Synthesis method of an aromatic sulfonyl fluoride compound

Abstract

The present invention discloses a method for synthesizing aromatic sulfonyl fluoride compounds, belonging to the field of organic chemistry. In the method of the present invention, inexpensive and readily available Na2S2O4 is used as the sulfur dioxide source, and nickel acetate tetrahydrate is used as the nickel source. The substrate has a wide applicability, the raw materials are simple and readily available, and the economic cost is low. In addition, the method of the present invention only needs to react for 15 hours to obtain the target product in a good yield, which is more rapid and efficient. The synthesis method of the present invention converts simple and readily available β-arylvinyl bromide or benzyl bromide into aromatic sulfonyl fluoride under relatively simple conditions, and realizes the sulfofluorination of β-arylvinyl bromide or benzyl bromide in one pot. The target compound has wide applications in the fields of new drug development, new material synthesis, etc.

Description

Technical Field

[0001] The present invention specifically relates to a method for synthesizing aromatic sulfonyl fluoride compounds, belonging to the field of organic chemistry. Background Art

[0002] In recent years, with the increasing attention of sulfonyl fluoride compounds in the academic and industrial fields, their research and applications in the fields of chemical biology, drug design, and biochemistry have been widely carried out. Introducing a sulfonyl fluoride group can not only enhance the drug efficacy but also endow the molecule with good biological activity, showing great research value and application prospects. Correspondingly, the synthesis methods of sulfonyl fluoride compounds have also become a frontier and hot field in current synthetic chemistry. The traditional synthesis methods of sulfonyl fluoride compounds are mainly based on fluorine-chlorine exchange reactions. In recent years, some new synthesis methods have been reported successively, such as the oxidative fluorination of low-valent sulfur compounds and radical fluorosulfonylation reactions, which have greatly enriched the synthesis methods of such compounds. In addition, the use of synthetic building blocks or multi-connected molecules containing sulfonyl fluoride groups can often achieve the rapid and structurally diverse construction of molecular library resources. Summary of the Invention

[0003] The present invention has developed a new method for synthesizing aromatic sulfonyl fluoride. The present invention reacts β-arylvinyl bromide or benzyl bromide with a sulfur dioxide source under the catalysis of a catalyst, and finally synthesizes aromatic sulfonyl fluoride compounds through the action of N-fluorobis(phenylsulfonyl)imide (NFSI), realizing the dehalogenation fluorosulfonylation of aryl halides conveniently, rapidly, and efficiently.

[0004] The object of the present invention is to provide a method for synthesizing aromatic sulfonyl fluoride. The method is that in an organic solvent, the aromatic brominated substrate shown in formula (1) and a sulfur dioxide source react for a period of time under the action of a catalyst and a ligand, and then NFSI is added to continue the reaction to synthesize the aromatic sulfonyl fluoride compound shown in formula (2);

[0005]

[0006] wherein, R is or

[0007] R 1 selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen (F, Cl, Br, I), cyano, trifluoromethylthio, C1-C8 alkoxy, acyl, and amido; R 2 and R 3 are selected from H, C1-C4 alkyl, aryl;

[0008] R 4Selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen (F, Cl, Br, I), cyano, trifluoromethylthio, C1-C8 alkoxy, acyl and amido;

[0009] In one embodiment of the present invention, the method is carried out in an organic solvent, using β-arylvinyl bromide shown in formula (1a) or benzyl bromide shown in formula (1b), a sulfur dioxide source and NFSI as reactants, and under the action of a catalyst, a functionalization reaction is carried out to correspondingly synthesize an aromatic sulfonyl fluoride compound shown in formula (2a) or formula (2b);

[0010]

[0011] In one embodiment of the present invention, the sulfur dioxide source is sodium dithionite Na2S2O4.

[0012] In one embodiment of the present invention, the ligand is any one or more of the following:

[0013]

[0014] In one embodiment of the present invention, the aryl includes a substituted or unsubstituted benzene ring or naphthalene ring; the substitution can be mono- to trisubstitution; the substituting groups are selected from halogen, C1-C8 alkyl, and C1-C8 alkoxy.

[0015] In one embodiment of the present invention, the acyl is -C(O)R', and R' is selected from C1-C8 alkyl.

