A method for synthesizing 2-(phenylsulfonamide)-3-oxo-3-heterocyclopropionates

Abstract

The application provides a synthesis method of 2-(phenyl sulfonamide)-3-oxo-3-heterocyclic propionic acid ester compounds and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: adding heterocyclic formyl acetic acid ethyl ester compounds, sulfonamide compounds and a photosensitizer into a solvent to configure a reaction solution, performing reaction under blue light irradiation, and preparing a target product after the reaction is completed. The application avoids the problem of a large amount of by-products caused by various oxidants in a traditional method; the organic photosensitizer 4CzIPN is used as a catalyst, the reaction time is greatly shortened, the reaction can be completed in only 10 minutes, the reaction efficiency is improved, and the product does not have metal residues; the reaction condition is mild, and the reaction can occur at room temperature in an air atmosphere.

Description

Technical Field

[0001] This invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate compounds. Background Technology

[0002] Nitrogen-containing compounds are of great significance due to their wide application in the functionalization of various heteroaromatic rings, serving as the core structure of many biologically and pharmacologically active ingredients. Because of their unique physicochemical properties and biological activities, nitrogen-containing structures are widely used in natural products, agrochemicals, pharmaceuticals, and functional materials. Therefore, the synthetic strategies for CN bonds have always been a hot topic in chemical research. With the continuous development of new reagents, methods, synthetic strategies, and analytical instruments, scientists' understanding of nitrogen-containing structures is constantly deepening. To effectively form CN bonds, various strategies have been developed to obtain different nitrogen-containing skeletons.

[0003] Traditionally, CN bond formation has been achieved using common nitrogen-containing nucleophiles and electrophiles, such as amines, amides, and imines. However, these methods sometimes present challenges in terms of functional group compatibility and require harsh reaction conditions. Given the importance of these compounds in scientific research, chemists have made significant efforts to develop efficient alternative synthetic strategies, particularly those that can introduce nitrogen sources under mild and green conditions, in line with the principles of sustainable and green chemistry.

[0004] Traditional carbon-nitrogen bond construction largely relies on transition metal catalysis or prefunctionalization of reactants. These methods can lead to heavy metal contamination of the products and generate a series of byproducts, such as acids, which are environmentally unfriendly. For example, Barluenga et al. (J. Barluenga, MA. Fernandez, F. Aznar, C. Valdes, Chem. Commun. 2004, 1400) used BINAP with prefunctionalized ethylene bromide to generate an amination product, which produced hydrogen bromide as a byproduct. In the synthetic route of indole cores, Willis et al. (MC. Willis, G.N. Brace, T.J. K. Findlay, I. P. Holmes, Adv. Synth. Catal. 2006, 348, 851) used 2-(2-haloalkenyl)aryl halides as coupling moieties of primary amines to synthesize a series of indole derivatives, which generated hydrogen chloride as a byproduct in the process. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention proposes a method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate esters. This method has high reaction efficiency and produces products without metal residues or byproducts.

[0006] To achieve the above objectives, the technical solution of the present invention is implemented as follows:

[0007] A method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate compounds includes the following steps: adding a heterocyclic formyl ethyl acetate compound, a sulfonamide compound, and a photosensitizer to a solvent to prepare a reaction solution, carrying out the reaction under blue light irradiation, and obtaining the target product after the reaction is completed;

[0008] The structural formula of the heterocyclic ethyl formanoate compound is as follows: X represents O and S.

[0009] The structural formula of the 4-methyl-N-(phenyl-3-iodoenyl)sulfonamide compound is as follows: R can be alkyl, halogen, nitro, trifluoromethyl, or trifluoromethoxy, etc.

[0010] The photosensitizer is 4CzIPN, with the following structural formula:

[0011] The solvent is dichloromethane, chloroform, acetonitrile, or ethyl acetate.

[0012] The molar ratio of the heterocyclic formyl ethyl acetate compound and the 4-methyl-N-(phenyl-3-iodoenyl)sulfonamide compound is 1:(2-4).

[0013] The amount of photosensitizer is 1-2 mol of the substance of the heterocyclic ethyl carbamate compound.

[0014] The ratio of the heterocyclic formyl ethyl acetate compound to the solvent is 0.1-0.2 mmol / mL.

[0015] The reaction was carried out at room temperature for 10 min to 4 h.

[0016] The structural formula of the 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate compound is as follows: In the formula, X represents O or S, and R represents alkyl, halogen, nitro, trifluoromethyl, or trifluoromethoxy, etc.

[0017] Preferably, the blue light wavelength is 465nm.

[0018] The beneficial effects of this invention are:

[0019] (1) This method avoids the problem of a large number of byproducts caused by the use of various oxidants in traditional methods;

[0020] (2) This method uses organic photosensitizer 4CzIPN as a catalyst, which greatly shortens the reaction time to only 10 minutes, improves the reaction efficiency, and the product will not have metal residue.

