Synthesis method of a multi-substituted 2,5-dihydrooxazole compound
Through the method of 2H-aziridine, acetone and trifluoromethanesulfonic acid catalyst, the synthesis problem of multi-substituted 2,5-dihydroxazole compounds was solved, and efficient and economical synthesis of multi-substituted 2,5-dihydroxazole compounds was achieved.
Patent Information
- Application Number
- CN202310776726.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-06-29
- Publication Date
- 2025-07-25
- Estimated Expiration
- 2043-06-29
AI Technical Summary
The prior art is difficult to efficiently synthesize mostly substituted 2,5-dihydroxazole compounds, especially reactants, and the synthesis method is uneconomical.
2H-azabine, acetone and trifluoromethanesulfonic acid were used as catalysts, and the reaction was carried out at a certain temperature and the polysubstituted 2,5-dihydroxazole compounds were separated by column chromatography.
It has achieved high yield synthesis of multi-substituted 2,5-dihydroxazole compounds, which is simple to operate, wide application area, and convenient post-processing.
Smart Images
Figure CN116768812B_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing polysubstituted 2,5-dihydrooxazole compounds based on 2H-aziridine compounds. Background Art
[0002] 2,5-dihydrooxazole compounds are a class of important organic molecules and key structural units of many bioactive substances. In food chemistry, various substituted 2,5-dihydrooxazoles are used as artificial food flavors (Agric. Food Chem. 2014, 62, 6487.); they can also be used as intermediates in the synthesis of organic pesticides for the protection of high-value crops (Pest Manage. Sci. 2013, 69, 1106.), etc.
[0003] 2,5-dihydrooxazole compounds have a complex heterocyclic system and are difficult to synthesize by general methods, especially the synthesis of polysubstituted 2,5-dihydrooxazole compounds. In this context, existing synthesis methods for 2,5-dihydrooxazole compounds include: synthesizing polysubstituted 2,5-dihydrooxazole compounds by the self-cyclization of alkenyl azide compounds under metal catalysis (Org. Lett. 2020, 22, 4766.); synthesizing polysubstituted 2,5-dihydrooxazole compounds by the reaction of ethylene oxide with nitrile compounds under the catalysis of Lewis acid (Org. Lett. 2015, 17, 2685.), but the reactants are difficult to store. Therefore, it is of great research value to invent an economical and practical synthesis method for polysubstituted 2,5-dihydrooxazole compounds. Summary of the Invention
[0004] The polysubstituted 2,5-dihydrooxazole synthesized by the present invention is not only the core skeleton of many bioactive molecules but also an important synthon in organic synthesis. Therefore, it is of great research significance to expand the scope of novel polysubstituted 2,5-dihydrooxazole compounds and achieve the efficient synthesis of bioactive molecules.
[0005] To achieve the above object, the present invention provides a method for synthesizing polysubstituted 2,5-dihydrooxazole compounds, and the polysubstituted 2,5-dihydrooxazole compounds have the structure shown in Formula I:
[0006]
[0007] Wherein, R 1 is selected from any one of aryl and substituted aryl.
[0008] R 2 is selected from any one of aryl and substituted aryl.
[0009] The substituent of the substituted aryl is any one of a halogen atom, an alkoxy group, and a saturated alkyl group.
[0010] This method includes: under nitrogen protection, successively adding 2H-aziridine, a catalyst, acetone, and a solvent into a dry reactor, stirring at a certain temperature until the reaction is completed, and a polysubstituted 2,5-dihydrooxazole compound can be obtained through column chromatography separation. The chemical process is shown in Reaction Formula II:
[0011]
[0012] The catalyst is trifluoromethanesulfonic acid.
[0013] The solvent is selected from any one of 1,4-dioxane, dichloroethane, acetonitrile, tetrahydrofuran, dimethylacetamide, dichloromethane, ethyl acetate, toluene, dimethyl sulfoxide, chloroform, 1,1,2,2-tetrachloroethane, and chlorobenzene.
[0014] The molar ratio of the 2H-aziridine, acetone, and the catalyst is 1:130:0.2.
[0015] The reaction time is 24 - 72 h.
[0016] The reaction temperature is 56 - 65 °C.
[0017] After the reaction, column chromatography separation is carried out using a mixed solvent of petroleum ether and ethyl acetate.
[0018] The beneficial effects of the present invention are as follows: The present invention provides a scientific and reasonable synthesis method for polysubstituted 2,5-dihydrooxazole compounds, which has the advantages of high yield, wide substrate applicability, simple operation, and convenient post-treatment. Description of the Drawings
[0019] Figure 1 For Example 1 1 H NMR spectrum; Figure 2 For Example 1 13 C NMR spectrum.
[0020] Figure 3 For Example 2 1 H NMR spectrum; Figure 4 For Example 2 13 C NMR spectrum.
[0021] Figure 5 For Example 3 1 H NMR spectrum; Figure 6 For Example 3 13 C NMR spectrum.
