Preparation method of benzenesulfonamide compound

Abstract

The invention provides a method for synthesizing a benzenesulfonamide compound by taking substituted benzene and NFSI as raw materials and directly heating in the presence or absence of a solvent. Compared with the existing synthesis method of the benzenesulfonamide compound, the method has the advantages that the used reagent raw materials are simple and easy to obtain, any catalyst and additive are not needed, even the sulfonamide reaction of the electron-rich aromatic ring can be realized by a one-step method under the solvent-free condition, and the production cost is greatly saved; the range of reaction substrates is wide, and benzene with various substituent groups can react smoothly; the reaction efficiency is high, and corresponding products can be almost obtained at high yield in most reactions.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis and chemical product synthesis, and particularly relates to a method for synthesizing benzenesulfonamide compounds by directly heating substituted benzene and NFSI as raw materials. Background Art

[0002] Nitrogen-containing aromatics are ubiquitous in natural products, drugs, agrochemicals and functional materials, so it is very important to explore methods for synthesizing such compounds. Direct functionalization of aromatic carbon-hydrogen bonds is of great significance for the formation of carbon-nitrogen bonds, and it has advantages in terms of steps and atom economy. This patent reports a new method for direct sulfonamidation of aromatics. The obtained sulfonamidobenzene product can be desulfonylated under the action of magnesium powder to obtain a deprotected amino compound (reaction formula 1: Nature Communications 2019 , 10 , 5467.), or it can be directly used as an important synthetic intermediate for further reaction (Reaction Formula 2: Eur. J. Org. Chem. 2014, 2014, 6385-6389.). 1. Remove one or two sulfonyl groups to prepare amino products 2. Used as a coupling reagent to prepare complex compounds Use of aromatic compounds containing sulfonamide substitution The known methods for preparing sulfonamide aromatic compounds are harsh and usually require additional metal catalysts or additives. For example, the most direct method for synthesizing sulfonamide aromatic compounds is to use acyl chlorides to perform classical sulfonylation of the amino groups of aromatic amine compounds. The disadvantage of this method is that the yield is not high, and the acyl chloride reagent used is easy to produce strong acid, resulting in high corrosiveness (reaction formula 3). The second type of preparation route is to use a coupling strategy, starting from bisbenzenesulfonyl imide and the corresponding aromatic compound through DDQ / TBN reagent and blue light catalysis to couple the two. In addition, one-fold amount of tetrabutylammonium acetate can be added to prepare and synthesize the target product through an electrochemical method (reaction formula 4). NFSI (N-fluorobisbenzenesulfonamide) is an easily available, stable, highly soluble crystalline powder, which is widely used as a fluorination agent or oxidant in organic reactions. In addition, NFSI has been shown to be an effective nitrogen source for CH bond amidation of aromatics, heteroaromatics, benzene, allyl groups and aldehydes. Therefore, there have been many literature reports that NFSI can efficiently perform sulfonamidation reactions on various aromatic rings under the action of metal catalysts such as copper, silver or ruthenium (reaction formula 5). This patent adopts the third type of synthesis method. Compared with the synthesis methods reported in the known literature, the reagents and raw materials used in the patent of the present invention are cheap and easy to obtain, do not require any catalysts and additives, and can even be carried out under solvent-free conditions. The experimental operation is simple, the steps are few, and the yield is high. 3.Eur.J.Org.Chem.2014,2014,6385-6389. 4.Chem.Eur.J.2017,23,18161-18165. 5.J.Am.Chem.Soc.2015,137,2460-2463. Sulfonamidation of aromatic rings Summary of the invention

