Preparation of α,n-dilithiotoluene equivalents. Synthesis of tamoxifen

The successive reaction of chlorobenzyl alcohols with n-butyllithium and lithium powder in the presence of a substoichiometric amount of 4,4′-di-tert-butylbiphenyl (DTBB) at −78°C yields the expected (lithiooxymethyl)phenyllithium derivative, which is trapped by reaction with different ketones. The subsequent arene-catalysed lithiation at 25°C permits the one-pot chemoselective lithiation of the primary benzyl alcoholate in the presence of a tertiary one. These new functionalised benzyllithium derivatives react with different electrophilic compounds, such as aldehydes, ketones and chlorotrimethylsilane, to give after hydrolysis the expected functionalised benzyl alcohols. Some of these alcohols are successfully transformed into mono- or di-olefins by acidic treatment. This whole strategy is applied to the preparation of anti-cancer drug tamoxifen.