A method for synthesizing an (e)-3-benzoyl-4-sulfophenyl crotonate derivative

Abstract

This invention discloses a ( E The method for synthesizing 3-benzoyl-4-sulfone crotonate derivatives belongs to the field of organic synthesis technology. E The synthetic steps of the β-benzoyl-4-sulfone crotonate derivative include: mixing β-carbonyl sulfone, propargyl ester, and a basic non-transition metal catalyst with a solvent, and reacting to obtain the β-benzoyl-4-sulfone crotonate derivative. E 3-benzoyl-4-sulfone crotonate derivative; wherein, the basic non-transition metal catalyst catalyzes the reaction of propynyl ester and β-carbonyl sulfone to generate a tertiary alcohol anion and undergoes C-C bond cleavage / rearrangement. The synthetic method provided by this invention is simple in steps and mild in reaction conditions, and the synthesized product... (E 3-benzoyl-4-sulfonyl crotonate derivatives can be used to prepare 4-isopropyl-3-phenyl-1-ylbenzoyl-4-sulfonyl crotonate derivatives. H 5-Pyrazole-5-carboxylic acid ethyl ester and 5-hydroxy-5-phenyl-4-(2-phenylsulfonepropyl)-2(5-phenylene ...-phenylenesulfonepropyl)-2 H Important heterocyclic compounds such as )-furanone.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a ( E Synthetic method of 3-benzoyl-4-sulfonyl crotonate derivative. Background Technology

[0002] 4-Sulfone crotonate and its derivatives are an important class of multifunctional compounds, containing ester, carbon-carbon double bonds, and sulfone groups in their molecular structure. These compounds are not only important pharmaceutical intermediates but also crucial building blocks for constructing cyclic compounds in organic synthesis. For example, the Menon group achieved polysubstituted phenyl sulfones in 2015 by cyclizing 4-sulfone crotonate with chalcones or orange ketones under basic conditions. Org. Lett. , 2015, 17,1449) or substituted dibenzofuran compounds (2026, Org. Biomol. Chem. The efficient synthesis of polysubstituted naphthone compounds was achieved by Wang's research group using the cyclization reaction of 4-sulfonyl crotonate with intramolecular alkynes. RSC Adv. , 2016, 6, 103919).

[0003] Traditional methods for synthesizing sulfonyl crotonate derivatives mainly utilize the nucleophilic substitution reaction between sulfinates and 4-bromocrotonate. However, this method presents challenges for synthesizing sulfonyl crotonates with substituents on the double bonds, as the sources of 4-bromocrotonate with substituents on the double bonds are not widely available. Alternatively, the substitution reaction of Morita-Baylis-Hillman (MBH) esters with sulfinates can also be used to synthesize sulfonyl crotonate derivatives, but the synthesis of some MBH esters with complex ester groups is costly, thus limiting this method as well. Furthermore, both of these traditional methods face the challenge of stereoselectivity control in the synthesis of substituent sulfonyl crotonates: precisely controlling the geometry (cis-trans isomerism) of the double bonds is a key challenge in constructing multi-substituted olefin skeletons. Summary of the Invention

[0004] The purpose of this invention is to provide a ( E Synthetic methods for 3-benzoyl-4-sulfonyl crotonate derivatives. These methods utilize readily available starting materials β-carbonyl sulfone and propynyl ester to efficiently synthesize ( )-3-benzoyl-4-sulfonyl crotonate derivatives under mild reaction conditions without the use of transition metal catalysts. E )-3-benzoyl-4-sulfonyl crotonate derivative.

