A method for preparing aryl primary sulfonamides

Abstract

The application discloses a preparation method of aryl primary sulfonamide compounds, which comprises the following steps: (1) mixing an iodoarene compound, a sulfur dioxide source, a palladium catalyst, a phase transfer catalyst, a base and an organic solvent, and performing a sulfonation reaction to obtain an intermediate reaction solution; and (2) adding an ammonia source into the intermediate reaction solution obtained in the step (1), and performing post-treatment after reaction to obtain the aryl primary sulfonamide compounds. The preparation method has the advantages of wide substrate source, simple reaction operation and high yield.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing aryl primary sulfonamide compounds. Background Technology

[0002] Sulfonamides are a class of synthetic drugs containing sulfonamide functional groups. They are among the oldest synthetic antibacterial drugs, and due to their low cost, low toxicity, and good activity against bacterial infections, they are still widely used today. Compared to carboxyl compounds, sulfonamides have better hydrophilicity and stability, possessing advantages such as high stability, good physicochemical properties, and ease of use. They have a significant advantage among a wide range of drugs, playing a crucial role in the history of drug development and continuing to be widely used in the pharmaceutical field today. Many well-known sulfonamide molecules are clinically used as drugs, such as tyrosine kinase inhibitors, the anti-inflammatory drug celecoxib, the antipsychotic drug sulpiride, the anti-inflammatory drug vardecoxib, and the carbonic anhydrase inhibitor bulazolamide. In 2018, among the best-selling small molecule drugs, 16 out of 200 (8%) active pharmaceutical ingredients (APIs) contained sulfonamide groups.

[0003] Primary sulfonamides have played a crucial role in the development of modern pharmacology, but their synthetic methods are very limited. The classic synthesis of primary sulfonamides involves the reaction of an activated sulfonyl electrophile (usually a sulfonyl chloride) with ammonia or an ammonia derivative, followed by a deprotection step. This method is suitable for readily available and inexpensive sulfonyl chlorides. [1] However, its drawbacks are also obvious. Sulfonyl chlorides are sensitive to moisture, and because their synthesis requires strong acidity and oxidizing chlorosulfonation conditions, their tolerance to functional groups in the molecule is significantly limited. Furthermore, the handling of gaseous ammonia is challenging, and using solid or liquid ammonia substitutes inevitably leads to reduced atomization and increased costs. Therefore, efficiently introducing sulfur dioxide into the organic framework is a solution to overcome this obstacle, and it has attracted widespread attention from chemists and become a research hotspot due to its atom economy, step economy, oxidation economy, and the recovery of harmful sulfur dioxide. In particular, the synthesis of primary sulfonamides has received considerable attention in recent years.

[0004] The synthesis of primary sulfonamides has seen widespread application not only in pesticides and materials science but also in organic synthesis, with significant breakthroughs. Furthermore, the development of transition metal catalysis strategies has enabled the participation of an increasing number of substrates and the discovery of more substrate activation methods. However, some challenging issues remain: for example, the substrate range is still limited, with aryl sources typically limited to halogenated aromatics or arylboronic acids, and aryl radicals mainly derived from aryl diazonium salts; additionally, the currently developed one-step reaction methods require stringent conditions, and many substrates are incompatible with high-temperature and high-pressure reaction conditions. Therefore, it is necessary to develop more efficient strategies to achieve the synthesis of diverse primary sulfonamide compounds. Summary of the Invention

[0005] This invention provides a method for preparing aryl primary sulfonamide compounds. The substrates for this preparation method are widely available, the reaction operation is simple, and the yield is high.

[0006] A method for preparing an aryl primary sulfonamide compound includes the following steps:

[0007] (1) Mix iodoaromatic compounds, sulfur dioxide source, palladium catalyst, phase transfer catalyst, base and organic solvent, and heat to carry out sulfonation reaction to obtain intermediate reaction solution;

[0008] (2) Add an ammonia source to the intermediate reaction solution obtained in step (1), and after the reaction is completed, perform post-treatment to obtain the aryl primary sulfonamide compound;

[0009] The structure of the iodinated aromatic compound is shown in formula (II):

[0010] Ar-I (II)

[0011] The structure of the aryl primary sulfonamide compounds is shown in formula (I):

[0012]

[0013] In formulas (I) to (II), Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0014] The substituents on the aryl or heteroaryl group are selected from at least one of phenyl, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, trifluoromethoxy, cyano, C1-C4 alkylacyl, and C1-C4 alkoxycarbonyl.

