CN113683492A - Preparation method of 3-phenoxybromopropane or analogue thereof - Google Patents
Preparation method of 3-phenoxybromopropane or analogue thereof Download PDFInfo
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Abstract
The invention discloses a preparation method of 3-phenoxy bromopropane or analogues thereof, which is characterized in that cheap and easily-obtained phenol or aromatic phenol thereof and allyl compounds are subjected to substitution reaction and addition reaction to obtain the 3-phenoxy bromopropane and analogues thereof, in order to avoid the inconvenience of using gaseous hydrogen bromide, bromide salt and acid are adopted to generate high-concentration hydrobromic acid in situ to realize the second-step addition reaction, the process operation is simple, the conditions are easy to control, the atom economy is good, the environment influence aspect is low-pollution and zero-emission, the synthesis direction accords with the current green chemical synthesis direction, and the cost economy aspect is that the cost is reduced to a great extent due to the direct utilization of olefin.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of 3-phenoxy bromopropane or an analogue thereof.
Background
3-phenoxybromopropane and analogues thereof are used as a common medical intermediate and have wide application in the research and development of anti-tumor, antibacterial and other medicines. In the case of 3-phenoxybromopropane, there are two major synthetic methods. The method 1 is that phenol and 1, 3-dibromopropane directly carry out nucleophilic substitution reaction to prepare a crude product, and the crude product is purified by decompression rectification. The method has the advantages of low conversion rate, poor selectivity, more byproducts and low purity of crude products, and high-temperature rectification and purification under reduced pressure are required, so that not only are more byproducts introduced after the decomposition of the products, but also the byproducts and the products form azeotropy and are difficult to completely separate. The method 2 is to prepare the product by nucleophilic substitution and bromination reaction of phenol and 3-bromo-1-propanol. In the route, 3-bromo-1-propanol which is used as a raw material is higher in price and poor in stability compared with 1, 3-dibromopropane, so that the product cost is increased and impurities are more, reagents with higher toxicity such as triphenylphosphine and carbon tetrabromide are used in the bromination reaction, anhydrous reaction conditions are required, phosphorus-containing wastewater is generated, and a crude product is purified by column chromatography or reduced pressure distillation. Although CN 111018678A discloses an improvement method of the method, the 3-phenoxy p-toluenesulfonate propyl ester intermediate is subjected to bromination after recrystallization refining, column chromatography and reduced pressure distillation purification are avoided, the method still needs raw material 3-bromo-1-propanol with higher price and poor stability, the synthesis steps are more, p-toluenesulfonate groups which have larger molecular mass and are not carried into product molecules are used, the atom economy is poor, green chemistry is not met, and the cost is increased to a great extent. Therefore, the above synthetic methods are not suitable for industrial production.
The development theme and direction of the chemical industry are green chemistry nowadays, and an ideal atom economic reaction should be found in the organic synthesis direction to realize a pollution-free zero-emission synthesis process. From the design and synthesis of terminal brominated compounds such as 3-phenoxybromopropane and analogs thereof, the direct addition reaction of olefin and hydrogen bromide to achieve hydrobromination of olefin to obtain the product is an ideal synthesis method. The method has good atom economy from the aspect of atom utilization efficiency, is low in pollution and zero in emission from the aspect of environmental influence, and accords with the current green chemical synthesis direction, and the cost is reduced to a great extent due to the direct utilization of the olefin from the aspect of cost economy. However, since the hydrogen bromide is gaseous, the difficulty of implementing the reaction is great, and the actual process operation is complicated, so that a suitable process flow is required to simply implement the process route.
Disclosure of Invention
The invention aims to provide a synthetic method of 3-phenoxybromopropane and analogues thereof.
The technical solution for realizing the purpose of the invention is as follows: a method for synthesizing 3-phenoxybromopropane or an analog thereof, comprising the steps of:
(1) under the condition of stirring, sequentially adding phenol or aromatic phenol and alkali into a polar aprotic organic solvent, heating to reach a target reaction temperature, then preserving heat, slowly dropwise adding an allyl compound, preserving heat after dropwise adding, reacting for a certain time, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, concentrating filtrate, then adding an extraction organic solvent, washing with an alkali solution, washing with water to be neutral, drying, and then concentrating under reduced pressure to obtain propenyl aryl ether;
(2) under the condition of stirring, sequentially adding propenyl aryl ether, an initiator and bromide salt into a polar aprotic organic solvent, slowly dripping acid when the temperature is raised to reach the target reaction temperature, keeping the temperature for reacting for a certain time after dripping is finished, cooling to room temperature after the reaction is finished, washing an organic layer with alkali liquor, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain the 3-phenoxy bromopropane or the like.
