Method for heteroarylation of tension ring under iron catalysis

Abstract

The invention discloses a method for catalyzing heteroarylation of a tension ring C (sp3)-H. The method comprises the following steps: in a solvent, by taking a heteroaromatic ring compound and a tension ring compound as substrates, peroxide as an oxidant, iron as a catalyst and amino acid and derivatives thereof as ligands, catalyzing the heteroarylation reaction of the tension ring C (sp3)-H. The heteroaromatic ring substituted tension ring compound is generated. The method has the advantages that the catalyst is wide in source, cheap and environment-friendly; the oxidant is wide in source and cheap; reaction conditions are mild, and selectivity is high; the functional group compatibility of the substrate is good, and the application range of the substrate is wide; complex molecules and natural products can be compatible, and C (sp3)-H bond functionalization reaction of a tension ring is achieved. Under optimized reaction conditions, the yield of the separated target product can reach 80%.

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 the heteroarylation of strained rings, particularly the iron-catalyzed oxidation of strained rings with a suitable oxidant to achieve C(sp) grouping of the smaller ring. 3 A method for direct heteroarylation of the )-H bond. Background Technology

[0002] Strained rings and their derivatives possess unique structural features and physicochemical properties, and are widely used in the design of small molecule drugs. In 2016, Professor Tanaji T. Talele of the College of Pharmacy at St. John's University published a review (J. Med. Chem. 2016, 59 (19), 8712 - 8756.) summarizing the applications of cyclopropane in drugs: enhancing potency, reducing off-target effects, and increasing metabolic stability. For example, replacing isopropyl with cyclopropyl, which has higher metabolic stability, yielded pitavastatin, resulting in higher bioavailability and a longer duration of action. Furthermore, a 1996 study by Roberto Pellicciari's team was the first to experimentally demonstrate the isosteric effect of benzene rings in bicyclic [1.1.1]pentanes (BCPs) (J. Med. Chem. 1996, 39, 2874-2876.). This discovery not only promoted the development of novel bioisosteres but also provided an important strategy for overcoming patent protection and optimizing drug properties. In summary, researchers have never stopped exploring the functionality of small rings, and heteroaryl rings are also important building blocks for drug molecules and natural active molecules. Significant progress has been made in the heteroarylization reaction of strained rings.

[0003] Since Walter Kurtz (Chem. Ber. 1975, 108, 3415-3432.) achieved C-C coupling with aromatic heterocycles using metal reagents such as cyclopropyllithium, breakthrough progress has been made in the heterocyclization of strained rings; subsequently, transition metal-catalyzed C(sp... 2 )-C(sp 3Coupling is also widely used in this reaction. For example, Satoshi Shuto's team (Adv. Synth. Catal. 2015, 357, 1022 - 1028) used boric acid-substituted heteroaryl rings and alkyl iodides in 2015 to achieve the heteroarylation of strained rings via a radical mechanism, but the prefunctionalization of the substrate increased the reaction steps and cost; Yu Jinquan's research group (Angew. Chem. Int. Ed. 2020, 59, 9594 - 9600) reported in 2020 a palladium-catalyzed coupling reaction of cyclobutane derivatives with heteroaryl rings, which used an equivalent amount of silver salt as an additive; Phil S. Baran's team (Angew. Chem. Int. Ed. 2024, 63, e202314617 (3 of 9) In 2024, a photo-nickel-silver synergistic catalysis was used to achieve strained ring coupling between aryl halides and tertiary carbons. Compared to previous studies, this method utilizes inexpensive and readily available metal catalysts, eliminating the need for pre-functionalization of the substrate and directly coupling the C(sp) ring of the strained ring. 3 The highly selective and efficient heteroarylation reaction of C(sp³)-H has great research value. On the one hand, it needs to meet the demand for efficient, low-cost, and diversified synthesis of strained ring-heteroaryl compounds in drug development; on the other hand, it is limited by problems such as pre-functionalization, dependence on noble metals, insufficient selectivity, and harsh conditions. Therefore, developing a direct C(sp³)-H heteroarylation method catalyzed by inexpensive metals (such as iron), without the need for pre-functionalization, and with high selectivity has become a key research direction in this field. Summary of the Invention

[0004] Objective of the Invention: Addressing the problems of existing technologies, this invention provides an iron-catalyzed method for heteroarylation of strained ring compounds. This method utilizes readily available and inexpensive iron and amino acid ligands, under the action of a suitable oxidant, to directly achieve highly selective heteroarylation of C(sp³)-H bonds in strained ring compounds. Its core features are: no need for pre-functionalization of the strained ring or heteroaryl ring substrate, simplifying the synthesis steps and improving atom economy; elimination of expensive additives such as precious metal catalysts and equivalent silver salts, significantly reducing reaction costs; mild reaction conditions and simple operation, requiring no special light source or strictly anhydrous and oxygen-free environment, suitable for large-scale production; broad substrate compatibility, efficiently applicable to the dehydrogenation cross-coupling reactions of various strained rings and heteroaryl rings with different substitution types, such as cyclopropane, bicyclo[1.1.1]pentane, and cyclobutane, effectively reducing side reactions such as ring opening, rearrangement, and oxidation, ensuring product purity and yield. This invention successfully solves the technical pain points of the prior art in strained ring heteroarylation reaction, which relies on noble metal catalysis, has complicated substrate preactivation, harsh reaction conditions, high cost, and narrow substrate range. It provides an economical, green, and universal new route for the efficient synthesis of drug active molecule building blocks, and has important application value in the fields of drug development and fine chemical synthesis.

[0005] Technical solution: To achieve the above objectives, the present invention provides an iron-catalyzed strain ring C(sp) 3 The method for heteroarylation of )-H includes the following steps: using a heteroaryl ring compound as the arylating agent, a peroxide as the oxidant, iron as the catalyst, and an amino acid or its derivative as the ligand, the C(sp) group of the strained ring compound is oxidized in a solvent. 3 The heteroarylation reaction of the )-H bond generates heteroaryl-substituted strained ring compounds;

[0006] The general formula for the reaction is as follows:

[0007] ;

[0008] The R 1 Substituents on heterocyclic aromatic compounds; R 2 The term indicates a substituent on a strained ring compound, where Het is an aromatic ring structure containing heteroatoms, and when the strained ring compound is a spirocyclic or bicyclic compound, n is not equal to 1 or 2.

[0009] Wherein, the heterocyclic compound is pyridine, pyrazine, pyridazine, pyrimidine, quinoline, thiazole, benzothiazole or 2,3-diazanaphthalene; the strained ring compound is cyclopropane, cyclobutane, cyclopropanol, cyclobutanol, N-heterocyclic butane, spiroheptane or bicyclopentane.

[0010] Wherein, the R 1Halogen, methyl, ester, acetyl, cyano, trifluoromethyl, nitro, ester, acetamino, N,N-diethylacetamino, sulfonamide

[0011] Group, ethanol group or tocopherol ester group.

[0012] Wherein, the R 2 It can be N-tert-butoxycarbonyl, hydroxyl, N-methanesulfonyl, methyl, carboxyl, ester, cyano, or acetyl.

[0013] The iron is selected from any one or more of potassium ferricyanide, potassium trioxalatoferrate, ferric thiocyanate, ferrocene, ferric acetylacetone, ferrous sulfide, ferric fluoride, sodium ferrite, ferrous phosphate, ferrous ammonium sulfate, ferrous oxalate, ferrous carbonate, ferrous chloride, ferric chloride, and ferric perchlorate.

[0014] The ligand is selected from any one or more of L-cysteine, N-acetyl-L-cysteine, β-thiovaline, aspartic acid, N-Boc-L-proline, N-Boc-D-phenylalanine, N-Boc-glycine-glycine, N,N'-bis(tert-butoxycarbonyl)-L-cysteine, N-Boc-L-leucine, L-citrulline, S-adenosylmethionine, N-acetyltryptophan, leucine, homocysteine, or N-fluorenemethoxycarbonyl-L-lysine.

