Process for the preparation of bicyclo[3.2.1]octane-2,4-dione

Abstract

The application discloses a method for preparing bicyclo[3.2.1]octane-2,4-dione, which takes norbornene as a starting material, and obtains the key intermediate bicyclo[3.2.1]octane-2,4-dione of the rice field herbicide bicyclo sulfonyl ketone and the corn field herbicide fluoropyrazole ketone through Wacker oxidation, Mannich condensation / elimination and oxidation rearrangement. The raw material is cheap and easy to obtain, the synthesis process route is short, the total yield is high, the production cost is low, the operation is safe, simple and convenient, and the method is environment-friendly. The method provides an efficient and green process route for realizing industrialized scale production of bicyclo[3.2.1]octane-2,4-dione, bicyclo sulfonyl ketone and fluoropyrazole ketone.

Description

Technical Field

[0001] This invention relates to the synthesis of bicyclic [3.2.1]octane-2,4-dione, specifically to a method for preparing bicyclic [3.2.1]octane-2,4-dione from norbornene as a starting material via Wacker oxidation, Mannich condensation / elimination, and oxidative rearrangement reactions, belonging to the field of organic synthesis technology. Background Technology

[0002] Bicyclo[3.2.1]octane-2,4-dione is a key intermediate in the synthesis of the rice herbicide bicyclosulfuron and the corn herbicide flupyradifurone (Tsukuba KK, Kawawaki TS, Mikami K, et al. US 5525580, 1996-01-11; Jackson DA, Edmunds A, Bowden M C. WO 2005 / 105754, 2005-11-10).

[0003] Bicyclosulfuron; Flupyridaben Bicyclosulfonyl ketone, chemically named 3-(2-chloro-4-methylsulfonylbenzoyl)-2-phenylthiobicyclo[3.2.1]oct-2-en-4-one, is a triketone herbicide that acts on 4-hydroxyphenylpyruvate dioxygenase (HPPD). It has a broad spectrum of weed control, a long residual effect, and high safety. It was developed and launched by SDS Bioscience Co., Ltd. of Japan in 2001 and is mainly used to control broadleaf weeds such as duckweed and wild vegetable in rice fields.

[0004] Flupyridone, chemically named 4-hydroxy-3-{2-[(2-methoxyethoxy)methyl]-6-(trifluoromethyl)pyridin-3-carbonyl]-bicyclo[3.2.1]oct-3-en-2-one, is also a triketone herbicide that acts on HPPD. It has a broad spectrum of weed control, a long application period, good systemic properties, and good safety. It was developed and launched by Syngenta in Switzerland in 2015 and is suitable for weed control in fields of crops such as corn, sugarcane, and wheat.

[0005] The main synthetic routes for bicyclic [3.2.1]octane-2,4-dione reported in the literature are: (1) Using norbornene as a raw material, bicyclic [3.2.1]octane-2,4-dione was obtained by addition / ring expansion with dichlorocarbene, hydrolysis, oxidation, and cyanidation / hydrolysis, with an overall yield of 47.7%~56.2% (Wang Yazhen, Lin Wei. Chemical Reagents, 2016, 38(8):779-783); the reaction formula is as follows:

[0006] This method involves a long synthetic route, uses large amounts of highly toxic cyanide, poses significant safety risks, and is unsuitable for large-scale industrial production.

[0007] (2) Using 2-norborneone as a raw material, bicyclic [3.2.1]octane-2,4-dione was obtained by Mannich condensation, Baeyer-Villiger oxidation, and ketone-ester condensation, with a total yield of 61.5% (Qian Chao, Gao Wucheng, Fu Shuixiang, et al. Journal of Chemical Engineering of Chinese Universities, 2017, 31(4): 906-910); the reaction formula is as follows:

[0008] This method involves expensive raw materials, generates a large amount of wastewater, and has a low yield in ketone-ester condensation reactions.

