Isoquinolinone and dihydropyrido-[1,2-a]indole spiro compounds, and methods of making and using the same

Abstract

This invention discloses an isoquinolinone dihydropyridine-[1,2-α]indole spirocyclic compound, its preparation method, and its applications, belonging to the field of organic compound synthesis technology. Using N-indole-linked o-alkynyl nitrone compounds as raw materials, this invention employs a two-step, one-pot method to provide a novel synthesis of isoquinolinone dihydropyridine-[1,2-α]indole spirocyclic compounds that are difficult to prepare using conventional methods. This method is based on a rhodium-catalyzed internal redox / dearomatization [3+2] cycloaddition reaction and a cerium ammonium nitrate-promoted oxidative debenzylation / spirocyclic tandem reaction strategy. The method of this invention has advantages such as simple operation, low catalyst loading, broad substrate range, single stereoselectivity, and high yield. The isoquinolinone dihydropyridine-[1,2-α]indole spirocyclic compound prepared by this invention has a certain inhibitory effect on plant pathogens and can be potentially applied to the control of tomato gray mold, wheat scab, and rice sheath blight.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to an isoquinolinone dihydropyridine-[1,2-α]indolespirocyclic compound, its preparation method, and its application. Background Technology

[0002] Isoquinolinones and pyridine indolones are common structural units in natural products and drug molecules. Molecules with such skeletons have excellent biological and pharmaceutical activities and are of great research value in the history of drug development and the treatment of human diseases. Therefore, exploring and developing effective strategies for their efficient construction has always been a hot topic in the field of organic synthetic chemistry research.

[0003] Isoquinolinone alkaloids, possessing an isoquinolinone core structure, are diverse and widely found in nature, such as in lotus leaves and purslane. These compounds exhibit a wide range of biological activities (J. Med. Chem. 2004, 47, 561), including analgesia and anti-inflammation (Tetrahedron Lett., 1998, 39, 3099), antitumor activity (J. Am. Chem. Soc. 2011, 133, 14952), antimalarial activity, antidepressant activity, and antibacterial activity. Many polycyclic compounds containing pyridine indoleone units have shown unique and diverse biological activities (Org. Biomol. Chem. 2022, 20, 2086-2095). For example, strychnine, isolated from the genus *Strychnos*, has been used as a stimulant in medicine and as an insecticide to control rodents due to its potent neurotoxicity (Nature. 2022, 607, 617-622). (±)-Mersicarpine, isolated from plants of the genus *Kopsia*, is a novel translation inhibitor that induces apoptosis and exhibits strong biological and pharmacological activity against the human leukemia cell line HL60, reversibly inhibiting the S phase of the cell cycle (Biosci. Biotechnol. Biochem. 2021, 85, 92-96). In addition to their excellent biological activity, these natural products can also serve as important organic synthetic intermediates for the synthesis of complex natural products and bioactive molecules.

[0004] Currently, there are no reported methods for synthesizing isoquinolinone-dihydropyridine-[1,2-α]indole spirocyclic compounds. Therefore, the rapid and efficient construction of isoquinolinone-dihydropyridine-[1,2-α]indole spirocyclic compounds from readily available raw materials is of great significance. Summary of the Invention

[0005] Based on the above, this invention provides an isoquinolinone dihydropyridine-[1,2-α]indole spirocyclic compound, its preparation method, and its applications, filling a technological gap in the synthesis of isoquinolinone dihydropyridine-[1,2-α]indole spirocyclic compounds. The purpose of this section is to summarize some aspects of the embodiments of the invention and briefly introduce some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of this section, the abstract, and the title of the invention; however, such simplifications or omissions should not be used to limit the scope of the invention.

[0006] In view of the problems existing in the above or prior art, the present invention is proposed.

[0007] One objective of this invention is to provide an isoquinolinone-dihydropyridine-[1,2-α]indolespirocyclic compound that has a certain inhibitory effect on plant pathogens and can be potentially applied to the prevention and control of tomato gray mold, wheat scab and rice sheath blight.

[0008] To solve the above-mentioned technical problems, the present invention provides the following technical solution: an isoquinolinone dihydropyridine-[1,2-α]indole spirocyclic compound, the structural formula of which is shown in formula (I):

[0009]

[0010] Among them, R 1 Selected from one of hydrogen, halogen, methyl, ethyl, methoxy, methoxy ester, or cyano; R 2 Selected from one of hydrogen, methyl, CH2CH2OAc or CH2CH2NHBoc; R 3 It is selected from one of hydrogen, methyl, halogen or trifluoromethyl.

[0011] Another objective of this invention is to provide a method for preparing isoquinolinone-dihydropyridine-[1,2-α]indolespirocyclic compounds, which has the advantages of simple operation, low catalyst loading, wide substrate range, and high yield.

[0012] To solve the above-mentioned technical problems, the present invention provides a method for preparing the isoquinolinone dihydropyridine-[1,2-α]indole spirocyclic compound as described above, comprising the following steps: using the o-alkynyl nitrone compound shown in formula (II) as raw material, heating and reacting in solvent A under the catalysis of rhodium catalyst, and after the reaction is completed, filtering, concentrating and reacting in solvent B under the promotion of cerium ammonium nitrate to obtain the compound;

[0013]

[0014] Among them, R 1 R 2 R3 With equation (Ⅰ) R 1 R 2 R 3 The correspondence is consistent.

[0015] The reaction equation is:

[0016]

[0017] In a preferred embodiment of the method for preparing the isoquinolinone dihydropyridine-[1,2-α]indolespirocyclic compound of the present invention, the rhodium catalyst is selected from (1,5-cyclooctadiene) rhodium chloride dimer, bis(1,5-cyclooctadiene) rhodium tetrafluoroborate, and tetracarbonyl dirhodium chloride; the molar ratio of the catalyst to the compound shown in formula (II) is 0.01 to 0.05:1.

