Method for preparing diiodoalkane compound through ring-opening iodination of cyclic ether

Abstract

According to the preparation method, sodium borohydride, iodine and a cyclic ether compound as shown in a formula I are taken as starting materials, dichloromethane is taken as a reaction solvent, metal cobalt salt is taken as a catalyst, and the ring-opening iodination reaction of the cyclic ether compound is realized under mild conditions, so that the diiodoalkane compound is prepared. And synthesizing the diiodoalkane compound (formula II). According to the method, a phosphorus-containing reagent does not need to participate, corrosion of an acid medium to reaction equipment is avoided, the used raw materials are wide in source and low in cost, aftertreatment operation is easy and convenient, safety and environment friendliness are achieved, the green chemical requirement is met, and the important practical value and the good application prospect are achieved.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing diiodoalkane compounds by ring-opening iodination of cyclic ethers. Background Technology

[0002] Dihaloalkanes have a wide range of applications in the chemical, chemical engineering, and fine chemical industries, especially in pharmaceuticals, pesticides, and surfactants, where they play an irreplaceable role as hydrophobic and alkylating groups. For example, indocyanine green has been approved for clinical use as a contrast agent for liver cancer and sentinel lymph node dispersive agents. However, the fluorescent molecule indocyanine green itself does not possess biological targeting properties. Typically, the targeting group and the luminescent group need to be linked together with a small molecule to give the fluorescent molecule targeting properties; this linking molecule is called a linker. Dihaloalkanes are currently the most widely used linkers, and their applications are expected to become increasingly widespread.

[0003] Among them, diiodoalkanes, as the most reactive dihaloalkanes, have attracted much attention for their synthesis. The nucleophilic substitution reaction of diols and thionyl chloride is commonly used, but this method is highly polluting, has poor atom economy, and is costly. With increasing environmental awareness, the reaction of hydroiodic acid and diols has begun to be used to produce diiodoalkanes. Although this method is economical and environmentally friendly, it suffers from low efficiency, low yield, and long reaction time, failing to meet the requirements of industrial production.

[0004] Since then, researchers have attempted to prepare diiodoalkane compounds by ring-opening iodination of cyclic ethers, such as 1,4-diiodobutane using potassium iodide, 85% phosphoric acid, phosphoric anhydride, and tetrahydrofuran under reflux. Although this method yields high yields, it requires sophisticated equipment and involves cumbersome post-treatment of phosphoric acid waste. Subsequently, Atsutaka Kunai et al. utilized the reaction of iodomethane and trimethylsilylamine to generate iodosilane in situ, achieving ring-opening cleavage of cyclic ethers to synthesize diiodoalkane compounds. However, the reagents used are sensitive to air, the operation is cumbersome, and the yield is relatively low. In 2024, Liu Haichao et al. reported that tetrahydrofuran ring-opening cleavage to 1,4-diiodobutane could be achieved in acetic acid medium under rhodium chloride catalysis (as shown in the figure). This method not only requires the precious metal rhodium catalysis but also has low selectivity, and acetic acid, as a reaction solvent, causes severe corrosion to the equipment.

[0005]

[0006] Therefore, developing a method for preparing diiodoalkane compounds by ring-opening iodination of cyclic ethers with mild conditions, high reaction efficiency, safety, and environmental friendliness has significant practical value and promising application prospects. Summary of the Invention

[0007] The purpose of this invention is to provide a method for preparing diiodoalkane compounds by ring-opening iodination of cyclic ethers. This method achieves the ring-opening iodination reaction of cyclic ether compounds without using precious metal catalysts and avoiding high-temperature and high-pressure reaction conditions, thus synthesizing diiodoalkane compounds (Formula II). Furthermore, it eliminates the need for phosphorus-containing reagents, avoids corrosion of reaction equipment by acidic media, utilizes widely available and low-cost raw materials, simplifies post-processing, and is safe and environmentally friendly, meeting the requirements of green chemistry.

[0008] This invention provides a method for preparing diiodoalkane compounds by ring-opening iodination of cyclic ethers, comprising the following steps: In a dry reaction flask, a cyclic ether compound of formula I, sodium borohydride, iodine, a cobalt salt as a catalyst, and dichloromethane as a reaction solvent are added sequentially. The reactants are stirred at 40-60 degrees Celsius for 12-24 hours, then cooled to room temperature. The reaction is quenched by adding a saturated ammonium chloride solution, and the mixture is extracted three times with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, and rotary evaporated to obtain diiodoalkane compounds of formula II. The structural formulas of formulas I and II are as follows:

[0009] In Formula I and Formula II, R can be any one of hydrogen or alkyl groups; n = 1, 2, 3, 4...

