CN112961054B - A kind of method of iron-catalyzed aromatic compound ethoxycarbonyl difluoromethylation - Google Patents

Abstract

The invention discloses a method for iron-catalyzed ethoxycarbonyl difluoromethylation of aromatic compounds. The method comprises the following steps: in a solvent, ethyl halodifluoroacetate is used as a fluorine reagent, peroxide is used as an oxidant, and iron is used as an oxidant. Using the catalyst, the amino acid or its derivative as the ligand, the aromatic ring of the oxidized aromatic compound undergoes ethoxycarbonyl difluoromethylation reaction to generate the ethoxycarbonyl difluoromethyl substituted aromatic compound. The method of the invention has the advantages of wide sources of catalysts, low cost and environmental protection; wide sources of oxidants, low cost and no waste generation; mild, stable and cheap fluorination reagents; mild reaction conditions, high selectivity and high yield; Stable; good compatibility of substrate functional groups and wide application range of substrates; compatible with complex molecules and natural products, and can well achieve ethoxycarbonyl difluoromethylation of aromatic rings. Under optimized reaction conditions, the yield of the target product can be as high as 90% after isolation.

Description

A kind of method of iron-catalyzed aromatic compound ethoxycarbonyl difluoromethylation

technical field

The invention belongs to the field of catalytic synthesis technology and fine chemical synthesis, and more particularly relates to a method for the ethoxycarbonyl difluoromethylation of an iron-catalyzed aromatic compound. Method for direct ethoxycarbonyl difluoromethylation.

Background technique

Functionalized difluoromethylarene is an important structural unit that is widely found in many biologically active compounds and functional materials. Aromatic compounds with functional _CF2 structures, such as ethoxycarbonyldifluoromethyl ( _-CF2COOEt ), have attracted special attention due to their unique properties. The _CF2 group can act as a biological isomer of an oxygen atom or a carbonyl group, and its presence can also enhance metabolic stability, conformational changes, and dipole moments, while increasing the acidity of adjacent groups. Meanwhile, the _-CF2COOEt group can serve as a powerful synthetic intermediate for post-functionalization, providing a large number of other functional groups. Therefore, the selective introduction of fluorine-containing functional groups at specific positions of organic substrates to synthesize various organic fluorides is one of the important topics in current organic chemistry research. There are still some challenges in current difluoromethylation reactions, such as harsh reaction conditions, poor functional group tolerance leading to substrate limitations (Ohtsuka, Y.; Yamakawa, T. Tetrahedron 2011, 67, 2323-2331.), Toxicity or explosiveness of fluorinated reagents, reactive prefunctionalization (Feng, Z.; Min, Q.-Q.; Xiao, Y.-L.; Zhang, B.; Zhang X. Angew. Chem. Int. Ed. .2014, 53, 1669-1673.), the use of precious metal catalysts (Tu, G.; Yuan, C.; Li, Y.; Zhang, J.; ZhaoY.Angew.Chem.Int.Ed.2018,57, 15597-15601.), which severely limit the large-scale application of this method.

SUMMARY OF THE INVENTION

Purpose of the invention: In view of the problems existing in the prior art, the present invention provides a method for the ethoxycarbonyl difluoromethylation of an iron-catalyzed aromatic compound to solve the harsh ethoxycarbonyl difluoromethylation reaction conditions of the existing aromatic compound , the toxicity or explosiveness of fluorination reagents, the pre-functionalization of the reaction, and the use of precious metal catalysts, resulting in low overall reaction yield, poor functional group compatibility, narrow application scope, large waste emissions, and unenvironmental, unsafe, uneconomical The problem,

The method of the invention only needs one step of reaction, does not need the participation of acid and alkali, and has the characteristics of wide source of catalyst, cheap and environmental protection; cheap oxidant, no waste; mild, stable and cheap fluorination reagent; wide and stable source of substrate ; Mild reaction conditions, good selectivity and high yield; good compatibility of substrate functional groups and wide application range of substrates; compatible with complex molecules and natural products, which can well realize the ethoxycarbonyl difluoromethane of aromatic ring base.

Technical scheme: In order to achieve the above purpose, a method for the iron-catalyzed ethoxycarbonyl difluoromethylation of an aromatic compound according to the present invention comprises the following steps: in a solvent, using ethyl halodifluoroacetate as a fluorine reagent, passing Oxide is an oxidant, iron is a catalyst, an amino acid or its derivative is a ligand, and the aromatic ring of the aromatic compound is oxidized to carry out ethoxycarbonyl difluoromethylation reaction to generate an ethoxycarbonyl difluoromethyl substituted aromatic compound, and the reaction The temperature is 25～150℃, and the time is 0.25～48 hours;

The general reaction formula is as follows:

In the formula: Ar represents aryl or heteroaryl; X represents bromine, chlorine or iodine;

Wherein, the aryl group is a substituted or unsubstituted phenyl group, biphenyl group, naphthyl group, anthracenyl group, phenanthrenyl group or pyrenyl group;

The heteroaryl group is a five- to thirteen-membered ring heteroaryl group containing N, O or S.