Preferably, in the step (1), the aromatic phenol includes any one of p-methylphenol, p-chlorophenol, p-bromophenol, 3, 4-methylenedioxyphenol, and 1-naphthol; the allyl compound comprises any one of 3-chloropropene, 3-bromopropylene, 3-iodopropylene, allylamine, allyl alcohol, allyl formate, diallyl carbonate, allyl ether, allyl mercaptan and allyl diethyl phosphate; the base includes any one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide.
Preferably, in the step (1), the polar aprotic organic solvent includes any one of acetone, butanone, acetonitrile, N-dimethylformamide and dimethyl sulfoxide; the extraction organic solvent comprises any one of ethyl acetate, dichloromethane, trichloromethane, 1, 2-dichloroethane and 1, 1-dichloroethane; the alkali solution comprises any one of potassium carbonate, sodium hydroxide and potassium hydroxide aqueous solution.
Preferably, in the step (1), the molar ratio of the phenol or the aromatic phenol to the allyl compound is 1: 1.0-1.5, and the molar ratio of the phenol or the aromatic phenol to the base is 1: 1.0-2.0; the target reaction temperature is 60-100 ℃, and the time is 4-12 h.
Preferably, in the step (2), the initiator comprises any one of benzoyl peroxide, acetyl peroxide, m-chloroperoxybenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, bis (tetrabutylammonium) peroxodisulfate, tert-butyl peroxybenzoate and azobisisobutyronitrile; the bromide salt comprises any one of sodium bromide, potassium bromide, lithium bromide and zinc bromide; the acid includes any one of sulfuric acid and phosphoric acid.
Preferably, in the step (2), the weak polar organic solvent comprises one or more of carbon tetrachloride, cyclohexane, trichloromethane, dichloromethane, 1, 2-dichloroethane and 1, 1-dichloroethane; the alkali solution comprises one or more of potassium carbonate, sodium hydroxide and potassium hydroxide aqueous solution.
Preferably, in the step (2), the molar ratio of the propenyl aryl ether to the bromide salt is 1: 1.1-2.0, the molar ratio of the propenyl aryl ether to the acid is 1: 1.0-2.0, and the amount of the initiator is 1 mol% -2 mol% of the propenyl aryl ether; the target reaction temperature is 40-100 ℃; the time is 1-5 h.
Compared with the prior art, the invention has the beneficial effects that: (1) according to the method, the high-concentration hydrobromic acid is generated in situ by the bromide salt and the acid to replace gaseous hydrogen bromide to realize the olefin addition reaction, so that a plurality of inconveniences caused by using gas are avoided, the used process is simple and convenient to operate, the reagent stability is high, the potential safety hazard is small, the transportation and the storage are convenient, and the control and the industrial large-scale use are easy. (2) Compared with the existing method, the method has better atom economy, low pollution and zero emission in the aspect of environmental influence, and accords with the current green chemical synthesis direction, and in the aspect of cost economy, the direct utilization of the olefin reduces the cost to a great extent, the raw materials are cheap and easy to obtain, the process operation is simple, the conditions are easy to control, meanwhile, the catalytic effect is good, the yield is higher, the waste liquid is easy to treat, and the method is convenient for industrial large-scale production.
Detailed Description
The invention is further illustrated by the following examples, to which, however, the patent claims are not restricted.
The invention adopts cheap and easily obtained phenol of formula I or aromatic phenol of analogues thereof and allyl compound of formula II as raw materials to obtain 3-phenoxybromopropane of formula IV and analogues thereof through nucleophilic substitution reaction and addition reaction. In addition, to avoid the use of gaseous hydrogen bromide, the present invention employs a bromide salt and an acid to generate high concentrations of hydrobromic acid in situ to effect the addition reaction.
The method comprises the following steps:
(1) adding a polar aprotic organic solvent into a reaction kettle, starting stirring, sequentially adding phenol of the formula I or aromatic phenol similar to the phenol of the formula I and alkali, heating to reach a target reaction temperature, preserving heat, slowly dropwise adding an allyl compound of the formula II, preserving heat for reacting for a certain time after dropwise adding is finished, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, concentrating the filtrate, adding an extraction organic solvent, washing with an alkali solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain propenyl aryl ether of the formula III;
(2) and (2) adding a weak-polarity organic solvent into the reaction kettle, starting stirring, sequentially adding the allyl aryl ether of the formula III, an initiator and bromide, slowly dripping acid when the temperature rises to reach the target reaction temperature, keeping the temperature for reacting for a certain time after dripping is finished, cooling to room temperature after the reaction is finished, washing an organic layer with alkali liquor, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain the product of the formula IV 3-phenoxybromopropane.
