CN112961054B - Method for iron-catalyzed ethoxycarbonyl difluoromethylation of aromatic compound - Google Patents

Method for iron-catalyzed ethoxycarbonyl difluoromethylation of aromatic compound Download PDF

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CN112961054B
CN112961054B CN202110188809.1A CN202110188809A CN112961054B CN 112961054 B CN112961054 B CN 112961054B CN 202110188809 A CN202110188809 A CN 202110188809A CN 112961054 B CN112961054 B CN 112961054B
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CN112961054A (en
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韩维
杨志远
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Nanjing Normal University
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Abstract

The invention discloses a method for catalyzing aromatic compound ethoxycarbonyl difluoromethylation by iron, which comprises the following steps: in a solvent, taking halodifluoroacetic acid ethyl ester as a fluorine reagent, peroxide as an oxidant, iron as a catalyst and amino acid or derivatives thereof as ligands, oxidizing aromatic rings of aromatic compounds to generate an ethoxycarbonyl difluoromethyl methylation reaction, and generating aromatic compounds substituted by ethoxycarbonyl difluoromethyl. The method has the advantages of wide catalyst source, low cost and environmental protection; the oxidant is wide in source, cheap and does not generate waste; the fluorination reagent is mild, stable and cheap; the reaction condition is mild, the selectivity is high and the yield is high; the substrate is wide and stable in source; the compatibility of the substrate functional group is good and the application range of the substrate is wide; the complex molecules and natural products can be compatible, and the ethoxycarbonyl difluoromethylation of the aromatic ring can be well realized. Under the optimized reaction conditions, the yield of the separated target product can reach as high as 90 percent.

Description

Method for iron-catalyzed ethoxycarbonyl difluoromethylation of aromatic compound
Technical Field
The invention belongs to the field of catalytic synthesis technology and fine chemical synthesis, and particularly relates to a method for catalyzing aromatic compound ethoxycarbonyl difluoromethylation by iron, which is a method for realizing direct ethoxycarbonyl difluoromethylation of aromatic rings by oxidizing aromatic compounds by using iron as a suitable oxidant.
Background
Functionalized difluoromethyl arene is an important structural unit and is widely present in a plurality of bioactive compounds and functional materials. Having a function CF2Aromatic compounds of structure, e.g. ethoxycarbonyldifluoromethyl (-CF)2COOEt), has attracted particular attention due to its unique properties. CF (compact flash)2The group may be a biological isomer of an oxygen atom or carbonyl group, the presence of which may also enhance metabolic stability, conformational changes and dipole moment, while increasing the acidity of adjacent groups. At the same time, -CF2The COOEt group can be used as a powerful synthetic intermediate for post-functionalization, providing a large number of other functional groups. Therefore, the synthesis of various organofluoro compounds by selectively introducing fluorine-containing functional groups at specific positions of organic substrates is one of the important issues in current organic chemistry research. There are still some challenges in the current difluoromethylation reaction, such as severe reaction conditions, poor functional group tolerance leading to substrate limitations (Ohtsuka, y.; Yamakawa, t. tetrahedron2011,67, 2323-.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the problems in the prior art, the invention provides a method for catalyzing aromatic compound ethoxycarbonyl difluoromethylation by iron, which solves the problems of lower total reaction yield, poor functional group compatibility, narrow application range, more waste discharge, environmental pollution, unsafety and uneconomic generation caused by harsh reaction conditions of the ethoxycarbonyl difluoromethylation reaction of the existing aromatic compound, toxicity or explosiveness of a fluorinating reagent, pre-functionalization of the reaction and the use of a noble metal catalyst,
the method only needs one-step reaction without acid and alkali participation, and has the characteristics of wide catalyst source, low cost and environmental protection; the oxidant is cheap and does not generate any waste; the fluorination reagent is mild, stable and cheap; the substrate is wide and stable in source; the reaction condition is mild, the selectivity is good and the yield is high; the compatibility of the substrate functional group is good and the application range of the substrate is wide; the complex molecules and natural products can be compatible, and the ethoxycarbonyl difluoromethylation of the aromatic ring can be well realized.
The technical scheme is as follows: in order to achieve the purpose, the invention provides a method for iron-catalyzed ethoxycarbonyl difluoromethylation of an aromatic compound, which comprises the following steps: in a solvent, taking halodifluoroacetic acid ethyl ester as a fluorine reagent, peroxide as an oxidant, iron as a catalyst and amino acid or a derivative thereof as a ligand, oxidizing an aromatic ring of an aromatic compound to perform an ethoxycarbonyl difluoromethylation reaction to generate an ethoxycarbonyl difluoromethyl substituted aromatic compound, wherein the reaction temperature is 25-150 ℃ and the reaction time is 0.25-48 hours;
the general reaction formula is shown as follows:
Figure BDA0002944379350000021
in the formula: ar represents an aryl or heteroaryl group; x represents bromine, chlorine or iodine;
wherein, the aryl is substituted or unsubstituted phenyl, biphenyl, naphthyl, anthryl, phenanthryl or pyrenyl;
the heteroaryl is a five to thirteen membered ring containing N, O or S.
Wherein the heteroaryl is furyl, benzofuryl, thienyl, pyrrolyl, indolyl, carbazolyl, pyridyl, isoxazolyl, pyrazolyl, imidazolyl, oxazolyl or thiazolyl.
Preferably, when Ar is pyrrolyl, indolyl, carbazolyl, pyrazolyl or imidazolyl, the substituent on the nitrogen atom is selected from hydrogen, C1-C20 alkyl, C1-C20 halogen substituted alkyl, C3-C20 cycloalkyl, aryl, benzyl or C1-C20 alkylcarbonyl.
Further, R represents a substituent group on an aryl group in Ar, R is used for mono-or multi-substituting hydrogen on an aryl ring, and is selected from hydrogen, alkyl, alkene and alkynyl of C1-C20, alkoxy of C1-C20, halogen substituted alkyl of C1-C20, cycloalkyl of C3-C20, aryl, aryloxy, heteroaryl, heteroaryloxy, heteroarylamine, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, mercapto of C1-C20, fluorine, chlorine, bromine or iodine, hydroxyl, alkyl carbonyl of C1-C20, carboxyl, alkoxy carbonyl of C1-C20, hydroxylC1-C20 alkylaminocarbonyl, arylcarbonyl, C1-C20 alkylsulfonyl, sulfonic acid group, -B (OH)2Aldehyde, cyano, amino or nitro.
