Acta Chimica Sinica ›› 2019, Vol. 77 ›› Issue (9): 874-878.DOI: 10.6023/A19050189 Previous Articles     Next Articles

Special Issue: 有机自由基化学



肖莹霞a, 柳忠全ab*()   

  1. a兰州大学化学化工学院 功能有机分子化学国家重点实验室 兰州 730000
    b南京中医药大学药学院 南京 210023
  • 投稿日期:2019-05-21 发布日期:2019-06-21
  • 通讯作者: 柳忠全
  • 基金资助:

Radical-Promoted Cross Dehydrogenative Coupling of Ketones and Esters with Electron-Rich Heteroarenes

Xiao, Yingxiaa, Liu, Zhong-Quanab*()   

  1. a State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000
    b College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023
  • Received:2019-05-21 Published:2019-06-21
  • Contact: Liu, Zhong-Quan
  • Supported by:
    Project supported by the National Natural Science Foundation of China(No.21672089);the State Key Laboratory of Applied Organic Chemistry of Lanzhou University and the Nanjing University of Chinese Medicine

The cross dehydrogenative coupling (CDC) via highly selective C—H bond functionalization represents one of the most atom-economical, environmentally-benign and efficient synthetic strategies. For a long time, the cleavage of C—H bonds initiated by free radicals has been regarded as unselective and useless. However, more and more studies have shown that free radical mediated strategies could also achieve C—H bond functionalization in high selectivity recently. In general, it’s well-known that nucleophilic free radical species tend to extract hydrogen atoms on electron-deficient C—H bonds, while electrophilic free radicals abstract hydrogen atoms on electron-rich C—H bonds. A recent study by our group shows that after thermal decomposition of peroxy tert-butyl ether, the electron-rich methyl radicals are produced. Then the radical cleavage of the C(sp 3)—H bond in ketone/ester would happen prior to the α-carbonyl-C—H bond. Subsequently, the electrophilic α-carbonyl-C-centered radical selectively reacted with electron-rich olefins to afford new C—C bonds. Here, a free-radical initiated highly selective cross dehydrogenative coupling reaction of simple ketones and esters with electron-rich heteroarenes was demonstrated. The ketones and esters were used as solvent, and they would afford the corresponding α-carbonyl C-centered radicals, which then add to heteroaromatics leading to a series of C(2)-functionalized heterocycles. The chemoselectivity of this system was well-controlled by application of the polar effect of free radicals. In addition, this protocol features fast, simple operation, good functional group tolerance and site specific etc. The potential of this method was demonstrated through the synthesis of non-steroidal anti-inflammatory and analgesic drug tolmetin. It is expected to have wide applications in synthetic organic chemistry. Typical reaction conditions are as follows: a mixture of heteroarenes (1 equiv., 0.20 mmol), TBPA (3 equiv., 0.06 mmol) and ketones/esters (6 mL) was heated under reflux at 130 ℃ for about 1 h. After completion of the reaction, the crude product was cooled to room temperature, the excess solvent was recovered by rotary evaporator and the residue was further purified by column chromatography on silica gel to obtain the desired product (eluent: petroleum ether/ethyl acetate).

Key words: free radical, C—H activation, ketone and ester, cross dehydrogenative coupling (CDC), electron-rich heteroarene