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

Duangdee N, Harnying W, Rulli G, Neudoerfl J-M, Gröger H, Berkessel A (2012)
Journal of the American Chemical Society 134(27): 11196-11205.

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Abstract
Aldol reactions with trifluoroacetophenones as acceptors yield chiral alpha-aryl, alpha-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 (F-19-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 F-19-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).
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Duangdee N, Harnying W, Rulli G, Neudoerfl J-M, Gröger H, Berkessel A. Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol Synthesis-A Caveat on Reaction Times and Product Isolation. Journal of the American Chemical Society. 2012;134(27):11196-11205.
Duangdee, N., Harnying, W., Rulli, G., Neudoerfl, J. - M., Gröger, H., & Berkessel, A. (2012). Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol Synthesis-A Caveat on Reaction Times and Product Isolation. Journal of the American Chemical Society, 134(27), 11196-11205.
Duangdee, N., Harnying, W., Rulli, G., Neudoerfl, J. - M., Gröger, H., and Berkessel, A. (2012). Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol Synthesis-A Caveat on Reaction Times and Product Isolation. Journal of the American Chemical Society 134, 11196-11205.
Duangdee, N., et al., 2012. Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol Synthesis-A Caveat on Reaction Times and Product Isolation. Journal of the American Chemical Society, 134(27), p 11196-11205.
N. Duangdee, et al., “Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol Synthesis-A Caveat on Reaction Times and Product Isolation”, Journal of the American Chemical Society, vol. 134, 2012, pp. 11196-11205.
Duangdee, N., Harnying, W., Rulli, G., Neudoerfl, J.-M., Gröger, H., Berkessel, A.: Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol Synthesis-A Caveat on Reaction Times and Product Isolation. Journal of the American Chemical Society. 134, 11196-11205 (2012).
Duangdee, Nongnaphat, Harnying, Wacharee, Rulli, Giuseppe, Neudoerfl, Joerg-M., Gröger, Harald, and Berkessel, Albrecht. “Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol Synthesis-A Caveat on Reaction Times and Product Isolation”. Journal of the American Chemical Society 134.27 (2012): 11196-11205.
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PMID: 22631871
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