Recent Advances in the Syntheses of N‐CF₃ Scaffolds up to Their Valorization

Abstract

This review provides a recent overview of the different synthetic routes of the N‐CF3 group. This scaffold can be prepared from the desulfurization of thiocabamoyl fluorides or isothiocyanates with fluoride ions. Electrophilic and radical trifluoromethylations are also a great way to generate this motif. This report also focuses on the valorization of some N‐CF3 compounds, which leads to new unknown N‐trifluoromethyl derivatives. Finally, the first metabolic stability studies will be given for certain structures.

Synthesis of Fluorinated Amines: A Personal Account

“…19 In parallel to carbamoyl fluorides, thiocarbamoyl fluorides are also attractive class of compounds. 17,36 The synthesis of these compounds has gained much attention these last years by using amine derivatives as starting materials and several complementary approaches have been developed. 37 It has been demonstrated that nucleophilic trifluoromethylthiolation reagents could be used in conjunction with amines to access the desired thiocarbamoyl fluorides (Scheme 5).…”

Access to N-Difluoromethyl Amides, (Thio)Carbamates, Ureas, and Formamides

“…As the R 2 NCO functionality is the key unit that dictates properties and function, its molecular editing to currently untapped chemical space is expected to unleash novel properties and/or function . With fluorination of organic molecules having become a well-established tool to alter physical properties (such as conformation, stability, pH, or lipophilicity), and N -methylation of peptides being known to enhance metabolic stabilities and cellular permeabilities, their combined N -CF 3 -carbamoyl motif has also recently gained significant traction . Access to a variety of N -CF 3 compounds, such as amides, , ureas, , carbamates, formamides, hydrazines, amines, indoles, and derivatives, , has recently been unlocked.…”

N-CF3 Imidoyl Chlorides: Scalable N-CF3 Nitrilium Precursors for the Construction of N-CF3 Compounds

“…Unfortunately, the preparation of N -CF 3 compounds is quite challenging. − Although the fluorination-based route (Scheme -I, strategy A) remains dominant in accessing such a scaffold, it classically requires tedious N -prefunctionalization and a large amount of fluorinating reagents, which lead to low functional group tolerance. By comparison, the N -trifluoromethylation provides a simpler and direct route (Scheme -I, strategy B) .…”

“…The trifluoromethyl (CF 3 ) modification has become an important strategy in drug design . In this field, the incorporation of the CF 3 group onto the N atom would result in a unique NCF 3 motif which features interesting physical and pharmacological properties. , For example, Asahina and co-workers observed an effectively enhanced antibacterial activity by replacing the N -alkyl group on the quinoline ring of norfloxacin/ciprofloxacin with the N -CF 3 group . Such innate potential has been reflected in intensive efforts toward the development of efficient tactics for the construction of the NCF 3 unit.…”