Synthesis of Multifunctionalized 1,2,3,4‐Tetrahydropyridines, 2,3‐Dihydropyridin‐4(1H)‐ones,and Pyridines from Tandem Reactions Initiated by [5+1] Cycloaddition of N‐Formylmethyl‐Substituted Enamides to Isocyanides: Mechanistic Insight and Synthetic Application |
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Authors: | Chuan‐Hu Lei Dr. De‐Xian Wang Dr. Liang Zhao Prof. Dr. Jieping Zhu Prof. Dr. Mei‐Xiang Wang |
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Affiliation: | 1. Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 (P.R. China);2. Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084 (P.R. China), Fax: (+86)?10‐6279‐6761;3. Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, EPFL‐SB‐ISIC‐LSPN, 1015 Lausanne (Switzerland) |
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Abstract: | Tandem reactions for the efficient synthesis of multifunctionalized 1,2,3,4‐tetrahydropyridines, 2,3‐dihydropyridin‐4(1H)‐ones, and pyridine derivatives have been developed and reaction mechanisms have been investigated. Synthetic cascades are initiated by the Zn(OTf)2‐mediated [5+1] cycloaddition of N‐formylmethyl‐substituted tertiary enamides to isocyanides, thus leading to the versatile heterocyclic enamino imine intermediates. Interception of the intermediates by diastereoselective reduction of imine functionality with Me4NBH(OAc)3 afforded 1,6‐disubstituted trans‐3‐hydroxy‐4‐arylamino‐ or ‐alkylamino‐1,2,3,4‐tetrahydropyridines, whereas acylation of the imino group followed by acidic hydrolysis produced 1,6‐disubstituted 3‐acyloxy‐2,3‐dihydropyridin‐4(1H)‐ones. Aerobic oxidation led to the aromatization followed by intermolecular acyl‐group transfer from the pyridinium nitrogen to the 3‐hydroxy moiety, thereby yielding substituted 3‐acyloxy‐4‐aminopyridines. Synthetic potentials of the resulting products have been demonstrated by expedient and highly stereoselective synthesis of cis,cis‐4,5‐dihydroxy‐2‐phenylpiperidine and trans,trans‐4‐amino‐5‐hydroxy‐2‐phenylpiperidine compounds, which are important in medicinal chemistry, through simple and practical reduction reactions. |
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Keywords: | cyanides cycloaddition enamides heterocycles reaction mechanisms |
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