4-ethyl guaiacol derivative and preparation method thereof

Abstract

The invention discloses a 4-ethyl guaiacol derivative and a preparation method thereof, and belongs to the technical field of organic compound synthesis. The invention relates to application of lignite residues as a catalyst to preparation of a 4-ethyl guaiacol derivative. The application comprises the following steps: mixing an aryl diazo ester compound and 4-ethyl guaiacol, adding acetonitrile, and stirring; carrying out a catalytic reaction by using lignite residues as a catalyst, carrying out a standing reaction at room temperature for 1 h, heating to 80 DEG C, and continuing the reaction for 10-12 h; stopping the reaction when the reaction of the raw materials is detected to be complete through TLC; and filtering the reacted raw materials, washing the filter cake with dichloromethane until the filter cake is colorless, carrying out reduced pressure concentration on the filtrate to remove volatile components, and carrying out silica gel column chromatography separation to obtain the 4-ethyl guaiacol derivative. According to the method, the lignite residues are adopted as the catalyst, the problem that the lignite residues are difficult to treat can be solved, a new thought can be provided for selection of the catalyst in the organic synthesis reaction, recycling of waste resources is achieved, and the purposes of green chemistry and environmental protection are achieved.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to 4-ethylguaiacol derivatives and their preparation methods. Background Technology

[0002] Lignite residue is the main residual material after lignite refining. It is rich in various metal ions and has a large content (Hydrometallurgy, 2017, 168: 141; Fuel, 2017, 203: 214). However, its post-processing has always been a difficult problem for environmental organizations at home and abroad (J.Anal. Appl. Pyrol., 2019, 139: 40; Energy,2022, 240: 122796). Currently, common treatment methods include using it as fertilizer (Sci. Total Environ., 2021,773: 145631; Coke. Chem., 2021, 64: 31; J. Air. Waste Manage., 2021, 71:1175), animal bedding (Waste Manage., 2021, 136: 113), adsorbent (Mine Water Environ.,2019, 38: 24), or degrading agent (J. Environ. Chem. Eng., 2021, 9: 104784; Chem. Eng. J.,2025, 521: 166275). If it could be used as an organic synthesis catalyst, it would not only alleviate the difficulty of treating lignite residue but also provide a new approach to catalyst selection in organic synthesis reactions. Simultaneously, it would enable the reuse of waste resources, aligning with the principles of green chemistry and environmental protection.

[0003] 4-Ethylguaiacol is a natural phenolic product with antioxidant, antibacterial, and expectorant properties. Industrially, it is also used as a fragrance or other pharmaceutical intermediate (J. Phys. Chem. B., 2012, 116: 7129; J. Chin. Inst. Food Sci. Technol., 2015, 15: 1; RSCAdvances, 2017, 7: 46395). Its wide range of applications makes structural modification and derivatization of 4-ethylguaiacol of significant research value. The CH insertion reaction of 4-ethylguaiacol to construct C-C bonds, generating 4-ethylguaiacol derivatives in a one-step reaction, is one of the important methods for the derivatization and structural modification of the natural product 4-ethylguaiacol.

[0004] CC bonds exist in various types of organic compounds and are one of the important chemical bonds constituting various substances (Acc.Chem. Res. 2023, 56: 2867; J. Am. Chem. Soc., 2023, 145: 17527). Currently reported methods for constructing CC bonds often require expensive transition metal catalysts or complex ligands (J. Am. Chem. Soc., 2008, 130: 1566; ACSCatal., 2025, 15: 3636). Therefore, we attempt to develop a simple and efficient method for constructing CC bonds. Diazo compounds (R1R2C=N2) are a class of highly reactive reaction intermediates that can participate in various reactions to construct CX (X=O, N, C, S, P, Si, B, etc.) bonds (Chem. Soc. Rev., 2016, 45: 506, NatureRev. Chem., 2019, 3: 347). Among these, they can form C-C bonds with phenolic compounds through CH insertion reactions (J. Am. Chem. Soc., 2008, 130: 1566; Green Chem., 2020, 22: 1594). Based on this, we intend to utilize metal ions in lignite residues to induce aryl diazo esters to form C-C bonds with 4-ethylguaiacol through metal carbene CH insertion reactions, thereby preparing the natural product 4-ethylguaiacol derivative and providing an effective strategy for natural product-based derivatization and drug development. Summary of the Invention

[0005] In view of this, the object of the present invention is to provide a 4-ethylguaiacol derivative and a method for preparing the same.

