A method for preparing azole-substituted ether compounds under visible light promotion

Abstract

The application relates to the technical field of organic synthetic chemistry, in particular to a preparation method of an azole group substituted ether compound promoted by visible light, the azole group substituted ether compound is prepared by stirring reaction of azole and ethylene ether as reaction raw materials under certain temperature conditions and light source irradiation to obtain an azole group hemiacetal amine compound. The application has the advantages of simple reaction condition, first realization of N-alkylation reaction of azole compound in the absence of a light catalyst, environmental friendliness, mild condition, simple operation, wide substrate application range and the like; and the application provides a convenient means for constructing azole hemiacetal amine compounds with potential biological activity and pharmacological action.

Description

Technical Field

[0001] This invention relates to the field of organic synthetic chemistry, specifically to a method for preparing azole-substituted ether compounds using visible light-promoted synthesis. Background Technology

[0002] Currently, more than half of drug molecules are nitrogen-containing heterocyclic compounds. As an important class of nitrogen heterocyclic structural units, azole compounds are widely found in a variety of natural products and drug molecules, and are important building blocks for constructing bioactive compounds in new drug development ((a) Kantheti S., Narayan R., Raju KVSNRSC Adv., 2015, 5, 3687; (b) Kane, Aidan; Carter, Dee A. Pharmaceuticals 2022, 15(4), 482). Among them, azolyl hemiacetals possess physiological and pharmaceutical activities such as antibacterial, anti-inflammatory, antiviral, and anticancer properties ((a) Bonnac, LF, Mansky, LM; Patterson, SE, J. Med. Chem. 2013, 56, 9403−9414. (b) Cho, S.; Oh, S., Um, Y., Jung, JH, Ham, J., Shin, WS, Lee, S., Bioorg. Med. Chem. Lett. 2009, 19, 382−385.). On the other hand, azolyl hemiacetals are also important chemical intermediates. With the deepening of various application research, their production capacity and properties have gradually become unable to meet further demands. Therefore, in recent years, the synthesis and performance study of azolyl hemiacetals and their derivatives have been a research hotspot. However, most existing reactions are carried out at high temperatures and under inert gas protection, with harsh reaction conditions, complex operation steps and post-processing, and low yields. They require the use of expensive transition metal catalysts or chemical oxidants, resulting in high reaction costs and serious environmental pollution.

[0003] Hydroamination is one of the most direct and efficient methods for preparing azole hemiacetals. This type of reaction can directly yield the azole hemiacetal skeleton from readily available azoles and alkenes in a single step. For example, in 2017, Myznikov et al. reported the hydroamination of azoles with alkenyl ethers to azole hemiacetals in the absence of a catalyst (Tetrahedron Letters 2017, 58, 3842–3845). However, this reaction requires high temperatures and 3 equivalents of alkenyl ether, which not only affects the functional group tolerance of the substrate but also produces environmental side effects and increases reaction costs. In 2022, Zeng and Xu et al. used diphenyldiselenes as a catalyst to achieve the hydroamination of azoles with alkenyl ethers via an electrochemical method (Org. Lett. 2022, 24, 5345−5350). However, this method requires expensive electrochemical equipment, resulting in high costs.

[0004] Visible light is a clean and pollution-free energy source, and in recent years, visible light-promoted organic synthesis reactions have seen tremendous development (M.-Y. Cao, X. Ren and Z. Lu, Tetrahedron Lett. (2015, 56, 3732). However, a literature review shows that no method for synthesizing azole hemiacetals based on the hydroamination reaction of azole compounds with alkenyl ethers involving visible light has been reported to date. Therefore, this application reports a novel visible light-promoted synthesis method for azole hemiacetals without the use of a photocatalyst. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing azole-substituted ether compounds that is promoted by visible light, so as to solve the problems mentioned in the background art.

[0006] To achieve the above objectives, the present invention provides the following technical solution: a method for preparing azole-substituted ether compounds with visible light-promoted reaction, comprising the following steps: In an organic solvent, using a azole having the structure shown in formula (I) and an alkenyl ether having the structure shown in formula (II) as reactants, the reaction was carried out under visible light irradiation and with open stirring at room temperature. 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 an azole hemiacetal amine compound with the structure shown in formula (III). The reaction equation is shown below: ; Wherein, the compound of formula (I) is a tetrazolium, triazole or purine containing a substituent, wherein the substituent R is benzyl, furanyl, thiophene, naphthyl, or a phenyl substituted with one or more substituents, and the substituent is alkoxy, alkyl, trifluoromethyl, nitro, halogen or amide.

