Stereoselective Synthesis of Trifluoromethylated Compounds: Nucleophilic Addition of Formaldehyde N,N-Dialkylhydrazones to Trifluoromethyl Ketones.

The nucleophilic 1,2-addition of formaldehyde N,N-dialkylhydrazones 1, 2, and 7-10 to trifluoromethyl ketones 3a-e takes place in the absence of any catalyst or promoter to afford a series of alpha-hydroxy-alpha-trifluoromethylhydrazones (4, 5, and 11-14) in good-to-excellent yields. From the several reagents studied, optimal results were achieved using 1-(methyleneamino)pyrrolidine (2) for the synthesis of racemic adducts and (S)-1-(methyleneamino)-2-[1-(methoxy)diphenyl-methyl]-pyrrolidine (10) for the asymmetric version of the reaction. The resolving properties of the chiral auxiliary carried by 10 allowed an easy chromatographic (flash) separation of any obtained diastereomeric mixture.

Synthesis of Enantiopure α-Alkoxy-α-Trifluoromethyl Aldehydes and Carboxylic Acids from Trifluoromethyl Ketones.

Formaldehyde dialkylhydrazones behave as neutral d synthons in their uncatalyzed reaction with trifluoromethyl ketones (see reaction). Both racemic and optically pure 1,2-adducts were obtained in good yields. Efficient deprotection of the hydrazone moiety afforded interesting fluorinated quaternary compounds such as 1 and 2.