2 spirocyclic indolinone compound of the present application, the concentration of the compound shown in formula (II) in the solvent is 0.1 mol / L.

[0022] As a preferred scheme of the preparation method of the C2 spirocyclic indolinone compound of the present application, the heating reaction is carried out at a temperature of 25-100℃ for 3-24 hours.

[0023] Another object of the present application is to provide the application of the C2 spirocyclic indolinone compound as described above in inhibiting plant pathogenic fungi or preparing a medicine for inhibiting plant pathogenic fungi, characterized in that the plant pathogenic fungi are one or more of Botrytis cinerea, Sclerotinia sclerotiorum and Botryosphaeria dothidea.

[0024] Compared with the prior art, the present application has the following beneficial effects:

[0025] The C2 spiro indole ketone compound prepared by the application has good inhibitory effect on plant pathogenic fungi, and can be used for prevention and treatment of tomato gray mold, oilseed rape sclerotinia disease and grape cavity disease, has the potential of developing new antibacterial agents, and is used for prevention and treatment of agricultural or forestry plant fungal diseases.

[0026] The preparation method of the application does not need to use expensive metal catalysts, nor additional reducing agents, has the advantages of simple operation, high chemical selectivity and wide range of reaction substrates. BRIEF DESCRIPTION OF DRAWINGS

[0027] In order to more clearly illustrate the technical solutions of the embodiments of the application, the drawings needed in the embodiment description will be briefly introduced below, and obviously, the drawings in the following description are only some embodiments of the application, and other drawings can also be obtained according to these drawings without creative labor for those skilled in the art. Among them:

[0028] Figure 1 The nuclear magnetic resonance hydrogen spectrum of the target product 1a prepared in the embodiment 1 of the application;

[0029] Figure 2 The nuclear magnetic resonance carbon spectrum of the target product 1a prepared in the embodiment 1 of the application;

[0030] Figure 3 The single crystal diffraction diagram of the target product 1a prepared in the embodiment 1 of the application;

[0031] Figure 4 The reaction mechanism schematic diagram represented by the raw material 2a in the embodiment 1 of the application;

[0032] Figure 5 The in vitro experiment (plate) schematic diagram of the oilseed rape sclerotinia disease fungus of the target products 1a, 1m, 1q and 1r of the application. DETAILED DESCRIPTION

[0033] In order to make the above-mentioned purposes, features and advantages of the application more obvious and easy to understand, the specific embodiments of the application will be described in detail below.

[0034] In the following description, many specific details are set forth in order to provide a thorough understanding of the application, but the application can also be implemented in other ways different from those described herein, and those skilled in the art can make similar generalizations without departing from the connotation of the application, therefore the application is not limited by the specific embodiments disclosed below.

[0035] Second, the term “one embodiment” or “an embodiment” as may appear in various places of the specification are not necessarily all referring to the same embodiment, nor are they necessarily mutually exclusive or alternative implementations.

[0036] The starting material used in the examples was prepared in one step by Sonogashira coupling of known 4-pentynyl-N-indole amide (J. Org. Chem. 2016, 81, 11444-11453; Org. Chem. Fron. 2023, 10, 140-149) with o-nitroiodobenzene to give the N-indole linked o-alkynyl nitrobenzene compound (compound of formula II). Other starting materials used in the examples were purchased commercially unless otherwise specified.

[0037] Example 1

[0038] A 10 mL vial was charged with N-indole linked o-alkynyl nitrobenzene compound 2a (0.2 mmol), tetrakis(acetonitrile)copper(I) triflate catalyst (0.04 mmol), and chlorobenzene (2 mL) was added under nitrogen atmosphere. The reaction mixture was heated at 100 °C for 4 h. After cooling to room temperature, the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 12 / 1 ~ 6 / 1, V / V) to give the target product 1a (42.3 mg, yellow solid, yield 70%).

[0039] The reaction scheme is as follows:

[0040]

[0041] The target product 1a was characterized, and the proton nuclear magnetic resonance spectrum is as shown in Figure 1 , and the carbon nuclear magnetic resonance spectrum is as shown in Figure 2 :

[0042] 1 H NMR (600 MHz, CDC13) δ 8.46 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 6.94 - 6.86 (m, 2H), 6.30 (s, 1H), 5.16 (s, 1H), 3.53 - 3.45 (m, 1H), 2.82 (dt, J = 17.7, 5.4 Hz, 1H), 2.30 (dt, J = 11.4, 5.5 Hz, 1H), 2.25 - 2.18 (m, 1H); 13C NMR (150 MHz, CDC13) δ 199.4, 168.2, 160.3, 138.0, 136.0, 135.4, 128.9, 125.6, 125.1, 124.2, 120.5, 120.1, 118.5, 116.5, 112.6, 104.9, 63.6, 30.4, 29.5.

[0043] The structure of the target product 1a was confirmed by single crystal diffraction, as shown in Figure 3

[0044] The reaction mechanism of the present application is shown in Figure 4

[0045] First, the carbon-carbon triple bond in 2a coordinates with copper (I) catalyst, and the attack of nitro group on the metal-activated alkyne occurs intramolecular 6-endo-dig cyclization to obtain intermediate A. Subsequently, intramolecular redox gives α-carbonyl copper carbene intermediate B. The chemoselective intramolecular nucleophilic oxygen attack of nitroso group on copper carbene intermediate B gives benzisoxazole intermediate C. Subsequently, under copper catalysis, benzisoxazole ring opening forms copper-nitrochrysene intermediate D, and D adds to the ketone carbonyl to form oxaziridine intermediate E or its electronic isomer nitroxide F. Under the catalysis of copper catalyst, oxaziridine intermediate E undergoes ring opening nucleophilic addition or spirocyclization of nitroxide F to generate C2 spirocyclization intermediate G with N-OH. Finally, the N-O bond is broken by copper catalyst reduction to obtain the final product 1a.

