Synthetic method of C4-site aryl phosphonyl substituted indole derivative

Abstract

The invention belongs to the technical field of organic synthesis, and particularly discloses a synthetic method of a C4-site aryl phosphonyl substituted indole derivative, which comprises the following steps: adding N-alkyl phosphine oxide substituted indole, diaryl phosphine oxide, a ruthenium catalyst, an oxidizing agent, alkali and a solvent into a reaction container, heating to 50-120 DEG C under the condition of inert gas, reacting for 20-30 hours, filtering, washing, and drying to obtain the C4-site aryl phosphonyl substituted indole derivative. And after the reaction is finished, removing the solvent, and carrying out column chromatography isolation to obtain the C4-site aryl phosphonyl substituted indole derivative. The method has atom economy and belongs to a cross dehydrogenation coupling reaction, the C4-site aryl phosphorylated indole derivative is constructed in one step, the cost is low, the reaction condition is green and friendly, and no ligand needs to be additionally added.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing an indole derivative substituted with an aryl phosphonyl group at the C4 position. Background Art

[0002] Indole derivatives are an important N-heterocyclic skeleton with good biological activities such as antiviral and antibacterial properties, and are widely used in natural products, spices, agricultural chemicals, materials chemistry and other fields. In recent years, the synthesis and structural modification of indole derivatives have attracted extensive attention from organic synthetic chemists. The electron-rich nature and ring strain of the pyrrole moiety facilitate a variety of functionalizations at the C2 and C3 positions. However, functionalization at the C4 position has been relatively understudied due to synthetic limitations. Indole phosphonates are useful bioactive molecular scaffolds, serving not only as phosphine ligands in organic synthesis but also in pharmaceuticals and materials due to their unique properties. Therefore, developing an efficient, sustainable, environmentally friendly, and highly positionally selective C–H phosphonylation protocol for indole C4 is highly valuable. Summary of the Invention

[0003] The first object of the present invention is to solve the above problems and provide a method for synthesizing an indole derivative substituted with an aryl phosphono group at the C4 position, which has mild reaction conditions, high yield, low cost and simple post-processing.

[0004] The second object of the present invention is to provide a product obtained by the above method.

[0005] The purpose of the present invention is specifically achieved through the following technical solutions:

[0006] A method for synthesizing an indole derivative substituted with an aryl phosphonyl group at the C4 position, characterized by adding an N-alkylphosphine oxide substituted indole, a diarylphosphine oxide, a ruthenium catalyst, an oxidant, a base, and a solvent to a reaction vessel, heating the reaction to 50-120° C. under inert gas conditions for 20-30 hours, removing the solvent after the reaction, and separating the indole derivative substituted with an aryl phosphonyl group at the C4 position by column chromatography;

[0007] The structural formula of the N-alkylphosphine oxide substituted indole is The diarylphosphine oxide is a condensed ring substituent or a structural formula The compound, wherein the structural formula of the indole derivative substituted with an aryl phosphono group at position C4 is

[0008] In the structural formula, the group R 1is one of alkyl, trifluoromethyl, nitro, acyl, cyano, halogen, alkoxy, oxyester, aryl, and hydrogen, and the group R 2 、R 3 Each is independently selected from one of alkyl, alkenyl, alkynyl, halogen, alkoxy, oxyester, aryl, and hydrogen.

[0009] Preferably, the diarylphosphine oxide containing a fused ring substituent is

[0010] Further preferably, the reaction formula of the method is any one of the following reaction formulas:

[0011]

[0012] Preferably, the solvent is one or more combinations of 1,4-dioxane, dichloroethane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, methyl tert-butyl ether, diethyl ether, ethylene glycol dimethyl ether, toluene or water;

[0013] The inert gas is argon or nitrogen;

[0014] The composition and volume ratio of the mobile phase used in the column chromatography are petroleum ether:ethyl acetate=8:1-0:1, and dichloromethane:methanol=30:1-5:1.

[0015] Preferably, the ruthenium catalyst is one of dichlorophenylruthenium (II) dimer, (p-cymene) ruthenium dichloro dimer, tris(triphenylphosphine)dichlororuthenium, metallic ruthenium, ruthenium trichloride, ruthenium acetate, ruthenium iodide, tris(triphenylphosphino)ruthenium dihydrogencarbonyl, dodecacarbonyl ruthenium, pentamethylcyclopentadienyl tris(acetonitrile)ruthenium (II) hexafluorophosphate.

[0016] Preferably, the oxidant is one or more of a metal cation, a high-valent compound containing a variable-valent element, or a non-metallic elemental oxidant.

