Highly enantioselective organocatalytic trifluoromethyl carbinol synthesis--a caveat on reaction times and product isolation.
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 ((19)F-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 (19)F-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).
Department of Chemistry (Organic Chemistry), University of Cologne, Greinstrasse 4, 50939 Cologne, Germany.
Nongnaphat
N
Duangdee
Wacharee
W
Harnying
Giuseppe
G
Rulli
Jörg-M
JM
Neudörfl
Harald
H
Gröger
Albrecht
A
Berkessel
D000096:Acetone / Q000138:chemical synthesis / Q000737:chemistry; D000098:Acetophenones / Q000138:chemical synthesis / Q000737:chemistry*; D000447:Aldehydes / Q000138:chemical synthesis / Q000737:chemistry*; D002384:Catalysis; D018360:Crystallography, X-Ray; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D000432:Methanol / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D013237:Stereoisomerism
D000098:Acetophenones; D000447:Aldehydes; D006845:Hydrocarbons, Fluorinated; D000096:Acetone; C116609:3-hydroxybutanal; D000432:Methanol