Method for synthesizing cis-allylamine compound through iron photocatalysis

Abstract

The invention belongs to the technical field of chemical synthesis, and relates to the technical field of synthesis of allylamine drug intermediates, in particular to a method for synthesizing cis-allylamine compounds through iron photocatalysis. In order to develop a simple, convenient and green photocatalytic technology for preparing the cis-allylamine compound, aryl-terminated alkyne or a derivative thereof and amino acid are used as raw materials, a one-pot reaction is carried out under purple light irradiation through iron catalysis, the corresponding Z-selective olefin compound can be obtained, the method is mild in reaction condition, simple to operate and high in cis-selectivity, and the method is suitable for industrial production. A catalytic system which is low in cost, green and good in biocompatibility is used, and the concept of green chemistry is met. In addition, the photocatalytic technology provided by the invention provides a green and efficient innovative approach for synthesis of cis-allylamine drugs.

Description

A method for synthesizing cis-allylamine compounds via iron photocatalysis Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically the field of synthesis technology of allylamine drug intermediates, and more specifically, a method for synthesizing cis-allylamine compounds by iron photocatalysis. Background Technology

[0002] Allylamines are a representative and important molecular skeleton, widely found in many physiologically active natural products and drug molecules (J. Am. Chem. Soc. 2001, 123, 1234–1235. DOI: 10.1021 / ja005689m; Tetrahedron Lett. 2005, 46, 1545–1549. DOI: 10.1016 / j.tetlet.2004.12.130; Org. Lett., 2014, 16, 1016–1019. DOI: 10.1021 / ol5000154; Chem. Sci., 2021, 12, 1915–1923. DOI: 10.1039 / D0SC04890A). For example, eponemycin, a proteasome inhibitor with anticancer activity, and angustifoline, an alkaloid extracted from narrow-leaved lupin, both contain this backbone in their molecular structures. Allylamine compounds have wide applications in the pharmaceutical field, particularly in antifungal treatment. They also demonstrate significant efficacy in treating inflammatory diseases such as hepatitis and pulmonary fibrosis, diabetes, stroke, and diseases related to apoptosis. Among these, cis-allylamine derivatives (Z-selective allylamine compounds) show potential inhibitory activity against vascular adhesion protein 1 (VAP-1) / aminourea-sensitive amine oxidase (SSAO), making them promising novel drugs for treating these diseases. The allylamine structure has become an important design starting point for medicinal chemists in developing novel anti-infective, antitumor, and neuroprotective drugs (J. Am. Chem. Soc., 2009, 131, 9473–9474. DOI: 10.1021 / ja902591g; Tetrahedron, 2011, 67, 8959–9061. DOI: 10.1016 / j.tet.2011.07.087; Synth. Commun., 2015, 45, 2259–2265. DOI: 10.1080 / 00397911.2015.1075218). Therefore, the synthesis of allylamine compounds, especially cis-allylamine derivatives, has become a hot research topic. Currently, researchers have developed various efficient synthetic methods for allylamine compounds, including allyl carbon-hydrogen bonding amination reactions, 1,3-diene hydrogenation amination reactions, reductive coupling reactions of alkynes with imines, and direct coupling reactions of alkenes with imines. However, the synthesis of cis-allylamine compounds faces significant challenges.Currently, the most common method for synthesizing cis-allylamines is the Wittig reaction, but this method is a non-catalytic reaction and generates stoichiometric amounts of phosphine oxide waste after the reaction. Therefore, developing a simple and green photocatalytic technology for the preparation of cis-allylamine compounds is of great significance.

[0003] Amino acids, as the basic building blocks of proteins, are a class of valuable and widely distributed organic compounds. Among them, four-membered ring azaamino acids, as common building blocks in drug synthesis, have received widespread attention in organic synthesis in recent years. Decarboxylation and hydroalkylation reactions are efficient strategies for the selective synthesis of cis-olefins and important means of constructing carbon-carbon bonds. Furthermore, visible light, as a green, clean, and renewable energy source, is increasingly favored in the field of organic synthesis. Photocatalytic reactions have advantages such as mild conditions, good functional group compatibility, and simple operation. With the continuous development of efficient novel photocatalysts, visible light-based α-amino acid functionalization modification routes are also receiving increasing attention.

