A ligand precursor compound containing a spirocyclic-indolinone skeleton, and a preparation method and application thereof

Abstract

The application provides a ligand precursor compound containing a spirocyclic-indole ketone skeleton and a preparation method and application thereof, the compound has the structure shown in the following formula I or formula II, and the ligand precursor compound containing the spirocyclic-indole ketone skeleton is obtained by reacting an indole-2,3-diketone compound with a 1,1-diaryl ethylene compound. The reaction condition is mild, raw materials are widely sourced, the yield is high, the speed is fast, post-treatment is simple, operation is simple, and the application is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, and relates to a ligand precursor compound containing a spirocyclic indole ketone skeleton, its preparation method and application. Background Technology

[0002] Spirocyclic indole ketones are an important class of natural and synthetic compounds with many novel biological properties. For example, spirocyclic indole ketone structural units are widely found in natural alkaloids and drug molecules and exhibit a wide range of biological activities, including anticancer, antimalarial, antidepressant, antibacterial, and antiviral activities.

[0003] For example, the following compounds all contain spirocyclic-indolone structural units:

[0004]

[0005] Furthermore, spirocyclic-indole ketone derivatives, due to their skeletal structure containing both spirocyclic and indole ketone structural units, play important roles in steric hindrance and electronic regulation. Therefore, the synthesis of bidentate phosphine ligands with spirocyclic-indole ketone skeletons is of great significance in the hydroformylation of alkenes. Since indole-2,3-diones are readily available and commonly used as dyes, direct activation at the C3 position of indole-2,3-diones is the simplest and most direct method for constructing spirocyclic-indole ketones. For example:

[0006] In 2007, Basavaiah's research group reported a method for synthesizing spirocyclic-cyclopentene-indolone derivatives using Lewis acid-promoted cyclization reactions. As shown in the following formula: This method uses titanium tetrachloride, the strongest Lewis acid reagent, as a catalyst, effectively promoting a tandem intermolecular Prins reaction and an intramolecular Friedel-Crafts reaction between indole-2,3-dione and 1,1-diarylethylene, synthesizing polysubstituted 3-phenylspiro[indan-1,3'-indoline]-2'-one, with the reaction formula as follows:

[0007]

[0008] In 2008, List's research group discovered... Acid-catalyzed cyclization reaction between indole-2,3-dione and 2-aminobenzamide. As shown below: They used this method to synthesize substituted 1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione:

[0009]

[0010] In 2011, Shi's research group discovered that in the presence of SnCl2, indole-2,3-dione reacts with 2-nitrobenzamide to yield substituted 3'-phenyl-1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione. SnCl2 first acts as a reducing agent, reducing the nitro group in the substrate molecule to an amino group, while itself is oxidized to SnCl4. Then, SnCl4 acts as a Lewis acid catalyzing the N,N-acetalization of the carbonyl group at the C3 position of indole-2,3-dione.

[0011]

[0012] In 2017, Tunge's group reported a novel method for synthesizing spirocyclic indole ketone derivatives via the tertiary amine effect. First, an indole-2,3-dione reacts with a diamine to yield an imine intermediate. Then, under FeCl3 catalysis, a substituted spiro[indole-3,6'-isoindolo[2,1-a]quinoline]-2-one is formed via [1,5]-hydrogen migration and cyclization.

[0013]

[0014] In 2022, Lalitha's research group reported a novel three-component one-pot method for synthesizing substituted 3,3-dimethyl-3,4-dihydro-2H-spiro[acridin-9,3'-indoline]-1,2'(10H)-diones using indole-2,3-dione, cyclohexanedione, and aromatic amines. This method uses a mixture of ethanol and water as a solvent and offers advantages such as simple reaction conditions, convenient separation, and a relatively environmentally friendly approach.

[0015]

[0016] Despite the existence of many methods for synthesizing spirocyclic indole ketones, most of them suffer from numerous drawbacks, such as cumbersome experimental procedures, complex substrate preparation, complex catalyst preparation, and poor functional group tolerance.