[0022] Figure 7 For Example 41 1H NMR spectrum; Figure 8 for Example 4 13 13C NMR spectrum.
[0023] Figure 9 for Example 5 1 1H NMR spectrum; Figure 10 for Example 5 13 13C NMR spectrum.
[0024] Figure 11 for Example 6 1 1H NMR spectrum; Figure 12 for Example 6 13 13C NMR spectrum, Figure 13 for Example 6 19 19F NMR spectrum. Detailed implementation
[0025] In this article, the method of the present invention is illustrated by specific examples, but the present invention is not limited thereto. Any modifications, equivalent substitutions, and improvements within the technical concept of the present invention should be included within the protection scope of the present invention.
[0026] Example 1:
[0027] The reaction equation is as follows:
[0028]
[0029] Under nitrogen protection, compound 1a (0.1 mmol) was added to a dry reactor, followed by 2a (1 mL) and TfOH (0.003 g, 1.8 μL). The reaction was carried out at 56 °C for 48 hours. After completion of the reaction, the solvent was evaporated and concentrated using a rotary evaporator to obtain a crude product. Column chromatography separation was performed using a mixed solution of petroleum ether and ethyl acetate with a gradient from 50:1 to 10:1 to obtain pure 1aa with a yield of 74%.
[0030] The NMR data of 1aa are as follows:
[0031] 1 1H NMR (400 MHz, CDCl3) δ 7.67 - 7.60 (m, 2H), 7.37 - 7.25 (m, 8H), 6.12 (s, 1H), 1.70 (s, 3H), 1.60 (s, 3H).
[0032] 1313C NMR (150 MHz, CDCl3) δ 165.73, 139.00, 131.14, 130.82, 128.99, 128.64, 128.55, 128.44, 128.34, 108.97, 87.41, 28.66, 27.98.
[0033] Example 2:
[0034] The reaction equation is as follows:
[0035]
[0036] Under nitrogen protection, compound 1b (0.1 mmol) was added to a dry reactor, then 2a (1 mL) and TfOH (0.003 g, 1.8 μL) were added, and the reaction was carried out at 56 °C for 48 hours. After completion of the reaction, the solvent was evaporated and concentrated using a rotary evaporator to obtain the crude product. Column chromatography separation was performed using a mixed solution of petroleum ether and ethyl acetate with a gradient from 50:1 to 10:1 to obtain pure 1ba with a yield of 75%.
[0037] The NMR data of 1ba are as follows:
[0038] 1 1H NMR (600 MHz, CDCl3) δ 7.49 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.37 - 7.27 (m, 5H), 6.07 (s, 1H), 1.68 (s, 3H), 1.58 (s, 3H).
[0039] 13 13C NMR (150 MHz, CDCl3) δ 164.83, 138.64, 131.69, 130.02, 129.08, 128.82, 128.28, 125.43, 109.06, 87.26, 28.57, 27.82.
[0040] Example 3:
[0041] The reaction equation is as follows:
[0042]
[0043] Under nitrogen protection, compound 1c (0.1 mmol) was added to a dry reactor, then 2a (1 mL) and TfOH (0.003 g, 1.8 μL) were added, and the reaction was carried out at 56 °C for 48 hours. After completion of the reaction, the solvent was evaporated and concentrated using a rotary evaporator to obtain the crude product. Column chromatography separation was performed using a mixed solution of petroleum ether and ethyl acetate with a gradient from 50:1 to 10:1 to obtain pure 1ca with a yield of 72%.
[0044] The NMR data of 1ca are as follows:
[0045] 1 H NMR(600MHz,CDCl3)δ7.52(d,J=8.3Hz,2H),7.34-7.28(m,5H),7.09-7.07(m,2H),6.09(s,1H),2.30(s,3H),1.68(s,3H),1.58(s,3H).。
[0046] 13 C NMR(150MHz,CDCl3)δ165.57,141.14,139.17,129.14,128.94,128.55,128.51,128.38,128.34,108.87,87.36,28.67,27.99,21.45.。
[0047] Example 4:
[0048] The reaction equation is as follows:
[0049]
[0050] Under nitrogen protection, compound 1d (0.1 mmol) was added to a dry reactor, followed by the addition of 2a (1 mL) and TfOH (0.003 g, 1.8 μL). The reaction was carried out at 56 °C for 48 hours. After completion of the reaction, the solvent was evaporated and concentrated using a rotary evaporator to obtain the crude product. Column chromatography separation was performed using a mixture of petroleum ether and ethyl acetate with a gradient from 50:1 to 10:1 to obtain pure 1da with a yield of 79%.
