A process for the preparation of 2-substituted benzoxazole compounds

Abstract

The application discloses a preparation method of a 2-substituted benzoxazole compound, which comprises the following steps: first, a hydroxyphenyl glycine derivative and a Lewis acid are added into an organic solvent according to a molar ratio of 1:0.2, visible light is used for irradiation, stirring is conducted in air at room temperature until a sufficient reaction is achieved, the organic solvent is removed by using reduced pressure distillation, and then column chromatography is adopted to obtain a 2-substituted benzoxazole derivative. The application has the advantages of mild reaction conditions, greenness, low cost and high efficiency.

Description

Technical Field

[0001] This invention belongs to the field of organic compound preparation technology, specifically a method for preparing 2-substituted benzoxazole compounds. Background Technology

[0002] The benzoxazole skeleton is widely found in various bioactive natural products and compounds. Variations in the substituents of benzoxazole significantly affect its activity. 2-substituted benzoxazoles possess a variety of pharmacological activities, such as antibacterial, antifungal, anticancer, and antiviral properties. However, reported methods for synthesizing 2-substituted benzoxazole compounds have the following drawbacks: 1) They require the addition of equivalent amounts of strong oxidants, including peroxides, leading to harsh reaction conditions and reduced reaction tolerance; 2) They require the addition of expensive and toxic ruthenium or iridium complexes and organic dyes as photosensitizers under visible light irradiation, limiting the application range of the reaction. In other words, existing methods for preparing 2-substituted benzoxazoles suffer from harsh reaction conditions, high cost, cumbersome operation, and environmental unfriendliness. Therefore, there is an urgent need to develop a simple, inexpensive, and efficient method for synthesizing 2-substituted benzoxazoles. Summary of the Invention

[0003] In view of the shortcomings of the existing technology, the purpose of this invention is to provide a method for preparing 2-substituted benzoxazole compounds, which has the advantages of mild reaction conditions, greenness, low cost and high efficiency.

[0004] To achieve the above objectives, the present invention employs the following technical solution:

[0005] A method for preparing a 2-substituted benzoxazole compound, comprising the following steps:

[0006] First, a hydroxyphenylglycine derivative and a Lewis acid were prepared at a molar ratio of 1:0.2 and added sequentially to an organic solvent. The mixture was then irradiated with visible light and stirred at room temperature until fully reacted. The organic solvent was removed by vacuum distillation, and the 2-substituted benzoxazole derivative was obtained by column chromatography. The chemical reaction formula is as follows:

[0007]

[0008] In the formula: R 1 The substituent is an electron-donating or electron-withdrawing group, R 2 The substituents are alkyl, alkoxy, aryl, or substituted amino groups.

[0009] Furthermore, the electron-donating group is an alkyl, alkoxy, or aryl group; the electron-withdrawing group is a halogen, trifluoromethyl, or nitro group.

[0010] Further, the hydroxyphenylglycine derivative is any one of (2-hydroxy-4-methylphenyl)glycine ethyl ester, (2-hydroxyphenyl)glycine methyl ester, (2-hydroxyphenyl)glycine tert-butyl ester, (2-hydroxyphenyl-4-methoxyphenyl)glycylglycine ethyl ester, (2-hydroxyphenyl)glycine N,N-dicarboxamide, (2-hydroxy-4-chlorophenyl)glycine ethyl ester, (2-hydroxy-4-trifluoromethylphenyl)glycine ethyl ester, or (2-hydroxy-4-nitrophenyl)glycine ethyl ester.

[0011] Furthermore, the Lewis acid is Cu(OTf)2, Fe(OTf)2, CuSO4, or FeSO4.

[0012] Furthermore, the organic solvent is any one of dichloromethane, toluene, 1,2-dichloroethane, or acetonitrile, or a mixture of 1,2-dichloroethane and acetonitrile.

[0013] Furthermore, the mixture of 1,2-dichloroethane and acetonitrile is prepared by mixing 1,2-dichloroethane and acetonitrile in a volume ratio of 1:2 or 3:1.

[0014] Furthermore, the visible light irradiation uses an energy-saving lamp, sunlight, or a blue LED lamp as the light source.

[0015] Furthermore, the stirring time is 10–20 hours.

[0016] Furthermore, the eluent used in the column chromatography is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 8:1 or 4:1.