[0006] To achieve the above objectives, the present invention provides the following technical solution: This invention provides the application of lignite residue as a catalyst in the preparation of 4-ethylguaiacol derivatives.

[0007] Furthermore, it also includes a method for preparing 4-ethylguaiacol derivatives, S1, mixing aryl diazo ester compounds and 4-ethylguaiacol, adding acetonitrile, and stirring; S2, and then lignite residue was used as a catalyst to catalyze the reaction. After standing at room temperature for 1 h, the reaction was heated to 80℃ and continued for 10-12 h. S3. Stop the reaction when the raw materials have reacted completely as detected by TLC. S4. Filter the reacted raw materials, wash the filter cake with dichloromethane until it is colorless, concentrate the filtrate under reduced pressure to remove volatile components, and then separate it by silica gel column chromatography to obtain the 4-ethylguaiacol derivative. The synthetic route for the reaction is shown below: .

[0008] Further, the aryl diazonium ester compound is any one of p-chlorophenyldiazoacetic acid methyl ester, m-chlorophenyldiazoacetic acid methyl ester, o-chlorophenyldiazoacetic acid methyl ester, phenyldiazoacetic acid isopropyl ester, 2,4-dichlorodiazoacetic acid methyl ester, and 3,4-dichlorodiazoacetic acid methyl ester.

[0009] Further, in step S1, when the amount of 4-ethylguaiacol is 0.75 mmol, the amount of aryl diazonium ester is 0.5 mmol, the amount of lignite residue is 150-200 mg, and the amount of solvent acetonitrile is 5 mL.

[0010] Furthermore, the stirring time after the acetonitrile is added is 10-20 minutes.

[0011] Furthermore, the entire reaction process is carried out in an air atmosphere, without the need for nitrogen or other inert gas protection.

[0012] Furthermore, the eluent used in the silica gel column chromatography separation is petroleum ether and ethyl acetate in a volume ratio of 6:1, and the boiling point of the petroleum ether is 60-90℃.

[0013] Furthermore, in the reaction formula, R 1 It is one or more of hydrogen, methyl, ethyl, methoxy, nitro, acyl, halogen, and trifluoromethyl, wherein the halogen is F, Cl, Br, or I; R 2 It can be methyl, ethyl, allyl, phenyl, benzyl, or alkyl.

[0014] The beneficial effects of this invention are as follows: 1. The catalyst used in the method of this invention is a lignite residue (Zhaotong, Yunnan), which is widely available, inexpensive and readily available. The reaction does not require the introduction of other transition metals or complex ligands. The raw materials are readily available, the reaction conditions are mild, the yield is good, and the reaction can be carried out on a gram-scale basis, which has industrialization prospects. This provides an effective strategy for the preparation of 4-ethylguaiacol derivatives.

[0015] 2. This invention uses lignite residue as a catalyst, which not only alleviates the problem of difficult lignite residue treatment, but also provides a new approach to the selection of catalysts in organic synthesis reactions, realizing the recycling of waste resources and conforming to the principles of green chemistry and environmental protection.

[0016] Other advantages, objectives, and features of the invention will be set forth in the following description and will be apparent to those skilled in the art in some respects, or may be learned by practice of the invention. The objectives and other advantages of the invention can be realized and obtained through the following description. Attached Figure Description

[0017] To make the purpose, technical solution, and beneficial effects of the invention clearer, the following figures are provided for illustration: Figure 1 Example 1 of this invention is a 4-ethylguaiacol derivative 3a 1 HNMR spectrum; Figure 2 Example 1 of this invention is a 4-ethylguaiacol derivative 3a 13 C NMR spectrum; Figure 3 The single-crystal structure of 4-ethylguaiacol derivative 3e in Example 5 of this invention. Detailed Implementation

[0018] like Figure 1-3 As shown, the present invention relates to a 4-ethylguaiacol derivative and its preparation method.

