A method for synthesizing N-(hetero)arylsulfonamides

Abstract

The application discloses a method for synthesizing N-(hetero) aryl sulfonamide compounds. The method uses bipyridine as a ligand, nickel acetate or nickel chloride as a catalyst, low-cost low-activity (hetero) aryl chloride and different types of sulfonamides as substrates, 1,8-diazabicycloundec-7-ene, tetramethyl guanidine, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene and the like as organic bases, and tetra-n-butylammonium iodide as an additive. The C-N coupling reaction of (hetero) aryl chloride and sulfonamide is realized by light-induced nickel catalysis in an argon atmosphere, so as to realize the synthesis of various (hetero) aryl sulfonamide compounds. The reaction system is simple, the operation is simple, the reaction condition is mild, the post-treatment is simple, the yield is good, the substrate range is wide, the use of traditional expensive metal catalysts and inorganic bases is avoided, the problems of complex catalytic system reaction and poor functional group compatibility are solved, and the method is a simple and efficient method for synthesizing (hetero) aryl sulfonamide compounds. The method has good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of (hetero)arylsulfonamide synthesis technology, specifically relating to a method for synthesizing N-aryl (heterocyclic aryl)sulfonamide compounds by photocatalysis. Background Technology

[0002] N-aryl (heterocyclic aryl) sulfonamides possess significant biological activities such as antibacterial and anti-inflammatory properties, and are an important core skeleton in drug molecules, with significant application value in medicinal chemistry and agrochemicals (Top. Curr. Chem. 2018, 376, 5; Top. Curr. Chem. 2017, 375, 82; J. Med. Chem. 2012, 55, 7849; WO2006 / 024823A1, March 09, 2006). Furthermore, sulfonamides can be used as chiral catalysts (Tetrahedron Lett. 1992, 33, 6661) and organic catalysts (Chem. Commun. 2009, 833) in reactions. In the traditional synthesis of N-arylsulfonamides, nucleophilic addition of amines to SO2 sources is mainly used (J.Org.Chem.1961,1136; J.Org.Chem.2003,68,115; Korean). Chem. Soc. 1992, 13, 357; Org. Lett. 2017, 19, 6012; Tetrahedron. 2019, 75, 3186; Angew. Chem. Int. Ed. 2021, 60, 1-7; Org. Lett. 2020, 22, 1841; J. Am. Chem. Soc. 2018, 140, 8781; Org. Lett. 2018, 20, 1167; Org. Lett. 2013, 15, 6226; Angew. Chem. Int. Ed. 2016, 55, 747; Org. Lett. 2020, 22, 4593; Angew. Chem. Int. Ed. 2021, 60, 7353) and sulfonyl chloride and amine compounds (Org. Process Nucleophilic substitution reactions (Res.Dev. 2009, 13, 285; Org. ProcessRes.Dev. 2010, 14, 960; Green.Chem. 2006, 8, 835; J.Am.Chem.Soc. 2013, 135, 10638) are performed. However, sulfonyl chlorides are difficult to obtain, unstable, and prone to potential toxicity problems. Their practicality is limited by their sensitivity to humidity and harsh reaction conditions. Therefore, developing methods to synthesize sulfonyl chlorides remains of great importance in the pharmaceutical industry. Transition metal catalysis for CN coupling reactions of aryl halides with sulfonamides is an attractive strategy.Through the development of ligands, Cu(Tetrahedron Letters. 2003, 44, 3385; Tetrahedron Lett. 2005, 46, 7295; Org. Lett. 2010, 12, 1532; Angew. Chem. Int. Ed. 2022, 61, e202210483; Org. Lett. 2014, 16, 338; ACS Catal. 2018, 8, 9560; Org. Lett. 2010, 12, 1532; ACS Ullmann coupling catalyzed by Pd (Tetrahedron. 1996, 52, 7525; Org. Lett. 2003, 5, 4373; Org. Lett. 2011, 13, 2564; Org. Chem. 2011, 76, 4552; J. Am. Chem. Soc. 2013, 135, 10638; Org. Lett. 2020, 22, 4593; Angew. Chem. Int. Ed., 2021, 60, 7353; ACS) Buchwald–Hartwig coupling catalyzed by Ni (Angew. Chem. Int. Ed. 2020, 59, 8952-8956; ACS Catal. 2022, 12, 2, 1475–1480. JACS Au 2021, 1, 1057–1065.) has seen rapid development. However, the high activity of the catalysts in these reactions requires the use of ligands with complex structures. Furthermore, the use of inorganic strong bases with low solubility and high temperatures limits the functional group compatibility of the substrates and restricts the substrate range. With the development of photocatalysis, electrocatalysis, and transition metal synergistic catalysis, the reaction of CN coupling with sulfonamides as N-nucleophiles has been further promoted, providing a new approach for mild and efficient carbon-heteroatom coupling reactions. Macmillan (Angew. Chem. Int. Ed. 2018, 57, 3488) and Roizen (J. Org. Chem. 2020, 85, 6380) and other groups (Chem. Catalysis, 2022, 2, 3546; Org. Lett. 2023, 25, 636; Angew. Chem. Int. Ed. 2019, 58, 12440; Chem. Commun. 2016, 52, 10918) have developed photonickel-co-catalyzed CN coupling reactions of sulfonamides of aryl halides. However, most of these works use expensive photocatalysts, generally have low yields without photocatalysts, have limited substrate applicability, and rarely involve abundant, inexpensive, and highly reactive low-activity aryl chlorides, thus limiting their application.Therefore, it remains very important to develop efficient CN coupling of aryl chlorides with sulfonamides using readily available ligands and mildly soluble tertiary amines. Summary of the Invention