[0009] (3) Using 1,1,2,2,3-pentachlorocyclopropane as a raw material, bicyclic [3.2.1]octane-2,4-dione was obtained through elimination, cycloaddition with cyclopentadiene, hydrolysis, and catalytic hydrogenation, with an overall yield of 46.5% (Baalouch M, De MA, Beaudegnies R. Tetrahedron Letters, 2013, 54(6): 557-561); the reaction formula is as follows:

[0010] This method involves a long synthetic route, and pentachlorocyclopropane is expensive, has a low boiling point, is highly toxic, and has a low product yield.

[0011] (4) Using dicyclopentadiene as a raw material, bicyclo[3.2.1]octane-2,4-dione was obtained through pyrolysis / cycloaddition with ethylene, oxidation, condensation, Baeyer-Villiger oxidation, and rearrangement. The yield of the last two steps was 41.4% (H. Schneider, C. Lüch. CN03109514.3, 2006-1-11); the reaction formula is as follows:

[0012] This method uses inexpensive and readily available raw materials, but involves many reaction steps, resulting in low yields. Furthermore, the rearrangement reaction requires the use of highly toxic cyanide, posing safety risks. Therefore, developing a process for synthesizing bicyclic [3.2.1]octane-2,4-dione with a short process route, high yield of the target product, simple reaction operation, inexpensive and non-toxic reagents, environmental friendliness, and ease of industrial production is of significant research importance. Summary of the Invention

[0013] The technical problem solved by the present invention is to provide a method for preparing bicyclic [3.2.1]octane-2,4-dione. The method uses inexpensive and readily available norbornene as the starting material and obtains bicyclic [3.2.1]octane-2,4-dione through Wacker oxidation, Mannich condensation / elimination, and oxidative rearrangement reaction.

[0014] This invention is achieved through the following technical solution: A method for preparing bicyclic [3.2.1]octane-2,4-dione includes the following steps: (1) In a three-necked flask, add norbornene, palladium catalyst and organic solvent, stir and heat to 40°C, add sulfuric acid and hydrogen peroxide, stir and heat to react; cool to room temperature, extract with ethyl acetate, wash the organic layer with water, dry with anhydrous sodium sulfate, remove the solvent by vacuum distillation to obtain 2-norbornone. (2) In a three-necked flask, add acetic acid, concentrated sulfuric acid and 2-norborneone. Add secondary amine slowly dropwise while stirring, and maintain a certain temperature during the dropwise addition. After the dropwise addition is complete, stir the reaction for a certain time. Add paraformaldehyde and then raise the temperature to carry out condensation / elimination reaction. Distill the reaction solution with steam to separate the organic phase and obtain 3-methylene-2-norborneone. (3) In a three-necked flask, add 3-methylene-2-norborneone, oxidant, palladium catalyst, acetonitrile and water, and stir the reaction at room temperature; add sodium hydroxide aqueous solution and stir; then add hydrochloric acid aqueous solution and stir; extract with ethyl acetate, wash the organic layer with water, dry with anhydrous sodium sulfate, and remove the solvent by vacuum distillation to obtain bicyclic [3.2.1]octane-2,4-dione.

[0015] The specific chemical reaction formula is described below:

[0016] In step (1), the molar ratio of norbornene to palladium catalyst is 1:0.02-0.1, preferably 1:0.05; the palladium catalyst is palladium acetate or palladium chloride, preferably palladium acetate; the organic solvent is acetonitrile or ethyl acetate, preferably acetonitrile; the amount of organic solvent is 5-20 mL / mmol norbornene, preferably 10 mL / mmol norbornene; the mass fraction of sulfuric acid is 60%-90%, preferably 70%; the molar ratio of sulfuric acid to norbornene is 0.02-0.1:1, preferably 0.05:1; the mass fraction of hydrogen peroxide is 30%, and the molar ratio of hydrogen peroxide to norbornene is 5-20:1, preferably 10:1; the reaction temperature is 50℃-80℃, preferably 70℃; and the reaction time is 4-10 h, preferably 6 h.

