A method for the synthesis of N-alkyl sulfonamides

Abstract

The application discloses a synthesis method of N-alkyl sulfonamide and belongs to the technical field of organic synthesis chemistry. The method is realized by reacting alcohol and sulfonamide in an organic solvent under the action of elemental iodine and organic hydrosilane. In the reaction process, no complex metal catalyst needs to be prepared, and there is no problem of metal residue in the synthesis process, which is environment-friendly. Moreover, the raw materials in the method are easy to store, the whole reaction operation is simple, and the method is suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis chemistry technology, and specifically relates to a method for synthesizing N-alkylsulfonamides. Background Technology

[0002] N-alkylsulfonamides are an important class of nitrogen-containing compounds, widely found in molecules with physiological and pharmacological activities. For example, these compounds can be used as thromboxane (A2) receptor antagonists, as antitrypanosome agents, and as inhibitors of secretory coil-associated proteins.

[0003] The synthesis of N-alkylsulfonamides using alcohols and sulfonamides is a recently developed synthetic method that avoids the use of highly toxic compounds such as sulfonyl chlorides, which are not easily stored for long periods. Existing methods for synthesizing N-alkylsulfonamides using alcohols and sulfonamides mostly employ metal catalysts. These methods require the preparation of complex metal catalysts and may result in metal residues during synthesis. Summary of the Invention

[0004] The purpose of this invention is to solve the problem of requiring the preparation of complex metal catalysts in the synthesis of N-alkylsulfonamides from alcohols and sulfonamides in the prior art. This invention provides a method for synthesizing N-alkylsulfonamides, which realizes the reaction of alcohols and sulfonamides into N-alkylsulfonamides under the action of elemental iodine and organohydrosilanes. The method of this invention has the advantages of easy storage of raw materials, simple operation, no metal residue, and environmental friendliness.

[0005] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: a method for synthesizing N-alkylsulfonamides, comprising the following steps:

[0006] S1. In a reaction vessel, sulfonamide, solvent, alcohol, base, organosilane and iodine are added in sequence to form a reaction mixture;

[0007] S2. After reacting the reaction mixture in S1 under reflux for 2 hours, the mixture was cooled to room temperature and quenched by adding sodium thiosulfate solution. The mixture was then extracted with ethyl acetate, dried with sodium sulfate, and the solvent was removed by rotary evaporation. Finally, the target compound N-alkylsulfonamide was obtained by column chromatography.

[0008] Preferably, the N-alkylsulfonamide is as shown in Formula I; the alcohol is as shown in Formula II; and the sulfonamide is as shown in Formula III.

[0009]

[0010] R1 is selected from phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl and 4-bromophenyl;

[0011] R2 is selected from 4-methylphenyl, phenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl and 4-bromophenyl.

[0012] Preferably, the solvent is one of ethyl acetate, acetonitrile, N,N-dimethylformamide, toluene, 1,4-dioxane, and 1,2-dichloroethane.

[0013] Preferably, the alkali is one of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and potassium hydroxide.

[0014] Preferably, the organohydrosilane is one of triethylsilane, polymethylhydrosiloxane, and 1,1,3,3-tetramethyldisiloxane.

[0015] Preferably, the molar ratio of sulfonamide to alcohol is 1.2 equiv.; the molar ratio of elemental iodine to alcohol is 1.0 equiv.; the molar ratio of organohydrosilane to alcohol is 1.0 equiv.; and the molar ratio of base to alcohol is 2.0 equiv.

[0016] Further preferably, the concentration of the sodium thiosulfate solution is 0.5 mol / L.

[0017] The beneficial effects of this invention are as follows: the method of this invention realizes the reaction of alcohol and sulfonamide to N-alkylsulfonamide under the action of elemental iodine and organohydrosilane. There is no need to prepare complex metal catalysts during the reaction process, and there is no problem of metal residue during the synthesis process, which is environmentally friendly. Moreover, the raw materials in the method of this invention are easy to store, the entire reaction operation is simple, the product yield is high, and it is suitable for large-scale industrial production. Attached Figure Description

[0018] Figure 1 This is the general reaction formula for the reaction of this invention. Detailed Implementation

[0019] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0020] The general reaction formula of the present invention is shown in the appendix. Figure 1 As shown.