[0018] In a preferred embodiment of the method for preparing the isoquinolinone dihydropyridine-[1,2-α]indolespirocyclic compound of the present invention, the reaction is carried out under heating in solvent A with a rhodium catalyst, and the method further includes adding a drying agent to the reaction system, wherein the drying agent is... Molecular sieve, wherein the amount of desiccant added is 100 mg per 0.1 mmol of the compound represented by formula (II).

[0019] As a preferred embodiment of the method for preparing the isoquinolinone-dihydropyridine-[1,2-α]indolespirocyclic compound of the present invention, wherein: the solvent A is toluene or dichloroethane, the concentration of the compound represented by formula (II) in solvent A is 0.1 mol / L, the reaction temperature is 100°C, and the reaction time is 12 to 24 hours.

[0020] In a preferred embodiment of the method for preparing the isoquinolinone dihydropyridine-[1,2-α]indolespirocyclic compound of the present invention, the molar ratio of the cerium ammonium nitrate to the compound represented by formula (II) is 4 to 6:1.

[0021] As a preferred embodiment of the method for preparing the isoquinolinone dihydropyridine-[1,2-α]indolespirocyclic compound of the present invention, wherein: the reaction is promoted by cerium ammonium nitrate in solvent B, solvent B is a mixed solvent of acetonitrile and water, wherein the volume ratio of acetonitrile to water is 1 to 4:1; the concentration of the compound represented by formula (II) in solvent B is 0.1 mol / L, the reaction temperature is room temperature, and the reaction time is 5 to 30 minutes.

[0022] Another object of the present invention is to provide the use of an isoquinolinone dihydropyridine-[1,2-α]indolespirocyclic compound in the preparation of the compound shown in formula (III), characterized in that: the structural formula shown in formula (III) is:

[0023]

[0024] Another object of the present invention is to provide the use of the isoquinolinone dihydropyridine-[1,2-α]indolespirocyclic compound as described above or the compound represented by formula (III) as described above in the inhibition of Botrytis cinerea (Bc), and / or Fusarium graminearum (Gz), and / or Sheath blight of rice (Rs); or, in the preparation of products inhibiting Botrytis cinerea (Bc), and / or Fusarium graminearum (Gz), and / or Sheath blight of rice (Rs).

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The isoquinolinone dihydropyridine-[1,2-α]indolespirocyclic compound prepared in this invention has a certain inhibitory effect on plant pathogens and can be potentially applied to the prevention and control of tomato gray mold, wheat scab and rice sheath blight.

[0027] This invention utilizes readily available indole as a starting material and conveniently synthesized N-indole-linked o-alkynyl nitrone compounds as raw materials. Employing a two-step, one-pot method, it provides a novel synthetic approach for isoquinolinone dihydropyridine-[1,2-α]indole spirocyclic compounds. This approach is based on a rhodium-catalyzed internal redox / dearomatization cycloaddition / cerium ammonium nitrate-promoted oxidative debenzylation / spirocyclization tandem reaction strategy, constructing compounds that are difficult to prepare using conventional methods. The method of this invention offers advantages such as simple operation, low catalyst loading, broad substrate scope, single stereoselectivity, and high yield. Attached Figure Description

[0028] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein:

[0029] Figure 1 The 1H NMR spectrum of the target product 1a prepared in Example 1 of this invention;

[0030] Figure 2 The nuclear magnetic resonance carbon spectrum of the target product 1a prepared in Example 1 of this invention;

[0031] Figure 3 The single-crystal diffraction pattern of the target product 1a prepared in Example 1 of this invention;

[0032] Figure 4 This is a schematic diagram of the reaction mechanism represented by raw material 2a in Example 1 of the present invention. Detailed Implementation

[0033] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0034] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0035] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0036] The starting material used in the examples is an N-indole-linked o-alkynyl nitrone compound. The method reported in the references (Angew. Chem. Int. Ed. 2008, 47, 7040–7043; Org. Chem. Fron., 2023, 10, 140-149; Org. Lett. 2024, 26, 31, 6631–6636.) starts from readily available indole and can obtain the starting material in high yield in just three steps.

[0037] Example 1

[0038] Take a 10 mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2a (0.2 mmol) sequentially. Molecular sieve (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol) were added toluene (2 mL) under an argon atmosphere, and the reaction was carried out at 100 °C for 12 hours. After cooling to room temperature, the molecular sieve was filtered off, and the filtrate was concentrated by rotary evaporation. Then, cerium ammonium nitrate (0.1 mmol), acetonitrile (1.6 mL), and water (0.4 mL) were added to the reaction system, and the reaction was carried out for another 30 minutes. After the reaction was completed, the mixture was extracted twice with water and ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4 / 1 to 2 / 1, V / V) to obtain the target product 1a.

[0039] (54.7 mg, yellow solid, yield 87%).

[0040] The reaction equation is:

[0041]

[0042] The target product 1a was characterized as follows: Figure 1 and 2 As shown.

[0043] 1 H NMR (600MHz, CDCl3) δ8.67(s,1H),8.53(d,J=8.3Hz,1H),8.13(d,J=7.7Hz,1H),7.88(t, J=7.5Hz,1H),7.73(t,J=7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.40(d,J=7.7Hz,1H),7.34(t ,J=7.5Hz,1H),7.23(t,J=7.5Hz,1H),6.15(s,1H),3.26(ddd,J=17.6,8.5,5.4Hz,1H),3 .09(ddd,J=17.7,7.3,5.2Hz,1H),2.60(ddd,J=13.6,8.5,5.2Hz,1H),2.39–2.33(m,1H); 13 C NMR (100MHz, CDCl3) δ198.3,168.4,157.2,137.1,136.2,135.0,132.9,130.4,1 28.9,128.3,127.9,126.2,125.2,124.0,120.5,116.6,106.1,66.5,31.7,29.8.