[0019] The reaction conditions in the embodiments of this invention are all based on the optimal reaction conditions described in the invention above.

[0020] All raw materials and reagents used in the examples are commercially available products. The yield of the synthesized compound is calculated as: actual reaction yield / theoretical reaction yield × 100%.

[0021] Example 1 S1. Weigh 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.75 mmol of 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 h, then heat to 80℃ and continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 6:1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3a.

[0022] In this embodiment, the target product obtained was 134 mg, with a yield of 80%.

[0023] The standard product was confirmed by nuclear magnetic resonance spectroscopy: Methyl 2-(4-chlorophenyl)-2-(2-ethyl-5-hydroxy-4-methoxyphenyl) acetate (3a):Colorless oil; 80% yield; 1 H NMR (400 MHz, CDCl3)δ 7.31–7.27 (m, 2H), 7.21 – 7.16 (m, 2H), 6.86 (s, 1H), 6.73 (s,1H), 5.55 (s,1H), 5.19 (s, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 2.67–2.53 (m, 2H), 1.18 (t, J= 7.6 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 173.23, 146.02, 143.79, 137.30,134.18, 133.09, 130.19, 128.71, 128.27, 114.79,111.48, 55.97, 52.56, 51.81,25.75, 15.65. HRMS (ESI) calcd for C 18 H 19 ClO4K [M+Na] + : 357.0864; Found: 357.0868. Example 2 S1. Weigh 0.5 mmol of m-chlorophenyldiazoacetic acid methyl ester and 0.75 mmol of 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 h, then heat to 80°C. o C continued to react for 12 hours.

[0024] S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and perform silica gel column chromatography separation using eluent (petroleum ether (75℃) / ethyl acetate, v / v = 6∶1) to obtain 4-ethylguaiacol derivative 3b, which is colorless, transparent and viscous.

[0025] In this embodiment, the target product obtained was 125 mg, with a yield of 75%.

[0026] The standard product was confirmed by nuclear magnetic resonance spectroscopy: Methyl 2-(3-chlorophenyl)-2-(2-ethyl-5-hydroxy-4-methoxyphenyl) acetate (3b):Colorless oil; 75% yield; 1 H NMR (400 MHz, CDCl3)δ 7.49 (s, 1H), 7.35 (dd, J = 5.2, 1.1 Hz, 3H), 6.90 (s, 1H), 6.75 (s, 1H),5.67 (s, 1H), 5.22 (s, 1H), 3.91 (s, 3H), 3.81 (s, 3H),2.67 – 2.57 (m, 2H),1.20 (t, J = 7.6 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 172.98, 146.08, 143.73,136.63, 134.60, 134.37, 130.39, 129.52, 128.67, 127.36, 127.02, 114.90,111.63, 56.00, 52.68, 50.13, 25.72,15.36. HRMS (ESI) calcd for C 18 H 19 ClO4K [M+Na] + Found: 357.0864; Found: 357.0869. Example 3 1. Weigh 0.5 mmol of o-chlorophenyl diazonoacetate and 0.75 mmol of 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 h, then heat to 80℃ and continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 6:1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3c.

[0027] In this embodiment, the target product obtained was 117 mg, with a yield of 71%.

