Synthesis method of 2-butadiene sulfone

Abstract

The invention relates to a synthesis method of 2-butadiene sulfone. The synthesis method comprises the following steps: mixing a compound I with an alkaline substance, and carrying out elimination reaction to obtain the 2-butadiene sulfone. According to the method, 3-substituted sulfolane is simply stirred in an alkaline substance for elimination reaction, and then simple separation and extraction are carried out, so that 2-sulfolane can be conveniently prepared. The method is simple to operate, has high selectivity, can specifically generate the target product 2-butadiene sulfone, and does not generate a byproduct 3-butadiene sulfone, so that the synthesis yield and the purification efficiency are greatly improved. The synthesis method of 2-butadiene sulfone provided by the invention has the characteristics of simple and convenient synthesis conditions, high selectivity, high yield and high purity.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing 2-cyclobutene sulfone. Background Technology

[0002] Cyclobutene sulfone is a highly reactive synthetic intermediate whose applications stem almost entirely from the combined effects of ring strain and electron-withdrawing sulfone groups in its molecular structure. This makes it readily involved in various important cycloaddition and ring-opening reactions, such as the Diels-Alder reaction and polymer polymerization. Therefore, it plays a crucial role in the synthesis of natural products and pharmaceutical molecules. Based on the position of the double bond on the ring, cyclobutene sulfone has two isomers: 3-cyclobutene sulfone and 2-cyclobutene sulfone. Currently, 3-cyclobutene sulfone can be produced industrially inexpensively and in large quantities, but the efficient preparation of 2-cyclobutene sulfone remains a challenge. According to structure-activity relationships in chemistry, 2-cyclobutene sulfone will exhibit significantly different molecular properties than 3-cyclobutene sulfone; therefore, there is an urgent need to develop convenient synthetic methods for its preparation. Currently, laboratory methods for preparing 2-cyclobutene sulfone are limited and yields are low. For example, a paper (William J. Bailey, Earl W. Cummins, Journal of the American Chemical Society, 1954, 76, 1932-1936) reported a method for converting 3-cyclobutene sulfone to 2-cyclobutene sulfone, but the yield was only 41%, and the separation and purification were complex. Some patents (US3293264A (1966), GB1057664A (1967) and PL108316 B2 (1980)) reported a method for preparing 2-cyclobutene sulfone using precursor thermal decomposition, but the preparation process and separation and purification were still very cumbersome.

[0003] Therefore, how to provide a convenient synthetic method for preparing high-purity 2-cyclobutene sulfone is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0004] To address the aforementioned technical problems, the present invention aims to provide a method for synthesizing 2-cyclobutene sulfone. 2-Cyclobutene sulfone can be conveniently prepared by simply stirring 3-substituted cyclobutene sulfone in an alkaline solution to induce an elimination reaction, followed by simple separation and extraction. This method is simple to operate, highly selective, and specifically generates the target compound 2-cyclobutene sulfone without producing the byproduct 3-cyclobutene sulfone, thus significantly improving the synthesis yield and purification efficiency. The method for synthesizing 2-cyclobutene sulfone provided by the present invention features simple synthesis conditions, high selectivity, high yield, and high purity.

[0005] To achieve this objective, the present invention adopts the following technical solution: In a first aspect, the present invention provides a method for synthesizing 2-cyclobutene sulfone, the method comprising the following steps: Compound 1 is mixed with a basic substance and subjected to an elimination reaction to obtain the 2-cyclobutene sulfone. The structure of compound one is as follows: Z can be any one of hydroxyl, nitro, cyano, F, Cl, Br or I.

[0006] In this invention, by limiting the substituents of 3-substituted sulfolane, the target product 2-cyclobutene sulfone can be specifically generated without producing the byproduct 3-cyclobutene sulfone.

[0007] Preferably, the structural formula of the 2-cyclobutene sulfone is as follows: .

[0008] Preferably, the alkaline substance comprises any one or a combination of at least two of the following: lithium aluminum hydride, calcium hydride, sodium hydride, sodium borohydride, butyllithium, lithium metal, sodium metal, potassium metal, sodium ethoxide, potassium tert-butoxide, sodium amino, 1,8-diazabicycloundec-7-ene, 1,5-diazabicyclonon-5-ene, diethylaminosulfuric acid, or bis(2-methoxyethyl)aminosulfuric acid.

[0009] In this invention, by selecting specific basic substances, the selectivity of the elimination reaction can be improved. The aforementioned basic substances are strongly basic, making it easier to abstract hydrogen protons from the ortho-position of 3-substituted sulfolane, thereby improving the kinetics of the elimination reaction.

[0010] Preferably, the molar ratio of the compound to the alkaline substance is 1.0:(0.2-5.0), for example, it can be 1.0:0.5, 1.0:1.0, 1.0:2.0, 1.0:3.0 or 1.0:4.0, etc.

[0011] Preferably, the molar ratio of the compound to the alkaline substance is 1.0:(1.0-3.0), for example, it can be 1.0:1.5, 1.0:1.8, 1.0:2.0, 1.0:2.5 or 1.0:2.8, etc.