[0017] Compared with the prior art, the present invention has the following technical effects:

[0018] This invention synthesizes 2-substituted benzoxazole compounds by oxidative cyclization of hydroxyphenylglycine derivatives under visible light catalysis. Visible light, which is inexpensive, abundant, and green, is used for catalysis, eliminating the need for external photosensitizers. Oxygen from the air is used as a green oxidant, eliminating the need for additional strong oxidants. Therefore, this invention has advantages such as inexpensive and readily available raw materials, mild reaction conditions, green operation, simple operation, and a wide variety of products. Furthermore, the yield of 2-substituted benzoxazole compounds is as high as 89%-98%. Attached Figure Description

[0019] Figure 1 Example 1: 6-methyl-2-ethyl benzoxazole 1 H NMR spectrum;

[0020] Figure 2 Example 1: 6-methyl-2-ethyl benzoxazole 13C NMR spectrum. Detailed Implementation

[0021] The specific content of the present invention will be further explained in detail below with reference to the embodiments.

[0022] In Examples 1 to 3 and Examples 6 to 8, the eluent used in column chromatography was a mixture of petroleum ether and ethyl acetate in a volume ratio of 8:1; in Examples 4 and 5, the eluent used in column chromatography was a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1.

[0023] Example 1

[0024] First, 10 mmol of (2-hydroxy-4-methylphenyl)glycine ethyl ester and 2 mmol of Cu(OTf)₂ were weighed and added sequentially to 30 mL of dichloromethane. The mixture was then irradiated with a 26W energy-saving lamp and stirred in air at room temperature for 12 h. The dichloromethane was then removed by vacuum distillation, followed by purification by column chromatography to obtain a pale yellow solid, 6-methyl-2-ethyl benzoxazole, with the following structural formula:

[0025]

[0026] The yield of 6-methyl-2-ethyl benzoxazole prepared in Example 1 was 96%, with a melting point of 60.1-63.7 °C. (See [link to example]). Figure 1 and Figure 2 The product 6-methyl-2-ethyl benzoxazole prepared in Example 1 was determined using nuclear magnetic resonance spectroscopy, and the results were as follows: 1 H NMR (400MHz, CDCl3) δ7.51-7.37(m,2H),7.32-7.21(m,1H),4.34(q,J=6.4Hz,2H),2.45(d,J=0.8Hz,3H),1.38(t,J=6.3Hz,3H); 13 C NMR(100MHz, CDCl3)δ164.60,152.47,151.58,137.34,135.86,125.79,120.94,112.98,63.64,21.79,14.10.HRMS(ESI)calcdfor C 11 H 12 NO3(M+H + )206.0812,found 206.0808.

[0027] Example 2

[0028] First, 10 mmol of (2-hydroxyphenyl)glycine methyl ester and 2 mmol of Cu(OTf)₂ were weighed and added sequentially to 30 mL of 1,2-dichloroethane. The mixture was then exposed to sunlight and stirred at room temperature for 10 h. The 1,2-dichloroethane was removed by vacuum distillation, followed by purification by column chromatography to obtain a brown solid, 2-ethyl benzoxazole, with the following structural formula:

[0029]

[0030] The yield of 2-ethyl benzoxazole prepared in Example 2 was 92%, with a melting point of 95.0-97.1℃. The results obtained using nuclear magnetic resonance spectroscopy were as follows: 1 H NMR (400MHz, CDCl3) δ7.90 (d, J = 8.0Hz, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.58-7.40 (m, 2H), 4.10 (s, 3H); 13 C NMR (100MHz, CDCl3) δ156.9,152.5,150.9,140.5,128.2,125.8,122.2,111.8,53.7.

[0031] Example 3

[0032] First, 10 mmol of (2-hydroxyphenyl)glycine tert-butyl ester and 2 mmol of Fe(OTf)₂ were weighed and added sequentially to 30 mL of toluene. The mixture was then irradiated with an 18W blue LED and stirred at room temperature for 15 h. Toluene was removed by vacuum distillation, followed by purification by column chromatography to obtain a yellow liquid, 2-tert-butyl benzoxazole, with the following structural formula:

[0033]

[0034] The yield of 2-tert-butyl benzoxazole prepared in Example 3 was 98%, and the results determined by nuclear magnetic resonance spectroscopy were as follows: 1 H NMR (400MHz, CDCl3) δ7.89 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.47 (dt, J = 27.9, 7.5 Hz, 2H), 1.69 (s, 9H); 13 C NMR (100MHz, CDCl3) δ155.6,153.7,150.8,140.6,127.8,125.6,122.1,111.7,85.2,28.

