A fluorosulfonyldifluoroacetic acid metal salt complex and its preparation method and application

Abstract

The present invention relates to a fluorosulfonyl difluoroacetic acid metal salt complex and its preparation method and application. The chemical formula is: L n M(O2CCF2SO2F) z The ligand L is selected from one of the following compounds: #imgabs0# wherein R1, R2, and R3 are each selected from hydrogen, alkyl, alkoxy, hydroxyl, carboxyl, ester, aryl, nitro, sulfonic acid, fluoroalkyl, or halogen; and the metal ion M is at least one of lithium, magnesium, calcium, strontium, barium, scandium, yttrium, titanium, zirconium, chromium, molybdenum, tungsten, iron, ruthenium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver, gold, zinc, cadmium, mercury, aluminum, indium, tin, lead, antimony, bismuth, manganese, sodium, or cesium. Compared with the prior art, the present invention has inexpensive and readily available starting materials, mild reaction conditions, simple post-processing, high yield, and the product can be used as a trifluoromethylation reagent, showing broad application prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry and relates to a fluorosulfonyldifluoroacetic acid metal salt complex and a preparation method and application thereof. Background Art

[0002] Trifluoromethyl is a very important fluorine-containing group, which is widely used in medicine, pesticides, materials and other fields. Due to the strong electronegativity of fluorine, the trifluoromethyl group has strong electron-withdrawing properties (Pauling electronegativity: 3.5). Introducing it into a molecule can significantly change the pKa of the molecule. It can also reduce the electron cloud density of the adjacent groups through the induction effect, thereby improving the metabolic stability of the drug molecule. Secondly, the van der Waals volume of the trifluoromethyl group is With ethyl The introduction of a trifluoromethyl group into a molecule can significantly change the molecular conformation, thereby affecting the activity of the drug molecule. In addition, the trifluoromethyl group is a strongly lipid-soluble group, and the introduction of a trifluoromethyl group into a molecule can often improve its transmission, diffusion, and absorption in the body. Therefore, compared with general fluorine-free drugs, fluorine-containing drugs have better biopenetration and can reach the target molecule faster and more selectively, thereby generally greatly reducing the dosage of the drug used. Finally, because the bond energy of the C-F bond is much greater than that of the C-H bond, the trifluoromethyl group is a very stable group, and introducing a trifluoromethyl group into a molecule can significantly improve the thermal stability and chemical stability of the molecule. Although molecules containing trifluoromethyl groups exhibit very unique properties, there are no naturally occurring molecules containing trifluoromethyl groups in nature. Therefore, how to effectively introduce trifluoromethyl groups into molecules has received extensive attention and has gradually become a hot topic of research among organic chemists.

[0003] The unique properties of the trifluoromethyl group make trifluoromethylation an important reaction. The industry initially used fluorination reagents such as F2, HF, and SF4 for fluorination. These fluorination reagents have harsh reaction conditions and poor selectivity when used. With the increasing requirements of medicinal chemistry and synthetic chemistry, the research on trifluoromethylation methods of organic compounds has gradually shifted to finding trifluoromethylation reagents with mild reaction conditions, good reactivity, and low cost. Currently, the trifluoromethylation reagents commonly used in the field of organic fluorine chemistry include Ruppert-Prakash reagent, Chen reagent (FSO2CF2COOMe), CF3Br, Umemoto reagent, Togni reagent, etc. However, the preparation methods of the above reagents require relatively expensive raw materials, a long process route, high equipment requirements, and are difficult to prepare.

[0004] Based on the importance of introducing a trifluoromethyl group into a molecule, this patent discloses a novel trifluoromethylation reagent prepared using a readily available metal salt of fluorosulfonyldifluoroacetic acid. This reagent can trifluoromethylate hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, and halogenated aromatic hydrocarbons under mild conditions. The synthesis method is simple, the reaction conditions are mild, the yield is high, and industrial production is readily feasible. Summary of the Invention

[0005] The present invention aims to provide a novel fluorosulfonyldifluoroacetic acid metal salt complex having low equipment requirements, convenient preparation, simple process, and high yield, as well as a preparation method and application in trifluoromethylation reactions. The present invention features readily available and inexpensive starting materials, mild reaction conditions, simple post-processing, and high yield. The product can be used as a trifluoromethylation reagent, thus possessing broad application prospects.