Example 1
Preparation of propenyl phenyl ethers
Adding 200mL of acetone into a reaction kettle, starting stirring, sequentially adding 18.8g of phenol, 41.5g of potassium carbonate and 26.6g of 3-bromopropylene, heating to 60 ℃, keeping the temperature for reacting for 8 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, concentrating the filtrate, adding ethyl acetate, and then addingThen washed by sodium carbonate aqueous solution and washed by water to be neutral, and after drying, the propenyl phenyl ether is obtained by decompression concentration, 24.1g, and the yield is 90%.1H NMR(400M Hz,CDCl3)δ7.38-7.28(m,2H),7.00-6.91(m,3H),6.09 (dd,J＝17.5,10.5Hz,1H),5.44(d,J＝17.5Hz,1H),5.31(d,J＝10.5Hz,1H),4.55(d,J＝5.5Hz, 2H)；13C NMR(100M Hz,CDCl3)δ158.7,133.5,129.6,120.9,117.7,114.8,68.8.。
Example 2
Preparation of propenyl phenyl ethers
Adding 200mL of N, N-dimethylformamide into a reaction kettle, starting stirring, sequentially adding 18.8g of phenol, 16g of sodium hydroxide and 22.8g of allylamine, heating to 100 ℃, keeping the temperature for reaction for 8 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, adding dichloromethane into the concentrated filtrate, washing with potassium carbonate aqueous solution and water to be neutral, drying, and concentrating under reduced pressure to obtain 20.9g of propenyl phenyl ether with the yield of 78%.1H NMR(400M Hz,CDCl3)δ7.38-7.28(m,2H),7.00-6.91(m, 3H),6.09(dd,J＝17.5,10.5Hz,1H),5.44(d,J＝17.5Hz,1H),5.31(d,J＝10.5Hz,1H),4.55(d,J ＝5.5Hz,2H)；13C NMR(100M Hz,CDCl3)δ158.7,133.5,129.6,120.9,117.7,114.8,68.8.。
Example 3
Preparation of propenyl phenyl ethers
Adding 200mL of dimethyl sulfoxide into a reaction kettle, starting stirring, sequentially adding 18.8g of phenol, 22.4g of potassium hydroxide and 23.2g of allyl alcohol, heating to 100 ℃, keeping the temperature for reaction for 8 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, concentrating the filtrate, adding trichloromethane, washing with sodium hydroxide aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 22.0g of propenyl phenyl ether with the yield of 82%.1H NMR(400M Hz,CDCl3)δ7.38-7.28(m,2H),7.00-6.91(m,3H), 6.09(dd,J＝17.5,10.5Hz,1H),5.44(d,J＝17.5Hz,1H),5.31(d,J＝10.5Hz,1H),4.55(d,J＝ 5.5Hz,2H)；13C NMR(100M Hz,CDCl3)δ158.7,133.5,129.6,120.9,117.7,114.8,68.8.。
Example 4
Preparation of propenyl phenyl ethers
Adding 200mL of acetone into a reaction kettle, starting stirring, sequentially adding 18.8g of phenol, 41.5g of potassium carbonate and 31.2g of diallyl carbonate, heating to 60 ℃, keeping the temperature for reaction for 12 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, concentrating the filtrate, adding 1, 2-dichloroethane, washing with sodium hydroxide aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 20.1g of propenyl phenyl ether with the yield of 78%.1H NMR(400M Hz,CDCl3)δ7.38-7.28(m,2H),7.00-6.91(m,3H), 6.09(dd,J＝17.5,10.5Hz,1H),5.44(d,J＝17.5Hz,1H),5.31(d,J＝10.5Hz,1H),4.55(d,J＝ 5.5Hz,2H)；13C NMR(100M Hz,CDCl3)δ158.7,133.5,129.6,120.9,117.7,114.8,68.8.。
Example 5
Preparation of propenyl phenyl ethers
Adding 200mL of N, N-dimethylformamide into a reaction kettle, starting stirring, sequentially adding 18.8g of phenol, 16g of sodium hydroxide and 23.6g of allyl ether, heating to 100 ℃, keeping the temperature for reaction for 7 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, adding 1, 1-dichloroethane after concentrating the filtrate, washing with sodium hydroxide aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 18.0g of propenyl phenyl ether with the yield of 70%.1H NMR(400M Hz,CDCl3)δ7.38-7.28(m,2H), 7.00-6.91(m,3H),6.09(dd,J＝17.5,10.5Hz,1H),5.44(d,J＝17.5Hz,1H),5.31(d,J＝10.5Hz, 1H),4.55(d,J＝5.5Hz,2H)；13C NMR(100M Hz,CDCl3)δ158.7,133.5,129.6,120.9,117.7, 114.8,68.8.。
Example 6
Preparation of propenyl phenyl ethers
