Acta Chim. Sinica ›› 2018, Vol. 76 ›› Issue (12): 945-950.DOI: 10.6023/A18080322 Previous Articles     Next Articles

Special Issue: 有机氟化学



刘青雲, 赵祥虎, 李佳录, 曹松   

  1. 华东理工大学 药学院 上海市化学生物学(芳香杂环)重点实验室 上海 200237
  • 投稿日期:2018-08-07 发布日期:2018-09-14
  • 通讯作者: 曹松,,Tel.:021-64253452
  • 基金资助:


Synthesis of Cyanated Difluorostyrene Derivatives via SN2' Cyanomethylation of α-(Trifluoromethyl)styrenes with Acetonitrile

Liu Qingyun, Zhao Xianghu, Li Jialu, Cao Song   

  1. Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology (ECUST), Shanghai 200237
  • Received:2018-08-07 Published:2018-09-14
  • Contact: 10.6023/A18080322
  • Supported by:

    Project supported by the National Natural Science Foundation of China (Nos. 21472043, 21272070).

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.

Key words: α-(trifluoromethyl)styrenes, acetonitrile, cyanomethylation, cyanated difluorostyrenes