[0006] The purpose of the present invention can be achieved by the following technical solutions:

[0007] A fluorosulfonyl difluoroacetic acid metal salt complex, the chemical formula of which is: L n M(O2CCF2SO2F) z ; wherein the ligand L has one of the following structural formulas:

[0008]

[0009] wherein R1, R2, and R3 are each one of hydrogen, alkyl, alkoxy, hydroxy, carboxyl, ester, aryl, nitro, sulfonic acid, fluoroalkyl, or halogen;

[0010] n = 1 or 2;

[0011] The metal ion M is at least one of lithium, magnesium, calcium, strontium, barium, scandium, yttrium, titanium, zirconium, chromium, molybdenum, tungsten, iron, ruthenium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver, gold, zinc, cadmium, mercury, aluminum, indium, tin, lead, antimony, bismuth, manganese, sodium or cesium; z is the valence state of the metal ion M.

[0012] A method for preparing a fluorosulfonyldifluoroacetic acid metal salt complex comprises:

[0013] M(OOCCF2SO2F)z+nL→L n M(OOCCF2SO2F)z

[0014] At a certain temperature, ligand L is slowly added to compound M (O2CCF2SO2F) z The reaction is carried out in an organic solvent and the temperature is slowly raised from low temperature to room temperature. After the reaction is completed, the filtrate is filtered and the filtrate is collected to obtain a fluorosulfonyl difluoroacetic acid metal salt complex.

[0015] Furthermore, the organic solvent includes at least one of diethyl ether, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, and n-hexane, preferably diethyl ether.

[0016] Furthermore, the ligand L and compound M (O2CCF2SO2F) z The molar ratio is 1:(1~20).

[0017] Furthermore, during the stirring reaction, the reaction time is 10 min to 24 h, preferably 1 h, and the reaction temperature is -196°C to 27°C, preferably -78°C to 20°C.

[0018] An application of a fluorosulfonyl difluoroacetic acid metal salt complex comprises using the fluorosulfonyl difluoroacetic acid metal salt complex as a trifluoromethylation reagent for a trifluoromethylation reaction:

[0019] L n M(OOCCF2SO2F)z+RX→R-CF3

[0020] L n M(O2CCF2SO2F) z and a compound of formula RX in an organic solvent to react to obtain a compound of formula R-CF3; wherein,

[0021] R is substituted or unsubstituted C1~C 20 Alkyl, substituted or unsubstituted C2~C 20 Alkenyl, substituted or unsubstituted C2~C 20 Alkynyl, substituted or unsubstituted C5~C 30 Aryl, substituted or unsubstituted C1~C 30 Heteroaryl, substituted or unsubstituted C3~C 30 Cycloalkyl, substituted or unsubstituted C1~C 30 The substituent is at least one of an alkyl group, an alkoxy group, a hydroxyl group, a carboxyl group, an ester group, an aryl group, a nitro group, an amino group, a cyano group, a sulfonic acid group, a fluoroalkyl group, and a halogen group;

[0022] X is a hydrogen atom, fluorine, chlorine, bromine or iodine.

[0023] Furthermore, the organic solvent is at least one of acetonitrile (MeCN), tetrahydrofuran (THF), ethyl acetate (CH3COOCH2CH3), N,N'-dimethylformamide (DMF), N,N'-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), and dimethyl sulfoxide (DMSO).

[0024] When X is H, acetonitrile is preferred; when X is halogen, N,N'-dimethylformamide is preferred.

[0025] Furthermore, in the mixed reaction, the reaction temperature is room temperature and the reaction time is 1 to 24 hours.

[0026] When X is H, the preferred reaction time is 5 h; when X is halogen, the preferred reaction time is 12 h.

[0027] Furthermore, when X is a halogen, an additive is also added to the mixing reaction;

[0028] The additive is at least one of lithium, magnesium, calcium, strontium, barium, scandium, yttrium, titanium, zirconium, chromium, molybdenum, tungsten, iron, ruthenium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver, gold, zinc, cadmium, mercury, aluminum, indium, tin, lead, antimony, bismuth, manganese, sodium, and cesium.

[0029] The compound of formula RX, L n M(O2CCF2SO2F) z The molar ratio to the additive is 1:(1-10):(1-10), preferably 1:2:2.