[0046] Example 2

[0047] Take 10 mL of ajar, add N-indole connected adjacent alkyne nitrobenzene compound 2b (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol) in turn, add chlorobenzene (2 mL) under nitrogen atmosphere, and react at 100°C for 4 hours. After cooling to room temperature, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 8 / 1 ~ 5 / 1, V / V) to obtain the target product 1b (31.4 mg, yellow solid, yield 40%).

[0048] The reaction equation is as follows:

[0049]

[0050] The target product 1b is characterized as follows:

[0051] 1 ​​H NMR (600 MHz, CDC13) δ 8.54 (d, J = 8.2 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.46 (td, J = 7.1, 1.2 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.22 (td, J = 7.1, 0.7 Hz, 1H), 7.13 - 7.06 (m, 3H), 6.89 (t, J = 7.5 Hz, 1H), 6.87 - 6.82 (m, 2H), 6.66 (d, J = 8.2 Hz, 1H), 4.95 (s, 1H), 3.91 (d, J = 16.4 Hz, 1H), 3.58 (d, J = 16.4 Hz, 1H), 3.33 (ddd, J = 17.4, 8.9, 4.8 Hz, 1H), 2.85 (ddd, J = 17.4, 7.7, 4.7 Hz, 1H), 2.32 (ddd, J = 12.9, 7.7, 4.9 Hz, 1H), 2.20 (ddd, J = 13.6, 9.0, 4.7 Hz, 1H); 13 C NMR (150 MHz, CDC13) δ 199.8, 168.2, 159.7, 139.6, 137.9, 134.9, 130.7, 130.4, 128.3, 127.6, 126.0, 125.6, 125.2, 124.1, 120.1, 119.3, 119.1, 118.1, 116.7, 112.8, 64.0, 31.9, 29.6, 29.5.

[0052] Example 3

[0053] Take 10 mL of ajar, add N-indole connected to the adjacent alkyne nitrobenzene compound 2c (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol), add chlorobenzene (2 mL) under nitrogen atmosphere, react at 100°C for 4 hours. After cooling to room temperature, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 9 / 1 ~ 5 / 1, V / V) to obtain the target product 1c (51.3 mg, yellow solid, yield 66%).

[0054] The reaction equation is as follows:

[0055]

[0056] The above target product 1c is characterized:

[0057] 1H NMR (600 MHz, CDC13) δ 8.47 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.51 (td, J = 7.1, 1.2 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.30 (td, J = 7.2, 1.0 Hz, 1H), 7.23 (td, J = 7.2, 0.7 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.13 (s, 1H), 3.53 (s, 3H), 3.27 (ddd, J = 17.4, 8.6, 5.0 Hz, 1H), 2.84 (ddd, J = 17.5, 7.9, 4.9 Hz, 1H), 2.71 - 2.60 (m, 2H), 2.50 (dt, J = 16.1, 8.0 Hz, 1H), 2.40 (ddd, J = 16.3, 8.6, 5.8 Hz, 1H), 2.30 (ddd, J = 13.1, 7.9, 5.0 Hz, 1H), 2.21 (ddd, J = 13.5, 8.6, 4.9 Hz, 1H); 13 C NMR (150 MHz, CDC13) δ 200.3, 173.4, 168.3, 160.3, 138.1, 134.9, 130.4, 129.3, 125.5, 125.3, 124.0, 119.9, 119.0, 118.4, 117.6, 116.8, 112.8, 64.0, 51.6, 33.3, 31.8, 29.6, 19.2.

[0058] Example 4

[0059] Take 10 mL of ajar, add N-indole connected to the adjacent alkyne nitrobenzene compound 2d (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol), add chlorobenzene (2 mL) under nitrogen atmosphere, react at 100°C for 4 hours. After cooling to room temperature, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 4 / 1 ~ 2 / 1, V / V) to obtain the target product Id (36.5 mg, brown solid, yield 57%).

[0060] The reaction equation is as follows:

[0061]

[0062] The above target product Id is characterized:

[0063] 1H NMR (600 MHz, CDC13) δ 8.20 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.51 (td, J = 7.3, 0.8 Hz, 1H), 7.21 (td, J = 8.2, 5.4 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.91 - 6.87 (m, 2H), 6.45 (s, 1H), 5.25 (s, 1H), 3.54 (ddd, J = 17.5, 10.0, 6.2 Hz, 1H), 2.86 (dt, J = 17.8, 5.2 Hz, 1H), 2.36 - 2.27 (m, 2H); 13 C NMR (150 MHz, CDC13) δ 199.2, 168.3, 160.3, 156.2, 154.6, 138.1, 137.4 (d, J = 8.8 Hz), 136.1 125.9 (d, J = 7.2 Hz), 125.6, 120.2, 118.2, 117.7 (d, J = 21.8 Hz), 112.5, 109.5 (d, J = 18.4 Hz), 100.4, 63.5, 30.2, 29.4; 19 F NMR (565 MHz, CDC13) δ -121.95 (dd, J = 9.6, 5.4 Hz).

