Method for electrochemical synthesis of trifluoromethyl selenoxazoline compounds and application thereof
By employing an electrochemical synthesis strategy, trifluoromethylselenoyl oxazoline compounds were prepared using N-allylamide compounds and trifluoromethylselenoyl tetramethylammonium as raw materials through electrolytic reaction. This approach overcomes the shortcomings of existing methods for synthesizing trifluoromethylselenoyl oxazoline compounds, achieving efficient, simple, and environmentally friendly compound preparation with significant antifungal activity.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- CHANGZHOU PENGSENFU BIOTECHNOLOGY CO LTD
- Filing Date
- 2026-03-12
- Publication Date
- 2026-06-05
AI Technical Summary
Existing technologies do not yet provide efficient, mild, simple and cost-effective methods for synthesizing trifluoromethylselenoyl oxazoline compounds.
An electrochemical synthesis strategy was adopted, using N-allylamide compounds and trifluoromethylselenomethylammonium as raw materials. The reaction was carried out in an organic solvent under constant current electrolysis, and the trifluoromethylselenomethyloxazoline compounds were purified by column chromatography.
We have achieved efficient construction of trifluoromethylselenoyl oxazoline compounds, which have excellent antifungal properties. The process is simple, environmentally friendly, and low-cost, and has broad prospects for pharmaceutical applications.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis chemistry, and in particular to a method and application for the electrochemical synthesis of trifluoromethylselenyl oxazoline compounds. Background Technology
[0002] Trifluoromethylselenoyl group is a selenium-containing functional group with unique reaction properties and important application value. It plays a key role in regulating the physicochemical properties of organic molecules, enhancing drug bioactivity, and constructing novel functional materials. These compounds, with their excellent lipophilicity, electronic effects, and structural stability, have shown broad application potential in cutting-edge fields such as drug discovery, organocatalysis, and advanced optoelectronic materials, and have received continuous attention in recent years. Currently, various efficient and highly selective trifluoromethylselenoylation strategies have been developed, and a series of structurally diverse trifluoromethylselenoyl compounds have been successfully synthesized, whose significant physiological activities and application prospects have attracted considerable attention.
[0003] Oxazolines are an important class of oxygen- and nitrogen-containing heterocyclic compounds with wide applications in asymmetric catalysis, drug modification, functional material synthesis, and ligand design. Therefore, introducing trifluoromethylselenoyl groups into the oxazoline skeleton to construct novel derivatives with potential functional properties not only contributes to enriching the structural diversity of selenium-containing heterocyclic compounds but also provides an important research direction for developing novel functional molecules. However, to date, no synthetic methods for trifluoromethylselenoyl oxazolines have been reported in the literature.
[0004] Based on the current research status, developing an efficient, mild, simple, and cost-effective synthetic method for trifluoromethylselenoyl oxazoline compounds is of significant research importance. Therefore, this application proposes a novel synthetic route based on an electrochemical strategy, aiming to provide a novel and practical synthetic path for the construction of this type of compound. Summary of the Invention
[0005] The purpose of this invention is to provide a method for electrochemical synthesis of trifluoromethylselenyl oxazoline compounds and its application.
[0006] The objective of this invention can be achieved through the following technical solutions: A method for the electrochemical synthesis of trifluoromethylselenoyl oxazoline compounds includes the following steps: An N-allylamide compound having the structure shown in formula (I), a trifluoromethylselenomethylammonium compound having the structure shown in formula (II), an electrolyte, and an acid were added to an organic solvent to form a reaction system. The reaction was carried out under constant current and room temperature conditions with stirring. After the reaction was completed, the solvent was removed from the reaction solution under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain a trifluoromethylselenomethyloxazoline compound having the structure shown in formula (III). The reaction equation is shown below:
[0007] Among them, R in compound (I) 1 and R 2 Each is independently selected from aryl groups.
[0008] Preferably, the molar ratio of the N-allylamide compound with the structure shown in formula (I) to the trifluoromethylselenomethyltetramethylammonium with the structure shown in formula (II) is 1:1 to 1:2, and more preferably 1:1.5.
