title: Regioselectivity and Mechanism of Synthesizing N-Substituted 2-Pyridones and 2-Substituted Pyridines via Metal-Free C-O and C-N Bond-Cleaving of Oxazoline[3,2-a]pyridiniums.
abstract: Novel intermediate oxazoline[3,2-a]pyridiniums were facilely prepared from 2-(2,2-dimethoxyethoxy)-pyridines via acid promoted intramolecular cyclization. Sequentially, the quaternary ammonium salts were treated with different nucleophiles for performing regioselective metal-free C-O and C-N bond-cleaving to afford prevalent heterocyclic structures of N-substituted pyridones and 2-substituted pyridines. The reaction mechanism and regioselectivity were then systematically explored by quantum chemistry calculations at B3LYP/6-31 g(d) level. The calculated free energy barrier of the reactions revealed that aniline and aliphatic amines (e.g., methylamine) prefer to attack C8 of intermediate 4a, affording N-substituted pyridones, while phenylmethanamine, 2-phenylethan-1-amine and 3-phenylpropan-1-amine favor to attack C2 of the intermediate to form 2-substituted pyridines. With the optimized geometries of the transition states, we found that the aromatic ring of the phenyl aliphatic amines may form cation-π interaction with the pyridinium of the intermediates, which could stabilize the transition states and facilitate the formation of 2-substituted pyridines.
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.|State Key Laboratory of Natural and Biomimetic Drugs, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: College of Chemistry and Environmental Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210097, China.
authors.forename: Susu
authors.initials: S
authors.lastname: Xue
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.|University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Nano Science and Technology Institute, University of Science and Technology of China, 166 Renai Road, Suzhou, 215123, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Feng
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhu
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Xu
authors.affiliation: UCB Biopharma SPRL, Chemin du Foriest, Braine-l'Alleud, Belgium.
authors.forename: Adrian
authors.initials: A
authors.lastname: Hall
authors.affiliation: College of Chemistry and Environmental Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210097, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.affiliation: UCB Biopharma SPRL, Chemin du Foriest, Braine-l'Alleud, Belgium.|Kellogg College, University of Oxford, 60-62 Banbury Road, Oxford, OX2 6PN, United Kingdom.
authors.forename: Jiye
authors.initials: J
authors.lastname: Shi
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.|University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu