A process for the preparation of (E)-4-(phenylsulfonyl)but-3-enoic acid

Abstract

This invention provides a method for synthesizing (E)-4-(benzenesulfonyl)but-3-enoic acid, comprising: 1) using 8-aminoquinoline and 3-butenoic acid as raw materials, and dichloromethane as solvent, reacting with HATU and 2,4,6-trimethylpyridine to obtain compound 3: N-(quinoline-8-yl)but-3-enamine; 2) using acetonitrile as solvent, reacting with sodium benzenesulfinate in the presence of palladium acetate, benzoic acid, and silver hexafluoroantimonate to obtain compound 5: (E)-4-(benzenesulfonyl)-N-(quinoline-8-yl)but-2-enamine; 3) hydrolyzing compound 5 in aqueous HCl solution to obtain the final product. The method of this invention uses the dehydration condensation of 3-butenoic acid and 8-aminoquinoline to obtain an amide; under palladium catalysis, the olefin bond in the amide reacts with sodium benzenesulfinate to obtain allyl sulfone; the amide bond in the allyl sulfone is hydrolyzed under acidic conditions, and the double bond shifts simultaneously to obtain the target product, exhibiting excellent regioselectivity.

Description

Technical Field

[0001] This invention relates to a method for synthesizing (E)-4-(benzenesulfonyl)but-3-enoic acid, belonging to the field of organic synthesis. Background Technology

[0002] Alkenyl sulfones possess unique chemical properties and biological activities, finding wide application not only in organic and pharmaceutical synthesis but also serving as structural units in many natural products and bioactive molecules. (E)-4-(benzenesulfonyl)but-3-enoic acid belongs to the alkenyl sulfone class. It contains not only active double bonds and bioactive sulfone groups but also carboxyl functional groups, providing more modification sites and facilitating the preparation of structurally diverse sulfone compounds. Therefore, developing efficient and widely applicable methods for constructing alkenyl sulfones has significant theoretical and practical value.

[0003] The existing method for synthesizing analogs of (E)-4-(benzenesulfonyl)but-3-enoic acid, namely (E)-4-(p-toluenesulfonyl)but-3-enoic acid, involves using butyryl-3-alkynic acid as a starting material, followed by hydrotination to obtain an alkenyltin product. This alkenyltin product is then coupled with p-toluenesulfonyl chloride under palladium catalysis to yield (E)-4-(p-toluenesulfonyl)but-3-enoic acid. However, organotin reagents are highly toxic, p-toluenesulfonyl chloride has a pungent and irritating odor, and the hydrotination reaction suffers from drawbacks such as the need for controlled regioselectivity and low product yield. Therefore, to reduce environmental pollution and achieve efficient and green organic synthesis, the synthesis of (E)-4-(aromaticsulfonyl)but-3-enoic acid compounds remains a topic requiring further research. Summary of the Invention

[0004] In view of the shortcomings of the prior art, the purpose of this invention is to provide a method for synthesizing (E)-4-(benzenesulfonyl)but-3-enoic acid.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] A method for preparing (E)-4-(benzenesulfonyl)but-3-enoic acid includes the following steps:

[0007] (1) Compound 3 was obtained by using 8-aminoquinoline and 3-butenoic acid as raw materials and dichloromethane as solvent in the presence of HATU and 2,4,6-trimethylpyridine.

[0008] (2) Using acetonitrile as a solvent, in the presence of palladium acetate, benzoic acid and silver hexafluoroantimonate, compound 3 reacts with sodium benzenesulfonate to obtain compound 5;

[0009] (3) Compound 5 was hydrolyzed in aqueous HCl solution to give target compound 6 and 8-aminoquinoline;

[0010] The HATU is: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate;

[0011] Compound 3 is: N-(quinolin-8-yl)but-3-enamine;

[0012] Compound 5 is: (E)-4-(benzenesulfonyl)-N-(quinolin-8-yl)but-2-enamine;

[0013] Compound 6 is (E)-4-(benzenesulfonyl)but-3-enoic acid.

