Synthesis of methyl 3-bromomethylbut-3-enoate and its reactions with aldehydes and tributylchlorostannane in the presence of zinc

Abstract

Methyl 3-bromomethylbut-3-enoate smoothly reacted with prenal, β-ionylideneacetaldehyde, benzyloxyacetaldehyde, and tributylchlorostannane in the presence of zinc and aqueous ammonium chloride in tetrahydrofuran to give the corresponding δ-hydroxy-β-methylidenecarboxylic acid esters. In the absence of ammonium chloride, satisfactory yields of the products were obtained only in the reactions with prenal and benzyloxyacetaldehyde; these reactions involved lactonization of intermediate δ-hydroxy-β-methylidenecarboxylic acid esters, and the double carbon-carbon bond migrated to the conjugated position with the lactone carbonyl group. The condensation of β-ionylideneacetaldehyde with methyl 3-bromomethylbut-3-enoate was successfully used to obtain isotretinoin. Initial methyl 3-bromomethylbut-3-enoate was synthesized in a good yield from readily accessible ethyl 3,3-diethoxypropionate via cyclopropanation with ethylmagnesium bromide in the presence of titanium tetra(isopropoxide), oxidation of the acetal moiety to ester, and cleavage of the cyclopropane ring in intermediate methyl (1-methylsulfonyloxycyclopropyl)acetate.