[0017] We found that using 1,1-diarylethylene as the nucleophile is the simplest and most direct method; however, this reaction requires titanium tetrachloride, the strongest Lewis acid, as a catalyst. It is well known that the use of titanium tetrachloride often involves three main drawbacks: (a) titanium tetrachloride is inconvenient and unsafe to handle, easily absorbing water and releasing fumes of HCl gas during transfer; (b) titanium tetrachloride is very easily hydrolyzed, requiring use in a dry system or in excess; (c) in acid-catalyzed dehydration equilibrium reactions of alcohols, it has the ability to convert water in the system into titanium dioxide, but the process is very slow and lacks practical application, often requiring 12 hours of hydrolysis to obtain the target compound. Therefore, the efficient synthesis of spirocyclic indole ketones using a novel reagent is of great significance. Summary of the Invention

[0018] To address the shortcomings of existing technologies, the present invention aims to provide a ligand precursor compound containing a spirocyclic indole ketone skeleton, its preparation method, and its application.

[0019] To achieve this objective, the present invention adopts the following technical solution:

[0020] On one hand, the present invention provides a ligand precursor compound containing a spirocyclic indole ketone skeleton, said compound having the structure shown in Formula I or Formula II:

[0021]

[0022] In equations (I) and (II), R 1 R 2 R 3 and R 4 Each is independently selected from any one of H, halogen, methyl, ethyl, methoxy, ethoxy, benzyl or allyl.

[0023] Preferably, the ligand precursor compound containing a spirocyclic indole ketone skeleton is any one of the following compounds:

[0024]

[0025] On the other hand, the present invention provides a method for preparing the ligand precursor compound containing a spirocyclic-indole ketone skeleton as described above, the preparation method comprising the following steps:

[0026] The indole-2,3-dione compound was reacted with the 1,1-diarylethylene compound to obtain the ligand precursor compound containing the spirocyclic-indole ketone skeleton;

[0027] The structure of the indole-2,3-dione compound is as follows:

[0028] The structure of the 1,1-diarylethylene compound is as follows:

[0029] The reaction equation is as follows:

[0030]

[0031]

[0032] Preferably, the molar ratio of the 1,1-diarylethylene compound to the indole-2,3-dione compound is 1.1-1.5:1, for example 1.1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5:1, preferably 1.2:1.

[0033] Preferably, the reaction is carried out in the presence of an acidic reagent.

[0034] Preferably, the acidic reagent is selected from trifluoromethanesulfonic acid.

[0035] Preferably, the molar ratio of the acidic reagent to the indole-2,3-dione compound is 0.2-5:1, for example 0.2:1, 0.5:1, 0.8:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1 or 5:1, preferably 4:1.

[0036] Preferably, the reaction is carried out in an organic solvent.

[0037] Preferably, the organic solvent is selected from at least one solvent selected from 1,2-dichloroethane, dichloromethane, trichloromethane, acetonitrile, benzonitrile or toluene, with 1,2-dichloroethane being the most preferred.

[0038] Preferably, the reaction is carried out in an air atmosphere.

[0039] Preferably, the reaction temperature is 25-80°C (e.g., 25°C, 28°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, or 80°C), and the reaction time is 1 hour-12 hours (e.g., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours).

[0040] Preferably, the reaction temperature is 25°C and the reaction time is 1 hour.

[0041] On the other hand, the present invention provides the use of ligand precursor compounds containing spirocyclic-indole ketone skeletons as described above in the preparation of spirocyclic-indole ketone compounds.

[0042] Compared with the prior art, the present invention has the following beneficial effects:

[0043] Since the steric hindrance and electronic interaction of ligands play an important role in the selectivity of carbonyl esterification reactions, the design of ligand precursor compounds containing spirocyclic-indole ketone skeletons in this invention aims to control steric hindrance through the spirocyclic structure and control electronic interaction through the indole structure containing nitrogen atoms by introducing spirocyclic-indole ketone skeletons into the ligands. In this way, the synthesized ligands may have both of these functions at the same time.