[0014] In step (1), the molar ratio of 8-aminoquinoline to 3-butenoic acid, HATU, and 2,4,6-trimethylpyridine is 1:1.3-1.5:1.3-1.5:2-2.5.

[0015] The step (1) involves stirring the reaction at room temperature for 12–18 hours.

[0016] The preparation method of compound 3 in step (1) is as follows:

[0017] 10.00 mmol of 8-aminoquinoline was added to a 250 mL round-bottom flask containing 30.0 mL of dichloromethane, followed by 13.00–15.00 mmol of HATU, 13.00–15.00 mmol of 3-butenoic acid, and 20.00–25.00 mmol of 2,4,6-trimethylpyridine. The mixture was stirred at room temperature for 16 h. The reaction was quenched with 200 mL of ethyl acetate. The system was transferred to a separatory funnel, and the organic phase was washed successively with 100 mL of saturated sodium bicarbonate solution and 100 mL of saturated brine, and then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and then separated by column chromatography with petroleum ether:ethyl acetate (v / v) = 20–25:1 to give compound 3.

[0018] In step (2), the molar ratio of compound 3 to sodium benzenesulfinate, benzoic acid, silver hexafluoroantimonate, and palladium acetate is 1:2-2.5:1-1.5:0.2-1:0.1-0.2.

[0019] In step (2), the reaction is stirred at 80-120°C for 12-24 hours.

[0020] The preparation method of compound 5 in step (2) is as follows:

[0021] 0.15 mmol of compound 3, 0.30–0.375 mmol of sodium benzenesulfinate, 0.15–0.225 mmol of benzoic acid, 0.015–0.03 mmol of palladium acetate, and 0.03–0.15 mmol of silver hexafluoroantimonate were added to a 10 mL reaction tube with 2.0 mL of acetonitrile as solvent. The mixture was stirred at 80–120 °C for 12–24 h. The reaction was quenched with ethyl acetate. The system was filtered through diatomaceous earth and separated by thin-layer chromatography with petroleum ether:ethyl acetate (v / v) = 2:1 as the developing solvent to obtain compound 5.

[0022] The preparation method of compound 6 in step (3) is as follows:

[0023] 0.10 mmol of compound 5 was added to a 10 mL high-pressure reaction tube containing 1.0 mL of 6 mol / L HCl and stirred at 110 °C for 16 h. The reaction was quenched with ethyl acetate, and the system was transferred to a 50 mL separatory funnel. The organic phase was separated, and the aqueous phase was washed three times with 3.0 mL of ethyl acetate each time. The ethyl acetate was combined, concentrated, and separated by thin-layer chromatography with petroleum ether:ethyl acetate (v / v) = 2:1 as the developing solvent to obtain the target product 6.

[0024] The synthetic process of (E)-4-(benzenesulfonyl)but-3-enoic acid is as follows:

[0025]

[0026] The synthetic scheme involves a series of processes: acid-amine condensation, olefin sulfonation, amide hydrolysis, and double bond translocation. Specifically, in the acid-amine condensation to form amide compound 3, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) acts as the condensing agent, activating the carboxyl group and promoting amide bond formation. In the reaction forming compound 5, 8-aminoquinoline (AQ) in compound 3 coordinates with Pd in ​​the palladium acetate catalyst. Under the guidance of AQ, Pd activates the olefin bond, which then reacts with sodium benzenesulfinate to yield compound 5. The amide bond in compound 5 undergoes hydrolysis upon heating in hydrochloric acid aqueous solution, simultaneously translocating the double bond to obtain the target product 6. Therefore, the synthetic method of this invention exhibits excellent regioselectivity.

