化学学报 ›› 2019, Vol. 77 ›› Issue (9): 879-883.DOI: 10.6023/A19050193 上一篇    下一篇

所属专题: 有机自由基化学

研究通讯

通过自由基串联环化反应合成4-喹诺酮类化合物

钱向阳, 熊鹏, 徐海超*()   

  1. 厦门大学化学化工学院 厦门 361005
  • 收稿日期:2019-05-25 出版日期:2019-09-15 发布日期:2019-07-01
  • 通讯作者: 徐海超 E-mail:haichao.xu@xmu.edu.cn
  • 基金资助:
    项目受国家自然科学基金(No. 21672178);中央高校科研业务费资助

Modular Synthesis of Functionalized 4-Quinolones via a Radical Cyclization Cascade Reaction

Qian, Xiangyang, Xiong, Peng, Xu, Hai-Chao*()   

  1. College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005
  • Received:2019-05-25 Online:2019-09-15 Published:2019-07-01
  • Contact: Xu, Hai-Chao E-mail:haichao.xu@xmu.edu.cn
  • Supported by:
    Project supported by the National Natural Science Foundation of China(No. 21672178);Fundamental Research Funds for the Central Universities

4-喹诺酮结构广泛存在于天然产物和药物分子中. 本工作以易得的N-芳基-O-炔丙基氨基甲酸酯为原料, CO为羰基源, 发展了一种高效、模块化合成4-喹诺酮结构的方法. 氨基甲酸酯底物经2-碘酰基苯甲酸(IBX)氧化产生酰胺氮自由基, 进而发生自由基串联环化反应得到4-喹诺酮结构.

关键词: 自由基, 环化, 4-喹诺酮, 氧化

4-Quinolones are structural motifs prevalent in natural products and biologically active compounds. However, it remains challenging to synthesize 4-quinolones that bears diverse substituents at 2- and 3-positions. Herein we report an efficient and modular method for the synthesis of 4-quinolones from easily available N-aryl-O-propargyl carbamates and CO. The reactions employ 2-iodoxybenzoic acid (IBX) as an oxidant to oxidize the N-H group of the carbamate to generate an amide radical, which undergoes radical cyclization cascade with CO to afford the 4-quinolone product. The reactions provide speedy access to a series of 2,3-disubstituted 4-quinolones by varying the substituents of the carbamate substrate. Late stage functionalization employing Ni-catalysis allows the conversion of an OMe group on the 4-quinonone benzene ring to alkyl substituents, further increasing the diversity of the 4-quinone product. The synthetic potential is further demonstrated by running the synthesis on gram scale and by preparation of an enantiomerically enriched 4-quinolone product. The typical procedure is detailed as follows: A magnetic stirring bar, the carbamate substrate (0.25 mmol), IBX (1.0 mmol), and anhydrous dimethyl sulfoxide (DMSO, 10 mL) were placed in a 50 mL stainless steel autoclave. The autoclave was sealed, vacuumed and purged five times with CO, and finally pressurized with 10 MPa of CO. The reaction vessel was heated at 90 ℃ for 12 h and then cooled to r.t.. Excess CO was released in a fume hood. The reaction mixture was diluted with ethyl acetate (20 mL) and 5% NaHCO3 (15 mL). The phases were separated. The aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic solution was washed with 5% NaHCO3 (20 mL) and brine (20 mL). The organic solution was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel eluting with ethyl acetate/hexanes to give the desired product.

Key words: radical, cyclization, 4-quinolone, oxidation