Studies On Transition-Metal-Catalyzed Three-component Reaction Of Iododifluoromethyl Ketones,Alkene/Alkyne,and TMSN₃

Azido groups are frequently found in pharmaceutical molecules and natural products,and are useful organic synthons.They can be easily converted into nitrogen-containing heterocyclic compounds,such as pyridine,triazole,and tetrazole or into amine and amide compounds by reductive reaction.On the other hand,the introduction of fluorine to the nitrogen-containing compounds could enhance their physiological activity and physical and chemical properties.Therefore,the development of efficient synthetic methodologies for such compounds containing fluorine and azide group has attracted much attention.Transition metal catalyzed three component reactions are widely considered to be one of the most effective methods for introducing two functional groups into molecules simultaneously due to their mild reaction conditions and good chemical selectivity.Firstly,we studied the three component reactions of iododifluoromethyl ketone,alkene,and TMSN₃ in order to achieve regioselective bifunctionalization of alkenes:azide and difluoroalkylation.Through the screening of iron catalysts,free radical initiators,and solvents,we determined the optimal reaction conditions as follows:Fe（OTf）₂ as the catalyst,TBPB as the free radical initiator,and 1,4-dioxane as the solvent.The target product was obtained in a yield of 93%.Subsequently,we expanded the substrates of iododifluoromethyl ketones and alkenes with different substituents,and obtained 31 new difluoroalkyl azides in yields of 52%to 97%.Secondly,we explored the three component reactions of iododifluoromethyl ketone,TMSN₃,and alkynes.Under the above standard conditions,we first synthesized azido difluoromethyl ketone blocks through a two-component reaction of iodo difluoromethyl ketone and TMSN₃.Without purification,we achieved a one-pot,two-step synthesis of potentially biologically activeα,α-difluoride-α-triazole-1-one compounds.Iododifluoromethyl ketones containing different substituents can also participate in the reaction smoothly,and the corresponding target compound can be obtained in a yield of 25%to 95%.