[0015] Preferably, Ar is a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted thiophene, a substituted or unsubstituted fluorenyl, a substituted or unsubstituted carbazolyl, or a substituted or unsubstituted dibenzothiophene.

[0016] The substituents on the phenyl, naphthyl, thiophene, fluorenyl, carbazole, and dibenzothiophene groups are selected from at least one of phenyl, methoxy, ethoxy, methyl, ethyl, isopropyl, F, Cl, Br, trifluoromethoxy, cyano, formyl, acetyl, methoxycarbonyl, and ethoxycarbonyl.

[0017] Preferably, in step (1), the sulfur dioxide source is thiourea dioxide, DABSO, K2S2O5, Na2S2O5, Na2S2O4, or sodium formaldehyde sulfoxylate dihydrate.

[0018] Preferably, in step (1), the palladium catalyst is PdCl2(dppf), Pd(PPh3)2(OAc)2, Pd(cod)Cl2, Pd(dppb)2Cl2, Pd(CH3CN)2Cl2, Pd(PPh3)4 or Pd(PPh3)2Cl2.

[0019] Preferably, in step (1), the phase transfer catalyst is at least one of tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium hexafluorophosphate, and 18-crown-6.

[0020] Preferably, in step (1), the alkali is at least one of sodium carbonate, potassium carbonate, and cesium carbonate.

[0021] Preferably, in step (1), at least one of the organic solvents DMF, dimethyl sulfoxide, N,N-dimethylaniline or N-methylpyrrolidone is used.

[0022] Preferably, in step (1), the reaction temperature is 85-95℃ and the reaction time is 0.5-5h.

[0023] Preferably, in step (2), the ammonia source is hydroxylamine sulfonic acid.

[0024] In step (2), the ammonia source is added directly to the intermediate reaction solution in solid form.

[0025] Preferably, the post-processing in step (2) is as follows:

[0026] After the reaction was completed, water was added to quench the reaction. The reaction solution was extracted with ethyl acetate, the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and then rotary evaporated. The product was obtained by column chromatography.

[0027] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0028] This invention utilizes inexpensive and readily available iodoaromatic compounds, sulfur dioxide source, and ammonia source to obtain aryl primary sulfonamide compounds in high yields under the action of a palladium catalyst. It has a broad substrate range, is simple to operate, and can be scaled up at the gram level. Detailed Implementation

[0029] Example 1

[0030] In a 25 mL reaction tube, 0.1120 g (0.4 mmol) of 4-iodobiphenyl, 0.0648 g (0.6 mmol) of thiourea dioxide, 0.0218 g (7.5 mol%) of PdCl2(dppf) ([1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, 0.0738 g (0.2 mmol) of cesium carbonate, and 4.0 mL of DMF were weighed. The reaction was heated and stirred at 90 °C for 1 h under nitrogen protection. After heating was stopped, the reaction was allowed to cool to room temperature, and 0.0678 g (0.6 mmol) of hydroxylamine sulfonic acid was added. The mixture was stirred at room temperature for 30 min. After the reaction was completed, 10 mL of water was added to quench the reaction. The reaction solution was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The product 1c was obtained by column chromatography with a yield of 63%.

[0031] The reaction formula is as follows:

[0032]

[0033] Examples 2-6

[0034] In Example 1, thiourea dioxide (sulfur dioxide source) was replaced with equimolar amounts of DABSO, potassium metabisulfite, sodium metabisulfite, sodium dithionite, and sodium formaldehyde sulfoxylate dihydrate, respectively, with other operations remaining the same. The results are shown in Table 1.

