Process for the halogenation of aromatic compounds

Abstract

The application discloses a halogenation synthesis method of an aromatic ring compound, and relates to the field of organic synthesis, and specifically relates to a halogenation synthesis method of an aromatic ring compound. The synthesis method comprises the following steps: under the condition that a catalyst (the catalyst is a sulfonic acid), a halogenation reagent and a solvent are present, performing halogenation reaction on an aromatic ring compound to obtain an aryl halide. According to the application, the aromatic ring compound is subjected to high-efficiency halogenation reaction under the condition that the catalyst (the catalyst is the sulfonic acid), the halogenation reagent and the solvent are present, and very useful aryl halides can be obtained with high activity and selectivity. According to the method, the aryl halides can be efficiently synthesized, and the method has a wide application prospect in actual production.

Description

Technical Field

[0001] This invention belongs to, but is not limited to, the field of chemical synthesis technology, and particularly relates to a halogenation synthesis method of aromatic compounds catalyzed by sulfonic acid. Background Technology

[0002] In organic synthesis, aryl halides are widely found in many bioactive natural products (Gribble, GWJChem.Edu. 2004, 81, 1441). Furthermore, aryl halides serve as important intermediates in organic synthesis, significantly improving the efficiency of the process (Neilson, AHEd. Organic Bromine and Iodine Compounds. In the Handbook of Enviromental Chemistry, Springer, Heidelberg, Berlin, 2003). Therefore, developing efficient synthetic methods for aryl halides is currently a hot research area in both academia and industry (Dagani, MJ; Barda, HJ; Benya, TJ; Sanders, DCEds. Ullmann's Encyclopedia of Industrial Chemistry: Bromine Compounds, Wiley-VCH, Weinheim, 2002). Electron-depleted aromatic rings exhibit significantly reduced nucleophilicity due to the presence of various electron-withdrawing groups (EWGs). Therefore, compared to electron-rich and moderately charged aromatic rings, the electrophilic halogenation of electron-poor aromatic rings is more challenging. To address this problem, chemists have developed numerous strategies over the past century, but these often require the addition of excess strong Lewis acids or sulfonic acids as activating agents. Such demanding reaction conditions undoubtedly lead to poor selectivity, low yields, and insufficient substrate compatibility, while the large amounts of acidic waste generated are also inconsistent with the principles of "green chemistry." Summary of the Invention

[0003] The following is an overview of the subject matter described in detail herein. This overview is not intended to limit the scope of the claims.

[0004] This invention represents the first successful catalytic halogenation reaction of electron-depleted aromatic rings. The mild reaction conditions, inexpensive halogenating reagents, and excellent functional group compatibility make this system suitable for the late-stage modification of a wide range of natural products and pharmaceutical molecules.

[0005] This invention provides a halogenation synthesis method for aromatic ring compounds, which solves the problems existing in the prior art.

[0006] Specifically, the present invention provides a halogenation synthesis method for aromatic ring compounds, comprising: halogenating aromatic ring compounds to obtain aryl halides in the presence of a catalyst, halogenation reagent XY and a solvent;

[0007]

[0008] Here, the aromatic ring compound has the structure shown in formula (I), and the aryl halide has the structure shown in formula (II); wherein Indicates aryl or heteroaryl; R 1 R 2 R 3 R 4 and R 5 At least one of the groups is selected from a conjugated group or an electron-withdrawing group, and the remaining groups are independently selected from hydrogen, halogen, nitro, C, etc. 1-5 Halogenated alkyl, hydroxyl, aryl, heteroaryl, amino, C 1-5 Alkyl-substituted monoalkylamino or dialkylamino, benzylamino, C 1-14 Alkyl, C 1-5 Alkoxy, C 1-5 Aldehyde group or C 1-5 Ester group; X is selected from chlorine, bromine or iodine;

[0009] The catalyst is sulfonic acid;

[0010] The halogenating agent is XY, wherein Y is selected from succinimide, imidazolidinedione, cyanuric acid, phthalimide, saccharin, amide group, tert-butoxy group, sulfonamide, and amidine; X is selected from chlorine, bromine, or iodine; optionally, the structure of the halogenating agent is as follows:

[0011]

[0012] The solvent is one or a mixture of several of the following: hexafluoroisopropanol, trifluoroethanol, trifluoroacetic acid, nitrobenzene, nitrobenzene, nitromethane, nitrobethanone, nitroboisopropane, nitrobenzene-n-propane, and nitrobenzene-n-butane.

[0013] In some preferred embodiments, the catalyst has the molecular structural formula R. 6 -SO3H; where R 6 Selected from hydrogen, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, benzoxy, acyloxy, acyl, ester, amide, monoalkylamino, dialkylamino, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

[0014] Preferably, the catalyst is CF3SO3H, methanesulfonic acid, benzenesulfonic acid, p-nitrobenzenesulfonic acid or o-nitrobenzenesulfonic acid.

[0015] In some preferred embodiments, wherein, The compounds are benzene, naphthalene, anthracene, pyrazole, binatol, indole, azaindole, pyrrole, tetrahydroquinoline, N-phenylmorpholine, xanthotoxin, propranolol, gefilrozil, naproxen, diclofenac, methadone, clopidogrel, chloramphenicol, apremilast, procaine, benzocyclohexane, 2-methylbenzocyclohexane, vanillin, papaverine, podophyllotoxin, rotenone, sinomenine, benzofuran, purine, thiophene, benzothiophene, indazole, pyrazole, imidazole, or imidazopyrazine;

[0016] Preferably, It can be benzene, pyridine, pyrimidine, pyrazine, imidazole, or pyrazole;

[0017] R 1 R 2 R 3 R 4 and R 5 Each of the following groups is independently selected from hydrogen, halogen, nitro, trifluoromethyl, hydroxyl, phenyl, amino, C 1-5 Alkyl-substituted monoalkylamino or dialkylamino, benzylamino, C 1-14 Alkyl, C 1-5 Alkoxy, C 1-5 Aldehyde group or C 1-5 Ester group.

[0018] In some preferred embodiments, the aromatic ring compound is selected from any one of the following compounds: clofibrate, fenofibrate, ornidazole, metronidazole, flurbiprofen, pioglitazone, rufenamide, atalulin methyl ester, bicalutamide, leflunomide, tinidazole, trifluorotoluene, 2,4-difluorobenzoic acid, nitrobenzene, methyl benzoate, benzoic acid, phenylmethyl sulfone, fluorobenzene, iodobenzene, p-bromonitrobenzene, p-nitrobenzyl alcohol. p-Methylnitrobenzene, methyl p-chlorobenzoate, methyl p-fluorobenzoate, p-methylbenzenesulfonamide, p-iodobenzaldehyde, p-bromotrifluorotoluene, p-bromobenzonitrile, 3-chlorobenzoic acid, 1,3-difluorobenzene, dimethyl 1,2-phthalate, 2-fluorobenzonitrile, 2-methoxypyridine, 2,6-dimethoxypyrimidine, 2-methoxypyrazine, p-bromotrifluorotoluene, p-fluorobenzoic acid, p-chlorobenzaldehyde, and 1,2,3-trifluorobenzene.

[0019] In some preferred embodiments, the halogenation reaction is carried out at a temperature of 0–150°C, preferably 60°C.

[0020] In some preferred embodiments, the molar ratio of the aromatic compound to the halogenating agent is 1:(0.4 to 10).

[0021] In some preferred embodiments, wherein,

[0022] For the chlorination reaction, the halogenating agent is trichloroisocyanuric acid (TCCA), and the molar ratio of the aromatic compound to the halogenating agent is 1:0.4.

[0023] For the bromination reaction, the halogenating agent is dibromohydantoin (DBDMH), and the molar ratio of the aromatic compound to the halogenating agent is 1:0.6;

[0024] For the iodination reaction, the halogenating agent is N-iodosuccinimide (NIS), and the molar ratio of the aromatic compound to the halogenating agent is 1:1.2.

[0025] In some preferred embodiments, the molar ratio of the aromatic compound to the catalyst is 1:(0.001 to 10), preferably 1:0.05.

[0026] In some preferred embodiments, the concentration of the aromatic compound is 0.001 to 10.0 M, preferably 0.5 M.

[0027] In some preferred embodiments, the halogenation reaction takes 0.1 to 72 hours, preferably 0.5 to 36 hours, and more preferably 1 to 25 hours.

[0028] The inventors compared the synthesis method of this invention with existing aromatic ring halogenation methods in the literature, and the results are as follows:

[0029]

[0030] TCCA: Trichloroisocyanuric acid; DMSO: Dimethyl sulfoxide; NCS: N-chlorosuccinimide; PIDA: Iodophenyl diacetic acid; m-NBSA: m-nitrobenzenesulfonic acid; NBS: N-bromosuccinimide.

[0031] When using tinidazole, antalulen methyl ester, clofibrate, or fenofibrate as substrates for chlorination or bromination reactions, our catalytic system can obtain the target product in good yield, while other reaction systems reported in the literature, such as TCCA / H2SO4, DMSO / NCS, PIDA / HCl, PIDA / HBr, and AuCl3 / NBS, can only achieve a maximum yield of 30%.

[0032] This invention, in the presence of a halogenating reagent, a catalyst, and a solvent, enables the highly reactive and selective synthesis of very useful aryl halides through the halogenation reaction of aromatic ring compounds. The method of this invention allows for the efficient synthesis of aryl halides and has broad application prospects in practical production.

[0033] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. The objects and other advantages of the invention may be realized and obtained by means of the structures particularly pointed out in the description and claims. Detailed Implementation

[0034] To make the objectives, technical solutions, and advantages of this application clearer, the embodiments of the present invention will be described in detail below. It should be noted that, unless otherwise specified, the embodiments and features described in these embodiments can be arbitrarily combined with each other.

[0035] EI source mass spectrometry was recorded using an Agilent 7890GC System with an Agilent 5975 Mass Selective Detector, and high-resolution mass spectrometry was recorded using a PE SCLEX QSTAR spectrometer.

[0036] The proton and carbon NMR spectra were recorded using a Bruker AVIII-400 spectrometer.

[0037] The reagents used in the examples were purchased from Acros, Aldrich Chemical Company, or Bailingwei, among others.

[0038] The following examples will help to further understand the present invention, but do not limit the scope of the invention. The preparation method of the present invention can be further illustrated by the preparation process of representative compounds as follows:

[0039] Example 1: Preparation of 3-bromo-4-methylnitrobenzene (Compound 1)

[0040]

[0041] a) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 171.6 mg of dibromohydantoin, 2.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 203.1 mg of 3-bromo-4-methylnitrobenzene, with a yield of 94%.

