Intramolecular cyclization manifolds of 4-alkylpyridines bearing ambiphilic side chains: construction of spirodihydropyridines or benzylic cyclization via anhydrobase intermediates

J Org Chem. 2012 Sep 21;77(18):8038-48. doi: 10.1021/jo301247c. Epub 2012 Sep 13.

Abstract

4-Alkylpyridines possessing nucleophilic β-dicarbonyl side chains have been converted to spirodihydropyridines upon treatment with ethyl chloroformate and sub-stoichiometric amounts of Ti(O(i)Pr)(4). Alternatively, inclusion of mild base in the reaction medium was found to facilitate generation of anhydrobase intermediates. Subsequent aldol-like condensations with electrophilic side chain moieties followed by hydrolysis delivered benzylically cyclized pyridines in good yield. In situ hydrogenation of cyclized anhydrobase intermediates afforded 4-substituted piperidines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclization
  • Hydrogenation
  • Hydrolysis
  • Molecular Structure
  • Organometallic Compounds / chemistry*
  • Pyridines / chemistry*
  • Spiro Compounds / chemistry*
  • Stereoisomerism
  • Titanium / chemistry*

Substances

  • Organometallic Compounds
  • Pyridines
  • Spiro Compounds
  • Titanium