Adding 200mL of N, N-dimethylformamide into a reaction kettle, starting stirring, sequentially adding 18.8g of phenol, 16g of sodium hydroxide and 29.6g of allyl mercaptan, heating to 90 ℃, carrying out heat preservation reaction for 10 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, adding dichloroethane after concentrating the filtrate, washing with sodium hydroxide aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 21.0g of propenyl phenyl ether with the yield of 80%.1H NMR(400M Hz,CDCl3)δ7.38-7.28(m,2H), 7.00-6.91(m,3H),6.09(dd,J＝17.5,10.5Hz,1H),5.44(d,J＝17.5Hz,1H),5.31(d,J＝10.5Hz, 1H),4.55(d,J＝5.5Hz,2H)；13C NMR(100M Hz,CDCl3)δ158.7,133.5,129.6,120.9,117.7, 114.8,68.8.。
Example 7
Preparation of propenyl phenyl ethers
Adding 200mL of N, N-dimethylformamide into a reaction kettle, starting stirring, sequentially adding 18.8g of phenol, 22.4g of potassium hydroxide and 71.2g of diethyl allylphosphate, heating to 100 ℃, keeping the temperature for reaction for 5 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, adding trichloroethane after concentrating the filtrate, washing with sodium hydroxide aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 20.1g of propenyl phenyl ether with the yield of 75%.1H NMR(400M Hz,CDCl3)δ7.38-7.28(m,2H), 7.00-6.91(m,3H),6.09(dd,J＝17.5,10.5Hz,1H),5.44(d,J＝17.5Hz,1H),5.31(d,J＝10.5Hz, 1H),4.55(d,J＝5.5Hz,2H)；13C NMR(100M Hz,CDCl3)δ158.7,133.5,129.6,120.9,117.7, 114.8,68.8.。
Example 8
Preparation of propenyl (4-methylphenyl) ether
Adding 200mL of acetonitrile into a reaction kettle, starting stirring, sequentially adding 21.6g of 4-methylphenol, 55.3g of potassium carbonate and 21.0g of 3-chloropropene, heating to 85 ℃, keeping the temperature for reaction for 6 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, adding ethyl acetate into the concentrated filtrate, washing with potassium hydroxide aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 28.1g of propenyl (4-methylphenyl) ether with the yield of 95%.1H NMR(400M Hz,CDCl3)δ7.07(d,J＝8.4Hz,2H), 6.81(d,J＝8.4Hz,2H),6.11-6.03(m,1H),5.41(d,J＝10.4Hz,1H),5.27(d,J＝10.4Hz,1H), 4.50(m,2H),2.27(s,3H)；13C NMR(100M Hz,CDCl3)δ156.9,133.7,130.2,130.0,117.7,114.8, 69.12,20.6.。
Example 9
Preparation of propenyl (4-chlorophenyl) ether
Adding 200mL of acetonitrile into the reaction kettle, starting stirring,adding 28.6g of 4-chlorophenol, 55.3g of potassium carbonate and 30.2g of 3-bromopropylene in sequence, heating to 85 ℃, carrying out heat preservation reaction for 8 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, adding ethyl acetate after concentrating the filtrate, washing with sodium carbonate aqueous solution, washing with water to be neutral, drying, and carrying out reduced pressure concentration to obtain 30.3g of propenyl (4-bromophenyl) ether with the yield of 90%.1H NMR(400MHz,CDCl3):δ7.31(d,J＝9.0Hz,2H),6.78 (d,J＝9.0Hz,2H),6.00(dd,J＝16.7,10.5Hz,1H),5.30(dd,J＝16.7,1.5Hz,1H),5.18(dd,J＝ 10.5,1.5Hz,1H),4.40(d,J＝7.5Hz,2H)；13C NMR(100MHz,CDCl3):δ155.6,130.8,129.2, 116.8,114.5,110.9,65.9.。
Example 10
Preparation of propenyl (4-bromophenyl) ether
Adding 200mL of acetonitrile into a reaction kettle, starting stirring, sequentially adding 34.6g of 4-bromophenol, 55.3g of potassium carbonate and 37.0g of 3-iodopropene, heating to 85 ℃, keeping the temperature for reaction for 8 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, adding ethyl acetate into the concentrated filtrate, washing with sodium carbonate aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 39.1g of propenyl (4-bromophenyl) ether with the yield of 92%.1H NMR(400MHz,CDCl3):δ7.39(d,J＝9.0Hz,2H),6.82 (d,J＝9.0Hz,2H),6.02(dd,J＝16.7,10.5Hz,1H),5.39(dd,J＝16.7,1.5Hz,1H),5.29(dd,J＝ 10.5,1.5Hz,1H),4.50(d,J＝7.5Hz,2H)；13C NMR(100MHz,CDCl3):δ157.6,132.8,132.2, 117.8,116.5,112.9,68.9.。
Example 11
Preparation of propenyl (3, 4-methylenedioxyphenyl) ethers