[0028] The target product was confirmed by nuclear magnetic resonance spectroscopy: Methyl 2-(2-chlorophenyl)-2-(2-ethyl-5-hydroxy-4-methoxyphenyl) acetate (3c):Colorless oil; 71% yield; 1 H NMR (400 MHz, CDCl3)δ 7.40–7.37 (m, 1H), 7.22–7.15 (m, 2H), 7.07 (dd, J = 7.2, 2.3 Hz, 1H), 6.77(d, J = 6.5 Hz, 1H), 6.73 (s, 1H), 5.54 (s, 1H), 5.51 (s, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 2.57–2.39(m, 2H), 1.12 (t, J = 7.5 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 172.98, 146.08, 143.73, 136.63, 134.60, 134.37, 130.39, 129.52,128.67, 127.36, 127.02, 114.90,111.63, 56.00, 52.68, 50.13, 25.72, 15.36.HRMS (ESI) calcd for C 18 H 19 ClO4K [M+K] + Found: 373.0603; Found: 373.0606. Examples 1-3 show that the product yields differed only slightly depending on the position of the same substituent (para 80%; meta 75%; ortho 71%), indicating that the steric hindrance effect of the reaction was not significant.

[0029] Example 4 S1. Weigh 0.5 mmol of isopropyl phenyldiazoacetate and 0.75 mmol of 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 h, then heat to 80℃ and continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 6:1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3d.

[0030] In this embodiment, the target product obtained was 130 mg, with a yield of 76%.

[0031] The target product was confirmed by nuclear magnetic resonance spectroscopy: Isobutyl 2-(2-ethyl-5-hydroxy-4-methoxyphenyl)-2-phenylacetate (3d):Colorless oil; 76% yield; 1 H NMR (400 MHz, CDCl3) δ 7.37–7.28 (m, 5H), 6.94 (s, 1H), 6.75 (s, 1H), 5.49 (s, 1H), 5.26(s, 1H), 3.99 (d, J = 6.5 Hz, 2H), 3.93 (s, 3H), 2.73–2.61 (m, 2H), 2.00–1.92 (m, 1H), 1.23 (t, J = 7.5 Hz, 3H), 0.93 (s, 3H), 0.91 (s, 3H). 13 C{ 1H} NMR (100MHz, CDCl3) δ 173.09, 169.51, 145.82, 143.68, 139.03, 134.24, 129.13, 128.82,128.57, 127.10, 125.33, 115.32,111.34, 71.36, 56.01, 52.70, 27.83, 25.87,19.15, 15.75. HRMS (ESI) calcd for C 21 H 26 O4K [M+K] + Found: 381.1463; Found: 381.1464. Example 5 S1. Weigh 0.5 mmol of methyl 2,4-dichlorodiazoacetate and 0.75 mmol of 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 h, then heat to 80 °C and continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 6:1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3e.

[0032] In this embodiment, the target product obtained was 129 mg, with a yield of 70%.

[0033] The target product was confirmed by nuclear magnetic resonance spectroscopy: Methyl 2-(2,4-dichlorophenyl)-2-(2-ethyl-5-hydroxy-4-methoxyphenyl) acetate (3e):Colorless oil; 70% yield; 1 H NMR (400MHz, CDCl3) δ 7.41–7.39 (m, 1H), 7.14 (dd, J = 8.4, 2.1 Hz, 1H), 6.98 (d, J= 8.4Hz, 1H), 6.76 (s, 1H), 6.73 (s, 1H), 5.53 (s, 1H), 5.46 (s, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 2.52–2.39 (m, 2H), 1.11 (t, J = 7.6 Hz, 3H). 13 C{ 1 H} NMR (100MHz, CDCl3) δ 172.49, 146.38, 144.85, 143.85, 135.47, 134.62, 133.82, 131.29,129.80, 129.33, 127.34, 114.78, 111.82, 56.02, 49.79, 46.28, 25.64,15.28.HRMS (ESI) calcd for C 18 H 18 Cl2O4K [M+K] + Found: 407.0214; Found: 407.0215. Example 6 S1. Weigh 0.5 mmol of methyl 3,4-dichlorodiazoacetate and 0.75 mmol of 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 h, then heat to 80℃ and continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 6:1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3f.

[0034] In this embodiment, the target product obtained was 136 mg, with a yield of 74%.

