A method for synthesizing coumest compounds by a four-chloranil / manganese acetate synergistic palladium catalysis one-pot method

Abstract

This invention provides a one-pot synthesis method for coumarin compounds via a tetrachlorobenzoquinone / manganese acetate synergistic palladium-catalyzed process, belonging to the field of organic synthesis technology. The method comprises the following steps: a 2-hydroxybenzaldehyde compound, a 2-hydroxyphenylacetic acid compound, a palladium catalyst, tetrachlorobenzoquinone, manganese acetate, and an organic base are reacted in a solvent in a one-pot reaction to obtain coumarin compounds. The method utilizes a tetrachlorobenzoquinone and manganese acetate combined system to achieve a condensation-cyclization tandem reaction in an alkaline anhydrous ethanol / piperidine medium, directly generating coumarin compounds. This provides a novel synthetic route that is simple in steps, mild in conditions, short in reaction time, and high in yield.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for one-pot synthesis of coumarin compounds using tetrachlorobenzoquinone / manganese acetate synergistic palladium catalysis. Background Technology

[0002] Coumarin compounds are a class of natural products with a 6H-benzofurano[3,2-c]chromene-6-one tetracyclic skeleton, whose core structure consists of a fused coumarin ring and a benzofuran ring. Representative members of this class include coumarin and psoralen. Coumarin exhibits significant biological activities, including anti-inflammatory, antioxidant, estrogenic, and antitumor effects. Psoralen is another important coumarin compound, also possessing various pharmacological activities such as antitumor, anti-inflammatory, antioxidant, and antibacterial activity. Given the importance of coumarin compounds in medicinal chemistry research, their total synthesis has been a continuously researched hot topic in the field of organic synthesis. To date, various synthetic methods for constructing the tetracyclic skeleton of coumarin compounds have been reported in the literature.

[0003] Based on the A, B, C, and D rings in the following structural formula, these methods can be classified into synthesizing CD rings based on AB rings and synthesizing AB rings based on CD rings.

[0004]

[0005] (1) Synthesizing CD rings based on AB rings

[0006] Marie et al. used NCS and CF3COOH for chlorination to obtain chlorocoumarin, followed by intramolecular arylation to yield coumarin skeleton compounds, with an overall yield of 40% (see: The Journal of Organic Chemistry. 2015, 80, 10904-10913). However, this route is time-consuming, requiring 72 hours of reaction time for the first step and 14 hours for the second step, while also requiring heating at 130°C.

[0007]

[0008] Du Yunfei et al. synthesized coumarin compounds by constructing carbon-oxygen bonds using 4-hydroxy-3-arylcoumarin as a substrate under the action of ferric chloride. 4-hydroxy-3-arylcoumarin was added to dichloroethane, followed by 2.5 equivalents of FeCl3 / SiO2. After reaction, the product was obtained by column chromatography, with a yield of 40-50% (see: The Journal of Organic Chemistry. 2011, 76, 2744-2752). However, this method still requires a reaction time of 12-24 hours, and the synthesis of 4-hydroxy-3-arylcoumarin requires two steps, making the overall route a three-step process.

[0009]

[0010] Mayuri et al. synthesized coumarin compounds via oxidative cyclization of 3-(2-hydroxyphenylcoumarin) (see: Tetrahedron, 2017, 73, 5528-5536). The reaction mechanism involves the action of Cu(OAc)₂ in intramolecular CO, leading to CH functionalization and the construction of these compounds. However, this method requires a reaction temperature of 258℃.

[0011]

[0012] (2) Synthesize AB ring based on CD ring.

[0013] Nawaf et al. yielded methyl 2,3-bis(2,4-dimethoxyphenyl)-3-oxopropionate via the condensation reaction of phenyl acetate and benzoyl chloride. Subsequent demethylation and intramolecular cyclization yielded coumarin. The overall yield was approximately 60% (see: Tetrahedron 2004, 60, 1637-1642). However, this method also requires three steps, with the final step taking over 72 hours.