[0015] The oxidant is selected from any one or more of peracetic acid, tert-butyl hydroperoxide, benzoyl peroxide, peroxybenzoic acid, monotert-butyl maleate peroxide, tetrabutylammonium persulfate, potassium monopersulfate complex salt, sodium persulfate, hydrogen peroxide, sodium superphosphate, and ammonium persulfate.

[0016] Wherein, the solvent is an organic solvent, water, or an aqueous solution of an organic solvent. The organic solvent is selected from diethyl ether, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, diisopropyl ether, ethylene glycol dimethyl ether, acetone, butanone, cyclohexanone, dimethyl carbonate, isopropyl acetate, isopropanol, n-butanol, cyclohexane, benzene, toluene, xylene, ethylbenzene, cumene, chlorobenzene, 1,2-dichloroethane, pyridine, N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, triethylamine, and carbon tetrachloride. When the solvent is an aqueous solution of an organic solvent, the volume ratio of the organic solvent to water is 1:(0.1-10).

[0017] The molar ratio of the heterocyclic aromatic compounds, strained ring compounds, peroxides, amino acids or their derivatives, and iron catalyst is 1:(2.5-40):(1-50):(0.005-30):(0.002-15); the reaction temperature is 25-110℃ and the reaction time is 0.5-12 hours.

[0018] This invention uses iron as the core catalyst, which possesses the characteristics of high natural abundance, low cost, and extremely low toxicity, perfectly meeting the core requirements of green chemistry for catalytic systems. To further enhance catalytic performance, specific amino acid compounds are introduced as ligands into the system. These ligands can form structurally stable, highly active iron-amino acid coordination species through coordination with the iron catalyst. These coordination species can synergistically interact with the oxidant and solvent in the reaction system, significantly improving the catalytic activity and stability of the catalytic system for heteroarylation reactions (especially strained ring heteroarylation reactions), and also precisely controlling the reaction selectivity, effectively solving the technical pain points of insufficient activity and poor selectivity in traditional iron catalytic systems.

[0019] Compared with the precious metal catalysts (such as palladium and rhodium) widely used in the prior art, the iron-amino acid coordination catalytic system of the present invention maintains or even surpasses its catalytic performance while significantly reducing the cost of the catalyst and avoiding the environmental risks and subsequent separation problems caused by precious metal residues.

[0020] This invention employs mild reaction reagents and a mild reaction environment (requiring no high temperature, high pressure, or highly corrosive conditions), effectively overcoming the dependence on harsh conditions in traditional heteroarylation reactions (especially strained ring reactions). This reduces the operational difficulty and safety risks, providing feasibility for large-scale reaction scaling. A key breakthrough is achieved in the selection of aryl sources—for the first time, specific mono- or di-substituted heteroaryl rings that do not require prior functionalization modifications (such as halogenation or borosilicate conversion) are used as aryl sources for heteroarylation reactions. These heteroaryl rings are not only low-cost and commercially available, but also avoid the problems of cumbersome processes and increased waste associated with pre-functionalization steps. Furthermore, these aryl sources exhibit excellent compatibility with iron-amino acid catalytic systems, achieving high substrate conversion rates, further balancing the economic and environmental benefits of the reaction.

[0021] This catalytic system exhibits broader compatibility with functional groups in the substrate (such as ester, carboxyl, and halogen groups, which can all be stably present), and can be directly applied to the later-stage modification of complex molecules. This characteristic makes it of outstanding application value in the field of drug active molecule synthesis, and can efficiently achieve heteroarylation modification of drug molecular skeletons, shortening the drug development cycle.

[0022] The amino acid ligand / iron catalyst of the present invention can form a high-valence ferro-oxygen intermediate with electrophilic hydrogen-snap activity under the action of an oxidant. This amino acid ligand can not only improve the hydrogen removal ability of the high-valence state of ferro-oxygen, but also effectively suppress the occurrence of side reactions such as "O-rebound" reaction and ring opening in the system, ensuring that the formed carbon radicals can react with heterocyclic compounds with high selectivity.

[0023] The core breakthrough of this system in the application of strained ring heteroarylation reaction lies in: (1) it can directly achieve strained ring C(sp) arylation without prefunctionalizing the substrate or introducing directing groups. 3 (1) Precise activation of heteroarylation of the -H bond; (2) Effective avoidance of side reactions such as ring opening and rearrangement of strained rings, significantly improving the selectivity of the target product; (3) The amino acid ligand / iron catalytic system can effectively inhibit oxygen rebound and reduce the generation of oxidation byproducts. This invention specifically solves the key problems of low activity and poor selectivity faced by traditional strained ring heteroarylation reactions. Its advantages can be verified by multi-dimensional data such as yield, selectivity, and substrate applicability, providing a green and economical new synthetic scheme for the efficient modification of strained ring compounds.

[0024] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0025] The "amino acid or its derivative ligand-promoted iron-catalyzed oxidation system" constructed in this invention exhibits multi-dimensional technical advantages in the heteroarylation reaction of strained ring compounds:

[0026] (1) Simplified reaction process: There is no need to introduce directing groups into the substrate in advance. C(sp³)-H and C(sp²)-H cross-coupling can be achieved in one step to form strained ring modified heteroaryl compounds, avoiding the cumbersome steps of substrate pre-modification in traditional methods. The operation is simple and safe.

[0027] (2) Compared with other strained ring C(sp) catalysts, this catalytic system has a higher efficiency and better performance. 3 The )-H arylation reaction system has the advantages that the catalyst (iron), ligand (amino acid or its derivatives) and oxidant are inexpensive, readily available and widely sourced. It replaces the precious metal catalysts (such as palladium and rhodium) commonly used in the prior art. Moreover, it does not require the modification of directing groups and prefunctionalization, which greatly reduces the cost and reduces the environmental burden caused by precious metal residues. It has high atom economy and is in line with the concept of green chemistry.

[0028] (3) Excellent reaction performance: The reaction conditions are mild (no need for high temperature, high pressure or strong corrosive environment), and it has both high selectivity and high yield. Under optimized reaction conditions, the target product separation yield can reach up to 80%. At the same time, the substrate has a wide range of applications. It is not only stable in source and easy to handle, but also has excellent compatibility with common functional groups such as ester group, carboxyl group, and methyl group, and can realize one-step coupling of strained ring and complex heteroaromatic hydrocarbons.

[0029] (4) The strained ring heteroarylized product synthesized by the method of this invention is an important organic synthesis intermediate that can be widely used in the large-scale synthesis of pharmaceutical intermediates and high-value-added fine chemicals (such as functional material precursors), providing key building blocks for downstream industries. The strained ring + heteroaryl ring skeleton in the product structure is a common core structure of active drug molecules. Therefore, this method can directly serve the field of drug development, providing an efficient technical path for the design and synthesis of novel active drug molecules, and has significant industrial application value. 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] In the embodiments of this invention, all substrates are known compounds. Compounds 1, 2, 5, 16, 17, and 29 in the products of this invention are known compounds.

[0034] Example 1

[0035] Synthesis of Compound 1

[0036] In an air-filled reaction flask, potassium ferricyanide (0.06 mmol), N-acetyl-L-cysteine ​​(0.12 mmol), substrate 1a (0.5 mmol), tetrahydrofuran (2 mL), water (1.5 mL), N-Boc-cyclopropylamine (2 mmol), and hydrogen peroxide (3 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 60 °C. o The reaction was carried out at C for 8 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 removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 50:1) to give product 1 with a yield of 46% and CAS: 3023274-25-8.

[0037] 1H NMR (400 MHz, CDCl3): δ 8.58 (d, J = 5.2 Hz, 1H), 7.81 (s, 1H), 7.19 (d, J = 5.2 Hz, 1H), 5.40 (s, 1H), 3.96 (s, 3H), 1.45 (s, 9H), 1.40 -1.27 (m, 4H) ppm. 13 C NMR (100 MHz, CDCl3): δ 165.8, 155.3, 154.8, 149.6,147.8, 122.2, 120.3, 80.2, 52.8, 34.3, 28.2, 20.9 ppm.