[0035] Table 1. Reaction results of Examples 2-6

[0036] Example Sulfur dioxide source Yield (%) 2 DABSO 39 3 <![CDATA[K2S2O5]]> 55 4 <![CDATA[Na2S2O5]]> 39 5 <![CDATA[Na2S2O4]]> 35 6 Sodium formaldehyde sulfoxylate dihydrate 58

[0037] Comparative Example 1

[0038] Replacing hydroxylamine sulfonic acid with an equimolar amount of 2,4,6-trimethylbenzenesulfonylhydrazine, while maintaining the same procedure in all other respects, showed that the reaction essentially did not occur.

[0039] Examples 7-12

[0040] In Example 1, the PdCl2(dppf) (catalyst) was replaced with equimolar amounts of Pd(PPh3)2(OAc)2, Pd(cod)Cl2, Pd(dppb)2Cl2, Pd(CH3CN)2Cl2, Pd(PPh3)4, and Pd(PPh3)2Cl2, respectively, while other operations were the same. The results are shown in Table 2.

[0041] Table 2

[0042]

[0043]

[0044] Examples 13-15

[0045] The DMF (solvent) in Example 1 was replaced with equal volumes of DMSO, DMA and NMP, respectively, while other operations remained the same. The results are shown in Table 3.

[0046] Table 3

[0047] Example solvent Yield (%) 13 DMSO 36 14 DMA 33 15 NMP 27

[0048] Examples 16-19

[0049] The TBAI (phase transfer catalyst) in Example 1 was replaced with equimolar amounts of tetrabutylammonium bromide (TBAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium hexafluorophosphate (TBAPF6), and 18-crown-6, respectively, with other operations remaining the same. The results are shown in Table 4.

[0050] Table 4

[0051] Example Phase transfer catalyst Yield (%) 16 TBAB 44 17 TBAF 48 18 <![CDATA[TBAPF6]]> 48 19 18-Crown-6 50

[0052] Examples 20-49

[0053] In a 25 mL reaction tube, weigh out iodoaromatic compound (0.4 mmol), thiourea dioxide (0.0648 g, 0.6 mmol), PdCl2(dppf) ([1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, 0.0218 g, 7.5 mol%), tetrabutylammonium iodide (0.0738 g, 0.2 mmol), cesium carbonate (0.2606 g, 0.8 mmol), and DMF (4.0 mL). The reaction mixture was heated and stirred at 90 °C for 1 h under nitrogen protection. After heating was stopped, the reaction mixture was allowed to cool to room temperature, and hydroxylamine sulfonic acid (0.0678 g, 0.6 mmol) was added. The mixture was stirred at room temperature for 30 min. After the reaction was complete, 10 mL of water was added to quench the reaction. The reaction solution was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and then rotary evaporated. Column chromatography was used to obtain aryl primary sulfonamide compounds 2a–3h, with the following reaction formula:

[0054]

[0055] The product structure and yield are as follows:

[0056]

[0057] Example 50 gram-level reaction

[0058] Weigh out 2.800 g (10 mmol) of 4-iodobiphenyl, 1.6200 g (15 mmol) of thiourea dioxide, 0.5480 g (7.5 mmol%) of PdCl2 (dppf), 1.8450 g (5 mmol) of tetrabutylammonium iodide, 6.5200 g (20 mmol) of cesium carbonate, and 100.0 mL of DMF at 350 mL. The reaction mixture was heated and stirred at 90 °C for 1 h under nitrogen protection. After heating was stopped, the mixture was allowed to cool to room temperature, and 1.6950 g (15 mmol) of hydroxylamine sulfonic acid was added. The mixture was stirred at room temperature for 30 min. After the reaction was complete, 200 mL of water was added to quench the reaction. The reaction solution was extracted with ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was filtered, rotary evaporated, and column chromatography yielded product 1c with a mass of 1.1200 g (yield 48%).