[0021] Example 1: N-Benzyl-4-methylbenzenesulfonamide

[0022]

[0023] 4-Methylbenzenesulfonamide (205.5 mg, 1.2 mmol), 1,2-dichloroethane (2 mL), benzyl alcohol (108.1 mg, 1.0 mmol), potassium carbonate (276.4 mg, 2.0 mmol), triethylsilane (116.3 mg, 1.0 mmol), and elemental iodine (253.8 mg, 1.0 mmol) were sequentially added to a 25 mL round-bottom flask. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and quenched with 10 mL of 0.5 mol / L sodium thiosulfate solution. The mixture was then extracted once with 30 mL of ethyl acetate. The organic phase was dried over sodium sulfate, and the solvent was removed by rotary evaporation. The target product was then obtained by column chromatography in 64% yield.

[0024] 1 H NMR(600MHz, CDCl3): δ7.76(d,J=8.4Hz,2H),7.30(d,J=7.8Hz,2H),7.28–7.2 4(m,3H),7.22-7.16(m,2H),4.78(s,1H),4.11(d,J=5.4Hz,2H),2.44(s,3H); 13 C NMR (150MHz, CDCl3): δ143.6,136.9,136.4,129.9,128.8,128.0,127.3,47.4,21.7.

[0025] Example 2: N-(4-methoxybenzyl)-4-methylbenzenesulfonamide

[0026]

[0027] 4-Methylbenzenesulfonamide (205.5 mg, 1.2 mmol), 1,2-dichloroethane (2 mL), 4-methoxybenzyl alcohol (138.2 mg, 1.0 mmol), potassium carbonate (276.4 mg, 2.0 mmol), triethylsilane (116.3 mg, 1.0 mmol), and elemental iodine (253.8 mg, 1.0 mmol) were sequentially added to a 25 mL round-bottom flask. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and quenched with 10 mL of 0.5 mol / L sodium thiosulfate solution. The mixture was then extracted once with 30 mL of ethyl acetate. The organic phase was dried over sodium sulfate, and the solvent was removed by rotary evaporation. The target product was then obtained by column chromatography in 83% yield.

[0028] 1H NMR(600MHz, CDCl3): δ7.76(d,J=8.4Hz,2H),7.30(d,J=7.8Hz,2H),7.28–7.2 4(m,3H),7.22-7.16(m,2H),4.78(s,1H),4.11(d,J=5.4Hz,2H),2.44(s,3H); 13 C NMR (150MHz, CDCl3): δ143.6,136.9,136.4,129.9,128.8,128.0,127.3,47.4,21.7.

[0029] Example 3: N-(4-trifluoromethylbenzyl)-4-methylbenzenesulfonamide

[0030]

[0031] 4-Methylbenzenesulfonamide (205.5 mg, 1.2 mmol), 1,2-dichloroethane (2 mL), 4-trifluoromethylbenzyl alcohol (176.1 mg, 1.0 mmol), potassium carbonate (276.4 mg, 2.0 mmol), triethylsilane (116.3 mg, 1.0 mmol), and elemental iodine (253.8 mg, 1.0 mmol) were sequentially added to a 25 mL round-bottom flask. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and quenched with 10 mL of 0.5 mol / L sodium thiosulfate solution. The mixture was then extracted once with 30 mL of ethyl acetate. The organic phase was dried over sodium sulfate, and the solvent was removed by rotary evaporation. The target product was then obtained by column chromatography in 47% yield.

[0032] 1 H NMR (600MHz, CDCl3): δ7.72(d,J=8.4Hz,2H),7.51(d,J=8.4Hz,2H),7.32(d,J=7.8Hz, 2H),7.28(d,J=7.8Hz,2H),4.95(t,J=6.6Hz,1H),4.20(d,J=6.0Hz,2H),2.43(s,3H); 13 C NMR (150MHz, CDCl3): δ143.9, 140.6, 136.9, 130.2 (q, J = 31.5Hz), 129.9, 128.2, 127.3, 125.7 (q, J = 1.8Hz), 124.1 (q, J = 270.0Hz), 46.8, 21.6.