[0042] (b) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 171.6 mg of dibromohydantoin, 2.0 mg of 3-nitrobenzenesulfonic acid, and 2 mL of trifluoroethanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 95.1 mg of 3-bromo-4-methylnitrobenzene, with a yield of 44%.

[0043] c) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 171.6 mg of dibromohydantoin, 1.0 mg of methanesulfonic acid, and 2 mL of hexafluoroisopropanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 86.4 mg of 3-bromo-4-methylnitrobenzene, with a yield of 40%.

[0044] d) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 171.6 mg of dibromohydantoin, 1.5 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 125.3 mg of 3-bromo-4-methylnitrobenzene, with a yield of 58%.

[0045] e) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 171.6 mg of dibromohydantoin, 1.6 mg of benzenesulfonic acid, and 2 mL of hexafluoroisopropanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 170.6 mg of 3-bromo-4-methylnitrobenzene, with a yield of 79%.

[0046] f) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 171.6 mg of dibromohydantoin, 2.0 mg of p-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 194.4 mg of 3-bromo-4-methylnitrobenzene, with a yield of 90%.

[0047] h) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 171.6 mg of dibromohydantoin, 2.0 mg of o-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 164.1 mg of 3-bromo-4-methylnitrobenzene, with a yield of 76%.

[0048] i) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 213.6 mg of N-bromosuccinimide, 2.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 69.1 mg of 3-bromo-4-methylnitrobenzene, with a yield of 32%.

[0049] j) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 271.2 mg of N-bromophthalimide, 2.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 75.6 mg of 3-bromo-4-methylnitrobenzene, with a yield of 35%.

[0050] k) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 171.6 mg of dibromohydantoin, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 213.8 mg of 3-bromo-4-methylnitrobenzene, with a yield of 99%.

[0051] 1) Take a 25 mL Schlenk reaction tube, add 1.37 g of 4-methylnitrobenzene, 1.72 g of dibromohydantoin, 100 mg of m-nitrobenzenesulfonic acid, and 20 mL of hexafluoroisopropanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation and then separate by column chromatography to obtain 1.80 g of 3-bromo-4-methylnitrobenzene, with a yield of 85%.

[0052] m) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 171.6 mg of dibromohydantoin, 15.0 mg of trifluoromethanesulfonic acid, and 2 mL of nitromethane, and stir at 120 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 198.7 mg of 3-bromo-4-methylnitrobenzene, with a yield of 92%.

[0053] 1 H NMR (400MHz, CDCl3) δ8.37 (d, J=2.4Hz, 1H), 8.05 (dd, J=8.3, 2.4Hz, 1H), 7.39 (d, J=8.4Hz, 1H), 2.49 (s, 3H). 13 C NMR (100MHz, CDCl3) δ146.5, 145.8, 131.0, 127.3, 124.9, 122.1, 23.2.MS (EI) m / z (%): 63.0 (59), 89.0 (100), 168.9 (35), 214.9 (M + ,45),216.9(45,for 81 Br).

[0054] Example 2: Preparation of 3-bromonitrobenzene (Compound 2)

[0055]

[0056] A 25 mL Schlenk reaction tube was used to add 123.1 mg of nitrobenzene, 171.6 mg of dibromohydantoin, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 107.1 mg of 3-bromonitrobenzene, with a yield of 53%.

[0057] 1 H NMR (400MHz, CDCl3) δ8.39 (d, J=2.3Hz, 1H), 8.18 (dd, J=8.3, 2.1Hz, 1H), 7.91-7.74 (m, 1H), 7.44 (t, J=8.1Hz, 1H). 13 C NMR (100MHz, CDCl3): δ148.8, 137.6, 130.6, 126.8, 122.9, 122.1. MS (EI) m / z (%): 75.0 (100), 154.9 (90), 156.9 (85), 200.9 (M + ,65),202.9(65,for 81 Br).

[0058] Example 3: Preparation of methyl 3-bromobenzoate (Compound 3)

[0059]

[0060] A 25 mL Schlenk reaction tube was used to add 136.1 mg of methyl benzoate, 171.6 mg of dibromohydantoin, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 152.7 mg of methyl 3-bromobenzoate, with a yield of 71%.

[0061] 1 H NMR (400MHz, CDCl3) δ8.15 (t, J=1.8Hz, 1H), 7.94 (dt, J=7.8, 1.3Hz, 1H), 7.66 (dd, J=7.9, 2.1, 1.1Hz, 1H), 7.29 (t, J=7.9Hz, 1H), 3.90 (s, 3H). 13 C NMR (100MHz, CDCl3) δ165.6, 135.8, 132.5, 132.0, 129.9, 128.1, 122.4, 52.3.MS (EI) m / z (%): 76.1 (90), 154.9 (60), 182.9 (100), 213.9 (M + ,39),215.9(40,for 81Br).

[0062] Example 4: Preparation of 3-bromobenzoic acid (Compound 4)

[0063]

[0064] A 25 mL Schlenk reaction tube was used to add 122.1 mg of benzoic acid, 171.6 mg of dibromohydantoin, 2.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 144.7 mg of 3-bromobenzoic acid, with a yield of 72%.

[0065] 1 H NMR (400MHz, DMSO-d6) δ13.30 (brs, 1H), 8.03 (t, J=1.8Hz, 1H), 7.92 (dt, J=7.8, 1.3Hz, 1H), 7.82-7.77 (m, 1H), 7.45 (t, J=7.9Hz, 1H). 13 C NMR (100MHz, DMSO-d6) δ166.0, 135.5, 133.1, 131.8, 130.8, 128.3, 121.7.MS (EI) m / z (%): 50.2 (100), 155.2 (15), 182.8 (30), 199.8 (M + ,25),201.8(25,for 81 Br).

[0066] Example 5: Preparation of 3-bromophenylmethyl sulfone (Compound 5)

[0067]

[0068] A 25 mL Schlenk reaction tube was used to add 156.2 mg of phenylmethyl sulfone, 171.6 mg of dibromohydantoin, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 94.0 mg of 3-bromophenylmethyl sulfone, with a yield of 40%.

[0069] 1 H NMR (400MHz, CDCl3) δ8.07 (s, 1H), 7.87 (d, J=7.8Hz, 1H), 7.76 (d, J=7.9Hz, 1H), 7.45 (t, J=7.9Hz, 1H), 3.06 (s, 3H). 13C NMR (100MHz, CDCl3) δ142.3, 136.7, 130.9, 130.3, 125.9, 123.2, 44.4.MS (EI) m / z (%): 154.9 (100), 156.9 (100), 233.9 (M + ,45),235.9(45,for 81 Br).

[0070] Example 6: Preparation of 4-bromofluorobenzene (Compound 6)

[0071]

[0072] A 25 mL Schlenk reaction tube was used to add 96.1 mg of fluorobenzene, 171.6 mg of dibromohydantoin, 2.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 157.5 mg of 4-bromofluorobenzene, with a yield of 90%.

[0073] 1 H NMR (400MHz, CDCl3) δ7.44 (dd, J=8.8, 4.9Hz, 2H), 6.99-6.90 (m, 2H). 13 C NMR (100MHz, CDCl3) δ161.8 (d, J=246.5Hz), 132.9 (d, J=8.1Hz), 117.2 (d, J=22.7Hz), 116.5 (d, J=3.3Hz). 19 F NMR (376MHz, CDCl3) δ-115.3.MS (EI) m / z (%): 75.1 (50), 94.9 (85), 173.9 (M + ,100),175.9(100,for 81 Br).

[0074] Example 7: Preparation of 4-bromoiodobenzene (Compound 7)

[0075]

[0076] A 25 mL Schlenk reaction tube was used to add 204.0 mg of iodobenzene, 171.6 mg of dibromohydantoin, 2.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 229.1 mg of 4-bromoiodobenzene, with a yield of 81%.

[0077] 1H NMR (400MHz, CDCl3) δ7.54 (d, J=8.6Hz, 2H), 7.22 (d, J=8.6Hz, 2H). 13 C NMR (100MHz, CDCl3) δ139.0, 133.4, 122.2, 92.0.MS (EI) m / z (%): 126.9 (35), 154.9 (75), 156.9 (75), 281.8 (M + ,100),283.8(100,for 81 Br).

[0078] Example 8: Preparation of 3,4-dibromonitrobenzene (Compound 8)

[0079]

[0080] A 25 mL Schlenk reaction tube was used to add 202.0 mg of 4-bromonitrobenzene, 171.6 mg of dibromohydantoin, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 89.9 mg of 3,4-dibromonitrobenzene, with a yield of 32%.

[0081] 1 H NMR (400MHz, CDCl3) δ8.45 (d, J=2.6Hz, 1H), 8.02 (dd, J=8.8, 2.6Hz, 1H), 7.81 (d, J=8.8Hz, 1H). 13 C NMR (100MHz, CDCl3) δ147.1, 134.2, 132.6, 128.4, 125.7, 123.0.MS (EI) m / z (%): 74.1 (100), 153.7 (15), 222.9 (30), 278.9 (M + ,10),280.9(20,for 81 Br), 282.9(8, for 81 Br).

[0082] Example 9: Preparation of 2-bromo-4-nitrobenzyl alcohol (Compound 9)

[0083]

[0084] A 25 mL Schlenk reaction tube was used to add 153.1 mg of 4-nitrobenzyl alcohol, 171.6 mg of dibromohydantoin, 4.1 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 92.8 mg of 2-bromo-4-nitrobenzyl alcohol, with a yield of 40%.

[0085] 1 H NMR (400MHz, CDCl3) δ8.40 (d, J=2.3Hz, 1H), 8.21 (dd, J=8.5, 2.2Hz, 1H), 7.76 (d, J=8.5Hz, 1H), 4.83 (d, J=5.5Hz, 2H), 2.19 (t, J=5.8Hz, 1H). 13 C NMR (100MHz, CDCl3) δ147.5, 147.1, 128.2, 127.4, 122.5, 121.6, 64.2.MS (EI) m / z (%): 77.0 (100), 152.0 (100), 184.9 (15), 230.8 (M + ,15),232.9(15,for 81 Br).

[0086] Example 10: Preparation of 4-ethyl-3-bromonitrobenzene (Compound 10)

[0087]

[0088] A 25 mL Schlenk reaction tube was used to add 151.2 mg of 4-ethylnitrobenzene, 171.6 mg of dibromohydantoin, 4.1 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 220.9 mg of 2-bromo-4-nitrobenzyl alcohol, with a yield of 96%.

[0089] 1 H NMR (400MHz, CDCl3) δ8.40 (d, J=2.3Hz, 1H), 8.10 (dd, J=8.4, 2.4Hz, 1H), 7.40 (d, J=8.5Hz, 1H), 2.85 (q, J=7.5Hz, 2H), 1.27 (t, J=7.5Hz, 3H). 13 C NMR (100MHz, CDCl3) δ151.0, 146.5, 129.7, 127.8, 124.3, 122.5, 29.6, 13.7.MS (EI) m / z (%): 51.1 (59), 77.1 (100), 103.1 (77), 229.0 (M + ,50),231.0(50,for 81 Br).