[0044] The preparation method provided by this invention features mild reaction conditions, readily available 1,1-diarylethylene which can be used as a nucleophile, a broad substrate range, and good functional group tolerance. This reaction is highly efficient, yield-rich, fast, and requires simple post-processing and operation, making it suitable for large-scale industrial production. This method avoids the need for pre-preparation of complex substrates and acidic catalysts required in traditional reactions. Furthermore, this method eliminates the metal catalysis necessary for traditional reactions. The compounds of this invention contain two hydroxyl functional groups, allowing for further reaction to introduce two phosphine atoms to prepare ligands containing two phosphine atoms, namely, bidentate phosphine ligands. Therefore, it can be used for the preparation of bidentate phosphine ligands in the hydroformylation reaction of olefins. Detailed Implementation

[0045] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention.

[0046] The data and purity of the new compounds presented in the following examples were determined by nuclear magnetic resonance.

[0047] Example 1

[0048] Synthesis of 3-phenyl-spiro[indan-1,3'-indoline]-2'-one:

[0049]

[0050] At room temperature and with stirring, indole-2,3-dione (73.5 mg, 0.5 mmol), 1,1-diphenylethylene (108 mg, 0.6 mmol), and DCE (2 mL) were added sequentially to a reaction tube (25 mL), followed by TfOH (300 mg, 177 μL, 1.5 mmol). The reaction tube was sealed and thoroughly stirred. The reaction process was monitored by thin-layer chromatography, and the reaction was completed after 10 minutes.

[0051] After the reaction was complete, 10 mL of DCM was added to the reaction tube to dilute the reaction solution, and then 0.5 mL of Et3N was added dropwise to quench the reaction. The mixture was stirred for another 10 min, and then the organic solvent was removed by rotary evaporation. The residue was purified by column chromatography (PE / EA = 3 / 1) to obtain a white solid in 97% yield.

[0052] The 1H NMR spectrum data of the obtained product are as follows:

[0053] 1HNMR (400MHz, CDCl3): δ9.52(s,1H),7.71-7.68(m,2H),7.64-7.62(m,1H),7.49-7.33(m,4H) ),7.22-7.16(m,2H),7.06-7.04(m,1H),6.96-6.88(m,2H),6.78-6.76(m,1H),6.33(s,1H).

[0054] The carbon NMR spectrum data of the obtained product are as follows:

[0055] 13 CNMR (100MHz, CDCl3): δ178.1,148.6,146.3,143.9,142.2,134.6,131.7,128.8,1 28.6(3C),128.3,127.9,127.8(2C),126.7,123.8,122.8(2C),121.3,110.5,65.1.

[0056] It is evident that the product obtained is 3-phenyl-spiro[indan-1,3'-indoline]-2'-one.

[0057] Example 2

[0058] Synthesis of 4-hydroxy-3-(2-hydroxyphenyl)-spiro[indan-1,3'-indoline]-2'-one:

[0059]

[0060] At room temperature and with stirring, indole-2,3-dione (73.5 mg, 0.5 mmol), 2,2'-(ethylene-1,1-diyl)diphenol (127.2 mg, 0.6 mmol), and DCE (2 mL) were added sequentially to a reaction tube (25 mL), followed by TfOH (300 mg, 177 μL, 1.5 mmol). The reaction tube was sealed and thoroughly stirred. The reaction process was monitored by thin-layer chromatography, and the reaction was completed after 1 hour.

[0061] After the reaction was complete, 10 mL of DCM was added to the reaction tube to dilute the reaction solution, and then 0.5 mL of Et3N was added dropwise to quench the reaction. The mixture was stirred for another 10 min, and then the organic solvent was removed by rotary evaporation. The residue was purified by column chromatography (PE / EA = 2 / 1) to obtain a white solid with a yield of 90%.

[0062] The 1H NMR spectrum data of the obtained product are as follows:

[0063] 1HNMR (400MHz, CDCl3): δ9.88(s,1H),7.67-7.53(m,1H),7.36-7.31(m,1H),7.49-7.33(m,2H),7.22-7.16(m,1H),7 .09-7.06(m,1H),7.01-6.97(m,2H),6.90-6.85(m,1H),6.78-6.76(m,2H),6.43(s,1H),4.83(s,1H),4.76(s,1H).

