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. Thus, a single operation rendered moderate-to-good amounts (42-75%) of optically pure adducts (S,S)-14 (de >/= 98%) by combining excellent chemical (82-92%) and moderate optical (51-81%) yields. Hydrazones 5 and (S,S)-14 were protected by benzylation [--> 16 and (S,S)-18] and then transformed into benzyl-protected alpha-trifluoromethyl cyanohydrins 21 by MMPP oxidative cleavage and into alpha-benzyloxy-alpha-trifluoromethyl aldehydes 22 by ozonolysis. Alternatively, adducts 5 and (S,S)-14 were methylated [--> 19 and (S,S)-20] and transformed into the corresponding alpha-methoxy-alpha-trifluoromethyl carboxylic acids 24 by successive ozonolysis and in situ oxidation (NaClO(2), (t)()BuOH, isobutene) of the crude alpha-methoxyaldehydes.
Pareja
Carmen
C
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado de Correos No. 553, E-41071 Seville, Spain, and Instituto de Investigaciones Químicas, CSIC-USe, c/Americo Vespuccio s/n, Isla de la Cartuja, E-41092 Seville, Spain.
Martín-Zamora
Eloísa
E
Fernández
Rosario
R
Lassaletta
José M.
JM