[0003] The object of the present invention is to provide a method for synthesizing benzenesulfonamide compounds by direct heating with or without solvent using substituted benzene and NFSI as raw materials. The purpose of the present invention can be achieved by the following technical solutions: A method for preparing benzenesulfonamide compounds: Under the protection of inert gas, a substituted benzene represented by general formula (I) and NFSI represented by general formula (II) are directly heated in the presence or absence of a solvent to obtain a benzenesulfonamide compound represented by general formula (III), and the chemical reaction formula thereof is shown as follows: Where R 1, R 2 , R 3 , R 4 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, aldehyde, C1-C4 alkylcarbonyl or C1-C4 alkoxycarbonyl; or R 2 and R 3 Linked together to form -O(CH2) n O-, wherein n=1-3; the solvent is an organic solvent. The method for preparing benzenesulfonamide compounds, preferably, wherein R 1 , R 2 , R 3 , R 4 is selected from H, C1-C2 alkyl, C1-C2 alkoxy, hydroxy, aldehyde, C1-C2 alkylcarbonyl or C1-C2 alkoxycarbonyl; or R 2 and R 3 Linked together to form -O(CH2) n O-, where n=1-2. More preferably, where R 1 , R 2 , R 3 , R 4 is selected from H, methyl, methoxy, ethoxy, hydroxy, aldehyde, methylcarbonyl or methoxycarbonyl; or R 2 and R 3 Linked together to form -O(CH2) n O-, where n=1-2. In the method for preparing benzenesulfonamide compounds, the organic solvent is selected from carbon tetrachloride, toluene and 1,2-dichloroethane (DCE). More preferably, the solvent is 1,2-dichloroethane. In the method for preparing benzenesulfonamide compounds, the reaction temperature is 40-130° C. More preferably, the reaction temperature is 60-120° C. The method for preparing benzenesulfonamide compounds, wherein: the molar ratio of the substituted benzene shown in (I) to the NFSI shown in the general formula (II) is 1:(1-5); and the inert gas includes nitrogen and argon. The method for preparing benzenesulfonamide compounds, the operating steps are as follows: Add a solvent to the reaction flask or add the substituted benzene shown in (I) and the NFSI shown in the general formula (II) to obtain a mixture under the protection of an inert gas, and heat and stir to react. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, and then separate and purify to obtain a benzenesulfonamide compound shown in the general formula (III). The method for preparing benzenesulfonamide compounds is more preferably, and its specific operating steps are as follows: Add an appropriate amount of solvent to the reaction flask or add the substituted benzene shown in (I) and the NFSI shown in the general formula (II) under solvent-free conditions to obtain a mixture, and heat and stir under the protection of inert gas to react. The reaction is continuously monitored by TLC during the reaction. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, and then separate and purify by column chromatography to obtain a benzenesulfonamide compound shown in the general formula (III). Compared with the existing synthesis methods of benzenesulfonamide compounds, the reagents and raw materials used in the present invention are simple and easy to obtain, do not require any catalysts and additives, and can even achieve the sulfonamidation reaction of electron-rich aromatic rings in a single step under solvent-free conditions, thereby greatly saving production costs; the reaction substrate range is relatively wide, and benzenes with various substituents can react smoothly; the reaction efficiency is high, and most reactions can almost obtain corresponding products in high yields. In summary, the technical solution of the present invention has the following beneficial effects: The raw materials and reagents used are cheap and easily available (no catalyst or additive is required), and some substrates can even react directly without solvent or any catalyst. The reaction system is simple, the operation is simple, the atom economy is high, it is green and environmentally friendly, and the production cost is greatly saved and the operation