Selective Intermolecular Dual Amino‐Trifluoromethylation of Alkenes by High‐Valent Cu(III)−CF₃Compounds

Abstract

A selective intermolecular amino‐trifluoromethylation of alkenes is developed to produce a range of biologically active β‐trifluoromethyl amines. This method exploits a crucial high‐valent Cu(III)−CF3 complex as a combined source of CF3 radical and Cu(II) oxidant through homolytic Cu(III)−CF3 bond cleavage. This unique mode of CF3 radical generation is distinct from current dominant methods that rely largely on photoredox catalysis or the use of sacrificing radical initiator. This represents a significant advantage in that it greatly simplifies the reaction conditions, brings about operational convenience, and is beneficial to suppress various side reactions under otherwise more complicated conditions. A tertiary alkyl radical generated from addition of CF3 radical to alkenes is proposed to react with amines to enable C−N formation with the assistance of in‐situ Cu(II) oxidant. This reaction shows good chemo‐ and regio‐selectivity, suppressing a number of potential side reactions. The free manipulation of readily available Cu(III)−CF3 compound and feedstock compounds of alkenes and anilines greatly broadens the reaction scope. The good chemo‐ and regioselectivity, and operational convenience make this reaction attractive from the synthetic viewpoint. The reactivity of high‐valent Cu(III)−CF3 compounds disclosed in this study may be exploited to develop other interesting reactions, and to enrich the currently underdeveloped Cu(III) chemistry.

Trifluoromethylarylation of alkenes using anilines

“…3–8 The ortho product is only observed when blocking the para position with a substituent (see ESI†), something that is in sharp contrast to the very few examples of amino trifluoromethylation of alkenes using anilines, that react via the amino group. 21 We have also identified by-products, from side reactions, including trifluoromethyl olefins (that are not competent intermediates of the reaction, see ESI†) and aniline polymerization. Limitations in the scope include the use of electron rich alkenes (aliphatic alkenes such as 1-hexene or 3-hexene are not viable substrates, ESI†), while anilines appear to be unique substrates (other aromatic sources such as anisoles, phenol, durene or aminopyridines are not competent substrates).…”

Dual Oxidation of Epoxides with a High-Valent Cu(III)–CF3 Compound and DMSO to Access 1,2-Diketones

“…To shed light on the reaction mechanism, 19 F NMR analysis of the crude reaction mixture of the model reaction was performed which detected the signals of Cu(I)−CF 3 , CF 3 H, and fluoride at around −23, −78, and −152 ppm (please refer to the Supporting Information for more details). Second, a radical trapping experiment was performed where TEMPO was added to the reaction solution to see whether radical species are involved during the reaction course.…”

“…High-valent Cu­(III)–CF 3 compounds have recently received increasing interest, owing to the impressive progress in the synthesis and isolation of stable and well-defined compounds. − They have been verified as highly reactive CF 3 group transfer reagents in a number of fundamental reactions (Scheme b). − They have also been shown to be novel bifunctional reagents to allow dual fluorination–trifluoromethylation of an alkyne wherein a hydrogen-bonding-assisted α-F elimination of CF 3 is involved to generate fluoride in situ . Furthermore, Cu­(III)–CF 3 compounds are also reported to mediate interesting reactions without incorporating CF 3 into the final products, for instance, as a coupling reagent to promote an esterification reaction of carboxylic acids and alcohols/phenols through activation of carboxylic acids …”

“…18 Furthermore, Cu(III)−CF 3 compounds are also reported to mediate interesting reactions without incorporating CF 3 into the final products, for instance, as a coupling reagent to promote an esterification reaction of carboxylic acids and alcohols/phenols through activation of carboxylic acids. 19 With the above background in mind, we report herein an efficient method of 1,2-diketone synthesis from epoxides by dual dehydrogenation and oxygen atom incorporation through a collaboration of Cu(III)−CF 3 compound and DMSO under an inert atmosphere (Scheme 1c). Cu(III)−CF 3 compound serves as a hydrogen abstraction reagent to initiate the reaction, giving an epoxide radical species A. Ring-opening rearrangement of A gives enolic radical A′.…”

High-valent Cu(iii)–CF3 compound-mediated esterification reaction

“…have been isolated and characterized in both solution and solid state. 2 Versatile reactivity has been disclosed for these well-defined Cu( iii )–CF 3 compounds, including C–CF 3 reductive elimination at the Cu( iii ) centre, 3 trifluoromethylation of aryl boronic acids, 2 d – f halides, 4 alkenes, 5 arenes 6 and alkanes, 7 and dual Nu-trifluoromethylation 8 of alkynes and alkenes (Nu denotes a nucleophilic group, such as halo, aryl, amino, oxy, or carboxylate). 9 These studies show the potential of Cu III –CF 3 compounds as one type of highly reactive trifluoromethylating organocopper reagent in organic synthesis.…”