Despite the high abundance of fluorine and nitrogen atoms in the pharmaceuticals, their combined functionality, Trifluoromethyl amines , remains much less investigated to date. This might be a consequence of the lack of safe,general,efficient and highly selective pathway to introduce N-CF3 moiety into target compounds as well as encountered difficulties in their purifications.
A mild, safe and operationlly simple synthetic route to N-CF3 compounds should be desirable and promising challenge, which may enable numerous avenues in life science and crop protection research. For examples, the frequently encountered problem of facile oxidation of amines in metabolic processes is possible to be solved under N-CF3 modification. Compared to N-Me moiety, N-CF3,as reported, exhibits similar comformational preferences but with high lopP values. Moreover, as shown in a promising isolated study,the N-CF3 analogue of floxacin can retain similar antibacterial activities as its methylated-counterpart.
The choice of reagent is an important issue for achieving efficient and N-selective trifluoromethylation reactions. Athough few, some new direct methods including electrophilic, radical and nucleophilic CF3-sources have been employed for the synthesis of various NCF3-containing compounds in the past decade.
1. Electriphilic N-Trifluoromethylation: In 2007 Umemoto and co-workers reported the direct trifluoromethylation of amines, anilines and pryridines as the first example of a direct N-trifluoromethylation. However, the electrophilic CF3 source used in such reactions is an unstable and very reactive O-(trifluoromethyl)dibenzofuranium salt with intrinsic drawbacks. A more stable hypervalent iodine reagent(Togni reagent,kumi3F10) was later developed by the Togni group and was utilized for synthesis of certain N-Trifluoromethylated imidoyl compounds and azoles through ritter-type reactions.
2.Radical N-Trifluoromethylation: Cheng and Bolm reported an unprecedented approach to N-trifluoromethylations of electron-rich nucleophilic sites following a radical pathway, in which various sulfoximines( 19 examples) were developped by employing TMSCF3(kumi3F01) and Ag2CO3 with satifying functionality tolerance in moderate to good yields. Very recently, Selander and co-workers employed sodium triflinate( Langlois Reagent,kumi3F19) as a CF3-radical source in combination with a copper catalyst and an oxidant for N-trifluoromethylation of Nitrosoarenes, this method is reported high-yielding,rapid, scalable,mild reactive and high functional group tolerant.
3. Nucleophilic N-Trifluoromethylation: Zhu and Wang, and their co-workers applied an in situ formed hypervalent iodine CF3-reagent from the Ruppert-Prakash reagent(TMSCF3,kumi3F01) in the N-trifluoromethylation of ketimines. Inoue and Handa recently disclosed a method for the nucleophilic trifluoromethylation of nitrosoarenes using TMSCF3(kumi3F01), in which O-acetylated ,N-trifluoromethylated hydroxylamines were developped. More recently, the Schoenebeck group developed a two-step strategy for the rapid and mild N-trifluoromethylation of secondary amines through the use of a bench-stable reagent (Me4N)SCF3( kumi3F25), the initially formed thiocarbamoyl fluoride intermediates were ,through a formal Umpolung strategy, then converted to the trifluoromethylated amines using AgF.
N-Trifluoromethylating Reagents Overview
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You can either buy our N-Trifluoroethylating reagents and then introduce trifluoromethyl Amine group into your own desired compounds, or you can simply order the building blocks pre-loaded with the N-CF3 subsitituent.
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