[0064] Example 5

[0065] Take 10 mL of ajar, add N-indole connected to the adjacent alkyne nitrobenzene compound 2e (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol), add chlorobenzene (2 mL) under nitrogen atmosphere, react at 100°C for 4 hours. After cooling to room temperature, remove the solvent by rotary evaporation, and separate the crude product by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 9 / 1 ~ 6 / 1, V / V) to obtain the target product le (32.9 mg, orange solid, yield 52%).

[0066] The reaction equation is as follows:

[0067]

[0068] The above target product le is characterized:

[0069] 1H NMR (600 MHz, CDC13) δ 8.30 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.50 (td, J = 7.3, 0.7 Hz, 1H), 7.10 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.2 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.19 (s, 1H), 5.16 (s, 1H), 3.45 (ddd, J = 17.5, 10.1, 5.5 Hz, 1H), 2.80 (dt, J = 17.7, 5.4 Hz, 1H), 2.38 (s, 3H), 2.28 (dt, J = 11.3, 5.6 Hz, 1H), 2.18 (ddd, J = 13.4, 10.2, 5.1 Hz, 1H); 13 CNMR (150 MHz, CDC13) δ 199.5, 168.0, 160.4, 137.9, 135.9, 133.8, 133.5, 129.1, 126.4, 125.6, 120.4, 120.0, 118.5, 116.0, 112.6, 104.7, 63.6, 30.3, 29.5, 21.3.

[0070] Example 6

[0071] Take 10 mL of ajar, add N-indole connected to the adjacent alkyne nitrobenzene compound 2f (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol), add chlorobenzene (2 mL) under nitrogen atmosphere, react at 100°C for 4 hours. After cooling to room temperature, spin evaporation to remove the solvent, and the crude product is separated by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 8 / 1 ~ 5 / 1, V / V) to obtain the target product If (44.2 mg, green solid, yield 58%).

[0072] The reaction equation is as follows:

[0073]

[0074] The above target product If is characterized:

[0075] 1H NMR (600 MHz, CDC13) δ 8.31 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.54 (td, J = 7.1, 1.2 Hz, 1H), 7.48 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 8.8, 1.9 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.26 (s, 1H), 5.09 (s, 1H), 3.54 (ddd, J = 17.7, 10.5, 5.8 Hz, 1H), 2.85 (dt, J = 17.8, 5.2 Hz, 1H), 2.36 - 2.25 (m, 2H); 13 C NMR (150 MHz, CDC13) δ 199.0, 168.1, 160.3, 138.1, 137.3, 134.1, 130.6, 127.9, 125.7, 123.1, 120.3, 118.3, 117.8, 117.5, 112.6, 104.0, 63.5, 30.4, 29.4.

[0076] Example 7

[0077] Take 10 mL of ajar, add N-indole connected to the adjacent alkyne nitrobenzene compound 2g (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol), add chlorobenzene (2 mL) under nitrogen atmosphere, react at 100°C for 4 hours. After cooling to room temperature, remove the solvent by rotary evaporation, and separate the crude product by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 9 / 1 ~ 6 / 1, V / V) to obtain the target product 1g (23.8 mg, green solid, yield 36%).

[0078] The reaction equation is as follows:

[0079]

[0080] The above target product 1g is characterized:

[0081] 1H NMR (600 MHz, CDC13) δ 9.98 (s, 1H), 8.57 (d, J = 8.6 Hz, 1H), 7.87 (s, 1H), 7.79 (dd, J = 8.6, 1.4 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.56 (td, J = 7.2, 1.1 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.94 (t, J = 7.4 Hz, 1H), 6.46 (s, 1H), 5.23 (s, 1H), 3.61 (dt, J = 17.6, 8.2 Hz, 1H), 2.93 (dt, J = 17.8, 5.1 Hz, 1H), 2.42 - 2.35 (m, 2H); 13 C NMR (150 MHz, CDC13) δ 198.9, 192.1, 168.3, 160.3, 139.0, 138.2, 138.2, 132.7, 129.2, 126.4, 125.8, 123.0, 120.4, 118.2, 116.9, 112.6, 105.1, 63.5, 30.3, 29.5.

[0082] Example 8

[0083] Take 10 mL of ajar, add N-indole connected to the adjacent alkyne nitrobenzene compound 2h (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol), add chlorobenzene (2 mL) under nitrogen atmosphere, react at 100°C for 4 hours. After cooling to room temperature, remove the solvent by rotary evaporation, and separate the crude product by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 8 / 1 ~ 5 / 1, V / V) to obtain the target product 1h (42.4 mg, brown solid, yield 67%).

[0084] The reaction equation is as follows:

[0085]

[0086] The above target product 1h is characterized:

[0087] 1H NMR (600 MHz, CDC13) δ 8.29 (s, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.95 - 6.84 (m, 2H), 6.24 (s, 1H), 5.14 (s, 1H), 3.47 (ddd, J = 17.5, 10.0, 5.5 Hz, 1H), 2.82 (dt, J = 17.7, 5.5 Hz, 1H), 2.45 (s, 3H), 2.30 (dt, J = 11.5, 5.6 Hz, 1H), 2.23 - 2.16 (m, 1H); 13 C NMR (150 MHz, CDC13) δ 199.6, 168.3, 160.3, 137.9, 135.8, 135.3, 135.2, 126.5, 125.6, 125.6, 120.0, 120.0, 118.5, 116.7, 112.6, 104.8, 63.7, 30.3, 29.6, 21.8.