[0003] The purpose of this invention is to provide a method for synthesizing N-(hetero)arylsulfonamide compounds by using an inexpensive nickel catalyst and a bipyridine system, with the addition of tetra-n-butylammonium iodide, to achieve CN coupling between (hetero)aryl chlorides and sulfonamides. This method not only solves the problem that low-activity aryl chlorides cannot participate in the reaction, but also avoids the use of complex ligands and inorganic bases in transition metal catalysis.

[0004] To achieve the above objectives, the technical solution adopted by the present invention is as follows: the (hetero)aryl chloride shown in Formula I, the sulfonamide shown in Formula II, bipyridine, nickel catalyst, tetra-n-butylammonium iodide, and organic base are added to an organic solvent and reacted under light in an argon atmosphere. After the reaction is complete, the product is separated and purified to obtain the N-(hetero)arylsulfonamide compound shown in Formula III.

[0005]

[0006] In the formula, Ar represents any one of aryl, substituted aryl, heterocyclic aryl, or substituted heterocyclic aryl; R represents any one of aryl, substituted aryl, heterocyclic aryl, or aliphatic; and R′ represents H or methyl.

[0007] In the above structural formula, Ar can specifically represent any one of phenyl, C1-C4 alkyl-substituted phenyl, trimethylsilyl-substituted phenyl, halophenyl, thiophene, pyridyl, halopyridyl, quinoxalinyl, or a substituted phenyl containing at least two of ester, cyano, cyclopropyl, pyrazolyl, carbonyl, pyridyl, piperidinyl, alkoxy chain, phenyl, C1-C4 alkyl-substituted phenyl, trifluoromethyl-substituted pyrazolyl; R represents any one of phenyl, C1-C4 alkyl-substituted phenyl, halophenyl, trifluoromethyl-substituted phenyl, pyridyl, thiophene, morpholinyl, C1-C6 alkyl, methyl-substituted cyclopropyl, trifluoromethyl, N,N-dimethyl-substituted amino, N,N-diethyl-substituted amino, p-oxodifluoro-substituted phenyl, cyclohexanone-substituted alkyl.

[0008] In the above synthesis method, the amount of sulfonamide is preferably 1.1 to 2 times the molar amount of (hetero)aryl chloride.

[0009] In the above synthesis method, the preferred amount of bipyridine is 5% to 10% of the molar amount of (hetero)aryl chloride.

[0010] In the above synthesis method, the preferred nickel catalyst is nickel bromide, nickel acetate, nickel chloride, etc., and its amount is 5% to 10% of the molar amount of (hetero)aryl chloride.

[0011] In the above synthesis method, tetra-n-butylammonium iodide (TBAI) is preferably used as an additive at an amount of 1.1 to 2 times the molar amount of (hetero)aryl chloride.

[0012] In the above synthesis method, the preferred organic bases are 1,8-diazabicycloundec-7-ene (DBU), tetramethylguanidine (TMG), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), etc., and their amounts are 2 to 3 times the molar amount of (hetero)aryl chloride.

[0013] In the above synthesis method, the preferred organic solvent is any one of dimethyl sulfoxide, toluene, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0014] In the above synthesis method, it is preferred to synthesize the mixture in an argon atmosphere at 80-90°C for 24-36 hours under irradiation with violet light of wavelength 360-430 nm.

[0015] The beneficial effects of this invention are as follows:

[0016] This invention features a simple reaction system, utilizing inexpensive nickel catalysis and a bipyridine system. The addition of tetra-n-butylammonium iodide, an iodine-containing additive, facilitates the reaction of (hetero)aryl chlorides with sulfonamides to synthesize N-(hetero)arylsulfonamides under light irradiation. This invention offers high economic efficiency, is environmentally friendly, and simplifies post-reaction processing. It not only solves the problem of low-activity (hetero)aryl chlorides but also avoids the use of complex ligands and inorganic bases in transition metal catalysis. Furthermore, the resulting (hetero)arylsulfonamide compounds exhibit good yields and excellent functional group compatibility. This method provides a simple and efficient way to synthesize (hetero)arylsulfonamides, aligning with current trends towards environmentally friendly, economical, and green chemistry, and possesses significant application potential. Detailed Implementation

[0017] The present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited to these embodiments.

[0018] Example 1

[0019] In an argon atmosphere, 22.4 mg (0.2 mmol) of chlorobenzene, 68.8 mg (0.4 mmol) of p-toluenesulfonamide, 1.9 mg (0.01 mmol) of bipyridine, 1.3 mg (0.01 mmol) of nickel chloride, 147.6 mg (0.4 mmol) of TBAI, 90 mg (0.6 mmol) of MTBD, 2 mL of N,N-dimethylacetamide, and a magnetic flux were added to a reaction tube. The reaction was carried out at 85 °C for 24 hours under 390–395 nm ultraviolet light. After the reaction was complete, the mixture was cooled to room temperature, diluted with saturated ammonium chloride aqueous solution and ethyl acetate to obtain an organic phase. The crude product was obtained by vacuum distillation. The product was separated by column chromatography using a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 to 1:1 as the eluent, yielding a pale yellow solid with the following structural formula, in 84% yield.