[0017] In step (2), the molar ratio of 2-norborneone, acetic acid, and concentrated sulfuric acid is 1:1 to 3:0.02 to 0.1, preferably 1:2:0.05; the secondary amine is diethylamine, piperidine, or pyrrolidine, preferably diethylamine; the molar ratio of the secondary amine to 2-norborneone is 1 to 2:1, preferably 1.5:1; the temperature is maintained at 30°C to 40°C during the addition of the secondary amine; the reaction time after the secondary amine is added is 10 min to 1 h, preferably 20 min; the molar ratio of paraformaldehyde to 2-norborneone is 0.3 to 1:1, preferably 0.5:1; the condensation / elimination reaction temperature is 80 to 110°C, preferably 100°C; the condensation reaction time is 2 to 8 h, preferably 5 h.

[0018] In step (3), the molar ratio of 3-methylene-2-norborneone, oxidant, and palladium catalyst is 1:1 to 2:0.02 to 0.1, preferably 1:1.5:0.05; the oxidant is hydrogen peroxide or potassium peroxymonosulfonate, preferably potassium peroxymonosulfonate with a mass fraction of 43%; the palladium catalyst is palladium acetate or palladium chloride, preferably palladium acetate; the amount of acetonitrile is 2 to 5 mL / mmol 3-methylene-2-norborneone, preferably 4 mL / mmol 3-methylene-2-norborneone; the amount of water is 0.5 to 2 mL / mmol 3-methylene-2-norborneone, preferably 1 mL / mmol 3-methylene-2-norborneone; the concentration of sodium hydroxide aqueous solution is 1 to 3 mol / L, preferably 2 mol / L; the concentration of hydrochloric acid aqueous solution is 1 to 3 mol / L, preferably 2 mol / L; and the reaction time is 1 to 5 h, preferably 2 h.

[0019] In step (1) of this invention, palladium acetate is used as a catalyst, resulting in mild reaction conditions, simple operation, avoidance of using expensive palladium-based catalysts, high product yield, and suitability for industrial production. Hydrogen peroxide is used as the oxidant, which is environmentally friendly. Acetonitrile, with a low boiling point, is used as the solvent, making post-processing simple and easy. The amount of sulfuric acid used is minimal, having little impact on the environment and equipment.

[0020] In step (2) of this invention, diethylamine, piperidine, or pyrrolidine can all catalyze the Mannich condensation reaction well, but diethylamine is inexpensive and readily available, making it more suitable for industrial production; therefore, diethylamine is preferred. Using paraformaldehyde instead of formaldehyde aqueous solution can reduce wastewater generation. The elimination reaction of the Mannich base requires a relatively high temperature, so the reaction temperature is selected as 95–100°C. Steam distillation can continuously distill off the product, allowing the remaining intermediate Mannich base to continuously undergo elimination reactions to generate the product, thereby improving the product yield and purity. The sulfuric acid used is the catalytic dosage, having minimal impact on the environment and equipment.

[0021] In step (3) of this invention, palladium acetate is used as a catalyst and potassium peroxymonosulfonate as an oxidant. 3-Methylene-2-norbornene can undergo a smooth oxidative rearrangement to obtain bicyclic [3.2.1]octane-2,4-dione. The reaction conditions are mild, the reaction time is short, and the product yield is high. Adding an appropriate amount of water to acetonitrile can promote the oxidative rearrangement reaction.

[0022] Compared with existing technologies, this invention uses norbornene as the starting material and obtains bicyclo[3.2.1]octane-2,4-dione through Wacker oxidation, Mannich condensation / elimination, and oxidative rearrangement. The raw materials are inexpensive and readily available, the synthesis process is short, the overall yield is high, the production cost is low, the operation is safe and simple, and it is environmentally friendly. This provides an efficient and green process route for the industrial-scale production of bicyclo[3.2.1]octane-2,4-dione, bicyclosulfonamide, and flupyradifurone. Detailed Implementation

[0023] The present invention will be further illustrated below with reference to the embodiments. The embodiments are only used to explain the present invention and should not be construed as limiting the present invention.

