Isoindolinone spirooxetaindoles and methods for their preparation

Abstract

The application discloses an isoindolinone spirooxetane indole derivative and a preparation method thereof, which is a left-handed or right-handed optical active body or a racemate with the following structural formula; the preparation method comprises the following steps: taking isoindoline alkynyl propanol and 2-indole methanol compound as raw materials, taking organic phosphoric acid as a catalyst, and reacting in an organic solvent to obtain the isoindolinone spirooxetane indole derivative. The isoindolinone spirooxetane indole derivative is synthesized by using a catalytic (4+3) cyclization reaction method, the reaction condition is mild, the process is simple, the operation is convenient, and the obtained product has good fluorescence properties, which is of great significance for screening of fluorescent materials.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine synthesis, and particularly relates to isoindolinone spirooxetanoin indole derivatives and a preparation method thereof. BACKGROUND

[0002] Oxetanoin indole derivatives are an important class of organic compounds, and widely exist in some natural products and pharmaceutically active molecules. Figure 1

[0003] Therefore, research on synthesis of axially chiral oxetanoin indole derivatives has been widely concerned. In addition, isoindolinone and its derivatives also have important pharmacological activities. Compounds containing indole ring structure units widely exist in nature, and are the most discovered class of alkaloids, accounting for one fifth of all alkaloids. Due to the unique biological characteristics of indole compounds, they have extremely wide applications in the research fields of organic synthesis, material science, agricultural chemistry and pharmacology. SUMMARY

[0004] The present application aims to provide isoindolinone spirooxetanoin indole derivatives and a preparation method thereof.

[0005] The isoindolinone spirooxetanoin indole derivative of the present application is optically active levorotatory or dextrorotatory or racemate having the following structural formula:

[0006]

[0007] In the formula, R1-R3 are independently selected from H, halogen, methyl, phenyl, cyclohexenyl, biphenyl, thienyl, methoxy, benzyloxy, substituted phenyl, and the substituent is selected from halogen, perfluoromethyl,

[0008] Ar is selected from phenyl and substituted phenyl, and the substituent is selected from halogen, methyl, methoxy, aryl and ester.

[0009] Preferably, the isoindolinone spirooxetanoin indole derivative has one of the following structural formulas:

[0010]

[0011] The preparation method of the isoindolinone spirooxetanoin indole derivative of the present application comprises the following steps: taking isoindolinyl propargyl alcohol compound and 2-indole methanol compound as raw materials, taking 9-anthracene spirocyclic phosphoric acid as a catalyst, reacting in an organic solvent for 24-48 hours, and purifying to obtain the isoindolinone spirooxetanoin indole derivative.

[0012] The 9-anthracene spirocyclic phosphoric acid is a compound having the structural formula (1), and can be optically active levorotatory or dextrorotatory or racemate: ​

[0013]

[0014] The isobenzazoline propargyl alcohol compound has the following structure shown in formula (2):

[0015]

[0016] The 2-indolmethanol compound has the following structure shown in formula (3):

[0017]

[0018] The isobenzazoline propargyl alcohol compound is preferably one of the following compounds:

[0019]

[0020] The 2-indolmethanol compound is preferably one of the following compounds:

[0021]

[0022] In the present application, the organic solvent is one or more of toluene, xylene, benzene, dichloromethane, chloroform, tetrahydrofuran, 1,2-dichloroethane, fluorobenzene, chlorobenzene or 1-fluoro-1,1-dichloroethane.

[0023] In the present application, the molar ratio of the isobenzazoline propargyl alcohol compound and the 2-indolmethanol compound is 1.1:1, the molar ratio of the 9-anthraspirocyclophosphoric acid catalyst and the 2-indolmethanol compound is 1-10:100, and the reaction temperature is 15-35℃.

[0024] After the reaction is completed, the final product is separated and the catalyst is recovered by column chromatography. The eluent of the column chromatography is a mixed solvent of ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate / petroleum ether is further preferably 1:2-3.

[0025] The reaction equation of the present application is as follows:

[0026]

[0027] Compared with the prior art, the present application has the following advantages:

[0028] 1) No metal catalyst is needed, and the reaction can be carried out under mild conditions;

[0029] 2) The isobenzazoline propargyl alcohol compound and the 2-indolmethanol compound are easily prepared, which reduces the preparation cost of the final product;

[0030] 3) High optical activity isobenzazoline ketone spirooxetanoin indole derivatives can be obtained;

[0031] 4) The product has good fluorescence properties and can have good biological activity.