[0027] Beneficial effects of this invention:

[0028] 1. The starting materials for synthesizing (E)-4-(benzenesulfonyl)but-3-enoic acid in this invention are 3-butenoic acid and sodium benzenesulfinate, with 8-aminoquinoline as the directing group. First, 3-butenoic acid and 8-aminoquinoline undergo dehydration condensation to obtain an amide; then, under palladium catalysis, the olefin bond in the amide reacts with sodium benzenesulfinate to obtain allyl sulfone; finally, the amide bond in the allyl sulfone is hydrolyzed under acidic conditions, and the double bond shifts simultaneously to obtain the target product (E)-4-(benzenesulfonyl)but-3-enoic acid.

[0029] 2. The method of this invention uses green synthetic raw materials and does not use organotin or toluenesulfonyl chloride reagents, thus achieving the greening of raw materials. Among them, 3-butenoic acid is inexpensive and readily available, sodium benzenesulfonate is inexpensive, stable, non-toxic and odorless, and 8-aminoquinoline can be recycled through hydrolysis in the final step, which reduces the impact on the environment and saves production costs. Attached Figure Description

[0030] Figure 1 The 1H NMR spectrum of compound 3 obtained in Example 1 is shown.

[0031] 1 H NMR (300MHz, CDCl3) δ9.97 (s, 1H), 8.85-8.73 (m, 2H), 8.16 (dd, J = 8.4, 1.2Hz, 1H), 7.58-7.49(m,2H),7.45(dd,J=8.4,4.2Hz,1H),6.23-6.07(m,1H),5.48-5.32(m,2H),3.36(d,J=7.2Hz,2H).

[0032] Figure 2 The 1H NMR spectrum of compound 5 obtained in Example 1 is shown below.

[0033] 1 H NMR (300MHz, CDCl3) δ9.90 (s, 1H), 8.83-8.76 (m, 2H), 8.18 (dd, J = 8.4, 1.6Hz, 1H), 7.96-7.89(m,2H),7.72-7.64(m,1H),7.63-7.52(m,4H),7.48(dd,J=8.4,4.2H z, 1H), 6.89-6.76 (m, 1H), 6.31 (d, J = 15.2Hz, 1H), 4.04 (dd, J = 7.8, 0.9Hz, 2H).

[0034] Figure 3 The image shows the carbon NMR spectrum of compound 5 obtained in Example 1.

[0035] 13 C NMR (75MHz, CDCl3) δ161.98,148.29,138.37,138.21,136.45,134.19,134.02,134.91, 129.82,129.42,128.47,127.92,127.35,122.17,121.79,116.96,59.10.

[0036] Figure 4The 1H NMR spectrum of compound 6 obtained in Example 1 is shown below.

[0037] 1 H NMR (600MHz, CDCl3) δ7.88 (d, J = 7.2Hz, 2H), 7.75-7.66 (m, 1H), 7.64-7.53 (m, 2H), 6.97-6.81(m,1H),5.86(d,J=15.0Hz,1H),3.96(d,J=7.2Hz,2H).

[0038] Figure 5 The image shows the carbon NMR spectrum of compound 6 obtained in Example 1.

[0039] 13 C NMR (150MHz, CDCl3) δ169.22, 138.05, 135.65, 134.36, 129.46, 128.57, 128.36, 59.15. Detailed Implementation

[0040] The specific embodiments of the present invention will be further described in detail below with reference to examples. Unless otherwise specified, the instruments and equipment involved in the examples are all conventional instruments and equipment; the reagents involved are all commercially available conventional reagents; and the experimental methods involved are all conventional methods.