[0004] Currently, methods for preparing Z-type allylamine products via photocatalytically mediated amino acid decarboxylation and hydroalkylation have been reported. For example, in 2020, Rueping and colleagues reported Ir / Ni photocatalyzed decarboxylation and alkylation of alkynes, yielding a variety of alkenes with good Z-selectivity (J. Am. Chem. Soc. 2018, 140, 5701-5705. DOI: 10.1021 / jacs.8b02834). In the same year, Pericàs and colleagues developed a similar alkyne photocatalytic reaction using a dual catalysis of copper and 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile photocatalysts (ACS Catal. 2020, 10, 6402-6408. DOI: 10.1021 / acscatal.0c01742). However, traditional photocatalytic methods often employ noble metal catalysts or co-catalysis of photosensitizers and metals. These strategies suffer from numerous drawbacks, including expensive catalysts, a narrow substrate range, low yields of cis-products, and environmental unfriendliness. These limitations significantly restrict their application in large-scale industrial production. Therefore, it is essential to develop a mild, readily available, and environmentally friendly method for the decarboxylation and alkenylation of amino acids to synthesize cis-allylamine compounds. Summary of the Invention

[0005] To overcome the shortcomings of the prior art, this invention provides a method for synthesizing cis-allylamine compounds by decarboxylation of amino acids using iron photocatalysis, providing a green, efficient, and environmentally friendly innovative approach for the synthesis of cis-allylamine drugs.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The first aspect of the present invention provides a method for synthesizing cis-allylamine compounds by iron photocatalysis, specifically: dissolving the amino acid derivative shown in Formula 1 and the acetylation shown in Formula 2 in a solvent, then adding an iron photocatalyst, an alkaline additive and a reducing agent to prepare a homogeneous solution, and then placing the obtained homogeneous solution under visible light irradiation for a one-pot reaction, and after the reaction, separating and purifying to obtain the cis-allylamine compounds shown in Formula 3; Among them, R 1 Selected from -Ac, -Boc, -Cbz, or amino acids and their derivatives; R 2 Substituents on amino acids (side chain groups of amino acids, i.e., the R groups unique to different amino acids); R 3 It is selected from alkyl, alkoxy, aryl, aryl derivatives, heterocyclic, or heterocyclic derivatives.

[0007] Preferably, the amino acid derivative represented by Formula 1 is selected from any one of the following structures: The acetylide shown in Formula 2 is selected from any of the following structures: .

[0008] Preferably, the cis-allylamine compound represented by Formula 3 is selected from any one of the following structures: .

[0009] Preferably, the iron photocatalyst is selected from at least one of ferric chloride (FeCl3), ferric tribromide (FeBr3), ferric trifluoromethanesulfonate (FeOTf3), ferric p-toluenesulfonate (FeOTs3), ferrous trifluoromethanesulfonate (FeOTf2), ferric nitrate nonahydrate (FeNO3·9H2O), ferrous acetylacetone (Fe(acac)2), ferrous chloride (FeCl2), ferrous glycinate, and ferrous acetate (II) tetrahydrate.

[0010] More preferably, the iron photocatalyst is iron nitrate nonahydrate (FeNO3·9H2O).

[0011] Preferably, the alkali additive is selected from at least one of triethylamine (Et3N), 4-dimethylaminopyridine (DMAP), 1,8-diazobispyrocyclo[5.4.0]undecyl-7-ene (DBU), triethylenediamine (DABCO), N,N-diisopropylethylamine (DIPEA), N,N,N',N'-tetramethylethylenediamine (TEMED), and pyridine (Py).

[0012] More preferably, the alkali additive is N,N-diisopropylethylamine (DIPEA).

[0013] Preferably, the reducing agent is selected from at least one of methanol (MeOH), ethanol (EtOH), isopropanol, 2,3-dimethyl-2-butene, 1,4-cyclohexadiene, cyclohexene, and cycloheptene.

[0014] More preferably, the reducing agent is 1,4-cyclohexadiene.

[0015] Preferably, the solvent is selected from at least one of acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF), 1,4-dioxane, dimethyl sulfoxide (DMSO), N,N-dimethylformamide, N,N-dimethylacetamide, chloroform, and acetone.

[0016] More preferably, the solvent is N,N-dimethylacetamide.

[0017] Preferably, the molar ratio of the amino acid derivative shown in Formula 1 to the acetylation shown in Formula 2 is 1 to 5:1, and more preferably 1.7:1.

[0018] Preferably, the molar ratio of the amino acid derivative, the iron photocatalyst, and the alkaline additive shown in Formula 1 is 1:0.01 to 0.1:1 to 2, and more preferably 1:0.03:1.05.

[0019] Preferably, the visible light source is a purple LED strip or bulb with a power of 5-60W and a wavelength of 360-460nm. More preferably, it is 50W and 400nm. A purple LED strip is also preferred.

[0020] Preferably, the temperature of the one-pot reaction is 0–30°C, and more preferably room temperature.

[0021] Preferably, the reaction time for the one-pot method is 8 h to 48 h, more preferably 8 h to 24 h, more preferably 8 h to 12 h, and most preferably 13 h.

[0022] Preferably, the distance between the visible light source and the reaction device carrying the homogeneous solution is 0.1 cm to 2.0 cm, more preferably 0.1 cm to 1 cm, and even more preferably 0.5 cm.

[0023] Preferably, the separation and purification are carried out by column chromatography using petroleum ether and ethyl acetate as eluents.

