Hydrotrifluoromethylation Of α-Keto Esters

Trifluoromethyl-containing compounds have wide applications in the fields of medicine,agriculture and material sciences,because of their unique physical,chemical and biological properties.Many methods for introducing trifluoromethyl into organic molecules have been reported,mainly through trifluoromethylating reagents,and the synthesis ofα-trifluoromethyl esters is no exception.However,most of these require activated substrates or catalysts,thus the substrate scope and applicability for the reaction are limited.Therefore,it is of great significance to develop a cost-effective and convenient method for the synthesis ofα-trifluoromethyl esters.In this study,the direct hydrotrifluoromethylation ofα-keto esters was realized with a difluoromethylating reagent,thus efficiently constructingα-trifluoromethyl esters.It is worth noting that the water in the reaction can promote the dissociation of CF₂groups to form CF₃ groups,thereby achieving the construction of trifluoromethylated products without the addition of extra fluoride ions and catalysts.Through this simple and economical method,we have obtained 32 derivatives ofα-trifluoromethyl esters,indicating a broad substrate scope and high functional group compatibility.Firstly,we studied the hydrotrifluoromethylation of olefin-substitutedα-keto esters.Using Ph₃P⁺CF₂COO^-as the fluorine source and H₂O as the additive,the target compounds were successfully obtained.It is worth mentioning that we introduced bioactive groups and natural product fragments into theα-keto esters to further evaluate the applicability of the method,achieving the correspondingα-trifluoromethyl esters in good yields.These results indicate that this method has certain application prospects in the later modification of complex compounds.Gram scale experiment and derivations of products further expanded the applicability of this reaction.Finally,we performed control experiments to explore the mechanism.A gem-difluoroalkene intermediate was synthesized and subjected to standard conditions,and the corresponding product could be obtained with or without Ph₃P⁺CF₂COO^-.Based on the above results and previously reported literatures,we speculated that phosphonium ylide and gem-difluoroalkene intermediate were generated and both of them could react with water to generate HF.Subsequently,HF and gem-difluoroalkene intermediate underwent nucleophilic addition to achieve trifluoromethylation.