A preparation method of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane

Abstract

The present invention discloses a method for preparing 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane. Under inert gas protection, an aryl Grignard reagent is reacted with [1.1.1] propeller alkane, and the resulting intermediate solution is reacted with an SO2 source. After the reaction is completed, 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane is obtained by post-processing. The present invention achieves efficient preparation of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane without adding any catalyst, and has low raw material cost, easy operation, mild conditions, and high reaction yield, and has broad application value.

Description

Technical Field

[0001] The present invention relates to a method for preparing 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane, which specifically comprises the following steps: utilizing an aryl Grignard reagent, [1.1.1]propellerane and DABSO to react, thereby realizing efficient preparation of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane. Background Art

[0002] Arylsulfenyl (aryl sulfoxide) compounds are widely present in various drug molecules. For example, bis-aryl sulfoxides containing nitrogen heterocyclic substituents have been shown to inhibit uric acid synthesis. Bicyclo[1.1.1]pentane, as a bioisostere of aryl groups, has been widely used in drug development. Designing corresponding aryl bicyclo[1.1.1]pentane sulfoxide bioisosteres based on the bis-aryl sulfoxide skeleton and developing efficient synthetic methods for them are of great significance.

[0003] Currently, there is no reported method for the efficient preparation of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane. In 2020, the Bräse group reported a multi-step synthesis route for this type of molecule: sodium bicyclo[1.1.1]pentanesulfonate reacts with thionyl chloride to form a bicyclo[1.1.1]pentanesulfinyl chloride intermediate, which is then reacted with thionyl chloride at -78°C. o C conditions with phenylmagnesium bromide to produce bicyclo[1.1.1]pentane sulfoxide (Chem. Eur. J, 2020, 26(19): 4242-4245.). Traditional sulfoxide preparation often requires the use of an equivalent amount of oxidant or metal catalyst, which has certain limitations in application. This patent develops a "one-pot" synthesis strategy, which uses an aryl Grignard reagent to react with [1.1.1] propellerane to produce a bicyclo[1.1.1]pentylmagnesium bromide intermediate, which then undergoes a nucleophilic substitution reaction with a "SO2 source" to efficiently prepare 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane. Summary of the Invention

[0004] In view of the above problems existing in the prior art, the object of the present invention is to provide a simple, efficient and low-cost method for synthesizing 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane.

[0005] The present invention provides a method for preparing 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane, comprising the following steps:

[0006] 1) Under inert gas protection, reacting an aryl Grignard reagent represented by formula (I) with a [1.1.1] propellerane represented by formula (II) at a certain temperature to obtain an aryl bicyclo[1.1.1]pentane magnesium bromide intermediate solution, which is cooled to room temperature for later use;

[0007] 2) Under the protection of inert gas, the SO2 source represented by formula (III) is dissolved in a solvent, and the aryl bicyclo[1.1.1]pentane magnesium bromide intermediate solution of step 1) is slowly added dropwise in an ice-water bath. After the addition is complete, the temperature is raised to room temperature for reaction, and the aryl Grignard reagent represented by formula (I) is added to continue the reaction. After the reaction is completed, the bicyclo[1.1.1]pentane sulfoxide product represented by formula (IV) is obtained by post-treatment. The reaction equation is as follows:

[0008]

[0009] In the formula, R is an electron-withdrawing group or an electron-donating group, the electron-withdrawing group is chlorine, bromine, iodine or cyano; the electron-donating group is an alkyl group, preferably a methyl group, an ethyl group or a tert-butyl group.

[0010] Furthermore, the present invention also defines the SO2 source as DABSO.

[0011] Furthermore, the present invention also limits the reaction solvent to tetrahydrofuran, N,N - one or a mixed solvent of two or more selected from dimethylformamide, dimethyl sulfoxide, dichloromethane, n-hexane, and ether.

[0012] Furthermore, the present invention also limits the inert gas to argon or nitrogen.

