Preparation method of sulfonyl-substituted indene compound

Abstract

The invention relates to the technical field of organic synthesis, in particular to a preparation method of a sulfonyl-substituted indene compound. The method comprises the following steps: mixing a propargyl alcohol compound, a sodium sulfinate compound, an acid accelerant and a solvent, and carrying out serial sulfonation-cyclization reaction to obtain the sulfonyl-substituted indene compound. The method has the advantages of easily available raw materials, no need of a catalyst, easiness in operation, greenness and high efficiency, and has a relatively good industrial application prospect.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing a sulfone-substituted indene compound. Background Art

[0002] Indene compounds are an important class of compounds and chemical intermediates. They are of great value in natural and synthetic compounds, and indene is also widely used in materials science, such as the preparation of photovoltaic solar cells and new fluorescent materials. Therefore, the synthesis of indene compounds has extremely important application prospects and has attracted the attention of organic synthesizers. Although there are many strategies for the synthesis of indene compounds, there are fewer methods for the preparation of sulfone-substituted indene compounds. In 2019, Hsing-Yin Chen's group reported that 2-sulfone aromatic olefins were first synthesized under the mediation of Amberlyst-15 using β-ketosulfone and aromatic aldehyde as raw materials, and then reduced under the action of Grignard reagent and NaBH4 to obtain 2-sulfone indene compounds.

[0003] However, the above-mentioned method for synthesizing sulfone-substituted indene compounds is relatively complicated and not suitable for industrial application. There is an urgent need for a simple, easy-to-operate, green and efficient synthesis method to meet the needs of industrial application. Summary of the invention

[0004] In order to overcome the above technical problems, the present invention provides a method for preparing a sulfone-substituted indene compound, which has the advantages of readily available raw materials, no need for catalysts, easy operation, and is green and efficient, and has good prospects for industrial application.

[0005] The present invention provides a method for preparing a sulfone-substituted indene compound, comprising the following steps:

[0006] The propargyl alcohol compound shown in formula I, the sodium sulfinate compound shown in formula II, an acid promoter and a solvent are mixed, and a sulfonation-cyclization reaction is carried out in series to obtain a sulfone-substituted indene compound shown in formula III.

[0007]

[0008] Among them, R 1 and R 2 is methoxy or R 1 and R 2 The ring forms a 1,3-dioxolane structure.

[0009] Ar 1 and Ar 2 are each independently aryl,

[0010] R is an alkyl group or an aryl group.

[0011] Optionally, the Ar 1and Ar 2 Each is independently phenyl, p-methoxyphenyl or p-chlorophenyl.

[0012] Optionally, R is phenyl, p-tolyl or p-bromophenyl.

[0013] Optionally, the acid promoter is trimethylchlorosilane.

[0014] Optionally, the temperature of the tandem sulfonation-cyclization reaction is 75-85° C. and the time is 5-10 min.

[0015] Optionally, the molar ratio of the propargyl alcohol compound represented by formula I, the sodium sulfinate compound represented by formula II and the acid promoter is 1:(1.5-3.0):(1.5-3.0).

[0016] Optionally, the solvent includes at least one of 1,2-dichloroethane, acetonitrile, nitromethane and 1,4-dioxane, and the usage ratio of the propargyl alcohol compound represented by Formula I to the solvent is 1 mmol: 5-15 mL.

[0017] Optionally, after the tandem sulfonation-cyclization reaction, purification is also included, and the purification includes the following steps:

[0018] Extracting the reaction solution obtained from the tandem sulfonation-cyclization reaction to obtain an organic phase;

[0019] The organic phase is washed and dried, and then the solvent is removed to obtain a crude product of a sulfone-substituted indene compound;

[0020] The crude product of the sulfone-substituted indene compound is subjected to silica gel column chromatography, the effluent containing the sulfone-substituted indene compound is collected, and the eluent is removed to obtain the sulfone-substituted indene compound.

[0021] Optionally, the extraction agent is ethyl acetate.

[0022] Optionally, the elution process of the silica gel column chromatography is gradient elution, and the eluent used in the gradient elution is a mixed solution of petroleum ether and ethyl acetate; during the gradient elution process, the mass ratio of petroleum ether and ethyl acetate in the eluent is reduced from 100:1 to 20:1.