[0059] The structural and characterization data of some products are as follows:

[0060]

[0061] [1,1'-biphenyl]-4-sulfonamide (1c). 57.8 mg, 62% yield. White solid, EA:PE = 1:2. mp = 226 °C, 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.5 Hz,

[0062] 1H),7.73(d,J=7.3Hz,1H),7.51(t,J=7.5Hz,1H),7.47–7.37(m,1H).13C NMR (101MHz, DMSO-d6) δ143.41, 142.97, 138.74, 129.14, 128.40, 127.20, 127.06, 126.35. GC-MS (EI): m / z=233.10 (M+).

[0063]

[0064] 4-Methoxybenzenesulfonamide (2a). 41.9 mg, 56% yield. White solid, EA:PE = 1:2, mp = 10⁴–10⁷ °C. 1H NMR (400 MHz, DMSO-d⁶) δ 7.75 (d, J = 8.3 Hz, 2H), 7.21 (s, 2H), 7.08

[0065] (d,J=8.3Hz,2H),3.82(s,3H).13C NMR(101MHz,DMSO-d6)δ161.66,136.21,127.70,114.04,55.62.GC-MS(EI):m / z=187.00(M+).

[0066]

[0067] 4-methylbenzenesulfonamide (2c). 39.7 mg, 58% yield. White solid, EA:PE = 1:2. mp = 133-137℃

[37] , 1H NMR (500 MHz, DMSO-d6) δ 7.63 (t, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.31 (s, 2H), 2.38 (s, 3H). 13 C NMR(126MHz, DMSO-d6)δ144.10,138.59,132.44,128.89,125.93,122.81,20.95.GC-MS(EI):m / z=171.10(M+ ).

[0068]

[0069] 4-fluorobenzenesulfonamide (2g). 31.5mg, 45% yield, white solid, EA:PE = 1:2. mp = 120-122℃. 1H NMR (500MHz, DMSO-d6) δ 7.88 (dd, J = 8.9, 5.2Hz, 2H), 7.41 (dd, J = 11.4, 6.3Hz, 4H). 13C NMR (126MHz, DMSO-d6) δ 163.78 (d, J = 249.7Hz), 140.63 (d, J = 3.3Hz), 128.63 (d, J = 9.3Hz), 116.09 (d, J = 22.8Hz). 19F NMR (376MHz, DMSO-d6) δ -109.74. GC-MS (EI): m / z = 175.05 (M+).

[0070]

[0071] 4-(trifluoromethyl)benzenesulfonamide(2k).47.7mg, 53% yield, white solid, EA: PE=1:2.mp=111-112℃ (Recrystallized from benzene.),1HNMR(400MHz,DMSO-d6)δ8.03(d,J=8.1Hz,2H),7.98(d,J=8.1Hz,2H),7.63(s,2H).13C NMR(101MHz,DMSO-d6)δ147.84,131.71(q,J=32.2Hz),126.65,126.30(q,J=3.6Hz),12 3.61(d,J=272.6Hz).19FNMR(376MHz,DMSO-d6)δ-67.91.GC-MS(EI):m / z=225.00(M+).

[0072]

[0073] 4-cyanobenzenesulfonamide (2L). 34.2 mg, 47% yield, white solid, EA:PE = 1:2, mp = 158-160℃. [41 ], 1H NMR (400MHz, DMSO-d6) δ8.08 (d, J = 8.0 Hz, 2H), 7.98 (d, J = 7.8 Hz, 2H), 7.67 (s, 2H). 13 C NMR (101MHz, DMSO-d6) δ148.00, 133.30, 126.46, 117.89, 114.35. GC-MS (EI): m / z=182.00 (M+).

[0074]

[0075] 9,9-dimethyl-9H-fluorene-2-sulfonamide (3b). 49.1 mg, 45% yield, white solid, EA:PE = 1:2. 1 H NMR(500MHz, DMSO-d6)δ8.02(d,J=8.2Hz,2H),7.94–7.90(m,1H),7.86(dd,J=7.9,1.7Hz,1H),7.62–7.58(m,1H),7.41–7.36(m,4H),1.46(s,6H).13C NMR(126MHz,DMSO-d6)δ154.13,153.65,142.94,142.03,137.09,128.70,127.46, 125.20,123.09,121.18,120.49,120.31,46.89,26.64.GC-MS(EI): m / z=273.10(M + ).HRMS:calcd.forC15H15NNaO2S:296.0716,found 296.0719.