Wherein the iron is selected from ferrous trifluoromethanesulfonate, ferric trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetonate, ferric acetylacetonate, ferrous 2,2,6, 6-tetramethyl-3, 5-heptanedionate, ferrous 1, 3-diphenylpropanedionate, ferric 1, 3-diphenylpropanedionate, ferrous benzoylacetonate, ferric benzoylacetonate, ferrous ferricyanide, ferric ferricyanide, ferrous acetate, ferrous sulfate, ferrous ammonium sulfate, ferric sulfate, ferrous oxalate, ferric oxalate, ferrous fluoride, ferric fluoride, ferrous bromide, ferric bromide, ferrous iodide, ferric trichloride, ferric perchlorate (III) hydrate, 1' -bis (diphenylphosphino) ferrocene, ferrous phthalocyanine, ferric nitrate, ferric oxide or ferroferric oxide.
Wherein the ligand is selected from the group consisting of S-acetamidomethyl-N-t-butoxycarbonyl-L-cysteine, N-acetyl-L-cysteine, N' -bis (t-butoxycarbonyl) -L-cystine, L-serine, D-cystine, aspartic acid, D-arginine, isoserine, L-threonine, L-tyrosine, BOC-L-proline, BOC-glycine, 2-allyl-N-FMOC-L-glycine, BOC-D-phenylalanine, L-cysteine, D-serine, beta-thioglycolic acid, D-proline, D-valine, L-proline, L-cysteine, L-arginine, and L-arginine, L-phenylalanine, N-BOC-N' -trityl-L-histidine, L-tryptophan, N-BOC-L-leucine, L-histidine, BOC-L-glutamic acid, L-cystine or L-homocystine.
Wherein the oxidant is selected from potassium persulfate, ammonium persulfate, sodium persulfate, tert-butyl hydroperoxide, hydrogen peroxide, peracetic acid, m-chloroperoxybenzoic acid, benzoyl peroxide tert-butyl peroxide, di-tert-butyl peroxide, potassium monopersulfate, dicumyl peroxide, 2-butanone peroxide or bis (trimethylsilyl) peroxide.
Wherein the solvent is an organic solvent, water or an aqueous solution of the organic solvent, and the organic solvent is selected from methanol, ethanol, ethylene glycol, N-propanol, isopropanol, 1, 3-propanediol, glycerol, N-butanol, isobutanol, tert-butanol, trifluoroethanol, 2-methyl-2-butanol, 3-methoxybutanol, sec-butanol, tert-amyl alcohol, 4-methyl-2-pentanol, isoamyl alcohol, 2-pentanol, 3-pentanol, cyclopentanol, N-pentanol, polyethylene glycol 200-10000, acetonitrile, benzonitrile, toluene, acetone, dichloromethane, 1, 2-dichloroethane, dimethyl sulfoxide, N-dimethylformamide, N-diethylamide, ethyl acetate, 1, 4-dioxane or tetrahydrofuran.
Preferably, when the solvent is an aqueous solution of an organic solvent, the volume ratio of the organic solvent to water is 1 (0.1-5).
Wherein the halogen difluoroethyl acetate is selected from difluorobromoethyl acetate, difluorochloroacetic acid ethyl ester or difluoroiodoethyl acetate.
Wherein the molar ratio of the aromatic compound, the ethyl halodifluoroacetate, the peroxide, the amino acid or the derivative thereof and the iron catalyst is 1 (2-50): 0.002-20): 0.001-10.
The iron catalyst in the method has the characteristics of high natural abundance, low price and low toxicity, the amino acid ligand is used to coordinate with the iron catalyst to form a high-activity catalytic species, and the catalytic species, the oxidant, the solvent and the like act together to enable halogenated ethyl difluoroacetate to form ethyl difluoroacetate free radicals to attack aromatic rings, so that the method has high activity and selectivity. In addition, the method of the invention uses mild reagents and mild environment, thus solving the problem of harsh reaction conditions; halogenated ethyl difluoroacetate is low in cost, easy to obtain, non-toxic and explosive; the reaction directly attacks the aromatic ring without pre-functionalization, iron is used as a catalyst, no noble metal is used, and the effect is obvious.
Has the advantages that: compared with the prior art, the invention has the following advantages:
(1) the invention provides a method for iron-catalyzed oxidation of aromatic compound ethoxycarbonyl difluoromethylation promoted by amino acid or derivative ligands, which only needs one-step reaction without participation of acid or alkali and has the unique advantages of cheap catalyst, ligand and oxidant, wide sources and environmental protection; the reaction condition is mild, and the selectivity and the yield are high; the substrate has wide source, stability and easy processing; the compatibility of the substrate functional group is good and the application range of the substrate is wide; the reaction is suitable for the advantages of complex micromolecule ethoxycarbonyl difluoromethylation;
(2) the method for ethoxycarbonyl difluoromethylation provided by the invention is simple, feasible and safe, the ethoxycarbonyl difluoromethylation product of the aromatic compound can be directly obtained by one-step method, the yield of the separated target product can reach 90% under the optimized reaction condition, and the method is universal, efficient, economic and environment-friendly;
(3) the method of the invention can use ideal iron as a catalyst for reaction, and the key point is that an amino acid ligand is used to coordinate with the iron catalyst to form a high-activity catalytic species, so that the reaction can carry out the ethoxycarbonyl difluoromethylation reaction of aromatic compounds under very mild conditions, and especially can obtain ideal catalytic effect on complex substrates.
(4) The ethoxycarbonyl difluromed aromatic compound synthesized by the method can be used as a medicine or a bioactive molecule, is an important organic intermediate, and is widely applied to synthesis of medical intermediates, heterocycles and fine chemicals with high added values.
Detailed Description
The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the description of the embodiments is only for illustrating the present invention and should not be taken as limiting the invention as detailed in the claims.
The experimental methods described in the examples are all conventional methods unless otherwise specified; the reagents and materials, unless otherwise specified, can be obtained from commercial sources or simply prepared by the prior art.
The specific structures of the substrates and products in the examples are shown in Table 1.
Example 1
Synthesis of Compound 1
To air, a 25mL reaction flask was charged with ferric bromide (0.05mmol) and D-serine (0) in that order.1mmol), substrate 1a (0.5mmol), ethanol (2.0mL), BrCF2COOEt (2mmol) and oxone (4 mmol). After mixing well at room temperature, the reaction mixture was refluxed at 80 ℃ for 3 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ethyl acetate V/V ═ 10:5) afforded product 1 in 78% yield.