[0010] The molar ratio of the feed ingredients is as follows: Sodium borohydride: Iodine = 1:1.5-3:2-3.

[0011] Furthermore, the alkyl group can be methyl, ethyl, butyl, etc.

[0012] The catalyst cobalt salt includes all cobalt-containing compounds such as cobalt chloride, cobalt bromide, cobalt iodide, and cobalt acetate, with cobalt bromide being preferred.

[0013] The advantages of this invention compared to the prior art are as follows: This invention uses cyclic ethers, iodine, and sodium borohydride as starting materials, and cobalt salt as a catalyst, to achieve the ring-opening iodination reaction of cyclic ether compounds under mild conditions, thereby synthesizing diiodoalkane compounds.

[0014] The method of this invention does not require the participation of phosphorus-containing reagents, avoids the corrosion of reaction equipment by acidic media, uses widely available and low-cost raw materials, has simple post-processing operation, is safe and environmentally friendly, meets the requirements of green chemistry, and has important practical value and good application prospects. Attached Figure Description

[0015] Figure 1 1,4-Diiodobutane prepared in Example 1 1 H NMR image Figure 21,4-Diiodobutane prepared in Example 1 13 C NMR spectrum Detailed Implementation

[0016] The following are specific embodiments provided merely for the purpose of illustrating the present invention in detail. These embodiments are not intended to limit the scope of protection of the present invention. Unless otherwise specified, the experimental methods used in the embodiments are conventional methods. Example 1

[0017]

[0018] In a dry 25 mL reaction flask, tetrahydrofuran (0.5 mmol), NaBH4 (1 mmol), I2 (1 mmol), CoBr2 (0.0025 mol), and dichloromethane (1 mL) were added sequentially. The reaction mixture was incubated at 60 °C for 20 hours. After the reaction was completed as detected by TCL, the mixture was cooled to room temperature and quenched with 10 mL of saturated sodium chloride solution. The mixture was extracted three times with ethyl acetate (10 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the target product (1,4-diiodobutane) with a yield of 92%. 1 H NMR (600 MHz, CDCl3) δ 3.28-3.15 (m, 4H), 2.02-1.85 (m, 4H). 13 C NMR (151 MHz, CDCl3) δ 33.93, 5.11. HRMS (ESI, m / z) calcd for C4H9I2 + : 310.8788, found:310.8787. Example 2

[0019]

[0020] In a dry 25 mL reaction flask, tetrahydropyran (0.5 mmol), NaBH4 (1 mmol), I2 (1 mmol), CoBr2 (0.0025 mol), and dichloromethane (1 mL) were added sequentially. The reaction mixture was reacted at 65°C for 18 hours. After the reaction was completed as detected by TCL, the mixture was cooled to room temperature and quenched with 10 mL of saturated sodium chloride solution. The mixture was extracted three times with ethyl acetate (10 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the target product (1,4-diiodopentane) with a yield of 95%. 1 H NMR (600MHz, CDCl3) δ 3.18 (t, J = 7.0 Hz, 4H), 1.84 (p, J= 7.1 Hz, 4H), 1.51 (p, J = 7.6Hz, 2H). 13 C NMR (151 MHz, CDCl3) δ32.45, 31.50, 6.42. HRMS (ESI, m / z) calcdfor C5H 11 I2 + : 324.8945, found: 324.8943. Example 3

[0021]

[0022] In a dry 25 mL reaction flask, 0.5 mmol of hexane oxide, 1 mmol of NaBH4, 1 mmol of I2, 0.0025 mol of CoBr2, and 1 mL of dichloromethane were added sequentially. The reaction mixture was reacted at 60 °C for 24 hours. After the reaction was completed as detected by TCL, the mixture was cooled to room temperature and quenched with 10 mL of saturated sodium chloride solution. The mixture was extracted three times with 10 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the target product (1,4-diiodohexane) with a yield of 97%. 1 H NMR (600MHz, CDCl3) δ 3.17 (t, J = 6.8 Hz, 4H), 1.82 (m, 4H), 1.41 (m, 4H). 13 C NMR (151MHz, CDCl3) δ 33.24, 29.46, 7.15. HRMS (ESI, m / z) calcd for C6H 13 I2 + : 338.9101,found: 338.9101. Example 4

