Preparation method and application of benzofuranone compound
By combining CuBr2/ethyl acetate and tert-butanol/sodium acetate systems, the problems of cumbersome reaction steps and highly toxic reagents in the synthesis of benzofuranone compounds have been solved, achieving a high-yield, low-cost synthesis process suitable for industrial applications.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- KUNMING UNIV OF SCI & TECH
- Filing Date
- 2025-12-15
- Publication Date
- 2026-04-21
AI Technical Summary
Existing methods for synthesizing benzofuranone compounds suffer from problems such as cumbersome reaction steps, use of highly toxic reagents, harsh reaction conditions, poor atom economy, and low yields, which increase the difficulty and cost of synthesis and pose a threat to the environment and the health of operators.
The CuBr2/ethyl acetate system is used for highly efficient and selective bromination of ketones at the α-position, combined with the tert-butanol/sodium acetate system for intramolecular cyclization. This avoids the use of traditional highly toxic or expensive brominating reagents and employs mild reaction conditions and a simple operating procedure.
It achieves a simple, safe, and efficient synthesis process with high product yield, is suitable for industrial production, reduces preparation costs, and conforms to the concept of green chemistry.
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Figure CN121895263A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing benzofuranone compounds and their applications. Background Technology
[0002] Benzofuranones are an important class of organic compounds. Due to the presence of fused benzene and furan rings in their structure, some benzofuranones possess anti-inflammatory, antibacterial, and antitumor biological activities. Given their unique physiological activities, benzofuranones hold an important position in medicinal chemistry and have attracted considerable attention in drug development. Furthermore, they are widely used in pharmaceuticals, pesticides, dyes, and materials science.
[0003] In 1942, Shriner's group reported the synthesis of benzofuranone compounds (J. Am. Chem. Soc. 1942, 64, 2, 382–384; https: / / doi.org / 10.1021 / ja01254a044). The synthesis involved a Hoesch reaction between phloroglucinol and chloroacetonitrile to produce 2,4,6-trihydroxyphenylchloromethyl ketone imine hydrochloride, which was then hydrolyzed to 2,4,6-trihydroxy-α-chloroacetophenone. Finally, ring closure was achieved using sodium acetate to yield the target compound, 4,6-dihydroxycoumarin-3-one. While this method has some synthetic value, its reaction steps are cumbersome, it uses highly toxic chloroacetonitrile, the reaction time is long, and the yield is low.
[0004]
[0005] In 2004, Subbaraju's group reported another synthetic method for benzofuranones (Biosci. Biotechnol. Biochem., 2004, 68, 10, 2183–2185; http: / / dx.doi.org / 10.1271 / bbb.68.2183). This group used pyrogallol and chloroacetic acid in the presence of boron trifluoride ether in a Friedal-Crafts reaction to obtain a chlorinated intermediate, which was then cyclized under reflux for 6 hours with sodium acetate as the base and ethanol as the solvent, yielding 6,7-dihydroxycoumarone in 85% yield. This method not only uses chloroacetic acid, which is highly toxic to aquatic organisms, but also includes boron trifluoride ether, a reagent with a strong, unpleasant odor. Therefore, even though this method yields a high amount of chloroacetic acid and boron trifluoride ether, and involves a long reaction time and complex operation, it has certain limitations.
[0006]
[0007] In 2018, Yang's research group reported a novel method for synthesizing benzofuranone compounds (Bioorganic & Medicinal Chemistry Letters, 2018, 28, 668–672; https: / / doi.org / 10.1016 / j.bmcl.2018.01.018). Their group first brominated the starting compound using copper bromide as the bromine source in an ethyl acetate / chloroform system, and then cyclized the brominated compound under KF and DMF conditions. This reaction can be carried out at room temperature, but the reaction time is relatively long, and the use of DMF as the reaction solvent makes it difficult to remove during post-reaction purification, posing significant challenges to the purification process. Furthermore, the use of chloroform as a solvent is problematic due to its toxicity and environmental hazards.