[0024] Example 1 Synthesis of 2-norborneone In a three-necked flask, 1.88 g (20 mmol) of norbornene, 0.22 g (1 mmol) of palladium acetate, and 200 mL of acetonitrile were added. The mixture was stirred and heated to 40 °C. Then, 0.14 g (1 mmol) of 70% sulfuric acid and 20.68 g (0.2 mol) of 30% hydrogen peroxide were added. The mixture was stirred and heated to 70 °C for 6 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (120 mL × 4), the organic layer was washed with water (200 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain 1.68 g of white solid 2-norbornone, with a yield of 87.3% and a melting point of 91.3–91.9 °C. 1 HNMR(600MHz, CDCl3), δ: 2.62(dp,J=13.7,6.9Hz,2H), 2.13(dd,J=12.4,7.0Hz,1H), 1.98(dd,J =12.4,7.0Hz,1H),1.79-1.75(m,3H),1.60-1.56(m,3H); 13 CNMR (150MHz, CDCl3), δ: 216.31, 48.74, 44.74, 38.04, 33.42, 27.15, 26.87.

[0025] Example 2 Synthesis of 2-norborneone In a three-necked flask, 1.88 g (20 mmol) of norbornene, 0.18 g (1 mmol) of palladium chloride, and 200 mL of acetonitrile were added. The mixture was stirred and heated to 40 °C. Then, 0.14 g (1 mmol) of 70% sulfuric acid and 20.68 g (0.2 mol) of 30% hydrogen peroxide were added. The mixture was stirred and heated to 70 °C for 6 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (120 mL × 4), the organic layer was washed with water (200 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain 1.07 g of white solid 2-norbornone, with a yield of 55.7%.

[0026] Example 3 Synthesis of 2-norborneone In a three-necked flask, 1.88 g (20 mmol) of norbornene, 0.22 g (1 mmol) of palladium acetate, and 200 mL of ethyl acetate were added. The mixture was stirred and heated to 40 °C. Then, 0.14 g (1 mmol) of 70% sulfuric acid and 20.68 g (0.2 mol) of 30% hydrogen peroxide were added. The mixture was stirred and heated to 70 °C for 6 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (120 mL × 4). The organic layer was washed with water (200 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain 1.12 g of white solid 2-norbornone, with a yield of 58.2%.

[0027] Example 4 Synthesis of 2-norborneone In a three-necked flask, 1.88 g (20 mmol) of norbornene, 0.44 g (2 mmol) of palladium acetate, and 200 mL of acetonitrile were added. The mixture was stirred and heated to 40 °C. Then, 0.28 g (2 mmol) of 70% sulfuric acid and 20.68 g (0.2 mol) of 30% hydrogen peroxide were added. The mixture was stirred and heated to 70 °C for 6 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (120 mL × 4). The organic layer was washed with water (200 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain 1.51 g of beige solid 2-norbornone, with a yield of 78.5%.

[0028] Example 5 Synthesis of 3-methylene-2-norborneone In a three-necked flask, 2.40 g (40 mmol) of acetic acid, 0.10 g (1 mmol) of concentrated sulfuric acid, and 2.20 g (20 mmol) of 2-norborneone were added. Diethylamine (30 mmol) was then slowly added dropwise with stirring, maintaining the temperature at 30°C–40°C. After the addition was complete, the mixture was stirred for 20 min. Paraformaldehyde (10 mmol) was then added, and the mixture was heated to 100°C and reacted for 5 h. The reaction solution was then steam distilled to separate the organic phase, yielding 2.27 g of a light brown oily liquid, 3-methylene-2-norborneone, with a yield of 92.9%. 1 HNMR(600MHz, CDCl3), δ: 6.11(d,J=2.5Hz,1H), 6.07(d,J=2.6Hz,1H), 2.91(p,J=6.8Hz,1H), 2.82(p,J=6.9Hz,1H),1.79-1.68(m,3H),1.66-1.58(m,3H); 13 CNMR (150MHz, CDCl3), δ: 205.65, 149.00, 113.29, 48.61, 41.17, 37.38, 28.13, 24.64.