Example 2
Synthesis of Compound 2
In the air, ferric trichloride (0.1mmol), L-homocystine (0.2mmol), substrate 1b (0.5mmol), methanol (2.0mL), BrCF are added into a 25mL reaction bottle in sequence2COOEt (1mmol) and dicumyl peroxide (1 mmol). After mixing well at room temperature, the reaction mixture was refluxed at 60 ℃ for 3 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ethyl acetate V/V ═ 10:3) afforded product 2 in 85% yield.
Example 3
Synthesis of Compound 3
In the air, 25mL reaction flask is sequentially added with ferrous trifluoromethanesulfonate (0.04mmol), aspartic acid (0.08mmol), a substrate 1c (0.5mmol), tert-butanol (2.0mL), BrCF2COOEt (1.5mmol) and di-tert-butyl peroxide (1 mmol). After mixing well at room temperature, the reaction mixture was refluxed at 25 ℃ for 3 h. At the end of the reaction, direct chromatographic separation (petroleum ether: dichloromethane V/V ═ 10:2) afforded product 3 in 88% yield.
Example 4
Synthesis of Compound 4
In air, a 25mL reaction flask was charged with ferrous chloride (0.5mmol), S-acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine (1.0mmol), substrate 1d (0.5mmol), isopropanol (1.5mL), water (2.5mL), and ICF2COOEt (1.5mmol) and hydrogen peroxide (1.5 mmol). After mixing well at room temperature, the reaction mixture was reacted at 100 ℃ for 24 h. After the reaction was completed, 5mL of water was added, and extraction was performed with ethyl acetate (5mL × 3), the organic phases were combined, the solvent was distilled off under reduced pressure, and column chromatography was performed (petroleum ether: dichloromethane V/V ═ 10:4) to obtain product 4 in a yield of 65%.
Example 5
Synthesis of Compound 5
In the air, 25mL reaction flask is sequentially added with ferrous acetylacetonate (0.02mmol), BOC-L-glutamic acid (0.04mmol), substrate 1e (0.5mmol), glycerol (1.5mL), water (0.5mL), BrCF2COOEt (4mmol) and peroxyacetic acid (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 60 ℃ for 2 h. After the reaction was completed, 5mL of water was added, and extraction was performed with diethyl ether (5mL × 3), the organic phases were combined, the solvent was distilled off under reduced pressure, and column chromatography was performed (petroleum ether: ethyl acetate V/V ═ 10:2) to obtain product 5 in 73% yield.
Example 6
Synthesis of Compound 6
In the air, 25mL reaction flask was charged with ferric acetylacetonate (0.08mmol), L-tyrosine (0.16mmol), substrate 1f (0.5mmol), n-butanol (2.0mL), ClCF2COOEt (1mmol) and t-butyl hydroperoxide (5 mmol). After mixing well at room temperature, the reaction mixture was reacted at 25 ℃ for 3 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ethyl acetate V/V ═ 10:1) afforded product 6 in 70% yield.
Example 7
Synthesis of Compound 7
Under normal pressure and nitrogen, ferric triflate (0.05mmol), L-cystine (0.1mmol), 1g (0.5mmol) of substrate, acetonitrile (2.0mL), BrCF were added to a 25mL reaction flask in sequence2COOEt (1mmol) and m-chloroperoxybenzoic acid (1.5 mmol). After mixing well at room temperature, the reaction mixture was reacted at 50 ℃ for 1 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ethyl acetate V/V ═ 20:3) afforded product 7 in 87% yield.
Example 8
Synthesis of Compound 8
In air, a 25mL reaction flask was charged with ferrous fluoride (0.1mmol), N, N' -bis (tert-butoxycarbonyl) -L-cystine (0.4mmol), substrate 1h (0.5mmol), acetonitrile (1.5mL), water (1.5mL), ICF2COOEt (1.5mmol) and potassium persulfate (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 80 ℃ for 2 h. After the reaction was completed, 5mL of water was added, and extraction was performed with ethyl acetate (5 mL. times.3), the organic phases were combined, the solvent was distilled off under reduced pressure, and column chromatography was performed (petroleum ether: ethyl acetate V/V ═ 10:3) to obtain a product 8 in 7 yield6％。
Example 9
Synthesis of Compound 9
In the air, ferrous iodide (0.08mmol), N-acetyl-L-cysteine (0.32mmol), substrate 1i (0.5mmol), trifluoroethanol (2.0mL), BrCF are added into a 25mL reaction bottle in sequence2COOEt (4mmol) and benzoyl peroxide (2 mmol). After mixing well at room temperature, the reaction mixture was reacted at 60 ℃ for 2 h. At the end of the reaction, direct chromatographic separation (petroleum ether: dichloromethane V/V ═ 10:5) afforded product 9 in 74% yield.
Example 10
Synthesis of Compound 10
In a 25mL reaction flask under normal pressure and nitrogen, ferrous sulfate (0.05mmol), L-cysteine (0.1mmol), a substrate 1j (0.5mmol), dimethyl sulfoxide (1.5mL), water (0.5mL) and BrCF are sequentially added2COOEt (2mmol) and sodium persulfate (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 80 ℃ for 1 h. After the reaction was completed, 5mL of water was added and extracted with ethyl acetate (5mL × 3), the organic phases were combined, washed with water (5mL × 3), the organic phase was collected, the solvent was distilled off under reduced pressure and column chromatography was performed to obtain the product 10 in a yield of 70%.
1H NMR(400MHz,CDCl3):δ7.51(d,J＝7.8Hz,1H),7.38(t,J＝7.8Hz,1H),6.99(t,J＝7.6Hz,1H),6.96(d,J＝8.4Hz,1H),4.36(q,J＝7.1Hz,2H),1.33ppm(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3):δ165.4(t,J＝34.6Hz),154.2(t,J＝4.4Hz),132.9,126.3(t,J＝7.8Hz),120.4,118.4(t,J＝24.1Hz),117.9,113.0(t,J＝250.2Hz),63.9,13.8ppm；19F NMR(376MHz,CDCl3):δ-103.6ppm.
Example 11
Synthesis of Compound 11
2,2,6, 6-tetramethyl-3, 5-heptanedionato ferrous (0.02mmol), L-serine (0.04mmol), substrate 1k (0.5mmol), dimethyl sulfoxide (4.0mL), BrCF (carbon black) were sequentially added to a 25mL reaction flask under normal pressure under nitrogen2COOEt (1mmol) and benzoyl peroxide tert-butyl ester (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 25 ℃ for 1 h. The reaction is finished5mL of water was added, extraction was performed with ethyl acetate (5 mL. times.3), the organic phases were combined, washed with water (5 mL. times.3), the organic phase was collected, the solvent was distilled off under reduced pressure, and column chromatography was performed (petroleum ether: ether V/V ═ 10:5) to obtain product 11 in 79% yield.
