A method for preparing a sulfone-substituted indene compound

Abstract

This invention relates to the field of organic synthesis technology, and more particularly to a method for preparing sulfone-substituted indene compounds. The method involves mixing a propargyl alcohol compound, a sodium sulfinate compound, an acid promoter, and a solvent, and carrying out a tandem sulfonation-cyclization reaction to obtain the sulfone-substituted indene compound. This method has the advantages of readily available raw materials, no catalyst required, ease of operation, and being green and efficient, showing good prospects for industrial application.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing sulfone-substituted indene compounds. Background Technology

[0002] Indene compounds are an important class of compounds and chemical intermediates, possessing significant value in both natural and synthetic compounds. Furthermore, indene has wide applications in materials science, such as in the preparation of photovoltaic solar cells and novel fluorescent materials. Therefore, the synthesis of indene compounds holds immense promise and has attracted considerable attention from organic synthesizers. While numerous strategies exist for synthesizing indene compounds, methods for preparing sulfone-substituted indene compounds are relatively few. In 2019, Hsing-Yin Chen's group reported the synthesis of 2-sulfonyl aromatics from β-ketosulfones and aromatic aldehydes via Amberlyst-15-mediated synthesis, followed by reduction with Grignard reagents and NaBH4 to obtain 2-sulfonyl indene compounds.

[0003] However, the above-mentioned methods for synthesizing sulfone-substituted indene compounds are quite cumbersome and unsuitable for industrial applications. There is an urgent need for a simple, easy-to-operate, green, and efficient synthesis method to meet the needs of industrial applications. Summary of the Invention

[0004] To overcome the above-mentioned technical problems, the present invention provides a method for preparing sulfone-substituted indene compounds. This method has the advantages of readily available raw materials, no need for catalysts, easy operation, and being green and efficient, and has good prospects for industrial application.

[0005] This 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 subjected to a tandem sulfonation-cyclization reaction to obtain the sulfone-substituted indene compound shown in Formula III.

[0007]

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

[0009] Ar 1 and Ar 2 Each is an aryl group,

[0010] R is an alkyl or aryl group.

[0011] Optionally, the Ar 1and Ar 2 Each can be independently classified as 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 sulfite compound represented by Formula II, and the acid accelerator 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 ratio of the propargyl alcohol compound represented by Formula I to the solvent is 1 mmol: 5-15 mL.

[0017] Optionally, the tandem sulfonation-cyclization reaction is followed by purification, which includes the following steps:

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

[0019] After washing and drying the organic phase, the solvent was removed to obtain a crude sulfone-substituted indene compound.

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

[0021] Optionally, the extractant used for extraction 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 to ethyl acetate in the eluent decreases from 100:1 to 20:1.

[0023] This invention provides a method for preparing sulfone-substituted indene compounds. Using propargyl alcohol compounds as substrates, and under the action of sodium sulfinate compounds and trimethylchlorosilane (TMSCl) acid promoters, a one-pot method is employed to prepare sulfone-substituted indene compounds. This method requires no metal catalysts, operates under mild conditions, and is not only highly atom-economical but also simple to operate and has broad substrate applicability, applicable to the preparation of indene compounds with different sulfone substitutions. Furthermore, the raw materials used in this preparation method are simple and readily available, and the yield is good, demonstrating promising prospects for industrial application. Detailed Implementation

[0024] The present invention will be described below through specific embodiments. Those skilled in the art will understand that the specific embodiments described below are for illustrative purposes only and do not limit the scope of the invention in any way. Furthermore, in the following embodiments, unless otherwise specified, the reagents and equipment used are commercially available. If specific processing conditions and methods are not explicitly described in the following embodiments, conditions and methods known in the art can be used for processing.

[0025] A method for preparing a sulfone-substituted indene compound includes 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 subjected to a tandem sulfonation-cyclization reaction to obtain the sulfone-substituted indene compound shown in Formula III.

[0027]

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

[0029] Ar 1 and Ar 2 Each is an aryl group,

[0030] R is an alkyl or aryl group.

