Indole C2 and C4 direct diarylation synthesis method

Abstract

The invention discloses a synthetic method for direct diarylation of indole C2 and C4 positions, and relates to the technical field of chemical organic synthesis. The invention discloses a synthesis method of a 10-phenylbenzo [4, 5] isothiazolo [2, 3-a] indole-5, 5-dioxide compound, which comprises the following steps: in the presence of a transition metal catalyst, an organic catalyst, an oxidizing agent and acid, taking indole-3-formaldehyde protected by aryl sulfonyl and aromatic hydrocarbon as raw materials, and synthesizing the 10-phenylbenzo [4, 5] isothiazolo [2, 3-a] indole-5, 5-dioxide compound through one-step reaction. The reaction operation is simple, the synthesis steps are short, and synthesis only needs one-time operation. The invention solves the problems of more reaction steps, high cost and poor selectivity of the existing synthesis method of the arylated indole derivative.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical organic synthesis, and in particular to a synthesis method for direct diarylation of indole C2 and C4 positions. Background Art

[0002] The indole nucleus, as an important structural unit, is widely present in natural products and bioactive compounds. Furthermore, polysubstituted indoles, as common structural fragments in clinical drugs, play a crucial role in the development of drug molecules in various therapeutic areas, including antiviral, antitumor, anti-inflammatory, and antibacterial drugs. Therefore, the development of efficient synthetic methods for the multifunctionalization of indoles is of great value in pharmaceutical research. Due to the inherently high reactivity of the pyrrole nucleus within the indole skeleton, current research on the difunctionalization of indoles has primarily focused on difunctionalization at the N1 and C2 positions, and at the C2 and C3 positions. However, reports on difunctionalization reactions involving the indole benzene nucleus (C4-C7) are limited. Furthermore, arylated indole derivatives are widely present in natural products, bioactive compounds, and drug molecules. The efficient, concise, economical, and site-selective preparation of arylated indole derivatives is of great research significance in the field of organic synthetic chemistry.

[0003] In existing reports on the synthesis of arylated indole derivatives, the arylation reagents used are mostly pre-activated aromatic hydrocarbons, such as aryl halides, borides, and sulfonates. These methods have limitations in terms of atom economy, step economy, substrate diversity, and mild reaction conditions, making them difficult to meet the requirements of ideal synthesis. Therefore, the development of new, efficient, and site-selective synthetic methods for the arylation of indole derivatives is a challenging but highly valuable research task. In particular, the direct and efficient one-step site-selective diarylation at both the C2 (pyrrole core) and C4 (benzene core) sites of indole is of great research value. Summary of the Invention

[0004] In order to solve the above technical problems, the purpose of the present invention is to provide a synthesis method for direct diarylation of indole C2 and C4 positions, so as to solve the problems of the existing synthesis methods of arylated indole derivatives such as multiple reaction steps, high cost and poor selectivity.

[0005] The present invention solves the above-mentioned technical problem with the following technical solution: A method for synthesizing direct diarylation of indole at C2 and C4 positions is provided, comprising the following steps: in the presence of a transition metal catalyst, an organic catalyst, an oxidant, and an acid, using an arylsulfonyl-protected indole-3-carboxaldehyde represented by the general formula (I) and an aromatic hydrocarbon represented by the general formula (II) as raw materials, and performing a one-step reaction to synthesize a 10-phenylbenzo[4,5]isothiazolo[2,3-a]indole-5,5-dioxide compound represented by the general formula (III), wherein the chemical reaction formula is as follows: ; Among them, R 1 is hydrogen, C1-C4 alkyl, C1-C5 alkoxy, phenyl, halogen, ester or nitrile; R 2 is hydrogen, C1-C5 alkyl, C1-C4 alkoxy, phenyl, di-C1-C3 alkylphenyl, halogen, dihalogen, ester or nitrile; R 3 is hydrogen, C1-C4 alkyl, C1-C2 alkoxy, phenyl, di-C1-C3 alkylphenyl, tri-C1-C2 alkylphenyl, halogen or dihalogen.

