Lithium Malonate Enolates as Precursors for Radical Reactions − Convenient Induction of Radical Cyclizations with either Radical or Cationic Termination

Abstract

Lithium malonate enolates 4 or 13 are oxidized to the corresponding radicals by ferrocenium hexafluorophosphate (1) or CuCl2 (2). Trapping by TEMPO (5) to produce 6, dimerization to 7, or radical 5-exo cyclizations are possible subsequent reaction steps following radical generation. The structure of the radical cyclization acceptor determines the outcome of the overall reaction sequence. Tertiary benzylic, alkyl, and α-alkoxy radicals are oxidized by 1. The carbenium ions are stabilized by nucleophilic trapping or deprotonation to give compounds 14 and 18. Secondary alkyl and vinyl radicals are not oxidized and, in the absence of trapping reagents, form radical-derived products. Radical 5-exo cyclization of 13 induced by CuCl2 (2) was also efficient. At least for alkyl radicals, however, ligand transfer is the exclusive stabilization pathway, giving access to chloroalkylcyclopentane derivatives 21. Radical scavenging studies revealed that malonyl radical trapping is slow, so that 5-exo cyclizations occurred. The cyclized radicals couple with TEMPO (5) to afford oxygenated cyclopentane derivatives 31, depending on the rate of radical SET oxidation. The reaction behavior of compounds 14, 22, 23, and 31 was investigated. Mechanistic issues are discussed and implications for synthetic planning are given.