[0035] Example 4

[0036] First, 10 mmol of (2-hydroxyphenyl-4-methoxyphenyl)glycylglycine ethyl ester and 2 mmol of CuSO4 were weighed and added sequentially to 30 mL of acetonitrile. The mixture was then irradiated with an 18W blue LED and stirred at room temperature for 18 h in air. Acetonitrile was then removed by vacuum distillation, followed by purification by column chromatography to obtain a brown solid, 2-glycamide benzoxazole, with the following structural formula:

[0037]

[0038] The yield of 2-glycineamide benzoxazole prepared in Example 4 was 89%, and the melting point was 110.0-110.4℃; the results determined by nuclear magnetic resonance spectroscopy were as follows: 1 H NMR (400MHz, CDCl3) δ7.82 (d, J = 7.2Hz, 2H), 7.66 (d, J = 8.0Hz, 1H), 7.56-7.34 (m, 2H), 4.31-4.26 (m, 4H), 1.32 (t, J = 7.2Hz, 3H); 13 CNMR (100MHz, CDCl3) δ168.9,155.8,154.9,151.1,140.2,127.6,125.6,121.5,111.8,61.9,41.5,14.2.

[0039] Example 5

[0040] First, 1,2-dichloroethane and acetonitrile were mixed in a volume ratio of 3:1 to obtain a mixed solvent. Then, 10 mmol of (2-hydroxyphenyl)glycine N,N-dicarboxamide and 2 mmol of FeSO4 were weighed and added sequentially to 30 mL of the mixed solvent. The mixture was irradiated with an 18W blue LED and stirred at room temperature for 12 h in air. 1,2-dichloroethane and acetonitrile were then removed by vacuum distillation, followed by purification by column chromatography to obtain a yellow solid, 2-N,N-dicarboxamide benzoxazole, with the following structural formula:

[0041]

[0042] The yield of 2-N,N-dicarboxamide benzoxazole prepared in Example 5 was 90%, with a melting point of 79.2-81.8℃. The results obtained using nuclear magnetic resonance spectroscopy were as follows: 1 H NMR (400MHz, CDCl3) δ7.82(d,J=7.6Hz,1H),7.65(d,J=8.1Hz,1H),7.44(dt,J=15.2,7.2Hz,2H),3.52(s,3H),3.21(s,3H); 13C NMR (100MHz, CDCl3) δ157.6,155.2,159.0,140.3,127.1,125.2,121.3,111.6,38.9,36.5.

[0043] Example 6

[0044] First, 1,2-dichloroethane and acetonitrile were mixed in a volume ratio of 1:2 to obtain a mixed solvent. Then, 10 mmol of (2-hydroxy-4-chlorophenyl)glycine ethyl ester and 2 mmol of Fe(OTf)₂ were weighed and added sequentially to 30 mL of the mixed solvent. The mixture was irradiated with a 26W energy-saving lamp and stirred in air at room temperature for 20 h. 1,2-dichloroethane and acetonitrile were then removed by vacuum distillation. Finally, column chromatography was used to purify the mixture to obtain a yellow solid, 6-chloro-2-ethyl benzoxazole, with the following structural formula:

[0045]

[0046] The yield of 6-chloro-2-ethyl benzoxazole prepared in Example 6 was 92%, with a melting point of 99.2-102.3℃. The results obtained using nuclear magnetic resonance spectroscopy were as follows: 1 H NMR (400MHz, CDCl3) δ7.88 (d, J = 2.0Hz, 1H), 7.68-7.40 (m, 2H), 4.57 (q, J = 7.2Hz, 2H), 1.50 (t, J = 7.2Hz, 3H); 13 C NMR (100MHz, CDCl3) δ156.1,153.9,149.4,141.5,131.5,128.7,121.9,112.6,63.5,14.1.

[0047] Example 7

[0048] First, 10 mmol of (2-hydroxy-4-trifluoromethylphenyl)glycine ethyl ester and 2 mmol of Fe(OTf)₂ were weighed and added sequentially to 30 mL of dichloromethane. The mixture was then irradiated with an 18W blue LED and stirred at room temperature for 20 h. The dichloromethane was then removed by vacuum distillation, followed by column chromatography purification to obtain a pale yellow liquid, 6-trifluoromethyl-2-ethyl benzoxazole, with the following structural formula:

[0049]

[0050] The yield of 6-trifluoromethyl-2-ethyl benzoxazole prepared in Example 7 was 91%, as determined by nuclear magnetic resonance spectroscopy. 1H NMR (500MHz, CDCl3) δ8.19 (s, 1H), 7.92-7.67 (m, 2H), 4.60 (q, J = 7.2Hz, 2H), 1.52 (t, J = 7.2Hz, 3H); 13 C NMR (125MHz, CDCl3) δ156.0, 154.3, 152.4, 140.5, 128.7 (q, J = 32.5Hz), 125.3 (q,J=3.75Hz),123.7(q,J=271.3Hz),120.0(q,J=3.75Hz),112.6,63.7,14.2; 19 F NMR (471MHz, CDCl3) δ-61.38 (s, 1F, CF3).