[0064] The carbon NMR spectrum data of the obtained product are as follows:

[0065] 13 CNMR (100MHz, CDCl3): δ179.1,158.6(2C),147.6,145.3,142.9,135.6,130.7,129.6, 128.3,127.8,127.7(2C),126.8,124.8,123.8(2C),121.3,118.2,116.3,110.5,65.1.

[0066] The high-resolution mass spectrometry data of the obtained product are as follows:

[0067] HRMS(ESI)m / z:[M+H] + C 23 H 18 NO + Calculated value: 342.1125; Test value: 342.1221.

[0068] It is evident that the product obtained is 4-hydroxy-3-(2-hydroxyphenyl)-spiro[indan-1,3'-indoline]-2'-one.

[0069] Example 3

[0070] Synthesis of 4-hydroxy-3-(2-hydroxyphenyl)-4'-methyl-spiro[indan-1,3'-indoline]-2'-one:

[0071]

[0072] At room temperature and with stirring, 4-methyl-indole-2,3-dione (80.5 mg, 0.5 mmol), 2,2'-(ethylene-1,1-diyl)diphenol (127.2 mg, 0.6 mmol), and DCE (2 mL) were added sequentially to a reaction tube (25 mL). Finally, TfOH (300 mg, 177 μL, 1.5 mmol) was added. After sealing the reaction tube, the mixture was stirred thoroughly. The reaction process was monitored by thin-layer chromatography, and the reaction was completed after 1 hour.

[0073] After the reaction was complete, 10 mL of DCM was added to the reaction tube to dilute the reaction solution, and then 0.5 mL of Et3N was added dropwise to quench the reaction. The mixture was stirred for another 10 min, and then the organic solvent was removed by rotary evaporation. The residue was purified by column chromatography (PE / EA = 2 / 1) to obtain a white solid in 82% yield.

[0074] The 1H NMR spectrum data of the obtained product are as follows:

[0075] 1 HNMR (400MHz, CDCl3): δ9.80(s,1H),7.28-7.25(m,1H),7.20-7.18(m,2H),7.15-7.13(m,1H),7.09-7.06(m,1H) ),6.95-6.90(m,1H),6.87-6.85(m,2H),6.79-6.75(m,2H),6.43(s,1H),4.91(s,1H),4.88(s,1H),2.31(s,3H).

[0076] The carbon NMR spectrum data of the obtained product are as follows:

[0077] 13 CNMR (100MHz, CDCl3): δ173.1,159.6(2C),146.6,144.3,142.0,136.3,134.7,130.1,128 .5,127.7,127.1(2C),126.7,125.1,124.1(2C),121.6,117.7,116.1,111.3,66.1,21.5.

[0078] The high-resolution mass spectrometry data of the obtained product are as follows:

[0079] HRMS(ESI)m / z:[M+H] + C 23 H 18 NO + Calculated value: 356.1281; Test value: 356.1285.

[0080] It is evident that the product obtained is 4-hydroxy-3-(2-hydroxyphenyl)-4'-methyl-spiro[indan-1,3'-indoline]-2'-one.

[0081] Example 4

[0082] Synthesis of 4-hydroxy-3-(2-hydroxyphenyl)-5'-methyl-spiro[indan-1,3'-indoline]-2'-one:

[0083]

[0084] At room temperature and with stirring, 5-methyl-indole-2,3-dione (80.5 mg, 0.5 mmol), 2,2'-(ethylene-1,1-diyl)diphenol (127.2 mg, 0.6 mmol), and DCE (2 mL) were added sequentially to a reaction tube (25 mL), followed by TfOH (300 mg, 177 μL, 1.5 mmol). The reaction tube was sealed and thoroughly stirred. The reaction process was monitored by thin-layer chromatography, and the reaction was completed after 1 hour.

