A method for iron-catalyzed bromination of ketone α-position

Abstract

The invention discloses a method for brominating α-position of ketone by iron catalysis, the method comprising the steps of: in a solvent, using bromide as a bromine reagent, peroxide as an oxidant, iron as a catalyst, an amino acid or its derivative as a ligand, catalyzing the synthesis of α-bromoketone by oxidation. The method of the invention has the advantages of wide source of catalysts, low cost and environmental protection; wide source of oxidants and low cost; mild, stable and cheap bromination reagents; mild reaction conditions, high selectivity and high yield; wide and stable substrate sources; good compatibility of substrate functional groups and wide application range of substrates; complex molecules and natural products are compatible, and α-position bromination of ketones can be well achieved. Under optimized reaction conditions, the yield of the target product after separation can be as high as 83%.

Description

Technical Field

[0001] The invention belongs to the field of catalytic synthesis technology and fine chemical synthesis, and specifically relates to a method for iron-catalyzed α-position bromination of ketones, which is a method for iron-catalyzed oxidation of carbonyl compounds with suitable oxidants to achieve α-position bromination of carbonyl compounds. Background Art

[0002] Organic halides are undoubtedly an important class of chemicals that have been widely used as precursors and target products for the synthesis. Carbon-halogen bonds play key functional regulatory roles in pesticides, materials, natural products, and pharmaceuticals. The α-bromination of ketones is an important reaction in synthetic organic chemistry because the resulting α-bromocarbonyl compounds are versatile intermediates for the synthesis of a variety of bioactive compounds. In particular, α-bromocarbonyl compounds have become important structural motifs for the development of various bioactive compounds such as thiazoles, quinoxalines, triazolothiadiazines, pyrroles, dihydropyrazines, imidazoles, etc. Over the past few decades, efforts have been devoted to the development of various useful reagents and methods for the synthesis of α-bromoketones. However, all these methods still have some disadvantages, such as the limitation of substrates caused by reaction conditions (S. Song, X. W. Li, X. Sun, Y. Z. Yuan, N. Jiao, Green Chem, 2015, 17, 3285-3289.), poor stability of bromination reagents, poor atom economy (T. A. Salama, Z. Novák, Tetrahedron Lett, 2011, 52, 4026-4029.), and generation of organic waste (R. B. Mohan, N. C. G. Reddy, Synthetic Commun, 2013, 43, 2603-2614.), which seriously limit the large-scale application of this method. Summary of the invention

[0003] Purpose of the invention: In view of the problems existing in the prior art, the present invention provides a method for the bromination of α-position of ketones by iron catalysis, which solves the problems of harsh reaction conditions for the bromination of α-position of ketones, poor stability or atom economy of bromination reagents, low total reaction yield, poor functional group compatibility, narrow application range, high waste generation, and environmental, safety and uneconomical.

[0004] The method of the invention only needs one step of reaction and does not require the participation of acid or alkali, and has the characteristics of wide source of catalyst, low cost and environmental protection; low cost of oxidant and no waste; mild, stable and low cost of bromination 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 substrate; and compatibility of complex molecules and natural products, so as to realize the α-position bromination of ketone well.

[0005] Technical solution: In order to achieve the above-mentioned purpose, the method of iron-catalyzed α-position bromination of ketones of the present invention is characterized by comprising the following steps: in a solvent, using bromide as a bromination reagent, peroxide as an oxidant, iron as a catalyst, and amino acids or their derivatives as ligands, catalyzing the α-position bromination reaction of oxidized ketones to generate α-position brominated ketones;

[0006] The general reaction formula is as follows:

[0007]

[0008] In the formula: R represents aryl, alkyl, alkenyl or heteroaryl; R 1 represents hydrogen, alkyl or halogen; X represents hydrogen, sodium, lithium or potassium.

[0009] Wherein, R represents an aryl, an alkyl, an alkenyl, or a heteroaryl, wherein the aryl is a substituted phenyl or naphthyl; the heteroaryl is a five-membered or six-membered heteroaryl containing at least one of nitrogen, oxygen, and sulfur; the alkyl is a C1-C20 alkyl; the alkenyl is a C1-C20 alkenyl;

[0010] Preferably, the heteroaryl group is furyl, thiazolyl or pyridyl.

[0011] Wherein, when R represents an aryl group, R 2 represents a substituent on an aromatic group, R 2 Mono- or poly-substituted hydrogen on the aromatic ring, R 2 Selected from hydrogen, C1-C20 alkyl, C1-C20 alkoxy, halogen, phenoxy or hydroxy.

[0012] Wherein, the iron is selected from ferrous trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetonate, ferrous acetylacetonate, ferrous 2,2,6,6-tetramethyl-3,5-heptanedione ferrous, 2,2,6,6-tetramethyl-3,5-heptanedione ferrous, 1,3-diphenylpropanedione ferrous, 1,3-diphenylpropanedione ferrous, ferrous benzoylacetonate, ferrous benzoylacetonate, ferrous ferrocyanide, ferrous ferrocyanide, ferrous acetate, ferrous sulfate, ammonium ferrous sulfate, ferrous sulfate, ferrous oxalate, ferrous oxalate, ferrous fluoride, ferrous fluoride, ferrous bromide, ferrous bromide, ferrous iodide, ferric chloride, iron (III) perchlorate hydrate, 1,1'-bis(diphenylphosphino)ferrocene, ferrous phthalocyanine, ferric nitrate, ferric oxide or ferric oxide.

[0013] Wherein, the ligand is selected from BCPOM, BCGOM, S-acetylaminomethyl-N-tert-butyloxycarbonyl-L-cysteine, N-acetyl-L-cysteine, N,N'-bis(tert-butyloxycarbonyl)-L-cystine, L-serine, D-cystine, aspartic acid, D-arginine, isoserine, L-threonine, L-tyrosine, BOC-L-proline, 2-allyl-N-FMOC-L-glycine, BOC-D-phenylalanine, L-cysteine, D-serine, β-thiovaline, D-proline, D-valine, L-proline, L-phenylalanine, N-BOC-N'-trityl-L-histidine, L-tryptophan, N-BOC-L-leucine, L-histidine, BOC-L-glutamate, L-cystine or L-homocystine.

[0014] Wherein, the oxidant is selected from potassium persulfate, ammonium persulfate, sodium persulfate, tert-butyl hydroperoxide, hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, benzoyl peroxide, tert-butyl benzoyl peroxide, di-tert-butyl peroxide, potassium monopersulfate, diisopropylbenzene peroxide, 2-methyl ethyl peroxide or bis(trimethylsilyl)peroxide.

[0015] Wherein, the solvent is an organic solvent, water or an aqueous solution of an organic solvent, the organic solvent is selected from tert-butanol, polyethylene glycol 200-10000, acetonitrile, benzonitrile, toluene, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-diformamide, N,N-diacetamide, ethyl acetate, 1,4-dioxane or tetrahydrofuran, and 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).

[0016] Preferably, the bromide is selected from sodium bromide, potassium bromide, lithium bromide and hydrobromic acid.