[0009] Preferably, the anode material is one of graphite felt, platinum sheet, zinc sheet, aluminum sheet, and carbon rod, with carbon rod being preferred; the cathode material is one of platinum sheet, nickel sheet, tin sheet, lead sheet, and copper sheet, with platinum sheet being preferred.
[0010] Preferably, the current for the constant current reaction is 8-15 mA, more preferably 10 mA, a diaphragm-free single-chamber electrolytic cell is used, the reaction time is 8-12 h, and the reaction temperature is room temperature.
[0011] Preferably, the organic solvent is any one of tetrahydrofuran, dichloromethane, dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, benzene, and acetonitrile, with acetonitrile being the most preferred.
[0012] Preferably, the electrolyte is any one of tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, sodium tetrafluoroborate, sodium perchlorate, and lithium perchlorate, with tetrabutylammonium hexafluorophosphate being the most preferred. The molar concentration of the electrolyte relative to the organic solvent in the reaction system (electrolyte / organic solvent) is 0.15 mol / L to 0.3 mol / L.
[0013] Preferably, the acid is any one of acetic acid, propionic acid, and trifluoroacetic acid, with trifluoroacetic acid being the most preferred.
[0014] Preferably, after the reaction is completed, the reaction solution is concentrated under reduced pressure, and the concentrate is separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent, wherein the volume ratio of petroleum ether to ethyl acetate is (1-50):1. The eluent is collected, and the solvent is evaporated by rotary evaporation to obtain the trifluoromethylselenoxazolinoid compound shown in formula (III).
[0015] The trifluoromethylselenoxazolinoid compound of formula (III) prepared by this invention has excellent antifungal properties and can be well applied to the preparation of antifungal drugs.
[0016] Furthermore, the trifluoromethylselenoxazolino compounds of the present invention can be formulated alone or in combination with one or more pharmaceutically acceptable carriers for drug delivery. For example, solvents, diluents, etc., can be used for oral dosage forms such as tablets, capsules, dispersible powders, granules, etc. Various dosage forms can be prepared according to methods well known in the pharmaceutical field. These pharmaceutical formulations may contain, for example, 0.05% to 90% by weight of the active ingredient in combination with the carrier, more commonly about 10% to 50% by weight of the active ingredient. The dosage of the trifluoromethylselenoxazolino compounds of the present invention can be from 0.005 to 5000 mg / kg / day, and may exceed this range depending on the severity of the disease or the dosage form.
[0017] The beneficial effects of this invention are: 1. Raw materials are readily available and the cost is low: The raw materials are inexpensive and readily available N-allylamide compounds and trifluoromethylselenomethyltetramethylammonium, which are widely available and easy to prepare on a large scale.
[0018] 2. The method is green and environmentally friendly: It adopts an electrochemical synthesis strategy, which does not require the use of chemical oxidants or metal catalysts. The reaction conditions are mild and in line with the concept of green chemistry.
[0019] 3. Simple operation and excellent efficiency: The target product can be efficiently constructed with only one reaction step. It has the advantages of high yield, good functional group compatibility and simple post-processing, and has good potential for practical application.
[0020] 4. The product exhibits significant activity and has broad application prospects: Experimental results show that the obtained trifluoromethylselenoyl oxazoline compounds exhibit excellent antifungal activity, demonstrating significant potential for development into antifungal drugs and showing significant prospects for pharmaceutical applications.
[0021] Of course, any product implementing this invention does not necessarily need to achieve all of the advantages described above at the same time. Detailed Implementation
[0022] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0023] This invention provides the following technical solution: a method for electrochemically synthesizing trifluoromethylselenoyl oxazoline compounds, comprising the following steps: In an organic solvent, an N-allyl amide compound having the structure shown in formula (I) and a trifluoromethylselenomethylammonium compound having the structure shown in formula (II) were used as reactants. The reaction was carried out under air, room temperature, and electrochemical conditions. After the reaction was completed, the solvent was removed from the reaction solution under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain a trifluoromethylselenooxazoline with the structure shown in formula (III). The reaction equation is shown below:
[0024] In the compound of formula (I), R1 and R2 are each independently selected from aryl groups.