[0029] Example 6 Synthesis of 3-methylene-2-norborneone In a three-necked flask, 2.40 g (40 mmol) of acetic acid, 0.10 g (1 mmol) of concentrated sulfuric acid, and 2.20 g (20 mmol) of 2-norborneone were added. Piperidine 2.55 g (30 mmol) was slowly added dropwise with stirring, maintaining the temperature at 30℃~40℃ during the addition. After the addition was complete, the mixture was stirred for 20 min. Paraformaldehyde 0.90 g (10 mmol) was added, and the temperature was raised to 100℃ for 5 h. The reaction solution was steam distilled to separate the organic phase, yielding 2.29 g of a light brown oily liquid, 3-methylene-2-norborneone, with a yield of 93.7%.

[0030] Example 7 Synthesis of 3-methylene-2-norborneone In a three-necked flask, 2.40 g (40 mmol) of acetic acid, 0.10 g (1 mmol) of concentrated sulfuric acid, and 2.20 g (20 mmol) of 2-norborneone were added. 2.13 g (30 mmol) of pyrrolidine was slowly added dropwise with stirring, maintaining the temperature at 30℃~40℃ during the addition. After the addition was complete, the mixture was stirred for 20 min. 0.90 g (10 mmol) of paraformaldehyde was added, and the temperature was raised to 100℃ for 5 h. The reaction solution was then subjected to steam distillation to separate the organic phase, yielding 2.16 g of a light brown oily liquid, 3-methylene-2-norborneone, with a yield of 88.4%.

[0031] Example 8 Synthesis of 3-methylene-2-norborneone In a three-necked flask, 2.40 g (40 mmol) of acetic acid, 0.20 g (2 mmol) of concentrated sulfuric acid, and 2.20 g (20 mmol) of 2-norborneone were added. Diethylamine (30 mmol) was then slowly added dropwise with stirring, maintaining the temperature at 30°C–40°C. After the addition was complete, the mixture was stirred for 20 min. Paraformaldehyde (10 mmol) was then added, and the temperature was raised to 100°C for 5 h. The reaction mixture was then subjected to steam distillation to separate the organic phase, yielding 2.20 g of a brown oily liquid, 3-methylene-2-norborneone, with a yield of 90.0%.

[0032] Example 9 Synthesis of 3-methylene-2-norborneone In a three-necked flask, 2.40 g (40 mmol) of acetic acid, 0.10 g (1 mmol) of concentrated sulfuric acid, and 2.20 g (20 mmol) of 2-norborneone were added. Diethylamine (30 mmol) was then slowly added dropwise with stirring, maintaining the temperature at 30°C–40°C during the addition. After the addition was complete, the mixture was stirred for 20 min. Paraformaldehyde (10 mmol) was then added, and the temperature was raised to 110°C for 5 h. The reaction mixture was then steam distilled to separate the organic phase, yielding 2.08 g of a brown oily liquid, 3-methylene-2-norborneone, with a yield of 85.1%.

[0033] Example 10 Synthesis of bicyclic [3.2.1]octane-2,4-dione In a three-necked flask, 1.95 g (16 mmol) of 3-methylene-2-norborneone, 8.48 g (24 mmol) of potassium peroxymonosulfonate (43% by mass), 0.18 g (0.8 mmol) of palladium acetate, 64 mL of acetonitrile, and 16 mL of water were added and stirred at room temperature (20 °C) for 2 h; 24 mL of 2 mol / L NaOH was added and stirred for 20 min; then 28 mL of 2 mol / L HCl was added and stirred for 5 min; the mixture was extracted with ethyl acetate (120 mL × 4), the organic layer was washed with water (200 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain 1.98 g of a white solid bicyclic [3.2.1]octane-2,4-dione, with a yield of 89.6% and a melting point of 123.6–124.1 °C; 1 HNMR (600MHz, CDCl3), δ: 3.17 (s, 2H), 2.86 (m, 2H), 1.93-1.87 (m, 2H), 1.84-1.76 (m, 4H); 13 CNMR (150MHz, CDCl3), δ: 206.01(2C), 55.73, 47.10(2C), 32.85, 26.09(2C).