[0033] Example 4: N-4-Fluorobenzyl-4-methylbenzenesulfonamide

[0034]

[0035] 4-Methylbenzenesulfonamide (205.5 mg, 1.2 mmol), 1,2-dichloroethane (2 mL), 4-fluorobenzyl alcohol (126.1 mg, 1.0 mmol), potassium carbonate (276.4 mg, 2.0 mmol), triethylsilane (116.3 mg, 1.0 mmol), and elemental iodine (253.8 mg, 1.0 mmol) were sequentially added to a 25 mL round-bottom flask. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and quenched with 10 mL of 0.5 mol / L sodium thiosulfate solution. The mixture was then extracted once with 30 mL of ethyl acetate. The organic phase was dried over sodium sulfate, and the solvent was removed by rotary evaporation. The target product was then obtained by column chromatography in 55% yield.

[0036] 1 H NMR (600MHz, CDCl3): δ7.74(d,J=8.4Hz,2H),7.30(d,J=8.4Hz,2H),7.20-7.13( m,2H),7.01-6.89(m,2H),4.93-4.78(m,1H),4.08(d,J=6.0Hz,2H),2.43(s,3H); 13 CNMR (150MHz, CDCl3): δ162.4 (d, J = 246.0Hz), 143.7, 136.9, 132.2 (d, J = 4.5Hz), 129.9, 129.7 (d, J = 9.0Hz), 127.2, 115.6 (d, J = 21.0Hz), 46.6, 21.7.

[0037] Example 5: N-4-chlorobenzyl-4-methylbenzenesulfonamide

[0038]

[0039] 4-Methylbenzenesulfonamide (205.5 mg, 1.2 mmol), 1,2-dichloroethane (2 mL), 4-chlorobenzyl alcohol (142.6 mg, 1.0 mmol), potassium carbonate (276.4 mg, 2.0 mmol), triethylsilane (116.3 mg, 1.0 mmol), and elemental iodine (253.8 mg, 1.0 mmol) were sequentially added to a 25 mL round-bottom flask. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and quenched with 10 mL of 0.5 mol / L sodium thiosulfate solution. The mixture was then extracted once with 30 mL of ethyl acetate. The organic phase was dried over sodium sulfate, and the solvent was removed by rotary evaporation. The target product was then obtained by column chromatography in 56% yield.

[0040] 1H NMR (600MHz, CDCl3): δ7.72(d,J=8.4Hz,2H),7.29(d,J=8.4Hz,2H),7.25-7.20( m,2H),7.15-7.11(m,2H),4.94-4.87(m,1H),4.08(d,J=6.0Hz,2H),2.44(s,3H); 13 CNMR (150MHz, CDCl3): δ143.8,136.9,135.0,133.8,129.9,129.3,128.9,127.3,46.7,21.7.

[0041] Example 6: N-4-Bromobenzyl-4-methylbenzenesulfonamide

[0042]

[0043] 4-Methylbenzenesulfonamide (205.5 mg, 1.2 mmol), 1,2-dichloroethane (2 mL), 4-bromobenzyl alcohol (187.0 mg, 1.0 mmol), potassium carbonate (276.4 mg, 2.0 mmol), triethylsilane (116.3 mg, 1.0 mmol), and elemental iodine (253.8 mg, 1.0 mmol) were sequentially added to a 25 mL round-bottom flask. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and quenched with 10 mL of 0.5 mol / L sodium thiosulfate solution. The mixture was then extracted once with 30 mL of ethyl acetate. The organic phase was dried over sodium sulfate, and the solvent was removed by rotary evaporation. The target product was then obtained by column chromatography in 58% yield.

[0044] 1 H NMR (600MHz, CDCl3): δ7.72(d,J=8.4Hz,2H),7.38(d,J=8.4Hz,2H),7.30(d,J=8.4Hz, 2H),7.07(d,J=8.4Hz,2H),4.84(t,J=6.0Hz,1H),4.07(d,J=6.0Hz,2H),2.44(s,3H); 13 C NMR (150MHz, CDCl3): δ143.8,136.9,135.5,131.8,129.9,129.7,127.2,121.9,46.7,21.7.