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

[0032]

[0033] In this invention, the R 1 and R 2 It is methoxy or R 1 and R 2 The rings form a 1,3-dioxolane ring structure.

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

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

[0036]

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

[0038] As an exemplary 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 trimethylchlorosilane. In the present invention, the acid promoter causes the propargyl alcohol compound to dehydrate to form an allene carbocation 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 this 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 5-10 min, specifically 5 min, 6 min, 7 min, 8 min, 9 min, and 10 min. This invention does not specifically limit the mixing temperature of the propargyl alcohol compound represented by Formula I, the sodium sulfinate compound represented by Formula II, the acid promoter, and the solvent; the reaction can be carried out at room temperature. This invention does not specifically limit the heating rate of the mixture of raw materials obtained after mixing to the temperature of the tandem sulfonation-cyclization reaction. The preparation method provided by this invention has a mild reaction temperature and a short reaction time. In actual production, those skilled in the art can monitor whether the reaction has ended and specifically determine the reaction time using thin-layer chromatography (TCL).

[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 accelerator 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 ratio of the propargyl alcohol compound represented by Formula I to the solvent is 1 mmol: 5-15 mL, specifically 1 mmol: 5 mL, 1 mmol: 10 mL, 1 mmol: 12 mL and 1 mmol: 15 mL.

[0044] In some embodiments of the present invention, the tandem sulfonation-cyclization reaction is followed by purification, which includes or is performed according to the following steps:

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

[0046] After washing and drying the organic phase, the solvent was removed to obtain a crude sulfone-substituted indene compound.

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

[0048] In some embodiments of the present invention, the extractant used for extraction is ethyl acetate. The present invention does not impose a particular limitation on the amount of the extractant used; those skilled in the art can determine the amount of extractant using conventional techniques.

[0049] This invention does not specifically limit the extraction method; any conventional extraction method in the art can be used. In some embodiments of this invention, the extraction includes 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 to separate into layers, resulting in an aqueous layer and an organic layer. The organic layer serves as the organic phase for subsequent steps.

[0051] This invention does not impose any particular limitation on the amount of saturated sodium bicarbonate solution and ethyl acetate used in the extraction process; those skilled in the art can determine this using conventional methods. In the embodiments of this 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 aqueous layer is extracted again with ethyl acetate, and the resulting ethyl acetate extract is combined with the aforementioned organic layer as the organic phase for subsequent steps. In embodiments of the present invention, the amount of ethyl acetate used when extracting the aqueous layer is the same as the amount used when extracting the reaction solution obtained from the tandem sulfonation-cyclization reaction.

[0053] This invention does not specifically limit the steps of washing and drying the organic phase, or removing the solvent; conventional methods in the art can be used. In this embodiment, the washing is performed using saturated brine, the drying uses anhydrous sodium sulfate as a desiccant, and the solvent removal is performed by distillation. This invention does not specifically limit the specific method and conditions of the distillation, as long as it can remove the extractant (ethyl acetate). In this embodiment, the distillation is vacuum 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 for 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 decreases from 100:1 to 20:1. The present invention does not specifically limit the specific gradient of the gradient elution, as long as it can separate the target product. In embodiments of the present invention, the gradient elution process uses mixed solutions of petroleum ether and ethyl acetate with mass ratios of 100:1, 60:1, 40:1, and 20:1 as eluents for sequential elution.

[0055] This invention does not specifically limit the method for removing the eluent, as long as the eluent can be removed. In this embodiment, the method for removing the eluent is to sequentially distill and dry the effluent containing the sulfone-substituted indene compound. This invention does not specifically limit the method of distillation and drying, as long as the eluent can be completely removed.

