CN109232330B - Method for synthesizing benzene sulfonamide compound from benzene sulfonyl chloride compound and triethylamine through metal-free catalysis - Google Patents
Method for synthesizing benzene sulfonamide compound from benzene sulfonyl chloride compound and triethylamine through metal-free catalysis Download PDFInfo
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- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
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Abstract
A method for synthesizing benzene sulfonamide compounds from benzene sulfonyl chloride compounds and triethylamine under the condition of metal-free catalysis is characterized in that in an air environment, benzene sulfonyl chloride compounds and triethylamine are used as substrates, iodine-containing compounds are used as catalysts, tert-butyl hydroperoxide is used as an oxidant, and S-N bond coupling reaction is carried out in a solvent to generate the benzene sulfonamide compounds. The catalyst used in the method is simple and easy to obtain, is stable in air, is easy to recover and has no pollution, and the method has wide application prospect in drug synthesis and industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis and drug synthesis, relates to synthesis of benzene sulfonamide compounds, and more particularly relates to a method for synthesizing benzene sulfonamide compounds by catalyzing benzene sulfonyl chloride compounds and triethylamine with iodine-containing compounds under the condition of metal catalysis.
Background
Benzenesulfonamides are frequently obtained by amination of benzenesulfonyl chloride. The substance has strong biological activities of resisting fungi, bacteria, cancers, antipsychotic drugs, HIV protease inhibitor and the like. Most have been used as potent inhibitors of cysteine proteases and carbonic acid proteases. Therefore, the development of a synthetic method of the benzene sulfonamide compound has important practical value. Currently, there are many methods for synthesizing benzenesulfonamide compounds under the catalysis of transition metals, such as: can be in FeCl2By reacting sodium arylsulfonate with sodium nitrateDirectly coupling aromatic hydrocarbon to construct S-N bond to catalytically synthesize sulfonamide in one step; by CuBr2The catalysis of (3) causes sulfonyl chloride to react with tertiary amine to generate sulfonamide and the like.
Therefore, the prior art for synthesizing benzene sulfonamide substances needs transition metal catalysis (containing some toxic metals), the toxic metals pollute the environment, the atom economy is general, most of reaction raw materials are expensive and are not easy to obtain, and the synthesis method has certain limitation in industrial production.
Disclosure of Invention
The invention aims to provide a method for preparing benzene sulfonamide compounds by catalyzing benzene sulfonyl chloride compounds and triethylamine under the condition of no metal catalysis. The method uses cheap and easily-obtained simple iodine-containing compounds as catalysts, and can generate the required benzene sulfonamide compounds with high yield in the air environment.
In order to achieve the purpose, the invention adopts the technical scheme that: a method for synthesizing benzene sulfonamide compounds by benzene sulfonyl chloride compounds and triethylamine under the condition of metal-free catalysis is characterized in that in an air environment, benzene sulfonyl chloride compounds and triethylamine are used as substrates, iodine-containing compounds are used as catalysts, tert-butyl hydroperoxide is used as an oxidant, S-N bond coupling reaction is carried out in a solvent, and the benzene sulfonamide compounds are generated, wherein the reaction general formula is as follows:
wherein R in the general formula of the benzene sulfonyl chloride compound is a halogen atom or a substituent.
Preferably, the above substituents are methyl, methoxy, fluoro, iodo, tert-butyl or cyano. Preferably, the substituent is methyl, methoxy, tert-butyl or cyano.
The iodine-containing compounds are KI and NH4I or tetrabutylammonium iodide, preferably NH4I; the solvent is THF, toluene, CH3CN or DMF, preferably THF; the reaction temperature is 80-120 ℃, and preferably 120 ℃; reaction timeThe time is 6-15h, preferably 12 h. When the reaction starts, the molar ratio of the benzene sulfonyl chloride compound to the triethylamine to the catalyst to the oxidant to the solvent is 1: 2: 0.1: 0.5.
in the air environment, the simple iodine-containing compound is used for catalyzing the benzenesulfonyl chloride compound and the grade-B amine to carry out S-N coupling reaction, and the used iodine-containing catalyst is cheap and easy to obtain, is easy to recover and has no pollution. The invention can realize a series of benzene sulfonamide compounds with high yield under mild conditions, wherein S-N coupling reaction has wide application prospect in the synthesis of natural products, medicines, pesticides and the like.