[0012] Preferably, the reaction time of the elimination reaction is 3-72 h, for example, it can be 5 h, 10 h, 20 h, 30 h, 40 h, 50 h or 60 h.

[0013] Preferably, the reaction temperature of the elimination reaction is -78~100℃, for example, it can be -50℃, -20℃, 0℃, 10℃, 20℃, 40℃, 50℃ or 80℃, etc.

[0014] Preferably, the elimination reaction is carried out in a solvent.

[0015] Preferably, the solvent is an organic solvent.

[0016] Preferably, the solvent includes any one or a combination of at least two of n-heptane, n-hexane, dichloromethane, chloroform, tetrahydrofuran, or 2-methyltetrahydrofuran.

[0017] Preferably, the elimination reaction further includes a post-treatment step; the post-treatment method includes the following steps: adding sodium bicarbonate aqueous solution to quench the reaction, filtering, taking the filtrate, evaporating the solvent, successively using isopropanol and methyl tert-butyl ether to slurry, filtering and drying to obtain 2-cyclobutene sulfone. Alternatively, the reaction can be quenched by adding an aqueous sodium bicarbonate solution, filtered, and the filtrate extracted with an organic solvent, followed by distillation to obtain 2-cyclobutene sulfone.

[0018] Preferably, in the synthesis method, the yield of 2-cyclobutene sulfone is above 90%, for example, it can be 92%, 94%, 95%, 96% or 98%, etc.

[0019] Compared with the prior art, the present invention has at least the following beneficial effects: The method for synthesizing 2-cyclobutene sulfone of the present invention, due to the preferred type of substituent, allows the reactants to undergo a selective elimination reaction, thereby specifically generating 2-cyclobutene sulfone. This reaction has a yield of over 90% and offers the advantages of simple post-processing purification, making it suitable for large-scale production. Attached Figure Description

[0020] Figure 1 This is the 1H NMR spectrum of the synthesized 2-cyclobutene sulfone.

[0021] Figure 2 This is the carbon NMR spectrum of the synthesized 2-cyclobutene sulfone. Detailed Implementation

[0022] The technical solution of the present invention will be further described below with reference to the accompanying drawings and specific embodiments. However, the following examples are merely simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention is determined by the claims.

[0023] In the following examples, all reagents are commercially available products unless otherwise stated.

[0024] Example 1 This embodiment provides a method for synthesizing 2-cyclobutene sulfone, the method comprising the following steps: Under a nitrogen atmosphere, 13.6 g (0.1 mol) of 3-hydroxycyclobutene sulfone was dissolved in 50 mL of anhydrous dichloromethane. 4.8 g (0.2 mol) of NaH was added at -20 °C, and the mixture was then allowed to rise naturally to room temperature with stirring for 48 h. After the reaction was complete, 0.5 M sodium bicarbonate aqueous solution was added to adjust the pH of the reaction system to 5. The mixture was filtered, and the filtrate was extracted three times with dichloromethane. The dichloromethane solvent was removed by rotary evaporation to obtain the crude product. The crude product was then distilled under reduced pressure at 150 °C to obtain pure 2-cyclobutene sulfone, with a yield of 92%. The 1H and 1C NMR spectra of pure 2-cyclobutene sulfone are shown below. Figure 1 and Figure 2 As shown. The NMR solvent was deuterated chloroform, and the instrument was 400 MHz.

[0025] The equation for the synthesis method is as follows: Example 2 This embodiment provides a method for synthesizing 2-cyclobutene sulfone, the method comprising the following steps: Under a nitrogen atmosphere, 13.6 g (0.1 mol) of 3-hydroxycyclobutane sulfone was dissolved in 50 mL of anhydrous dichloromethane. Then, 30 mL of a dichloromethane solution containing 32.4 g (0.2 mol) diethylaminotrifluoride was added dropwise at -70 °C. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 24 h. After the reaction was complete, 0.5 M sodium bicarbonate aqueous solution was added dropwise to adjust the pH of the reaction system to 5. The mixture was filtered, and the filtrate was extracted three times with dichloromethane. The dichloromethane solvent was removed by rotary evaporation to obtain the crude product. The crude product was recrystallized from ethyl acetate to obtain pure 2-cyclobutene sulfone in 94% yield.

[0026] The equation for the synthesis method is as follows: .

[0027] Example 3 This embodiment provides a method for synthesizing 2-cyclobutene sulfone, the method comprising the following steps: Under a nitrogen atmosphere, 13.8 g (0.1 mol) of 3-fluorocyclobutane sulfone was dissolved in 50 mL of anhydrous dichloromethane, and 4.2 g (0.1 mol) of CaH₂ was added at room temperature. After stirring for 48 h, the pH of the reaction system was adjusted to 5.5 with 0.5 M sodium bicarbonate aqueous solution. The mixture was filtered, and the filtrate was extracted three times with dichloromethane. The dichloromethane solvent was removed by rotary evaporation to obtain the crude product. The crude product was then distilled under reduced pressure at 150 °C to obtain pure 2-cyclobutene sulfone in 90% yield.