[0088] Example 9

[0089] Take 10 mL of ajar, add N-indole connected to the adjacent alkyne nitrobenzene compound 2i (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol) in turn, add chlorobenzene (2 mL) under nitrogen atmosphere, react at 100°C for 4 hours. After cooling to room temperature, the solvent was removed by rotary evaporation, and the crude product was separated by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 8 / 1 ~ 5 / 1, V / V) to obtain the target product 1i (48.0 mg, light yellow solid, yield 63%).

[0090] The reaction equation is as follows:

[0091]

[0092] The above target product 1i was characterized:

[0093] 1H NMR (600 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.04 (s, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.43 (dd, J = 8.3, 1.2 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.82 (t, J = 7.4 Hz, 1H), 6.42 (s, 1H), 3.26 (ddd, J = 17.6, 8.8, 5.7 Hz, 1H), 2.96 (dt, J = 17.8, 5.7 Hz, 1H), 2.38 - 2.31 (m, 1H), 2.31 - 2.25 (m, 1H); 13 C NMR (150 MHz, DMSO-d6) δ 200.1, 169.2, 161.8, 138.7, 138.5, 135.7, 128.5, 127.3, 125.4, 123.0, 119.0, 118.6, 117.7, 117.5, 113.0, 104.0, 63.8, 29.7, 29.5.

[0094] Example 10

[0095] Take 10 mL of ajar, add N-indole connected to the adjacent alkyne nitrobenzene compound 2j (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol), add chlorobenzene (2 mL) under nitrogen atmosphere, react at 100 °C for 4 hours. After cooling to room temperature, remove the solvent by rotary evaporation, and separate the crude product by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 9 / 1 ~ 6 / 1, V / V) to obtain the target product 1j (34.8 mg, orange solid, yield 55%).

[0096] The reaction equation is as follows:

[0097]

[0098] The above target product 1j is characterized:

[0099] 1H NMR (600 MHz, CDC13) δ 7.56 (d, J = 7.7 Hz, 1H), 7.47 (td, J = 7.3, 0.8 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.94 - 6.80 (m, 2H), 6.29 (s, 1H), 5.16 (s, 1H), 3.52 - 3.43 (m, 1H), 2.79 (dt, J = 17.0, 5.6 Hz, 1H), 2.63 (s, 3H), 2.29 (dt, J = 11.8, 5.7 Hz, 1H), 2.13 (ddd, J = 13.4, 10.0, 5.3 Hz, 1H); 13 C NMR (150 MHz, CDC13) δ 199.6, 167.7, 160.4, 137.9, 137.5, 135.4, 130.7, 128.4, 127.1, 125.5, 124.6, 119.9, 118.3, 118.2, 112.5, 105.7, 64.1, 30.4, 30.3, 22.9.

[0100] Example 11

[0101] Take 10 mL of ajar, add N-indole connected to the adjacent alkyne nitrobenzene compound 2k (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol), add chlorobenzene (2 mL) under nitrogen atmosphere, react at 100°C for 4 hours. After cooling to room temperature, remove the solvent by rotary evaporation, and separate the crude product by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 12 / 1 ~ 6 / 1, V / V) to obtain the target product 1k (35.0 mg, light yellow solid, yield 52%).

[0102] The reaction equation is as follows:

[0103]

[0104] The above target product 1k is characterized:

[0105] 1H NMR (600 MHz, CDC13) δ 7.62 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.15 (t, J = 7.7 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 6.27 (s, 1H), 5.32 (s, 1H), 3.48 - 3.41 (m, 1H), 2.88 (dt, J = 17.1, 6.1 Hz, 1H), 2.44 - 2.38 (m, 1H), 2.28 - 2.21 (m, 1H); 13 C NMR (150 MHz, CDC13) δ 199.2, 166.6, 160.4, 139.2, 138.1, 133.1, 132.8, 127.3, 125.6, 125.3, 121.8, 120.1, 119.4, 118.6, 112.7, 105.2, 64.1, 30.7, 30.4.

[0106] Example 12

[0107] Take 10 mL of ajar, add N-indole connected to the adjacent alkyne nitrobenzene compound 2l (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol) in turn, add chlorobenzene (2 mL) under nitrogen atmosphere, react at 100°C for 4 hours. After cooling to room temperature, remove the solvent by rotary evaporation, and separate the crude product by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 8 / 1 ~ 6 / 1, V / V) to obtain the target product 1l (41.8 mg, light yellow solid, yield 66%).

[0108] The reaction equation is as follows:

[0109]

[0110] The above target product 1l is characterized:

[0111] 1H NMR (600 MHz, CDC13) δ 8.45 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 6.74 - 6.66 (m, 2H), 6.27 (s, 1H), 5.17 (s, 1H), 3.46 (ddd, J = 17.4, 10.1, 5.5 Hz, 1H), 2.80 (dt, J = 17.7, 5.5 Hz, 1H), 2.37 (s, 3H), 2.27 (dt, J = 11.4, 5.6 Hz, 1H), 2.21 - 2.13 (m, 1H); 13 C NMR (150 MHz, CDC13) δ 198.8, 168.3, 160.9, 149.9, 136.3, 135.3, 128.9, 125.2, 125.0, 124.1, 121.8, 120.5, 116.4, 116.1, 112.6, 104.8, 63.8, 30.4, 29.6, 22.5.