[0006] The beneficial effects of the present invention are as follows: The purpose of the present invention is to provide a method for direct diarylation of indole C2 and C4 positions. The synthesis mechanism of the present invention is as follows: Figure 2 Arylsulfonyl-protected indole-3-carboxaldehyde (I) and β -Amino acid condensation forms an imine, which is then coordinated with a palladium catalyst and subsequently activated to give the [6,6] bicyclic palladium intermediate C. The oxidant oxidizes Pd(II) to Pd(IV), which then undergoes arylation with the unconjugated benzene compound (II) to give intermediate E. E undergoes reductive elimination to give intermediate F, which may then undergo two pathways: Path 1: Intermediate F further activates indole C2-H to obtain intermediate H, which is oxidized to obtain Pd(IV) intermediate I. I undergoes intramolecular arylation with the aromatic ring of the arylsulfonyl group to obtain intermediate J. J is reduced and eliminated to obtain intermediate K. K is dissociated by the catalyst to regenerate Pd(II) and continue the catalytic cycle to simultaneously obtain imine intermediate L. L is hydrolyzed to obtain product (III).

[0007] Pathway 2: Intermediate F undergoes catalytic dissociation to produce the imine intermediate G, which is hydrolyzed to produce intermediate (IV). Intermediate (IV) condenses with the imine and then coordinates with Pd(II) to produce intermediate F, which then proceeds as described in Pathway 1.

[0008] On the basis of the above technical solution, the present invention can also be improved as follows: Furthermore, the arylsulfonyl-protected indole-3-carboxaldehyde represented by general formula (I) is prepared by the following method: Sodium hydride and N,N-dimethylformamide are mixed to obtain a suspension. An N,N-dimethylformamide solution of the compound represented by general formula (a) is added dropwise under ice bath conditions. The mixture is reacted under ice bath conditions. Then, an N,N-dimethylformamide solution of the compound represented by general formula (b) is added dropwise. The mixture is heated to room temperature and stirred for reaction to obtain a reaction mixture. The mixture is then diluted, extracted, dried, filtered, concentrated, and finally purified to obtain an arylsulfonyl-protected indole-3-carboxaldehyde represented by general formula (I). The chemical reaction formula is as follows: ; Among them, R 1 is hydrogen, C1-C4 alkyl, C1-C5 alkoxy, phenyl, halogen, ester or nitrile; R 2 It is hydrogen, C1-C5 alkyl, C1-C4 alkoxy, phenyl, di-C1-C3 alkylphenyl, halogen, dihalogen, ester or nitrile.

[0009] Furthermore, in the suspension, the molar volume ratio of sodium hydride to N,N-dimethylformamide is 6 mmol:10 mL.

[0010] Furthermore, the molar ratio of sodium hydride, the compound represented by general formula (a), and the compound represented by general formula (b) is 6:5:5.5.

[0011] Furthermore, in the N,N-dimethylformamide solution of the compound represented by general formula (a), the molar volume ratio of the compound represented by general formula (a) to N,N-dimethylformamide is 5 mmol:10 mL.

[0012] Furthermore, in the N,N-dimethylformamide solution of the compound represented by general formula (b), the molar volume ratio of the compound represented by general formula (b) to N,N-dimethylformamide is 5.5 mmol:10 mL.

[0013] Furthermore, the reaction was carried out in an ice bath for 30 min.

[0014] Furthermore, the reaction was stirred for 4 h.

[0015] Further, H2O was used for dilution.

[0016] Further, extraction was performed with CH2Cl2.

[0017] Furthermore, it was dried with anhydrous magnesium sulfate.

[0018] Furthermore, the molar volume ratio of the transition metal catalyst, the organic catalyst, the oxidant, the arylsulfonyl-protected indole-3-carboxaldehyde represented by the general formula (I), the acid, and the aromatic hydrocarbon represented by the general formula (II) is 0.01-0.02 mmol: 0.05-0.1 mmol: 0.2-0.6 mmol: 0.1-0.3 mmol: 1-2 mmol: 1-3 mL.

[0019] Furthermore, the molar volume ratio of the transition metal catalyst, the organic catalyst, the oxidant, the arylsulfonyl-protected indole-3-carboxaldehyde represented by the general formula (I), the acid, and the aromatic hydrocarbon represented by the general formula (II) is 0.02 mmol: 0.1 mmol: 0.4 mmol: 0.2 mmol: 1.4 mmol: 2 mL.

