A method for preparing N-arylsulfonamide derivatives

Abstract

The invention belongs to the technical field of organic synthetic chemistry and discloses a N A green and efficient preparation method for arylsulfonamide derivatives. The method uses sulfinic acid as the sulfonyl source and N A series of core skeletons of sulfonamide drugs were prepared by using copper-catalyzed dehydration N-S bond coupling reaction with arylhydroxylamine as the arylamine source and ethanol as the green reaction solvent. N The reaction only produces water as a byproduct, which is green and environmentally friendly. It not only solves the problems of high toxicity and stoichiometric waste acid production faced by the traditional preparation of sulfonamide drugs, but also efficiently prepares a series of potential pharmaceutical and physiologically active N ‑Arylsulfonamide compounds.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthetic chemistry and relates to a green and efficient preparation method of N-aryl sulfonamide derivatives. Background Art

[0002] N-arylsulfonamides, as the core skeleton of sulfonamide drugs, are widely present in drugs, agrochemicals and other functional molecules due to their rich biological and pharmaceutical activities as well as chemical and metabolic stability ((a) Drews, J. Science 2000, 287, 1960; (b) Devendar, P.; Yang, GF Top. Curr. Chem. 2017, 375, 82. (c) Lucking, U. Org. Chem. Front. 2019, 6, 1319; (d) Casini, A.; Scozzafava, A.; Mastrolorenzo, A.; Supuran, CT Curr. Cancer Drug Targets 2002,2,55;(e)Petkowski,JJ;Bains,W.;Seager,SJNat.Prod.2018,81,2;(f)Rakesh,KP;Wang,SM;Leng,J.;Ravindar,L.;Asiri,AM;Marwani,HM;Qin,H.-L.Anti-Cancer Agents Med. Chem. 2018, 18, 488; (g) Das, P.; Delost, MD; Qureshi, MH; Smith, DT; Njardarson, JTJMed. Chem. 2019, 62, 4265; (h) Scott, KA; Njardarson, JT Top. Curr. Chem. 2018, 376, 5.). In addition, since the synthesis of the first sulfonamide antifungal drug (Prontosil) in 1932, many N-arylsulfonamide drugs have been developed and applied to the treatment of various diseases (such as cancer, inflammation, stroke, hypoglycemia, etc.) ((a) Supuran, CT; Casini, A.; Scozzafava, A. Med. Res. Rev. 2003, 23, 535; (b) Apayd1n, S.; M. Bioorg. Med. Chem. Lett. 2019, 29, 2042.). Therefore, the exploration and preparation of this type of compound has aroused widespread interest among chemists and pharmacists. At present, the methods for preparing N-arylsulfonamide derivatives mainly include the following four aspects: (1) Sulfonyl halide and amine nucleophilic substitution reaction. The classic sulfonamide drug molecule construction is prepared by sulfonyl chloride and amine by removing a molecule of hydrogen halide under alkaline conditions. In recent years, Ball et al. used sulfonyl fluoride and amine as reaction raw materials and achieved efficient preparation of sulfonamide drug molecules and precursors by using Ca(NTf2)2 / DABCO-mediated method (Org. Lett. 2020, 22, 4389; Org. Lett. 2018, 20, 3943.). Although the above transformation has the advantages of high yield and fast reaction rate, it requires the use of toxic sulfonyl chloride or sulfonyl fluoride and the waste acid (HX, X=F, Cl) produced in the reaction pollutes the environment and causes serious waste of resources. (2) Coupling reaction of sulfonamides with halogenated aromatic hydrocarbons. MacMillan et al. prepared a series of important biological / pharmaceutical active structural skeletons of N-aryl and N-heteroaryl sulfonamides by coupling benzenesulfonamide with the CN bond of bromoaryl hydrocarbons under Ir / Ni co-catalysis (Angew. Chem. Int. Ed. 2018, 57, 3488; Synlett 2014, 25, 505.). Although the reaction conditions are mild and the preparation range is wide, the catalyst is expensive and the cost is high. The byproduct hydrogen bromide pollutes the environment and corrodes the equipment, which seriously limits the application of this method. (3) Chan-Lam coupling reaction of (hetero)aromatic boronic acid and sulfonyl azide. Kim et al. used relatively cheap CuCl as a catalyst. The reaction did not require the addition of base and ligand, and achieved the synthesis of N-aryl sulfonamide target molecules at room temperature. However, the reaction uses unstable and explosive sulfonyl azide as the amine source and the reaction atom economy is poor, resulting in a waste of resources, which greatly limits the large-scale application of the reaction (Org. Lett. 2014, 16, 338.). (4) Coupling of sulfinates with aromatic amines. In 2015, Song et al. achieved the synthesis of sulfonamide drug skeletons under non-metallic conditions without additional bases, ligands and additives. The reaction has the advantages of excellent yield, mild conditions, and good functional group tolerance. However, the reaction requires the use of a double amount of toxic and volatile iodine as an oxidant, which is bound to cause unnecessary environmental pollution. Subsequently, Ma et al. reported the rapid synthesis of functionalized aromatic sulfonamide derivatives by dehydrogenative cross-coupling (CDC) of sodium sulfinate and aromatic amines using CuBr2 as catalyst, potassium persulfate as oxidant, and Na4P2O7 as base (Green Chem. 2015, 17, 1395; J. Org. Chem. 2022, 87, 8802.).Although this method is simple to operate and has excellent yield, the use of explosive potassium persulfate and corrosive acetic acid solvents makes the reaction unsuitable for industrial application. In summary, it is urgent to prepare N-arylsulfonamide derivatives through green, atom- and step-economical methods, reduce production costs and avoid environmental pollution.