[0038] Example 2

[0039] Synthesis of Compound 2

[0040] In an air-filled reaction flask, potassium tris(oxalato)ferrate (0.05 mmol), β-thiovaline (CAS: 52-67-5) (0.6 mmol), substrate 2a (0.5 mmol), acetonitrile (2 mL), water (2 mL), N-Boc-cyclopropylamine (1.5 mmol), and ammonium persulfate (3 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 85°C. o The reaction was carried out at C for 3 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 removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 40:1) to give product 2 with a yield of 64% and CAS: 1159735-34-8.

[0041] 1 H NMR (400 MHz, CDCl3): δ 8.97 (d, J = 2.3 Hz, 1H), 8.13 (dd, J =8.4, 2.3 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 5.43 (s, 1H), 2.57 (s, 3H), 1.70 (t, J = 3.9 Hz, 2H), 1.46 (s, 9H), 1.34 (t, J = 3.9 Hz, 2H) ppm. 13 C NMR (100MHz, CDCl3): δ 196.4, 167.0, 155.6, 149.6, 135.7, 129.4, 118.7, 80.0, 37.0,28.3, 26.5, 20.9 ppm.

[0042] Example 3

[0043] Synthesis of Compound 3

[0044] In an air-filled reaction flask, ferric thiocyanate (0.034 mmol), N-Boc-L-proline (0.12 mmol), substrate 3a (0.5 mmol), toluene (2.0 mL), N-Boc-cyclopropylamine (1.5 mmol), and potassium persulfate complex salt (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 75°C. o The reaction was carried out at C for 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, the solvent was removed under reduced pressure, and the product was separated by column chromatography (petroleum ether: ethyl acetate V / V = 30:1) to give product 3, with a yield of 53%.

[0045] 1 H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 5.38 (s, 1H), 1.70 (t, J = 5.5 Hz, 2H), 1.46 (s,9H), 1.35 (t, J = 5.5 Hz, 2H) ppm; 13 C NMR (100 MHz, CDCl3): δ 167.1, 155.5,151.9, 139.1, 118.9, 117.0, 106.1, 80.2, 37.1, 28.2, 21.5 ppm; [M + H] + m / z260.1394, found 260.1390; MP: 97.9-99.3 o C.

[0046] Example 4

[0047] Synthesis of Compound 4

[0048] In an air-filled reaction flask, ferrocene (0.023 mmol), aspartic acid (0.13 mmol), substrate 4a (0.5 mmol), 1,4-dioxane (2.0 mL), water (1.75 mL), N-Boc-cyclopropylamine (1.75 mmol), and peracetic acid (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 78°C. oThe reaction was carried out at C for 2 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 removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: dichloromethane V / V = 30:1) to give product 4, with a yield of 68%.

[0049] 1 H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 7.82 (dd, J = 8.5, 2.4 Hz,1H), 7.49 (d, J = 8.5 Hz, 1H), 5.40 (s, 1H), 1.69 (q, J = 4.6 Hz, 2H), 1.47(s, 9H), 1.33 (q, J = 4.6 Hz, 2H) ppm; 13 C NMR (100 MHz, CDCl3): δ 166.2,155.6, 146.0 (q, J = 3.9 Hz), 133.2, 123.7 (q, J = 271.9 Hz), 123.4 (q, J =32.5 Hz), 118.6, 80.1, 36.8, 28.3, 20.8 ppm; 19 F NMR (376 MHz, CDCl3): δ -62.16 ppm; [M + H] + m / z 303.1315, found 303.1315; MP: 124.3-125.9 o C.

[0050] Example 5

[0051] Synthesis of Compound 5

[0052] In an air-filled reaction flask, ferric acetylacetone (0.065 mmol), N-Boc-D-phenylalanine (0.35 mmol), substrate 5a (0.5 mmol), dimethyl sulfoxide (1.5 mL), and water (1.0 mL), N-Boc-cyclopropylamine (2.5 mmol), and tert-butyl hydroperoxide (1.8 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was heated to 100 °C. o The reaction was carried out at C for 7 h. After the reaction was completed, 5 mL of water was added and the mixture was extracted with diethyl ether (5 mL × 3). The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 35:1) to give product 5, with a yield of 51%, CAS: 828911-20-2.

[0053] 1H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 8.45 (d, J = 4.9 Hz, 1H), 7.49 (s, 1H), 5.63 (s, 1H), 1.35 (s, 9H), 1.24 (t, J = 6.4 Hz, 2H), 1.12 (t,J = 6.4 Hz, 2H) ppm. 13 C NMR (100 MHz, CDCl3): δ 155.1, 151.8, 148.5, 148.3,126.6, 123.8, 35.7, 28.2, 14.9 ppm.

[0054] Example 6

[0055] Synthesis of Compound 6

[0056] In an air-filled reaction flask, ferrous sulfide (0.05 mmol), N-Boc-glycine-glycine-glycine (0.1 mmol), substrate 6a (0.5 mmol), isopropanol (2 mL), N-Boc-cyclopropylamine (1.7 mmol), and benzoyl peroxide (2.6 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 25°C. o The reaction was carried out at C for 2 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 removed under reduced pressure, and the product was separated by column chromatography (petroleum ether: ethyl acetate V / V = 50:1) to give product 6, with a yield of 66%.

[0057] 1 H NMR (400 MHz, CDCl3): δ 9.02 (d, J = 2.2 Hz, 1H), 8.19 (dd, J =8.4, 2.2 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 5.42 (s, 1H), 4.37 (q, J = 7.1Hz, 2H), 1.69 (t, J = 3.8 Hz, 2H), 1.47 (s, 9H), 1.37 (t, J = 7.2 Hz, 3H), 1.33(t, J = 3.8 Hz, 2H) ppm; 13 C NMR (100 MHz, CDCl3): δ 166.6, 165.4, 155.6,150.4, 137.2, 123.1, 118.4, 79.9, 61.1, 36.9, 28.3, 20.8, 14.2 ppm; [M + H]+ m / z 307.1653, found 307.1651; MP: 134.8-135.3 o C.

[0058] Example 7

[0059] Synthesis of Compound 7

[0060] In an air-filled reaction flask, ferric fluoride (0.05 mmol), N,N'-bis(tert-butyloxycarbonyl)-L-cysteine ​​(0.1 mmol), substrate 7a (0.5 mmol), cyclohexane (3 mL), N-Boc-cyclopropylamine (2 mmol), and peroxybenzoic acid (1.7 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 120 °C. o The reaction was carried out at 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, the solvent was removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 30:1) to give product 7, with a yield of 74%.

[0061] 1 H NMR (400 MHz, DMSO-d6): δ 8.85 (d, J = 2.2 Hz, 1H), 8.12 (dd, J =8.3, 2.2 Hz, 1H), 8.07 (s, 1H), 7.84 (s, 1H), 7.51 (s, 1H), 7.38 (d, J = 8.3Hz, 1H), 1.46 (q, J = 4.2 Hz, 2H), 1.41 (s, 9H), 1.16 (q, J = 4.2 Hz, 2H) ppm; 13 C NMR (100 MHz, DMSO-d6): δ 166.5, 165.3, 155.7, 148.2, 135.3, 126.5, 118.3,78.1, 36.3, 28.2, 19.8 ppm; [M + H] + m / z 278.1499, found 278.1498.

[0062] Example 8

[0063] Synthesis of Compound 8

[0064] In an air-filled reaction flask, sodium ferrate (0.23 mmol), L-citrulline (0.4 mmol), substrate 8a (0.5 mmol), pyridine (2.0 mL), N-Boc-cyclopropylamine (2.2 mmol), and mono-tert-butyl maleate peroxide (1.7 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 60 °C. o The reaction was carried out at C for 2 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 removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 20:1) to give product 8, with a yield of 61%.

[0065] 1 H NMR (400 MHz, CDCl3): δ 8.43 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 5.65 (s, 1H), 3.51 (q, J = 7.0 Hz, 2H), 3.24 (q, J= 7.0 Hz, 2H), 1.60 (t, J = 5.5 Hz, 2H), 1.44 (s, 9H), 1.33 (t, J = 5.5 Hz, 2H), 1.28-1.25 (m, 3H), 1.25-1.19 (m, 3H) ppm; 13 C NMR (100 MHz, CDCl3): δ168.9, 163.0, 155.7, 146.6, 134.4, 129.5, 118.5, 79.7, 43.3, 39.3, 36.4,28.2, 20.1, 14.2, 12.7 ppm; [M + H] + m / z 334.2125, found 334.2125; MP: 130.3-132.4 o C.