Example 12
Synthesis of Compound 12
In air, a 25mL reaction flask was charged with ferrous acetate (0.02mmol), D-cystine (0.04mmol), substrate 1l (0.5mmol), dichloromethane (2.0mL), BrCF2COOEt (1mmol) and 2-butanone peroxide (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 25 ℃ for 0.5 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ethyl acetate V/V ═ 10:3) afforded product 12 in 86% yield.
Example 13
Synthesis of Compound 13
In air, a 25mL reaction flask was charged with iron ferricyanide (0.001mmol), BOC-glycine (0.002mmol), substrate 1m (0.5mmol), 1, 2-dichloroethane (2.0mL), BrCF2COOEt (1mmol) and bis (trimethylsilyl) peroxide (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 40 ℃ for 1 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ether V/V ═ 10:5) afforded product 13 in 90% yield.
Example 14
Synthesis of Compound 14
In air, a 25mL reaction flask was charged with ferrous bromide (0.05mmol), BOC-D-phenylalanine (0.1mmol), substrate 1n (0.5mmol), acetonitrile (1.0mL), water (1.0mL), BrCF2COOEt (1.5mmol) and ammonium persulfate (1.5 mmol). After mixing well at room temperature, the reaction mixture was reacted at 60 ℃ for 2 h. After the reaction was completed, 5mL of water was added, and extraction was performed with ethyl acetate (5mL × 3), the organic phases were combined, the solvent was distilled off under reduced pressure, and column chromatography was performed (petroleum ether: ethyl acetate V/V ═ 10:2) to obtain the product 14 in 89% yield.
1H NMR(400MHz,CDCl3):δ7.30(s,2H),5.29(s,1H),4.32(q,J＝7.1Hz,2H),3.23-3.13(m,2H),1.32(t,J＝7.1Hz,3H),1.27ppm(d,J＝6.9Hz,12H)；13C NMR(100MHz,CDCl3):δ164.7(t,J＝36.0Hz),152.3,134.0,124.5(t,J＝25.5Hz),120.9(t,J＝6.1Hz),113.9(t,J＝249.8Hz),62.9,27.1,22.5,13.8ppm；19F NMR(376MHz,CDCl3):δ-102.1ppm；HRMS(ESI)m/z calcd for C16H22F2O3Na+(M+Na)+323.1429,found 323.1437；IR(KBr,cm-1):νmax 3524,2965,2873,1765,1470,1290,1189,937,828,772,504.
Example 15
Synthesis of Compound 15
2,2,6, 6-tetramethyl-3, 5-heptanedionato-iron (0.1mmol), D-arginine (0.2mmol), substrate 1o (0.5mmol), N, N-dimethylamide (2.0mL), BrCF (carbon dioxide gas) were added to a 25mL reaction flask in this order under normal pressure and nitrogen2COOEt (2.5mmol) and benzoyl peroxide tert-butyl ester (1.5 mmol). After mixing well at room temperature, the reaction mixture was reacted at 80 ℃ for 6 h. After the reaction was completed, 5mL of water was added, and extraction was performed with ethyl acetate (5mL × 3), the organic phases were combined, the solvent was distilled off under reduced pressure, and column chromatography was performed (petroleum ether: ethyl acetate V/V ═ 10:1) to obtain a product 15 in a yield of 70%.
1H NMR(400MHz,CDCl3):δ10.08(s,1H),7.98(d,J＝8.1Hz,2H),7.79(d,J＝8.2Hz,2H),4.31(q,J＝7.1Hz,2H),1.30ppm(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3):δ191.3,163.5,138.1,133.8,129.8,126.3(t,J＝6.1Hz),112.8(t,J＝251.7Hz),63.5,13.8ppm；19F NMR(376MHz,CDCl3):δ-104.5ppm.
Example 16
Synthesis of Compound 16
In air, a 25mL reaction flask was charged with 1, 3-diphenylpropanedione iron (0.05mmol), D-valine (0.1mmol), substrate 1p (0.5mmol), ethyl acetate (2.0mL), BrCF2COOEt (1.5mmol) and t-butyl hydroperoxide (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 80 ℃ for 3 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ethyl acetate V/V ═ 10:2) afforded product 16 in 81% yield.
Example 17
Synthesis of Compound 17
In the air, 1, 3-diphenyl-propanedione ferrous iron (0.5mmol), BOC-L-proline (1.5mmol), substrate 1q (0.5mmol), 1, 4-dioxane (2.0mL) and ICF are sequentially added into a 25mL reaction bottle2COOEt (1.5mmol) and hydrogen peroxide (1.5mmol) were mixed well at room temperature and the reaction mixture was reacted at 100 ℃ for 6 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ethyl acetate V/V ═ 20:3) afforded product 17 in 52% yield.
Example 18
Synthesis of Compound 18
In the air, 25mL reaction flask was sequentially charged with ferrous benzoylacetonate (0.05mmol), D-proline (0.1mmol), substrate 1r (0.5mmol), tetrahydrofuran (2.0mL), BrCF2COOEt (1mmol) and benzoyl peroxide (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 80 ℃ for 3 h. At the end of the reaction, direct chromatographic separation (petroleum ether: dichloromethane V/V ═ 10:6) afforded product 18 in 64% yield.
Example 19
Synthesis of Compound 19
In the air, a 25mL reaction flask is sequentially added with ferric benzoylacetonate (0.2mmol), N-BOC-L-leucine (0.4mmol), a substrate 1s (0.5mmol), sec-butanol (2.0mL), BrCF2COOEt (1.5mmol) and peroxyacetic acid (1.5 mmol). After mixing well at room temperature, the reaction mixture was reacted at 60 ℃ for 12 h. At the end of the reaction, direct chromatographic separation (petroleum ether: dichloromethane V/V ═ 10:5) afforded product 19 in 48% yield.