[0025] Example 1 The reaction equation is shown below:
[0026] Under air atmosphere, N-(2-phenylallyl)benzamide (0.1 mmol), trifluoromethylselenomethyltetramethylammonium (0.15 mmol), tetrabutylammonium hexafluorophosphate (0.003 mol), trifluoroacetic acid (0.1 mL), and acetonitrile solvent (10 mL) were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, and the electrolysis current was set to 10 mA. The electrolysis reaction was continued for 10 hours under air atmosphere and room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 8:1) to obtain 31 mg of a colorless oily liquid, with a yield of 80%.
[0027] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.05-8.03 (m, 2H), 7.56-7.50 (m, 1H), 7.49-7.45 (m, 2H), 7.42-7.39 (m, 4H), 7.35-7.31 (m, 1H), 4.42(d, J = 15.0 Hz, 1H), 4.22 (d, J = 15.0 Hz, 1H), 3.58 (d, J = 13.6 Hz, 1H), 3.49 (d, J = 13.6 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 163.29, 143.26, 131.94,130.37 (q,J = 306.4 Hz), 129.16, 129.22, 128.62, 128.23, 127.31, 125.71,85.96, 67.92, 40.54. 19 F NMR (376 MHz, CDCl3) δ -40.90. Example 2 The reaction equation is shown below:
[0028] Under air atmosphere, N-(2-(4-fluorophenyl)allyl)benzamide (0.1 mmol), trifluoromethylselenomethyltetramethylammonium (0.15 mmol), 0.003 mol of tetrabutylammonium hexafluorophosphate, trifluoroacetic acid (0.1 mL), and acetonitrile solvent (10 mL) were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and a platinum sheet cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, and the electrolysis current was set to 10 mA. The electrolysis reaction was continued for 10 hours under air atmosphere and room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 10:1) to obtain 33 mg of a colorless oily liquid, with a yield of 81%.
[0029] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.13-8.11 (m, 2H), 7.59-7.53 (m, 1H), 7.47-7.45 (m, 2H), 7.41-7.32 (m, 2H), 7.18-7.08 (m, 2H), 4.43(d, J = 15.0 Hz, 1H), 4.28 (d, J = 15.0 Hz, 1H), 3.52 (d, J = 13.6 Hz, 1H), 3.41 (d, J = 13.6 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 165.86, 163.63 (d, J =247.7 Hz), 137.91 (d, J = 3.1 Hz), 132.95, 131.68 (q, J= 306.3 Hz), 128.99,128.52, 127.75, 126.91 (d, J = 8.3 Hz), 115.98 (d, J = 21.8 Hz), 86.69, 67.00, 40.52. 19 F NMR (376 MHz, CDCl3) δ -40.98, -113.47. Example 3
[0030] Under air atmosphere, N-(2-(4-chlorophenyl)allyl)benzamide (0.1 mmol), trifluoromethylselenomethyltetramethylammonium (0.15 mmol), 0.003 mol of tetrabutylammonium hexafluorophosphate, trifluoroacetic acid (0.1 mL), and acetonitrile solvent (10 mL) were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and a platinum sheet cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, and the electrolysis current was set to 10 mA. The electrolysis reaction was continued for 10 hours under air atmosphere and room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 5:1) to obtain 37 mg of a colorless oily liquid, with a yield of 89%.