Adding 200mL of N, N-dimethylformamide into a reaction kettle, starting stirring, sequentially adding 27.6g of 3, 4-methylenedioxyphenol, 48.4g of potassium carbonate and 30.2g of 3-bromopropylene, heating to 100 ℃, keeping the temperature for reaction for 8h, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, concentrating the filtrate, adding ethyl acetate, washing with sodium carbonate aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 29.2g of propenyl (3, 4-methylenedioxyphenyl) ether with the yield of 82%.1H NMR(400MHz, CDCl3):δ6.83(d,J＝8.4Hz,1H),6.61(d,J＝8.4Hz,1H),6.49(s,1H),6.10-6.04(m,3H),5.42(d, J＝17.5Hz,1H),5.31(d,J＝10.5Hz,1H),4.62(d,J＝5.5Hz,2H)；13C NMR(100MHz,CDCl3): δ155.8,148.8,145.6,132.8,119.2,109.1,107.5,101.0,101.9,70.1.。
Example 12
Preparation of propenyl (1-naphthyl) ether
Adding 200mL of N, N-dimethylformamide into a reaction kettle, starting stirring, sequentially adding 28.8g of 1-naphthol, 55.3g of potassium carbonate and 25.7g of allyl formate, heating to 80 ℃, keeping the temperature for reaction for 12 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, adding ethyl acetate into the concentrated filtrate, washing with sodium carbonate aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 31.3g of propenyl (1-naphthyl) ether with the yield of 85%.1H NMR(400MHz,CDCl3)δ8.35(d,J＝8.4Hz, 1H),8.11(d,J＝8.4Hz,1H),7.61-7.55(m,3H),7.41-7.38(m,1H),6.22-6.18(m,1H),6.11(dd,J ＝17.5,10.5Hz,1H),5.46(d,J＝17.5Hz,1H),5.35(d,J＝10.5Hz,1H),4.65(d,J＝5.5Hz,2H)；13C NMR(100MHz,CDCl3)δ158.8,136.1,135.5,134.5,130.1,128.8,125.6,124.8,121.2,119.8, 118.5,105.9,70.9.。
Example 13
Preparation of 3-phenoxybromopropane
Adding 200ml of carbon tetrachloride into a reaction kettle, starting stirring, sequentially adding 26.8g of propenyl phenyl ether, 1g of benzoyl peroxide and 30.6g of sodium bromide, slowly dropwise adding 18g of sulfuric acid when the temperature is raised to 50 ℃, preserving heat for reaction for 1h after dropwise adding, cooling to room temperature after the reaction is finished, washing an organic layer with sodium carbonate aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 41.0g of 3-phenoxy bromopropane with the yield of 95%.1H NMR(400M Hz,CDCl3)δ7.28(t,J＝8.0Hz,2H),6.95(t,J＝ 7.6Hz,1H),6.90(d,J＝8.0Hz,2H),4.09(t,J＝6.0Hz,2H),3.59(t,J＝6.4Hz,2H),2.33-2.27(m, 2H)；13C NMR(100MHz,CDCl3)δ158.8,129.6,121.0,114.6,65.3,32.5,30.2.。
Example 14
Preparation of 3-phenoxybromopropane
Adding 200ml of cyclohexane into a reaction kettle, starting stirring, sequentially adding 26.8g of propenyl phenyl ether, 1g of acetyl peroxide and 35.3g of potassium bromide, slowly dropwise adding 18g of sulfuric acid when the temperature is raised to 60 ℃, preserving the temperature for reaction for 1.5h after dropwise adding is finished, cooling to room temperature after the reaction is finished, washing an organic layer with potassium carbonate aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 39.3g of 3-phenoxy bromopropane, wherein the yield is 91%.1H NMR(400M Hz,CDCl3)δ7.28(t,J＝8.0Hz,2H),6.95(t,J＝ 7.6Hz,1H),6.90(d,J＝8.0Hz,2H),4.09(t,J＝6.0Hz,2H),3.59(t,J＝6.4Hz,2H),2.33-2.27(m, 2H)；13C NMR(100MHz,CDCl3)δ158.8,129.6,121.0,114.6,65.3,32.5,30.2.。
Example 15
Preparation of 3-phenoxybromopropane
Adding 200ml of 1, 2-dichloroethane into a reaction kettle, starting stirring, sequentially adding 26.8g of propenyl phenyl ether, 1g of m-chloroperoxybenzoic acid and 30.3g of lithium bromide, slowly dropwise adding 18g of phosphoric acid when the temperature is raised to 70 ℃, preserving heat for reaction for 2 hours after dropwise adding is finished, cooling to room temperature after the reaction is finished, washing an organic layer with sodium hydroxide aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 38.9g of 3-phenoxybromopropane, wherein the yield is 90%.1H NMR(400M Hz,CDCl3)δ7.28(t,J＝8.0Hz,2H), 6.95(t,J＝7.6Hz,1H),6.90(d,J＝8.0Hz,2H),4.09(t,J＝6.0Hz,2H),3.59(t,J＝6.4Hz,2H), 2.33-2.27(m,2H)；13C NMR(100MHz,CDCl3)δ158.8,129.6,121.0,114.6,65.3,32.5,30.2.。