[0035] The target product was confirmed by nuclear magnetic resonance spectroscopy: Methyl 2-(3,4-dichlorophenyl)-2-(2-ethyl-5-hydroxy-4-methoxyphenyl)acetate (3f):White solid; mp 95-98 o C; 74% yield; 1 HNMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.06(dd, J = 8.3, 2.1 Hz, 1H), 6.82 (s, 1H), 6.70 (s, 1H), 5.51 (s, 1H), 5.12 (s,1H), 3.88 (s, 3H),3.74 (s, 3H), 2.60 –2.49 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 172.79, 146.21, 143.93, 139.03, 134.24, 132.65,131.42, 130.81, 130.46, 128.28, 127.60, 114.65,111.57, 56.02, 52.72, 51.54,25.80, 15.68. HRMS (ESI) calcd for C 18 H 18 Cl2O4K [M+K] + : 407.0214; Found: 407.0204. Example 7 (Grame-scale scale-up reaction) S1. Weigh 5 mmol of methyl p-chlorophenyldiazoacetate (1.05 g) and 7.5 mmol of 4-ethylguaiacol (1.14 g) into a dry, clean Schlenk reaction tube with a capacity of 250 mL. Add 50 mL of acetonitrile under air atmosphere and stir at room temperature for 40 minutes. S2. After adding 2 g of lignite residue catalyst, react at room temperature for 1 h, then heat to 80℃ and continue the reaction for 14 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 6:1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3a.

[0036] In this embodiment, the target product obtained was 1.27 g, with a yield of 76%.

[0037] The target product was confirmed by nuclear magnetic resonance spectroscopy: Methyl 2-(4-chlorophenyl)-2-(2-ethyl-5-hydroxy-4-methoxyphenyl) acetate (3a):Colorless oil; 76% yield; 1 H NMR (400 MHz, CDCl3)δ 7.31–7.27 (m, 2H), 7.21 – 7.16 (m, 2H), 6.86 (s, 1H), 6.73 (s,1H), 5.55 (s,1H), 5.19 (s, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 2.67–2.53 (m, 2H), 1.18 (t, J= 7.6 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 173.23, 146.02, 143.79, 137.30,134.18, 133.09, 130.19, 128.71, 128.27, 114.79,111.48, 55.97, 52.56, 51.81,25.75, 15.65. HRMS (ESI) calcd for C 18 H 19 ClO4K [M+Na] + : 357.0864; Found: 357.0868. The successful execution of the gram-scale reaction in Example 7, with little difference in yield before and after scale-up, confirms that the method of the present invention may have industrialization potential.

[0038] Example 8 (Lignite residue from Yimin, Inner Mongolia) S1. Weigh 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.75 mmol of 4-ethylguaiacol derivative into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. Add 200 mg of lignite residue (Yimin, Inner Mongolia) as a catalyst, react at room temperature for 1 h, and then heat to 80℃ to continue the reaction for 12 h.

[0039] S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 6:1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3a.

[0040] In this embodiment, the target product obtained was 125 mg, with a yield of 75%.

[0041] Example 9 (Lignite residue from Hegang, Heilongjiang) S1. Weigh 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.75 mmol of 4-ethylguaiacol derivative into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. Add 200 mg of lignite residue (Hegang, Heilongjiang) as a catalyst, react at room temperature for 1 h, and then heat to 80℃ to continue the reaction for 12 h.

[0042] S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 6:1, to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3a.

[0043] In this embodiment, the target product obtained was 129 mg, with a yield of 77%.

[0044] Examples 8-9 show that the catalytic efficiency of lignite residue catalysts from different origins is not significantly different (catalytic yield of lignite residues from different origins: Zhaotong, Yunnan 80%; Yimin, Inner Mongolia 75%; Hegang, Heilongjiang 77%), revealing that lignite residue catalysts have universality.

[0045] Example 10: Evaluation of antioxidant activity ( Chemico-Biological Interactions,2015,231: 231: 53; Coord. Chem. Rev ,1998, 178 : 699) In vitro antioxidant activity study: Experimental principle (inhibition of DPPH) DPPH (1,1-diphenyl-2-picrylhydrazine) is a common free radical. DPPH is measured by spectrophotometry. The hydrogen atom or electron donation capacity of the corresponding 4-ethylguaiacol derivative is determined by bleaching a purple methanol solution of DPPH. The antioxidant activity is evaluated by comparing the inhibitory effect on DPPH.

