Metal-free decarboxylative hetero-Diels–Alder synthesis of 3-hydroxypyridines: a rapid access to N-fused bicyclic hydroxypiperidine scaffolds

J Org Chem. 2014 Feb 7;79(3):1303-19. doi: 10.1021/jo402729a.

Abstract

A complete experimental and theoretical study of the thermally controlled metal-free decarboxylative hetero-Diels–Alder (HDA) reaction of 5-alkoxyoxazoles with acrylic acid is reported. This strategy offers a new entry to valuable 2,6-difunctionalized 3-hydroxypyridines from readily available 2- and 4-disubstituted 5-alkoxyoxazoles. The reaction conditions proved compatible with, among others, ketone, amide, ester, ether, and nitrile groups. The broad functional group tolerance of the protocol allows a rapid and versatile access to both hydroxyindolizidine and hydroxyquinolizidine derivatives via a pyridine dearomatization strategy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cycloaddition Reaction
  • Indolizidines / chemical synthesis*
  • Indolizidines / chemistry
  • Metals / chemistry*
  • Molecular Structure
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyrimidines / chemistry*
  • Quinolizidines / chemical synthesis
  • Quinolizidines / chemistry
  • Stereoisomerism

Substances

  • Indolizidines
  • Metals
  • Piperidines
  • Pyridines
  • Pyrimidines
  • Quinolizidines
  • N-hydroxypiperidine
  • 3-hydroxypyridine