Catalytic Diastereo- and Enantioselective Synthesis of Tertiary Trifluoromethyl Carbinols through a Vinylogous Aldol Reaction of Alkylidenepyrazolones with Trifluoromethyl Ketones

A diastereo- and
enantioselective organocatalytic aldol reaction
between alkylidenepyrazolones and trifluoromethyl ketones leading
to chiral tertiary alcohols bearing a trifluoromethyl group is presented.
The methodology is based on the use of a bifunctional organocatalyst
in order to activate the γ-hydrogen atoms of the alkylidenepyrazolone
nucleophile and the carbonyl group of the trifluoromethylarylketone
providing highly functionalized trifluoromethyl alcohols with moderate
yields, excellent diastereoselectivity, and moderate to good enantioselectivity.
Experiments monitoring the conversion by 1H NMR and the
enantiomeric excess by HPLC with the reaction time showed that full
conversion of the starting materials is not achieved and that the
enantiomeric excess decreases upon extended times, probably due to
the reversibility of the reaction.