[0024] Compared with existing technologies, the beneficial effects of this invention are as follows: This invention discloses a method for the decarboxylation and alkenylation of amino acids using visible light photocatalysis. Using terminal aryl alkynes or their derivatives and amino acids as raw materials, a one-pot reaction is carried out under ultraviolet light irradiation via iron catalysis to obtain the corresponding Z-selective olefin compounds. This method features mild reaction conditions, simple operation, high cis-selectivity, and uses an inexpensive, green, and biocompatible catalytic system, conforming to the principles of green chemistry. Furthermore, the photocatalytic technology proposed in this invention provides a green and efficient innovative route for the synthesis of cis-allylamine drugs.

[0025] Specifically, the present invention has the following advantages: (1) The present invention does not require the use of expensive metal catalysts or photosensitizers, which greatly reduces the reaction cost and solves the environmental pollution problem caused by post-processing.

[0026] (2) The light source used in this invention is visible light, which is a sustainable energy source and conforms to the development concept of green chemistry.

[0027] (3) The alkynylating reagent used in this invention can be synthesized from inexpensive and readily available raw materials through simple steps, avoiding the use of complex alkynylating reagents required by the original method.

[0028] (4) The method of the present invention can synthesize cis-allylamine compounds with a yield of 63% to 93% and high selectivity. Attached Figure Description

[0029] Figure 1 shows a diagram of the visible light iron catalytic reaction apparatus (before the lights are turned on).

[0030] Figure 2 shows a diagram of the visible light iron catalytic reaction device (after the light is turned on).

[0031] Figure 3 shows the hydrogen spectrum of compound 3aa: tert-butyl(Z)-2-styrylazane-1-carboxylic acid ester.

[0032] Figure 4 shows the carbon spectrum of compound 3aa: tert-butyl(Z)-2-styrylazane-1-carboxylic acid ester.

[0033] Figure 5 shows the proton NMR spectrum of compound 3ba: tert-butyl(Z)-(2-oxo-2-(2-styrylpyrrolidine-1-yl)ethyl)carbamate.

[0034] Figure 6 shows the carbon spectrum of compound 3ba: tert-butyl(Z)-(2-oxo-2-(2-styrylpyrrolidine-1-yl)ethyl)carbamate.

[0035] Figure 7 shows the hydrogen spectrum of compound 3ca: benzyl(Z)-2-styrylpyrrolidine-1-carboxylic acid ester.

[0036] Figure 8 shows the carbon spectrum of compound 3ca: benzyl(Z)-2-styrylpyrrolidine-1-carboxylic acid ester.

[0037] Figure 9 shows the proton NMR spectrum of compound 3da: tert-butyl(Z)-(2-methyl-4-phenylbut-3-en-2-yl)carbamate.

[0038] Figure 10 shows the carbon spectrum of compound 3da: tert-butyl(Z)-(2-methyl-4-phenylbut-3-en-2-yl)carbamate.

[0039] Figure 11 shows the hydrogen spectrum of compound 3ab: tert-butyl(Z)-2-(4-(tert-butyl)styryl)azatetracyclobutylcarboxylate.

[0040] Figure 12 shows the carbon spectrum of compound 3ab: tert-butyl(Z)-2-(4-(tert-butyl)styryl)azatetracyclobutylcarboxylate.

[0041] Figure 13 shows the hydrogen spectrum of compound 3ac: tert-butyl(Z)-2-(4-iodostyryl)azatetracyclobutane-1-carboxylic acid ester.

[0042] Figure 14 shows the carbon spectrum of compound 3ac: tert-butyl(Z)-2-(4-iodostyryl)azatetracyclobutane-1-carboxylic acid ester.

[0043] Figure 15 shows the hydrogen spectrum of compound 3ad: tert-butyl(Z)-2-(2-(thiophen-2-yl)vinyl)azatetracyclobutane-1-carboxylic acid ester.

[0044] Figure 16 shows the carbon spectrum of compound 3ad: tert-butyl(Z)-2-(2-(thiophen-2-yl)vinyl)azatetracyclobutane-1-carboxylic acid ester. Detailed Implementation

[0045] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0046] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all available through conventional commercial channels.

[0047] This invention provides a method for synthesizing Z-selective allylamine compounds by photocatalytic decarboxylation coupling reaction of amino acids and terminal aryl alkynes. The terminal aryl alkynes and their derivatives are reacted with amino acids in a one-pot reaction under ultraviolet light irradiation via iron catalysis to obtain the corresponding Z-selective olefin compounds. The reaction conditions are mild, the operation is simple, and the cis selectivity is high.

[0048] To fully and clearly present the technical solution and significant advantages of the present invention, the present invention will be described in detail below with reference to specific embodiments.