[0013] Furthermore, the present invention also defines the reaction temperature of step 1) as 80-100° C., preferably 100° C., and the reaction time as 0.5-1.5 h, preferably 1 h.

[0014] Furthermore, the present invention also defines the reaction time of the aryl Grignard reagent and the aryl bicyclo[1.1.1]pentane sulfonate intermediate in step 2) as 2-12 h, preferably 4-8 h.

[0015] Furthermore, the present invention also defines the molar ratio of the SO2 source, [1.1.1] propellerane and the initial aryl Grignard reagent as 1:(1-6):(1-4), preferably 1:4:2; the molar ratio of the supplementary aryl Grignard reagent to the initial aryl Grignard reagent is 1-2:1, preferably 1.5:1.

[0016] Furthermore, the present invention also defines that the reaction time of the SO2 source solution and the arylbicyclo[1.1.1]pentanemagnesium bromide intermediate solution in step 2) at room temperature is 1-3 hours, preferably 2 hours.

[0017] Furthermore, the present invention also defines the post-reaction treatment process in step 2) as follows: adding 1M hydrochloric acid solution to the reaction solution to quench the reaction, then adding ethyl acetate and water to dilute, extracting three times with ethyl acetate, collecting the organic phase, and separating by column to obtain 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane.

[0018] By adopting the above technology, compared with the prior art, the beneficial effects of the present invention are embodied in:

[0019] The present invention involves reacting a [1.1.1] propeller alkane with an aryl Grignard reagent to obtain an aryl bicyclo[1.1.1]pentane magnesium bromide intermediate solution. The resulting bicyclo[1.1.1]pentane Grignard reagent intermediate is then reacted with an SO2 source at room temperature to efficiently prepare 1-aryl-3-arylsulfinyl bicyclo[1.1.1]pentane. This reaction does not require the addition of any catalyst, has low raw material costs, and has the advantages of simple operation, mild conditions, and high reaction yield. Implementation Method

[0020] The synthesis scheme of the present invention is described below with reference to specific examples, but the protection scope of the present invention is not limited thereto.

[0021] Example 1 Synthesis of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane

[0022]

[0023] Under an argon atmosphere, phenylmagnesium bromide (0.2 mmol) and [1.1.1] propane (0.67 mL, 0.6 M, 0.4 mmol) were added to a sealed tube. The mixture was reacted in a 100°C oil pan for 1 hour, then stopped and allowed to cool to room temperature. In a separate reactor, DABSO (0.11 mmol) and dichloromethane (1 mL) were added. The reaction mixture was placed in an ice-water bath. Using a long needle, the dicyclopentylmagnesium bromide solution was withdrawn and slowly added dropwise (20 drops / minute) to the reaction tube. After the addition was complete, the mixture was transferred to room temperature and allowed to react for 2 hours. Phenylmagnesium bromide (0.35 mmol) was added and the reaction continued for 6 hours. The reaction was monitored by TLC. Upon completion, the reaction was quenched with 1 M hydrochloric acid. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio 3:1) as eluent to obtain 38 mg of 1-phenyl-3-phenylbicyclo[1.1.1]pentane sulfoxide as a white solid in a yield of 72%. 1H NMR (400 MHz, Chloroform-d) δ7.64 – 7.46 (m, 5H), 7.32 – 7.21 (m, 3H), 7.17 – 7.09 (m, 2H), 2.12 (q, J = 1.2 Hz, 6H). 13 C NMR (100 MHz, Chloroform-d) δ 141.70, 138.44,130.93, 128.94, 128.33, 127.19, 125.92, 124.21, 51.20, 50.73, 42.18.

