Indolicolide-2-carboxylic acid derivative as well as preparation method and application thereof

Abstract

The invention discloses an indolizine-2-carboxylic acid derivative as well as a preparation method and application thereof. The indolizine-2-carboxylic acid derivative is structurally a racemate as shown in a formula (1) and a levorotatory or dextrorotatory optical active body. The preparation method of the 1-(3-substituted isoindolinone)-indolizine-2-carboxylic ester derivative comprises the following steps: by taking Bronsted acid as a catalyst and taking an indolizine-2-carboxylic ester compound and a 3-hydroxy-3-substituent-isoindolinone compound as raw materials, carrying out Friedel-Crafts reaction in an organic solvent to obtain the 1-(3-substituted isoindolinone)-indolizine-2-carboxylic ester derivative. Performing alkaline hydrolysis and acidification to obtain a racemate of a formula (1); the corresponding levorotatory and dextrorotatory optical active bodies of the formula (1) can be obtained through conventional chiral preparative chromatography. The method is mild in reaction condition, simple in process, convenient to operate and high in yield, and the prepared indolizine-2-carboxylic acid derivative can be used as a ligand to be applied to a metal-catalyzed hydrocarbon activation reaction. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a preparation method of indolizine derivatives, in particular to an indolizine-2-carboxylic acid derivative and its preparation method and use. Background Art

[0002] Transition metal-catalyzed C-H activation can construct various new skeletons by one-step functionalization of C-H bonds in organic compounds. Compared with traditional coupling synthesis, it is more simple and efficient and has great potential application value, and has developed into a frontier and popular field in catalytic research. In the C-H activation catalyzed by transition metals such as palladium, rhodium, iridium, cobalt, ruthenium, etc., acid radical ions are often added to assist in the base-assisted metallization process, and an acid is added to the reaction system as an in-situ formed anionic ligand to achieve C-H activation. Among them, chiral acids can achieve asymmetric C-H activation. Such acids can be amino acids, phosphoric acids, various carboxylic acids, etc., such as the literature (Angew.Chem., Int.Ed.2008, 47, 4882-4886), (Angew.Chem., Int.Ed.2018, 57, 12048-12052; Angew.Chem.Int.Ed.2021, 60, 23187-231; 92Acs Catal.2020, 10, 7117-7122; Angew.Chem., Int.Ed.2019, 58, 1153-1157; J.Am.Chem.Soc.2021, 143, 6810; Org.Lett.2019, 21, 1895). The development of ligands plays a crucial role in C-H activation reactions, especially in asymmetric reactions. However, for the field of C-H activation, the types of carboxylic acids are still too few, and there are no matching chiral carboxylic acids for many reactions, especially asymmetric C-H activation reactions, to achieve good chiral control.

[0003] The present invention aims to disclose the synthesis of a novel carboxylic acid, namely indolizine-2-carboxylic acid, and use the synthesized carboxylic acid or further resolved chiral carboxylic acid as a ligand in transition metal-catalyzed C-H activation reactions, which is of great significance to the field of chemical synthesis. Summary of the Invention

[0004] One object of the present invention is to provide an indolizine-2-carboxylic acid containing an isoindolinone substituent.

[0005] Another object of the present invention is to provide a preparation method of the above carboxylic acid.

[0006] A third object of the present invention is to provide the application of the above carboxylic acid or further resolved chiral carboxylic acid as a ligand in transition metal-catalyzed C-H activation reactions.

[0007] An indene-2-carboxylic acid derivative, which is a racemate, a left-handed or right-handed optically active form having the structure of formula (1);

[0008]

[0009] In the formula: R 1 is selected from C1-C6 alkyl, halogen, benzyl, heteroaryl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclohexyl, condensed aryl, aryl or substituted aryl; R 2 -R 9 are independently selected from H, halogen, difluoromethyl, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, aryloxy, benzyl, aryl or substituted aryl; the substituents on the said substituted aryl are selected from any 1-5 of halogen, trifluoromethyl, nitro, aryl, cyclopropyl, cyclohexyl, C1-C6 alkyl, C1-C6 alkoxy, aryloxy.

