Preparation Of N-trifluoromethylsuccinimide And Its Application In Trifluoromethylation Of Aromatic Amine

As a unique structural motif,trifluoromethyl(TFM)plays an increasingly important role in pharmaceuticals,pesticides,and materials due to its significant impact on permeability,lipophilicity,and metabolic stability.The introduction of CF3 groups into organic molecules,especially the development of novel trifluoromethylation reagents,has gradually become a hot topic.Based on the analysis of the structure and properties of various trifluoromethylation reagents,a new type of trifluoromethylation reagent N-trifluoromethylsuccinimide(NTFS)was designed and prepared through the newly prepared AgCF3 solution and N-bromosuccinimide(NBS),and various data were characterized in detail.Then,using NTFS,two types of trifluoromethylation reactions with different mechanisms were developed:direct trifluoromethylation of the C-H bond of aromatic amines and palladium catalyzed C-H bond activation trifluoromethylation of aromatic amides,which proved that the reagent can not only generate trifluoromethyl radicals,but also generate trifluoromethyl positive ionization,with a wide range of applications.In the reaction of aromatic amines,the optimal reaction conditions were obtained through screening:aromatic amines as the substrate,NTFS as the source of trifluoromethyl,(Diacetoxyiodo)benzene(PIDA)as an oxidant,K2CO3 as a base,Dimethyl sulfoxide(DMSO)as a solvent,reacted at 45℃ for 12 hours.Under this condition,29 2-trifluoromethyl aromatic amines were synthesized and characterized;The mechanism verification experiment proves that the reaction involves a trifluoromethyl radical process,and a reasonable reaction mechanism were proposed;Finally,the synthesis route of the anti asthma drug mabutrol was optimized using this system and a new synthesis route was used to synthesize mabutrol,demonstrating the practicality of this scheme.In the reaction of aromatic amides,the optimal reaction conditions were obtained through screening:aromatic amides as substrates,NTFS as a source of trifluoromethyl,Pd(OAc)2 as a metal catalyst,Cu(OAc)2 as an oxidant,PivOH as an additive,and 1,2-dichloroethane(DCE)as a solvent.Under this condition,18 2-trifluoromethyl aromatic amides were synthesized and characterized;and the mechanism verification experiment proved that the reaction was an ion type reaction without free radicals,and a reasonable reaction mechanism was proposed.