Example 20
Synthesis of Compound 20
In the air, 25mL reaction flask was sequentially charged with ferric ferricyanide (0.05mmol), L-histidine (0.15mmol), substrate 1t (0.5mmol), polyethylene glycol-2000 (1.0g), water (1.0mL), BrCF2COOEt (2mmol) and m-chloroperoxybenzoic acid (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 120 ℃ for 3 h. After the reaction was completed, 5mL of water was added, and extraction was performed with diethyl ether (5 mL. times.3), the organic phases were combined, and the solvent was distilled off under reduced pressure and column chromatography was performed (petroleum ether: ethyl acetate V/V ═ 10:3) to obtain a product 20 in a yield of 70%.
Example 21
Synthesis of Compound 21
In air, a 25mL reaction flask was charged with iron iodide (0.05mmol), L-tryptophan (0.1mmol), substrate 1u (0.5mmol), 4-methyl-2-pentanol (2.0mL), BrCF2COOEt (1mmol) and benzoyl peroxide tert-butyl ester (2 mmol). After mixing well at room temperature, the reaction mixture was reacted at 80 ℃ for 18 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ethyl acetate V/V ═ 10:1) afforded product 21 in 51% yield.
Example 22
Synthesis of Compound 22
In air, a 25mL reaction flask was charged with iron oxalate (0.05mmol), N-BOC-N' -trityl-L-histidine (0.1mmol), substrate 1v (0.5mmol), cyclopentanol (2.0mL), BrCF2COOEt (1.5mmol) and di-tert-butyl peroxide (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 80 ℃ for 2 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ethyl acetate V/V ═ 10:1) afforded product 22 in 65% yield.
1H NMR(400MHz,CD3COCD3):δ7.55(s,2H),7.23(s,2H),4.30(q,J＝7.1Hz,2H),3.84(s,6H),1.28ppm(t,J＝7.1Hz,3H)；13C NMR(100MHz,CD3COCD3):δ164.9(t,J＝32.7Hz),159.3,130.6,114.2(t,J＝246.4Hz),111.0,62.9,56.5,14.3ppm；19F NMR(376MHz,CD3COCD3):δ-98.0ppm；11B NMR(128MHz,CD3COCD3):δ28.5ppm；HRMS(ESI)m/z calcd for C12H16BF2O6 +(M+H)+305.1003,found 305.1007；IR(KBr,cm-1):νmax 3746,2921,1770,1455,1372,1274,952,855,749,599.
Example 23
Synthesis of Compound 23
In the air, 25mL reaction flask was sequentially charged with iron oxide (0.1mmol), L-threonine (0.4mmol), substrate 1w (0.5mmol), isoamyl alcohol (2.0mL), and BrCF2COOEt (1.5mmol) and dicumyl peroxide (1.5 mmol). After mixing evenly at room temperature, reacting and mixingThe reaction was carried out at 80 ℃ for 3 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ethyl acetate V/V ═ 10:4) afforded product 23 in 63% yield.
Example 24
Synthesis of Compound 24
In the air, ferric sulfate (0.2mmol), isoserine (0.5mmol), a substrate 1x (0.5mmol), dimethyl sulfoxide (2.0mL) and BrCF (BrCF) are sequentially added into a 25mL reaction bottle2COOEt (1.5mmol) and 2-butanone peroxide (2 mmol). After mixing well at room temperature, the reaction mixture was reacted at 60 ℃ for 1 h. After the reaction was completed, 5mL of water was added and extracted with ethyl acetate (5mL × 3), the organic phases were combined, washed with water (5mL × 3), the organic phase was collected, the solvent was distilled off under reduced pressure and column chromatography was performed (petroleum ether: dichloromethane V/V ═ 10:8) to obtain the product 24 in a yield of 71%.
Example 25
Synthesis of Compound 25
In air, 25mL reaction flask was charged with iron (III) perchlorate hydrate (0.15mmol), 2-allyl-N-FMOC-L-glycine (0.3mmol), substrate 1y (0.5mmol), N, N-diethylamide (1.5mL), water (0.5mL), ICF2COOEt (1mmol) and hydrogen peroxide (2 mmol). After mixing well at room temperature, the reaction mixture was reacted at 80 ℃ for 24 h. After the reaction was complete, aqueous ammonia (0.5mL, 25%) was added and stirred for 1 h. Subsequently, 5mL of water was added, and extraction was performed with diethyl ether (5mL × 3), the organic phases were combined, the solvent was distilled off under reduced pressure, and column chromatography was performed (petroleum ether: dichloromethane V/V ═ 10:1) to obtain a product 25 in a yield of 65%.
Example 26
Synthesis of Compound 26
In the air, 1' -bis (diphenylphosphino) ferrocene (0.05mmol), L-proline (0.1mmol), a substrate 1z (0.5mmol), acetone (2.0mL), BrCF (BrCF) are sequentially added into a 25mL reaction bottle2COOEt (1mmol) and t-butyl hydroperoxide (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 50 ℃ for 6 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ether V/V ═ 10:2) afforded product 26 in 74% yield.
Example 27
Synthesis of Compound 27
In the air, ferrous ammonium sulfate (0.1mmol), beta-sulfenyl valine (0.3mmol), a substrate 1aa (0.5mmol), dimethyl sulfoxide (1.5mL), water (0.5mL) and BrCF (carbon black) are added into a 25mL reaction bottle in sequence2COOEt (3mmol) and ammonium persulfate (2 mmol). After mixing well at room temperature, the reaction mixture was reacted at 80 ℃ for 6 h. After the reaction was complete, aqueous ammonia (0.5mL, 25%) was added and stirred for 1 h. Subsequently, 5mL of water was added, and extraction was performed with ethyl acetate (5mL × 3), the organic phases were combined, the solvent was distilled off under reduced pressure, and column chromatography separation was performed (petroleum ether: dichloromethane V/V ═ 10:7) to obtain the product 27 in a yield of 87%.
Example 28
Synthesis of Compound 28
In air, a 25mL reaction flask was charged with ferric fluoride (0.05mmol), L-phenylalanine (0.1mmol), substrate 1ab (0.5mmol), acetonitrile (2mL), BrCF2COOEt (1mmol) and di-tert-butyl peroxide (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 80 ℃ for 3 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ethyl acetate V/V ═ 10:1) afforded product 28 in 55% yield.
Example 29
Synthesis of Compound 29
In air, a 25mL reaction flask was charged with ferrous phthalocyanine (0.005mmol), L-cysteine (0.02mmol), substrate 1ac (0.5mmol), N, N-dimethylamide (1.5mL), water (0.5mL), BrCF2COOEt (1mmol) and sodium persulfate (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 25 ℃ for 24 h. After the reaction was complete, aqueous ammonia (0.5mL, 25%) was added and stirred for 1 h. Subsequently, 5mL of water was added, and extraction was performed with ethyl acetate (5mL × 3), the organic phases were combined, the solvent was distilled off under reduced pressure, and column chromatography separation was performed (petroleum ether: ethyl acetate V/V ═ 10:6) to obtain a product 29 in 49% yield.
