A sulfide ligand and a synthesis method of a 2-arylindole compound catalyzed by palladium

Abstract

The application provides a sulfide ligand and a synthesis method of a 2-arylindole compound catalyzed by palladium, designs the application of a biphenyl sulfide ligand and a palladium catalyst in the preparation of the 2-arylindole compound. The biphenyl sulfide ligand is used in the reaction of indole and aryl boronic acid under the action of a palladium catalyst and the biphenyl sulfide ligand, wherein the structural formula of the biphenyl sulfide ligand is as follows: Ar is a phenyl, furanyl, thienyl, naphthyl or phenyl substituted by one or more substituents; R 1 is a methyl, methoxy, fluorine atom, chlorine atom, or bromine atom or methyl ester group; R 2 is a methyl, methoxy, fluorine atom, chlorine atom, or bromine atom or methyl ester group; R 3 is an alkoxy, alkylthio, substituted amino or halogen; and the palladium catalyst is a divalent palladium compound.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for synthesizing 2-arylindole compounds using thioether ligands and palladium catalysis, and the application of such ligands in the highly selective oxidative coupling of indole and arylboronic acid to 2-arylindole under divalent palladium catalysis. Background Technology

[0002] Indoles are an important class of nitrogen-containing heterocyclic compounds, and their arylated derivatives, especially 2-arylindoles, are widely found in natural products and drug molecules. For example, OXi8006 is a microtubule inhibitor with anticancer activity, and Arcyriacyanin A is a tyrosine kinase inhibitor that can be used for targeted cancer therapy. Therefore, developing efficient and selective methods for constructing 2-arylindoles is of great value.

[0003] .

[0004] In the direct functionalization of the CH bond in indole, achieving regioselective arylation at the C2 site has been a long-standing challenge due to the high reactivity of both the C2 and C3 positions. Transition metal catalysis provides a powerful tool for the direct functionalization of the CH bond. In 2008, Larrosa's group first achieved the direct C-2 arylation of indole with aryl iodine at room temperature without phosphine ligands. This reaction is applicable to indole substrates with protected nitrogen atoms (J. Am. Chem. Soc. 2008, 130, 2926-2927). In 2011, Ackermann's group achieved ruthenium-catalyzed activation arylation of the C2-CH bond in indole using a removable directing group (Org. Lett. 2011, 13, 3332-3335). In 2017, Song Maoping achieved the C2-position oxidative arylation of indole under air conditions, using Co(acac)2 as a catalyst and Mn(OAc)2·4H2O as a co-oxidant, with pyrimidine as the directing group (Org. Lett. 2017, 19, 596−599). In 2019, Punji achieved the C2-position coupling reaction of indole and aryl chloride under Ni catalysis and 2-pyridine directing (J. Org. Chem. 2019, 84, 12800−12808).

[0005] However, in the coupling reaction of indole and arylboronic acid, how to precisely control the regioselectivity (C2 vs C3) of the reaction through ligand design while using an environmentally friendly oxidation system remains a technical challenge that those skilled in the art are striving to solve. Existing technologies either have unsatisfactory selectivity or require the use of expensive, complex ligands and environmentally unfriendly stoichiometric oxidants, limiting their practical application.

[0006] Therefore, there is an urgent need and broad application prospects for developing a catalytic system that can achieve high C2 selectivity, mild conditions, environmental friendliness, and readily available ligands. Summary of the Invention

[0007] There is relatively little research on the application of thioether ligand / palladium catalysis systems in the preparation of 2-arylindole compounds, or a lack of groundbreaking research results.

[0008] The first objective of this invention is to provide a synthetic method for preparing 2-arylindole compounds by using biphenyl sulfide ligands and palladium-catalyzed oxidative Suzuki coupling of indole and phenylboronic acid.

[0009] A second objective of this invention is to provide a method for synthesizing biphenyl sulfide ligands.