[0016] In one embodiment of the present invention, the amido is -C(O)-NR a R b ,R a 、R b are each independently selected from C1-C8 alkyl, or -NR a R b is n = 1 or 2.

[0017] In one embodiment of the present invention, the aryl includes a substituted or unsubstituted benzene ring or naphthalene ring; the substitution can be mono- to trisubstitution; the substituting groups are selected from halogen, C1-C8 alkyl, and C1-C8 alkoxy.

[0018] In one embodiment of the present invention, the organic solvent includes any one or more of methanol and ethanol. Methanol is preferred.

[0019] In one embodiment of the present invention, the catalyst is one or more of palladium acetate, palladium dichloride, tetrakis(triphenylphosphine)palladium, and palladium catalysts containing phosphine ligands, bis(triphenylphosphine)nickel chloride, nickel chloride, nickel acetate or its hydrate, nickel sulfate, nickel bromide, nickel carbonate, nickel, and nickel catalysts containing phosphine ligands.

[0020] In one embodiment of the present invention, the method further includes adding an additive, that is: the aromatic brominated substrate shown in formula (1) and the sulfur dioxide source first react for a period of time under the action of a catalyst, a ligand, and an additive, and then NFSI is added to continue the reaction to synthesize the aromatic sulfonyl fluoride compound shown in formula (2). The additive is any one or more of triethylamine, sodium acetate, 1,8-diazabicycloundec-7-ene, potassium carbonate, potassium tert-butoxide, acetic acid, ammonium acetate, tetrabutylammonium bromide, tetrabutylammonium fluoride, and lithium hydroxide monohydrate. Sodium acetate is preferred.

[0021] In one embodiment of the present invention, the molar ratio of the aromatic brominated substrate (β-arylvinyl bromide or benzyl bromide) to the catalyst is 1:(0 - 1). Specifically, 1:0.1 can be selected.

[0022] In one embodiment of the present invention, the molar feeding ratio of the aromatic brominated substrate (β-arylvinyl bromide or benzyl bromide) to the sulfur dioxide source is 1:(0.5 - 2.0); preferably 1:(0.9 - 1.5); specifically, 1:1.2 can be selected.

[0023] In one embodiment of the present invention, the molar ratio of the aromatic brominated substrate (β-arylvinyl bromide or benzyl bromide) to the ligand is 1:(0.1 - 1.1). Specifically, 1:0.2 can be selected.

[0024] In one embodiment of the present invention, the molar ratio of the aromatic brominated substrate (β-arylvinyl bromide or benzyl bromide) to NFSI is 1:(1.0 - 3.0). Specifically, 1:2 can be selected.

[0025] In one embodiment of the present invention, the molar ratio of the aromatic brominated substrate (β-arylvinyl bromide or benzyl bromide) to the additive is 1:(0.0 - 2.0). Specifically, 1:1 can be selected.

[0026] In one embodiment of the present invention, the reaction concentration of the aromatic brominated substrate (β-arylvinyl bromide or benzyl bromide) is 0.05 - 5 mmol / mL. Specifically, 0.1 mmol / mL is preferred.

[0027] In one embodiment of the present invention, the reaction is carried out in an inert atmosphere. For example: nitrogen (N2) atmosphere.

[0028] In one embodiment of the present invention, the molar ratio of the aromatic brominated substrate (β-arylvinyl bromide or benzyl bromide), Na2S2O4, NFSI, catalyst, ligand, and additive is specifically optional as 1:1.2:2:0.1:0.2:1.

[0029] In one embodiment of the present invention, the method is to first react at 30 - 100 °C for 0.5 - 15 h, and then return to room temperature and add NFSI to continue the reaction for 2 - 5 h.

[0030] Further, when R is react at 55 - 100 first for 0.5 - 1 h, and then return to room temperature and add NFSI to continue the reaction for 2 - 5 h. Specifically, it can be optionally to react at 65 °C for 0.5 h first, and then return to room temperature and add NFSI to continue the reaction for 3 h.