[0066] Example 9

[0067] Synthesis of Compound 9

[0068] In an air-filled reaction flask, ferrous carbonate (0.1 mmol), S-adenosylmethionine (0.1 mmol), substrate 9a (0.5 mmol), butanone (1.0 mL), water (1.0 mL), N-Boc-cyclopropylamine (1.5 mmol), and tetrabutylammonium persulfate (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 90°C. oThe reaction was carried out at C for 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, the solvent was removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 30:1) to give product 9, with a yield of 49%.

[0069] 1 H NMR (400 MHz, CDCl3): δ 8.84 (s, 1H), 7.85 (dd, J = 11.8, 1.8 Hz,1H), 5.46 (s, 1H), 3.92 (s, 3H), 1.68 (q, J = 4.6 Hz, 2H), 1.40 (s, 9H), 1.29(q, J = 4.6 Hz, 2H) ppm; 13 C NMR (100 MHz, CDCl3): δ 164.7 (d, J = 1.6 Hz), 158.7, 156.1 (d, J = 13.9 Hz), 153.9 (d, J = 7.2 Hz), 145.3 (d, J = 5.4 Hz), 125.3 (d, J = 3.6 Hz), 124.2 (d, J = 22.1 Hz), 79.8, 52.4, 35.5, 28.2, 18.5ppm; 19 F NMR (376 MHz, CDCl3): δ -126.00, -117.83 ppm; [M + H] + m / z 311.1402, found 311.1400; MP: 109.7-111.2 o C.

[0070] Example 10

[0071] Synthesis of Compound 10

[0072] In an air-filled reaction flask, ferrous phosphate (0.05 mmol), N-acetyltryptophan (0.15 mmol), substrate 10a (0.5 mmol), ethylene glycol dimethyl ether (2.0 mL), N-Boc-cyclopropylamine (1.55 mmol), and sodium peroxymonosulfate (2.7 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was heated to 100 mL. o The reaction was carried out at C for 3 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, washed with water (5 mL × 3), collected, and separated by column chromatography (petroleum ether: diethyl ether V / V = 20:1) after removing the solvent under reduced pressure to obtain product 10 with a yield of 51%.

[0073] 1 H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 7.73 (s, 1H), 5.37 (s, 1H), 3.94 (s, 3H), 1.61 (q, J = 4.6 Hz, 2H), 1.47 (s, 9H), 1.26 (q, J = 4.6 Hz,2H) ppm; 13 C NMR (100 MHz, CDCl3): δ 164.7, 161.2, 155.6, 150.5, 136.4, 126.7,119.9, 80.1, 52.7, 36.4, 28.2, 20.0 ppm; [M + H] + m / z 327.1106, found327.1105; MP: 99.3-101.5 o C.

[0074] Example 11

[0075] Synthesis of Compound 11

[0076] In an air-filled reaction flask, ferrous ammonium sulfate (0.04 mmol), ortholeucine (0.068 mmol), substrate 11a (0.5 mmol), isopropyl acetate (1.5 mL), N-Boc-cyclopropylamine (1.8 mmol), and sodium superphosphate (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 120 °C. o The reaction was carried out at C for 1 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, washed with water (5 mL × 3), collected, and separated by column chromatography (petroleum ether: dichloromethane V / V = 10:4) after removing the solvent under reduced pressure to obtain product 11 with a yield of 72%.

[0077] 1 H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.43 (s, 1H), 2.08 (s, 1H), 1.51 (q, J = 4.3 Hz, 2H), 1.42 (s, 9H), 1.25 (q,J = 4.3 Hz, 2H) ppm; 13C NMR (100 MHz, DMSO-d6): δ 168.6, 156.2, 149.1, 141.3,134.4, 121.4, 79.0, 36.9, 28.5, 20.7 ppm; [M + H] + m / z 348.0780, found348.0781; MP: 229.3-231.1 o C.

[0078] Example 12

[0079] Synthesis of Compound 12

[0080] In an air-filled reaction flask, ferrous oxalate (0.02 mmol), homocysteine ​​(0.28 mmol), substrate 12a (0.5 mmol), benzene (1.5 mL), water (0.5 mL), N-Boc-cyclopropylamine (2.1 mmol), and hydrogen peroxide (1.75 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was heated to 95 °C. o The reaction was carried out at 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 removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 30:1) to give product 12, with a yield of 54%.

[0081] 1 H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 8.46 (s, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 1.71 (q, J = 5.0 Hz, 2H), 1.31 (s, 9H), 1.25 (q, J = 5.0 Hz,2H) ppm; 13 C NMR (100 MHz, CDCl3): δ 167.8, 164.9, 164.8, 155.0, 151.4, 138.4,125.8, 123.2, 79.6, 52.8, 52.3, 37.1, 28.1, 18.2 ppm; [M + H] + m / z 264.1343, found 264.1342; MP: 90.3.1-91.7 o C.

[0082] Example 13

[0083] Synthesis of Compound 13

[0084] In a 25 mL reaction flask, ferrous chloride (0.035 mmol), N-fluorenemethoxycarbonyl-L-lysine (0.02 mmol), substrate 13a (0.5 mmol), triethylamine (1.8 mL), water (0.3 mL), N-Boc-cyclopropylamine (1.8 mmol), and ammonium persulfate (1.1 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 70 °C. o The reaction was carried out at C for 3 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 removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 20:1) to give product 13, with a yield of 56%.

[0085] 1 H NMR (400 MHz, CDCl3): δ 9.14 (s, 1H), 9.07 (d, J = 5.3 Hz, 2H), 7.37 (dd, J = 5.3, 2.4 Hz, 2H), 6.39 (d, J = 9.2 Hz, 1H), 4.05 (dtd, J =16.5, 9.1, 7.3 Hz, 1H), 3.18 (ddd, J = 17.5, 9.9, 7.4 Hz, 1H), 2.97 (s, 3H), 2.90 (qd, J = 7.7, 3.8 Hz, 2H), 2.29 (qd, J = 9.2, 2.8 Hz, 2H) ppm; 13 C NMR (100 MHz, CDCl3): δ 151.1, 150.9, 143.4, 124.6, 44.4, 41.4, 38.1, 30.0 ppm; [M + H] + m / z 179.0815, found 179.0815; MP: 145.2-146.7 o C.

[0086] Example 14

[0087] Synthesis of Compound 14

[0088] In an air-filled reaction flask, ferric chloride (0.165 mmol), L-cysteine ​​(0.37 mmol), substrate 14a (0.5 mmol), acetone (2.0 mL), water (0.5 mL), N-Boc-cyclopropylamine (2 mmol), and potassium persulfate complex salt (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was heated to 50 °C. oThe reaction was carried out at C for 12 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 removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 20:1) to give product 14, with a yield of 37%.

[0089] 1 H NMR (400 MHz, CDCl3): δ 8.89 (d, J = 9.1 Hz, 1H), 8.23 ​​(dd, J =17.6, 8.1 Hz, 2H), 7.97-7.61 (m, 2H), 5.52 (s, 1H), 1.82 (q, J = 4.5 Hz, 2H),1.50 (s, 9H), 1.41 (q, J = 4.5 Hz, 2H) ppm; 13 C NMR (100 MHz, CDCl3): δ 164.2,155.9, 147.9, 145.3, 136.1, 131.8, 127.1, 123.5, 120.3, 119.2, 80.0, 37.2,28.3, 20.7 ppm; [M + H] + m / z 330.1449, found 330.1449; MP: 104.1-106.3 o C.