[0010] To achieve the above technical objectives, the present invention adopts the following technical solution:

[0011] In a first aspect, this invention provides the application of biphenyl sulfide ligands and palladium catalysts in the preparation of 2-arylindole compounds. This invention provides a method for preparing 2-arylindole compounds involving biphenyl sulfide ligands. In the presence of an organic solvent and an oxidant, an indole compound and an arylboronic acid compound undergo an oxidative Suzuki coupling reaction catalyzed by a palladium catalyst and biphenyl sulfide ligands, as shown in the following reaction formula:

[0012] ,

[0013] Where: R 1 It can be a methyl, methoxy, fluorine, chlorine, bromine, or methyl ester group;

[0014] Ar is phenyl, furanyl, thiophene, naphthyl, or a phenyl group substituted with one or more substituents, wherein each substituent is independently methyl, tert-butyl, phenyl, methoxy, trifluoromethyl, or halogen.

[0015] The above-mentioned oxidation Suzuki coupling reaction of the present invention is carried out with the participation of biphenyl sulfide ligands, and a palladium catalyst is also required in the reaction.

[0016] The palladium catalyst can be palladium acetate, palladium trifluoroacetate, palladium chloride, etc.

[0017] The oxidant is a co-oxidation system of copper acetate or silver acetate with air or oxygen, such as a co-oxidation system of oxygen with copper acetate (Cu(OAc)2).

[0018] The detailed process for further oxidation of the Suzuki coupling reaction is as follows: Indole compounds, arylboronic acid, palladium catalyst, ligand, oxidant and organic solvent are added to a reaction flask, nitrogen is purged three times, then connected to an oxygen bulb, and the reaction is heated to 50~120℃ for 8~24 hours. After the reaction is completed by TLC monitoring, water is added to the reaction solution, and the organic phase is extracted 2~3 times with dichloromethane. The organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, separated by column chromatography with ethyl acetate:n-hexane = 1:5~20, and concentrated under reduced pressure to obtain 2-arylindole compounds.

[0019] The molar ratio of the indole compound, arylboronic acid, palladium catalyst, ligand, and oxidant is in the range of 1:1~3:0.01~0.3:0.03~0.3:0.1~1.0.

[0020] More preferably, the molar ratio of indole compound: arylboronic acid: palladium catalyst: ligand: oxidant is in the range of 1:1~2:0.01~0.1:0.03~0.2:0.1~0.5.

[0021] Furthermore, the palladium catalyst used in the reaction is preferably palladium acetate, palladium trifluoroacetate, or palladium chloride.

[0022] Furthermore, the organic solvent used in the reaction is selected from DMF, DMSO, 1,2-dichloroethane, or 1,4-dioxane.

[0023] Furthermore, the volume fraction of the organic solvent in the reaction is 5V~15V.

[0024] Furthermore, the oxidant in the reaction is selected from a co-oxidation system composed of oxygen and a catalytic amount of copper acetate (Cu(OAc)2).

[0025] Furthermore, the reaction temperature is preferably 50~120℃.

[0026] Furthermore, the post-treatment method of the reaction solution is as follows: water is added to the reaction solution, and the solution is extracted with dichloromethane 2-3 times to obtain an organic phase. The organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, separated by column chromatography with ethyl acetate:n-hexane = 1:5-20, and concentrated under reduced pressure to obtain a 2-arylindole compound.