Detailed Description
The following examples will help to understand the present invention, but the contents of the present invention are not limited thereto.
Example 1: n, N-diethyl-2-methylbenzenesulfonamide
57.19mg (0.3mmol) of 2-methyl-1-benzenesulfonyl chloride as well as 60.71mg (0.6mmol) of triethylamine, 4.98mg (0.03mmol) of potassium iodide as a catalyst, tert-butyl hydroperoxide as an oxidant (0.12mL) and THF as a solvent (2mL) were added to a 30mL lock tube under an air atmosphere. Then the sealed tube is put into an oil bath at 120 ℃ for reaction for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, and an appropriate amount of ethyl acetate was added to dilute the reaction solution, which was then filtered through a sand core funnel, and the filtrate was subjected to rotary evaporation and then to silica gel column chromatography (ethyl acetate/petroleum ether: 1/2 as an eluent) to obtain 35.40mg of a yellow oily liquid with a yield of 54.4%.
Subjecting the obtained liquid to hydrogen spectrum1H NMR(400MHz,CDCl3): δ 7.62(t, J ═ 16.0Hz,2H),7.38(t, J ═ 8.0Hz,2H),3.26-3.21(m,4H),2.42(s,3H),1.13(t, J ═ 8.0Hz,6H), carbon spectrum13C NMR(101MHz,CDCl3): delta 140.19,139.21,133.12,128.94,127.43,124.17,42.17,21.52,14.28, and mass spectrometry (molecular weight is 227.2) analysis and identification, and the structural formula is shown in the specification
Example 2: n, N-diethyl-4-methoxybenzenesulphonamide
61.99mg (0.3mmol) of 4-methoxy-1-benzenesulfonyl chloride and 60.17mg (0.6mmol) of triethylamine, 4.35mg (0.03mmol) of ammonium iodide as a catalyst, t-butyl hydroperoxide as an oxidant (0.12mL), and toluene as a solvent (2mL) were added to a 30mL lock tube under an air atmosphere. Then the sealed tube is put into an oil bath at 120 ℃ for reaction for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, and an appropriate amount of ethyl acetate was added to dilute the reaction solution, which was then filtered through a sand core funnel, and the filtrate was subjected to rotary evaporation and silica gel column chromatography (ethyl acetate/petroleum ether: 1/2 as an eluent) to obtain 37.70mg of a yellow oily liquid with a yield of 46.7%.
Subjecting the resulting liquid to a hydrogen spectrum of1H NMR(400MHz,CDCl3): δ 7.74(d, J ═ 8.0Hz,2H),6.96(d, J ═ 8.0Hz,2H),3.86(s,3H),3.24-3.19(m,4H),1.12(t, J ═ 8.0Hz, 6H)), carbon spectrum: (c13C NMR(101MHz,CDCl3): delta 162.65,132.14,129.15,114.21,55.66,42.03,14.21.) and mass spectrum (molecular weight of 243.1) analysis and identification, and the structure is
Example 3: n, N-diethyl-4-iodobenzenesulfonamide
90.75mg (0.3mmol) of 4-iodo-1-benzenesulfonyl chloride and 60.71mg (0.6mmol) of triethylamine as substrates, 4.34mg (0.03mmol) of ammonium iodide as a catalyst, t-butylhydroperoxide (0.12mL) as an oxidant, and CH as a solvent3CN (2mL) was added to a 30mL lock tube under air. Then the sealed tube is put into an oil bath at 120 ℃ for reaction for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, and an appropriate amount of ethyl acetate was added to dilute the reaction solution, which was filtered through a sand core funnel, and the filtrate was subjected to rotary evaporation and silica gel column chromatography (ethyl acetate/petroleum ether: 1/2 as eluent) to obtain 62.90mg of a yellow oily liquid with a yield of 66.9%.