[0041] Example 1

[0042] A method for synthesizing (E)-4-(benzenesulfonyl)but-3-enoic acid includes the following steps:

[0043] (1) 1.44 g (10.00 mmol) of 8-aminoquinoline (compound 1) was added to a 250 mL round-bottom flask containing dichloromethane (30.0 mL, DCM). Then, 4.94 g (13.00 mmol) of HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate), 1.12 g (13.00 mmol) of 3-butenoic acid (compound 2), and 2.42 g (20.00 mmol) of 2,4,6-trimethylpyridine (collidine) were added sequentially. The mixture was stirred at room temperature for 16 h. The reaction was quenched with ethyl acetate (200 mL). The system was transferred to a separatory funnel, and the organic phase was washed sequentially with 100 mL of saturated sodium bicarbonate solution and 100 mL of saturated brine, and then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 25–20:1) to give the target product (compound 3) (1.70 g, yield 80.1%). The 1H NMR spectrum of the obtained compound 3 is shown below. Figure 1 As shown.

[0044]

[0045] (2) 31.8 mg (0.15 mmol) (compound 3), 49.3 mg (0.30 mmol) sodium benzenesulfinate (compound 4), 18.3 mg (0.15 mmol) benzoic acid, 3.4 mg (0.015 mmol) Pd(OAc)2, and 51.5 mg (0.15 mmol) AgSbF6 were added to a 10 mL reaction tube with 2.0 mL acetonitrile as solvent. The mixture was stirred at 110 °C for 12 h, with palladium acetate as catalyst, silver hexafluoroantimonate as oxidant, and benzoic acid providing H to assist in the cyclic catalysis of Pd. The reaction was quenched with ethyl acetate. The system was filtered through diatomaceous earth and separated by thin-layer chromatography with petroleum ether:ethyl acetate (v / v) = 2:1 as the developing solvent, yielding a solid product (compound 5) (42.4 mg, yield 80.2%). The 1H and 1C NMR spectra of the obtained compound 5 are shown below. Figure 2 , Figure 3 As shown.

[0046]

[0047] (3) 35.2 mg (0.10 mmol) of compound 5 was added to a 10 mL high-pressure reaction tube containing 1.0 mL of HCl (6 mol / L) and stirred at 110 °C for 16 h. The reaction was quenched by ethyl acetate. The system was transferred to a 50 mL separatory funnel, the organic phase was separated, and the aqueous phase was washed with ethyl acetate (3.0 mL × 3). The ethyl acetates were combined, concentrated, and separated by thin-layer chromatography. The developing solvent was petroleum ether:ethyl acetate (v / v) = 2:1, to obtain target product 6 (15.0 mg, yield 66.3%) and compound 1 (10.2 mg, yield 70.7%).

[0048]

[0049] Calculations show that the overall yield of compound 6 in the three-step reaction is 42.6%, as confirmed by 1H NMR and 1C NMR (e.g., NMR spectroscopy). Figure 4 , Figure 5 ), and mass spectrometry (ESI / MS (m / z), [MH] - Compound 6 was confirmed to be (E)-4-(benzenesulfonyl)but-3-enoic acid. (225.02)

[0050] Example 2

[0051] A method for synthesizing (E)-4-(benzenesulfonyl)but-3-enoic acid includes the following steps:

[0052] (1) Add 1.44 g (10.00 mmol) of 8-aminoquinoline (compound 1) to a 250 mL round-bottom flask containing dichloromethane (30.0 mL), then add 5.32 g (14.00 mmol) of HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate), 1.21 g (14.00 mmol) of 3-butenoic acid (compound 2), and 2.67 g (22.00 mmol) of 2,4,6-trimethylpyridine (collidine) sequentially. Stir at room temperature for 16 h. Quench the reaction with ethyl acetate (200 mL), transfer the system to a separatory funnel, wash the organic phase sequentially with 100 mL of saturated sodium bicarbonate solution and 100 mL of saturated brine, and then dry with anhydrous sodium sulfate. The mixture was filtered, concentrated, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 25-20:1) to give the target product (compound 3) (1.74 g, yield 82.0%).

