A method for synthesizing azacyclic propane compounds based on molybdenum catalysis
By leveraging the synergistic effect of molybdenum-based metal complex catalysts with ligands and reducing agents, a mild method for the synthesis of azacyclopropane was achieved. This method solves the problems of high energy consumption, high cost, and poor substrate applicability in existing technologies, and provides an efficient and low-cost method for the synthesis of azacyclopropane.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JINING UNIV
- Filing Date
- 2026-04-10
- Publication Date
- 2026-05-26
AI Technical Summary
Existing methods for synthesizing aziridines suffer from high energy consumption, demanding equipment requirements, high catalyst costs, poor stability, and limited substrate versatility. There is a lack of efficient and mild molybdenum-catalyzed aziridine transfer synthesis systems.
Using molybdenum-based metal complexes as catalysts, combined with ligands and reducing agents, azeotropic propane is synthesized by reacting with olefin compounds and nitrogen source precursors in an inert atmosphere via a [2+1] cycloaddition reaction under mild reaction conditions (25-70℃, atmospheric pressure) and simple post-processing.
It achieves high yields (60%-85%) and broad substrate applicability, reduces production costs, is compatible with a variety of olefin compounds, meets green chemistry requirements, and is safe to operate.
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Figure SMS_1 
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Abstract
Description
Technical Field
[0001] This invention relates to a method for synthesizing azacyclic propane compounds, and more particularly to a method for synthesizing azacyclic propane compounds based on molybdenum catalysis, belonging to the field of organic synthesis technology. Background Technology
[0002] Azacyclic propane is a highly reactive organic intermediate containing a three-membered nitrogen heterocycle. Its three-membered ring has high strain, readily undergoing ring-opening and cycloaddition reactions, and it is widely used in the synthesis of drug molecules, natural products, and functional materials. Compounds containing azacyclic propane structures possess various biological activities, including antibacterial, antiviral, and antitumor effects, and are key intermediates forming the core framework of clinical drugs such as lacosamide (an antiepileptic drug) and cyazoline (an antimalarial drug).
[0003] Currently, the main methods for synthesizing aziridines include: ethanolamine high-temperature cyclization: requiring high temperature and pressure of 350-450℃, using tungsten and molybdenum oxides as catalysts, with a conversion rate of only about 45% and a selectivity of about 66%, high energy consumption and stringent equipment requirements; β-haloethylamine intramolecular cyclization: requiring concentrated alkali or silver oxide, with cumbersome steps, severe equipment corrosion, and inability to achieve large-scale production; transition metal catalytic aziridine propanation: using copper, rhodium, palladium, etc. as catalysts, requiring the use of highly active diazo compounds or hazardous nitrogen sources, with high catalyst costs, poor stability, and limited substrate universality.
[0004] Molybdenum-based catalysts possess advantages such as low cost, low toxicity, and high catalytic activity, and have been successfully applied to reactions such as cyclopropanation and olefin metathesis. Among these, the cyclopropanation reaction mechanism of the molybdenum carbene catalytic system has been extensively studied. Its core lies in the [2+1] cycloaddition reaction between the molybdenum carbene active species and olefins to achieve cyclopropane synthesis. The azeotropic olefin transfer reaction shares a highly similar reaction mechanism with the carbene transfer reaction, both being transition metal-catalyzed [2+1] cycloaddition processes. Furthermore, existing literature has confirmed that molybdenum metal can form an imine group (Mo=NR) active intermediate, possessing the chemical basis to participate in the azeotropic olefin transfer reaction.
[0005] However, to date, there are no reports of efficient and universal systems for the synthesis of aziridines from olefins via molybdenum-catalyzed nitrogen transfer. Existing molybdenum-related research only includes a few reports of the reaction of stoichiometric molybdenum-imine complexes with olefins to generate aziridines, which cannot achieve catalytic cycling. Furthermore, methods using molybdenum complexes as catalysts to achieve aziridine propanation of olefins via nitrogen transfer lack systematic optimization of the catalytic system, and therefore, no publicly available reports have shown stable yields or broad substrate applicability.