[0031] When R is react at 30 - 50 °C for 10 - 15 h first, and then return to room temperature and add NFSI to continue the reaction for 2 - 5 h. Specifically, it can be optionally to react at 35 °C for 12 h first, and then return to room temperature and add NFSI to continue the reaction for 3 h.

[0032] In one embodiment of the present invention, the steps of a novel green economy synthesis method are as follows:

[0033] Using β-arylvinyl bromide or benzyl bromide and Na2S2O4 as raw materials, adding a catalyst, ligand, and additive, stirring and reacting at 30 °C - 100 °C for a period of time to obtain a crude product of the aromatic sulfonyl fluoride compound or benzyl bromide, and then obtaining a pure aromatic sulfonyl fluoride compound through filtration, washing, vacuum distillation, and column chromatography separation.

[0034] In one embodiment of the present invention, the separation method is to use flash column chromatography separation to obtain the final product aromatic sulfonyl fluoride compound.

[0035] In one embodiment of the present invention, the method is preferably carried out as follows: Add β-arylvinyl bromide or benzyl bromide, Na2S2O4, catalyst, ligand, and additive into a reaction vessel containing methanol solvent according to a molar ratio of 1:1.2:0.1:0.2:1, stir at 60 °C - 80 °C for 12 hours, then return to room temperature, add 2 equivalents of NFSI to continue the reaction for 3 hours, and separate and purify to obtain the target product.

[0036] In one embodiment of the present invention, the reaction mechanism of the present invention is as follows: First, under the catalysis of copper, β-arylvinyl bromide or benzyl bromide coordinates with nickel. Sodium dithionite homolytically cleaves to generate a sulfite radical anion, which reduces nickel and generates one molecule of sulfur dioxide. The sulfur dioxide inserts between the metal and the carbon atom, and finally eliminates to form one molecule of aryl sulfite. Finally, NFSI is added to react with it to obtain the final product.

[0037] In one embodiment of the present invention, the uses of the β-arylvinylsulfonyl fluoride compound represented by formula (2a) include:

[0038] (a) The β-arylvinylsulfonyl fluoride compound itself as an active small molecule; for example: The literature (JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY. 2018, 33(1), 1266 - 1270) reports that the β-arylvinylsulfonyl fluoride compound has certain telomerase TERT inhibitory activity and can be used as a TERT inhibitor; the literature (European Journal of Medicinal Chemistry. 2019, 162, 364 - 377) reports that the β-arylvinylsulfonyl fluoride compound has certain antibacterial activity and can be used as an antibacterial drug; and the literature (Bioorganic Chemistry. 2019, 89, 103015) reports the good antioxidant and anti-inflammatory activities of the β-arylvinylsulfonyl fluoride compound.

[0039] (b) The β-arylvinylsulfonyl fluoride compound can also be used as an intermediate to further synthesize drugs / fine chemical products; for example: The literature (Journal of Organometallic Chemistry. 2019, 899, 120912) reports that the β-arylvinylsulfonyl fluoride compound is used as a raw material and further reacts with HPPh2 to synthesize a chiral phosphine. Chiral phosphines play an important role in the production of drugs and fine chemicals. Generally, these optically active compounds participate in the manufacturing process as organic catalysts or ligands in metal-mediated catalytic systems to induce asymmetry.

[0040] In one embodiment of the present invention, the uses of the arylmethylsulfonyl fluoride compound represented by formula (2b) include:

[0041] It can be used as a serine protease inhibitor, see the literature Chem.Sci. 2015, 6, 2650 - 2659.

[0042] Vinylsulfonyl fluoride can be used in a "one-pot click" reaction to directly convert the product into an aryl-substituted β-sultam. These compounds were found to be selectively addressable bis-electrophiles for sulfur(VI) fluoride exchange (SuFEx) click chemistry, where the vinyl moiety or the sulfonyl fluoride group can be the exclusive site of nucleophilic attack.

[0043] Beneficial effects:

[0044] In the method of the present invention, under a nitrogen (N2) atmosphere, using β-arylvinylic bromide or benzyl bromide as the substrate and Na2S2O4 as the sulfur dioxide reagent, in the presence of a catalyst, a ligand, and NFSI, the debromosulfofluorination of β-arylvinylic bromide or benzyl bromide can be achieved to obtain the target compound.