[0014]

[0015] Based on a comprehensive analysis of the existing synthesis methods, the following problems exist: (1) The steps are relatively long, with most synthesis routes requiring 2 to 3 steps and many intermediate separation and purification steps; (2) The reaction temperature is high, with the reaction temperature required to reach 258℃ for two-step synthesis methods using copper acetate as a catalyst; (3) The reaction time is long, with most reactions requiring 12 to 24 hours or even 72 hours of reaction time; (4) The yield is moderate, with most reactions having a yield of 40 to 60%.

[0016] Therefore, developing a new synthetic method for coumarin compounds that is simple in steps, mild in conditions, short in reaction time, and high in yield remains an important problem that urgently needs to be solved in the field of organic synthesis. Summary of the Invention

[0017] The purpose of this invention is to provide a one-pot method for synthesizing coumarin compounds using a tetrachlorobenzoquinone / manganese acetate synergistic palladium catalysis, addressing the shortcomings of existing technologies.

[0018] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for the one-pot synthesis of coumarin compounds via a tetrachlorobenzoquinone / manganese acetate synergistic palladium-catalyzed process, comprising the following steps: A condensation-cyclization tandem reaction of 2-hydroxybenzaldehyde compounds, 2-hydroxyphenylacetic acid compounds, palladium catalyst, tetrachlorobenzoquinone, manganese acetate, and organic base in a solvent yields coumarin compounds. The structural formula of the 2-hydroxybenzaldehyde compounds is Formula 1: , where R 1 Selected from hydrogen, chlorine, methyl, trifluoromethoxy; R 2 Selected from hydrogen, hydroxyl, methyl, benzyloxy, fluorine; R 3 Selected from hydrogen, nitro, 3-methyl-2-butenyl, methoxy, chlorine, tert-butyl, trifluoromethoxy; R 4 Selected from hydrogen, fluorine, and methyl; The structural formula of the 2-hydroxyphenylacetic acid compound is Formula 2: , where R 5 Selected from hydrogen and hydroxyl groups.

[0019] Preferably, the palladium catalyst is Pd(OAc)2 or PdCl2, the organic base is piperidine, and the solvent is anhydrous ethanol.

[0020] Preferably, the molar ratio of the 2-hydroxybenzaldehyde compound, the 2-hydroxyphenylacetic acid compound, and the organic base is 1:0.9~1.1:1.5~3.0.

[0021] Preferably, the molar amount of the palladium catalyst is 0.5 to 5% of the molar amount of the 2-hydroxybenzaldehyde compound.

[0022] Preferably, the molar amount of the tetrachlorobenzoquinone is 5 to 20% of the molar amount of the 2-hydroxybenzaldehyde compound.

[0023] Preferably, the molar amount of manganese acetate is 5 to 10% of the molar amount of the 2-hydroxybenzaldehyde compound.

[0024] Preferably, the condensation cyclization tandem reaction takes 4 to 6 hours.

[0025] The beneficial effects of this invention are: 1) The overall yield is significantly higher than that of the traditional stepwise route: The one-pot synthesis yield of this invention (over 80%) is higher than that of existing synthesis methods, and its convenience is improved, demonstrating the synergistic advantages of tandem reactions.

[0026] 2) Short reaction time: Compared with existing synthesis methods, the reaction time of the method of the present invention is shortened to 4-6 hours.

[0027] 3) Wide range of substrates: The method of this invention uses simple aromatic small molecule raw materials to synthesize coumarin compounds. The substrates are highly selectable and can synthesize coumarin compounds with different types of substituents. Detailed Implementation

[0028] This invention provides a method for the one-pot synthesis of coumarin compounds via a tetrachlorobenzoquinone / manganese acetate synergistic palladium-catalyzed process, comprising the following steps: A condensation-cyclization tandem reaction of 2-hydroxybenzaldehyde compounds, 2-hydroxyphenylacetic acid compounds, palladium catalyst, tetrachlorobenzoquinone, manganese acetate, and organic base in a solvent yields coumarin compounds. The structural formula of the 2-hydroxybenzaldehyde compounds is Formula 1: , where R 1 Selected from hydrogen, chlorine, methyl, trifluoromethoxy; R 2 Selected from hydrogen, hydroxyl, methyl, benzyloxy, fluorine; R 3 Selected from hydrogen, nitro, 3-methyl-2-butenyl, methoxy, chlorine, tert-butyl, trifluoromethoxy; R 4 Selected from hydrogen, fluorine, and methyl; The structural formula of the 2-hydroxyphenylacetic acid compound is Formula 2: , where R 5 Selected from hydrogen and hydroxyl groups.

