1,2‐(Bis)trifluoromethylation of Alkynes: A One‐Step Reaction to Install an Underutilized Functional Group

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.

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

Chen

Zhang

2022

Adv Synth Catal

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Geminal/Vicinal Amino‐ and Oxy‐Trifluoromethylation of ortho‐Ethynyl Anilines and Phenols by Cu(III)−CF₃ Compounds

Chen

Zhang

2023

Adv Synth Catal

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This study reports geminal amino‐ and oxy‐trifluoromethylation of ortho‐ethynyl anilines/phenols by phenCu(III)(CF3)3 (phen denotes 1,10‐phenanthroline), which constructs indole and benzofuran skeleton with concurrent incorporation of a CF3 group to the C2 position. Sequential trifluoromethylation of the terminal alkyne followed by 5‐endo‐trig cyclization of amino/hydroxyl with alkyne is involved. This method addresses the troublesome regioselectivity issue in C−H trifluoromethylation of arenes/heteroarenes wherein complicated mixtures of regioisomers were often obtained. A competing vicinal fluoro‐trifluoromethylation of terminal alkynes is suppressed under the optimal conditions wherein the Cu(III)−CF3 compound acts as a bifunctional reagent to provide both CF3 and F. Interestingly, when an acylamino group is present at the ortho‐position of phenylacetylene, vicinal syn‐amidate‐trifluoromethylation of the alkyne group occurs preferentially through 6‐exo‐trig cyclization to produce benzoxazines with a trifluoroethylidene at the C4‐position. The controllable and concise synthesis of valuable trifluoromethylated N‐ and O‐heterocyclic compounds shows the synthetic value of Cu(III)−CF3 compounds in medicinal chemistry.

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Recent Advances in the Functionalization of Terminal and Internal Alkynes

et al. 2022

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Alkynes are one of the most fundamental and diverse functional groups utilized in organic synthesis. Over the past few years, the development of efficient synthetic methodologies for the functionalization of alkynes has been an active area of research. A plethora of alkyne functionalization reactions have been reported in the literature to construct functionalized alkynes and alkene scaffolds, which are important building blocks in many natural products, pharmaceuticals, and key intermediates in various synthetic transformations. In this review, we describe the most recent advances in the functionalization of alkynes with an emphasis on substrate scope, limitations, regioselectivity control and applications of these reactions. This review covers the literature from 2016 to 2021.

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1,2‐(Bis)trifluoromethylation of Alkynes: A One‐Step Reaction to Install an Underutilized Functional Group

Cited by 7 publications

References 59 publications

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

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

Geminal/Vicinal Amino‐ and Oxy‐Trifluoromethylation of ortho‐Ethynyl Anilines and Phenols by Cu(III)−CF₃ Compounds

Recent Advances in the Functionalization of Terminal and Internal Alkynes

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1,2‐(Bis)trifluoromethylation of Alkynes: A One‐Step Reaction to Install an Underutilized Functional Group

Cited by 7 publications

References 59 publications

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

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

Geminal/Vicinal Amino‐ and Oxy‐Trifluoromethylation of ortho‐Ethynyl Anilines and Phenols by Cu(III)−CF3 Compounds

Recent Advances in the Functionalization of Terminal and Internal Alkynes

Contact Info

Product

Resources

About

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

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

Geminal/Vicinal Amino‐ and Oxy‐Trifluoromethylation of ortho‐Ethynyl Anilines and Phenols by Cu(III)−CF₃ Compounds