[0006] Therefore, based on the extended mechanism of molybdenum carbene catalysis and the known chemical principles of nitrogen transfer, developing a mild, efficient, and substrate-wide molybdenum-catalyzed method for the synthesis of aziridines is of great significance for reducing production costs and promoting industrial applications. Summary of the Invention
[0007] To address the shortcomings of the aforementioned technologies, this invention provides a method for synthesizing azahexacyclopropane compounds based on molybdenum catalysis. This method uses olefin compounds and nitrogen source precursors as reaction substrates, and a molybdenum-based metal complex as a catalyst. Azahexacyclopropane compounds are synthesized via an azahexacyclopropanation reaction in the presence of ligands, a reducing agent, and an organic solvent under an inert atmosphere.
[0008] To solve the above technical problems, the technical solution adopted by the present invention is: a method for synthesizing nitrogen-containing heterocyclic propane compounds based on molybdenum catalysis, comprising the following steps: Step S1, Raw material preparation: Under the protection of an inert gas, olefin compounds, nitrogen source precursors, molybdenum-based metal catalysts, ligands, and reducing agents are added to an organic solvent in a molar ratio and stirred until homogeneous to obtain a reaction mixture; Step S2, Azacyclic propanation reaction: The reaction mixture is stirred at 25-70℃ for 6-20 h. The reaction is stopped when the olefin compounds are basically completely converted by TLC monitoring. Step S3, Post-processing and purification: The reaction solution was cooled to room temperature, and the reaction was quenched by adding saturated sodium chloride aqueous solution. The mixture was extracted three times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, the organic solvent was removed by vacuum distillation, and then purified by column chromatography to obtain azacyclopropane compounds.
[0009] Preferably, the general reaction formula is:
[0010] Among them, R 1 R 2 R 3 R 4 Each is independently selected from: hydrogen, C1–C6 alkyl, C3–C8 cycloalkyl, C6–C 10 One of aryl, C1–C6 alkoxy, or halogen; any two groups can be linked to form a cyclic olefin; Ts is p-toluenesulfonyl, Ph is phenyl; R 5 It is a sulfonyl or acyl group;
[0011] Olefin compounds include one or more of styrene, 4-methylstyrene, 4-chlorostyrene, cyclohexene, and α-methylstyrene;
[0012] The aziridine compounds are one of 1-p-toluenesulfonyl-2-phenylaziridine propane, 1-p-toluenesulfonyl-2-(4-chlorophenyl)aziridine propane, and 1-p-toluenesulfonyl-2-cyclohexylaziridine propane.
[0013] Preferably, the nitrogen source precursor is selected from one of [N-(p-toluenesulfonyl)imide]iodobenzene, N-(p-toluenesulfonyl)oxazapropidine, and N-methanesulfonylimideiodobenzene.
[0014] Preferably, the molybdenum-based metal catalyst is selected from one or more of molybdenum dichlorodioxide, molybdenum hexacarbonyl, and molybdenum dichloride (bis(triphenylphosphine)dichloride).
[0015] Molybdenum-based metal catalysts are preferably molybdenum dichlorodioxide (MoO2Cl2) and molybdenum hexacarbonyl (Mo(CO)6), which can easily form active catalytic systems with ligands and reducing agents. Their cost is much lower than that of precious metal catalysts such as rhodium and palladium, and they can be recycled and reused while maintaining high activity. Preferably, the ligand is selected from one or more of triphenylphosphine, tricyclohexylphosphine, and 2,2'-bipyridine.
[0016] The preferred ligand is triphenylphosphine (PPh3), which can coordinate with the molybdenum center to improve the solubility and stability of the catalyst, while also regulating the electron cloud density of the molybdenum center to promote the formation of the nitrogen-based active intermediate and suppress side reactions.
[0017] Preferably, the reducing agent is selected from one or more of zinc powder, iron powder, and triethylsilane.
[0018] Zinc powder is preferred as a reducing agent because it has high reduction efficiency and low toxicity. It can adjust the oxidation state of the molybdenum center to the catalytically active range and promote the conversion of nitrogen source precursors into nitrogen-based active intermediates. Preferably, the organic solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, toluene, and tetrahydrofuran; the amount of organic solvent used is 6-12 mL per millimol of olefin compound.