[0008]
[0009] In 2023, Reddy's group reported a one-step strategy for the direct synthesis of benzofuran compounds (The Journal of Organic Chemistry, 2023, 88, 8889; https: / / doi.org / 10.1021 / ACS.JOC.3C00671). This group constructed benzofuran derivatives under mild reaction conditions via a palladium(II)-catalyzed tandem cycloaddition-alkenylation reaction of o-alkynylphenol / aniline with (E)-β-iodovinyl sulfone. Although both electron-donating and electron-withdrawing substrates were successfully used to produce vinyl sulfone-linked benzofurans in good yields, the reaction conditions used palladium acetate as a catalyst, which was expensive and suffered from the same problem as Yang's group—difficult post-processing (i.e., the use of DMF as a solvent).
[0010]
[0011] In summary, existing methods for synthesizing benzofuranones suffer from numerous problems, such as cumbersome reaction steps, use of highly toxic reagents, harsh reaction conditions, poor atom economy, and low yields. These problems not only increase the difficulty and cost of synthesis but also pose potential threats to the environment and the health of operators. Therefore, finding a simple and efficient way to prepare benzofuranones is a research topic that needs to be addressed. Summary of the Invention
[0012] To address the shortcomings of existing technologies, this invention provides a method for preparing benzofuranone compounds and their applications.
[0013] The technical solution of the present invention is as follows:
[0014] A method for preparing a benzofuranone compound includes the following steps:
[0015]
[0016] (1) Compound a undergoes a substitution reaction in the presence of copper bromide and solvent A to produce compound b.
[0017] (2) Compound b undergoes a substitution reaction in the presence of a base and solvent B to produce compound c.
[0018] In some implementations, solvent A in step (1) is selected from one or more of ethyl acetate, chloroform, methanol, ethanol, and anhydrous diethyl ether.
[0019] In some implementations, in step (1), the equivalent ratio of compound a to copper bromide is 1:(1.0-3.5).
[0020] In some implementations, in step (1), the reaction temperature is between 60°C and 100°C, and the reaction time is 7-10 hours.
[0021] In some implementations, in step (2), the base is anhydrous sodium acetate and the solvent B is tert-butanol.
[0022] In some implementations, in step (2), the reaction temperature is between 60°C and 100°C, and the reaction time is 2-7 hours.
[0023] In some implementations, in step (2), the equivalent ratio of compound b to anhydrous sodium acetate is 1:5.
[0024] In some implementations, in step (2), the mass-to-volume ratio of compound b to tert-butanol is 366:4.7 (mg / ml).
[0025] In some typical embodiments, the method for preparing the benzofuranone compound includes the following steps:
[0026] Under nitrogen protection, 670 mg of CuBr2 was dissolved in 4 mL of ethyl acetate and stirred vigorously. The reaction solution was heated to 80 °C and refluxed for 1 hour. Then, 200 mg (1.2 mmol) of 1-(2-hydroxy-4-methoxyphenyl)ethane-1-one was added, and reflux was continued for 7 hours. After TLC detection (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete, the reaction solution was cooled to room temperature, filtered through a short silica gel column, and the solvent was removed under reduced pressure. The crude product was subjected to silica gel column chromatography (gradient eluent V(ethyl acetate):V(petroleum ether) = 1:100 to 1:50) to give a pale yellow solid.
[0027] Under nitrogen protection, 366 mg of 3-bromo-1-(2-hydroxy-4-methoxyphenyl)ethane-1-one was dissolved in 4.7 mL of tert-butanol, and then 615 mg of anhydrous sodium acetate was added. The reaction solution was refluxed at 70 °C for 2 hours. After TLC detection (petroleum ether: ethyl acetate = 3:1 as the developing solvent) showed that the reaction was complete, the reaction solution was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed by vacuum distillation. The residue was subjected to silica gel column chromatography (gradient eluent V(ethyl acetate):V(petroleum ether) = 1:100 to 1:20) to give a pale yellow liquid.
[0028] The beneficial effects of this invention are:
[0029] The main drawbacks of existing technologies include:
[0030] 1. It has certain limitations, requiring harsh reaction conditions, such as the use of strong acids and bases, and highly toxic reagents (chloroacetonitrile, boron trifluoride ether, etc.); 2. The steps are complicated, usually requiring multiple reaction steps to obtain the target product; 3. It requires harsh conditions such as strong acids, strong bases or high temperatures, which increases the difficulty and cost of waste disposal; 4. It has poor atom economy, high preparation cost, and low overall yield.