[0010] A method for preparing an indene-2-carboxylic acid derivative, using a Bronsted acid as a catalyst, indene-2-carboxylic acid ester compounds having the structure of formula (2) and 3-hydroxy-3-substituted-isatinone compounds having the structure of formula (3) as raw materials, and after carrying out a Friedel-Crafts reaction in an organic solvent, obtaining 1-(3-substituted isatinone)-indene-2-carboxylic acid ester derivatives, then carrying out alkaline hydrolysis, acidification and separation and purification to obtain; the left-handed and right-handed optically active forms of formula (1) with high enantioselectivity can be further prepared by conventional chiral preparative chromatography;

[0011]

[0012] In the formula: R 1 -R 9 are defined as described in claim 1, R 10 is selected from C1-C6 alkyl or cycloalkyl, benzyl, trifluoromethyl. The said alkaline hydrolysis can occur smoothly according to the hydrolysis reaction conditions of conventional carboxylic acid esters.

[0013] In the method for preparing an indene-2-carboxylic acid derivative, the said organic solvent is preferably toluene, xylene, benzene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, fluorobenzene, chlorobenzene or ethylbenzene.

[0014] In the method for preparing an indene-2-carboxylic acid derivative, the said Bronsted acid is preferably methanesulfonic acid, diphenyl phosphate, p-toluenesulfonic acid, acetic acid, trifluoromethanesulfonic acid, benzoic acid.

[0015] In the method for preparing an indene-2-carboxylic acid derivative, the reaction temperature is preferably 0-120 °C, and the reaction time is preferably 1-48 hours; molecular sieves, anhydrous sodium sulfate and other water absorbents can be added to the reaction, or no water absorbent is added.

[0016] In the method for preparing indene-2-carboxylic acid derivatives, the molar ratio among the indene-2-carboxylic acid ester compounds of formula (2), the 3-hydroxy-3-substituted-isoisoindolinone compounds of formula (3) and the Bronsted acid is preferably 1:0.8-1.5:0.001-0.2.

[0017] Use of an indene-2-carboxylic acid derivative, wherein the compound is used as a ligand in a C-H activation reaction catalyzed by a transition metal catalyst, especially as an optically pure compound as a chiral ligand in an asymmetric catalytic C-H activation reaction of a transition metal catalyst; the transition metal catalysts include palladium, ruthenium, rhodium, iridium, cobalt, etc.

[0018] The indene-2-carboxylic acid derivative is used as a ligand in a C-H activation reaction catalyzed by a transition metal, especially: using the indene-2-carboxylic acid derivative of formula (1) as a ligand in the cyclization reaction of a sulfinimine derivative with 4,4-dimethyl-2,6-dioxocyclohexylphenyl iodonium inner salt or 3-bromo-1,1,1-trifluoroacetone catalyzed by ruthenium or rhodium to prepare a sulfinimine derivative. Or the indene-2-carboxylic acid derivative is used as a ligand in the cyclization reaction of a sulfinimine derivative with an α-carbonyl sulfonium ylide derivative catalyzed by ruthenium to prepare a sulfinimine derivative.

[0019] It should be noted that the optically active form of the indene-2-carboxylic acid derivative can be prepared by an asymmetric catalytic method, or obtained by a conventional chemical resolution method, or the enantiomers can be obtained by a chiral preparative chromatography method.

[0020] The indene-2-carboxylic acid ester compounds of formula (2) can be prepared according to known literature (Angew. Chem. Int. Ed. 2017, 56, 7967), or according to the typical synthetic reaction formula:

[0021]

[0022] The 3-hydroxy-3-substituted-isoisoindolinone compounds of formula (3) can be prepared according to known literature (Chem. Commun., 2019, 55, 8317), or according to the typical synthetic method as follows:

[0023]

[0024] The present invention has the following advantages:

[0025] 1) The reaction conditions are mild; the reaction has strong generality;

[0026] 2) The feeding and post-treatment are both very simple. Indene-2-carboxylic acid can be used as a ligand for transition metal-catalyzed reactions and can also be used as a ligand for asymmetric catalytic reactions.

[0027] 3) The starting materials for the reaction can be easily obtained according to the methods similar to those disclosed in the literature.