[0020] Further, R 1 is hydrogen, C1-C2 alkyl, C1-C2 alkoxy, halogen or ester; R 2 is hydrogen, C1-C2 alkyl, C1-C2 alkoxy, phenyl or halogen; R 3 is hydrogen, C1-C4 alkyl, C1-C2 alkoxy, phenyl, tri-C1-C3 alkylphenyl or halogen.

[0021] Further, R 1 is hydrogen, methyl, fluorine, chlorine or bromine; R 2 is hydrogen, methyl, methoxy, fluorine, chlorine or bromine; R 3 is hydrogen, methyl, methoxy, fluorine or chlorine.

[0022] Further, R 1 is hydrogen; R 2 is methyl; R 3 is hydrogen, methyl, methoxy or fluorine.

[0023] Furthermore, the transition metal catalyst is palladium trifluoroacetate, palladium acetate, palladium chloride or bistriphenylphosphine palladium dichloride.

[0024] Furthermore, the transition metal catalyst is palladium trifluoroacetate or palladium acetate.

[0025] Furthermore, the transition metal catalyst is palladium acetate.

[0026] Furthermore, the organic catalyst is α -amino acids or β -amino acids.

[0027] Furthermore, the organic catalyst is β -amino acids.

[0028] Furthermore, the organic catalyst is β -Alanine.

[0029] Furthermore, the oxidant is copper acetate, silver oxide, potassium peroxodisulfate or oxygen.

[0030] Furthermore, the oxidant is potassium persulfate or oxygen.

[0031] Furthermore, the oxidizing agent is potassium peroxodisulfate.

[0032] Furthermore, the acid is trifluoroacetic acid, acetic acid or benzoic acid.

[0033] Furthermore, the acid is trifluoroacetic acid.

[0034] Furthermore, the reaction temperature in one step is 60-130°C. Furthermore, the reaction temperature in one step is 90-100°C.

[0035] Furthermore, the reaction temperature in one step is 100°C.

[0036] Furthermore, the reaction time for one step is 30-40 h.

[0037] Furthermore, the reaction time for one step was 36 h.

[0038] Furthermore, the method includes the following steps: sequentially adding a transition metal catalyst, an organic catalyst, an oxidant, an arylsulfonyl-protected indole-3-carboxaldehyde represented by the general formula (I), an aromatic hydrocarbon represented by the general formula (II), and an acid into a reactor, stirring evenly, performing a one-step reaction, and then cooling to room temperature, separating and purifying to obtain a 10-phenylbenzo[4,5]isothiazolo[2,3-a]indole-5,5-dioxide compound represented by the general formula (III).

[0039] Furthermore, the reaction process was detected by TLC, and the reactor was cooled to room temperature after the reaction was completed.

[0040] Furthermore, the reaction mixture cooled to room temperature is filtered through silica gel, the filtrate is concentrated in vacuo, and then separated and purified by column chromatography to complete the separation and purification process.

[0041] Furthermore, when filtering the silica gel, it was first washed with petroleum ether and then with ethyl acetate.

[0042] The present invention also provides 10-phenylbenzo[4,5]isothiazolo[2,3-a]indole-5,5-dioxide compounds prepared by the above method.

[0043] The present invention also provides the use of the above-mentioned 10-phenylbenzo[4,5]isothiazolo[2,3-a]indole-5,5-dioxide compounds in the preparation of arylated indole derivative drugs.

[0044] The present invention has the following beneficial effects: 1. The present invention uses cheap, readily available, and unactivated benzene compounds as C4 arylation reagents and the protecting group (arylsulfonyl) of indole N as C2 arylation reagent. Under the synergistic catalysis of transition metal catalysts and organic catalysts, a one-step reaction is performed to achieve direct diarylation of indole C2 and C4 positions, thereby synthesizing previously unreported 10-phenylbenzo[4,5]isothiazolo[2,3-a]indole-5,5-dioxide compounds. After nucleophilic substitution ring opening, these compounds directly give C2 and C4 diarylated indole compounds. This type of structure is often found in molecules with important biological and pharmaceutical activities, see Figure 3 For example, compound 1-1 can act as an inhibitor of Bruton's tyrosine kinase (BTK); compound 1-2 exhibits antagonistic activity, potentially useful for preventing or treating conditions, disorders, or diseases associated with MRGPRX4; and compound 1-3 exhibits HIV replication inhibition. This invention aims to address the existing problems of synthesizing arylated indole derivatives, which utilize aryl halides, borides, sulfonates, and other arylating agents, require pre-activation of the aromatic hydrocarbon, and suffer from multiple reaction steps and high synthesis costs. Furthermore, the synthetic method described in this invention exhibits excellent site selectivity for both indole and the two arylating agents.

