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

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-dim ethyl-1,3-dioxanyl group. The lithio anion was quenched with a variety of e lectrophiles such as alkyl halides, aldehydes, TMSCl, and Me3SnCl in good t o excellent yields. The lithiation of the unprotected compound and the 4-ac etyl group protected as 1,3-dioxolanyl both failed. The effects of differen t bases have been investigated and the addition of LiCl significantly incre ased yields. Based on variable temperature NMR studies the 5,5-dimethyl-1,3 -dioxanyl group appears to occupy a single chair conformation which may fac ilitate lateral metalation. This represents a facile entry into 5-functiona lized 3-isoxazolyl carboxylic acid derivatives as prodrugs for the AMPA glu tamate neurotransmitters of the central nervous system. (C) 2001 Elsevier S cience Ltd. All rights reserved.