[0046] Experimental methods: S1. Add 5 µL of 4-ethylguaiacol derivatives (30-300 µM) with different methanol concentrations to 5 mL of 0.004% DPPH methanol solution; S2. After incubating at room temperature and in the dark for 30 minutes, read the absorbance at 517 nm as a control (DPPH test is effective in the micromolar range). The antioxidant activity of 4-ethylguaiacol derivatives requires an IC50% inhibition rate of DPPH radical formation. 50 The value (μM) is calculated by plotting the percentage of inhibition relative to the extract concentration; Three replicate tests were performed on each sample concentration and compared with an appropriate standard trolox (antioxidant: water-soluble vitamin E) to evaluate the antioxidant activity of the tested 4-ethylguaiacol derivatives, confirming the practicality of the preparation method and further highlighting the superiority of this invention.

[0047] The percentage inhibition of DPPH free radicals was obtained using the following equation, where control is the absorbance of the control (DPPH solution without the test sample), and Atest is the absorbance of the test sample (DPPH solution with the scavenger). The control contains all reagents except the scavenger.

[0048] The experimental results are shown in Table 1: Table 1: Antioxidant activity of 4-ethylguaiacol derivatives Conclusion: Based on the actual reference " Green Chem.,The experimental method described in "2020, 22: 1594" was used for preliminary in vitro anti-inflammatory activity screening. As shown in Table 1: using DPPH as the antioxidant activity target and trolox as the positive control, preliminary antioxidant activity studies revealed that after the natural phenolic product 4-ethylguaiacol was derivatized via CH insertion reaction, except for 3f and 3g, the antioxidant activities of the remaining tested derivatized products (3a-e, 3h-i) were all superior to those of underivatized 4-ethylguaiacol; among them, the antioxidant activities of 3d, 3e, 3h, and 3i were even superior to the positive control trolox (IC50). 50 Value 155.38 μM), at 3i (IC) 50 The performance at 151.27 μM was particularly outstanding, suggesting potential for development into novel antioxidant drugs. The above experimental results indicate that the method of this invention may provide an effective strategy for the derivatization of natural phenolic products and the development of new drugs, further highlighting the practicality of this invention.

[0049] To demonstrate the rationality, practicality, and superiority of this invention, the applicant compared the catalytic efficiencies of acid catalysts, base catalysts, metal catalysts, and sludge catalysts under the same reaction conditions (Comparative Examples 1-4). The applicant also compared the reusability efficiency of lignite residue catalysts (Comparative Examples 5-7) and the yield effects of different aryl diazonium ester compounds on the preparation of 4-ethylguaiacol derivatives (Comparative Examples 8-10).

[0050] Comparative Example 1 (Acid Catalyst) S1. Weigh 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.75 mmol of 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. Add 25 µL of trifluoromethanesulfonic acid as a catalyst, react at room temperature for 1 h, and then heat to 80 °C to continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 6:1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3a.

[0051] In this comparative example, the target product was 104 mg, with a yield of 62%.

[0052] Comparative Example 2 (Alkali Catalyst) S1. Weigh 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.75 mmol of 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. Add 25 µL of triethylamine as a catalyst, react at room temperature for 1 h, and then heat to 80 °C to continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 6:1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3a.

[0053] In this comparative example, the target product was 63 mg, with a yield of 38%.

[0054] Comparative Example 3 (Metal Catalyst) S1. Weigh 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.75 mmol of 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. Add 200 mg of ferric chloride catalyst as a catalyst, react at room temperature for 1 h, and then heat to 80℃ to continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 6:1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3a.

[0055] In this comparative example, the target product was 95 mg, with a yield of 57%.