[0030] Furthermore, when X is a hydrogen atom, the reaction conditions of the mixed reaction also include:

[0031] A: The reaction is carried out under light, and the light source used is a 400-480 nm blue light source; the compound of formula RX, the oxidant and L n M(O2CCF2SO2F) z The molar ratio is 1:(1-20):(1-10); or,

[0032] B: Add oxidant and react under light;

[0033] The light source used is a 400-480nm blue light source; preferably a 440-445nm blue light source;

[0034] The oxidant is at least one of potassium persulfate complex, potassium persulfate, sodium persulfate, and ammonium persulfate;

[0035] The compound of formula RX, the oxidant and L n M(O2CCF2SO2F) z The molar ratio is 1:(1-20):(1-10), preferably 1:5:3.

[0036] Compared with the prior art, the present invention has the following characteristics:

[0037] 1) This novel trifluoromethylation reagent is simple and convenient to prepare, with high yield, good purity, and low-cost raw materials. Compared with similar trifluoromethylation reagents, it has better industrial prospects.

[0038] 2) This novel trifluoromethylation reagent has mild reaction conditions and a wide range of substrates when performing trifluoromethylation reactions.

[0039] 3) This novel trifluoromethylation reagent can decompose to produce various trifluoromethyl metal complexes. This method can be used to study the properties of various trifluoromethyl metal complexes, and has broad scientific research and application value.

[0040] 4) The starting materials of this invention, particularly tetrafluoroethane-β-sultone and fluorosulfonyldifluoroacetic acid, are common fluorine chemical raw materials with widespread availability, low cost, and high suitability for industrial production. Compared to other similar complex trifluoromethylation reagents, the present invention offers mild preparation conditions and simple post-processing. Furthermore, it can easily introduce trifluoromethyl groups into various molecules and further prepare a range of pharmaceuticals, pesticides, materials, and fine chemicals, possessing broad application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 The product obtained in Example 1 ( t X-ray structure diagram of Bu-bpy)Cu(O2CCF2SO2F)2.

[0042] Figure 2 7-chloro-2-(trifluoromethyl)thiophene[3,2-b]pyridine 1 H NMR.

[0043] Figure 3 7-chloro-2-(trifluoromethyl)thiophene[3,2-b]pyridine 19 F NMR.

[0044] Figure 4 7-chloro-2-(trifluoromethyl)thiophene[3,2-b]pyridine 13 C NMR. DETAILED DESCRIPTION

[0045] The present invention is described in detail below with reference to the accompanying drawings and specific examples. This example is implemented based on the technical solution of the present invention, and provides detailed implementation methods and specific operating procedures. However, the scope of protection of the present invention is not limited to the following examples. In addition, the reagents used in the present invention are all commercially available reagents.

[0046] Example 1: Synthesis of 4,4'-di-tert-butyl-2,2'-bipyridylsulfonylcopper difluoroacetate

[0047] Add copper fluorosulfonyl difluoroacetate (Cu(O2CCF2SO2F)2) (208.86g, 0.5mol) and diethyl ether (200mL) to a 500mL three-necked flask and cool it to -78°C. After the system temperature drops to -78°C, add 4,4'-di-tert-butyl-2,2'-bipyridyl difluoroacetate (120.78g, 0.45mol) in diethyl ether dropwise. After the addition is complete, naturally warm to room temperature and react for 1h. After the reaction is completed, filter and wash the filter residue with a small amount of diethyl ether to obtain a blue solid 4,4'-di-tert-butyl-2,2'-bipyridyl difluorosulfonyl copper fluoroacetate ((tBubpy)Cu(O2CCF2SO2F)2) with a yield of 95%. The correctness of the structure was confirmed by single crystal diffraction, see Figure 1 .

[0048] Comparative Example 1: Synthesis of 2,2'-Bipyridyl Fluorosulfonyl Copper Difluoroacetate

[0049] Basic copper carbonate (44.2 mg, 0.2 mmol) or copper hydroxide (39.0 mg, 0.4 mmol) and 2,2'-bipyridine (31.2 mg, 0.2 mmol) were added to a 10 mL sealed tube, and 2 mL of anhydrous ether was added. Fluorosulfonyldifluoroacetic acid (35.6 mg, 0.2 mmol) was added dropwise at room temperature and stirred for 1 h. The system turned black and no target compound was obtained.

