Studies On The Friedel-Crafts Reaction Of Indoles With Trifluoroacetaldehyde Hemiacetal And Synthesis Of Perfluorocarbons Modulated Anilinoquinazolines

The incorporation of the trifluoromethyl group into organic molecules often significantly enhances their acidity,dipole moment,lipophilicity,bioavailability and metabolic stability owing to their special physical and chemical properties.Trifluoromethyl-containing compounds are playing an increasing important role in the fields of chemistry,pharmaceuticals and materials etc.Therefore the efficient construction of trifluoromethy-containing molecules is becoming a significant topic in organic chemistry.The Friedel-Crafts reaction of indoles catalyzed by small organic molecules is one of the most straightforward and powerful methods to acquire a diverse number of indole derivatives.The enantioselective Friedel-Crafts reaction of indoles with prochiral trifluoromethyl building blocks provides direct access to chiral trifluoromethyl-containing indole compouds.In this regard,we chose trifluoroacetaldehyde methyl hemiacetal as trifluoromethyl building blocks.Firstly,we developed the asymmetric Friedel-Crafts reaction of indoles with trifluoroacetaldehyde methyl hemiacetal.With systematic screening on the catalysts,solvents,reaction temperatures and additives,the asymmetric Friedel-Crafts reaction was achieved in moderate to high yield and moderate ee with quinidine alkaloid-derived bifunctional thioure as the catalyst.With this methodology,a series of indole-derived chiral trifluoromethyl substituted secondary alcohols were obtained.Subsequently,we studied the double-Friedel-Crafts reaction of indoles with trifluoroacetaldehyde methyl hemiacetal.The reaction was achieved with racemic phosphoric acid as the catalyst.A series of trifluoromethyl-containing bisindole compounds were obtained.Over the past decades,structural modification of 4-anilinoquinazoline by all kinds of functions is a promising approach to improve their anticancer activity and has attracted great interest.Perfluorocarbons(PFCs),wherein all hydrogen atoms are replaced by fluorine,have found a wide range of applications in pharmaceuticals and material science.The high electronegativity of fluorine endows perfluorocarbons(PFCs)with unique chemical and biological behavior.In the second part of this thesis,we expect to introduce a perfluorocarbon moiety into the anilinoquinazoline framework to synthesize a new kind of pharmaceutical active molecules using the properties of fluorine atom.With multi-step synthesis,a series of novel perfluorocarbons modulated 4-anilinoquinazolines were achieved.In addition,the PFCs modulated analogues of gefitinib and erlotinib were also obtained in good yield respectively,which may have potential for developing new EGFR tyrosine kinase inhibitors.