[0007] Compounds of formula (II) are non-cyclic alkenyl ethers and 2,3-dihydrofuran and 3,4-dihydropyran. Substituent R' is a C1-C20 alkyl, C4-C7 cycloalkyl, benzyl, or a phenyl group substituted with one or more substituents, wherein the substituent is alkoxy, alkyl, trifluoromethyl, nitro, halogen, or amide.

[0008] Preferably, the molar ratio of the azole structure shown in formula (I) to the ether structure shown in formula (II) is 1:1 to 1:1.2, and more preferably 1:1.1.

[0009] Preferably, the organic solvent is any one of dichloromethane, dichloroethane, chloroform, and nitromethane, with chloroform being the most preferred.

[0010] Preferably, the visible light is any one of sunlight, mercury lamp, fluorescent lamp, tungsten lamp, and LED lamp, with LED lamp being the most preferred.

[0011] Preferably, the reaction time is 50-70 hours.

[0012] 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 (1-30):1. The eluent is collected, and the solvent is evaporated by rotary evaporation to obtain the azolyl hemiaminal compound shown in formula (III).

[0013] Compared with the prior art, the beneficial effects of the present invention are: This invention uses inexpensive and readily available nitrogen azoles and alkenyl ethers as raw materials.

[0014] This invention requires no photocatalyst, is low in cost, and has high reaction efficiency.

[0015] This invention contains no metals or oxidants, making it green and environmentally friendly.

[0016] This invention can obtain the target product in just one step, with high yield, good functional group compatibility, and simple post-processing. The obtained product is an important pharmaceutical and organic synthesis intermediate. Attached Figure Description

[0017] Figure 1 The hydrogen spectrum of the product obtained in Example 1 of this invention; Figure 2 The carbon spectrum of the product obtained in Example 1 of this invention; Figure 3 The hydrogen spectrum of the product obtained in Example 2 of this invention; Figure 4 The carbon spectrum of the product obtained in Example 2 of this invention; Figure 5The hydrogen spectrum of the product obtained in Example 3 of this invention; Figure 6 The carbon spectrum of the product obtained in Example 3 of this invention; Figure 7 The hydrogen spectrum of the product obtained in Example 4 of this invention; Figure 8 The carbon spectrum of the product obtained in Example 4 of this invention; Figure 9 The hydrogen spectrum of the product obtained in Example 5 of this invention; Figure 10 The carbon spectrum of the product obtained in Example 5 of this invention; Figure 11 The hydrogen spectrum of the product obtained in Example 6 of this invention; Figure 12 The carbon spectrum of the product obtained in Example 6 of this invention; Figure 13 The hydrogen spectrum of the product obtained in Example 7 of this invention; Figure 14 The carbon spectrum of the product obtained in Example 7 of this invention; Figure 15 The hydrogen spectrum of the product obtained in Example 8 of this invention; Figure 16 The carbon spectrum of the product obtained in Example 8 of this invention; Figure 17 The hydrogen spectrum of the product obtained in Example 9 of this invention; Figure 18 The carbon spectrum of the product obtained in Example 9 of this invention; Figure 19 The hydrogen spectrum of the product obtained in Example 10 of this invention; Figure 20 The carbon spectrum of the product obtained in Example 10 of this invention; Figure 21 The hydrogen spectrum of the product obtained in Example 11 of this invention; Figure 22 The carbon spectrum of the product obtained in Example 11 of this invention; Figure 23 The hydrogen spectrum of the product obtained in Example 12 of this invention; Figure 24 The carbon spectrum of the product obtained in Example 12 of this invention; Figure 25 The hydrogen spectrum of the product obtained in Example 13 of this invention; Figure 26 The carbon spectrum of the product obtained in Example 13 of this invention; Figure 27 The hydrogen spectrum of the product obtained in Example 14 of this invention; Figure 28The carbon spectrum of the product obtained in Example 14 of this invention; Figure 29 The hydrogen spectrum of the product obtained in Example 15 of this invention; Figure 30 This is the carbon spectrum of the product obtained in Example 15 of the present invention. Detailed Implementation

[0018] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. 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.

[0019] Please see Figure 1-30 The present invention provides the following technical solution: a method for preparing azole-substituted ether compounds promoted by visible light, comprising the following steps: In an organic solvent, using a azole having the structure shown in formula (I) and an alkenyl ether having the structure shown in formula (II) as reactants, the reaction was carried out under visible light irradiation and with open stirring at room temperature. 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 an azole hemiacetal amine compound with the structure shown in formula (III). The reaction equation is shown below: ; Wherein, the compound of formula (I) is a tetrazolium, triazole or purine containing a substituent, wherein the substituent R is benzyl, furanyl, thiophene, naphthyl, or a phenyl substituted with one or more substituents, and the substituent is alkoxy, alkyl, trifluoromethyl, nitro, halogen or amide.