[0031] To address these drawbacks, the present invention aims to provide a novel synthesis process that offers the following advantages:
[0032] 1. An innovative CuBr2 / ethyl acetate system was used to achieve efficient and selective bromination of the α-position of ketones. This method eliminates the need for traditional highly toxic or expensive brominating reagents (such as liquid bromine or NBS), making the operation safer and simpler. It avoids complex initiators or strictly anhydrous conditions, embodying the concept of green chemistry.
[0033] 2. The unconventional and mild system of "tert-butanol / sodium acetate" efficiently drives the intramolecular cyclization reaction. This combination avoids side reactions that may be caused by strong bases and highly polar solvents, providing a new, mild, and highly selective method for the synthesis of benzofuran heterocycles.
[0034] 3. It operates without protecting groups and is atom-economical;
[0035] 4. Overall, the synthetic method of this invention has advantages such as a simple route, readily available raw materials, low preparation cost, high product yield, and easy operation, making it suitable for industrial production. Furthermore, by optimizing reaction conditions and purification steps, this process significantly improves the yield of benzofuran: the yield of the bromination reaction reaches 70%, the yield of the cyclization reaction reaches 88%, and the overall yield is significantly higher than that of existing technologies. Attached Figure Description
[0036] Figure 1The NMR spectrum of 2-bromo-1-(2-hydroxy-4-methoxyphenyl)ethane-1-one prepared according to the present invention (using deuterated chloroform as solvent).
[0037] Figure 2 The NMR spectrum of benzofuranone prepared in this invention (using deuterated chloroform as solvent). Detailed Implementation
[0038] The following embodiments are intended to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention to the scope of the embodiments described.
[0039] This invention provides a high-yield synthesis process for benzofuranone, mainly using excess copper bromide and paeonol as reactants, and ethyl acetate as the reaction solvent. Under reflux for 8 hours, 3-bromo-1-(2-hydroxy-5-methoxyphenyl)propane-1-one is generated, which serves as the substrate in the second step, dissolved in isopropanol, and reacted with potassium carbonate as a catalyst. The specific preparation process includes the following steps:
[0040] Example 1: Preparation of 3-bromo-1-(2-hydroxy-5-methoxyphenyl)propane-1-one
[0041]
[0042] Under nitrogen protection, CuBr2 (670 mg, 3 mmol) was dissolved in ethyl acetate (4 mL) with vigorous stirring. The reaction mixture was heated to 80 °C and refluxed for 1 hour. Then, 1-(2-hydroxy-4-methoxyphenyl)ethane-1-one (200 mg, 1.2 mmol) was added, and reflux was continued for 7 hours. After TLC analysis (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete, the reaction mixture was cooled to room temperature, filtered through a short silica gel column, and the solvent was removed under reduced pressure. The crude product was subjected to silica gel column chromatography (gradient eluent V(ethyl acetate):V(petroleum ether) = 1:100–1:50) to give 205 mg of a pale yellow solid, with a yield of 70%.
[0043] Structural data representation:
[0044] 1 H NMR (400MHz, CDCl3) δ: 12.23 (d, J = 2.8 Hz, 1H), 7.64 (dd, J = 8.9, 3.0 Hz, 1 H),6.53–6.40(m,2H),4.36(d,J=1.4Hz,2H),3.85(d,J=2.6Hz,3H);
[0045] 13C NMR (101MHz, CDCl3) δ: 195.16, 166.94, 166.31, 131.98, 111.13, 108.46, 101.14, 55.75, 29.77;
[0046] IR(KBr):2947.66,1628.70,1505.66,1265.56,777.37,581.89;
[0047] ESI-HRMS calcd for C9H8BrO3[MH] - 242.9755, found 242.9748.
[0048] Example 2: Preparation of benzofuranone
[0049]
[0050] Under nitrogen protection, 3-bromo-1-(2-hydroxy-4-methoxyphenyl)ethane-1-one (366 mg, 1.5 mmol) was dissolved in tert-butanol (4.7 mL), followed by the addition of anhydrous sodium acetate (615 mg, 7.5 mmol). The reaction mixture was refluxed at 70 °C for 2 hours. After TLC analysis (petroleum ether: ethyl acetate = 3:1) showed complete reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed by vacuum distillation. The residue was subjected to silica gel column chromatography (gradient eluent V(ethyl acetate):V(petroleum ether) = 1:100–1:20) to give 217 mg of a pale yellow liquid, with a yield of 88%.