[0056] Comparative Example 4 (Sludge Catalyst, Reference: Green Chem 2020 22 : 1594.) S1. Weigh 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.75 mmol of 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. Add 200 mg of sludge catalyst as a catalyst, react at room temperature for 1 h, and then heat to 80℃ to continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 6:1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3a.

[0057] In this comparative example, the target product was 105 mg, with a yield of 63%.

[0058] Comparative Examples 1-4 revealed that, under the same reaction conditions, the catalytic efficiency of the lignite residue catalyst (80%) was superior to that of the acid (62%) / alkali (38%) catalyst, the metal catalyst (57%), and the sludge catalyst (63%), highlighting the rationality and superiority of selecting the lignite residue catalyst in this invention.

[0059] Comparative Example 5 (First reuse experiment of catalyst: Referring to Example 1, the five-fold scale-up experiment of Example 1 was first carried out. After the reaction was completed, the mixture was filtered, and the filter cake, i.e. the lignite residue catalyst after one use, was taken for the first reuse experiment.) S1. Weigh 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.75 mmol of 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. Add 200 mg of used lignite residue as a catalyst, react at room temperature for 1 h, then heat to 80℃ and continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless (keep the filter cake as a catalyst for the second reuse experiment). Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 6:1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3a.

[0060] In this comparative example, the target product was 122 mg, with a yield of 73%.

[0061] Comparative Example 6 (Second reuse experiment of catalyst: referring to Example 1, first a three-fold scale-up experiment of Comparative Example 5 was carried out, and then the lignite residue catalyst used in Comparative Example 5 was used for a second reuse experiment) S1. Weigh 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.75 mmol of 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. Add 200 mg of lignite residue from Comparative Example 5 as a catalyst, react at room temperature for 1 h, and then heat to 80℃ to continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless (keep the filter cake as a catalyst for the third reuse experiment). Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 6:1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3a.

[0062] In this comparative example, the target product was 107 mg, with a yield of 64%.

[0063] Comparative Example 7 (Third Reuse Experiment of Catalyst: Referring to Example 1, a double-scale experiment of Comparative Example 6 was first conducted, and then the lignite residue catalyst used in Comparative Example 6 was used for a third reuse experiment.) S1. Weigh 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.75 mmol of 4-ethylguaiacol derivative into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. Add 200 mg of lignite residue from Comparative Example 6 as a catalyst, react at room temperature for 1 h, and then heat to 80℃ to continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and perform silica gel column chromatography separation using eluent (petroleum ether (75℃) / ethyl acetate, v / v = 6∶1) to obtain 4-ethylguaiacol derivative 3a, which is colorless, transparent and viscous.

[0064] In this comparative example, the target product was 87 mg, with a yield of 52%.

[0065] The comparative experiments of lignite residue catalyst reuse in Examples 5-7 (product yield of lignite residue reuse: 73% in the first time, 64% in the second time, and 52% in the third time) highlight the practicality of lignite residue catalyst and the superiority of selecting lignite residue as catalyst in this invention.

[0066] Comparative Example 8 S1. Weigh 0.5 mmol benzyl phenyldiazoacetate and 0.75 mmol 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 h, then heat to 80℃ and continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75 °C) / ethyl acetate, v / v = 6:1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3e.

[0067] In this comparative example, the target product was 128 mg, with a yield of 68%.

[0068] Comparative Example 9 S1. Weigh 0.5 mmol of ethyl p-methoxyphenyl diazoate and 0.75 mmol of 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 h, then heat to 80°C. o C continued to react for 12 hours.

[0069] S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and perform silica gel column chromatography separation using eluent (petroleum ether (75 ℃) / ethyl acetate, v / v = 6∶1) to obtain a colorless, transparent, viscous 4-ethylguaiacol derivative 3f.

[0070] In this comparative example, the target product was 112 mg, with a yield of 65%.

[0071] Comparative Example 10 S1. Weigh 0.5 mmol of naphthyldiazoacetic acid methyl ester and 0.75 mmol of 4-ethylguaiacol into a dry, clean Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 h, then heat to 80℃ and continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75 °C) / ethyl acetate, v / v = 6:1) to obtain 3g of 4-ethylguaiacol derivative, which is colorless, transparent and viscous.