[0050] Table 1 Synthesis attempts of 2,2'-bipyridylsulfonylcopper difluoroacetate

[0051]

[0052]

[0053] Add anhydrous copper fluorosulfonyl difluoroacetate (83.5 mg, 0.2 mmol) to a 10 mL sealed tube and cool to low temperature. Once the system temperature drops to the low temperature bath temperature, add a solution of 2,2'-bipyridine in diethyl ether (31.2 mg, 0.2 mmol) dropwise. After the addition is complete, naturally warm to room temperature and react for 1 hour. After the reaction is complete, filter and wash the residue with a small amount of diethyl ether to obtain a blue solid of 2,2'-bipyridine copper fluorosulfonyl difluoroacetate.

[0054] Table 2 Synthesis attempts of 2,2'-bipyridylsulfonylcopper difluoroacetate

[0055]

[0056]

[0057] Example 2: Synthesis of 1,10-phenanthroline fluorosulfonyl copper difluoroacetate

[0058] A 500mL three-necked flask was charged with copper fluorosulfonyl difluoroacetate (Cu(O2CCF2SO2F)2) (208.86g, 0.5mol) and diethyl ether (200mL) and cooled to -78°C. After the system temperature dropped to -78°C, a diethyl ether solution of 1,10-phenanthroline (81.09g, 0.45mol) was added dropwise. After the addition was complete, the temperature was naturally raised to room temperature and the reaction was allowed to proceed for 1h. After the reaction was completed, the reaction was filtered and the filter residue was washed with a small amount of diethyl ether to obtain a blue solid 1,10-phenanthroline copper fluorosulfonyl difluoroacetate ((phen)Cu(O2CCF2SO2F)2) in a yield of 90%.

[0059] Example 3: Synthesis of 2,2'-bipyridylsulfonylsilver difluoroacetate

[0060] Under light-shielding conditions, silver fluorosulfonyl difluoroacetate (Ag(O2CCF2SO2F)) (14.25 g, 50 mmol) and diethyl ether (20 mL) were added to a 50 mL three-necked flask and cooled at -78°C. After the system temperature dropped to -78°C, a diethyl ether solution of 2,2'-bipyridyl (7.03 g, 45 mmol) was added dropwise. After the addition was complete, the temperature was naturally raised to room temperature and the reaction was carried out for 1 hour. After the reaction was completed, the reaction was filtered and the filter residue was washed with a small amount of diethyl ether to obtain a white solid of 2,2'-bipyridyl fluorosulfonyl difluoroacetate ((bpy)Ag(O2CCF2SO2F)) with a yield of 90%.

[0061] Example 4: Synthesis of 2,2'-Bipyridyl Fluorosulfonyl Copper Difluoroacetate

[0062] A 500mL three-necked flask was charged with copper fluorosulfonyl difluoroacetate (Cu(O2CCF2SO2F)2) (208.86g, 0.5mol) and diethyl ether (200mL) and cooled to -78°C. After the system temperature dropped to -78°C, a diethyl ether solution of 2,2'-bipyridine (70.28g, 0.45mol) was added dropwise. After the addition was complete, the temperature was naturally raised to room temperature and the reaction was allowed to proceed for 1h. After the reaction was completed, the mixture was filtered and the filter residue was washed with a small amount of diethyl ether to obtain a blue solid, 2,2'-bipyridyl copper fluorosulfonyl difluoroacetate ((bpy)Cu(O2CCF2SO2F)2), in a yield of 97%.

[0063] Application of copper fluorosulfonyl difluoroacetate as a trifluoromethylation reagent

[0064] 1. When X is a hydrogen atom

[0065] Taking the synthesis of trifluoromethylcyclohexane as an example

[0066] Synthesis Condition Screening Example 1: Synthesis of Trifluoromethylcyclohexane

[0067] 2,2'-Bipyridyl fluorosulfonyl copper difluoroacetate ((bpy)Cu(O2CCF2SO2F)2, 172.2 mg, 0.3 mmol) and Oxone (307.4 mg, 0.5 mmol) were added to the reaction flask, the N2 atmosphere was replaced three times, the solvent MeCN (3 mL) was added, cyclohexane (8.4 mg, 0.1 mmol) was added, and the reaction was irradiated with 440-445 nm blue light. The reaction was stirred at room temperature for 6 hours, the reaction was stopped, and trifluorotoluene was added as an internal standard. The F spectrum yield was 50%. 19 FNMR (376MHz, CDCl3) δ-74.18 (t, J=9.1Hz).

