Synthesis method of 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate compound

Abstract

The invention provides a synthesis method of a 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate compound, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: adding a heterocyclic formyl ethyl acetate compound, a sulfonamide compound and a photosensitizer into a solvent to prepare a reaction solution, reacting under blue light irradiation, and obtaining a target product after the reaction is finished. According to the invention, the problem of a large number of byproducts caused by various oxidants used in the traditional method is avoided; an organic photosensitizer 4CzIPN is used as a catalyst, so that the reaction time is greatly shortened, the reaction can be completed only in 10 minutes, the reaction efficiency is improved, and the product does not have metal residues; the reaction conditions of the reaction are mild, and the reaction can be carried out in a room-temperature air atmosphere.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate ester compounds. Background Art

[0002] Nitrogen-containing compounds are of great significance due to their wide applications in functionalizing various heteroaromatic rings and are the core structures of many biologically and pharmacologically active ingredients. Due to their unique physicochemical properties and biological activities, nitrogen-containing structures are widely used in natural products, agrochemicals, drugs, and functional materials. Therefore, the synthetic strategy of C-N bonds has always been a hot area of ​​chemical research. With the continuous development of new reagents, new methods, new synthetic strategies, and analytical instruments, scientists' understanding of nitrogen-containing structures has been continuously deepened. In order to effectively form C-N bonds, various strategies have been developed to obtain different nitrogen-containing skeletons.

[0003] Traditionally, C-N bond formation is usually achieved by using common nitrogen-containing nucleophiles and electrophiles such as amines, amides, and imines. However, these methods sometimes have problems with functional group compatibility and require harsh reaction conditions. Given the importance of these compounds in scientific research, chemists have made great efforts to develop efficient alternative synthetic strategies, especially those that can introduce nitrogen sources under mild and green conditions to comply with the principles of sustainable and green chemistry.

[0004] Traditional carbon-nitrogen bond construction mostly relies on transition metal catalysis or pre-functionalization of reactants. These methods may not only cause heavy metal contamination of the product, but also produce a series of by-products, such as acids, which are environmentally unfriendly. For example, Barluenga et al. (J.Barluenga, MA Fernandez, F.Aznar, C.Valdes, Chem. Commun. 2004, 1400) use BINAP and pre-functionalized vinyl bromide to generate an amination product, which will produce hydrogen bromide by-products. In the synthetic route of indole core, Willis et al. (MC Willis, GNBrace, TJK Findlay, I P Holmes, Adv. Synth. Catal. 2006, 348, 851) use 2-(2-haloalkenyl) aryl halides as the coupling part of primary amines to synthesize a series of indole derivatives, and hydrogen chloride by-products will be generated in the process. Summary of the invention

[0005] In view of the above technical problems, the present invention provides a method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate compounds, which has high reaction efficiency and the product has no metal residue and by-products.

[0006] In order to achieve the above object, the technical solution of the present invention is achieved as follows:

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

[0008] The structural formula of the heterocyclic ethyl formyl acetate compound is X is O, S.

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

[0010] The photosensitizer is 4CzIPN, and the structural formula is

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

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

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

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

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

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

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

[0018] Beneficial effects of the present invention:

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

[0020] (2) This method uses an organic photosensitizer 4CzIPN as a catalyst, which greatly shortens the reaction time and only takes 10 minutes to complete the reaction, improves the reaction efficiency, and does not have any metal residue in the product;

[0021] (3) The reaction conditions are mild and the reaction can occur at room temperature in an air atmosphere. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0023] Figure 1 It is the H NMR spectrum of ethyl 2-((4-methylphenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propanoate;

[0024] Figure 2 It is the NMR carbon spectrum of ethyl 2-((4-methylphenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propanoate;

[0025] Figure 3 It is the H NMR spectrum of ethyl 2-((3-bromophenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propanoate;

[0026] Figure 4 It is the NMR carbon spectrum of ethyl 2-((3-bromophenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propanoate;

[0027] Figure 5 It is the H NMR spectrum of ethyl 2-((2-methylphenyl)sulfonamido)-3-oxo-3-(thiophen-2-yl)propanoate;

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

[0029] Figure 7 It is the H NMR spectrum of ethyl 2-((4-methylphenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propanoate;

[0030] Figure 8 It is the NMR carbon spectrum of ethyl 2-((4-methylphenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propanoate;

