A method for iron-catalyzed coupling of alkanes with aromatic heterocyclic compounds

Abstract

The application discloses a method for coupling of alkanes and aromatic heterocyclic compounds catalyzed by iron, which comprises the following steps: using peroxide as an oxidant, iron as a catalyst, amino acid or its derivative as a ligand, and acid as an additive to catalyze C-H bond activation and C-C bond coupling reaction of aromatic heterocyclic compounds and alkanes in a solvent to generate alkyl-substituted aromatic heterocyclic compounds. The method has the advantages of wide source, low cost and low toxicity of the catalyst, green and friendly oxidant, mild reaction condition, high selectivity, good compatibility of various aromatic heterocyclic compounds and alkane compounds and other substrates containing inert non-activated sp3 C-H bonds, such as acids, nitriles, amines and ketones, and very wide substrate application range; high selectivity is shown to the aromatic heterocyclic compounds and inert sp3 C-H bonds, and the alkylation reaction of the aromatic heterocyclic compounds can be well realized, and the yield of the target product can reach 93% after separation.

Description

Technical Field

[0001] This invention belongs to the fields of catalytic synthesis technology and fine chemical synthesis, specifically relating to an iron-catalyzed method for coupling alkanes with aromatic heterocyclic compounds. Background Technology

[0002] Aromatic heterocyclic compounds have been extensively studied in natural product and medicinal chemistry due to their rich biological activities. Statistics show that in 2008, one-third of the top 200 drugs by global retail sales were aromatic heterocyclic compounds, and more than a quarter of these were alkyl-substituted aromatic heterocyclic compounds. The demand for introducing alkyl groups into aromatic heterocyclic compounds is increasing, and developing different strategies for synthesizing alkyl-substituted aromatic heterocyclic compounds is one of the hottest research topics internationally. The classic synthetic route for alkyl-substituted aromatic heterocyclic compounds uses alkyl (pseudo)halides for coupling reactions, but this requires prior "pre-activation," resulting in low atom economy and high costs. Therefore, synthetic methods based on the direct alkylation of aromatic heterocyclic compounds via CH bonds are of great significance.

[0003] Several challenges remain in the current CH alkylation of aromatic heterocyclic compounds. For example, the limitation on substrates due to the restriction to modifying only the fixed positions of the N and O alkyl chains (Wu, X., Zhang, H., Tang, N., Wu, Z., Zhu, C. Nat. Commun. 2018, 9, 3343.), the need to add alkane compounds with varying solvent amounts (Xu, P., Chen, PY, Xu, HCAngew. Chem. Int. Ed. 2020, 59, 14275-14280.), the use of noble metal catalysts (Chen, H., Fan, W., Yuan, XA, Yu, S. Nat. Commun. 2019, 10, 4743.), and the production of mixtures of mono- and dialkylated products (Huang, CY, Li, J., Li, CJ Nat. Commun. 2021, 12, 4010.). These factors severely limit the large-scale application of this method. Summary of the Invention

[0004] Objective of the Invention: To address the problems existing in the prior art, this invention provides a method for iron-catalyzed coupling of alkanes with aromatic heterocyclic compounds. This method not only provides an economical and applicable new approach for the synthesis of alkyl-substituted aromatic heterocyclic compounds, but also solves the problems of harsh conditions, the need for solvent addition in the sp2CH alkylation of aromatic heterocyclic compounds leading to mixtures of mono- and dialkylated products, the prefunctionalization of the reaction, and the use of noble metal catalysts, resulting in low overall yields, poor functional group compatibility, narrow applicability, poor selectivity, inability to be used in industrial production, and being environmentally unfriendly, unsafe, and uneconomical. In existing methods, for aromatic heterocyclic compounds with two or more sites, such as 3-cyanopyridine (compound 1e) and 2-chloropyrimidine (compound 1m), similar structures, mono- and di-coupled products with alkane compounds are produced, and existing synthetic routes have poor selectivity for aromatic heterocyclic compounds. This method, by pre-protonating the aromatic heterocycle with acid before it participates in the reaction, yields a more stable alkyl-aromatic heterocyclic radical cation, thus producing only a single coupling product with the aromatic heterocyclic compound. This demonstrates excellent selectivity for aromatic heterocyclic compounds and provides a supplementary tool for this type of synthesis. Furthermore, unlike previous methods using amino acid ligands and iron catalysts, when multiple reaction sites exist in alkane compounds, the high-valent ferrooxide radical cation formed after amino acid and iron coordination is electrophilic and has a good ability to abstract hydrogen, preferentially activating the relatively inert sp3C-H bond. This avoids the conventional α-site product (such as compounds 27 and 28), thus also exhibiting good selectivity for the inert sp3CH bond in alkane compounds.

[0005] The method of this invention requires only one reaction step and features a wide range of readily available, inexpensive, and low-toxicity catalysts; a green and environmentally friendly oxidant; widely available and stable substrates; low dosage of alkane compounds; mild reaction conditions; good selectivity and high yield; good compatibility of substrate functional groups and a wide range of substrate applications; compatibility with drug molecules and drug molecule derivatives, including imidazole aldehyde (compound 33), a drug molecule containing the sensitive aldehyde group. Notably, the drug molecule structure contains a more reactive benzylic CH bond. Unlike previous methods that preferentially yield benzylic products, this method preferentially obtains the coupling product of the distal methylene group and the aromatic heterocyclic compound, indicating that this method can not only complete the later-stage synthesis and modification of drug molecules but also exhibits high site selectivity.

[0006] Technical solution: In order to achieve the above objectives, the present invention provides a method for iron-catalyzed coupling of alkanes and aromatic heterocyclic compounds, comprising the following steps: using peroxide as an oxidant, iron as a catalyst, amino acids or their derivatives as ligands, and acids as additives, catalyzing the reaction of aromatic heterocyclic compounds with alkanes in a solvent to undergo CH bond activation and C-C bond coupling to generate alkyl-substituted aromatic heterocyclic compounds.

[0007] The general formula for the reaction is as follows:

[0008]

[0009] In the formula: Het represents an aromatic heterocyclic group; wherein, the aromatic heterocyclic group is a substituted or unsubstituted pyridinyl, quinolinyl, isoquinolinyl, pyrazinyl, pyrimidinyl, pyridazinyl, phthalazinyl, quinoxalinyl or benzothiazolyl;

[0010] R1 represents a substituent in an aromatic heterocyclic compound, wherein R1 is selected from hydrogen, methyl, methoxy, hydroxy, aryl, cyano, ester, trifluoromethyl, halogen, or carbonyl.