[0068] Other conditions were the same as above. The specific data of the trifluoromethylation reaction under different light sources, time, solvents, temperatures, etc. are shown in Table 1.

[0069] Table 1 Investigation of reaction conditions

[0070]

[0071] Through the above condition screening, when X is a hydrogen atom, the optimal conditions obtained are: trifluoromethylation reagent (0.3 mmol, 3.0 eq.), Oxone (0.5 mmol, 5.0 eq.), RX (0.1 mmol, 1.0 eq.), acetonitrile as solvent, irradiation with 440-445 nm blue light, and stirring at room temperature for 12 hours.

[0072] Example 5: Synthesis of trifluoromethylcyclooctane

[0073] 2,2'-bipyridyl fluorosulfonyl copper difluoroacetate ((bpy)Cu(O2CCF2SO2F)2, 172.2 mg, 0.3 mmol) and Oxone (307.4 mg, 0.5 mmol) were added to the reaction flask, the N2 atmosphere was replaced three times, the solvent MeCN (3 mL) was added, cyclooctane (11.2 mg, 0.1 mmol) was added, and the reaction was irradiated with 440-445 nm blue light. The reaction was stirred at room temperature for 12 hours, the reaction was stopped, and trifluorotoluene was added as an internal standard. The F spectrum yield was 68%. 1 HNMR (400MHz, CDCl3) δ2.32–2.13(m,1H),1.92–1.73(m,4H),1.65–1.45(m,10H). 19 F NMR (376MHz, CDCl3) δ-73.39 (d, J=10.0Hz). 13C NMR (101MHz, CDCl3) δ128.96 (q, J = 279.5Hz), 41.91 (q, J = 24.3Hz), 26.37, 26.28, 25.56 (q, J = 2.6Hz), 25.10.

[0074] Example 6: Synthesis of 1-trifluoromethylphenylacetylene

[0075] 2,2'-bipyridyl fluorosulfonyl copper difluoroacetate ((bpy)Cu(O2CCF2SO2F)2, 172.2 mg, 0.3 mmol) was added to the reaction flask, N2 was replaced three times, solvent MeCN (3 mL) was added, phenylacetylene (10.2 mg, 0.1 mmol) was added, and irradiation with 440-445 nm blue light was performed. The reaction was stirred at room temperature for 12 hours, the reaction was stopped, dichloromethane (10 mL) was added, the mixture was washed three times with water, and dried; after spin drying, flash column chromatography was performed to obtain a light yellow oily compound 1-trifluoromethylphenylacetylene with a yield of 80%. 1 H NMR (400MHz, CDCl3, 293K, TMS): δppm 7.56 (d, J = 8.1Hz, 2H), 7.47 (d, J = 7.5Hz, 1H), 7.66 (t, J = 6.9Hz, 2H). 19 F NMR (376MHz, CDCl3): δppm-49.5 (s, 3F). 13 C NMR (100.7MHz, CDCl3, 293K, TMS): δppm 132.41 (d, J=2.1Hz), 130.88, 128.65, 118.45 (q, J=1.9Hz), 114.85 (q, J=255.6Hz), 86.55 (q, J=6.4Hz), 75.62 (q, J=52.4Hz). GC-MS: 170 (M+).

[0076] 2. When X is a halogen atom

[0077] Taking the synthesis of trifluoromethyltoluene as an example

[0078] Synthesis Condition Screening Example 2: Synthesis of 1-(Trifluoromethyl)-naphthalene

