Citation: Liu Qingyun, Zhao Xianghu, Li Jialu, Cao Song. Synthesis of Cyanated Difluorostyrene Derivatives via S_N2' Cyanomethylation of α-(Trifluoromethyl)styrenes with Acetonitrile[J]. Acta Chimica Sinica, ;2018, 76(12): 945-950. doi: 10.6023/A18080322 shu

Synthesis of Cyanated Difluorostyrene Derivatives via S_N2' Cyanomethylation of α-(Trifluoromethyl)styrenes with Acetonitrile

Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology (ECUST), Shanghai 200237

Corresponding author: Cao Song, scao@ecust.edu.cn
Received Date: 7 August 2018
Available Online: 14 December 2018
Fund Project: Project supported by the National Natural Science Foundation of China (Nos. 21472043, 21272070)the National Natural Science Foundation of China 21272070the National Natural Science Foundation of China 21472043

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Nitriles are important structural motifs found in agrochemicals, pharmaceuticals, and natural products. Furthermore, nitriles are versatile synthetic precursors for organic synthesis because they can be easily converted into various functionalities, such as amides, ketones, esters, primary amines, aldehydes, carboxylic acids, and nitrogen-containing heterocycles. Therefore, the development of efficient methods for the synthesis of nitrile compounds has attracted much attention from synthetic chemists. Cyanomethylation of various substrates is a synthetically useful reaction because a variety of diversely cyano-containing compounds could be readily prepared. Acetonitrile is the simplest commercially available alkyl nitrile, which can act as the cyanomethyl carbanion source. The traditional method for the cyanomethylation of organic molecules is deprotonation of acetonitrile in the presence of strong base. Alternatively, transition-metal-catalyzed C—H bond activation of acetonitrile represents an attractive approach to cyanomethylated compounds due to its atom and step economy. In this communication, we developed a simple and highly efficient method for the synthesis of cyanated difluorostyrene derivatives by cyanomethylation of α-(trifluoromethyl)styrenes using cheap and commercially available acetonitrile as the CH₂CN^- source. The reaction proceeded smoothly in the presence of LiHMDS at room temperature and was finished within 1 h, affording the cyanated gem-difluoroalkenes in moderate to good yields. Furthermore, the cyanomethylation reaction exhibited good substrate scope and functional group compatibility. A general procedure for the cyanomethylation of α-(trifluoromethyl)styrenes with acetonitrile is as following: α-(trifluoromethyl)styrenes 1 (0.5 mmol) was dissolved in acetonitrile 2a (4 mL) at room temperature under argon atmosphere. Subsequently, a solution of the LiHMDS in THF (1.5 mL, 1.0 mol/L, 1.5 mmol, 3.0 equiv.) was added dropwise within 50 min and stirring was continued for further 10 min (monitored by TLC). After completion of the reaction, the reaction mixture was quenched with saturated aqueous solution of NH₄Cl (15 mL) and extracted with ethyl acetate (5 mL×3). The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was then purified by column chromatography on silica gel [(V(hexane)/V(ethyl acetate)＝10:1~6:1] directly to afford the pure target compounds.
- α-(trifluoromethyl)styrenes,
- acetonitrile,
- cyanomethylation,
- cyanated difluorostyrenes
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Synthesis of Cyanated Difluorostyrene Derivatives via SN2' Cyanomethylation of α-(Trifluoromethyl)styrenes with Acetonitrile

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Synthesis of Cyanated Difluorostyrene Derivatives via S_N2' Cyanomethylation of α-(Trifluoromethyl)styrenes with Acetonitrile