[0112] Example 13

[0113] Take 10 mL of ajar, add N-indole connected to the adjacent alkyne nitrobenzene compound 2m (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol) in turn, add chlorobenzene (2 mL) under nitrogen atmosphere, react at 100°C for 4 hours. After cooling to room temperature, remove the solvent by rotary evaporation, and separate the crude product by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 7 / 1 ~ 5 / 1, V / V) to obtain the target product Im (29.5 mg, red solid, yield 46%).

[0114] The reaction equation is as follows:

[0115]

[0116] The above target product Im is characterized:

[0117] 1H NMR (600 MHz, CDC13) δ 8.45 (d, J = 8.3 Hz, 1H), 7.59 (dd, J = 8.4, 5.7 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.31 (td, J = 7.3, 0.7 Hz, 1H), 7.23 (t, J = 7.3 Hz, 1H), 6.63 - 6.55 (m, 2H), 6.32 (s, 1H), 5.29 (s, 1H), 3.50 (ddd, J = 17.6, 10.4, 5.5 Hz, 1H), 2.82 (dt, J = 17.8, 5.3 Hz, 1H), 2.32 (dt, J = 13.2, 5.5 Hz, 1H), 2.23 (ddd, J = 13.4, 10.5, 5.2 Hz, 1H); 13 C NMR (150 MHz, CDC13) δ 197.4, 170.6, 168.9, 168.1, 161.7 (d, J = 14.3 Hz), 135.5 (d, J = 11.1 Hz), 128.8, 128.1 (d, J = 12.6 Hz), 125.3, 124.3, 120.6, 116.5, 114.8, 108.8 (d, J = 24.8 Hz), 105.1, 98.9 (d, J = 26.1 Hz), 64.3, 30.3, 29.4; 19 F NMR (565 MHz, CDC13) δ

[0118] -97.61 (td, J = 9.2, 5.7 Hz).

[0119] Example 14

[0120] Take 10 mL of ajar, add N-indole connected to the adjacent alkyne nitrobenzene compound 2n (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol), add chlorobenzene (2 mL) under nitrogen atmosphere, react at 100°C for 12 hours. After cooling to room temperature, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 9 / 1 ~ 6 / 1, V / V) to obtain the target product In (48.8 mg, light yellow solid, yield 64%).

[0121] The reaction equation is as follows:

[0122]

[0123] The above target product In is characterized:

[0124] 1H NMR (600 MHz, CDC13) δ 8.50 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.35 (td, J = 7.3, 1.0 Hz, 1H), 7.28 - 7.24 (m, 1H), 7.16 (d, J = 1.2 Hz, 1H), 7.07 (dd, J = 8.2, 1.4 Hz, 1H), 6.40 (s, 1H), 4.98 (s, 1H), 3.63 - 3.55 (m, 1H), 2.89 (dt, J = 17.8, 5.2 Hz, 1H), 2.42 - 2.31 (m, 2H); 13 C NMR (150 MHz, CDC13) δ 198.1, 168.0, 160.5, 135.4, 135.3, 133.5, 128.7, 126.7, 125.3, 124.3, 123.7, 120.6, 117.2, 116.5, 115.5, 105.1, 64.0, 30.3, 29.4.

[0125] Example 15

[0126] Take 10 mL of ajar, add N-indole connected to the adjacent alkyne nitrobenzene compound 2o (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol), add chlorobenzene (2 mL) under nitrogen atmosphere, react at 100°C for 4 hours. After cooling to room temperature, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 9 / 1 ~ 6 / 1, V / V) to obtain the target product lo (39.6 mg, yellow solid, yield 60%).

[0127] The reaction equation is as follows:

[0128]

[0129] The above target product lo is characterized:

[0130] 1 H NMR (600 MHz, CDC13) δ 8.50 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.35 (td, J = 7.3, 1.0 Hz, 1H), 7.28 - 7.24 (m, 1H), 7.16 (d, J = 1.2 Hz, 1H), 7.07 (dd, J = 8.2, 1.4 Hz, 1H), 6.40 (s, 1H), 4.98 (s, 1H), 3.63 - 3.55 (m, 1H), 2.89 (dt, J = 17.8, 5.2 Hz, 1H), 2.42 - 2.31 (m, 2H); 13C NMR (150 MHz, CDC13) δ 199.3, 191.9, 168.0, 159.9, 143.0, 135.3, 135.1, 128.7, 126.3, 125.3, 124.3, 122.2, 120.7, 120.6, 116.4, 112.6, 105.1, 64.3, 30.1, 29.3.

[0131] Example 16

[0132] Take 10 mL of a flask, add N-indole connected to the adjacent alkyne nitrobenzene compound 2p (0.2 mmol), tetra (acetonitrile) trifluoromethanesulfonic acid cuprous catalyst (0.04 mmol), add chlorobenzene (2 mL) under nitrogen atmosphere, react at 100°C for 4 hours. After cooling to room temperature, the solvent was removed by rotary evaporation, and the crude product was separated by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 7 / 1 ~ 5 / 1, V / V) to obtain the target product Ip (41.1 mg, brown solid, yield 65%).