[0079] 2,2'-bipyridyl fluorosulfonyl copper difluoroacetate ((bpy)Cu(O2CCF2SO2F)2, 114.8 mg, 0.2 mmol) and copper powder (12.7 mg, 0.2 mmol) were added to the reaction flask, the N2 was replaced three times, the solvent NMP (2 mL) was added, 1-iodonaphthalene (25.4 mg, 0.1 mmol) was added, and the mixture was stirred at 60°C for 5 hours. The reaction was stopped, and dichloromethane (10 mL) was added. The mixture was washed with water three times and dried; after spin drying, flash column chromatography was performed to obtain a yellow liquid 1-(trifluoromethyl)-naphthalene with a yield of 89%. 1 H NMR (400MHz, CDCl3): δ8.25 (d, J = 8Hz, 1H), δ8.03 (d, J = 8.0Hz, 1H), δ7.92 (q, J = 8.0Hz, 2H), δ7.67-7.58 (m, 2H), δ7.51 (t, J = 8Hz, 1H). 13 C NMR (100MHz, CDCl3): δ134.0, 132.9, 129.1, 128.9, 127.8, 126.7, 126.2 (q, J = 30Hz), 124.8 (q, J = 6Hz), 124.4 (q, J = 3Hz), 124.3, 124.9 (q, J = 271Hz). 19 FNMR (376MHz, CDCl3): δ-59.72 (s, 3F).

[0080] Other conditions are the same as above. The specific data of the trifluoromethylation reagent in different solvents, temperatures, additives, etc. are shown in Table 2.

[0081] Table 2

[0082]

[0083]

[0084] Through the above condition screening, when X is halogen, the optimal conditions obtained are: trifluoromethylation reagent (0.2 mmol, 2.0 eq.), additive (0.2 mmol, 2.0 eq.), RX (0.1 mmol, 1.0 eq.), NMP as solvent, and stirring at 60°C for 5 hours.

[0085] Example 7: Synthesis of 1-methoxy-3-(2,2,2-trifluoroethyl)benzene

[0086] 2,2'-bipyridyl fluorosulfonyl copper difluoroacetate ((bpy)Cu(O2CCF2SO2F)2, 114.8 mg, 0.2 mmol) and copper powder (12.7 mg, 0.2 mmol) were added to the reaction flask, N2 was replaced three times, solvent NMP (2 mL) was added, 3-methoxybenzyl bromide (20.1 mg, 0.1 mmol) was added, and the mixture was stirred at 60°C for 5 hours. The reaction was stopped, and dichloromethane (10 mL) was added. The mixture was washed with water three times and dried; after spin drying, flash column chromatography was performed to obtain 1-methoxy-3-(2,2,2-trifluoroethyl)benzene as a white solid with a yield of 66%. 1 H NMR (400MHz, CDCl3): δ7.29 (t, J = 7.8Hz, 1H), 6.94-6.88 (m, 2H), 6.86 (s, 1H), 3.83 (s, 3H), 3.36 (q, J = 10.8Hz, 2H). 13 C NMR (126MHz, CDCl3): δ159.7,131.5,129.6,125.8,122.4,115.9,113.4,55.2,40.2. 19 F NMR (376MHz, CDCl3): δ-65.8 (t, J=10.8Hz, 3F).

[0087] Example 8: Synthesis of 2-trifluoromethylpyridine

[0088] 2,2'-bipyridyl fluorosulfonyl copper difluoroacetate ((bpy)Cu(O2CCF2SO2F)2, 114.8 mg, 0.2 mmol) and copper powder (12.7 mg, 0.2 mmol) were added to the reaction flask, and N2 was replaced three times. The solvent DMF (2 mL) was added, and 2-iodopyridine (20.5 mg, 0.1 mmol) was added. The mixture was stirred at 50°C for 5 hours, and the reaction was stopped. Trifluorotoluene was added as an internal standard. The F spectrum yield was 68%. 19 FNMR(376MHz, CDCl3)δ-67.8(s,3F).

[0089] Example 9: Synthesis of trifluoromethyltoluene

[0090] 2,2'-Bipyridyl fluorosulfonyl copper difluoroacetate ((bpy)Cu(O2CCF2SO2F)2, 114.8 mg, 0.2 mmol) and copper powder (12.7 mg, 0.2 mmol) were added to the reaction flask, the N2 atmosphere was replaced three times, the solvent MeCN (2 mL) was added, iodobenzene (20.4 mg, 0.1 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction was stopped, and dichloromethane (10 mL) was added. The mixture was washed with water three times and dried; after spin drying, the mixture was subjected to flash column chromatography to obtain trifluorotoluene as a colorless oil with a yield of 25%. 1H NMR (400MHz, CDCl3): δ = 7.61 (d, J = 7.7Hz, 2H), 7.53 (t, J = 7.4Hz, 1H), 7.46 (t, J = 7.6Hz, 2H) ppm; 19 F NMR (377MHz, CDCl3); δ=-62.80ppm.

