Nickel Catalyzed Trifluoroalkylation:Synthesis Of Trifluoromethylated Terminal Alkene And Benzylamine

Trifluoromethyl group has unique physicochemical properties that can significantly change the acidic-alkaline property,dipole moment,and polarity of organic molecules.The introduction of trifluoromethyl group into drug molecules alters the lipophilicity,metabolic stability,biocompatibility and binding selectivity of the structure to a notable extent.Organic molecules containing trifluoromethyl groups are widely used in fields such as pharmaceutical and pesticide production.Therefore,selective introduction of the trifluoromethyl group into molecule is of great research importance.Branched allyl methyl segments and methylamino segments,as common structural units in organic chemistry,are widely present in natural and bioactive molecules.As a bioisosteric alternative of methyl group,the ’fluorine effect’demonstrated by trifluoromethyl group discloses a considerable potential to improve pharmacological parameters of molecules.Although the synthesis of allyl trifluoromethyl terminal olefins/α-CF3 benzylamines have been reported by previous works in literature,limitations still exist in these synthetic strategies rendering the development of efficient,safe and more generalized methods as the focus of our research.This thesis focuses on using trifluoroalkyl bromides and α-CF3 pyrrolidone chlorides as substrates for synthesis of allyl trifluoromethyl terminal alkenes and α-CF3 benzylaminesThe thesis is consisted of three main sections;Chapter 1 Synthesis of trifluoromethyl compounds by transition metal catalysisIn this chapter we focused on the classification and summary of methods to introduce trifluoromethyl groups into molecules.Catalytic systems were divided by metals such as palladium,copper,nickel and other transition metals,direct trifluoromethylation and indirect ones from another perspective in order to construct trifluoromethyl substitution centers.Chapter 2 Nickel-catalyzed hydrotrifluoroalkylation of alkynesWe have realized the hydrotrifluoroalkylation of terminal alkynes based on nickel catalyzed three component reductive coupling.The reaction was characterized as with mild conditions,high reactivity and good substrate compatibility,and could be smoothly followed by derivative transformation to obtain molecules containing trifluoromethyl groups.Free radical inhibition experiments and deuteration substitution showed that the reaction cycle underwent a free radical mechanism and isomerization of alkenyl nickel species.Chapter 3 Nickel-catalyzed construction of α-CF3 amines by reduction couplingWe have realized the arylation reaction of α-CF3 pyrrolidinone chloro-substitutes using nickel-catalyzed reductive coupling.The reaction exhibited advantages such as facile operation,good atomic economy,high reactivity and mild condition,providing a novel strategy for synthesis of α-CF3 amides.