[0020]

[0021] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ7.68 (dd, J=8.2, 2.7Hz, 2H), 7.38–7.17 (m, 5H), 7.08 (dd, J=8.6, 4.6Hz, 3H), 2.36 (s, 3H); 13 C NMR (100MHz, CDCl3) δ143.9,136.6,136.1,129.7,129.3,127.3,125.2,121.5,21.5; HRMS (ESI) m / z C 13 H 13 NNaO2S[M+Na] + Theoretical value: 270.0559, measured value: 270.0555.

[0022] Example 2

[0023] In this embodiment, 1-chloro-4-(trimethylsilyl)benzene was used to replace the chlorobenzene in Example 1, and the other steps were the same as in Example 1, resulting in a pale yellow solid product with the following structural formula, with a yield of 81%.

[0024]

[0025] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 11 H NMR (400MHz, CDCl3) δ7.51(d,J=8.2Hz,2H),7.16(d,J=8.1Hz,2H),7.07–6.99(m,3H),6.85(d,J=8.1Hz,2H),6.80(br,1H),2.17(s,3H),0.00(s,9H); 13C NMR (100MHz, CDCl3) δ145.0,138.3,137.9,137.6,135.5,130.8,128.4,121.2,22.7,-0.0; HRMS (ESI) m / z C 16 H 21 NNaO2SSi[M+Na] + Theoretical value: 342.0954, measured value: 342.0959.

[0026] Example 3

[0027] In this embodiment, 1-[1-(4-chlorobenzene)cyclopropyl]nitrile was replaced with an equimolar amount of 1-[1-(4-chlorobenzene)cyclopropyl]nitrile, and the other steps were the same as in Example 1, to obtain a white solid product with the following structural formula, with a yield of 88%.

[0028]

[0029] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR(400MHz,d6-DMSO)δ10.35(br,1H),7.72(d,J=8.0Hz,2H),7.35(t,J=8.8Hz,4H ),7.19(d,J=8.5Hz,2H),2.37(s,3H),1.65(q,J=5.0Hz,2H),1.38(t,J=6.2Hz,2H); 13 C NMR(100MHz,d6-DMSO)δ143.8,142.3,137.6,131.9,129.7,127.1,126.1,122.9,120.4,21.4,18.1,13.2; HRMS(ESI)m / zC 17 H 16 N₂NaO₂S[M+Na] + Theoretical value: 335.0825, measured value: 335.0826.

[0030] Example 4

[0031] In this embodiment, 3-fluorochlorobenzene was replaced with equimolar 3-fluorochlorobenzene in Example 1, and the other steps were the same as in Example 1, resulting in a white solid product with the following structural formula, with a yield of 84%.

[0032]

[0033] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ7.75(d,J=8.2Hz,2H),7.46(br,1H),7.27(d,J=8.2Hz,2H),7.19(dd,J=14.7,8.1Hz,1H),6.98–6.72(m,3H),2.40(s,3H); 13 C NMR(100MHz,d6-DMSO)δ158.3(d,J=246.5Hz),139.5,133.5(d,J=10.3Hz),131.0,125.8(d,J= 9.3Hz), 125.1, 122.54, 111.5 (d, J = 3.0Hz), 107.1 (d, J = 21.2Hz), 103.3 (d, J = 25.4Hz)., 16.8; 19 F NMR (376MHz, CDCl3) δ-110.95 (s, F); HRMS (ESI) m / zC 13 H 12 FNNaO2S[M+Na] + Theoretical value: 288.0465, measured value: 288.0463.

[0034] Example 5

[0035] In this embodiment, 3,5-difluorochlorobenzene was used to replace the chlorobenzene in Example 1, and the other steps were the same as in Example 1, resulting in a white solid product with the following structural formula, with a yield of 89%.

[0036]

[0037] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ7.80 (t, J = 13.4Hz, 2H), 7.71 (br, 1H), 7.36–7.24 (m, 2H), 6.83–6.61 (m, 2H), 6.59–6.50 (m, 1H), 2.42 (s, 3H); 13 C NMR(100MHz,d6-DMSO)δδ158.54(dd,J=248.2,14.5Hz),139.9,134.43(dd,J=13.0,13.0 Hz),130.7,125.3,122.5,98.5(dd,J=8.7,11.5Hz).,95.34(dd,J=25.5,25.5Hz),16.8; 19 FNMR (376MHz, CDCl3) δ-107.90 (s, F); HRMS (ESI) m / zC 13 H 11F2NNaO2S[M+Na] + Theoretical value: 306.0371, measured value: 306.0373.

[0038] Example 6

[0039] In this embodiment, 2-fluorochlorobenzene was replaced with equimolar 2-fluorochlorobenzene in Example 1, and the other steps were the same as in Example 1, to obtain a yellow solid product with the following structural formula, with a yield of 80%.

