Acta Chimica Sinica ›› 2012, Vol. 70 ›› Issue (18): 1917-1922.DOI: 10.6023/A12080542 Previous Articles     Next Articles



肖开炯, 黄应红, 黄培强   

  1. 化学生物学福建省重点实验室 厦门大学化学化工学院化学系 厦门 361005
  • 投稿日期:2012-08-11 发布日期:2012-08-31
  • 通讯作者: 黄培强
  • 基金资助:

    项目受国家重点基础研究发展计划(973 计划)(No. 2010CB833200)、国家自然科学基金(Nos. 21072160, 20832005)和教育部博士研究生学术新人奖(2010)资助.

General Direct Transformation of Secondary Amides to Ketones via Amide Activation

Xiao Kaijiong, Huang Yinghong, Huang Peiqiang   

  1. Fujian Provincial Key Laboratory of Chemical Biology, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005
  • Received:2012-08-11 Published:2012-08-31
  • Supported by:

    Supporting information for this article is available free of charge via the Internet at Project supported by the National Basic Research Program (973 Program) of China (No. 2010CB833200), the National Natural Science Foundation of China (Nos. 21072160, 20832005), and a Scholarship Award for Excellent Doctoral Student granted by Ministry of Education of China (2010).

Carbon-carbon bond formation and functional group transformation are two cornerstones of organic synthesis. Generally, most of the established methods involve the transformation of a more reactive molecule to a more stable one, while the inverse transformation from a more stable molecule to a more reactive one is challenging. Secondary amides are a class of quite stable compounds, and ketones are a class of extremely versatile compounds enabling a number of fundamental transformations. The direct transformation of secondary amides into ketones is of high relevance in organic synthesis. Nonetheless, no such method has been reported when this work was disclosed. Here, we report in detail the general direct transformation of secondary amides into ketones by Tf2O-mediated deaminative alkylation with organocerium reagents. The influence of the base additive and the organometallic reagent on this transformation was investigated. It was found that 2-fluoropyridine gave the best results of the bases screened, and both organocerium reagents (RCeCl2) generated in situ from RLi and CeCl3 and cerium complexes generated in situ from RMgX and CeCl3 are superior to organomagnesium, organolithium and organozinc reagents. The optimum reaction condition was thus determined as successive treatment of a dichloromethane (0.25 mol/L) solution of secondary amide (1.0 equiv.) and 2-fluoropyridine (1.2 equiv.) with 1.1 molar equivalents of Tf2O (-78℃, then 0℃), and 3.0 molar equivalents of RM/CeCl3 (-78℃), followed by hydrolysis with 2 mol/L aqueous HCl solution. This protocol shows wide substrate applicability. Using the developed method, a variety of ketones including alkyl-alkyl ketones, alkyl-aryl ketones, aryl-aryl ketones, α,β-unsaturated ketones, and β-chloroenones have been synthesized in 65%~90% yields. It should be noted that the reaction of α,β-unsaturated amides led to a highly selective 1,2-addition and the use of alkynyl cerium reagents generated from lithium acetylides yielded β-chloroenones. Moreover, weakly basic alkynylborane reagents and allyltrimethyl silane, and even weakly nucleophilic styrene can also be applied as nucleophiles for the deaminative alkylation of secondary amides. On the basis of the experimental results, a plausible mechanism involving nitrilium ion intermediate and ketimine is proposed. As one significance of these transformations, secondary amides successfully serve as effective acylating reagents in the intermolecular reactions with organometallic reagents, allyltrimethyl silane and styrene (reductive acylation).

Key words: secondary amides, ketones, organocerium reagents, molecular activation, C-C bond formation, reductive acylation