[0023] The invention provides a method for preparing a sulfonated indene compound. The method uses a propargyl alcohol compound as a substrate, and in the presence of a sodium sulfinate compound and trimethylsilyl chloride (TMSCl) acid promoter, a sulfone-substituted indene compound is prepared by a "one-pot method". The method does not require a metal catalyst and has mild conditions. It has high atom economy, is easy to operate, and has wide substrate applicability. The method can be applied to the preparation of indene compounds with different sulfone-substituted groups. In addition, the raw materials of the preparation method of the invention are simple and easy to obtain, and the yield is good, and the method has good prospects for industrial application. DETAILED DESCRIPTION

[0024] The present invention will be described below by specific embodiments, and it will be appreciated by those skilled in the art that the following specific embodiments are only for illustrative purposes, and do not limit the scope of the present invention in any way. In addition, in the following embodiments, unless otherwise specified, the reagents and equipment used are all commercially available. If in the following embodiments, specific treatment conditions and treatment methods are not clearly described, then conditions and methods known in the art can be adopted to process.

[0025] A method for preparing a sulfone-substituted indene compound comprises the following steps:

[0026] The propargyl alcohol compound shown in formula I, the sodium sulfinate compound shown in formula II, an acid promoter and a solvent are mixed, and a sulfonation-cyclization reaction is carried out in series to obtain a sulfone-substituted indene compound shown in formula III.

[0027]

[0028] Among them, R 1 and R 2 is methoxy or R 1 and R 2 The ring forms a 1,3-dioxolane structure.

[0029] Ar 1 and Ar 2 are each independently aryl,

[0030] R is an alkyl group or an aryl group.

[0031] In the present invention, the reaction formula of the tandem sulfonation-cyclization reaction is shown in the following reaction formula I:

[0032]

[0033] In the present invention, the R 1 and R 2 is methoxy or R 1 and R 2 The ring forms a 1,3-dioxolane structure.

[0034] In some embodiments of the present invention, the Ar 1 and Ar 2 Each is independently phenyl, p-methoxyphenyl or p-chlorophenyl.

[0035] As an illustrative example, the propargyl alcohol compound represented by Formula I may be one of the compounds represented by the following Formulas I-1 to I-4:

[0036]

[0037] In some embodiments of the present invention, R is phenyl, p-tolyl or p-bromophenyl. As an illustrative example, the sodium sulfinate compound represented by formula II can be at least one of sodium p-toluenesulfinate and sodium 4-bromobenzenesulfinate.

[0038] As an illustrative example, the sulfone-substituted indene compound may be at least one of Formula III-1 to Formula III-5:

[0039]

[0040] In some embodiments of the present invention, the acid promoter is trimethylsilyl chloride. In the present invention, the acid promoter dehydrates the propargyl alcohol compound to form an allene carbonium ion intermediate, which is then captured by the nucleophilic sodium sulfinate compound and further undergoes intramolecular cyclization to obtain the target product.

[0041] In some embodiments of the present invention, the temperature of the tandem sulfonation-cyclization reaction is 75-85°C, specifically 75°C, 77°C, 79°C, 80°C, 82°C, 84°C and 85°C; the time of the tandem sulfonation-cyclization reaction is 5-10min, specifically 5min, 6min, 7min, 8min, 9min and 10min. The present invention has no special restrictions on the temperature at which the propargyl alcohol compound shown in formula I, the sodium sulfinate compound shown in formula II, the acid promoter and the solvent are mixed, and the mixture can be carried out at room temperature; the present invention has no special restrictions on the heating rate of the raw material mixture obtained after the mixing to the temperature of the tandem sulfonation-cyclization reaction. The preparation method provided by the present invention has a mild reaction temperature and a short reaction time. In actual production, those skilled in the art can monitor whether the reaction is completed by thin layer chromatography (TCL) to specifically determine the reaction time.

[0042] In some embodiments of the present invention, the molar ratio of the propargyl alcohol compound represented by formula I, the sodium sulfinate compound represented by formula II and the acid promoter is 1:(1.5-3.0):(1.5-3.0), specifically 1:1.5:1.5, 1:1.5:2.0, 1:2.0:1.5, 1:2.0:2.0, 1:2.0:3.0, etc.

[0043] In some embodiments of the present invention, the solvent includes at least one of 1,2-dichloroethane, acetonitrile, nitromethane and 1,4-dioxane, and the usage ratio of the propargyl alcohol compound represented by Formula I to the solvent is 1mmol:5-15mL, specifically 1mmol:5mL, 1mmol:10mL, 1mmol:12mL and 1mmol:15mL.

[0044] In some embodiments of the present invention, after the tandem sulfonation-cyclization reaction, purification is further included, and the purification includes the following steps or is carried out according to the following steps:

[0045] Extracting the reaction solution obtained from the tandem sulfonation-cyclization reaction to obtain an organic phase;

[0046] The organic phase is washed and dried, and then the solvent is removed to obtain a crude product of a sulfone-substituted indene compound;

[0047] The crude product of the sulfone-substituted indene compound is subjected to silica gel column chromatography, the effluent containing the sulfone-substituted indene compound is collected, and the eluent is removed to obtain the sulfone-substituted indene compound.