[0003] Arylhydroxylamine (ArNHOH) has been well known and reported, but its research mainly utilizes its reducibility and nucleophilicity, and its electrophilicity is rarely reported. Therefore, taking advantage of the electrophilicity of N-arylhydroxylamine, dehydrating it with sulfinic acid under copper-catalyzed redox neutral conditions to prepare N-arylsulfonamide is an effective way to achieve its green, environmentally friendly and efficient preparation, which has important theoretical research significance and application value. Summary of the invention

[0004] The purpose of the present invention is to provide a simple, green and efficient method for preparing N-aryl sulfonamide derivatives.

[0005] To achieve the purpose of the present invention, the present invention uses cheap and easily available sulfinic acid as a sulfonyl source, easily prepared arylhydroxylamine as an arylamine source, and ethanol as a green reaction solvent, and is achieved through a copper-catalyzed dehydration NS bond coupling reaction.

[0006] The specific technical solutions are as follows:

[0007] In a dry reactor, sulfinic acid compound 1, hydroxylamine compound 2, CuI and 4,4'-di-tert-butyl-2,2'-bipyridine are added in sequence, and then ethanol solution is added, nitrogen is filled, the mouth of the reactor is sealed, and heating and stirring are performed for reaction. After the reaction is completed, the reaction system is cooled to room temperature and distilled water is added thereto; the organic phase is extracted, combined, dried and distilled under reduced pressure to remove the organic solvent; and the target product is obtained after purification.

[0008] The reaction equation is as follows:

[0009]

[0010] R 1 represents phenyl, substituted phenyl, naphthyl, thienyl, pyridyl, cyclopropyl, C1-3 alkyl; R 2 , R 3 R represents hydrogen, phenyl, phenyl mono- or di-substituted by C1-4 alkyl, hydroxymethyl, phenylthio, acetyl, methoxycarbonyl, trifluoromethyl, C1-4 alkyl substituted by phenyl; and 2 , R 3 Not at the same time hydrogen;

[0011] R 1 The substituted phenyl group is selected from phenyl groups substituted by C1-4 alkyl, halogen, trifluoromethyl and nitro.

[0012] The sulfinic acid compound 1 is preferably selected from benzenesulfinic acid, 4-methylbenzenesulfinic acid, 4-tert-butylbenzenesulfinic acid, 4-fluorobenzenesulfinic acid, 4-trifluoromethylbenzenesulfinic acid, 4-nitrobenzenesulfinic acid, 4-chlorobenzenesulfinic acid, 4-bromobenzenesulfinic acid, 2-naphthalenesulfinic acid, 2-thiophenesulfinic acid, 3-pyridinesulfinic acid, cyclopropylsulfinic acid and ethylsulfinic acid.

[0013] The hydroxylamine compound 2 is selected from N-phenylhydroxylamine, N-(4-methylphenyl)hydroxylamine, N-(4-ethylphenyl)hydroxylamine, N-(4-hydroxymethylphenyl)hydroxylamine, N-(4-phenylthiophenyl)hydroxylamine, N-(4-acetylphenyl)hydroxylamine, N-(4-methoxycarbonylphenyl)hydroxylamine, N-(4-trifluoromethylphenyl)hydroxylamine, N-(3-methylphenyl)hydroxylamine, N-(2-methylphenyl)hydroxylamine, N-(2,4-dimethylphenyl)hydroxylamine, N-(5-bromo-2-methylphenyl)hydroxylamine, and N-(phenylethyl)hydroxylamine.