[0032] In summary, the present application uses catalytic (4+3) cyclization reaction method to synthesize isoindolinone spirooxetanoin indole derivatives, which has mild reaction conditions, simple process, convenient operation, and the obtained product has potential good fluorescence properties, which will have important significance for the development of new luminescent materials. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 is a partial structure diagram of oxetanoin indole derivatives;

[0034] Figure 2 is a fluorescence performance result diagram of the compound obtained in Example 5. DETAILED DESCRIPTION

[0035] The following examples will help to understand the present application, but are not limited to the content of the present application.

[0036] Example 1

[0037] A reaction bottle is added with 3-hydroxy-3-phenylacetylene-isoindoline (0.1 mmol), (2-indolyl)-2-phenylmethanol (0.11 mmol), the aforementioned 9-anthracene spirocyclic phosphoric acid shown in structural formula (1) (0.01 mmol), hexafluoroisopropanol (12 mg), 5 mL of 1-fluoro-1,1-dichloroethane is injected, and the reaction is carried out at room temperature for 48 hours. After the reaction is completed, it is directly subjected to silica gel column chromatography, and the eluent is ethyl acetate / petroleum ether=1:3, to obtain the corresponding optically active isoindolinone spirooxetanoin indole derivative, with a yield of 91%; the product is characterized as follows:

[0038] Structural formula:

[0039]

[0040] Property: white solid;

[0041] m.p. 293-295℃;

[0042] Optical purity: 92% ee;

[0043] HPLC analysis conditions: (Daiso Chiralpak column, same below) Chiralpak IE-3 (n-hexane / i-PrOH=80 / 20, 1.0 mL / min), t R (major) 9.865 min, t R (minor) 14.954 min;

[0044] Optical rotation: [α] D20 = +55° (c 1.00, CH2Cl2);

[0045] 1 H NMR (400 MHz, CD2Cl2) δ 7.88 (s, 1H), 7.72 - 7.64 (m, 2H), 7.61 (t, J = 7.5, 1H), 7.48 (t, J = 7.4, 1H), 7.37 - 7.30 (m, 2H), 7.29 - 7.14 (m, 12H), 7.14 - 7.08 (m, 3H), 6.92 - 6.83 (m, 1H), 6.71 (d, J = 8.0, 1H), 6.60 (s, 1H), 6.18 (s, 1H);

[0046] HRMS m / z (ESI + ): calculated for C 37 H 27 N2O2([M+H] + ) 531.2067, found 531.2069.

[0047] Example 2

[0048] Into a reaction vial was added 3-hydroxy-4-trifluoromethylphenylacetylene (0.1 mmol), (2-indolyl)-2-phenylmethanol (0.11 mmol), 9-anthraspirocyclophosphoric acid (0.01 mmol) as shown in the above structural formula (1), hexafluoroisopropanol (12 mg), 5 mL of 1-fluoro-1,1-dichloroethane was injected, and the reaction was allowed to proceed at room temperature for 48 hours. After the reaction was completed, the reaction mixture was directly subjected to silica gel column chromatography using ethyl acetate / petroleum ether = 1:3 as the eluent to obtain the corresponding optically active isoindolinone spirooxetanoindole derivative in 84% yield. The product was characterized as follows:

[0049] Structural formula:

[0050]

[0051] Property: white solid;

[0052] m.p. 321-323 °C;

[0053] Optical purity: 87% ee;

[0054] HPLC analysis conditions: Chiralpak IE-3 (n-hexane / i-PrOH = 80 / 20, 1.0 mL / min), t R (minor) 6.809 min, t R (major) 11.521 min;

[0055] Optical rotation: [a]D 20 = +29° (c 1.0, CH2Cl2);

[0056] 1 H NMR (400 MHz, CD2Cl2) δ 8.11 (s, 1H), 7.80 - 7.68 (m, 3H), 7.63 - 7.51 (m, 3H), 7.45 - 7.19 (m, 14H), 7.00 (t, J = 7.6, 1H), 6.79 (d, J = 8.1, 1H), 6.72 (s, 1H), 6.35 (s, 1H);

[0057] HRMS m / z (ESI + ): calculated for C 38 H 26 F3N2O2([M+H] + ) 599.1941, found 599.1945.