[0021] (3) The reaction conditions are mild and the reaction can occur at room temperature in air. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art 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.

[0023] Figure 1 The 1H NMR spectrum of ethyl 2-((4-methylphenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propionate;

[0024] Figure 2 The carbon NMR spectrum of ethyl 2-((4-methylphenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propionate;

[0025] Figure 3 The 1H NMR spectrum of ethyl 2-((3-bromophenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propionate;

[0026] Figure 4 The carbon NMR spectrum of ethyl 2-((3-bromophenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propionate;

[0027] Figure 5 The 1H NMR spectrum of ethyl 2-((2-methylphenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propionate;

[0028] Figure 6 The carbon NMR spectrum of ethyl 2-((2-methylphenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propionate;

[0029] Figure 7 The 1H NMR spectrum of ethyl 2-((4-methylphenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propionate;

[0030] Figure 8 The carbon NMR spectrum of ethyl 2-((4-methylphenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propionate;

[0031] Figure 9The 1H NMR spectrum of ethyl 2-((3-bromophenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propionate;

[0032] Figure 10 The carbon NMR spectrum of ethyl 2-((3-bromophenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propionate;

[0033] Figure 11 The 1H NMR spectrum of ethyl 2-((2-methylphenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propionate;

[0034] Figure 12 The carbon NMR spectrum of ethyl 2-((2-methylphenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propionate. Detailed Implementation

[0035] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0036] Example 1

[0037] The structural formula of ethyl 2-((4-methylphenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propionate in this embodiment is:

[0038]

[0039] In a test tube, 39.6 mg (0.2 mmol) of ethyl 3-(thiophen-2-yl)-3-oxopropionate, 149.2 mg (0.4 mmol) of 4-methyl-N-(phenyliodoethylene)benzenesulfonamide, 1.58 mg (1 mol%) of 4CzIPN, and 1.0 mL of dichloromethane were added. The mixture was magnetically stirred in air under 465 nm blue light irradiation and reacted at room temperature for 10 min. TLC analysis showed that the ethyl benzoylpropionate reacted completely. The product, ethyl 2-((4-methylphenyl)sulfonamide)-3-oxo-3-(thiophen-2-yl)propionate, was purified by vacuum rotary evaporation and thin-layer chromatography. The mass of the product was 57.2 mg, with a yield of 78%. The product was further purified by... 1 HNMR, 13 C NMR confirmed, such as Figure 1 and 2 As shown. 1H NMR (600MHz, CDCl3) δ8.01(dd,J=3.9,1.1Hz,1H),7.78(dd,J=4.9,1.1Hz,1H),7.76-7.71(m,2H),7.28-7.24(m,2H),7.19( dd,J=4.9,3.9Hz,1H),6.00(d,J=9.1Hz,1H),5.42(d,J=9.1Hz,1H),4.08-3.97(m,2H),2.40(s,3H),1.11(t,J=7.1Hz,3H). 13 C NMR (151MHz, CDCl3) δ182.6,165.8,144.0,140.2,136.45,136.42,135.2,129.6,128.6,127.3,62.7,61.6,21.5,13.7.

[0040] Example 2

[0041] The structural formula of ethyl 2-((3-bromophenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propionate in this embodiment is:

[0042]

[0043] The preparation method is as follows: In a test tube, add 39.6 mg (0.2 mmol) of ethyl 3-(thiophen-2-yl)-3-oxopropionate, 161.6 mg (0.4 mmol) of 3-bromo-N-(phenyliodoethylene)benzenesulfonamide, 1.58 mg (1 mol%) of 4CzIPN, and 1.0 mL of dichloromethane. Stir magnetically in air under 465 nm blue light irradiation and react at room temperature for 10 min. TLC analysis showed that the ethyl benzoyl acetate starting material had reacted completely. The product, ethyl 2-((3-bromophenyl)sulfonamide)-3-oxo-3-(thiophen-2-yl)propionate, was purified by vacuum rotary evaporation and thin-layer chromatography. The mass of the product was 61.5 mg, with a yield of 71%. The product was further purified by... 1 H NMR, 13 CNMR confirmed, such as Figure 3 and 4 As shown. 1H NMR(600MHz,Chloroform-d)δ8.00(dd,J=3.9,1.1Hz,1H),7.97(t,J=1.9Hz,1H),7.79(dt,J=5.4,2.5Hz,2H),7.67(d,J=8.0Hz, 1H),7.35(t,J=7.9Hz,1H),7.20(t,1H),6.14(d,J=9.1Hz,1H),5.47(d,J=9.0Hz,1H),4.10-3.99(m,2H),1.13(t,J=7.1Hz,3H). 13 C NMR (151MHz, Chloroform-d) δ182.2,165.6,141.4,140.0,136.8,136.0,135.3,130.6,130.1,128.7,125.7,123.0,63.0,61.5,13.7.