[0024] Example 2 Synthesis of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane

[0025]

[0026] Under an argon atmosphere, phenylmagnesium bromide (0.1 mmol) and [1.1.1] propane (0.67 mL, 0.6 M, 0.4 mmol) were added to a sealed tube. The mixture was reacted in a 100°C oil pan for 1 hour, then stopped and allowed to cool to room temperature. In a separate reactor, DABSO (0.11 mmol) and dichloromethane (1 mL) were added. The reaction mixture was placed in an ice-water bath. Using a long needle, the dicyclopentylmagnesium bromide solution was withdrawn and slowly added dropwise (20 drops / minute) to the reaction tube. After the addition was complete, the mixture was transferred to room temperature and allowed to react for 2 hours. Arylmagnesium bromide (0.35 mmol) was added and the reaction continued for 6 hours. The reaction was monitored by TLC. Upon completion, the reaction was quenched with 1 M hydrochloric acid. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio 3:1) as eluent to obtain 15 mg of 1-phenyl-3-phenylbicyclo[1.1.1]pentane sulfoxide as a white solid in a yield of 27%.

[0027] Example 3 Synthesis of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane

[0028]

[0029] Under a nitrogen atmosphere, phenylmagnesium bromide (0.1 mmol) and [1.1.1] propane (0.17 mL, 0.6 M, 0.1 mmol) were added to a sealed tube. The mixture was allowed to react in a 100°C oil pan for 1 hour, then stopped and allowed to cool to room temperature. In a separate reactor, DABSO (0.1 mmol) and dichloromethane (1 mL) were added. The reaction mixture was placed in an ice-water bath. Using a long needle, the dicyclopentylmagnesium bromide solution was withdrawn and slowly added dropwise (20 drops / minute) to the reaction tube. After the addition was complete, the mixture was transferred to room temperature and allowed to react for 2 hours. Arylmagnesium bromide (0.35 mmol) was added and the reaction continued for 6 hours. The reaction was monitored by TLC. Upon completion, the reaction was quenched with 1 M hydrochloric acid. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio 3:1) as eluent to obtain 4 mg of 1-phenyl-3-phenylbicyclo[1.1.1]pentane sulfoxide as a white solid in a yield of 7%.

[0030] Example 4 Synthesis of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane

[0031]

[0032] Under a nitrogen atmosphere, phenylmagnesium bromide (0.4 mmol) and [1.1.1] propane (0.17 mL, 0.6 M, 0.1 mmol) were added to a sealed tube. The mixture was reacted in a 100°C oil pan for 1 hour, then stopped and allowed to cool to room temperature. In a separate reactor, DABSO (0.1 mmol) and dichloromethane (1 mL) were added. The reaction mixture was placed in an ice-water bath. Using a long needle, the dicyclopentylmagnesium bromide solution was withdrawn and slowly added dropwise (20 drops / minute) to the reaction tube. After the addition was complete, the mixture was transferred to room temperature and allowed to react for 2 hours. Arylmagnesium bromide (0.35 mmol) was added and the reaction continued for 6 hours. The reaction was monitored by TLC. Upon completion, the reaction was quenched with 1 M hydrochloric acid. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio 3:1) as eluent to obtain 6 mg of 1-phenyl-3-phenylbicyclo[1.1.1]pentane sulfoxide as a white solid in an 11% yield.

[0033] Example 5 Synthesis of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane

[0034]

[0035] Under a nitrogen atmosphere, phenylmagnesium bromide (0.2 mmol) and [1.1.1] propane (0.67 mL, 0.6 M, 0.4 mmol) were added to a sealed tube. The mixture was reacted in a 100°C oil pan for 3 h. The reaction was then stopped and allowed to cool to room temperature. In a separate reactor, DABSO (0.11 mmol) and dichloromethane (1 mL) were added. The reaction mixture was placed in an ice-water bath. Using a long needle, the dicyclopentylmagnesium bromide solution was withdrawn and slowly added dropwise (20 drops / minute) to the reaction tube. After the addition was complete, the mixture was transferred to room temperature and allowed to react for 2 h. Arylmagnesium bromide (0.35 mmol) was added and the reaction continued for 6 h. The reaction was monitored by TLC. Upon completion, the reaction was quenched with 1 M hydrochloric acid. The reaction mixture was then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio of 3:1) as eluent to obtain 27 mg of 1-phenyl-3-phenylbicyclo[1.1.1]pentane sulfoxide as a white solid in a yield of 50%.