[0017] More preferably, the metal cation is Fe 3+ 、Cu 2+ 、Ag + ; The high-valent compound containing the variable-valence element is perchlorate, dichromate, persulfate, manganese dioxide, and ferric chloride; the non-metallic elemental oxidant is such as O2 and S.

[0018] Preferably, the base is one of cesium acetate, potassium acetate, sodium acetate, potassium phosphate, sodium phosphate, potassium carbonate, potassium pivalate, and triethylamine.

[0019] Preferably, the molar ratio of the ruthenium catalyst to the N-alkylphosphine oxide substituted indole is 0.1:1, the molar ratio of the diarylphosphine oxide to the N-alkylphosphine oxide substituted indole is 4:1, the molar ratio of the base to the N-alkylphosphine oxide substituted indole is 3:1, and the molar ratio of the oxidant to the N-alkylphosphine oxide substituted indole is 0.3-3:1.

[0020] The indole derivative substituted with a C4 arylphosphonyl group is obtained by any of the above methods.

[0021] Compared with the prior art, the present invention has the following advantages:

[0022] The synthesis method of the C4-arylphosphonyl-substituted indole derivative provided by the present invention is atom-economical. The reaction belongs to a cross-dehydrogenative coupling (CDC) reaction, and the 4-arylphosphonylated indole derivative is constructed in one step. The method is low in cost and the catalyst is inexpensive. The reaction conditions are environmentally friendly and no additional ligand needs to be added. The solvent does not need to be further treated. The operation steps are simple. DETAILED DESCRIPTION

[0023] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0024] Unless otherwise specified, the raw materials in the examples of the present invention were purchased through commercial channels, among which N-alkylphosphine oxide substituted indoles were prepared according to relevant reported literature (Wang, Z.-L.; Cheng, J.-K.; Wang, F., Angew. Chem. Int. Ed. 2024, 63(45), e202412103.), and the synthesis methods of N-di-tert-butylphosphine oxide substituted indole and N-di-tert-butylphosphine oxide substituted 6-methylindole are as follows; diphenylphosphine oxide was purchased through commercial channels, manufacturer: Anaiji Chemical.

[0025]

[0026] Indole (4.0 mmol, 1.0 eq.) was dissolved in 10 mL of anhydrous tetrahydrofuran. n-Butyl lithium (1.0 M in hexane, 1.2 eq.) was added dropwise at 0°C. After stirring for 15 minutes, a dialkyl phosphine chloride (4.8 mmol, 1.2 eq.) was added dropwise. The reaction mixture was slowly warmed to room temperature with stirring and continued stirring for 3 hours. 2 mL of methanol was added, and most of the solvent was removed under reduced pressure. The residue was suspended in 30 mL of methanol and cooled to 0°C. Excess hydrogen peroxide (approximately 8 mmol) was slowly added to dissolve the suspension, forming a light yellow solution. 8 mL of aqueous sodium sulfite solution was then added, and the mixture was warmed to room temperature and stirred for 2 hours. After the reaction, the resulting mixture was neutralized with hydrochloric acid. The solvent was removed under reduced pressure, and the mixture was extracted with dichloromethane (3 times, 25 mL each). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to yield the product as an orange solid. Finally, the product is purified by flash column chromatography using a dichloromethane / methanol system to obtain the corresponding indole compound substituted with N-di-tert-butylphosphine oxide.

[0027] Example 1

[0028]

[0029] To a 25 mL reaction tube, N-di-tert-butylphosphine oxide-substituted indole (0.2 mmol, 55.4 mg), diphenylphosphine oxide (0.8 mmol, 162 mg), ruthenium trichloride (0.02 mmol, 4.2 mg), potassium persulfate (0.6 mmol, 162 mg), silver nitrate (0.06 mmol, 10 mg), and sodium acetate (0.6 mmol, 49 mg) were added. Acetonitrile (1 mL) and water (1 mL) were then added under an argon atmosphere. The tube was sealed with a lid. The resulting black suspension was stirred at room temperature for 10 minutes and then placed in a preheated oil bath at 60°C at 900-1200 rpm for 24 hours. After completion of the reaction, the solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1-0:1; dichloromethane:methanol = 30:1-5:1) to obtain a white solid (78.2 mg, 82% yield).

[0030] Product testing data are as follows:

[0031] 1 H NMR (400MHz, CDCl3) δ8.79–8.71(m,1H),7.73–7.67(m,4H),7.56–7.52(m,2H),7.48–7.43(m,4H ),7.25(dd,J=3.5,1.5Hz,1H),7.21–7.16(m,1H),7.03–6.97(m,2H),1.34(s,9H),1.30(s,9H).

