Palladium-catalyzed Trifluoroacetylation Of Boronic Acid With Thioester And Cu-mediated C-H Thioetherification Of Arenes At Room Temperature

Objective:The particularity of the fluorine atom structure leads to extraordinary functions of the fluorinated compounds,especially the introduction of fluorine atoms in the design of the drug structure is crucial for the improvement of drug targeting selectivity,the increase of drug metabolic stability,and the improvement of drug bioavailability Important role.Therefore,the introduction of fluorine atoms in compounds has always been favored by scientific researchers;aromatic sulfides are widely found in natural compounds and are an important class of structural units and synthetic raw materials.Their mature rare metal catalyzed C-H thioetherification Synthetic methods are expensive for catalytic metals and harsh reaction conditions.This article aims to develop a trifluoroacetylation method with mild conditions,easy operation,easy substrate availability,and good compatibility,and a cheap metal hydrocarbon sulfide synthesis method with mild conditions and simple operation.Methods:（1）Based on the Libeskind coupling reaction,develop a palladium-catalyzed trifluoromethyl ketone synthesis method of boric acid and thioester:（1）Trifluoroacetylation source-thioester substrate synthesis（2）Palladium-catalyzed trifluoroacetylation reaction conditions of boric acid and thioester Optimization（3）Expansion of trifluoromethyl ketone synthesis reaction substrate（4）Research on reaction mechanism（2）Copper is the catalytic metal and ethylene sulfide is the source of thioetherification,the development of novel thioether compound synthesis method（1）Design and synthesis of the guide group（2）Preparation of reaction substrate（3）Selection and optimization of conditions,expansion of reaction substrate,analysis of reaction mechanism.Results:（1）Based on the Libeskind coupling reaction,0.2 mmol boric acid as the reaction substrate,and 0.3 mmol thioester as the trifluoroacetyl source,through the corresponding investigation of the ligand type,palladium catalyst,thioester reagent,reaction temperature,and thioester dosage,At 30 ^o C,0.002 mmol Pd₂（dba）₃ is the catalytic metal,0.006 mmol TFP is the system ligand,3 ml of tetrahydrofuran is the reaction solvent,and the reaction substrate is expanded under the most suitable conditions for 18 h,and 16 trifluorocarbons are realized.Synthesis of methyl ketone and 15 difluoromethyl ketones:（2）0.1 mmol of benzoic acid derivative is the reaction substrate,0.2 mmol of ethylene sulfide is the sulfidation reagent.Type of base,reaction solvent,directing group,type of copper,amount of copper,reaction concentration,and reaction time should be checked accordingly to confirm that at room temperature,0.1 mmol NaOAc is the base,0.1 mmol Cu（OAc）₂ is the catalytic metal,2 ml DMSO is the reaction solvent,and the reaction substrate is expanded under the optimal conditions for 18 hours of reaction.The aromatic sulfide with rich structure is produced in excellent yield.Through the verification of kinetic isotope effect and free radical reaction,a relatively reasonable copper-mediated C-H activated thioetherification reaction mechanism was finally proposed.Conclusion:（1）Through the synthesis and screening of thioester substrates,a new class of trifluoroacetylation reagents has been developed,based on the design of Libeskind coupling reaction,which provides a direct and powerful method for the synthesis of trifluoromethyl ketone compounds.Regardless of the electron-withdrawing or electron-donating substrate;whether it is a fused aromatic ring or a heteroaromatic ring,the corresponding trifluoroacetyl product can be produced in a satisfactory yield.（2）Based on the method of hydrocarbon activation,air as an oxidant,anhydrous sodium acetate as a base,ethylene sulfide as a thioetherification source,anhydrous copper acetate as a catalytic metal,developed an economic and convenient at room temperature Thioether compound synthesis method.