[0014] The molar ratio of the sulfinic acid compound 1 to the hydroxylamine compound 2 is 1:1.5-2.5.

[0015] The molar ratio of the ligand 4,4'-di-tert-butyl-2,2'-bipyridine to the sulfinic acid compound 1 is 10-20:100;

[0016] The molar ratio of the catalyst CuI to the sulfinic acid compound 1 is 10-20:100.

[0017] The innovation and advantage of the present invention are: the reaction does not require an external oxidant, is green and environmentally friendly (the byproduct is water, and the solvent is ethanol), is simple to operate, and is highly efficient. The reaction yield is more than 65%, and the highest is more than 85%. The raw materials used are cheap and easy to obtain, the operation is simple, the reaction conditions are mild, and the method has good functional group compatibility. It not only solves the problems of high toxicity and generation of stoichiometric waste acid faced by the traditional preparation of sulfonamide drugs, but also efficiently prepares a series of N-aryl sulfonamide compounds with potential pharmaceutical and physiological activities. Therefore, the reaction has important theoretical significance and potential application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 For N-arylsulfonamide 3a 1 H NMR and 13 C NMR spectrum;

[0019] Figure 2 For N-arylsulfonamide 3h 1 H NMR and 13 C NMR spectrum;

[0020] Figure 3 For N-arylsulfonamide 3j1 H NMR and 13 C NMR spectrum;

[0021] Figure 4 For N-arylsulfonamide 4d 1 H NMR and 13 C NMR spectrum;

[0022] Figure 5 For N-arylsulfonamide 4e 1 H NMR and 13 C NMR spectrum;

[0023] Figure 6 For N-arylsulfonamide 4g 1 H NMR and 13 C NMR spectrum. DETAILED DESCRIPTION

[0024] In order to better illustrate the present invention, the following embodiments are given:

[0025] Embodiment 1:

[0026]

[0027] A magnetic particle was added to a 25 mL dry reaction tube, followed by benzenesulfinic acid 1a (0.2 mmol), N-phenylhydroxylamine 2a (0.5 mmol), CuI (0.04 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.04 mmol). Then, 2 mL of ethanol solution was added, liquid nitrogen was frozen and replaced with nitrogen 3 times, the tube mouth was sealed with a stopcock, and stirred at 80 ° C for 12 hours. After TLC detection, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, it was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the organic solvent. Finally, the white solid product 3a was purified by silica gel column chromatography with a yield of 82%.

[0028] 3a Spectrum data analysis:

[0029] White solid; (38mg, 82%); mp:104–108℃; R f =0.23(hexane / ethyl acetate5:1); 1 H NMR (400MHz, CDCl3): δ7.82–7.80(m,2H),7.51(t,J=7.6Hz,1H),7.42(t,J=7.6Hz,2H),7.34(brs,1H),7.24–7.20(m,2H),7.09(t,J=7.2Hz,2H);13 C NMR (100MHz, CDCl3): δ138.9,136.4,133.0,129.3,129.0,127.2,125.3,121.6; ESI-HRMS (ESI, m / z): Calcd for C 12 H 12 NO2S,[M+H] + :234.0583,found 234.0580.

[0030] Embodiment 2:

[0031]

[0032] A magnetic particle was added to a 25 mL dry reaction tube, followed by 4-bromobenzenesulfinic acid 1h (0.2 mmol), N-phenylhydroxylamine 2a (0.5 mmol), CuI (0.04 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.04 mmol). Then, 2 mL of ethanol solution was added, liquid nitrogen was frozen and replaced with nitrogen 3 times, the tube mouth was sealed with a stopcock, and stirred at 80 ° C for 12 hours. After TLC detection, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, it was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the organic solvent. Finally, the yellow solid product 3h was purified by silica gel column chromatography with a yield of 72%.

[0033] 3h spectrum data analysis:

[0034] Yellow solid; (45mg, 72%); mp:110–112℃; R f =0.38(hexane / ethyl acetate5:1); 1 H NMR (400MHz, CDCl3): δ7.62(d,J=8.8Hz,2H),7.56(d,J=8.4Hz,2H),7.26(t,J=7.6Hz,2H),7.14(t,J=7.6Hz,1H),7.07(d,J=7.6Hz,2H),6.91(s,1H); 13 C NMR (100MHz, CDCl3): δ137.9,135.9,132.3,129.5,128.7,128.1,125.9,122.0; ESI-HRMS (ESI, m / z): Calcd for C 12 H 11 BrNO2S,[M+H] +:311.9688, found 311.9693.