[0049] Example 1: 68.4 mg of (tert-butoxycarbonyl)-azacyclobutane-2-carboxylic acid (compound 1a; 0.34 mmol, 1.7 equiv.), 20.4 mg of phenylacetylene (compound 2a; 0.2 mmol, 1.0 equiv.), 46.4 mg of N,N-diisopropylethylamine (0.36 mmol, 1.8 equiv.), 4.0 mg of ferric nitrate nonahydrate (0.01 mol, 5.0 mol%), and 28.8 mg of 1,4-cyclohexadiene (0.36 mmol, 1.8 equiv.) were weighed and added to a reaction tube containing 2 mL of N,N-dimethylacetamide. The reaction tube was then sealed (Figure 1), and the reaction was conducted under ultraviolet light (50 W, 400 nm; lamp distance 0.5 m). The reaction was carried out under light irradiation at room temperature for 13 hours (Figure 2). The reaction progress was monitored by TLC. After the reaction was completed, the reaction was quenched and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 8:1) to obtain 21.0 mg of the final product tert-butyl(Z)-2-styrylazino-1-carboxylic acid ester (compound 3aa), with a yield of 81% and Z / E > 99:1 (cis / trans ratio was determined by...). 1 (H NMR determination). Characterization data are as follows (Figures 3 and 4): 1 H NMR (600 MHz, Chloroform-d) δ 7.34 – 7.20 (m,5H), 6.50 (d, J = 11.6 Hz, 1H), 5.93 (t, J = 9.2 Hz, 0.94H), 5.14 (tdd, J =8.4, 6.3, 1.3 Hz, 1H), 3.91 – 3.79 (m, 2H), 2.44 (dtd, J = 11.3, 8.8, 5.3 Hz,1H), 2.04 – 1.97 (m, 1H), 1.39 (s, 9H). 13C NMR (151 MHz, Chloroform-d) δ156.4, 136.7, 133.6, 130.0, 128.8, 128.6, 128.3, 127.2, 79.5, 59.0, 46.1, 29.8, 28.5, 24.0.

[0050] Example 2: This example is a further scale-up of Example 1 for the preparation of Z-selective allylamine compounds: Following the above reaction formula, 0.342 g of (tert-butoxycarbonyl)-azacyclobutane-2-carboxylic acid (compound 1a; 1.7 mmol, 1.7 equiv.), 0.102 mg of phenylacetylene (compound 2a; 1 mmol, 1.0 equiv.), 0.232 mg of N,N-diisopropylethylamine (1.8 mmol, 1.8 equiv.), 20 mg of ferric nitrate nonahydrate (catalyst; 0.05 mol, 5.0 mol%), and 0.144 mg of 1,4-cyclohexadiene (1.8 mmol, 1.8 equiv.) were dissolved in a reaction tube containing 2 mL of N,N-dimethylacetamide. The reaction tube was then sealed, and the mixture was subjected to ultraviolet light (50 W, 400 nm; lamp distance 0.5 m from the reaction tube). The reaction was carried out under light irradiation at room temperature for 13 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction was quenched and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 8:1) to obtain the final product tert-butyl(Z)-2-styrylazinobutane-1-carboxylic acid ester (compound 3aa) 0.21 g, with a yield of 80%.

[0051] Example 3: As shown in Table 1, following the above reaction formula, 92.6 mg of (tert-butyloxycarbonyl)-glycine-L-proline (compound 1b; 0.34 mmol, 1.7 equiv.), 20.4 mg of phenylacetylene (compound 2a; 0.20 mmol, 1.0 equiv.), 46.4 mg of N,N-diisopropylethylamine (0.36 mmol, 1.8 equiv.), 4.0 mg of ferric nitrate nonahydrate (catalyst; 0.01 mol, 5.0 mol%), and 28.8 mg of 1,4-cyclohexadiene (0.36 mmol, 1.8 equiv.) were weighed and added to a reaction tube containing 2 mL of N,N-dimethylacetamide. After dissolving, the reaction tube was sealed, and then the reaction was conducted under a UV lamp (50 W, 400 nm; lamp distance 0.5 m). The reaction was carried out under light irradiation at room temperature for 13 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction was quenched and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain the final product tert-butyl(Z)-(2-oxo-2-(2-styrylpyrrolidone-1-yl)ethyl)carbamate (compound 3ba) 56.8 mg, with a yield of 86% and Z / E = 90:10. The characterization data of the product are as follows (Figures 5 and 6): 1 H NMR (600 MHz, Chloroform-d) δ 7.40 – 7.26 (m, 4H), 7.23 (dq, J = 7.8, 1.7 Hz, 1H), 6.53 (dd, J = 54.0, 11.6 Hz, 0.83H), 6.42 – 6.36 (m, 0.19H), 6.08 (ddd, J = 15.9,6.2, 2.1 Hz, 0.15H), 5.56 (ddd, J = 54.8, 11.6, 9.1 Hz, 1.27H), 5.01 (td, J =8.3, 4.1 Hz, 0.37H), 4.63 (td, J = 8.4, 3.2 Hz, 0.46H), 3.94 – 3.84 (m, 0.89H), 3.81 – 3.75 (m, 0.55H), 3.62 – 3.56 (m, 1H), 3.51 – 3.38 (m, 1H), 2.36 – 1.65 (m, 6H), 1.43 – 1.37 (m, 9H). 13C NMR (151 MHz, Chloroform-d) δ168.0, 167.0, 156.0, 136.9, 135.9, 132.5, 131.9, 130.9, 129.6, 128.9, 128.8,128.7, 128.4, 127.7, 127.1, 126.6, 79.6, 58.9, 55.8, 54.8, 46.9, 46.0, 43.3,42.8, 34.7, 32.4, 29.8, 28.5, 24.7, 23.0. HRMS (ESI) m / z calculated for (C 19 H 26 N₂O₃Na) 353.1841 [M+Na] + ; found 353.1845.