Wherein, the heteroaryl group is furyl, benzofuranyl, thienyl, pyrrolyl, indolyl, carbazolyl, pyridyl, isoxazolyl, pyrazolyl, imidazolyl, oxazolyl or thiazole base.

Preferably, when Ar is pyrrolyl, indolyl, carbazolyl, pyrazolyl or imidazolyl, the substituents on its nitrogen atom are arbitrarily selected from hydrogen, C1-C20 alkyl, C1-C20 halo-substituted alkyl group, C3-C20 cycloalkyl, aryl, benzyl, or C1-C20 alkylcarbonyl.

Further, R represents the substituent on the aryl group in Ar, R is the hydrogen on the mono- or multi-substituted aromatic ring, R is selected from hydrogen, C1-C20 alkyl, alkene, alkynyl, C1-C20 alkoxy base, C1-C20 halogen-substituted alkyl, C3-C20 cycloalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heteroarylamino, arylcarbonyl, heteroarylcarbonyl, aryl Oxycarbonyl, heteroaryloxycarbonyl, C1～C20 mercapto, fluorine, chlorine, bromine or iodine, hydroxyl, C1～C20 alkylcarbonyl, carboxyl, C1～C20 alkoxycarbonyl, C1～C20 alkylaminocarbonyl, Arylcarbonyl, C1-C20 alkanesulfonyl, sulfonic acid, -B(OH) ₂ , aldehyde, cyano, amino or nitro.

Wherein, the iron is selected from ferrous trifluoromethanesulfonate, ferric trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetonate, iron acetylacetonate, 2,2,6,6-tetramethyl-3, Ferrous 5-heptanedione, ferrous 2,2,6,6-tetramethyl-3,5-heptanedione, ferrous 1,3-diphenylpropanedione, 1,3-diphenylpropanedione Ferric diketone, 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 iodide, ferric trichloride, iron(III) perchlorate hydrate, 1,1'-bis( diphenylphosphine) ferrocene, ferrous phthalocyanine, ferric nitrate, ferric oxide or ferric tetroxide.

Wherein, the ligand is selected from S-acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine, N-acetyl-L-cysteine, N,N'-bis(tert-butoxycarbonyl) Carbonyl)-L-cystine, L-serine, D-cystine, aspartic acid, D-arginine, isoserine, L-threonine, L-tyrosine, BOC-L-pro Amino acid, BOC-glycine-glycine-glycine, 2-allyl-N-FMOC-L-glycine, BOC-D-phenylalanine, L-cysteine, D-serine, β-thiovale Amino acid, D-proline, D-valine, L-proline, L-phenylalanine, N-BOC-N'-trityl-L-histidine, L-tryptophan acid, 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, benzene peroxide tert-butyl formyl ester, 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 an 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, isopentanol Alcohol, 2-pentanol, 3-pentanol, cyclopentanol, n-pentanol, polyethylene glycol 200-10000, acetonitrile, benzonitrile, toluene, acetone, dichloromethane, 1,2-dichloroethane, Dimethyl sulfoxide, N,N-diformamide, N,N-diacetamide, 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 ethyl halodifluoroacetate is selected from ethyl difluorobromoacetate, ethyl difluorochloroacetate or ethyl difluoroiodoacetate.

Wherein, the molar ratio of the aromatic compound, ethyl halodifluoroacetate, peroxide, amino acid or its derivative, and iron catalyst is 1:(2-50):(2-50):(0.002-20) : (0.001～10).

In the method of the invention, the iron catalyst has the characteristics of large natural abundance, low price and low toxicity, and amino acid ligands are used to coordinate with the iron catalyst to form a highly active catalytic species, which is combined with an oxidant, The combined action of the solvent, etc., makes the halogenated ethyl difluoroacetate form ethyl difluoroacetate free radical to attack the aromatic ring, which has high activity and selectivity. In addition, the method of the present invention uses mild reagents and a mild environment to solve the problem of harsh reaction conditions; the halogenated ethyl difluoroacetate has low cost, easy availability, no toxicity and explosiveness; the reaction directly attacks the aromatic ring, No pre-functionalization is required, iron is the catalyst, no precious metals are used, and the effect is remarkable.

Beneficial effect: Compared with the prior art, the present invention has the following advantages:

(1) the invention provides a kind of method for the iron-catalyzed oxidation of aromatic compound ethoxycarbonyl difluoromethylation promoted by amino acid or its derivative ligand, the method only needs one-step reaction without the participation of acid or base, And it has the unique advantages of cheap catalysts, ligands and oxidants, wide sources and environmental protection; mild reaction conditions, high selectivity and high yield; wide range of substrate sources, stable and easy to handle; It has a wide range of applications; the reaction is suitable for the advantages of ethoxycarbonyl difluoromethylation of complex small molecules;

(2) the ethoxycarbonyl difluoromethylation method provided by the invention is simple, feasible and safe, the one-step method directly obtains the ethoxycarbonyl difluoromethylation product of the aromatic compound, and under optimized reaction conditions, the target product is separated The post-yield can be as high as 90%, which is a general, efficient, economical and environmentally friendly method for ethoxycarbonyl difluoromethylation;

(3) The reason why the method of the present invention can use ideal iron as a catalyst for the reaction is that the amino acid ligand is used to coordinate with the iron catalyst to form a highly active catalytic species, so that the reaction can be carried out under very mild conditions. The ethoxycarbonyl difluoromethylation reaction of aromatic compounds can be carried out under the following conditions, and the ideal catalytic effect can be obtained especially for complex substrates.