[0036] Example 6 Synthesis of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane

[0037]

[0038] Under an argon or nitrogen atmosphere, add phenylmagnesium bromide (0.2 mmol) and [1.1.1] propane (0.67 mL, 0.6 M, 0.4 mmol) to a sealed tube. Incubate in a 100°C oil pan for 1 hour, then stop the reaction and allow it to cool to room temperature. In a separate reactor, add DABSO (0.11 mmol) and ether (1 mL). Place the reaction mixture in an ice-water bath. Use a long needle to withdraw the dicyclopentylmagnesium bromide solution and slowly add it dropwise to the reaction tube (20 drops / minute). After the addition is complete, transfer the mixture to room temperature and allow it to react for 2 hours. Add arylmagnesium bromide (0.35 mmol) and continue the reaction for another 6 hours. Monitor the reaction by TLC. Upon completion, quench the reaction with 1 M hydrochloric acid. The reaction mixture is then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio of 3:1) as eluent to obtain 19 mg of 1-phenyl-3-phenylbicyclo[1.1.1]pentane sulfoxide as a white solid in a yield of 35%.

[0039] Example 7 Synthesis of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane

[0040]

[0041] Under an argon or nitrogen atmosphere, add phenylmagnesium bromide (0.2 mmol) and [1.1.1] propane (0.67 mL, 0.6 M, 0.4 mmol) to a sealed tube. Incubate in a 100°C oil pan for 1 hour, then stop the reaction and allow it to cool to room temperature. In a separate reactor, add DABSO (0.11 mmol) and tetrahydrofuran (1 mL). Place the reaction mixture in an ice-water bath. Use a long needle to withdraw the dicyclopentylmagnesium bromide solution and slowly add it dropwise to the reaction tube (20 drops / minute). After the addition is complete, transfer the mixture to room temperature and allow it to react for 2 hours. Add arylmagnesium bromide (0.35 mmol) and continue the reaction for another 6 hours. Monitor the reaction by TLC. Upon completion, quench the reaction with 1 M hydrochloric acid. The reaction mixture is then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio of 3:1) as eluent to obtain 28 mg of 1-phenyl-3-phenylbicyclo[1.1.1]pentane sulfoxide as a white solid in a yield of 52%.

[0042] Example 8 Synthesis of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane

[0043]

[0044] Under an argon or nitrogen atmosphere, add phenylmagnesium bromide (0.2 mmol) and [1.1.1] propane (0.67 mL, 0.6 M, 0.4 mmol) to a sealed tube. Incubate in a 100°C oil pan for 1 hour, then stop the reaction and allow it to cool to room temperature. In a separate reactor, add DABSO (0.11 mmol) and dichloroethane (1 mL). Place the reaction mixture in an ice-water bath. Use a long needle to withdraw the dicyclopentylmagnesium bromide solution and slowly add it dropwise to the reaction tube (20 drops / minute). After the addition is complete, transfer the mixture to room temperature and allow it to react for 2 hours. Add arylmagnesium bromide (0.35 mmol) and continue the reaction for another 6 hours. Monitor the reaction by TLC. Upon completion, quench the reaction with 1 M hydrochloric acid. The reaction mixture is then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio of 3:1) as eluent to obtain 28 mg of 1-phenyl-3-phenylbicyclo[1.1.1]pentane sulfoxide as a white solid in a yield of 52%.

[0045] Example 9 Synthesis of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane

[0046]

[0047] Under an argon or nitrogen atmosphere, add phenylmagnesium bromide (0.2 mmol) and [1.1.1] propane (0.67 mL, 0.6 M, 0.4 mmol) to a sealed tube. Incubate in a 100°C oil pan for 1 hour, then stop the reaction and allow it to cool to room temperature. In a separate reactor, add DABSO (0.11 mmol) and dichloromethane (1 mL). Place the reaction mixture in an ice-water bath. Use a long needle to withdraw the dicyclopentylmagnesium bromide solution and slowly add it dropwise to the reaction tube (20 drops / minute). After the addition is complete, transfer the mixture to room temperature and allow it to react for 2 hours. Add arylmagnesium bromide (0.35 mmol) and continue the reaction for another hour. Monitor the reaction by TLC. Upon completion, quench the reaction with 1 M hydrochloric acid. The reaction mixture is then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio of 3:1) as eluent to obtain 12 mg of 1-phenyl-3-phenylbicyclo[1.1.1]pentane sulfoxide as a white solid in a yield of 22%.