steps are simplified. The reaction conditions are mild, the reaction speed is fast, the chemical selectivity and regioselectivity are good, the side reactions are few, the subsequent product separation is convenient, the reaction yield is high (mostly 80-95%), and industrial production can be realized, with significant economic and social benefits. DETAILED DESCRIPTION The present invention is described in detail by the following examples, but the present invention is not limited to the examples. Example 1: Solvent-free synthesis of N-(phenylsulfonyl)-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide IIIa. Trimethoxybenzene Ia (1.0 mmol) and NFSI (2.0 mmol) were added to the flask, and the temperature was raised to 110°C under argon protection, and the reaction was continuously monitored by TLC. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIa as a light brown solid with a yield of 91%. 1 H NMR (600MHz, CDCl3) δ7.99 (d, J = 8.0Hz, 4H), 7.69 (t, J = 7.4Hz, 2H), 7.57 (t, J = 7.7Hz, 4H), 6.16 (s, 2H), 3.87 (s, 3H), 3.65 (s, 6H); 13C NMR(151MHz, CDCl3)δ153.14,139.42,134.03,128.98,128.73,108.99,60.96,56.12; HRMS(ESI)m / z:[M+H] + Calculate for C 21 H 22 NO7S2:464.0832; Found:464.0828. Example 2: Synthesis of N-(phenylsulfonyl)-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide IIIa in DCE. 5 ml of DCE, trimethoxybenzene Ia (1.0 mmol) and NFSI (2.0 mmol) were added to a two-necked flask connected to a reflux condenser. The mixture was heated to 80°C under argon protection and stirred for reaction. The reaction was continuously monitored by TLC. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and then separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIa as a light brown solid with a yield of 95%. Example 3: Solvent-free synthesis of N-(4-hydroxy-3,5-dimethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIb. 2,6-dimethoxyphenol Ib (1.0 mmol) and NFSI (2.0 mmol) were added to the flask, and the temperature was raised to 110°C under argon protection and stirred for reaction. The reaction was continuously monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and separated and purified by column chromatography using petroleum ether-ethyl acetate as the eluent to obtain IIIb as a brown solid with a yield of 74%. 1 H NMR (600MHz, CDCl3) δ8.07–7.89(m,4H),7.68(t,J=7.5Hz,2H),7.56(t,J=7.9Hz,4H),6.17(s,2H),5.70(s,1H),3.70(s,6H); 13 C NMR(151MHz, CDCl3)δ146.77,139.42,136.74,133.98,128.96,128.69,125.06,108.81,56.34; HRMS(ESI)m / z:[M+H] + Calculate for C 20 H 20 NO7S2:450.0676; Found:450.0685. Example 4: Synthesis of N-(4-hydroxy-3,5-dimethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIb in DCE. Add 5 ml of DCE, 2,6-dimethoxyphenol Ib (1.0 mmol) and NFSI (2.0 mmol) to a two-necked flask connected to a reflux condenser. The mixture is heated to 80°C under argon protection and stirred for reaction. The reaction is continuously monitored by TLC. After the reaction is completed, it is cooled to room temperature, concentrated under reduced pressure, and then separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIb as a brown solid with a yield of 67%. Example 5: Solvent-free synthesis of N-(3,4-dimethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIc. 1,2-Dimethoxybenzene Ic (1.0 mmol) and NFSI (2.0 mmol) were added to the flask, and the temperature was raised to 110°C under argon protection, and the reaction was continuously monitored by TLC. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIc as a brown solid with a yield of 92%. 1 H NMR(600MHz, CDCl3) δ7.96(d,J=7.7Hz,4H),7.68(t,J=7.4Hz,2H),7.55(t,J=7.8Hz,4H),6.80 (d,J=8.6Hz,1H),6.63(dd,J=8.5,2.1Hz,1H),6.38(d,J=2.0Hz,1H),3.89(s,3H),3.66(s,3H); 13 C NMR(151MHz, CDCl3)δ150.63,148.96,139.49,133.94,128.98,128.63,126.38,124.37,114.35,110.73,55.98,55.91; HRMS(ESI)m / z:[M+H] + Calculate for C 20 H 20 NO6S2:434.0727; Found:434.0734. Example 6: Synthesis of N-(3,4-dimethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIc in DCE. 5 ml of DCE, 1,2-dimethoxybenzene Ic (1.0 mmol) and NFSI (2.0 mmol) were added to a two-necked flask connected to a reflux condenser. The mixture was heated to 80°C under argon protection and stirred for reaction. The reaction was continuously monitored by TLC. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and then separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIc as a brown solid with a yield of 91%. Example 7: Solvent-free synthesis of N-(2,5-dimethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIId. 1,4-dimethoxybenzene Id (1.0 mmol) and NFSI (2.0 mmol) were added to the flask, and the temperature was raised to 110°C under argon protection, and the reaction was continuously monitored by TLC. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIId as a white solid with a yield of 86%. 1 H NMR (600MHz, CDCl3) δ8.02–7.91(m,4H),7.69–7.59(m,2H),7.57–7.44(m,4H),6.95(dd,J =9.0,3.1Hz,1H),6.76(d,J=9.1Hz,1H),6.66(d,J=3.1Hz,1H),3.68(s,3H),3.33(s,3H); 13 C NMR (151MHz, CDCl3) δ153.16,151.98,139.99,133.71,128.88,128.62,122.73,118.34,117.56,112.54,55.82,55.45; HRMS (ESI) m / z: [M+H] + Calculate for C 20 H 20 NO6S2:434.0727; Found:434.0738. Example 8: Synthesis of N-(2,5-dimethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIId in DCE. 5 ml of DCE, 1,4-dimethoxybenzene Id (1.0 mmol) and NFSI (2.0 mmol) were added to a two-necked flask connected to a reflux condenser. The mixture was heated to 80°C under argon protection and stirred for reaction. The reaction was continuously monitored by TLC. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and then separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIId as a white solid with a yield of 82%. Example 9: Solvent-free synthesis of N-(3,4-diethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIe. 1,2-diethoxybenzene Ie (1.0 mmol) and NFSI (2.0 mmol) were added to the flask, and the temperature was raised to 110°C under argon protection and stirred for reaction. The reaction was continuously monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and separated and purified by column chromatography using petroleum ether-ethyl acetate as the eluent to obtain IIIe as a white solid with a yield of 83%. 1 H NMR (600MHz, CDCl3) δ7.95(d,J=7.5Hz,4H),7.66(t,J=7.5Hz,2H),7.54(t,J=7.9Hz,4H),6.78(d,J=8.6Hz,1H),6.59(dd,J=8. 6,2.4Hz,1H),6.40(d,J=2.4Hz,1H),4.10(q,J=7.0Hz,2H),3.86(q,J=7.0Hz,2H),1.46(t,J=7.0Hz,3H),1.35(t,J=7.0Hz,3H); 13 C NMR (151MHz, CDCl3) δ150.42,148.48,139.57,133.84,128.94,128.60,126.13,124.32,116.27,112.26,64.53,14.72,14.55; 1 H NMR (400MHz, DMSO-d6) δ7.85–7.79(m,6H),7.73–7.65(m,4H),6.97(d,J=8.7Hz,1H),6.58(dd,J=8.6,2.5Hz,1H), 6.30(d,J=2.5Hz,1H),4.04(q,J=7.0Hz,2H),3.77(q,J=7.0Hz,2H),1.33(t,J=7.0Hz,3H),1.22(t,J=7.0Hz,3H); 13C NMR(101MHz,DMSO-d6)δ150.40,148.24,139.10,135.15,130.08,128.57,128.56, 125.70,124.80,116.09,113.06,64.41,64.36,15.13,14.96; HRMS(ESI)m / z:[M+H] + Calculate for C 22 H 24 NO6S2:462.1040; Found:462.1048. Example 10: Synthesis of N-(3,4-diethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIe in DCE. 5 ml of DCE, 1,2-diethoxybenzene Ie (1.0 mmol) and NFSI (2.0 mmol) were added to a two-necked flask connected to a reflux condenser. The mixture was heated to 80°C under argon protection and stirred for reaction. The reaction was continuously monitored by TLC. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and then separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIe as a white solid with a yield of 88%. Example 11: Solvent-free synthesis of N-(2,3-dihydrobenzo[b][1,4]dioxo-6-substituted)-N-(phenylsulfonyl)benzenesulfonamide IIIf. 1,4-Benzodioxin If (1.0 mmol) and NFSI (2.0 mmol) were added to the flask, and the temperature was raised to 110°C under argon protection and stirred for reaction. The reaction was continuously monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and separated and purified by column chromatography using petroleum ether-ethyl acetate as the eluent to obtain IIIf as a white solid with a yield of 87%. 