(4) The ethoxycarbonyl difluoromethylated aromatic compounds synthesized by the method of the present invention can be used as medicines or biologically active molecules, and at the same time are important organic intermediates, and are widely used in pharmaceutical intermediates, heterocycles and high value-added fine Synthesis of chemicals.

Detailed ways

The present invention can be better understood from the following examples. However, those skilled in the art can easily understand that the contents described in the embodiments are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

The experimental methods described in the examples are conventional methods unless otherwise specified; the reagents and materials, unless otherwise specified, can be obtained from commercial channels or simply prepared by existing technologies.

The specific structures of the substrates and products in the examples are shown in Table 1.

Example 1

Synthesis of Compound 1

In the air, iron bromide (0.05mmol), D-serine (0.1mmol), substrate 1a (0.5mmol), ethanol (2.0mL), BrCF ₂ COOEt (2mmol) and monopersulfate were added to a 25mL reaction flask in turn. Potassium (4 mmol). After mixing uniformly at room temperature, the reaction mixture was refluxed at 80 °C for 3 h. After the reaction was completed, direct chromatographic separation (petroleum ether:ethyl acetate V/V=10:5) yielded product 1 with a yield of 78%.

Example 2

Synthesis of Compound 2

In the air, ferric chloride (0.1 mmol), L-homocysteine (0.2 mmol), substrate 1b (0.5 mmol), methanol (2.0 mL), BrCF ₂ COOEt (1 mmol) and Dicumyl peroxide (1 mmol). After mixing uniformly at room temperature, the reaction mixture was refluxed at 60 °C for 3 h. After the reaction was completed, direct chromatographic separation (petroleum ether:ethyl acetate V/V=10:3) yielded product 2 with a yield of 85%.

Example 3

Synthesis of Compound 3

In the air, ferrous trifluoromethanesulfonate (0.04mmol), aspartic acid (0.08mmol), substrate 1c (0.5mmol), tert-butanol (2.0mL), BrCF ₂ COOEt ( 1.5 mmol) and di-tert-butyl peroxide (1 mmol). After mixing uniformly at room temperature, the reaction mixture was refluxed at 25 °C for 3 h. After the reaction was completed, direct chromatographic separation (petroleum ether:dichloromethane V/V=10:2) yielded product 3 with a yield of 88%.

Example 4

Synthesis of compound 4

In the air, ferrous chloride (0.5 mmol), S-acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine (1.0 mmol), and substrate 1d (0.5 mmol) were successively added to the 25 mL reaction flask. , isopropanol (1.5 mL) and water ( _2.5 mL), ICF2COOEt (1.5 mmol) and hydrogen peroxide (1.5 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 100 °C for 24 h. After the reaction was completed, 5 mL of water was added, and extracted with ethyl acetate (5 mL×3), the organic phases were combined, and the solvent was evaporated under reduced pressure, and then the solvent was removed by column chromatography (petroleum ether: dichloromethane V/V=10:4) to obtain product 4 , the yield is 65%.

Example 5

Synthesis of compound 5

In the air, ferrous acetylacetonate (0.02 mmol), BOC-L-glutamic acid (0.04 mmol), substrate 1e (0.5 mmol), glycerol (1.5 mL) and water (0.5 mL) were sequentially added to a 25 mL reaction flask, BrCF2COOEt ( ₄ mmol) and peracetic acid (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 60° C. for 2 h. After the reaction was completed, 5 mL of water was added, extracted with ether (5 mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then the solvent was removed by column chromatography (petroleum ether: ethyl acetate V/V=10:2) to obtain product 5, which was Yield 73%.

Example 6

Synthesis of compound 6

In the air, iron acetylacetonate (0.08mmol), L-tyrosine (0.16mmol), substrate 1f (0.5mmol), n-butanol (2.0mL), ClCF ₂ COOEt (1mmol) and tert-Butyl hydroperoxide (5 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 25 °C for 3 h. After the reaction was completed, direct chromatographic separation (petroleum ether:ethyl acetate V/V=10:1) yielded product 6 with a yield of 70%.

Example 7

Synthesis of compound 7

Under normal pressure nitrogen, iron trifluoromethanesulfonate (0.05mmol), L-cystine (0.1mmol), substrate 1g (0.5mmol), acetonitrile (2.0mL), BrCF ₂ COOEt ( 1 mmol) and m-chloroperoxybenzoic acid (1.5 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 50° C. for 1 h. After the reaction was completed, direct chromatographic separation (petroleum ether:ethyl acetate V/V=20:3) yielded product 7 with a yield of 87%.

Example 8

Synthesis of Compound 8

In the air, ferrous fluoride (0.1mmol), N,N'-bis(tert-butoxycarbonyl)-L-cystine (0.4mmol), substrate 1h (0.5mmol), acetonitrile were added to the 25mL reaction flask in turn. (1.5 mL) and water (1.5 mL), _ICF2COOEt (1.5 mmol) and potassium persulfate (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80° C. for 2 h. After the reaction was completed, 5 mL of water was added, and extracted with ethyl acetate (5 mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and the solvent was removed by column chromatography (petroleum ether: ethyl acetate V/V=10:3) to obtain product 8 , its yield is 76%.