[0044] The structure and relative configuration of the target product 1a were confirmed by single-crystal diffraction, such as... Figure 3 As shown.

[0045] Taking raw material 2a as an example, the reaction mechanism of this invention is as follows: Figure 4 As shown.

[0046] First, the carbon-carbon triple bond in 2a complexes with the catalyst (1,5-cyclooctadiene) rhodium chloride dimer to obtain complex A. The attack of the nitrone on the metal-activated alkyne results in an intramolecular 6-exo-dig cyclization reaction to produce intermediate B, which is then internally redox-induced to give α-carbonyl carbene C. Subsequently, the imine undergoes nucleophilic attack on the rhodium carbene to give cyclic imine ylide intermediate D. The highly reactive imine ylide undergoes intramolecular dearomatization [3+2] cycloaddition with the C(2)=C(3) bond of the side-chain indole to give E, and regenerates the Rh(I) salt. Under cerium ammonium nitrate-mediated oxidation conditions, E is first oxidized to secondary amine F, generating benzaldehyde as a byproduct. The single-electron oxidation of F by cerium ammonium nitrate produces radical cation G, which undergoes homolytic cleavage of the carbon-carbon bond to form a new spirocyclic carbon radical H. Further oxidation with cerium ammonium nitrate leads to deprotonation, yielding carbocation intermediate I, which is then further deprotonated to obtain the target product 1a.

[0047] Example 2

[0048] Take a 10 mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2b (0.2 mmol) sequentially. Molecular sieve (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol) were added toluene (2 mL) under an argon atmosphere, and the reaction was carried out at 100 °C for 12 hours. After cooling to room temperature, the molecular sieve was filtered off, and the filtrate was concentrated by rotary evaporation. Then, cerium ammonium nitrate (0.1 mmol), acetonitrile (1.6 mL), and water (0.4 mL) were added to the reaction system, and the reaction was carried out for another 30 minutes. After the reaction was completed, the mixture was extracted twice with water and ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4 / 1 to 1 / 1, V / V) to obtain the target product 1b.

[0049] (41.6 mg, yellow solid, yield 52%).

[0050] The reaction equation is:

[0051]

[0052] 1H NMR (600MHz, CDCl3) δ8.75(s,1H),8.56(d,J=8.3Hz,1H),8.15(d,J=7.7Hz,1H),7.90(td,J=7.6,1.0Hz,1H),7.74(td ,J=7.6,0.9Hz,1H),7.65(d,J=7.6Hz,1H),7.54(d,J=7.7Hz,1H),7.39–7.35(m,1H),7.31–7.27(m,1H),4.12(ddd,J=1 0.8,8.2,5.9Hz,1H),4.05–3.99(m,1H),3.05(ddd,J=17.3,7.5,4.8Hz,1H),2.91(ddd,J=17.3,9.0,4.9Hz,1H),2.72 –2.66(m,1H),2.61(ddd,J=14.1,8.0,5.9Hz,1H),2.38(ddd,J=13.8,9.0,4.8Hz,1H),2.30–2.24(m,1H),1.85(s,3H); 13 C NMR (150MHz, CDCl3) δ198.6,170.7,168.0,157.1,136.3,134.8,133.6,133.0,130.2,130.0, 128.5,127.7,126.2,125.4,123.9,118.6,116.9,115.5,67.7,62.8,33.1,29.2,24.2,20.8;

[0053] Example 3

[0054] Take a 10 mL round-bottom flask and add 2c (0.2 mmol) of N-indole-linked o-alkynyl nitrone. Molecular sieve (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol) were added toluene (2 mL) under an argon atmosphere, and the reaction was carried out at 100 °C for 12 hours. After cooling to room temperature, the molecular sieve was filtered off, and the filtrate was concentrated by rotary evaporation. Then, cerium ammonium nitrate (0.1 mmol), acetonitrile (1.6 mL), and water (0.4 mL) were added to the reaction system, and the reaction was carried out for another 30 minutes. After the reaction was completed, the mixture was extracted twice with water and ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4 / 1 to 1 / 1, V / V) to obtain the target product 1c.

[0055] (54.9 mg, yellow solid, yield 60%).

[0056] The reaction equation is:

[0057]

[0058] 1 H NMR (600MHz, CDCl3) δ8.73 (s, 1H), 8.56 (d, J = 8.2Hz, 1H), 8.15 (d, J = 7.7Hz, 1H), 7.89 (t, J = 7.5Hz, 1H),7.74(t,J=7.6Hz,1H),7.63(d,J=7.6Hz,1H),7.52(d,J=7.4Hz,1H),7.37(t,J=7.7Hz,1H),7. 28(t,J=7.5Hz,1H),4.85(s,1H),3.30–3.13(m,2H),3.08–3.00(m,1H),2.94–2.85(m,1H),2.59–2 .50(m,1H),2.49–2.42(m,1H),2.37(ddd,J=13.5,8.8,4.8Hz,1H),2.31–2.24(m,1H),1.36(s,9H); 13 C NMR (150MHz, CDCl3) δ198.9,168.0,157.1,155.7,136.3,134.9,133.4,133.1,130.2,129.9,12 8.5,127.7,126.2,125.4,123.9,118.9,117.0,116.8,78.9,67.7,39.5,33.2,29.3,28.4,25.1.