[0052] Example 4: As shown in Table 1, following the above reaction formula, 84.8 mg of (benzyloxycarbonyl)-L-proline (compound 1c; 0.34 mmol, 1.7 equiv.), 20.4 mg of phenylacetylene (compound 2a; 0.2 mmol, 1.0 equiv.), 46.4 mg of N,N-diisopropylethylamine (0.36 mmol, 1.8 equiv.), 4.0 mg of ferric nitrate nonahydrate (catalyst; 0.01 mol, 5.0 mol%), and 28.8 mg of 1,4-cyclohexadiene (0.36 mmol, 1.8 equiv.) were weighed and added to a reaction tube containing 2 mL of N,N-dimethylacetamide. After dissolving, the reaction tube was sealed, and then the reaction was conducted under a UV lamp (50 W, 400 nm; lamp distance 0.5 m). The product (compound 3ca) was subjected to a light-induced reaction at room temperature for 13 hours. The reaction progress was monitored by TLC. After complete reaction, the reaction was quenched and separated by column chromatography (eluent: petroleum ether:ethyl acetate = 8:1) to obtain 55.8 mg of benzyl(Z)-2-styrylpyrrolidine-1-carboxylic acid ester (compound 3ca), with a yield of 91% and a Z / E ratio of 67:33. The characterization data of the product are as follows (Figures 7 and 8): 1H NMR (600 MHz, Chloroform-d) δ 7.4 – 7.3 (m, 6H), 7.2 –7.1 (m, 4H), 6.5 – 6.3 (m, 1H), 6.1 (ddd, J = 22.1, 15.7, 7.8 Hz, 0.35H), 5.6(q, J = 11.0, 8.2 Hz, 0.65H), 5.2 – 5.0 (m, 2H), 4.9 – 4.8 (m, 0.65H), 4.6 –4.5 (m, 0.36H), 3.6 – 3.4 (m, 2H), 2.2 – 2.1 (m, 1H), 2.0 – 1.9 (m, 1H), 1.8(dddt, J = 12.3, 9.4, 6.4, 4.1 Hz, 2H). 13 C NMR (151 MHz, Chloroform-d) δ155.2, 155.1, 136.9, 134.1, 133.7, 132.7, 130.3, 130.0, 129.3, 129.0, 128.6,128.3, 128.0, 127.8, 127.7, 127.0, 126.5, 66.9, 66.7, 59.0, 55.7, 55.0, 47.1,46.9, 46.8, 46.4, 34.1, 33.4, 32.7, 31.7, 25.9, 25.1, 23.9, 23.1.

[0053] Example 5: As shown in Table 1, following the above reaction formula, 69.0 mg of 2-((tert-butyloxycarbonyl)amino)-2-methylpropionic acid (compound 1d; 0.34 mmol, 1.7e quiv.), 20.4 mg of phenylacetylene (compound 2a; 0.2 mmol, 1.0 equiv.), 46.4 mg of N,N-diisopropylethylamine (0.36 mmol, 1.8 equiv.), 4.0 mg of ferric nitrate nonahydrate (catalyst; 0.01 mol, 5.0 mol%), and 28.8 mg of 1,4-cyclohexadiene (0.36 mmol, 1.8 equiv.) were weighed and added to a reaction tube containing 2 mL of N,N-dimethylacetamide. After dissolving, the reaction tube was sealed, and then the reaction was conducted under a UV lamp (50 W, 400 nm; lamp distance 0.5 m). The product (compound 3da) was subjected to a light-induced reaction at room temperature for 13 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction was quenched and separated by column chromatography (eluent: petroleum ether:ethyl acetate = 8:1) to obtain the final product, tert-butyl(Z)-(2-methyl-4-phenylbut-3-en-2-yl)carbamate (compound 3da), in 48.6 mg, with a yield of 93% and a Z / E ratio of 86:14. The characterization data of the product are shown in Figures 9 and 10. 1 H NMR (600 MHz, Chloroform-d) δ7.36 – 7.26 (m, 2H), 7.24 – 7.18 (m, 3H), 6.48 (d, J = 12.6 Hz, 0.91H), 6.42(d, J = 16.1 Hz, 0.16H), 5.74 (d, J = 12.7 Hz, 0.97H), 4.50 (s, 1H), 1.44 (d,J = 25.3 Hz, 3H), 1.37 (s, 6H), 1.31 – 1.27 (m, 6H). 13 C NMR (151 MHz, Chloroform-d) δ 153.9, 138.1, 137.9, 137.2, 128.9, 128.6, 128.4, 127.9,127.4, 126.8, 126.6, 126.5, 78.7, 53.3, 53.1, 29.8, 29.5, 28.5, 28.4.