1 H NMR (600MHz, CDCl3) δ8.00–7.91(m,4H),7.67(t,J=7.5Hz,2H),7.55(t,J=7.9Hz,4H),6.79(d,J=8.6Hz,1H), 6.60(d,J=2.5Hz,1H), 6.45(dd,J=8.6,2.5Hz,1H), 4.27(dd,J=5.7,2.4Hz,2H), 4.23(dd,J=5.7,2.4Hz,2H); 13C NMR (151MHz, CDCl3) δ145.47,143.65,139.52,133.95,129.01,128.57,126.79,124.77,120.45,117.48,64.35,64.07; 1 H NMR(400MHz,DMSO-d6)δ7.87–7.78(m,6H),7.73–7.66(m,4H),6.88(d,J=8.6Hz,1H),6 .48(d,J=2.5Hz,1H), 6.40(dd,J=8.6,2.6Hz,1H), 4.27(ddd,J=12.1,3.5,1.6Hz,4H); 13 C NMR(101MHz,DMSO-d6)δ145.80,143.91,139.04,135.20,130.12,130.10,128.5 2,128.51,126.28,124.95,120.28,117.97,64.71,64.45; HRMS(ESI)m / z:[M+H] + Calculate for C 20 H 18 NO6S2:432.0570; Found:432.0560. Example 12: Synthesis of N-(2,3-dihydrobenzo[b][1,4]dioxo-6-substituted)-N-(phenylsulfonyl)benzenesulfonamide IIIf in DC E. Add 5 ml of DCE, 1,4-benzodioxane If (1.0 mmol) and NFSI (2.0 mmol) to a two-necked flask connected to a reflux condenser. The mixture was heated to 80°C under argon protection and stirred for reaction. The reaction was continuously monitored by TLC. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and then separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIf as a white solid with a yield of 80%. Example 13: Solvent-free synthesis of N-(benzo[d][1,3]dioxy-5-substituted)-N-(phenylsulfonyl)benzenesulfonamide IIIg. Add benzo[d][1,3]dioxolane Ig (1.0 mmol) and NFSI (2.0 mmol) to the flask, heat to 110°C under argon protection, stir and react, and monitor the reaction by TLC. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, and separate and purify by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIg as a white solid with a yield of 90%. 1 H NMR(600MHz, CDCl3)δ8.03–7.92(m,4H),7.68(t,J=7.5Hz,2H),7.56(t,J=7.9Hz,4H), 6.73(d,J=8.2Hz,1H),6.49(d,J=2.1Hz,1H),6.45(dd,J=8.2,2.1Hz,1H),6.02(s,2H); 13 C NMR (151MHz,CDCl3)δ 149.37,148.07,139.40,134.01,129.04,128.58,127.29,125.96,111.84,108.16,102.14; 1 H NMR (400MHz, DMSO-d6) δ7.89–7.79(m,6H),7.74–7.64(m,4H),6.92(d,J=8.3Hz,1H),6.58(d,J=2.1Hz,1H),6.39(dd,J=8.3,2.2Hz,1H),6.13(s,2H); 13 C NMR(101MHz,DMSO-d6)δ154.32,153.03,143.71,139.98,134.87,133.31,131.63,131.10,116.65,113.55,107.67; HRMS(ESI)m / z:[M+H] + Calculate for C 19 H 16 NO6S2:418.0414; Found:418.0409. Example 14: Synthesis of N-(benzo[d][1,3]dioxo-5-substituted)-N-(phenylsulfonyl)benzenesulfonamide IIIg in DCE. Add 5 ml of DCE, benzo[d][1,3]dioxolane Ig (1.0 mmol) and NFSI (2.0 mmol) to a two-necked flask connected to a reflux condenser. The mixture was heated to 80°C under argon protection and stirred for reaction. The reaction was continuously monitored by TLC. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and then separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIg as a white solid with a yield of 92%. Example 15: Solvent-free synthesis of N-(5-acetyl-2,3,4-trimethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIh. 1-(2,3,4-trimethoxyphenyl)ethanone Ih (1.0 mmol) and NFSI (2.0 mmol) were added to the flask, and the temperature was raised to 110°C under argon protection and stirred for reaction. The reaction was continuously monitored by TLC. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIh as a yellow solid with a yield of 54%. 1 H NMR (600MHz, CDCl3) δ8.16–8.01(m,4H),7.68(d,J=7.5Hz,2H),7.57(t,J=7.9Hz,4H),5.99(s,1H),3.92(d,J=7.2Hz,6H),3.50(s,3H),2.46(s,3H); 13 C NMR (151MHz, CDCl3) δ199.51,153.34,151.37,143.51,138.39,134.16,131.34,1 29.94,128.57,125.25,112.26,61.79,61.00,55.88,32.06; HRMS(ESI)m / z:[M+H] + Calculate for C 23 H 24 NO8S2:506.0938; Found:506.0930. Example 16: Synthesis of N-(5-acetyl-2,3,4-trimethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIh in DCE. Add 5 ml of DCE, 1-(2,3,4-trimethoxyphenyl)ethanone Ih (1.0 mmol) and NFSI (2.0 mmol) to a two-necked flask connected to a reflux condenser. The mixture was heated to 80°C under argon protection and stirred for reaction. The reaction was continuously monitored by TLC. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and then separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIh as a yellow solid with a yield of 51%. Example 17: Solvent-free synthesis of N-(3-formyl-4,5-dimethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIi. 2,3-Dimethoxybenzaldehyde Ii (1.0 mmol) and NFSI (2.0 mmol) were added to the flask, and the temperature was raised to 110°C under argon protection, and the reaction was continuously monitored by TLC. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIi as a white solid with a yield of 55%. 