[0028] The equation for the synthesis method is as follows: Example 4 This embodiment provides a method for synthesizing 2-cyclobutene sulfone, the method comprising the following steps: Under a nitrogen atmosphere, 13.8 g (0.1 mol) of 3-fluorocyclobutene sulfone was dissolved in 50 mL of dichloromethane, and 2.8 g (0.4 mol) of lithium metal powder was added at room temperature. After heating to 60 °C and stirring for 72 h, the mixture was filtered, and the dichloromethane solvent was removed by rotary evaporation to obtain a crude product. 20 g of isopropanol was added and the mixture was stirred for 2 h, filtered, and the solid was collected. Then, 20 g of methyl tert-butyl ether was added and stirred for 2 h, filtered, and the solid was dried to obtain pure 2-cyclobutene sulfone, with a yield of 95.3%.

[0029] The equation for the synthesis method is as follows: .

[0030] Comparative Example 1 This comparative example provides a method for synthesizing 2-cyclobutene sulfone, which differs from Example 1 only in that 3-hydroxycyclobutene sulfone is replaced with the same number of moles of 3-methoxycyclobutene sulfone, and the yield of 2-cyclobutene sulfone is 5%.

[0031] Comparative Example 2 This comparative example provides a method for synthesizing 2-cyclobutene sulfone, which differs from Example 1 only in that NaH is replaced with the same number of moles of NaOH, and the yield of 2-cyclobutene sulfone is 0.

[0032] The test results show that: (1) As can be seen from Examples 1-4, the present invention can conveniently prepare 2-cyclobutene sulfone by simply stirring 3-substituted sulfolane in an alkaline substance to carry out an elimination reaction, and then by simple separation and extraction.

[0033] (2) By comparing Example 1 and Comparative Example 1, it can be seen that if the Z substituent of Compound 1 is not a substituent as defined in this invention, the yield of 2-cyclobutene sulfone is significantly reduced.

[0034] A comparison between Example 1 and Comparative Example 2 shows that if the alkaline substance is not one of the alkaline substances defined in this invention, the yield of 2-cyclobutene sulfone is significantly reduced.

[0035] In summary, by limiting the substituents of 3-substituted sulfolane, the present invention can specifically generate the target product 2-cyclobutene sulfone without producing the byproduct 3-cyclobutene sulfone.

[0036] The applicant declares that the above description is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention fall within the protection and disclosure scope of the present invention.

Claims

1. A method for synthesizing 2-cyclobutene sulfone, characterized in that, The synthesis method includes the following steps: Compound 1 is mixed with a basic substance and subjected to an elimination reaction to obtain the 2-cyclobutene sulfone. The structure of compound one is as follows: Z can be any one of hydroxyl, nitro, cyano, F, Cl, Br or I.

2. The synthesis method according to claim 1, characterized in that, The alkaline substance includes any one or a combination of at least two of the following: lithium aluminum hydride, calcium hydride, sodium hydride, sodium borohydride, butyllithium, lithium metal, sodium metal, potassium metal, sodium ethoxide, potassium tert-butoxide, sodium amino, 1,8-diazabicycloundec-7-ene, 1,5-diazabicyclonon-5-ene, diethylaminosulfuric acid, or bis(2-methoxyethyl)aminosulfuric acid.

3. The synthesis method according to claim 1 or 2, characterized in that, The molar ratio of compound one to the alkaline substance is 1.0:(0.2-5.0).

4. The synthesis method according to any one of claims 1-3, characterized in that, The molar ratio of compound one to the alkaline substance is 1.0:(1.0-3.0).

5. The synthesis method according to any one of claims 1-4, characterized in that, The elimination reaction takes 3-72 hours.

6. The synthesis method according to any one of claims 1-5, characterized in that, The elimination reaction is carried out at a temperature of -78 to 100°C.

7. The synthesis method according to any one of claims 1-6, characterized in that, The elimination reaction is carried out in a solvent.

8. The synthesis method according to claim 7, characterized in that, The solvent is an organic solvent.

9. The synthesis method according to claim 7 or 8, characterized in that, The solvent includes any one or a combination of at least two of the following: n-heptane, n-hexane, dichloromethane, chloroform, tetrahydrofuran, or 2-methyltetrahydrofuran.

10. The synthesis method according to any one of claims 1-9, characterized in that, The elimination reaction also includes a post-processing step; The post-processing includes the following steps: quenching the reaction with sodium bicarbonate aqueous solution, filtering, taking the filtrate, removing the solvent by evaporation, and successively slurrying with isopropanol and methyl tert-butyl ether, filtering and drying to obtain 2-cyclobutene sulfone; or, quenching the reaction with sodium bicarbonate aqueous solution, filtering and extracting the filtrate with an organic solvent, and then distilling to obtain 2-cyclobutene sulfone.

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