[0090] Example 11: Preparation of 4-isopropyl-3-bromonitrobenzene (Compound 11)

[0091]

[0092] A 25 mL Schlenk reaction tube was used to add 165.2 mg of 4-isopropylnitrobenzene, 171.6 mg of dibromohydantoin, 4.1 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 197.7 mg of 4-isopropyl-3-bromonitrobenzene, with a yield of 81%.

[0093] 1 H NMR (400MHz, CDCl3) δ8.41 (d, J=2.4Hz, 1H), 8.13 (dd, J=8.6, 2.4Hz, 1H), 7.44 (d, J=8.6Hz, 1H), 3.49-3.41 (m, 1H), 1.28 (d, J=6.8Hz, 6H). 13 C NMR (100MHz, CDCl3) δ155.0, 146.3, 127.9, 127.1, 124.2, 122.6, 33.3, 22.5.MS (EI) m / z (%): 51.1 (22), 102.1 (42), 228.0 (100), 243.0 (M + ,38),245.0(35,for 81 Br).

[0094] Example 12: Preparation of methyl 3-bromo-4-chlorobenzoate (Compound 12)

[0095]

[0096] A 25 mL Schlenk reaction tube was used to add 170.6 mg of methyl 4-chlorobenzoate, 171.6 mg of dibromohydantoin, 2.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 212.0 mg of methyl 3-bromo-4-chlorobenzoate, with a yield of 85%.

[0097] 1 H NMR (400MHz, CDCl3) δ8.24 (d, J=2.0Hz, 1H), 7.87 (dd, J=8.4, 2.0Hz, 1H), 7.49 (d, J=8.3Hz, 1H), 3.92 (s, 3H). 13 C NMR (100MHz, CDCl3) δ164.7, 139.3, 134.6, 130.1, 129.8, 129.1, 122.4, 52.4.MS (EI) m / z (%): 74.0 (100), 110.0 (38), 218.9 (53), 247.9 (M+ ,15),249.9(15,for 81 Br).

[0098] Example 13: Preparation of methyl 3-bromo-4-fluorobenzoate (Compound 13)

[0099]

[0100] A 25 mL Schlenk reaction tube was used to add 154.1 mg of methyl 4-fluorobenzoate, 171.6 mg of dibromohydantoin, 4.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 20 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 212.0 mg of methyl 3-bromo-4-fluorobenzoate, with a yield of 91%.

[0101] 1 H NMR (400MHz, CDCl3) δ8.21 (dd, J=6.8, 2.1Hz, 1H), 7.94 (dd, J=8.7, 4.8Hz, 1H), 7.13 (t, J=8.3Hz, 1H), 3.89 (s, 3H). 13 C NMR (100MHz, CDCl3) δ164.83, 161.90 (d, J=254.7Hz), 135.23 (d, J=2.0Hz), 130.66 (d , J=8.3Hz), 127.58 (d, J=3.6Hz), 116.35 (d, J=23.0Hz), 109.15 (d, J=21.5Hz), 52.37. 19 Calculated F NMR (376MHz, CDCl3) δ-100.0.HRMS (ESI) value [C8H5BrFO2, MH] - : 230.9431, Actual measurement: 230.9431, 232.9411 (for 81 Br).

[0102] Example 14: Preparation of ethyl 3-bromo-4-chlorobenzoate (Compound 14)

[0103]

[0104] A 25 mL Schlenk reaction tube was used to add 184.6 mg of ethyl 4-chlorobenzoate, 171.6 mg of dibromohydantoin, 4.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 14 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 245.1 mg of ethyl 3-bromo-4-chlorobenzoate, with a yield of 93%.

[0105] 1H NMR (400MHz, CDCl3) δ8.28 (d, J=2.0Hz, 1H), 7.91 (dd, J=8.4, 2.0Hz, 1H), 7.52 (d, J=8.3Hz, 1H), 4.38 (q, J=7.1Hz, 2H), 1.40 (t, J=7.1Hz, 3H). 13 C NMR (100MHz, CDCl3) δ164.6, 139.4, 134.8, 130.35, 130.29, 129.3, 122.6, 61.6, 14.3. MS (EI) m / z (%): 190.8 (45), 218.9 (100), 235.9 (50), 261.9 (M + ,20),263.9(20,for 81 Br).

[0106] Example 15: Preparation of 3-bromo-4-methylbenzenesulfonamide (Compound 15)

[0107]

[0108] A 25 mL Schlenk reaction tube was used to add 171.2 mg of 4-methylbenzenesulfonamide, 171.6 mg of dibromohydantoin, 4.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 215.1 mg of methyl 3-bromo-4-fluorobenzoate, with a yield of 86%.

[0109] 1 H NMR (400MHz, DMSO-d6) δ 8.05-8.02 (m, 1H), 7.78-7.73 (m, 1H), 7.53 (d, J=8.0Hz, 1H), 7.48 (s, 2H), 2.40 (s, 3H). 13 C NMR (100MHz, DMSO-d6) δ143.4, 141.6, 131.5, 129.2, 124.8, 124.1, 22.5.MS (EI) m / z (%): 64.1 (84), 80.2 (100), 170.9 (20), 249.0 (M + ,13),251.0(10,for 81 Br).

[0110] Example 16: Preparation of 3-bromo-4-iodobenzaldehyde (Compound 16)

[0111]

[0112] A 25 mL Schlenk reaction tube was used to add 232.0 mg of 4-iodobenzaldehyde, 171.6 mg of dibromohydantoin, 2.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 4 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 139.9 mg of 3-bromo-4-iodobenzaldehyde, with a yield of 45%.

[0113] 1 H NMR (400MHz, CDCl3) δ9.89 (s, 1H), 8.05-8.02 (m, 2H), 7.45 (dd, J=8.1, 1.9Hz, 1H). 13 C NMR (100MHz, CDCl3) δ190.0, 141.1, 137.2, 133.0, 130.9, 128.4, 109.8.MS (EI) m / z (%): 50.1 (28), 74.1 (83), 127.0 (100), 309.8 (M + ,23),311.9(20,for 81 Br).

[0114] Example 17: Preparation of 3,4-dibromotrifluorotoluene (Compound 17)

[0115]

[0116] A 25 mL Schlenk reaction tube was used to add 225.0 mg of 4-bromotrifluorotoluene, 171.6 mg of dibromohydantoin, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 243.1 mg of 3,4-dibromotrifluorotoluene, with a yield of 80%.

[0117] 1 H NMR (400MHz, CDCl3) δ7.86 (d, J=2.0Hz, 1H), 7.73 (d, J=8.4Hz, 1H), 7.40 (dd, J=8.4, 2.1Hz, 1H). 13 C NMR (100MHz, CDCl3) δ134.12, 130.96 (q, J=33.7Hz), 130.55 (q, J=3.9Hz), 129.14 (q, J=1.8Hz), 125.48, 125.13 (q, J=3.7Hz), 122.87 (q, J=270.8Hz). 19 FNMR (376MHz, CDCl3) δ-62.9.MS (EI) m / z (%): 50.2 (29), 69.0 (100), 124.8 (100), 301.9 (M+ ,17),303.9(15,for 81 Br).

[0118] Example 18: Preparation of 3,4-dibromobenzonitrile (Compound 18)

[0119]

[0120] A 25 mL Schlenk reaction tube was used to add 182.0 mg of 4-bromobenzonitrile, 171.6 mg of dibromohydantoin, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 133.1 mg of 3,4-dibromobenzonitrile, with a yield of 51%.

[0121] 1 H NMR (400MHz, CDCl3) δ7.95-7.87 (m, 1H), 7.75 (dd, J=8.3, 1.0Hz, 1H), 7.52-7.41 (m, 1H). 13 C NMR (100MHz, CDCl3) δ136.6, 134.5, 131.4, 130.9, 125.9, 116.7, 112.7. MS (EI) m / z (%): 179.9 (40), 288.8 (M + ,50),260.8(100,for 81 Br), 262.8 (50, for 81 Br).

[0122] Example 19: Preparation of 2-bromo-5-chlorobenzoic acid (Compound 19)

[0123]

[0124] A 25 mL Schlenk reaction tube was used to add 156.6 mg of 3-chlorobenzoic acid, 171.6 mg of dibromohydantoin, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 5 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 155.4 mg of 2-bromo-5-chlorobenzoic acid, with a yield of 66%.

[0125] 1 H NMR (400MHz, DMSO-d6) δ13.80 (brs, 1H), 7.92 (d, J=2.4Hz, 1H), 7.73 (dd, J=8.5, 2.5Hz, 1H), 7.51 (d, J=8.5Hz, 1H). 13C NMR (100MHz, DMSO-d6) δ 165.4, 135.2, 133.4, 133.1, 132.6, 131.0, 119.9. HRMS (ESI) calculated values ​​[C7H3BrClO2, MH] - : 234.8986, Actual measurement: 234.8986, 236.8966 (for 81 Br).

[0126] Example 20: Preparation of 2,4-difluorobromobenzene (Compound 20)

[0127]

[0128] A 25 mL Schlenk reaction tube was used to add 114.1 mg of 1,3-difluorobenzene, 171.6 mg of dibromohydantoin, 2.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 191.1 mg of 2,4-difluorobromobenzene, with a yield of 99%.

[0129] 1 H NMR (400MHz, CDCl3) δ7.56-7.45 (m, 1H), 6.90 (td, J=8.6, 3.2Hz, 1H), 6.81 (dd, J=8.8, 5.7Hz, 1H). 13 C NMR (100MHz, CDCl3) δ162.1 (dd, J=249.6, 10.5Hz), 159.2 (dd, J=249.6, 10.5Hz), 133.8 (dd, J=9.2, 1.8Hz), 112.7 (dd, J=22.4, 4.0Hz), 105.2 (t, J=26.2Hz), 103.7 (dd, J=20.9, 4.4Hz). 19 F NMR (376MHz, CDCl3) δ-102.5, -110.6.MS (EI) m / z (%): 63.0 (40), 113.0 (80), 191.9 (M + ,100),193.9(100,for 81 Br).

[0130] Example 21: Preparation of dimethyl 3-bromophthalate (Compound 21)

[0131]

[0132] A 25 mL Schlenk reaction tube was used to add 194.2 mg of dimethyl phthalate, 171.6 mg of dibromohydantoin, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 14 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 125.6 mg of dimethyl 3-bromophthalate, with a yield of 46%.