1 H NMR (600MHz, CDCl3) δ10.34(s,1H),7.99–7.86(m,4H),7.70(t,J=7.5Hz,2H),7.57(t, J=7.9Hz,4H),7.06(d,J=2.5Hz,1H),6.69(d,J=2.5Hz,1H),4.04(s,3H),3.72(s,3H); 13 C NMR (151MHz, CDCl3) δ188.53,153.91,153.31,139.14,134.24,129.91,129.58,129.13,128.63,122.33,120.63,62.36,56.19; HRMS (ESI) m / z: [M+H] + Calculate for C 21 H 20 NO7S2:462.0676; Found:462.0683. Example 18: Synthesis of N-(3-formyl-4,5-dimethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIi in DCE. Add 5 ml of DCE, 2,3-dimethoxybenzaldehyde 1i (1.0 mmol) and NFSI (2.0 mmol) to a two-necked flask connected to a reflux condenser. The mixture is heated to 80°C under argon protection and stirred for reaction. The reaction is continuously monitored by TLC. After the reaction is completed, it is cooled to room temperature, concentrated under reduced pressure, and then separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIi as a white solid with a yield of 68%. Example 19: Solvent-free synthesis of N-(5-formyl-2,3-dimethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIj. 3,4-dimethoxybenzaldehyde Ij (1.0 mmol) and NFSI (2.0 mmol) were added to the flask, and the temperature was raised to 110°C under argon protection, and the reaction was continuously monitored by TLC. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and separated and purified by column chromatography using petroleum ether-ethyl acetate as the eluent to obtain IIIj as a white solid with a yield of 43%. 1 H NMR (600MHz, CDCl3) δ9.31 (s, 1H), 7.95 (dt, J = 3.1, 2.1Hz, 4H), 7.72 (t, J = 7.5Hz ,2H),7.58(t,J=7.9Hz,4H),7.44(s,1H),6.32(s,1H),3.96(s,3H),3.70(s,3H); 13 CNMR(151MHz,CDCl3)δ187.36,153.49,150.78,138.18,134.61,130.22,129.66 ,129.32,128.98,128.84,128.63,114.65,109.03,56.32,56.30; HRMS(ESI)m / z: [M+H] + Calculate for C 21 H 20 NO7S2:462.0676; Found:462.0670. Example 20: Synthesis of N-(5-formyl-2,3-dimethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIj in DCE. Add 5 ml of DCE, 3,4-dimethoxybenzaldehyde Ij (1.0 mmol) and NFSI (2.0 mmol) to a two-necked flask connected to a reflux condenser. The mixture is heated to 80°C under argon protection and stirred for reaction. The reaction is continuously monitored by TLC. After the reaction is completed, it is cooled to room temperature, concentrated under reduced pressure, and then separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIj as a white solid with a yield of 49%. Example 21: Solvent-free synthesis of methyl 3,4-dimethoxy-5-(N-(phenylsulfonyl)benzenesulfonamide)benzoate IIIk. Add 3,4-dimethoxybenzoic acid methyl ester Ik (1.0 mmol) and NFSI (2.0 mmol) to the flask, heat to 110°C under argon protection and stir to react, and monitor the reaction by TLC. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, and separate and purify by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIk as a brown oil with a yield of 58%. 1 H NMR (600MHz, CDCl3) δ8.02–7.93(m,4H),7.71–7.64(m,2H),7.58–7.51(m,5H),6.42(s,1H),3.96(s,3H),3.71(s,3H),3.30(s,3H); 13 C NMR (151MHz, CDCl3) δ164.95,151.47,149.95,139.81,133.83,129.18,128.7 6,126.71,124.47,116.06,113.85,56.26,56.19,51.69; HRMS(ESI)m / z:[M+H] + Calculate for C 22 H 22 NO8S2:492.0781; Found:492.0773. Example 22: Synthesis of methyl 3,4-dimethoxy-5-(N-(phenylsulfonyl)benzenesulfonamide)benzoate IIIk in DCE. Add 5 ml of DCE, methyl 3,4-dimethoxybenzoate Ik (1.0 mmol) and NFSI (2.0 mmol) to a two-necked flask connected to a reflux condenser. The mixture is heated to 80°C under argon protection and stirred for reaction. The reaction is continuously monitored by TLC. After the reaction is completed, it is cooled to room temperature, concentrated under reduced pressure, and then separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIk as a brown oil with a yield of 46%. Example 23: Solvent-free synthesis of N-(5-acetyl-2,3-dimethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIl. 1-(3,4-dimethoxyphenyl)ethanone Il (1.0 mmol) and NFSI (2.0 mmol) were added to the flask, and the temperature was raised to 110°C under argon protection and stirred for reaction. The reaction was continuously monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and separated and purified by column chromatography using petroleum ether-ethyl acetate as the eluent to obtain IIIl as a yellow solid with a yield of 51%. 