CN107513050B - A kind of preparation method of enoic acid bromolactonization - Google Patents

Abstract

The present invention relates to the preparation method of enoic acid bromolactonization as shown in the following structural formula: The method steps: at -78 ℃, the methylene chloride solution of dimethyl sulfoxide (1.5eq) is first added dropwise to the methylene chloride solution of oxalyl bromide (1.5eq), then the raw material alkenoic acid is added dropwise, and then returned to React at 0°C to obtain the corresponding bromolactonization products, 3-enoic acid and 4-enoic acid to obtain γ-lactone products, and 5-enoic acid to obtain δ-lactone products, with a yield of 45-85%.

Description

A kind of preparation method of enoic acid bromolactonization

The invention relates to a preparation method of enoic acid bromolactonization.

Bromolactonization reaction refers to the intramolecular ring closure of enoic acid compounds under the action of bromine-containing reagents to obtain bromolactone compounds. During this reaction, the olefinic bonds involved in the reaction generate two new carbon-hetero (O-C-C-Br) single bonds in one step. For enoic acid substrates that simultaneously generate two chiral centers, the bromolactonization reaction exhibits stereospecificity. This reaction has occupied an important position in organic synthetic chemistry since its discovery, and is widely used in the research of total synthesis of natural products, and it is a very effective synthetic method.

In view of the importance of bromolactonization reaction, its synthetic method has received more and more attention in recent years. The reaction of enoic acid and bromine is the most widely used and the most common method of bromolactonization. However, the application of this method is limited because bromine is a toxic, corrosive, and volatile liquid that is not easy to handle. As a result, more and more researches have improved the traditional method, looking for brominated reagents that can replace liquid bromine. At present, there are two main synthetic methods: (1) bromolactonization of enoic acid under the action of N-bromosuccinimide (NBS) and its analogs; Bromide under the action of bromide. These improved methods provide abundant and safe alternative routes for bromolactonization reactions, but there are different defects: expensive reagents, low yields, and poor regioselectivity.

The purpose of the present invention is to provide a new preparation method of bromolactonization of enoic acid. It is characterized in that enoic acid (3-enoic acid, 4-enoic acid, 5-enoic acid) is used as raw material, and dichloromethane is used as solvent, and under the action of dimethyl sulfoxide/oxalyl bromide combination reagent, the corresponding bromide products. The preparation method of the invention has the advantages of cheap reagents, easy operation, high yield and good selectivity. The reaction formula is as follows:

The present invention relates to the preparation method of enoic acid bromolactonization as shown in the following structural formula:

The main process is: at -78 ° C, first drop dimethyl sulfoxide (1.5eq) in dichloromethane solution into oxalyl bromide (1.5eq) in dichloromethane solution, then add the raw material dichloromethane dropwise, and then return to React at 0°C to obtain the corresponding bromolactonization products, 3-enoic acid and 4-enoic acid to obtain γ-lactone products, and 5-enoic acid to obtain δ-lactone products, with a yield of 45-85%.

The structures of the enoic acid bromolactonization products prepared in the method of the present invention are all confirmed by nuclear magnetic resonance. Analysis result is appended after embodiment.

Detailed ways

(1) Preparation of (4R ^* , 5S ^* )-4-bromo-5-phenyl-dihydrofuran-2(3H)-one

Under nitrogen protection, add oxalyl bromide (7.5mmol, 1.1mL, 1.5eq) and anhydrous dichloromethane (10mL) into a 100mL three-necked flask equipped with a thermometer. A solution of dimethylsulfoxide (7.5mmol, 0.53mL, 1.5eq) in anhydrous dichloromethane (10mL) was slowly added dropwise into a liquid nitrogen-ethanol bath at -78°C using a constant pressure dropping funnel. After the dropwise addition, stirring was continued at -78°C for 10 min, and a solution of (E)-4-phenyl-3-butenoic acid (5 mmol, 810 mg, 1.0 eq) in anhydrous dichloromethane (10 mL) was added dropwise. After the dropwise addition was completed, stirring was continued at -78°C for 10 min, and then returned to 0°C for 2 h. In ice bath at 0°C, add 30 mL aqueous sodium bicarbonate solution (5%), separate the layers, take the organic phase, wash with saturated aqueous sodium chloride solution (50 mL), and dry over anhydrous sodium sulfate. Filtration, rotary evaporation to remove the solvent to obtain a crude product, which was separated and purified by column chromatography (petroleum ether/ethyl acetate=15:1) to obtain (4R ^* , 5S ^* )-4-bromo-5-phenyl-dihydrofuran- 2(3H)-ketone 915 mg, yield 76%. ¹ H NMR (300MHz, CDCl ₃ ) δ7.46-7.36 (m, 5H), 5.66 (d, J=5.1Hz, 1H), 4.37 (ddd, J=7.2, 6.3, 5.1Hz, 1H), 3.24( dd, J=18.3, 7.5 Hz, 1H), 2.97 (dd, J=18.3, 6.6 Hz, 1H). ¹³ C NMR (75 MHz, CDCl ₃ ) δ 173.08, 135.98, 129.48, 129.18, 125.52, 87.99, 45.70, 38.94.

