An Efficient Diastereoselective Synthesis of Chiral Oxazolinylferrocene Compounds

Abstract

Chiral oxazolinylferrocenes 7 and 8 are synthesized from ethyl ferrocenecarboxylate and amino acid-derived amino alcohols in overall 81−85% yields, through trimethylaluminum-mediated transamidation followed by ring formation with p-toluenesulfonyl chloride and triethylamine. Lithiation of the oxazolinylferrocenes under various reaction conditions and subsequent coupling reactions with electrophiles such as ClPPh2, ClSnBu3, ClSiMe3, PhSSPh, DMF, and CO2 are described. Lithiated intermediates are found to have limited stability, depending on the solvent and the temperature. In THF, the lithiated intermediate rapidly decomposes at 25 °C: In Et2O, it is quite stable at 0 °C but mostly decomposes at 25 °C within 6 h. Lithiation of the oxazolinylferrocenes is directed by the oxazoline moiety and is highly diastereoselective in the case of 8. With s-BuLi in THF−cyclohexane, several ferrocene derivatives 11 are produced with diastereoselectivities of ≥96:4. s-BuLi and n-BuLi give better selectivities and yields than t-BuLi. With s-BuLi, generally better diastereoselectivities are obtained in THF−cyclohexane than in Et2O−cyclohexanes. When ClPPh2 is used as the electrophile, the s-BuLi in THF−cyclohexane system, however, gives variable yields depending on reaction temperature and time. With n-BuLi in Et2O−hexanes at 25 °C, phosphino(oxazolinyl)ferrocene 11a is consistently obtained in moderate yields with a 97:3 diastereoselectivity. Determination of the diastereoselectivity and characterization of new chiral ferrocene compounds including one X-ray crystal structure are described.