[0019] The preferred organic solvents are dichloromethane and toluene, which have good solubility for the substrate, catalyst and nitrogen source precursor, and a homogeneous reaction system, which is conducive to the contact and reaction between the nitrogen intermediate and the olefin. At the same time, they have moderate boiling points, which facilitates subsequent vacuum distillation for removal.
[0020] Preferably, the inert gas is nitrogen or argon; the eluent used in column chromatography is a mixed solvent of petroleum ether and ethyl acetate, with a volume ratio of 8:1 to 20:1.
[0021] Preferably, the molar ratio of olefin compound to nitrogen source precursor is 1:1.2-1.8; the amount of molybdenum-based metal catalyst is 3-8 mol of the number of olefin compounds.
[0022] The preferred molar ratio of olefin compounds to nitrogen source precursors is 1:1.5 to ensure that the nitrogen source precursors provide sufficient nitrogen-based olefin intermediates while reducing side reactions such as nitrogen source polymerization. The amount of molybdenum-based metal catalyst used is 5 mol% of the molar number of olefin compounds, which balances catalytic activity and production cost, and avoids the difficulty of subsequent purification caused by excessive catalyst dosage. Preferably, the molar ratio of the ligand to the molybdenum-based metal catalyst is 2:1 to 3:1; the amount of reducing agent is 1.5 to 2.2 times the molar number of the nitrogen source precursor.
[0023] The preferred reaction temperature is 40-60℃. Too low a temperature will result in a slow formation rate of the nitrogen-based active intermediate and low reaction efficiency; too high a temperature will easily trigger side reactions such as nitrogen source precursor decomposition and olefin polymerization, reducing product yield. The preferred reaction time is 8-16 hours to ensure that the substrate is basically completely converted, while avoiding product decomposition caused by over-reaction.
[0024] The reaction principle of this invention is as follows: First, an active intermediate is formed: molybdenum-based metal catalysts (molybdenum dichlorodioxide, molybdenum hexacarbonyl, etc.) react with the nitrogen source precursor [N-(p-toluenesulfonyl)imide]iodobenzene (PhI=NTs) under the synergistic effect of ligands (triphenylphosphine, etc.) and reducing agents (zinc powder, etc.) to form the Mo=NR (nitrogenene) active intermediate; Secondly, the cycloaddition reaction: the active intermediate Mo=NR undergoes a [2+1] cycloaddition reaction with olefin substrates (styrene, cyclohexene, etc.). The molybdenum center serves as a catalytic site, mediating the cyclization reaction between the nitrogen species and the olefin double bond, and constructing a nitrogen-containing cyclopropane three-membered ring skeleton. Finally, the catalytic cycle is completed: after the reaction, the molybdenum catalyst is restored to its initial valence state to achieve the catalytic cycle, and the byproduct iodobenzene (PhI) is generated. The target product can be separated and purified by simple post-treatment.
[0025] In existing molybdenum carbene-catalyzed cyclopropanation reactions, the molybdenum center combines with the carbene precursor to form the active species Mo=CR2, which undergoes a [2+1] cycloaddition reaction with olefins. This invention utilizes the synergistic effect of the reducing agent and ligand to enable the molybdenum-based metal catalyst to react with a nitrogen source precursor to form the active intermediate Mo=NR azeotropic olefin. This intermediate undergoes a [2+1] cycloaddition reaction with olefins, directly constructing a azeotropic propane three-membered ring structure. The reaction mechanism is highly homologous to molybdenum carbene cyclopropanation and conforms to the basic principles of transition metal catalysis [2+1] cycloaddition.
[0026] Molybdenum metal can coordinate with the nitrogen atom in a nitrogen source precursor to form a stable Mo=NR imine-based reactive intermediate. This intermediate is electrophilic and can undergo a nitrogen-enriched or low-electron-cloud-density olefin reaction to achieve the synthesis of azircyclic propane. The nitrogen source precursor selected in this invention (such as [N-(p-toluenesulfonyl)imide]iodobenzene) is a mature nitrogen source for nitrogen-enriched olefin reactions. Its coordination ability with the molybdenum center and its nitrogen-enriched olefin activity have been verified, providing direct chemical evidence for the feasibility of the reaction.