Example 9

Synthesis of compound 9

In the air, add ferrous iodide (0.08mmol), N-acetyl-L-cysteine (0.32mmol), substrate 1i (0.5mmol), trifluoroethanol (2.0mL), BrCF to a 25mL reaction flask in turn _2COOEt (4 mmol) and benzoyl peroxide (2 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 60° C. for 2 h. After the reaction was completed, the product 9 was obtained by direct chromatographic separation (petroleum ether:dichloromethane V/V=10:5) with a yield of 74%.

Example 10

Synthesis of Compound 10

Under normal pressure nitrogen, ferrous sulfate (0.05mmol), L-cysteine (0.1mmol), substrate 1j (0.5mmol), dimethyl sulfoxide (1.5mL) and water ( 0.5 mL), BrCF2COOEt ( ₂ mmol) and sodium persulfate (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80° C. for 1 h. After the reaction was completed, 5 mL of water was added, and extracted with ethyl acetate (5 mL×3), the organic phases were combined, washed with water (5 mL×3), the organic phases were collected, and the solvent was evaporated under reduced pressure and separated by column chromatography (petroleum ether: ether V /V=10:2) to give product 10 in 70% yield.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.51 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 6.99 (t, J=7.6 Hz, 1H), 6.96 ( d, J=8.4 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 1.33 ppm (t, J=7.1 Hz, 3H); ¹³ CNMR (100 MHz, CDCl ₃ ): δ 165.4 (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, 13.8 ppm; ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ-103.6 ppm.

Example 11

Synthesis of Compound 11

Under normal pressure nitrogen, 2,2,6,6-tetramethyl-3,5-heptanedione ferrous (0.02mmol), L-serine (0.04mmol), substrate 1k (0.5 mmol), dimethylsulfoxide (4.0 mL), BrCF2COOEt ( ₁ mmol) and tert-butyl benzoyl peroxide (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 25° C. for 1 h. After the reaction was completed, 5 mL of water was added, and extracted with ethyl acetate (5 mL×3), the organic phases were combined, washed with water (5 mL×3), the organic phases were collected, and the solvent was evaporated under reduced pressure and separated by column chromatography (petroleum ether: ether V /V=10:5) to give product 11 in 79% yield.

Example 12

Synthesis of Compound 12

In the air, ferrous acetate (0.02mmol), D-cystine (0.04mmol), substrate 1l (0.5mmol), dichloromethane (2.0mL), BrCF ₂ COOEt (1mmol) and 2-Butanone peroxide (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 25° C. for 0.5 h. After the reaction was completed, direct chromatographic separation (petroleum ether:ethyl acetate V/V=10:3) yielded product 12 with a yield of 86%.

Example 13

Synthesis of Compound 13

In the air, ferric ferricyanide (0.001mmol), BOC-glycine-glycine-glycine (0.002mmol), substrate 1m (0.5mmol), 1,2-dichloroethane (2.0mL) were added to the 25mL reaction flask in turn. ), BrCF2COOEt ( ₁ mmol) and bis(trimethylsilyl) peroxide (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 40° C. for 1 h. After the reaction was completed, direct chromatographic separation (petroleum ether:diethyl ether V/V=10:5) gave the product 13 with a yield of 90%.

Example 14

Synthesis of compound 14

In the air, ferrous bromide (0.05 mmol), BOC-D-phenylalanine (0.1 mmol), substrate 1n (0.5 mmol), acetonitrile (1.0 mL) and water (1.0 mL) were sequentially added to a 25 mL reaction flask , _BrCF2COOEt (1.5 mmol) and ammonium persulfate (1.5 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 60° C. for 2 h. After the reaction was completed, 5 mL of water was added, extracted with ethyl acetate (5 mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and the solvent was removed by column chromatography (petroleum ether: ethyl acetate V/V=10:2) to obtain product 14 , its yield is 89%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.30 (s, 2H), 5.29 (s, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.23-3.13 (m, 2H), 1.32 (t , J=7.1Hz, 3H), 1.27ppm (d, J=6.9Hz, 12H); ¹³ C NMR (100MHz, CDCl ₃ ): δ 164.7 (t, J=36.0Hz), 152.3, 134.0, 124.5 ( t, J=25.5 Hz), 120.9 (t, J=6.1 Hz), 113.9 (t, J=249.8 Hz), 62.9, 27.1, 22.5, 13.8 ppm; ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ-102.1 ppm; HRMS (ESI) m/z calcd for C ₁₆ H ₂₂ F ₂ O ₃ Na ⁺ (M+Na) ⁺ 323.1429, found 323.1437; IR (KBr, cm ^-1 ): ν _max 3524, 2965, 2873, 1765 ,1470,1290,1189,937,828,772,504.