1 H NMR (600MHz, CDCl3) δ8.03–7.92(m,4H),7.74–7.58(m,2H),7.58–7.48(m,4H),7.17(s,1H),6.25(s,1H),3.93(s,3H),3.59(s,3H),2.34(s,3H); 13 C NMR (151MHz, CDCl3) δ197.15,150.62,149.83,138.69,134.20,133.59,129.5 3,128.78,124.65,115.67,111.81,56.21,56.00,29.47; HRMS(ESI)m / z:[M+H] + Calculate for C 22 H 22 NO7S2:476.0832; Found:476.0837. Example 24: Synthesis of N-(5-acetyl-2,3-dimethoxyphenyl)-N-(phenylsulfonyl)benzenesulfonamide III in DCE. Add 5 ml of DCE, 1-(3,4-dimethoxyphenyl)ethanone Il (1.0 mmol) and NFSI (2.0 mmol) to a two-necked flask connected to a reflux condenser. The mixture was heated to 80°C under argon protection and stirred for reaction. The reaction was continuously monitored by TLC. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and then separated and purified by column chromatography using petroleum ether-ethyl acetate as the eluent to obtain IIIl as a yellow solid with a yield of 57%. Example 25: Solvent-free synthesis of N-(4,5-dimethoxy-2-methylphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIm. 1,2-dimethoxy-4-methylbenzene Im (1.0 mmol) and NFSI (2.0 mmol) were added to the flask, and the temperature was raised to 110°C under argon protection and stirred for reaction. The reaction was continuously monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and separated and purified by column chromatography using petroleum ether-ethyl acetate as the eluent to obtain IIIm as a white solid with a yield of 59%. 1H NMR (600MHz, CDCl3) δ7.96 (d, J=7.5Hz, 4H), 7.68 (t, J=7.5Hz, 2H), 7.55 (t, J= 7.9Hz,4H),6.68(s,1H),6.23(s,1H),3.88(s,3H),3.59(s,3H),1.88(s,3H); 13 C NMR (151MHz, CDCl3) δ150.33,146.78,139.56,134.00,133.49,128.95,128.93,124.60,114.64,113.05,55.89,55.85,17.77; HRMS (ESI) m / z: [M+H] + Calculate for C 21 H 22 NO6S2:448.0883; Found:448.0891. Example 26: Synthesis of N-(4,5-dimethoxy-2-methylphenyl)-N-(phenylsulfonyl)benzenesulfonamide IIIm in DCE. Add 5 ml of DCE, 1,2-dimethoxy-4-methylbenzene Im (1.0 mmol) and NFSI (2.0 mmol) to a two-necked flask connected to a reflux condenser. The mixture is heated to 80°C under argon protection and stirred for reaction. The reaction is continuously monitored by TLC. After the reaction is completed, it is cooled to room temperature, concentrated under reduced pressure, and then separated and purified by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIm as a white solid with a yield of 78%. Example 27: Solvent-free synthesis of N-(phenylsulfonyl)-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide IIIa. Add an appropriate amount of carbon tetrachloride, trimethoxybenzene Ia (1.0 mmol), and NFSI (1.2 mmol) to a two-necked flask connected to a reflux condenser, and heat to 75°C under argon protection to stir and react, and monitor the reaction by TLC. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, and separate and purify by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIa as a light brown solid with a yield of 75%. Example 28: Solvent-free synthesis of N-(phenylsulfonyl)-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide IIIa. Add appropriate amount of toluene, trimethoxybenzene Ia (1.0 mmol), NFSI (2 mmol) to a two-necked flask connected to a reflux condenser, heat to 110°C under argon protection, stir and react, and monitor the reaction by TLC. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, and separate and purify by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIa as a light brown solid with a yield of 62%. Example 29: Solvent-free synthesis of N-(phenylsulfonyl)-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide IIIa. Add appropriate amount of carbon tetrachloride, trimethoxybenzene Ia (1.0 mmol), NFSI (4 mmol) to a two-necked flask connected to a reflux condenser, heat to 75°C under nitrogen protection, stir and react, and monitor the reaction by TLC. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, and separate and purify by column chromatography using petroleum ether-ethyl acetate as eluent to obtain IIIa as a light brown solid with a yield of 80%.

