Synthesis Of Fluorine-Containing Heterocycles From Fluoroalkylimidoyl Halide Derivatives

Fluorinated heterocycles have received considerable attention in recent years due to their unique chemical and biological properties compared with non-fluorinated analogs. It would not be an exaggeration to say that currently every new drug discovery and development program without exception explores fluorine-containing drug candidates. Therefore, a wide variety of fluorine-containing compounds based either on known natural products or on new skeletons is needed for biological evaluation. However, in many cases, synthetic methods developed for ordinary organic molecules do not work well for fluorochemicals because of their unique reactivity, and selective introduction of fluorine into molecule at a specified position is another challenge. So it is necessary to develop efficient synthetic methods applicable to fluorine-containing organic compounds.This dissertation is focused on the study of reactions of fluoroalkyl enaminoketones and fluoroalkyl alkynylimines, and its application in fluoro-heterocycle synthesis through transition metal catalysis. It consists of five chapters.1)An efficient strategy for the synthesis of 2,2-difluoro-2,3-dihydrofuran products fromβ-fluoroalkyl-β-enaminoketones is described. The reaction occurred via intramolecular halophilic attack-initiated cascade process. A series of 2,3-dihydrofurans were prepared in high yields. And an intermolecular domino process achieved providing polysubstituted dihydrofurans.2 ) A new, rapid and high-yielding method to prepare 3,4-disubstituded 2-trifluoromethylquinolines by palladium catalyzed tandem Sonogashira?alkyne carbocyclization ofβ-trifluoromethylβ-enaminoketones with aryl alkynes is described. This reaction can also be expanded to the non-fluorine containing substrates.3)Treatment of various types of N-(o-haloaryl)alkynylimines in the presence of palladium catalyst gave 2-trifluoromethyl indoles in high yields. Another strategy developed through Pd-catalyzed cascade carbopalladation/C-H activation process using fluoroalkyl alkynylimines and aryl iodides provided a series of 2-fluoroalkyl 3-methylene-3H-indoles in good yields. Method for reduction of these products was also developed. This reaction can also be expanded to the non-fluorine containing substrates.4)Novel tricyclic 4-(trifluoromethyl)-[1,2,3]triazolo[1,5-a]quinoxalines were readily prepared from N-(o-haloaryl)alkynylimines and sodium azide via copper(I)-catalyzed tandem reactions.5)A chemoselective strategy for the synthesis of poly-substituted pyridines and fluoroalkyl dihydropyrimidines based on C-F bond breaking of the anionically activated fluoroalkyl group was described. A series of pyridines and dihydropyrimidines were prepared through this domino process in high yields under noble metal-free conditions.