[0045] In the method of the present invention, inexpensive and readily available Na2S2O4 is used as the sulfur dioxide source, and nickel acetate is used as the catalyst. The substrate has a wide applicability, the raw materials are simple and readily available, and the economic cost is low. In addition, the method of the present invention only requires a reaction of 15 hours to obtain the target product in a good yield, which is more rapid and efficient.

[0046] The synthesis method of the present invention converts easily available β-arylvinylic bromide or benzyl bromide into aromatic sulfonyl fluoride compounds under relatively simple conditions, and realizes the sulfofluorination of β-arylvinylic bromide or benzyl bromide in one pot. The target compound has wide applications in the fields of new drug development, new material synthesis, etc. Description of the drawings

[0047] Figure 1 It is the synthesis route diagram of the method of the present invention. Detailed implementation manners

[0048] The following are the detailed implementation manners of the present invention.

[0049] The synthesis route diagram of the embodiment of the present invention is as Figure 1 shown:

[0050] β-Arylvinylic bromide or benzyl bromide, Na2S2O4, a catalyst, a ligand, and an additive are added to a reaction flask containing a methanol solvent according to a molar ratio of 1:1.2:0.1:0.2, stirred at 50 °C - 100 °C for 12 hours, then returned to room temperature, and 2 equivalents of NFSI are added and the reaction continues for 3 hours. After separation and purification, the target product is obtained. The reaction expression is Figure 1 .

[0051] The ligand structures involved are as follows:

[0052]

[0053] Example 1: Synthesis of 4-methoxystyrenesulfonyl fluoride

[0054] Under nitrogen protection, 4-methoxystyryl bromide (1 mmol), Na2S2O4 (1.2 mmol), sodium acetate (1 mmol), nickel acetate tetrahydrate (0.1 mmol), bis(2-diphenylphosphinophenyl) ether (ligand L7, 0.2 mmol) and methanol (10 mL) were added to a 25 ml reaction tube equipped with a magnetic stir bar. The mixture was reacted at 65 °C for 0.5 h. After returning to room temperature, NFSI (2 mmol) was added and the reaction was continued for 3 h. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate as an additive and washed with distilled water and saturated sodium chloride solution respectively. The solvent was removed by vacuum concentration, and the target product was separated and purified by column chromatography to obtain 149 mg of the product, with a yield of 69% (77% yield in 19F NMR).

[0055] 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 15.4 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.01 - 6.90 (m, 2H), 6.70 (dd, J = 15.4, 2.6 Hz, 1H), 3.87 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 163.28 (s), 148.62 (d, J = 2.5 Hz), 131.11 (s), 123.61 (d, J = 0.9 Hz), 114.88 (s), 114.67 (d, J = 27.6 Hz), 55.58 (s). 19 F NMR (376 MHz, CDCl3) δ 63.03 (s).

[0056] Example 2: Synthesis of 4-chlorostyrenesulfonyl fluoride

[0057] Under nitrogen protection, 4-chloro-β-styryl bromide (1 mmol), Na2S2O4 (1.2 mmol), sodium acetate (1 mmol), nickel acetate tetrahydrate (0.1 mmol), bis(2-diphenylphosphinophenyl) ether (ligand L7, 0.2 mmol) and methanol (10 mL) were added to a 25 ml reaction tube equipped with a magnetic stir bar. The mixture was reacted at 65 °C for 0.5 h. After returning to room temperature, NFSI (2 mmol) was added and the reaction was continued for 3 h. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate as an additive and washed with distilled water and saturated sodium chloride solution respectively. The solvent was removed by vacuum concentration, and the target product was separated and purified by column chromatography to obtain 154 mg of the product, with a yield of 70%.

[0058] 11H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 15.5 Hz, 1H), 7.54 - 7.41 (m, 4H), 6.86 (dd, J = 15.5, 2.5 Hz, 1H). 13 13C NMR (101 MHz, CDCl3) δ 147.49 (d, J = 2.8 Hz), 139.00 (s), 130.30 (s), 129.88 (s), 129.53 (d, J = 0.9 Hz), 118.60 (d, J = 28.5 Hz). 19 19F NMR (376 MHz, CDCl3) δ 62.34 (s).