[0027] Secondly, the present invention provides a method for synthesizing biphenyl sulfide ligands, wherein the biphenyl sulfide ligands are prepared according to the following synthetic method:

[0028]

[0029] Where R 2 The same or different can be methyl, ethyl, isopropyl, isobutyl, cyclohexyl, benzyl, n-propyl, or n-pentyl, etc. R 3It can be alkoxy, alkylthio, substituted amino, or halogen, etc. The specific reaction process is as follows:

[0030] The thiophenol compound was dissolved in an organic solvent at 20°C, and then a base was added at 0°C. The mixture was stirred at 0°C for 5–15 minutes, maintaining an internal temperature of 0°C. A haloalkane was slowly added dropwise to the reaction system. After the addition was complete, the reaction was allowed to proceed at room temperature for 2–5 hours. After the reaction was monitored by TLC until complete, water was added and the mixture was stirred for 0.5–1 hour. The mixture was extracted 2–3 times with ethyl acetate to obtain an organic phase. The organic phase was dried and concentrated, then separated and concentrated by rapid column chromatography on a short silica gel column to prepare an aryl thioether intermediate. The molar ratio of the thiophenol compound, base, and haloalkane was 1.0:2.0–4.0:5.0–10.0.

[0031] Furthermore, the organic solvent is selected from DMSO, DMF, and DMA.

[0032] The volume of the organic solvent is further 10–30 V.

[0033] Furthermore, the alkali is selected from potassium carbonate, sodium hydroxide, and potassium hydroxide.

[0034] The aryl sulfide intermediate was dissolved in a 15V solvent, and arylboronic acid, a base, a palladium catalyst, and water were added. After purging with nitrogen three times, the reaction was heated to 75°C and refluxed for 12–20 hours. After the reaction was completed by TLC monitoring, it was cooled to room temperature. Water was added to the reaction solution, and the mixture was extracted 2–3 times with ethyl acetate to obtain the organic phase. The organic phase was dried and concentrated, and then separated and concentrated by column chromatography with ethyl acetate:n-hexane = 1:10–30 to prepare biphenyl sulfide ligands. The molar ratio of the aryl sulfide intermediate, arylboronic acid, base, and palladium catalyst was 1.0:1.0–2.0:1.0–3.0:0.01–0.1.

[0035] Furthermore, the organic solvent is selected from tetrahydrofuran, 1,4-dioxane, toluene, and ethylene glycol dimethyl ether.

[0036] Furthermore, the alkali is selected from potassium carbonate, sodium carbonate, cesium carbonate, and potassium phosphate.

[0037] Furthermore, the palladium catalyst is selected from tetra(triphenylphosphine)palladium or di(triphenylphosphine)palladium dichloride.

[0038] Furthermore, the volume ratio of organic solvent to water is 1 to 5:1.

[0039] Specifically, and preferably, the biphenyl sulfide ligand is selected from one of the following:

[0040] .

[0041] The beneficial effects of this invention lie in the successful oxidative Suzuki coupling of indole and arylboronic acid in a divalent palladium catalytic system using biphenyl sulfide ligands, achieving highly selective and efficient synthesis of 2-arylindole. In the synthetic method described in this invention, on the one hand, a novel biphenyl sulfide ligand is obtained by coupling a modified thiophenol with arylboronic acid; on the other hand, a divalent palladium catalyst / sulfide ligand is used as a catalyst to catalyze the selective oxidative coupling reaction of indole and arylboronic acid, followed by post-treatment separation to obtain the 2-arylindole compound. The 2-arylindole compound structure is an important structural unit widely found in the pharmaceutical field, showing broad application prospects in new drug development. The preparation method provided by this invention has mild conditions, readily available reaction materials, and strong operability. Detailed Implementation

[0042] The present invention will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention. These all fall within the scope of protection of the present invention.

[0043] Example 1: Preparation of ligand (3)-a

[0044]

[0045] In a 100 mL reaction flask, 2-bromothiophenol (3.0 g, 15.9 mmol, 1.0 eq.) and 30 mL of DMF solvent were added sequentially. The flask was then placed in an ice bath at 0 °C. Potassium carbonate (2.2 g, 15.9 mmol, 1.0 eq.) was added and mixed thoroughly. Bromoethane (4.3 g, 39.8 mmol, 2.5 eq.) was slowly added dropwise. The reaction mixture was then allowed to react at room temperature for 2 hours. After the reaction was complete, 100 mL of water was added and the mixture was stirred for 0.5 hours. The mixture was extracted twice with ethyl acetate to obtain the organic phase. The organic phase was dried and concentrated, and then separated and concentrated by rapid column chromatography on a short silica gel column to obtain 3.2 g of an aryl sulfide intermediate, with a yield of 93%.