[0048] Example 10 Synthesis of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane

[0049]

[0050] Under an argon or nitrogen atmosphere, add phenylmagnesium bromide (0.2 mmol) and [1.1.1] propane (0.67 mL, 0.6 M, 0.4 mmol) to a sealed tube. Incubate in a 100°C oil pan for 1 hour, then stop the reaction and allow it to cool to room temperature. In a separate reactor, add DABSO (0.11 mmol) and dichloromethane (1 mL). Place the reaction mixture in an ice-water bath. Use a long needle to withdraw the dicyclopentylmagnesium bromide solution and slowly add it dropwise to the reaction tube (20 drops / minute). After the addition is complete, transfer the mixture to room temperature and allow it to react for 2 hours. Add arylmagnesium bromide (0.35 mmol) and continue the reaction for 12 hours. Monitor the reaction by TLC. Upon completion, quench the reaction with 1 M hydrochloric acid. The reaction mixture is then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio of 3:1) as eluent to obtain 30 mg of 1-phenyl-3-phenylbicyclo[1.1.1]pentane sulfoxide as a white solid in a yield of 56%.

[0051] Example 11 Synthesis of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane

[0052]

[0053] Under an argon or nitrogen atmosphere, add phenylmagnesium bromide (0.2 mmol) and [1.1.1] propane (0.67 mL, 0.6 M, 0.4 mmol) to a sealed tube. Incubate in a 100°C oil pan for 1 hour, then stop the reaction and allow it to cool to room temperature. In a separate reactor, add DABSO (0.11 mmol) and dichloromethane (1 mL). Place the reaction mixture in an ice-water bath. Use a long needle to withdraw the dicyclopentylmagnesium bromide solution and slowly add it dropwise to the reaction tube (20 drops / minute). After the addition is complete, transfer the mixture to room temperature and react for 2 hours. Add arylmagnesium bromide (0.2 mmol) and continue the reaction for 6 hours. Monitor the reaction by TLC. Upon completion, quench the reaction with 1 M hydrochloric acid. The reaction mixture is then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio 3:1) as eluent to obtain 25 mg of 1-phenyl-3-phenylbicyclo[1.1.1]pentane sulfoxide as a white solid in a yield of 46%.

[0054] Example 12 Synthesis of 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane

[0055]

[0056] Under an argon or nitrogen atmosphere, add phenylmagnesium bromide (0.2 mmol) and [1.1.1] propane (0.67 mL, 0.6 M, 0.4 mmol) to a sealed tube. Incubate in a 100°C oil pan for 1 hour, then stop the reaction and allow it to cool to room temperature. In a separate reactor, add DABSO (0.11 mmol) and dichloromethane (1 mL). Place the reaction mixture in an ice-water bath. Use a long needle to withdraw the dicyclopentylmagnesium bromide solution and slowly add it dropwise to the reaction tube (20 drops / minute). After the addition is complete, transfer the mixture to room temperature and allow it to react for 2 hours. Add arylmagnesium bromide (0.4 mmol) and continue the reaction for another 6 hours. Monitor the reaction by TLC. Upon completion, quench the reaction with 1 M hydrochloric acid. The reaction mixture is then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio of 3:1) as eluent to obtain 35 mg of 1-phenyl-3-phenylbicyclo[1.1.1]pentane sulfoxide as a white solid in a yield of 65%.