[0029] In this invention, the route for synthesizing coumarin compounds from 2-hydroxybenzaldehyde and 2-hydroxyphenylacetic acid compounds is as follows: .

[0030] In this invention, the palladium catalyst is preferably Pd(OAc)2 or PdCl2, the organic base is preferably piperidine, and the solvent is preferably anhydrous ethanol.

[0031] In this invention, the molar ratio of the 2-hydroxybenzaldehyde compound, the 2-hydroxyphenylacetic acid compound, and the organic base is preferably 1:0.9~1.1:1.5~3.0, more preferably 1:0.95~1.05:1.8~2.6, and even more preferably 1:1.0:2.0~2.3.

[0032] In this invention, the molar amount of the palladium catalyst is preferably 0.5-5% of the molar amount of the 2-hydroxybenzaldehyde compound, more preferably 1-4%, and even more preferably 2-3%.

[0033] In this invention, the molar amount of tetrachlorobenzoquinone is preferably 5-20% of the molar amount of 2-hydroxybenzaldehyde compound, more preferably 8-16%, and even more preferably 10-15%; the molar amount of manganese acetate is preferably 5-10% of the molar amount of 2-hydroxybenzaldehyde compound, more preferably 6-9%, and even more preferably 7-8%.

[0034] In this invention, anhydrous ethanol is used as the reaction medium, piperidine is used as an organic base and coordination stabilizer, tetrachlorobenzoquinone is used as the main oxidant, and manganese acetate is used as a co-oxidant / electron transfer medium.

[0035] In this invention, the condensation cyclization tandem reaction time is preferably 4-6 hours, more preferably 4.5-5.5 hours, and even more preferably 5 hours.

[0036] In this invention, the atmosphere for the condensation cyclization tandem reaction is air, and the reaction is carried out at atmospheric pressure.

[0037] In this invention, the coumarin compounds include compounds 3a to 3n, with the following structural formulas: .

[0038] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0039] Example 1 Synthesis of 5-nitrocoumarestrol derivative 3a in tetrachlorobenzoquinone / manganese acetate system

[0040] 5-Nitrosalicylaldehyde (CAS: 97-51-8, 1.7 g, 10.0 mmol), o-hydroxyphenylacetic acid (CAS: 614-75-5, 1.5 g, 10.0 mmol), piperidine (20.0 mmol, 1.7 g), Pd(OAc)2 (0.2 mmol, 45 mg), tetrachlorobenzoquinone (1 mmol, 246 mg), manganese acetate (0.6 mmol, 104 mg), and anhydrous ethanol (30 mL) were added sequentially to a 100 mL reaction flask. The mixture was heated to reflux and monitored by TLC (the volume ratio of petroleum ether to ethyl acetate was 5:1) until the starting spot disappeared (reaction time 6 h).

[0041] After the reaction was complete, the reaction solution was cooled to room temperature. The pH of the reaction solution was slowly adjusted to 3.5 with 1M hydrochloric acid, followed by extraction with ethyl acetate (40 mL × 3 times). The organic phases were combined and washed successively with saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was dissolved in 20 mL of anhydrous ethanol by heating, impurities were adsorbed onto silica gel, filtered while hot, cooled to crystallize, and filtered again to obtain 2.4 g of pale white solid product 3a, with a yield of 85.4%.

[0042] 1H NMR data for product 3a (known compound): 1 H NMR (400 MHz, CDCl3) d 8.97 (d, J = 4.0 Hz, 1H), 8.48 (dd, J = 8.0, 4.0 Hz, 1H), 8.18 (d, J = 4.0 Hz, 1H), 7.75 (d, J =8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.60-7.52 (m, 2H); Carbon spectral data: 13 C NMR (100MHz, CDCl3) d 158.2, 156.6, 156.4, 155.9, 144.2, 127.9, 126.4, 125.8, 122.8,122.1, 118.7, 118.2, 113.1, 112.1, 107.3; ESI-MS: m / z calculated for C 15 H7NO5[MH] — : 280.02, found 280.03.