[0058] Example 3

[0059] Into a reaction vial was placed 3-hydroxy-4-iodophenylacetylenyl- isoindoline (0.1 mmol), (2-indolyl)-2-phenylmethanol (0.11 mmol), 9- anthracenespirocyclic phosphoric acid of the aforementioned structural formula (1) (0.01 mmol), hexafluoroisopropanol (12 mg), 5 mL of 1-fluoro-1,1- dichloroethane was injected, and the reaction was allowed to proceed at room temperature for 48 hours. After the reaction was completed, the reaction mixture was directly subjected to silica gel column chromatography using ethyl acetate / petroleum ether = 1:3 as the eluent to obtain the corresponding optically active isoindolinone spirooxetanoindole derivative in a yield of 87%. The product was characterized as follows:

[0060] Structural formula:

[0061]

[0062] Property: white solid;

[0063] m.p. 314-316 °C;

[0064] Optical purity: 90% ee;

[0065] HPLC analysis conditions: Chiralpak IE-3 (n-hexane / i-PrOH = 85 / 15, 1.0 mL / min), t R (major) 11.170 min, t R (minor) 20.114 min;

[0066] Optical rotation: [a] D 20= + 68° (c 1.0, CH2Cl2);

[0067] 1 H NMR (400 MHz, CD2Cl2) δ 7.99 (s, 1H), 7.81 - 7.67 (m, 3H), 7.64 - 7.54 (m, 3H), 7.51 - 7.12 (m, 12H), 7.04 - 6.92 (m, 3H), 6.84 (d, J = 7.9, 1H), 6.68 (s, 1H), 6.27 (s, 1H);

[0068] HRMS m / z (ESI + ): calculated for C 37 H 26 IN2O2([M+H] + ) 657.1033, found 657.1036.

[0069] Example 4

[0070] A reaction flask was charged with 3-hydroxy-3-thiophene ethynyl- isoindoline (0.1 mmol), (2-indolyl)-2-phenylmethanol (0.11 mmol), 9-anthracene spirocyclic phosphoric acid (0.01 mmol) as shown in the above structural formula (1), hexafluoroisopropanol (12 mg), 5 mL of 1-fluoro-1,1-dichloroethane was injected, and the reaction was allowed to proceed at room temperature for 48 hours. After the reaction was completed, the product was directly purified by silica gel column chromatography using ethyl acetate / petroleum ether = 1:3 as the eluent to obtain the corresponding optically active isoindoline ketone spirooxetane indole derivative with a yield of 83%. The product was characterized as follows:

[0071] Structural formula:

[0072]

[0073] Property: white solid;

[0074] m.p. 270-272 °C;

[0075] Optical purity: 95% ee;

[0076] HPLC analysis conditions: Chiralpak IE-3 (n-hexane / i-PrOH = 80 / 20, 1.0 mL / min), t R (minor) 8.738 min, t R (major) 13.767 min;

[0077] Optical rotation: [a] D 20 = + 65° (c 1.0, CH2Cl2);

[0078] 1 H NMR (400 MHz, CD2Cl2) δ 7.87 (s, 1H), 7.71 - 7.57 (m, 3H), 7.47 (t, J = 7.2, 1H), 7.37 - 7.11 (m, 13H), 7.05 (d, J = 8.0, 1H), 6.97 (t, J = 7.5, 1H), 6.91 - 6.85 (m, 2H), 6.48 (s, 1H), 6.21 (s, 1H);

[0079] HRMS m / z (ESI + ): calculated for C 35 H 25 N2O2S ([M+H] + ) 537.1631, found 537.1634.

[0080] Example 5

[0081] A reaction flask was charged with 3-hydroxy-1-cyclohexene ethynyl- isoindoline (0.1 mmol), (2-indolyl)-2-phenylmethanol (0.11 mmol), 9-anthraspirocyclophosphoric acid (0.01 mmol) as shown in the above structural formula (1), hexafluoroisopropanol (12 mg), 5 mL of 1-fluoro-1,1-dichloroethane was injected, and the reaction was allowed to proceed at room temperature for 48 hours. After the reaction was completed, the reaction mixture was directly subjected to silica gel column chromatography using ethyl acetate / petroleum ether = 1:3 as the eluent to obtain the corresponding optically active isoindoline ketone spirooxetanoindole derivative in 76% yield. The product was characterized as follows:

[0082] Structural formula:

