Synthesis of α- and β-branched ethers from alcohols by reaction of acetals with grignard reagents: synthesis of isopropyl and isobutyl ethers of (1S*,2R*S*,4R*)-6-methylenebicyclo[2.2.2]octan-2-ol

Abstract

Non-symmetrical acetals have been combined with Grignard reagents in toluene at reflux to generate α-and β-branched ethers in moderate to high yields. The synthesis of isopropyl and isobutyl ethers of the bicyclic alcohol 1 was accomplished using this methodology, although reactions in the syn-series were complicated by the formation of tricyclic products by an intramolecular cyclisation. The scope and limitations of the ether-forming reactions were explored with a series of acetals derived from primary, secondary and tertiary alcohols. The halide component of the Grignard reagent and the solvent were found to be an important factor in facilitating these reactions.