[0053] (2) 31.8 mg (0.15 mmol) of compound 3, 49.3 mg (0.30 mmol) of sodium benzenesulfinate (compound 4), 18.3 mg (0.15 mmol) of benzoic acid, 3.4 mg of Pd(OAc)2 (0.015 mmol) and 10.3 mg (0.03 mmol) of AgSbF6 were added to a 10 mL reaction tube, with 2.0 mL of acetonitrile as solvent, and stirred at 110 °C for 12 h. The reaction was quenched with ethyl acetate, and the system was filtered through diatomaceous earth and separated by thin-layer chromatography with petroleum ether:ethyl acetate (v / v) = 2:1 as the developing solvent to give solid product (compound 5) (33.3 mg, yield 63.0%).

[0054] (3) 35.2 mg (0.10 mmol) of compound 5 was added to a 10 mL high-pressure reaction tube containing 1.0 mL of HCl (6 mol / L) and stirred at 110 °C for 16 h. The reaction was quenched by ethyl acetate, and the system was transferred to a 50 mL separatory funnel. The organic phase was separated, and the aqueous phase was washed three times with ethyl acetate (3.0 mL × 3). The ethyl acetate was combined, concentrated, and separated by thin-layer chromatography. The developing solvent was petroleum ether:ethyl acetate (v / v) = 2:1, to obtain the target product compound 6 (15.0 mg, yield 66.3%).

[0055] Calculations showed that the overall yield of compound 6 in the three-step reaction was 34.2%. The results of nuclear magnetic resonance (NMR) 1H NMR, 1C NMR, and mass spectrometry confirmed that compound 6 was (E)-4-(benzenesulfonyl)but-3-enoic acid.

[0056] Example 3

[0057] A method for synthesizing (E)-4-(benzenesulfonyl)but-3-enoic acid includes the following steps:

[0058] (1) 1.44 g (10.00 mmol) of 8-aminoquinoline (compound 1) was added to a 250 mL round-bottom flask containing dichloromethane (30.0 mL), followed by 5.70 g (15.00 mmol) of HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate), 1.29 g (15.00 mmol) of 3-butenoic acid (compound 2), and 3.03 g (25.00 mmol) of 2,4,6-trimethylpyridine. The mixture was stirred at room temperature for 16 h. The reaction was quenched with ethyl acetate (200 mL), and the system was transferred to a separatory funnel. The organic phase was washed successively with 100 mL of saturated sodium bicarbonate solution and 100 mL of saturated brine, and then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 25-20:1) to give the target product (compound 3) (1.73 g, yield 81.5%).

[0059] (2) 31.8 mg (0.15 mmol) of compound 3, 61.6 mg (0.375 mmol) of sodium benzenesulfinate (compound 4), 27.5 mg (0.225 mmol) of benzoic acid, 6.7 mg of Pd(OAc)2 (0.03 mmol) and 51.5 mg (0.15 mmol) of AgSbF6 were added to a 10 mL reaction tube, with 2.0 mL of acetonitrile as solvent, and stirred at 110 °C for 24 h. The reaction was quenched with ethyl acetate, and the system was filtered through diatomaceous earth and separated by thin-layer chromatography with petroleum ether:ethyl acetate (v / v) = 2:1 as the developing solvent to give solid product (compound 5) (41.2 mg, yield 77.9%).

[0060] (3) 35.2 mg (0.10 mmol) of compound 5 was added to a 10 mL high-pressure reaction tube containing 1.0 mL of HCl (6 mol / L) and stirred at 110 °C for 16 h. The reaction was quenched by ethyl acetate. The system was transferred to a 50 mL separatory funnel, the organic phase was separated, and the aqueous phase was washed with ethyl acetate (3.0 mL × 3). The ethyl acetates were combined, concentrated, and separated by thin-layer chromatography. The developing solvent was petroleum ether:ethyl acetate (v / v) = 2:1, to obtain the target product (compound 6) (15.0 mg, yield 66.3%).

[0061] Calculations show that the overall yield of compound 6 in the three-step reaction is 42.1%. The results of nuclear magnetic resonance (NMR) 1H NMR, 1C NMR, and mass spectrometry confirm that compound 6 is (E)-4-(benzenesulfonyl)but-3-enoic acid.

