Copper‐Mediated Trifluoromethylation of Benzylic Csp³−H Bonds

Abstract

Trifluoromethyl-containing compounds play a significant role in medicinal chemistry, materials and fine chemistry. Although direct C-H trifluoromethylation has been achieved on Csp -H bonds, direct conversion of Csp -H bonds to Csp -CF remains challenging. We report herein an efficient protocol for the selective trifluoromethylation of benzylic C-H bonds. This process is mediated by a combination Cu -CF species and persulfate salts. A wide range of methylarenes can be selectively trifluoromethylated at the benzylic positions. A combination of experimental and theoretical mechanistic studies suggests that the reaction involves a radical intermediate and a Cu -CF species as the CF transfer reagent.

The Persistent Radical Effect in Organic Synthesis

“…Radicals can also be trifluoromethylated using stoichiometric Cu À CF 3 complexes as scavengers.S ome protocols operate with as toichiometric (bpy)Cu III (CF 3 ) 3 to trap alkyl radicals [327] or acyl radicals [328] that are generated by intermolecular Habstraction by reactive Oradicals derived from persulfates.I nterestingly,t he Cu II species,a ble to trap Cradicals,i sg enerated upon UV irradiation to homolyze aC u À CF 3 bond in the (bpy)Cu III (CF 3 ) 3 complex. The cogenerated trifluoromethyl radical is directly reduced by at rialkylsilane to suppress side reactions such as homolytic aromatic trifluoromethylation.…”

Der “Persistent Radical Effect” in der organischen Chemie

“…Manna und Antonchick entwickelten einen Zugang zu Cyclopropanen 155 [325] und Furanen 156 [326] 3 ,u mA lkyl- [327] oder Acyl-Radikale [328] [331] hierzu ist die Cu-katalysierte Atomtransfer-Radikalcyclisierung des a,a,a-Tr ichloracetats 157 zu erwähnen, welche über eine intramo-Abbildung 50. a) Cu-katalysierte Herstellung von Cyclopropanen [325] und Furanen [326] und b) vorgeschlagener Mechanismus. [322] Abbildung 51.…”

Synthesis of 2,2,2‐Trifluoroethyl Oxazoles, Oxazolines and Furans via Alkyne Oxytrifluoromethylation

“…[8] Benzylic trifluoromethylation is an alternative method to prepare ArCH 2 CF 3 , relying on the cross-coupling of benzylic halides or boronic acids or CÀ H bond with various CF 3 reagents (Scheme 1b). [9,10] Despite these two major types of aromatic post-functionalization methods, it is highly desirable to prepare ArCH 2 CF 3 compounds involving de novo construction of the aromatic ring and concurrent CH 2 CF 3 incorporation. [11] With the above challenges in mind, we report herein the development of oxy-trifluoromethylation of terminal alkynes with a Cu(III)À CF 3 compound [12][13][14] that efficiently constructs oxazoles, oxazolines and furans with concurrent incorporation of an ortho 2,2,2trifluoro ethyl or ethylene group on the 5-member ring (Scheme 1c).…”