New versatile fluorinated chiral building blocks: Synthesis and reactivity of optically pure alpha-(fluoroalkyl)-beta-sulfinylenamines

Efficient synthesis of optically pure alpha-(fluoroalkyl)-beta-sulfinyl enamines has been achieved by aza-Wittig reaction of triphenyliminophosphoranes with the corresponding alpha-fluorinated-alpha'-sulfinyl ketones. The title compounds 3,4 showed an overwhelming preference for the Z stereochemistry of the enamine form. Their general reactivity has been studied. The reaction with some electrophiles (i.e. benzyl chloroformate and benzyl and allyl bromide) occurs at the nitrogen atom providing the corresponding N,N-disubstituted enamines. Nucleophiles add smoothly to C-2: heteroatom-centered nucleophiles like methanol, ammonia, and thiophenol afford gem-disubstituted derivatives under thermodynamic control, while a C-centered nucleophile like nitromethane adds in irreversible fashion. The hydride- and deuteride-promoted reduction of 3,4 to the N-Cbz-protected (14) and N-unprotected (15) alpha-fluorinated-alpha'-sulfinyl amines has been studied. Hydride addition was stereoselective, while low stereoselection was obtained with the other tested nucleophiles. Desulfurization of the optically pure 1,1,1-trifluoro-3-sulfinyl amine 15a afforded (R)-1-(trifluoromethyl)ethylamine 17. The Pummerer rearrangement of 14 occurs in an unusual nonoxidative way affording the sulfenamide 24, that readily provided (R)-(2-H)- and -(2-D)-3,3,3-trifluoroalaninol (19) and (R)-3,3,3-trifluoroalanine (22).