[0048] In some embodiments of the present invention, the extractant for extraction is ethyl acetate. The present invention has no special limitation on the amount of the extractant, and those skilled in the art can determine the amount of the extractant according to conventional technical means.

[0049] The present invention does not specifically limit the specific method of the extraction, and conventional extraction methods in the art can be used. In some embodiments of the present invention, the extraction comprises the following steps:

[0050] The reaction solution obtained from the tandem sulfonation-cyclization reaction is mixed with saturated sodium bicarbonate and ethyl acetate, and then allowed to stand for stratification to obtain an aqueous layer and an organic layer. The organic layer is used as an organic phase to carry out subsequent steps.

[0051] The present invention does not specifically limit the amount of saturated sodium bicarbonate solution and ethyl acetate used in the extraction process, and those skilled in the art can determine it by conventional methods. In an embodiment of the present invention, the volume ratio of the solvent to the saturated sodium bicarbonate solution and ethyl acetate is 1:2:10.

[0052] In some embodiments of the present invention, in order to fully extract the product from the reaction solution, the water layer is extracted again with ethyl acetate, and the obtained ethyl acetate extract is combined with the aforementioned organic layer as an organic phase for subsequent steps. In an embodiment of the present invention, when the water layer is extracted, the amount of ethyl acetate used is the same as the amount used when the reaction solution obtained by the tandem sulfonation-cyclization reaction is extracted.

[0053] The present invention has no special restrictions on the washing and drying of the organic phase and the steps of removing the solvent, and conventional methods in the art can be used. In an embodiment of the present invention, the washing is carried out using saturated salt water, the drying uses anhydrous sodium sulfate as a desiccant, and the method of removing the solvent is distillation. The present invention has no special restrictions on the specific method and conditions of the distillation, as long as the extractant (ethyl acetate) can be removed. In an embodiment of the present invention, the distillation is a reduced pressure distillation.

[0054] In some embodiments of the present invention, the elution process of the silica gel column chromatography is gradient elution, and the eluent used in the gradient elution is a mixed solution of petroleum ether and ethyl acetate; in the gradient elution process, the mass ratio of petroleum ether to ethyl acetate in the eluent is reduced from 100:1 to 20:1. The present invention has no special limitation on the specific gradient of the gradient elution, as long as the target product can be separated. In an embodiment of the present invention, the gradient elution process is to use a mixed solution of petroleum ether and ethyl acetate with a mass ratio of 100:1, 60:1, 40:1 and 20:1 as the eluent for elution in sequence.

[0055] The present invention has no particular limitation on the specific method of removing the eluent, as long as the eluent can be removed. In an embodiment of the present invention, the method of removing the eluent is to distill and dry the effluent containing the sulfone-substituted indene compound in sequence. The present invention has no particular limitation on the method of distillation and drying, as long as the eluent can be completely removed.

[0056] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments. The embodiments of the present application are only used as examples, and all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0057] Example 1

[0058] The reaction formula involved in this embodiment is as follows:

[0059]

[0060] At room temperature, propargyl alcohol compound I-1 (34.4 mg, 0.1 mmol) and sodium p-toluenesulfinate (35.6 mg, 0.2 mmol) were dissolved in 1 mL of nitromethane, and then TMSCl (25.5 μL, 0.2 mmol) was added to obtain a raw material mixture. When the raw material mixture was heated to 80 ° C and reacted for 5 min, the reaction was tracked by TLC to confirm the end of the reaction. The obtained reaction solution was mixed with 2 mL of saturated sodium bicarbonate solution and 10 mL of ethyl acetate, and the mixture was allowed to stand for stratification to obtain an aqueous layer and a first organic layer. The aqueous layer was mixed with 10 mL of ethyl acetate and allowed to stand for stratification to obtain a second organic layer. The first organic layer and the second organic layer were combined as an organic phase, and then washed with saturated brine and dried over anhydrous sodium sulfate to obtain a dry organic phase. The dried organic phase was distilled under reduced pressure at 35°C until no liquid flowed out to remove ethyl acetate, and the obtained product was separated by silica gel column chromatography, wherein the elution process was to use a mixed solution of petroleum ether and ethyl acetate with a mass ratio of 100:1, 60:1, 40:1 and 20:1 as an eluent to sequentially elute, and collect the effluent containing the sulfone-substituted indene compound. After the effluent containing the sulfone-substituted indene compound was distilled under reduced pressure at 35°C until no liquid flowed out, the obtained residue was dried to obtain 42.9 mg of the sulfone-substituted indene compound III-1 as a yellow solid, with a yield of 89%.