[0085] After the reaction was complete, 10 mL of DCM was added to the reaction tube to dilute the reaction solution, and then 0.5 mL of Et3N was added dropwise to quench the reaction. The mixture was stirred for another 10 min, and then the organic solvent was removed by rotary evaporation. The residue was purified by column chromatography (PE / EA = 2 / 1) to obtain a white solid in 92% yield.

[0086] The 1H NMR spectrum data of the obtained product are as follows:

[0087] 1 HNMR (400MHz, CDCl3): δ9.83(s,1H),7.43-7.37(m,1H),7.30-7.22(m,2H),7.19-7.16(m,1H),7.10-7.07(m,1H) ),6.99-6.93(m,1H),6.83-6.78(m,2H),6.65-6.58(m,2H),6.41(s,1H),4.85(s,1H),4.75(s,1H),2.21(s,3H).

[0088] The carbon NMR spectrum data of the obtained product are as follows:

[0089] 13 CNMR (100MHz, CDCl3): δ172.2,158.6(2C),147.1,146.3,142.6,137.1,133.2,130.9,127 .9,127.6,127.0(2C),126.3,125.4,124.2(2C),120.3,118.2,117.1,111.6,65.8,21.3.

[0090] The high-resolution mass spectrometry data of the obtained product are as follows:

[0091] HRMS(ESI)m / z:[M+H] + C 23 H 18 NO +Calculated value: 356.1281; Test value: 356.1285.

[0092] It is evident that the product obtained is 4-hydroxy-3-(2-hydroxyphenyl)-5'-methyl-spiro[indan-1,3'-indoline]-2'-one.

[0093] Example 5

[0094] Synthesis of 4-hydroxy-3-(2-hydroxyphenyl)-6'-fluoro-spiro[indan-1,3'-indoline]-2'-one:

[0095]

[0096] At room temperature and with stirring, 6-fluoro-indole-2,3-dione (82.5 mg, 0.5 mmol), 2,2'-(ethylene-1,1-diyl)diphenol (127.2 mg, 0.6 mmol), and DCE (2 mL) were added sequentially to a reaction tube (25 mL), followed by TfOH (300 mg, 177 μL, 1.5 mmol). The reaction tube was sealed and thoroughly stirred. The reaction process was monitored by thin-layer chromatography, and the reaction was completed after 1 hour.

[0097] After the reaction was complete, 10 mL of DCM was added to the reaction tube to dilute the reaction solution, and then 0.5 mL of Et3N was added dropwise to quench the reaction. The mixture was stirred for another 10 min, and then the organic solvent was removed by rotary evaporation. The residue was purified by column chromatography (PE / EA = 2 / 1) to obtain a white solid in 86% yield.

[0098] The 1H NMR spectrum data of the obtained product are as follows:

[0099] 1 HNMR (400MHz, CDCl3): δ9.79(s,1H),7.73-7.67(s,1H),7.33-7.25(m,2H),7.18-7.13(m,1H),7.11-7.06 (m,1H),6.91-6.86(m,1H),6.82-6.76(m,2H),6.66-6.53(m,2H),6.43(s,1H),4.86(s,1H),4.77(s,1H).

[0100] The carbon NMR spectrum data of the obtained product are as follows:

[0101] 13CNMR (100MHz, CDCl3): δ172.8,161.0(d,J=244.1Hz),148.5,145.6,143.8,143.6(d,J=11.5Hz),135.4,131.6,128.8(2C), 128.3, 128.0, 127.8 (2C), 126.7, 124.5 (d, J = 9.5Hz), 123.6, 122.8, 121.3, 109.5 (d, J = 22.8Hz), 99.2 (d, J = 27.7Hz), 64.5.

[0102] The high-resolution mass spectrometry data of the obtained product are as follows:

[0103] HRMS(ESI)m / z:[M+H] + C 22 H 15 FNO3 + Calculated value: 360.1031; Test value: 360.1033.

[0104] It is evident that the product obtained is 4-hydroxy-3-(2-hydroxyphenyl)-6'-fluoro-spiro[indan-1,3'-indoline]-2'-one.