[0057] Example 13 Synthesis of 1-p-tolyl-3-p-tolylsulfinylbicyclo[1.1.1]pentanesulfoxide

[0058]

[0059] Under an argon or nitrogen atmosphere, add p-tolylmagnesium bromide (0.2 mmol) and [1.1.1] propane (0.67 mL, 0.6 M, 0.4 mmol) to a sealed tube. Incubate in a 100°C oil pan for 1 hour, then stop the reaction and allow it to cool to room temperature. In a separate reactor, add DABSO (0.11 mmol) and dichloromethane (1 mL). Place the reaction mixture in an ice-water bath. Use a long needle to withdraw the dicyclopentylmagnesium bromide solution and slowly add it dropwise to the reaction tube (20 drops / minute). After the addition is complete, transfer the mixture to room temperature and allow it to react for 2 hours. Add p-tolylmagnesium bromide (0.35 mmol) and continue the reaction for another 6 hours. Monitor the reaction by TLC. Upon completion, quench the reaction with 1 M hydrochloric acid. The reaction mixture is then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio of 3:1) as eluent to obtain 42 mg of 1-p-tolyl-3-p-tolylbicyclo[1.1.1]pentane sulfoxide as a white solid in a yield of 71%. 1 H NMR (400 MHz, Chloroform-d) δ 7.47 (d, J = 8.2 Hz, 2H), 7.33 (d, J =8.0 Hz, 2H), 7.09 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 8.2 Hz, 2H), 2.42 (s,3H), 2.30 (s, 3H), 2.09 (s, 6H). 13 C NMR (100 MHz, Chloroform-d) δ 141.25,138.38, 136.80, 135.53, 129.59, 128.93, 125.79, 124.19, 51.09, 50.63, 41.92,21.36, 21.01.

[0060] Example 14 Synthesis of 1-p-tert-butylphenyl-3-p-tert-butylphenylsulfinylbicyclo[1.1.1]pentanesulfoxide

[0061]

[0062] Under an argon or nitrogen atmosphere, add p-tert-butylphenylmagnesium bromide (0.2 mmol) and [1.1.1] propane (0.67 mL, 0.6 M, 0.4 mmol) to a sealed tube. Incubate in a 100°C oil pan for 1 hour, then stop the reaction and transfer to room temperature. In a separate reactor, add DABSO (0.11 mmol) and dichloromethane (1 mL). Place the reaction mixture in an ice-water bath. Use a long needle to withdraw the dicyclopentylmagnesium bromide solution and slowly add it dropwise to the reaction tube (20 drops / minute). After the addition is complete, transfer the mixture to room temperature and react for 2 hours. Add p-tert-butylphenylmagnesium bromide (0.35 mmol) and continue the reaction for 6 hours. Monitor the reaction by TLC. Upon completion, quench the reaction with 1 M hydrochloric acid. The reaction mixture is then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio of 3:1) as eluent to obtain 49 mg of 1-p-tert-butylphenyl-3-p-tert-butylphenylbicyclo[1.1.1]pentane sulfoxide as a white solid in a yield of 64%. 1 H NMR (400 MHz, Chloroform-d) δ 7.52 (q, J = 8.8 Hz,4H), 7.32 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 2.12 (s, 6H), 1.35(s, 9H), 1.29 (s, 9H). 13 C NMR (100 MHz, Chloroform-d) δ 154.44, 150.17,138.22, 135.55, 125.92, 125.70, 125.21, 124.07, 51.13, 50.70, 41.91, 34.95,34.46, 31.25, 31.21.

[0063] Example 15 Synthesis of 1-p-chlorophenyl-3-p-chlorophenylsulfinylbicyclo[1.1.1]pentane sulfoxide

[0064]