[0045] 2. The raw materials, catalysts, oxidants and acids used in the present invention are cheap and readily available, the reaction operation is simple, and the synthesis steps are short (synthesis in one operation).

[0046] 3. The indole C2 and C4 arylation reagents used in the present invention are both unactivated benzene compounds, which avoids pre-activation of the arylation reagent, has good atom and step economy, good site selectivity for indole and aromatic hydrocarbons, a wide range of substrate applicability, good functional group compatibility, simple operation, and can be scaled up to gram levels. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 is the reaction formula of the reaction of the present invention; Figure 2 is the reaction mechanism of the present invention; Figure 3 Indole compounds with C2 and C4 diarylation; Figure 4 The compound III-1 obtained in Example 1 1 H NMR; Figure 5 The compound III-1 obtained in Example 1 13 C NMR; Figure 6 The compound III-2 obtained in Example 2 1 H NMR; Figure 7 The compound III-2 obtained in Example 213 C NMR; Figure 8 The compound III-3 obtained in Example 3 1 H NMR; Figure 9 The compound III-3 obtained in Example 3 13 C NMR; Figure 10 The compound III-4 obtained in Example 4 1 H NMR; Figure 11 The compound III-4 obtained in Example 4 13 C NMR; Figure 12 For compound IV-1 1 H NMR; Figure 13 For compound IV-1 13 C NMR; Figure 14 For compound IV-2 1 H NMR; Figure 15 For compound IV-2 13 C NMR. DETAILED DESCRIPTION

[0048] The principles and features of the present invention are described below in conjunction with the accompanying drawings. The examples are only used to explain the present invention and are not intended to limit the scope of the invention. In the embodiments, if specific conditions are not specified, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0049] The general reaction formula of the present invention is shown in Figure 1 .

[0050] In the following examples, 1-[(4-methylphenyl)sulfonyl]-1H-indole-3-carbaldehyde was prepared by the following method: Sodium hydride (240 mg, 6 mmol, 1.2 equiv.) was weighed into a 100 mL round-bottom flask, followed by the addition of anhydrous N,N-dimethylformamide (10 mL) to obtain a suspension. A solution of indole-3-carboxaldehyde (5 mmol, 1.0 equiv.) in anhydrous N,N-dimethylformamide (10 mL) was slowly added dropwise to the suspension under an ice bath. The mixture was allowed to react under an ice bath for 30 min, followed by the slow dropwise addition of a solution of arylsulfonyl chloride (5.5 mmol, 1.1 equiv.) in anhydrous N,N-dimethylformamide (10 mL). The resulting solution was warmed to room temperature and stirred for 4 h. After completion of the reaction, the reaction mixture was diluted with H₂O (30 mL) and extracted with CHCl₂ (3 × 50 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain the desired product I-1.

[0051] The reaction formula is as follows:

[0052] Example 1: A synthetic method for direct diarylation of indole C2 and C4 positions comprises the following steps: In a 15 mL pressure bottle, palladium acetate (4.5 mg, 0.02 mmol, 10 mol%), β 5-Alanine (8.9 mg, 0.1 mmol, 50 mol%), potassium peroxodisulfate (108.1 mg, 0.4 mmol, 2 equiv.), 1-[(4-methylphenyl)sulfonyl]-1H-indole-3-carbaldehyde (59.8 mg, 0.2 mmol, 1 equiv.), anisole (2 mL) and trifluoroacetic acid (0.107 mL, 1.4 mmol, 7 equiv.); after sealing the pressure bottle, stir at room temperature for 20 minutes, and then place it in a 100 ° C oil bath to react for 36 hours; after the reaction is complete, the pressure bottle is cooled to room temperature, the reaction mixture is filtered through silica gel (first washed with petroleum ether and then with ethyl acetate), the filtrate is concentrated in vacuo, and finally separated and purified by column chromatography to obtain compound III-1 (71.8 mg, 89%).