Example 30
Synthesis of Compound 30
In the air, ferrous sulfate (0.05mmol), L-cystine (0.1mmol), substrate 1ad (0.5mmol), ethanol (2.0mL), BrCF are added into a 25mL reaction bottle in sequence2COOEt (1mmol) and t-butyl hydroperoxide (1 mmol). After being mixed evenly at room temperature, the mixture is reactedThe mixture was reacted at 60 ℃ for 12 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ethyl acetate V/V ═ 10:4) afforded product 30 in 68% yield.
Example 31
Synthesis of Compound 31
In air, 25mL reaction flask was charged with ferric oxalate (0.05mmol), L-serine (0.1mmol), substrate 1ae (0.5mmol), dichloromethane (2.0mL), BrCF2COOEt (1mmol) and dicumyl peroxide (1.5 mmol). After mixing well at room temperature, the reaction mixture was reacted at 25 ℃ for 12 h. At the end of the reaction, direct chromatography (petroleum ether: ethyl acetate V/V ═ 10:4) afforded product 31 in 74% yield.
Example 32
Synthesis of Compound 32
In air, a 25mL reaction flask was charged with ferric nitrate (0.1mmol), L-proline (0.1mmol), substrate 1af (0.5mmol), ethanol (1.5mL), water (0.5mL), BrCF2COOEt (2mmol) and potassium persulfate (1.5 mmol). After mixing well at room temperature, the reaction mixture was reacted at 60 ℃ for 24 h. After the reaction was complete, aqueous ammonia (0.5mL, 25%) was added and stirred for 1 h. Subsequently, 5mL of water was added, and extraction was performed with diethyl ether (5mL × 3), the organic phases were combined, the solvent was distilled off under reduced pressure, and column chromatography was performed (petroleum ether: dichloromethane V/V ═ 10:5) to obtain the product 32 in a yield of 72%.
Example 33
Synthesis of Compound 33
In air, a 25mL reaction flask was charged with ferric chloride (0.05mmol), BOC-L-glutamic acid (0.1mmol), substrate 1ag (0.5mmol), acetonitrile (1.5mL), and water (0.5mL), ClCF2COOEt (1mmol) and oxone (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 80 ℃ for 2 h. After the reaction was complete, aqueous ammonia (0.5mL, 25%) was added and stirred for 1 h. Subsequently, 5mL of water was added, and extraction was performed with ethyl acetate (5mL × 3), the organic phases were combined, the solvent was distilled off under reduced pressure, and column chromatography separation was performed (petroleum ether: ethyl acetate V/V ═ 10:2) to obtain 33 as a product in a yield of 69%.
1H NMR(400MHz,CD3COCD3):δ10.07(s,1H),7.46(d,J＝8.0Hz,1H),6.94(d,J＝8.0Hz,1H),2.33ppm(s,3H)；13C NMR(100MHz,CD3COCD3):δ165.9(t,J＝29.3Hz),143.1(t,J＝6.6Hz),136.8,132.3,132.2,118.3(t,J＝21.0Hz),111.9(t,J＝248.6Hz),111.2,18.7ppm；19F NMR(376MHz,CD3COCD3):δ-116.0ppm；HRMS(ESI)m/z calcd for C9H7ClF2NO+(M+H)+218.0179,found 218.0176；IR(KBr,cm-1):νmax 3866,3716,2924,2853,1697,1471,1393,1213,823,765,590,468；Mp:199.5-201.3℃.
Example 34
Synthesis of Compound 34
In air, ferrous chloride (0.5mmol), L-histidine (1.0mmol), substrate 1ah (0.5mmol), dimethyl sulfoxide (4.0mL), BrCF were added to a 25mL reaction flask in sequence2COOEt (5mmol) and benzoyl peroxide tert-butyl ester (4 mmol). After mixing well at room temperature, the reaction mixture was reacted at 80 ℃ for 3 h. After the reaction was completed, 5mL of water was added and extracted with ethyl acetate (5mL × 3), the organic phases were combined, washed with water (5mL × 3), the organic phase was collected, the solvent was distilled off under reduced pressure and column chromatography was performed to obtain the product 34 in 77% yield.
Example 35
Synthesis of Compound 35
In air, a 25mL reaction flask was sequentially charged with ferrous acetylacetonate (0.1mmol), N-BOC-L-leucine (0.2mmol), substrate 1ai (0.5mmol), dimethyl sulfoxide (1.5mL), water (0.5mL), BrCF2COOEt (1.5mmol) and peroxyacetic acid (1.5 mmol). After mixing well at room temperature, the reaction mixture was reacted at 80 ℃ for 6 h. After the reaction was completed, 5mL of water was added, and extraction (5mL × 3) was performed with ethyl acetate (petroleum ether: ethyl acetate V/V ═ 10:3), and the organic phases were combined, washed with water (5mL × 3), collected, evaporated under reduced pressure, and separated by column chromatography to obtain product 35 in 52% yield.
1H NMR(400MHz,CD3COCD3):δ8.25(s,1H),7.92(s,1H),7.68-7.62(m,1H),7.18-7.11(m,2H),4.34(q,J＝7.1Hz,2H),1.27ppm(t,J＝7.1Hz,3H)；13C NMR(100MHz,CD3COCD3):δ173.3,164.4,164.0(t,J＝33.3Hz),161.8(td,J＝13.8Hz,3.5Hz),160.3,159.3(d,J＝12.0Hz),134.4,132.6(dd,J＝9.6Hz,4.6Hz),131.6,125.4,124.8(dd,J＝13.3Hz,3.8Hz),122.2,113.1(t,J＝245.9Hz),112.7(dd,J＝21.2Hz,3.7Hz),105.1(t,J＝26.3Hz),63.5,14.1ppm；19F NMR(376MHz,CD3COCD3):δ-103.0,-112.7,-115.2ppm；HRMS(ESI)m/z calcd for C19H26F2O5Na+(M+Na)+395.1641,found 395.1649；IR(KBr,cm-1):νmax2929,2317,1766,1593,1507,1456,1373,1268,968,850,723,472.Mp:186.9-189.3℃.