[0043] Example 2 Preparation of compounds 3b-3n

[0044] Based on products 3b~3n, select the corresponding sites (R). 1 ~R 5 Products 3b-3n were prepared from starting materials (o-hydroxybenzaldehyde compounds and o-hydroxyphenylacetic acid compounds) containing the same groups as the products, using the method of Example 1 (the only difference from Example 1 is the starting materials and reaction time): The starting materials for the preparation of 3b (a known compound, psoralen) were 2,4-dihydroxy-5-(3-methylbut-2-enyl)benzaldehyde (CAS: 21422-02-6) and 2,4-dihydroxyphenylacetic acid (CAS: 614-82-4); the reaction time was 5 h; the yield of product 3b was 82.2%. 3b 1H NMR data: 1 H NMR (400 MHz, DMSO-D6) d 10.753 (s, 1H), 10.031 (s, 1H), 7.682 (d, J = 8.4 Hz, 1H), 7.606 (s, 1H), 7.175 (d, J = 2.0 Hz, 1H), 6.942(dd, J = 8.4, 2.0 Hz 1H), 6.921 (s, 1H), 5.378-5.333 (m, 1H), 3.320 (d, J =7.6 Hz, 2H), 1.751 (s, 3H), 1.715 (s, 3H); Carbon spectral data: 13 C NMR (100 MHz, DMSO-D6) d 159.5, 158.9, 157.7, 157.0, 155.9, 152.9, 132.5, 126.5, 121.7, 121.0,120.6, 114.7, 113.9, 103.8, 102.4, 102.0, 98.7, 27.5, 25.6, 17.7; ESI-MS:m / zcalculated for C 20 H 16 O5[MH] — : 335.09, found 335.03. The starting materials for the preparation of 3c (known compound, coumarin) were 2,4-dihydroxybenzaldehyde (CAS: 95-01-2) and 2,4-dihydroxyphenylacetic acid (CAS: 614-82-4); the reaction time was 5.5 h; the yield was 83.5%. 3C proton spectrum data: 1 H NMR (400 MHz, DMSO-D6) d 10.72 (s, 1H), 10.05 (s, 1H),7.86 (d, J = 8.0 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.18 (d, J = 4.0 Hz, 1H), 6.97-6.91 (m, 3H); Carbon spectral data: 13 C NMR (100 MHz, DMSO-D6) d 161.2, 159.5, 157.6,157.0, 155.9, 154.6, 122.7, 120.6, 114.6, 114.0, 113.8, 104.2, 103.0, 102.0,98.7; ESI-MS: m / z calculated for C 15 H8O5 [MH] — : 267.02, found 267.08. The starting materials for the preparation of 3d (known compound) were 2-hydroxy-4-methylbenzaldehyde (CAS: 698-27-1) and o-hydroxyphenylacetic acid (CAS: 614-75-5); the reaction time was 6 h; and the yield was 86.3%. 3D proton spectrum data: 1 H NMR (400 MHz, CDCl3) d 8.10–8.08 (m, 1H), 7.84 (d, J =8.0 Hz, 1H), 7.62-7.60 (m, 1H), 7.44-7.42 (m, 2H), 7.25 (s, 1H), 7.18 (d, J =8.0 Hz, 1H), 2.47 (s, 3H); Carbon spectral data: 13 C NMR (100 MHz, CDCl3) d 160.2, 158.2,155.3, 153.8, 143.2, 126.4, 125.8, 125.0, 123.5, 121.6, 121.5, 117.5, 111.6,110.0, 104.9, 21.9; ESI-MS: m / z calculated for C 16 H 10 O3 [M+Na] + : 273.05, found273.09. The starting materials for the preparation of 3e (a known compound) were 4-benzyloxy-2-hydroxybenzaldehyde (CAS: 52085-14-0) and o-hydroxyphenylacetic acid (CAS: 614-75-5); the reaction time was 6 h; and the yield was 84.7%. 3e proton spectrum data: 1 H NMR (400 MHz, CDCl3) d 8.11–8.08 (m, 1H), 7.93 (d, J =12.0 Hz, 1H), 7.64-7.62 (m, 1H), 7.47-7.37 (m, 7H), 7.07-7.06 (m, 2H), 5.17 (s, 2H); Carbon spectrum data (some carbon signals are not listed due to overlap): 13 C NMR (100 MHz, CDCl3) d 162.1,160.6, 158.4, 155.5, 155.3, 135.7, 128.8, 128.4, 127.5, 126.2, 125.1, 123.6,122.9, 121.5, 113.8, 111.5, 106.1, 103.5, 102.5, 70.6; ESI-MS: m / z calculated for C 22 H 14 O4 [M+H] + : 343.09, found 343.02. The starting materials for the preparation of 3f (known compound) were 2-hydroxy-5-methoxybenzaldehyde (CAS: 672-13-9) and o-hydroxyphenylacetic acid (CAS: 614-75-5); the reaction time was 4.5 h; the yield was 85.0%. 