[0133] The reaction equation is as follows:

[0134]

[0135] The above target product Ip was characterized:

[0136] 1 H NMR (600 MHz, CDC13) δ 8.45 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.33 (dd, J = 8.4, 1.7 Hz, 1H), 7.29 (td, J = 6.3, 1.1 Hz, 1H), 7.21 (td, J = 6.9, 0.9 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.27 (s, 1H), 5.04 (s, 1H), 3.46 (ddd, J = 17.7, 10.0, 5.4 Hz, 1H), 2.82 (dt, J = 17.7, 5.5 Hz, 1H), 2.33 - 2.26 (m, 4H), 2.19 (ddd, J = 13.4, 10.0, 5.2 Hz, 1H); 13 C NMR (150 MHz, CDC13) δ 199.6, 168.3, 158.9, 139.4, 136.3, 135.3, 129.8, 128.9, 125.0, 124.8, 124.1, 120.5, 118.7, 116.5, 112.6, 104.8, 64.0, 30.4, 29.6, 20.5.

[0137] Example 17

[0138] Take 10 mL of a vial, add N-indole connected to the adjacent alkyne nitrobenzene compound 2q (0.2 mmol), tetra(acetonitrile) trifluoromethanesulfonate copper catalyst (0.04 mmol), add chlorobenzene (2 mL) under a nitrogen atmosphere, and react at 100°C for 4 hours. After cooling to room temperature, the solvent was removed by rotary evaporation, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 9 / 1 ~ 5 / 1, V / V) to obtain the target product 1q (30.1 mg, light green solid, yield 47%).

[0139] The reaction equation is as follows:

[0140]

[0141] The above target product 1q was characterized:

[0142] 1 H NMR (600 MHz, CDCl3) δ 8.49 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.34 (td, J = 7.2, 1.0 Hz, 1H), 7.30 (d, J = 7.9 Hz, 2H), 7.27 - 7.23 (m, 1H), 6.96 - 6.91 (m, 1H), 6.37 (s, 1H), 4.84 (s, 1H), 3.52 (ddd, J = 17.7, 10.1, 5.5 Hz, 1H), 2.90 (dt, J = 17.8, 5.5 Hz, 1H), 2.39 (dt, J = 13.2, 5.7 Hz, 1H), 2.31 (ddd, J = 13.4, 10.1, 5.2 Hz, 1H); 13 CNMR (150 MHz, CDCl3) δ 199.1, 168.1, 157.9, 156.9, 156.3, 135.5 (d, J = 30.0 Hz), 128.8, 126.0 (d, J = 25.5 Hz), 125.3, 124.3, 120.6, 119.2 (d, J = 7.3 Hz), 116.5, 113.9 (d, J = 7.5 Hz), 110.4 (d, J = 22.7 Hz), 105.0, 64.8, 30.4, 29.5; 19 F NMR (377 MHz, CDCl3) δ -122.45 - -123.07 (m).

[0143] Example 18

[0144] Take 10 mL of a tomato-shaped bottle, add N-indole-attached o-alkynyl nitrobenzene compound 2r (0.2 mmol), tetra(acetonitrile) trifluoromethanesulfonate copper catalyst (0.04 mmol) in turn, add chlorobenzene (2 mL) under a nitrogen atmosphere, and react at 100°C for 4 hours. After cooling to room temperature, the solvent was removed by rotary evaporation, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 8 / 1 ~ 5 / 1, V / V) to obtain the target product 1r (40.5 mg, white solid, yield 64%).

[0145] The reaction equation is as follows:

[0146]

[0147] The above target product 1r was characterized:

[0148] 1 H NMR (600 MHz, CDCl3) δ 8.47 (d, J = 8.3 Hz, 1H), 7.40-7.34 (m, 2H), 7.30 (t, J = 7.7 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 7.3 Hz, 1H), 6.32 (s, 1H), 5.02 (s, 1H), 3.59-3.49 (m, 1H), 2.82 (dt, J = 17.7, 5.2 Hz, 1H), 2.54 (s, 3H), 2.31 (dt, J = 13.0, 5.4 Hz, 1H), 2.22 (ddd, J = 13.3, 10.7, 5.2 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 199.9, 168.3, 160.8, 141.1, 137.3, 136.4, 135.4, 128.9, 125.0, 124.1, 121.6, 120.4, 116.5, 116.4, 109.7, 104.8, 63.4, 30.5, 29.5, 18.2.

[0149] Example 19

[0150] To verify the practicability of the present application, a gram-scale scale-up experiment was also carried out. When N-indole-attached o-alkynyl nitrobenzene compound 2a was scaled up to 4 mmol (1.273 g), the expected product was still obtained in a yield of 58%, fully demonstrating the practicability of the present application.

[0151] Into a 100 mL vial, N-indole linked o-alkynyl nitrobenzene compound 2a (4 mmol, (1.273 g), tetrakis(acetonitrile)copper(I) trifluoromethanesulfonate (0.8 mmol), chlorobenzene (40 mL) was added under nitrogen atmosphere, the reaction was carried out at 100 °C for 9 hours (thin plate chromatography to track the reaction until the reaction was complete), after the reaction was completed, the solvent was removed by rotary evaporation, and the crude product was separated by silica gel column chromatography (eluent was petroleum ether: ethyl acetate = 12 / 1 ~ 6 / 1, V / V) to obtain the target product 1a (0.7 g, yellow solid, yield 58%).