Claims

1. A method for preparing (E)-4-(benzenesulfonyl)but-3-enoic acid, characterized in that, Includes the following steps: (1) Compound 3 was obtained by using 8-aminoquinoline and 3-butenoic acid as raw materials and dichloromethane as solvent in the presence of HATU and 2,4,6-trimethylpyridine. (2) Using acetonitrile as a solvent, in the presence of palladium acetate, benzoic acid and silver hexafluoroantimonate, compound 3 reacts with sodium benzenesulfonate to obtain compound 5; (3) Compound 5 was hydrolyzed in aqueous HCl solution to give target compound 6 and 8-aminoquinoline; The HATU is: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; Compound 3 is: N-(quinolin-8-yl)but-3-enamine; Compound 5 is: (E)-4-(benzenesulfonyl)-N-(quinolin-8-yl)but-2-enamine; Compound 6 is (E)-4-(benzenesulfonyl)but-3-enoic acid.

2. The method as described in claim 1, characterized in that, In step (1), the molar ratio of 8-aminoquinoline to 3-butenoic acid, HATU, and 2,4,6-trimethylpyridine is 1:1.3-1.5:1.3-1.5:2-2.

5.

3. The method as described in claim 1, characterized in that, The step (1) involves stirring the reaction at room temperature for 12–18 hours.

4. The method as described in claim 1, characterized in that, The preparation method of compound 3 in step (1) is as follows: 10.00 mmol of 8-aminoquinoline was added to a 250 mL round-bottom flask containing 30.0 mL of dichloromethane, followed by 13.00–15.00 mmol of HATU, 13.00–15.00 mmol of 3-butenoic acid, and 20.00–25.00 mmol of 2,4,6-trimethylpyridine. The mixture was stirred at room temperature for 16 h. The reaction was quenched with 200 mL of ethyl acetate. The system was transferred to a separatory funnel, and the organic phase was washed successively with 100 mL of saturated sodium bicarbonate solution and 100 mL of saturated brine, and then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and then separated by column chromatography with petroleum ether:ethyl acetate (v / v) = 20–25:1 to give compound 3.

5. The method as described in claim 1, characterized in that, In step (2), the molar ratio of compound 3 to sodium benzenesulfinate, benzoic acid, silver hexafluoroantimonate, and palladium acetate is 1:2-2.5:1-1.5:0.2-1:0.1-0.

2.

6. The method as described in claim 1, characterized in that, In step (2), the reaction is stirred at 80-120°C for 12-24 hours.

7. The method as described in claim 1, characterized in that, The preparation method of compound 5 in step (2) is as follows: 0.15 mmol of compound 3, 0.30–0.375 mmol of sodium benzenesulfinate, 0.15–0.225 mmol of benzoic acid, 0.015–0.03 mmol of palladium acetate, and 0.03–0.15 mmol of silver hexafluoroantimonate were added to a 10 mL reaction tube with 2.0 mL of acetonitrile as solvent. The mixture was stirred at 80–120 °C for 12–24 h. The reaction was quenched with ethyl acetate. The system was filtered through diatomaceous earth and separated by thin-layer chromatography with petroleum ether:ethyl acetate (v / v) = 2:1 as the developing solvent to obtain compound 5.

8. The method as described in claim 1, characterized in that, The preparation method of compound 6 in step (3) is as follows: 0.10 mmol of compound 5 was added to a 10 mL high-pressure reaction tube containing 1.0 mL of 6 mol / L HCl and stirred at 110 °C for 16 h. The reaction was quenched with ethyl acetate, and the system was transferred to a 50 mL separatory funnel. The organic phase was separated, and the aqueous phase was washed three times with 3.0 mL of ethyl acetate each time. The ethyl acetate was combined, concentrated, and separated by thin-layer chromatography with petroleum ether:ethyl acetate (v / v) = 2:1 as the developing solvent to obtain the target product 6.

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