[0011] R represents a substituted or unsubstituted alkyl or cycloalkyl group, carboxylic acid group, cyano group, amino group, or ketone group of C1-C16.

[0012] Wherein, R1 is selected from hydrogen, methyl, methoxy, hydroxy, trifluoromethyl or halogen.

[0013] Wherein, R represents a substituted or unsubstituted alkyl or cycloalkyl group, carboxylic acid group, or ketone group of C1-C6.

[0014] The iron is selected from any one or more of the following: ferrous trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, ferrous fluoride, ferrous fluoride, ferrous bromide, ferrous bromide, ferrous iodide, ferrous iodide, ferrous chloride, ferric chloride, ferrous acetylacetone, ferric acetylacetone, ferrous 1,3-diphenylpropanedione, ferric 1,3-diphenylpropanedione, ferric benzoylacetone, ferrous ferric ferric cyanide, ferrous acetate, ferrous sulfate, ferric sulfate, ferrous oxalate, ferric oxalate, ferric perchlorate (III) hydrate, 1,1'-bis(diphenylphosphine)ferrocene, ferrous phthalocyanine, ferric nitrate, iron oxide, or iron(III) oxide.

[0015] The ligands are selected from L-cysteine, S-acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine, N-acetyl-L-cysteine, L-cysteine, N,N'-bis(tert-butoxycarbonyl)-L-cysteine, BOC-L-glutamic acid-L-cysteine, D-cysteine, L-homocysteine, L-serine, D-serine, isoserine, L-threonine, L-tyrosine, L-proline, and BOC-L-proline. The following are one or more of the following: D-proline, L-phenylalanine, L-tryptophan, aspartic acid, D-arginine, L-histidine, N-BOC-N'-triphenylmethyl-L-histidine, BOC-glycine-glycine-glycine, BOC-glycyl-glycine, 2-allyl-N-FMOC-L-glycine, BOC-D-phenylalanine, β-thiovaline, D-valine, or N-BOC-L-leucine.

[0016] The oxidant is selected from any one or more of oxygen, hydrogen peroxide, tert-butyl hydrogen peroxide, di-tert-butyl peroxide, benzoyl peroxide, benzoyl tert-butyl peroxide, peracetic acid, potassium persulfate, ammonium persulfate, sodium persulfate, potassium monopersulfate, or dicumyl peroxide.

[0017] The acid is selected from any one or more of sulfuric acid, trifluoroacetic acid, acetic acid, hydrochloric acid, fluoroboric acid, methanesulfonic acid, and trifluoromethanesulfonic acid.

[0018] Wherein, the solvent is an organic solvent, water, or an aqueous solution of an organic solvent, wherein the organic solvent is selected from any one or more of methanol, ethanol, ethylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, trifluoroethanol, 2-methyl-2-butanol, 3-methoxybutanol, sec-butanol, tert-amyl alcohol, 4-methyl-2-pentanol, isoamyl alcohol, 2-pentanol, 3-pentanol, cyclopentanol, n-pentanol, polyethylene glycol 200-10000, acetonitrile, toluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dicarboxamide, 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).

[0019] The molar ratio of the aromatic heterocyclic compound, alkane compound, peroxide, acid, amino acid or its derivative, and iron catalyst is 1:(2-5):(2-50):(1-50):(0.002-20):(0.001-10).

[0020] Preferably, the molar ratio of the aromatic heterocyclic compound, alkane compound, peroxide, acid, amino acid or its derivative, and iron catalyst is 1:(2-5):(2-10):(1-10):(0.01-1):(0.01-1).

[0021] The reaction is carried out at a temperature of 25–100°C for 3–14 hours.

[0022] Preferably, the aromatic heterocyclic compound is reacted with an acid in a solvent first, and then a peroxide, catalyst, ligand, and alkane compound are added to continue the reaction. By pre-treating the aromatic heterocyclic compound with acid, the yield of the target product is significantly improved.

[0023] The iron catalyst in this invention is characterized by its high natural abundance, low cost, and low toxicity. Specific amino acid ligands are used to coordinate with the iron catalyst, reacting with the oxidant to form a highly active, high-valence ferrooxy radical cation intermediate. This catalytic intermediate, along with the solvent, enables the alkyl radicals formed under oxidation to attack aromatic heterocyclic compounds, exhibiting high activity and selectivity. Furthermore, the method of this invention uses mild reagents and a mild environment, solving the problem of harsh reaction conditions; the reaction directly attacks aromatic heterocycles without pre-functionalization; iron is used as the catalyst, eliminating the need for precious metals; and the effect is significant. Only a normal equivalent of alkylating agent is needed to achieve the coupling of aromatic heterocyclic compounds with alkanes. The method of this invention has the advantages of a wide range of readily available, inexpensive, and low-toxicity catalysts; an environmentally friendly oxidant; mild reaction conditions and high selectivity; good compatibility with various aromatic heterocyclic compounds, alkanes, and other substrates containing inert, non-activated sp3 CH bonds, acids, nitriles, amines, ketones, etc. (e.g., valeric acid, valeronitrile, 2,2,6,6-tetramethylpiperidine, cyclohexanone, and 4-heptanone; compounds 30, 29, 31, 27, 28), exhibiting a very broad substrate applicability; it can achieve the modification of aromatic heterocyclic compounds and alkyl drug derivatives, and can effectively realize the alkylation reaction of aromatic heterocyclic compounds; the substrate functional groups have good compatibility and a wide range of applicability, exhibiting high selectivity for both aromatic heterocyclic compounds and inert sp3 CH bonds. Under optimized reaction conditions, the yield of the target product after separation can reach 93%.