[0059] Example 4

[0060] Take a 10 mL round-bottom flask and add 2 d (0.2 mmol) of N-indole-linked o-alkynyl nitrone. Molecular sieve (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol) were added toluene (2 mL) under an argon atmosphere, and the reaction was carried out at 100 °C for 12 hours. After cooling to room temperature, the molecular sieve was filtered, and the filtrate was concentrated by rotary evaporation. Then, cerium ammonium nitrate (0.1 mmol), acetonitrile (1.6 mL), and water (0.4 mL) were added to the reaction system, and the reaction was carried out for another 30 minutes. After the reaction was completed, the mixture was extracted twice with water and ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4 / 1 to 1 / 1, V / V) to obtain the target product 1d.

[0061] (51.8 mg, yellow solid, yield 78%).

[0062] The reaction equation is:

[0063]

[0064] 1 H NMR (600MHz, CDCl3) δ8.73(s,1H),8.29(d,J=8.3Hz,1H),8.13(d,J=7.7Hz,1H),7.88( t,J=7.4Hz,1H),7.74(t,J=7.6Hz,1H),7.64(d,J=7.5Hz,1H),7.29–7.23(m,1H),6.91( t,J=8.9Hz,1H),6.28(s,1H),3.23(ddd,J=17.7,7.7,5.5Hz,1H),3.10(ddd,J=17.8,7 .7,5.3Hz,1H),2.56(ddd,J=13.3,7.8,5.3Hz,1H),2.40(ddd,J=13.4,7.6,5.6Hz,1H); 13 C NMR (150MHz, CDCl3) δ197.6,168.4,158.0,155.5(d,J=248.3Hz),137.0(d,J=9.0Hz),136.9,136.4,133.4,130.1,128.7, 127.7, 126.3, 126.1 (d, J = 7.2Hz), 117.7 (d, J = 21.7Hz), 112.7 (d, J = 3.7Hz), 109.4 (d, J = 18.5Hz), 101.7, 66.4, 31.6, 29.6; 19 FNMR (565MHz, CDCl3) δ-122.19 (dd, J = 9.5, 5.4Hz).

[0065] Example 5

[0066] Take a 10 mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2e (0.2 mmol) sequentially. Molecular sieve (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol) were added toluene (2 mL) under an argon atmosphere, and the reaction was carried out at 100 °C for 12 hours. After cooling to room temperature, the molecular sieve was filtered off, and the filtrate was concentrated by rotary evaporation. Then, cerium ammonium nitrate (0.1 mmol), acetonitrile (1.6 mL), and water (0.4 mL) were added to the reaction system, and the reaction was carried out for another 30 minutes. After the reaction was completed, the mixture was extracted twice with water and ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4 / 1 to 1 / 1, V / V) to obtain the target product 1e.

[0067] (62.9 mg, yellow solid, yield 80%).

[0068] The reaction equation is:

[0069]

[0070] 1 H NMR (600MHz, CDCl3) δ8.71(s,1H),8.46(d,J=8.2Hz,1H),8.12(d,J=7.7Hz,1H ),7.86(t,J=7.5Hz,1H),7.72(t,J=7.6Hz,1H),7.61(d,J=7.5Hz,1H),7.38(d ,J=7.8Hz,1H),7.18(t,J=8.0Hz,1H),6.24(s,1H),3.20(dt,J=17.5,6.3Hz,1 H),3.08(ddd,J=13.2,7.1,5.7Hz,1H),2.54–2.47(m,1H),2.43–2.36(m,1H); 13 C NMR (150MHz, CDCl3) δ197.7,168.3,157.8,137.8,136.3,135.3,133.2,130.1,1 29.6,128.6,127.6,126.9,126.3,126.1,115.6,114.3,105.9,66.5,31.7,29.6.

[0071] Example 6

[0072] Take a 10 mL round-bottom flask and add 2f (0.2 mmol) of N-indole-linked o-alkynyl nitrone sequentially. Molecular sieve (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol) were added toluene (2 mL) under an argon atmosphere, and the reaction was carried out at 100 °C for 12 hours. After cooling to room temperature, the molecular sieve was filtered off, and the filtrate was concentrated by rotary evaporation. Then, cerium ammonium nitrate (0.1 mmol), acetonitrile (1.6 mL), and water (0.4 mL) were added to the reaction system, and the reaction was carried out for another 30 minutes. After the reaction was completed, the mixture was extracted twice with water and ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4 / 1 to 1 / 1, V / V) to obtain the target product 1f.

[0073] (40.6 mg, brown solid, yield 59%).

[0074] The reaction equation is:

[0075]

[0076] 1 H NMR (600MHz, CDCl3) δ8.66(s,1H),8.40(d,J=9.0Hz,1H),8.12(d,J=7.7Hz,1H),7.87(td,J =7.6,1.2Hz,1H),7.72(td,J=7.6,1.1Hz,1H),7.60(d,J=7.4Hz,1H),6.93(dd,J=9.0,2.5H z,1H),6.86(d,J=2.5Hz,1H),6.08(s,1H),3.79(s,3H),3.22(ddd,J=17.6,8.5,5.4Hz,1H) ,3.05(ddd,J=17.7,7.4,5.2Hz,1H),2.58(ddd,J=13.6,8.5,5.2Hz,1H),2.38–2.31(m,1H); 13 C NMR (150MHz, CDCl3) δ198.3,168.0,157.2,156.7,137.7,136.2,132.9,130.4,129. 9,129.8,128.3,127.9,126.2,117.4,113.4,105.9,103.4,66.5,55.6,31.8,29.6.

[0077] Example 7

[0078] Take a 10 mL round-bottom flask and add 2 g (0.2 mmol) of N-indole-linked o-alkynyl nitrone. Molecular sieve (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol) were added toluene (2 mL) under an argon atmosphere, and the reaction was carried out at 100 °C for 12 hours. After cooling to room temperature, the molecular sieve was filtered off, and the filtrate was concentrated by rotary evaporation. Then, cerium ammonium nitrate (0.1 mmol), acetonitrile (1.6 mL), and water (0.4 mL) were added to the reaction system, and the reaction was carried out for another 30 minutes. After the reaction was completed, the mixture was extracted twice with water and ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4 / 1 to 1 / 1, V / V) to obtain 1 g of the target product.