[0031] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.05-8.02 (m, 2H), 7.54-7.50 (m, 1H), 7.48-7.46 (m, 2H), 7.41-7.35 (m, 4H), 4.36 (d, J = 15.0 Hz, 1H), 4.25 (d, J = 15.0 Hz, 1H), 3.59 (d, J = 13.7 Hz, 1H), 3.41 (d, J = 13.7Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 163.91, 141.71, 134.62, 132.13, 130.93 (q, J= 306.4 Hz), 129.56, 128.73, 128.23, 127.29, 126.18, 86.04, 66.99, 40.67. 19 F NMR (376 MHz, CDCl3) δ -40.91. Example 4 The reaction equation is shown below:
[0032] Under air atmosphere, N-(2-(4-bromophenyl)allyl)benzamide (0.1 mmol), trifluoromethylselenomethyltetramethylammonium (0.15 mmol), 0.003 mol of tetrabutylammonium hexafluorophosphate, trifluoroacetic acid (0.1 mL), and acetonitrile solvent (10 mL) were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and a platinum sheet cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, and the electrolysis current was set to 10 mA. The electrolysis reaction was continued for 10 hours under air atmosphere and room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 7:1) to obtain 42 mg of a colorless oily liquid, with a yield of 90%.
[0033] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 7.3 Hz, 2H),7.56-7.53 (m, 3H), 7.48-7.44 (m, 2H), 7.25 (d, J = 8.6 Hz, 2H), 4.41 (d, J =15.0 Hz, 1H), 4.33 (d, J = 15.0 Hz, 1H), 3.53 (d, J = 13.7 Hz, 1H), 3.41 (d, J = 13.7 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 163.66, 142.41, 132.71, 131.89,130.46 (q, J= 306.3 Hz), 128.76, 128.52, 127.17, 126.57, 123.56, 87.65,68.04, 40.62. 19 F NMR (376 MHz, CDCl3) δ -40.85. Example 5 The reaction equation is shown below:
[0034] Under air atmosphere, N-(2-(p-tolyl)allyl)benzamide (0.1 mmol), trifluoromethylselenomethyltetramethylammonium (0.15 mmol), 0.003 mol of tetrabutylammonium hexafluorophosphate, trifluoroacetic acid (0.1 mL), and acetonitrile solvent (10 mL) were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and a platinum sheet cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, and the electrolysis current was set to 10 mA. The electrolysis reaction was continued for 10 hours under air atmosphere and room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 10:1) to obtain 34 mg of a colorless oily liquid, with a yield of 86%.
[0035] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 7.6 Hz, 2H),7.55-7.51 (m, 1H), 7.48-7.43 (m, 2H), 7.26-7.24 (m, 2H), 7.22 (d, J = 7.7 Hz, 2H), 4.56 (d, J = 15.0 Hz, 1H), 4.34 (d, J = 15.0 Hz, 1H), 3.76 (d, J = 13.5Hz, 1H), 3.36 (d, J = 13.5 Hz, 1H), 2.37 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ163.04, 139.28, 138.26, 131.76, 130.51 (q, J= 306.2 Hz), 129.88, 128.69,128.32, 127.42, 124.73, 86.95, 66.91, 40.58, 21.28. 19 F NMR (376 MHz, CDCl3) δ-40.84. Example 6 The reaction equation is shown below:
[0036] Under air atmosphere, N-(2-(3-methoxyphenyl)allyl)benzamide (0.1 mmol), trifluoromethylselenomethyltetramethylammonium (0.15 mmol), 0.003 mol of tetrabutylammonium hexafluorophosphate, trifluoroacetic acid (0.1 mL), and acetonitrile solvent (10 mL) were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, and the electrolysis current was set to 10 mA. The electrolysis reaction was continued for 10 hours under air atmosphere and room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 2:1) to obtain 36 mg of a colorless oily liquid, with a yield of 87%.