[0051] Structural data representation:
[0052] 1 H NMR (400MHz, CDCl3) δ: 7.53 (d, J = 8.6 Hz, 1H), 6.63 (dd, J = 8.6, 2.1 Hz, 1H), 6.53 (d, J = 2.1 Hz, 1H), 4.62 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H);
[0053] 13 C NMR (101MHz, CDCl3) δ: 197.51, 176.45, 168.13, 124.94, 114.25, 111.66, 96.24, 75.50, 55.88;
[0054] IR(KBr):2938.75,1601.71,1445.98,1245.31;
[0055] ESI-HRMS calcd for C9H8O3[MH] - 163.0474, found 163.0475.
[0056] Comparison of existing technologies:
[0057] In 2018, Yang's research group reported a novel method for synthesizing benzofuranone compounds (Bioorganic & Medidicinal Chemistry Letters, 2018, 28, 668–672; https: / / doi.org / 10.1016 / j.bmcl.2018.01.018). The main difference between this method and the method discussed in this study lies in the solvent used. Yang's group used DMF, a solvent that is difficult to process, while we innovatively use the green solvent n-butanol. The details are as follows: Yang's group first brominated the starting compound using copper bromide as the bromine source in an ethyl acetate / chloroform system. Then, they cyclized the brominated compound under KF and DMF conditions. This reaction can be carried out at room temperature, but the reaction time is long, and the use of DMF as the reaction solvent makes it difficult to remove during post-reaction purification. Furthermore, the use of chloroform as a solvent poses certain toxicity and environmental hazards. In contrast, the alcohol solvent system developed in this invention has mild reaction conditions, low solvent toxicity, easy recovery, and simple post-processing, which is particularly in line with the needs of green synthesis and industrial production; at the same time, it shows significant advantages in terms of process cost and ease of operation.
[0058]
[0059] In 2004, Subbaraju's group reported another synthetic method for benzofuranones (Biosci. Biotec hnol. Biochem, 2004, 68, 10, 2183–2185; http: / / dx.doi.org / 10.1271 / bbb.68.2183). This group used pyrogallol and chloroacetic acid in the presence of boron trifluoride ether in a Friedal-Crafts reaction to obtain a chlorinated intermediate, followed by cyclization under reflux for 6 hours with sodium acetate as the base and ethanol as the solvent (a relatively long reaction time), yielding 6,7-dihydroxycoumarone in 85% yield. This method not only uses chloroacetic acid, which is highly toxic to aquatic organisms, but also includes boron trifluoride ether, a reagent with a strong, unpleasant odor. Therefore, even though this method yields a high amount of chloroacetic acid and boron trifluoride ether, and involves a long reaction time and complex operation, it has certain limitations.
[0060]
[0061] In summary, this invention relates to a mild cyclization method using tert-butanol (t-BuOH) as a solvent and sodium acetate (NaOAc) as a base, for the efficient conversion of ortho-hydroxyl-containing aryl α-bromoketones into the corresponding cyclized products at relatively low temperatures. Compared to the prior art disclosed by the Subbaraju research group, which uses α-chloroketones as substrates, employs highly toxic reagents chloroacetic acid and boron trifluoride diethyl ether, and requires prolonged reflux, this invention exhibits significant advantages in reaction efficiency, selectivity, process scalability, and overall cost. Furthermore, compared to the Yang research group's use of DMF as a solvent, it is environmentally friendly and easy to handle.
[0062] ① Regarding reaction efficiency and energy consumption, this invention uses α-bromoketones as substrates and can complete the reaction in about 2 hours at approximately 70°C, achieving a separation yield of up to 88% for representative substrates. In contrast, the α-chloroketone system disclosed by the Subbaraju group typically requires continuous reaction under solvent reflux for about 6 hours, with a yield of approximately 80%. This invention achieves a comprehensive improvement by reducing reaction time by about two-thirds, significantly decreasing energy consumption, and increasing yield to approximately 90%, bringing direct time and energy savings for both laboratory and industrial scale-up. Furthermore, compared to the Yang group's use of DMF as a solvent, this invention greatly reduces the difficulties of post-processing.
[0063] ② Regarding reaction driving and selectivity, this invention utilizes the intrinsic property that bromine leaving groups are superior to chlorine, combined with the weakly basic sodium acetate and the protic, bulky tert-butanol solvent environment, to facilitate intramolecular nucleophilic substitution / cyclization processes and effectively suppress side reactions. This reaction scenario balances reaction rate and mildness, avoiding the use of strong bases or strongly nucleophilic / strongly polar aprotic solvents, thereby improving compatibility with sensitive functional groups and the chemical purity of the target product.