[0090] Example 15

[0091] Synthesis of Compound 15

[0092] In a nitrogen atmosphere at atmospheric pressure, ferric perchlorate (0.055 mmol), N-Boc-L-leucine (0.065 mmol), substrate 15a (0.5 mmol), cyclohexanone (1.7 mL), and water (0.3 mL), N-Boc-cyclopropylamine (2 mmol), and peracetic acid (1.85 mmol) were added sequentially to a reaction flask. After thorough mixing at room temperature, the reaction mixture was incubated at 65°C. o The reaction was carried out at C for 8 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 removed under reduced pressure, and the product was separated by column chromatography (petroleum ether: ethyl acetate V / V = 15:1) to give product 15, with a yield of 45%.

[0093] 1H NMR (400 MHz, CDCl3): δ 9.43 (s, 1H), 8.23-7.73 (m, 4H), 5.66 (s, 1H), 1.71-1.46 (m, 4H), 1.32 (s, 9H) ppm; 13 C NMR (100 MHz, CDCl3): δ 159.6,154.8, 151.2, 132.4, 132.1, 127.1, 126.5, 126.08, 125.6, 79.6, 35.2, 28.1,14.9 ppm; [M + H] + m / z 286.1550, found 286.1548; MP: 206.9-207.3 o C.

[0094] Example 16

[0095] Synthesis of Compound 16

[0096] In an air-filled reaction flask, potassium ferricyanide (0.055 mmol), aspartic acid (0.3 mmol), substrate 16a (0.5 mmol), methyl tert-butyl ether (2.0 mL), water (1.0 mL), N-Boc-cyclopropylamine (2.8 mmol), and tert-butyl hydroperoxide (2.3 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 75°C. o The reaction was carried out at C for 1 h. 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 removed under reduced pressure, and the product was separated by column chromatography (petroleum ether: ethyl acetate V / V = 5:1) to give product 16 with a yield of 80%. CAS: 1333968-80-1.

[0097] 1 H NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 8.99 (d, J = 1.5 Hz, 1H), 7.42 - 7.37 (m, 1H), 1.57 - 1.52 (m, 2H), 1.22 - 1.16 (m, 2H) ppm. 13 C NMR (100 MHz, CDCl3): δ 150.3, 147.5, 146.5, 121.2, 53.2, 20.7 ppm.

[0098] Example 17

[0099] Synthesis of Compound 17

[0100] In an air-filled reaction flask, potassium tris(oxalato)ferrate (0.1 mmol), L-citrulline (0.08 mmol), substrate 16a (0.5 mmol), diisopropyl ether (2.0 mL), water (1.5 mL), cyclopropanol (2 mmol), and benzoyl peroxide (1.25 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was heated to 100 °C. o The reaction was carried out at C for 4 h. 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 removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 10:7) to give product 17 with a yield of 61%.

[0101] 1 H NMR (400 MHz, CDCl3): δ 8.95 (d, J = 5.6 Hz, 1H), 8.88 (s, 1H), 7.14 (d, J = 5.6 Hz, 1H), 5.91 (s, 1H), 1.45 (t, J = 7.2 Hz, 2H), 1.40 (s,9H), 1.30 (d, J = 7.2 Hz, 2H) ppm. 13 C NMR (100 MHz, CDCl3): δ 155.4, 150.3, 148.0, 144.1, 121.4, 80.1, 32.5, 28.1, 20.5 ppm.

[0102] Example 18

[0103] Synthesis of Compound 18

[0104] In an air-filled reaction flask, ferric thiocyanate (0.1 mmol), S-adenosylmethionine (0.15 mmol), substrate 16a (0.5 mmol), n-butanol (1.8 mL), water (0.5 mL), cyclopropylacetic acid (1.5 mmol), and peroxybenzoic acid (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 95°C. o The reaction was carried out at C for 7 h. After the reaction was completed, the product 18 was obtained by direct chromatography (dichloromethane:methanol V / V = 15:1), with a yield of 41%.

[0105] 1H NMR (400 MHz, CDCl3): δ 9.07 (s, 1H), 9.00 (d, J = 5.4 Hz, 1H), 7.16 (dd, J = 5.6, 2.4 Hz, 1H), 2.66 (dd, J = 16.5, 6.0 Hz, 1H), 2.35 (dd, J= 16.5, 8.0 Hz, 1H), 1.81 (dt, J = 9.1, 4.9 Hz, 1H), 1.55 (dddt, J = 8.2,6.3, 4.0, 2.0 Hz, 1H), 1.23-1.20 (m, 1H), 1.18-1.14 (m, 1H)ppm; 13 C NMR (100MHz, CDCl3): δ 175.4, 150.7, 150.3, 144.5, 123.2, 38.2, 20.8, 20.1, 16.5 ppm; [M + H] + m / z 179.0815, found 179.0815; MP: 125.1-126.7 o C.

[0106] Example 19

[0107] Synthesis of Compound 19

[0108] In an air-filled reaction flask, ferrocene (0.08 mmol), N-Boc-D-phenylalanine (0.15 mmol), substrate 16a (0.5 mmol), xylene (1.5 mL), water (1.5 mL), cyclobutyric acid (1.75 mmol), and mono-tert-butyl maleate peroxide (1.55 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was heated to 105 °C. o The reaction was carried out at C for 2 h. After the reaction was completed, the product 19 was obtained by direct chromatography (dichloromethane:methanol V / V = 10:1) with a yield of 65%.

[0109] 1H NMR (400 MHz, DMSO-d6): δ 12.33 (s, 1H), 9.17 (s, 1H, minor), 9.12 (dd, J = 8.2, 4.4 Hz, 2H), 7.60 (ddt, J = 7.7, 5.2, 2.6 Hz, 1H), 7.54 (dt, 3.23-3.01 (m, 1H), 2.70-2.50 (m, 2H), 2.48-2.34 (m, 1H, minor), 2.26 (qd, J = 9.6, 2.5 Hz, 2H,minor), 2.22-2.13 (m, 1H, minor), 2.08 (qd, J = 11.3, 10.6, 5.9 Hz, 2H,minor) ppm; 13 C NMR (100 MHz, DMSO-d6): δ 176.9, 175.9, 175.2, 151.7 (d, J =4.6 Hz), 151.58 (d, J = 2.4 Hz), 144.7, 144.2, 143.1, 124.9, 124.7, 43.8,35.6, 34.6, 34.1, 33.8, 32.1, 31.82-31.33 (m), 31.04-30.38 (m), 24.3, 22.0ppm; [M + H] + m / z 179.0815, found 179.0815.

[0110] Example 20

[0111] Synthesis of Compound 20

[0112] In an air-filled reaction flask, ferric acetylacetone (0.06 mmol), N-acetyl-L-cysteine ​​(0.13 mmol), substrate 16a (0.5 mmol), ethylbenzene (0.5 mL), water (1.5 mL), cyclobutanedione (1.65 mmol), and tetrabutylammonium persulfate (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 120 °C. oThe reaction was carried out at C for 1 h. After the reaction was completed, 5 mL of water was added and the mixture was extracted with diethyl ether (5 mL × 3). The organic phases were combined, the solvent was removed under reduced pressure, and the product was separated by column chromatography (dichloromethane:methanol V / V = 30:1) to give product 20, with a yield of 84%.

[0113] 1 H NMR (400 MHz, CDCl3): δ 9.16 - 8.41 (m, 2H), 7.29 (ddd, J = 15.3,7.1, 4.0 Hz, 1H), 3.89 (dt, J = 15.5, 8.3 Hz, 0.5H), 3.70-3.44 (m, 0.5H),3.18 (td, J = 10.9, 10.5, 7.5 Hz, 1H), 2.81 (td, J = 16.0, 12.6, 7.3 Hz, 2H), 2.67-2.35 (m, 3H) ppm; 13 C NMR (100 MHz, CDCl3): δ 150.9 (d, J = 8.0 Hz),150.4, 141.9, 141.5, 124.5, 123.5 (d, J = 4.2 Hz), 121.9, 120.7, 38.1, 34.3,33.8, 32.8, 31.6, 24.4, 23.1, 19.7, 18.2 ppm;

[0114] 1 H NMR (400 MHz, CDCl3): δ 9.14 (d, J = 5.3 Hz, 1H), 9.09 (s, 1H), 7.32 (dd, J = 5.4, 2.5 Hz, 1H), 3.88 (td, J = 10.1, 7.8 Hz, 1H), 3.34 - 3.10(m, 1H), 2.72 - 2.38 (m, 3H), 2.38-2.23 (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 151.0, 149.9, 139.9, 123.4, 119.8, 41.5, 27.9, 25.4, 23.5 ppm; [M + H] + m / z160.0869, found 160.0868.