Claims

1. A method for preparing benzenesulfonamide compounds, characterized in that: Under the protection of inert gas, the substituted benzene represented by the general formula (I) and the NFSI represented by the general formula (II) are directly heated in the presence or absence of a solvent to obtain a benzenesulfonamide compound represented by the general formula (III), and the chemical reaction formula thereof is shown as follows: Where R 1 , R 2 , R 3 , R 4 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, aldehyde, C1-C4 alkylcarbonyl or C1-C4 alkoxycarbonyl; or R 2 and R 3 Linked together to form -O(CH2) n O-, wherein n=1-3; the solvent is an organic solvent.

2. The method for preparing benzenesulfonamide compounds according to claim 1, characterized in that: R 1 , R 2 , R 3 , R 4 is selected from H, C1-C2 alkyl, C1-C2 alkoxy, hydroxy, aldehyde, C1-C2 alkylcarbonyl or C1-C2 alkoxycarbonyl; or R 2 and R 3 Linked together to form -O(CH2) n O-, where n=1-2.

3. The method for preparing benzenesulfonamide compounds according to claim 2, characterized in that: R 1 , R 2 , R 3 , R 4 is selected from H, methyl, methoxy, ethoxy, hydroxy, aldehyde, methylcarbonyl or methoxycarbonyl; or R 2 and R 3 Linked together to form -O(CH2) n O-, where n=1-2.

4. The method for preparing benzenesulfonamide compounds according to claim 1, characterized in that: The organic solvent is selected from carbon tetrachloride, toluene and 1,2-dichloroethane.

5. The method for preparing benzenesulfonamide compounds according to claim 4, characterized in that: The organic solvent is 1,2-dichloroethane.

6. The method for preparing benzenesulfonamide compounds according to claim 1, characterized in that: The reaction temperature is 40-130°C.

7. The method for preparing benzenesulfonamide compounds according to claim 6, characterized in that: The reaction temperature is 60-120°C.

8. The method for preparing benzenesulfonamide compounds according to claim 1, characterized in that: The molar ratio of the substituted benzene shown in (I) to the NFSI shown in the general formula (II) is 1:(1-5); the inert gas includes nitrogen and argon.

9. The method for preparing benzenesulfonamide compounds according to claim 1, characterized in that: The operation steps are as follows: add a solvent to a reaction bottle or add the substituted benzene shown in (I) and the NFSI shown in the general formula (II) to obtain a mixture under the protection of an inert gas, heat and stir to react, and after the reaction is completed, cool to room temperature, concentrate under reduced pressure, and then separate and purify to obtain the benzenesulfonamide compound shown in the general formula (III).

10. The method for preparing benzenesulfonamide compounds according to claim 9, characterized in that: The specific operation steps are as follows: add an appropriate amount of solvent to a reaction bottle or add the substituted benzene shown in (I) and the NFSI shown in the general formula (II) under solvent-free conditions to obtain a mixture, heat and stir under the protection of inert gas to react, and continuously monitor the reaction by TLC during the reaction. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, and then separate and purify by column chromatography to obtain a benzenesulfonamide compound shown in the general formula (III).

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