[0065] Under an argon or nitrogen atmosphere, add p-tert-butylphenylmagnesium bromide (0.2 mmol) and [1.1.1] propane (0.67 mL, 0.6 M, 0.4 mmol) to a sealed tube. Incubate in a 100°C oil pan for 1 hour, then stop the reaction and transfer to room temperature. In a separate reactor, add DABSO (0.11 mmol) and dichloromethane (1 mL). Place the reaction mixture in an ice-water bath. Use a long needle to withdraw the dicyclopentylmagnesium bromide solution and slowly add it dropwise to the reaction tube (20 drops / minute). After the addition is complete, transfer the mixture to room temperature and react for 2 hours. Add p-chlorophenylmagnesium bromide (0.35 mmol) and continue the reaction for 6 hours. Monitor the reaction by TLC. Upon completion, quench the reaction with 1 M hydrochloric acid. The reaction mixture is then diluted with ethyl acetate and water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:ethyl acetate (volume ratio of 3:1) as eluent to obtain 36 mg of 1-p-chlorophenyl-3-p-chlorophenylbicyclo[1.1.1]pentane sulfoxide as a white solid in a yield of 53%. 1 H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 8.8 Hz, 2H), 7.39 (d, J= 8.2 Hz, 2H), 7.14 (d, J = 2.7 Hz, 4H), 2.14 (s, 5H). 13 C NMR (100 MHz, Chloroform-d) δ 151.17, 151.15, 148.43, 139.93, 136.86, 127.47, 125.99,121.36, 121.00, 51.20, 50.81, 41.77.

Claims

1. A 1-aryl-3-arylsulfinyl bicyclic [ 1.1.1] A method for preparing pentane, characterized in that The steps include: 1) Under inert gas protection, reacting an aryl Grignard reagent represented by formula (I) with a [1.1.1] propellerane represented by formula (II) at a certain temperature to obtain an aryl bicyclo[1.1.1]pentane magnesium bromide intermediate solution, which is cooled to room temperature for later use; 2) Under the protection of inert gas, the SO2 source represented by formula (III) is dissolved in a solvent, and the aryl bicyclo[1.1.1]pentane magnesium bromide intermediate solution of step 1) is slowly added dropwise in an ice-water bath. After the addition is complete, the temperature is raised to room temperature for reaction, and the aryl Grignard reagent represented by formula (I) is added to continue the reaction. After the reaction is completed, the bicyclo[1.1.1]pentane sulfoxide product represented by formula (IV) is obtained by post-treatment. The reaction equation is as follows: In the formula, R is an electron-withdrawing group or an electron-donating group, the electron-withdrawing group is chlorine, bromine, iodine or cyano; the electron-donating group is an alkyl group, specifically methyl, ethyl or tert-butyl.

2. The method for preparing 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane according to claim 1, wherein The SO2 source is DABSO.

3. The method for preparing 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane according to claim 1, wherein The reaction solvent is tetrahydrofuran, N, N - one or a mixed solvent of two or more selected from dimethylformamide, dimethyl sulfoxide, dichloromethane, n-hexane, and ether.

4. The method for preparing 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane according to claim 1, wherein The inert gas is argon or nitrogen.

5. The method for preparing 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane according to claim 1, characterized in that The reaction temperature of step 1) is 80 - 100℃, reaction time is 0.5-1.5h.

6. The method for preparing 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane according to claim 1, characterized in that The reaction time of the aryl Grignard reagent in step 2) and the aryl bicyclo[1.1.1]pentanesulfonate intermediate is 2 to 12 hours.

7. The method for preparing 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane according to claim 1, characterized in that The molar ratio of the SO2 source, [1.1.1] propellerane and the initial aryl Grignard reagent is 1:(1~6):(1~4); the molar ratio of the supplementary aryl Grignard reagent to the initial aryl Grignard reagent is 1~2:

1.

8. The method for preparing 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane according to claim 1, characterized in that The reaction time of the SO2 source solution in step 2) and the arylbicyclo[1.1.1]pentanemagnesium bromide intermediate solution at room temperature is 1-3 hours.

9. A 1-aryl-3-arylsulfinyl bicyclo[ 1.1.1] A method for preparing pentane, characterized in that The post-reaction treatment process in step 2) is as follows: 1M hydrochloric acid solution is added to the reaction solution to quench the reaction, followed by dilution with ethyl acetate and water, extraction with ethyl acetate three times, collection of the organic phase, and column separation to obtain 1-aryl-3-arylsulfinylbicyclo[1.1.1]pentane.

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