Development of tough S_N2 reactions at the α-carbon to trifluoromethyl group

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Intramolecular S_N2 reactions of α-trifluoromethylated secondary alcohols and utilization of them to preparations of fluorinated amino acids have been studied.2-Trifluoromethyl aziridines are synthesized from N-alkyl-3,3,3-trifluoro-2-hydroxypropylamine with triphenylphosphine-tetrachloromethane or dichlorotriphenyl-phosphorane. Similarly, 2-trifluoromethylated pyrroridines was prepared. A stereoselective intramolecular cyclization of 3-substituted-3-cyano-l-trifluoromefliylpropyl sulfonate via the cyano stabilized carbanion provides l-substituted-1-cyano-2-trifluoromefliylcyclopropanes in good yields. The stereochemistry of the product at the carbon attached to trifluoromethyl group was completely inverted its configuration from the starting alcohol, revealing the reaction underwent in S_N2 manner with Walden inversion at the reaction center. Intramolecular electrostatic repulsions between the local negative charge on a trifluoromethyl group and that on ortho positions of aryl moiety of nucleophile was found to be a controlling factor of the diastereoselectivity in the cyclopropanation. The reaction was applied for syntheses of optically active trifluoro-norcoronamic acid and its diastereomer.