[0024] This invention first oxidizes low-valent iron to high-valent iron using an oxidant, which then combines with an amino acid or its derivative ligand to generate a corresponding high-valent ferro-oxygen radical cation intermediate. The radical cation then attacks alkanes, providing alkyl radicals. An acid protonates the aromatic heterocycle and combines with the alkyl radical to generate an alkyl-substituted aromatic heterocycle radical cation. Finally, the high-valent iron gains electrons and reverts to low-valent iron, and the alkyl-substituted aromatic heterocycle undergoes deprotonation to yield an alkyl-based aromatic heterocycle compound, thus completing the catalytic cycle. This invention introduces amino acids or their derivatives for coordination with an iron catalyst. Practical application has demonstrated excellent results. This is the first time that the method using amino acid ligands and an iron catalyst has been applied to the coupling of alkanes and aromatic heterocycles. Unlike existing synthetic routes with poor selectivity for aromatic heterocycles, this method, because the aromatic heterocycle is pre-protonated by the acid before participating in the reaction, yields a more stable alkyl-aromatic heterocycle radical cation, thus producing only a single coupling product with the aromatic heterocycle compound. This method exhibits good selectivity for aromatic heterocycles and provides a supplementary tool for this type of synthetic method. Unlike previous methods using amino acid ligands and iron catalysts, when alkane compounds have multiple reaction sites, the high-valent ferrooxide radical cations formed after amino acid and iron coordination are electrophilic and have a good ability to abstract hydrogen from the alkane, preferentially activating the relatively inert sp3 CH bonds and not yielding the conventional α-site product. For imidazole aldehydes, a drug molecule containing sensitive groups and active benzylic CH bonds, unlike previous methods that preferentially obtain benzylic products, this method preferentially obtains the coupling product of the distal methylene group and aromatic heterocyclic compound, exhibiting high site selectivity. This solves the problems of existing methods for sp2 CH alkylation of aromatic heterocyclic compounds using solvent amounts of alkane compounds, producing mixed mono- and dialkylated products, poor selectivity, limited industrial applications, and substrate limitations due to poor functional group tolerance.

[0025] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0026] (1) This invention provides a method for iron-catalyzed coupling of alkanes and aromatic heterocyclic compounds promoted by amino acid and its derivative ligands. This method requires only one reaction and has the unique advantages of inexpensive, widely available and environmentally friendly catalysts, ligands and oxidants; mild reaction conditions and high selectivity; widely available, stable and easy-to-handle substrates; good compatibility of substrate functional groups and wide applicability of substrates; experimental results show that the reaction is suitable for the late modification of drug molecules.

[0027] (2) The iron-catalyzed coupling method of alkane and aromatic heterocyclic compound provided by the present invention is simple, easy and safe. The alkylation product of aromatic heterocyclic compound can be obtained directly in one step. Under optimized reaction conditions, the yield of the target product after separation can reach 93%. It is a general, efficient, economical and environmentally friendly method for coupling aromatic heterocyclic compound and alkane compound.

[0028] (3) The key to the method of this invention being able to use ideal iron as a catalyst lies in the use of amino acid ligands, which coordinate with the iron catalyst and, under the action of an oxidant, form a highly active, high-valence ferrooxy free radical cation catalytic intermediate. This intermediate can efficiently extract hydrogen from alkanes to form highly active alkyl free radicals, enabling the reaction to proceed under very mild conditions for the coupling reaction of aromatic heterocyclic compounds with alkanes. In particular, it achieves ideal catalytic effects for drug molecules and their derivatives. This is the first time that amino acids or their derivatives have been used as ligands and iron catalysts in a method for catalyzing the coupling of alkane compounds with aromatic heterocyclic compounds.

[0029] (4) The alkylated products of aromatic heterocyclic compounds synthesized by the method of the present invention can be used as drugs or bioactive molecules, and are also important organic intermediates, which are widely used in the synthesis of pharmaceutical intermediates and high value-added fine chemicals. Detailed Implementation

[0030] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0031] Unless otherwise specified, the experimental methods described in the embodiments are conventional methods; unless otherwise specified, the reagents and materials can be obtained commercially or through simple preparation using existing technologies.

[0032] The specific structures of the substrates and products in the embodiments are shown in Table 1.

[0033] The reaction substrates 1a-1z and 2a-2k in this invention are all reported compounds. The products for which NMR / mass spectrometry data are not provided in this invention are all known compounds. The synthesized products compounds 1-6 and 13-25 in this invention are all known compounds. Compounds 7-12 and 26-34 are new compounds, and their corresponding NMR / mass spectrometry data have been provided.

[0034] Example 1

[0035] Synthesis of Compound 1

[0036] In a 25 mL reaction flask, substrate 1a (0.5 mmol), ethanol (2.0 mL), and trifluoroacetic acid (5.0 mmol) were added sequentially. After reacting at room temperature for 5 h, ferric chloride (0.02 mmol), L-threonine (0.3 mmol), substrate 2a (1.0 mmol), and hydrogen peroxide (2.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 80 °C for 1 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate:triethylamine V / V / V = 10:3:0.1) yielded product 1 in 88% yield.

[0037] 1 H NMR (400MHz, CDCl3) δ8.72(dd,J=5.2,1.2Hz,1H),7.72-7.60(m,2H),7.63-7.54(m,2H),7.49-7.42(m,2H),7.40-7.38(m,1H),2.85(tt,J =12.0,3.2Hz,1H),2.10-2.00(m,2H),1.96-1.85(m,2H),1.83-1.75(m,1H),1.65-1.55(m,2H),1.50-1.40(m,2H),1.40-1.30ppm(m,1H); 13 C NMR (100MHz, CDCl3) δ168.2,149.9,149.0,138.5,129.5,128.3,127.1,119.2,119.0,46.8,33.0,26.5,26.1ppm.

[0038] Example 2

[0039] Synthesis of Compound 2

[0040] In a 25 mL reaction flask, substrate 1b (0.5 mmol), sec-butanol (2.0 mL), and sulfuric acid (3.5 mmol) were added sequentially. After reacting at room temperature for 2 h, ferrous acetate (0.005 mmol), L-serine (0.15 mmol), substrate 2a (1.5 mmol), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 90 °C for 2 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate:triethylamine V / V / V = 10:4:0.1) yielded product 2 in 87% yield.

[0041] Example 3

[0042] Synthesis of Compound 3

[0043] In a 25 mL reaction flask, substrate 1c (0.5 mmol), n-pentanol (2.0 mL), and sulfuric acid (1.5 mmol) were added sequentially. After reacting at room temperature for 3 h, ferric sulfate (0.05 mmol), L-tryptophan (0.1 mmol), substrate 2a (1.0 mmol), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 3 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:5:0.1) yielded product 3 in 86% yield.

[0044] Example 4

[0045] Synthesis of Compound 4

[0046] In a 25 mL reaction flask, substrate 1d (0.5 mmol), acetone (2.0 mL), and sulfuric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 3 h, ferrous acetylacetone (0.05 mmol), N,N'-bis(tert-butyloxycarbonyl)-L-cysteine ​​(0.1 mmol), substrate 2a (1.0 mmol), and hydrogen peroxide (1.0 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 2 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate:triethylamine V / V / V = 10:3:0.1) yielded product 4 in 84% yield.