[0044] Example 3

[0045] The structural formula of ethyl 2-((2-methylphenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propionate in this embodiment is:

[0046]

[0047] The preparation method is as follows: In a test tube, add 39.6 mg (0.2 mmol) of ethyl 3-(thiophen-2-yl)-3-oxopropionate, 174.7 mg (0.4 mmol) of 2-methyl-N-(phenyliodomyloyl)benzenesulfonamide, 1.58 mg (1 mol%) of 4CzIPN, and 1.0 mL of dichloromethane. Stir magnetically in air under 465 nm blue light irradiation and react at room temperature for 10 min. TLC analysis showed that the ethyl benzoyl acetate reacted completely. The product, ethyl 2-((2-methylphenyl)sulfonamide)-3-oxo-3-(thiophen-2-yl)propionate, was purified by vacuum rotary evaporation and thin-layer chromatography. The mass of the product was 39.1 mg, with a yield of 53%. The product was further purified by... 1 HNMR, 13 C NMR confirmed, such as Figure 5 and 6 As shown. 1HNMR(600MHz,Chloroform-d)δ7.94-7.91(m,2H),7.75(dd,J=4.9,1.1Hz,1H),7.42(m,1H),7.28(d,J=7.5Hz,1H),7.23(t,J=7.9Hz, 1H),7.14(dd,J=4.9,3.9Hz,1H),6.11(d,J=8.9Hz,1H),5.38(d,J=8.9Hz,1H),4.04-3.89(m,2H),2.68(s,3H),1.08(t,J=7.2Hz,3H). 13 C NMR (151MHz, Chloroform-d) δ182.5,165.8,140.1,137.8,137.3,136.5,135.1,133.2,132.6,129.3,128.6,126.0,62.8,61.4,20.2,13.7.

[0048] Example 4

[0049] The structural formula of ethyl 2-((4-methylphenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propionate in this embodiment is:

[0050]

[0051] The preparation method is as follows: In a test tube, add 36.4 mg (0.2 mmol) of ethyl 3-oxo-3-(furan-2-yl)propionate, 149.2 mg (0.4 mmol) of 4-methyl-N-(phenyliodomylide)benzenesulfonamide, 1.58 mg (1 mol%) of 4CzIPN, and 1.0 mL of dichloromethane. Stir magnetically in air under 465 nm blue light irradiation and react at room temperature for 10 min. TLC analysis showed that the ethyl benzoyl acetate reacted completely. The product, ethyl 2-((4-methylphenyl)sulfonamide)-3-oxo-3-(furan-2-yl)propionate, was purified by vacuum rotary evaporation and thin-layer chromatography. The mass of the product was 60.6 mg, with a yield of 86%. The product was further purified by... 1 HNMR, 13 C NMR confirmed, such as Figure 7 and 8 As shown. 1HNMR (600MHz, CDCl3) δ7.75(d,J=8.2Hz,2H),7.68(d,J=1.6Hz,1H),7.44(d,J=3.7Hz,1H),7.28(d,J=7.9Hz,2H),6.62(d d,J=3.7,1.7Hz,1H),5.89(d,J=9.0Hz,1H),5.37(d,J=8.9Hz,1H),4.10-4.00(m,2H),2.42(s,3H),1.12(t,J=7.1Hz,3H). 13 C NMR (151MHz, CDCl3) δ178.3,165.7,149.8,148.2,143.9,136.5,129.6,127.2,120.9,112.9,62.7,60.7,21.5,13.7.

[0052] Example 5

[0053] The structural formula of ethyl 2-((3-bromophenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propionate in this embodiment is:

[0054]

[0055] The preparation method is as follows: In a test tube, add 36.4 mg (0.2 mmol) of ethyl 3-oxo-3-(furan-2-yl)propionate, 161.6 mg (0.4 mmol) of 3-bromo-N-(phenyliodoethylene)benzenesulfonamide, 1.58 mg (1 mol%) of 4CzIPN, and 1.0 mL of dichloromethane. Stir magnetically in air under 465 nm blue light irradiation and react at room temperature for 10 min. TLC analysis showed that the ethyl benzoyl acetate starting material had reacted completely. The product, ethyl 2-((3-bromophenyl)sulfonamide)-3-oxo-3-(furan-2-yl)propionate, was purified by vacuum rotary evaporation and thin-layer chromatography. The mass of the product was 45.8 mg, with a yield of 55%. The product was further purified by... 1 H NMR, 13 CNMR confirmed, such as Figure 9 and 10 As shown. 1HNMR(600MHz,Chloroform-d)δ7.98(s,1H),7.79(d,J=7.9Hz,1H),7.68(d,J=8.7Hz,2H),7.43(d,J=3.7Hz,1H),7.36(t,J=7. 9Hz,1H),6.62(dd,J=3.7,1.7Hz,1H),6.03(d,J=9.0Hz,1H),5.42(d,J=9.0Hz,1H),4.11-4.02(m,2H),1.13(t,J=7.1Hz,3H). 13 C NMR (151MHz, Chloroform-d) δ178.0,165.5,149.7,148.4,141.5,136.0,130.6,130.1,125.7,122.9,121.1,113.1,62.9,60.6,13.7.