Example 16
Preparation of 3-phenoxybromopropane
Adding 200ml of 1, 1-dichloroethane into a reaction kettle, starting stirring, sequentially adding 26.8g of propenyl phenyl ether, 2g of hydrogen peroxide and 33.4g of zinc bromide, slowly dropwise adding 18g of phosphoric acid when the temperature is raised to 80 ℃, preserving heat for reaction for 4 hours after dropwise adding is finished, cooling to room temperature after the reaction is finished, washing an organic layer with potassium hydroxide aqueous solution, washing to be neutral, drying, and concentrating under reduced pressure to obtain 34.6g of 3-phenoxy bromopropane with the yield of 80%.1H NMR(400M Hz,CDCl3)δ7.28(t,J＝8.0Hz,2H),6.95(t,J＝ 7.6Hz,1H),6.90(d,J＝8.0Hz,2H),4.09(t,J＝6.0Hz,2H),3.59(t,J＝6.4Hz,2H),2.33-2.27(m, 2H)；13C NMR(100MHz,CDCl3)δ158.8,129.6,121.0,114.6,65.3,32.5,30.2.。
Example 17
Preparation of 3-phenoxybromopropane
Adding 200ml of trichloromethane into a reaction kettle, starting stirring, sequentially adding 26.8g of propenyl phenyl ether, 1g of azodiisobutyronitrile and 35.6g of sodium bromide, slowly dropwise adding 18g of sulfuric acid when the temperature is raised to 80 ℃, preserving heat for reaction for 4 hours after dropwise adding is finished, cooling to room temperature after the reaction is finished, washing an organic layer with sodium carbonate aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 36.7g of 3-phenoxy bromopropane, wherein the yield is 85%.1H NMR(400M Hz,CDCl3)δ7.28(t,J＝8.0Hz,2H),6.95(t,J＝ 7.6Hz,1H),6.90(d,J＝8.0Hz,2H),4.09(t,J＝6.0Hz,2H),3.59(t,J＝6.4Hz,2H),2.33-2.27(m, 2H)；13C NMR(100MHz,CDCl3)δ158.8,129.6,121.0,114.6,65.3,32.5,30.2.。
Example 18
Preparation of 3-phenoxybromopropane
Adding 200ml of dichloromethane into a reaction kettle, starting stirring, sequentially adding 26.8g of propenyl phenyl ether, 1g of bis (tetrabutylammonium) peroxodisulfate and 35.6g of sodium bromide, slowly dropwise adding 18g of sulfuric acid when the temperature is raised to 60 ℃, preserving the temperature for reaction for 5h after the dropwise adding is finished, cooling to room temperature after the reaction is finished, washing an organic layer with sodium carbonate aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 33.7g of 3-phenoxy bromopropane, wherein the yield is 78%.1H NMR(400M Hz,CDCl3)δ7.28(t,J＝8.0Hz,2H), 6.95(t,J＝7.6Hz,1H),6.90(d,J＝8.0Hz,2H),4.09(t,J＝6.0Hz,2H),3.59(t,J＝6.4Hz,2H), 2.33-2.27(m,2H)；13C NMR(100MHz,CDCl3)δ158.8,129.6,121.0,114.6,65.3,32.5,30.2.。
Example 19
Preparation of 3-phenoxybromopropane
After putting 200ml of carbon tetrachloride into a reaction kettle, starting stirring, adding 26.8g of propenyl phenyl ether, 1g of tert-butyl peroxybenzoate and 35.6g of sodium bromide in sequence, and risingSlowly dripping 18g of sulfuric acid when the temperature reaches 80 ℃, preserving heat for reaction for 5h after dripping is finished, cooling to room temperature after the reaction is finished, washing an organic layer with sodium carbonate aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 32.4g of 3-phenoxy bromopropane with the yield of 75%.1H NMR(400M Hz,CDCl3)δ7.28(t,J＝8.0Hz,2H),6.95 (t,J＝7.6Hz,1H),6.90(d,J＝8.0Hz,2H),4.09(t,J＝6.0Hz,2H),3.59(t,J＝6.4Hz,2H), 2.33-2.27(m,2H)；13C NMR(100MHz,CDCl3)δ158.8,129.6,121.0,114.6,65.3,32.5,30.2.。
Example 20
Preparation of 3- (4-methylphenoxy) bromopropane
Adding 200ml of carbon tetrachloride into a reaction kettle, starting stirring, sequentially adding 29.6g of propenyl (4-methylphenyl) ether, 1g of benzoyl peroxide and 30.6g of sodium bromide, slowly dropwise adding 18g of sulfuric acid when the temperature is raised to 60 ℃, preserving the temperature for reaction for 2h after the dropwise adding is finished, cooling to room temperature after the reaction is finished, washing an organic layer with sodium carbonate aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 43.1g of 3- (4-methylphenoxy) bromopropane with the yield of 94%.1H NMR(400M Hz,CDCl3)δ7.13(d,J＝ 8.0Hz,2H),6.85(d,J＝7.6Hz,2H),4.07(t,J＝6.0Hz,2H),3.51(t,J＝6.4Hz,2H),2.33-2.27 (m,2H),2.25(s,3H)；13C NMR(100MHz,CDCl3)δ156.8,130.1,127.6,114.6,67.3,32.5,29.9, 21.3.。