[0017] The molar ratio of the ketone, bromide, peroxide, amino acid or its derivative, and iron catalyst is 1:(2-50):(2-50):(0.002-20):(0.001-10).

[0018] The temperature of the catalytic oxidation of ketone to generate α-brominated ketone is 25-150° C. and the time is 0.25-48 hours.

[0019] The iron catalyst in the method of the present invention has the characteristics of high natural abundance, low price and low toxicity. Amino acid ligands and unique tripeptide structure ligands are used to coordinate with the iron catalyst to form a highly active catalytic species. The present invention proposes a new method for generating α-brominated ketone. First, sodium bromide is oxidized by K2S2O8 through a single electron transfer process to generate a bromine free radical (Br.), and the free radical then undergoes free radical addition with the olefinic bond of the ketone enol form to generate a brominated free radical intermediate. The Fe(III) complex oxidizes the intermediate to form a cationic species, and finally deprotonates and converts it into an α-brominated ketone product. The present invention uses amino acid ligands and unique tripeptide structure ligands and is applied to this type of bromination reaction for the first time, which can effectively realize the cheap, easy to obtain and environmentally friendly iron-catalyzed α-bromination reaction of ketones, and has significant advantages over the existing catalytic ketone α-bromination method. The method of the present invention uses mild reagents and a mild environment to solve the problem of harsh reaction conditions; bromides are low in cost, easy to obtain, stable, and have good atom economy; and the solvent is non-toxic.

[0020] Ligands can improve the reactivity and selectivity of iron catalysts, but due to the differences in the raw materials and oxidants used, the catalytically active species are different and the reaction mechanisms are different. The present invention uses amino ligands in a specific iron-catalyzed α-position bromination reaction method of ketones. Amino acid ligands and unique tripeptide structure ligands are used in the present invention. The specific tripeptide ligand is formed by dehydration condensation of three amino acid derivative molecules, which is better than a single amino acid ligand. Overall, the yield of Example 15 using tripeptide ligands is 80%, the yield of Example 17 is 83%, and the yield of Example 34 is 82%. The yields are higher than those of other embodiments using ordinary amino acid ligands; at the same time, the comparative example 4 of the present invention can also prove it. And amino acid ligands are better than non-amino acids such as nitrogen-containing ligands 1,10-phenanthroline. The present invention is the first to coordinate and catalyze the α-position bromination reaction of ketones with amino acid ligands, especially unique tripeptide structure ligands and iron catalysts.

[0021] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0022] (1) In the α-position bromination reaction of ketones, the present invention uses amino acids for the first time, especially unique tripeptide structure ligands to promote iron-catalyzed α-position bromination of ketones, which has significant advantages over existing methods for catalyzing α-position bromination of ketones: good compatibility of substrate functional groups, and some oxidation-sensitive functional groups such as hydroxyl groups are well compatible; the substrate has a wide range of applications, and inert aliphatic ketones can achieve good catalytic effects; the reaction is applicable to the α-position bromination of carbonyl groups of complex molecules and their derivatives; the product has high selectivity and high yield. In addition, this method uses cheap, easily available, and widely available sodium bromide as a bromination reagent, which solves the existing problems of generating organic waste when using NBS, poor atom economy, and strong volatility, toxicity, and corrosiveness when using bromine alone. No acid or base is required, the reaction conditions are mild, and it is green and environmentally friendly.

[0023] (2) The method for α-bromination of ketones provided by the present invention is simple, easy and safe. The iron-catalyzed α-bromination product of ketones can be directly obtained in one step. Under the optimized reaction conditions, the yield of the target product after separation can be as high as 83%. It is a universal, efficient, economical and environmentally friendly method for α-bromination of ketones.

[0024] (3) The present invention provides amino acid ligands, especially unique tripeptide structure ligands, which significantly improve the yield and accelerate the reaction process compared with non-amino acid nitrogen-containing ligands. The ligand is coordinated with the iron catalyst to form a highly active catalytic species, which enables the enol intermediate formed by the ketone and the bromine free radical to undergo addition reaction under very mild conditions, and then deprotonate to form α-bromo ketone, and can also achieve an ideal catalytic effect for complex substrates. DETAILED DESCRIPTION

[0025] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0026] The experimental methods described in the examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available or can be prepared using existing technologies unless otherwise specified.

[0027] The specific structures of the substrates and products in the examples are shown in Table 1.

[0028] Among them, the synthesis references of ligands BCPOM and BCGOM: L.Cheng, HHWang, HRCai, J.Zhang, X.Gong, W.Han, Science, 2021, 374, 77-81.

[0029] Synthesis method of ligand BCPOM

[0030] N,N'-bis-(tert-butoxycarbonyl)-L-cystine (449.5 mg, 1.0 mmol, 1.0 equiv) and L-proline methyl ester hydrochloride (341.5 mg, 2.0 mmol, 2 equiv) were added to the reaction flask, followed by evacuation and backfilling with dry pure N2. 6 mL of anhydrous CH2Cl2 was added and the mixture was stirred at -5°C (ice-salt bath). N-methylmorpholine (NMM) (266.5 uL, 2.4 mmol, 2.4 equiv) was then added to the solution, and 10 mL of anhydrous CH2Cl2 solution of N,N'-dicyclohexylcarbodiimide (DCC) (425.4 mg, 2.2 mmol, 2.2 equiv) was added dropwise. The resulting reaction mixture was stirred at -5°C for 2 hours and then reacted at room temperature overnight. After filtering the precipitate, it was washed with 20 mL of water, brine, saturated sodium bicarbonate, brine, and water in sequence, and the organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The BCPOM ligand was then purified by column chromatography using a mixture of ethyl acetate / petroleum ether as the eluent.

[0031] Synthesis method of ligand BCGOM

[0032] N,N'-bis-(tert-butoxycarbonyl)-L-cystine (449.5 mg, 1.0 mmol, 1.0 equiv) and glycine methyl ester hydrochloride (256.2 mg, 2.0 mmol, 2 equiv) were added to the reaction flask, followed by evacuation and backfilling with dry pure N2. After adding 6 mL of anhydrous CH2Cl2, the mixture was stirred at -5°C (ice-salt bath). Then, N-methylmorpholine (NMM) (266.5 uL, 2.4 mmol, 2.4 equiv) was added to the solution, and 10 mL of anhydrous CH2Cl2 solution of N,N'-dicyclohexylcarbodiimide (DCC) (425.4 mg, 2.2 mmol, 2.2 equiv) was added dropwise. The resulting reaction mixture was stirred at -5°C for 2 hours and then stirred at room temperature overnight. After filtering the precipitate, it was washed with 20 mL of water, brine, saturated sodium bicarbonate, brine, and water in sequence, and the organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The BCGOM ligand was then purified by column chromatography using a mixture of ethyl acetate / petroleum ether as the eluent.

[0033] All raw materials 1a-1ai in the examples of the present invention are known compounds, which have been reported or can be synthesized by existing methods.