[0035] Embodiment 3:

[0036]

[0037] A magnetic particle was added to a 25 mL dry reaction tube, followed by the addition of 2-thiophenesulfinic acid 1j (0.2 mmol), N-phenylhydroxylamine 2a (0.5 mmol), CuI (0.04 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.04 mmol). Then, 2 mL of ethanol solution was added, liquid nitrogen was frozen and replaced with nitrogen 3 times, the tube mouth was sealed with a stopcock, and stirred at 80 ° C for 12 hours. After TLC detection, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, the mixture was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation. Finally, the yellow solid product 3j was purified by silica gel column chromatography with a yield of 65%.

[0038] 3j spectrum data analysis:

[0039] Yellow solid; (31mg, 65%); mp:89–92℃; R f =0.41(hexane / ethyl acetate 3:1); 1 H NMR (400MHz, CDCl3): δ7.53 (dd, J=1.2Hz, J=5.2Hz, 1H), 7.50 (dd, J=1.2Hz, J=4.0Hz, 1H ),7.30–7.26(m,2H),7.18–7.13(m,3H),7.00(dd,J=4.0Hz,J=4.8Hz,1H),6.89(s,1H); 13 C NMR (100MHz, CDCl3): δ139.3,136.1,132.9,132.4,129.4,127.3,125.8,121.9; ESI-HRMS (ESI, m / z): Calcd for C 10 H 10 NO2S2,[M+H] + :240.0147,found 240.0149.

[0040] Embodiment 4:

[0041]

[0042] A magnetic particle was added to a 25 mL dry reaction tube, followed by benzenesulfinic acid 1a (0.2 mmol), N-(4-hydroxymethylphenyl)hydroxylamine 2d (0.5 mmol), CuI (0.04 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.04 mmol). Then, 2 mL of ethanol solution was added, liquid nitrogen was frozen and replaced with nitrogen 3 times, the tube mouth was sealed with a stopcock, and stirred at 80 ° C for 12 hours. After TLC detection, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, it was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the organic solvent. Finally, the yellow oily product 4d was purified by silica gel column chromatography with a yield of 77%.

[0043] 4D spectrum data analysis:

[0044] Yellow oil;(41mg,77%);R f =0.25(hexane / ethyl acetate 3:1); 1 H NMR (400MHz, CDCl3): δ7.77(d,J=7.6Hz,2H),7.51(t,J=7.6Hz,1H),7.41(t,J=7. 6Hz,2H),7.32(s,1H),7.19(d,J=8.0Hz,2H),7.03(d,J=8.0Hz,2H),4.58(s,2H); 13 C NMR (100MHz, CDCl3): δ138.9,137.9,135.7,133.0,129.0,128.0,127.2,121.7,64.6; ESI-HRMS (ESI, m / z): Calcd for C 13 H 14 NO3S,[M+H] + :264.0689,found 264.0686.

[0045] Embodiment 5:

[0046]

[0047] A magnetic particle was added to a 25 mL dry reaction tube, followed by benzenesulfinic acid 1a (0.2 mmol), N-(4-phenylthiophenyl)hydroxylamine 2e (0.5 mmol), CuI (0.04 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.04 mmol). Then, 2 mL of ethanol solution was added, liquid nitrogen was frozen and replaced with nitrogen 3 times, the tube mouth was sealed with a stopcock, and stirred at 80 ° C for 12 hours. After TLC detection, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, it was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the organic solvent. Finally, the gray solid product 4e was purified by silica gel column chromatography with a yield of 85%.

[0048] 4e spectrum data analysis:

[0049] Gray solid; (58mg, 85%); mp:89–93℃; R f =0.46(hexane / ethyl acetate 3:1); 1 H NMR (400MHz, CDCl3): δ7.78(d,J=7.2Hz,2H),7.56(t,J=7.6Hz,1H),7.46(t,J=7.6Hz,2H),7.30–7.20(m,7H),7.00(d,J=8.4Hz,2H),6.76(s,1H); 13 C NMR (100MHz, CDCl3): δ138.9,135.5,135.4,133.2,132.6,132.2,130.8,129.2,129.1,127.2,127.1,122.3; ESI-HRMS (ESI, m / z): Calcd for C 18 H 16 NO2S2,[M+H] + :342.0617, found 342.0613.

