Direct Electrophilic N‐Trifluoromethylation of Azoles by a Hypervalent Iodine Reagent

Abstract

Effective CF(3) transfer: Various electron-rich nitrogen heterocycles (pyrazoles, triazoles, and tetrazoles) can be directly N-trifluoromethylated by a hypervalent iodine reagent in an efficient manner. The optimized procedure, which includes an in situ silylation of the substrate followed by an acid-catalyzed CF(3) transfer, provides ready access to a series of new and previously challenging or inaccessible NCF(3) compounds.

Recent advances in the trifluoromethylation methodology and new CF3-containing drugs

“…An early procedure for trifluoromethylation of amines, anilines or pyridines relied on a thermally unstable O-(trifluoromethyl)-dibenzofuranium salt [78]. Togni's reagent has been effectively used for constructing N-CF 3 bonds but thus far this procedure was limited to the trifluoromethylation of azoles [79].…”

Electrophilic fluorination using a hypervalent iodine reagent derived from fluoride

“…With just 0.2 equivalents of TREAT-HF (Scheme 3) the fluoroiodane 8 was isolated in a 63% yield on a 1.0 g scale. The reaction between the tosyliodane 10 and TBAF in the presence of TREAT-HF was also successful giving a 100% conversion to the fluoroiodane 8 and a 46 % yield after 55 recrystallization from hexane. Neither the trifluoroacetoxyiodane 9 nor the tosyliodane 10 react with TREAT-HF (1.2 equivalents) at room temperature and in both cases unreacted starting material was recovered at the end of the reaction showing that it is the fluoride ion from the TBAF that is undergoing the nucleophilic 60 substitution to form the fluoroiodane 8.…”

“…____________________________________________________ Scheme 1 Syntheses of hypervalent iodine reagents 50 Alternative reagents such as (difluoroiodo)arenes have been prepared from aqueous HF, but they are extremely moisture sensitive and are commonly used as a freshly prepared solution, without isolation, or they can be generated in situ. 9 Inspired by Togni's seminal work on electrophilic trifluoromethylation, 3 we 55 were interested in developing a new class of stable fluorinating reagents based on the cyclic hypervalent iodine(III) skeleton, but generated from cheap sources of fluoride. Here, we will report three different methods for the preparation of an air and moisture stable fluorinated hypervalent iodine reagent 8 and preliminary 60 results on its' fluorination of a series of 1,3-dicarbonyl substrates.…”

Enamine‐Mediated Azide‐Ketone [3 + 2] Cycloaddition of Azidoperfluoroalkanes

“…The introduction of perfluoroalkyl groups into organic compounds to form C‐, O‐ and S‐bound structures has been widely investigated. In sharp contrast, strategies towards the synthesis of N ‐perfluoroalkyl compounds are scarce . Recently, we have reported a new method for the synthesis of azidoperfluoroalkanes (R F ‐N 3 ) which opened new possibilities to access N ‐perfluoroalkyl compounds …”

“…In sharp contrast, strategies towards the synthesis of N-perfluoroalkyl compounds are scarce. [5][6][7] Recently, we have reported a new method for the synthesis of azidoperfluoroalkanes (R F -N 3 ) which opened new possibilities to access N-perfluoroalkyl compounds. [8] An important class of N-heterocycles is the 1,2,3-triazoles, often present in pharmaceuticals, high-value materials and connecting units in chemical biology.…”