[0040]

[0041] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR(400MHz, CDCl3)δ7.66(d,J=8.3Hz,2H),7.69–7.46(m,1H),7.22(d,J=8 .1Hz,2H),7.13–7.02(m,2H),7.15–7.02(m,1H),6.76(br,1H),2.37(s,3H); 13 C NMR (100MHz, CDCl3) δ153.93 (d, J = 244.5Hz), 144.2, 135.9, 129.7, 127.2, 126. 1(d,J=7.5Hz),124.74(d,J=3.9Hz),124.7,123.2,115.40(d,J=19.5Hz),21.5; 19 F NMR(376MHz, CDCl3)δ-110.21(s,F); HRMS(ESI)m / z C 13 H 12 FNNaO2S[M+Na] + Theoretical value: 288.0465, measured value: 288.0462.

[0042] Example 7

[0043] In this embodiment, 4-chloropyridinebenzene was replaced with an equimolar amount in Example 1, and the other steps were the same as in Example 1, resulting in a yellow solid product with the following structural formula, with a yield of 79%.

[0044]

[0045] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ8.82(s,2H),7.85(d,J=8.3Hz,2H),7.75(d,J=3.1Hz,2H),7.35(d,J=8.2Hz,2H),2.43(s,3H); 13C NMR(100MHz, CDCl3)δ151.2,150.2,145.4,136.7,130.3,128.2,120.5,21.7; HRMS(ESI)m / z calc.forC 12 H 12 N₂NaO₂S[M+Na] + Theoretical value: 271.0512, measured value: 271.0513.

[0046] Example 8

[0047] In this embodiment, 3-chloropyridine was used to replace chlorobenzene in Example 1, and the other steps were the same as in Example 1, resulting in a yellow solid product with the following structural formula, with a yield of 69%.

[0048]

[0049] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR(400MHz,d6-DMSO)δ10.49(br,1H),8.34–8.21(m,2H),7.65(d,J=8.2Hz,2 H),7.58–7.47(m,1H),7.36(d,J=8.1Hz,2H),7.38–7.28(m,1H),2.34(s,3H); 13 C NMR(100MHz,d6-DMSO)δ145.7,144.1,142.2,136.7,134.9,130.3,127.7,127.2,124.4,21.4; HRMS(ESI)m / z calc.for C 12 H 12 N₂NaO₂S[M+Na] + Theoretical value: 2271.0512, measured value: 271.0510.

[0050] Example 9

[0051] In this embodiment, 2,6-dichloropyridine was used to replace chlorobenzene in Example 1, the reaction time was extended to 36 hours, and the other steps were the same as in Example 1, resulting in a white solid product with the following structural formula, with a yield of 68%.

[0052]

[0053] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ7.73(d,J=8.3Hz,2H),7.49(t,J=8.0Hz,1H),7.44(s,1H),7.28–7.15(m,3H),6.91(d,J=7.7Hz,1H),2.32(s,3H); 13 CNMR(100MHz, CDCl3)δ149.3,148.7,143.6,139.8,135.0,128.9,126.4,118.5,108.9,20.6; HRMS(ESI)m / z C 12 H 11 ClN2NaO2S[M+Na] + Theoretical value: 305.0122, measured value: 305.0125.

[0054] Example 10

[0055] In this embodiment, 6-chloroquinoxaline was replaced with an equimolar amount of chloroquinoxaline in Example 1, the reaction time was extended to 36 hours, and the other steps were the same as in Example 1, yielding a white solid product with the following structural formula, with a yield of 72%.

[0056]

[0057] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR(400MHz, CDCl3) δ8.76(dd,J=14.7,1.8Hz,2H),8.00(d,J=9.0Hz,1H),7.80(d,J=8.3Hz,2 H),7.74(d,J=2.4Hz,1H),7.61(dd,J=9.1,2.5Hz,1H),7.25(s,1H),7.23(s,1H),2.35(s,3H); 13 C NMR (100MHz, CDCl3) δ145.6,144.5,144.1,143.5,140.4,138.4,135.8,130.8,123.0,127.4,123.9,116.9,21.6; HRMS (ESI) m / z C 15 H 13 N3NaO2S[M+Na] + Theoretical value: 322.0621, measured value: 322.0625.

[0058] Example 11

[0059] In this embodiment, 5-chlorobenzothiophene was used to replace chlorobenzene in Example 1, the reaction time was extended to 36 hours, and the other steps were the same as in Example 1, resulting in a white solid product with the following structural formula, with a yield of 76%.

[0060]

[0061] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ8.53(d,J=5.0Hz,1H),8.21(s,1H),7.80(d,J=8.3Hz,2H),7.4 1–7.31(m,1H),7.30(d,J=8.1Hz,2H),7.17–7.08(m,2H),5.00(br,1H),2.43(s,3H); 13 C NMR(100MHz, CDCl3)δ156.0,148.9,148.3,143.6,139.2,129.7,127.1,126.4,124.7,123.0,122.1,114.9,108.4,21.2; HRMS(ESI)m / zcalc.for C 16 H 17 NNaO4S[M+Na] + Theoretical value: 342.0770, measured value: 342.0775.