[0083]

[0084] Property: yellow solid;

[0085] m.p. 291-293 °C;

[0086] Optical purity: 83% ee;

[0087] HPLC analysis conditions: Chiralpak IE-3 (n-hexane / i-PrOH = 90 / 10, 1.0 mL / min), t R (minor) 15.418 min, t R (major) 17.001 min;

[0088] Optical rotation: [a] D 20 = +94° (c 1.0, CH2Cl2);

[0089] 1H NMR (400 MHz, CD2Cl2) δ 7.84 (s, 1H), 7.74 (d, J = 7.8, 1H), 7.71 (d, J = 7.5, 1H), 7.60 (t, J = 7.6, 1H), 7.51 - 7.37 (m, 7H), 7.37 - 7.31 (m, 3H), 7.24 (t, J = 7.5, 2H), 7.20 - 7.13 (m, 2H), 6.99 (t, J = 7.6, 1H), 6.86 (s, 1H), 6.39 (s, 1H), 4.54 (s, 1H), 2.72 - 2.52 (m, 1H), 2.24 - 2.14 (m, 1H), 2.07 - 1.97 (m, 1H), 1.89 - 1.79 (m, 3H), 1.31 - 1.23 (m, 2H);

[0090] HRMS m / z (ESI + ): calculated for C 37 H 31 N2O2([M+H] + ) 535.2380, found 535.2382.

[0091] Example 6

[0092] Into a reaction vial was placed 3-hydroxy-5,6-dimethyl-3-phenyl ethynyl- isoindoline (0.1 mmol), (2-indolyl)-2-phenylmethanol (0.11 mmol), 9-anthracene spirocyclic phosphoric acid (0.01 mmol) as shown in the above structural formula (1), hexafluoroisopropanol (12 mg), 5 mL of 1-fluoro-1,1-dichloroethane was injected, and the reaction was allowed to proceed at room temperature for 48 hours. After the reaction was completed, the reaction mixture was directly subjected to silica gel column chromatography using ethyl acetate / petroleum ether = 1:3 as the eluent to obtain the corresponding optically active isoindolinone spirooxetane indole derivative in 83% yield. The product was characterized as follows:

[0093] Structural formula:

[0094]

[0095] Property: white solid;

[0096] m.p. 327-329 °C;

[0097] Optical purity: 94% ee;

[0098] HPLC analysis conditions: Chiralpak IE-3 (n-hexane / i-PrOH = 80 / 20, 1.0 mL / min), t R (minor) 9.129 min, t R (major) 14.977 min;

[0099] Optical rotation: [α] D 20 = -38° (c 1.0, CH2Cl2);

[0100] 1 H NMR (400 MHz, CD2Cl2) δ 11.42 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.60 (ddd, J = 8.3, 6.9, 1.1 Hz, 1H), 7.46 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 7.30 - 6.98 (m, 8H), 6.78 (dd, J = 7.8, 0.6 Hz, 1H), 6.19 (dd, J = 8.2, 0.6 Hz, 1H), 4.25 - 4.04 (m, 2H), 0.87 (t, J = 7.1 Hz, 3H);

[0101] HRMS m / z (ESI + ): calculated for C 39 H 31 N2O2([M+H] + ) 559.2380, found 559.2387.

[0102] Example 7

[0103] Into a reaction vial was placed 3-hydroxy-5,6-dibromo-3-phenyl ethynyl- isoindoline (0.1 mmol), (2-indolyl)-2-phenylmethanol (0.11 mmol), 9-anthracene spirocyclic phosphoric acid (0.01 mmol) as shown in the above structural formula (1), hexafluoroisopropanol (12 mg), 5 mL of 1-fluoro-1,1-dichloroethane was injected, and the reaction was allowed to proceed at room temperature for 48 hours. After the reaction was completed, the reaction mixture was directly subjected to silica gel column chromatography using ethyl acetate / petroleum ether = 1:3 as the eluent to obtain the corresponding optically active isoindolinone spirooxetanoindole derivative in 88% yield. The product was characterized as follows:

[0104] Structural formula:

[0105]

[0106] Property: white solid;

[0107] m.p. 332-334 °C;

[0108] Optical purity: 95% ee;

[0109] HPLC analysis conditions: Chiralpak IE-3 (n-hexane / i-PrOH = 85 / 15, 1.0 mL / min), t R(minor) 7.712 min,t R (major) 11.678 min;

[0110] Optical rotation: [α] D 20 = -10° (c 1.0, CH2Cl2);

[0111] 1 H NMR(400MHz,CD2Cl2)δ8.01(s,1H),7.86(s,1H),7.75–7.61(m,2H),7.46–7.1 6(m,16H),6.98(t,J=7.6,1H),6.81(d,J=8.1,1H),6.70(s,1H),6.22(s,1H);

[0112] HRMS m / z(ESI + ): Calculated value C 37 H 24 Br2N2NaO2([M+Na] + )711.0076, detected value 711.0066.