[0105] Example 6

[0106] Synthesis of 4-hydroxy-3-(2-hydroxyphenyl)-1'-methyl-spiro[indan-1,3'-indoline]-2'-one:

[0107]

[0108] At room temperature and with stirring, 1-methyl-indole-2,3-dione (80.5 mg, 0.5 mmol), 2,2'-(ethylene-1,1-diyl)diphenol (127.2 mg, 0.6 mmol), and DCE (2 mL) were added sequentially to a reaction tube (25 mL), followed by TfOH (300 mg, 177 μL, 1.5 mmol). The reaction tube was sealed and thoroughly stirred. The reaction process was monitored by thin-layer chromatography, and the reaction was completed after 1 hour.

[0109] After the reaction was complete, 10 mL of DCM was added to the reaction tube to dilute the reaction solution, and then 0.5 mL of Et3N was added dropwise to quench the reaction. The mixture was stirred for another 10 min, and then the organic solvent was removed by rotary evaporation. The residue was purified by column chromatography (PE / EA = 2 / 1) to obtain a white solid in 83% yield.

[0110] The 1H NMR spectrum data of the obtained product are as follows:

[0111] 1 HNMR (400MHz, CDCl3): δ7.71-7.67(m,1H),7.61-7.55(m,2H),7.20-7.16(m,2H),7.09-7.05(m,1H),6.97 -6.93(m,1H),6.81-6.78(m,2H),6.67-6.59(m,2H),6.31(s,1H),4.82(s,1H),4.77(s,1H),3.41(s,3H).

[0112] The carbon NMR spectrum data of the obtained product are as follows:

[0113] 13 CNMR (100MHz, CDCl3): δ175.8,149.4,147.3,145.6,143.7,135.1,132.1,129.6,128.3 (2C),128.1,127.7,127.6(3C),126.3,123.6,122.8,122.6,121.5,108.7,66.5,26.9.

[0114] The high-resolution mass spectrometry data of the obtained product are as follows:

[0115] HRMS(ESI)m / z:[M+H] + C 23 H 18 NO + Calculated value: 356.1281; Test value: 356.1285.

[0116] It is evident that the product obtained is 4-hydroxy-3-(2-hydroxyphenyl)-1'-methyl-spiro[indan-1,3'-indoline]-2'-one.

[0117] Example 7

[0118] Synthesis of 4',5'-dihydroxy-3-phenyl-spiro[indan-1,3'-indoline]-2'-one:

[0119]

[0120] At room temperature and with stirring, 4,5-dihydroxy-indole-2,3-dione (89.5 mg, 0.5 mmol), 1,1-diphenylethylene (108 mg, 0.6 mmol), and DCE (2 mL) were added sequentially to a reaction tube (25 mL), followed by TfOH (300 mg, 177 μL, 1.5 mmol). The reaction tube was sealed and thoroughly stirred. The reaction process was monitored by thin-layer chromatography, and the reaction was completed after 1 hour.

[0121] After the reaction was complete, 10 mL of DCM was added to the reaction tube to dilute the reaction solution, and then 0.5 mL of Et3N was added dropwise to quench the reaction. The mixture was stirred for another 10 min, and then the organic solvent was removed by rotary evaporation. The residue was purified by column chromatography (PE / EA = 1 / 1) to obtain a white solid in 88% yield.

[0122] The 1H NMR spectrum data of the obtained product are as follows:

[0123] 1 HNMR (400MHz, CDCl3): δ9.88(s,1H),7.73-7.68(m,2H),7.54-7.52(m,1H),7.49-7.36(m,1H),7.25-7.16 (m,1H),7.07-7.04(m,2H),6.96-6.88(m,2H),6.79-6.76(m,2H),6.37(s,1H),6.10(s,1H),5.21(s,1H).

[0124] The carbon NMR spectrum data of the obtained product are as follows:

[0125] 13 CNMR (100MHz, CDCl3): δ178.8,148.6,147.7,146.3,146.1,143.8,142.1,135.6,133. 7,128.8,128.6,128.3(2C),127.7(2C),126.7,123.5,122.6(2C),121.7,110.2,65.5.

