Research On Nucleophilic Addition Of Fluorinated Imines

Fluorinated amines, especially bearing the (trifluoro)ethylamine moiety, represent an important class of compounds in life science and medicinal chemistry because of their diverse biological and pharmaceutical properties. Besides, auxiliary-based Mannich-type reaction of imines or their precursors have been the most efficient synthetic routs to organic amines.As a source of introducing fluorine into target compounds, trifluoromethyl group could also activate the C=N double bond. Besides,N-tert-butanesulfinamides have been proved to be highly efficient chiral auxiliaries in the synthesis of chiral amines by the virtue of their excellent diastereocontrol and easy cleavage. Consequently, the chemistry of (Ss)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine has been actively studied with the aim of developing a general synthetic methodology for preparation of fluorine-containing amino compounds in the recent years.However, the reported asymmetric Mannich-type reactions of (Ss)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine so far are rather limited to the types of nucleophiles. Herein, we expect to develop some new nucleophiles into this asymmetric imine addition. This thesis mainly contains four parts of research work as follows:(1) An efficient method for the asymmetric synthesis of β-trifluoromethylated β-amino ketones via addition of ketone-derivative enolates to (Ss)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine has been developed, with good chemical yields and excellent diastereoselectivities. This practical method was also proved to be suitable for large scale preparation. The absolute configuration of products was confirmed by the X-ray diffraction analysis, and a non-chelated transition state model of mechanism was proposed.(2) Asymmetric Mannich-type reactions of imidazo[2,1-b]thiazole-derived nucleophiles with (Ss)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine were found to proceed with reasonably good yields (55-79%) and exceptionally high stereoselectivities (>99:1dr). This method presents a general approach for preparation of new type of biologically relevant class of compounds containing pharmacophiric imidazo[2,1-b]thiazole and (trifluoro)ethylamine groups. The addition reactions can be conducted on relatively large scale (1g) allowing preparation of these compounds for systematic biological studies. A non-chelated transition state model of mechanism was proposed.(3) Asymmetric Mannich-type reactions of thiazolo[3,2-6][1,2,4]triazole-derived nucleophiles with (Ss)-N-tert-butanesulfinyl-(3,3,3)-trifluoroacetaldimine were found to proceed with good chemical yields (up to78%) and virtually complete diastereoselectivities (98:2to>99:1dr). The same stereochemical outcome was obtained using1.05g scale of the starting (3,3,3)-trifluoroacetaldimine. The method developed in this work provides a concise and generalized access to thiazolo[3,2-6][1,2,4]triazoles containing chiral (trifluoro)ethylamine group.(4) Mannich-type addition reactions between lithiated benzo[d]thiazoles and N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine occur with anomalous outcome giving rise to bis-benzo[d]thiazole products instead of the expected2,2,2-trifluoro-ethylamino derivatives. As a synthetic bonus of this unexpected finding, we developed a simple, general and scalable one-pot procedure for preparation of (E)-1,2-bis(2-benzothiazolyl)ethenes without recourse to the traditional purification techniques such as column chromatography or recrystallization.