[0079] (48.8 mg, yellow solid, yield 70%).

[0080] The reaction equation is:

[0081]

[0082] 1 H NMR (600MHz, CDCl3) δ8.69(s,1H),8.38(d,J=8.8Hz,1H),8.07(d,J=7.6Hz,1H),7.82(t, J=7.2Hz,1H),7.68(t,J=7.5Hz,1H),7.58(d,J=7.5Hz,1H),7.32(d,J=1.9Hz,1H),7.22(d d,J=8.8,2.0Hz,1H),6.10(s,1H),3.17(ddd,J=17.7,7.6,5.5Hz,1H),3.03(ddd,J=17.8 ,7.8,5.3Hz,1H),2.49(ddd,J=13.2,7.6,5.3Hz,1H),2.37(ddd,J=13.5,7.8,5.5Hz,1H); 13 C NMR (150MHz, CDCl3) δ197.5,168.0,157.9,138.2,136.2,133.2,130.1,129. 9,129.3,128.6,127.5,126.1,125.1,120.0,117.4,105.3,66.3,31.5,29.4.

[0083] Example 8

[0084] Take a 10 mL round-bottom flask and add N-indole-linked o-alkynyl nitrone (0.2 mmol) sequentially for 2 hours. Molecular sieve (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol) were added toluene (2 mL) under an argon atmosphere, and the reaction was carried out at 100 °C for 12 hours. After cooling to room temperature, the molecular sieve was filtered, and the filtrate was concentrated by rotary evaporation. Then, cerium ammonium nitrate (0.1 mmol), acetonitrile (1.6 mL), and water (0.4 mL) were added to the reaction system, and the reaction was carried out for another 30 minutes. After the reaction was completed, the mixture was extracted twice with water and ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4 / 1 to 1 / 1, V / V) to obtain the target product 1 h.

[0085] (55.1 mg, yellow solid, yield 74%).

[0086] The reaction equation is:

[0087]

[0088] 1H NMR (600MHz, CDCl3) δ8.71(s,1H),8.56(d,J=8.7Hz,1H),8.13(d,J=7.2Hz,2H),8.03(d,J=8.7Hz,1H),7.90(t,J=7.3Hz,1H),7.74(t,J= 7.5Hz,1H),7.63(d,J=7.4Hz,1H),6.24(s,1H),3.91(s,3H),3.29–3.20(m,1H),3.14–3.05(m,1H),2.59–2.52(m,1H),2.44–2.36(m,1H); 13 C NMR (150MHz, CDCl3) δ197.9,168.4,167.3,157.8,138.5,137.7,136.4,133.2,130.3,1 28.8,128.5,127.8,126.5,126.3,125.9,122.7,116.3,106.4,66.5,52.0,31.7,29.7.

[0089] Example 9

[0090] Take a 10 mL round-bottom flask and add 2i (0.2 mmol) of N-indole-linked o-alkynyl nitrone. Molecular sieve (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol) were added toluene (2 mL) under an argon atmosphere, and the reaction was carried out at 100 °C for 12 hours. After cooling to room temperature, the molecular sieve was filtered off, and the filtrate was concentrated by rotary evaporation. Then, cerium ammonium nitrate (0.1 mmol), acetonitrile (1.6 mL), and water (0.4 mL) were added to the reaction system, and the reaction was carried out for another 30 minutes. After the reaction was completed, the mixture was extracted twice with water and ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4 / 1 to 1 / 1, V / V) to obtain the target product 1i.

[0091] (44 mg, yellow solid, yield 67%).

[0092] The reaction equation is:

[0093]

[0094] 1H NMR (600MHz, CDCl3) δ8.66 (s, 1H), 8.36 (s, 1H), 8.12 (d, J = 7.7Hz, 1H), 7.87 (td, J = 7.6, 1.1Hz,1H),7.72(td,J=7.6,0.9Hz,1H),7.60(d,J=7.6Hz,1H),7.27(d,J=7.3Hz,1H),7 .05(d,J=7.9Hz,1H),6.09(s,1H),3.23(ddd,J=17.6,8.4,5.4Hz,1H),3.08(ddd,J=17. 7,7.4,5.2Hz,1H),2.58(ddd,J=13.6,8.4,5.2Hz,1H),2.47(s,3H),2.37–2.31(m,1H); 13 C NMR (150MHz, CDCl3) δ198.3,168.5,157.2,136.3,136.1,135.4,135.4,132.9,130. 4,128.3,128.0,126.6,126.2,125.4,120.0,116.9,106.0,66.5,31.6,29.8,21.9.

[0095] Example 10

[0096] Take a 10 mL round-bottom flask and add 2j (0.2 mmol) of N-indole-linked o-alkynyl nitrone. Molecular sieve (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol) were added toluene (2 mL) under an argon atmosphere, and the reaction was carried out at 100 °C for 12 hours. After cooling to room temperature, the molecular sieve was filtered, and the filtrate was concentrated by rotary evaporation. Then, cerium ammonium nitrate (0.1 mmol), acetonitrile (1.6 mL), and water (0.4 mL) were added to the reaction system, and the reaction was carried out for another 30 minutes. After the reaction was completed, the mixture was extracted twice with water and ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4 / 1 to 1 / 1, V / V) to obtain the target product 1j.

[0097] (40.1 mg, yellow solid, yield 61%).