[0037] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 7.7 Hz, 2H),7.54-7.51 (m, 1H), 7.45-7.43 (m, 2H), 7.36-7.31 (m, 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 4.39 (d, J = 15.0 Hz, 1H), 4.29 (d, J = 15.0Hz, 1H), 3.81 (s, 3H), 3.66 (d, J = 13.6 Hz, 1H), 3.56 (d, J = 13.6 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 163.45, 160.68, 143.98, 132.81, 131.36 (q,J =306.4 Hz), 131.21, 128.61, 128.56, 128.40, 127.30, 116.95, 113.20, 111.18,86.91, 66.86, 55.43, 40.51. 19 F NMR (376 MHz, CDCl3) δ -40.55. Example 7 The reaction equation is shown below:
[0038] Under air atmosphere, N-(2-(2-naphthyl)allyl)benzamide (0.1 mmol), trifluoromethylselenomethyltetramethylammonium (0.15 mmol), 0.003 mol of tetrabutylammonium hexafluorophosphate, trifluoroacetic acid (0.1 mL), and acetonitrile solvent (10 mL) were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and a platinum sheet cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, and the electrolysis current was set to 10 mA. The electrolysis reaction was continued for 10 hours under air atmosphere and room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 5:1) to obtain 39 mg of a colorless oily liquid, with a yield of 91%.
[0039] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.10-8.08 (m, 2H), 7.91-7.88 (m, 2H), 7.87-7.83 (m, 2H), 7.57-7.43 (m, 6H), 4.48 (d, J = 15.1 Hz, 1H), 4.36 (d, J = 15.1 Hz, 1H), 3.67 (d, J = 13.6 Hz, 1H), 3.58 (d, J = 13.6Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 163.06, 139.31, 133.10, 133.04, 131.89,130.56 (q, J= 306.5 Hz), 129.22, 128.66, 128.49, 128.36, 127.82, 127.33,126.88, 126.75, 123.80, 122.42, 87.12, 66.95, 40.39. 19 F NMR (376 MHz, CDCl3)δ -40.87. Example 8 The reaction equation is shown below:
[0040] Under air atmosphere, 0.1 mmol of 4-fluoro-N-(2-phenylallyl)benzamide, 0.15 mmol of trifluoromethylselenomethyltetramethylammonium, 0.003 mol of tetrabutylammonium hexafluorophosphate, 0.1 mL of trifluoroacetic acid, and 10 mL of acetonitrile solvent were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 10 mA, and the electrolysis reaction was continued for 10 hours under air atmosphere and room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 10:1) to obtain 37 mg of a colorless oily liquid, with a yield of 91%.
[0041] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.10-8.05 (m, 2H), 7.51-7.37 (m, 5H), 7.15-7.02 (m, 2H), 4.49 (d, J = 15.0 Hz, 1H), 4.25 (d, J = 15.0Hz, 1H), 3.57 (d, J = 13.6 Hz, 1H), 3.41 (d, J = 13.6 Hz, 1H). 13 C NMR (100MHz, CDCl3) δ 165.16 (d, J = 252.4 Hz), 164.81, 141.13, 131.71 (d, J = 8.9Hz), 130.83 (q, J= 306.1 Hz), 130.56, 129.16, 128.61, 124.70, 123.64 (d, J =3.1 Hz), 115.82 (d, J = 22.0 Hz), 87.31, 66.92, 40.51. 19 F NMR (376 MHz, CDCl3) δ -40.92, -106.78. Example 9 The reaction equation is shown below:
[0042] Under air atmosphere, 0.1 mmol of 4-chloro-N-(2-phenylallyl)benzamide, 0.15 mmol of trifluoromethylselenomethyltetramethylammonium, 0.003 mol of tetrabutylammonium hexafluorophosphate, 0.1 mL of trifluoroacetic acid, and 10 mL of acetonitrile solvent were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, and the electrolysis current was set to 10 mA. The electrolysis reaction was continued for 10 hours under air atmosphere and room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5:1) to obtain 37 mg of a colorless oily liquid, with a yield of 89%.