Subjecting the obtained liquid to hydrogen spectrum1H NMR(400MHz,CDCl3): δ 7.85(d, J ═ 8.0Hz,2H),7.53(d, J ═ 4.0Hz,2H),3.26-3.21(m,4H),1.13(t, J ═ 4.0Hz,6H), carbon spectrum13C NMR(101MHz,CDCl3): delta 138.22,136.58,128.81,99.96,47.93,25.20, and mass spectrum (molecular weight is 339.2) analysis identification, and the structural formula is
Example 4: n, N-diethyl-4-fluorobenzenesulfonamides
54.64mg (0.3mmol) of 4-fluoro-1-benzenesulfonyl chloride and 60.71mg (0.6mmol) of triethylamine, 4.98mg (0.03mmol) of potassium iodide as a catalyst, tert-butyl hydroperoxide as an oxidizing agent (0.12mL), and DMF (2mL) as a solvent were added to a 30mL lock tube under an air atmosphere. Then the sealed tube is put into an oil bath at 120 ℃ for reaction for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, and an appropriate amount of ethyl acetate was added to dilute the reaction solution, which was filtered through a sand core funnel, and the filtrate was subjected to rotary evaporation and silica gel column chromatography (ethyl acetate/petroleum ether: 1/2 as eluent) to obtain 52.50mg of a yellow oily liquid with a yield of 80.03%.
Subjecting the obtained liquid to hydrogen spectrum1H NMR(400MHz,CDCl3): δ 7.83(d, J ═ 8.2,5.4Hz,2H),7.17(t, J ═ 8.5Hz,2H),3.24(q, J ═ 7.1Hz,4H),1.13(t, J ═ 7.1Hz,6H), carbon spectrum13C NMR(101MHz,CDCl3): delta 166.11,163.64,136.65,129.71,129.63,116.33,116.11,42.00,14.11 and mass spectrum (molecular weight 231.3) analysis identification, and the structural formula is
Example 5: n, N-diethyl-4-tert-butyl benzenesulfonamide
132.13mg (0.3mmol) of 4-tert-butyl-1-benzenesulfonyl chloride and 60.71mg (0.6mmol) of triethylamine, 0.03mmol of tetrabutylammonium iodide as a catalyst, tert-butylhydroperoxide (0.12mL) as an oxidant, and THF (2mL) as a solvent were added under an air atmosphere in a 30mL lock tube. Then the sealed tube is put into an oil bath at 120 ℃ for reaction for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, and an appropriate amount of ethyl acetate was added to dilute the reaction solution, which was filtered through a sand core funnel, and the filtrate was subjected to rotary evaporation and silica gel column chromatography (ethyl acetate/petroleum ether: 1/2 as eluent) to obtain 80.40mg of a yellow oily liquid with a yield of 56.22%.
Subjecting the obtained liquid to hydrogen spectrum1H NMR(400MHz,CDCl3)：δ7.72(d,J＝8.3Hz,2H),7.49(d,J＝8.4Hz,2H),3.23(q,J＝7.1Hz,4H) 1.34(s,9H),1.14(t, J ═ 7.1Hz,6H), carbon spectrum13C NMR(101MHz,CDCl3): delta 155.91,137.33,126.95,125.91,42.12,35.02,31.16,14.39, and mass spectrum (molecular weight 269.4) analysis and identification, and the structural formula is
Example 6: n, N-diethyl-3-methylbenzenesulfonamide
57.19mg (0.30mmol) of 3-methyl-1-benzenesulfonyl chloride and 60.71mg (0.6mmol) of triethylamine, 4.34mg (0.03mmol) of ammonium iodide as a catalyst, t-butyl hydroperoxide (0.12mL) as an oxidant, and THF (2mL) as a solvent were added to a 30mL lock tube under an air atmosphere. Then the sealed tube is put into an oil bath at 120 ℃ for reaction for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, and an appropriate amount of ethyl acetate was added to dilute the reaction solution, which was filtered through a sand core funnel, and the filtrate was subjected to rotary evaporation and silica gel column chromatography (ethyl acetate/petroleum ether: 1/2 as eluent) to obtain 51.1mg of a yellow oily liquid with a yield of 74.98%.