[0059] Example 3: Synthesis of Benzylsulfonyl Fluoride

[0060] Under nitrogen protection, benzyl bromide (1 mmol), Na2S2O4 (1.2 mmol), sodium acetate (1 mmol), nickel acetate tetrahydrate (0.1 mmol), bis(2-diphenylphosphinophenyl) ether (ligand L7, 0.2 mmol) and methanol (10 mL) were added to a 25 ml reaction tube equipped with a magnetic stirrer. The mixture was reacted at 35 °C for 12 h. After returning to room temperature, NFSI (2 mmol) was added and the reaction continued for 3 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate as an additive and washed with distilled water and saturated sodium chloride solution respectively. The solvent was removed by vacuum concentration, and the target product was purified by column chromatography to obtain 87 mg of the product with a yield of 50%.

[0061] 1 1H NMR (400 MHz, CDCl3) δ 7.71 - 7.34 (m, 5H), 4.60 (d, J = 3.2 Hz, 2H). 13 13C NMR (101 MHz, CDCl3) δ 131.69 (s), 130.94 (s), 130.35 (s), 126.55 (s), 57.88 (d, J = 17.7 Hz). 19 19F NMR (376 MHz, CDCl3) δ 51.44 (s).

[0062] According to the synthesis process in Example 1, replacing the substrate 4-methoxystyryl bromide with other unsubstituted styryl bromides, styryl bromides with C1-C8 alkyl, cyano, trifluoromethylthio, -C(O)R', -C(O)-NR a R b substituted styryl bromides, etc., can all obtain β-arylethenylsulfonyl fluoride compounds with good yields.

[0063] According to the synthesis process in Example 3, replace the substrate benzyl bromide with other C1-C8 alkyl groups, C1-C8 haloalkyl groups, aryl groups, halogens, cyano groups, trifluoromethylthio groups, C1-C8 alkoxy groups, -C(O)R', -C(O)-NR a R b Substituted benzyl bromide can also obtain arylmethylsulfonyl fluoride compounds with good yields.

[0064] Example 4 Influence of different catalysts

[0065] Referring to Example 1, replace the catalyst nickel acetate tetrahydrate with palladium acetate, nickel sulfate, nickel, nickel carbonate respectively. In addition, add a group of experiments without any catalyst, and keep other conditions unchanged to synthesize the corresponding 4-methoxystyrenesulfonyl fluoride (2a). The specific yield results are shown in Table 1.

[0066] Table 1 Influence of different catalysts on the synthesis of 4-methoxystyrenesulfonyl fluoride a

[0067] Catalyst Yield (%) Not added 0 Nickel acetate (Example 1) 77 Palladium acetate 25 Nickel 55 Nickel sulfate 45 Nickel carbonate 66

[0068] a. The yield is the yield determined by fluorine spectrum.

[0069] It was found that: without catalyst or using palladium acetate or other nickel-based catalysts, the yields of the obtained products are worse than those in Example 1, and the yields do not exceed 70%.

[0070] Example 5 Influence of different ligands

[0071] Referring to Example 1, replace the ligand L7 with 2,2'-bipyridine (L2), 1,10-phenanthroline (L3), triphenylphosphine, tricyclohexylphosphine (L6), 1,1-binaphthalene-2,2-bis(diphenylphosphine) (L5) respectively. In addition, add a group of experiments without any ligand, and keep other conditions unchanged to synthesize the corresponding 4-methoxystyrenesulfonyl fluoride (2a). The specific yield results are shown in Table 2.

[0072] Table 2 Influence of different ligands on the synthesis of 4-methoxystyrenesulfonyl fluoride a

[0073] Ligand Yield (%) Not added 0 Bis(2-diphenylphosphinophenyl) ether (L7, Example 1) 77 2,2'-Bipyridine (L2) 0 1,10-Phenanthroline (L3) 0 Tricyclohexylphosphine (L6) 0 1,1'-Binaphthalene-2,2-bis(diphenylphosphine) (L5) 45 Triphenylphosphine (L9) 65

[0074] a. The yield is the yield determined by fluorine spectrum.

