Trifluoromethylation Of Aromatic/Heterocycle Ring And Derivatives Catalyzed By Transition Metal

The trifluoromethyl group, because of the properties of strongelectron-withdrawing inductive effects, lipophilicity and stable C-F bond, has beenwidely used in many fields such as Medicinal Chemistry, pesticide chemistry andmaterial science. When the trifluoromethyl group was introduced into organicmolecules, it can significantly change the electric dipole moment, solubility, acid-baseproperty, metabolic stability, biological activity of organic molecules. Thetrifluoromethyl group does not exist in the natural products, which makes thedevelopment of new, simple and practical methods of introducing trifluoromethylgroup more important.The trifluoromethylthio group is a derivative group of trifluoromethyl, which isdifferent with trifluoromethyl in the structure and properties. As the properties ofhigher lipophilicity and strong electron-withdrawing inductive effects, it can alter themolecules’ electric density, acid-base property and improve lipid-solubility of the cellmembrane when the group was introduced into drug molecules, which makes thegroup be widely used in fields of medicine and pesticide. The trifluoromethylthiogroup, also a kind of important intermediates, can be used in industrial production forthe preparation of trifluoromethyl reagents, sulfone, sulfoxide and a series of industrialproducts. Development of new methods of introducing trifluoromethylthio group hasbecome a focus of chemical research.Pyrazole, as another important molecular skeleton, can express unique biologicalactivity when interact with some biological receptors. Pyrazole and derivatives havebeen developing gradually in the fields of medicine and pesticide for more than acentury with the increase of human awareness, so the building of organic compoundscontaining pyrazole unit has a broad application prospect. If the trifluoromethyl groupwas introduced into pyrazole compounds, it can obviously change membranepermeability and improve molecules’ biological activity. Celecoxib, a drug containingpyrazole unit and trifluoromethyl group, can effectively restrict the production ofinflammatory prostaglandins so as to achieve the desired effect of anti-inflammatory,analgesic and antifebrile. The traditional synthetic method is to construct pyrozole ring firstly then introduce trifluoromethyl group or trifluoromethylate firstly then cyclize,but there are a series of negative factors just like poor selectivity, isomer, fussyoperation, isolating difficulty, which limit the popularization and application of thesemethods.In the paper, a new synthetic method introducing trifluoromethyl group intopyrazole unit without metal catalysis was developed. Firstly, propynol was oxidizedinto propiolaldehyde, then reacted with hydrazine to obtain alkynyl hydrazone, andthen with trifluoromethyl reagent (Togni reagent) to realize trifluoromethylation. Inorder to verify the innovation of this reaction, we explored the mechanism, andconfirmed the process of the reaction via a design of possible intermediates.Diazo compounds are important dinitrogen organics, as well as methylationreagents. Diazonium, as precursors of a series of important metal carbene, reactingwith some transition metal such as Cu, Rh, Ru, can form metal carbene, a kind ofimportant intermediate, which can be used as a method of introducing functionalgroups in the fields of medicine and pesticide. In this paper, a new method oftrifluoromethylthiolation of diazo compounds was developed, which realized thetrifluoromethylthiolation of benzyl compounds. Not only the method is a breakthroughin methodology, but also has a broad prospect in industrial production.