[0005] To achieve the above objectives, the present invention provides the following technical solution: One of the technical solutions of this invention: provides a (E A method for synthesizing 3-benzoyl-4-sulfonyl crotonate derivatives includes the following steps: β-carbonyl sulfone, propargyl ester, and a basic non-transition metal catalyst are mixed with a solvent, and the reaction yields the desired product. E )-3-benzoyl-4-sulfonyl crotonate derivative; The basic non-transition metal catalyst catalyzes the formation of tertiary alcohol anions from propyne ester and β-carbonyl sulfone. The structural formula of the β-carbonyl sulfone is shown below: ; The structural formula of the propynyl ester is shown below: ; The ( E The structural formula of the 3-benzoyl-4-sulfonyl crotonate derivative is shown below: ; The β-carbonyl sulfone, propargyl ester and ( E In the structural formula of 3-benzoyl-4-sulfonyl crotonate, Ar is phenyl, methyl, ethyl, phenyl, methoxy, fluorine- or chlorine-substituted phenyl, or naphthyl; R 1 It is a phenyl, methyl, methoxy, trifluoromethyl, halogen, or tetrahydrofuranyl-substituted phenyl, thiophene, or naphthyl group; R 2 and R 3 The individual compounds are selected independently from methyl, ethyl, benzyl, allyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0006] The reaction principle of this invention is as follows: First, a tertiary alcohol anion intermediate is generated by reacting propynyl ester with β-carbonyl sulfone. Then, unexpected C / C bond cleavage and migration occur to obtain a product with a specified stereoconfiguration. E The target product is a 3-benzoyl-4-sulfonyl crotonate derivative (configuration). One of the key points in the synthesis is R 2 and R 3 It cannot contain hydrogen, otherwise the reaction will not proceed.

[0007] Preferably, the alkaline non-transition metal catalyst is at least one selected from tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium iodide, sodium tert-butoxide, potassium tert-butoxide, and magnesium tert-butoxide.

[0008] Preferably, the amount of the alkaline non-transition metal catalyst added is 20% of the molar amount of the β-carbonyl sulfone.

[0009] Preferably, the solvent includes tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylacetamide, acetonitrile, ethyl acetate, or dichloromethane.

[0010] Preferably, the reaction temperature is 20±10℃.

[0011] The second technical solution of the present invention: providing the above-mentioned (E The synthetic method of 3-benzoyl-4-sulfonyl crotonate is based on the synthesis of 4-isopropyl-3-phenyl-1 H Applications of ethyl pyrazole-5-carboxylate.

[0012] The second technical solution of the present invention: providing the above-mentioned (E The synthetic method of 3-benzoyl-4-sulfonyl crotonate is based on the synthesis of 5-hydroxy-5-phenyl-4-(2-phenylsulfonylpropyl)-2(5-phenyl-4-phenyl-4-(2-phenylsulfonylpropyl)-2(5-phenyl-4-phenyl-4-(2-phenyl-4- ... H Applications of )-furanone.

[0013] The beneficial technical effects of the present invention are as follows: This invention directly obtains [the desired product] using β-carbonyl sulfone and propynyl ester as raw materials under the catalysis of a basic non-transition metal catalyst. (E The provided synthetic method for 3-benzoyl-4-sulfonyl crotonate is simple and uses mild reaction conditions. The synthesized... (E 3-benzoyl-4-sulfonyl crotonate can be used to prepare 4-isopropyl-3-phenyl-1- H -Pyrazole-5-carboxyethyl ester and 5-hydroxy-5-phenyl-4-(2-phenylsulfonepropyl)-2(5 H )-Furfural is an important heterocyclic compound. Attached Figure Description

[0014] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0015] Figure 1 The target product in Example 1 ( E )-3-benzoyl-4-sulfonyl-crotonate ethyl ester derivative 2a 1 HNMR spectrum.

[0016] Figure 2 The target product in Example 1 ( E )-3-benzoyl-4-sulfonyl-crotonate ethyl ester derivative 2a 13 CNMR spectrum.

[0017] Figure 3 The target product in Example 1 ( E XRD single-crystal diffraction pattern of ethyl 3-benzoyl-4-sulfonyl-crotonate derivative 2a.

[0018] Figure 4 The product used in Example 6 is 4-isopropyl-3-phenyl-1 H 3a of pyrazole-5-carboxylic acid ethyl ester 1 H NMR spectrum.