[0051] The NMR data of 1da are as follows:
[0052] 1 H NMR(600MHz,CDCl3)δ7.96-7.94(m,1H),7.88(dd,J=8.6,1.7Hz,1H),7.76(d,J=8.5Hz,2H),7.69(dd,J=8.1,1.2Hz,1H),7.47(ddd,J=8.2,6.8,1.3Hz,1H),7.42(ddd,J=8.0,6.7,1.3Hz,1H),7.39-7.36(m,2H),7.35-7.31(m,2H),7.29-7.24(m,1H),6.24(s,1H),1.73(s,3H),1.63(s,3H).。
[0053] 1313C NMR (150 MHz, CDCl3) δ 165.80, 139.14, 134.33, 132.64, 129.41, 129.03, 128.82, 128.69, 128.58, 128.38, 128.25, 127.71, 127.49, 126.49, 125.03, 109.07, 87.47, 28.72, 28.06.
[0054] Example 5:
[0055] The reaction equation is as follows:
[0056]
[0057] Under nitrogen protection, compound 1e (0.1 mmol) was added to a dry reactor, followed by the addition of 2a (1 mL) and TfOH (0.003 g, 1.8 μL). The reaction was carried out at 56 °C for 48 hours. After completion of the reaction, the solvent was evaporated and concentrated using a rotary evaporator to obtain the crude product. Column chromatography separation was performed using a mixture of petroleum ether and ethyl acetate with a gradient from 50:1 to 10:1 to obtain pure 1ea with a yield of 70%.
[0058] The NMR data of 1ea are as follows:
[0059] 1 1H NMR (600 MHz, CDCl3) δ 7.65 - 7.62 (m, 2H), 7.36 - 7.33 (m, 1H), 7.28 (dd, J = 8.3, 6.9 Hz, 2H), 7.21 - 7.18 (m, 2H), 7.13 (d, J = 7.8 Hz, 2H), 6.09 (s, 1H), 2.31 (s, 3H), 1.67 (s, 3H), 1.58 (s, 3H).
[0060] 13 13C NMR (150 MHz, CDCl3) δ 165.81, 138.41, 136.08, 131.24, 130.74, 129.66, 128.54, 128.40, 128.22, 108.74, 87.19, 28.68, 27.98, 21.23.
[0061] Example 6:
[0062] The reaction equation is as follows:
[0063]
[0064] Under nitrogen protection, compound 1f (0.1 mmol) was added into a dry reactor, followed by the addition of 2a (1 mL) and TfOH (0.003 g, 1.8 μL). The reaction was carried out at 56 °C for 48 hours. After completion of the reaction, the solvent was evaporated and concentrated using a rotary evaporator to obtain the crude product. Column chromatography separation was performed using a mixture of petroleum ether and ethyl acetate with a gradient from 50:1 to 10:1 to obtain pure 1fa with a yield of 60%.
[0065] The NMR data of 1fa are as follows:
[0066] 1 H NMR (400 MHz, CDCl3) δ 7.62 - 7.59 (m, 2H), 7.36 - 7.27 (m, 5H), 7.04 - 6.99 (m, 2H), 6.10 (s, 1H), 1.67 (s, 3H), 1.57 (s, 3H).
[0067] 13 C NMR (150 MHz, CDCl3) δ 165.51, 135.00, 130.92, 130.09, 130.03, 128.49, 116.05, 115.91, 109.00, 86.51, 28.69, 27.89.
[0068] 19 F NMR (565 MHz, CDCl3) δ -113.13.
[0069] As can be seen from the above examples, according to the present invention, diversified and efficient synthesis of multi-substituted 2,5-dihydrooxazole compounds can be carried out.
Claims
1. A method for synthesizing a multi-substituted 2,5-dihydrooxazole compound, the method comprising: Under nitrogen protection, 2H-aziridine, a catalyst, acetone and a solvent were successively added to a dry reactor, and stirred at 56 - 65 °C for a certain time until the reaction was completed. The polysubstituted 2,5-dihydrooxazole compounds could be obtained by column chromatography separation; Among them, the catalyst is trifluoromethanesulfonic acid; among them, R 1 , R 2 is selected from any one of aryl and substituted aryl; among them, the substituent of the substituted aryl is any one of a halogen atom, an alkoxy group, and a saturated alkyl group; the polysubstituted 2,5-dihydrooxazole compound has the structure shown in Formula I, and its chemical process is shown in Formula II 2. The synthesis method according to claim 1, wherein, The solvent was selected from any one of 1,4-dioxane, dichloroethane, acetonitrile, tetrahydrofuran, dimethylacetamide, dichloromethane, ethyl acetate, toluene, dimethyl sulfoxide, chloroform, 1,1,2,2-tetrachloroethane, and chlorobenzene.
3. The synthesis method according to claim 1, wherein, The molar ratio of the 2H-aziridine, acetone, and the catalyst was 1:130:0.
2.
4. The synthesis method according to claim 1, wherein The reaction time was 24 - 72 h.
5. According to the synthesis method described in claim 1, wherein, Column chromatography separation was carried out with a mixed solvent of petroleum ether and ethyl acetate.