[0046] An intermediate (2.17 g, 10.0 mmol, 1.0 eq.) was added to a 250 mL three-necked flask, followed by the addition of 2-methoxyphenylboronic acid (2.28 g, 15.0 mmol, 1.5 eq.), potassium carbonate (3.45 g, 25.0 mmol, 2.5 eq.), tetra(triphenylphosphine)palladium (0.58 g, 0.5 mmol, 0.05 eq.), 30 mL of tetrahydrofuran, and 10 mL of water. The mixture was thoroughly mixed and refluxed in an oil bath at 75 °C for 16 hours. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. 100 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate to obtain the organic phase. The organic phase was dried over anhydrous magnesium sulfate and concentrated. Separation and concentration by column chromatography (ethyl acetate:n-hexane = 1:20) yielded 1.85 g of the dry product (76% yield). 1 H-NMR, the structure is correct. 1 H NMR (400 MHz, CDCl3): δ7.40-7.33 (m, 2H), 7.32-7.27 (m, 1H), 7.24-7.19 (m, 2H), 7.19-7.16 (m, 1H), 7.04-6.99 (m, 1H), 6.98-6.95 (m, 1H), 3.77 (s, 3H), 2.80 (q, J = 8.0 Hz, 2H), 1.20 (t, J = 8.0 Hz, 3H).

[0047] Example 2: Preparation of ligand (3)-b

[0048]

[0049] The difference from Reaction Example 1 is that the haloalkane used is 1-bromoisobutane, and the other reaction conditions and operating steps are the same as those in Reaction Example 1 (yield: 80%). 1 H NMR (400 MHz, CDCl3): δ 7.46-7.42 (m, 1H),7.41-7.37 (m, 1H), 7.36-7.30 (m, 1H), 7.29-7.21 (m, 3H), 7.08-7.03 (m, 1H),7.01 (dd, J = 8.0, 1.2 Hz, 1H), 3.81 (s, 3H), 2.67 (t, J = 6.8 Hz, 2H), 1.77(dt, J = 13.4, 6.8 Hz, 1H), 0.95 (d, J = 6.8 Hz, 6H).

[0050] Example 3: Preparation of ligand (3)-c

[0051]

[0052] The difference from Reaction Example 1 is that the haloalkane used is 1-bromobutane, and the other reaction conditions and operating steps are the same as those in Reaction Example 1 (yield: 71%). 1 H NMR (400 MHz, CDCl3): δ 7.48-7.38 (m, 2H), 7.36-7.30 (m, 1H), 7.27-7.18 (m, 3H), 7.09-6.97 (m, 2H), 3.80 (s, 3H), 2.86-2.76 (m, 2H), 1.55 (tt, J = 7.2, 1.7 Hz, 2H), 1.41-1.32 (m, 2H), 0.89 (t, J =7.2 Hz, 3H).

[0053] Example 4: Preparation of ligand (3)-d

[0054]

[0055] The difference from Reaction Example 1 is that the haloalkane used is 1-bromohexane, and the other reaction conditions and operating steps are the same as those in Reaction Example 1 (yield: 75%). 1 H NMR (400 MHz, CDCl3): δ 7.45-7.38 (m, 2H), 7.37-7.32 (m, 1H), 7.27-7.18 (m, 3H), 7.05 (td, J = 7.6, 1.2 Hz, 1H), 7.01 (dd, J = 8.4, 1.2 Hz, 1H), 3.81 (s, 3H), 2.80 (td, J = 7.2, 3.2 Hz, 2H), 1.60-1.52 (m, 2H), 1.38-1.24 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H).