[0032] 31 P NMR (243MHz, CDCl3) δ64.22, 30.26.

[0033] 13 C NMR (101MHz, CDCl3) δ141.83 (d, J = 12.1Hz), 132.63 (d, J = 104.3Hz), 132.02 ( d,J=10.0Hz),131.74(d,J=2.7Hz),131.02(dd,J=9.2,5.2Hz),128.39(d,J=1 2.1Hz),127.80(d,J=4.6Hz),127.12(d,J=10.9Hz),122.64(d,J=106.4Hz),1 22.39(d,J=13.4Hz),107.78–107.60(m),38.59(d,J=68.5Hz),26.55,26.55.

[0034] HRMS(ESI)m / z:[M+H] + Calcd for C 28 H 34 NO2P2478.2059;Found 478.2061.

[0035] Example 2

[0036]

[0037] To a 25 mL reaction tube, N-di-tert-butylphosphine oxide-substituted 6-methylindole (0.2 mmol, 66.1 mg), diphenylphosphine oxide (0.8 mmol, 162 mg), ruthenium trichloride (0.02 mmol, 4.2 mg), potassium persulfate (0.6 mmol, 162 mg), silver nitrate (0.06 mmol, 10 mg), and sodium acetate (0.6 mmol, 49 mg) were added. Acetonitrile (1 mL) and water (1 mL) were then added under an argon atmosphere. The tube was sealed with a lid. The resulting black suspension was stirred at room temperature for 10 minutes and then placed in a preheated oil bath at 60°C at 900-1200 rpm for 24 hours. After completion of the reaction, the solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1-0:1; dichloromethane:methanol = 30:1-5:1) to obtain a white solid (71.5 mg, 73% yield).

[0038] Product testing data are as follows:

[0039] 1H NMR (400MHz, CDCl3) δ8.62–8.56(m,1H),7.73–7.67(m,4H),7.54–7.50(m,2H),7.48–7.43(m,4H),7.1 7(dd,J=3.5,1.5Hz,1H),6.96–6.89(m,1H),6.86–6.80(m,1H),2.37(s,3H),1.32(d,J=14.8Hz,18H).

[0040] 31 P NMR (162MHz, CDCl3) δ63.87,29.96.

[0041] 13 C NMR (151MHz, CDCl3) δ 142.31 (d, J = 12.7Hz), 132.88 (d, J = 104.0Hz), 132.31 (d, J = 13.3Hz), 131.99 (d, J = 9.8Hz), 131.61 (d, J = 2.9Hz), 130.59 (d, J = 11. 6Hz),128.30(d,J=12.1Hz),127.05(d,J=4.6Hz),122.20(d,J=105.8Hz),1 20.20(d,J=2.3Hz),107.53–107.32(m),38.52(d,J=68.8Hz),26.53,21.79.

[0042] HRMS(ESI)m / z:[M+H] + Calcd for C 29 H 36 NO2P2492.2216;Found 492.2219.

[0043] Subsequently, tetrabutylammonium fluoride (TBAF) was used to deprotect the target compound generated in this example, a C4-phenylphosphono-substituted indole derivative, efficiently yielding a phosphonylated indole compound with a free N–H group in a single step. This strategy provides a novel, atom-economical approach to constructing structurally diverse functionalized phosphonylated indole frameworks.

[0044] Example 3

[0045]

[0046] In a 25 mL reaction tube, the C4-phenylphosphonyl-substituted indole compound (0.2 mmol, 95.4 mg) synthesized in Example 2 was dissolved in tetrahydrofuran (2.0 mL), and tetrabutylammonium fluoride (1 M THF solution, 0.6 eq) was added under air atmosphere, and the mixture was stirred at 65 ° C. for 10 hours; after the reaction was completed, the reaction mixture was extracted with ethyl acetate, the organic layers were combined and concentrated under reduced pressure, and finally purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1-0:1; dichloromethane: methanol = 30:1-5:1) to give a white solid (54.5 mg, yield 86%).

[0047] Product testing data are as follows:

[0048] 1 H NMR (600MHz, CD3OD) δ7.7–7.6(m,7H),7.5–7.5(m,4H),7.3(d,J=3.2Hz,1H),7.2–7.2(m,1H),7.1–7.0(m,1H),6.3–6.3(m,1H).

[0049] 31 P NMR (162 MHz, CD3OD) δ 33.4.