[0056] Example 6

[0057] The structural formula of ethyl 2-((2-methylphenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propionate in this embodiment is:

[0058]

[0059] The preparation method is as follows: In a test tube, add 36.4 mg (0.2 mmol) of ethyl 3-oxo-3-(furan-2-yl)propionate, 174.7 mg (0.4 mmol) of 2-methyl-N-(phenyliodomyloyl)benzenesulfonamide, 1.58 mg (1 mol%) of 4CzIPN, and 1.0 mL of dichloromethane. Stir magnetically in air under 465 nm blue light irradiation and react at room temperature for 10 min. TLC analysis showed that the ethyl benzoylpropionate had reacted completely. The product, ethyl 2-((2-methylphenyl)sulfonamide)-3-oxo-3-(furan-2-yl)propionate, was purified by vacuum rotary evaporation and thin-layer chromatography. The mass of the product was 35.2 mg, with a yield of 50%. The product was further purified by... 1 HNMR, 13 C NMR confirmed, such as Figure 11 and 12 As shown. 1H NMR(600MHz,Chloroform-d)δ7.94(dd,J=7.9,1.4Hz,1H),7.63(d,J=1.6Hz,1H),7.42(m,1H),7.37(d,J=3.7Hz,1H),7.28(d,J=7.6Hz,1H),7.24( t,J=7.7Hz,1H),6.57(dd,J=3.7,1.7Hz,1H),6.02(d,J=8.8Hz,1H),5.33 (d,J=8.8Hz,1H),4.05-3.97(m,2H),2.68(s,3H),1.09(t,J=7.1Hz,3H). 13 C NMR (151MHz, Chloroform-d) δ178.3,165.7,149.7,148.2,137.8,137.4,133.1,132.6,129.3,125.9,120.9,113.0,62.7,60.5,20.2,13.7.

[0060] Comparative Example 1

[0061] The structural formula of ethyl 2-((4-methylphenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propionate in this comparative example is: The structural formula of the catalyst [Ir(dtbbpy)(ppy)2]PF6 is:

[0062]

[0063] In a test tube, 39.6 mg (0.2 mmol) of ethyl 3-(thiophen-2-yl)-3-oxopropionate, 149.2 mg (0.4 mmol) of 4-methyl-N-(phenyliodoethylene)benzenesulfonamide, 1.83 mg (1 mol%) of [Ir(dtbbpy)(ppy)2]PF6, and 1.0 mL of dichloromethane were added. The mixture was magnetically stirred in air under 465 nm blue light irradiation and reacted at room temperature for 10 min. TLC analysis confirmed that the ethyl benzoylpropionate had reacted completely. The product, ethyl 2-((4-methylphenyl)sulfonamide)-3-oxo-3-(thiophen-2-yl)propionate, was purified by vacuum rotary evaporation and thin-layer chromatography. The mass of the product was 57.2 mg, with a yield of 78%.

[0064] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate compounds, characterized in that, The reaction mixture includes the following steps: adding ethyl heterocyclic formamide, sulfonamide, and photosensitizer to a solvent to prepare a reaction solution, reacting under blue light irradiation, and obtaining the target product after the reaction is complete; The structural formula of the heterocyclic ethyl formanoate compound is as follows: X is either O or S; The structural formula of the sulfonamide compound is as follows: R is an alkyl, halogen, nitro, trifluoromethyl, or trifluoromethoxy group; The photosensitizer is 4CzIPN, with the following structural formula: ; The structural formula of the 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate compound is as follows: In the formula, X is O or S; R is alkyl, halogen, nitro, trifluoromethyl or trifluoromethoxy.

2. The method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate esters according to claim 1, characterized in that, The solvent is dichloromethane, chloroform, acetonitrile, or ethyl acetate.

3. The method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate esters according to claim 1, characterized in that, The molar ratio of the heterocyclic formyl ethyl acetate compound to the sulfonamide compound is 1:(2-4).

4. The method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate esters according to claim 1, characterized in that, The amount of photosensitizer is 1-2 mol of the substance of the heterocyclic ethyl carbamate compound.

5. The method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate esters according to claim 1, characterized in that, The ratio of the heterocyclic ethyl formamide compound to the solvent is 0.1-0.2 mmol / mL.

6. The method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate esters according to claim 1, characterized in that, The reaction was carried out at room temperature for 10 min–4 h.

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