Synthesis of 2,4-disubstituted piperidines via radical cyclization: unexpected enhancement in diastereoselectivity with tris(trimethylsilyl)silane

J Org Chem. 2006 Jul 7;71(14):5198-207. doi: 10.1021/jo060495w.

Abstract

A novel approach to 2,4-disubstituted piperidines is reported, involving the radical cyclization of 7-substituted-6-aza-8-bromooct-2-enoates. Cyclization with tributyltin hydride affords the trans piperidines with trans/cis diastereomeric ratios ranging typically from 3:1 to 6:1. Cyclization with tris(trimethylsilyl)silane affords the same products with diastereomeric ratios of up to 99:1 in certain cases. The enhancement in diastereoselectivity results from the selective rearrangement of the minor stereoisomer through a cascade process involving radical cyclization to the piperidine radical, 1,5-radical translocation, and attack of the translocated radical onto the sulfonamide with extrusion of SO2 in a Smiles-type rearrangement. Slower trapping of the piperidine radical by tris(trimethylsilyl)silane compared to tributyltin hydride accounts for the occurrence of the rearrangement cascade in the former case.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclization
  • Free Radicals / chemical synthesis
  • Free Radicals / chemistry
  • Molecular Structure
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Silanes / chemistry*
  • Stereoisomerism

Substances

  • Free Radicals
  • Piperidines
  • Silanes
  • tris(trimethylsilyl)silane