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

A diastereo- and enantioselective organocatalyticaldol reaction between alkylidenepyrazolones and trifluoromethylketones leading to chiral tertiary alcohols bearing a trifluoromethylgroup is presented. The methodology is based on the use of abifunctional organocatalyst in order to activate the gamma-hydrogenatoms of the alkylidenepyrazolone nucleophile and the carbonylgroup of the trifluoromethylarylketone providing highly functionalized trifluoromethyl alcohols with moderate yields, excellentdiastereoselectivity, and moderate to good enantioselectivity. Experiments monitoring the conversion by1H NMR and theenantiomeric excess by HPLC with the reaction time showed that full conversion of the starting materials is not achieved and thatthe enantiomeric excess decreases upon extended times, probably due to the reversibility of the reaction.

Automated summary

A diastereo- and enantioselective organocatalyticaldol reaction was developed for the synthesis of chiral tertiary alcohols bearing a trifluoromethyl group from alkylidenepyrazolones and trifluoromethylketones. Despite moderate yields, the reaction showed excellent diastereoselectivity and moderate to good enantioselectivity.