Development of a [3+3] cycloaddition strategy toward functionalized piperidines

J Org Chem. 2003 May 30;68(11):4286-92. doi: 10.1021/jo030002c.

Abstract

This paper describes a novel route to functionalized piperidines via a formal [3+3] cycloaddition reaction of activated aziridines and palladium-trimethylenemethane (Pd-TMM) complexes. The cycloaddition reaction generally proceeds enantiospecifically with ring opening at the least hindered site of the aziridine. Therefore, readily available enantiomerically pure 2-substituted aziridines can be utilized to prepare enantiomerically pure 2-substituted piperidines in good to excellent yield. The N-substituent on the aziridine proved to be crucial to the success of this reaction with only 4-toluenesulfonyl (Ts) and 4-methoxybenzenesulfonyl (PMBS) aziridines permitting smooth cycloaddition to take place. Additionally, spirocyclic aziridines have been found to participate in the [3+3] cycloaddition reaction, whereas 2,3-disubstituted aziridines can be applied to provide fused bicyclic piperidines, albeit in low yield.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aziridines / chemistry
  • Catalysis
  • Combinatorial Chemistry Techniques*
  • Cyclization
  • Indicators and Reagents
  • Molecular Structure
  • Palladium / chemistry
  • Piperidines / analysis
  • Piperidines / chemical synthesis*

Substances

  • Aziridines
  • Indicators and Reagents
  • Piperidines
  • Palladium