[0076]

[0077] Dibenzothiophenesulfonamide (3g). 42.1mg, 40% yield, white solid, EA:PE = 1:2. 11H NMR (500 MHz, DMSO-d6) δ 8.61 (d, J = 7.7 Hz, 1H), 8.44 (d, J = 7.3 Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 8.04 (d, J = 7.4 Hz, 1H), 7.75 (s, 2H), 7.71 (s, 1H), 7.61–7.52 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 139.63, 138.11, 137.02, 135.05, 133.84, 127.94, 125.71, 125.35, 125.16, 125.05, 122.77, 122.40. GC-MS (EI): m / z = 263.05 (M+). HRMS: calcd. for C 12 H9NNaO2S2: 285.9967, found 285.9972。

[0078]

[0079] thiophene-2-sulfonamide (3h). 21.5 mg, 33% yield. White solid, EA: PE = 1:2. mp = 141-144 °C, 1 1H NMR (500 MHz, DMSO-d6) δ 7.83 (dd, J = 5.0, 1.3 Hz, 1H), 7.66 (s, 2H), 7.55 (dd, J = 3.7, 1.3 Hz, 1H), 7.14 (dd, J = 4.9, 3.7 Hz, 1H). 13 13C NMR (126 MHz, DMSO-d6) δ 145.69, 131.19, 130.14, 127.39. GC-MS (EI): m / z = 163.00 (M + )。

Claims

1. A method for preparing an aryl primary sulfonamide compound, characterized in that, Includes the following steps: (1) Mix iodoaromatic compounds, sulfur dioxide source, palladium catalyst, phase transfer catalyst, base and organic solvent, and heat to carry out sulfonation reaction to obtain intermediate reaction solution; (2) Add an ammonia source to the intermediate reaction solution obtained in step (1), and after the reaction is completed, perform post-treatment to obtain the aryl primary sulfonamide compound; The structure of the iodoaromatic compound is shown in formula (II): (II) The structure of the aryl primary sulfonamide compounds is shown in formula (I): （I） In formulas (I) to (II), Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; The substituents on the aryl or heteroaryl group are selected from at least one of phenyl, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, trifluoromethoxy, cyano, C1-C4 alkylacyl, and C1-C4 alkoxycarbonyl. In step (1), the sulfur dioxide source is thiourea dioxide, DABSO, K2S2O5, Na2S2O5, Na2S2O4 or sodium formaldehyde sulfoxylate dihydrate. In step (1), the palladium catalyst is PdCl2(dppf), Pd(PPh3)2(OAc)2, Pd(cod)Cl2, Pd(dppb)2Cl2, Pd(CH3CN)2Cl2, Pd(PPh3)4 or Pd(PPh3)2Cl2; In step (1), the phase transfer catalyst is at least one of tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium hexafluorophosphate, and 18-crown-6; In step (1), the alkali is at least one of sodium carbonate, potassium carbonate, and cesium carbonate; In step (1), the organic solvent is DMF, dimethyl sulfoxide, N,N At least one of dimethylaniline or N-methylpyrrolidone; In step (2), the ammonia source is hydroxylamine sulfonic acid.

2. The method for preparing aryl primary sulfonamide compounds according to claim 1, characterized in that, Ar represents substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thiophene, substituted or unsubstituted fluorenyl, substituted or unsubstituted carbazolyl, or substituted or unsubstituted dibenzothiophene. The substituents on the phenyl, naphthyl, thiophene, fluorenyl, carbazole, and dibenzothiophene groups are selected from at least one of phenyl, methoxy, ethoxy, methyl, ethyl, isopropyl, F, Cl, Br, trifluoromethoxy, cyano, formyl, acetyl, methoxycarbonyl, and ethoxycarbonyl.

3. The method for preparing aryl primary sulfonamide compounds according to claim 1, characterized in that, In step (1), the reaction temperature is 85~95 ℃ and the reaction time is 0.5~5h.

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