[0028] 4) By using the method of the present invention, inden-2-carboxylic acid derivatives with high optical activity can be obtained as needed.

[0029] Specific implementation methods

[0030] The following examples will help to understand the present invention, but are not limited to the content of the present invention:

[0031] Example 1

[0032] General process and characterization of typical products:

[0033]

[0034] To the reaction flask, successively add indene-2-carboxylate substrate 2 (2 mmol, 1.0 equiv), 3-hydroxy-3-substituted isoindolinone 3 (2 mmol, 1.0 equiv), and diphenyl phosphate (0.2 mmol, 0.1 equiv) as a Bronsted acid catalyst. Add 40 mL of dichloromethane and react at room temperature for 48 hours. After monitoring the reaction to the end point by TLC, concentrate the reaction solution under vacuum. Through flash column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1), after desolvation and drying, the corresponding compound 1-1 is obtained. Take 1 mmol of compound 1-1 and 6 mmol of sodium hydroxide and dissolve them in a mixed solution composed of 20 mL of tetrahydrofuran, 20 mL of methanol, and 5 mL of water. Reflux and stir the reaction for 6 hours, acidify to pH 2.0 with 1 mol / L hydrochloric acid, then extract with ethyl acetate 3 times. After removing the solvent, use flash column chromatography (eluent: petroleum ether / ethyl acetate / formic acid = 1 / 1 / 0.015), and after desolvation and drying, the corresponding indene-2-carboxylic acid compound 1 is obtained.

[0035] The structure of product 1-1a is as follows:

[0036]

[0037] Yield 88%; 11H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.98–7.88 (m, 3H), 7.56 (d, J = 7.0 Hz, 4H), 7.37 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 7.5 Hz, 3H), 7.22 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 9.9 Hz, 1H), 5.87 (d, J = 9.9 Hz, 1H), 3.60 (s, 3H) ppm.

[0038] The structure of Product 1a is as follows:

[0039]

[0040] Yield: 86%; 1 1H NMR (400 MHz, CD2Cl2) δ 13.32 (s, 1H), 10.38 (s, 1H), 8.57 (s, 1H), 7.91 (m, 2H), 7.60 (m, 2H), 7.52 (m, 2H), 7.47–7.43 (m, 1H), 7.38–7.24 (m, 5H), 6.75 (d, J = 10.0 Hz, 1H), 6.11 (d, J = 10.0 Hz, 1H) ppm. The compound was resolved by high performance liquid chiral preparative chromatography with the resolution conditions: Daicel AD-H column (250×4.6 mm), n-hexane / i-PrOH / HCOOH = 80 / 20 / 0.1, 1.0 mL·min-1, 254 nm; the retention time of the levorotatory isomer (-)-1a was 21.8 min, [α] 20 D = -560° (c 0.14, CH2Cl2), 98% ee; the retention time of the dextrorotatory isomer (+)-1a was 12.6 min, [α] 20 D = +560° (c 0.14, CH2Cl2), 98% ee;

[0041] The structure of Product 1-1b is as follows:

[0042]

[0043] Yield: 96%; 1 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.25 (d, J = 6.9 Hz, 1H), 8.07 (s, 1H), 7.76 (d, J = 6.8 Hz, 1H), 7.59–7.50 (m, 3H), 7.24 (m, 5H), 6.54 (m, 2H), 6.11 (d, J = 9.3 Hz, 1H), 3.25 (s, 3H) ppm.

[0044] The yield of product 1b is 90%, and the structure is as follows:

[0045]

[0046] The structure of product 1-1c is as follows:

[0047]

[0048] The yield is 95%; 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.30 (d, J = 6.6 Hz, 1H), 8.17 (s, 1H), 7.80 (d, J = 6.9 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.58 (m, 3H), 7.48 (d, J = 8.1 Hz, 2H), 6.64–6.52 (m, 2H), 6.15 (d, J = 9.0 Hz, 1H), 3.29 (s, 3H) ppm.