[0133] 1 H NMR (400MHz, CDCl3) δ7.83 (d, J=1.9Hz, 1H), 7.66 (dd, J=8.1, 1.9Hz, 1H), 7.62 (d, J=8.3Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H). 13 C NMR (100MHz, CDCl3) δ167.0, 166.8, 134.0, 133.9, 131.8, 130.5, 130.2, 125.8, 52.9, 52.8.MS (EI) m / z (%): 63.0 (30), 113.0 (60), 272.0 (M + ,100),274.0(100,for 81 Br).

[0134] Example 22: Preparation of 2-iodo-5-bromotrifluorotoluene (Compound 22)

[0135]

[0136] A 25 mL Schlenk reaction tube was used to add 272.0 mg of 2-iodotrifluorotoluene, 171.6 mg of dibromohydantoin, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 1 hour. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 256.2 mg of 2-iodo-5-bromotrifluorotoluene, with a yield of 73%.

[0137] 1 H NMR (400MHz, CDCl3) δ7.84 (d, J=8.4Hz, 1H), 7.75 (d, J=2.7Hz, 1H), 7.31 (d, J=8.4Hz, 1H). 13 C NMR (100MHz, CDCl3) δ143.2, 135.9, 135.2 (q, J=31.5Hz), 130.7 (q, J=5.8Hz), 122.3, 121.8 (q, J=274.6Hz), 89.0. 19F NMR (376MHz, CDCl3) δ-63.2.MS (EI) m / z (%): 69.0 (19), 126.9 (100), 223.0 (15), 349.9 (M + ,16),351.8(15,for 81 Br).

[0138] Example 23: Preparation of 2-fluoro-5-bromobenzonitrile (Compound 23)

[0139]

[0140] A 25 mL Schlenk reaction tube was used to add 121.1 mg of 2-fluorobenzonitrile, 171.6 mg of dibromohydantoin, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 99.3 mg of 2-fluoro-5-bromobenzonitrile, with a yield of 82%.

[0141] 1 H NMR (400MHz, CDCl3) δ7.79-7.66 (m, 2H), 7.13 (t, J=8.6Hz, 1H). 13 C NMR (100MHz, CDCl3) δ162.1 (d, J=260.1Hz), 138.1 (d, J=8.1Hz), 135.7, 118.2 (d, J=20.9Hz), 117.0 (d, J=3.8Hz), 112.4, 103.4 (d, J=16.8Hz). 19 F NMR (376MHz, CDCl3) δ-108.2.MS (EI) m / z (%): 100.0 (45), 120.0 (85), 198.9 (M + ,100),200.9(100,for 81 Br).

[0142] Example 24: Preparation of 2-bromo-9H-fluorenone (Compound 24)

[0143]

[0144] A 25 mL Schlenk reaction tube was used to add 180.2 mg of fluorenone, 171.6 mg of dibromohydantoin, 4.1 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 139.9 mg of 2-bromo-9H-fluorenone, with a yield of 54%.

[0145] 1H NMR (400MHz, CDCl3) δ7.71 (s, 1H), 7.62 (d, J=7.4Hz, 1H), 7.57 (d, J=8.2Hz, 1H), 7.52-7.42 (m, 2H), 7.39-7.25 (m, 2H). 13 C NMR (100MHz, CDCl3) δ192.2, 143.5, 142.9, 137.0, 135.6, 134.9, 133.6, 129.3, 127.4, 124.5, 122.8, 121.6, 120.4.MS (EI) m / z (%): 75.1 (25), 151.0 (90), 231.9 (10), 257.9 (M + ,100),259.9(100,for 81 Br).

[0146] Example 25: Preparation of 2-methoxy-5-bromopyridine (Compound 25)

[0147]

[0148] A 25 mL Schlenk reaction tube was used to add 109.1 mg of 2-methoxypyridine, 171.6 mg of dibromohydantoin, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 126.0 mg of 2-methoxy-5-bromopyridine, with a yield of 67%.

[0149] 1 H NMR (400MHz, CDCl3) δ8.23-8.12 (m, 1H), 7.62 (dd, J=8.8, 1.2Hz, 1H), 6.64 (dd, J=8.8, 1.2Hz, 1H), 3.89 (s, 3H). 13 C NMR (100MHz, CDCl3) δ162.9, 147.5, 141.0, 112.6, 111.6, 53.7. MS (EI) m / z (%): 156.9 (65), 158.9 (65), 186.9 (M + ,100),188.9(100,for 81 Br).

[0150] Example 26: Preparation of 5-bromo-2,4-dimethoxypyrimidine (Compound 26)

[0151]

[0152] A 25 mL Schlenk reaction tube was used to add 140.1 mg of 2,4-dimethoxypyrimidine, 171.6 mg of dibromohydantoin, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 162.1 mg of 5-bromo-2,4-dimethoxypyrimidine, with a yield of 74%.

[0153] 1 H NMR (400MHz, CDCl3) δ8.26 (s, 1H), 4.01 (s, 3H), 3.94 (s, 3H). 13 C NMR (100MHz, CDCl3) δ166.7, 164.2, 159.1, 98.0, 55.2, 54.8.MS (EI) m / z (%): 202.9 (40), 204.9 (40), 217.9 (M + ,100),219.9(100,for 81 Br).

[0154] Example 27: Preparation of 2-bromo-5-methoxypyrazine (Compound 28)

[0155]

[0156] A 25 mL Schlenk reaction tube was used to add 110.1 mg of 2-methoxypyrazine, 171.6 mg of dibromohydantoin, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 79.4 mg of 2-bromo-5-methoxypyrazine, with a yield of 42%.

[0157] 1 H NMR (400MHz, CDCl3) δ8.18 (d, J=1.3Hz, 1H), 8.01 (d, J=1.3Hz, 1H), 3.95 (s, 3H). 13 C NMR (100MHz, CDCl3) δ159.9, 142.8, 135.3, 130.1, 54.2.MS (EI) m / z (%): 157.9 (35), 159.9 (35), 187.9 (M + ,100),189.9(100,for 81 Br).

[0158] Bromination of aromatic hydrocarbons a

[0159]

[0160] HFIP: Hexafluoroisopropanol.

[0161] a Reaction conditions: substrate (1.0 mmol), DBDMH (0.60 mmol), m-NBSA (0.01 mmol), HFIP (2.0 mL), 60 °C. Separation yield. b Use 5 mol% m-NBSA. c The NMR yield was reported. d Use 2 mol% m-NBSA.

[0162] Example 28: Preparation of 4-iodofluorobenzene (Compound 34)

[0163]

[0164] A 25 mL Schlenk reaction tube was used to add 96.1 mg of fluorobenzene, 270.0 mg of N-iodosuccinimide, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 210.9 mg of 4-iodofluorobenzene, with a yield of 95%.

[0165] 1 H NMR (400MHz, CDCl3) δ7.73-7.58 (m, 2H), 6.84 (t, J=8.7Hz, 2H). 13 C NMR (100MHz, CDCl3) δ162.7 (d, J=247.6Hz), 138.9 (d, J=7.7Hz), 117.7 (d, J=22.0Hz), 86.9 (d, J=3.3Hz). 19 F NMR (376MHz, CDCl3) δ-114.3.MS (EI) m / z (%): 75.0 (70), 95.0 (100), 126.9 (20), 221.9 (M + ,100).

[0166] Example 29: Preparation of 3-iodotrifluorotoluene (Compound 36)

[0167]

[0168] A 25 mL Schlenk reaction tube was used to add 146.1 mg of trifluorotoluene, 270.0 mg of N-iodosuccinimide, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 231.2 mg of 3-iodotrifluorotoluene, with a yield of 85%.

[0169] 1H NMR (400MHz, CDCl3) δ7.97 (s, 1H), 7.89 (d, J=8.1Hz, 1H), 7.60 (d, J=7.9Hz, 1H), 7.23 (t, J=7.9Hz, 1H). 13 C NMR (100MHz, CDCl3) δ140.9 (d, J=1.5Hz), 134.2 (q, J=4.0Hz), 132.4 (q, J=32.8Hz), 130.4, 124.5 (q, J=3.7Hz), 122.9 (q, J=272.7Hz), 93.8. 19 FNMR (376MHz, CDCl3) δ-62.9.MS (EI) m / z (%): 125.0 (10), 145.0 (80), 252.9 (20), 271.9 (M + ,100).

[0170] Example 30: Preparation of 3-iodobenzoic acid (Compound 39)

[0171]

[0172] A 25 mL Schlenk reaction tube was used to add 122.1 mg of benzoic acid, 270.0 mg of N-iodosuccinimide, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 178.6 mg of 3-iodobenzoic acid, with a yield of 72%.

[0173] 1 H NMR (400MHz, DMSO-d6) δ13.24 (brs, 1H), 8.23 ​​(t, J=1.7Hz, 1H), 7.97-7.93 (m, 2H), 7.29 (t, J=7.8Hz, 1H). 13 C NMR (100MHz, DMSO-d6) δ165.9, 141.3, 137.6, 132.9, 130.7, 128.6, 94.6.MS (EI) m / z (%): 51.1 (10), 76.1 (32), 127.0 (100), 248.0 (M + ,8).

[0174] Example 31: Preparation of methyl 3-iodobenzoate (Compound 40)

[0175]

[0176] A 25 mL Schlenk reaction tube was used to add 136.2 mg of methyl benzoate, 270.0 mg of N-iodosuccinimide, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 10 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 230.6 mg of methyl 3-iodobenzoate, with a yield of 88%.

[0177] 1 H NMR (400MHz, CDCl3) δ8.35 (t, J=1.8Hz, 1H), 7.97 (dt, J=7.9, 1.4Hz, 1H), 7.85 (dd, J=7.9, 1.9Hz, 1H), 7.16 (t, J=7.8Hz, 1H), 3.90 (s, 3H). 13 C NMR (100MHz, CDCl3) δ165.5, 141.6, 138.4, 131.9, 130.0, 128.6, 93.7, 52.3.MS (EI) m / z (%): 76.1 (80), 127.0 (69), 230.9 (53), 263.0 (M + ,94).

[0178] Example 32: Preparation of 3-iodo-4-methylnitrobenzene (Compound 41)

[0179]

[0180] A 25 mL Schlenk reaction tube was used to add 137.1 mg of 4-methylnitrobenzene, 270.0 mg of N-iodosuccinimide, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 22 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 210.4 mg of 3-iodo-4-methylnitrobenzene, with a yield of 80%.

[0181] 1 H NMR (400MHz, CDCl3) δ8.63 (d, J=2.4Hz, 1H), 8.10 (dd, J=8.4, 2.4Hz, 1H), 7.38 (d, J=8.4Hz, 1H), 2.53 (s, 3H). 13 C NMR (100MHz, CDCl3) δ149.3, 146.2, 133.8, 129.7, 123.0, 99.9, 28.3.MS (EI) m / z (%): 51.0 (22), 89.1 (58), 126.9 (100), 263.9 (M + ,48).