[0031] Fig. 9is the H NMR spectrum of ethyl 2-((3-bromophenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propanoate;

[0032] Fig.10 It is the NMR carbon spectrum of ethyl 2-((3-bromophenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propanoate;

[0033] Fig.11 It is the H NMR spectrum of ethyl 2-((2-methylphenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propanoate;

[0034] Fig.12 This is the carbon NMR spectrum of ethyl 2-((2-methylphenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propanoate. DETAILED DESCRIPTION

[0035] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work 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-(thiophene-2-yl)propionate in this embodiment is:

[0038]

[0039] In a test tube, add 39.6 mg (0.2 mmol) of ethyl 3-(thiophene-2-yl)-3-oxopropanoate, 149.2 mg (0.4 mmol) of 4-methyl-N-(phenyliodoidene)benzenesulfonamide, 1.58 mg (1 mol%) of 4CzIPN, and 1.0 mL of dichloromethane, stir magnetically in an air atmosphere under 465 nm blue light irradiation, and react at room temperature for 10 minutes. According to TLC analysis, the raw material ethyl benzoyl acetate has reacted completely. Vacuum rotary evaporation, thin layer chromatography separation and purification, the mass of the product ethyl 2-((4-methylphenyl)sulfonamido)-3-oxo-3-(thiophene-2-yl)propanoate is 57.2 mg, and the yield is 78%. The product is 1 HNMR, 13 C NMR confirmed that Figure 1 and 2 shown. 1 H NMR (600 MHz, CDCl 3)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 (151 MHz, CDCl 3 )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 3-(thiophene-2-yl)-3-oxopropionic acid ethyl ester, 161.6 mg (0.4 mmol) of 3-bromo-N-(phenyliodoidene)benzenesulfonamide, 1.58 mg (1 mol%) of 4CzIPN, and 1.0 mL of dichloromethane, stir magnetically in an air atmosphere under 465 nm blue light irradiation, and react at room temperature for 10 minutes. According to TLC analysis, the raw material ethyl benzoyl acetate has reacted completely. After vacuum rotary evaporation and thin layer chromatography separation and purification, the mass of the product 2-((3-bromophenyl)sulfonamido)-3-oxo-3-(thiophene-2-yl)propionic acid ethyl ester is 61.5 mg, and the yield is 71%. The product is 1 H NMR, 13 CNMR confirms that Figure 3 and 4 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-(thiophene-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 3-(thiophene-2-yl)-3-oxopropionic acid ethyl ester, 174.7 mg (0.4 mmol) of 2-methyl-N-(phenyliodoidene)benzenesulfonamide, 1.58 mg (1 mol%) of 4CzIPN, and 1.0 mL of dichloromethane, stir magnetically in an air atmosphere under 465 nm blue light irradiation, and react at room temperature for 10 minutes. According to TLC analysis, the raw material ethyl benzoyl acetate has reacted completely. After vacuum rotary evaporation and thin layer chromatography separation and purification, the mass of the product 2-((2-methylphenyl)sulfonamido)-3-oxo-3-(thiophene-2-yl)propionic acid ethyl ester is 39.1 mg, and the yield is 53%. The product is 1 HNMR, 13 C NMR confirmed that Figure 5 and 6 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 of this embodiment is:

[0050]

[0051] The preparation method is as follows: in a test tube, add 36.4 mg (0.2 mmol) of 3-oxo-3-(furan-2-yl)propionic acid ethyl ester, 149.2 mg (0.4 mmol) of 4-methyl-N-(phenyliodoidene)benzenesulfonamide, 1.58 mg (1 mol%) of 4CzIPN, and 1.0 mL of dichloromethane, stir magnetically in an air atmosphere under 465 nm blue light irradiation, and react at room temperature for 10 minutes. According to TLC analysis, the raw material ethyl benzoyl acetate has reacted completely. After vacuum rotary evaporation and thin layer chromatography separation and purification, the mass of the product 2-((4-methylphenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propionic acid ethyl ester is 60.6 mg, and the yield is 86%. The product is 1 HNMR, 13 C NMR confirmed that Figure 7 and 8 shown. 1 HNMR (600MHz, CDCl 3)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(dd,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 (151 MHz, CDCl 3 )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 of this embodiment is:

[0054]