[0061] The sulfone-substituted indene compound III-1 was subjected to nuclear magnetic resonance detection, and the results are shown below, confirming that its structure is as shown in formula III-1 in the above reaction formula.

[0062] 1 H NMR (400MHz, CDCl3): δppm 7.86(d,J=8.0Hz,2H),7.48(s,1H),7.30(d,J=8.0Hz,2H),7.25-7.24(m,6H),7.17(s,1H ),7.09(dd,J=2.0Hz,J=5.6Hz,4H),6.79(s,1H),3.88(s,3H),3.77(s,3H),2.41(s,3H). 13 C NMR (100MHz, CDCl3):150.5,149.0,144.7,143.3,142.2,141.1,137.6,129.9 ,128.7,128.4,127.8,127.6,127.5,109.0,105.3,66.2,56.22,56.19,21.6.

[0063] Example 2

[0064] The reaction formula involved in this embodiment is as follows:

[0065]

[0066] The sulfone-substituted indene compound was prepared according to the method described in Example 1, except that the propargyl alcohol compound I-1 was replaced by the propargyl alcohol compound I-2 (37.4 mg, 0.1 mmol). 44.0 mg of the sulfone-substituted indene compound III-2 was obtained as a yellow solid with a yield of 86%.

[0067] The sulfone-substituted indene compound III-2 was subjected to nuclear magnetic resonance detection, and the results are shown below, confirming that its structure is as shown in Formula III-2 in the above reaction formula.

[0068] 1 H NMR (400MHz,CDCl3): 1 H NMR (400MHz, CDCl3): δppm 7.85(d,J=8.4Hz,2H),7.46(s,1H),7.30(d,J=8.0Hz,2H),7.25-7.23(m,3H),7.16(s,1H),7.11-7.0 9(m,2H),7.01(d,J=8.8Hz,2H),6.78(d,J=6.8Hz,3H),3.88(s,3H),3.78-3.77(m,6H),2.41(s,3H). 13 C NMR (100MHz, CDCl3):158.9,150.7,148.97,148.94,144.6,143.6,141.9,141.3,137.6,132.7,129 .9,128.9,128.7,128.3,127.7,127.6,127.4,114.1,108.9,105.3,65.6,56.21,56.18,55.3,21.6.

[0069] Example 3

[0070] The reaction formula involved in this embodiment is as follows:

[0071]

[0072] The sulfone-substituted indene compound was prepared according to the method described in Example 1, except that the propargyl alcohol compound I-1 was replaced by the propargyl alcohol compound I-3 (41.2 mg, 0.1 mmol). 47.3 mg of the sulfone-substituted indene compound III-3 was obtained as a yellow solid with a yield of 86%.

[0073] The sulfone-substituted indene compound III-3 was subjected to nuclear magnetic resonance detection, and the results are shown below, confirming that its structure is as shown in formula III-3 in the above reaction formula.

[0074] 1 H NMR (400MHz, CDCl3): δppm 7.85(d,J=8.0Hz,2H),7.35(s,1H),7.31(d,J=8.0Hz,2H),7.23(d,J=8.4Hz,4H),7.1 8(s,1H),7.01(d,J=8.4Hz,4H),6.70(s,1H),3.89(s,3H),3.77(s,3H),2.42(s,3H). 13 CNMR (100MHz, CDCl3):149.3,149.1,144.9,143.2,142.5,139.2,137.3,133.7,1 30.0,129.1,129.02,128.98,128.2,127.6,108.6,105.5,65.1,56.3,56.2,21.6.

[0075] Example 4

[0076] The reaction formula involved in this embodiment is as follows:

[0077]

[0078] The sulfone-substituted indene compound was prepared according to the method described in Example 1, except that the propargyl alcohol compound I-1 was replaced by the propargyl alcohol compound I-4 (32.8 mg, 0.1 mmol). 28.4 mg of the sulfone-substituted indene compound III-4 was obtained as a white solid with a yield of 61%.

[0079] The sulfone-substituted indene compound III-4 was subjected to nuclear magnetic resonance detection, and the results are shown below, confirming that its structure is as shown in formula III-4 in the above reaction formula.