[0043] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.97-7.95 (m, 2H), 7.46-7.33 (m, 7H), 4.41 (d, J = 15.1 Hz, 1H), 4.27 (d, J = 15.1 Hz, 1H), 3.56 (d, J = 13.7 Hz, 1H), 3.49 (d, J = 13.8 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ163.15, 143.27, 139.13, 130.71 (q, J= 306.6 Hz), 129.56, 129.28, 128.91,128.64, 125.71, 124.67, 87.30, 67.11, 40.61. 19 F NMR (376 MHz, CDCl3) δ -40.91. Example 10 The reaction equation is shown below:
[0044] Under air atmosphere, 0.1 mmol of 4-bromo-N-(2-phenylallyl)benzamide, 0.15 mmol of trifluoromethylselenomethyltetramethylammonium, 0.003 mol of tetrabutylammonium hexafluorophosphate, 0.1 mL of trifluoroacetic acid, and 10 mL of acetonitrile solvent were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, and the electrolysis current was set to 10 mA. The electrolysis reaction was continued for 10 hours under air atmosphere and room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 7:1) to obtain 43 mg of a colorless oily liquid, with a yield of 92%.
[0045] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.1 Hz, 2H),7.63-7.55 (m, 2H), 7.45-7.32 (m, 5H), 4.43 (d, J = 15.1 Hz, 1H), 4.36 (d, J =15.1 Hz, 1H), 3.66 (d, J = 13.7 Hz, 1H), 3.56 (d, J = 13.7 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 164.24, 141.06, 132.94, 130.81 (q, J = 306.3 Hz), 129.91,129.57, 128.64, 126.82, 126.42, 124.81, 87.31, 67.21, 40.55. 19F NMR (376 MHz, CDCl3) δ -40.74. Example 11 The reaction equation is shown below:
[0046] Under air atmosphere, N-(2-phenylallyl)thiophene-2-carboxamide (0.1 mmol), trifluoromethylselenomethyltetramethylammonium (0.15 mmol), tetrabutylammonium hexafluorophosphate (0.003 mol), trifluoroacetic acid (0.1 mL), and acetonitrile solvent (10 mL) were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, and the electrolysis current was set to 10 mA. The electrolysis reaction was continued for 10 hours under air atmosphere and room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 7:1) to obtain 31 mg of a colorless oily liquid, with a yield of 79%.
[0047] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 4.0, 1.5Hz, 1H), 7.50 (dd, J = 5.0, 1.5 Hz, 1H), 7.42-7.37 (m, 4H), 7.35-7.32 (m,1H), 7.12 (dd, J = 5.0, 3.5 Hz, 1H), 4.38 (d, 1H, J = 14.5 Hz), 4.24 (d, J =15.0 Hz, 1H), 3.56 (d, J = 13.5 Hz, 1H), 3.48 (d, J = 14.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 158.7, 141.8, 130.8, 130.6 (q, J = 304.6 Hz), 130.4,129.7, 128.9, 128.4, 127.7, 124.6, 87.5, 66.8, 40.2 (d, J = 2.1 Hz). 19F NMR (376 MHz, CDCl3) δ -40.9. Example 12 The reaction equation is shown below:
[0048] Under air atmosphere, 0.1 mmol of 4-methyl-N-(2-phenylallyl)benzamide, 0.15 mmol of trifluoromethylselenomethyltetramethylammonium, 0.003 mol of tetrabutylammonium hexafluorophosphate, 0.1 mL of trifluoroacetic acid, and 10 mL of acetonitrile solvent were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 10 mA, and the electrolysis reaction was continued for 10 hours under air atmosphere and room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 10:1) to obtain 36 mg of a colorless oily liquid, with a yield of 90%.
[0049] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.8 Hz, 2H), 7.42 (d, J = 3.5 Hz, 4H), 7.38-7.32 (m, 1H), 7.28 (d, J = 7.3 Hz, 2H), 4.37(d, J = 14.9 Hz, 1H), 4.22 (d, J = 14.9 Hz, 1H), 3.56 (d, J = 13.5 Hz, 1H), 3.49 (d, J = 13.5 Hz, 1H), 2.41 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 164.10,143.33, 131.78 (q, J = 306.6 Hz), 129.85, 129.11, 128.51, 124.63, 124.31,87.18, 66.19, 40.05, 21.67. 19 F NMR (376 MHz, CDCl3) δ -40.47. Example 13 The reaction equation is shown below:
[0050] Under air atmosphere, 0.1 mmol of 4-methoxy-N-(2-phenylallyl)benzamide, 0.15 mmol of trifluoromethylselenomethyltetramethylammonium, 0.003 mol of tetrabutylammonium hexafluorophosphate, 0.1 mL of trifluoroacetic acid, and 10 mL of acetonitrile solvent were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, and the electrolysis current was set to 10 mA. The electrolysis reaction was continued for 10 hours under air atmosphere and room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 2:1) to obtain 32 mg of a colorless oily liquid, with a yield of 78%.