[0055] The preparation method is as follows: in a test tube, add 36.4 mg (0.2 mmol) of 3-oxo-3-(furan-2-yl)propionic acid ethyl ester, 161.6 mg (0.4 mmol) of 3-bromo-N-(phenyliodoidene)benzenesulfonamide, 1.58 mg (1 mol%) of 4CzIPN, and 1.0 mL of dichloromethane, stir magnetically in an air atmosphere under 465 nm blue light irradiation, and react at room temperature for 10 minutes. According to TLC analysis, the raw material ethyl benzoyl acetate has reacted completely. After vacuum rotary evaporation and thin layer chromatography separation and purification, the mass of the product 2-((3-bromophenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propionic acid ethyl ester is 45.8 mg, and the yield is 55%. The product is 1 H NMR, 13 CNMR confirms that Fig. 9 and 10 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 of the present embodiment is:

[0058]

[0059] The preparation method is as follows: in a test tube, add 36.4 mg (0.2 mmol) of 3-oxo-3-(furan-2-yl)propionic acid ethyl ester, 174.7 mg (0.4 mmol) of 2-methyl-N-(phenyliodoidene)benzenesulfonamide, 1.58 mg (1 mol%) of 4CzIPN, and 1.0 mL of dichloromethane, stir magnetically in an air atmosphere under 465 nm blue light irradiation, and react at room temperature for 10 minutes. According to TLC analysis, the raw material ethyl benzoyl acetate has reacted completely. After vacuum rotary evaporation and thin layer chromatography separation and purification, the mass of the product 2-((2-methylphenyl)sulfonamido)-3-oxo-3-(furan-2-yl)propionic acid ethyl ester is 35.2 mg, and the yield is 50%. The product is 1 HNMR, 13 C NMR confirmed that Fig.11 and 12 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 of this comparative example is: Catalyst [Ir(dtbbpy)(ppy) 2 ]PF 6 The structural formula is

[0062]

[0063] In a test tube, 39.6 mg (0.2 mmol) of ethyl 3-(thiophen-2-yl)-3-oxopropanoate, 149.2 mg (0.4 mmol) of 4-methyl-N-(phenyliodoylidene)benzenesulfonamide, and 1.83 mg (1 mol%) of [Ir(dtbbpy)(ppy) 2 ]PF 6 , 1.0 mL of dichloromethane, magnetic stirring in air atmosphere under 465 nm blue light irradiation, and reacting at room temperature for 10 min. According to TLC analysis, the raw material ethyl benzoyl acetate has reacted completely. Vacuum rotary evaporation, thin layer chromatography separation and purification, the mass of the product ethyl 2-((4-methylphenyl)sulfonyl)-3-oxo-3-(thiophen-2-yl)propanoate is 57.2 mg, and the yield is 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 principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionic acid ester compounds, characterized in that: The method comprises the following steps: adding a heterocyclic formyl ethyl acetate compound, a sulfonamide compound and a photosensitizer into a solvent to prepare a reaction solution, reacting under blue light irradiation, and obtaining a target product after the reaction is completed.

2. The method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate compounds according to claim 1, characterized in that: The structural formula of the heterocyclic ethyl formyl acetate compound is X is O or S.

3. The method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate compounds according to claim 1, characterized in that: The structural formula of the sulfonamide compound is R is alkyl, halogen, nitro, trifluoromethyl or trifluoromethoxy.

4. The method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate compounds according to claim 1, characterized in that: The photosensitizer is 4CzIPN, and the structural formula is 5. The method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate ester compounds according to claim 1, characterized in that: The solvent is dichloromethane, chloroform, acetonitrile or ethyl acetate.

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

7. The method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate compounds according to claim 1, characterized in that: The amount of the photosensitizer is 1-2 mol% of the amount of the ethyl heterocyclic carboxylate compound.

8. The method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionic acid ester compounds according to claim 1, characterized in that: The ratio of the ethyl heterocyclic carboxylate compound to the solvent is 0.1-0.2 mmol / mL.

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

10. The method for synthesizing 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionic acid ester compounds according to claim 1, characterized in that: The structural formula of the 2-(benzenesulfonamide)-3-oxo-3-heterocyclic propionate ester compound is In the formula, X is O or S; R is alkyl, halogen, nitro, trifluoromethyl or trifluoromethoxy.

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