[0064] ③ In terms of process operability and post-processing, the conditions of this invention are simple and environmentally friendly. After the reaction, a high-purity crude product can be obtained by conventional quenching-extraction-washing-concentration. The main byproducts are inorganic salts (NaBr) and a small amount of solvent, which can be effectively removed by filtration and solvent recovery, significantly reducing column chromatography dependence and solvent consumption. The lower reaction temperature is also beneficial for thermal management and process safety control, providing a more robust heat load and mass transfer guarantee for scale-up experiments.
[0065] ④ From the perspective of overall cost and greening, this invention has a shorter reaction time, lower temperature, simplified post-processing, and recyclable solvent (t-BuOH can be recovered, and sodium acetate is inexpensive and easy to process). Therefore, the overall material and energy input is expected to be better than the control process of Subbaraju's group, which uses α-chloroketone as substrate and requires long-term reflux, and better than the Yang group's group, which uses DMF as solvent. This demonstrates better economic efficiency and environmental friendliness.
[0066]
[0067] In summary, this invention, through a combined technical solution of "α-bromoketone + t-BuOH / NaOAc + efficient, short-time, and mild cyclization," achieves quantifiable and industrially applicable improvements in reaction efficiency, selectivity, scalability, and overall cost compared to existing technologies: approximately 90% yield is obtained at 70℃ for 2 hours (compared to approximately 80% yield with reflux for about 6 hours). This difference represents a significant and substantial improvement.
Claims
1. A method for preparing a benzofuranone compound, comprising the following steps: (1) Compound a undergoes a substitution reaction in the presence of copper bromide and solvent A to produce compound b. (2) Compound b undergoes a substitution reaction in the presence of a base and solvent B to produce compound c.
2. The preparation method according to claim 1, characterized in that, Solvent A in step (1) is selected from one or more of ethyl acetate, chloroform, methanol, ethanol, and anhydrous diethyl ether.
3. The preparation method according to claim 1, characterized in that, In step (1), the equivalent ratio of compound a to copper bromide is 1:(1.0-3.5).
4. The preparation method according to claim 1, characterized in that, In step (1), the reaction temperature is between 60℃ and 100℃, and the reaction time is 7-10 hours.
5. The preparation method according to claim 1, characterized in that, In step (2), the base is anhydrous sodium acetate and the solvent B is tert-butanol.
6. The preparation method according to claim 1, characterized in that, In step (2), the reaction temperature is between 60℃ and 100℃, and the reaction time is 2-7 hours.
7. The preparation method according to claim 1, characterized in that, In step (2), the equivalent ratio of compound b to anhydrous sodium acetate is 1:
5.
8. The preparation method according to claim 1, characterized in that, In step (2), the mass-to-volume ratio of compound b to tert-butanol is 366:4.7 (mg / ml).
9. The preparation method according to claim 1, characterized in that, The method for preparing the benzofuranone compound includes the following steps: Under nitrogen protection, 670 mg of CuBr2 was dissolved in 4 mL of ethyl acetate and stirred vigorously. The reaction solution was heated to 80 °C and refluxed for 1 hour. Then, 200 mg of 1-(2-hydroxy-4-methoxyphenyl)ethane-1-one (1.2 mmol) was added, and reflux was continued for 7 hours. After TLC detection (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete, the reaction solution was cooled to room temperature, filtered through a silica gel short column, and the solvent was removed by vacuum distillation. The crude product was subjected to silica gel column chromatography (gradient eluent V(ethyl acetate):V(petroleum ether) = 1:100 to 1:50) to give a pale yellow solid. Under nitrogen protection, 366 mg of 3-bromo-1-(2-hydroxy-4-methoxyphenyl)ethane-1-one was dissolved in 4.7 mL of tert-butanol, and then 615 mg of anhydrous sodium acetate was added. The reaction solution was refluxed at 70 °C for 2 hours. After TLC detection (petroleum ether: ethyl acetate = 3:1 as the developing solvent) showed that the reaction was complete, the reaction solution was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed by vacuum distillation. The residue was subjected to silica gel column chromatography (gradient eluent V(ethyl acetate):V(petroleum ether) = 1:100 to 1:20) to give a pale yellow liquid.