[0047] Example 5

[0048] Synthesis of Compound 5

[0049] In a 25 mL reaction flask, substrate 1e (0.5 mmol), acetonitrile (2.0 mL), and trifluoromethanesulfonic acid (2.5 mmol) were added sequentially. After reacting at room temperature for 2 h, ferrous chloride (0.025 mmol), BOC-L-proline (0.125 mmol), substrate 2a (2.5 mmol), and tert-butyl hydroperoxide (4.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 3 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate:triethylamine V / V / V = 10:3:0.1) yielded product 5 in 85% yield.

[0050] Example 6

[0051] Synthesis of Compound 6

[0052] In a 25 mL reaction flask, substrate 1f (0.5 mmol), N,N-diacetamide (2.0 mL), and sulfuric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 2 h, benzoyl acetone iron (0.05 mmol), BOC-L-glutamic acid-L-cysteine ​​(0.1 mmol), substrate 2a (1.0 mmol), and ammonium persulfate (2.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 40 °C for 12 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:4:0.1) yielded product 6 in 86% yield.

[0053] Example 7

[0054] Synthesis of Compound 7

[0055] In a 25 mL reaction flask, 1 g (0.5 mmol) of substrate, 2.0 mL of isoamyl alcohol, and 1.5 mmol of fluoroboric acid were added sequentially. After reacting at room temperature for 3 h, ferric trifluoromethanesulfonate (0.02 mmol), BOC-glycine-glycine-glycine (0.04 mmol), substrate 2b (1.0 mmol), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 6 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate:triethylamine V / V / V = 10:4:0.1) yielded product 7 in 83% yield.

[0056] 1 H NMR (400MHz, CDCl3): δ8.83(d,J=1.2Hz,1H),7.91(dd,J=8.0,2.0Hz,1H),7.34(d,J=8.0Hz,1H),3 .70-3.59(m,1H),2.75-2.58(m,2H),2.55-2.39(m,2H),2.36-2.26(m,1H),2.19-2.11ppm(m,1H); 13 C NMR (100MHz, CDCl3): δ217.3,166.8,152.3,139.7,122.2,116.7,108.0,44.2,44.0,38.0,30.0ppm.

[0057] Example 8

[0058] Synthesis of Compound 8

[0059] In a 25 mL reaction flask, substrate 1 h (0.5 mmol), dimethyl sulfoxide (2.0 mL), and sulfuric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 1 h, ferrous trifluoromethanesulfonate (0.05 mmol), BOC-D-phenylalanine (0.1 mmol), substrate 2b (2.5 mmol), and sodium persulfate (5.0 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 3 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:5:0.1) yielded product 8 in 83% yield.

[0060] 1 H NMR (400MHz, CDCl3): δ9.16 (d, J=2.0Hz, 1H), 8.24 (dd, J=8.0, 2.0Hz, 1H), 7.28 (d, J=8.4Hz, 1H), 4.40 (q, J=10.6Hz, 2H), 3.67-3.56(m,1H),2.76-2.57(m,2H),2.56-2.39(m,2H),2.36-2.26(m,1H),2.22-2.11(m,1H),1.40ppm(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ218.1,166.6,165.2,150.8,137.7,124.6,121.6,61.3,44.3,44.1,38.2,30.1,14.3ppm.

[0061] Example 9

[0062] Synthesis of Compound 9

[0063] In a 25 mL reaction flask, substrate 1i (0.5 mmol), dichloromethane (2.0 mL), and hydrochloric acid (2.0 mmol) were added sequentially. After reacting at room temperature for 2 h, ferric acetylacetone (0.5 mmol), BOC-glycyl-glycine (0.5 mmol), substrate 2b (2.5 mmol), and hydrogen peroxide (1.0 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 25 °C for 3 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:6:0.1) yielded product 9 in 80% yield.

[0064] 1H NMR(400MHz, CDCl3)δ9.10(s,1H),8.18(d,J=8.0Hz,1H),7.31(d,J=8.0Hz,1H),3.73-3.51(m,1 H),2.75-2.63(m,2H),2.62(s,3H),2.55-2.39(m,2H),2.36-2.26(m,1H),2.22-2.11ppm(m,1H); 13 C NMR (100MHz, CDCl3) δ217.9,196.4,167.0,149.9,136.1,130.8,122.0,44.2,44.1,38.1,30.1,26.7ppm.

[0065] Example 10

[0066] Synthesis of Compound 10

[0067] In a 25 mL reaction flask, substrate 1j (0.5 mmol), 4-methyl-2-pentanol (2.0 mL), and sulfuric acid (2.5 mmol) were added sequentially. After reacting at room temperature for 2 h, ferrous oxalate (0.045 mmol), L-homocysteine ​​(0.03 mmol), substrate 2b (1.5 mmol), and benzoyl peroxide (2.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 90 °C for 3 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:5:0.1) yielded product 10 in 87% yield.

[0068] 1 H NMR (400MHz, CDCl3): δ8.81(s,1H),7.87(dd,J=8.4,2.4Hz,1H),7.33(d,J=8.4Hz,1H),3.69- 3.59(m,1H),2.74-2.57(m,2H),2.56-2.40(m,2H),2.36-2.25(m,1H),2.22-2.13ppm(m,1H); 13 C NMR (100MHz, CDCl3): δ217.8, 166.3, 146.5 (q, J = 4.0Hz), 133.7 (q, J = 3.0Hz), 124.8(q,J=33.5Hz), 123.5(q,J=270.5Hz), 121.8, 44.2, 44.0, 38.1, 30.1ppm; 19 F NMR (376MHz, CDCl3) δ-62.29ppm.

[0069] Example 11

[0070] Synthesis of Compound 11

[0071] In a 25 mL reaction flask, substrate 1k (0.5 mmol), isopropanol (2.0 mL), and sulfuric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 1 h, ferrous 1,3-diphenylpropanedione (0.035 mmol), S-acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine ​​(0.01 mmol), substrate 2b (1.0 mmol), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 60 °C for 3 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate:triethylamine V / V / V = 10:4:0.1) yielded product 11 in 85% yield.

[0072] 1 H NMR (400MHz, Acetone-d6) δ8.92(br,1H),8.03(d,J=4.4Hz,1H),7.27(d,J=8.0Hz,1H),7.10(dd,J=8.0,4.4Hz,1H),4. 05-3.90(m,1H),2.67(dd,J=17.6,8.4Hz,1H),2.40(dd,J=18.0,7.6Hz,1H),2.36-2.24(m,2H),2.23-2.07ppm(m,2H); 13 C NMR (100MHz, Acetone) δ218.2,151.5,151.2,140.7,123.0,122.3,43.2,38.1,37.9,29.3ppm.