[0115] Example 21

[0116] Synthesis of Compound 21

[0117] In an air-filled reaction flask, ferrous sulfide (0.045 mmol), β-thiovaline (0.35 mmol), substrate 16a (0.5 mmol), cumene (1.0 mL), water (1.0 mL), bicyclo[1.1.1]pentane-1-carboxylic acid (1.55 mmol), and sodium peroxymonosulfate (3 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 85°C. o The reaction was carried out at C for 5 h. After the reaction was completed, the product 21 was obtained by direct chromatography (petroleum ether: ethyl acetate V / V = 10:3), with a yield of 38%.

[0118] 1 H NMR (400 MHz, DMSO-d6): δ 9.21-9.10 (m, 2H), 7.65 (d, J = 3.4 Hz,1H), 2.36 (s, 3H), 2.32 (s, 3H) ppm; 13 C NMR (100 MHz, DMSO-d6): δ 171.0,170.8, 160.0, 151.2, 150.5, 150.2, 138.3, 127.0, 124.8, 124.2, 52.6, 52.5,40.6, 38.2, 37.6, 37.6ppm;

[0119] 1 H NMR (400 MHz, DMSO-d6): δ 9.25-9.06 (m, 2H), 7.56 (dd, J = 5.7, 2.3Hz, 1H), 3.62 (d, J = 6.6 Hz, 2H), 2.90 (s, 1H), 2.12 (d, J = 1.6 Hz, 1H),2.10 (d, J = 1.7 Hz, 1H), 2.08-2.02 (m, 1H) ppm; 13 C NMR (101 MHz, DMSO-d6): δ169.8, 152.3, 151.0, 138.1, 126.6, 60.6, 49.1, 47.47, 45.5, 30.1ppm; [M + H] + m / z 191.0815, found 191.0812.

[0120] Example 22

[0121] Synthesis of Compound 22

[0122] In an air-filled reaction flask, ferric fluoride (0.075 mmol), N,N'-bis(tert-butyloxycarbonyl)-L-cysteine ​​(0.12 mmol), substrate 16a (0.5 mmol), chlorobenzene (0.5 mL), and water (2.0 mL), N-methanesulfonylcyclobutylamine (CAS: 1075233-88-3) (1.3 mmol), and sodium superphosphate (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 75°C. o The reaction was carried out at C for 5 h. After the reaction was completed, the product 22 was obtained by direct chromatography (dichloromethane:methanol V / V = 30:1) with a yield of 63%.

[0123] 1 H NMR (400 MHz, CDCl3): δ 9.26 (s, 1H), 9.21 (d, J = 5.4 Hz, 1H), 7.59 (dd, J = 5.4, 2.3 Hz, 1H), 5.35 (t, J = 8.6 Hz, 1H), 4.19 (q, J = 8.6Hz, 1H), 3.83 (ddd, J = 9.0, 7.6, 3.7 Hz, 1H), 2.88 (s, 3H), 2.69 (dtd, J =11.1, 9.0, 3.7 Hz, 1H), 2.30 (dq, J = 11.1, 8.6 Hz, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 151.3, 149.5, 139.8, 123.5, 60.5, 47.3, 37.8, 24.0 ppm; [M + H] + m / z214.0645, found 214.0644.

[0124] Example 23

[0125] Synthesis of Compound 23

[0126] 2-azaspiro[3.3]heptane hydrochloride (CAS: 1420271-08-4, 2 mmol, 275.5 mg) and sodium bicarbonate (2 mmol, 1 equiv, 169.8 mg) were added to a flask. 10 mL of dichloromethane was added and stirred for ten minutes. Then, triethylamine (2 equiv, 4 mmol, 0.56 mL) was added and stirred until homogeneous. Methanesulfonic anhydride (1.2 equiv, 2.4 mmol, 430 mg) was added under an ice-water bath. The mixture was stirred overnight at room temperature. After the reaction was completed by TLC monitoring, the reaction solution was washed with dilute hydrochloric acid and saturated sodium bicarbonate solution. Finally, the reaction solution was extracted with saturated sodium chloride solution. The organic solvent was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product N-methanesulfonyl-2-azaspiro[3.3]heptane.

[0127] N-Methanesulfonyl-2-azaspiro[3.3]heptane: 1 H NMR (400 MHz, CDCl3) δ 3.46 (d, J =1.6 Hz, 2H), 3.35 (d, J = 1.8 Hz, 2H), 2.78 (s, 3H), 1.63 - 1.47 (m, 6H).

[0128] In air, sodium ferrate (0.05 mmol), ortholeucine (0.15 mmol), substrate 16a (0.5 mmol), diethyl ether (5.0 mL), N-methanesulfonyl-2-azaspiro[3.3]heptane (1.4 mmol), and hydrogen peroxide (1.35 mmol) were added sequentially to the reaction flask. After thorough mixing at room temperature, the reaction mixture was incubated at 25°C. o The reaction was carried out at C for 6 h. After the reaction was completed, the product 23 was obtained by direct chromatography (petroleum ether: ethyl acetate V / V = 10:1), with a yield of 57%.

[0129] 1 H NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 8.68 (d, J = 4.9 Hz, 0.2H), 8.58 (d, J = 5.1 Hz, 0.8H), 7.17 (d, J = 5.3 Hz, 0.8H), 7.13 (t, J = 4.9 Hz,0.2H), 4.33 (h, J = 7.0, 6.0 Hz, 1H), 3.14 - 3.02 (m, 1H), 2.80 (ddt, J =12.5, 10.0, 7.0 Hz, 2H), 2.24 (dddd, J = 12.4, 9.4, 6.3, 2.6 Hz, 2H) ppm;13 CNMR (100 MHz, CDCl3): δ 171.9, 158.6, 156.9, 156.7, 119.4, 118.5, 64.1, 63.7,39.3, 39.1, 34.4, 32.5 ppm; [M + H] + m / z 151.0866, found 151.0865.

[0130] Example 24

[0131] Synthesis of Compound 24

[0132] In a 25 mL reaction flask, ferrous carbonate (0.08 mmol), homocysteine ​​(0.2 mmol), substrate 17a (0.5 mmol), dimethyl carbonate (3.0 mL), cyclobutanol (1.7 mmol), and ammonium persulfate (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 60 °C. o The reaction was carried out at C for 3 h. After the reaction was completed, the product 24 was obtained by direct chromatography (dichloromethane:methanol V / V = 50:1) with a yield of 65%.

[0133] 1 H NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 8.68 (d, J = 4.9 Hz, 0.2H), 8.58 (d, J = 5.1 Hz, 0.8H), 7.17 (d, J = 5.3 Hz, 0.8H), 7.13 (t, J = 4.9 Hz,0.2H), 4.33 (h, J = 7.0, 6.0 Hz, 1H), 3.14-3.02 (m, 1H), 2.80 (ddt, J = 12.5,10.0, 7.0 Hz, 2H), 2.24 (dddd, J = 12.4, 9.4, 6.3, 2.6 Hz, 2H) ppm; 13 C NMR (100 MHz, CDCl3): δ 171.9, 158.6, 156.9, 156.7, 119.4, 118.5, 64.1, 63.7,39.3, 39.1, 34.4, 32.5 ppm; [M + H] + m / z 151.0866, found 151.0865.

[0134] Example 25

[0135] Synthesis of Compound 25

[0136] In an air-filled reaction flask, ferrous phosphate (0.1 mmol), N-Boc-L-proline (0.25 mmol), substrate 18a (0.5 mmol), N,N-dimethylacetamide (2.0 mL), water (2.0 mL), 1-methylcyclobutanol (0.85 mmol), and potassium persulfate complex salt (2.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 45°C. o The reaction was carried out at C for 7 hours. After the reaction was completed, the product 25 was obtained by direct chromatography (petroleum ether: ethyl acetate V / V = 10:1), with a yield of 44%.