[0019] Figure 5 The product used in Example 6 is 4-isopropyl-3-phenyl-1 H 3a of pyrazole-5-carboxylic acid ethyl ester 13 C10 NMR spectrum.

[0020] Figure 6 The product used in Example 7 is 5-hydroxy-5-phenyl-4-(2-phenylsulfonylpropyl)-2(5 H )-Furfural 4a 1 H NMR spectrum.

[0021] Figure 7 The product used in Example 7 is 5-hydroxy-5-phenyl-4-(2-phenylsulfonylpropyl)-2(5 H )-Furfural 4a 13 C10 NMR spectrum. Detailed Implementation

[0022] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention. It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the present invention.

[0023] It should be noted that any aspects not described in detail in this invention are conventional practices in the field and are not the focus of this invention.

[0024] Furthermore, regarding the numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, are also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0025] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this invention.

[0026] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0027] Unless otherwise specified, room temperature in this invention refers to a temperature of 20±10℃.

[0028] Example 1 0.5 mmol of β-carbonyl sulfone 1a and 0.6 mmol of ethyl propargylate were added to a 10 mL reaction tube, along with 3 mL of tetrahydrofuran (solvent) and tetrabutylammonium fluoride (catalyst) at 20% molar weight of ethyl propargylate. The mixture was stirred at room temperature for 20 h. After the reaction, the mixture was washed with 30 mL of saturated sodium chloride and extracted with ethyl acetate (2 × 15 mL). The organic phases were combined, concentrated, and purified by column chromatography to obtain the target product, ethyl 3-benzoyl-4-sulfone crotonate derivative 2a [(systematic nomenclature: ( E [Ethyl 3-benzoyl-4-methyl-4-benzenesulfonyl-pent-2-enoate], with a yield of 30%.

[0029] The reaction process in Example 1 is as follows: Target product in Example 1 ( E )-3-benzoyl-4-sulfonyl crotonate ethyl ester derivative 2a 1 The H NMR spectrum is shown in [reference]. Figure 1 .

[0030] Target product in Example 1 ( E )-3-benzoyl-4-sulfonyl crotonate ethyl ester derivative 2a 13 The C NMR spectrum is shown below. Figure 2 .

[0031] Target product in Example 1 ( E The XRD pattern of ethyl crotonate derivative 2a of 3-benzoyl-4-sulfonyl crotonate is shown in the figure. Figure 3 .

[0032] Example 2 0.5 mmol of β-carbonyl sulfone 1b and 0.6 mmol of ethyl propargylate were added to a 10 mL reaction tube, along with 3 mL of tetrahydrofuran (solvent) and tetrabutylammonium fluoride (catalyst) at 20% molar weight of ethyl propargylate. The mixture was stirred at room temperature for 20 h. After the reaction, the mixture was washed with 30 mL of saturated sodium chloride and extracted with ethyl acetate (2 × 15 mL). The organic phases were combined, concentrated, and purified by column chromatography to obtain the target product. E )-4-carbonyl-4-phenyl-3-sulfone methyl crotonate ethyl ester derivative 2b [systematic nomenclature name: ( E [4-carbonyl-4-phenyl-3-phenylsulfone methyl-but-2-enoate ethyl ester], yield 0%, raw material recovery rate >99%. The reason is that the active methylene group in the structure of substance 1b can undergo enol tautomerism, thus having a certain acidity, which prevents the added amount of alkaline catalyst from catalyzing the formation of tertiary alcohol anions from propynyl ester and β-carbonyl sulfone.

[0033] The reaction process designed in Example 2 is as follows: Example 3 0.5 mmol of β-carbonyl sulfone 1a and 0.6 mmol of ethyl propynate were added to a 10 mL reaction tube, followed by 3 mL of tetrahydrofuran (solvent). The mixture was stirred at room temperature for 20 h. After the reaction, the mixture was washed with 30 mL of saturated sodium chloride and extracted with ethyl acetate (2 × 15 mL). The organic phases were combined, concentrated, and purified by column chromatography to obtain the target product. E The yield of ethyl propargyl-4-sulfonyl-crotonate derivative 2a was 0%, with a feed recovery rate >99%. This was because, in the absence of a basic catalyst, ethyl propargylate and β-carbonyl sulfone could not effectively generate the tertiary alcohol anion intermediate, preventing the reaction from proceeding.