[0053] 1H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 8.80 (s, 1H), 7.81 – 7.74 (m,2H), 7.57 – 7.43 (m, 2H), 7.45 – 7.34 (m, 2H), 7.29 – 7.18 (m, 1H), 7.07 –6.97 (m, 2H), 3.89 (s, 3H), 2.56 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 187.2,159.8, 146.6, 137.2, 136.4, 135.6, 133.3, 132.3, 132.2, 130.0, 129.5, 128.3,126.6, 126.4, 126.2, 122.3, 116.1, 114.6, 110.7, 55.5, 22.3. See Figure 4-5 ; The reaction formula is as follows:

[0054] Example 2: A synthetic method for direct diarylation of indole C2 and C4 positions comprises the following steps: In a 15 mL pressure bottle, palladium acetate (4.5 mg, 0.02 mmol, 10 mol%), β -Alanine (8.9 mg, 0.1 mmol, 50 mol%), potassium peroxodisulfate (108.1 mg, 0.4 mmol, 2 equiv.), 1-[(4-methylphenyl)sulfonyl]-1H-indole-3-carbaldehyde (59.8 mg, 0.2 mmol, 1 equiv.), benzene (2 mL) and trifluoroacetic acid (0.107 mL, 1.4 mmol, 7 equiv.); after sealing the pressure bottle, stir at room temperature for 20 minutes, then place it in a 100 ° C oil bath to react for 36 hours; after the reaction is complete, the pressure bottle is cooled to room temperature, the reaction mixture is filtered through silica gel (first washed with petroleum ether and then with ethyl acetate), the filtrate is concentrated in vacuo, and finally separated and purified by column chromatography to obtain compound III-2 (50.7 mg, 68%).

[0055] 1H NMR (400 MHz, CDCl3) δ 9.51 (s, 1H), 8.80 (s, 1H), 7.83 – 7.68 (m,2H), 7.55 – 7.36 (m, 7H), 7.31 – 7.25 (m, 1H), 2.55 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 186.9, 146.6, 140.9, 137.4, 136.5, 135.5, 132.3, 132.1, 129.2,129.2, 128.9, 128.5, 128.3, 126.6, 126.2, 126.1, 122.3, 115.9, 111.06, 22.3. See Figure 6-7 ; The reaction formula is as follows:

[0056] Example 3: A synthetic method for direct diarylation of indole C2 and C4 positions comprises the following steps: In a 15 mL pressure bottle, palladium acetate (4.5 mg, 0.02 mmol, 10 mol%), β -Alanine (8.9 mg, 0.1 mmol, 50 mol%), potassium peroxodisulfate (108.1 mg, 0.4 mmol, 2 equiv.), 1-[(4-methylphenyl)sulfonyl]-1H-indole-3-carbaldehyde (59.8 mg, 0.2 mmol, 1 equiv.), toluene (2 mL) and trifluoroacetic acid (0.107 mL, 1.4 mmol, 7 equiv.); after sealing the pressure bottle, stir at room temperature for 20 min, then place it in a 100 ° C oil bath to react for 36 h; after the reaction is complete, the pressure bottle is cooled to room temperature, the reaction mixture is filtered through silica gel (first washed with petroleum ether and then with ethyl acetate), the filtrate is concentrated in vacuo, and finally separated and purified by column chromatography to obtain compound III-3 (55.0 mg, 71%).