[0080] 1 H NMR (400MHz, CDCl3): δppm 7.84(d,J=8.4Hz,2H),7.54(s,1H),7.30(d,J=7.6Hz,2H),7.25-7.24(m,6H),7.11-7.09(m,5H),6.76(s,1H),5.93(s,2H),2.40(s,3H). 13 CNMR(100MHz, CDCl3):150.9,147.7,147.5,145.0,144.7,142.1,140.9,137. 4,130.0,129.3,128.7,127.7,127.6,127.5,106.9,103.0,101.7,65.9,21.6.

[0081] Example 5

[0082] The reaction formula involved in this embodiment is as follows:

[0083]

[0084] At room temperature, propargyl alcohol compound I-1 (34.4 mg, 0.1 mmol) and sodium 4-bromobenzenesulfinate (48.4 mg, 0.2 mmol) were dissolved in 1 mL of nitromethane, and then TMSCl (25.5 μL, 0.2 mmol) was added to obtain a raw material mixture. When the raw material mixture was heated to 75°C and reacted for 10 min, the reaction was tracked by TLC to confirm the end of the reaction. The obtained reaction solution was treated according to the treatment method of the reaction solution in Example 1 to obtain 47.8 mg of sulfone-substituted indene compound III-5 as a yellow solid with a yield of 88%.

[0085] The sulfone-substituted indene compound III-5 was subjected to nuclear magnetic resonance detection, and the results are shown below, confirming that its structure is as shown in formula III-5 in the above reaction formula.

[0086] 1 H NMR (400MHz, CDCl3): δppm 7.84(d,J=8.8Hz,2H),7.67(d,J=8.4Hz,2H),7.55(s,1H),7.29(d,J=2.4Hz, 6H),7.18(s,1H),7.13-7.11(m,4H),6.83(s,1H),3.92(s,3H),3.81(s,3H). 13 C NMR (100MHz, CDCl3):151.5,149.3,149.1,143.3,141.5,140.8,139.7,13 2.6,129.0,128.9,128.8,127.9,127.7,127.6,109.1,105.1,66.4,56.3.

[0087] While preferred embodiments of the present invention have been shown and described, it is contemplated that those skilled in the art may devise various modifications of the present invention within the spirit and scope of the appended claims.

Claims

1. A method for preparing a sulfone-substituted indene compound, comprising the following steps: The propargyl alcohol compound shown in formula I, the sodium sulfinate compound shown in formula II, an acid promoter and a solvent are mixed, and a sulfonation-cyclization reaction is carried out in series to obtain a sulfone-substituted indene compound shown in formula III. Among them, R 1 and R 2 is methoxy or R 1 and R 2 The ring forms a 1,3-dioxolane structure. Ar 1 and Ar 2 are each independently aryl, R is an alkyl group or an aryl group.

2. The preparation method according to claim 1, characterized in that: The Ar 1 and Ar 2 Each is independently phenyl, p-methoxyphenyl or p-chlorophenyl.

3. The preparation method according to claim 1, characterized in that: The R is phenyl, p-tolyl or p-bromophenyl.

4. The preparation method according to claim 1, characterized in that: The acid promoter is trimethylchlorosilane.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The temperature of the tandem sulfonation-cyclization reaction is 75-85° C. and the time is 5-10 min.

6. The preparation method according to any one of claims 1 to 4, characterized in that: The molar ratio of the propargyl alcohol compound represented by formula I, the sodium sulfinate compound represented by formula II and the acid promoter is 1:(1.5-3.0):(1.5-3.0).

7. The preparation method according to any one of claims 1 to 4, characterized in that: The solvent includes at least one of 1,2-dichloroethane, acetonitrile, nitromethane and 1,4-dioxane, and the usage ratio of the propargyl alcohol compound represented by formula I to the solvent is 1 mmol:5-15 mL.

8. The preparation method according to any one of claims 1 to 4, characterized in that: After the tandem sulfonation-cyclization reaction, purification is also included, and the purification includes the following steps: Extracting the reaction solution obtained from the tandem sulfonation-cyclization reaction to obtain an organic phase; The organic phase is washed and dried, and then the solvent is removed to obtain a crude product of a sulfone-substituted indene compound; The crude product of the sulfone-substituted indene compound is subjected to silica gel column chromatography, the effluent containing the sulfone-substituted indene compound is collected, and the eluent is removed to obtain the sulfone-substituted indene compound.

9. The preparation method according to claim 8, characterized in that: The extraction agent is ethyl acetate.

10. The preparation method according to claim 8, characterized in that: The elution process of the silica gel column chromatography is gradient elution, and the eluent used in the gradient elution is a mixed solution of petroleum ether and ethyl acetate; during the gradient elution process, the mass ratio of petroleum ether to ethyl acetate in the eluent is reduced from 100:1 to 20:1.

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