3f proton NMR data: 1 H NMR (400 MHz, CDCl3) d 8.101 (dd, J = 7.2, 1.6 Hz, 1H),7.632-7.610 (m, 1H), 7.474-7.425 (m, 2H), 7.381-7.346 (m, 2H), 7.121 (dd, J =9.2, 3.2 Hz, 1H), 3.911 (s, 3H); Carbon spectrum data: 13 C NMR (100 MHz, CDCl3) d159.8,158.1, 156.3, 155.4, 148.1, 126.7, 125.1, 123.5, 121.8, 120.2, 118.6, 112.7,111.6, 105.9, 103.3, 55.9; ESI-MS: m / z calculated for C 16 H 10 O4 [M+Na] + : 289.04, found 289.08. The starting materials for preparing 3 g (of known composition) were 2,4-dihydroxybenzaldehyde (CAS: 95-01-2) and o-hydroxyphenylacetic acid (CAS: 614-75-5); the reaction time was 5 h; and the yield was 86.7%. 3g hydrogen spectrum data: 1 H NMR (400 MHz, DMSO-D6) d 10.836 (s, 1H), 7.928-7.898 (m, 2H), 7.833 (dd, J = 6.4, 2.0 Hz, 1H), 7.527-7.458 (m, 2H), 6.959 (dd, J =8.8, 2.4 Hz, 1H), 6.926 (d, J = 2.0 Hz, 1H); Carbon spectrum data: 13 C NMR (100 MHz, DMSO-D6) d 161.9, 160.6, 157.4, 155.3, 154.5, 126.2, 125.2, 123.2, 123.1, 120.3,113.9, 111.9, 103.8, 103.1, 101.7; ESI-MS: m / z calculated for C 15 H8O4 [M+Na] + :275.03, found 275.06. The starting materials for the preparation of the known product (3h) were 5-chlorosalicylaldehyde (CAS: 635-93-8) and o-hydroxyphenylacetic acid (CAS: 614-75-5); the reaction time was 6h; and the yield was 84.1%. 3-hour proton NMR data: 1 H NMR (400 MHz, CDCl3) d 8.14 (d, J= 4.0 Hz, 1H), 8.00(s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.55-7.44 (m, 4H); Carbon spectral data: 13 C NMR (100MHz, CDCl3) d 158.6, 157.4, 155.7, 151.9, 131.8, 130.3, 127.2, 125.4, 123.2,122.0, 121.3, 118.9, 113.7, 111.9, 106.6; ESI-MS: m / z calculated for C 15 H7ClO3[M+Na] + : 292.99, found 292.99. The starting materials for the preparation of 3i (a new compound) were 2,4-difluoro-6-hydroxybenzaldehyde (CAS: 136516-64-8) and o-hydroxyphenylacetic acid (CAS: 614-75-5); the reaction time was 5.5 h; and the yield was 83.4%. 3i proton NMR data: 1 H NMR (400 MHz, CDCl3) d 8.125 (dd, J = 6.8, 2.0 Hz, 1H), 7.710 (d, J = 7.2, 1.6 Hz, 1H), 7.539-7.464 (m, 2H), 7.078 (dt, J = 8.8, 2.0Hz, 1H), 6.937 (td, J = 8.8, 2.0 Hz, 1H); Carbon spectral data: 13 C NMR (100 MHz, CDCl3) d 164.08 (dd, J = 253.0, 14.0 Hz), 157.86 (dd, J = 259.0, 15.0 Hz), 156.87,155.73, 154.83 (dd, J = 15.0, 8.0 Hz), 128.95 (d, J = 28.0 Hz), 128.53 (d, J= 8.0 Hz), 127.11, 125.49, 122.46, 121.68, 112.01, 101.40 (dd, J = 53.0, 4.0Hz), 101.38, 101.16 (d, J = 55.0 Hz); HRMS (ESI+): m / z calculated for C 15 H6F2O3[M+Na] + : 295.0183, found 295.0179. The starting materials for the preparation of compound 3j (new compound) were 3,5-dichloro-2-hydroxybenzaldehyde (CAS: 90-60-8) and o-hydroxyphenylacetic acid (CAS: 614-75-5); the reaction time was 4.5 h; the yield was 87.0%. 3J 1H NMR data: 1 H NMR (400 MHz, CDCl3) d 8.14 (d, J = 8.0 Hz, 1H), 7.92(d, J = 4.