[0098] The reaction equation is:

[0099]

[0100] 1H NMR (600MHz, CDCl3) δ8.66(s,1H),8.11(d,J=7.7Hz,1H),7.85(td,J=7.6,0.9Hz,1H),7.71(t,J=7.6Hz,1H),7.58(d,J=7.6Hz,1H),7.20(dd,J=6.8Hz,1 .8Hz,1H),7.16–7.11(m,2H),6.14(s,1H),3.26(ddd,J=17.3,8.7,5.7Hz,1H ),3.10(ddd,J=17.3,6.8,5.6Hz,1H),2.69–2.62(m,4H),2.38–2.32(m,1H); 13 C NMR (150MHz, CDCl3) δ198.3,167.7,157.1,138.6,136.1,134.9,132.9,130.7,130. 4,128.5,128.3,127.9,127.1,126.2,124.5,118.1,106.9,67.0,31.6,30.5,23.0.

[0101] Example 11

[0102] Take a 10 mL round-bottom flask and add 2 kJ (0.2 mmol) of N-indole-linked o-alkynyl nitrone. Molecular sieve (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol) were added toluene (2 mL) under an argon atmosphere, and the reaction was carried out at 100 °C for 12 hours. After cooling to room temperature, the molecular sieve was filtered off, and the filtrate was concentrated by rotary evaporation. Then, cerium ammonium nitrate (0.1 mmol), acetonitrile (1.6 mL), and water (0.4 mL) were added to the reaction system, and the reaction was carried out for another 30 minutes. After the reaction was completed, the mixture was extracted twice with water and ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5 / 1 to 3 / 1, V / V) to obtain the target product 1k.

[0103] (55.8 mg, yellow solid, yield 73%).

[0104] The reaction equation is:

[0105]

[0106] 1H NMR(600MHz, CDCl3)δ8.72(s,1H),8.51(d,J=8.3Hz,1H),8.24(d,J=8.0Hz,1H), 7.96(d,J=8.0Hz,1H),7.88(s,1H),7.40(d,J=7.7Hz,1H),7.34(t,J=7.8Hz,1H), 7.23(t,J=7.5Hz,1H),6.13(s,1H),3.26(ddd,J=17.7,8.4,5.4Hz,1H),3.08(ddd ,J=17.7,7.2,5.3Hz,1H),2.60(ddd,J=13.6,8.4,5.2Hz,1H),2.42–2.35(m,1H); 13 C NMR (150MHz, CDCl3) δ197.3,168.1,155.8,137.4(d,J=33.4Hz),136.3,135.0,130.6,130.1,129.4(dd,J= 7.0, 3.5Hz), 128.7, 127.1, 125.4, 125.3 (dd, J = 7.3, 3.6Hz), 124.1, 120.5, 116.6, 106.2, 66.8, 31.6, 29.7; 19 F NMR(377MHz, CDCl3)δ-63.35(s).

[0107] Example 12

[0108] To verify the application value of this invention, a millimolecular scale-up experiment was also conducted. When the raw material N-indole-linked o-alkynyl nitrone 2a was scaled up to 1 mmol (406.5 mg), and the loading of the catalyst (1,5-cyclooctadiene) rhodium chloride dimer was further reduced to 0.5 mol%, the reaction still achieved a yield of 87% of the expected product, fully demonstrating the potential application value of this invention.

[0109] Take a 100 mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2a (1 mmol, 406.5 mg) sequentially. Molecular sieve (1 g) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.5 mmol) were added toluene (10 mL) under an argon atmosphere, and the reaction was carried out at 100 °C for 12 hours. After cooling to room temperature, the molecular sieve was filtered off, and the filtrate was concentrated by rotary evaporation. Then, cerium ammonium nitrate (5 mmol), acetonitrile (8 mL), and water (2 mL) were added to the reaction system, and the reaction was carried out for another 30 minutes. After the reaction was completed, the mixture was extracted twice with water and ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4 / 1 to 2 / 1, V / V) to give the target product 1a (273.5 mg, yellow solid, yield 87%).

[0110] The reaction equation is:

[0111]

[0112] 1 H NMR (600MHz, CDCl3) δ8.67(s,1H),8.53(d,J=8.3Hz,1H),8.13(d,J=7.7Hz,1H),7.88(t, J=7.5Hz,1H),7.73(t,J=7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.40(d,J=7.7Hz,1H),7.34(t ,J=7.5Hz,1H),7.23(t,J=7.5Hz,1H),6.15(s,1H),3.26(ddd,J=17.6,8.5,5.4Hz,1H),3 .09(ddd,J=17.7,7.3,5.2Hz,1H),2.60(ddd,J=13.6,8.5,5.2Hz,1H),2.39–2.33(m,1H); 13 C NMR (100MHz, CDCl3) δ198.3,168.4,157.2,137.1,136.2,135.0,132.9,130.4,1 28.9,128.3,127.9,126.2,125.2,124.0,120.5,116.6,106.1,66.5,31.7,29.8.

[0113] Example 13

[0114] Examples 1-12 yielded isoquinolinone-dihydropyridine-[1,2-α]indolespirocyclic compounds, which are important organic synthesis intermediates that can be further structurally modified and chemically transformed into various compounds.

[0115] Taking the isoquinolinone-dihydropyridine-[1,2-α]indole spirocyclic compound 1a prepared in Example 12 as an example, it can selectively reduce the carbon-nitrogen double bond to give compound 3a under the action of sodium cyanoborohydride. The reaction equation is as follows:

[0116]

[0117] Take a 10 mL round-bottom flask, add isoquinolinone-dihydropyridine-[1,2-α]indole spirocyclic compound 1a (0.2 mmol), followed by sodium cyanoborohydride (0.6 mmol) and methanol (2 mL), and react at room temperature for 3 hours (tear-layer chromatography was used to monitor the reaction until it was complete). After the reaction was completed, ammonium chloride was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 6 / 1 to 2 / 1, V / V) to give the target product 3a (50 mg, brownish-yellow solid, yield 79%).