Subjecting the obtained liquid to hydrogen spectrum1H NMR(400MHz,CDCl3): δ 7.63(d, J ═ 8.0Hz,2H),7.41(t, J ═ 12.0Hz,2H),3.24(s,4H),2.43(s,3H),1.75(s,4H), carbon spectrum13C NMR(101MHz,CDCl3): delta 139.14,136.55,133.42,128.87,127.79,124.58,47.92,25.18,21.37, and mass spectrum (molecular weight of 227.3) analysis and identification, and the structural formula is
Example 7: n, N-diethyl-4-cyanobenzenesulfonamide
60.48mg (0.3mmol) of 4-cyano-1-benzenesulfonyl chloride and 60.17mg (0.6mmol) of triethylamine, 4.34mg (0.03mmol) of ammonium iodide as a catalyst, tert-butyl hydroperoxide as an oxidizing agent (0.12mL), and THF as a solvent (2mL) were added to a 30mL lock tube under an air atmosphere. Then the sealed tube is put into an oil bath at 120 ℃ for reaction for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, and an appropriate amount of ethyl acetate was added to dilute the reaction solution, which was filtered through a sand core funnel, and the filtrate was subjected to rotary evaporation and silica gel column chromatography (ethyl acetate/petroleum ether: 1/2 as eluent) to obtain 65.60mg of a yellow oily liquid with a yield of 91.8%.
Subjecting the obtained liquid to hydrogen spectrum1H NMR(400MHz,CDCl3): δ 7.93(d, J ═ 8.4Hz,2H),7.80(d, J ═ 8.3Hz,2H),3.27(q, J ═ 7.1Hz,4H),1.15(q, J ═ 7.1Hz,6H), carbon spectrum13C NMR(101MHz,CDCl3): delta 140.2,139.1,133.0,128.9,127.4,124.1,42.07,21.4,14.2, and mass spectrum (molecular weight is 238.1) analysis identification, and the structural formula is
Claims (4)
1. A method for synthesizing benzene sulfonamide compounds from benzene sulfonyl chloride compounds and triethylamine under the condition of metal-free catalysis is characterized in that in the air environment, benzene sulfonyl chloride compounds and triethylamine are used as substrates, iodine-containing compounds are used as catalysts, tert-butyl hydroperoxide is used as an oxidant, S-N bond coupling reaction is carried out in a solvent, and the benzene sulfonamide compounds are generated, wherein the reaction general formula is as follows:
wherein R is halogen, methyl, methoxy, tert-butyl or cyano, and the iodine-containing compound is NH4I or tetrabutylammonium iodide.
2. The method for synthesizing benzene sulfonamide compounds with the benzene sulfonyl chloride compounds and the triethylamine in the metal-free catalysis manner according to claim 1, wherein the method comprises the following steps: the solvent is THF, toluene and CH3CN or DMF.
3. The method for synthesizing benzene sulfonamide compounds with the benzene sulfonyl chloride compounds and the triethylamine in the metal-free catalysis manner according to claim 1, wherein the method comprises the following steps: the molar ratio of the benzene sulfonyl chloride compound to the triethylamine to the catalyst to the oxidant to the solvent is 1: 2: 0.1: 0.5.
4. the method for synthesizing benzene sulfonamide compounds with the benzene sulfonyl chloride compounds and the triethylamine in the metal-free catalysis manner according to claim 1, wherein the method comprises the following steps: the temperature of the reaction is 80-120 ℃.
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