Fluoro- or Trifluoromethyl-Substituted Benzyl and Phenethyl Alcohols: Substrates for Metal-Mediated Site-Selective Functionalization

Abstract

It was possible to functionalize the three fluorobenzyl alcohols and the three 2-(fluorophenyl)ethanols by metalation and subsequent carboxylation, the prototype electrophilic trapping reaction. Triisopropylsilyl (TIPS) outperformed methoxymethyl (MOM) as an O-protective group making seven new fluorobenzoic acids accessible in 63% average yield. Moreover, the TIPS group tolerates weakly basic and acidic media and, therefore, may facilitate further structural elaboration. The unprotected alcohols reacted more sluggishly and were unable to provide two of the targeted products (acids 1 and 2). The yield averaged only 46% in the five other cases (acids 3−7). The direct metalation of fluorinated benzyl and phenethyl alcohols remains nevertheless an attractive option because of its operational simplicity. All three (trifluoromethyl)benzyl alcohols and two of the three (trifluoromethyl)phenethyl alcohol isomers were successfully submitted to the metalation/functionalization sequence. These five starting materials gave rise to a total of nine new benzoic acids or lactones (compounds 8−14 and 17−18). Despite the poor yields (31% on average), the organometallic methods employed are, in general, extremely selective, economical and easy to perform. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)