[0182] Example 33: Preparation of 3-iodo-4-bromotrifluorotoluene (Compound 44)

[0183]

[0184] A 25 mL Schlenk reaction tube was used to add 225.0 mg of 4-bromotrifluorotoluene, 270.0 mg of N-iodosuccinimide, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 140.4 mg of 3-iodo-4-bromotrifluorotoluene, with a yield of 40%.

[0185] 1 H NMR (400MHz, CDCl3) δ8.09 (s, 1H), 7.72 (d, J=8.3Hz, 1H), 7.45 (dd, J=8.5, 2.0Hz, 1H). 13 C NMR (100MHz, CDCl3) δ137.0 (q, J=3.8Hz), 134.0 (q, J=1.5Hz), 132.9, 130.6 (q, J=33.3Hz), 126.1 (q, J=3.6Hz), 122.6 (q, J=272.8Hz), 101.4. 19 F NMR (376MHz, CDCl3) δ-62.8.MS (EI) m / z (%): 74.1 (30), 126.9 (100), 223.0 (15), 349.9 (M + ,20),351.8(20,for 81 Br).

[0186] Example 34: Preparation of 2,4-difluoroiodobenzene (Compound 45)

[0187]

[0188] A 25 mL Schlenk reaction tube was used to add 114.1 mg of 1,3-difluorobenzene, 270.0 mg of N-iodosuccinimide, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 168.1 mg of 2,4-difluoroiodobenzene, with a yield of 70%.

[0189] 1 H NMR (400MHz, CDCl3) δ7.76-7.65 (m, 1H), 6.90-6.80 (m, 1H), 6.76-6.66 (m, 1H). 13C NMR (100MHz, CDCl3) δ165.0-162.8(m), 162.5-160.4(m), 139.6(dd, J=9.2, 2.9Hz) , 113.4 (dd, J=22.0, 3.7Hz), 104.5 (dd, J=27.7, 25.9Hz), 74.6 (dd, J=25.9, 4.2Hz). 19 FNMR (376MHz, CDCl3) δ-89.3, -109.7.MS (EI) m / z (%): 63.0 (80), 113.0 (90), 126.9 (20), 239.9 (M + ,100).

[0190] Example 35: Preparation of 2-methyl-5-iodonitrobenzene (Compound 46)

[0191]

[0192] A 25 mL Schlenk reaction tube was used to add 137.1 mg of 2-methylnitrobenzene, 270.0 mg of N-iodosuccinimide, 10.0 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 17 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 142.0 mg of 2-methyl-5-iodonitrobenzene, with a yield of 54%.

[0193] 1 H NMR (400MHz, CDCl3) δ8.27 (d, J=1.8Hz, 1H), 7.80 (dd, J=8.1, 1.8Hz, 1H), 7.08 (dd, J=8.1, 0.9Hz, 1H), 2.54 (s, 3H). 13 C NMR (100MHz, CDCl3) δ149.5, 141.7, 134.2, 133.1, 89.7, 20.0.MS (EI) m / z (%): 89.0 (100), 126.9 (35), 245.9 (100), 262.9 (M + ,40).

[0194] Example 36: Preparation of 4-chlorofluorobenzene (Compound 49)

[0195]

[0196] A 25 mL Schlenk reaction tube was used to add 96.1 mg of fluorobenzene, 93.0 mg of trichloroisocyanuric acid, 7.5 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 10 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 122.7 mg of 4-chlorofluorobenzene, with a yield of 94%.

[0197] 1 H NMR (400MHz, CDCl3) δ7.35-7.26 (m, 2H), 7.05-6.95 (m, 2H). 13 C NMR (100MHz, CDCl3) δ161.3 (d, J=245.8Hz), 129.9 (d, J=8.4Hz), 129.1 (d, J=3.3Hz), 116.7 (d, J=23.1Hz). 19 F NMR (376MHz, CDCl3) δ-115.9.MS (EI) m / z (%): 84.0 (30), 95.0 (50), 130.0 (M + ,100),132.0(35,for 37 Cl).

[0198] Example 37: Preparation of 3-chloro-4-methylnitrobenzene (Compound 50)

[0199]

[0200] a) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 93.0 mg of trichloroisocyanuric acid, 7.5 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 157.9 mg of 3-chloro-4-methylnitrobenzene, with a yield of 92%.

[0201] (b) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 93.0 mg of trichloroisocyanuric acid, 7.5 mg of trifluoromethanesulfonic acid, and 2 mL of trifluoroethanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 51.5 mg of 3-chloro-4-methylnitrobenzene, with a yield of 30%.

[0202] c) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 93.0 mg of trichloroisocyanuric acid, 7.5 mg of trifluoromethanesulfonic acid, and 2 mL of nitromethane, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 46.3 mg of 3-chloro-4-methylnitrobenzene, with a yield of 27%.

[0203] d) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 93.0 mg of trichloroisocyanuric acid, 7.5 mg of trifluoromethanesulfonic acid, and 2 mL of nitropropane, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 20.6 mg of 3-chloro-4-methylnitrobenzene, with a yield of 12%.

[0204] e) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 93.0 mg of trichloroisocyanuric acid, 40.2 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 73.8 mg of 3-chloro-4-methylnitrobenzene, with a yield of 43%.

[0205] f) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 93.0 mg of trichloroisocyanuric acid, 40.2 mg of o-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 54.9 mg of 3-chloro-4-methylnitrobenzene, with a yield of 32%.

[0206] g) Take a 25 mL Schlenk reaction tube, add 137.1 mg of 4-methylnitrobenzene, 93.0 mg of trichloroisocyanuric acid, 40.2 mg of p-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol, and stir at 60 °C for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation, and then separate by column chromatography to obtain 73.6 mg of 3-chloro-4-methylnitrobenzene, with a yield of 43%.

[0207] 1 H NMR (400MHz, CDCl3) δ8.23 (d, J=2.2Hz, 1H), 8.03 (dd, J=8.4, 2.3Hz, 1H), 7.40 (d, J=8.4Hz, 1H), 2.48 (s, 3H). 13 C NMR (100MHz, CDCl3) δ146.7, 144.0, 135.2, 131.3, 124.2, 121.6, 20.4.MS (EI) m / z (%): 63.0 (60), 89.0 (100), 125.0 (60), 171.0 (M + ,60),173.0(20,for 37 Cl).

[0208] Example 38: Preparation of 3-chloro-4-bromonitrobenzene (Compound 51)

[0209]

[0210] A 25 mL Schlenk reaction tube was used to add 202.0 mg of 4-bromonitrobenzene, 93.0 mg of trichloroisocyanuric acid, 30.0 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 118.2 mg of 3-chloro-4-bromonitrobenzene, with a yield of 50%.

[0211] 1 H NMR (400MHz, CDCl3) δ8.33 (d, J=2.5Hz, 1H), 8.00 (dd, J=8.8, 2.6Hz, 1H), 7.83 (d, J=8.8Hz, 1H). 13 C NMR (100MHz, CDCl3) δ147.3, 135.9, 134.4, 130.3, 125.2, 122.5.MS (EI) m / z (%): 74.0 (100), 110.0 (75), 190.9 (80), 234.9 (M + ,60),236.9(100,for 81 Br), 238.9(30, for 37 Cl and 81 Br).

[0212] Example 39: Preparation of 3-chloro-4-fluorobenzoic acid (Compound 52)

[0213]

[0214] A 25 mL Schlenk reaction tube was used to add 140.1 mg of 4-fluorobenzoic acid, 93.0 mg of trichloroisocyanuric acid, 30.0 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 113.5 mg of 3-chloro-4-fluorobenzoic acid, with a yield of 65%.

[0215] 1 H NMR (400MHz, DMSO-d6) δ13.42 (brs, 1H), 8.06 (dd, J=7.3, 2.1Hz, 1H), 7.96 (dd, J=8.7, 4.8Hz, 1H), 7.55 (t, J=8.8Hz, 1H). 13C NMR (100MHz, DMSO-d6) δ165.4, 160.0 (d, J=253.1Hz), 131.6, 130.5 (d, J=8.7Hz), 128.7 (d, J=3.6Hz), 120.0 (d, J=17.9Hz), 117.3 (d, J=21.5Hz). 19 F NMR (376MHz, DMSO-d6) δ-110.0.MS (EI) m / z (%): 94.0 (20), 129.0 (55), 157.0 (100), 174.0 (M + ,65),176.0(20,for 37 Cl).

[0216] Example 40: Preparation of methyl 3,4-dichlorobenzoate (Compound 53)

[0217]

[0218] A 25 mL Schlenk reaction tube was used to add 170.6 mg of methyl 4-chlorobenzoate, 93.0 mg of trichloroisocyanuric acid, 7.5 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 184.5 mg of methyl 3,4-dichlorobenzoate, with a yield of 90%.

[0219] 1 H NMR (400MHz, CDCl3,) δ8.09 (d, J=2.0Hz, 1H), 7.84 (dd, J=8.3, 2.0Hz, 1H), 7.50 (d, J=8.4Hz, 1H), 3.92 (s, 3H). 13 C NMR (100MHz, CDCl3) δ165.1, 137.5, 132.8, 131.4, 130.4, 129.8, 128.5, 52.5.MS (EI) m / z (%): 109.0 (25), 145.0 (40), 173.0 (100), 204.0 (M + ,30),226.0(10,for 37 Cl).

[0220] Example 41: Preparation of 3-chloro-4-iodotrifluorotoluene (Compound 55)

[0221]

[0222] A 25 mL Schlenk reaction tube was used to add 272.0 mg of 4-iodotrifluorotoluene, 93.0 mg of trichloroisocyanuric acid, 7.5 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 260.5 mg of 3-chloro-4-iodotrifluorotoluene, with a yield of 85%.

[0223] 1 H NMR (400MHz, CDCl3,) δ7.98 (d, J=8.3Hz, 1H), 7.68 (d, J=2.4Hz, 1H), 7.19 (dd, J=8.3, 2.3Hz, 1H). 13 C NMR (100MHz, CDCl3) δ140.9, 139.5, 132.1 (q, J=33.4Hz), 126.0 (q, J=3.8Hz), 124.4 (q, J=3.5Hz), 123.1 (q, J=272.5Hz), 102.8. 19 F NMR (376MHz, CDCl3) δ-63.1.MS (EI) m / z (%): 75.0 (25), 144.0 (25), 179.0 (55), 306.0 (M + ,100),308.0(30,for 37 Cl).