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

[0057] Example 1

[0058] The specific 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 starting material mixture. The starting material mixture was heated to 80 °C and reacted for 5 min. The reaction was monitored by TLC to confirm the completion of the reaction. The resulting reaction solution was mixed with 2 mL of saturated sodium bicarbonate solution and 10 mL of ethyl acetate, and allowed to stand to separate into two layers, yielding an aqueous layer and a first organic layer. The aqueous layer was mixed with 10 mL of ethyl acetate and allowed to stand to separate into two layers to obtain a second organic layer. The first and second organic layers were combined as the organic phase, washed successively with saturated brine, and dried with anhydrous sodium sulfate to obtain a dry organic phase. The dried organic phase was distilled under reduced pressure at 35°C until no liquid eluent was obtained to remove ethyl acetate. The resulting product was then subjected to silica gel column chromatography, with elution using a mixture of petroleum ether and ethyl acetate at mass ratios of 100:1, 60:1, 40:1, and 20:1 sequentially. The eluent containing the sulfone-substituted indene compound was collected. This eluent was then distilled under reduced pressure at 35°C until no liquid eluent was obtained. The residue was dried to give 42.9 mg of 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 NMR analysis, and the results are shown below, confirming its structure as shown in the above reaction formula III-1.

[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 specific 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 propargyl alcohol compound I-1 was replaced with propargyl alcohol compound I-2 (37.4 mg, 0.1 mmol). 44.0 mg of sulfone-substituted indene compound III-2 was obtained as a yellow solid, in a yield of 86%.

[0067] The sulfone-substituted indene compound III-2 was subjected to NMR analysis, and the results are shown below, confirming its structure as shown in the above reaction formula III-2.

[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 specific 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 propargyl alcohol compound I-1 was replaced with propargyl alcohol compound I-3 (41.2 mg, 0.1 mmol). 47.3 mg of sulfone-substituted indene compound III-3 was obtained as a yellow solid, in a yield of 86%.

[0073] The sulfone-substituted indene compound III-3 was subjected to NMR analysis, and the results are shown below, confirming its structure as shown in the above reaction formula III-3.

[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 specific 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 propargyl alcohol compound I-1 was replaced with propargyl alcohol compound I-4 (32.8 mg, 0.1 mmol). 28.4 mg of sulfone-substituted indene compound III-4 was obtained as a white solid, in a yield of 61%.

[0079] The sulfone-substituted indene compound III-4 was subjected to NMR analysis, and the results are shown below, confirming its structure as shown in the above reaction formula III-4.

[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 specific 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 starting material mixture. The mixture was heated to 75 °C and reacted for 10 min. The reaction was monitored by TLC to confirm completion. The resulting reaction solution was processed according to the method described 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 NMR analysis, and the results are shown below, confirming its structure as shown in the above reaction formula III-5.

[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] Although preferred embodiments of the invention have been shown and described, it is conceivable that those skilled in the art can devise various modifications to the 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 subjected to a tandem sulfonation-cyclization reaction to obtain the sulfone-substituted indene compound shown in Formula III. Formula I, Formula II, Formula III, Among them, R 1 and R 2 It is methoxy or R 1 and R 2 It forms a 1,3-dioxolane ring structure. Ar 1 and Ar 2 Each can be independently classified as phenyl, p-methoxyphenyl, or p-chlorophenyl. R is phenyl, p-tolyl, or p-bromophenyl. The acid accelerator is trimethylchlorosilane.

2. The preparation method according to claim 1, characterized in that, The tandem sulfonation-cyclization reaction is carried out at a temperature of 75-85°C for 5-10 minutes.

3. The preparation method according to claim 1, characterized in that, The molar ratio of the propargyl alcohol compound represented by Formula I, the sodium sulfite compound represented by Formula II, and the acid accelerator is 1:(1.5-3.0):(1.5-3.0).

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

5. The preparation method according to claim 1, characterized in that, Following the tandem sulfonation-cyclization reaction, purification is further included, which comprises the following steps: The reaction solution obtained from the tandem sulfonation-cyclization reaction was extracted to obtain an organic phase; After washing and drying the organic phase, the solvent was removed to obtain a crude sulfone-substituted indene compound. The crude sulfone-substituted indene compound was subjected to silica gel column chromatography. The eluent containing the sulfone-substituted indene compound was collected, and the eluent was removed to obtain the sulfone-substituted indene compound.

6. The preparation method according to claim 5, characterized in that, The extractant used for extraction is ethyl acetate.

7. The preparation method according to claim 5, 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 decreases from 100:1 to 20:1.

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