N‐Trifluoromethyl Hydrazines, Indoles and Their Derivatives

Abstract

Reported herein is the first efficient strategy to synthesize a broad range of unsymmetrical N‐CF3 hydrazines, which served as platform to unlock numerous currently inaccessible derivatives, such as tri‐ and tetra‐substituted N‐CF3 hydrazines, hydrazones, sulfonyl hydrazines, and valuable N‐CF3 indoles. These compounds proved to be remarkably robust, being compatible with acids, bases, and a wide range of synthetic manipulations. The feasibility of RN(CF3)‐NH2 to function as a directing group in C−H functionalization is also showcased.

Synthesis of N-Trifluoromethyl Thiocarbamates and Ureas from 3-Aminopyridine-Derived Carbamates

“…1 2 3 4 The introduction of the trifluoromethyl group into organic molecules has also been of major interest because this moiety can significantly alter metabolic stability, physical and chemical properties (lipophilicity, pKa, membrane permeability, solubility, and conformation), and bioavailability of these molecules in numerous applications. 5–9 Compared with N -trifluoromethyl amides, 10 11 12 13 14 15 the synthetic strategies for N -trifluoromethyl ureas and thiocarbamates are relatively poor. 12…”

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

“…According to the following mechanism, the migration of the R‐ N ‐CF 3 group was involved (Scheme 11). [9] …”

“…Equally, hydrazine 19 a could be obtained in quantitative yield after heating at 80 °C for 3 h in acetic acid with aldehyde (Scheme 13). [9] …”

N-Trifluoromethyl Amines and Azoles: An Underexplored Functional Group in the Medicinal Chemist’s Toolbox

“…Very recently, the Schoenebeck group reported on the synthesis of N -trifluoromethyl hydrazine derivatives. Even though these might be promising intermediates to access various N -trifluoromethyl azoles, this strategy has so far only been applied to the synthesis of N -trifluoromethyl indoles …”

“…Until very recently, synthetic methods for N -trifluoromethylation of amines generally required the use of highly toxic HF-based reagents or thermally unstable compounds like O -trifluoromethyl benzofuranium reagents (for an overview on methods to synthesize N -trifluoromethyl azoles, see the end of the Results and Discussion section). Whereas no significant improvement in the synthesis of N ‑trifluoromethyl azoles has been reported until a very recently described synthesis specific to N -trifluoromethyl indoles ( vide infra ), four operationally simple methods for the synthesis of tertiary N -trifluoromethyl amines have been published in the last four years (additionally, a synthesis of N ‑trifluoromethyl azepines was recently described). All four methods generate a thiocarbamoyl fluoride intermediate, which is then transformed into the desired N -trifluoromethyl amine using silver­(I) fluoride.…”