[0062] Example 12

[0063] In this embodiment, chlorobenzene in Example 1 was replaced with equimolar chlorofibrate, and the other steps were the same as in Example 1, resulting in a white solid product with the following structural formula, with a yield of 89%.

[0064]

[0065] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ7.73–7.55(m,2H),7.01(t,J=8.6Hz,2H),6.86(d,J=8.9Hz,3H, NH),6.65(d,J=8.9Hz,2H),4.14(q,J=7.1Hz,2H),1.47(s,6H),1.15(t,J=7.1Hz,3H); 13C NMR (100MHz, CDCl3) δ174.0,165.18(d,J=255.2Hz),153.8,134.86(d,J=3.1Hz),130.1,130 .0,124.5,120.08(d,J=16.2Hz),116.2(d,J=22.6Hz),79.5,61.5,25.3,14.0; HRMS(ESI)m / z C 18 H 20 FNNaO5S[M+Na] + Theoretical value: 404.0938, measured value: 404.0935.

[0066] Example 13

[0067] In this embodiment, equimolar cymoxanil was used to replace chlorobenzene in Example 1, and the other steps were the same as in Example 1, resulting in a white solid product with the following structural formula, with a yield of 85%.

[0068]

[0069] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ10.36(br,1H),8.06(s,1H),7.96(s,1H),7.65(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),7.31(d,J=8.4Hz,2H),7 .13(d,J=8.4Hz,2H),4.99–4.80(m,2H),2.38(s,3H),2.20–2.10(m,2H),1.37–1.17(m,3H),1.04–0.89(m,1H),0.82(t,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3) δ156.7,150.1,148.5,143.0,141.7,136.1,134.8,132.3 ,131.9,125.7,125.5,60.6,53.8,41.3,31.9,27.0,26.2,18.8; HRMS(ESI)m / z C 22 H 25 N5NaO2S[M+Na] + Theoretical value: 446.1621, measured value: 446.1623.

[0070] Example 14

[0071] In this embodiment, equimolar fenofibrate was used to replace chlorobenzene in Example 1, and the other steps were the same as in Example 1, resulting in a white solid product with the following structural formula, with a yield of 73%.

[0072]

[0073] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR(400MHz, CDCl3)δ7.96–7.85(m,2H),7.75–7.66(m,4H),7.63(br,1H),7.25–7.0 6(m,4H),7.00–6.77(m,2H),5.12–5.03(m,1H),1.66(s,6H),1.20(d,J=6.3Hz,6H); 13 C NMR (100MHz, CDCl3) δ194.4, 173.2, 165.44 (d, J = 256.2Hz), 159.6, 140.1, 134.95 (d, J = 3.3Hz), 134.3, 131.9,131.5,130.4,130.1(d,J=9.5Hz),119.2,117.3,116.61(d,J=22.7Hz),79.4,69.4,25.4,21.5; 19 F NMR (376MHz, CDCl3) δ-103.56 (s, F); HRMS (ESI) m / z C 26 H 26 FNNaO6S[M+Na] + Theoretical value: 522.1357, measured value: 522.1359.

[0074] Example 15

[0075] In this embodiment, chlorobenzene in Example 1 was replaced with equimolar loratadine, and the other steps were the same as in Example 1, resulting in a white solid product with the following structural formula, with a yield of 76%.

[0076]

[0077] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ8.28–8.19(m,1H),7.91(br,1H),7.85–7.68(m,2H),7.37–7.29(m,1H),7.29–7.23(m,1H),7.02–6.83(m,5H),4.06–3. 98(m,2H),3.63(d,J=32.7Hz,2H),3.06–2.92(m,2H),2.85(s,2H),2.7 7(s,2H),2.70–2.50(m,2H),2.26–2.10(m,2H),1.14(d,J=7.1Hz,3H); 13 C NMR (100MHz, CDCl3) δ164.84 (d, J = 254.2Hz), 162.6, 157.4, 155.5, 146.4, 138.6, 137.3, 136.7, 136.3, 135.5, 134. 5,133.6,131.1,130.0,129.8,122.1,119.0,115.9(d,J=22.6Hz),61.2,59.0,44.7,36.5,24.1,19.7,14.6,13.6; 19 F NMR (376MHz, CDCl3) δ-107.6 (s, F); HRMS (ESI) m / z C 28 H 28 FN3NaO4S[M+Na] + Theoretical value: 544.1677, measured value: 544.1679.

[0078] Example 16

[0079] In this embodiment, 3,5-dimethylchlorobenzene was replaced with an equimolar amount of chlorobenzene in Example 1, and p-methylbenzenesulfonamide was replaced with an equimolar amount of methanesulfonamide in Example 1. The other steps were the same as in Example 1, and a pale yellow solid product with the following structural formula was obtained with a yield of 74%.

[0080]

[0081] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ6.84(s,2H),6.83(s,1H),6.60(br,1H),3.01(s,3H),2.31(s,6H); 13 C NMR (100MHz, CDCl3) δ139.6, 136.6, 127.2, 118.4, 39.2, 21.3; HRMS (ESI) m / z C9H 13NNaO2S[M+Na] + Theoretical value: 222.0559, measured value: 222.0554.