[0045] Example 7 N-Benzylbenzenesulfonamide

[0046]

[0047] Benzenesulfonamide (188.6 mg, 1.2 mmol), 1,2-dichloroethane (2 mL), benzyl alcohol (108.1 mg, 1.0 mmol), potassium carbonate (276.4 mg, 2.0 mmol), triethylsilane (116.3 mg, 1.0 mmol), and elemental iodine (253.8 mg, 1.0 mmol) were sequentially added to a 25 mL round-bottom flask. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and quenched with 10 mL of 0.5 mol / L sodium thiosulfate solution. The mixture was then extracted once with 30 mL of ethyl acetate. The organic phase was dried over sodium sulfate, and the solvent was removed by rotary evaporation. The target product was then obtained by column chromatography in 62% yield.

[0048] 1 H NMR (600MHz, CDCl3): δ7.89-7.85(m,2H),7.60-7.57(m,1H),7.53-7.49(m,2H), 7.29-7.23(m,3H),7.21-7.15(m,2H),4.95-4.76(m,1H),4.15(d,J=6.0Hz,2H); 13 C NMR (150MHz, CDCl3): δ140.0,136.3,132.8,129.3,128.8,128.1,128.0,127.2,47.4.

[0049] Example 8: N-Benzyl-4-methoxybenzenesulfonamide

[0050]

[0051] 4-Methoxybenzenesulfonamide (224.7 mg, 1.2 mmol), 1,2-dichloroethane (2 mL), benzyl alcohol (108.1 mg, 1.0 mmol), potassium carbonate (276.4 mg, 2.0 mmol), triethylsilane (116.3 mg, 1.0 mmol), and elemental iodine (253.8 mg, 1.0 mmol) were sequentially added to a 25 mL round-bottom flask. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and quenched with 10 mL of 0.5 mol / L sodium thiosulfate solution. The mixture was then extracted once with 30 mL of ethyl acetate. The organic phase was dried over sodium sulfate, and the solvent was removed by rotary evaporation. The target product was then obtained by column chromatography in 62% yield.

[0052] 1H NMR (600MHz, CDCl3): δ7.81 (d, J = 9.0Hz, 2H), 7.30-7.23 (m, 3H), 7.21-7.17 (m ,2H),6.97(d,J=9.0Hz,2H),4.72(s,1H),4.11(d,J=5.4Hz,2H),3.88(s,3H); 13 C NMR (150MHz, CDCl3): δ163.1,136.4,131.5,129.5,128.8,128.1,128.0,114.4,55.8,47.4.

[0053] Example 9: N-Benzyl-4-Fluorobenzenesulfonamide

[0054]

[0055] 4-Fluorobenzenesulfonamide (210.2 mg, 1.2 mmol), 1,2-dichloroethane (2 mL), benzyl alcohol (108.1 mg, 1.0 mmol), potassium carbonate (276.4 mg, 2.0 mmol), triethylsilane (116.3 mg, 1.0 mmol), and elemental iodine (253.8 mg, 1.0 mmol) were sequentially added to a 25 mL round-bottom flask. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and quenched with 10 mL of 0.5 mol / L sodium thiosulfate solution. The mixture was then extracted once with 30 mL of ethyl acetate. The organic phase was dried over sodium sulfate, and the solvent was removed by rotary evaporation. The target product was then obtained by column chromatography in 55% yield.

[0056] 1 H NMR (600MHz, CDCl3): δ7.88-7.83(m,2H),7.30-7.23(m,3H),7.20-7.13(m,4H),4.89(t,J=6.0Hz,1H),4.15(d,J=6.0Hz,2H); 13 C NMR (150MHz, CDCl3): δ165.2 (d, J = 253.5Hz), 136.2 (d, J = 3.0Hz), 136.1, 130.0 (d, J = 9.0Hz), 128.9, 128.2, 128.0, 116.4 (d, J = 22.5Hz), 47.4.