[0034] The synthesis method of 1ah:

[0035] Under air, dehydroabietic acid (659.2 mg, 2 mmol, 1 equiv), ferrocene (37.6 mg, 0.2 mmol, 0.1 equiv), ferrocyanine (12.0 mg, 0.02 mmol, 0.01 equiv), potassium persulfate (546.4 mg, 2 mmol, 1 equiv), acetonitrile 2 mL, water 2 mL, PMHS (1360.0 uL, 6 mmol, 3 equiv) were added to a 25 mL reaction bottle in sequence, and then stirred at 80 ° C for 24 hours, extracted with ethyl acetate (3×20 mL), and purified by column chromatography to obtain the product. HRMS (ESI) calcd.forC 20 H 26 3H + [M+H + ]m / z315.1955, found m / z 315.1953.

[0036] Example 1

[0037] Synthesis of compound 1

[0038] In nitrogen, ferrous sulfate (0.01mmol), L-cysteine ​​(0.5mmol), substrate 1a (0.5mmol), dimethyl sulfoxide (1.5mL) and water (0.5mL), NaBr (2mmol) and sodium persulfate (1.5mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was refluxed at 60°C for 3h. After the reaction was completed, the product 1 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:1) with a yield of 65%.

[0039] 1 H NMR (400MHz, CDCl3): δ7.98 (d, J = 7.2Hz, 2H), 7.61 (t, J = 7.4Hz, 1H), 7.49 (t, J = 7.7Hz, 2H), 4.46ppm (s, 2H); 13 C NMR (100MHz, CDCl3): δ191.2,133.9,128.9,128.8,128.5,30.9ppm.

[0040] Example 2

[0041] Synthesis of compound 2

[0042] In air, ferrous iodide (0.5 mmol), N-acetyl-L-cysteine ​​(0.35 mmol), substrate 1b (0.5 mmol), tert-butyl alcohol (2.0 mL), KBr (4 mmol) and benzoyl peroxide (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was refluxed at 70 ° C for 4 h. After the reaction was completed, the product 2 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 73%.

[0043] 1 H NMR (400MHz, CDCl3): δ7.93 (d, J = 8.7Hz, 2H), 7.50 (d, J = 8.7Hz, 2H), 4.44 (s, 2H), 1.34ppm (s, 9H); 13 C NMR (100MHz, CDCl3): δ190.9,157.9,131.3,128.9,125.8,35.2,31.0,30.9ppm.

[0044] Example 3

[0045] Synthesis of compound 3

[0046] Iron trifluoromethanesulfonate (0.05 mmol), BCGOM (0.15 mmol), substrate 1c (0.5 mmol), acetonitrile (2.0 mL), LiBr (1 mmol) and m-chloroperbenzoic acid (1.5 mmol) were added to a 25 mL reaction bottle in air. After mixing well at room temperature, the reaction mixture was refluxed at 35 °C for 3 h. After the reaction was completed, the product 3 was directly separated by chromatography (petroleum ether: dichloromethane V / V = 20:1) with a yield of 71%.

[0047] 1 H NMR (400MHz, CDCl3): δ7.67 (d, J = 8.1Hz, 1H), 7.43 (t, J = 7.5Hz, 1H), 7.30 (d, J = 7.1Hz, 1H), 7.29 (t, J = 6.9Hz, 1H), 4.43 (s, 2H), 2.53ppm (s, 3H); 13 C NMR (100MHz, CDCl3): δ194.2,139.7,134.4,132.4,132.3,129.0,125.8,33.7,21.4ppm.

[0048] Example 4

[0049] Synthesis of compound 4

[0050] In air, ferrous fluoride (0.1mmol), L-cystine (0.4mmol), substrate 1d (0.5mmol), acetonitrile (1.5mL) and water (1.5mL), NaBr (1.5mmol) and potassium persulfate (1mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 70℃ for 24h. After the reaction was completed, 5mL of water was added, and extracted with ethyl acetate (5mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was separated (petroleum ether: dichloromethane V / V=10:1) to obtain product 4 with a yield of 68%.

[0051] 1 H NMR (400MHz, CDCl3): δ7.52(d,J=7.7Hz,1H),7.47(s,1H),7.37(t,J=7.9Hz,1H),7.13(d,J=8.2Hz,1H),4.43(s,2H),3.83ppm(s,3H); 13 C NMR (100MHz, CDCl3): δ191.0,159.8,135.1,129.7,121.3,120.3,113.0,55.4,31.1ppm.

[0052] Example 5

[0053] Synthesis of compound 5

[0054] In air, ferric acetylacetonate (0.08 mmol), L-tyrosine (0.16 mmol), substrate 1e (0.5 mmol), benzonitrile (2.0 mL), HBr (1 mmol) and tert-butyl hydroperoxide (5 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 90 ° C for 12 h. After the reaction was completed, 5 mL of water was added, and ether was extracted (5 mL × 3). The organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was separated (petroleum ether: ethyl acetate V / V = 40:1) to obtain product 5 with a yield of 72%.

[0055] 1 H NMR (400MHz, CDCl3): δ7.93 (d, J=8.6Hz, 2H), 7.47 (d, J=8.6Hz, 2H), 4.41ppm (s, 2H); 13 C NMR (100MHz, CDCl3): δ190.2,140.5,132.2,130.3,129.2,30.4ppm.

[0056] Example 6

[0057] Synthesis of compound 6

[0058] In air, ferrous chloride (0.4 mmol), S-acetylaminomethyl-N-tert-butyloxycarbonyl-L-cysteine ​​(1.0 mmol), substrate 1f (0.5 mmol), acetonitrile (1.5 mL) and water (2.5 mL), NaBr (1.5 mmol) and hydrogen peroxide (1.5 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 70 ° C for 1 h. After the reaction was completed, the product 6 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 40:1) with a yield of 61%.

[0059] 1 H NMR (400MHz, CDCl3): δ8.03 (d, J = 7.2Hz, 2H), 7.60 (t, J = 7.4Hz, 1H), 7.49 (t, J = 7.6Hz, 2H), 5.27-5.32 (q, J = 6.6Hz, 1H), 1.91ppm (d, 3H); 13 CNMR (100MHz, CDCl3): δ193.3,134.0,133.7,128.9,128.7,41.4,20.1ppm.

[0060] Example 7

[0061] Synthesis of compound 7

[0062] Under normal pressure nitrogen, ferrous acetylacetonate (0.02mmol), L-homocystine (0.04mmol), substrate 1g (0.5mmol), dichloromethane (1.5mL) and water (0.5mL), LiBr (4mmol) and peracetic acid (1mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 55°C for 2h. After the reaction was completed, the product 7 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:3) with a yield of 62%.

[0063] 1 H NMR (400MHz, CDCl3): δ7.93 (d, J = 8.2Hz, 2H), 7.28 (d, J = 8.0Hz, 2H), 5.32-5.27 (q, J = 6.6Hz, 1H), 2.42 (s, 3H), 1.90ppm (d, J = 6.7Hz, 3H); 13 CNMR (100MHz, CDCl3): δ192.8,144.5,131.3,129.3,128.9,41.5,21.6,20.0ppm

[0064] Example 8

[0065] Synthesis of compound 8

[0066] In air, ferrous trifluoromethanesulfonate (0.04mmol), aspartic acid (0.08mmol), substrate 1h (0.5mmol), benzonitrile (2.0mL), NaBr (1.5mmol) and di-tert-butyl peroxide (1mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 90°C for 12h. After the reaction was completed, 5mL of water was added, and extracted with ethyl acetate (5mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was separated (petroleum ether: ethyl acetate V / V=40:3) to obtain product 8 with a yield of 71%.