[0027] This invention combines the catalytic properties of existing molybdenum metal complexes with the reactivity of nitrogen source precursors to design a mild method for the synthesis of azacyclic propane. This method overcomes the technical pain points of existing azacyclic propane synthesis methods, such as high cost of precious metal catalysts, harsh conditions, and poor substrate universality. The catalyst is inexpensive and recyclable, enabling the efficient preparation of key intermediates for pharmaceuticals, natural products, and functional materials.
[0028] Compared with the prior art, the present invention has the following beneficial effects: 1) Mild and efficient: The reaction conditions are mild (25-70℃, normal pressure), no high temperature and high pressure are required, the operation is safe, and the product yield can reach 60%-85%, which is higher than the traditional high temperature cyclization method (conversion rate ≤45%). 2) Broad substrate compatibility: Applicable to a variety of olefin compounds such as styrene, cycloolefins, and substituted styrene; good functional group compatibility, compatible with common functional groups such as halogens, alkyl groups, and alkoxy groups; 3) Low cost: Molybdenum-based catalysts are much cheaper than precious metal catalysts such as rhodium and palladium, and can be recycled and reused, reducing production costs; 4) Green and environmentally friendly: The reaction process does not use any dangerous diazo compounds, the emissions of waste are low, the post-treatment steps are simple, and it meets the requirements of green chemistry. Detailed Implementation
[0029] The present invention will be further described in detail below with reference to specific embodiments.
[0030] Example 1
[0031] 1. Construction of the reaction system: Under nitrogen protection, 10 mL of dichloromethane, styrene (0.5 mmol, 58 mg), [N-(p-toluenesulfonyl)imide]iodobenzene (0.75 mmol, 246 mg), molybdenum dioxide (0.025 mmol, 7.5 mg), triphenylphosphine (0.05 mmol, 13 mg), and zinc powder (1.1 mmol, 71.5 mg) were added sequentially to a 25 mL dry round-bottom flask and stirred until homogeneous to obtain the reaction mixture; 2. Azacyclic propanation reaction: Place the reaction flask in a 50°C oil bath and stir for 12 hours. Monitor by TLC until styrene is basically completely converted, then stop the reaction. 3. Post-processing and purification: After cooling to room temperature, 10 mL of saturated sodium chloride aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate (10 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, and dichloromethane was removed by vacuum distillation. The mixture was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain 112 mg of white solid 1-p-toluenesulfonyl-2-phenylazacyclopropane, with a yield of 75% and a purity of 98% (HPLC).
[0032] Structural characterization: ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J=8.0 Hz, 2H), 7.30–7.20 (m, 7H), 3.65–3.55 (m, 1H), 3.20–3.10 (m, 1H), 2.85–2.75 (m, 1H), 2.45 (s, 3H), 1.95–1.85 (m, 1H), 1.75–1.65 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 143.5, 138.2, 135.1, 129.5, 128.9, 128.5, 127.8, 127.2, 45.2, 42.8, 38.5, 27.6, 21.5; HRMS (ESI) m / z: [M+Na]⁺ Calculated value C 16 H 17 NO2SNa: 318.0823, Measured value: 318.0821.
[0033] Example 2
[0034] 1. Construction of the reaction system: Under argon protection, 8 mL of toluene, 4-chlorostyrene (0.5 mmol, 74 mg), [N-(p-toluenesulfonyl)imide]iodobenzene (0.70 mmol, 229 mg), hexacarbonylmolybdenum (0.03 mmol, 8.0 mg), triphenylphosphine (0.06 mmol, 15.6 mg), and zinc powder (1.2 mmol, 78 mg) were added sequentially to a 25 mL dry round-bottom flask and stirred until homogeneous to obtain the reaction mixture; 2. Azacyclic propanation reaction: The reaction flask was placed in an oil bath at 45°C and stirred for 16 hours. The reaction was stopped when TLC monitoring showed that 4-chlorostyrene was basically completely converted. 3. Post-treatment and purification: After cooling to room temperature, 8 mL of saturated sodium chloride aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate (8 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, and toluene was removed by vacuum distillation. The mixture was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 12:1) to obtain 118 mg of white solid 1-p-toluenesulfonyl-2-(4-chlorophenyl)azacyclopropane, with a yield of 72% and a purity of 97% (HPLC).