Example 36
Synthesis of Compound 36
In air, a 25mL reaction flask was charged with ferric acetylacetonate (0.05mmol), BOC-Glycine (0.1mmol), substrate 1aj (0.5mmol), N, N-diacetamide (1.0mL), and water (0.1mL), BrCF2COOEt (1mmol) and t-butyl hydroperoxide (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 100 ℃ for 6 h. After the reaction was complete, aqueous ammonia (0.5mL, 25%) was added and stirred for 1 h. Subsequently, 5mL of water was added, and extraction was performed with ethyl acetate (5mL × 3), the organic phases were combined, the solvent was distilled off under reduced pressure, and column chromatography separation was performed (petroleum ether: ethyl acetate V/V ═ 10:4) to obtain the product 36 in a yield of 59%.
Example 37
Synthesis of Compound 37
In air, ferric perchlorate (III) hydrate (0.05mmol), L-homocystine (0.1mmol), substrate 1ak (0.5mmol), dichloromethane (2.0mL), BrCF (carbon black) are sequentially added into a 25mL reaction bottle2COOEt (1mmol) and hydrogen peroxide (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 40 ℃ for 6 h. At the end of the reaction, direct chromatographic separation (petroleum ether: ethyl acetate V/V ═ 10:2) gave product 37 in 67% yield.
1H NMR(400MHz,CDCl3):δ8.09(s,1H),7.24(s,1H),7.07(d,J＝8.1Hz,1H),6.77(d,J＝8.2Hz,1H),5.17(d,J＝8.2Hz,1H),4.49(q,J＝6.6Hz,1H),4.28(q,J＝7.1Hz,2H),3.68(s,3H),3.07-2.93(m,2H),1.38(s,9H),1.26ppm(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3):δ172.2,164.7(t,J＝34.2Hz),155.3,153.3,133.1,127.3,126.8(t,J＝7.0Hz),119.1(t,J＝23.8Hz),117.0,112.5(t,J＝248.0Hz),80.4,63.2,54.5,52.3,37.4,28.1,13.6ppm；19F NMR(376MHz,CDCl3):δ-103.2ppm；HRMS(ESI)m/z calcd for C19H25F2NO7Na+(M+Na)+440.1491,found440.1497；IR(KBr,cm-1):νmax 3370,2933,1686,1587,1444,1369,1215,1028,832,757,598,486.
Example 38
Synthesis of Compound 38
In air, ferrous bromide (0.05mmol), D-valine (0.1mmol), substrate 1al (0.5mmol), dimethyl sulfoxide (2.0mL), BrCF were sequentially added to a 25mL reaction flask2COOEt (1mmol) and 2-butanone peroxide (1 mmol). After mixing well at room temperature, the reaction mixture was reacted at 80 ℃ for 3 h. After the reaction was completed, 5mL of water was added, and extraction was performed with ether (5mL × 3), the organic phases were combined, washed with water (5mL × 3), the organic phase was collected, the solvent was distilled off under reduced pressure, and column chromatography was performed (petroleum ether: dichloromethane V/V ═ 10:7) to obtain the product 38 in 89% yield.
The structural formulas of the raw materials and the products of the embodiments 1 to 38 and the corresponding experimental results are shown in the following table 1:
TABLE 1
Figure BDA0002944379350000141
Figure BDA0002944379350000151
Figure BDA0002944379350000161
Figure BDA0002944379350000171
Figure BDA0002944379350000181
Example 39
Example 39 the same procedure as in example 1, except that: the molar ratio of the aromatic compound to the halodifluoroacetic acid ethyl ester to the peroxide to the amino acid derivative to the iron catalyst is 1:2:2:0.002: 0.001.
Example 40
Example 40 the same procedure as in example 1, except that: the molar ratio of the aromatic compound to the halodifluoroacetic acid ethyl ester to the peroxide to the amino acid derivative to the iron catalyst is 1:50:50:20: 10.
EXAMPLE 41
Example 41 the same procedure as in example 8 was followed, except that: the solvent is all water, and the total volume is kept unchanged.
Example 42
Example 42 is the same as the process of example 8, except that: solvent (dimethyl sulfoxide and water), and the volume ratio of the organic solvent to the water is 1: 0.1.
Example 43
Example 43 the same procedure as in example 8, except that: solvents (ethanol and water), the volume ratio of organic solvent to water is 1: 5.
Example 44
Example 44 the same procedure as in example 6 was followed, except that: the reaction temperature was 25 ℃ and the reaction time was 48 hours.
Example 45
Example 45 the same procedure as in example 20, except that: the reaction temperature was 150 ℃ and the reaction time was 0.25 hour.
Comparative example 1
Comparative example 1 is the same as example 15 except that: without the addition of iron catalyst, the yield of the target product was 0.
Comparative example 2
Comparative example 2 the same procedure as in example 15, except that: without adding amino acid ligand, the reaction yield is greatly reduced and is less than 40 percent.
Although the present invention has been described in terms of the preferred embodiment, it is not intended to be limited thereto, and various iron catalysts in the present invention can be theoretically coordinated with amino acid ligands to form highly active iron catalyst species, thereby facilitating the reaction; the amino acid ligand is an accelerant for generating ethoxycarbonyl difluoromethylation reaction, the coordination effect of the amino acid ligand and iron is utilized, theoretically, various amino acids and derivatives thereof have coordination functions and can obtain similar effects; various peroxides are oxidizing agents; the activation of carbon-hydrogen bonds occurs on aromatic substrates, and various substituents on aromatic rings influence the density of electron clouds in the rings and the steric hindrance during reaction, namely, the modification of the substituents only influences the reaction to a certain extent and does not determine the occurrence of the reaction. It will be understood by those skilled in the art that the process of the present invention can be carried out while variations or modifications can be made to the corresponding embodiments without departing from the scope of the present invention, for example, substitutions, changes or modifications can be made to the substituents described within the scope of the present invention. However, any modification, equivalence and equivalent changes made to the above embodiments according to the present invention are still within the scope of the technical solution of the present invention, without departing from the spirit of the technical solution of the present invention.

