An improved procedure for the lateral lithiation of ethyl 4-acetyl-5-methyl-3-isoxazolyl carboxylate

David J. Burkhart, Peiwen Zhou, Alex Blumenfeld, Brendan Twamley, Nicholas R. Natale

Research output: Contribution to journalArticlepeer-review

Abstract

Ethyl 4-acetyl-5-methyl-3-isoxazolyl carboxylate was smoothly lithiated at the 5-methyl position, when the 4-acetyl group was protected with a 5,5-dimethyl-1,3-dioxanyl group. The lithio anion was quenched with a variety of electrophiles such as alkyl halides, aldehydes, TMSCl, and Me3SnCl in good to excellent yields. The lithiation of the unprotected compound and the 4-acetyl group protected as 1,3-dioxolanyl both failed. The effects of different bases have been investigated and the addition of LiCl significantly increased yields. Based on variable temperature NMR studies the 5,5-dimethyl-1,3-dioxanyl group appears to occupy a single chair conformation which may facilitate lateral metalation. This represents a facile entry into 5-functionalized 3-isoxazolyl carboxylic acid derivatives as prodrugs for the AMPA glutamate neurotransmitters of the central nervous system.

Original languageEnglish
Pages (from-to)8039-8046
Number of pages8
JournalTetrahedron
Volume57
Issue number38
DOIs
StatePublished - Sep 17 2001

Keywords

  • AMPA
  • Isoxazole
  • Lateral lithiation

Fingerprint

Dive into the research topics of 'An improved procedure for the lateral lithiation of ethyl 4-acetyl-5-methyl-3-isoxazolyl carboxylate'. Together they form a unique fingerprint.

Cite this