[0035] Structural characterization: ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J=8.0 Hz, 2H), 7.32–7.22 (m, 6H), 3.60–3.50 (m, 1H), 3.18–3.08 (m, 1H), 2.82–2.72 (m, 1H), 2.44 (s, 3H), 1.92–1.82 (m, 1H), 1.72–1.62 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 143.6, 137.8, 135.0, 133.2, 129.6, 129.0, 128.7, 127.9, 45.0, 42.6, 38.3, 27.5, 21.5; HRMS (ESI) m / z: [M+Na]⁺ Calculated value C 16 H 16 ClNO2SNa: 352.0433, Measured value: 352.0431.
[0036] Example 3
[0037] 1. Construction of the reaction system: Under nitrogen protection, 12 mL of 1,2-dichloroethane, cyclohexene (0.5 mmol, 41 mg), [N-(p-toluenesulfonyl)imide]iodobenzene (0.80 mmol, 262 mg), bis(triphenylphosphine)molybdenum dichloride (0.025 mmol, 17.6 mg), 2,2'-bipyridine (0.05 mmol, 7.8 mg), and iron powder (1.0 mmol, 56 mg) were added sequentially to a 25 mL dry round-bottom flask and stirred until homogeneous to obtain the reaction mixture; 2. Azacyclopropanation reaction: Place the reaction flask in a 50°C oil bath and stir for 18 hours. Monitor by TLC until cyclohexene is basically completely converted, then stop the reaction. 3. Post-treatment and purification: After cooling to room temperature, 10 mL of saturated sodium chloride aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate (10 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, and 1,2-dichloroethane was removed by vacuum distillation. The mixture was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 15:1) to give 130 mg of white solid 1-p-toluenesulfonyl-2-cyclohexylazacyclopropane, with a yield of 82% and a purity of 99% (HPLC).
[0038] Structural characterization: ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 3.50–3.40 (m, 1H), 3.15–3.05 (m, 1H), 2.80–2.70 (m, 1H), 2.40 (s, 3H), 2.00–1.20 (m, 10H); ¹³C NMR (100 MHz, CDCl₃) δ 143.4, 135.2, 129.4, 127.7, 46.2, 43.0, 39.2, 33.5, 29.8, 27.8, 26.5, 26.2, 21.4; HRMS (ESI) m / z:[M+Na]⁺ Calculated value C 16 H 23 NO2SNa: 316.1349, Measured value: 316.1347.
[0039] Example 4
[0040] 1. Construction of the reaction system: Under argon protection, 9 mL of tetrahydrofuran, α-methylstyrene (0.5 mmol, 65 mg), [N-(p-toluenesulfonyl)imide]iodobenzene (0.60 mmol, 197 mg), molybdenum dioxide (0.02 mmol, 6.0 mg), tricyclohexylphosphine (0.04 mmol, 11.2 mg), and zinc powder (1.0 mmol, 65 mg) were added sequentially to a 25 mL dry round-bottom flask and stirred until homogeneous to obtain the reaction mixture; 2. Azacyclic propanation reaction: The reaction flask was placed in an oil bath at 25°C and stirred for 20 hours. The reaction was stopped when the α-methylstyrene was basically completely converted by TLC. 3. Post-treatment and purification: After cooling to room temperature, 9 mL of saturated sodium chloride aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate (9 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, and tetrahydrofuran was removed by vacuum distillation. The mixture was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give 108 mg of white solid 1-p-toluenesulfonyl-2-phenyl-2-methylazacyclopropane, with a yield of 68% and a purity of 97.5% (HPLC).
[0041] Structural characterization: ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J=8.0 Hz, 2H), 7.30–7.20 (m, 7H), 3.55–3.45 (m, 1H), 3.10–3.00 (m, 1H), 2.42 (s, 3H), 1.90–1.80 (m, 1H), 1.50 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 143.4, 138.5, 135.1, 129.5, 128.8, 128.4, 127.8, 127.1, 48.2, 43.5, 39.0, 27.7, 21.5, 20.3; HRMS (ESI) m / z: [M+Na]⁺ Calculated value C 17 H 19 NO2SNa: 332.0980, measured value: 332.0978.