[0050] 13 C NMR (151MHz, CD3OD) δ137.8, 133.5 (d, J = 2.9Hz), 133.3 (d, J = 105.2Hz), 133.1 (d, J = 10.4Hz), 130.3 (d, J = 10.3Hz), 129.8 (d, J=12.2Hz), 127.7, 126.4 (d, J=10.9Hz), 121.9 (d, J=111.0Hz), 121.5 (d, J=13.4Hz), 117.4 (d, J=2.9Hz), 103.1 (d, J=2.9Hz).

[0051] As can be seen from the examples, the method for synthesizing the C4-arylphosphonyl-substituted indole derivatives of the present invention has the characteristics of mild reaction conditions, high yield, low cost and simple post-processing.

[0052] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art will be able to modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein with equivalents. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing an indole derivative substituted with an arylphosphonyl group at position C4, characterized in that: Adding an N-alkylphosphine oxide-substituted indole, a diarylphosphine oxide, a ruthenium catalyst, an oxidant, a base, and a solvent to a reaction vessel, heating to 50-120° C. under inert gas conditions to react for 20-30 hours, removing the solvent after the reaction, and separating by column chromatography to obtain an indole derivative substituted with an arylphosphonyl group at the C4 position; The structural formula of the N-alkylphosphine oxide substituted indole is The diarylphosphine oxide is a condensed ring substituent or a structural formula The compound, wherein the structural formula of the indole derivative substituted with an aryl phosphono group at position C4 is In the structural formula, the group R 1 is one of alkyl, trifluoromethyl, nitro, acyl, cyano, halogen, alkoxy, oxyester, aryl, and hydrogen, and the group R 2 、R 3 Each is independently selected from one of alkyl, alkenyl, alkynyl, halogen, alkoxy, oxyester, aryl, and hydrogen.

2. The method for synthesizing a C4-arylphosphono-substituted indole derivative according to claim 1, characterized in that: The diarylphosphine oxide containing a fused ring substituent is 3. The method for synthesizing a C4-arylphosphono-substituted indole derivative according to claim 1 or 2, characterized in that: The reaction formula of the method is any of the following reaction formulas:

4. The method for synthesizing a C4-arylphosphonyl-substituted indole derivative according to claim 1, wherein: The solvent is one or more combinations of 1,4-dioxane, dichloroethane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, methyl tert-butyl ether, diethyl ether, ethylene glycol dimethyl ether, toluene or water; The inert gas is argon or nitrogen; The composition and volume ratio of the mobile phase used in the column chromatography are petroleum ether:ethyl acetate=8:1-0:1, and dichloromethane:methanol=30:1-5:

1.

5. The method for synthesizing a C4-arylphosphonyl-substituted indole derivative according to claim 1, wherein: The ruthenium catalyst is one of dichlorophenylruthenium (II) dimer, (p-cymene) ruthenium dichloro dimer, tris(triphenylphosphine)dichlororuthenium, metallic ruthenium, ruthenium trichloride, ruthenium acetate, ruthenium iodide, tris(triphenylphosphino)ruthenium dihydrogencarbonyl, dodecacarbonyl ruthenium, pentamethylcyclopentadienyl tris(acetonitrile)ruthenium (II) hexafluorophosphate.

6. The method for synthesizing a C4-arylphosphonyl-substituted indole derivative according to claim 1, wherein: The oxidant is one or more of a metal cation, a high-valent compound containing a valence-changing element, or a non-metallic elemental oxidant.

7. The method for synthesizing a C4-arylphosphonyl-substituted indole derivative according to claim 6, characterized in that: The metal cation is Fe 3+ 、Cu 2+ 、Ag + ; The high-valent compound containing the variable-valence element is perchlorate, dichromate, persulfate, manganese dioxide, and ferric chloride; the non-metallic elemental oxidant is such as O2 and S.

8. The method for synthesizing a C4-arylphosphonyl-substituted indole derivative according to claim 1, wherein: The base is one of cesium acetate, potassium acetate, sodium acetate, potassium phosphate, sodium phosphate, potassium carbonate, potassium pivalate, and triethylamine.

9. The method for synthesizing a C4-arylphosphonyl-substituted indole derivative according to claim 1, wherein: The molar ratio of the ruthenium catalyst to the N-alkylphosphine oxide substituted indole is 0.1:1, the molar ratio of the diarylphosphine oxide to the N-alkylphosphine oxide substituted indole is 4:1, the molar ratio of the base to the N-alkylphosphine oxide substituted indole is 3:1, and the molar ratio of the oxidant to the N-alkylphosphine oxide substituted indole is 0.3-3:

1.

10. An indole derivative substituted with a C4 arylphosphonyl group obtained according to the process of any one of claims 1 to 9.

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