[0067] 1 H NMR (400MHz, CDCl3): δ8.02(d,J=7.3Hz,2H),7.59(t,J=7.4Hz,1H),7.49(t,J=7.7Hz,2H ),5.14(t,J=7.1Hz,1H),2.07-2.24(m,2H),1.34-1.53(m,4H),0.92ppm(t,J=7.1Hz,3H); 13 C NMR (100MHz, CDCl3): δ193.3,134.5,133.6,128.8,128.7,47.2,33.2,29.6,22.2,13.9ppm.

[0068] Example 9

[0069] Synthesis of compound 9

[0070] In air, ferric chloride (0.1 mmol), L-homocystine (0.2 mmol), substrate 1i (0.5 mmol), ethyl acetate (2.0 mL), KBr (1 mmol) and diisopropylbenzene peroxide (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 65 ° C for 7 h. After the reaction was completed, the product 9 was directly separated by chromatography (petroleum ether: dichloromethane V / V = 40:1) with a yield of 70%.

[0071] 1 H NMR (400MHz, CDCl3): δ7.71(d,J=8.2Hz,1H),7.24(s,1H),7.23(d,J=5.8Hz,1H),4.63(dd,J= 7.5,3.2Hz,1H),3.78(dd,J=18.1,7.5Hz,1H),3.36(dd,J=18.1,3.1Hz,1H),2.45ppm(s,3H); 13C NMR (100MHz, CDCl3): δ199.1,151.6,147.5,131.2,129.5,126.7,124.8,44.4,37.8,22.2ppm; HRMS(ESI)calcd.for C 10 H9BrOH + [M+H + ]m / z 224.9910,foundm / z 224.9906.

[0072] Example 10

[0073] Synthesis of compound 10

[0074] Under normal pressure nitrogen, ferric bromide (0.05mmol), D-serine (0.1mmol), substrate 1j (0.5mmol), acetonitrile (2.0mL), NaBr (2mmol) and potassium monopersulfate (4mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 70°C for 1h. 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), and the organic phases were collected. The solvent was evaporated under reduced pressure and separated by column chromatography (petroleum ether: ether V / V=20:3) to obtain product 10 with a yield of 63%.

[0075] 1 H NMR (400MHz, CDCl3): δ7.77(s,1H),7.61(d,J=8.2Hz,1H),7.40(d,J=8.2Hz,1H),4.66(dd,J=7.5,3.1Hz,1H),3.77-3.83(m,1H),3.34-3.39ppm(m,1H); 13 C NMR (100MHz, CDCl3): δ198.3,149.1,135.9,134.9,134.6,127.6,124.7,43.8,37.5ppm.

[0076] Embodiment 11

[0077] Synthesis of compound 11

[0078] Under nitrogen atmosphere at normal pressure, ferrous bromide (0.03 mmol), D-valine (0.1 mmol), substrate 1k (0.5 mmol), dimethyl sulfoxide (2.0 mL), KBr (1 mmol) and 2-methylperoxide (1 mmol) were added to a 25 mL reaction bottle in sequence. After being mixed evenly at room temperature, the reaction mixture was reacted at 80 °C for 0.5 h. After the reaction was completed, 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined and washed with water (5 mL × 3). The organic phases were collected, the solvent was evaporated under reduced pressure, and then separated by column chromatography (petroleum ether: ether V / V = 10:3) to obtain product 11 with a yield of 61%.

[0079] 1 H NMR (400MHz, CDCl3): δ7.89 (s, 1H), 7.34 (d, J = 8.2Hz, 1H), 7.17 (d, J = 8.2Hz, 1H), 4.71 (t, J = 8. 2Hz,1H),3.22-3.29(m,1H),2.87(dt,J=17.0,4.4Hz,1H),2.58–2.41(m,2H),2.36ppm(s,3H); 13 C NMR (100MHz, CDCl3): δ190.8,140.1,136.8,135.1,129.6,128.64,128.58,50.6,32.0,25.7,20.9ppm.

[0080] Example 12

[0081] Synthesis of compound 12

[0082] In air, iron (III) perchlorate hydrate (0.01 mmol), L-cystine (0.1 mmol), substrate 1l (0.5 mmol), dichloromethane (2.0 mL), LiBr (1 mmol) and hydrogen peroxide (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 25 °C for 6 h. After the reaction was completed, the product 12 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 40:1) with a yield of 66%.

[0083] 1 H NMR (400MHz, CDCl3) δ8.04(s,1H),7.47(d,J=8.2Hz,1H),7.24(d,J=8.2Hz,1H),4.71(t,J= 4.1Hz,1H),3.33-3.20(m,1H),2.89(dt,J=17.3,4.3Hz,1H),2.48(dt,J=10.0,4.3Hz,2H); 13C NMR (100MHz, CDCl3): δ189.4,141.1,134.0,133.3,131.1,130.3,128.2,49.5,31.5,25.4ppm.

[0084] Embodiment 13

[0085] Synthesis of compound 13

[0086] In air, ferric nitrate (0.1 mmol), L-histidine (0.2 mmol), substrate 1m (0.5 mmol), dimethyl sulfoxide (1.5 mL) and water (0.5 mL), KBr (1.5 mmol) and peracetic acid (1.5 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 80 ° C for 1 h. After the reaction was completed, the product 13 was directly separated by chromatography (petroleum ether: ether V / V = 10:8) with a yield of 72%.

[0087] 1 H NMR (400MHz, CDCl3) δ8.20(s,1H),7.62(d,J=8.2Hz,1H),7.17(d,J=8.2Hz,1H),4.71 (t,J=4.1Hz,1H),3.32-3.17(m,1H),2.87(dt,J=17.3,4.4Hz,1H),2.54-2.43(m,2H); 13 C NMR (100MHz, CDCl3): δ189.3,141.6,136.9,131.3,131.2,130.6,121.0,49.5,31.4,25.5ppm

[0088] Embodiment 14

[0089] Synthesis of compound 14

[0090] In air, ferric fluoride (0.05 mmol), N-BOC-L-leucine (0.1 mmol), substrate 1n (0.5 mmol), N,N-diethylamide (1.0 mL) and water (0.1 mL), KBr (1 mmol) and tert-butyl hydroperoxide (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 50 ° C for 10 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 then column chromatography was separated (petroleum ether: ethyl acetate V / V = 40:1) to obtain product 14 with a yield of 67%.

[0091] 1H NMR (400MHz, CDCl3): δ8.04(d,J=9.0Hz,2H), 6.95(d,J=9.0Hz,2H), 6.70(s,1H), 3.87ppm(s,3H); 13 C NMR (100MHz, CDCl3): δ184.5,164.4,132.1,123.1,114.1,55.6,40.0ppm.

