Synthesis of 2,4-Disubstituted Piperidines via Radical Cyclization:  Unexpected Enhancement in Diastereoselectivity with Tris(trimethylsilyl)silane

Lucile A. Gandon, Alexander G. Russell, Tatyana Güveli, Angela E. Brodwolf, Benson M. Kariuki, Neil Spencer, and John S. Snaith*
School of Chemistry, The University of Birmingham, Edgbaston, Birmingham, B15 2TT, U.K.
J. Org. Chem., 2006, 71 (14), pp 5198–5207
DOI: 10.1021/jo060495w
Publication Date (Web): June 13, 2006
Copyright © 2006 American Chemical Society
*

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, j.s.snaith@bham.ac.uk

Abstract

Abstract Image

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.

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History

  • Published In Issue July 07, 2006
  • Received March 7, 2006

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