[0073] Example 12

[0074] Synthesis of Compound 12

[0075] In a 25 mL reaction flask, substrate 1L (0.5 mmol), tert-butanol (2.0 mL), and sulfuric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 3 h, ferrous bromide (0.05 mmol), L-tyrosine (0.15 mmol), substrate 2b (2.0 mmol), and hydrogen peroxide (3.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 3 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:5:0.1) yielded product 12 in 84% yield.

[0076] 1H NMR (400MHz, CDCl3): δ8.25(s,1H),8.24(d,J=5.2Hz,1H),7.12(d,J=4.8Hz,1H),3.94 (s,3H),3.66(m,1H),2.66(dd,J=18.0,7.2Hz,1H),2.46-2.25(m,4H),2.01ppm(m,1H); 13 C NMR (100MHz, CDCl3): δ217.8,153.8,142.6,140.1,132.6,121.2,56.0,43.7,38.4,36.1,28.5ppm.

[0077] Example 13

[0078] Synthesis of Compound 13

[0079] In a 25 mL reaction flask, substrate 1m (0.5 mmol), ethylene glycol (2.0 mL), and sulfuric acid (1.5 mmol) were added sequentially. After reacting at room temperature for 2 h, benzoyl acetone iron (0.015 mmol), N-acetyl-L-cysteine ​​(0.1 mmol), substrate 2a (1.0 mmol), and potassium persulfate (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 100 °C for 4 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:4:0.1) yielded product 13 in 87% yield.

[0080] 1 H NMR (400MHz, CDCl3) δ8.61(d,J=5.2Hz,1H),7.18(d,J=5.2Hz,1H),2.69(tt,J=12.0,3.6Hz,1H),2.11-1. 90(m,2H),1.95-1.85(m,2H),1.83-1.73(m,1H),1.58-1.40(m,2H),1.47-1.32(m,2H),1.35-1.20(m,1H); 13 C NMR (100MHz, CDCl3) δ181.4,162.0,159.5,117.5,45.5,31.8,26.1,25.9ppm.

[0081] Example 14

[0082] Synthesis of Compound 14

[0083] In a 25 mL reaction flask, substrate 1n (0.5 mmol), trifluoroethanol (2.0 mL), and acetic acid (0.5 mmol) were added sequentially. After reacting at room temperature for 1 h, ferrous ferricyanide (0.05 mmol), D-arginine (0.1 mmol), substrate 2a (1.0 mmol), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 100 °C for 2 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:4:0.1) yielded product 14 in 83% yield.

[0084] Example 15

[0085] Synthesis of Compound 15

[0086] In a 25 mL reaction flask, substrate 1o (0.5 mmol), isobutanol (2.0 mL), and sulfuric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 5 h, ferric ferricyanide (0.025 mmol), D-proline (0.1 mmol), substrate 2a (1.5 mmol), and hydrogen peroxide (2.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 80 °C for 4 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:5:0.1) yielded product 15 in 89% yield.

[0087] 1 H NMR (400MHz, CDCl3) δ8.10 (d, J = 8.4Hz, 2H), 7.75-7.65 (m, 1H), 7.55-7.45 (m, 1H), 7.20 (s, 1H), 3.38-3. 25(m,1H),2.75(s,3H),2.09-1.98(m,2H),1.96-1.82(m,3H),1.65-1.50(m,4H),1.45-1.32ppm(m,1H); 13 C NMR (100MHz, CDCl3) δ160.5,152.3,148.7,129.9,128.8,125.1,125.0,123.0,120.0,39.2,33.9,27.3,26.5,25.7ppm.

[0088] Example 16

[0089] Synthesis of Compound 16

[0090] In a 25 mL reaction flask, substrate 1p (0.5 mmol), ethyl acetate (2.0 mL), and hydrochloric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 2 h, ferrous sulfate (0.5 mmol), L-phenylalanine (0.01 mmol), substrate 2a (1.0 mmol), and benzoyl tert-butyl peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 60 °C for 4 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate:triethylamine V / V / V = 10:5:0.1) yielded product 16 in 87% yield.

[0091] Example 17

[0092] Synthesis of Compound 17

[0093] In a 25 mL reaction flask, substrate 1q (0.5 mmol), 2-methyl-2-butanol (2.0 mL), and sulfuric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 3 h, ferrous fluoride (0.02 mmol), L-cysteine ​​(0.3 mmol), substrate 2a (1.0 mmol), and peracetic acid (1.0 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 3 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:3:0.1) yielded product 17 in 87% yield.

[0094] Example 18

[0095] Synthesis of Compound 18

[0096] In a 25 mL reaction flask, substrate 1r (0.5 mmol), 3-methoxybutanol (2.0 mL), and sulfuric acid (1.5 mmol) were added sequentially. After reacting at room temperature for 2 h, ferrous iodide (0.05 mmol), D-serine (0.1 mmol), substrate 2a (1.0 mmol), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 90 °C for 4 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate:triethylamine V / V / V = 10:4:0.1) yielded product 18 in 83% yield.

[0097] Example 19

[0098] Synthesis of Compound 19

[0099] In a 25 mL reaction flask, substrate 1s (0.5 mmol), toluene (2.0 mL), and sulfuric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 3 h, ferric perchlorate (III) hydrate (0.05 mmol), L-cysteine ​​(0.005 mmol), substrate 2a (2.5 mmol), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 5 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:4:0.1) yielded product 19 in 78% yield.

[0100] Example 20

[0101] Synthesis of Compound 20

[0102] In a 25 mL reaction flask, substrate 1t (0.5 mmol), n-butanol (2.0 mL), and hydrochloric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 5 h, ferric oxalate (0.01 mmol), L-proline (0.1 mmol), substrate 2a (1.0 mmol), and hydrogen peroxide (2.0 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 80 °C for 6 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:3:0.1) yielded product 20 in 79% yield.

[0103] Example 21

[0104] Synthesis of Compound 21

[0105] In a 25 mL reaction flask, substrate 1u (0.5 mmol), acetonitrile (2.0 mL), and trifluoroacetic acid (0.5 mmol) were added sequentially. After reacting at room temperature for 5 h, ferric fluoride (0.05 mmol), D-valine (0.15 mmol), substrate 2a (1.0 mmol), and potassium persulfate (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 6 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:4:0.1) yielded product 21 in 82% yield.