Example 21
Preparation of 3- (4-chlorophenoxy) bromopropane
Adding 200ml of carbon tetrachloride into a reaction kettle, starting stirring, sequentially adding 33.8g of propenyl (4-chlorophenyl) ether, 1g of benzoyl peroxide and 30.6g of sodium bromide, slowly dropwise adding 18g of sulfuric acid when the temperature is raised to 60 ℃, preserving heat for reaction for 3h after the dropwise adding is finished, cooling to room temperature after the reaction is finished, washing an organic layer with sodium carbonate aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 44.4g of 3- (4-chlorophenoxy) bromopropane, wherein the yield is 89%.1H NMR(400M Hz,CDCl3)δ7.36(d,J＝8.0Hz, 2H),6.82(d,J＝7.6Hz,2H),4.06(t,J＝6.0Hz,2H),3.51(t,J＝6.4Hz,2H),2.31-2.24(m,2H)；13C NMR(100MHz,CDCl3)δ156.2,130.1,115.5,113.1,65.1,31.4,29.1.。
Example 22
Preparation of 3- (4-bromophenoxy) bromopropane
Adding 200ml of carbon tetrachloride into a reaction kettle, starting stirring, sequentially adding 42.6g of propenyl (4-bromophenyl) ether, 1g of benzoyl peroxide and 35.7g of sodium bromide, slowly dropwise adding 18g of sulfuric acid when the temperature is raised to 70 ℃, preserving heat for reacting for 5 hours after dropwise adding, cooling to room temperature after the reaction is finished, washing an organic layer with sodium carbonate aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 55.9 of 3- (4-bromophenoxy) bromopropane with the yield of 95%.1H NMR(400M Hz,CDCl3)δ7.48(d,J＝8.0Hz, 2H),6.97(d,J＝7.6Hz,2H),4.08(t,J＝6.0Hz,2H),3.55(t,J＝6.4Hz,2H),2.33-2.27(m,2H)；13C NMR(100MHz,CDCl3)δ158.8,132.6,118.6,114.7,66.1,32.8,30.1.。
Example 23
Preparation of 3- (3, 4-methylenedioxyphenoxy) bromopropane
Adding 200ml of carbon tetrachloride into a reaction kettle, starting stirring, sequentially adding 35.6g of propenyl (3, 4-methylenedioxyphenyl) ether, 1g of benzoyl peroxide and 35.7g of sodium bromide, slowly dropwise adding 18g of sulfuric acid when the temperature is raised to 50 ℃, preserving heat for reacting for 3 hours after dropwise adding, cooling to room temperature after the reaction is finished, washing an organic layer with sodium carbonate aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 44.1g of 3- (3, 4-methylenedioxyphenoxy) bromopropane, wherein the yield is 85%.1H NMR(400M Hz,CDCl3) δ2.14-2.41(m,2H),3.59(t,J＝6.4Hz,2H),4.03(t,J＝5.9Hz,2H),5.91(2H,s),6.32(dd,J＝8.4, 2.4Hz,1H),6.50(d,J＝2.4Hz,1H),6.70(d,J＝8.4Hz,1H)；13C NMR(100MHz,CDCl3)δ 152.8,149.4,145.4,109.7,107.1,100.3,101.8,67.1,32.8,29.9.。
Example 24
Preparation of 3- (1-naphthoxy) bromopropane
Adding 200ml of carbon tetrachloride into a reaction kettle, starting stirring, sequentially adding 36.8g of propenyl (1-naphthyl) ether, 1g of benzoyl peroxide and 35.7g of sodium bromide, slowly dropwise adding 18g of sulfuric acid when the temperature is raised to 100 ℃, and preserving heat to react after dropwise addingAnd cooling to room temperature after the reaction is finished for 5 hours, washing an organic layer with sodium carbonate aqueous solution, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain 45.6g of 3- (1-naphthoxy) bromopropane with the yield of 86%.1H NMR(400M Hz,CDCl3)δ8.24(d,J＝7.0Hz,1H), 7.81-7.79(m,1H),7.50-7.41(m,4H),6.81(d,J＝7.5Hz,1H),4.27-4.25(m,2H),3.71-3.68(m, 2H),2.45-2.41(m,2H)；13C NMR(100M Hz,CDCl3)δ154.6,134.8,127.8,126.7,126.1,125.8, 125.5,122.1,120.7,105.0,65.7,32.8,30.5。
Claims (7)
1. A method for preparing 3-phenoxybromopropane or an analog thereof, which is characterized by comprising the following steps:
(1) under the condition of stirring, sequentially adding phenol or aromatic phenol and alkali into a polar aprotic organic solvent, heating to reach a target reaction temperature, then preserving heat, slowly dropwise adding an allyl compound, preserving heat after dropwise adding, reacting for a certain time, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, concentrating filtrate, then adding an extraction organic solvent, washing with an alkali solution, washing with water to be neutral, drying, and then concentrating under reduced pressure to obtain propenyl aryl ether;
(2) under the condition of stirring, sequentially adding propenyl aryl ether, an initiator and bromide salt into a polar aprotic organic solvent, slowly dripping acid when the temperature is raised to reach the target reaction temperature, keeping the temperature for reacting for a certain time after dripping is finished, cooling to room temperature after the reaction is finished, washing an organic layer with alkali liquor, washing with water to be neutral, drying, and concentrating under reduced pressure to obtain the 3-phenoxy bromopropane or the like.
2. The method according to claim 1, wherein in the step (1), the aromatic phenol includes any one of p-methylphenol, p-chlorophenol, p-bromophenol, 3, 4-methylenedioxyphenol, and 1-naphthol; the allyl compound comprises any one of 3-chloropropene, 3-bromopropylene, 3-iodopropylene, allylamine, allyl alcohol, allyl formate, diallyl carbonate, allyl ether, allyl mercaptan and allyl diethyl phosphate; the base includes any one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide.
3. The method according to claim 1, wherein in the step (1), the polar aprotic organic solvent comprises any one of acetone, butanone, acetonitrile, N-dimethylformamide, dimethylsulfoxide; the extraction organic solvent comprises any one of ethyl acetate, dichloromethane, trichloromethane, 1, 2-dichloroethane and 1, 1-dichloroethane; the alkali solution comprises any one of potassium carbonate, sodium hydroxide and potassium hydroxide aqueous solution.
4. The method according to claim 1, wherein in the step (1), the molar ratio of the phenol or aromatic phenol to the allyl compound is 1:1.0 to 1.5, and the molar ratio of the phenol or aromatic phenol to the base is 1:1.0 to 2.0; the target reaction temperature is 60-100 ℃, and the time is 4-12 h.
5. The method of claim 1, wherein in step (2), the initiator comprises any one of benzoyl peroxide, acetyl peroxide, m-chloroperoxybenzoic acid, hydrogen peroxide, t-butyl hydroperoxide, bis (tetrabutylammonium) peroxodisulfate, t-butyl peroxybenzoate, azobisisobutyronitrile; the bromide salt comprises any one of sodium bromide, potassium bromide, lithium bromide and zinc bromide; the acid includes any one of sulfuric acid and phosphoric acid.
6. The method of claim 1, wherein in step (2), the weakly polar organic solvent comprises one or more of carbon tetrachloride, cyclohexane, chloroform, dichloromethane, 1, 2-dichloroethane, 1-dichloroethane; the alkali solution comprises one or more of potassium carbonate, sodium hydroxide and potassium hydroxide aqueous solution.
7. The method of claim 1, wherein in step (2), the molar ratio of propenyl aryl ether to bromide salt is 1:1.1 to 2.0, the molar ratio of propenyl aryl ether to acid is 1:1.0 to 2.0, and the amount of initiator is 1 mol% to 2 mol% of propenyl aryl ether; the target reaction temperature is 40-100 ℃; the time is 1-5 h.
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| Title |
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| MARZIA GALLI等: ""Scalable anti-Markovnikov hydrobromination of aliphatic and aromatic olefins"", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 14, pages 5622 - 5626 * |
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