[0224] Example 42: Preparation of 3,4-dichlorobenzaldehyde (Compound 56)

[0225]

[0226] A 25 mL Schlenk reaction tube was used to add 140.6 mg of 4-chlorobenzaldehyde, 93.0 mg of trichloroisocyanuric acid, 7.5 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 112.0 mg of 3,4-dichlorobenzaldehyde, with a yield of 64%.

[0227] 1 H NMR (400MHz, CDCl3,) δ9.95 (s, 1H), 7.95 (d, J=2.0Hz, 1H), 7.72 (dd, J=8.2, 1.9Hz, 1H), 7.63 (d, J=8.3Hz, 1H). 13 C NMR (100MHz, CDCl3) δ189.6, 139.0, 135.7, 133.9, 131.2, 131.1, 128.3.MS (EI) m / z (%): 75.0 (45), 111.0 (25), 145.0 (45), 174.0 (M+ ,100),176.0(30,for 37 Cl).

[0228] Example 43: Preparation of 1-chloro-2,4-difluorobenzene (Compound 57)

[0229]

[0230] A 25 mL Schlenk reaction tube was used to add 114.1 mg of 1,3-difluorobenzene, 93.0 mg of trichloroisocyanuric acid, 7.5 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 14 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 92.1 mg of 1-chloro-2,4-difluorobenzene, with a yield of 64%.

[0231] 1 H NMR (400MHz, CDCl3) δ7.62-7.53 (m, 2H), 7.23-7.14 (m, 1H). 13 C NMR (100MHz, CDCl3) δ161.6 (d, J=259.7Hz), 135.1 (d, J=8.1Hz), 132.8, 130.1 (d, J=3.7Hz), 117.9 (d, J=20.9Hz), 112.6, 102.9 (d, J=17.2Hz). 19 F NMR (376MHz, CDCl3) δ-108.8.MS (EI) m / z (%): 100.0 (10), 120.0 (20), 155.0 (M + ,100),157.0(35,for 37 Cl).

[0232] Example 44: Preparation of 2,3,4-trifluorochlorobenzene (Compound 59)

[0233]

[0234] A 25 mL Schlenk reaction tube was used to add 132.1 mg of 1,2,3-trifluorobenzene, 93.0 mg of trichloroisocyanuric acid, 7.5 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 20 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 141.5 mg of 2,3,4-trifluorochlorobenzene, with a yield of 85%.

[0235] 1 H NMR (400MHz, CDCl3) δ7.19-7.09 (m, 1H), 7.00-6.89 (m, 1H). 13C NMR (100MHz, CDCl3) δ151.7-148.5(m), 149.6-146.4(m), 140.8(dt, J=254.9, 15.6H z), 123.9 (dd, J=7.5, 4.2Hz), 117.8 (dd, J=14.9, 4.2Hz), 112.2 (dd, J=18.5, 4.2Hz). 19 F NMR (376MHz, CDCl3) δ-133.4, -135.0, -156.0.MS (EI) m / z (%): 81.0 (35), 131.0 (30), 165.9 (M + ,100),167.9(35,for 37 Cl).

[0236] Chlorination and iodination of aromatic hydrocarbons a

[0237]

[0238] TfOH: Trifluoromethanesulfonic acid.

[0239] a For chlorination, the reaction conditions were: substrate (1.0 mmol), TCCA (0.40 mmol), TfOH (0.05 mmol), HFIP (2.0 mL), 60 °C; for iodination, the reaction conditions were: substrate (1.0 mmol), NIS (1.2 mmol), m-NBSA (0.05 mmol), HFIP (2 mL), 60 °C. Separation yields were also discussed. b The NMR yield was reported. c 20 mol% TfOH was used as the catalyst.

[0240] Example 45: Preparation of bromochlorofibrate (Compound 60)

[0241]

[0242] A 25 mL Schlenk reaction tube was used to add 121.4 mg of chlorofibrate, 85.8 mg of dibromohydantoin, 5.1 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 153.4 mg of bromochlorofibrate, with a yield of 96%.

[0243] 1H NMR (400MHz, CDCl3) 7.52 (d, J=2.6Hz, 1H), 7.13 (dd, J=8.8, 2.6Hz, 1H), 6.80 (d, J=8.9Hz, 1H), 4.23 (q, J=7.2Hz, 2H), 1.59 (s, 6H), 1.25 (t, J=7.1Hz, 3H). 13 C NMR (100MHz, CDCl3) δ 173.6, 151.4, 132.9, 127.8, 120.0, 116.7, 81.2, 77.3, 77.0, 76.7, 61.5, 25.0, 14.0. HRMS (ESI) calculated values ​​[C 12 H 15 BrClO3, M+H] + : 320.9893, Actual measurement: 320.9887, 322.9856 (for 81 Br).

[0244] Example 46: Preparation of bromofenofibrate (Compound 61)

[0245]

[0246] A 25 mL Schlenk reaction tube was used to add 180.4 mg of fenofibrate, 85.8 mg of dibromohydantoin, 5.1 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 186.9 mg of bromofenofibrate, with a yield of 85%.

[0247] 1 H NMR (400MHz, CDCl3) δ8.01 (d, J=2.2Hz, 1H), 7.69-7.61 (m, 3H), 7.43 (d, J=8.5Hz, 2H), 6.81 (d, J=8.6Hz, 1H), 5.12-5.01 (m, 1H), 1.68 (s, 6H), 1.20 (d, J=6.3Hz, 6H). 13 C NMR (100MHz, CDCl3) δ 192.8, 172.5, 156.3, 138.7, 135.7, 135.4, 131.4, 131.0, 130.1, 128.6, 116.5, 114.8, 81.0, 77.3, 77.0, 76.7, 69.4, 25.2, 21.4. HRMS (ESI) calculated values ​​[C 20 H 21 O4ClBr, M+H] + : 439.0312, Actual measurement: 439.0314, 441.0294 (for81 Br).

[0248] Example 47: Preparation of Bromoornidazole (Compound 62)

[0249]

[0250] A 25 mL Schlenk reaction tube was used to add 109.8 mg of ornidazole, 85.8 mg of dibromohydantoin, 5.1 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 110.5 mg of bromo-ornidazole, with a yield of 74%.

[0251] 1 H NMR (400MHz, CDCl3) δ4.57 (d, J=5.1Hz, 1H), 4.47-4.41 (m, 1H), 4.24 (dd, J=14.5, 2.7Hz, 1H), 4.10-3.98 (m, 1H), 3.74 (d, J=5.3Hz, 2H), 2.51 (s, 3H). 13 C NMR (100MHz, CDCl3) δ 147.0, 143.3, 104.9, 69.1, 50.1, 46.2, 14.6. HRMS (ESI) calculated values ​​[C7H 10 [N3O3VlBr,M+H] + : 297.9594, Actual measurement: 297.9593, 299.9571 (for 81 Br).

[0252] Example 48: Preparation of metronidazole bromo (Compound 63)

[0253]

[0254] A 25 mL Schlenk reaction tube was used to add 85.6 mg of metronidazole, 85.8 mg of dibromohydantoin, 5.1 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 110.0 mg of bromometronidazole, with a yield of 88%.

[0255] 1 H NMR (400MHz, DMSO-d6) δ5.08 (brs, 1H), 4.11 (t, J=5.4Hz, 2H), 3.69 (t, J=5.4Hz, 2H), 2.45 (s, 3H). 13C NMR (100MHz, DMSO-d6) δ 146.3, 143.1, 106.6, 58.9, 48.6, 13.9. HRMS (ESI) calculated values ​​[C6H9N3O3Br], M+H] + : 249.9827, Actual measurement: 249.9827, 251.9807 (for 81 Br).

[0256] Example 49: Preparation of bromofluprofen (Compound 64)

[0257]

[0258] A 25 mL Schlenk reaction tube was used to add 122.1 mg of flurbiprofen, 85.8 mg of dibromohydantoin, 5.1 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 109.9 mg of bromoflurbiprofen, with a yield of 68%.

[0259] 1 H NMR (400MHz, CDCl3) δ10.98 (brs, 1H), 7.57 (d, J=8.2Hz, 2H), 7.43-7.33 (m, 3H), 7.21-7.10 (m, 2H), 3.79 (q, J=7.1Hz, 1H), 1.56 (d, J=7.2Hz, 3H). 13 C NMR (100MHz, CDCl3) δ179.7, 159.5 (d, J=248.9Hz), 141.5 (d, J=7.6Hz), 134.2, 131.6, 130.6, 130. 48 (d, J=3.2Hz), 126.9 (d, J=13.4Hz), 123.8 (d, J=3.4Hz), 122.0, 115.5 (d, J=23.7Hz), 44.8, 17.9. 19 F NMR (376MHz, CDCl3) δ-117.2.HRMS (ESI) calculated values ​​[C 15 H 11 BrFO2, MH] - : 320.9926, Actual measurement: 320.9927, 322.9908 (for 81 Br).

[0260] Example 50: Preparation of brominated pioglitazone (compound 65)

[0261]

[0262] A 25 mL Schlenk reaction tube was used to add 196.4 mg of pioglitazone hydrochloride, 85.8 mg of dibromohydantoin, 10.2 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 169.8 mg of bromopyglitazone, with a yield of 78%.

[0263] 1 H NMR (400MHz, CDCl3) δ12.05 (brs, 1H), 8.38 (d, J=2.3Hz, 1H), 7.60 (dd, J=8.0, 2.3Hz, 1H), 7 .45 (d, J=2.1Hz, 1H), 7.34 (d, J=7.9Hz, 1H), 7.20 (dd, J=8.4, 2.1Hz, 1H), 7.09 (d, J=8.5Hz, 1 H), 4.91 (dd, J=8.8, 4.6Hz, 1H), 4.37 (t, J=6.6Hz, 2H), 3.30 (dd, J=14.2, 4.6Hz, 1H), 3.18 ( t, J=6.6Hz, 2H), 3.08 (dd, J=14.2, 8.8Hz, 1H), 2.60 (q, J=7.6Hz, 2H), 1.18 (t, J=7.6Hz, 3H). 13 C NMR (100MHz, CDCl3) δ 175.52, 171.48, 155.1, 153.6, 148.2, 136.8, 135.9, 133.6, 130.4, 129.8, 123.4, 113.5, 110.7, 68.0, 52.5, 36.6, 35.6, 24.9, 15.3. HRMS (ESI) calculated values ​​[C 19 H 20 [N2O3SBr, M+H] + : 435.0378, Actual measurement: 435.0372, 437.0353 (for 81 Br).

[0264] Example 51: Preparation of brominated bicalutamide (compound 66)

[0265]

[0266] A 25 mL Schlenk reaction tube was used to add 215.2 mg of bicalutamide, 85.8 mg of dibromohydantoin, 10.2 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 203.7 mg of brominated bicalutamide, with a yield of 80%.