[0023]

[0024] In a dry 25 mL reaction flask, 3-methylfuran (0.5 mmol), NaBH4 (1 mmol), I2 (1 mmol), CoBr2 (0.0025 mol), and dichloromethane (1 mL) were added sequentially. The reaction mixture was reacted at 60 °C for 24 hours. After the reaction was completed as detected by TCL, the mixture was cooled to room temperature and quenched with 10 mL of saturated sodium chloride solution. The mixture was extracted three times with ethyl acetate (10 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the target product (1,4-diiodo-2-methylbutane) with a yield of 93%.1 H NMR (400 MHz, Chloroform- d ) δ 3.26-3.13 (m, 4H), 1.92 (dq, J = 13.6, 7.1 Hz, 1H), 1.74 (dq, J = 14.1, 7.1 Hz, 1H), 1.61 (dq, J = 11.9, 5.9 Hz, 1H), 1.00 (d, J = 6.5Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 39.94, 35.01, 19.92, 16.14, 3.84.HRMS (ESI, m / z) calcd for C5H 11 I2 + : 324.8945, found: 324.8944. Example 5

[0025]

[0026] In a dry 25 mL reaction flask, 4-methylpyran (0.5 mmol), NaBH4 (1 mmol), I2 (1 mmol), CoBr2 (0.0025 mol), and dichloromethane (1 mL) were added sequentially. The reaction mixture was reacted at 50 °C for 24 hours. After the reaction was completed as detected by TCL, the mixture was cooled to room temperature and quenched with 10 mL of saturated sodium chloride solution. The mixture was extracted three times with ethyl acetate (10 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the target product (1,5-diiodo-3-methylpentane) with a yield of 94%. 1 H NMR (400 MHz, Chloroform- d ) δ 3.24 (td, J = 9.1, 8.4, 5.4 Hz, 2H), 3.20-3.10 (m,2H), 1.95-1.83 (m, 2H), 1.76-1.64 (m, 3H), 0.91 (d, J = 6.0 Hz, 3H). 13 C NMR (101MHz, Chloroform- d ) δ 40.22, 35.13, 17.93, 4.08. HRMS (ESI, m / z) calcd forC6H13 I2 + : 338.9101, found: 338.9099。

Claims

1. A method for preparing diiodoalkane compounds by ring-opening iodination of cyclic ethers, characterized in that, The process includes the following steps: In a dry reaction flask, the cyclic ether compound of Formula I, sodium borohydride, and iodine are added sequentially; a cobalt salt is used as a catalyst, and dichloromethane is used as the reaction solvent. The reactants are stirred at 40-60 degrees Celsius for 12-24 hours, then cooled to room temperature. The reaction is quenched by adding a saturated ammonium chloride solution, and the mixture is extracted three times with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the diiodoalkane compound of Formula II. The structural formulas of Formulas I and II are as follows: ， In Formula I and Formula II, R is a hydrogen group or any one of an alkyl group; n includes, but is not limited to, 1, 2, 3 or 4.

2. The method for preparing diiodoalkane compounds by ring-opening iodination of cyclic ethers as described in claim 1, characterized in that, The alkyl group is methyl, ethyl, or butyl.

3. The method for preparing diiodoalkane compounds by ring-opening iodination of cyclic ethers as described in claim 1, characterized in that, The n is equal to 1, 2, 3 or 4.

4. The method for preparing diiodoalkane compounds by ring-opening iodination of cyclic ethers as described in claim 1, characterized in that, The catalyst cobalt salt is cobalt chloride, cobalt bromide, cobalt iodide, or cobalt acetate.

5. The method for preparing diiodoalkane compounds by ring-opening iodination of cyclic ethers as described in claim 4, characterized in that, The catalyst, a cobalt metal salt, is cobalt bromide.

6. The method for preparing diiodoalkane compounds by ring-opening iodination of cyclic ethers as described in claim 1, characterized in that, The molar ratio of the reactants in the reaction step is as follows: compound shown in Formula I: sodium borohydride: iodine = 1:1.5-3:2-3.

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