[0057] 1 H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.79 (s, 1H), 7.78 (dd, J = 8.2,0.9 Hz, 2H), 7.52 – 7.43 (m, 2H), 7.40 – 7.36 (m, 2H), 7.30 (d, J= 7.7 Hz,2H), 7.28 – 7.23 (m, 1H), 2.56 (s, 3H), 2.45 (s, 3H). 13 C NMR (101 MHz, CDCl3)δ 187.2, 146.6, 138.3, 138.0, 137.5, 136.4, 135.5, 132.3, 132.2, 129.9,129.3, 128.7, 128.3, 126.6, 126.3, 126.2, 122.3, 116.0, 110.8, 22.4, 21.5. See Figure 8-9 ; The reaction formula is as follows:

[0058] Example 4: A synthetic method for direct diarylation of indole C2 and C4 positions comprises the following steps: In a 15 mL pressure bottle, palladium acetate (4.5 mg, 0.02 mmol, 10 mol%), β -Alanine (8.9 mg, 0.1 mmol, 50 mol%), potassium peroxodisulfate (108.1 mg, 0.4 mmol, 2 equiv.), 1-[(4-methylphenyl)sulfonyl]-1H-indole-3-carbaldehyde (59.8 mg, 0.2 mmol, 1 equiv.), fluorobenzene (2 mL) and trifluoroacetic acid (0.107 mL, 1.4 mmol, 7 equiv.); after sealing the pressure bottle, stir at room temperature for 20 minutes, then place it in a 100 ° C oil bath to react for 36 hours; after the reaction is complete, the pressure bottle is cooled to room temperature, the reaction mixture is filtered through silica gel (first washed with petroleum ether and then with ethyl acetate), the filtrate is concentrated in vacuo, and finally separated and purified by column chromatography to obtain compound III-4 (66.5 mg, 85%).

[0059] 1 H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.79 (s, 1H), 7.78 (dd, J = 8.2,0.9 Hz, 2H), 7.52 – 7.43 (m, 2H), 7.40 – 7.36 (m, 2H), 7.30 (d, J= 7.7 Hz,2H), 7.28 – 7.23 (m, 1H), 2.56 (s, 3H), 2.45 (s, 3H). 13 C NMR (101 MHz, CDCl3)δ 187.2, 146.6, 138.3, 138.0, 137.5, 136.4, 135.5, 132.3, 132.2, 129.9,129.3, 128.7, 128.3, 126.6, 126.3, 126.2, 122.3, 116.0, 110.8, 22.4, 21.5. See Figure 10-11 ; The reaction formula is as follows:

[0060] Test example Compound III-2 prepared in Example 2 was subjected to nucleophilic ring-opening to synthesize C2 and C4 diarylated indole compounds.

[0061] 1. Compound III-2 (37.3 mg, 0.1 mmol, 1.0 equiv.) and n-propylamine (1.0 mL) were added to a 5 mL round-bottom flask in sequence and stirred at 40 o The mixture was stirred at 40°C for 2 h. The mixture was then diluted with H₂O (2 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified by column chromatography to obtain compound IV-1 (35.0 mg, 81%).

[0062] 1 H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 9.49 (s, 1H), 7.95 – 7.90 (m,1H), 7.55 – 7.50 (m, 2H), 7.49 – 7.43 (m, 2H), 7.43 – 7.28 (m, 5H), 7.19 (dd, J = 6.8, 1.6 Hz, 1H), 4.14 – 4.07 (m, 1H), 2.73 (s, 2H), 2.42 (s, 3H), 1.38 –1.27 (m, 2H), 0.74 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 187.1, 143.4,142.1, 141.3, 136.0, 135.5, 135.4, 134.2, 130.4, 130.1, 129.6, 129.0, 128.7,127.8, 124.8, 124.4, 123.9, 115.9, 111.4, 45.3, 22.9, 21.4, 11.2. See Figure 12-13 ; The reaction formula is as follows:

[0063] 2. Compound III-2 (37.3 mg, 0.1 mmol, 1.0 equiv.) and tetrahydrofuran (1 mL) were added sequentially to a 5 mL round-bottom flask. A solution of sodium ethoxide (7.5 mg, 0.11 mmol, 1.1 equiv.) in ethanol (1 mL) was then added at room temperature. After stirring at room temperature for 30 min, the reaction was quenched by the dropwise addition of H₂O (2 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified by column chromatography to yield compound IV-2 (37.7 mg, 90%).

