A Study On The Generation Of Alkyl Radicals And Their Reaction With Imines Enabled By Single-Electron-Transfer Catalysis

Amino acids are the basic units of proteins,and their derivatives are ubiquitous structural motifs in drugs and bioactive molecules.However,the number and types of natural amino acids can't satisfy its applications in medicine,life science,chemical industry and other fields.In the investigation of organic synthesis,the synthetic methods of unnatural amino acids have been widely concerned.The reactions of imine as electrophilic reagent to synthesize amines and unnatural amino acid derivatives have been extensively studied.In recent years,with the development of radical chemistry,the single electron transfer reactions involving imines have also attracted the attention of many scientists.In this thesis,we mainly studied the radical addition reaction of a series of nucleophilic alkyl radicals with imines.A series of unnatural amino acid derivatives were successfully synthesized by exploring novel,mild and compatible alkyl radical generation methods,and the excellent application prospect of the radical cascade reaction mode of imine under the catalysis of single electron transfer has been shown.1)The radical addition reaction of ?-position in cyclic ethers(1,3-dioxolane,tetrahydrofuran)to fluoroalkylimines was realized through the highly efficient synergistic catalysis of photosensitizers and hydrogen atom transfer reagents.In this mild reaction condition,a series of fluorinated amino acetals were synthesized with specific site selectivity and high yield.The mechanism study shows that there is an efficient synergistic catalytic effect between the photosensitizer and the hydrogen atom transfer reagent.Through the study of derivatization,the products can be further converted into fluorinecontaining amino alcohols and amino acid esters.2)In view of the high radical reactivity of ?-position of ethers and imines,we attempt to generate oxygen ?-position radical by the addition of electrophilic radicals to enol ethers,and then react with imines,thus achieving the polarity reversal three-component radical addition cascade reaction.We have found that azido trimethylsilane can be oxidized by small molecular ketone photosensitizers to generate electrophilic azide radical.After addition to electron rich enol ether,the nucleophilic oxygen ?-position radicals are trapped by imines,and the products are opposite to the traditional Mannich reaction region selection.Under the optimal conditions,a series of azide-containing unnatural amino acids were synthesized.After further functional group transformation,azide-containing amino alcohol,amino acid and morpholine were synthesized.Azide group can also undergo highly selective reactions to prepare derivatives such as 1,3-diamine and triazole.A series of kinetic results show that the addition of azide radical to enol ethers is a relatively fast step in the reaction,which has no obvious effect on the overall reaction speed,while the the oxygen ?-position radical addition to imine is the rate-determining step in this reaction.3)Under the irradiation of visible light,organic dye can oxidize sulfinate to sulfone radical,which adds to alkene to generate alkyl radical.On this basis,the three-component addition cascade reaction of imine and alkene initiated by sulfone radical was realized.We found that this reaction has better substrate scope than the reaction initiated by azide radical.It is not only suitable for electron rich enol ethers,but also can transform the unactivated alkenes into radical intermediate and incorporate into the target product.In this reaction system,various sulfone-containing amino acid esters were synthesized.Through the experiments of radical clock,it can be strongly proved that the reaction proceeds through the mechanism of radical.4)Under the catalysis of cheap metal iron,cyclobutanone oxime esters was reduced by low valent iron species,after N–O bond breaking and ? C–C bond cleavage to generate the alkyl radical intermediate.At the same time,glycine ester was oxidized by high valence iron complex to form imine in situ.After the alkyl radical addition to the imine,the obtained nitrogen radical intermediate is reduced by low valent iron catalyst again,and finally the selective C–C cross-coupling reaction of the glycine eaters is achieved.This method can be used to prepare a series of ?-or ?-substituted lysine derivatives and many other unnatural amino acids derivatives.Compared with other cheap metal catalysts,iron catalyst play an important role in the site selectivity of the coupling reaction between glycine esters and alkyl radicals.Through a series of kinetic and control experiments,we can further confirm that the imine generated in situ is alkyl radical acceptor of the reaction.