[0092] Embodiment 15

[0093] Synthesis of compound 15

[0094] Under nitrogen atmosphere at normal pressure, ferrous benzoylacetonate (0.03 mmol), BCPOM (0.1 mmol), substrate 1o (0.5 mmol), acetonitrile (1.5 mL) and water (0.5 mL), LiBr (1 mmol) and potassium monopersulfate (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 65 °C for 6 h. After the reaction was completed, 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, the solvent was evaporated under reduced pressure, and then separated by column chromatography (petroleum ether: ethyl acetate V / V = 20:1) to obtain product 15 with a yield of 80%.

[0095] 1 H NMR (400MHz, CDCl3): δ7.60(d,J=7.6Hz,1H),7.41(t,J=7.4Hz,1H),7.30(t,J=7.5Hz,1H),7.20(d,J=7.6Hz,1H),4.87(d d,J=7.8,4.2Hz,1H),3.05-2.09(m,1H),2.93-2.86(m,1H),2.43-2.35(m,1H),2.32-2.24(m,1H),2.05-1.99ppm(m,1H); 13 C NMR (100MHz, CDCl3): δ199.9,139.5,137.6,132.1,129.7,129.5,126.7,54.4,33.7,33.3,23.9ppm.

[0096] Example 16

[0097] Synthesis of compound 16

[0098] In air, iron benzoyl acetonate (0.1 mmol), L-proline (0.1 mmol), substrate 1p (0.5 mmol), tetrahydrofuran (1.5 mL) and water (0.5 mL), NaBr (2 mmol) and potassium persulfate (1.5 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 70 ° C for 3 h. After the reaction was completed, the product 16 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:3) with a yield of 60%.

[0099] 1 H NMR (400MHz, CDCl3): δ8.06(d,J=7.3Hz,2H),7.52(t,J=7.4Hz,1H),7.41(t,J=7.6Hz,1H),2.3 6-2.30(m,2H),2.20-2.15(m,2H),1.83-1.74(m,2H),1.60-1.50(m,3H),1.43-1.35ppm(m,1H); 13 C NMR (100MHz, CDCl3): δ197.5,135.8,132.0,129.7,128.1,67.9,38.2,24.9,23.5ppm.

[0100] Embodiment 17

[0101] Synthesis of compound 17

[0102] In air, ferric iodide (0.3 mmol), BCGOM (1.0 mmol), substrate 1q (0.5 mmol), dimethyl sulfoxide (4.0 mL), NaBr (5 mmol) and tert-butyl benzoyl peroxide (4 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 90 ° C for 8 h. After the reaction was completed, the product 17 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 83%.

[0103] 1 H NMR (400MHz, CDCl3) δ7.11(d,J=8.5Hz,2H),6.83(d,J=8.5Hz,2H),4.42(t,J=7.5Hz,1H ),3.77(s,3H),3.37(dd,J=14.4,7.7Hz,1H),3.10(dd,J=14.4,7.3Hz,1H),2.30(s,3H); 13 C NMR (100MHz, CDCl3): δ201.4,158.6,130.1,128.9,113.9,55.1,53.4,38.6,26.9ppm.

[0104] Embodiment 18

[0105] Synthesis of compound 18

[0106] In air, ferric oxalate (0.08 mmol), L-serine (0.1 mmol), substrate 1r (0.5 mmol), dichloromethane (2.0 mL), NaBr (1 mmol) and diisopropylbenzene peroxide (1.5 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 60 ° C for 3 h. After the reaction was completed, the product 18 was directly separated by chromatography (petroleum ether: dichloromethane V / V = 20:3) with a yield of 68%.

[0107] 1 H NMR (400MHz, CD3COCD3) δ7.96 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.63 (s, 2H); 13 C NMR (100MHz, CD3COCD3) δ190.3,163.3,132.3,127.1,116.3,32.5ppm.

[0108] Embodiment 19

[0109] Synthesis of compound 19

[0110] In air, ferrous phthalocyanine (0.001 mmol), L-cysteine ​​(0.02 mmol), substrate 1s (0.5 mmol), N,N-diformamide (1.5 mL) and water (0.5 mL), NaBr (1 mmol) and sodium persulfate (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 50 ° C for 14 h. After the reaction was completed, the product 19 was directly separated by chromatography (petroleum ether: dichloromethane V / V = 10:3) with a yield of 71%.

[0111] 1 H NMR (400MHz, CDCl3) δ7.36 (d, J = 1.5 Hz, 1H), 6.69 (d, J = 1.7 Hz, 1H), 4.54 (t, J = 3. 8Hz,1H),3.14-3.06(m,1H),2.86(dt,J=8.4,4.5Hz,1H),2.54-2.47ppm(m,2H); 13 CNMR (100MHz, CDCl3): δ187.0,165.6,143.3,118.5,107.2,48.8,31.4,20.7ppm.

[0112] Embodiment 20

[0113] Synthesis of compound 20

[0114] In air, 1,3-diphenylpropanedione ferrous acid (0.08mmol), BOC-L-glutamic acid (0.4mmol), substrate 1t (0.5mmol), tetrahydrofuran (1.0mL) and water (1.0mL), KBr (2mmol) and m-chloroperbenzoic acid (1mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 110℃ for 12h. After the reaction was completed, 5mL of water was added, and ether was extracted (5mL×3). The organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed (petroleum ether: ethyl acetate V / V=10:3) to obtain product 20 with a yield of 70%.

[0115] 1 H NMR (400MHz, CD3COCD3) δ8.01(d,J=8.2Hz,2H),7.37(d,J=7.9Hz,2H),5.73(dd,J=9.1,5.5Hz,1H),3.48(m,1H),3.15(m,1H),2.41(s,3H); 13 CNMR(100MHz,CD3COCD3)δ206.6,192.6,171.7,145.5,132.3,130.2,129.7,40.7,38.8,21.6ppm; HRMS(ESI)calcd.for C 11 H 11 BrO3H + [M+H + ]m / z 270.9965, found m / z 270.9961.

[0116] Embodiment 21

[0117] Synthesis of compound 21

[0118] In air, ammonium ferrous sulfate (0.1 mmol), β-thiovaline (0.3 mmol), substrate 1u (0.5 mmol), dimethyl sulfoxide (1.5 mL) and water (0.5 mL), NaBr (3 mmol) and ammonium persulfate (2 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 40 ° C for 3 h. After the reaction was completed, the product 21 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 40:1) with a yield of 68%.

[0119] 1H NMR (400MHz, CD3COCD3) δ8.43–7.99(m,3H),5.07(s,2H),2.75(s,3H); 13 C NMR (100MHz, CD3COCD3): δ198.9,192.3,153.6,151.4,139.8,126.2,125.8,33.2,25.6ppm.

[0120] Embodiment 22

[0121] Synthesis of compound 22

[0122] In air, ferrocyanide (0.01mmol), L-phenylalanine (0.1mmol), substrate 1v (0.5mmol), acetonitrile (2mL), LiBr (1mmol) and di-tert-butyl peroxide (1mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 90℃ for 18h. After the reaction was completed, the product 22 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:1) with a yield of 65%.

