A method for metal-free multiple halogenation of alkyne

Abstract

The application provides a metal-catalyzed alkyne polyhalogenation reaction method, and relates to the technical field of synthesis.The alkyne and a polyhalogenated reagent are stirred in a mixed solvent of 1,2-dichloroethane and hexafluoroisopropanol, the solvent is removed after the reaction is completed, and polyhalogenated alkenes are obtained after purification.The reaction of the application does not need inert atmosphere protection, and the reaction condition is mild, so that the polyhalogenated alkenes can be synthesized.The application does not need to use metal catalysts or alkalis, effectively reduces the synthesis cost, and is suitable for industrial production.

Description

Technical Field

[0001] This invention provides a metal-free catalytic method for polyhalogenation of alkynes, belonging to the field of synthetic technology. Background Technology

[0002] Polyhalogenated alkenes are alkene compounds in which two or more halogen atoms are attached to the carbon atom of the alkene bond. Among them, geminal dihalogenated alkenes, due to the two halogen atoms being attached to the same alkene carbon atom, exhibit high reactivity and good structural transformation capabilities, making them an important class of halogen-containing compounds in the field of organic synthesis. Polyhalogenated alkenes are widely found in natural products, pharmaceutical active molecules, and pesticide molecules, and can also serve as important intermediates in organic synthesis. Through reactions such as coupling, substitution, elimination, and functional group transformation, they can be further used to construct carbon-carbon or carbon-heteroatom bonds, thereby preparing more complex functionalized organic compounds. Therefore, developing efficient, mild, and highly selective synthetic methods for polyhalogenated alkenes is of great significance.

[0003] Alkynes have two unsaturated carbon atoms, and their carbon-carbon triple bonds can undergo various addition reactions, making them important raw materials for the preparation of polyhalogenated alkenes. By introducing halogen atoms and carbon-containing groups into the carbon-carbon triple bonds of alkynes, carbon skeleton construction and polyhalogenation can be achieved simultaneously in a one-step reaction. Therefore, alkyne polyhalogenation reactions have become an important route for the synthesis of geminidihalogenated alkenes and other polyhalogenated alkenes.

[0004] Existing polyhalogenation reactions of alkynes typically require transition metal catalysts such as palladium, copper, rhodium, and iridium. While transition metal catalysis systems can promote the activation of alkynes and the formation of carbon-halogen bonds, the metal catalysts and ligands used are usually expensive. Furthermore, metal residues may remain after the reaction, increasing the difficulty of product purification, which is particularly detrimental to the preparation of pharmaceuticals, pesticides, and fine chemicals. Simultaneously, some transition metal catalytic reactions are sensitive to oxygen and moisture, requiring inert gas protection and strictly anhydrous conditions, which places high demands on reaction equipment and operational processes.

[0005] Besides transition metal catalysis, existing technologies also disclose alkyne halogenation reactions initiated by free radicals, promoted by Lewis acids, or involving strong oxidants. Free radical reactions typically involve multiple competing reaction pathways, which can easily lead to reduced regioselectivity or stereoselectivity, substrate polymerization, and increased byproducts. Lewis acid-promoted systems may be affected by the coordination of nitrogen-, oxygen-, or sulfur-containing functional groups, which limits the substrate structure and the types of functional groups. Reactions using strong oxidants or highly reactive halogenating reagents may suffer from harsh reaction conditions, strong reagent corrosivity, and low operational safety.

[0006] Furthermore, polyhalogenation reactions of alkynes may involve simultaneous additions in different directions, potentially generating regioisomers, geometric isomers, or overhalogenated products. Existing methods struggle to effectively control the attachment positions of halogen atoms and other substituents at both ends of the alkyne, resulting in insufficient regioselectivity and stereoselectivity of the products. For alkyne substrates containing hydroxyl, amino, carbonyl, heterocyclic, or other sensitive functional groups, existing reaction systems may also induce functional group destruction or side reactions, limiting the applicability of the reaction substrates.

[0007] Therefore, existing polyhalogenation reactions of alkynes still suffer from problems such as dependence on metal catalysts, strict reaction conditions, insufficient tolerance to air and moisture, limited substrate applicability, and difficulty in controlling regioselectivity and stereoselectivity. It is necessary to develop a metal-free method for polyhalogenation reactions of alkynes that can be carried out under relatively mild conditions, while also possessing advantages such as simple operation, good functional group tolerance, high reaction selectivity, and easy product separation. This would reduce the cost of preparing polyhalogenated alkenes, minimize metal residues, and enhance the application value of this type of reaction in the synthesis of pharmaceuticals, pesticides, and fine chemicals. Summary of the Invention

[0008] Based on this, the present invention provides a metal-free catalytic method for polyhalogenation of alkynes. The present invention utilizes a specific mixed solvent system (1,2-dichloroethane DCE / hexafluoroisopropanol HFIP) to react at room temperature, yielding structurally well-defined polyhalogenated alkenes.

[0009] The present invention is specifically implemented using the following technical solutions: A metal-free catalytic method for polyhalogenation of alkynes involves reacting alkynes and polyhalogenated reagents in a mixed solvent of 1,2-dichloroethane and hexafluoroisopropanol with stirring. After the reaction is complete, the solvent is removed, and the polyhalogenated olefins are obtained after purification.

