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Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol SynthesisA Caveat on Reaction Times and Product Isolation

Duangdee, Nongnaphat, Harnying, Wacharee, Rulli, Giuseppe, Neudörfl, Jörg-M., Gröger, Harald, Berkessel, Albrecht
Journal of the American Chemical Society 2012 v.134 no.27 pp. 11196-11205
X-radiation, X-ray diffraction, acids, alcohols, ammonium chloride, catalysts, enantiomers, high performance liquid chromatography, monitoring, solvents
Aldol reactions with trifluoroacetophenones as acceptors yield chiral α-aryl, α-trifluoromethyl tertiary alcohols, valuable intermediates in organic synthesis. Of the various organocatalysts examined, Singh’s catalyst [(2S)-N-[(1S)-1-hydroxydiphenylmethyl-3-methylbutyl]-2-pyrrolidinecarboxamide] was found to efficiently promote this organocatalytic transformation in a highly enantioselective manner. Detailed reaction monitoring (¹⁹F-NMR, HPLC) showed that, up to full conversion, the catalytic transformation proceeds under kinetic control and affords up to 95% ee in a time-independent manner. At longer reaction times, the catalyst effects racemization. For the product aldols, even weak acids (such as ammonium chloride) or protic solvents, can induce racemization, too. Thus, acid-free workup, at carefully chosen reaction time, is crucial for the isolation of the aldols in high (and stable) enantiomeric purity. As evidenced by ¹⁹F-NMR, X-ray structural analysis, and independent synthesis of a stable intramolecular variant, Singh’s catalyst reversibly forms a catalytically inactive (“parasitic”) intermediate, namely a N,O-hemiacetal with trifluoroacetophenones. X-ray crystallography also allowed the determination of the product aldols’ absolute configuration (S).