[0051] Example 8

[0052] First, 10 mmol of (2-hydroxy-4-nitrophenyl)glycine ethyl ester and 2 mmol of Fe(OTf)₂ were weighed and added sequentially to 30 mL of dichloromethane. The mixture was then irradiated with an 18W blue LED and stirred at room temperature for 20 h in air. The dichloromethane was then removed by vacuum distillation, followed by purification by column chromatography to obtain a pale yellow solid, 6-nitro-2-ethyl benzoxazole, with the following structural formula:

[0053]

[0054] The 6-nitro-2-ethyl benzoxazole prepared in Example 8 had a yield of 90% and a melting point of 112.1-113.9 °C. The results obtained using nuclear magnetic resonance spectroscopy were as follows: 1 H NMR (400MHz, CDCl3) δ8.33(d,J=2.0Hz,1H),8.12(dd,J=8.9,1.9Hz,1H),7.90(d,J=9.0Hz,1H),4.34(q,J=6.4Hz,2H),1.38(t,J=6.3Hz,3H); 13 CNMR(100 MHz, CDCl3)δ164.60,152.92,152.75,145.49,143.12,120.87,120.51,109.57,63.64,14.10.HRMS(ESI)calcd for C 10 H8N2O5(M+H + )237.0506,found 237.0503.

Claims

1. A method for preparing a 2-substituted benzoxazole compound, characterized in that, Includes the following steps: First, the hydroxyphenylglycine derivative and Lewis acid shown in formula (I) were added sequentially to an organic solvent at a molar ratio of 1:0.

2. The mixture was then irradiated with visible light and stirred at room temperature until fully reacted. The organic solvent was then removed by vacuum distillation. Finally, column chromatography was used to obtain the 2-substituted benzoxazole compound shown in formula (II). The chemical reaction formula is as follows: In the formula: R 1 The substituents are H, 4-methyl, 4-Cl, 4-nitro, or 4-trifluoromethyl; R 2 The substituents are methoxy, ethoxy, tert-butoxy, N,N-dimethylamino, or -NHCH2COOEt; The Lewis acid is Cu(OTf)2, Fe(OTf)2, CuSO4, or FeSO4.

2. The method for preparing the 2-substituted benzoxazole compound according to claim 1, characterized in that, The hydroxyphenylglycine derivative is any one of (2-hydroxy-4-methylphenyl)glycine ethyl ester, (2-hydroxyphenyl)glycine methyl ester, (2-hydroxyphenyl)glycine tert-butyl ester, (2-hydroxyphenyl-4-methoxyphenyl)glycylglycine ethyl ester, (2-hydroxyphenyl)glycine N,N-dicarboxamide, (2-hydroxy-4-chlorophenyl)glycine ethyl ester, (2-hydroxy-4-trifluoromethylphenyl)glycine ethyl ester, or (2-hydroxy-4-nitrophenyl)glycine ethyl ester.

3. The method for preparing the 2-substituted benzoxazole compound according to claim 1, characterized in that, The organic solvent is any one of dichloromethane, toluene, 1,2-dichloroethane, or acetonitrile, or a mixture of 1,2-dichloroethane and acetonitrile.

4. The method for preparing the 2-substituted benzoxazole compound according to claim 3, characterized in that, The mixture of 1,2-dichloroethane and acetonitrile is prepared by mixing 1,2-dichloroethane and acetonitrile in a volume ratio of 1:2 or 3:

1.

5. The method for preparing the 2-substituted benzoxazole compound according to claim 1, characterized in that, The visible light irradiation uses energy-saving lamps, sunlight, or blue LED lights as the light source.

6. The method for preparing the 2-substituted benzoxazole compound according to claim 1, characterized in that, The stirring time is 10-20 h.

7. The method for preparing the 2-substituted benzoxazole compound according to claim 1, characterized in that, The column chromatography uses a mixture of petroleum ether and ethyl acetate as the eluent, with a volume ratio of 8:1 or 4:1 between the two.

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