(2) Preparation of 5-(bromomethyl)-3,3-dimethyl-dihydrofuran-2(3H)-one

Under nitrogen protection, add oxalyl bromide (7.5mmol, 1.1mL, 1.5eq) and anhydrous dichloromethane (10mL) into a 100mL three-necked flask equipped with a thermometer. A solution of dimethylsulfoxide (7.5mmol, 0.53mL, 1.5eq) in anhydrous dichloromethane (10mL) was slowly added dropwise into a liquid nitrogen-ethanol bath at -78°C using a constant pressure dropping funnel. After the dropwise addition, stirring was continued at -78°C for 10 min, and a solution of 2,2-dimethyl-4-pentenoic acid (5 mmol, 640 mg, 1.0 eq) in anhydrous dichloromethane (10 mL) was added dropwise. After the dropwise addition was completed, stirring was continued at -78°C for 10 min, and then returned to 0°C for 2 h. In ice bath at 0°C, add 30 mL aqueous sodium bicarbonate solution (5%), separate the layers, take the organic phase, wash with saturated aqueous sodium chloride solution (50 mL), and dry over anhydrous sodium sulfate. Filtration, rotary evaporation to remove the solvent to obtain a crude product, separation and purification by column chromatography (petroleum ether/ethyl acetate=10:1) to obtain 5-(bromomethyl)-3,3-dimethyl-dihydrofuran-2 (3H)-ketone 880 mg, yield 85%. ¹ H NMR (300 MHz, CDCl ₃ ) δ4.66-4.57 (m, 1H), 3.54 (dd, J=10.8, 5.1 Hz, 1H), 3.47 (dd, J=10.8, 6.0 Hz, 1H), 2.25 ( dd, J = 12.9, 6.3 Hz, 1H), 1.91 (dd, J = 12.9, 9.3 Hz, 1H), 1.28 (s, 3H), 1.26 (s, 3H). ¹³ C NMR (75 MHz, CDCl ₃ ) δ 180.97, 74.74, 41.87, 40.61, 33.74, 24.96, 24.91.

(3) Preparation of 6-(bromomethyl)-tetrahydropyran-2-one

Under nitrogen protection, add oxalyl bromide (7.5mmol, 1.1mL, 1.5eq) and anhydrous dichloromethane (10mL) into a 100mL three-necked flask equipped with a thermometer. A solution of dimethylsulfoxide (7.5mmol, 1.52g, 1.5eq) in anhydrous dichloromethane (10mL) was slowly added dropwise into a liquid nitrogen-ethanol bath at -78°C using a constant pressure dropping funnel. After the dropwise addition, stirring was continued at -78°C for 10 min, and a solution of 5-hexenoic acid (5 mmol, 570 mg, 1.0 eq) in anhydrous dichloromethane (10 mL) was added dropwise. After the dropwise addition was completed, stirring was continued at -78°C for 10 min, potassium carbonate (25 mmol, 3.45 g, 5.0 eq) and 18-crown-6 (0.25 mmol, 66 mg, 0.05 eq) were added, and then returned to room temperature for 5 h. Suction filtration, add 30 mL of distilled water to the filtrate, separate the layers, take the organic phase, wash with saturated aqueous sodium chloride solution (50 mL), and dry over anhydrous sodium sulfate. Filtration, rotary evaporation to remove the solvent to obtain a crude product, separation and purification by column chromatography (petroleum ether/ethyl acetate=10:1), to obtain 435 mg of 6-(bromomethyl)-tetrahydropyran-2-one, the yield is 45%. ¹ H NMR (600MHz, CDCl ₃ ) δ 4.52-4.47 (m, 1H), 3.52 (dd, J=10.8, 4.2Hz, 1H), 3.47 (dd, J=10.8, 6.0Hz, 1H), 2.60( dddd, J=18.0, 6.6, 4.8, 1.2Hz, 1H), 2.46(ddd, J=17.4, 9.6, 7.2Hz, 1H), 2.14-2.08(m, 1H), 1.97(ddq, J=13.8, 7.2 , 4.8Hz, 1H), 1.91-1.83 (m, 1H), 1.70 (dtd, J=13.8, 11.4, 5.4Hz, 1H). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.45, 78.70, 33.89, 29.50, 26.42, 18.27.

Claims (1)

1. The preparation method of product 1. olefin(e) acid bromine described in a kind of Formula II lactonizes, it is characterised in that with 3- olefin(e) acid shown in Formulas I, 4- Olefin(e) acid, 5- alkene acid compounds are raw material, using methylene chloride as solvent, in the effect of dimethyl sulfoxide and oxalyl bromine composite reagent Under, it obtains bromine shown in corresponding Formula II and lactonizes product, main process is: at -78 DEG C first by the dichloromethane of dimethyl sulfoxide Alkane solution is added dropwise in the dichloromethane solution of oxalyl bromine, then alkene acid compounds shown in Formulas I are added dropwise, and is then back to 0 DEG C of reaction, Reaction equation is as follows:

   R=H, Ph or C_mH_2m+1, m=1-5.