[0056] Example 5: Preparation of ligand (3)-e

[0057]

[0058] The difference from Reaction Example 1 is that the haloalkane used is β-bromophenylethane, while the other reaction conditions and operating steps are the same as in Reaction Example 1 (yield: 64%). 1H NMR (400 MHz, CDCl3): δ 7.49 (dt, J = 8.0,1.2 Hz, 1H), 7.44-7.38 (m, 1H), 7.38-7.33 (m, 1H), 7.31-7.27 (m, 4H), 7.25-7.20 (m, 2H), 7.16-7.11 (m, 2H), 7.09-7.04 (m, 1H), 7.01 (dd, J = 8.4, 1.2Hz, 1H), 3.79 (s, 3H), 3.08-2.98 (m, 2H), 2.81 (t, J = 8.0 Hz, 2H).

[0059] Example 6: Preparation of ligand (3)-f

[0060]

[0061] The difference from Reaction Example 1 is that the haloalkane used is β-bromophenylethane, the arylboronic acid used is 2-methylthiophenylboronic acid, and the other reaction conditions and operating steps are the same as those in Reaction Example 1 (yield: 55%). 1 H NMR (400MHz, CDCl3): δ7.46-7.41 (m, 1H), 7.40-7.34 (m, 2H), 7.31-7.26 (m, 3H), 7.25-7.22 (m, 2H), 7.21 (d, J = 1.6 Hz, 2H), 7.19-7.12 (m, 4H), 3.07-2.96 (m, 2H), 2.88-2.77 (m, 2H), 2.37 (s, 3H).

[0062] Example 7:

[0063]

[0064] Indole (58.6 mg, 0.5 mmol, 1.0 eq.), phenylboronic acid (91.5 mg, 0.75 mmol, 1.5 eq.), palladium trifluoroacetate (8.3 mg, 0.05 eq.), ligand (3)-b (13.6 mg, 0.10 eq.), copper acetate (9.1 mg, 0.10 eq.), and 2 mL of 1,2-dichloroethane were added to a reaction flask. After purging with nitrogen three times, the flask was connected to an oxygen bulb, and the reaction was heated to 80 °C and reacted for 16 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted three times with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, separated by column chromatography of ethyl acetate:n-hexane = 1:10, and concentrated under reduced pressure to obtain 79.2 mg of 2-phenylindole, with a yield of 82%.

[0065] Example 8:

[0066]

[0067] The difference from Reaction Example 7 is that the arylboronic acid used is 4-fluorophenylboronic acid, while the other reaction conditions and operating steps are the same as in Reaction Example 7 (yield: 75%).

[0068] Example 9:

[0069]

[0070] The difference from Reaction Example 7 is that the indole used is 5-chloroindole, and the other reaction conditions and operating steps are the same as those in Reaction Example 7 (yield: 83%).

Claims

1. A method for preparing a 2-arylindole compound, characterized in that, In the presence of organic solvents and oxidants, indole compounds and arylboronic acid compounds undergo oxidative Suzuki coupling reactions catalyzed by palladium catalysts and biphenyl sulfide ligands: ， Specifically, the biphenyl sulfide ligands are: ； R 1 It is a chlorine atom; Ar is either phenyl or fluorophenyl; The palladium catalyst is palladium trifluoroacetate; The organic solvent is 1,2-dichloroethane; The oxidant is a co-oxidation system of copper acetate or silver acetate with air or oxygen.

2. The preparation method according to claim 1, characterized in that, The reaction temperature is 50~120℃.

3. The preparation method according to claim 1, characterized in that, The preparation reaction of the biphenyl sulfide ligands is as follows: 。 4. The preparation method according to claim 3, characterized in that, The preparation reaction of the biphenyl sulfide ligands was carried out in the presence of a base.

5. The preparation method according to claim 4, characterized in that, The alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, cesium carbonate, or potassium phosphate.

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