[0049] The yield of product 1c is 88%; the structure is as follows:

[0050]

[0051] The structure of product 1-1d is as follows:

[0052]

[0053] The yield is 90%; 1 H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.01–7.95 (m, 2H), 7.90 (d, J = 8.7 Hz, 1H), 7.58–7.51 (m, 4H), 7.45 (m, 1H), 7.36 (t, J = 7.3 Hz, 1H), 7.11–7.08 (m, 1H), 6.85 (d, J = 3.2 Hz, 2H), 6.73 (d, J = 9.9 Hz, 1H), 5.80 (d, J = 9.9 Hz, 1H), 3.65 (s, 3H) ppm.

[0054] The yield of product 1d is 80%, and the structure is as follows:

[0055]

[0056] The structure of product 1-1e is as follows:

[0057]

[0058] The yield is 85%; 11H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.92 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.0 Hz, 1H), 7.76–7.69 (m, 2H), 7.67–7.59 (m, 3H), 7.49–7.42 (m, 3H), 7.05 (d, J = 10.0 Hz, 1H), 6.16 (d, J = 9.8 Hz, 1H), 3.43 (s, 3H) ppm.

[0059] The structure of product 1e is as follows:

[0060]

[0061] Yield 89%; 1 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.27 (br, 1H), 8.50 (s, 1H), 8.29 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 6.8 Hz, 1H), 7.72–7.60 (m, 4H), 7.54 (t, J = 7.7 Hz, 1H), 7.38–7.33 (m, 3H), 6.87 (d, J = 9.8 Hz, 1H), 6.18 (d, J = 9.8 Hz, 1H) ppm. The compound was separated by high performance liquid chiral preparative chromatography under the conditions of Daicel AD-H column (250×4.6 mm), n-hexane / i-PrOH / HCOOH = 80 / 20 / 0.1, 1.0 mL·min -1 , 254 nm; the retention time of the levorotatory isomer (-)-1e was 29.1 min, [α] 20 D = -605° (c 0.35, CH2Cl2), 99% ee; the retention time of the dextrorotatory isomer (+)-1e was 12.4 min, [α] 20 D = +605° (c 0.35, CH2Cl2), 99% ee.

[0062] Example 2

[0063] During the preparation of product 1a, diphenyl phosphate as the Bronsted acid catalyst was replaced with methanesulfonic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid with the same amount of substance respectively, and the yields of the corresponding indolizine-2-carboxylic acid compound 1a were 65%, 85% and 72% respectively. During the preparation of product 1a, dichloromethane was replaced with the same volume of chloroform and 1,2-dichloroethane respectively, and the yields of the corresponding indolizine-2-carboxylic acid compound 1a were 85% and 82% respectively.

[0064] Example 3

[0065]

[0066] Add indolizine-2-carboxylic acid compound (±)-1e (0.02 mmol, 0.2 equiv.), diethylamine (0.04 mmol, 0.4 equiv.), and hexafluoroisopropanol (1 mL) to a 10 mL reaction tube, and stir at room temperature for 5 minutes. Then add S,S-diphenylsulfoximine 4a (0.1 mmol, 1.0 equiv.), 4,4-dimethyl-2,6-dioxocyclohexylphenyl iodonium inner salt 5 (0.12 mmol, 1.2 equiv.), and pentamethylcyclopentadienylrhodium(III) dichloride dimer (0.005 mmol, 0.05 equiv.) to the reaction tube, and heat in a sealed tube at 100 °C for 12 hours. After the reaction solution is cooled to room temperature, it is filtered through silica gel and concentrated under vacuum. The corresponding potentially pharmacologically active molecule 1,2-benzothiazine compound (±)-6a is obtained by flash column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1), and the yield is 76% after desolvation and drying. 1 H NMR (400 MHz, CDCl3) δ 9.31 (d, J = 8.6 Hz, 1H), 7.89–7.85 (m, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.64–7.57 (m, 3H), 7.34 (dd, J = 8.0, 1.6 Hz, 1H), 7.32–7.28 (m, 1H), 2.81 (d, J = 9.2 Hz, 2H), 2.53 (d, J = 3.5 Hz, 2H), 1.15 (s, 6H).

[0067] It should be noted that when ligand 1b, 1c, and 1d are used to replace indolizine-2-carboxylic acid compound (±)-1e in the above reaction process, the yields of 1,2-benzothiazine compound (±)-6a are 84%, 88%, and 78% respectively.