[0123] 1 H NMR (400MHz, CD3COCD3) δ4.59 (dd, J=9.1, 5.3Hz, 1H), 2.80 -2.73 (m, 1H), 2.66-2.58 (m, 1H), 2.20 -2.15(m,1H),1.99–1.90(m,1H),1.73–1.58(m,2H),1.36–1.31(m,20H); 13 C NMR (100MHz, CD3COCD3): δ204.9,53.2,38.8,34.4,28.2,27.4,27.3,27.0,26.9,26.8,26.77,24.0ppm.

[0124] Embodiment 23

[0125] Synthesis of compound 23

[0126] In air, ferric ferrocyanide (0.05 mmol), L-cystine (0.5 mmol), substrate 1w (0.5 mmol), 1,4-dioxane (2.0 mL), NaBr (1.5 mmol) and 2-methylperoxide (1.5 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 120 ° C for 3 h. After the reaction was completed, the product 23 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 63%.

[0127] 1H NMR (400MHz, CDCl3) δ7.97(d,J=8.9Hz,2H),7.41(t,J=7.9Hz,2H),7.23(t,J=7.4Hz,1H),7.09(d,J=7.8Hz,2H),7.01(d,J=8.9Hz,2H),4.40ppm(s,2H); 13 C NMR (100MHz, CDCl3): δ189.9,162.7,155.0,131.3,130.1,128.3,124.9,120.4,117.3,117.2,30.6ppm.

[0128] Embodiment 24

[0129] Synthesis of compound 24

[0130] In air, iron oxide (0.2mmol), L-homocystine (0.1mmol), substrate 1x (0.5mmol), benzonitrile (2.0mL), NaBr (1.5mmol) and 2-methylperoxide (2mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 70°C for 3h. After the reaction was completed, 5mL of water was added, and ethyl acetate was extracted (5mL×3), the organic phases were combined, washed with water (5mL×3), and the organic phases were collected. The solvent was evaporated under reduced pressure and separated by column chromatography (petroleum ether: dichloromethane V / V=10:3) to obtain product 24 with a yield of 71%.

[0131] 1 H NMR (400MHz, CDCl3) δ4.15 (s, 2H), 2.06 (s, 3H), 1.87 (d, J = 2.6Hz, 6H), 1.72ppm (q, J = 12.3Hz, 6H); 13 C NMR (100MHz, CDCl3): δ205.5, 46.6, 38.5, 36.3, 31.9, 27.8ppm.

[0132] Embodiment 25

[0133] Synthesis of compound 25

[0134] In air, 1,3-diphenylpropanedione iron (0.5mmol), 2-allyl-N-FMOC-L-glycine (0.3mmol), substrate 1y (0.5mmol), N,N-diethylamide (1.5mL) and water (0.5mL), KBr (1mmol) and hydrogen peroxide (2mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 80℃ for 9h. After the reaction was completed, ammonia water (0.5mL, 25%) was added and stirred for 1h. Then, 5mL of water was added and extracted with ether (5mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was separated (petroleum ether: dichloromethane V / V=20:3) to obtain product 25 with a yield of 69%.

[0135] 1 H NMR (400MHz, CDCl3) δ8.51(s,1H),8.03(dd,J=8.6,1.7Hz,1H),7.98(d,J=8.1Hz,1H),7.91(dd,J=12.1,8.4Hz,2H),7.67–7.55(m,2H),4.59ppm(s,2H); 13 C NMR (100MHz, CDCl3): δ191.3,135.9,132.4,131.2,131.0,129.7,129.0,128.8,127.8,127.1,124.1,30.9ppm.

[0136] Embodiment 26

[0137] Synthesis of compound 26

[0138] In air, ferrous oxalate (0.15 mmol), 2-allyl-N-FMOC-L-glycine (0.08 mmol), substrate 1z (0.5 mmol), tert-butyl alcohol (2.0 mL), NaBr (1 mmol) and bis(trimethylsilyl) peroxide (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing well at room temperature, the reaction mixture was reacted at 30 °C for 6 h. After the reaction was completed, the product 26 was directly separated by chromatography (petroleum ether: ether V / V = 10:3) with a yield of 68%.

[0139] 1 H NMR (400MHz, CDCl3) δ7.64 (s, 1H), 7.34 (d, J = 3.6Hz, 1H), 6.60 (dd, J = 3.6, 1.6Hz, 1H), 4.32ppm (s, 2H); 13 C NMR (100MHz, CDCl3): δ180.3, 150.3, 147.3, 119.1, 112.8, 30.0ppm.

[0140] Embodiment 27

[0141] Synthesis of compound 27

[0142] In air, 2,2,6,6-tetramethyl-3,5-heptanedione ferrous acid (0.02mmol), D-serine (0.1mmol), substrate 1aa (0.5mmol), acetonitrile (1.5mL) and water (0.5mL), NaBr (3mmol) and ammonium persulfate (2mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 90℃ for 2h. After the reaction was completed, 5mL of water was added, and the mixture was extracted with ethyl acetate (5mL×3). The organic phases were combined, the solvent was evaporated under reduced pressure, and then separated by column chromatography (petroleum ether: dichloromethane V / V=10:7) to obtain product 27 with a yield of 67%.

[0143] 1 H NMR (400MHz, CDCl3) δ8.05 (d, J = 3.0Hz, 1H), 7.77 (d, J = 3.0Hz, 1H), 4.72ppm (s, 2H); 13 C NMR (100MHz, CDCl3): δ184.8, 163.7, 145.1, 127.6, 30.9ppm.

[0144] Embodiment 28

[0145] Synthesis of compound 28

[0146] In air, 2,2,6,6-tetramethyl-3,5-heptanedione iron (0.5 mmol), L-threonine (0.4 mmol), substrate 1ab (0.5 mmol), polyethylene glycol 200-10000 (2.0 mL), KBr (1.5 mmol) and diisopropylbenzene peroxide (1.5 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 70 ° C for 3 h. After the reaction was completed, the product 28 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:1) with a yield of 60%.

[0147] Embodiment 29

[0148] Synthesis of compound 29

[0149] In air, 1,1'-bis(diphenylphosphino)ferrocene (0.05mmol), L-cystine (0.1mmol), substrate 1ac (0.5mmol), N,N-diformamide (1.5mL) and water (0.5mL), NaBr (1mmol) and sodium persulfate (1.5mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 75°C for 24h. After the reaction was completed, ammonia water (0.5mL, 25%) was added and stirred for 1h. Then, 5mL of water was added and extracted with ethyl acetate (5mL×3). The organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed (petroleum ether: ethyl acetate V / V=10:3) to obtain product 29 with a yield of 62%.

[0150] 1 H NMR (400MHz, CDCl3) δ3.83(d,J=3.1Hz,1H),2.53(d,J=15.0Hz,2H),2.20-2.08(m,3H),2.07-1.94(m,2H) ,1.80(dd,J=15.7,8.5Hz,2H),1.34(ddd,J=25.1,12.5,6.2Hz,1H),1.14(ddd,J=18.9,12.6,6.2Hz,2H); 13 C NMR (100MHz, CDCl3): δ210.4,53.3,49.5,48.9,45.7,41.1,32.5,31.5,29.1,27.9ppm.