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 4.0 Hz, 1H), 7.55-7.47 (m, 2H); Carbon spectral data: 13 C NMR (100 MHz, CDCl3) d 158.0, 156.5, 155.8,147.9, 131.9, 130.1, 127.6, 125.6, 123.5, 122.9, 122.2, 119.8, 114.6, 111.9,107.1; HRMS (ESI+): m / z calculated for C 15 H6Cl2O3 [M+Na] + : 326.9592, found326.9587. The starting materials for the preparation of 3k (a new compound) were 2-hydroxy-3,6-dimethylbenzaldehyde (CAS: 1666-04-2) and o-hydroxyphenylacetic acid (CAS: 614-75-5); the reaction time was 4 h; and the yield was 85.6%. 3K proton spectrum data: 1 H NMR (400 MHz, CDCl3) d8.17-8.15 (m, 1H), 7.66-7.64 (m,1H), 7.46-7.44 (m, 2H), 7.29-7.26 (m, 1H), 7.05 (d, J = 8.0 Hz, 1H), 2.87 (s, 3H), 2.49 (s, 3H); Carbon spectral data: 13 C NMR (100 MHz, CDCl3) d 161.48, 158.09, 155.36,152.64, 132.62, 132.55, 126.35, 126.20, 125.04, 124.35, 123.05, 121.80,111.64, 111.57, 105.66, 21.13, 16.13; HRMS (ESI+): m / z calculated for C 17 H 12 O3[M+Na] + : 287.0684, found 287.0683. The starting materials for the preparation of 3l (a new compound) were 5-tert-butyl-2-hydroxybenzaldehyde (CAS: 2725-53-3) and o-hydroxyphenylacetic acid (CAS: 614-75-5); the reaction time was 5.5 h; and the yield was 82.9%. 3L proton NMR data: 1 H NMR (400 MHz, CDCl3) d 8.14–8.12 (m, 1H), 8.01 (d, J =4.0 Hz, 1H), 7.66 (dd, J = 8.0, 4.0 Hz, 2H), 7.49-7.42 (m, 3H), 1.43 (s, 9H); Carbon spectrum data (some carbon signals are not listed due to overlap): 13 C NMR (100 MHz, CDCl3) d HRMS (ESI+): m / z calculated for C 19 H 16 O3 [M+Na] +315.0997, found 315.0993. The starting materials for the preparation of 3m (a new compound) were 2-hydroxy-3-(trifluoromethoxy)benzaldehyde (CAS: 497959-31-6) and o-hydroxyphenylacetic acid (CAS: 614-75-5); the reaction time was 5 h; and the yield was 88.0%. 3m proton spectrum data: 1 H NMR (400 MHz, CDCl3) d 8.128 (dd, J = 7.6, 1.2 Hz, 1H), 7.963 (dd, J = 8.0, 1.6 Hz, 1H), 7.663 (d, J = 7.6 Hz, 1H), 7.558-7.396 (m, 4H); Carbon spectral data: 13 C NMR (100 MHz, CDCl3) d HRMS (ESI+): m / z calculated for C 16 H7F3O4 [M+Na] + : 343.0194, found 343.0189. The starting materials for the preparation of 3n (a new compound) were 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (CAS: 93249-62-8) and o-hydroxyphenylacetic acid (CAS: 614-75-5); the reaction time was 6 h; and the yield was 86.4%. 3n proton NMR data: 1 H NMR (400 MHz, CDCl3) d 8.13 (d, J = 8.0 Hz, 1H), 7.87(s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.55-7.44 (m, 4H); Carbon spectral data: 13 C NMR (100MHz, CDCl3) dHRMS (ESI+): m / z calculated for C 16 H7F3O4 [M+Na] + : 343.0194, found 343.0189. Example 3: Scale-up Experiment To verify the practicality and stability of the method of the present invention in large-scale synthesis, taking compound 3n as an example, the feed amounts of 2-hydroxy-5-(trifluoromethoxy)benzaldehyde and o-hydroxyphenylacetic acid were increased from 10 mmol to 100 mmol, respectively, Pd(OAc)2 was 2 mmol, tetrachlorobenzoquinone was 10 mmol, manganese acetate was 6 mmol, piperidine was 200 mmol, and anhydrous ethanol was 300 mL. Other process conditions and post-treatment methods were the same as in Example 1.

