Acta Chimica Sinica ›› 2019, Vol. 77 ›› Issue (12): 1263-1267.DOI: 10.6023/A19090325 Previous Articles     Next Articles

Communication

由芳基卤化物、芳基硼酸和芳烃一锅法合成单氟甲氧基芳烃

赵小淳, 丁天琪, 蒋绿齐, 易文斌   

  1. 南京理工大学化工学院 南京 210094
  • 投稿日期:2019-09-03 发布日期:2020-01-07
  • 通讯作者: 易文斌 E-mail:yiwb@njust.edu.cn
  • 基金资助:
    项目受国家自然科学基金(Nos.21776138,21476116)、中央高校基本科研专项资金(Nos.30916011102,30918011314)、江苏省自然科学基金(No.BK20180476)、青蓝工程、六大人才高峰以及江苏高校优势学科建设工程资助.

One-Pot Synthesis of Monofluoromethoxy Arenes from Aryl Halides, Arylboronic Acids and Arenes

Zhao Xiaochun, Ding Tianqi, Jiang Lüqi, Yi Wenbin   

  1. Chemical Enginering College, Nanjing University of Science and Technology, Nanjing 210094
  • Received:2019-09-03 Published:2020-01-07
  • Supported by:
    Project supported by the National Natural Science Foundation of China (Nos. 21776138, 21476116), the Fundamental Research Funds for the Central Universities (Nos. 30916011102, 30918011314), the Natural Science Foundation of Jiangsu Province (No. BK20180476), the Qing Lan and Six Talent Peaks in Jiangsu Province and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Fluorine-containing compounds have been widely used in the fields of pharmaceuticals, agrochemicals and functional materials, mainly due to the well-known "fluorine effect" of the fluoroalkyl groups on the physical, chemical and biological properties of molecules. Tri- and difluoromethyl ethers play an important role in many medicinally compounds. Among various fluorinated moieties, ORf-containing groups have attracted much more attention very recently owing to the impressive conformational changes and maximal shifts in electron distribution brought by fluorine. The α-fluorine substitution of ethers shortens and strengthens the C-O bond and thus improves the in vivo oxidative stability of the ether moiety of a drug. Over the past few decades, there are some reliable ways on accessing trifluoromethyl ethers and difluomethyl ethers. Considering the importance of synthesis of monofluoromethoxy arenes and the substrate limitation (phenols or alcohols) of current state, a method was developed to access monofluoromethoxy arenes from aryl halides, arylboronic acids and arenes via a one-pot synthesis. Phenols can be prepared by the hydroxylation of aryl halides catalyzed by transition-metal complexes. In this work, a new strategy was envisioned a two-step sequence for the conversion of aryl halides to monofluoromethoxy arenes based on the palladium-catalyzed conversion of aryl phenols and in situ conversion of the resulting phenoxides with monofluoromethylating reagents. The investigation began with optimization of the conversion of 1-chloro-4-methoxy-benzene. The approach was achieved by using Pd2(dba)3 (2 mol%) as the catalyst under an inert atmosphere, di-tert-bu-tyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (8 mol%) as the ligand, KOH (1 equiv.) as the nucleophile, and 1,4-dioxane/H2O (V:V=5:3) as the solvent. Further monofluoromethylation used fluoromethyl iodide (2 equiv.) as the monofluoromethylating reagent and CH3CN as the co-solvent. Finally, the desired product was obtained in 82% yield. Therefore, this method was also applied to drugs, for example, Loratadine could be converted to the corresponding product (2o) in 53% yield and Fenofibrate, reacting to form the monofluoromethoxy arenes (2p) in modest yield. One-pot method to access aryl monofluoromethyl ethers from arylboronic acids and arenes were also under consideration and the yields were objective.

Key words: monofluoromethoxy arene, aryl halide, arylboronic acid, arene, late-stage