[0126] The high-resolution mass spectrometry data of the obtained product are as follows:

[0127] HRMS(ESI)m / z:[M+H] + C 22 H 16 NO3 + Calculated value: 342.1125; Test value: 342.1127.

[0128] It is evident that the product obtained is 4',5'-dihydroxy-3-phenyl-spiro[indan-1,3'-indoline]-2'-one.

[0129] Example 8

[0130] Synthesis of 4',5'-dihydroxy-6-methyl-3-(4-tolyl)-spiro[indan-1,3'-indoline]-2'-one:

[0131]

[0132] At room temperature and with stirring, 4,5-dihydroxy-indole-2,3-dione (89.5 mg, 0.5 mmol), 4,4'-dimethyl-diphenylethylene (124.8 mg, 0.6 mmol), and DCE (2 mL) were added sequentially to a reaction tube (25 mL), followed by TfOH (300 mg, 177 μL, 1.5 mmol). The reaction tube was sealed and thoroughly stirred. The reaction process was monitored by thin-layer chromatography, and the reaction was completed after 1 hour.

[0133] After the reaction was complete, 10 mL of DCM was added to the reaction tube to dilute the reaction solution, and then 0.5 mL of Et3N was added dropwise to quench the reaction. The mixture was stirred for another 10 min, and then the organic solvent was removed by rotary evaporation. The residue was purified by column chromatography (PE / EA = 2 / 1) to obtain a white solid with a yield of 90%.

[0134] The 1H NMR spectrum data of the obtained product are as follows:

[0135] 1 HNMR (400MHz, CDCl3): δ9.76(s,1H),7.71-7.68(m,1H),7.43-7.37(m,1H),7.31-7.28(m,1H),7.20-7.15(m,1H),7.08 -7.06(m,1H),6.88-6.82(m,2H),6.79-6.75(m,2H),6.37(s,1H),6.10(s,1H),5.21(s,1H),2.41(s,3H),2.32(s,3H).

[0136] The carbon NMR spectrum data of the obtained product are as follows:

[0137] 13 CNMR (100MHz, CDCl3): δ177.8,147.6,146.7,146.3,145.1,143.8,142.2,135.6,134.7,128 .8,128.7,128.1(2C),127.3(2C),126.5,123.1,122.3(2C),121.2,110.2,66.5,22.5,21.7.

[0138] The high-resolution mass spectrometry data of the obtained product are as follows:

[0139] HRMS(ESI)m / z:[M+H] + C 24 H 20 NO3 + Calculated value: 370.1438; Test value: 370.1440.

[0140] It can be seen that the product obtained is 4',5'-dihydroxy-6-methyl-3-(4-tolyl)-spiro[indan-1,3'-indoline]-2'-one.

[0141] Examples 9 to 16

[0142] Except for the different reaction solvents, Examples 9 to 16 were identical to Example 1 in all other operations. The organic solvents used in each example and the yields of the corresponding products are shown in Table 1 below:

[0143] Table 1

[0144] Example 9 Dimethyl sulfoxide NR Example 10 N,N-Dimethylformamide NR Example 11 Tetrahydrofuran NR Example 12 Acetonitrile 30％ Example 13 Toluene 41％ Example 14 dichloromethane 89％ Example 15 chloroform 85％ Example 16 Benzonitrile 29％

[0145] From the table above (where NR represents no reaction), we can see that:

[0146] (1) When using a nonprotic solvent, the reaction yield is high, especially when using a haloalkanes as the reaction solvent. Among them, the reaction is best in 1,2-dichloroethane (Example 1), with a separation yield of 97%.

[0147] (2) When other protic solvents are used, the reaction is poor or even non-reacting.

[0148] Taking all factors into consideration, 1,2-dichloroethane is the optimal reaction solvent.

[0149] In Examples 1 to 8, trifluoromethanesulfonic acid was used as the acid. Experiments showed that hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, sulfuric acid, and Lewis acids BF3·Et2O and FeCl3 could not effectively replace trifluoromethanesulfonic acid in this invention.