[0045] After the reaction was completed, 26.1 g of compound 3n was obtained, with a separation yield of 81.6%. This result is basically consistent with the small-scale test (10 mmol, yield 86.4%), indicating that the catalytic system of the present invention has good scale-up effect and industrial application prospects.

[0046] Example 4: Determination of the inhibitory activity of the new compound against xanthine oxidase

[0047] Solution preparation: Phosphate-buffered saline (PBS, pH 7.4) was prepared according to standard methods. Xanthine oxidase (SigmaX4875) was diluted with PBS to the appropriate activity. Xanthine substrate was prepared into a 280 µmol / L solution with PBS. The test compound and the positive control febuxostat were prepared into stock solutions with DMSO, and diluted to the target concentration with PBS containing an equal proportion of DMSO before use (final DMSO concentration ≤ 0.1%).

[0048] Sample addition and reaction system (96-well plate, total volume 200µL): The experiment was divided into four groups. Enzyme activity control group: 20µL PBS containing DMSO + 80µL enzyme solution; Sample group: 20µL working solution of the test compound + 80µL enzyme solution; Sample background group: 20µL working solution of the test compound + 80µL PBS (as a substitute for enzyme); Substrate background group: 20µL PBS containing DMSO + 80µL PBS (as a substitute for enzyme). After mixing all the above wells, incubate at 37℃ for 5 min, then add 100µL xanthine substrate solution to each well to start the reaction.

[0049] Detection and Data Processing: Place the sample in an ELISA reader and monitor continuously at 295 nm for 5 minutes, recording the absorbance value every 30 seconds. Calculate the slope (V) of each well within the linear reaction interval. Subtract the substrate background slope from the slope of each group (i.e., subtract the measured slope of the substrate background slope from the measured slope of each group), and then calculate the inhibition rate using the following formula: Inhibition rate (%) = [1 - (V 样品 -V 样品背景 ) / V 酶活性对照 ]×100% Experimental results: The inhibition rates of the new compounds 3i~3n on xanthine oxidase at a concentration of 100 µmol / L are shown in Table 1.

[0050] Table 1. Inhibition rate of the new compound on xanthine oxidase

[0051] As shown in Table 1, the novel compounds of this invention exhibit significant inhibitory effects on xanthine oxidase at a concentration of 100 µmol / L, with inhibition rates all exceeding 65%. These results indicate that these novel compounds can lower uric acid levels by inhibiting xanthine oxidase activity and blocking the uric acid production pathway, thus possessing potential application value as drugs for treating hyperuricemia or gout.

[0052] Comparative Example 1

[0053] The difference between this comparative example and Example 1 is that the addition of manganese acetate was omitted, and TLC monitoring showed that a large amount of the starting material remained after 6 hours of reaction. Compound 3a was obtained with a yield of 18.4%.

[0054] Comparative Example 2

[0055] The difference between this comparative example and Example 1 is that the addition of tetrachlorobenzoquinone was omitted, and the reaction almost stopped after 6 hours as monitored by TLC. Compound 3a was obtained in 12.3% yield.

[0056] Comparative Example 3

[0057] The difference between this comparative example and Example 1 is that manganese acetate was replaced with an equal amount of copper acetate, and TLC monitoring showed that precipitation occurred in the reaction system after 6 hours. Compound 3a was obtained with a yield of 24.6%.

