Asymmetric Hydrogenation Of Fluorinated Heteroaromatics And Beyond

Fluorinated molecules are widely used in pharmaceuticals, agrochemicals, tracers for positron emission tomography and new materials for their improved properties of lipophilicity, bioavailability, metabolic stability, and etc. Therefore, the construction of fluorinated molecules, especially chiral fluorinated molecules is of significant importance and potential application. Based on the progress of hydrogenation mechanism of heteroaromatics, in this dissertation, asymmetric hydrogenation of fluorinated heteroaromatics,3-(trifluoromethyl)quinolines and4-fluoroisoquinolines has been developed. Moreover, a novel fluorination of heteroaromatics featuring a triple relay transformation of rapid dearomatization, fluorination, and rearomatization processes has also been explored to access fluorinated heteroaromatics.Firstly, with chiral phosphoric acid as catalyst and1,4-dihydropyridine as hydrogen source, a highly efficient asymmetric transfer hydrogenation of3-(trifluoromethyl)quinolines has been successfully developed, providing a series of valuable enantiopure chiral2,3-disubstituted1,2,3,4-tetrahydroquinoline derivatives containing a stereogenic trifluoro-methyl group with up to98%ee. This is the first report on asymmetric reduction of CF3-substituted aromatics.Secondly, an efficient pr(COD)Cl]2/SynPhos/DCDMH catalytic system with dual activation strategy, catalyst activation and substrate activation, has been employed in the asymmetric hydrogenation of4-fluoroisoquinolines with up to97%yield and93%ee. This methodology is based on the enamine-imine isomerization process in asymmetric hydrogenation of isoquinolines, thus providing an efficient route to chiral fluorinated tetrahydroisoquinoline derivatives with inhibition of the hydrodefluorination pathway.Finally, by combination of the partial hydrogenation of3-nitroquinolines and electrophilic fluorination, an efficient and transition metal-free approach has been developed to transform3-nitroquinolines to3-fluoroquinoline derivatives with up to95%yields. The reaction has the advantages of fast reaction rate, mild reaction conditions, high yields and broad substrate scopes. This one-pot procedure features a triple relay transformation of rapid dearomatization, fluorination, and rearomatization processes, and presents a conceptually novel route to fluorinated heteroaromatics.