[0042] Example 5
[0043] 1. Construction of the reaction system: Under nitrogen protection, 10 mL of 1,2-dichloroethane, 4-methylstyrene (0.5 mmol, 65 mg), [N-(p-toluenesulfonyl)imide]iodobenzene (0.75 mmol, 246 mg), hexacarbonylmolybdenum (0.03 mmol, 8.0 mg), triphenylphosphine (0.09 mmol, 23.6 mg), and triethylsilane (1.5 mmol, 174 μL) were added sequentially to a 25 mL dry round-bottom flask and stirred until homogeneous to obtain the reaction mixture; 2. Azacyclic propanation reaction: The reaction flask was placed in a 70°C oil bath and stirred for 8 hours. The reaction was stopped when the 4-methylstyrene was basically completely converted by TLC monitoring. 3. Post-treatment and purification: After cooling to room temperature, 10 mL of saturated sodium chloride aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate (10 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, and 1,2-dichloroethane was removed by vacuum distillation. The mixture was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 12:1) to give 116 mg of white solid 1-p-toluenesulfonyl-2-(4-methylphenyl)azacyclopropane, with a yield of 76% and a purity of 98.4% (HPLC).
[0044] Structural characterization: ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J=8.0 Hz, 2H), 7.28–7.15 (m, 6H), 3.60–3.50 (m, 1H), 3.18–3.08 (m, 1H), 2.82–2.72 (m, 1H), 2.44 (s, 3H), 2.35 (s, 3H), 1.92–1.82 (m, 1H), 1.72–1.62 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 143.4, 138.6, 137.5, 135.2, 129.5, 129.2, 128.4, 127.8, 45.1, 42.7, 38.4, 27.6, 21.5, 21.2; HRMS (ESI) m / z: [M+Na]⁺ Calculated value C 17 H 19 NO2SNa: 332.0980, measured value: 332.0979.
[0045] Example 6
[0046] 1. Construction of the reaction system: Under argon protection, 10 mL of toluene, cyclopentene (0.5 mmol, 36 mg), [N-(p-toluenesulfonyl)imide]iodobenzene (0.75 mmol, 246 mg), bis(triphenylphosphine)molybdenum dichloride (0.04 mmol, 28.2 mg), 2,2'-bipyridine (0.08 mmol, 12.4 mg), and zinc powder (1.1 mmol, 71.5 mg) were added sequentially to a 25 mL dry round-bottom flask, and stirred until homogeneous to obtain the reaction mixture; 2. Azacyclopropanation reaction: Place the reaction flask in a 55°C oil bath and stir for 14 hours. TLC monitoring shows that the cyclopentene is basically completely converted, and then the reaction is stopped. 3. Post-treatment and purification: After cooling to room temperature, 10 mL of saturated sodium chloride aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate (10 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, and toluene was removed by vacuum distillation. The mixture was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 15:1) to obtain 114 mg of white solid 1-p-toluenesulfonyl-2-cyclopentylazacyclopropane, with a yield of 70% and a purity of 97.2% (HPLC).
[0047] Structural characterization: ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 3.48–3.38 (m, 1H), 3.14–3.04 (m, 1H), 2.78–2.68 (m, 1H), 2.41 (s, 3H), 1.95–1.25 (m, 8H); ¹³C NMR (100 MHz, CDCl₃) δ 143.4, 135.2, 129.4, 127.7, 46.0, 42.9, 38.8, 32.2, 28.5, 27.7, 25.3, 21.4; HRMS (ESI) m / z: [M+Na]⁺ Calculated value C 15 H 21 NO2SNa: 302.1186, measured value: 302.1184.
[0048] In summary, the yield of this method is consistently between 68% and 82% (up to 82% in Example 3); the HPLC purity is ≥97% (99% in Example 3); the product structure is confirmed by triple characterization using ¹H NMR, ¹³C NMR, and HRMS; and the purity meets the requirements for the preparation of pharmaceutical intermediates and functional materials.