[0150] Examples 17 to 22

[0151] Except for the different acids, Examples 17 to 22 are identical to Example 1 in all other operations. The acids used in each example and the yields of the corresponding products are shown in the table below:

[0152] Example 17 hydrochloric acid NR Example 18 Trifluoroacetic acid NR Example 19 p-Toluenesulfonic acid 5％ Example 20 Fluorosulfonic acid 20％ Example 21 <![CDATA[BF3·Et2O]]> NR Example 22 <![CDATA[FeCl3]]> NR

[0153] From the table above (where NR represents no reaction), we can see that:

[0154] (1) Other organic acids, inorganic acids, and Lewis acids cannot effectively replace trifluoromethanesulfonic acid in catalytic reactions;

[0155] (2) Trifluoromethanesulfonic acid has a unique function of catalyzing substrate-selective reactions.

[0156] Taking all factors into account, trifluoromethanesulfonic acid is the best acid.

[0157] In Examples 1 to 22:

[0158] (1) The optimal molar ratio of 1,1-diarylethylene to indole-2,3-dione is 1.2:1, and other ratios are not limited to this ratio.

[0159] (2) The optimal molar ratio of trifluoromethanesulfonic acid to indole-2,3-dione is 4:1, and other ratios are not limited to this.

[0160] (3) The reaction temperature is 25℃ and the reaction time is 1 hour. Through experiments, the reaction temperature can be appropriately adjusted within the range of 25-80℃, and the corresponding reaction time can be appropriately adjusted within the range of 10 minutes-12 hours.

[0161] The applicant declares that this invention illustrates the ligand precursor compound containing a spirocyclic indole ketone skeleton and its preparation method through the above embodiments. However, this invention is not limited to the above embodiments, i.e., it does not mean that this invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of raw materials for the products of this invention, addition of auxiliary components, and selection of specific methods, etc., all fall within the protection scope and disclosure scope of this invention.

Claims

1. A method for preparing a ligand precursor compound containing a spirocyclic indole ketone skeleton, characterized in that, The preparation method includes the following steps: The indole-2,3-dione compound was reacted with the 1,1-diarylethylene compound to obtain the ligand precursor compound containing the spirocyclic-indole ketone skeleton; The structure of the indole-2,3-dione compound is as follows: or ; The structure of the 1,1-diarylethylene compound is as follows: or ; The reaction equation is as follows: ； ； R 1 R 2 R 3 and R 4 Each is independently selected from any one of H, halogen, methyl, ethyl, methoxy, ethoxy, benzyl or allyl; The reaction is carried out in the presence of an acidic reagent selected from trifluoromethanesulfonic acid.

2. The preparation method according to claim 1, characterized in that, The molar ratio of the 1,1-diarylethylene compound to the indole-2,3-dione compound is 1.1-1.5:

1.

3. The preparation method according to claim 2, characterized in that, The molar ratio of the 1,1-diarylethylene compound to the indole-2,3-dione compound is 1.2:

1.

4. The preparation method according to claim 1, characterized in that, The molar ratio of the acidic reagent to the indole-2,3-dione compound is 0.2-5:

1.

5. The preparation method according to claim 4, characterized in that, The molar ratio of the acidic reagent to the indole-2,3-dione compound is 4:

1.

6. The preparation method according to claim 1, characterized in that, The reaction is carried out in an organic solvent.

7. The preparation method according to claim 6, characterized in that, The organic solvent is selected from at least one of 1,2-dichloroethane, dichloromethane, trichloromethane, acetonitrile, benzonitrile, or toluene.

8. The preparation method according to claim 7, characterized in that, The organic solvent is selected from 1,2-dichloroethane.

9. The preparation method according to claim 1, characterized in that, The reaction takes place in an air atmosphere.

10. The preparation method according to claim 1, characterized in that, The reaction temperature is 25-80℃, and the reaction time is 1 hour-12 hours.

11. The preparation method according to claim 10, characterized in that, The reaction was carried out at a temperature of 25°C for 1 hour.

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