Proton Transfer Can Govern Regioselectivity Assisted by Iron Catalysis
Yudong Li,
Liyan Fu,
Xiaolin Jiang,
Dongmei Zhao,
Hui-Fang Wang,
Chungu Xia,
Yuehui Li
Affiliations
Yudong Li
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Center for Excellence in Molecular Synthesis, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P. R. China
Liyan Fu
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Center for Excellence in Molecular Synthesis, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P.R. China
Xiaolin Jiang
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Center for Excellence in Molecular Synthesis, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P.R. China; Shenyang Pharmaceutical University, Shenyang 110016, P.R. China
Dongmei Zhao
Shenyang Pharmaceutical University, Shenyang 110016, P.R. China
Hui-Fang Wang
State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P.R. China; Corresponding author
Chungu Xia
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Center for Excellence in Molecular Synthesis, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P.R. China; Corresponding author
Yuehui Li
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Center for Excellence in Molecular Synthesis, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P.R. China; Corresponding author
Summary: Ortho-selective aromatic C-H functionalization is frequently used in organic synthesis and chemical/pharmaceutical industries. However, this reaction relies heavily on the use of directing groups suffering from limited substrate scope and extra steps to put on and remove the directing/protecting groups. Herein we present the previously neglected concept that enables good to nearly complete selective ortho position. Proton transfer was utilized to tune the electron density on the aryl ring and determine the positional selectivity of electrophilic substitution. Consistently with deuteration experiments and DFT studies, this work demonstrates that acid-promoted proton transfer directs accelerated ortho-selective halogenation of NH/OH contained aromatic amines/phenols with excellent selectivity (>40 examples; up to 98:2 ortho/para selectivity). The application potential of this Fe-catalyzed method is demonstrated by the convenient synthesis of three alkaloids and tizanidine. This report raises the possibility that proton transfer could serve as the basis of developing new selective C-H functionalization reactions.