[0151] Embodiment 30

[0152] Synthesis of compound 30

[0153] In air, 2,2,6,6-tetramethyl-3,5-heptanedione iron (0.1mmol), N-BOC-N'-trityl-L-histidine (0.2mmol), substrate 1ad (0.5mmol), toluene (2.0mL), NaBr (1mmol) and tert-butyl hydroperoxide (1mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 25°C for 8h. After the reaction was completed, the product 30 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:7) with a yield of 71%.

[0154] 1H NMR (400MHz, CDCl3) δ6.73(d,J=7.8Hz,1H),6.68(s,1H),6.64(d,J=7.9Hz,1H),5.93(d,J=1.6Hz,2H ), 4.39 (t, J = 7.5Hz, 1H), 3.34 (dd, J = 14.4, 7.6Hz, 1H), 3.06 (dd, J = 14.4, 7.3Hz, 1H), 2.31ppm (s, 2H); 13 C NMR (100MHz, CDCl3): δ147.7,146.6,130.6,122.4,109.5,108.3,101.0,53.2,39.2,27.1ppm.

[0155] Embodiment 31

[0156] Synthesis of compound 31

[0157] In air, ferric oxalate (0.01 mmol), L-serine (0.1 mmol), substrate 1ae (0.5 mmol), 1,2-dichloroethane (2.0 mL), KBr (1 mmol) and diisopropylbenzene peroxide (1.5 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 90 °C for 12 h. After the reaction was completed, the product 31 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:3) with a yield of 69%.

[0158] 1 H NMR (400MHz, CD3COCD3) δ8.70(s,1H),7.64(d,J=8.3Hz,1H),7.58(s,1H),6.94(d,J=8.3Hz,1H),4.67(s,2H),3.91(s,3H); 13 C NMR (100MHz, CD3COCD3): δ190.3,153.0,148.4,127.3,124.9,115.5,112.1,56.3,32.5ppm.

[0159] Embodiment 32

[0160] Synthesis of compound 32

[0161] In air, ferric nitrate (0.5 mmol), L-proline (0.1 mmol), substrate 1af (0.5 mmol), dichloromethane (1.5 mL) and water (0.5 mL), KBr (2 mmol) and potassium persulfate (1.5 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 60 ° C for 8 h. After the reaction was completed, 5 mL of water was added, and ether was extracted (5 mL × 3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was separated (petroleum ether: dichloromethane V / V = 10:7) to obtain product 32 with a yield of 63%.

[0162] 1 H NMR (400MHz, CDCl3) δ7.70(s,1H),7.68(s,1H),7.59(s,1H),7.29(dd,J=8.4,1.2Hz,1H),7.15(dd,J=8.9,2.4Hz,1H),7.11(d, J=2.1Hz,1H),4.55(t,J=7.5Hz,1H),3.91(s,3H),3.58(dd,J=14.3,7.6Hz,1H),3.29(dd,J=14.3,7.3Hz,1H),2.32ppm(s,3H); 13 C NMR (100MHz, CDCl3): δ201.4,157.6,133.5,132.1,129.1,128.8,127.9,127.6,127.1,119.1,105.5,55.3,53.1,39.4,27.1ppm.

[0163] Embodiment 33

[0164] Synthesis of compound 33

[0165] In air, ferric chloride (0.05 mmol), BOC-L-glutamic acid (0.1 mmol), substrate 1ag (0.5 mmol), acetonitrile (1.5 mL) and water (0.5 mL), NaBr (1 mmol) and potassium monopersulfate (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly 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 ethyl acetate was extracted (5 mL × 3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was separated (petroleum ether: ethyl acetate V / V = 20:7) to obtain product 33 with a yield of 70%.

[0166] 1H NMR (400MHz, CDCl3) δ6.84(d,J=7.6Hz,1H),6.70(s,1H),6.69(d,J=8.3Hz,1H),4.42(t,J=7.4 Hz,1H),3.87(s,3H),3.37(dd,J=14.3,7.8Hz,1H),3.08(dd,J=14.4,7.1Hz,1H),2.30(s,3H); 13 C NMR (100MHz, CDCl3): δ201.6,146.4,144.7,128.8,121.9,114.4,111.8,55.9,53.2,39.2,27.1ppm; HRMS(ESI)calcd.for C 11 H 13 BrO3NH4 + [M+NH4 + ]m / z 290.0386, found 290.0390.

[0167] Embodiment 34

[0168] Synthesis of compound 34

[0169] In air, ferrous chloride (0.1mmol), BCGOM (1.0mmol), substrate 1ah (0.5mmol), dimethyl sulfoxide (4.0mL), NaBr (5mmol) and tert-butyl benzoyl peroxide (4mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 70°C for 3h. 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), and the organic phases were collected. The solvent was evaporated under reduced pressure and separated by column chromatography (petroleum ether: dichloromethane V / V=10:1) to obtain product 34 with a yield of 82%.

[0170] 1 H NMR (400MHz, CDCl3) δ7.83(s,1H),7.43(d,J=8.1Hz,1H),7.26(d,J=8.1Hz,1H),4.98(d,J=12.6Hz,1H),3.19(d,J=12.6Hz,1H ),2.93(dq,J=13.5,6.7Hz,1H),2.32(d,J=6.4Hz,1H),1.85-1.71(m,5H),1.48(s,3H),1.25(s,3H),1.25ppm(d,J=6.0Hz,6H); 13C NMR (100MHz, CDCl3): δ192.9,184.4,151.4,147.8,132.9,130.0,126.5,122.6,54.2,49 .6,46.5,39.4,38.9,37.3,33.6,24.9,23.8,23.7,17.6,17.5ppm; HRMS(ESI)calcd.forC 20 H 25 BrO3H + [M+H + ]m / z393.1060, found m / z 393.1058.

[0171] Embodiment 35

[0172] Synthesis of compound 35

[0173] In air, ferric acetylacetonate (0.02mmol), L-histidine (0.1mmol), substrate 1ai (0.5mmol), N,N-diethylamide (1.0mL) and water (0.1mL), NaBr (1mmol) and tert-butyl hydroperoxide (1mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 100℃ for 12h. After the reaction was completed, 5mL of water was added, and extracted with ethyl acetate (5mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was separated (petroleum ether: ethyl acetate V / V=10:1) to obtain product 35 with a yield of 73%.

[0174] 1 H NMR (400MHz, CDCl3) δ6.14 (s, 1H), 5.62 (s, 1H), 5.16 (d, J = 12.6Hz, 1H), 4.02 (s, 3 H),3.96(s,3H),3.62(s,3H),2.97(dq,J=13.1,6.6Hz,1H),1.13(d,J=6.6Hz,3H); 13 CNMR(100MHz, CDCl3)δ191.4,189.1,170.3,169.2,165.0,157.8,104.5,102.9,97.2,89.8,57.1,56.9,56.4,54.7,44.2,14.1ppm; HRMS(ESI)calcd.for C 17 H 16 BrClO6H + [M+H + ]m / z430.9892, found m / z 430.9881.