[0051] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.6 Hz, 2H),7.42 (s, 4H), 7.36-7.31 (m, 1H), 6.98 (d, J = 8.6 Hz, 2H), 4.33 (d, J = 14.8Hz, 1H), 4.21 (d, J = 14.8 Hz, 1H), 3.92 (s, 3H), 3.66 (d, J = 13.5 Hz, 1H), 3.51 (d, J = 13.5 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 163.83, 162.63, 142.75,130.91 (q, J = 306.3 Hz), 130.09, 128.68, 128.29, 125.64, 119.68, 114.12,86.09, 66.99, 55.08, 40.59. 19 F NMR (376 MHz, CDCl3) δ -40.96. Example 14: Antifungal Activity Study This invention provides oxazoline compounds with antifungal activity, their synthesis methods, and applications. The oxazoline test strains cover three major pathogenic fungi (Candida, Cryptococcus, and Aspergillus), and fluconazole and itraconazole are used as positive controls. The in vitro antifungal activity of the target compounds is evaluated by the minimum inhibitory concentration (MIC, μg / mL).
[0052] The testing method is as follows: Five susceptible pathogenic fungi were selected (Candida albicans SC5314, Candida albicans GIM2.194, Candida tropicalis GIM2.183, Cryptococcus neoformans GIM2.209, and Aspergillus fumigatus CGMCC3.7795). Fungal cultures cultured to the logarithmic growth phase were prepared into standard concentration suspensions and inoculated into fungal growth medium (RPMI 1640 medium) conforming to the National Committee for Clinical Laboratory Standards (NCCLS) protocol. In each well of a 96-well plate, medium containing serially diluted compounds (all target compounds were dissolved in dimethyl sulfoxide (DMSO) and serially diluted to a concentration range of 0.03-64 μg / mL) was added, followed by inoculation with the adjusted fungal suspension. The plates were incubated at 30°C and 200 rpm in a constant temperature shaking incubator. Candida and Cryptococcus species were incubated for 18-24 hours, while the incubation time for Aspergillus fumigatus was appropriately extended according to its growth characteristics. After incubation, the results were observed. The minimum drug concentration that completely inhibited visible fungal growth in the wells was defined as the minimum inhibitory concentration (MIC). A negative control group (fungal growth medium containing the same DMSO content) and a positive control group (fluconazole and itraconazole at the same concentration gradient as the compound) were also set up.
[0053] Detailed test results are shown in the table below:
[0054] Among the tested oxazoline compounds, different derivatives showed significant differences in inhibitory activity against pathogenic fungi of the genera *Candida*, *Cryptococcus*, and *Aspergillus*. Compounds 1c, 1i, and 1j exhibited broad-spectrum antifungal activity comparable to the positive control itraconazole, with minimum inhibitory concentrations (MICs) as low as <0.03 μg / mL against *Candida albicans* and *Candida tropicalis*, and also showed good inhibitory effects against *Cryptococcus neoformans* and *Aspergillus fumigatus*. Compounds 1b and 1h showed good inhibitory effects against a variety of fungi. In contrast, compounds 1a, 1e, and 1l showed weaker activity, with MIC values >16 μg / mL against most tested strains. Overall, some oxazoline derivatives possess excellent antifungal potential, especially their outstanding inhibitory activity against *Candida*, and warrant further development.
