仲酰胺经酰胺活化直接合成酮的普适性方法

doi:10.6023/A12080542

摘要/Abstract

本文报道仲酰胺经去胺基烷基化反应直接合成酮的通用性方法. 这一新的C-C 键形成方法是基于Tf₂O 对仲酰胺的活化及有机铈试剂对活化所形成活性中间体的加成而实现的. 该方法可用于各种酮的合成, 包括烷基-烷基酮、烷基-芳基酮、芳基-芳基酮、α,β-不饱和酮以及β-氯-α,β-不饱和酮等, 收率65%～90%. 研究表明, 除了有机铈试剂外, 碱性较弱的炔基硼试剂、温和亲核性的烯丙基三甲基硅烷以及低亲核性的苯乙烯均可与仲酰胺的活化中间体进行加成反应, 水解后生成相应的酮. 因此, 该方法具有较好的普适性和重要的合成应用价值. 基于实验结果和验证实验, 提出经由腈鎓中间体的可能反应机理. 本法使仲酰胺成为形式上的酰化试剂, 不但可与有机金属试剂反应, 还可与烯丙基三甲基硅烷和苯乙烯进行还原酰化反应.

关键词: 仲酰胺, 酮, 有机铈试剂, 分子活化, C-C 键形成, 还原酰化

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

引用此文

肖开炯, 黄应红, 黄培强. 仲酰胺经酰胺活化直接合成酮的普适性方法[J]. 化学学报, 2012, 70(18): 1917-1922.

Xiao Kaijiong, Huang Yinghong, Huang Peiqiang. General Direct Transformation of Secondary Amides to Ketones via Amide Activation[J]. Acta Chimica Sinica, 2012, 70(18): 1917-1922.

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