[0020] Compounds of formula (II) are non-cyclic alkenyl ethers and 2,3-dihydrofuran and 3,4-dihydropyran. Substituent R' is a C1-C20 alkyl, C4-C7 cycloalkyl, benzyl, or a phenyl group substituted with one or more substituents, wherein the substituent is alkoxy, alkyl, trifluoromethyl, nitro, halogen, or amide.

[0021] Example 1 The reaction equation is shown below: ; Under open conditions, 0.5 mmol of 5-phenyltetrazazole, 0.6 mmol of 2,3-dihydrofuran, and 2 mL of chloroform were added to a 20 mL test tube equipped with a magnetic stirrer. After addition, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5:1) to obtain 90 mg of the target compound, with a yield of 83%. The obtained NMR spectrum data of the product are as follows: .

[0022] Example 2 The reaction equation is shown below: ; Under open conditions, 0.5 mmol of 5-(4-bromophenyl)tetrazole, 0.6 mmol of 2,3-dihydrofuran, and 2 mL of chloroform were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5:1) to obtain 118 mg of the target compound, with a yield of 80%. The obtained NMR spectrum data of the product are as follows: .

[0023] Example 3 The reaction equation is shown below: ; Under open conditions, 0.5 mmol of 5-(4-trifluoromethylphenyl)tetrazole, 0.6 mmol of 2,3-dihydrofuran, and 2 mL of chloroform were added to a 20 mL test tube equipped with a magnetic stirrer. After addition, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5:1) to obtain 111 mg of the target compound, with a yield of 78%. The obtained NMR spectrum data of the product are as follows: ; Example

[0024] ; Under open conditions, 0.5 mmol of 5-(4-benzylphenyl)tetrazole, 0.6 mmol of 2,3-dihydrofuran, and 2 mL of chloroform were added to a 20 mL test tube equipped with a magnetic stirrer. After addition, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5:1) to obtain 130 mg of the target compound, with a yield of 85%. The obtained NMR spectrum data of the product are as follows: .

[0025] Example 5 The reaction equation is shown below: ; Under open conditions, 5-phenyl-1-ethylhexylene was added to a 20 mL test tube equipped with a magnetic stir bar. H 1,2,3-triazole (0.5 mmol), 2,3-dihydrofuran (0.6 mmol), and chloroform (2 mL) were added. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was removed from the solvent by rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 10:1) to give 99 mg of the target compound, with a yield of 92%. The obtained NMR spectrum data of the product are as follows: ; Example

[0026] The reaction equation is shown below: ; Under open conditions, 5-(4-chlorophenyl)-1-methyl-1-ethylhexylene was added to a 20 mL test tube equipped with a magnetic stir bar. H 1,2,3-triazole (0.5 mmol), 2,3-dihydrofuran (0.6 mmol), and chloroform (2 mL) were added. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was purified by rotary evaporator to remove the solvent. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 10:1) to obtain 110 mg of the target compound, with a yield of 88%. The obtained NMR spectrum data of the product are as follows: .

[0027] Example 7 The reaction equation is shown below: ; Under open conditions, 5-(4-methoxyphenyl)-1-methyl ... H 1,2,3-triazole (0.5 mmol), 2,3-dihydrofuran (0.6 mmol), and chloroform (2 mL) were added. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was removed from the solvent by rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 3:1) to obtain 111 mg of the target compound, with a yield of 91%. The obtained NMR spectrum data of the product are as follows: .

[0028] Example 8 The reaction equation is shown below: ; Under open conditions, 5-(2-naphthyl)-1-propionate was added to a 20 mL test tube equipped with a magnetic stir bar. H 1,2,3-triazole (0.5 mmol), 2,3-dihydrofuran (0.6 mmol), and chloroform (2 mL) were added. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was purified by rotary evaporator to remove the solvent. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 6:1) to obtain 123 mg of the target compound, with a yield of 93%. The obtained NMR spectrum data of the product are as follows: .

[0029] Example 9 ; Under open conditions, 5-(2-thiophene)-1 was added to a 20 mL test tube equipped with a magnetic stir bar. H 1,2,3-triazole (0.5 mmol), 2,3-dihydrofuran (0.6 mmol), and chloroform (2 mL) were added. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was purified by rotary evaporator to remove the solvent. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 4:1) to give 97 mg of the target compound, with a yield of 88%. The obtained NMR spectrum data of the product are as follows: .

[0030] Example 10 ; Under open conditions, 6-chloro-7 was added to a 20 ml test tube equipped with a magnetic stir bar. H 2,3-Purine (0.5 mmol), 2,3-dihydrofuran (0.6 mmol), and chloroform (2 mL) were added. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was purified by rotary evaporator to remove the solvent. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 1:1) to give 92 mg of the target compound, with a yield of 82%. The obtained NMR spectrum data of the product are as follows: .

