title: 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.
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.
authors.affiliation: 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).
authors.forename: Chuan-Hu
authors.initials: CH
authors.lastname: Lei
authors.forename: De-Xian
authors.initials: DX
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.forename: Jieping
authors.initials: J
authors.lastname: Zhu
authors.forename: Mei-Xiang
authors.initials: MX
authors.lastname: Wang
mesh_terms: D003486:Cyanides / Q000138:chemical synthesis* / Q000737:chemistry*; D061565:Cycloaddition Reaction; D008698:Mesylates / Q000737:chemistry*; D010084:Oxidation-Reduction; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry*; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry*
chemical_list: C000590001:4,5-dihydroxy-2-phenylpyridine; D003486:Cyanides; D008698:Mesylates; D011725:Pyridines; D011728:Pyridones; D015032:Zinc; C023666:pyridine
keywords: cyanides; cycloaddition; enamides; heterocycles; reaction mechanisms