[0137] 1 H NMR (400 MHz, CDCl3): δ 8.55 (dd, J = 2.6, 1.5 Hz, 1H), 8.53 (t, J= 2.1 Hz, 1H, minor), 8.46 (d, J = 1.5 Hz, 1H), 8.44 (s, 1H, minor), 8.43 (d,J = 2.3 Hz, 2H), 8.38 (d, J = 2.6 Hz, 1H, minor), 3.83 (p, J = 8.5 Hz, 1H, minor)), 3.34-3.22 (m, 1H), 2.64-2.56 (m, 2H), 2.53-2.44 (m, 4H, minor),2.41-2.22 (m, 2H, minor), 1.47 (s, 3H), 1.42 (s, 3H, minor) ppm; 13 C NMR (100MHz, CDCl3): δ 159.6, 144.0 (minor), 144.0, 143.9, 143.7 (minor), 142.5,142.1 (minor), 72.28 (minor), 70.1, 44.0, 41.9 (minor), 31.4 (minor), 30.1,29.1 (minor), 27.2 ppm; [M + H] + m / z 165.1023, found 165.1022.

[0138] Example 26

[0139] Synthesis of Compound 26

[0140] In an air-filled reaction flask, ferrous ammonium sulfate (0.15 mmol), N-fluorenemethoxycarbonyl-L-lysine (0.15 mmol), substrate 19a (0.5 mmol), diisopropyl ether (1.0 mL), water (3.0 mL), cyclobutanol (1 mmol), and peracetic acid (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 60 °C. o The reaction was carried out at C for 10 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, washed with water (5 mL × 3), collected, and separated by column chromatography (petroleum ether: dichloromethane V / V = 15:1) after removing the solvent under reduced pressure to obtain product 26 with a yield of 47%.

[0141] 1 H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 2.6 Hz, 1H), 8.28-8.21 (m,2H), 4.32 (dp, J = 8.6, 7.0 Hz, 1.5H), 3.38-3.20 (m, 1H), 3.14 (q, J = 8.2Hz, 0.5H), 2.77 (dddp, J = 11.9, 7.1, 4.9, 2.5 Hz, 3H), 2.54 (s, 1.5H), 2.51(s, 3H), 2.38-2.16 (m, 3H) ppm; 13 C NMR (100 MHz, CDCl3): δ 157.6, 156.7,153.1, 151.9, 142.0, 141.3, 141.0, 140.2, 64.1, 63.7, 39.4, 38.3, 38.1, 30.6,29.0, 21.5, 21.5 ppm; [M + H] + m / z 165.1023, found 165.1024.

[0142] Example 27

[0143] Synthesis of Compound 27

[0144] In a 25 mL reaction flask, ferrous oxalate (0.05 mmol), L-cysteine ​​(0.1 mmol), substrate 20a (0.5 mmol), acetone (1.0 mL), water (3.0 mL), cyclobutanol (2 mmol), and tert-butyl hydroperoxide (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was heated to 100 mL. oThe reaction was carried out at C for 4 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 removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 4:1) to give product 27, with a yield of 64%.

[0145] 1 H NMR (400 MHz, CDCl3): δ 3.85 (s, 3H), 2.70 (s, 3H), 2.63 (ddd, J =13.4, 8.7, 5.2 Hz, 2H), 2.45 (tdd, J = 9.6, 7.7, 2.6 Hz, 2H), 2.12-1.87 (m,2H) ppm; 13 C NMR (100 MHz, CDCl3): δ 179.6, 162.7, 160.0, 121.4, 76.4, 52.1,37.8, 17.3, 12.7 ppm; [M + H] + m / z 228.0689, found 228.0686; MP: 99.1-101.3 o C.

[0146] Example 28

[0147] Synthesis of Compound 28

[0148] In a 25 mL reaction flask, ferrous chloride (0.08 mmol), N-Boc-glycine-glycine-glycine (0.1 mmol), substrate 21a (0.5 mmol), acetonitrile (2.0 mL), water (2.0 mL), cyclobutanol (1.5 mmol), and benzoyl peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 90 °C. o The reaction was carried out at 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 removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 10:1) to give product 28, with a yield of 62%.

[0149] 1H NMR (400 MHz, CDCl3): δ 3.79 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 6.4Hz, 2H), 2.57 (ddd, J = 13.3, 8.7, 5.1 Hz, 2H), 2.49-2.35 (m, 2H), 2.31 (s,3H), 2.08-1.93 (m, 1H), 1.85 (dp, J = 11.7, 8.4 Hz, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 173.3, 148.1, 127.7, 75.9, 62.7, 37.6, 29.7, 14.8, 12.8 ppm; [M +H] + m / z 214.0896, found 214.0897; MP: 75.8-77.3 o C.

[0150] Example 29

[0151] Synthesis of Compound 29

[0152] In an air-filled reaction flask, ferric chloride (0.08 mmol), N-acetyltryptophan (0.1 mmol), substrate 22a (0.5 mmol), toluene (2.0 mL), water (2.0 mL), cyclobutanol (1.5 mmol), and peroxybenzoic acid (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 75°C. o The reaction was carried out at C for 10 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 removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 20:1) to give product 29, with a yield of 47%, CAS: 2930060-03-8.

[0153] 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.0Hz, 1H), 7.47 (ddd, J = 8.2, 7.1, 1.3 Hz, 1H), 7.37 (ddd, J = 8.4, 7.3, 1.2Hz, 1H), 2.76 (dddd, J = 10.0, 8.5, 5.6, 2.8 Hz, 2H), 2.54 (tdd, J = 9.4,8.3, 3.0 Hz, 2H), 2.18 - 2.01 (m, 2H) ppm. 13 C NMR (100 MHz, CDCl3): δ 177.7,152.7, 135.1, 126.0, 124.9, 122.8, 121.7, 76.6, 37.8, 12.7 ppm. (Chin. J.Org. Chem. 2022, 42, 1493-1500)

[0154] Example 30

[0155] Synthesis of Compound 30

[0156] In a 25 mL reaction flask, ferric perchlorate (0.06 mmol), N-Boc-L-leucine (0.2 mmol), substrate 23a (0.5 mmol), dimethyl sulfoxide (2.0 mL), and water (2.0 mL), N-Boc-cyclopropylamine (1.75 mmol), and mono-tert-butyl maleate peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 25 °C. o The reaction was carried out at C for 8 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 removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 40:1) to give product 30, with a yield of 58%.

[0157] 1H NMR (400 MHz, CDCl3): δ 9.26 (d, J = 2.1 Hz, 1H), 8.39 (dd, J =8.3, 2.2 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 5.47 (s, 1H), 2.62 (t, J = 6.8Hz, 2H), 2.12 (s, 3H), 2.04 (s, 3H), 2.00 (s, 3H), 1.84 (dt, J = 14.1, 7.2Hz, 2H), 1.76 (q, J = 4.6 Hz, 2H), 1.58-1.53 (m, 2H), 1.49 (s, 9H), 1.46 -1.34 (m, 5H), 1.31-1.21 (m, 16H), 1.20-1.13 (m, 2H), 1.12 - 1.05 (m, 2H),0.86 (t, J = 6.7 Hz, 12H) ppm; 13 C NMR (100 MHz, CDCl3): δ 167.4, 164.0,155.7, 150.9, 149.5, 140.3, 137.7, 126.7, 125.0, 123.1, 122.3, 118.6, 117.4,80.0, 75.0, 60.3, 39.3, 37.5, 37.4, 37.3, 37.2, 32.7, 32.7, 32.6, 28.3, 27.9,24.7, 24.4, 24.1, 23.6, 22.6, 22.5, 21.0, 20.5, 19.7, 19.6, 19.6, 19.6, 19.5,14.1, 12.9, 12.1, 11.8 ppm.

