Copper-catalyzed Cyanomonofluoroalkylation Of Alkenes/Alkynes

Owing to the unique properties of the fluorine element,different classes of fluorinecontaining organic compounds have been developed and used as pharmaceuticals and agrochemicals.The development of new monofluorinated reagents and their applications in the synthesis of monofluorinated compounds are noteworthy.The cyano group(CN)is not only a prevalent structural moiety in bioactive natural products and pharmaceuticals,but also serve as a versatile precursor that can be transformed into many other functional groups.It is high in demand to develop cyanofluoroalkylation reactions due to the incorporation of both monofluoroalkyl and cyano groups have become a powerful tool in drug discovery.This dissertation is based on the group’s previous work on monofluoroalkyl block iodomethyl ketone.The copper catalyzed cyano monofluoroalkylation of alkenes/alkynes was studied.In the first part,copper catalyzed three component reactions of iodo monofluoromethyl ketone with olefins and TMSCN were studied.After optimizing the conditions,the optimal conditions were obtained: under nitrogen protection,using Cu(OAc)2 as the catalyst,2,9-dimethyl-1,10-phenanthroline as the ligand,dichloromethane as the solvent,and LPO(bislauryl peroxide)as a free radical initiator.And twenty-six monofluoronitrile compounds with different structures were synthesized,with moderate to excellent yields and a diastereomeric ratio of about 1:1.Then the mechanism study found that free radicals were involved.At the same time,the product can be transformed.Next,the possibility of asymmetric reactions was explored.First,the possibility of asymmetric monofluorocyanation products based on unsubstituted groups was discussed,and then the two-handed asymmetry of cyanation products with monofluoroquaternary carbon centers was explored.Finally,optimization of chiral ligands and temperature was carried out,and in terms of a single chiral center,the ee value can reach up to 92%.In the second part,copper catalyzed three component reactions of iodo monofluoromethyl ketones with alkynes and TMSCN were studied.Conditions involved in screening reactions: catalysts,ligands,free radical initiators,etc.The optimal conditions were obtained: under nitrogen protection,using Cu I as a catalyst,α,α,α-Tripyridine as ligand,methanol as solvent,and LPO(bislauryl peroxide)as free radical initiator reacted at 70 ℃ for5 hours.The substrate tolerance of alkynes was evaluated,and four monofluoroacrylonitrile compounds with different structures were obtained.The yield was moderate,and the stereoselectivity was good.The E-configuration was dominant.