[0034] The reaction process designed in Example 3 is as follows: Example 4 0.5 mmol of β-carbonyl sulfone 1a and 0.6 mmol of ethyl propargylate were added to a 10 mL reaction tube, followed by 3 mL of tetrahydrofuran (solvent) and tetrabutylammonium bromide (catalyst) at 20% molar weight of ethyl propargylate. The mixture was stirred at room temperature for 20 h. After the reaction, the mixture was washed with 30 mL of saturated sodium chloride and extracted with ethyl acetate (2 × 15 mL). The organic phases were combined, concentrated, and purified by column chromatography to obtain the target product. EThe yield of ethyl 3-benzoyl-4-sulfonyl-crotonate derivative 2a was 0%, with a feed recovery rate >99%. This was because when tetrabutylammonium bromide was used to replace tetrabutylammonium fluoride, ethyl propargylate and β-carbonyl sulfone could not effectively generate tertiary alcohol anion intermediates, preventing the reaction from proceeding.

[0035] The reaction process designed in Example 4 is as follows: Example 5 0.5 mmol of β-carbonyl sulfone 1a and 0.6 mmol of ethyl propargylate were added to a 10 mL reaction tube, followed by 3 mL of N,N-dimethylacetamide (DMA, solvent) and 20% tetrabutylammonium fluoride (catalyst) of ethyl propargylate. The mixture was stirred at room temperature for 20 h. After the reaction, the mixture was washed with 30 mL of saturated sodium chloride and extracted with ethyl acetate (2 × 15 mL). The organic phases were combined, concentrated, and purified by column chromatography to obtain the target product. E )-3-benzoyl-4-sulfonyl-crotonic acid ethyl ester derivative 2a, with a yield of 92%.

[0036] The reaction process in Example 5 is as follows: The NMR characterization data of product 2a from Example 5 are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.90 (dd, J = 8.3, 1.1 Hz, 2H), 7.81 (d, J = 7.3Hz, 2H), 7.72 (t, J = 7.5 Hz, 1H), 7.58 (t, J = 7.9 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 6.89 (s, 1H), 3.98 (q, J = 7.1 Hz, 2H), 1.56 (s, 6H), 1.06 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 194.8, 164.2, 152.5, 136.0, 135.1, 134.1,133.4, 130.8, 128.8, 128.5, 126.0, 65.3, 61.0, 23.5, 13.6. Example 6 Add 0.5 mmol ( ) to a 25 mL Shrek reaction tube. E A solution of ethyl 3-benzoyl-4-sulfonyl-crotonate derivative 2a, 95 vol% ethanol (3 mL), and 80 vol% hydrazine hydrate (5 equivalents) was reacted with the mixture under air at 100 °C for 12 h. The reaction mixture was then diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (n-hexane / ethyl acetate = 3 / 1, v / v) to give the applied product 3a (4-isopropyl-3-phenyl-1-ethylhexane-4-sulfonyl ... H 35% pyrazole-5-carboxylic acid ethyl ester.

[0037] The reaction process in Example 6 is as follows: In Example 6, the product 4-isopropyl-3-phenyl-1- H 3a of pyrazole-5-carboxylic acid ethyl ester 1 The H NMR spectrum is shown in [reference]. Figure 4 .

[0038] In Example 6, the product 4-isopropyl-3-phenyl-1- H 3a of pyrazole-5-carboxylic acid ethyl ester 13 The C NMR spectrum is shown below. Figure 5 .