[0106] Example 22

[0107] Synthesis of Compound 22

[0108] In a 25 mL reaction flask, substrate 1v (0.5 mmol), dichloromethane (2.0 mL), and hydrochloric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 2 h, ferrous phthalocyanine (0.015 mmol), N-BOC-L-leucine (0.25 mmol), substrate 2a (1.0 mmol), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 30 °C for 4 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:5:0.1) yielded product 22 in 84% yield.

[0109] Example 23

[0110] Synthesis of Compound 23

[0111] In a 25 mL reaction flask, substrate 1w (0.5 mmol), 2-pentanol (2.0 mL), and hydrochloric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 5 h, ferrous chloride (0.05 mmol), β-thiovaline (0.1 mmol), substrate 2a (1.0 mmol), and hydrogen peroxide (4.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 5 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:4:0.1) yielded product 23 in 81% yield.

[0112] Example 24

[0113] Synthesis of Compound 24

[0114] In a 25 mL reaction flask, substrate 1x (0.5 mmol), 1,2-dichloroethane (2.0 mL), and acetic acid (0.5 mmol) were added sequentially. After reacting at room temperature for 5 h, ferric bromide (0.005 mmol), L-cysteine ​​(0.1 mmol), substrate 2a (1.0 mmol), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 35 °C for 6 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:4:0.1) yielded product 24 in 87% yield.

[0115] Example 25

[0116] Synthesis of Compound 25

[0117] In a 25 mL reaction flask, substrate 1y (0.5 mmol), N,N-diformamide (2.0 mL), and sulfuric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 5 h, ferrous chloride (0.05 mmol), β-thiovaline (0.1 mmol), substrate 2a (1.0 mmol), and dicumyl peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 90 °C for 8 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate:triethylamine V / V / V = 10:5:0.1) yielded product 25 in 75% yield.

[0118] Example 26

[0119] Synthesis of Compound 26

[0120] In a 25 mL reaction flask, substrate 1n (0.5 mmol), methanol (2.0 mL), and sulfuric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 2 h, ferric nitrate (0.05 mmol), 2-allyl-N-FMOC-L-glycine (0.5 mmol), substrate 2c (1.0 mmol), and hydrogen peroxide (5.0 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 60 °C for 3 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate:triethylamine V / V / V = 10:4:0.1) yielded product 26 in 93% yield.

[0121] 1 H NMR (400MHz, CDCl3): δ8.61 (s, 1H), 8.46 (s, 1H), 8.39 (d, J = 2.4Hz, 1H), 4.79 (t, J = 4.0Hz, 1H), 4.64 (d, J = 4.8Hz, 1H), 3. 17(dd,J=8.0,6.0Hz,1H),2.06(d,J=7.2Hz,2H),1.82(dd,J=4.4,3.2Hz,2H),1.71-1.62(m,1H),1.61-1.55ppm(m,1H); 13 C NMR (100MHz, CDCl3): δ159.9,144.0,143.5,142.3,81.1,76.6,49.0,39.0,30.2,29.6ppm.

[0122] Example 27

[0123] Synthesis of Compound 27

[0124] In a 25 mL reaction flask, substrate 1n (0.5 mmol), polyethylene glycol 200-10000 (2.0 mL), and sulfuric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 5 h, 1,1'-bis(diphenylphosphine)ferrocene (0.015 mmol), L-cysteine ​​(0.1 mmol), substrate 2d (1.0 mmol), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 6 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:4:0.1) yielded product 27 in 90% yield.

[0125] Example 28

[0126] Synthesis of Compound 28

[0127] In a 25 mL reaction flask, substrate 1n (0.5 mmol), 3-pentanol (2.0 mL), and sulfuric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 5 h, ferrous chloride (0.05 mmol), D-cysteine ​​(0.1 mmol), substrate 2e (1.0 mmol), and di-tert-butyl peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 6 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:5:0.1) yielded product 28 in 88% yield.

[0128] 1 H NMR (400MHz, CDCl3) δ8.52(s,1H),8.44(d,J=1.2Hz,1H),8.38(s,1H),3.63-3.42(m,1H),3.07(dd,J=17.2,7.6Hz,1H),2.69( dd,J=17.2,5.6Hz,1H),2.35(t,J=7.6Hz,2H),1.59-1.46(m,2H),1.28(dd,J=7.0,1.2Hz,3H),0.85ppm(td,J=7.2,1.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ209.4,160.5,144.4,143.7,142.3,48.2,45.1,34.1,20.8,17.2,13.6ppm.

[0129] Example 29

[0130] Synthesis of Compound 29

[0131] In a 25 mL reaction flask, substrate 1z (0.5 mmol), acetonitrile (2.0 mL), and hydrochloric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 3 h, ferric 1,3-diphenylpropanedione (0.05 mmol), aspartic acid (0.1 mmol), substrate 2f (1.0 mmol), and di-tert-butyl peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 6 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:4:0.1) yielded product 29 in 85% yield.

[0132] 1 H NMR(400MHz, CDCl3):9.12(d,J=5.2,1H)9.09(s,1H),7.31(dd,J=5.6,2.4Hz,1H),2.99-2.8 5(m,1H),2.38-2.30(m,1H),2.25-2.17(m,1H),2.04-1.92(m,2H),1.35ppm(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ151.4,151.2,143.9,124.5,118.5,36.0,32.1,20.3,15.3ppm.

[0133] Example 30

[0134] Synthesis of Compound 30

[0135] In a 25 mL reaction flask, substrate 1z (0.5 mmol), cyclopentanol (2.0 mL), and fluoroboric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 3 h, ferric iodide (0.025 mmol), L-histidine (0.1 mmol), substrate 2 g (1.0 mmol), and hydrogen peroxide (3.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 90 °C for 6 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:5:0.1) yielded product 30 in 83% yield.

[0136] 1 H NMR (400MHz, CDCl3): δ10.65(s,1H),9.09(s,2H),7.44(s,1H),2.87(dd,J=13.2 ,6.4Hz,1H),2.29(t,J=6.8Hz,2H),2.03-1.88(m,2H),1.31ppm(d,J=6.4Hz,3H); 13CNMR (100MHz, CDCl3): δ176.5,151.5,150.7,147.1,125.7,36.4,31.9,31.8,20.5ppm.