[0075] It was found that: the selection of ligands is still relatively important. Using some ligands, such as 2,2'-bipyridine, 1,10-phenanthroline, tricyclohexylphosphine, the target product cannot be effectively obtained.

[0076] Example 6 Influence of different solvents

[0077] Referring to Example 1, the solvent was replaced with acetonitrile, ethanol, etc. respectively while other conditions remained unchanged, and the corresponding β-styrenesulfonyl fluoride (2a) was synthesized. The specific yield results are shown in Table 3.

[0078] Table 3 Effects of Different Solvents on the Synthesis of β-Styrenesulfonyl Fluoride a

[0079] Solvent Yield (%) MeOH (Example 1) 77 EtOH 30 <![CDATA[CH3CN]]> 0 DMSO tace DMF tace MeCN 0 i-PrOH 0 Dioxane 0 <![CDATA[H2O]]> 0 Toluene 0 Acetone 0 DCE 0

[0080] a. The yield is the yield determined by fluorine spectrum; trace means trace amount that cannot be separated and obtained.

[0081] Example 7 Effects of Different Reaction Temperatures

[0082] Referring to Example 1, the reaction temperature was replaced with 25 °C, 55 °C, 100 °C respectively while other conditions remained unchanged, and 4-methoxystyrenesulfonyl fluoride was synthesized.

[0083] The specific yield results are shown in Table 5.

[0084] Table 5 Effects of Different Reaction Temperatures on the Synthesis of β-Styrenesulfonyl Fluoride a

[0085] Temperature (°C) Yield (%) 25 0 55 42 100 55

[0086] a. The yield is the yield determined by fluorine spectrum.

[0087] It was found that: when replacing 65 °C in Example 1 with 25 °C, 55 °C, 100 °C, the yields of the obtained products were all worse than that in Example 1, and the yields did not exceed 55%.

Claims

1. A method for synthesizing an aromatic sulfonyl fluoride, characterized in that, The method is that in an organic solvent, an aromatic brominated substrate shown by formula (1), a sulfur dioxide source react for a period of time under the action of a catalyst, a ligand and an additive, and then NFSI is added to continue the reaction to synthesize an aromatic sulfonyl fluoride compound shown by formula (2); ， wherein, R is or ; R 1 is selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, cyano, trifluoromethylthio, C1-C8 alkoxy, acyl and amido; R 2 and R 3 are each independently selected from H, C1-C4 alkyl, aryl; R 4 selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, cyano, trifluoromethylthio, C1-C8 alkoxy, acyl and amido; The aryl group is a substituted or unsubstituted benzene ring or naphthalene ring; the substitution is one to three substitutions; the substituted groups are selected from halogen, C1-C8 alkyl, C1-C8 alkoxy; The acyl group is -C(O)R', and R' is selected from C1-C8 alkyl; The amide group is -C(O)-NR a R b ,R a 、R b are each independently selected from C1-C8 alkyl, or -NR a R b is , n = 1 or 2; The organic solvent is methanol; The ligand is ; The catalyst is one or more of bis(triphenylphosphine) nickel chloride, nickel chloride, nickel acetate or its hydrate, nickel sulfate, nickel bromide, nickel carbonate, nickel; The additive is sodium acetate, acetic acid, ammonium acetate; The method is to react at 30-100 °C for 0.5-15 h first, and then return to room temperature and add NFSI to continue the reaction for 2-5 h.

2. The method according to claim 1, characterized in that, The sulfur dioxide source is Na2S2O4.

3. The method according to claim 1, characterized in that The molar ratio of the aromatic brominated substrate to the catalyst is 1:(0.1-1); the molar feeding ratio of the aromatic brominated substrate to the sulfur dioxide source is 1:(0.5-2.0); the dosage of the catalyst relative to the aromatic brominated substrate is 0.1-1 molar equivalent; the molar ratio of the aromatic brominated substrate to the ligand is 1:(0.1-1.1); the molar ratio of the aromatic brominated substrate to NFSI is 1:(1.0-3.0); the reaction concentration of the aromatic brominated substrate is 0.05-5 mmol / mL.

4. The method according to claim 1, wherein The molar ratio of the aromatic brominated substrate to the additive is 1:(1.0-2.0).

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