[0082] Example 17

[0083] In this embodiment, 3,5-dimethylchlorobenzene was used to replace chlorobenzene in Example 1, and cyclopropylmethylsulfonamide was used to replace p-methylbenzenesulfonamide in Example 1. The reaction time was extended to 36 hours. Other steps were the same as in Example 1, and a yellow solid product with the following structural formula was obtained with a yield of 79%.

[0084]

[0085] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ6.97(br,1H),6.82(s,2H),6.71(s,1H),2.21(s,6H),1.43(s,3H),1.33–1.23(m,2H),0.71–0.55(m,2H); 13 CNMR(100MHz, CDCl3)δ139.1,137.1,126.8,119.2,35.9,21.3,18.5,12.7; HRMS(ESI)m / zC 12 H 17 NNaO2S[M+Na] + Theoretical value: 262.0872, measured value: 262.0876.

[0086] Example 18

[0087] In this embodiment, chlorobenzene in Example 1 was replaced with equimolar 3,5-dimethylchlorobenzene, and p-methylbenzenesulfonamide in Example 1 was replaced with equimolar ((1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonamide. The other steps were the same as in Example 1, and a white solid product with the following structural formula was obtained with a yield of 63%.

[0088]

[0089] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ7.60(br,1H),6.90(s,2H),6.82(s,1H),3.41(d,J=15.3Hz,1H),2.86(d,J=15.3Hz,1H),2.50–2.36( m,1H),2.29(s,6H),2.27–2.20(m,2H),2.19–2.10(m,3H),2.08–1.95(m,2H),1.52–1.40(m,1H),0.97(s,3H),0.87(s,3H); 13 C NMR (100MHz, CDCl3) δ217.3,139.2,137.4,127.3,119.9,59.7,49.1,48.9,43.1,42.8,27.7,27.1,21.3,19.9,19.4; HRMS(ESI)m / zC 18 H 27 NNaO3S[M+Na] + Theoretical value: 360.1604, measured value: 360.1606.

[0090] Example 19

[0091] In this embodiment, 3,5-dimethylchlorobenzene was used to replace chlorobenzene in Example 1, and trifluoromethylsulfonamide was used to replace p-methylbenzenesulfonamide in Example 1. Other steps were the same as in Example 1, and a white solid product with the following structural formula was obtained with a yield of 81%.

[0092]

[0093] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ6.94(s,1H),6.88(s,2H),6.77(br,1H),2.32(s,6H); 13 C NMR (100MHz, CDCl3) δ139.6, 133.4, 129.3, 121.3, 119.76 (d, J = 322.8Hz), 115.5, 21.2; 19 F NMR (376MHz, CDCl3) δ-75.25 (s, CF3); HRMS (ESI) m / zC9H 10 F3NNaO2S[M+Na] + Theoretical value: 276.0277, measured value: 276.0278.

[0094] Example 20

[0095] In this embodiment, chlorobenzene in Example 1 was replaced with an equimolar amount of 3,5-dimethylchlorobenzene, and p-methylbenzenesulfonamide in Example 1 was replaced with an equimolar amount of N,N-dimethylsulfonamide. The other steps were the same as in Example 1, and a white solid product with the following structural formula was obtained with a yield of 72%.

[0096]

[0097] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ6.85(br,1H),6.81(s,2H),6.75(s,1H),2.85(s,6H),2.28(s,6H); 13 C NMR(100MHz, CDCl3)δ139.1,137.1,126.3,117.8,38.3,21.3; HRMS(APCI)m / z C 10 H 16 N₂NaO₂S[M+Na] + Theoretical value: 251.0825, measured value: 251.0826.

[0098] Example 21

[0099] In this embodiment, 3,5-dimethylchlorobenzene was used to replace chlorobenzene in Example 1, and p-methylbenzenesulfonamide in Example 1 was used to replace p-oxodifluorobenzenesulfonamide in Example 1. Other steps were the same as in Example 1, and a yellow solid product with the following structural formula was obtained with a yield of 75%.

[0100]

[0101] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ7.77(d,J=8.9Hz,2H),7.15(d,J=8.8Hz,2H),6.77(s,1H),6.67(s,2H),6.56(t,J=72.6Hz,1H),6.41(br,1H),2.23(s,6H); 13 C NMR (100MHz, CDCl3) δ154.3, 139.3, 135.9, 135.8, 129.4, 127.5, 119.5, 119.2, 115.14 (t, J = 262.5Hz), 21.23 (s); 19 F NMR(376MHz, CDCl3)δ-82.00(s,F),-82.20(s,F); HRMS(ESI)m / z C 15 H 15F2NNaO3S[M+Na] + Theoretical value: 350.0633; Measured value: 350.0634.

[0102] Example 22

[0103] In this embodiment, 3,5-dimethylchlorobenzene was used to replace chlorobenzene in Example 1, and p-methylbenzenesulfonamide in Example 1 was used to replace p-trifluoromethylbenzenesulfonamide in Example 1. Other steps were the same as in Example 1, and a yellow solid product with the following structural formula was obtained with a yield of 91%.