Example 15

Synthesis of compound 15

Under normal pressure nitrogen, 2,2,6,6-tetramethyl-3,5-heptanedione iron (0.1mmol), D-arginine (0.2mmol), and substrate 1o ( 0.5 mmol), N,N-diformamide (2.0 mL), BrCF2COOEt ( _2.5 mmol) and tert-butyl benzoyl peroxide (1.5 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80 °C for 6 h. After the reaction was completed, 5 mL of water was added, extracted with ethyl acetate (5 mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and the solvent was removed by column chromatography (petroleum ether: ethyl acetate V/V=10:1) to obtain product 15 , the yield is 70%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.08 (s, 1H), 7.98 (d, J=8.1 Hz, 2H), 7.79 (d, J=8.2 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 1.30 ppm (t, J=7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 191.3, 163.5, 138.1, 133.8, 129.8, 126.3 (t, J=6.1 Hz), 112.8 ( t, J=251.7 Hz), 63.5, 13.8 ppm; ¹⁹ FNMR (376 MHz, CDCl ₃ ): δ-104.5 ppm.

Example 16

Synthesis of Compound 16

In the air, 1,3-diphenylpropanedione iron (0.05mmol), D-valine (0.1mmol), substrate 1p (0.5mmol), and ethyl acetate (2.0mL) were successively added to a 25mL reaction flask. , _BrCF2COOEt (1.5 mmol) and tert-butyl hydroperoxide (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80° C. for 3 h. After the reaction was completed, direct chromatographic separation (petroleum ether:ethyl acetate V/V=10:2) yielded product 16 with a yield of 81%.

Example 17

Synthesis of compound 17

In the air, add ferrous 1,3-diphenylpropanedione (0.5mmol), BOC-L-proline (1.5mmol), substrate 1q (0.5mmol), 1,4- Dioxane (2.0 mL), ICF ₂ COOEt (1.5 mmol) and hydrogen peroxide (1.5 mmol) were mixed uniformly at room temperature, and the reaction mixture was reacted at 100° C. for 6 h. After the reaction was completed, direct chromatographic separation (petroleum ether: ethyl acetate V/V=20:3) yielded product 17 with a yield of 52%.

Example 18

Synthesis of compound 18

In the air, ferrous benzoylacetonate (0.05mmol), D-proline (0.1mmol), substrate 1r (0.5mmol), tetrahydrofuran (2.0mL), BrCF ₂ COOEt (1mmol) were sequentially added to a 25mL reaction flask and benzoyl peroxide (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80° C. for 3 h. After the reaction was completed, direct chromatographic separation (petroleum ether:dichloromethane V/V=10:6) gave the product 18 with a yield of 64%.

Example 19

Synthesis of compound 19

In the air, add iron benzoylacetonate (0.2mmol), N-BOC-L-leucine (0.4mmol), substrate 1s (0.5mmol), sec-butanol (2.0mL), BrCF to a 25mL reaction flask in sequence ₂ COOEt (1.5 mmol) and peracetic acid (1.5 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 60 °C for 12 h. After the reaction was completed, direct chromatographic separation (petroleum ether:dichloromethane V/V=10:5) yielded product 19 with a yield of 48%.

Example 20

Synthesis of Compound 20

In the air, ferric ferricyanide (0.05mmol), L-histidine (0.15mmol), substrate 1t (0.5mmol), polyethylene glycol-2000 (1.0g) and water (1.0g) were successively added to a 25mL reaction flask. mL), BrCF2COOEt ( ₂ mmol) and m-chloroperoxybenzoic acid (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 120° C. for 3 h. After the reaction was completed, 5 mL of water was added, and extracted with ether (5 mL×3), the organic phases were combined, and the solvent was evaporated under reduced pressure, and then column chromatography (petroleum ether: ethyl acetate V/V=10:3) was used to obtain product 20, which was Yield 70%.

Example 21

Synthesis of Compound 21

In the air, iron iodide (0.05mmol), L-tryptophan (0.1mmol), substrate 1u (0.5mmol), 4-methyl-2-pentanol (2.0mL), BrCF were added to a 25mL reaction flask in turn. ₂ COOEt (1 mmol) and tert-butyl benzoyl peroxide (2 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80 °C for 18 h. After the reaction was completed, direct chromatographic separation (petroleum ether:ethyl acetate V/V=10:1) yielded product 21 with a yield of 51%.

Example 22

Synthesis of Compound 22

In the air, add ferrous oxalate (0.05mmol), N-BOC-N'-trityl-L-histidine (0.1mmol), substrate 1v (0.5mmol), cyclopentanol to a 25mL reaction flask in turn (2.0 mL), _BrCF2COOEt (1.5 mmol) and di-tert-butyl peroxide (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80° C. for 2 h. After the reaction was completed, direct chromatographic separation (petroleum ether:ethyl acetate V/V=10:1) yielded product 22 in a yield of 65%.

¹ H NMR (400 MHz, CD ₃ COCD ₃ ): δ 7.55 (s, 2H), 7.23 (s, 2H), 4.30 (q, J=7.1 Hz, 2H), 3.84 (s, 6H), 1.28 ppm ( t, J=7.1 Hz, 3H); ¹³ C NMR (100 MHz, CD ₃ COCD ₃ ): δ 164.9 (t, J=32.7 Hz), 159.3, 130.6, 114.2 (t, J=246.4 Hz), 111.0, 62.9, 56.5, 14.3 ppm; ¹⁹ F NMR (376 MHz, CD ₃ COCD ₃ ): δ-98.0 ppm; ¹¹ B NMR (128 MHz, CD ₃ COCD ₃ ): δ 28.5 ppm; HRMS (ESI) m/zcalcd for C ₁₂ H ₁₆ BF ₂ O ₆ ⁺ (M+H) ⁺ 305.1003, found 305.1007; IR (KBr, cm ^-1 ): ν _max 3746, 2921, 1770, 1455, 1372, 1274, 952, 855, 749, 599.