[0034] Example 11 Synthesis of bicyclic [3.2.1]octane-2,4-dione In a three-necked flask, 1.95 g (16 mmol) of 3-methylene-2-norborneone, 2.27 g (24 mmol) of 30% hydrogen peroxide, 0.18 g (0.8 mmol) of palladium acetate, 64 mL of acetonitrile, and 16 mL of water were added and stirred at room temperature (20 °C) for 2 h. Then, 24 mL of 2 mol / L NaOH was added and stirred for 20 min. Next, 28 mL of 2 mol / L HCl was added and stirred for 5 min. The mixture was extracted with ethyl acetate (120 mL × 4), the organic layer was washed with water (200 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain 0.84 g of a white solid bicyclic [3.2.1]octane-2,4-dione, with a yield of 38.0%.

[0035] Example 12 Synthesis of bicyclic [3.2.1]octane-2,4-dione In a three-necked flask, 1.95 g (16 mmol) of 3-methylene-2-norborneone, 8.48 g (24 mmol) of 43% potassium peroxymonosulfonate, 0.14 g (0.8 mmol) of palladium chloride, 64 mL of acetonitrile, and 16 mL of water were added and stirred at room temperature (20 °C) for 2 h. 24 mL of 2 mol / L NaOH was added and stirred for 20 min. 28 mL of 2 mol / L HCl was added and stirred for 5 min. The mixture was extracted with ethyl acetate (120 mL × 4), the organic layer was washed with water (200 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain 1.49 g of a white solid, bicyclic [3.2.1]octane-2,4-dione, with a yield of 67.4%.

[0036] Example 13 Synthesis of bicyclic [3.2.1]octane-2,4-dione In a three-necked flask, 1.95 g (16 mmol) of 3-methylene-2-norborneone, 8.48 g (24 mmol) of 43% potassium peroxymonosulfonate, 0.18 g (0.8 mmol) of palladium acetate, 72 mL of acetonitrile, and 8 mL of water were added and stirred at room temperature (20 °C) for 2 h. 24 mL of 2 mol / L NaOH was added and stirred for 20 min. 28 mL of 2 mol / L HCl was then added and stirred for 5 min. The mixture was extracted with ethyl acetate (120 mL × 4), the organic layer was washed with water (200 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain 1.66 g of a white solid, bicyclic [3.2.1]octane-2,4-dione, with a yield of 75.1%.

Claims

1. A method for preparing bicyclic [3.2.1]octane-2,4-dione, characterized in that... Includes the following steps: (1) In a three-necked flask, add 20 mmol of norbornene, 1 mmol of palladium acetate, and 200 mL of acetonitrile. Stir and heat to 40 °C. Add 1 mmol of 70% sulfuric acid and 200 mmol of 30% hydrogen peroxide. Stir and heat to 70 °C and react for 6 h. Cool to room temperature, extract with ethyl acetate, wash the organic layer with water, dry with anhydrous sodium sulfate, and remove the solvent by vacuum distillation to obtain 2-norbornone. (2) In a three-necked flask, add 40 mmol of acetic acid, 1 mmol of concentrated sulfuric acid, and 20 mmol of 2-norborneone. While stirring, slowly add 30 mmol of diethylamine, keeping the reaction temperature at 30℃~40℃ during the addition. After the addition is complete, stir the reaction for 20 min. Add 10 mmol of paraformaldehyde, and then raise the temperature to 100℃ and react for 5 h. Distill the reaction solution with steam to separate the organic phase and obtain 3-methylene-2-norborneone. (3) In a three-necked flask, add 16 mmol of 3-methylene-2-norborneone, 24 mmol of potassium peroxymonosulfonate (43% by mass), 0.8 mmol of palladium acetate, 64 mL of acetonitrile, and 16 mL of water, and stir at room temperature for 2 h; add 24 mL of 2 mol / L NaOH and stir for 20 min; then add 28 mL of 2 mol / L HCl and stir for 5 min; extract with ethyl acetate, wash the organic layer with water, dry with anhydrous sodium sulfate, and remove the solvent by vacuum distillation to obtain bicyclic [3.2.1]octane-2,4-dione.

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