[0010] Preferably, the polyhalogenated reagent is a mixture of trimethylchlorosilane and N-bromosuccinimide.

[0011] Preferably, the molar ratio of trimethylchlorosilane to N-bromosuccinimide is 1:1.

[0012] Preferably, the alkyne is selected from one of the following structural formulas: , , , One of them.

[0013] Preferably, the molar ratio of the alkyne to the polyhalogenated reagent is 1:6.

[0014] Preferably, the volume ratio of 1,2-dichloroethane to hexafluoroisopropanol is 2:0.5.

[0015] Preferably, the reaction temperature is 20~30℃ and the reaction time is 6~24 hours.

[0016] Compared with the prior art, the present invention has the following beneficial effects: This invention utilizes the reaction of alkynes with polyhalogenated reagents in a mixed solvent of 1,2-dichloroethane and hexafluoroisopropanol at room temperature. This reaction requires no inert atmosphere and operates under mild conditions, enabling the synthesis of polyhalogenated alkenes. Furthermore, this invention eliminates the need for metal catalysts or bases, effectively reducing synthesis costs and making it suitable for industrial production. Attached Figure Description

[0017] Figure 1 Compound 1b prepared in Example 1 1 H NMR spectrum; Figure 2 Compound 1b prepared in Example 1 13 C NMR spectrum; Figure 3 Compound 2b prepared in Example 2 1 H NMR spectrum; Figure 4 Compound 2b prepared in Example 2 13 C NMR spectrum; Figure 5 Compound 3b prepared in Example 3 1 H NMR spectrum; Figure 6 Compound 3b prepared in Example 3 13 C NMR spectrum; Figure 7 Compound 4b prepared in Example 4 1 H NMR spectrum; Figure 8 Compound 4b prepared in Example 4 13 C10 NMR spectrum. Detailed Implementation

[0018] To make the objectives, technical solutions, and advantages of this invention clearer, the preferred embodiments of this invention will be described in further detail below with reference to the examples. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort are within the scope of protection of this invention.

[0019] Example 1: Preparation of (2,2-dibromo-1,1-dichloroethyl)benzene Alkyne 1a (0.5 mmol) was weighed and transferred to a 15 mL Schlenk tube equipped with a stir bar. Using a syringe, a mixed solvent of 1,2-dichloroethane / hexafluoroisopropanol (DCE:HFIP = 2.0 mL : 0.5 mL), trimethylchlorosilane (TMSCl, 1.5 mmol), and N-bromosuccinimide (NBS, 1.5 mmol) were added sequentially to the tube. The reaction mixture was stirred at room temperature for 8 hours. After the reaction was monitored for completeness by TLC and 1H NMR, it was cooled to room temperature. The solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by rapid column chromatography (using petroleum ether as eluent) to give the corresponding polyhalogenated alkene 1b in 80% yield.

[0020] The NMR characterization of compound 1b prepared in Example 1 was performed, and the obtained data and spectra are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.82-7.80 (m, 2H), 7.50-7.41 (m, 3H), 6.25 (s, 1H). 13 C NMR (151 MHz, CDCl3) δ 138.2, 130.1, 128.3, 127.6, 93.0, 53.4. Example 2: Preparation of 1-(2,2-dibromo-1,1-dichloroethyl)-4-methoxybenzene Alkyne 2a (0.5 mmol) was weighed and transferred to a 15 mL Schlenk tube equipped with a stir bar. Using a syringe, a mixed solvent of 1,2-dichloroethane / hexafluoroisopropanol (DCE:HFIP = 2.0 mL : 0.5 mL), trimethylchlorosilane (TMSCl, 1.5 mmol), and N-bromosuccinimide (NBS, 1.5 mmol) were added sequentially to the tube. The reaction mixture was stirred at room temperature for 8 hours. After the reaction was monitored for completeness by TLC and 1H NMR, it was cooled to room temperature. The solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by rapid column chromatography (using petroleum ether as eluent) to give the corresponding polyhalogenated alkene 2b in 95% yield.

[0021] The NMR characterization of compound 2b prepared in Example 2 was performed, and the obtained data and spectra are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.10-8.05 (m, 2H), 7.90-7.85 (m, 2H), 6.25 (s, 1H), 3.94 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 184.6, 164.5, 132.2, 123.3, 114.2, 55.6, 39.9. Example 3: Preparation of 1-bromo-4-(2,2-dibromo-1,1-dichloroethyl)benzene Alkyne 3a (0.5 mmol) was weighed and transferred to a 15 mL Schlenk tube equipped with a stir bar. Using a syringe, a mixture of 1,2-dichloroethane / hexafluoroisopropanol (DCE:HFIP = 2.0 mL : 0.5 mL), trimethylchlorosilane (TMSCl, 1.5 mmol), and N-bromosuccinimide (NBS, 1.5 mmol) were added sequentially to the tube. The reaction mixture was stirred at room temperature for 8 hours. The mixture was analyzed by TLC and... 1 After the reaction was monitored by 1H NMR to be complete, it was cooled to room temperature. The solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by rapid column chromatography (using petroleum ether as eluent) to give the corresponding polyhalogenated olefin 3b in 89% yield.