[0091] Example 10: Synthesis of 2-methoxy-3-(trifluoromethyl)-pyridine

[0092] 2,2'-bipyridyl fluorosulfonyl copper difluoroacetate ((bpy)Cu(O2CCF2SO2F)2, 114.8 mg, 0.2 mmol) and copper powder (12.7 mg, 0.2 mmol) were added to the reaction flask, the N2 was replaced three times, the solvent NMP (2 mL) was added, 3-iodo-2-methoxypyridine (23.5 mg, 0.1 mmol) was added, and the mixture was stirred at 60°C for 5 hours. The reaction was stopped, and dichloromethane (10 mL) was added. The mixture was washed with water three times and dried; after spin drying, flash column chromatography was performed to obtain a colorless liquid 2-methoxy-3-(trifluoromethyl)-pyridine with a yield of 72%. 1 HNMR (400M, CDCl3): δ8.32(d,J=4.0Hz,1H)ppm, δ7.84(d,J=8.0Hz,1H), δ6.95(dd,J=4.0Hz,1H)ppm, δ4.03(s,3H)ppm. 19 F NMR (376MHz, CDCl3): δ-64.03(s,3F)ppm. 13 C NMR (101MHz, CDCl3): δ161.0, 150.6, 136.4 (q, J = 5Hz), 123.2 (q, J = 270Hz), 116.0, 113.4 (q, J = 33Hz), 54.1ppm.

[0093] Example 11: Synthesis of 5-chloro-2-(trifluoromethyl)-pyrimidine

[0094] 2,2'-bipyridyl fluorosulfonyl copper difluoroacetate ((bpy)Cu(O2CCF2SO2F)2, 114.8 mg, 0.2 mmol) and copper powder (12.7 mg, 0.2 mmol) were added to the reaction flask, the N2 was replaced three times, the solvent NMP (2 mL) was added, 2-iodo-5-chloropyrimidine (23.5 mg, 0.1 mmol) was added, and the mixture was stirred at 60°C for 5 hours. The reaction was stopped, and dichloromethane (10 mL) was added. The mixture was washed three times with water and dried; after spin drying, flash column chromatography was performed to obtain 5-chloro-2-(trifluoromethyl)-pyrimidine as a white solid with a yield of 92%. 1H NMR (400MHz, CDCl3): δ8.96 (s, 2H). 13 C NMR (101MHz, CDCl3): δ156.7, 154.6 (q, J = 37Hz), 134.1, 119.4 (q, J = 274Hz). 19 F NMR (376MHz, CDCl3): δ-70.04 (s, 3F).

[0095] Example 12: Synthesis of 7-chloro-2-(trifluoromethyl)thiophene[3,2-b]pyridine

[0096] 2,2'-bipyridyl fluorosulfonyl copper difluoroacetate ((bpy)Cu(O2CCF2SO2F)2, 114.8 mg, 0.2 mmol) and copper powder (12.7 mg, 0.2 mmol) were added to the reaction flask, N2 was replaced three times, solvent NMP (2 mL) was added, 7-chloro-2-iodothiophene[3,2-b]pyridine (29.6 mg, 0.1 mmol) was added, and the mixture was stirred at 60°C for 5 hours. The reaction was stopped, and dichloromethane (10 mL) was added. The mixture was washed with water three times and dried; after spin drying, flash column chromatography was performed to obtain 7-chloro-2-(trifluoromethyl)thiophene[3,2-b]pyridine as a white solid in a yield of 61%. 1 H NMR (400MHz, CDCl3): δ8.70 (d, J = 5.0 Hz, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.42 (d, J = 5.0 Hz, 1H). 13 C NMR (101MHz, CDCl3): δ155.3,149.5,138.7,136.5,136.2,134.2,127.5,123.4,120.7. 19 F NMR (376MHz,CDCl3):δ-57.33(s,3F), respectively Figures 2-4 shown.

[0097] Under the above optimal conditions (when X is halogen), the present invention also synthesized a series of trifluoromethylation products. The structures, yields and characterizations of the trifluoromethylation products are shown in Table 3.