[0267] 1H NMR (400MHz, CDCl3) δ9.97 (s, 1H), 9.72 (s, 2H), 8.72 (s, 2H), 8.58 (d, J = 8.7Hz, 1H), 8.03 (s, 2H), 7.94-7.87 (m, 6H), 7.77 (d, J = 8.7Hz, 1H ), 7.15 (td, J=8.4, 3.7Hz, 6H), 5.09 (d, J=4.6Hz, 3H), 3.99 (dd, J=14.5, 5.9Hz, 3H), 3.52 (dd, J=14.5, 1.9Hz, 3H), 1.63 (d, J=3.5Hz, 9H). 13 C NMR (100MHz, CDCl3) δ171.7, 171.7, 167.5, 164.9, 140.6, 139.4, 138.1, 135.1, 134.9, 134.9, 133.4, 133.1, 131.12, 131.08, 13 1.0, 131.0, 123.2, 122.8, 120.5, 117.9, 117.9, 116.9, 116.7, 116.0, 115.3, 114.1, 106.9, 105.7, 74.7, 74.5, 61.6, 61.5, 27.7. 19 F NMR (376MHz, CDCl3) δ -58.6, -62.2, -101.3, -101.4. HRMS (ESI) calculated values ​​[C 18 H 12 BrF4N2O4S, MH] - : 506.9639, Actual measurement: 506.9639, 508.9618 (for 81 Br).

[0268] Example 52: Preparation of bromo-leflunomide (Compound 67)

[0269]

[0270] A 25 mL Schlenk reaction tube was used to add 135.1 mg of leflunomide, 85.8 mg of dibromohydantoin, 10.2 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 167.6 mg of brominated leflunomide, with a yield of 96%.

[0271] 1H NMR (400MHz, CDCl3) δ8.61 (d, J=8.7Hz, 1H), 8.51 (s, 1H), 8.06 (s, 1H), 7.84 (d, J=2.0Hz, 1H), 7.61 (dd, J=8.8, 2.0Hz, 1H), 2.81 (s, 3H). 13 C NMR (100MHz, CDCl3) δ173.4, 158.9, 147.7, 138.2, 129.4 (q, J=3.9Hz), 127.3 (q, J =33.4Hz), 125.8 (q, J=3.7Hz), 124.3 (q, J=270.7Hz), 121.2, 112.9, 112.0, 12.8. 19 F NMR (376MHz, CDCl3) δ-62.3.HRMS (ESI) calculated values ​​[C 12 H7N2O2F3Br, MH] - : 346.9650, Actual measurement: 346.9650, 348.9625 (for 81 Br).

[0272] Example 53: Preparation of bromorufenamide (Compound 68)

[0273]

[0274] A 25 mL Schlenk reaction tube was used to add 119.1 mg of rufenamide, 85.8 mg of dibromohydantoin, 5.1 mg of m-nitrobenzenesulfonic acid, 75.0 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 134.7 mg of bromoleflunomide, with a yield of 85%.

[0275] 1 H NMR (400MHz, DMSO-d6) δ8.61 (s, 1H), 7.91-7.77 (m, 2H), 7.58-7.44 (m, 1H), 7.22 (t, J=9.0 Hz, 1H), 5.76 (s, 2H). 13 C NMR (100MHz, DMSO-d6) δ161.2, 160.0 (dd, J=249.2, 7.5Hz), 157.0 (dd, J=249.2, 7.5Hz), 142.9, 134.5 (d, J=9 .9Hz), 127.0, 113.6 (dd, J=22.9, 3.9Hz), 112.8 (t, J=20.0Hz), 103.7 (dd, J=21.5, 3.9Hz), 41.6 (t, J=3.5Hz). 19FNMR (376MHz, DMSO-d6) δ -106.8, -114.4. HRMS (ESI) calculated values ​​[V 10 H8F2N4O, M+H] + : 316.9850, Actual measurement: 316.9842, 318.9821 (for 81 Br).

[0276] Example 54: Preparation of methyl bromoantalenyl ester (Compound 69)

[0277]

[0278] A 25 mL Schlenk reaction tube was used to add 149.1 mg of methyl antalugenate, 85.8 mg of dibromohydantoin, 5.1 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 101.8 mg of bromoantalugenate, with a yield of 54%.

[0279] 1 H NMR (400MHz, CDCl3) δ8.82 (t, J=1.8Hz, 1H), 8.43-8.30 (m, 2H), 8.20 (dt, J=7.8, 1.5Hz, 1H), 7.70 (dd, J=8.9, 4.3Hz, 1H), 7.60 (t, J=7.8Hz, 1H), 7.19 (dd, J=9.8, 8.9Hz, 1H), 3.98 (s, 3H). 13 C NMR (100MHz, CDCl3) δ171.8 (d, J=4.5Hz), 168.1, 166.3, 159.8 (d, J=261.6Hz), 137.4 (d, J=8.6Hz), 133.4 (d, J=1.4H z), 132.4, 131.7, 131.1, 129.1, 128.7, 126.9, 119.0 (d, J=22.5Hz), 117.2 (d, J=3.7Hz), 114.4 (d, J=12.8Hz), 52.4. 19 FNMR (376MHz, VDVl3)δ-110.6.HRMS (ESI) calculated value [V 16 H 11 [N2O3FBr, M+H] + : 376.9937, Actual measurement: 376.9950, 378.9928 (for 81 Br).

[0280] Example 55: Preparation of chlorofenofibrate (Compound 70)

[0281]

[0282] A 25 mL Schlenk reaction tube was used to add 180.4 mg of fenofibrate, 46.5 mg of trichloroisocyanuric acid, 3.8 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 18 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 148.2 mg of chlorofenofibrate, with a yield of 75%.

[0283] 1 H NMR (400MHz, CDCl3) δ7.83 (d, J=2.2Hz, 1H), 7.75-7.62 (m, 2H), 7.57 (dd, J=8.6, 2.2Hz, 1H), 7.4 9-7.37 (m, 2H), 6.84 (d, J=8.6Hz, 1H), 5.07 (p, J=6.3Hz, 1H), 1.67 (s, 6H), 1.20 (d, J=6.3Hz, 6H). 13 C NMR (100MHz, CDCl3) δ 192.9, 172.5, 155.3, 138.7, 135.7, 132.3, 131.0, 129.3, 128.6, 125.4, 116.8, 80.9, 77.3, 77.0, 76.7, 69.4, 25.1, 21.4. HRMS (ESI) calculated values ​​[C 20 H 21 O4Cl2, M+H] + : 395.0817, Actual measurement: 395.0817, 397.0794 (for 37 Cl).

[0284] Example 56: Preparation of chlorochlorofibrate (Compound 71)

[0285]

[0286] A 25 mL Schlenk reaction tube was used to add 121.4 mg of chlorofibrate, 46.5 mg of trichloroisocyanuric acid, 3.8 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 20 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 127.5 mg of chlorofibrate, with a yield of 92%.

[0287] 1H NMR (400MHz, CDCl3) δ7.37 (d, J=2.6Hz, 1H), 7.10 (dd, J=8.8, 2.6Hz, 1H), 6.86 (d, J=8.8Hz, 1H), 4.25 (q, J=7.1Hz, 2H), 1.60 (s, 6H), 1.27 (t, J=7.2Hz, 3H). 13 C NMR (100MHz, CDCl3) δ 173.5, 150.3, 130.0, 127.6, 127.5, 127.1, 120.6, 81.1, 61.5, 24.9, 14.0. HRMS (ESI) calculated values ​​[V 12 H 15 Vl2O3, M+H] + : 277.0398, Actual measurement: 277.0395, 279.0371 (for 37 Cl).

[0288] Example 57: Preparation of chloroornidazole (compound 72)

[0289]

[0290] A 25 mL Schlenk reaction tube was used to add 109.8 mg of ornidazole, 46.5 mg of trichloroisocyanuric acid, 3.8 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 18 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 48.3 mg of chloro-ornidazole, with a yield of 38%.

[0291] 1 H NMR (400MHz, CDCl3) δ4.76 (s, 1H), 4.37 (h, J=4.3Hz, 1H), 4.20 (dd, J=14.5, 2.7 Hz, 1H), 4.01 (dd, J=14.5, 9.9Hz, 1H), 3.71 (dd, J=5.4, 3.3Hz, 2H), 2.45 (s, 3H). 13 CNMR (100MHz, CDCl3) δ 145.1, 140.3, 118.8, 68.9, 49.0, 46.1, 14.3. HRMS (ESI) calculated values ​​[C7H 10 [N3O3Cl2, M+H] + : 254.0099, Actual measurement: 254.0104, 256.0074 (for 37 Cl).

[0292] Example 58: Preparation of chloroantalulin methyl ester (compound 73)

[0293]

[0294] A 25 mL Schlenk reaction tube was used to add 149.1 mg of methyl antacid, 46.5 mg of trichloroisocyanuric acid, 3.8 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 106.5 mg of chloromethyl antacid, with a yield of 64%.

[0295] 1 H NMR (400MHz, CDCl3) δ8.82 (t, J=1.8Hz, 1H), 8.35 (dt, J=7.8, 1.5Hz, 1H), 8.25-8.16 (m, 2H), 7.65-7.51 (m, 2H), 7.30-7.20 (m, 1H), 3.98 (s, 3H). 13 C NMR (100MHz, CDCl3) δ171.9 (d, J=4.5Hz), 168.1, 166.2, 159.2 (d, J=261.2Hz), 134.4 (d, J=8.7Hz), 132.3, 131.7, 13 1.1, 130.4 (d, J = 1.6Hz), 130.1 (d, J = 3.7Hz), 129.1, 128.7, 126.9, 118.6 (d, J = 22.8Hz), 113.9 (d, J = 13.1Hz), 52.3. 19 F NMR (376MHz, CDCl3) δ-112.1.HRMS (ESI) calculated values ​​[C 16 H 11 [N2O3FCl, M+H] + : 333.0442, Actual measurement: 333.0440, 335.0418 (for 37 Vl).

[0296] Example 59: Preparation of iodoleflunomide (Compound 74)

[0297]

[0298] A 25 mL Schlenk reaction tube was used to add 135.1 mg of leflunomide, 135.0 mg of N-iodosuccinimide, 10.2 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 188.1 mg of iodoleflunomide, with a yield of 94%.

[0299] 1H NMR (400MHz, CDCl3) δ8.55 (d, J=0.6Hz, 1H), 8.50 (dd, J=8.7, 0.7Hz, 1H), 8.05 (dd, J=2.1, 0.7Hz, 1H), 7.92 (s, 1H), 7.64 (dd, J=8.7, 2.2Hz, 1H), 2.82 (s, 3H). 13 C NMR (100MHz, CDCl3) δ173.7, 158.9, 147.6, 140.6, 135.7 (q, J=3.9Hz), 127.8 (q, J=33.4Hz), 126.6 (q, J=3.9Hz), 122.7 (q, J=272.5Hz), 120.8, 111.8, 88.9, 12.8. 19 F NMR (376MHz, CDCl3) δ-62.3.HRMS (ESI) calculated values ​​[C 12 H9N2O2F3I,M+H] + 396.9661, Actual measurement: 396.9664.