[0054] Example 6: As shown in Table 1, following the above reaction formula, 68.4 mg of (tert-butyloxycarbonyl)-azacyclobutane-2-carboxylic acid (compound 1a; 0.34 mmol, 1.7 equiv.), 31.6 mg of 4-tert-butylphenylacetylene (compound 2b; 0.20 mmol, 1.0 equiv.), 46.4 mg of N,N-diisopropylethylamine (0.36 mmol, 1.8 equiv.), 4.0 mg of ferric nitrate nonahydrate (catalyst; 0.01 mol, 5.0 mol%), and 28.8 mg of 1,4-cyclohexadiene (0.36 mmol, 1.8 equiv.) were weighed and added to a reaction tube containing 2 mL of N,N-dimethylacetamide. After dissolving, the reaction tube was sealed, and then the reaction was conducted under a UV lamp (50 W, 400 nm; lamp distance 0.5 m). The reaction was carried out under light irradiation at room temperature for 13 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction was quenched and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 8:1) to obtain the final product tert-butyl(Z)-2-(4-(tert-butyl)styryl)azatetracyclobutylcarboxylate (compound 3ab) 51.8 mg, with a yield of 82% and Z / E = 94:6. The characterization data of the product are as follows (Figures 11 and 12): 1 H NMR (600 MHz, Chloroform-d) δ 7.37 – 7.32 (m, 2.12H), 7.19 – 7.16 (m, 1.90H), 6.48 (d, J =11.6 Hz, 1H), 6.30 (dd, J = 15.9, 7.0 Hz, 0.05H), 5.90 (t, J = 10.3 Hz, 0.83H), 5.18 (tdd, J = 8.4, 6.3, 1.3 Hz, 0.91H), 4.79 (d, J = 7.7 Hz, 0.03H), 3.94 – 3.79 (m, 2H), 2.46 (dtd, J = 11.3, 8.8, 5.2 Hz, 1H), 2.07 – 1.96 (m,1H), 1.41 (d, J = 5.8 Hz, 9H), 1.32 (d, J = 3.1 Hz, 9H). 13C NMR (151 MHz, Chloroform-d) δ 156.8, 156.4, 150.8, 150.1, 133.9, 133.0, 130.7, 129.8,129.4, 128.6, 126.3, 125.2, 79.5, 59.2, 46.1, 34.6, 31.4, 29.8, 28.5, 24.1.HRMS (ESI) m / z calculated for (C 20 H 29 NO₂Na) 338.2096 [M+Na] + ; found 338.2100.

[0055] Example 7: As shown in Table 1, following the above reaction formula, 68.4 mg of (tert-butyloxycarbonyl)-azacyclobutane-2-carboxylic acid (compound 1a; 0.34 mmol, 1.7 equiv.), 45.6 mg of 4-iodophenylacetylene (compound 2c; 0.20 mmol, 1.0 equiv.), 46.4 mg of N,N-diisopropylethylamine (0.36 mmol, 1.8 equiv.), 4.0 mg of ferric nitrate nonahydrate (catalyst; 0.01 mol, 5.0 mol%), and 28.8 mg of 1,4-cyclohexadiene (0.36 mmol, 1.8 equiv.) were weighed and added to a reaction tube containing 2 mL of N,N-dimethylacetamide. After dissolving, the reaction tube was sealed, and then the reaction was conducted under a UV lamp (50 W, 400 nm; lamp distance 0.5 m). The reaction was carried out under light irradiation at room temperature for 13 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction was quenched and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 8:1) to obtain the final product tert-butyl(Z)-2-(4-iodostyryl)azatetracyclobutane-1-carboxylic acid ester (compound 3ac) 53.8 mg, yield 70%, Z / E = 83:17. The characterization data of the product are as follows (Figures 13 and 14): 11H NMR (600 MHz, Chloroform-d) δ 7.66 – 7.30 (m, 2H), 7.25 – 7.09 (m, 2H), 6.98 (d, J = 7.9 Hz, 0.31H), 6.47 (dd, J = 56.5, 11.6 Hz, 0.85H), 6.34 (dd, J = 15.6, 6.9 Hz, 0.15H), 5.94 (d, J = 11.3 Hz, 0.72H), 5.11 (dtdd, J = 42.4, 8.5, 6.3, 1.3 Hz, 0.78H), 4.78 (s, 0.15H), 3.91 – 3.80 (m, 2H), 2.44 (dddd, J = 18.2, 11.4, 9.0, 5.3 Hz, 1H), 2.09 – 1.96 (m, 1H), 1.40 (d, J = 7.0 Hz, 9H). 13 13C NMR (151 MHz, Chloroform-d) δ 156.4, 137.7, 137.4, 136.7, 136.3, 136.2, 134.4, 133.6, 131.0, 130.7, 130.0, 128.8, 128.3, 127.2, 93.0, 92.7, 79.6, 59.0, 46.1, 29.8, 24.0, 23.3. HRMS (ESI) m / z calculated for (C 16 1H 20 NO2NaI) 408.0436 [M+Na] + ; found 408.0434。

