Studies On The Ring-forming Reactions Of Fluoroalkyl Anhydrides And Its Derivatives

Fluorine atom has the inherent characteristics of small atomic radius and the strongest electronegativity,which makes the fluoroalkyl group（R_f）formed by fluorine atom and carbon atom show particularity.R_f can significantly improve the electrophilicity of the carbonyl group when it is connected to the carbonyl group,so the trifluoroacetyl group has a stronger electron-withdrawing ability than the acetyl group.When the hydrogen atom or methyl group in the candidate drugs is replaced by a trifluoromethyl group（-CF₃）,they show an improved chemical and metabolic stability,membrane permeability,lipophilicity,bioavailability,protein affinity and antioxidant capacity.Therefore,we investigated the reaction properties of fluoroalkyl anhydrides and their derivatives,and developed some methods to construct R_f-and R_fCO-substituted（hetero）aryl compounds.This dissertation includes the following five chapters:Chapter 1 This chapter briefly describes the development of fluorine chemistry and the properties of organic fluorine compounds,and focuses on the research advances of fluoroalkyl anhydride and trifluoropyruvate.Chapter 2 This chapter reports some methods for fluoroalkyl anhydrides-promoted copper（I）-catalyzed interrupted Click Reaction（Cu AAC）to synthesize 3-fluoroalkyl-1,2,4-triazinone derivatives,including（CF₃CO）₂O,（CF₂HCO）₂O,（CF₂Cl CO）₂O,（C₂F₅CO）₂O and（C₃F₇CO）₂O.The survey results have shown that Cu I is the best catalyst for this system.The bidentate ligands of bipyridine analogs with electron-donating substituents can significantly enhance the catalytic activity of Cu I.Fluoroalkyl anhydrides with stronger electron-withdrawing exhibits higher reactivity to prepare the corresponding 3-fluoroalkyl-1,2,4-triazinone product.Difluoroacetic anhydride including weak electron-withdrawing has low reaction activity,while acetic anhydride is completely inactive.These reactions are also affected by solvent and temperature.These methods exhibits broad functional-group tolerance,and can complete gram-level reactions of products and late-stage modification of complex molecules.Mechanism experiments proves that fluoroalkyl anhydrides can promote the ring-opening of the five-membered5-copper（I）triazole intermediate of Cu AAC to form the six-membered3-fluoroalkyl-1,2,4-triazinone core fragment.Chapter 3 This chapter reports a new protocol for the synthesis of polysubstituted 5-（trifluoromethyl）isoxazoles from vinyl azides and trifluoroacetic anhydride under metal-free conditions.This protocol is suitable for（hetero）aromatics,alkanes and cycloalkane substituted vinyl azides,and can realize gram-level preparation of products and late-stage modification of complex molecules.At the same time,（C₂F₅CO）₂O and（C₃F₇CO）₂O can also be applied to the synthesis method.According to demonstration experiment and literature reports,the5-（trifluoromethyl）isoxazoles are obtained by denitrogenative cyclization of vinyl azides with trifluoroacetic anhydride in the presence of Et₃N.Chapter 4 This chapter reports an efficient method of the cascade reaction of（hetero）aryl tetrafluoroborate diazonium salts with hexafluoroacetylacetone to synthesize pertrifluoromethyl pyridazine derivatives.The method has the advantages of simple operation,mild conditions,no additives and easy conversion of products.These products are dehydrated in the presence of conc.H₂SO₄ to form carbocation intermediates,which subsequently underwent cascade reaction with phenols to obtain benzo[5,6]chromeno[3,4-c]pyridazine productsChapter 5 This chapter reports the trifluoroacetylation reaction of（hetero）aryl tetrafluoroborate diazonium salts with ethyl trifluoropyruvate under mild conditions to synthesize（hetero）aryl trifluoromethyl ketones.This method exhibits good functional-group tolerant,and can complete gram-level reactions of products and late-stage modification of complex molecules.Mechanism experiments demonstrate that the reaction undergoes a free radical process.