[0057] Example 10N-Benzyl-4-chlorobenzenesulfonamide

[0058]

[0059] 4-Chlorobenzenesulfonamide (230.0 mg, 1.2 mmol), 1,2-dichloroethane (2 mL), benzyl alcohol (108.1 mg, 1.0 mmol), potassium carbonate (276.4 mg, 2.0 mmol), triethylsilane (116.3 mg, 1.0 mmol), and elemental iodine (253.8 mg, 1.0 mmol) were sequentially added to a 25 mL round-bottom flask. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and quenched with 10 mL of 0.5 mol / L sodium thiosulfate solution. The mixture was then extracted once with 30 mL of ethyl acetate. The organic phase was dried over sodium sulfate, and the solvent was removed by rotary evaporation. The target product was then obtained by column chromatography in 73% yield.

[0060] 1 H NMR (600MHz, CDCl3): δ7.78 (d, J = 8.4Hz, 2H), 7.47 (d, J = 8.4Hz, 2H), 7.30-7.25 (m, 3H), 7.21-7.15 (m, 2H), 4.82 (t, J = 6.0Hz, 1H), 4.15 (d, J = 6.0Hz, 2H); 13 C NMR (150MHz, CDCl3): δ139.4,138.6,136.0,129.5,128.9,128.7,128.2,128.0,47.5.

[0061] Example 11: N-Benzyl-4-bromobenzenesulfonamide

[0062]

[0063] 4-Bromobenzenesulfonamide (283.3 mg, 1.2 mmol), 1,2-dichloroethane (2 mL), benzyl alcohol (108.1 mg, 1.0 mmol), potassium carbonate (276.4 mg, 2.0 mmol), triethylsilane (116.3 mg, 1.0 mmol), and elemental iodine (253.8 mg, 1.0 mmol) were sequentially added to a 25 mL round-bottom flask. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and quenched with 10 mL of 0.5 mol / L sodium thiosulfate solution. The mixture was then extracted once with 30 mL of ethyl acetate. The organic phase was dried over sodium sulfate, and the solvent was removed by rotary evaporation. The target product was then obtained by column chromatography in 61% yield.

[0064] 1H NMR (600MHz, CDCl3): δ7.71 (d, J = 9.0Hz, 2H), 7.63 (d, J = 9.0Hz, 2H), 7.31-7.26 (m, 3H), 7.20-7.16 (m, 2H), 4.75 (t, J = 6.0Hz, 1H), 4.16 (d, J = 6.0Hz, 2H); 13 C NMR (150MHz, CDCl3): δ139.2,136.0,132.5,128.9,128.8,128.2,128.0,127.8,47.4.

[0065] The specification and drawings of this invention are intended to be illustrative rather than restrictive. Based on this invention, those skilled in the art can make substitutions and modifications to some of the technical features without creative effort, and all such modifications are within the scope of protection of this invention.

Claims

1. A method for synthesizing N-alkylsulfonamides, characterized in that, Includes the following steps: S1. In a reaction vessel, sulfonamide, solvent, alcohol, base, organosilane and iodine are added in sequence to form a reaction mixture; The molar ratio of the sulfonamide to the alcohol is: The molar ratio of iodine to alcohol is: ; The molar ratio of organosilanes to alcohols is The molar ratio of base to alcohol is: ; The alkali is one of potassium carbonate, sodium carbonate, cesium carbonate, and sodium bicarbonate; the organohydrosilane is one of triethylsilane, polymethylhydrosiloxane, and 1,1,3,3-tetramethyldisiloxane. S2. After reacting the reaction mixture in S1 under reflux for 2 hours, it was cooled to room temperature and quenched by adding sodium thiosulfate solution. Then it was extracted with ethyl acetate, the organic phase was dried with sodium sulfate, the solvent was removed by rotary evaporation, and finally the target compound N-alkylsulfonamide was obtained by column chromatography. The N-alkylsulfonamide is as shown in Formula I; the alcohol is as shown in Formula II; the sulfonamide is as shown in Formula III; ； Wherein, R1 is selected from phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl or 4-bromophenyl; R2 is selected from 4-methylphenyl, phenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl or 4-bromophenyl.

2. The synthesis method according to claim 1, characterized in that, The solvent is one of ethyl acetate, acetonitrile, N,N-dimethylformamide, toluene, 1,4-dioxane, and 1,2-dichloroethane.

3. The synthesis method according to claim 1, characterized in that, The concentration of the sodium thiosulfate solution is 0.5 mol / L.

Images