[0104]

[0105] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ7.82(d,J=8.2Hz,2H),7.64(d,J=8.3Hz,2H),6.71(br,1H),6.65(s,1H),6.62(s,2H),2.16(s,6H); 13 CNMR (100MHz, CDCl3) δ142.7, 139.4, 135.5, 134.6 (q, J = 33.2Hz), 127.7, 126.14 (q, J = 3.7Hz), 123.16 (d, J = 272.9Hz), 119.6, 21.2; 19 F NMR(376MHz,d6-DMSO)δ-60.37(s,CF3); HRMS(ESI)m / zC 15 H 14 F3NNaO2S[M+Na] + Theoretical value: 352.0590, measured value: 352.0596.

[0106] Example 23

[0107] In this embodiment, 3,5-dimethylchlorobenzene was used to replace chlorobenzene in Example 1, and p-methylbenzenesulfonamide was used to replace p-fluorobenzenesulfonamide in Example 1. Other steps were the same as in Example 1, and a white solid product with the following structural formula was obtained with a yield of 91%.

[0108]

[0109] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 HNMR (400MHz, CDCl3) δ7.86–7.73(m,2H),7.19–7.08(m,2H),7.00(br,1H),6.75(s,1H),6.70(s,2H),2.21(s,6H);13 C NMR (100MHz, CDCl3) δ 165.21 (d, J = 255.0Hz), 139.2, 136.0, 135.2, 130.01 (d, J = 9.4Hz), 127.4, 119.3, 116.25 (d, J = 22.7Hz), 21.2; 19 F NMR (376MHz, CDCl3) δ-104.69 (s, F); HRMS (ESI) m / z C 14 H 14 FNNaO2S[M+Na] + Theoretical value: 302.0621, measured value: 302.0626.

[0110] Example 24

[0111] In this embodiment, 3,5-dimethylchlorobenzene was used to replace chlorobenzene in Example 1, and 2,6-difluorobenzenesulfonamide was used to replace p-methylbenzenesulfonamide in Example 1. Other steps were the same as in Example 1, and a white solid product amine with the following structural formula was obtained with a yield of 84%.

[0112]

[0113] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 HNMR (400MHz, CDCl3) δ7.54–7.39(m,1H),6.98(t,J=8.8Hz,2H),6.90(br,1H),6.78(s,2H),6.75(s,1H),2.23(s,6H); 13 C NMR (100MHz, CDCl3) δ 159.8 (dd, J = 258.6, 3.8 Hz), 139.3, 135.4, 134.78 (dd, J = 11.2, 11.2 Hz), 127.6, 118.5, 113.1 (dd, J = 23.3, 3.7 Hz), 21.2; 19 F NMR (376MHz, CDCl3) δ-107.44 (s, F); HRMS (ESI) m / zC 14 H 13 F2NNaO2S[M+Na] + Theoretical value: 320.0527, measured value: 320.0529.

[0114] Example 25

[0115] In this embodiment, chlorobenzene in Example 1 was replaced with equimolar 3,5-dimethylchlorobenzene, and p-methylbenzenesulfonamide in Example 1 was replaced with equimolar 3,5-difluorobenzenesulfonamide. The reaction time was extended to 36 hours. Other steps were the same as in Example 1, and a white solid product with the following structural formula was obtained with a yield of 77%.

[0116]

[0117] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, d6-DMSO) δ10.32(br,1H),7.61–7.49(m,1H),7.50–7.38(m,2H),6.77(s,2H),6.73(s,1H),2.18(s,6H); 13 C NMR (100MHz, d6-DMSO) δ162.57 (dd, J=251.9, 12.3Hz), 143.51 (dd, J=7.4, 7.4Hz), 138.8, 137. 3,126.7,118.6,110.9(dd,J=19.9,8.5Hz),108.93(dd,J=25.9,25.9Hz),21.1; HRMS(ESI)m / zC 14 H 13 F2NNaO2S[M+Na] + Theoretical value: 320.0527, measured value: 320.0535.

[0118] Example 26

[0119] In this embodiment, 3,5-dimethylchlorobenzene was replaced with an equimolar amount of chlorobenzene in Example 1, and 2-pyridinesulfonamide was replaced with an equimolar amount of p-methylbenzenesulfonamide in Example 1. The other steps were the same as in Example 1, and a white solid product with the following structural formula was obtained with a yield of 64%.

[0120]

[0121] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 HNMR(400MHz,d6-DMSO)δ10.37(br,1H),8.84–8.57(m,1H),8.05(td,J=7.7,1.8Hz,1 H),7.95(d,J=7.9Hz,1H),7.76–7.54(m,1H),6.74(s,2H),6.63(s,1H),2.13(s,6H); 13C NMR(100MHz,d6-DMSO)δ157.0,150.6,139.1,138.5,137.9,127.8,125.9,122.9,118.1,21.4; HRMS(ESI)m / zC 13 H 14 N₂NaO₂S[M+Na] + Theoretical value: 285.0668, measured value: 285.0667.

[0122] Example 27

[0123] In this embodiment, 3,5-dimethylchlorobenzene was replaced with an equimolar amount of chlorobenzene in Example 1, and 2-thiophene sulfonamide was replaced with an equimolar amount of p-methylbenzene sulfonamide in Example 1. The other steps were the same as in Example 1, and a white solid product with the following structural formula was obtained with a yield of 85%.