Example 23

Synthesis of Compound 23

In the air, iron oxide (0.1 mmol), L-threonine (0.4 mmol), substrate 1w (0.5 mmol), isoamyl alcohol (2.0 mL), BrCF ₂ COOEt (1.5 mmol) and Dicumyl peroxide (1.5 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80° C. for 3 h. After the reaction was completed, direct chromatographic separation (petroleum ether:ethyl acetate V/V=10:4) yielded product 23 with a yield of 63%.

Example 24

Synthesis of compound 24

In the air, ferric sulfate (0.2 mmol), isoserine (0.5 mmol), substrate 1x (0.5 mmol), dimethyl sulfoxide (2.0 mL), BrCF ₂ COOEt (1.5 mmol) and 2 were sequentially added to a 25 mL reaction flask. - Butanone peroxide (2 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 60° C. for 1 h. After the reaction was completed, 5 mL of water was added, extracted with ethyl acetate (5 mL×3), the organic phases were combined, washed with water (5 mL×3), the organic phases were collected, and the solvent was evaporated under reduced pressure, and then separated by column chromatography (petroleum ether: dichloromethane). Methane V/V=10:8) gave product 24 in 71% yield.

Example 25

Synthesis of compound 25

In the air, add iron(III) perchlorate hydrate (0.15mmol), 2-allyl-N-FMOC-L-glycine (0.3mmol), substrate 1y (0.5mmol), N , N-diacetamide (1.5 mL) and water (0.5 mL), ICF2COOEt ( ₁ mmol) and hydrogen peroxide (2 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80 °C for 24 h. After the reaction was completed, ammonia water (0.5 mL, 25%) was added and stirred for 1 h. Then, 5 mL of water was added, and extracted with ether (5 mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and the solvent was removed by column chromatography (petroleum ether: dichloromethane V/V=10:1) to obtain the product 25, which was Yield 65%.

Example 26

Synthesis of compound 26

In the air, 1,1'-bis(diphenylphosphino)ferrocene (0.05mmol), L-proline (0.1mmol), substrate 1z (0.5mmol), acetone (2.0 mL), BrCF2COOEt ( ₁ mmol) and tert-butyl hydroperoxide (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 50° C. for 6 h. After the reaction was completed, direct chromatographic separation (petroleum ether:diethyl ether V/V=10:2) gave the product 26 with a yield of 74%.

Example 27

Synthesis of compound 27

In the air, ferrous ammonium sulfate (0.1 mmol), β-thiovaline (0.3 mmol), substrate 1aa (0.5 mmol), dimethyl sulfoxide (1.5 mL) and water (0.5 mmol) were sequentially added to a 25 mL reaction flask. mL), BrCF2COOEt ( ₃ mmol) and ammonium persulfate (2 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80 °C for 6 h. After the reaction was completed, ammonia water (0.5 mL, 25%) was added and stirred for 1 h. Next, 5 mL of water was added, and extracted with ethyl acetate (5 mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and the solvent was removed by column chromatography (petroleum ether: dichloromethane V/V=10:7) to obtain the product 27 , its yield is 87%.

Example 28

Synthesis of Compound 28

In the air, iron fluoride (0.05mmol), L-phenylalanine (0.1mmol), substrate 1ab (0.5mmol), acetonitrile (2mL), BrCF ₂ COOEt (1mmol) and di-tert Butyl peroxide (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80° C. for 3 h. After the reaction was completed, direct chromatographic separation (petroleum ether:ethyl acetate V/V=10:1) yielded product 28 with a yield of 55%.

Example 29

Synthesis of compound 29

In the air, add ferrocyanine (0.005mmol), L-cysteine (0.02mmol), substrate 1ac (0.5mmol), N,N-diformamide (1.5mL) and water to a 25mL reaction flask in sequence (0.5 mL), BrCF2COOEt ( ₁ mmol) and sodium persulfate (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 25 °C for 24 h. After the reaction was completed, ammonia water (0.5 mL, 25%) was added and stirred for 1 h. Then, 5 mL of water was added, and extracted with ethyl acetate (5 mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then the solvent was removed by column chromatography (petroleum ether: ethyl acetate V/V=10:6) to obtain the product 29 , its yield is 49%.

Example 30

Synthesis of compound 30

In the air, ferrous sulfate (0.05 mmol), L-cystine (0.1 mmol), substrate 1ad (0.5 mmol), ethanol (2.0 mL), BrCF ₂ COOEt (1 mmol) and tert-butyl were sequentially added to a 25 mL reaction flask. base hydrogen peroxide (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 60 °C for 12 h. After the reaction was completed, direct chromatographic separation (petroleum ether:ethyl acetate V/V=10:4) yielded product 30 with a yield of 68%.