[0137] Example 31

[0138] Synthesis of Compound 31

[0139] In a 25 mL reaction flask, substrate 1z (0.5 mmol), n-propanol (2.0 mL), and trifluoroacetic acid (0.5 mmol) were added sequentially. After reacting at room temperature for 3 h, ferric oxide (0.05 mmol), L-cysteine ​​(0.1 mmol), substrate 2h (1.0 mmol), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 6 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:4:0.1) yielded product 31 in 81% yield.

[0140] 1 H NMR (400MHz, CDCl3): δ9.10 (s, 1H), 9.09 (d, J = 5.2Hz, 1H), 7.30 (dd, J = 5.2, 2.4Hz, 1H), 3.10-3.00 (m, 1H) ,1.78(dd,J=12.8,3.2Hz,2H),1.31(s,6H),1.35(d,J=7.2Hz,1H),1.26(d,J=7.2Hz,1H),1.20ppm(s,6H); 13 C NMR (100MHz, CDCl3): δ152.0,151.2,145.4,124.3,50.7,44.6,34.8,33.3,28.1ppm.

[0141] Example 32

[0142] Synthesis of Compound 32

[0143] In a 25 mL reaction flask, substrate 1n (0.5 mmol), 1,4-dioxane (2.0 mL), and sulfuric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 4 h, ferrous chloride (0.5 mmol), isoserine (0.1 mmol), substrate 2i (1.0 mmol), and hydrogen peroxide (2.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 25 °C for 9 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate:triethylamine V / V / V = 10:3:0.1) yielded product 32 in 72% yield.

[0144] 1 H NMR (400MHz, CDCl3): δ8.50(d,J=10.0Hz,2H),8.41(s,1H),8.02(d,J=7.2Hz,1H),7.90(d,J=7.2Hz,1H),7.87-7.7 7(m,2H),3.73(t,J=7.2Hz,2H),3.16-3.05(m,1H),2.45-2.33(m,1H),2.21-2.11(m,1H),1.36ppm(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3) δ160.0,158.9,144.2,144.2,142.6,137.6,134.7,134.3,127.2,125.1,120.9,37.5,36.6,34.2,20.6ppm.

[0145] Example 33

[0146] Synthesis of Compound 33

[0147] In a 25 mL reaction flask, substrate 1n (0.5 mmol), tert-amyl alcohol (2.0 mL), and hydrochloric acid (0.5 mmol) were added sequentially. After reacting at room temperature for 4 h, ferrous chloride (0.05 mmol), N-BOC-N'-triphenylmethyl-L-histidine (0.1 mmol), substrate 2j (1.0 mmol), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 10 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:4:0.1) yielded product 33 in 68% yield.

[0148] 1 H NMR (400MHz, CDCl3): δ9.59(s,1H),8.51(dd,J=4.8,1.2Hz,2H),8.42(d,J=2.4Hz,1H ),3.06-2.93(m,1H),2.78-2.63(m,2H),2.26-2.07(m,2H),1.36ppm(d,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ177.6,160.2,153.4,143.9,143.9,142.6,141.2,126.0,38.5,34.3,26.7,20.3ppm.

[0149] Example 34

[0150] Synthesis of Compound 34

[0151] In a 25 mL reaction flask, substrate 1n (0.5 mmol), acetonitrile (3.0 mL), and methanesulfonic acid (1.5 mmol) were added sequentially. After reacting at room temperature for 3 h, ferrous chloride (0.005 mmol), L-cysteine ​​(0.1 mmol), substrate 2k (1.0 mmol), and hydrogen peroxide (3.0 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 70 °C for 6 h. Upon completion of the reaction, direct chromatography (petroleum ether: ethyl acetate: triethylamine V / V / V = 10:3:0.1) yielded product 34 in 63% yield.

[0152] 1 H NMR (400MHz, CDCl3) δ8.77 (s, 1H), 8.51-8.48 (m, 1H), 8.45 (d, J = 2.4Hz, 1H), 5.22(dd,J=9.6,2.4Hz,1H),2.39-2.32(m,1H),2.11-2.06(m,1H),1.87-1.81 (m,2H),1.64(dd,J=13.2,3.6Hz,2H),1.54(dd,J=13.6,6.8Hz,2H),1.40-1.2 9(m,4H),1.17-1.07(m,3H),1.02-0.94(m,2H),0.88(s,6H),0.83ppm(s,3H); 13 C NMR (100MHz, CDCl3) δ159.4,143.6,142.8,142.4,82.8,76.8,58.4,57.2, 42.3,39.9,39.8,36.2,33.5,33.1,30.4,21.8,21.1,20.7,18.3,15.1ppm.

[0153] The structural formulas of the raw materials and products in Examples 1-34 and the corresponding experimental results are shown in Table 1 below:

[0154]

[0155] Table 1

[0156]

[0157]

[0158]

[0159]

[0160]

[0161] Example 35

[0162] Example 35 uses the same method as Example 26, except that the molar ratio of aromatic heterocyclic compound, alkanes, sulfuric acid, peroxide, amino acid derivative, and iron catalyst is 1:2:4:3:0.02:0.01.

[0163] Example 36

[0164] Example 36 uses the same method as Example 26, except that the molar ratio of aromatic heterocyclic compound, alkanes, sulfuric acid, peroxide, amino acid derivative, and iron catalyst is 1:3:1:1:0.2:0.5.

[0165] Example 37

[0166] Example 37 uses the same method as Example 26, except that the molar ratio of aromatic heterocyclic compound, alkanes, sulfuric acid, peroxide, amino acid derivative, and iron catalyst is 1:5:10:10:1:1.

[0167] Example 38

[0168] Example 38 uses the same method as Example 26, except that the solvent is entirely water and the total volume remains unchanged.

[0169] Comparative Example 1

[0170] The method of Comparative Example 1 is the same as that of Example 26, except that no iron catalyst is added and the yield of the target product is 0.

[0171] Comparative Example 2

[0172] Comparative Example 2 uses the same method as Example 26, except that no amino acid ligands are added, and the yield of the target product is extremely low, only 6%.

[0173] Comparative Example 3

[0174] Comparative Example 3 uses the same method as Example 26, except that no oxidant is added and the yield of the target product is 0.

[0175] Comparative Example 4

[0176] Comparative Example 4 uses the same method as Example 26, except that it uses the non-amino acid ligand bipyridine, and the yield is only 5%.

[0177] Comparative Example 5

[0178] Comparative Example 5 uses the same method as Example 26, except that it uses other phosphorus-containing ligands, such as triphenylphosphine and diethylphenylphosphine, with a yield of only about 8%.