[0064] 1 H NMR (400 MHz, Chloroform- d ) δ 9.69 (s, 1H), 9.51 (s, 1H), 8.04 –7.97 (m, 1H), 7.57 – 7.51 (m, 2H), 7.50 – 7.38 (m, 6H), 7.36 – 7.30 (m, 1H),7.19 (dd, J = 7.2, 1.1 Hz, 1H), 3.90 (q, J = 7.0 Hz, 2H), 2.45 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CHLOROFORM- D) δ 186.4, 144.5, 142.3, 140.5,136.0, 135.6, 135.3, 131.8, 130.8, 130.5, 130.2, 129.0, 128.7, 127.7, 124.9,124.4, 123.8, 115.9, 111.3, 68.3, 21.5, 14.4. See Figure 14-15 ; The reaction formula is as follows:

[0065] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for the direct diarylation of indole C2 and C4 positions, characterized in that: The following steps are involved: In the presence of a transition metal catalyst, an organic catalyst, an oxidant and an acid, 10-phenylbenzo[4,5]isothiazolo[2,3-a]indole-5,5-dioxide compounds represented by general formula (III) are synthesized in a one-step reaction using an arylsulfonyl-protected indole-3-carboxaldehyde represented by general formula (I) and an aromatic hydrocarbon represented by general formula (II) as raw materials. The chemical reaction formula is as follows: ； Among them, R 1 is hydrogen, C1-C4 alkyl, C1-C5 alkoxy, phenyl, halogen, ester or nitrile; R 2 is hydrogen, C1-C5 alkyl, C1-C4 alkoxy, phenyl, di-C1-C3 alkylphenyl, halogen, dihalogen, ester or nitrile; R 3 is hydrogen, C1-C4 alkyl, C1-C2 alkoxy, phenyl, di-C1-C3 alkylphenyl, tri-C1-C2 alkylphenyl, halogen or dihalogen.

2. The method for synthesizing indole C2 and C4 direct diarylation according to claim 1, characterized in that: The molar volume ratio of the transition metal catalyst, the organic catalyst, the oxidant, the arylsulfonyl-protected indole-3-carboxaldehyde represented by the general formula (I), the acid, and the aromatic hydrocarbon represented by the general formula (II) is 0.01-0.02 mmol: 0.05-0.1 mmol: 0.2-0.6 mmol: 0.1-0.3 mmol: 1-2 mmol: 1-3 mL.

3. The method for synthesizing direct diarylation of indole C2 and C4 according to claim 1, characterized in that: The transition metal catalyst is palladium trifluoroacetate, palladium acetate, palladium chloride or bistriphenylphosphine palladium dichloride.

4. The method for synthesizing direct diarylation of indole C2 and C4 according to claim 1, characterized in that: Organic catalysts are α -amino acids or β -amino acids.

5. The method for synthesizing direct diarylation of indole C2 and C4 according to claim 1, characterized in that: The oxidizing agent is copper acetate, silver oxide, potassium peroxodisulfate or oxygen.

6. The method for synthesizing indole C2 and C4 direct diarylation according to claim 1, characterized in that: The acid is trifluoroacetic acid, acetic acid or benzoic acid.

7. The method for synthesizing indole C2 and C4 direct diarylation according to claim 1, characterized in that: The one-step reaction temperature is 60-130°C.

8. The method for synthesizing indole C2 and C4 direct diarylation according to claim 1, characterized in that: The method comprises the following steps: sequentially adding a transition metal catalyst, an organic catalyst, an oxidant, an arylsulfonyl-protected indole-3-carboxaldehyde represented by the general formula (I), an aromatic hydrocarbon represented by the general formula (II), and an acid into a reactor, stirring the mixture evenly, performing a one-step reaction, and then cooling the mixture to room temperature, separating and purifying the mixture to obtain a 10-phenylbenzo[4,5]isothiazolo[2,3-a]indole-5,5-dioxide compound represented by the general formula (III).

9. 10-Phenylbenzo[4,5]isothiazolo[2,3-a]indole-5,5-dioxide compounds prepared by the synthesis method of direct diarylation of indole C2 and C4 positions according to any one of claims 1 to 8.

10. Use of the 10-phenylbenzo[4,5]isothiazolo[2,3-a]indole-5,5-dioxide compound according to claim 9 in the preparation of arylated indole derivative drugs.

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