Background and overview[1]
α-Haloketones, as a type of organic synthetic building blocks with extremely high electrophilic activity, have been widely used in organic synthetic chemistry. At the same time, as an important structural unit, it also plays an extremely important role in medicinal chemistry and pesticide chemistry. Therefore, the preparation of such compounds has important practical significance. So far, many methods have been used to realize the halogenation of the α position of the ketone. The more common halogenation reagents include: elemental bromine, copper halide, N-halogenated butyl Diimide etc. Most of the methods for preparing α-haloketones from ketones require long reaction times, harsh reaction conditions, and produce polyhalogenated by-products.
In order to overcome the above shortcomings, many scientific researchers have invented other halogenating reagents to directly convert ketones into α-haloketones, or use ketone derivatives to prepareα-Haloketones. Studies have reported that iodobenzene diacetate (PIDA) was used to achieve the α-functionalization reaction of 1,3-dicarbonyl compounds. In similar research work, iodobenzene diacetate has been used as a mild oxidant, and then connected to the carbonyl carbonyl group in the form of an electrophile.
When a new nucleophile acts, such high-iodine compound intermediates can show good leaving properties and leave with iodobenzene. During the entire conversion process, iodobenzene diacetate achieves the polar conversion of the substrate. Here, by utilizing the properties of iodobenzene diacetate and using trimethylsilyl chloride as the chlorination reagent under mild reaction conditions, the preparation of α-haloketones from ketoenol silyl ethers including (alpha-chloropropiophenone).
α-Chloropropiophenone is also known as 2-chloropropiophenone in Chinese, CAS number 6084-17-9, chemical formula C9H9ClO. Molecular weight 242.02600. Density 1.129g/cm3, melting point 125-128 °C (lit.), boiling point 241.8ºC at 760 mmHg, flash point 118.4ºC, refractive index 1.524. α-Chloropropiophenone is an important chemical raw material and pharmaceutical intermediate.
Preparation [1]
Step 1: Preparation of enol silyl ether: Add phenylacetone (1 g, 8 mmol) to a 50 mL two-necked flask. Under nitrogen protection, cool the solution to 0 °C, and then add 10 mL of non-alcoholic acid. aqueous THF solution, and then add lithium diisopropylamide (2mol/L, 4.2 mL) dropwise to it. After the dropwise addition is completed, remove the ice-water mixture used for cooling and stir at room temperature for 1 h. When the solution turns yellow, cool the reaction mixture to 0°C again, add trimethylsilyl chloride (1.04 g, 9.6 mmol) dropwise, stir at room temperature, and detect by TLC until the reaction is complete. The solvent is evaporated under reduced pressure. , the finally obtained oily liquid was separated by column chromatography (pure petroleum ether) to obtain product 1a (1.3 g, yield: 84%).
Step 2: Preparation of α-chloropropiophenone: Add iodobenzene diacetate (2a) (0.244 g, 0.75 mmol) into a 50 mL two-neck bottle, under nitrogen protection , then a solution of phenylacetone enolsilyl ether (1a) (0.096 g, 0.5 mmol) and trimethylchlorosilane (3a) (0.108 g, 1 mmol) in MeCN (5 mL) was added to the system. The reaction system was stirred at room temperature and detected by TLC until the reaction was complete. After the solvent was evaporated under reduced pressure, the residue was separated by column chromatography [V(petroleum ether):V(ethyl acetate)=10:1]. Finally, the product 4l (α-chloropropiophenone) was separated as a colorless liquid with a yield of 84%.
Using iodobenzene diacetate and trimethylchlorosilane as the chlorine source, a method for preparing α-chloroaryl ketones from aryl ketone enol silyl ethers was realized. This method has the characteristics of simple operation and mild reaction conditions. Through this reaction, the products α-chloroaryl ketones including α-chloropropiophenone can be obtained in moderate or good yields.
Reference materials
[1] Chen Xiaowei, Zhong Siying, Du Gang, Huang Danfeng, Wang Kehu, Su Yingpeng, & Hu Yulai. (2016). Iodobenzene diacetate promotes the chlorination reaction of aryl ketone silyl ethers. Organic Chemistry, 36( 5), 1028-1033.
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