[0124]

[0125] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 HNMR (400MHz, CDCl3) δ7.51 (d, J = 4.4Hz, 2H), 7.00 (t, J = 4.4Hz, 1H), 6.97 (br, 1H), 6.77 (s, 1H), 6.75 (s, 2H), 2.24 (s, 6H); 13 CNMR(100MHz, CDCl3)δ139.1,136.0,132.8,132.3,127.4,127.3,119.3,113.2,21.3; HRMS(ESI)m / zC 12 H 13 NNaO2S2[M+Na] + Theoretical value 290.0280, measured value 290.0281.

[0126] Example 28

[0127] In this embodiment, 3,5-dimethylchlorobenzene was used to replace chlorobenzene in Example 1, and N-methylbenzenesulfonamide was used to replace p-methylbenzenesulfonamide in Example 1. Other steps were the same as in Example 1, and a white solid product with the following structural formula was obtained with a yield of 71%.

[0128]

[0129] The nuclear magnetic resonance (NMR) spectra of the obtained products are as follows: HNMR (400MHz, CDCl3) δ 7.47 (d, J = 8.1Hz, 2H), 7.26 (s, 2H), 7.24 (s, 1H), 6.89 (s, 1H), 6.70 (s, 2H), 3.12 (s, 3H), 2.43 (s, 3H), 2.25 (s, 6H); 13 CNMR(100MHz, CDCl3)δ143.4,141.5,138.5,133.9,129.2,129.0,128.0,124.4,38.3,21.6,21.2; HRMS(ESI)m / z C 16 H 19 NNaO2S[M+Na] + Theoretical value: 312.1029, measured value: 312.1028.

[0130] Example 29

[0131] In this embodiment, equimolar celecoxib was used to replace p-methylbenzenesulfonyl in Example 1, and the other steps were the same as in Example 1, resulting in a white solid amination product with the following structural formula, with a yield of 63%.

[0132]

[0133] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ7.77–7.66(m,2H),7.40–7.35(m,2H),7.26–7.23(m,2H), 7.19–7.12(m,3H),7.10-7.00(m,4H),6.72(s,1H),6.50(br,1H),2.37(s,3H); 13 C NMR (100MHz, CDCl3) δ165.4,145.3,142.7,139.8,138.3,135.8,129.7,129.5,128.7, 128.3,126.1,125.6,125.4,123.6(d,J=251.9Hz).122.3,106.3,21.3; HRMS(ESI)m / z C 23 H 18 F3N3NaO2S[M+Na] + Theoretical value: 480.0964, measured value: 480.0960.

Claims

1. A method for synthesizing N-(hetero)arylsulfonamide compounds, characterized in that: The heteroaryl chloride shown in Formula I, along with the sulfonamide shown in Formula II, bipyridine, nickel catalyst, tetra-n-butylammonium iodide, and organic base, were added to an organic solvent and reacted under light in an argon atmosphere. After the reaction was complete, the product was separated and purified to obtain the N-(heteroaryl)sulfonamide compound shown in Formula III. In the formula, Ar represents any one of phenyl, C1-C4 alkyl-substituted phenyl, trimethylsilyl-substituted phenyl, halophenyl, thienyl, pyridyl, halopyridyl, and quinoxalinyl, or a substituted phenyl containing at least two of ester, cyano, cyclopropyl, pyrazolyl, pyridyl, piperidinyl, alkoxy, phenyl, C1-C4 alkyl-substituted phenyl, and trifluoromethyl-substituted pyrazolyl; R represents any one of phenyl, C1-C4 alkyl-substituted phenyl, halophenyl, trifluoromethyl-substituted phenyl, pyridyl, thienyl, morpholinyl, C1-C6 alkyl, methyl-substituted cyclopropyl, trifluoromethyl, N,N-dimethyl-substituted amino, N,N-diethyl-substituted amino, and cyclohexanone-substituted alkyl; R′ represents H or methyl; The nickel catalyst is nickel bromide or nickel chloride, and the organic base is any one of 1,8-diazabicycloundec-7-ene, tetramethylguanidine, and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene; The organic solvent is any one of dimethyl sulfoxide, toluene, N,N-dimethylformamide, and N,N-dimethylacetamide; The wavelength of the photoreaction is 360–430 nm, the reaction temperature is 80–90 °C, and the reaction time is 24–36 hours.

2. The method for synthesizing N-(hetero)arylsulfonamide compounds according to claim 1, characterized in that: The amount of sulfonamide used is 1.1 to 2 times the molar amount of (hetero)aryl chloride.

3. The method for synthesizing N-(hetero)arylsulfonamide compounds according to claim 1, characterized in that: The amount of bipyridine used is 5% to 20% of the molar amount of (hetero)aryl chloride.

4. The method for synthesizing N-(hetero)arylsulfonamide compounds according to claim 1, characterized in that: The amount of nickel catalyst used is 5% to 20% of the molar amount of (hetero)aryl chloride.

5. The method for synthesizing N-(hetero)arylsulfonamide compounds according to claim 1, characterized in that: The amount of tetra-n-butylammonium iodide used as an additive is 1.1 to 2 times the molar amount of (hetero)aryl chloride.

6. The method for synthesizing N-(hetero)arylsulfonamide compounds according to claim 1, characterized in that: The amount of the organic base used is 2 to 3 times the molar amount of the (hetero)aryl chloride.

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