[0300] Example 60: Preparation of iodochlorofibrate (Compound 75)

[0301]

[0302] A 25 mL Schlenk reaction tube was used to add 121.4 mg of clofibrate, 135.0 mg of N-iodosuccinimide, 10.2 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 188.1 mg of iodoclofibrate, with a yield of 94%.

[0303] 1 H NMR (400MHz, CDCl3) δ8.55 (d, J=0.6Hz, 1H), 8.50 (dd, J=8.7, 0.7Hz, 1H), 8.05 (dd, J=2.1, 0.7Hz, 1H), 7.92 (s, 1H), 7.64 (dd, J=8.7, 2.2Hz, 1H), 2.82 (s, 3H). 13 C NMR (100MHz, CDCl3) δ173.7, 158.9, 147.6, 140.6, 135.7 (q, J=3.9Hz), 127.8 (q, J=33.4Hz), 126.6 (q, J=3.9Hz), 122.7 (q, J=272.5Hz), 120.8, 111.8, 88.9, 12.8. 19F NMR (376MHz, CDCl3) δ-62.3.HRMS (ESI) calculated values ​​[C 12 H9N2O2F3I,M+H] + 396.9661, Actual measurement: 396.9664.

[0304] Example 61: Preparation of iodinated fenofibrate (compound 76)

[0305]

[0306] A 25 mL Schlenk reaction tube was used to add 180.4 mg of fenofibrate, 135.0 mg of N-iodosuccinimide, 10.2 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 236.1 mg of iodofenofibrate, with a yield of 97%.

[0307] 1 H NMR (400MHz, CDCl3) δ8.20 (d, J=2.2Hz, 1H.), 7.66-7.58 (m, 3H), 7.39 (d, J=8.5Hz, 2 H), 6.69 (d, J=8.6Hz, 1H), 5.03 (p, J=603Hz, 1H), 1.66 (s, 6H), 1.16 (d, J=6.3Hz, 6H). 13 C NMR (100MHz, CDCl3) δ 192.4, 172.3, 158.4, 141.4, 138.5, 135.6, 131.7, 131.1, 130.9, 128.5, 114.8, 89.4, 81.1, 77.3, 77.0, 76.7, 69.2, 25.2, 21.3. HRMS (ESI) calculated values ​​[C 20 H 21 O4ClI, M+H] + : 487.0173, Actual measurement: 487.0171, 489.0148 (for 37 Cl).

[0308] Example 62: Preparation of chlorinated nitroazole (compound 77)

[0309]

[0310] A 25 mL Schlenk reaction tube was used to add 123.6 mg of tinidazole, 93.0 mg of trichloroisocyanuric acid, 3.5 mg of trifluoromethanesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 95.8 mg of iodinated fenofibrate, with a yield of 68%.

[0311] 1 H NMR (400MHz, CDCl3) δ4.52 (t, J=6.4Hz, 2H), 3.39 (t, J=6.5Hz, 2H), 3.06 (q, J=7.1Hz, 2H), 2.55 (s, 3H), 1.44 (t, J=7.0Hz, 3H). 13 C NMR (100MHz, CDCl3) δ 143.7, 117.4, 49.7, 49.0, 37.7, 14.0, 6.5. HRMS (ESI) calculated values ​​[C8H 13 [N3O4SCl, M+H] + : 282.0315, Actual measurement: 282.0319, 284.0291 (for 37 Cl)

[0312] Example 63: Preparation of bromine instead of nitroazole (Compound 78)

[0313]

[0314] A 25 mL Schlenk reaction tube was used to add 123.6 mg of tinidazole, 85.8 mg of dibromohydantoin, 5.1 mg of m-nitrobenzenesulfonic acid, and 2 mL of hexafluoroisopropanol. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by column chromatography to obtain 123.9 mg of bromo-substituted tinidazole, with a yield of 76%.

[0315] 1 H NMR (400MHz, CDCl3) δ4.55 (t, J=7.2Hz, 2H), 3.39 (t, J=7.2Hz, 2H), 3.06 (q, J=7.5Hz, 2H), 2.58 (s, 3H), 1.44 (t, J=7.5Hz, 3H). 13 C NMR (100MHz, CDCl3) δ 145.5, 103.6, 49.9, 48.9, 38.8, 14.2, 6.6. HRMS (ESI) calculated values ​​[C8H 13 [N3O4SBr, M+H] + : 325.9810, Actual measurement: 325.9809, 327.9788 (for 81 Br).

[0316] Although the embodiments disclosed in this application are as described above, the content described is merely for the purpose of understanding this application and is not intended to limit this application. Any person skilled in the art to which this application pertains may make any modifications and changes in the form and details of the implementation without departing from the spirit and scope disclosed in this application; however, the scope of patent protection of this application shall still be determined by the scope defined in the appended claims.

Claims

1. A method of halogenating an aromatic ring compound comprising: Aryl halides are obtained by halogenation of aromatic ring compounds in the presence of a catalyst, halogenating reagent XY and solvent. Here, the aromatic ring compound has the structure shown in formula (I), and the aryl halide has the structure shown in formula (II); wherein It is benzene, pyridine, pyrimidine, pyrazine, imidazole, or pyrazole; R 1 R 2 R 3 R 4 and R 5 At least one of them is an electron-withdrawing group, and the remaining groups are independently selected from hydrogen, halogen, nitro, trifluoromethyl, hydroxyl, phenyl, amino, C 1-5 Alkyl-substituted monoalkylamino or dialkylamino, benzylamino, C 1-14 Alkyl, C 1-5 Alkoxy, C 1-5 Aldehyde group or C 1-5 Ester group; X is selected from chlorine, bromine or iodine; wherein the aromatic ring compound is not 1,4-dinitrobenzene or 1,4-dicyanobenzene; The catalyst is CF3SO3H, methanesulfonic acid, benzenesulfonic acid, p-nitrobenzenesulfonic acid or o-nitrobenzenesulfonic acid; The halogenating agent is dibromohydantoin, N-bromosuccinimide, N-bromophthalimide, N-iodosuccinimide, or trichloroisocyanuric acid; The solvent is one or a mixture of several of the following: hexafluoroisopropanol, trifluoroethanol, nitromethane, nitromethane, nitromisopropane, nitromethane, and nitromethane.

2. A method for the halogenation synthesis of an aromatic ring compound, comprising: Aryl halides are obtained by halogenation of aromatic ring compounds in the presence of a catalyst, halogenating reagent XY and solvent. Here, the aromatic ring compound has the structure shown in formula (I), and the aryl halide has the structure shown in formula (II); wherein the aromatic ring compound is selected from any one of the following compounds: clofibrate, fenofibrate, ornidazole, metronidazole, flurbiprofen, pioglitazone, rufenamide, atalulin methyl ester, bicalutamide, leflunomide, tinidazole, trifluorotoluene, 2,4-difluorobenzoic acid, nitrobenzene, methyl benzoate, benzoic acid, phenylmethyl sulfone, fluorobenzene, iodobenzene, p-bromonitrobenzene, p-nitrobenzyl alcohol, p-methylnitrobenzene, 4-ethylnitrobenzene, 4-isopropyl methylnitrobenzene. 4-Nitrobenzene, methyl p-chlorobenzoate, methyl p-fluorobenzoate, ethyl 4-chlorobenzoate, p-toluenesulfonamide, p-iodobenzaldehyde, p-bromotrifluorotoluene, p-bromobenzonitrile, 3-chlorobenzoic acid, 1,3-difluorobenzene, dimethyl 1,2-phthalate, 2-iodotrifluorotoluene, 2-fluorobenzonitrile, 2-methoxypyridine, 2,6-dimethoxypyrimidine, 2,4-dimethoxypyrimidine, 2-methoxypyrazine, chlorobenzene, bromobenzene, p-iodotrifluorotoluene, p-fluorobenzoic acid, p-chlorobenzaldehyde, 1,2,3-trichlorobenzene, and 1,2,3-trifluorobenzene; X is selected from chlorine, bromine, or iodine; The catalyst is CF3SO3H, methanesulfonic acid, benzenesulfonic acid, p-nitrobenzenesulfonic acid or o-nitrobenzenesulfonic acid; The halogenating agent is dibromohydantoin, N-bromosuccinimide, N-bromophthalimide, N-iodosuccinimide, or trichloroisocyanuric acid; The solvent is one or a mixture of several of the following: hexafluoroisopropanol, trifluoroethanol, nitromethane, nitromethane, nitromisopropane, nitromethane, and nitromethane.

3. The halogenation synthesis method according to claim 1 or 2, wherein, The reaction temperature for the halogenation reaction is 0–150 °C.

4. The halogenation synthesis method according to claim 3, wherein, The halogenation reaction is carried out at a temperature of 60 °C.

5. The halogenation synthesis method according to any one of claims 1-2 and 4, wherein, The molar ratio of the aromatic compound to the halogenating agent is 1:(0.4~10).

6. The halogenation synthesis method according to claim 5, wherein, For the chlorination reaction, the halogenating agent is trichloroisocyanuric acid (TCCA), and the molar ratio of the aromatic compound to the halogenating agent is 1:0.4; For the bromination reaction, the halogenating agent is dibromohydantoin (DBDMH), and the molar ratio of the aromatic compound to the halogenating agent is 1:0.6; or For the iodination reaction, the halogenating agent is N-iodosuccinimide (NIS), and the molar ratio of the aromatic compound to the halogenating agent is 1:1.

2.

7. The halogenation synthesis method according to any one of claims 1-2 and 4, wherein, The molar ratio of the aromatic compound to the catalyst is 1:(0.001-10).

8. The halogenation synthesis method according to claim 7, wherein, The molar ratio of the aromatic compound to the catalyst is 1:0.

05.

9. The halogenation synthesis method according to any one of claims 1-2 and 4, wherein, The concentration of the aromatic compound is 0.001~10.0 M.

10. The halogenation synthesis method according to claim 9, wherein, The concentration of the aromatic compound is 0.5 M.

11. The halogenation synthesis method according to any one of claims 1-2 and 4, wherein, The halogenation reaction takes 0.1 to 72 hours.

12. The halogenation synthesis method according to claim 11, wherein, The halogenation reaction takes 0.5 to 36 hours.

13. The halogenation synthesis method according to claim 12, wherein, The halogenation reaction takes 1 to 25 hours.

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