[0175] The raw materials and product structural formulas of Examples 1 to 35 and the corresponding experimental results are shown in Table 1 below:

[0176] Table 1

[0177]

[0178]

[0179]

[0180]

[0181] Embodiment 37

[0182] The method of Example 37 is the same as that of Example 17, except that the molar ratio of ketone, bromide, peroxide, amino acid derivative, and iron catalyst is 1:30:30:20:10.

[0183] Embodiment 38

[0184] The method of Example 38 is the same as that of Example 17, except that the solvent is all water and the total volume remains unchanged.

[0185] Embodiment 39

[0186] The method of Example 39 is the same as that of Example 17, except that the reaction temperature is 25° C. and the reaction time is 48 hours.

[0187] Comparative Example 1

[0188] The method of Comparative Example 1 is the same as that of Example 17, except that no iron catalyst is added and the yield of the target product is 0.

[0189] Comparative Example 2

[0190] The method of Comparative Example 2 is the same as that of Example 17, except that no amino acid ligand is added, and the reaction yield is greatly reduced, and the yield is less than 10%.

[0191] Comparative Example 3

[0192] Comparative Example 3 is the same as Example 17, except that the ligand is replaced by a non-amino acid nitrogen-containing ligand 1,10-phenanthroline, and the reaction yield is reduced to about 20%.

[0193] Comparative Example 4

[0194] Comparative Example 4 is the same as Example 17, except that the ligand is replaced by N-BOC-L-leucine, and the reaction yield is reduced to about 40%.

[0195] The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment, it is not used to limit the present invention. The various iron catalysts in the present invention can theoretically 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 bromination reaction of ketone α position, and the effect of its coordination with iron is utilized. The various amino acids and their derivatives given in theory have coordination functions and should be able to achieve similar effects; various peroxides are oxidants; what occurs on ketones is the activation of carbon-hydrogen bonds, and the various substituents on ketones affect the size of the electron cloud density in the ring and the size of the steric hindrance during the reaction, that is, the modification of the substituents only affects the reaction to a certain extent, and does not play a decisive role in the occurrence of the reaction. Any technician familiar with this profession will not find it difficult to understand that without departing from the scope of the technical solution of the present invention, when changes or modifications can be made to obtain corresponding embodiments, for example, the substituents can be replaced, changed or modified within the scope of the present invention, and the method of the present invention can be realized. Any modification, alteration or 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 shall still fall within the scope of the technical solution of the present invention.

Claims

1. A method for iron-catalyzed bromination of α-position of ketones, characterized in that: The method comprises the following steps: in a solvent, using bromide as a bromination reagent, peroxide as an oxidant, iron as a catalyst, and amino acid or its derivative as a ligand, catalyzing the oxidative ketone to undergo an α-position bromination reaction to generate an α-position brominated ketone; the general reaction formula is as follows: ； In the formula: R represents aryl, alkyl, alkenyl or heteroaryl; R 1 represents hydrogen, alkyl or halogen; X represents hydrogen, sodium, lithium or potassium; The iron is selected from ferrous trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetonate, ferrous acetylacetonate, ferrous 2,2,6,6-tetramethyl-3,5-heptanedione, ferrous 2,2,6,6-tetramethyl-3,5-heptanedione, ferrous 1,3-diphenylpropanedione, ferrous 1,3-diphenylpropanedione, ferrous benzoylacetonate, ferrous benzoylacetonate, ferrous ferrocyanide, ferrous ferrocyanide, ferrous acetate, ferrous sulfate, ammonium ferrous sulfate, ferrous sulfate, ferrous oxalate, ferrous oxalate, ferrous fluoride, ferrous fluoride, ferrous bromide, ferrous bromide, ferrous iodide, ferric chloride, iron (III) perchlorate hydrate, 1,1'-bis(diphenylphosphino)ferrocene, ferrous phthalocyanine, ferric nitrate, ferric oxide or ferric oxide; The ligand is selected from BCPOM, BCGOM, S-acetylaminomethyl-N-tert-butyloxycarbonyl-L-cysteine, N-acetyl-L-cysteine, N,N'-bis(tert-butyloxycarbonyl)-L-cystine, L-serine, D-cystine, aspartic acid, D-arginine, isoserine, L-threonine, L-tyrosine, BOC-L-proline, BOC-glycine-glycine-glycine, 2-allyl-N-FMOC-L-glycine, BOC-D-phenylalanine, L-cysteine, D-serine, β-thiovaline, D-proline, D-valine, L-proline, L-phenylalanine, N-BOC-N'-trityl-L-histidine, L-tryptophan, N-BOC-L-leucine, L-histidine, BOC-L-glutamate, L-cystine or L-homocysteine; The solvent is an organic solvent or an aqueous solution of an organic solvent, and the organic solvent is selected from tert-butyl alcohol, polyethylene glycol 200-10000, acetonitrile, benzonitrile, toluene, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-diformamide, N,N-diacetamide, ethyl acetate, 1,4-dioxane or tetrahydrofuran. 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).

2. The method for iron-catalyzed bromination of ketone α-position according to claim 1, characterized in that: The R represents an aryl group, an alkyl group, an alkenyl group or a heteroaryl group, wherein the aryl group is a substituted phenyl group or a naphthyl group; the heteroaryl group is a five-membered or six-membered heteroaryl group containing at least one of nitrogen, oxygen and sulfur; the alkyl group is a C1 to C20 alkyl group; and the alkenyl group is a C1 to C20 alkenyl group.

3. The method for iron-catalyzed bromination of ketone α-position according to claim 2, characterized in that: The heteroaryl group is furyl, thiazolyl or pyridyl.

4. The method for iron-catalyzed bromination of ketone α-position according to claim 2, characterized in that: When R represents an aryl group, R 2 represents a substituent on an aromatic group, R 2 Mono- or poly-substituted hydrogen on the aromatic ring, R 2 Selected from hydrogen, C1-C20 alkyl, C1-C20 alkoxy, halogen, phenoxy or hydroxy.

5. The method for iron-catalyzed bromination of ketone α-position according to claim 1, characterized in that: The oxidant is selected from potassium persulfate, ammonium persulfate, sodium persulfate, tert-butyl hydroperoxide, hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, benzoyl peroxide, tert-butyl benzoyl peroxide, di-tert-butyl peroxide, potassium monopersulfate, diisopropylbenzene peroxide, 2-methyl ethyl peroxide or bis(trimethylsilyl)peroxide.

6. The method for iron-catalyzed bromination of ketone α-position according to claim 1, characterized in that: The molar ratio of the ketone, bromide, peroxide, amino acid or its derivative, and iron catalyst is 1:(2-50):(2-50):(0.002-20):(0.001-10).

7. The method for iron-catalyzed bromination of ketone α-position according to claim 1, characterized in that: The temperature of the catalytic oxidation of ketone to generate α-brominated ketone by α-bromination reaction is 25-150° C. and the time is 0.25-48 hours.

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