[0098] Table 3 Trifluoromethylation products and characterization

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105] The above description of the embodiments is intended to facilitate understanding and use of the invention by those skilled in the art. It will be apparent that those skilled in the art can readily make various modifications to these embodiments and apply the general principles described herein to other embodiments without requiring inventive effort. Therefore, the present invention is not limited to the above-described embodiments. Improvements and modifications made by those skilled in the art based on the disclosure of the present invention, without departing from the scope of the present invention, should be within the scope of protection of the present invention.

Claims

1. A fluorosulfonyl difluoroacetic acid metal salt complex, characterized in that: It is 2,2'-bipyridyl fluorosulfonyl copper difluoroacetate, and its chemical structure is as follows: 。 2. The method for preparing a fluorosulfonyl difluoroacetic acid metal salt complex according to claim 1, wherein: The method comprises: mixing copper fluorosulfonyl difluoroacetate and 2,2'-bipyridine in an organic solvent, and stirring the mixture for reaction at -196°C to -40°C to prepare the copper fluorosulfonyl difluoroacetate metal salt complex.

3. The method for preparing a fluorosulfonyl difluoroacetic acid metal salt complex according to claim 2, wherein: The organic solvent includes at least one of ether, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate and n-hexane.

4. The method for preparing a fluorosulfonyl difluoroacetic acid metal salt complex according to claim 2, wherein: The molar ratio of the 2,2'-bipyridine to the copper fluorosulfonyl difluoroacetate is 1:(1-20).

5. The method for preparing a fluorosulfonyl difluoroacetic acid metal salt complex according to claim 2, wherein: The reaction time is 10 min ~ 24 h under stirring.

6. The use of a fluorosulfonyl difluoroacetic acid metal salt complex according to claim 1, characterized in that: The fluorosulfonyl difluoroacetic acid metal salt complex is used as a trifluoromethylation reagent for trifluoromethylation reaction: The fluorosulfonyl difluoroacetic acid metal salt complex and the compound of formula RX are mixed and reacted in an organic solvent to obtain a compound of formula R-CF3; wherein X in the compound of formula RX is H; the compound of formula RX is selected from cyclohexane, cyclooctane or phenylacetylene; When the compound of formula RX is phenylacetylene, the compound of formula R-CF3 obtained is 1-trifluoromethylphenylacetylene.

7. The use of a fluorosulfonyl difluoroacetic acid metal salt complex according to claim 6, characterized in that: The organic solvent is at least one of acetonitrile, tetrahydrofuran, ethyl acetate, N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide.

8. The use of a fluorosulfonyl difluoroacetic acid metal salt complex according to claim 6, characterized in that: The reaction conditions for the mixing reaction include: Add an oxidant and allow the reaction to proceed under light; The light source used was a 400-480 nm blue light source; The oxidant is at least one of potassium persulfate complex, potassium persulfate, sodium persulfate, and ammonium persulfate; The molar ratio of the compound of formula RX, the oxidant and the fluorosulfonyl difluoroacetic acid metal salt complex is 1:(1-20):(1-10).

9. The use of a fluorosulfonyl difluoroacetic acid metal salt complex according to claim 1, characterized in that: The fluorosulfonyl difluoroacetic acid metal salt complex is used as a trifluoromethylation reagent for trifluoromethylation reaction: The fluorosulfonyl difluoroacetic acid metal salt complex is mixed with the compound of formula RX in an organic solvent to react, thereby obtaining a compound of formula R-CF3; wherein, X in the compound of formula RX is selected from I, Br or Cl; When X is I, the compound of formula RX is selected from 1-iodonaphthalene, 2-iodopyridine, iodobenzene, 3-iodo-2-methoxypyridine, 2-iodo-5-chloropyrimidine, 7-chloro-2-iodothienyl[3,2-b]pyridine, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or One of the following; When X is Br, the compound of formula RX is selected from 3-methoxybenzyl bromide, 、 or One of the following; When X is Cl, the compound of formula RX is selected from or One of the following; The organic solvent is at least one of tetrahydrofuran, ethyl acetate, N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; An additive is also added to the mixed reaction; the additive is copper; The molar ratio of the compound of formula RX, the fluorosulfonyl difluoroacetic acid metal salt complex and the additive is 1:(1-10):(1-10).

10. The use of a fluorosulfonyl difluoroacetic acid metal salt complex according to claim 9, characterized in that: In the mixed reaction, the reaction temperature is -196°C to 80°C, and the reaction time is 1 to 24 hours.

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