[0058] Comparative Example 4

[0059] The difference between this comparative example and Example 1 is that tetrachlorobenzoquinone and manganese acetate were omitted, and 1.6 mmol of FeCl3 was added, followed by heating to reflux. After 30 minutes of reaction, a large amount of precipitate appeared in the system, and the system became heterogeneous. Post-treatment (requiring additional filtration to remove the precipitate) yielded compound 3a in 16.8% yield.

[0060] Comparative Example 5

[0061] The difference between this comparative example and Example 1 is that anhydrous ethanol was replaced with an equal volume of toluene. The mixture was heated to 114°C under air and refluxed. After 6 hours of TLC monitoring, a large amount of starting material remained. The reaction was continued for 12 hours, but the yield was still unsatisfactory. Compound 3a was obtained with a yield of 21.5%.

[0062] Comparative Example 6

[0063] The difference between this comparative example and Example 1 is that piperidine was not added, and the reaction was carried out under reflux of anhydrous ethanol for 8 hours. TLC showed that almost no product was formed. The reaction time was extended to 24 hours, but the yield was still <5%.

[0064] The method of this invention employs a tetrachlorobenzoquinone and manganese acetate combined system to achieve a condensation cyclization tandem reaction in an alkaline anhydrous ethanol / piperidine medium, directly generating coumarin compounds. This provides a novel synthetic route that is simple in steps, mild in conditions, short in reaction time, and yields high results.

[0065] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for one-pot synthesis of coumarin compounds via a tetrachlorobenzoquinone / manganese acetate co-catalyzed palladium process, characterized in that, It includes the following steps: A condensation-cyclization tandem reaction of 2-hydroxybenzaldehyde compounds, 2-hydroxyphenylacetic acid compounds, palladium catalyst, tetrachlorobenzoquinone, manganese acetate, and organic base in a solvent yields coumarin compounds. The structural formula of the 2-hydroxybenzaldehyde compounds is Formula 1: , where R 1 Selected from hydrogen, chlorine, methyl, trifluoromethoxy; R 2 Selected from hydrogen, hydroxyl, methyl, benzyloxy, fluorine; R 3 Selected from hydrogen, nitro, 3-methyl-2-butenyl, methoxy, chlorine, tert-butyl, trifluoromethoxy; R 4 Selected from hydrogen, fluorine, and methyl; The structural formula of the 2-hydroxyphenylacetic acid compound is Formula 2: , where R 5 Selected from hydrogen and hydroxyl groups; The structural formula of the coumarin compound is Formula 3: ； The palladium catalyst is Pd(OAc)2 or PdCl2, the organic base is piperidine, and the solvent is anhydrous ethanol.

2. The method for one-pot synthesis of coumarin compounds via tetrachlorobenzoquinone / manganese acetate synergistic palladium catalysis according to claim 1, characterized in that, The molar ratio of the 2-hydroxybenzaldehyde compound, the 2-hydroxyphenylacetic acid compound, and the organic base is 1:0.9~1.1:1.5~3.

0.

3. The method for one-pot synthesis of coumarin compounds via tetrachlorobenzoquinone / manganese acetate synergistic palladium catalysis according to claim 2, characterized in that, The molar amount of the palladium catalyst is 0.5 to 5% of the molar amount of the 2-hydroxybenzaldehyde compound.

4. The method for one-pot synthesis of coumarin compounds via tetrachlorobenzoquinone / manganese acetate synergistic palladium catalysis according to claim 3, characterized in that, The molar amount of the tetrachlorobenzoquinone is 5 to 20% of the molar amount of the 2-hydroxybenzaldehyde compound.

5. The method for one-pot synthesis of coumarin compounds via tetrachlorobenzoquinone / manganese acetate synergistic palladium catalysis according to claim 3 or 4, characterized in that, The molar amount of manganese acetate is 5 to 10% of the molar amount of the 2-hydroxybenzaldehyde compound.

6. The method for one-pot synthesis of coumarin compounds via tetrachlorobenzoquinone / manganese acetate synergistic palladium catalysis according to claim 5, characterized in that, The condensation cyclization tandem reaction takes 4-6 hours.

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