[0031] Example 11 The reaction equation is shown below: ; Under open conditions, 0.5 mmol of 5-phenyltetrazazole, 0.6 mmol of 3,4-dihydropyran, and 2 mL of chloroform were added to a 20 mL test tube equipped with a magnetic stirrer. After addition, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 8:1) to obtain 90 mg of the target compound, with a yield of 78%. The obtained NMR spectrum data of the product are as follows: .

[0032] Example 12 The reaction equation is shown below: ; Under open conditions, 0.5 mmol of 5-phenyltetrazazole, 0.6 mmol of n-butyl vinyl ether, and 2 mL of chloroform were added to a 20 mL test tube equipped with a magnetic stirrer. After addition, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 12:1) to obtain 105 mg of the target compound, with a yield of 85%. The obtained NMR spectrum data of the product are as follows: .

[0033] Example 13 The reaction equation is shown below: ; Under open conditions, 0.5 mmol of 5-phenyltetrazazole, 0.6 mmol of n-octadecyl vinyl ether, and 2 mL of chloroform were added to a 20 mL test tube equipped with a magnetic stirrer. After addition, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 20:1) to obtain 183 mg of the target compound, with a yield of 83%. The obtained NMR spectrum data of the product are as follows: .

[0034] Example 14 The reaction equation is shown below: ; Under open conditions, 0.5 mmol of 5-phenyltetrazazole, 0.6 mmol of cyclohexyl vinyl ether, and 2 mL of chloroform were added to a 20 mL test tube equipped with a magnetic stirrer. After addition, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5:1) to obtain 110 mg of the target compound, with a yield of 81%. The obtained NMR spectrum data of the product are as follows: ; Example

[0035] The reaction equation is shown below: ; Under open conditions, 0.5 mmol of 5-phenyltetrazazole, 0.6 mmol of benzyl vinyl ether, and 2 mL of chloroform were added to a 20 mL test tube equipped with a magnetic stirrer. After addition, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 60 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15:1) to obtain 126 mg of the target compound, with a yield of 90%. The obtained NMR spectrum data of the product are as follows: .

[0036] In summary, this invention uses inexpensive and readily available azoles and alkenyl ethers as raw materials, eliminating the need for photocatalysts; the reaction conditions are relatively mild and the operation is simple; the cost is low and the reaction efficiency is high; this invention has high atom economy, conforming to the concept of "green chemistry"; this invention can obtain the target product in just one step, with high yield, good functional group compatibility, and simple post-processing, demonstrating good application potential.

[0037] Any aspects of this invention not described in detail are well-known to those skilled in the art.

[0038] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

Claims

1. A method for preparing azole-substituted ether compounds by visible light-promoted synthesis, characterized in that: Includes the following steps: In an organic solvent, using a nitrazole having the structure shown in formula (I) and an alkenyl ether having the structure shown in formula (II) as reactants, the reaction was carried out under visible light irradiation and with open stirring at room temperature. 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 compound with the structure shown in formula (III). The reaction equation is shown below: ； Wherein, the compound of formula (I) is a tetrazolium containing a substituent, a triazole containing a substituent, or a purine containing a substituent, wherein the substituent R is benzyl, furanyl, thiophene, naphthyl, or a phenyl substituted with one or more substituents, and the substituent is alkoxy, alkyl, trifluoromethyl, nitro, halogen, or amide. Compound (II) is 2,3-dihydrofuran or 3,4-dihydropyran; substituent R' is C1-C20 alkyl, C4-C7 cycloalkyl, benzyl, or a phenyl group substituted with one or more substituents, wherein the substituent is alkoxy, alkyl, trifluoromethyl, nitro, halogen, or amide. The organic solvent is chloroform; the visible light is an LED lamp.

2. The method for preparing a visible light-promoted azole-substituted ether compound according to claim 1, characterized in that: The molar ratio of the azole structure shown in formula (I) to the alkenyl ether structure shown in formula (II) is 1:1-1:1.

2.

3. The method for preparing a visible light-promoted azole-substituted ether compound according to claim 2, characterized in that: The molar ratio of the azole structure shown in formula (I) to the alkenyl ether structure shown in formula (II) is 1:1.

1.

4. The method for preparing a visible light-promoted azole-substituted ether compound according to claim 1, characterized in that: The reaction time is 50-70 hours.

5. The method for preparing a visible light-promoted azole-substituted ether compound according to claim 1, characterized in that: After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was 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 was (1-30):

1. The eluent was collected, and the solvent was rotary evaporated to obtain the compound shown in formula (III).

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