Example 31

Synthesis of compound 31

In the air, iron oxalate (0.05 mmol), L-serine (0.1 mmol), substrate 1ae (0.5 mmol), dichloromethane (2.0 mL), BrCF ₂ COOEt (1 mmol) and diperoxide were added to a 25 mL reaction flask in turn. Cumene (1.5 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 25 °C for 12 h. After the reaction was completed, direct chromatographic separation (petroleum ether:ethyl acetate V/V=10:4) yielded product 31 with a yield of 74%.

Example 32

Synthesis of compound 32

In the air, ferric nitrate (0.1 mmol), L-proline (0.1 mmol), substrate 1af (0.5 mmol), ethanol (1.5 mL) and water (0.5 mL), BrCF ₂ COOEt ( 2 mmol) and potassium persulfate (1.5 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 60° C. for 24 h. After the reaction was completed, ammonia water (0.5 mL, 25%) was added and stirred for 1 h. Then, 5 mL of water was added, and extracted with ether (5 mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and the solvent was removed by column chromatography (petroleum ether: dichloromethane V/V=10:5) to obtain product 32, which was Yield 72%.

Example 33

Synthesis of compound 33

In the air, ferric chloride (0.05 mmol), BOC-L-glutamic acid (0.1 mmol), substrate 1ag (0.5 mmol), acetonitrile (1.5 mL), water (0.5 mL), and ClCF were added to a 25 mL reaction flask in turn. ₂ COOEt (1 mmol) and potassium monopersulfate (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80° C. for 2 h. After the reaction was completed, ammonia water (0.5 mL, 25%) was added and stirred for 1 h. Then, 5 mL of water was added, and extracted with ethyl acetate (5 mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and the solvent was removed by column chromatography (petroleum ether: ethyl acetate V/V=10:2) to obtain product 33 , its yield is 69%.

¹ H NMR (400 MHz, CD ₃ COCD ₃ ): δ 10.07 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 2.33 ppm (s, 3H); ¹³ C NMR (100 MHz, CD ₃ COCD ₃ ): δ 165.9 (t, J=29.3 Hz), 143.1 (t, J=6.6 Hz), 136.8, 132.3, 132.2, 118.3 (t, J=21.0 Hz), 111.9 (t, J=248.6 Hz), 111.2, 18.7 ppm; ¹⁹ F NMR (376 MHz, CD ₃ COCD ₃ ): δ-116.0 ppm; HRMS (ESI) m/z calcd for C ₉ H ₇ ClF ₂ NO ⁺ (M+H) ⁺ 218.0179, found 218.0176; IR (KBr, cm ^-1 ): ν _max 3866, 3716, 2924, 2853, 1697, 1471, 1393, 1213, 823, 765, 590, 468; Mp: 199.5-201.3℃.

Example 34

Synthesis of compound 34

In the air, ferrous chloride (0.5 mmol), L-histidine (1.0 mmol), substrate 1ah (0.5 mmol), dimethyl sulfoxide (4.0 mL), BrCF ₂ COOEt ( 5 mmol) and tert-butyl benzoyl peroxide (4 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80° C. for 3 h. After the reaction was completed, 5 mL of water was added, extracted with ethyl acetate (5 mL×3), the organic phases were combined, washed with water (5 mL×3), the organic phases were collected, and the solvent was evaporated under reduced pressure, and then separated by column chromatography (petroleum ether: dichloromethane). Methane V/V=10:4) gave product 34 in 77% yield.

Example 35

Synthesis of compound 35

In the air, ferrous acetylacetonate (0.1 mmol), N-BOC-L-leucine (0.2 mmol), substrate 1ai (0.5 mmol), dimethyl sulfoxide (1.5 mL) and Water (0.5 mL), _BrCF2COOEt (1.5 mmol) and peracetic acid (1.5 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80 °C for 6 h. After the reaction was completed, 5 mL of water was added, and extracted with ethyl acetate (petroleum ether: ethyl acetate V/V=10:3) (5 mL×3), the organic phases were combined, washed with water (5 mL×3), the organic phases were collected, and the After autoclaving off the solvent, the product 35 was obtained by column chromatography in 52% yield.

¹ H NMR (400MHz, CD ₃ COCD ₃ ): δ8.25(s, 1H), 7.92(s, 1H), 7.68-7.62(m, 1H), 7.18-7.11(m, 2H), 4.34(q, J=7.1 Hz, 2H), 1.27 ppm (t, J=7.1 Hz, 3H); ¹³ C NMR (100 MHz, CD ₃ COCD ₃ ): δ 173.3, 164.4, 164.0 (t, J=33.3 Hz), 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; ¹⁹ F NMR (376MHz, CD ₃ COCD ₃ ): δ-103.0, -112.7, -115.2ppm; HRMS (ESI) m/z calcd for C ₁₉ H ₂₆ F ₂ O ₅ Na ⁺ (M+Na) ⁺ 395.1641, found 395.1649; IR (KBr ,cm ^-1 ):ν _max 2929,2317,1766,1593,1507,1456,1373,1268,968,850,723,472.Mp:186.9-189.3℃.