[0179] Comparative Example 6

[0180] The method used in Comparative Example 6 is the same as that in Example 26, except that no acid is added and the yield of the target product is less than 10%. In contrast, without pre-treating the aromatic heterocyclic compound with acid, and with the acid added along with other starting materials, the yield of the target product is significantly reduced to only about 40%.

[0181] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the invention. Theoretically, various iron catalysts in this invention can coordinate with amino acid ligands to form highly active iron catalyst intermediates, thereby facilitating the smooth progress of the reaction. Amino acid ligands are promoters for coupling reactions between alkanes and aromatic heterocyclic compounds, utilizing their ability to coordinate with iron. Theoretically, various amino acids and their derivatives all possess coordination functions and should achieve similar effects. Various peroxides are oxidizing agents. The reaction on alkanes involves the activation of carbon-hydrogen bonds, while the various substituents on aromatic heterocyclic compounds affect the electron cloud density within the ring and the steric hindrance during the reaction. That is, the modification of substituents only affects the reaction to a certain extent and does not play a decisive role in the occurrence of the reaction. Anyone skilled in the art will readily understand that, without departing from the scope of the present invention, variations 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 to achieve the method of the present invention. Any modifications, alterations, or equivalent changes made to the above embodiments based on the present invention without departing from the spirit of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for iron-catalyzed coupling of alkanes with aromatic heterocyclic compounds, characterized in that, The process includes the following steps: using peroxide as an oxidant, iron as a catalyst, amino acids or their derivatives as ligands, and acids as additives, catalyzing aromatic heterocyclic compounds in a solvent to undergo CH bond activation and C-C bond coupling reactions with alkanes to generate alkyl-substituted aromatic heterocyclic compounds. The general formula for the reaction is as follows: ; In the formula: Het represents an aromatic heterocyclic group; wherein, the aromatic heterocyclic group is a substituted or unsubstituted pyridinyl, quinolinyl, isoquinolinyl, pyrazinyl, pyrimidinyl, pyridazinyl, phthalazinyl, quinoxalinyl or benzothiazolyl; R1 represents a substituent in an aromatic heterocyclic compound, wherein R1 is selected from hydrogen, methyl, methoxy, hydroxy, aryl, cyano, ester, trifluoromethyl, halogen, or carbonyl. R represents a C1-C16 unsubstituted alkyl or cycloalkyl group; The iron is selected from any one or more of the following: ferrous trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, ferrous fluoride, ferrous fluoride, ferrous bromide, ferrous bromide, ferrous iodide, ferrous iodide, ferrous chloride, ferric chloride, ferrous acetylacetone, ferric acetylacetone, ferrous 1,3-diphenylpropanedione, ferric 1,3-diphenylpropanedione, ferric benzoylpropanedione, ferrous ferric ferric cyanide, ferrous acetate, ferrous sulfate, ferric sulfate, ferrous oxalate, ferric oxalate, ferric perchlorate (III) hydrate, 1,1'-bis(diphenylphosphine)ferrocene, ferrous phthalocyanine, ferric nitrate, iron oxide, or iron(III) oxide. The ligands are selected from L-cysteine, S-acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine, N-acetyl-L-cysteine, L-cysteine, N,N'-bis(tert-butoxycarbonyl)-L-cysteine, BOC-L-glutamate-L-cysteine, D-cysteine, L-homocysteine, L-serine, D-serine, isoserine, L-threonine, L-tyrosine, L-proline, BOC-L-proline, D... The following are any one or more of the following: proline, L-phenylalanine, L-tryptophan, aspartic acid, D-arginine, L-histidine, N-BOC-N'-triphenylmethyl-L-histidine, BOC-glycine-glycine-glycine, BOC-glycyl-glycine, 2-allyl-N-FMOC-L-glycine, BOC-D-phenylalanine, β-thiovaline, D-valine, or N-BOC-L-leucine.

2. The method for iron-catalyzed coupling of alkanes and aromatic heterocyclic compounds according to claim 1, characterized in that, R1 is selected from hydrogen, methyl, methoxy, hydroxy, trifluoromethyl, or halogen, and R represents a C1-C6 non-substituted alkyl group.

3. The method for iron-catalyzed coupling of alkanes and aromatic heterocyclic compounds according to claim 1, characterized in that, The oxidant is selected from any one or more of hydrogen peroxide, tert-butyl hydrogen peroxide, di-tert-butyl peroxide, benzoyl peroxide, benzoyl tert-butyl peroxide, peracetic acid, potassium persulfate, ammonium persulfate, sodium persulfate, potassium monopersulfate, or dicumyl peroxide.

4. The method for iron-catalyzed coupling of alkanes and aromatic heterocyclic compounds according to claim 1, characterized in that, The acid is selected from any one or more of sulfuric acid, trifluoroacetic acid, acetic acid, hydrochloric acid, fluoroboric acid, methanesulfonic acid, and trifluoromethanesulfonic acid.

5. The method for iron-catalyzed coupling of alkanes and aromatic heterocyclic compounds according to claim 1, characterized in that, The solvent is an organic solvent, water, or an aqueous solution of an organic solvent. The organic solvent is selected from any one or more of methanol, ethanol, ethylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, trifluoroethanol, 2-methyl-2-butanol, 3-methoxybutanol, sec-butanol, tert-amyl alcohol, 4-methyl-2-pentanol, isoamyl alcohol, 2-pentanol, 3-pentanol, cyclopentanol, n-pentanol, polyethylene glycol 200-10000, acetonitrile, toluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dicarboxamide, 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).

6. The method for iron-catalyzed coupling of alkanes and aromatic heterocyclic compounds according to claim 1, characterized in that, The molar ratio of the aromatic heterocyclic compound, alkane compound, peroxide, acid, amino acid or its derivative, and iron catalyst is 1:(2-5):(2-50):(1-50):(0.002-20):(0.001-10).

7. The method for iron-catalyzed coupling of alkanes and aromatic heterocyclic compounds according to claim 1, characterized in that, The molar ratio of the aromatic heterocyclic compound, alkane compound, peroxide, acid, amino acid or its derivative, and iron catalyst is 1:(2-5):(2-10):(1-10):(0.01-1):(0.01-1).

8. The method for iron-catalyzed coupling of alkanes and aromatic heterocyclic compounds according to claim 1, characterized in that, The reaction is carried out at a temperature of 25–100°C for 3–14 hours.

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