[0113] Example 8: Fluorescence Measurement

[0114] The skeleton of the compound isoindolineone spiroxaphenoindole can be used in new functional materials and is a structural unit with high application value, including organic light-emitting diodes, electroluminescent materials and organic transistors.

[0115] This invention investigates the fluorescence spectral properties of some compounds obtained in the examples. For example... Figure 2 The image shows the fluorescence properties of the compound obtained in Example 5. First, the fluorescence spectrum was measured in a diluted dichloromethane solution. The compound of Example 5, tested in liquid fluorescence, showed a wavelength range between 400 and 650 nm, with a maximum wavelength of approximately 490 nm in the DCM solution. Figure 2 (a) Furthermore, we also tested the fluorescence quantum yield of the selected compounds, which was 0.15, and observed a light green color when photographed under a UV lamp (λex = 365 nm). In addition, all tested compounds also exhibited solid-state fluorescence emission (…). Figure 2 In example b), the compound of Example 5 exhibits extremely high fluorescence intensity in the solid state, within a wavelength range of 425 to 650 nm, with a maximum wavelength of approximately 505 nm. Furthermore, the solid compound, when photographed under a UV lamp (λex = 365 nm), shows a bright yellow color. The compounds obtained in other examples also show similar characteristics. The isoindolinone spirooxazopinendole derivatives obtained in this invention possess excellent fluorescence properties, which is of great significance for the development of novel luminescent materials.

Claims

1. An isoindolinone spiroxazophenoindole derivative, characterized in that, It is an optically active body with the following structural formula; ， In the formula: R1 is selected from phenyl, cyclohexenyl, thiophene, or substituted phenyl, and the substituent is selected from halogen or perfluoromethyl; R2 and R3 are both selected from H; Ar is selected from phenyl; Alternatively, the isoindolinone spiroxazolide indole derivative may have one of the following structures: 、 。 2. The isoindolinone spirooxacontinole derivative according to claim 1, characterized in that, It is one of the following structural formulas: 。 3. A method for preparing the isoindolinetone spirooxacontinole derivative of claim 1, characterized in that, The method involves reacting isoindolinyl propargyl alcohol compounds and 2-indole methanol compounds as raw materials in an organic solvent at room temperature for 24–48 hours using 9-anthracenespirocyclic phosphoric acid as a catalyst, and then purifying to obtain isoindolinone spiroxazophenoindole derivatives. The 9-anthracenespirophosphate is a compound having the structural formula (1): ， Equation (1) The structure of the isoindoline-propargyl alcohol compounds is shown in formula (2) below: ， Equation (2) It may be one of the following structures: 、 ； The structure of the 2-indole methanol compound is shown in formula (3) below: ， Equation (3).

4. The method for preparing the isoindolinone spiroxazolidenindole derivative according to claim 3, characterized in that, The isoindoline-propargyl alcohol compounds mentioned are one of the following compounds: 。 5. The method for preparing the isoindolinone spirooxacontinole derivative according to claim 3, characterized in that, The 2-indole methanol compounds mentioned are one of the following compounds: 。 6. The method for preparing the isoindolinone spirooxacontinole derivative according to claim 3, characterized in that, The organic solvent is one or more of toluene, xylene, benzene, dichloromethane, chloroform, tetrahydrofuran, 1,2-dichloroethane, fluorobenzene, chlorobenzene, hexafluoroisopropanol, or 1-fluoro-1,1-dichloroethane.

7. The method for preparing the isoindolinone spiroxaphene indole derivative according to claim 3, characterized in that, The molar ratio of the isoindolinyl propargyl alcohol compound and the 2-indole methanol compound is 1.1:1, and the molar ratio of the 9-anthracene spirocyclic phosphoric acid catalyst and the 2-indole methanol compound is 1 to 10:100.

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