[0158] 1H NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 8.77 (d, J = 5.1 Hz, 1H), 7.75 - 7.69 (m, 1H), 6.16 (s, 1H), 2.65 (t, J = 6.8 Hz, 2H), 2.15 (s, 3H),2.12 (s, 3H), 2.08 (s, 3H), 1.83 (td, J = 13.0, 12.5, 6.3 Hz, 2H), 1.66 -1.55 (m, 2H), 1.56 - 1.49 (m, 2H), 1.48- 1.44 (m, 1H), 1.33 (s, 9H), 1.27(t, J = 5.6 Hz, 16H), 1.18 - 1.03 (m, 8H), 0.86 (t, J = 6.5 Hz, 12H) ppm; 13 CNMR (100 MHz, CDCl3): δ 164.7, 155.4, 153.5, 152.2, 151.8, 149.8, 140.1,126.6, 125.9, 125.2, 124.9, 123.4, 117.6, 79.3, 75.2, 40.6, 39.3, 37.5, 37.4,37.3, 37.2, 34.0, 32.7, 32.6, 28.2, 27.9, 24.7, 24.4, 24.2, 23.6, 22.6, 22.6,21.0, 20.6, 19.7, 19.6, 19.6, 19.6, 19.5, 15.2, 13.1, 12.2, 11.8 ppm; [M + H] + m / z 691.5045, found 691.5045

[0159] The structural formulas of the raw materials and products in Examples 1-30 and the corresponding experimental results are shown in Table 1 below:

[0160] Table 1 .

[0161] Example 31

[0162] Example 31 uses the same method as Example 16, except that the solvent is acetonitrile and water, and the volume ratio of organic solvent to water is 1:1.

[0163] Example 32

[0164] Example 32 uses the same method as Example 16, except that the reaction temperature is 85 °C and the reaction time is 5 hours.

[0165] Example 33

[0166] Example 33 uses the same method as Example 16, except that the solvent is entirely water and the total volume remains unchanged.

[0167] Comparative Example 1

[0168] Comparative Example 1 uses the same method as Example 16, except that no iron catalyst is added and the yield of the target product is 0.

[0169] Comparative Example 2

[0170] Comparative Example 2 uses the same method as Example 16, except that no amino acid ligands are added, which greatly reduces the reaction yield to less than 10%.

[0171] Comparative Example 3

[0172] Comparative Example 3 uses the same method as Example 16, except that no oxidant is added and the yield of the target product is 0.

[0173] Comparative Example 4

[0174] Comparative Example 4 uses the same method as Example 16, except that a non-amino acid ligand 1,10-phenanthroline is used, and the yield is only 6%.

[0175] Comparative Example 5

[0176] Comparative Example 5 uses the same method as Example 16, except that porphyrin iron is used as a catalyst and the yield of the target product is 0.

[0177] Comparative Example 6

[0178] Comparative Example 6 uses the same method as Example 16, except that potassium permanganate is used as the oxidant and the yield of the target product is only 12%.

[0179] Comparative Example 7

[0180] Comparative Example 7 uses the same method as Example 16, except that the heteroarylating agent used is triazole, and the yield of the target product is only 4%.

[0181] Comparative Example 8

[0182] Comparative Example 8 uses the same method as Example 16, except that the heteroarylating agent used is indole, and the yield of the target product is only 7%.

[0183] Comparative Example 9

[0184] Comparative Example 9 uses the same method as Example 16, except that the heteroarylating agent used is benzotriazole, and the yield of the target product is only 2%.

[0185] 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 species, thereby facilitating the smooth progress of the reaction and improving selectivity. Amino acid ligands are promoters of methylation reactions, 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 oxidants. The activation of carbon-hydrogen bonds occurs on strained ring substrates, while various substituents on the structure of heteroaromatic 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. An iron-catalyzed strain ring C(sp) 3 The method for H-heteroarylation is characterized by, The process includes the following steps: using a strained ring compound as a substrate, a heteroaromatic compound as an arylating agent, a peroxide as an oxidant, iron as a catalyst, and an amino acid or its derivative as a ligand, the C(sp) group of the strained ring compound is oxidized in a solvent. 3 The -H bond undergoes a heteroaromatic reaction to generate a heteroaryl-substituted strained ring compound; The general formula for the reaction is as follows: ； The R 1 R represents a substituent on a heterocyclic aromatic compound; 2 The term "n" indicates a substituent on a strained ring compound, where n is not equal to 1 or 2 when the strained ring compound is a spirocyclic or bicyclic compound.

2. The iron-catalyzed strain ring C(sp) according to claim 1 3 The method for H-heteroarylation is characterized by, The heterocyclic compound is pyridine, pyrazine, pyridazine, pyrimidine, quinoline, thiazole, benzothiazole or 2,3-diazanaphthalene; the strained ring is cyclopropane, cyclobutane, cyclopropanol, cyclobutanol, N-heterocyclic butane, spiroheptane or bicyclopentane.

3. The iron-catalyzed strain ring C(sp) according to claim 1 3 The method for H-heteroarylation is characterized by, The R 1 It can be hydrogen, halogen, methyl, ester, acetyl, cyano, trifluoromethyl, nitro, ester, acetamino, N,N-diethylacetamino, sulfonamide, ethanol, or tocopherol ester.

4. The iron-catalyzed strain ring C(sp) according to claim 1 3 The method for H-heteroarylation is characterized by, The R 2 It can be hydrogen, N-tert-butoxycarbonyl, hydroxyl, N-methanesulfonyl, methyl, carboxyl, ester, cyano, or acetyl.

5. The iron-catalyzed strain ring C(sp) according to claim 1 3 The method of )-H heteroarylation is characterized by The iron is selected from any one or more of potassium ferricyanide, potassium trioxalatoferrate, ferric thiocyanate, ferrocene, ferric acetylacetone, ferrous sulfide, ferric fluoride, sodium ferrite, ferrous carbonate, ferrous phosphate, ferrous ammonium sulfate, ferrous oxalate, ferrous carbonate, ferrous chloride, ferric chloride, ferrous oxalate, and ferric perchlorate.

6. The iron-catalyzed strain ring C(sp) according to claim 1 3 The method for H-heteroarylation is characterized by, The ligand is selected from any one or more of L-cysteine, N-acetyl-L-cysteine, β-thiovaline, aspartic acid, N-Boc-L-leucine, N-Boc-L-proline, N-Boc-D-phenylalanine, N-Boc0-glycine-glycine, N,N'-bis(tert-butoxycarbonyl)-L-cysteine, N-Boc-L-leucine, L-citrulline, S-adenosylmethionine, N-acetyltryptophan, leucine, homocysteine, or N-fluorenemethoxycarbonyl-L-lysine.

7. The iron-catalyzed strain ring C(sp) according to claim 1 3 The method for H-heteroarylation is characterized by, The oxidant is selected from any one or more of peracetic acid, tert-butyl hydroperoxide, benzoyl peroxide, perbenzoic acid, monotert-butyl maleate peroxide, tetrabutylammonium persulfate, potassium monopersulfate complex salt, sodium persulfate, hydrogen peroxide, sodium superphosphate, and ammonium persulfate.

8. The iron-catalyzed strain ring C(sp) according to claim 1 3 The method for H-heteroarylation is characterized by, The solvent is an organic solvent, water, or an aqueous solution of an organic solvent. The organic solvent is selected from diethyl ether, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, diisopropyl ether, ethylene glycol dimethyl ether, acetone, butanone, cyclohexanone, dimethyl carbonate, isopropyl acetate, isopropanol, n-butanol, cyclohexane, benzene, toluene, xylene, ethylbenzene, cumene, chlorobenzene, 1,2-dichloroethane, pyridine, N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, triethylamine, or carbon tetrachloride. When the solvent is an aqueous solution of an organic solvent, the volume ratio of the organic solvent to water is 1:(0.5-20).

9. The iron-catalyzed strain ring C(sp) according to claim 1 3 The method for H-heteroarylation is characterized by, The molar ratio of the heterocyclic aromatic compounds, strained ring compounds, peroxides, amino acids or their derivatives, and iron catalysts is 1:(2.5-40):(1-50):(0.005-30):(0.002-15).

10. The iron-catalyzed strain ring C(sp) according to claim 1 3 The method for H-heteroarylation is characterized by, The reaction temperature is 25-110℃ and the time is 0.5-12 hours.

Images