[0152] The reaction equation is as follows:

[0153]

[0154] Example 20

[0155] On the basis of Example 1, the reaction conditions such as the type of metal catalyst, the catalyst loading, and the reaction solvent were optimized, and the specific optimization results are shown in Table 1:

[0156]

[0157] Table 1

[0158] Catalyst (x mol%) Solvent (0.1 M) Temperature Reaction time Yield (%) 1 [Cu(OTf)2(10 mol %)] Dichloroethane 80 12h 52 2 [Cu(OTf)2(20 mol %)] Dichloroethane 80 8h 53 3 InBr3 Dichloroethane 80 8h 38 4 [Cu(OTf)2(20 mol %)] Toluene 100 3h 42 5 [Cu(OTf)2(20 mol %)] Fluorobenzene 100 4h 55 6 [Cu(OTf)2(20 mol %)] Chlorobenzene 100 3h 59 7 [Cu(OTf)2(20 mol %)] Trifluorotoluene 100 6h 54 8 CuOTf (20 mol%) Chlorobenzene 100 8h 65 9 [Cu(MeCN)4]OTf (20 mol%)]] Chlorobenzene 100 5h 70 10 [Cu(MeCN)4]PF6(20 mol %) Chlorobenzene 100 5h 31 11 [Cu(MeCN)4BF4(20 mol %)] Chlorobenzene 100 5h 42 12 [Cu(MeCN)4OTf (20 mol %)] Chlorobenzene 25 24h -

[0159] As can be seen from Table 1, the yield is increased when the catalyst loading is increased; the yield is the highest when chlorobenzene is used as the solvent; the yield is the highest when tetrakis(acetonitrile)copper(I) trifluoromethanesulfonate is used as the catalyst under the conditions of chlorobenzene as the solvent, 100 °C, and 20 mol% catalyst loading; the yield is reduced when the catalyst anion trifluoromethanesulfonate is replaced by hexafluorophosphate or tetrafluoroborate; the reaction does not occur when the temperature is reduced to room temperature and the reaction time is 24 hours.

[0160] Further, the optimal reaction conditions obtained are as follows: tetrakis(acetonitrile)copper(I) trifluoromethanesulfonate is used as the catalyst under the conditions of 20 mol% catalyst loading, chlorobenzene as the solvent, and 100 °C under nitrogen atmosphere.

[0161] Example 21

[0162] Botrytis cinerea (B.c), also known as gray mold, is a broad-host plant pathogen that can cause wilting, defoliation, flower rot, fruit rot, and cellar rot of various plant seedlings, fruits, and storage organs. A large amount of gray mold (conidiophore and conidium) is produced on the surface of the diseased part under humid conditions, which is called gray mold disease. The characteristics of fast reproduction rate, large genetic variation, and high adaptability have brought great impact on the prevention and control of the disease.

[0163] Sclerotinia sclerotiorum (S.s), also known as sclerotinia stem rot, is an important disease of rapeseed in China, which is caused by Sclerotinia sclerotiorum. The disease mainly harms stems, leaves, flowers, silique and seeds of rapeseed. The host range of the pathogen is very wide, which can infect various plants. In addition to various cruciferous plants, common hosts also include lettuce, sunflower, carrot, soybean, broad bean and pea.

[0164] Botryosphaeria dothidea (B.d) belongs to Botryosphaeria. The fungi of this genus are widely distributed in the world and have a very wide host range. They can cause branch dieback, canker, gum flow and fruit rot of various trees and fruits, and also cause root rot leading to the death of the whole tree. The diseases caused by Botryosphaeria have caused serious harm and economic loss, including degradation of timber quality, reduction of economic forest yield, fruit rot and quality deterioration.

[0165] Further, it is of great significance to effectively control these diseases.

[0166] Further, the compounds 1a-1r prepared in Examples 1-18 were subjected to antibacterial activity determination by mycelial growth rate inhibition method. Different compounds were weighed and dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mg / mL drug solution, which was filtered through a 0.22 μm sterile filter membrane under sterile conditions and added to a sterilized PDA medium to prepare a drug-containing medium with a concentration of 50 mg / L. A 5 mm diameter fungus cake was taken from the edge of the culture for 3-7 days, inoculated in the center of the PDA plate containing different drug solutions, and the PDA plate without drug solution was used as a control. Each treatment was set up in triplicate. The mycelium was cultured at 28°C. After 3-7 days, the colony diameter was determined by cross method, and the mycelial growth inhibition rate was calculated. Each treatment was set up in triplicate. The calculation formula is as follows:

[0167]

[0168] Further, the mycelial growth rate inhibition method was used to determine the antibacterial activity of different compounds on Botrytis cinerea (B.c), Sclerotinia sclerotiorum (S.s) and Botryosphaeria dothidea (B.d), and Tetramethylthiuram Disulfide (Thiram) and Chlorothalonil (Chlorothalonil) were used as positive controls. The mycelial growth inhibition rate was calculated, and the results are shown in Table 2.

