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Synthesis of Multifunctionalized 1,2,3,4‐Tetrahydropyridines, 2,3‐Dihydropyridin‐4(1 H )‐ones, and Pyridines from Tandem Reactions Initiated by [5+1] Cycloaddition of N ‐Formylmethyl‐Substituted Enamides to Isocyanides: Mechanistic Insight and Synthetic Application
Author(s) -
Lei ChuanHu,
Wang DeXian,
Zhao Liang,
Zhu Jieping,
Wang MeiXiang
Publication year - 2013
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201303221
Subject(s) - chemistry , cycloaddition , aromatization , pyridine , imine , moiety , medicinal chemistry , acylation , cascade reaction , pyridinium , stereochemistry , combinatorial chemistry , organic chemistry , catalysis
Tandem reactions for the efficient synthesis of multifunctionalized 1,2,3,4‐tetrahydropyridines, 2,3‐dihydropyridin‐4(1 H )‐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 Me 4 NBH(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(1 H )‐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.