[0056] Example 8: As shown in Table 1, following the above reaction formula, 68.4 mg of (tert-butyloxycarbonyl)-azacyclobutane-2-carboxylic acid (compound 1a; 0.34 mmol, 1.7 equiv.), 21.6 mg of 2-thiopheneacetylene (compound 2d; 0.2 mmol, 1.0 equiv.), 46.4 mg of N,N-diisopropylethylamine (0.36 mmol, 1.8 equiv.), 4.0 mg of ferric nitrate nonahydrate (catalyst; 0.01 mol, 5.0 mol%), and 28.8 mg of 1,4-cyclohexadiene (0.36 mmol, 1.8 equiv.) were weighed and added to a reaction tube containing 2 mL of N,N-dimethylacetamide. The reaction tube was then sealed and the mixture was subjected to ultraviolet light (50 W, 400 nm; lamp distance 0.5 m). The reaction was carried out under light irradiation at room temperature for 13 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction was quenched and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 8:1) to obtain the final product tert-butyl(Z)-2-(2-(thiophen-2-yl)vinyl)azatetracyclobutane-1-carboxylic acid ester (compound 3ad) 33.4 mg, with a yield of 63% and Z / E > 99:1. The characterization data of the product are as follows (Figures 15 and 16): 1 H NMR (600 MHz, Chloroform-d)δ 7.31 – 7.21 (m, 1H), 7.00 (dd, J = 5.1, 3.6 Hz, 1H), 6.95 (dt, J = 3.6, 1.0Hz, 1H), 6.58 – 6.52 (m, 1H), 5.87 (s, 1H), 5.40 – 5.28 (m, 1H), 3.89 (ddd, J= 7.8, 7.1, 0.6 Hz, 2H), 2.60 (ddt, J = 11.3, 8.4, 6.9 Hz, 1H), 2.06 – 1.93(m, 1H), 1.42 – 1.34 (m, 9H). 13 C NMR (151 MHz, Chloroform-d) δ 156.4, 139.5,132.1, 128.0, 127.1, 126.0, 122.0, 79.6, 29.8, 28.5, 23.7. HRMS (ESI) m / zcalculated for (C 14 H 19 NO₂NaS) 288.1034 [M+Na] + ; found 288.1038.

[0057] Table 1: Photocatalytic synthesis of cis-allylamine compounds using iron Continued from the previous table: Comparative Examples 1-7: The synthesis methods were the same as in Examples 1 and 3-8, except that the iron photocatalyst in Examples 1 and 3-8 was replaced with bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2,2'-bi(4-tert-butylpyridine)]iridium hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbbpy)PF6; CAS No.: 870987-63-6) catalyst. The yields and Z / E are shown in Table 2.

[0058] Table 2: Synthesis of cis-allylamine compounds using bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2,2'-bi(4-tert-butylpyridine)]iridium hexafluorophosphate as a catalyst Continued from the previous table: Comparative Examples 8-14: The synthesis methods were the same as in Examples 1 and 3-8, except that the iron photocatalyst in Examples 1 and 3-8 was replaced with a mixed catalyst of bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2,2'-bi(4-tert-butylpyridine)]iridium hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbbpy)PF6; CAS No.: 870987-63-6) and nickel chloride dimethoxyethane (NiCl2·dme; CAS No.: 29046-78-4), i.e., the catalyst used in the literature (J. Am. Chem. Soc. 2018, 140, 5701-5705. DOI: 10.1021 / jacs.8b02834). The yields and Z / E are shown in Table 3.

[0059] Table 3: Synthesis of cis-allylamine compounds using bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2,2'-bi(4-tert-butylpyridine)]iridium hexafluorophosphate and nickel chloride dimethoxyethane as co-catalysts Continued from the previous table: Comparative Examples 15-21: The synthesis methods were the same as those in Examples 1 and 3-8, except that the iron photocatalyst in Examples 1 and 3-8 was replaced with 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN; CAS No.: 1416881-52-1). The yields and Z / E are shown in Table 4.

[0060] Table 4: Synthesis of cis-allylamine compounds using 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile as a catalyst Continued from the previous table: Comparative Examples 22-28: The synthesis methods were the same as in Examples 1 and 3-8, except that the iron photocatalyst in Examples 1 and 3-8 was replaced with a mixed catalyst of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN; CAS No.: 1416881-52-1) and copper acetate, i.e., the catalyst used in the literature (ACS Catal. 2020, 10, 6402-6408. DOI: 10.1021 / acscatal.0c01742). The yields and Z / E are shown in Table 5.

[0061] Table 5: Synthesis of cis-allylamine compounds using 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile and copper acetate as co-catalysts Comparing the synthesis data of cis-allylamine compounds under different catalytic systems in Tables 1 and 2-5, it can be seen that, compared with the noble metal catalyst system, photosensitive catalyst system, and noble metal-photosensitive catalyst co-catalytic system commonly used in the prior art, the iron photocatalytic synthesis scheme adopted in this invention has achieved significant improvements in both the yield and cis-selectivity of the target product.

[0062] In summary, this invention uses terminal aryl alkynes or their derivatives and amino acid derivatives as raw materials, and carries out a one-pot reaction under ultraviolet light irradiation via iron catalysis to obtain the corresponding Z-selective olefin compounds. The reaction conditions are mild, the operation is simple, and the cis selectivity is high, providing a green, efficient, and environmentally friendly innovative route for the synthesis of cis-allylamine drugs.

[0063] The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. For those skilled in the art, various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and these variations still fall within the protection scope of the present invention.

Claims

1. A method for synthesizing cis-allylamine compounds via iron photocatalysis, characterized in that, The amino acid derivative shown in Formula 1 and the acetylation shown in Formula 2 are dissolved in a solvent, and then an iron photocatalyst, an alkaline additive and a reducing agent are added to prepare a homogeneous solution. The resulting homogeneous solution is then placed under visible light irradiation for a one-pot reaction. After the reaction, the cis-allylamine compound shown in Formula 3 is obtained by separation and purification. Among them, R 1 Selected from -Ac, -Boc, -Cbz, or amino acids and their derivatives; R 2 R is a substituent on an amino acid; 3 It is selected from alkyl, alkoxy, aryl, aryl derivatives, heterocyclic, or heterocyclic derivatives.

2. The method for synthesizing cis-allylamine compounds by iron photocatalysis according to claim 1, characterized in that, The amino acid derivative shown in Formula 1 is selected from any of the following structures: The acetylide shown in Formula 2 is selected from any of the following structures: 。 3. The method for synthesizing cis-allylamine compounds via iron photocatalysis according to claim 1, characterized in that, The cis-allylamine compounds shown in Formula 3 are selected from any of the following structures: 。 4. The method for synthesizing cis-allylamine compounds by iron photocatalysis according to claim 1, characterized in that, The iron photocatalyst is selected from at least one of ferric chloride, ferric tribromide, ferric trifluoromethanesulfonate, ferric p-toluenesulfonate, ferrous trifluoromethanesulfonate, ferric nitrate nonahydrate, ferrous acetylacetone, ferrous chloride, ferrous glycinate, and ferrous acetate (II) tetrahydrate.

5. The method for synthesizing cis-allylamine compounds by iron photocatalysis according to claim 1, characterized in that, The alkali additive is selected from at least one of triethylamine, 4-dimethylaminopyridine, 1,8-diazobisspirocyclo[5.4.0]undecyl-7-ene, triethylenediamine, N,N-diisopropylethylamine, N,N,N',N'-tetramethylethylenediamine, and pyridine.

6. The method for synthesizing cis-allylamine compounds by iron photocatalysis according to claim 1, characterized in that, The reducing agent is selected from at least one of methanol, ethanol, isopropanol, 2,3-dimethyl-2-butene, 1,4-cyclohexadiene, cyclohexene, and cycloheptene.

7. The method for synthesizing cis-allylamine compounds by iron photocatalysis according to claim 1, characterized in that, The solvent is selected from at least one of acetonitrile, dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, chloroform, and acetone.

8. The method for synthesizing cis-allylamine compounds by iron photocatalysis according to claim 1, characterized in that, The molar ratio of the amino acid derivative shown in Formula 1 to the acetylation shown in Formula 2 is 1 to 5:

1.

9. The method for synthesizing cis-allylamine compounds by iron photocatalysis according to claim 1, characterized in that, The molar ratio of the amino acid derivative, iron photocatalyst and alkaline additive shown in Formula 1 is 1:0.01~0.1:1~2.

10. The method for synthesizing cis-allylamine compounds by iron photocatalysis according to claim 1, characterized in that, The visible light source is a purple LED strip or bulb with a power of 5-60W and a wavelength of 360-460nm; the temperature of the one-pot reaction is 0-30℃ and the time is 8-48h.

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