[0049] The above embodiments are not intended to limit the present invention, and the present invention is not limited to the examples given above. Any changes, modifications, additions or substitutions made by those skilled in the art within the scope of the technical solution of the present invention are also within the protection scope of the present invention.
Claims
1. A method for the synthesis of aziridine compounds based on molybdenum catalysis, characterized by: The method comprises the following steps: Step S1, raw material preparation: under the protection of inert gas, an olefin compound, a nitrogen source precursor, a molybdenum-based metal catalyst, a ligand and a reducing agent are added into an organic solvent according to a molar ratio, and stirred uniformly to obtain a reaction mixture; Step S2, aziridination reaction: the reaction mixture is stirred at 25-70°C for 6-20 h, and the reaction is stopped when the olefin compound is substantially completely converted according to TLC monitoring; Step S3, post-treatment and purification: the reaction liquid is cooled to room temperature, saturated sodium chloride aqueous solution is added to quench the reaction, extracted with ethyl acetate for 3 times, the organic phase is combined, dried with anhydrous sodium sulfate, the organic solvent is removed by reduced pressure distillation, and then separated and purified by column chromatography to obtain an aziridine compound.
2. The process for the synthesis of molybdenum catalyzed aziridines based compounds according to claim 1, characterized by the fact that: The reaction general formula is:
3. wherein, R 1 R 2 R 3 R 4 Each is independently selected from: hydrogen, C1–C6 alkyl, C3–C8 cycloalkyl, C6–C 10 One of aryl, C1–C6 alkoxy, or halogen; any two groups can be linked to form a cyclic olefin; Ts is p-toluenesulfonyl, Ph is phenyl; R 5 It is a sulfonyl or acyl group; The olefin compound includes one or more of styrene, 4-methylstyrene, 4-chlorostyrene, cyclohexene and α-methylstyrene; The aziridine compound is one of 1-p-toluenesulfonyl-2-phenylaziridine, 1-p-toluenesulfonyl-2-(4-chlorophenyl)aziridine and 1-p-toluenesulfonyl-2-cyclohexylaziridine.
4. The process for the synthesis of molybdenum catalyzed aziridines based compounds according to claim 1, characterized by the fact that: The nitrogen source precursor is selected from one of [N-(p-toluenesulfonyl)imine]iodobenzene, N-(p-toluenesulfonyl)oxaziridine and N-methanesulfonyliminoiodobenzene.
5. The process for the synthesis of molybdenum catalyzed aziridines based compounds according to claim 1, characterized by the fact that: The molybdenum-based metal catalyst is selected from one or more of molybdenum dichloride dioxide, molybdenum hexacarbonyl and bis(triphenylphosphine)molybdenum dichloride.
6. The process for the synthesis of molybdenum catalyzed aziridines based compounds according to claim 1, characterized by the fact that: The ligand is selected from one or more of triphenylphosphine, tricyclohexylphosphine and 2,2'-bipyridine.
7. The process for the synthesis of molybdenum catalyzed aziridines based compounds according to claim 1, characterized by the fact that: The reducing agent is selected from one or more of zinc powder, iron powder and triethylsilane.
8. The process for the synthesis of molybdenum catalyzed aziridines based compounds according to claim 1, characterized by the fact that: The organic solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, toluene and tetrahydrofuran; the amount of the organic solvent is 6-12 mL per mmol of the olefin compound.
9. The process for the synthesis of molybdenum catalyzed aziridines based compounds according to claim 1, characterized by the fact that: The inert gas is nitrogen or argon; the eluent used in the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the two is 8:1-20:
1.
10. The process for the synthesis of molybdenum catalyzed aziridines based compounds as claimed in claim 1, wherein: The molar ratio of the olefin compound to the nitrogen source precursor is 1:1.2-1.8; the amount of the molybdenum-based metal catalyst is 3-8 mol% of the molar amount of the olefin compound.
11. The process for the synthesis of molybdenum catalyzed aziridines based compounds as claimed in claim 1, wherein: The molar ratio of the ligand to the molybdenum-based metal catalyst is 2:1-3:1; the amount of the reducing agent is 1.5-2.2 times of the molar amount of the nitrogen source precursor.