[0118] 1 H NMR (600MHz, CDCl3) δ8.50(d,J=8.3Hz,1H),8.16(d,J=7.8Hz,1H),7.59(t,J=7.5Hz,1H),7.45(t,J=7.6Hz,1H),7.39(d,J=7.7Hz,1H),7.33(t,J=7.7 Hz,1H),7.23(t,J=7.5Hz,2H),6.18(s,1H),4.18(d,J=17.4Hz,1H),4.09( d,J=17.4Hz,1H),3.21–3.12(m,1H),2.94–2.83(m,2H),2.11–2.06(m,1H); 13 C NMR (150MHz, CDCl3) δ194.3,168.5,143.5,135.6,135.1,134.1,130.3,128.6,1 28.1,127.6,125.9,125.3,124.0,120.5,116.6,107.1,59.6,42.9,29.7,29.2.

[0119] Example 14

[0120] Based on Example 1, the reaction conditions, such as the type and loading of catalyst, the type of reaction solvent, the reaction time, the loading of cerium ammonium nitrate, and the ratio of acetonitrile to water, were optimized. The specific optimization results are shown in Table 1 below:

[0121] Table 1

[0122]

[0123]

[0124] As can be seen from the data in Table 1, under the same reaction conditions, the product yield is the highest when using (1,5-cyclooctadiene) rhodium chloride dimer as a catalyst. When using other catalysts, such as gold tribromide, platinum dibromide, platinum tetraiodide, bis(1,5-cyclooctadiene) rhodium tetrafluoroborate, and rhodium tetracarbonyl dichloride, the product yield decreases to varying degrees.

[0125] When using (1,5-cyclooctadiene) rhodium chloride dimer as a catalyst, the yield decreased slightly when solvent A was replaced with dichloroethane.

[0126] Using (1,5-cyclooctadiene)rhodium chloride dimer as a catalyst and toluene as a solvent, the yield decreased with both increasing and decreasing the loading of cerium ammonium nitrate.

[0127] When using (1,5-cyclooctadiene)rhodium chloride dimer as a catalyst, toluene as a solvent, and cerium ammonium nitrate loading of 5 equivalents, the yield was significantly reduced when the ratio of solvent B acetonitrile to water was changed from 4:1 to 1:1.

[0128] Using (1,5-cyclooctadiene) rhodium chloride dimer as a catalyst and toluene as a solvent, with a cerium ammonium nitrate loading of 5 equivalents and an acetonitrile to water ratio of 4:1, reducing the catalyst (1,5-cyclooctadiene) rhodium chloride dimer loading to 1 mol% did not significantly change the yield.

[0129] Furthermore, the optimal reaction conditions obtained were: 1 mol% (1,5-cyclooctadiene) rhodium chloride dimer as catalyst, toluene as solvent A, 5 equivalents of cerium ammonium nitrate, and an acetonitrile:water volume ratio of 4:1.

[0130] Example 15

[0131] Botrytis cinerea (Bc), also known as gray mold, is a broad-host fungus that can cause damping-off, leaf drop, flower rot, fruit rot, and cellar rot in various plant seedlings, fruits, and storage organs. In tomatoes, the disease causes extensive fruit rot in early spring, generally reducing yield by 20-30%, and in severely affected areas by up to 50%. When the stems are infected, small water-soaked spots initially appear, later expanding into oblong or irregular shapes, light brown in color. In high humidity, a gray mold layer (conidia and conidiophores of the fungus) develops on the surface of the lesions. In severe cases, the stems and leaves above the infected area wither and die, leading to wilt disease.

[0132] Fusarium head blight (GZ) is one of the major fungal diseases affecting wheat crops, widespread throughout China, and consistently one of the most serious diseases in wheat-growing areas south of the Huai River and in the middle and lower reaches of the Yangtze River. Wheat can be infected from the seedling stage to the heading stage, causing various damages such as seedling blight, basal rot, stem rot, and ear rot. Wheat infected with GZ suffers from reduced dry grain weight, decreased germination rate, weakened germination vigor, low flour yield, poor flour quality, and a dull color. This not only reduces wheat yield but also, due to the presence of emetic toxins and estrogen-like toxins in the pathogen's metabolic products, can cause acute poisoning in humans and animals if ingested.

[0133] Rice sheath blight (Rs) is a disease of rice caused by Rhizoctonia solani. It primarily affects the leaf sheaths and leaves. In the early stages, oval, dark green, water-soaked lesions appear on the leaf sheaths near the water surface. These lesions gradually enlarge into cloud-like patterns, with a grayish-white center that turns grayish-green in humid conditions. The disease is highly susceptible to infection in high temperatures and humidity; within suitable ranges, higher humidity leads to more severe outbreaks.

[0134] Furthermore, effective prevention and control of these diseases is of great significance.

[0135] Furthermore, based on Examples 1-12, the antibacterial activity was determined using the mycelial growth rate inhibition method. Different compounds were weighed and dissolved in dimethyl sulfoxide (DMSO) by sonication to prepare a 10 mg / mL solution. This solution was filtered through a 0.22 μm sterile filter membrane and added aseptically to sterilized PDA medium to prepare a 50 mg / L drug-containing medium. Five-mm diameter mycelial discs were taken from the edge of the tested colonies after 5 days of cultivation and inoculated into the center of PDA plates containing different drug solutions. PDA plates without drug solutions served as controls. Each treatment was repeated in triplicate. The mycelial side was facing down, and the plates were incubated at 28°C. After 5 days, the colony diameter was measured using the cross-hatching method, and the mycelial growth inhibition rate was calculated. Each treatment was repeated in triplicate. The calculation formula is as follows:

[0136]

[0137] Furthermore, the mycelial growth rate inhibition method was used to determine the antibacterial activity of different compounds against Botrytis cinerea (Bc), Fusarium graminearum (Gz), and Rhizoctonia solani (Rs), with Tetramethylthiuram Disulfide and Chlorothalonil as positive controls. The mycelial growth inhibition rate was calculated, and the results are shown in Table 2.