Example 36

Synthesis of compound 36

In the air, add iron acetylacetonate (0.05mmol), BOC-glycine-glycine-glycine (0.1mmol), substrate 1aj (0.5mmol), N,N-diacetamide (1.0mL) and water to a 25mL reaction flask in sequence (0.1 mL), BrCF2COOEt ( ₁ mmol) and tert-butyl hydroperoxide (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 100 °C for 6 h. After the reaction was completed, ammonia water (0.5 mL, 25%) was added and stirred for 1 h. Then, 5 mL of water was added, and extracted with ethyl acetate (5 mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and the solvent was removed by column chromatography (petroleum ether: ethyl acetate V/V=10:4) to obtain product 36 , its yield is 59%.

Example 37

Synthesis of compound 37

In the air, iron (III) perchlorate hydrate (0.05 mmol), L-homocysteine (0.1 mmol), substrate 1ak (0.5 mmol), and dichloromethane (2.0 mL) were sequentially added to a 25 mL reaction flask, BrCF2COOEt ( ₁ mmol) and hydrogen peroxide (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 40 °C for 6 h. After the reaction was completed, direct chromatographic separation (petroleum ether:ethyl acetate V/V=10:2) yielded product 37 with a yield of 67%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.09 (s, 1H), 7.24 (s, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.77 (d, J=8.2 Hz, 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), 1.26 ppm (t, J=7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 172.2, 164.7 (t, J=34.2 Hz), 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; ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ-103.2 ppm; HRMS (ESI) m/z calcd for C ₁₉ H ₂₅ F ₂ NO ₇ Na ⁺ (M+Na) ⁺ 440.1491, found 440.1497; IR (KBr, cm ^-1 ): ν _max 3370,2933,1686,1587,1444,1369,1215,1028,832,757,598,486.

Example 38

Synthesis of compound 38

In the air, ferrous bromide (0.05 mmol), D-valine (0.1 mmol), substrate 1al (0.5 mmol), dimethyl sulfoxide (2.0 mL), BrCF ₂ COOEt ( 1 mmol) and 2-butanone peroxide (1 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80° C. for 3 h. After the reaction was completed, 5 mL of water was added, and extracted with ether (5 mL×3), the organic phases were combined, washed with water (5 mL×3), the organic phases were collected, and the solvent was evaporated under reduced pressure, and separated by column chromatography (petroleum ether: dichloromethane V /V=10:7) to give product 38 in 89% yield.

The raw materials and product structural formulas of Examples 1-38 and the corresponding experimental results are shown in Table 1 below:

Table 1

Example 39

Example 39 is the same as Example 1, except that the molar ratio of aromatic compound, ethyl halodifluoroacetate, peroxide, amino acid derivative and iron catalyst is 1:2:2:0.002:0.001 .

Example 40

Example 40 is the same as Example 1, except that the molar ratio of aromatic compound, ethyl halodifluoroacetate, peroxide, amino acid derivative, and iron catalyst is 1:50:50:20:10 .

Example 41

The method of Example 41 is the same as that of Example 8, except that the solvent is all water, and the total volume remains unchanged.

Example 42

The method of Example 42 is the same as that of Example 8, except that: the solvent (dimethyl sulfoxide and water), the volume ratio of organic solvent to water is 1:0.1.

Example 43

The method of Example 43 is the same as that of Example 8, except that: the volume ratio of solvent (ethanol and water), organic solvent and water is 1:5.

Example 44

The method of Example 44 is the same as that of Example 6, except that the reaction temperature is 25° C. and the time is 48 hours.

Example 45

The method of Example 45 is the same as that of Example 20, except that the reaction temperature is 150° C. and the time is 0.25 hours.

Comparative Example 1

The method of Comparative Example 1 is the same as that of Example 15, except that no iron catalyst is added, and the yield of the target product is 0.

Comparative Example 2

The method of Comparative Example 2 is the same as that of Example 15, the difference is that: no amino acid ligand is added, the reaction yield is greatly reduced, and the yield is less than 40%.

The above descriptions are only preferred embodiments of the present invention, and do not limit the present invention in any form. Although the present invention has been disclosed above with preferred embodiments, it is not intended to limit the present invention. In theory, all kinds of iron catalysts can coordinate with amino acid ligands to form highly active iron catalyst species, which is conducive to the smooth progress of the reaction; amino acid ligands are promoters for the ethoxycarbonyl difluoromethylation reaction. The most important thing is that it can coordinate with iron. In theory, various amino acids and their derivatives have coordination functions, and they should all achieve similar effects; various peroxides are oxidants; It is the activation of carbon-hydrogen bonds, and the various substituents on the aromatic ring affect the electron cloud density in the ring and the steric hindrance during the reaction, that is, the modification of the substituents only affects the reaction to a certain extent. The occurrence of the reaction plays a decisive role. It is not difficult for any person skilled in the art to understand that, without departing from the scope of the technical solution of the present invention, changes or modifications can be made to obtain corresponding embodiments, for example, the substituents can be replaced and changed within the scope of the present invention. or modification, the method of the present invention can be realized. However, any modification, modification or equivalent and equivalent changes made to the above embodiments according to the present invention without departing from the purpose of the technical solution of the present invention still fall within the scope 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:

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.