[0169] Table 2 In vitro activity of target compounds 1a-1r against plant pathogenic fungi at 50 mg / L (inhibition rate %)

[0170]

[0171] It can be concluded from the data in Table 2 that the compounds have good inhibitory activity on plant pathogenic fungi Botrytis cinerea, Sclerotinia sclerotiorum and Botryosphaeria dothidea. For Botrytis cinerea, the inhibitory effect of all compounds except compound 1b is better than that of positive drug thiram, and the inhibitory rate of compounds 1j, 1k, 1p and 1q is more than 80 %; for Sclerotinia sclerotiorum, the inhibitory effect of all compounds except compounds 1b, 1c, 1g and 1i is better than that of positive drugs chlorothalonil and thiram, and the inhibitory rate of compounds 1a, 1m, 1q and 1r is more than 90 %; for Botryosphaeria dothidea, the inhibitory effect of compounds 1e and 1g is close to that of positive drugs chlorothalonil and thiram, and the inhibitory effect of compounds 1d, 1f and 1h is better than that of positive drugs chlorothalonil and thiram.

[0172] Further, compounds 1a, 1m, 1q and 1r have good inhibitory activity on Sclerotinia sclerotiorum, and the EC 50 values of the four compounds are tested, and the test results are shown in Table 3, and the schematic diagram of in vitro experiment (plate) is shown in Figure 1. Figure 5 The concentrations from left to right are 50 mg / L, 25 mg / L, 12.5 mg / L, 6.25 mg / L and 3.125 mg / L.

[0173] Table 3: In vitro antibacterial median effective inhibition concentration (EC 50 )

[0174]

[0175] It can be concluded from the data in Table 3 that the EC 50 values of compounds 1a, 1m, 1q and 1r on Sclerotinia sclerotiorum are lower than those of positive controls chlorothalonil and thiram, and the EC 50 value of compound 1r is as low as 0.164 mg / L.

[0176] The C2 spirocyclic indole ketone compound prepared in the application has good inhibitory effect on plant pathogenic fungi, and can be used for prevention and treatment of Botrytis cinerea, Sclerotinia sclerotiorum and Botryosphaeria dothidea; and the inhibitory rate of part of the compounds on Sclerotinia sclerotiorum is more than 90 %, and the EC 50 value of compound 1r is as low as 0.164 mg / L, which has the potential to develop a new antibacterial agent for preventing and treating fungal diseases of agricultural or forestry plants.

[0177] The preparation method of the application uses N-indole connected o-alkynyl nitrobenzene compound which is simple and easy to obtain as raw material, uses cheap copper (III) chloride as catalyst, and uses chlorobenzene as solvent to react at 100 DEG C to obtain C2 spirocyclic indole ketone compound. The application does not need to use expensive metal catalyst and additional reducing agent, and has the advantages of simple operation, high chemical selectivity and wide reaction substrate range.

[0178] It should be noted that the above examples are only used to illustrate the technical solutions of the present application but not to limit 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 equivalently replaced, without departing from the spirit and scope of the technical solutions of the present application, and all these modifications and equivalents should be included in the scope of the claims of the present application.

Claims

1. A C2 spirocyclic indole ketone compound, characterized in that: The structural formula of the compound is shown in formula (I): Among them, R 1 One selected from hydrogen, methyl, halogen or aldehyde; R 2 One selected from hydrogen, methyl, benzyl, CH2CH2CO2Me, CH2CH2OAc or CH2CH2NHBoc; R 3 One selected from hydrogen, halogen, methyl, ethyl, methoxy, aldehyde or methoxyester.

2. The method for preparing a C2 spirocyclic indole ketone compound according to claim 1, wherein: include, Using an o-alkynylnitrobenzene compound represented by formula (II) as a raw material, heating the reaction in a solvent under the catalysis of a metal catalyst to obtain a compound represented by formula (I); The structural formula of the compound is shown in formula (II): Among them, R in formula (II) 1 、R 2 、R 3 With R in formula (I) 1 、R 2 、R 3 The corresponding consistency.

3. The method for preparing a C2 spirocyclic indole ketone compound according to claim 2, wherein: The metal catalyst is selected from one of indium tribromide, copper trifluoromethanesulfonate, cuprous trifluoromethanesulfonate, tetrakis(acetonitrile) cuprous trifluoromethanesulfonate, tetrakis(acetonitrile) cuprous tetrafluoroborate or tetrakis(acetonitrile) cuprous hexafluorophosphate.

4. The method for preparing a C2 spirocyclic indole ketone compound according to claim 3, wherein: The molar ratio of the metal catalyst to the compound represented by formula (II) is 0.1-0.2:

1.

5. The method for preparing a C2 spirocyclic indole ketone compound according to claim 2, wherein: The solvent is selected from one of dichloroethane, toluene, fluorobenzene, chlorobenzene or trifluorotoluene.

6. The method for preparing a C2 spirocyclic indole ketone compound according to claim 5, wherein: The concentration of the compound represented by formula (II) in the solvent is 0.1 mol / L.

7. The method for preparing a C2 spirocyclic indole ketone compound according to claim 2, wherein: The heating reaction has a reaction temperature of 25 to 100° C. and a reaction time of 3 to 24 hours.

8. Use of the C2 spirocyclic indole one compound according to claim 1 in inhibiting plant pathogens or preparing a drug for inhibiting plant pathogens, characterized in that: The plant pathogenic bacteria are one or more of tomato gray mold, rapeseed sclerotinia, and Botrytis cinerea.

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