[0072] In this comparative example, the target product was 107 mg, with a yield of 61%.

[0073] Comparative Examples 8-10 show that the yield of 4-ethylguaiacol derivatives was also very low when the basic diazonium ester compounds specified in this invention were not used, highlighting the superiority of the basic diazonium ester compounds specified in this invention.

[0074] In summary, it was found that, under the same reaction conditions, the product yields obtained by Comparative Examples 1-4 using other acid or base catalysts, metal catalysts, or sludge catalysts were all lower than those obtained by the lignite residue catalyst used in this application. This invention uses lignite residue as a catalyst, which is widely available and inexpensive; the reaction conditions are mild, the substrate range is broad, and the yield is good (the highest separation yield can reach 80%), enabling gram-scale reactions and possessing industrialization potential. It provides an effective strategy for the derivatization of natural phenolic products and the development of new drugs. Simultaneously, it achieves the recycling of waste resources (the product separation yield can still reach over 50% after the lignite residue catalyst is reused three times), and alleviates the problem of lignite residue treatment to a certain extent, aligning with the principles of green environmental protection and green chemistry.

[0075] Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes can be made to it in form and detail without departing from the scope defined by the claims of the present invention.

Claims

1. Application of lignite residue as a catalyst in the preparation of 4-ethylguaiacol derivatives.

2. The application according to claim 1 further includes a method for preparing 4-ethylguaiacol derivatives, characterized in that: Includes the following steps, S1. Mix aryl diazonium esters and 4-ethyl guaiacol, then add acetonitrile and stir. S2, and then lignite residue was used as a catalyst to catalyze the reaction. After standing at room temperature for 1 hour, the reaction was heated to 80°C and continued for 10-12 hours. S3. Stop the reaction when the raw materials have reacted completely as detected by TLC. S4. Filter the reactants and wash the filter cake with dichloromethane until it is colorless. After the filtrate is concentrated under reduced pressure to remove volatile components, it is separated by silica gel column chromatography to obtain the 4-ethylguaiacol derivative. The synthetic route for the reaction is shown below: 。 3. The method for preparing 4-ethylguaiacol derivatives according to claim 2, characterized in that: The aryl diazonium ester compound is any one of p-chlorophenyldiazoacetic acid methyl ester, m-chlorophenyldiazoacetic acid methyl ester, o-chlorophenyldiazoacetic acid methyl ester, phenyldiazoacetic acid isopropyl ester, 2,4-dichlorodiazoacetic acid methyl ester, and 3,4-dichlorodiazoacetic acid methyl ester.

4. The method for preparing 4-ethylguaiacol derivatives according to claim 3, characterized in that: In step S1, when the amount of 4-ethylguaiacol is 0.75 mmol, the amount of aryl diazonium ester is 0.5 mmol, the amount of lignite residue is 150-200 mg, and the amount of solvent acetonitrile is 5 mL.

5. The method for preparing 4-ethylguaiacol derivatives according to claim 4, characterized in that: The stirring time after adding acetonitrile is 10-20 minutes.

6. The method for preparing 4-ethylguaiacol derivatives according to any one of claims 2-5, characterized in that: The entire reaction process is carried out in an air atmosphere, without the need for nitrogen or other inert gas protection.

7. The method for preparing 4-ethylguaiacol derivatives according to claim 2, characterized in that: The eluent used in the silica gel column chromatography separation is petroleum ether and ethyl acetate in a volume ratio of 6:1, and the boiling point of the petroleum ether is 60-90℃.

8. The method for preparing 4-ethylguaiacol derivatives according to claim 2, characterized in that: In the reaction formula, R 1 It is one or more of hydrogen, methyl, ethyl, methoxy, nitro, acyl, halogen, and trifluoromethyl, wherein the halogen is F, Cl, Br, or I; R 2 It can be methyl, ethyl, allyl, phenyl, benzyl, or alkyl.

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