[0050] Embodiment 6:

[0051]

[0052] A magnetic particle was added to a 25 mL dry reaction tube, followed by benzenesulfinic acid 1a (0.2 mmol), N-(4-methoxycarbonylphenyl)hydroxylamine 2g (0.5 mmol), CuI (0.04 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.04 mmol). Then, 2 mL of ethanol solution was added, liquid nitrogen was frozen and replaced with nitrogen 3 times, the tube mouth was sealed with a stopcock, and stirred at 80 ° C for 12 hours. After TLC detection, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, the mixture was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was removed by reduced pressure distillation. Finally, 4 g of a white solid product was obtained by silica gel column chromatography with a yield of 79%.

[0053] 4g spectrum data analysis:

[0054] White solid; (46mg, 79%); mp:145–150℃; R f =0.40(hexane / ethyl acetate3:1); 1 H NMR (400MHz, CDCl3): δ7.92 (d, J = 8.4Hz, 2H), 7.84 (d, J = 7.6Hz, 2H), 7.56 (t, J = 7. 6Hz,1H),7.46(t,J=7.6Hz,2H),7.14(d,J=8.8Hz,2H),7.04(s,1H),3.87(s,3H); 13 CNMR(100MHz, CDCl3): δ166.3,140.7,138.8,133.4,131.1,129.2,127.2,126.4,119.2,52.1; ESI-HRMS(ESI,m / z): Calcd for C 14 H 14 NO4S,[M+H] + :292.0638,found 292.0640.

Claims

1. A method for preparing a compound of general formula 3 N - a method for producing arylsulfonamide derivatives, characterized in that This is accomplished by the following steps: Add sulfinic acid compound 1, hydroxylamine compound 2, CuI and 4,4'-di-tert-butyl-2,2'-bipyridine to a dry reactor in sequence, then add ethanol solution, introduce nitrogen, seal the reactor port, and heat to react; after the reaction is completed, cool the reaction system to room temperature and add distilled water; The organic phases were extracted, combined, dried and distilled under reduced pressure to remove the organic solvent, and purified to obtain the target product 3; R 1 represents phenyl, substituted phenyl, naphthyl, thienyl, pyridyl, cyclopropyl or C1-3 alkyl; R 2 , R 3 represents hydrogen, phenyl, phenyl mono- or di-substituted by C1-4 alkyl, hydroxymethyl, phenylthio, acetyl, methoxycarbonyl, trifluoromethyl, C1-4 alkyl substituted by phenyl; and R 2 , R 3 Not at the same time hydrogen; R 1 wherein the substituted phenyl group is selected from phenyl group monosubstituted by C1-4 alkyl, halogen, trifluoromethyl or nitro.

2. The method according to claim 1 N -A method for preparing an arylsulfonamide derivative, characterized in that: The sulfinic acid compound 1 is selected from benzenesulfinic acid, 4-methylbenzenesulfinic acid, 4-tert-butylbenzenesulfinic acid, 4-fluorobenzenesulfinic acid, 4-trifluoromethylbenzenesulfinic acid, 4-nitrobenzenesulfinic acid, 4-chlorobenzenesulfinic acid, 4-bromobenzenesulfinic acid, 2-naphthalenesulfinic acid, 2-thiophenesulfinic acid, 3-pyridinesulfinic acid, cyclopropylsulfinic acid, ethylsulfinic acid; The hydroxylamine compound 2 is selected from N -phenylhydroxylamine, N -(4-Methylphenyl)hydroxylamine, N -(4-ethylphenyl)hydroxylamine, N -(4-Hydroxymethylphenyl)hydroxylamine, N -(4-phenylthiophenyl)hydroxylamine, N -(4-Acetylphenyl)hydroxylamine, N -(4-methoxycarbonylphenyl)hydroxylamine, N -(4-trifluoromethylphenyl)hydroxylamine, N -(3-methylphenyl)hydroxylamine, N -(2-methylphenyl)hydroxylamine, N -(2,4-Dimethylphenyl)hydroxylamine, N -(Phenylethyl)hydroxylamine.

3. The method according to claim 1 or 2 N -A method for preparing an arylsulfonamide derivative, characterized in that: The sulfinate The molar ratio of compound 1 to hydroxylamine compound 2 is 1:1.5-2.

5.

4. The method according to claim 1 or 2 N -A method for preparing an arylsulfonamide derivative, characterized in that: The 4,4'- The molar ratio of di-tert-butyl-2,2'-bipyridine to the sulfinic acid compound 1 is 10-20:100; the CuI and the sulfinic acid compound 1 The molar ratio of compound 1 is 10-20:100.

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