[0022] The NMR characterization of compound 3b prepared in Example 3 was performed, and the obtained data and spectra are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.70-7.65 (m, 2H), 7.57-7.55 (m, 2H), 6.20 (s, 1H). 13 C NMR (151 MHz, CDCl3) δ 137.1, 131.4, 129.3, 124.7, 92.1, 52.9. Example 4: Preparation of (2,2,2-tribromo-1,1-dichloroethyl)benzene Alkyne 4a (0.5 mmol) was weighed and transferred to a 15 mL Schlenk tube equipped with a stir bar. Using a syringe, a mixture of 1,2-dichloroethane / hexafluoroisopropanol (DCE:HFIP = 2.0 mL : 0.5 mL), trimethylchlorosilane (TMSCl, 1.5 mmol), and N-bromosuccinimide (NBS, 1.5 mmol) were added sequentially to the tube. The reaction mixture was stirred at room temperature for 8 hours. The mixture was analyzed by TLC and... 1 After the reaction was monitored by 1H NMR to be complete, it was cooled to room temperature. The solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by rapid column chromatography (using petroleum ether as eluent) to give the corresponding polyhalogenated olefin 4b in 80% yield.

[0023] The NMR characterization of compound 4b prepared in Example 4 was performed, and the obtained data and spectra are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.43-7.35 (m, 5H). 13 C NMR (151 MHz, CDCl3) δ135.6, 135.6, 133.0, 130.2, 128.8, 89.9. Comparative Example 1 The method of Example 1 was followed, except that only 2.5 mL of 1,2-dichloroethane (DCE) was used as the solvent. No product was detected after the reaction was completed.

[0024] Comparative Example 2 The method of Example 1 was followed, except that only 2.5 mL of hexafluoroisopropanol (HFIP) was used as the solvent. After the reaction, the product yield was only 29%.

[0025] Comparative Example 3 The method of Example 1 was followed, except that the volumes of 1,2-dichloroethane and hexafluoroisopropanol were 4.0 mL and 0.5 mL, respectively. After the reaction, the yield of the product was 55%.

[0026] Comparative Example 4 The method of Example 1 was followed, except that the volumes of 1,2-dichloroethane / hexafluoroisopropanol were 3.0 mL and 1.5 mL, respectively. After the reaction, the yield of the product was 62%.

[0027] Comparative Example 5 The method of Example 1 was followed, except that the volumes of 1,2-dichloroethane / hexafluoroisopropanol were 1.0 mL and 3.5 mL, respectively. After the reaction, the yield of the product was 48%.

[0028] Comparative Example 6 The method of Example 1 was followed, except that 4.5 mL of dichloromethane was used as the solvent. No product was detected after the reaction was completed.

[0029] Comparative Example 7 The method of Example 1 was followed, except that 4.5 mL of trifluoroethanol was used as the solvent. After the reaction was completed, the yield of the product was 17%.

[0030] Comparative Example 8 The method of Example 1 was followed, except that 0.5 mL of hexafluoroisopropanol and 2.0 mL of toluene were used as reaction solvents, and the yield of the product was 45% after the reaction was completed.

[0031] Comparative Example 9 The method of Example 1 was followed, except that 0.5 mL of hexafluoroisopropanol and 2.0 mL of tetrahydrofuran were used as reaction solvents, and the yield of the product was 18% after the reaction was completed.

[0032] The embodiments described above are some, but not all, embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

Claims

1. A metal-free catalytic method for polyhalogenation of alkynes, characterized in that, Alkynes and polyhalogenated reagents were reacted with a mixed solvent of 1,2-dichloroethane and hexafluoroisopropanol under stirring. After the reaction was completed, the solvent was removed and the product was purified to obtain polyhalogenated alkenes.

2. The metal-free catalytic polyhalogenation reaction method for alkynes as described in claim 1, characterized in that, The polyhalogenated reagent is a mixture of trimethylchlorosilane and N-bromosuccinimide.

3. The metal-free catalytic polyhalogenation reaction method for alkynes as described in claim 2, characterized in that, The molar ratio of trimethylchlorosilane to N-bromosuccinimide is 1:

1.

4. The metal-free catalytic polyhalogenation reaction method for alkynes as described in claim 1, characterized in that, The alkyne is selected from one of the following structural formulas: , , , One of them.

5. The metal-free catalytic polyhalogenation reaction method for alkynes as described in claim 1, characterized in that, The molar ratio of the alkyne to the polyhalogenated reagent is 1:

6.

6. The metal-free catalytic polyhalogenation reaction method for alkynes as described in claim 1, characterized in that, The volume ratio of 1,2-dichloroethane to hexafluoroisopropanol is 2:0.

5.

7. The metal-free catalytic polyhalogenation reaction method for alkynes as described in claim 1, characterized in that, The reaction temperature is 20~30℃, and the reaction time is 6~24 hours.

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