[0055] In summary, this invention uses inexpensive and readily available N-allylamide compounds and trifluoromethylselenomethylammonium as raw materials, eliminating the need for transition metal catalysts and chemical oxidants, making the reaction green and environmentally friendly. The reaction conditions are relatively mild, the operation is simple, the cost is low, and the reaction efficiency is high. This invention requires only one step to obtain the target product, with high yield, good functional group compatibility, and simple post-processing, demonstrating excellent application potential.
[0056] Any aspects of this invention not described in detail are well-known to those skilled in the art.
[0057] The above description is merely an example and illustration of the concept of the present invention. Those skilled in the art can make various modifications or additions to the specific embodiments described or use similar methods to replace them, as long as they do not deviate from the concept of the invention or exceed the scope defined in the claims, they should all fall within the protection scope of the present invention.
Claims
1. A method for the electrochemical synthesis of trifluoromethylselenoyloxazoline compounds, characterized in that: An N-allylamide compound having the structure shown in formula (I), a trifluoromethylselenomethylammonium compound having the structure shown in formula (II), an electrolyte, and an acid were added to an organic solvent to form a reaction system. The reaction was carried out under constant current and room temperature conditions with stirring. After the reaction was completed, the solvent was removed from the reaction solution under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain a trifluoromethylselenomethyloxazoline compound having the structure shown in formula (III). The reaction equation is shown below: ； Among them, R in compound (I) 1 and R 2 Each is independently selected from aryl groups.
2. The method for electrochemical synthesis of trifluoromethylselenoyl oxazoline compounds according to claim 1, characterized in that: The molar ratio of the N-allylamide compound with the structure shown in formula (I) to the trifluoromethylselenomethyltetramethylammonium compound with the structure shown in formula (II) is 1:1 to 1:
2.
3. The method for electrochemical synthesis of trifluoromethylselenoyl oxazoline compounds according to claim 1, characterized in that: The anode material used in the electrochemical process is one of graphite felt, platinum sheet, zinc sheet, aluminum sheet, and carbon rod, and the cathode material is one of platinum sheet, nickel sheet, tin sheet, lead sheet, and copper sheet.
4. The method for electrochemical synthesis of trifluoromethylselenoyl oxazoline compounds according to claim 1, characterized in that: The stirring reaction time is 8-12 h, the constant current is 8-15 mA, and the electrochemical synthesis is performed using a diaphragmless single-chamber electrolytic cell.
5. The method for electrochemical synthesis of trifluoromethylselenoyl oxazoline compounds according to claim 1, characterized in that: The organic solvent is any one of tetrahydrofuran, dichloromethane, dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, benzene, and acetonitrile.
6. The method for electrochemical synthesis of trifluoromethylselenoyl oxazoline compounds according to claim 1, characterized in that: The electrolyte is any one of tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, sodium tetrafluoroborate, sodium perchlorate, and lithium perchlorate, and the molar concentration of the electrolyte relative to the organic solvent in the reaction system is 0.15 mol / L-0.3 mol / L.
7. The method for electrochemical synthesis of trifluoromethylselenoxazole compounds according to claim 1, characterized in that: The acid mentioned is one of acetic acid, propionic acid, and trifluoroacetic acid.
8. The method for electrochemical synthesis of trifluoromethylselenoyloxazoline compounds according to claim 1, characterized in that: The column chromatography purification is specifically as follows: the crude product is separated by column chromatography, using a mixture of petroleum ether and ethyl acetate as the eluent, wherein the volume ratio of petroleum ether to ethyl acetate is (1-50):
1. The eluent is collected, and the solvent is rotary evaporated to obtain the trifluoromethylselenoxazolinoid compound shown in formula (III).
9. The application of a trifluoromethylselenyl oxazoline compound with the structure shown in formula (III) prepared by the electrochemical synthesis of trifluoromethylselenyl oxazoline compounds as described in claim 1, characterized in that: The trifluoromethylselenoxazolinoid compound or its medically acceptable salt or pharmaceutically acceptable carrier or excipient can be used to prepare drugs for the treatment or prevention of fungal infections.