Claims (9)

1. A method for iron-catalyzed ethoxycarbonyl difluoromethylation of aromatic compounds is characterized by comprising the following steps: in a solvent, taking halodifluoroacetic acid ethyl ester as a fluorine reagent, peroxide as an oxidant, iron as a catalyst and amino acid or a derivative thereof as a ligand, oxidizing an aromatic ring of an aromatic compound to generate an ethoxycarbonyl difluoromethyl methylation reaction to generate an ethoxycarbonyl difluoromethyl substituted aromatic compound, wherein the reaction temperature is 25-150 ℃ and the reaction time is 0.25-48 hours;
the general reaction formula is shown as follows:
Figure DEST_PATH_IMAGE001
in the formula: ar represents an aryl or heteroaryl group; x represents bromine, chlorine or iodine;
wherein, the aryl is substituted or unsubstituted phenyl, biphenyl, naphthyl, anthryl, phenanthryl or pyrenyl; r represents a substituent group on an aryl group in Ar, R is used for mono-or multi-substituting hydrogen on an aryl ring, and is selected from alkyl, alkene and alkynyl of C1-C20, alkoxy of C1-C20, halogen substituted alkyl of C1-C20, cycloalkyl of C3-C20, aryl, aryloxy, heteroaryl, heteroaryloxy, heteroarylamino, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, mercapto of C1-C20, fluorine, chlorine, bromine or iodine, hydroxyl, alkyl carbonyl of C1-C20, carboxyl, alkoxy carbonyl of C1-C20, alkylamino carbonyl of C1-C20, aryl carbonyl, alkyl sulfonyl of C1-C20, sulfonic acid group, -B (OH)2Aldehyde, cyano, amino or nitro; the heteroaryl is a five to thirteen membered ring containing N, O or S.
2. The method of iron-catalyzed ethoxycarbonyldifluoromethylation of an aromatic compound according to claim 1, wherein said heteroaryl is furyl, benzofuryl, thienyl, pyrrolyl, indolyl, carbazolyl, pyridyl, isoxazolyl, pyrazolyl, imidazolyl, oxazolyl, or thiazolyl.
3. The method of claim 1, wherein when Ar is pyrrolyl, indolyl, carbazolyl, pyrazolyl or imidazolyl, the substituent on nitrogen atom is selected from hydrogen, C1-C20 alkyl, C1-C20 halogen substituted alkyl, C3-C20 cycloalkyl, aryl, benzyl or C1-C20 alkylcarbonyl.
4. The method of iron-catalyzed ethoxycarbonyldifluoromethylation of aromatic compounds according to any one of claims 1 to 3, wherein the iron is selected from the group consisting of ferrous triflate, ferric triflate, ferrous chloride, ferrous acetylacetonate, ferric acetylacetonate, ferrous 2,2,6, 6-tetramethyl-3, 5-heptanedionate, ferrous 1, 3-diphenylpropanedionate, ferric 1, 3-diphenylpropanedionate, ferrous benzoylacetonate, ferric benzoylacetonate, ferrous hexacyanate, ferric ferricyanide, ferrous acetate, ferrous sulfate, ammonium ferrous sulfate, ferric sulfate, ferrous oxalate, ferric oxalate, ferrous fluoride, ferric fluoride, ferrous bromide, ferric bromide, ferrous iodide, ferric trichloride, ferric perchlorate (III) hydrate, ferric chloride (III) hydrate, 1,1' -bis (diphenylphosphino) ferrocene, ferrous phthalocyanine, ferric nitrate, ferric oxide or ferroferric oxide.
5. The iron-catalyzed ethoxycarbonyldifluoromethylation of aromatic compounds according to any one of claims 1-3, wherein the ligand is selected from the group consisting of S-acetamidomethyl-N-t-butoxycarbonyl-L-cysteine, N-acetyl-L-cysteine, N '-bis (t-butoxycarbonyl) -L-cystine, L-serine, D-cystine, aspartic acid, D-arginine, isoserine, L-threonine, L-tyrosine, BOC-L-proline, BOC-glycine, 2-allyl-N-FMOC-L-glycine, BOC-D-phenylalanine, L-cysteine, N-butyloxycarbonyl-L-cysteine, N' -bis (t-butoxycarbonyl) -L-cystine, L-serine, D-cystine, aspartic acid, D-arginine, isoserine, L-threonine, L-tyrosine, BOC-L-proline, BOC-glycine, 2-allyl-N-FMOC-L-glycine, BOC-D-phenylalanine, L-cysteine, L-tyrosine, L-proline, L-glycine, and L-glycine, and a, D-serine, beta-thioglycolic acid, D-proline, D-valine, L-proline, L-phenylalanine, N-BOC-N' -trityl-L-histidine, L-tryptophan, N-BOC-L-leucine, L-histidine, BOC-L-glutamic acid, L-cystine or L-homocystine.
6. The iron-catalyzed ethoxycarbonyldifluoromethylation of aromatic compounds according to any one of claims 1-3, wherein the oxidant is selected from the group consisting of potassium persulfate, ammonium persulfate, sodium persulfate, t-butyl hydroperoxide, hydrogen peroxide, peracetic acid, m-chloroperoxybenzoic acid, benzoyl peroxide, benzoyl tert-butyl peroxide, di-t-butyl peroxide, potassium monopersulfate, dicumyl peroxide, 2-butanone peroxide, and bis (trimethylsilyl) peroxide.
7. The method for iron-catalyzed ethoxycarbonyldifluoromethylation of aromatic compounds according to any one of claims 1 to 3, wherein the solvent is an organic solvent selected from methanol, ethanol, ethylene glycol, N-propanol, isopropanol, 1, 3-propanediol, glycerol, N-butanol, isobutanol, t-butanol, trifluoroethanol, 2-methyl-2-butanol, 3-methoxybutanol, sec-butanol, t-pentanol, 4-methyl-2-pentanol, isoamyl alcohol, 2-pentanol, 3-pentanol, cyclopentanol, N-pentanol, polyethylene glycol 200-10000, acetonitrile, benzonitrile, toluene, acetone, dichloromethane, 1, 2-dichloroethane, dimethylsulfoxide, N-dimethylamide, N-diethylamide, N-diethylamide, water or an aqueous solution of an organic solvent, Ethyl acetate, 1, 4-dioxane or tetrahydrofuran, wherein when the solvent is an aqueous solution of an organic solvent, the volume ratio of the organic solvent to water is 1 (0.1-5).
8. The iron-catalyzed ethoxycarbonyldifluoromethylation of aromatic compounds according to any one of claims 1-3, wherein said ethyl halodifluoroacetate is selected from ethyl difluorobromoacetate, ethyl difluorochloroacetate or ethyl difluoroiodoacetate.
9. The method of iron-catalyzed ethoxycarbonyl difluoromethylation of an aromatic compound as claimed in any one of claims 1 to 3, wherein the molar ratio of the aromatic compound, ethyl halodifluoroacetate, peroxide, amino acid or its derivative, and iron catalyst is 1 (2-50): 0.002-20: 0.001-10.
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