[0138] Table 2 Inhibition rate of compounds against plant pathogens

[0139]

[0140] The results showed that compounds 1a, 1c-1d, 1f, 1h-1j, and 3a all exhibited inhibitory activity against the plant pathogen *Botrytis cinerea* (Bc), and their inhibitory effects were significantly better than those of the positive control, thiram. For *Fusarium graminearum* (Gz), compounds 1a, 1d-1e, 1g, 1j, and 3a all showed inhibitory activity against the plant pathogen *Fusarium graminearum*, and their inhibitory effects were better than those of the positive control, thiram. Compounds 1d and 1j showed significantly better inhibitory effects than chlorothalonil. For *Rhizoctonia solani* (Rs), compounds 1a-1k and 3a all showed inhibitory activity against the plant pathogen *Rhizoctonia solani*, and their inhibitory effects were significantly better than those of the positive control, thiram. Compounds 1a and 1c-1d showed significantly better inhibitory effects than chlorothalonil.

[0141] This invention utilizes readily available indole as a starting material and readily synthesizes N-indole-linked o-alkynyl nitrone compounds as raw materials. Employing a two-step, one-pot method, it provides a novel synthetic approach for isoquinolinone-dihydropyridine-[1,2-α]indole spirocyclic compounds. This approach is based on a rhodium-catalyzed internal redox / dearomatization [3+2] cycloaddition reaction followed by a cascade reaction strategy of cerium ammonium nitrate-promoted oxidative debenzylation / spirocyclization, which is difficult to prepare using conventional methods. The method of this invention offers advantages such as simple operation, low catalyst loading, broad substrate range, single stereoselectivity, and high yield.

[0142] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. An isoquinolinone dihydropyridine-[1,2- α Indolespirocyclic compounds, characterized in that: The structural formula is shown in equation (Ⅰ): （Ⅰ）； Among them, R 1 Selected from one of hydrogen, halogen, methyl, ethyl, methoxy, methoxyacyl, or cyano; R 2 Selected from one of hydrogen, methyl, CH2CH2OAc or CH2CH2NHBoc; R 3 It is selected from one of hydrogen, methyl, halogen or trifluoromethyl.

2. The isoquinolinone dihydropyridine-[1,2-] according to claim 1 α A method for preparing indolespirocyclic compounds, characterized in that: include, Using the o-alkynyl nitrone compound shown in formula (II) as a raw material, the reaction is carried out in solvent A under the catalysis of rhodium catalyst. A desiccant, namely a 4 Å molecular sieve, is added to the reaction system. After the reaction is completed, the mixture is filtered, concentrated, and then reacted in solvent B under the promotion of cerium ammonium nitrate. （Ⅱ）； Among them, R 1 R 2 R 3 With equation (Ⅰ) R 1 R 2 R 3 Consistent correspondence; The rhodium catalyst is selected from one of (1,5-cyclooctadiene) rhodium chloride dimer, bis(1,5-cyclooctadiene) rhodium tetrafluoroborate, or tetracarbonyl dirhodium chloride.

3. The isoquinolinone dihydropyridine-[1,2-] as described in claim 2 α A method for preparing indolespirocyclic compounds, characterized in that: The molar ratio of the rhodium catalyst to the compound shown in formula (II) is 0.01 to 0.05:

1.

4. The isoquinolinone dihydropyridine-[1,2-] as described in claim 2 or 3 α A method for preparing indolespirocyclic compounds, characterized in that: The amount of desiccant added is 100 mg per 0.1 mmol of the compound represented by formula (II).

5. The isoquinolinone dihydropyridine-[1,2-] as described in claim 4 α A method for preparing indolespirocyclic compounds, characterized in that: The solvent A is toluene or dichloroethane, the concentration of the compound represented by formula (II) in solvent A is 0.1 mol / L, the reaction temperature is 100 °C, and the reaction time is 12~24 hours.

6. The isoquinolinone dihydropyridine-[1,2-] as described in any one of claims 2, 3, and 5 α A method for preparing indolespirocyclic compounds, characterized in that: The molar ratio of the cerium ammonium nitrate to the compound shown in formula (II) is 4~6:

1.

7. The isoquinolinone dihydropyridine-[1,2-] as described in claim 6 α A method for preparing indolespirocyclic compounds, characterized in that: Solvent B is a mixed solvent of acetonitrile and water, wherein the volume ratio of acetonitrile to water is 1~4:

1.

8. The isoquinolinone dihydropyridine-[1,2-] as described in any one of claims 2, 3, 5, and 7 α A method for preparing indolespirocyclic compounds, characterized in that: The concentration of the compound represented by formula (Ⅱ) in solvent B is 0.1 mol / L, the reaction temperature is room temperature, and the reaction time is 5 to 30 minutes.

9. The isoquinolinone dihydropyridine-[1,2-] as described in claim 1 α The application of indolespirocyclic compounds in the preparation of compounds represented by formula (III) is characterized by: The structural formula shown in equation (Ⅲ) is: （Ⅲ）。 10. The isoquinolinone dihydropyridine-[1,2-] as described in claim 1 α The use of indolespirocyclic compounds or compounds of formula (III) as described in claim 9 in inhibiting *Botrytis cinerea* of tomatoes, and / or *Fusarium graminearum* of wheat, and / or *Rhizoctonia solani* of rice; or in the preparation of products inhibiting *Botrytis cinerea* of tomatoes, and / or *Fusarium graminearum* of wheat, and / or *Rhizoctonia solani* of rice.

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