[0068] Example 4

[0069]

[0070] Add indolizine-2-carboxylic acid compound (±)-1e (0.015 mmol, 0.15 equiv.), diethylamine (0.03 mmol, 0.3 equiv.), and hexafluoroisopropanol (0.5 mL) to a 10 mL reaction tube and stir at room temperature for 5 minutes. Then add S,S-diphenylsulfoximine 4a (0.1 mmol, 1.0 equiv.), 3-bromo-1,1,1-trifluoroacetone 7 (0.12 mmol, 1.2 equiv.), pentamethylcyclopentadienyliridium(III) dichloride dimer (0.005 mmol, 0.05 equiv.), and silver carbonate (0.075 mmol, 0.75 equiv.) to the reaction tube, seal the tube, and heat at 60 °C for 24 hours. After the reaction solution is cooled to room temperature, filter it through silica gel and concentrate it under vacuum. The corresponding 1,2-benzothiazine compound (±)-6b is obtained by flash column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1), and the yield is 65% after evaporation of the solvent and drying. 1 H NMR (400 MHz, CDCl3) δ 7.99–7.96 (m, 2H), 7.72–7.67 (m, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.59 (dd, J = 8.1, 1.1 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 8.2 Hz, 1H), 6.79 (s, 1H) ppm.

[0071] It should be noted that when the above reaction process uses ligands 1b, 1c, and 1d to replace indolizine-2-carboxylic acid compound (±)-1e respectively, the yields of 1,2-benzothiazine compound (±)-6b are 64%, 78%, and 88% respectively.

[0072]

[0073] Add indolizine-2-carboxylic acid compound (+)-1e (0.015 mmol, 0.15 equiv.), diethylamine (0.03 mmol, 0.3 equiv.), and hexafluoroisopropanol (0.5 mL) to a 10 mL reaction tube and stir at room temperature for 5 minutes. Then add S,S-bis(4-methylphenyl)sulfoximine 4b (0.1 mmol, 1.0 equiv.), 3-bromo-1,1,1-trifluoroacetone 7 (0.12 mmol, 1.2 equiv.), pentamethylcyclopentadienyliridium(III) dichloride dimer (0.005 mmol, 0.05 equiv.), and silver carbonate (0.075 mmol, 0.75 equiv.) to the reaction tube, seal the tube, and heat at 60 °C for 24 hours. After the reaction solution is cooled to room temperature, filter it through silica gel and concentrate it under vacuum. The corresponding 1,2-benzothiazine compound 6c is obtained by flash column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1), and after desolvation and drying, the yield is 62% and the ee is 92%. 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 6.7 Hz, 2H), 7.20 (d, J = 8.3 Hz, 1H), 6.69 (s, 1H), 2.46 (s, 3H), 2.42 (s, 3H). The compound was separated by high-performance liquid chromatography on a chiral column. The separation conditions were a Daicel IA column (250 × 4.6 mm), n-hexane / i-PrOH = 90 / 10, 1.0 mL·min -1 , 254 nm; the retention times of the two isomers were 14.2 min and 19.4 min, respectively.

[0074] Example 6

[0075]

[0076] Add indolizine-2-carboxylic acid compound (+)-1e (0.02 mmol, 0.2 equiv.), diethylamine (0.04 mmol, 0.4 equiv.), and hexafluoroisopropanol (1 mL) to a 10 mL reaction tube and stir at room temperature for 5 minutes. Then add S,S-diphenylsulfinimine 4a (0.1 mmol, 1.0 equiv.), 4,4-dimethyl-2,6-dioxocyclohexylphenyl iodonium inner salt 5 (0.12 mmol, 1.2 equiv.), and pentamethylcyclopentadienylrhodium(III) dichloride dimer (0.005 mmol, 0.05 equiv.) to the reaction tube, seal the tube, and heat at 60 °C for 24 hours. After the reaction solution is cooled to room temperature, filter it through silica gel and concentrate it under vacuum. The corresponding 1,2-benzothiazine compound 6a is obtained by flash column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1). After evaporation of the solvent and drying, the yield is 72%, 80% ee. 1 1H NMR (400 MHz, CDCl3) δ 9.31 (d, J = 8.6 Hz, 1H), 7.89–7.85 (m, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.64–7.57 (m, 3H), 7.34 (dd, J = 8.0, 1.6 Hz, 1H), 7.32–7.28 (m, 1H), 2.81 (d, J = 9.2 Hz, 2H), 2.53 (d, J = 3.5 Hz, 2H), 1.15 (s, 6H). The compound was separated by high performance liquid chiral preparative chromatography under the conditions of Daicel IA column (250×4.6 mm), n-hexane / i-PrOH = 70 / 30, 1.0 mL·min -1 , 254 nm; the retention times of the two isomers were 8.4 min and 14.6 min, respectively.