[0039] Example 7 Add 0.5 mmol ( ) to a 10 mL reaction tube. E 2a of ethyl 3-benzoyl-4-sulfonyl-crotonate derivative, tetrahydrofuran (2 mL), and water (1 mL) were dissolved by stirring, and lithium hydroxide (5 equivalents) was added to the solution. The reaction system was stirred at room temperature under air for 12 h, and then cooled to 0 °C. Subsequently, concentrated hydrochloric acid was added to the solution in portions until the pH of the solution reached 5-6. The reaction system was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the applied product 4a (5-hydroxy-5-phenyl-4-(2-phenylsulfonylpropyl)-2(5 ... H()-furanone), this product can be used directly for structural analysis without further purification, with a yield >99%.

[0040] The reaction process in Example 7 is as follows: In Example 7, the product 5-hydroxy-5-phenyl-4-(2-phenylsulfonylpropyl)-2(5-phenylenesulfonylpropyl)-2 ( ... H )-Furfural 4a 1 See the HNMR spectrum. Figure 6 .

[0041] In Example 7, the product 5-hydroxy-5-phenyl-4-(2-phenylsulfonylpropyl)-2(5-phenylenesulfonylpropyl)-2 ( ... H )-Furfural 4a 13 See CNMR spectrum Figure 7 .

[0042] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A kind of ( E A method for synthesizing 3-benzoyl-4-sulfonyl crotonate derivatives, characterized in that, Includes the following steps: β-carbonyl sulfone, propargyl ester, and a basic non-transition metal catalyst are mixed with a solvent, and the reaction yields the desired product. E )-3-benzoyl-4-sulfonyl crotonate derivative; The basic non-transition metal catalyst catalyzes the formation of tertiary alcohol anions from the propynyl ester and β-carbonyl sulfone. The structural formula of the β-carbonyl sulfone is shown below: ； The structural formula of the propynyl ester is shown below: ； The ( E The structural formula of the 3-benzoyl-4-sulfonyl crotonate derivative is shown below: ； The β-carbonyl sulfone, propargyl ester and ( E In the structural formula of 3-benzoyl-4-sulfonyl crotonate, Ar is phenyl, methyl, ethyl, phenyl, methoxy, fluorine- or chlorine-substituted phenyl, or naphthyl; R 1 It is a phenyl, methyl, methoxy, trifluoromethyl, halogen, or tetrahydrofuranyl-substituted phenyl, thiophene, or naphthyl group; R 2 and R 3 The individual compounds are selected independently from methyl, ethyl, benzyl, allyl, cyclobutyl, cyclopentyl, or cyclohexyl.

2. As described in claim 1 ( E A method for synthesizing 3-benzoyl-4-sulfonyl crotonate derivatives, characterized in that, The alkaline non-transition metal catalyst is at least one selected from tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium iodide, sodium tert-butoxide, potassium tert-butoxide, and magnesium tert-butoxide.

3. As described in claim 1 ( E A method for synthesizing 3-benzoyl-4-sulfonyl crotonate derivatives, characterized in that, The amount of the alkaline non-transition metal catalyst added is 20% of the molar amount of the β-carbonyl sulfone.

4. As described in claim 1 ( E A method for synthesizing 3-benzoyl-4-sulfonyl crotonate derivatives, characterized in that, The solvent includes tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylacetamide, acetonitrile, ethyl acetate, or dichloromethane.

5. As described in claim 1 ( E A method for synthesizing 3-benzoyl-4-sulfonyl crotonate derivatives, characterized in that, The reaction temperature is 20±10℃.

6. A device as described in any one of claims 1 to 5 (E The synthetic method of 3-benzoyl-4-sulfonyl crotonate derivatives is based on the synthesis of 4-isopropyl-3-phenyl-1 H Applications of ethyl pyrazole-5-carboxylate.

7. The method described in any one of claims 1 to 5 (E The synthetic method for 3-benzoyl-4-sulfonyl crotonate derivatives is based on the synthesis of 5-hydroxy-5-phenyl-4-(2-phenylsulfonylpropyl)-2(5-phenyl-4-phenyl-4-(2-phenylsulfonylpropyl)-2(5-phenyl-4-phenyl-4-(2-phenyl-4- ... H Applications of )-furanone.

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