Claims

1. An indene-2-carboxylic acid derivative, characterized in that Its structure is a racemate, a left-handed or right-handed optically active form as shown in formula (1); Wherein: R 1 is selected from alkyl of C1-C6, halogen, benzyl, heteroaryl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclohexyl, fused aryl, aryl or substituted aryl; R 2 -R 9 are independently selected from H, halogen, difluoromethyl, trifluoromethyl, alkyl of C1-C6, alkoxy of C1-C6, aryloxy, benzyl, aryl or substituted aryl; the substituents on the said substituted aryl are selected from any 1-5 of halogen, trifluoromethyl, nitro, aryl, cyclopropyl, cyclohexyl, alkyl of C1-C6, alkoxy of C1-C6, aryloxy.

2. A method for preparing the indene-2-carboxylic acid derivative according to claim 1, characterized by using Using a Bronsted acid as a catalyst, indene-2-carboxylate compounds with a structure as shown in formula (2) and 3-hydroxy-3-substituted-isoisoindolinone compounds with a structure as shown in formula (3) as raw materials, a Friedel-Crafts reaction occurs in an organic solvent to obtain 1-(3-substituted isoindolinone)-indene-2-carboxylate derivatives, followed by alkaline hydrolysis, acidification, and separation and purification; the left-handed and right-handed optically active forms of formula (1) with high enantioselectivity can be further prepared by conventional chiral preparative chromatography; Wherein: R 1 ~R 9 is defined as in claim 1, R 10 is selected from C1-C6 alkyl or cycloalkyl, benzyl, trifluoromethyl.

3. The method for preparing the indene-2-carboxylic acid derivative according to claim 2, characterized in that, The organic solvent is preferably toluene, xylene, benzene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, fluorobenzene, chlorobenzene or ethylbenzene.

4. The method for preparing the indene-2-carboxylic acid derivative according to claim 2, characterized in that, The Bronsted acid is preferably methanesulfonic acid, diphenyl phosphate, p-toluenesulfonic acid, acetic acid, trifluoromethanesulfonic acid, benzoic acid.

5. The method for preparing the indene-2-carboxylic acid derivative according to claim 2, characterized in that, The reaction temperature is preferably 0 to 120 °C, and the reaction time is preferably 1 to 48 hours.

6. The method for preparing the indene-2-carboxylic acid derivative according to claim 2, characterized in that, The molar ratio between the indene-2-carboxylate compounds of formula (2), the 3-hydroxy-3-substituted-isoisoindolinone compounds of formula (3) and the Bronsted acid is preferably 1:0.8 to 1.5:0.001 to 0.

2.

7. The use of the indene-2-carboxylic acid derivative according to claim 1 or the indene-2-carboxylic acid derivative prepared by the method according to any one of claims 2-6, characterized in that The compound is used as a ligand in the hydrocarbon activation reaction catalyzed by a transition metal catalyst, especially as an optically pure compound as a chiral ligand in the asymmetric catalytic hydrocarbon activation reaction of a transition metal catalyst; The transition metal catalysts include palladium, ruthenium, rhodium, iridium, cobalt, etc.

8. The use of the indene-2-carboxylic acid derivative according to claim 7, characterized in that The indene-2-carboxylic acid derivative of formula (1) is used as a ligand in the cyclization reaction of sulfoximine derivatives with 4,4-dimethyl-2,6-dioxocyclohexylphenyl iodonium inner salt or 3-bromo-1,1,1-trifluoroacetone catalyzed by ruthenium or rhodium to prepare sulfoximine derivatives.

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